Injectable Fillers: Principles and PracticeEDITED BY

Derek Jones, MDClinical Associate Professor, Department of Medicine, Division of Dermatology,

David Geffen School of Medicine, University of California at Los Angeles

A John Wiley & Sons, Ltd., Publication

Injectable Fillers: Principles and Practice

Companion – CD-ROM

This book is accompanied by video of procedures described in the text:

• Radiesse and Evolence Breeze

for augmentation of the

cheeks, oral commissures,

lateral brow, nasolabial fold

and lips

Injector: Jean Carruthers, MD

• Hyaluronic Acid: Juvederm

Ultra and Ultra Plus for

augmentation of the nasolabial

folds, oral commissures, labial

mental groove, and lips

Injector: Derek Jones, MD

• Sculptra for treatment of facial

lipoatrophy (non-HIV)

Injector: Derek Jones, MD

• Liquid Injectable Silicone

(Silikon-1000) for treatment of

HIV-associated facial

lipoatrophy

Injector: Derek Jones, MD

Total running time: 50 minutes

Injectable Fillers: Principles and PracticeEDITED BY

Derek Jones, MDClinical Associate Professor, Department of Medicine, Division of Dermatology,

David Geffen School of Medicine, University of California at Los Angeles

A John Wiley & Sons, Ltd., Publication

This edition fi rst published 2010, © 2010 by Blackwell Publishing Ltd

Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientifi c, Technical and Medical business to form Wiley-Blackwell.

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The contents of this work are intended to further general scientifi c research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specifi c method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifi cally disclaim all warranties, including without limitation any implied warranties of fi tness for a particular purpose. In view of ongoing research, equipment modifi cations, changes in governmental regulations, and the constant fl ow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Library of Congress Cataloging-in-Publication Data

Injectable fi llers : principles and practice / [edited by] Derek Jones. p. ; cm. Includes bibliographical references. ISBN 978-1-4051-9289-7 1. Tissue expansion. 2. Fillers (Materials) 3. Surgery, Plastic. 4. Face–Surgery.I. Jones, Derek, 1965- [DNLM: 1. Face. 2. Cosmetic Techniques. 3. Dermatologic Agents.4. Injections. 5. Rejuvenation. WE 705 I505 2010] RD119.5.T57I55 2010 617.9′52–dc22 2009030111

ISBN: 9781405192897

A catalogue record for this book is available from the British Library.

Set in 9.5 on 13 pt Meridien by Toppan Best-set Premedia LimitedPrinted in Singapore

1st impression 2010

Contents

Preface, vi

Contributors, viii

1 The Cosmetic Patient Consultation, 1

Phil Werschler

2 Guidelines for Local Anesthesia in Use of Injectable Fillers, 8

Mariano Busso

3 Hyaluronic Acids: Basic Science, 19

Nowell Solish and Kenneth Beer

4 Calcium Hydroxylapatite Microspheres in Facial Augmentation, 27

Alastair Carruthers and Jean Carruthers

5 Evolence and Evolence Breeze, 43

Jean Carruthers and Alastair Carruthers

6 Poly-L-Lactic Acid, 54

Rebecca Fitzgerald and Danny Vleggaar

7 Liquid Injectable Silicone, 75

Chad L. Prather

8 Hydrogel Polymers, 91

Naissan O. Wesley

9 Artefi ll: the First to Last, 103

Adam M. Rotunda and Rhoda S. Narins

10 Complications from Soft-Tissue Augmentation of the Face:

A Guide to Understanding, Avoiding, and Managing

Periprocedural Issues, 121

Marc D. Glashofer and Joel L. Cohen

11 The Mathematics of Facial Beauty: A Cheek Enhancement Guide

for the Aesthetic Injector, 140

Arthur Swift

12 Hyaluronic Acids: Clinical Applications, 158

Derek Jones and Timothy C. Flynn

Index, 175

“This book is accompanied by a CD-ROM with videos

showing procedures described in the book.”

v

Preface

vi

Since the Food and Drug Administration (FDA) approval of the fi rst inject-

able hyaluronic acid for correction of facial wrinkles in 2003, there has

been an explosion of natural and synthetic fi llers in the medical cosmetic

market and millions of procedures are now performed annually. At the

time of writing, we currently have 14 injectable devices approved by the

FDA from which to chose: fi ve collagen products of bovine (Zyplast,

Zyderm), porcine (Evolence) or human origin (Cosmoplast, Cosmoderm);

six hyaluronic acid products (Restylane/Perlane, Juv é derm Ultra and

Ultra Plus, Elevess, Prevelle Silk); calcium hydroxylapatite (Radiesse); and

the synthetic poly - L - lactic acid (Sculptra) and the permanent polyme-

thylmethacrylate (Artefi ll). Liquid injectable silicone (Silikon - 1000) is

available only off - label as a permanent injectable fi ller. There is no “ one

best ” fi ller or “ one right way ” to achieve a beautiful and natural result.

Although the hyaluronic acids dominate the marketplace, all of these

fi llers have an important and useful role, and are often used to best effect

in combination.

The goal of this book is to present the basic science, review safety and

effi cacy data that have led to FDA approval, and outline patient selection,

safe, and effective injection techniques, and appropriate indications for

each fi ller. It should be noted that most FDA studies leading to approval

have formally studied most fi llers only in the nasolabial fold. Other indica-

tions that are outlined (such as volumizing the lip and cheek) in this book

are considered “ off - label ” in the USA, meaning that, although it is legal

to inject these areas, the FDA has not reviewed safety or effi cacy data and

granted a formal indication for such use.

Lastly, a procedural DVD, running for about 1 hour, is included with

this book and demonstrates appropriate injection techniques for most of

the fi llers discussed. When assessing volume loss in the face, the physician

will do best to not concentrate only on one area (such as the nasolabial

fold) as a discrete entity, but assess multiple areas of volume loss (lips,

cheeks, oral commissures) in relationship to each other and tailor the

treatment plan accordingly. A great deal of effort has been put in to teach

the reader how to avoid complications and, when they may occasionally

Preface vii

happen, how to properly identify and treat them. The novice should thor-

oughly master the anatomy of the skin and subcutaneous tissue of the

face, including vascular, muscular, and neural structures, before starting

actual injections. In general when injecting, I advocate a very slow, steady,

and deliberate injection technique with absolute attention given to the

correct plane of injection (intradermal, subcutaneous, epiperiosteal),

which is different for each fi ller and is crucial to achieving a good result.

Derek Jones

Contributors

viii

Kenneth Beer MD Director, Kenneth Beer MD PA, Esthetic, Surgical and General Dermatology

Voluntary Assistant Professor

Department of Dermatology

University of Miami

West Palm Beach

Florida, USA

Mariano Busso MD Private practice in South Florida

Voluntary Assistant Clinical Professor at the University of Miami

Coral Gables

Florida

USA

Alastair Carruthers MA, BM, BCH, FRCPC, FRCP (Lon) Clinical Professor

Department of Dermatology and Skin Science

University of British Columbia

Vancouver

Canada

Jean Carruthers MD, FRCS (C), FRC(Ophth) Clinical Professor

Department of Ophthalmology and Visual Sciences

University of British Columbia

Vancouver

Canada

Joel L. Cohen MD Director, About Skin Dermatology and DermSurgery

Associate Clinical Professor

University of Colorado

Department of Dermatology

Englewood

Colorado, USA

Contributors ix

Rebecca Fitzgerald MD Dermatology Private Practice

Los Angeles

Assistant Clinical Instructor

David Geffen School of Medicine

University of California

Los Angeles

USA

Timothy C. Flynn MD Medical Director, Cary Skin Center

Cary

North Carolina

Clinical Professor, Department of Dermatology

University of North Carolina

Chapel Hill, North Carolina

USA

Marc D. Glashofer MD, MS Dermatologic Surgeon

Island Dermatology

Long Beach

New York

USA

Derek Jones MD Founder and Director Skin Care and Laser Physicians of Beverly Hills

Clinical Associate Professor Dermatology

David Geffi n School of Medicine

University of California

Los Angeles

USA

Rhoda S. Narins MD Director, Dermatology Surgery and Laser Center

Clinical Professor of Dermatology

New York University School of Medicine

New York

USA

Chad L. Prather MD Director, Dermasurgery Center

Baton Rouge

Louisiana

Clinical Assistant Professor

Department of Dermatology

Louisiana State University

New Orleans

USA

Adam M. Rotunda MD Assistant Clinical Professor, Division of Dermatology (Medicine)

David Geffen School of Medicine

University of California

Los Angeles

USA

x Contributors

Nowell Solish MD, FRCP Assistant Professor, Dermatology

University of Toronto

Toronto

Canada

Arthur Swift MD, Cm, FRCS(C) Director West Mount Institute of Plastic Surgery and

Victoria Park Memorial Spa

Montreal, Canada

Clinical Lecturer, Department of Plastic Surgery, McGill University

Montreal

Canada

Danny Vleggaar MD Medical Director, Centre Dermato - Cosmetique ‘ Roseraie ’

Geneva

Switzerland

Phil Werschler MD, FAAD, FAACS Assistant Clinical Professor of Medicine/Dermatology

University of Washington School of Medicine

Seattle

USA

Naissan O. Wesley MD Skin Care and Laser Physicians of Beverly Hills

Los Angeles, California

USA

The Cosmetic Patient Consultation Phil Werschler Department of Medicine/Dermatology, University of Washington School of Medicine, Seattle, Washington, USA

CHAPTER 1

As aesthetic, or cosmetic, dermatologists, an integral part of successful

practice includes the “ cosmetic patient consult ” (CPC). Although this term

is used liberally, its actual defi nition remains somewhat nebulous.

Certainly, there are portions that are universally agreed upon, such as

consent form signing, price quotation, and pre - treatment photographs.

However, there are many more less well - defi ned components to the

process that are equally important to both the treating provider and the

treated patient for optimal outcome.

For the purposes of this introductory chapter, certain assumptions will

be made about the CPC process. Chief among these is the accomplished

skill set of the treating provider, whether a physician, mid - level provider,

registered nurse, or aesthetician/offi ce staff. It is assumed that the CPC

will not be performed for the benefi t of training the staff in the particular

procedure. It is also assumed that the offi ce possesses the requisite

resources and capabilities to fully perform and complete the particular

procedure being offered. Finally, it is also assumed that the CPC is

being conducted in “ good faith, ” i.e. with full disclosure of the training,

experience, and outcomes of the same or similar procedures being fully

discussed.

Cosmetic o ffi ce p ractice

With that as a background, the next step is to determine the cosmetic

offi ce practice (COP) level of the dermatology practice. First proposed in

the mid - 1990s by Craze and Werschler, 1 this is a simplifi ed method of

determining the relative contribution of resources that a practice devotes

to the development of “ desire ” dermatology. Using a four - point scale, this

descriptive methodology is capable of generally categorizing the relative

level of sophistication of a dermatology practice toward the delivery of

elective cosmetic services.

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

1

2 Chapter 1

Briefl y, the four levels are described as follows:

1. Non - cosmetic, i.e. no particular skills, resources, equipment, market-

ing, or other efforts made beyond that of the usual general “ disease ” -

focused dermatology practice.

2. Some cosmetic, usually represented by a particular focus of expertise

of equipment, skills, or other assets that provide elective services. A

good example of this would be a center of excellence in lasers within

a dermatology practice.

3. Balanced, or blended, practice of disease and desire dermatology:

usually represented by a broad range of skills across multiple areas of

expertise, all being considered in the “ core scope ” of dermatology and

dermatologic surgery. Many practices in the USA and Canada are con-

sidered “ balanced. ”

4. All cosmetic, or a practice that typically offers only elective services that

would be considered cosmetic in nature. These practices may exceed

the usual scope of dermatology to refl ect the unique skill sets of the

providers. Examples of this could include facelift and breast augmenta-

tion procedures.

Considering that most dermatology offi ces today operate at the second

and third levels of COP (focused or balanced) and those that aspire to

these levels all share the same basic challenges, the following discussion

targets COP levels 2 and 3.

The t hree c omponents of CPC

The three essential components to a successful CPC consist of the setting,

education, and assessment. These three integrated pieces are the prover-

bial three - legged stool: if any one is missing, the result is an unbalanced

and hazardous situation. Of the three, the provider is most crucial in the

assessment and, in some cases, assessment cannot be performed without

the treating provider. Depending on the personal preferences of the pro-

vider, both the setting and education can be either a “ hands - on ” or

“ hands - off ” affair.

Setting Understanding organizational selling is the fi rst step in achieving a proper

“ setting ” for the CPC process. Although many physicians mistakenly believe

that the initial face - to - face contact is the most important step in the process

of a successful CPC, it is actually close to the last step of the process.

For most cosmetic dermatology practices, there is a preframed geo-

graphically determined catchment area. If the practice has been in

existence for any signifi cant length of time, there is usually limited general

The Cosmetic Patient Consultation 3

public awareness of the types of procedures and products available. This

awareness may be founded on reputation, advertising, marketing efforts,

location, etc. Identifying and controlling this “ general awareness ” is really

the fi rst step of the setting for the CPC.

Although this chapter is not intended to discuss marketing, advertising,

and communication efforts for cosmetic dermatology practices, suffi ce it

to say that this is a commonly overlooked area of practice development.

Expert consultation is certainly available for those interested in pursuing

further evaluation in this area.

What organizational selling means to the cosmetic dermatology practice

is the education of all employees on the products, services, and procedures

offered by the business. Organizational selling does not mean that every

offi ce employee is a salesperson; indeed the actual selling of a product or

service needs to be a tightly managed affair.

Organizational selling is the systematic, methodical process of educating

internally on the resources and capabilities of the entire offi ce. This

includes the unique assets of the providers, the equipment, the offi ce

setting, design, accreditation, etc. In its truest form, it means that any

employee, from the billing clerk to the records clerk to the Mohs ’ techni-

cian to the medical assistant, is capable of responding to a question, a

request, a phone call, or even a third party inquiry about the services

offered. This type of education takes dedicated training and frequent com-

munication from the leadership of the offi ce to be relevant and effective.

It is essential to the success of the cosmetic dermatology practice.

This type of staff training also facilitates the entire process of the setting

in that it allows the prospective cosmetic patient to progress seamlessly

from being an interested party to an offi ce visitor without receiving any

confl icting information.

Organizational training also supports collateral information dissemina-

tion, such as telephone information scripting, patient handouts, brochures,

internet presence, etc. Ideally, the prospect (individuals are not patients

until they are actually treated; during the consultative process they are

technically a prospect) continues to receive the same, non - confl icting

information fl ow from the fi rst contact with the offi ce (internet, tele-

phone, direct mail, etc.) to their fi rst visit, to the actual consultation, to

the day of procedure, and fi nally to the time of completion of follow - up

of any procedure(s) performed. This process should be seamless from the

patient ’ s perspective.

Once the patient reaches the offi ce for the scheduled consultation, great

care should be taken to ensure that he or she is promptly and politely

received. As dermatology differs so greatly from plastic surgery in terms

of offi ce patient numbers and fl ow, it is recommended that consultations

not be scheduled during busy clinic hours if performed by the provider.

4 Chapter 1

In addition, consideration should be given to alternate times and days of

the week, including weekends, for scheduling of the CPC. Further, certain

types of procedures or services may be offered in a group setting, such as

an evening offi ce information seminar. A good example of this would be

new skin care products or services that are generally applicable to larger

number of individuals.

The actual consultation may be performed by a dedicated patient cos-

metic coordinator or by the treating provider, depending on the particular

preferences of the offi ce and the nature of the procedure. Certainly, the

information needed for a simple botulinum toxin injection requires a more

basic level of education than that needed for liposuction.

There should be a defi ned time limit for the consultation; this avoids

the potential issue of “ not enough time ” in the patient ’ s mind. Commonly,

this is 30 minutes and can be varied for different types or combinations

of procedures. More than 30 minutes may be excessive, and can actually

be counterproductive if the conversation is not kept tightly focused.

The actual location of the CPC needs to be carefully evaluated. Although

there is no actual correct or incorrect way to locate the consultation, it is

generally felt that a separate room is best. This can be the physician ’ s

offi ce, an exam room, or ideally a dedicated space within the offi ce.

Sometimes referred to as the “ closing ” room, a dedicated space provides

optimal comfort for both the prospect and the consultant.

The dedicated consultation room also has many advantages, including

privacy, d é cor, and ready access to all materials including printed, video,

internet, and even photographic. The space is kept free of staff transit during

the consultation, and generally there is a different ambiance in the room.

Here, patients feel much more comfortable discussing their personal desires

and fears, feel more relaxed, and less nervous than in an exam room.

The room should be well lit for exam and use of a mirror. Mirrors should

include hand - held, magnifying, and full - length varieties. Some offi ces

even use a dressing room - style three - way mirror, especially if body work

such as liposuction is discussed. The furnishings should include as a

minimum one or two large comfortable chairs and perhaps a small couch.

Remember, frequently a cosmetic consult consists of more than just the

prospect, and can include spouse/partner, family member(s), or friend.

The room may have a completely different interior design and color

scheme to the rest of the offi ce, including fl oor coverings, window treat-

ments, and furnishings. It should be equipped with the necessary hard-

ware and software to access and schedule the patient procedure in private.

All necessary collateral materials, including consent forms, lab requisi-

tions, release of information requests, etc., should be readily on hand.

The room should be kept spotless at all times and be supplied with fresh

bottled water and possibly hot water/coffee for patient convenience.

The Cosmetic Patient Consultation 5

The room should be very quiet, even adding extra soundproofi ng materials

if necessary. The necessary diplomas, certifi cates, awards, etc. should be

displayed as a form of external reference for the reassurance of the client.

Finally, it is recommended that a clock be prominently displayed in easy

view. This helps to establish a timeline for both parties. Consultations can

always be extended and/or rescheduled if more time is necessary.

With regard to the actual time scheduling of consultations, it is recom-

mended that they not be performed on a “ back - to - back ” timeline. This is

because the consultant should have suffi cient time between clients to

perform the needed chart documentation, write any personal notes,

including a thank - you note to the client, and prepare for the next consul-

tation. Generally, 15 minutes is suffi cient for these tasks. Also, this 15 -

minute block in the schedule helps to maintain an on - time performance

for late - arriving patients, phone messages, follow - up calls, etc.

Education The ideal CPC is really an exercise in patient education. Generally, in

dermatology, the prospective patient will arrive with a narrow set of

desires and expectations. They may not know which dermal fi ller they

desire, but they know that they would like bigger lips or higher cheek-

bones. They usually have some limited education and knowledge from a

friend who has had a similar procedure or from a fashion magazine or

internet site. Their primary purpose of the consultation is to determine

three things: Do you do this procedure (skill)? Do you want to do it to

me (appropriate candidate)? How much does it cost?

The role of the consultant is to answer these three questions in an

expanded format and to include risks, benefi ts, and alternatives available,

whether through this offi ce or another (fi llers vs facelift; plastic surgeon vs

dermatologist) more appropriate specialty. In addition, the consultant

needs to help determine if the patient has the appropriate mental capacity

and awareness to give consent and be able to comply with any needed fol-

low - up care or visits. Although the treatment provider will ultimately make

this decision, the consultant can play a vital screening role in the process.

Once the prospect has been given the basics of education, support mate-

rials may be used, such as brochures and consents. These are add - on

materials, and should not be used in place of a consultation. Some offi ces

use additional customized materials such as DVDs and photograph

albums. Others use reprints of journal articles, website printouts, etc.

Regardless of the materials used, all should be documented in the patient

chart, and all CPCs should result in a medical chart, even if the prospect

has never been and is never treated in the future by the offi ce. This

is thorough record keeping, and is an essential part of smart medicolegal

practice.

6 Chapter 1

For some procedures this entire education process is a simple matter. It

may be accomplished in a few minutes, documented, and scheduled or

performed before the patient leaves the offi ce. For other procedures, it

may be just the fi rst step in a lengthy process that may include several

pre - treatment visits and sessions to include photography, review of lab

work, consultation with referring physicians, and pre - procedure physical

examination and even psychological screening questionnaires.

With regard to price quotes, there are generally two schools of thought:

the fi rst is that every patient is a unique treatment challenge, and prices

are individually determined based on these unique attributes. The other

is to use a predetermined price list, and if deviations are needed these are

explained to the patient individually. Dermatology offi ces, given the

nature of the procedures performed, typically use price lists. Regardless of

the approach, the price quote needs to be openly discussed and agreed

upon by the patient before performing the procedure.

The best method to accomplish this is with the use of consultation

sheets. These are two - or three - piece carbon - copy - type forms with a listing

of procedures and prices typically hand written on a graphic of the face

and/or body. The patient receives a copy of the completed form either at

the end of the consultation or in the mail in a day or two after the consult.

The other copy is placed in the chart. For price quotes, there is typically

a 90 - day guarantee that the price will be honored. This allows the prospect

to have a reasonable time to consider the options and the procedure before

committing. If they have additional questions, they can follow up with a

phone call or a second consultation. For the actual cosmetic consultation,

offi ce policies very widely with regard to charging: most offi ces do not

charge when the consultation is not performed by the physician. When

the physician is using his or her time to do the actual 30 - minute consult,

it is common to charge a fee. Typically, this ranges from US$100 to $500.

This fee is applied to the fi rst procedure. Somewhat different from our

plastic surgery colleagues, most cosmetic dermatology procedures are less

than $5000, with many in the $1000 – 2500 range. Therefore, the rationale

is that it is diffi cult to recoup lost revenue with these smaller charges, and

the consult fee is one method to minimize these lost fees.

The cosmetic coordinator should follow up in 7 – 10 days (with permis-

sion) if the prospect has not scheduled the procedure or contacted the

offi ce for additional information. This closure provides for a call to action,

and increases the effi ciency rate of the cosmetic coordinator. Frequently

prospects have a few remaining questions and, if answered to their satis-

faction, they will book the procedure.

When booking, similar to paying the fi rst night when making a hotel

reservation, the usual approach is to pay half of the quoted procedure

price to “ reserve ” the appointment slot; the second half is then usually

paid the day of the procedure, before having it done. For cancellation or

The Cosmetic Patient Consultation 7

“ no - shows, ” there should be a very clear and precise written policy that

is signed when the appointment is made. Commonly, a 24 - to 48 - hour

cancellation is required to receive a refund. Anything less than 24 hours,

unless an emergency, is problematic for the offi ce. Some offi ces, as a gesture

of goodwill, will apply all or a portion of the forfeited deposit to the next

appointment if scheduled at the time of cancellation. Good judgment is

necessary to manage these last minute no - shows and cancellations.

For some minor procedures such as toxins and fi llers, where there is a

variable in the fi nal price, a deposit of $100 is common to book the

appointment. This can be requested by the front offi ce scheduling desk at

the time that the appointment is made to facilitate patient convenience.

Assessment For the actual procedure on any specifi c patient, it is clearly the responsibil-

ity of the treating provider to determine to the appropriateness of the

patient and the requested procedure. This may consist of the actual physical

evaluation, a mental status evaluation, comorbidities and overall health

status, and any other complicating factors. Remembering the acronym

“ ICG/RBE ” for informed consent given and risks and benefi ts explained

for the particular patient is an excellent way to approach the assessment.

Some patients are clearly not good candidates for their desired proce-

dures. Although this alone is not cause to withhold or deny cosmetic treat-

ment, it should always be explored with the patient. Some, by virtue of age,

health, medication, risk tolerance, timeline, or budget, may actually be

better candidates for a suboptimal treatment than one would expect. The

facelift patient who requests non - surgical facial tightening may be doing so

because of a variety of valid reasons. However, if they discuss the procedure

as a shortcut or budget version of what they really desire, or because their

spouse or signifi cant other wants them to have it done, it may be a better

option to decline treatment. There is an old adage in cosmetic work that

“ you don ’ t regret the patients you turn down, you regret the ones you

should have turned down. ” From personal experience I fi nd this to be true.

As the experience level of the cosmetic dermatology offi ce develops, it

will become easier and easier to create a smooth and seamless experience

for the prospect who becomes a client who then becomes a patient, and

when satisfi ed with their experience, becomes an advocate for your prac-

tice. When careful, purposeful, and consistent staff education and training

are combined with a dedicated approach to patient education, it is a natural

result for the cosmetic portion of a dermatology practice to fl ourish.

References

1. Werschler WP , Craze MG. Cosmetic Offi ce Practice – A Novel Perspective . Progressive

Clinical Insights January/February 1998 ; 6 ( 1 ): 24 – 5 .

Guidelines for Local Anesthesia in Use of Injectable Fillers Mariano Busso Private practice, South Florida

CHAPTER 2

Anticipation of – and treatment for – pain remains an important consid-

eration for physicians preparing to administer injectable dermal fi llers.

Historically, anesthesia protocols constituted the “ pre - treatment ” part of

the injecting regimen. Recently, some physicians have started to combine

anesthesia, such as lidocaine, with the injectable dermal fi ller itself. The

combined solution of dermal fi ller and anesthesia is administered together.

Both of these categories – mixing and pre - treating – are discussed in this

chapter.

Option I: Mixing a nesthetic with d ermal fi ller i mmediately b efore a dministration

In the relatively short period of the arrival of dermal fi llers for aesthetic

applications, the conventional anesthetic protocol has been pre - treatment

of the area with anesthetic agents. However, some of the dermal fi llers

lend themselves nicely to a different anesthetic approach, namely mixing

the anesthetic with the dermal fi ller itself, just before treatment. This

mixing approach with calcium hydroxylapatite (CaHA – Radiesse) fi rst

appeared in the literature in late 2007. 1 Anecdotal reports suggest both

rapid and widespread adoption by physicians (personal communication,

Brian Pilcher, Vice President of Medical Affairs, BioForm Medical, 2009).

The mixing itself is fairly straightforward. It requires the injectable

dermal fi ller in one syringe and the lidocaine – or lidocaine plus

epinephrine – in another. In the case of Radiesse, the 1.3 mL syringe is

connected to a 3.0 mL syringe of anesthetic, using a Rapid Fill Luer -

Lok - to - Luer - Lok adapter (Baxa, Englewood, CO). The dermal fi ller is

introduced into the syringe containing the anesthetic fi rst; then the newly

combined Radiesse and lidocaine is pushed back and forth from syringe

to syringe (Figure 2.1 ). Approximately 10 passes are suffi cient for homo-

geneous distribution of Radiesse and anesthetic. 2

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

8

Guidelines for Local Anesthesia in Use of Injectable Fillers 9

An article published in 2008 explored in detail possible changes to the

calcium hydroxylapatite that might arise when the compound was mixed

with lidocaine. 2 In setting up the study, researchers examined several

lidocaine concentrations to determine the dynamic viscosity, extrusion

force, and needle jamming rate of the mixture compared with the com-

mercially available Radiesse. Researchers found that the pH of the

Radiesse – lidocaine admixture remains closely equivalent to the pH of the

Radiesse alone. The viscosity of the blend is lower than the viscosity of

the Radiesse by itself, as is the extrusion force. In addition, the “ spreadabil-

ity ” of the dermal fi ller is improved, making it more malleable after its

injection into soft tissue. Nevertheless, the mixing does not appear to

compromise the inherent physical properties of the dermal fi ller.

Interestingly enough, the use of this admixture fi rst arose in the context

of treatment options for the aging hand. Treatment of the hand had here-

tofore been considerably constrained by the pain induced by injection of

any dermal fi ller in that area. An alternate approach was conceptualized.

Rather than administer anesthetic to the hand, a bolus of the dermal fi ller

plus lidocaine mixture was instead injected directly under the skin. The

mixture was then spread throughout the hand using fi rm massage. The

immediate result of this approach – mixing anesthetic with CaHA – was

a treatment that is easier to massage and disseminate, less painful to the

Figure 2.1 Radiesse (1.3 mL) combined with lidocaine (0.1 mL), immediately before

injection.

10 Chapter 2

patient than conventional hand injection, and characterized by less swell-

ing and bruising, with minimal post - treatment downtime. Benefi ts for

physicians who choose to mix this dermal fi ller with lidocaine may include

reduction of “ confounding edema ” that arises from pretreatment infi ltra-

tion of the lidocaine alone, less need for nerve blocks, and shortened

treatment times. The authors opine that mixing the dermal fi ller with

lidocaine “ allow larger volumes to be injected in one treatment session,

such as those necessary for full facial recontouring. ” 2

Note Injection of the dermal fi ller Radiesse mixed with lidocaine received

approval by the Food and Drug Administration in the second half of

2009. Although this mixing approach would appear to be applicable

to other dermal fi llers in addition to calcium hydroxylapatite, some

caution is warranted until more information appears in the clinical

literature.

Option II: Pre - t reatment with a nesthetic a gents

Unless the physician is using the mixed combination of anesthetic and

injectable dermal fi ller, the use of local anesthesia is ordinarily advised.

Pre - treatment anesthetic agents include nerve blocks, tissue infi ltration,

topical anesthetic, and skin cooling. Nerve blocks provide total anesthesia

to the area being treated, by anesthetizing the main trunk of a nerve. In

tissue infi ltration, anesthesia is injected just below the skin in the sur-

rounding area that is to be treated with dermal fi ller.

Topical a nesthetics EMLA Cream, one of the fi rst and most studied topical creams, is a eutectic

mixture of local anesthetics, a prilocaine 2.5% and lidocaine 2.5% cream.

Onset of action is within 1 hour and duration 1 – 2 hours after removal of

the cream. 3

LMX - 4 (previously called ELA - Max) is a liposomal delivery system that

allows a 4% lidocaine preparation to be rapidly absorbed by the skin. The

rapid absorption also results in a rapid dissipation of the drug, with dimin-

ishing anesthesia approximately 40 – 60 min after application. 4

Synera (formerly S - Caine Patch) consists of tetracaine and lidocaine

mixed 7%:7% in a self - contained patch. The product is designed to

look like a child ’ s bandage and is recommended for children aged 3 years

and older. Synera contains a heating element that, when activated,

enhances absorption, allowing for rapid anesthesia and some degree of

vasodilation.

Guidelines for Local Anesthesia in Use of Injectable Fillers 11

Side effects of topicals warrant discussion. EMLA, in particular, is associ-

ated with angioedema, contact dermatitis, burning, stinging, and even

methemoglobinemia. Although rare, methemoglobinemia is more likely in

preterm infants. It is contraindicated in children less than 1 month of age. 3

All of these topical agents likely require some time before numbing is

complete. In addition, lidocaine tips ( “ Caine tips ” ) and mucosal swabs are

helpful for numbing the mouth.

Physical a ids Physical aids include vibrating, icing, and cooling (Zimmer Chiller). The

use of vibration for analgesic purposes is based on the gate control theory.

Vibration information is received by vibration receptors (pacinian corpus-

cles and Meissner ’ s corpuscles) and is conducted by A β nerve fi bers which

stimulate inhibitory interneurons in the spinal cord. These neurons reduce

the amount of pain signal transmitted from thinly myelinated A δ - fi bres

and fi ne unmyelinated C - fi bers across the midline of the spinal cord and

from there to the brain. Vibrations, icing, and chilling provide a temporary

anesthetic condition so that the pain of injection is somewhat mitigated.

Environmental a ids Finally, environmental aspects can be modulated so that anxieties of the

patient are lessened. These include soothing music and talking softly

( “ talkesthesia ” ) with the patient throughout the injection period.

Tips for r educing d iscomfort Pain is always a consideration by providers and patients alike. These tips

can help reduce discomfort of anesthesia as well as injection of dermal

fi ller:

• Introduce the needle as slowly as possible

• Inject as slowly as possible

• Use the thinnest needle gauge possible

• Inject through areas that are already numb

• Use longer needles if possible, to reduce the likelihood of needle pricks

• Warm up anesthetics and injectable fi llers to body temperature

• Buffer xylocaine, if possible.

General c omments a bout u se of l ocal a nesthesia u sing l idocaine s olutions

Generally speaking, use of 1% or 2% solutions is preferred, due to safety of

the decreased milligram per milliliter concentration. Epinephrine may be

added to help reduce tissue swelling and bruising. However, side effects of

12 Chapter 2

its administration include tachycardia and increased anxiety. Before the

addition of epinephrine, the physician should determine whether the

patient has a known sensitivity to it. In addition, the weight of the patient is

a consideration in use of epinephrine. Maximum lidocaine dosing without

epinephrine should not exceed 3.5 mg/lb of body weight. Maximum lido-

caine dosing with epinephrine should not exceed 2.0 mg/lb of body weight.

Use of 1.0 mg/lb reduces the likelihood of untoward lesser adverse events.

Treatment s upplies for d ermal fi ller i njections The following list of supplies may be helpful for physicians as they develop

their protocols for pretreatment anesthesia and dermal injection:

• 27G 1 ¼ - inch and ½ - inch needles

• Nerve block medication – lidocaine 1 – 2%

• Localized infi ltration medication – lidocaine 1 – 2% with 1:100 000

epinephrine

• 3 mL syringes and needles for numbing

• 30G 1 - inch or 27G 1 ¼ - or ½ - inch needles for numbing

• Crushed ice or gel cool packs

• Non - latex gloves

• Mirror

• 3 × 3 gauze pads

• Sharps container

• Camera for before and after photos

• Signed consent form

• White eyeliner pencil for marking

• Alcohol pads for cleansing area

• Arnica gel or other topical ointment for massaging area (optional).

Distribution of s ensory n erves in the m id - and l ower f ace

Sensation for the middle and lower thirds of the face is provided by the

two branches of the trigeminal nerve (cranial nerve V – Figure 2.2 ). The

infraorbital nerve (V2) exits the infraorbital foramen. It supplies sensations

to the middle third of the face, i.e. infraorbital area, nasolabial folds (NLFs),

and cutaneous lip. The mental nerve (V3) exits the mental foramen. It

supplies sensation to the lower third of the face, i.e. the lower lip, the

medial/lateral chin, and parts of the jawline.

An i nfraorbital b lock From the author ’ s clinical perspective, a true infraorbital nerve block

is required only when treating the lips. Nevertheless, some physicians

Guidelines for Local Anesthesia in Use of Injectable Fillers 13

maintain that an infraorbital nerve block is ordinarily required for midface

augmentation, unless the anesthetic is being added to the dermal fi ller

itself (see “ Mixing anesthetic with dermal fi ller immediately before admin-

istration ” above). The anatomy of the infraorbital nerve is easily located.

It exits the foramen along a line between the patient ’ s pupil and canine

tooth, bifurcating almost completely medially, then again down toward

the ala, with a third large branch descending almost directly beneath the

foramen to just above the oral commissure (Figure 2.3 ).

A 30G, 1 ¼ - inch needle is typically used. Injection is into the buccal

mucosal groove, in line with the base of the ala, aiming diagonally up

toward the pupil. Aspiration should be deployed to avoid injection of

anesthetic intravascularly. With the needle inserted from ½ inch to ¾ inch

and with the bevel facing down toward the bone, one microdrop should

be injected, followed by a pause, and then additional microdrop injections

for a total of 0.5 – 0.75 mL of lidocaine solution. The area should be mas-

saged before repeating the procedure on the contralateral side. Care must

be taken with large volumes of injected lidocaine; they may distort tissues

and mask the area to be augmented.

A “ m ini - b lock ” for t reatment of NLF When treating NLF, a total infraorbital block is usually not required.

Instead, a “ mini - block ” can provide enough anesthesia to the area of injec-

tion (Figure 2.4 ). This mini - block limits the length of time that the patient ’ s

Figure 2.2 Distribution of sensory

nerves in the mid - and lower face.

14 Chapter 2

Figure 2.3 Anesthetic injection route

and pathways of the infraorbital nerve.

Figure 2.4 Anesthetic injection routes

for “ mini - block. ”

face will be numbed. This procedure will infi ltrate branches of the infra-

orbital nerve but it is not a true infraorbital block. For the mini - block,

either a 27 or 30G 1 ¼ - inch needle is acceptable. Injection of anesthetic

may be transcutaneous or through the mucosa. If injecting through the

Guidelines for Local Anesthesia in Use of Injectable Fillers 15

Figure 2.5 Anesthetic injection routes

and pathways of the mental nerve.

mucosa, injection of local anesthetic (0.25 or 0.3 mL) should be above each

canine and the second bicuspid of the buccal mucosal groove. The needle

should be inserted slightly lateral to the canine (third tooth from midline),

with the tip of the needle directed toward the ala.

Insertion of the needle should only be approximately 2 – 3 mm above the

canine. No further insertion is recommended. The syringe should be aspi-

rated, so that intravascular anesthetic is avoided. One microdrop can be

injected, followed by a momentary stop, and then advancement of needle

another millimeter or so, continuing to inject microdrops. The key to pain-

less injection is to inject very slowly. Pain upon injection of local anesthe-

sia is associated with distension of tissues from too - rapid injection.

A m ental n erve b lock

A mental nerve block is ordinarily required for lower - third face augmenta-

tion, unless the anesthetic is being added to the dermal fi ller. The mental

nerve can be visualized by pulling the lower lip away from the gum

(Figure 2.5 ).

The same length and gauges mentioned earlier may be used. Injection

is a two - phase process: fi rst, the needle is inserted into the buccal mucosal

groove, aiming toward the “ papillary ” line. One microdrop should be

injected, followed by a pause, then a resumption of microdrop injection

16 Chapter 2

of 0.5 – 0.75 mL of anesthetic. When the lateral microdrop injections have

been completed, the needle is backed toward the insertion point, and

reoriented halfway between the previous injection area and the chin

midline, i.e., moving vertically toward the midjowl sulcus. Another

0.25 mL anesthetic can be injected in this area. The injected region should

be massaged, and the procedure repeated before dermal fi ller injections

on the contralateral side.

Local t issue i nfi ltration

Some of the areas injected in facial contouring applications are not served

by either the infraorbital or the mental nerves (Figure 2.6 ). These areas

include the lateral brow, malar and submalar regions, the nasal dorsum,

inferior NLF, corners of the mouth, marionette lines, the prejowl and

mandibular lines, and areas of scar tissue.

Injection is performed in the subdermal layer of the skin to provide

anesthesia to the immediate areas of injection. Tissue infi ltration is used

to provide anesthesia to areas not supplied by infraorbital or mental

nerves. Tissue infi ltration may also be a substitute for blocks and used to

numb any area where fi ller is to be placed, incorporating blanching prop-

erties of epinephrine in the area of potential fi ller injection. However, the

infi ltration may also distort the tissue.

Figure 2.6 Areas not served by

infraorbital and/or mental nerves may

require tissue infi ltration.

Guidelines for Local Anesthesia in Use of Injectable Fillers 17

Injection of small volumes is preferable, to minimize distortion of the

augmentation area. A lidocaine solution containing epinephrine can sig-

nifi cantly reduce ecchymoses, edema, and erythema due to the accompa-

nying vasoconstriction. The recommended ratio of lidocaine to epinephrine

is 1% : 2% lidocaine, with 1:100 000 epinephrine. Although diluting the

epinephrine even further can reduce the risk of these adverse events,

patients who are sensitive to epinephrine should still be counseled about

potential tachycardia and generalized anxiety.

For malar, submalar, prejowl sulcus, inferior mandible, and midface

infi ltration, a 30G, 1 ¼ - inch needle should be used. For marionette lines,

oral commissures, nasal dorsum, and lateral brow, a ½ - inch, 27G needle

is appropriate. Before injection of anesthetic, areas should be cleaned with

alcohol. Ice before anesthetic injection helps minimize bruising potential.

Post anesthetic injection, the area should be massaged lightly to help dis-

perse the solution into the tissue.

Conclusion

Physicians have a choice of mixing their dermal fi ller with anesthetic or,

if they choose, administering conventional pre - treatment anesthetic agents

and then administering injectable dermal fi ller. Those topical agents can

be supplemented with physical and environmental aids to reduce discom-

fort. The option of combining the dermal fi ller to be injected with the

anesthetic of choice provides physicians the benefi t of faster treatment

times without sacrifi cing outcomes. Moreover, patients who feel less pain

tend to be more satisfi ed patients, who in turn tell their friends. The result

for the physician is a larger and more satisfi ed patient base. The result for

the patient is higher satisfaction. Both results are equally desirable.

Acknowledgments

Some of this material originally appeared in a publication produced by

BioForm Medical, Inc. (ML00299 - 00). The author appreciates the coop-

eration of BioForm Medical, Inc. in the use of the illustrations in this

chapter and the editorial assistance of David J. Howell, PhD, RRT (San

Francisco, CA).

References

1. Busso M , Applebaum D . Hand augmentation with Radiesse ® (calcium hydroxylapa-

tite) . J Dermatol Ther 2007 ; 20 : 315 – 17 .

18 Chapter 2

2. Busso M , Voigts R . An investigation of changes in physical properties of injectable

calcium hydroxylapatite in a carrier gel when mixed with lidocaine and with lido-

caine/epinephrine . Dermatol Surg 2008 ; 34 : S16 – 24 .

3. Lacy CF , Armstrong LL , Goldman MP , Lance LL, eds. Drug Information Handbook ,

9th edn . Hudson, Ohio : Lexi - Comp Inc. , 2001 .

4. Britt R . Using EMLA cream before venipuncture . Nursing 2005 ; 35 ( 1 ): 17 .

Hyaluronic Acids: Basic Science Nowell Solish Dermatologic Surgery University of Toronto, Toronto Canada

Kenneth Beer Esthetic, Surgical and General Dermatology and Department of Dermatology, University of Miami, Florida, USA

CHAPTER 3

Differences in hyaluronic acid fi llers have profound consequences for their

interactions when injected into the skin and subcutaneous tissues. The

literature about fi llers is replete with anecdotal evidence and opinions

about which hyaluron is better or worse, more or less inclined to bruise,

softer, harder, or more durable. The science behind these various claims

is not only fascinating but also helpful in understanding the strengths and

weaknesses of the various products. This, in turn, may help clinicians

select products to achieve optimal patient outcomes.

In order to understand the differences between the hyaluronic acid

fi llers (also known as hyalurons, HAs), it is useful to understand their

similarities. All HA molecules are naturally occurring linear polysaccha-

rides which are uniquely conserved throughout species. These polymeric

chains are identical in all species. There is no antigenic specifi city for

species or tissue, and therefore a low potential for allergic reactions, so

different sources of HA will produce identically structured polymers. The

only difference is that bacterially derived HA chains tend to be shorter

than those that are derived from animals.

Hyalurons are found in the extracellular matrix of connective tissue,

synovial fl uid, and other tissues including the ground substance of the

dermis, fascia, extracellular matrix of the eye, hyaline cartilage, synovial

joint fl uid, and many other support structures in the body. 1

Structurally, these molecules are polyanionic disaccharide units of glu-

curonic acid and N - acetylglucosamine 2,3 (Figure 3.1 ). The disaccharide

monomer has a molecular weight of approximately 400 Da. 2 Monomers

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

19

20 Chapter 3

are connected by alternating β 1 – 3 and β 1 – 4 bonds. 2 When connected

these repeating disaccharide units form long linear chains. This is referred

to as a polymer. These, in turn, may be crosslinked to form very large

macromolecules.

When exposed to aqueous solutions, hydrogen bonding between

adjacent carboxyl and N - acetyl groups occurs. Hydrogen bonding results

in a clear viscous gel which is not only stiff but also retains water.

Hyaluronic acid molecules are very hygroscopic and 1 g HA can bind up to

6 L of water. 1

Hyaluronic a cids a s d ermal fi llers

HAs have a very short half - life when injected into human tissues. The

half - life in humans is at most only a few days. After injection, naturally

occurring hyaluronidase will digest non - crosslinked HAs, resulting in

water and carbon dioxide. In order to stabilize these molecules and make

them persist, it is necessary to crosslink the chains. There are various

methods to crosslink these chains and various degrees of crosslinkage that

occur. The method and degree of crosslinking have a signifi cant impact

on the physical characteristics of the molecules.

The raw HA used by various companies to produce their soft tissue

augmentation products is frequently obtained from similar sources.

Supplied as a raw powder, this material forms a viscous liquid when

exposed to water. However, in order to create a gel that is able to

persist once injected, the raw material gel must be modifi ed. It is the

method of modifi cation that imparts the various attributes to the

diffe rent gels and it is essential to understand these differences in order

Figure 3.1 Hyaluronic acid monomeric unit.

Hyaluronic Acids: Basic Science 21

to understand what is or is not different between various commercial

preparations.

Crosslinking

Crosslinking is a must for stabilization of the HA for cosmetic injection.

Most companies obtain their HAs from similar sources, usually

supplied as a powder of raw HAs. Being hygroscopic they form a viscous

structure when exposed to water. This gel starts to resemble the products

injected into patients for soft - tissue augmentation as well as for intra -

articular injections for arthritis. However, it is still unstable and must be

crosslinked to provide stability or it will quickly degrade once injected into

a person.

To link the HA chains and prevent them from being digested, at the

present time, there are three different crosslinkers approved by the Food

and Drug Administration (FDA). Restylane, Perlane, and the Juv é derm line

use BDDE (1,4 - butanediol diglycidyl ether) as the crosslinking agent.

Prevelle Silk uses DVS (divinyl sulfone) and Elevess uses BCDI (biscarbodi-

imide). 1,2,4 Each of these chemical agents will provide stability to the HA

chains and has its own advantages. However, once these products have

done their job, it is essential that they be removed from the fi nished product,

mostly by extensive washing steps built into the manufacturing process.

Each of these agents is toxic to tissue in any meaningful concentrations,

and their fi nal concentrations are limited to trace amounts by the FDA.

The residual concentration of crosslinking molecules is a potential hazard

for the safety of the fi nal product and is one factor considered by the

FDA and physicians injecting these products. For practical purposes, the

amount of crosslinking molecule in many of the HA fi llers is virtually

non - detectable.

As each of the molecules has its own proprietary crosslinking mecha-

nism and each has a different degree of crosslinking, it is important to

have some benchmarks against which to measure. Typically, the amount

of crosslinking is reported as a percentage or degree. This compares the

ratio of disaccharides with crosslinkers present in the formulation. One

consequence of increased crosslinking is to increase the viscosity as well

as the longevity of the HAs (all other factors remaining equal. 2,5,6 This

implies that increased crosslinking is optimal for injectable HA products.

However, crosslinking the molecules beyond a certain point might make

the product less biocompatible and result in a foreign body reaction.

However, none of the currently FDA - approved products has passed this

point of extensive crosslinking.

22 Chapter 3

Plate 1

Plate 2 FixedHA

Figure 3.2 Gel Harness is measured by placing the gel between two plates. The

bottom plate is fi xed and the top plate is moved horizontally. The force required to

move the top plate relative to the lower plate results in the G ′ (Elastic modulus).

Concentration

One of the most important determinants of the degree of correction

obtained is the amount of HA concentration, but this is not a straightfor-

ward measurement. The concentration of HA (mg/mL) includes both

crosslinked HA and free (non - crosslinked) HA. Non - crosslinked HA is

added to the various fi llers as a lubricant and it helps to make the products

fl ow. However, the non - crosslinked products add nothing to the fi nal

correction and a new term, ‘ effective HA concentration ’ (effective HA

(EFA) = total HA – non - crosslinked HA) is a better measure of the HA

that will contribute to tissue correction.

The concentration of HA has not only important implications for long -

term correction but also material bearing on initial reactions once injected.

Their hygroscopic nature means that the more concentrated products will

tend to imbibe more water and, thus, have more tissue swelling after

injection. After a steady - state equilibrium has been reached with the sur-

rounding tissue, more concentrated products will maintain more swelling

and have more fullness in the area injected.

Gel h ardness

Gel hardness is affected primarily by the degree of crosslinking between

the chains and the total HA concentration. More heavily crosslinked

products tend to be stiffer than less crosslinked products. 2,5,6 Gel hardness

is measured as different values of G ′ , the elastic modulus. Every other

parameter being equal, gels with low G ′ will have less crosslinking and

be less stiff than those with higher G ′ . Products with higher G ′ will be

stiffer, harder to displace. 2,5,6 Again every other parameter being equal,

the higher the G ′ the more diffi cult it will be to push the product through

a needle.

Measuring G ′ is typically done by putting a gel between two metal

plates. The amount of resistance encountered by the top plate as it slides

over the gel correlates with the G ′ for that gel (Figure 3.2 ). Besides HA

Hyaluronic Acids: Basic Science 23

concentration, other factors will also effect the G ′ and these can include

the amount of free HA present in a gel and the molecular weight of the

raw material used in the formulation, e.g. the more free HA present, the

more lubricant the gel and the easier the product will fl ow.

Particle s ize

HA gels are usually produced in large blocks of material (Figure 3.3 ). Once

the gel blocks are manufactured they have to be reduced in size in order

to pass through a syringe and needle. The gel blocks may be reduced by

methods that behave as screens, as is done with NASHA particles. These

NASHA particles (Restylane and Perlane) are produced so that the fi nal

particles are of a similar size with standardized shapes. Particulate gel

particles have some interesting physical features. Some will conform and

bend when pushed through a needle, and others will become sheared if

pushed through a small orifi ce with suffi cient force.

One hypothesis holds that the larger particles found in Restylane, and

especially in Perlane, have a surface to volume ratio that is resistant to

Figure 3.3 NAHSA ™ molecule prior to shearing.

24 Chapter 3

enzymatic breakdown by hyaluronidase. This implies that larger particles

will have longer tissue residence and that they will maintain more of a

correction for increased amounts of time. However, contradicting this

assertion is the fact that both Restylane and Perlane (which have very

different particle sizes) have the same duration of correction in the nasola-

bial crease. This is believed to be due to the porous nature of the particles

which negates the surface area affects.

A second way of changing the size of the gel - blocked produced is

referred to as homogenization. This method is used for the Juv é derm

family of products. 2 Homogenization results in particles that are less con-

sistent in their size. The variation in particle size is partially responsible

for the lower G ′ of the products. This lower G ′ has positive effects on the

fl ow characteristics, not only as it passes through the needle orifi ce but

also as it dissects the dermal plane once injected. The increased homogeni-

zation products have more consistent injection properties, resulting in

better injection characteristics. It should be noted that easier injections

may also be obtained by adding free HA but the latter will not result in

any meaningful correction or duration.

In addition to the method of particle production and free HA, another

variable that affects the extrusion force is the viscosity ( η ′ ) of the gel par-

ticle. 2,5,6 A gel that has a higher degree of crosslinking will have a higher

viscosity and therefore a higher extrusion force. Higher extrusion force

products are more diffi cult to inject and require more force to get them

into the dermal planes.

One other variable that affects the physical characteristics of the gel is

the cohesivity of the product. This is the parameter that is related to the

product ’ s ability to retain its shape on injection. When a dermal fi ller is

implanted into the skin, the natural elasticity or tension of the skin will

tend to deform and fl atten out the implant, reducing the initial desired

correction. In principle, the “ lifting ” capabilities of a dermal fi ller (opposing

its deformation) primarily rely in two material properties, namely the

elastic (also known as storage) modulus G ′ and the cohesivity of the fl uid.

Of these two parameters G ′ can be measured using a standard test protocol

on a rheometer. 2,5,6 Cohesivity, on the other hand, can be measured with

the use of a parallel plate rheometer, by lowering the upper plate at a

constant speed against a known mass of the fi ller, while measuring the

normal force opposing its deformation. A higher value of the normal force

represents a higher resistance to deformation and a higher cohesivity of

the product.

Nowadays, some dermal fi ller products in the market rely on high

values of G ′ to provide the lift necessary to achieve optimal correction.

However, these products require the incorporation of higher amounts

of non - crosslinked HA in order to aid the extrusion of the gel through a

Hyaluronic Acids: Basic Science 25

thin needle; as a counteraction the addition of non - crosslinked HA

(acting as a lubricant) will result in decreased cohesivity of the product.

Thus, it can be inferred that the presence of the non - crosslinked HA

surrounding the gel particles will lubricate and therefore facilitate the

motion of the gel particles within the material, whereas products with

less free HA (i.e. the Juv é derm line of dermal fi llers) the gel particles tend

to be held together, being harder to deform or pull the material apart

(therefore retaining its form or shape under stress), resulting in higher

cohesivity.

An example of when lifting characteristics are paramount is injections

into the cheek and zygomatic arches. These are at the level of the perios-

teum and their goal is to lift the midface upward and outward. Thus, gels

that have better lifting characteristics are better suited for this area and

indication than those that are smoother.

Conclusion

The plethora of HA gel products that are presently approved or under

consideration for approval come with a plethora of product claims: some

claim to be smooth, others claim to be the longest lived and still others

purport to be ideal at lifting the face. To decipher these claims and

understand how to select the correct product for a given indication in a

particular individual, it behooves the physician to understand the physical

chemical properties that are responsible for the various clinical features

observed.

The concentration of HA, degree of crosslinking, cohesivity, G ′ , and

particle size all interact to create the unique properties of a particular

product. Each of these factors may be determined and compared with

those of other products being considered. Once they are understood, one

should have a better appreciation of how to use the various HA products

to obtain optimal patient outcomes.

References

1. Monheit GD , Coleman KM . Hyaluronic acid fi llers . Dermatol Ther 2006 ; 19 : 141 – 50 .

2. Tezel A , Fredrickson GH . The science of hyaluronic acid dermal fi llers . J Cosmet Laser

Ther 2008 ; 10 ( 1 ): 35 – 42 .

3. Price RD , Berry MG , Navsaria HA . Hyaluronic acid: the scientifi c and clinical

evidence . J Plast Reconstr Aesthet Surg 2007 ; 60 : 1110 – 19 .

4. Monheit GD , Prather CL . Juv é derm: a hyaluronic acid dermal fi ller . J Drugs Dermatol

2007 ; 6 : 1091 – 5 .

26 Chapter 3

5. Falcone SJ , Berg RA . Crosslinked hyaluronic acid dermal fi llers: a comparison of

rheological properties . J Biomed Mater Res A 2008 ; 87 : 264 – 71 .

6. Collins MN , Birkinshaw C . Physical properties of crosslinked hyaluronic acid

hydrogels . J Mater Sci Mater Med 2008 ; 19 : 3335 – 43

Calcium Hydroxylapatite Microspheres in Facial Augmentation Alastair Carruthers Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada

Jean Carruthers Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada

CHAPTER 4

Over the last decade, the popularity of non - invasive procedures in facial

rejuvenation – compared with surgical intervention – has risen dramati-

cally. In particular, the number of soft - tissue fi llers available has grown

exponentially and includes collagen, cross - linked hyaluronic acid (HA),

poly - L - lactic acid, and polymethylmethacrylate beads, among others.

Calcium hydroxylapatite (CaHA) microspheres (Radiesse; Bioform Medical,

Inc., San Mateo, CA) is the latest of these augmenting agents designed to

combat the signs of volume loss in the face. Approved in 2006 by the Food

and Drug Administration (FDA) for the correction of moderate - to - severe

facial folds and wrinkles (nasolabial folds), and for the correction of signs

of lipoatrophy associated with human immunodefi ciency virus (HIV),

CaHA is considered an effective, long - lasting, biocompatible, easy - to - use

fi lling agent with a favorable safety profi le and a high level of patient

satisfaction.

Properties and m echanism of a ction

An injectable implant, Radiesse is composed of uniform, smooth, synthetic

CaHA microspheres (25 - 45 μ m) suspended in an aqueous carboxymeth-

ylcellulose gel carrier. CaHA comes in pre - fi lled 1.5 - mL (initial treatment)

and 0.3 - mL (touch - up applications) syringes for ease of use, is delivered

via a fi ne - gauge needle (usually 27G), and provides immediate correction

for facial folds and depressions. After implantation, the carrier gel is gradu-

ally absorbed; the remaining synthetic implant acts as a scaffold for new

tissue formation, inducing local histiocytic and fi broblastic response and

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

27

28 Chapter 4

stimulating the production of collagen around the CaHA microspheres

(Figure 4.1 ). 1 The particles are fi xed in place as fi broblasts grow, discour-

aging migration. 2 Over time, the synthetic microspheres, which are identi-

cal in composition to the mineral content of human bone and teeth, 3 are

broken down into calcium and phosphate ions and are excreted. 4,5

Injectable CaHA has been shown to be nontoxic, nonirritating, and non-

antigentic. 6 No calcifi cation or ossifi cation has been observed, and skin

testing is not required before treatment. 4

Pivotal t rials

Two pivotal trials led to the FDA approval of CaHA for the treatment of

nasolabial folds and HIV - associated lipoatrophy in 2006. In a multicenter,

randomized, bilateral, evaluator - blinded trial, Smith and colleagues com-

pared the effi cacy and safety of CaHA microspheres versus collagen in 117

patients with moderate - to - severe nasolabial folds. 7 Individuals received

injections of CaHA on one side of the face, and human collagen

(Cosmoplast; Allergan Inc., Irvine, CA) on the other, with up to two

touch - ups. At 6 months, evaluators rated nasolabial folds treated with

CaHA more improved in 79% of those treated, compared with only 5%

in those who received collagen ( p < 0.0001), with signifi cantly less volume

and fewer injections required. Adverse event (AE) rates and duration were

similar for both groups, although the incidence of bruising and edema was

slightly higher with CaHA than with collagen.

A second, pivotal, open - label, 18 - month trial of CaHA in 100 individuals

with HIV - associated lipoatrophy demonstrated high levels of effi cacy and

safety over 18 months. 8 All assessable patients were rated as improved or

better at all time points through 12 months, as measured by the Global

Aesthetic Improvement Scale (GAIS), and 91% were improved or better

(a) (b)

Figure 4.1 Photomicrograph of beads after implantation showing collagen formation.

Calcium Hydroxylapatite Microspheres in Facial Augmentation 29

at 18 months. Moreover, patient satisfaction remained high: at 12 months,

100% considered treatment benefi cial. Skin - thickness measurements at

12 months remained statistically better than those at baseline, and AEs

(ecchymosis, edema, erythema, pain, and pruritis) were mild and gener-

ally short in duration.

Clinical e xperience

The use of CaHA has been well documented for the treatment of nasolabial

folds 3,7,9 – 13 and HIV - associated lipoatrophy, 3,14 – 17 and has had FDA clear-

ance for the treatment of oral – maxillofacial defects, vocal fold insuffi -

ciency, and radiographic tissue marking in the USA for over 20 years. 4

In addition, practitioners use CaHA off - label for a variety of aesthetic

applications, including nasal contouring, cheek augmentation, and the

correction of marionette lines and depressed scars. 2,3,8,9,16,18,19 Published

reports consistently show a high level of patient and injector satisfaction,

with minimal side effects and long - lasting results.

Effi cacy In a study of 609 patients who received CaHA in the nasolabial folds,

marionette lines, oral commissure, cheeks, chin, lips, and radial lip lines,

Jansen and Graivier conducted follow - up patient satisfaction surveys (via

self - evaluation of preoperative photographs) at 6 months (155 individu-

als), and again between 12 and 24 months (112 individuals). 11 At 12

months, 89% of those involved stated that they would receive the treat-

ment again. Likewise, Roy and colleagues evaluated 82 indivi duals injected

with CaHA for facial rejuvenation (most commonly in the meilolabial

folds); both individuals and physicians reported satisfaction with the look

and feel of the implants at 3 and 6 months. 20 A multicenter, blinded, ran-

domized trial compared CaHA with two HA derivatives in terms of patient

satisfaction (surveys), effi cacy (GAIS), and duration of correction in 205

individuals who received treatment in the nasolabial folds. 21 Individuals

received touch - ups at 4 months and were followed for an additional 12

months after the second injection. More individuals who received CaHA

were “ satisfi ed ” or “ extremely satisfi ed ” than those who received either

HA product, and CaHA showed a higher level of effi cacy in the treatment

of nasolabial folds at 8 months, as measured by the GAIS. Sadick and col-

leagues investigated the effi cacy of CaHA in the nasolabial folds and other

areas of the face 6 months after treatment and found that 90% of 41

individuals reported very good or excellent results. 13 Average physician

ratings of the look and feel of the implant were 4.5 and 4.9, respectively,

on a scale of 1 to 5 (1 = unsatisfactory; 5 = excellent).

30 Chapter 4

(a) (b)

(c) (d)

Figure 4.2 Representative photographs of PSR - stained histologic specimens. (a) 4

weeks; (b) 16 weeks; (c) 32 weeks; (d) 78 weeks. Original magnifi cation: a,b, × 40;

c,d, × 60.

A 12 - month, open - label, prospective trial investigated the effi cacy of

CaHA in 30 individuals with HIV - associated lipoatrophy; 17 29 men and 1

woman received up to two injections given 30 days apart, with assessment

3, 6, and 12 months after the last treatment session. Touch - ups were

offered at 6 and 12 months. Effi cacy was measured by changes from base-

line on the GAIS and in cheek thickness at follow - up. In addition, patients

completed satisfaction surveys at every visit. All patients were rated as

improved or better on the GAIS at all time points; there were no ratings of

no improvement or worse. Likewise, changes from baseline in cheek thick-

ness were statistically signifi cant at all follow - up assessments. At 3, 6, and

Calcium Hydroxylapatite Microspheres in Facial Augmentation 31

12 months, 100% of patients reported treatment satisfaction at all visits on

all measures.

Duration Clinical experience suggests that injectable CaHA provides correction for

an average duration of 12 months in the face, 4,5,16,22 though some reports

suggest a longer duration of 12 – 18 months 2,10,11 (Figure 4.2 ). In 1000

individuals treated for a variety of facial augmentation procedures (prima-

rily nasolabial folds, marionette lines, prejowl depressions, acne scars,

malar eminence enhancement, and generalized soft - tissue defects) over a

period of 52 months, Tzikas found that patients experienced at least 80%

persistence at 1 - year follow - up without retreatment, and the majority

returned for follow - up injections between 12 and 18 months. 5

Safety of C a HA in f acial a ugmentation

CaHA is generally well tolerated. To date, there have been no reports of

antibody formation or hypersensitivity. Transient erythema, edema,

ecchymosis, pain on injection, and pruritis are the most frequently reported

AEs, 23 and reports indicate that most side effects are mild, minimal, and

transient in nature. 5,7,8,10,13,17

Sadick and colleagues investigated the safety of CaHA in 113 patients

treated primarily in the nasolabial folds, among other sites; 13 75 and 38

patients had single or multiple injection sessions, respectively, with

volumes of 1.0 – 2.0 mL per session, and were followed for 6 – 12 months

after the last treatment. Injections were well tolerated in all patients.

There were no allergic reactions, and mild erythema and minimal edema

lasting from a few hours to a few days were the most common side effects.

Seven patients reported minor, transient AEs (ecchymosis, infl ammation,

and edema, and two cases of submucosal nodules of the lip that were

treated successfully with triamcinolone injections). Tzikas injected 1000

patients with CaHA for a variety of facial aesthetic applications (primarily

nasolabial folds and marionette lines) over 52 months. 5 Injections were

mostly well tolerated. Erythema and ecchymosis were the most commonly

reported side effects but were mild and transient, typically resolving within

2 weeks. The incidence of nodules in patients treated for lip augmentation

was 5.9%.

Nodules Marmur and colleagues examined punch biopsy samples from human

volunteers at 1 and 6 months after injection of CaHA into the dermis

32 Chapter 4

and found no evidence of granuloma formation, migration, or other

foreign - body reactions. 1 However, nodules and foreign - body reaction to

CaHA in the lips are the most commonly reported complications, 3,5,11,13,19,24

including one case of nodule formation from a distant injection site, 25

with a 5 – 8% rate of nodule formation reported in the literature. 2 Nodu-

les require treatment with either intralesional steroids or incision and

drainage. 3,19

Some practitioners believe that lack of experience and poor injection

technique may affect the incidence of nodule formation. Jansen and

Graivier found nodules in 12.4% of patients treated for lip augmentation

and in 3.7% of those treated for radial lip lines. 11 However, the incidence

decreased to 8.8% by using a smaller injection volume and more con-

servative threading technique. A 47 - month study investigated the safety

profi le of CaHA for the treatment of nasolabial folds and other areas of

the face in 113 patients. 13 Two of 14 individuals (15%) who received

CaHA in the lips experienced nongranulomatous submucosal nodules;

the authors postulate that the higher rate of nodule formation was due

to small sample size. In 349 lip augmentation procedures performed over

52 months, Tzikas found an overall incidence of nodule formation of

5.9%, but the incidence declined to less than 2% for the last 100 lips

treated. 5 The formation of nodules outside of the lips was rare (0.002%)

and resulted from an injection technique that was too superfi cial.

However, some practitioners, the author included, prefer to avoid CaHA

for lip augmentation.

Radiographic p roperties Radiopaque in nature, CaHA particles are clearly visible on computed

tomography (CT) scans and may be visible in standard radiography.

However, there is no indication that CaHA potentially masks abnormal

tissues or may be interpreted as tumors on CT scans. 26 The authors and

colleagues investigated whether the implant presented any confounding

radiographic properties that could cause problems in the interpretation of

radiographs or CT scans; 58 patients with facial lipoatrophy or pronounced

nasolabial folds who had been treated with CaHA underwent radiographic

and CT imaging studies over an extended time period (up to 427 days after

injection) and with varying amounts of CaHA (from 1.3 mL to 34.1 mL in

total). Although CaHA appeared inconsistently on the radiographs

(Figure 4.3 ), the implant was easily visualized on CT scans in almost all

patients, with no obscuration of underlying structures and no evidence of

migration (Figure 4.4 ). With proper patient history, the material is there-

fore easily seen soon after injection and does not compromise the assess-

ment of adjacent structures.

Calcium Hydroxylapatite Microspheres in Facial Augmentation 33

(a) (b)

Figure 4.3 (a) Radiograph after injection of Radiesse showing no radiopacity resulting

from the Radiesse.

(a) (b)

Figure 4.4 CT Scan of an individual before (a) and 2 weeks after (b) injection of

Radiesse into the nasolabial fold. The opacity can be seen in the underlying tissue.

Considerations for f acial a ugmentation with C a HA

As with any augmentation procedure, proper patient education and com-

munication are critical in ensuring optimal satisfaction and understanding

of the associated risks and benefi ts. A pre - injection discussion should

include a review of past medical history and current prescription or non-

prescription medications, counseling about pain or other common side

34 Chapter 4

effects that may occur with treatment, as well as expected short - term and

long - term outcomes. CaHA is contraindicated in individuals with a history

of anaphylaxis or the presence of multiple severe allergies and should not

be used in those with known hypersensitivity to any of the product com-

ponents. 23 Likewise, treatment should be deferred in any person with

active skin infl ammation or infection in or near the treatment areas. CaHA

has been reported to activate herpes zoster; 27 patients with a history of

herpesvirus infection may wish to receive prophylactic antiviral therapy. 28

The safety of CaHA has not been studied in pregnancy or lactation, or in

individuals under the age of 18 years.

Pain m anagement As a result of the size of the needle used (in most cases, 27G), injec-

tions of CaHA can be painful and may even deter patients from repeat-

ing the procedure. Pain can be alleviated by ice, nerve - block anesthesia,

topical anesthesia, or infi ltration of small amounts of local anesthetic

into the treatment area 4,29 and will depend on physician and patient

preference, as well as site of implantation. For the treatment of HIV -

associated lipoatrophy, for example, infraorbital blocks are sometimes

used to provide anesthesia extending from the lower lids down through

the cheeks to the upper lip. 4 In the authors ’ experience, however, a

combination of topical anesthesia and local infi ltration (as described

below) provides adequate relief. Regardless of the method used, the

treatment area should be marked on the skin before any anesthetic

application. 4

In addition to using a topical anesthetic 30 min before injection (see

Injection techniques below), the author always adds approximately

0.15 mL of 2% lidocaine with 1:100 000 epinephrine, drawn up in a 1 - mL

Luer - Lok syringe and connected to the CaHA syringe with a Braun fl uid -

dispensing connector (FDC 1000; Braun Medical Inc., Melsungen,

Germany). The fi ller is passed into the lidocaine solution and back into

the CaHA syringe about 10 times minimum. The addition of lidocaine to

CaHA does not appear to alter the physical properties of the fi lling agent,

although 10 mixing passes are recommended to ensure optimal homoge-

neity. 30 The diluted material is then divided equally between the two

syringes.

Injection t echniques A 27G, ½ - or 1 ¼ - inch needle is recommended due to the product ’ s relative

viscosity. 4,23 Needle jams are more likely to occur with needles smaller than

27G. 23 The author uses a wide - bore, 1 - inch, 28G needle or, on occasion, a

1 ½ - inch, 25G needle. Before treatment, the injection site is marked with a

soft white pencil, and pretreatment photographs are taken. The author pre-

Calcium Hydroxylapatite Microspheres in Facial Augmentation 35

pares the skin with an antiseptic solution, then applies a topical anesthetic

(Betacaine; 15% lidocaine, 5% prilocaine in an occlusive base) left on for

approximately 30 min. After the skin has been wiped clean, the patient is

positioned appropriately so that the volume defects can be seen – usually

an upright position with head supported. The skin is tensed, and the needle

is gently inserted through the skin bevel down at an approximate 30 ° angle

to the skin, 23 with the needle tip positioned at the appropriate depth.

Injection techniques and volumes vary according to the size and location

of the fold or volume defi cit. CaHA can be injected at the subdermal plane,

just in the subcutaneous space but superior to the periosteum, or on the

periosteum itself. 4 It is always the authors ’ practice to inject CaHA deeply,

either close to the bone or deep in the subcutaneous tissues. An attempt

to inject too superfi cially is likely to produce short - or long - term lumpi-

ness, and deep injections can reduce the incidence of prolonged swelling,

particularly in the cheek or midface area. Placement close to the bone

usually requires a bolus injection, with massage of the treated area to

ensure proper distribution. Depending on the location, CaHA may be

injected in a retrograde fashion, using a linear threading, cross - hatching,

or fanning technique to deposit transversing threads of material in multi-

ple layers as needed. 4,5 In general, it is best to avoid numerous percutane-

ous punctures or too much motion at the tip of the needle, as both will

increase the incidence of bruising.

CaHA provides a 1 : 1 correction, with less volume required than col-

lagen or HA fi lling agents, 7,21 particularly when layered with other prod-

ucts, 31 and no need for overcorrection. 5 Massage is often used after

injection to evenly distribute the fi ller material. In some instances, addi-

tional follow - up treatments may be necessary, depending on the size of

the defect and the needs of the patient, and some injectors prefer to use

smaller amounts in a scheduled sequence of treatment sessions.

Midface i njections Signs of aging can be most apparent in the midface, where volume

loss initiates the descent of malar fat pads, in turn leading to drooping

and increasing prominence of folds and depressions in the lower face

(Figure 4.5 ). Malar and submalar augmentation with a volumizing fi ller

such as CaHA produces a healthier, rounded appearance of youth, and

can affect the face as a whole (Figure 4.6 ); for that reason, cheek augmen-

tation should always be performed fi rst when treating multiple sites on

the face in one session. 16 Injections are placed in crisscrossing linear

threads, with cross - hatching and layering as the needle is withdrawn for

structural support (Figure 4.7 ), and should be avoided above the orbital

rim or into the tear troughs. 4 Deep (subcutaneous to pre - periosteal) place-

ment of injections can lower the risk of prolonged swelling that can occur

36 Chapter 4

(a) (b)

Figure 4.5 Woman with marionette lines before (a) and after (b) Radiesse treatment.

The replacement of volume in the entire area is apparent in these photographs.

(a)

(b)

(c)

(d)

(e)

(f)

Figure 4.6 (a – c) Woman with volume loss in the cheeks from the front before (a),

from the side before (b,c); (d – f) similar images of the same patient 2 weeks after

volume replacement to the cheeks.

Calcium Hydroxylapatite Microspheres in Facial Augmentation 37

in the midface. Extension of the correction laterally and slightly inferiorly

along the zygoma may provide better support for crow ’ s feet and can

enhance the overall appearance of the face. 16 Some practitioners use

the intraoral – supraperiosteal injection approach, which may lessen the

need for additional fi ller in the nasolabial fold and marionette lines,

and reduce the incidence of short - term side effects, such as bruising

and swelling. 4

HIV - associated facial lipoatrophy primarily affects the temporal, infra-

orbital, submalar, and malar regions, as well as the nasolabial folds

(Figure 4.8 ). Although injections are usually placed deeply in the submalar

area using a fanning technique, with additional threads layered into a

deeper plane, some practitioners fi nd that extending the fi lling agent to

the malar eminence and periorbital region may result in a more complete

correction. 4

Lower f ace As faces lose volume from the malar and medial cheek pads, nasolabial

folds begin to deepen. CaHA is particularly benefi cial for the treatment of

nasolabial folds (Figure 4.9 ). Deep dermal injections fi ll the creases, while

deeper injections in the subdermal plane using a linear threading and

fanning technique can add structural support. 4 Using a V formation or

injecting the material in a triangular shape, cross - hatching with trans-

versely oriented threads, adds greater support and can lead to a more

pleasing aesthetic result. 4

Figure 4.7 Diagram showing the

fanning technique for enhancement of

the malar/zygomatic area.

38 Chapter 4

(a) (b)

Figure 4.8 HIV - positive individual with grade 1 – 2 facial lipoatrophy before (a) and

after (b) correction with 2.6 mL of Radiesse per side.

(a) (b)

Figure 4.9 Correction of volume loss of the cheeks and nasolabial folds with

Radiesse.

Superfi cial lines in the oral commissure are best treated with an HA

derivative or collagen, although deeper lines can be fi lled with CaHA.

However, this area is more at risk of palpability or nodule formation.

Adequate correction involves volume to fi ll the lines and folds and lift the

corners of the mouth. Injections are placed in the deep dermis inferior to

the corner of the mouth, extending into the marionette lines, with threads

of small amounts (around 0.05 mL) deposited in a fanning and crisscross-

ing pattern. Marionette lines are diffi cult to eradicate completely and may

need adjunctive therapy with additional fi llers (Figure 4.10 ). To fi ll, con-

servative amounts of CaHA are injected subdermally, with HA layered

superfi cially. Some practitioners prefer to schedule multiple sessions using

very small amounts of material at each session. 4

Calcium Hydroxylapatite Microspheres in Facial Augmentation 39

Treatment of marionette lines and the oral commissure should include

additional augmentation of the prejowl and perimental area. In the prejowl

sulcus, CaHA is deposited in the subdermal plane, taking care to recreate

the inferior border of the mandible rather than focusing on simple volume

replacement in the body of the mandible (Figure 4.11 ). For the best results

along the chin and jaw, the fi ller should be injected in increments, fol-

lowed by gentle massage to help the material blend with the chin and jaw

contours. 4 An atrophic jawline can be treated with injections placed along

the periosteum of the inferior mandible. The marionette and jawline,

where the facial artery is superfi cial, are particularly susceptible to bruis-

ing. There are two ways to avoid bruising in this area: inject the chin

from the midline or anteriorly (as described above), or insert the material

via intraoral – supraperiosteal bolus placement of CaHA (through the oral

mucosa). There are defi nite risks associated with injecting through the oral

cavity, with a signifi cant increase in the likelihood of infection. The authors

recommend using a prophylactic dose of oral antibiotic 30 min before

injecting (1000 mg Kefl ex or 500 mg Biaxin for individuals who are allergic

to penicillin), as well as the use of an antiseptic mouthwash before the

(a) (b)

Figure 4.10 Marionette lines before and after correction with Radiesse and a

hyaluronic acid.

(a) (b)

Figure 4.11 Enhancement of the jawline with Radiesse.

40 Chapter 4

procedure. The needle can then be inserted through the sulcus and posi-

tioned accurately, and the risk of bruising and swelling is dramatically

reduced. As there is no percutaneous puncture, the short - term side effects

are generally much reduced.

Post - t reatment p rocedures Post - procedure photographs accurately document response to treatment

and may be taken immediately after injection and at any follow - up visits.

Edema and ecchymosis can be alleviated by gentle compression with an

ice - pack for several hours after treatment. 5 Advising patients to remain

upright for a period of time after treatment and sleeping with their heads

elevated may also aid in relieving swelling. 4 Patients should avoid exces-

sive sun or heat exposure for approximately 24 hours, or until transient

redness or swelling has subsided. 21 Follow - up appointments can be sched-

uled beginning at 2 weeks to assess improvement and address any adverse

events. Depending on age, skin elasticity, and depth of defi cit, CaHA

usually lasts for 10 – 12 months, and most patients return between 12 and

18 months for follow - up treatment. 5

Conclusion

CaHA is a durable and versatile injectable fi ller that has received high

marks from practitioners for its durability, versatility, and safety. Approved

by the FDA for facial augmentation in 2006, CaHA provides immediate

correction of wrinkles and folds, and is particularly useful for fi lling lines

and depressions and replacing volume lost through illness or the aging

process. CaHA augmentation lasts for up to a year (or more), and is

remarkably popular among patients and physicians alike. With volume

enhancement an integral component of any cosmetic practice, the use of

CaHA is only likely to increase.

References

1. Marmur ES , Phelps R , Goldberg DJ . Clinical, histologic, and electron microscopic

fi ndings after injection of a calcium hdroxylapatite fi ller . J Cosmet Laser Ther

2004 ; 6 : 223 – 6 .

2. Goldberg DJ . Calcium Hydroxylapatite. Fillers in cosmetic dermatology . Abingdon : Informa

UK Ltd , 2006 .

3. Tzikas TL. Evaluation of Radiance FN soft tissue fi ller for facial soft tissue augmenta-

tion . Arch Facial Plast Surg 2004 ; 6 : 234 – 9 .

4. Graivier MH , Bass LS , Busso M , Jasin ME , Narins RS , Tzikas TL . Calcium hydroxy-

lapatite (Radiesse) for correction of the mid - and lower face: consensus recommen-

dations . Plast Reconstr Surg 2007 ; 120 ( 6 suppl): 55S – 66S .

Calcium Hydroxylapatite Microspheres in Facial Augmentation 41

5. Tzikas TL. A 52 - month summary of results using calcium hydroxylapatite for facial

soft tissue augmentation . Dermatol Surg 2008 ; 34 ( suppl 1 ): S9 – 15 .

6. Hubbard W. BioForm Implants: Biocompatibility . Franksville, WI : BioForm, Inc. , 2003 .

7. Smith S , Busso M , McClaren M , Bass LS. A randomized, bilateral, prospective com-

parison of calcium hydroxylapatite microspheres versus human - based collagen for

the correction of nasolabial folds . Dermatol Surg 2007 ; 33 ( suppl 2 ): S112 – 21 .

8. Silvers SL , Eviatar JA , Echavez MI , Pappas AL . Prospective, open - label, 18 - month

trial of calcium hydroxylapatite (Radiesse) for facial soft - tissue augmentation in

patients with human immunodefi ciency virus - associated lipoatrophy: one - year

durability . Plast Reconstr Surg 2006 ; 118 ( 3 suppl): 34S – 45S .

9. Cuevas S , Rivas MP , Amini S , Weiss E . Radiesse for aesthetic soft tissue augmenta-

tion . Am J Cosmet Surg 2006 ; 23 : 190 – 6 .

10. Jacovella PF , Peiretti CB , Cunille D , Salzamendi M , Schechtel SA . Long - lasting

results with hydroxylapatite (Radiesse) facial fi ller . Plast Reconstr Surg 2006 ; 118

( 3 suppl): 15S – 21S .

11. Jansen DA , Graivier MH . Evaluation of a calcium hydroxylapatite - based implant

(Radiesse) for facial soft tissue augmentation . Plast Reconstr Surg 2006 ; 118

(suppl): 22S – 30S .

12. Alam M , Yoo SS . Technique for calcium hydroxylapatite injection for correction of

nasolabial fold depressions . J Am Acad Dermatol 2007 ; 56 : 285 – 9 .

13. Sadick NS , Katz BE , Roy D . A multicenter, 47 - month study of safety and effi cacy

of calcium hydroxylapatite for soft tissue augmentation of nasolabial folds and other

areas of the face . Dermatol Surg 2007 ; 33 ( suppl 2 ): S122 – 6 .

14. Comite SL , Liu JF , Balasubramanian S , Christian MA. Treatment of HIV - associated

facial lipoatrophy with Radiance FN (Radiesse) . Dermatol Online J 2004 ; 10 : 2 .

15. Roth JS. Restorative approaches for HIV - associated lipoatrophy . PRS Notebook

2005 ; 10 : 24 – 8 .

16. Busso M , Karlsberg PL . Cheek augmentation and rejuvenation using injectable

calcium hydroxylapatite (Radiesse) . Cosmet Dermatol 2006 ; 19 : 583 – 8 .

17. Carruthers A , Carruthers J . Evaluation of injectable calcium hydroxylapatite for the

treatment of facial lipoatrophy associated with human immunodefi ciency virus .

Dermatol Surg 2008 ; 34 : 1486 – 99 .

18. Flaharty P. Radiance . Facial Plast Surg 2004 ; 20 : 165 – 9 .

19. Sklar JA , White SM. Radiance FN: A new soft tissue fi ller . Dermatol Surg 2004 ;

30 : 764 – 8 .

20. Roy D , Sadick N , Mangat D . Clinical trial of a novel fi ller material for soft - tissue

augmentation of the face containing synthetic calcium hydroxylapatite micro-

spheres . Dermatol Surg 2006 ; 32 : 1134 – 9 .

21. Moers - Carpi M , Vogt S , Santos BM , Planas J , Vallve SR , Howell DJ. A multicenter,

randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for

treatment of nasolabial folds . Dermatol Surg 2007 ; 33 ( suppl 2 ): S144 – 51 .

22. Felderman LI. Radiesse for facial rejuvenation . Cosmetic Dermatol 2005 ; 18 : 823 – 6 .

23. BioForm Medical, Inc . Radiesse ® Injectable Implant: Instructions for use . Franksville, WI :

BioForm Medical, Inc. , 2008 .

24. Sankar V , McGuff HS. Foreign body reaction to calcium hydroxylapatite after lip

augmentation . J Am Dent Assoc 2007 ; 138 : 1093 – 6 .

25. Beer KR. Radiesse nodule of the lips from a distant injection site: report of a case

and consideration of etiology and management . J Drugs Dermatol 2007 ; 6 : 846 – 7 .

26. Carruthers A , Liebeskind M , Carruthers J , Forster BB . Radiographic and computed

tomographic studies of calcium hydroxylapatite for treatment of HIV - associated

facial lipoatrophy and correction of nasolabial folds . Dermatol Surg 2008 ; 34 ( suppl

1 ): S78 – 84 .

42 Chapter 4

27. Sires B , Laukaitis S , Whitehouse P . Radiesse - induced herpes zoster . Ophthal Plast

Reconstr Surg 2008 ; 24 : 218 – 19 .

28. Jones JK. Patient safety considerations regarding dermal fi ller injections . Plast Surg

Nursing 2006 ; 26 : 156 – 63 .

29. Comite S , Greene A , Cieszynski SA , Zaroovabeli P , Marks K . Minimizing discomfort

during the injection of Radiesse with the use of either local anesthetic or ice .

Dermatol Online J 2007 ; 13 : 5 .

30. Busso M , Voigts R . An investigation of changes in physical properties of injectable

calcium hydroxylapatite in a carrier gel when mixed with lidocaine and with lido-

caine/epinephrine . Dermatol Surg 2008 ; 34 ( suppl 1 ): S16 – 23 .

31. Godin MS , Majmundar MV , Chrzanowski DS , Dodson KM . Use of Radiesse in

combination with Restylane for facial augmentation . Arch Facial Plast Surg

2006 ; 8 : 92 – 7 .

Evolence and Evolence Breeze Jean Carruthers Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada

Alastair Carruthers Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada

CHAPTER 5

Injectable bovine collagen (Zyderm; Collagen Corporation, Santa Barbara,

CA) was the fi rst soft - tissue augmenting agent approved by the Food and

Drug Administration (FDA) for use in humans in 1981. 1 Dermal correction

with bovine collagen implants is generally of short duration and requires

frequent touch - ups after 3 – 4 months. In addition, hypersensitivity reac-

tions are common, and skin testing is necessary before treatment. 2 Human

bioengineered collagen (CosmoDerm and CosmoPlast; Inamed Aesthetics,

Santa Barbara, CA), the second - generation injectable collagen, was devel-

oped to give the same fi ne texture and quality of injectable product with

a great advantage: its human origin meant that skin testing was no longer

required. However, bioengineered collagen, similar to its animal - based

counterpart, typically lasts for only 3 months before dissipating. 3 Evolence

and Evolence Breeze (ColB ar Life Science Ltd, Herzeliya, Israel) are newly

approved, third - generation collagen fi llers with enormous potential in the

fi eld of facial rejuvenation. Specifi cally designed with a reduced risk of

antigenicity and an increased durability of up to 12 months, this third -

generation collagen has a real value in our armamentarium of dermal

fi llers, delivering good correction with immediate results and minimal

down time.

History of i njectable c ollagen i mplants

The fi rst indication that collagen – the most abundant protein in the body

– could play an important role in a variety of applications came when

Gross and Kirk formed a rigid gel by heating collagen extracted from fresh

calf skin in 1958. 4 In the late 1960s, investigators purifi ed collagen, iden-

tifi ed subtypes in mammals, and discovered that the immunogenicity of

the material could be reduced by removing the nonhelical amino acid

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

43

44 Chapter 5

carboxy - terminal telopeptides. 5,6 In 1977, Knapp and colleagues demon-

strated the fi rst successful dermal implants in rats using human, rabbit,

and rat collagen, 7 and the fi rst injections of human and bovine collagen

were performed shortly thereafter in 28 patients for the correction of acne

scars, subcutaneous atrophy, and wrinkling. 8 Results demonstrated a 50 –

85% correction sustained over 3 – 18 months. Stegman and Tromovitch

assessed bovine collagen for the correction of depressed scars (mainly

acne) and found a 50 – 80% improvement after three to fi ve treatments. 9

By 1981, when the US Food and Drug Administration (FDA) approved

bovine collagen (Zyderm I) for general use in the nasolabial fold, 728

physician investigators had treated 5109 patients with a high level of safety

and effi cacy. 10 The FDA subsequently approved two other injectable for-

mulations, Zyderm II and Zyplast, in 1983 and 1985, respectively.

The initial collagen fi llers are xenografts, in that they are derived from

a different animal species (bovine), and do meet many of the criteria of

the ideal soft - tissue fi lling agent: ambulatory, reproducible, minimally

invasive with few side effects or little down time, and predictable effi cacy.

Human - derived collagen (CosmoDerm I, CosmoDerm II, and CosmoPlast)

was developed to reduce the skin - test requirement or risk of antigenicity,

and was approved by the FDA in 2003. 11

Vertebrate collagen has a natural triple helical structure. If the three

collagen chains are not crosslinked, the injected material will be rapidly

removed from the body and the clinical aesthetic effect will be lost. The

crosslinking agent in the fi rst two generations of injectable collagen was

glutaraldehyde, an electron microscopy fi xative. Thus very small amounts

of crosslinking were possible and the clinical effect, while excellent, waned

unacceptably quickly. Bovine and human collagens typically dissipate after

3 or 4 months. 2,3

Evolence/Evolence Breeze

Evolence – developed in Haifa, Israel, by ColBar Corporation, now a divi-

sion of Johnson and Johnson – uses only type I collagen harvested from

the porcine Achilles tendon. Type I collagen forms the largest and strong-

est of fi bers, and has been used for heart valve replacements, corneal

shields, wound dressings, and surgical meshes for tissue repair. 12 Evolence

is prepared via a process that includes enzymatic digestion to carefully

remove the N - terminus, the locus of major antigenicity between collagens

of differing vertebrate origin: pepsin separates the monomeric collagen

fi bers from the immunogenic telopeptides, which are thus removed to

eliminate the risk of xenogenic allergy. The fi bers are then polymerized

as reconstituted polymeric collagen and crosslinked with a naturally occur-

Evolence and Evolence Breeze 45

ring sugar metabolite, D - ribose, via Glymatrix technology to slow the rate

of absorption in vivo (Figure 5.1 ). 13 The Glymatrix process of crosslinking

is unique to fi llers and, as organic sugar produces no toxicity, larger

amounts can be used, unlike glutaraldehyde, 1,4 - butanediol diglycidyl

ether (BDDE), or other cross - linking agents that may be potentially toxic

and are used sparingly according to FDA safety parameters. The Glymatrix

technology creates a longer - lasting, more robust product, which can

provide correction for up to 1 year. Despite this strength, the viscosity of

Evolence, Evolence Breeze, and Zyplast is extremely similar when extruded

through the appropriate needles (Figure 5.2 ).

Figure 5.1 Glymatrix technology. Pepsin separates collagen fi bers from the

immunogenic telopeptides ; fi bers are polymerized as reconstituted collagen and

crosslinked with D - ribose.

1800

1500

1200

900

600

300

00.0 1.0 2.0 3.0 4.0

Shear Rate (rad/s)

Vis

cosi

ty (

pas)

5.0 6.0 7.0

EVOLENCEEVOLENCE BreezeZyplast

Figure 5.2 Viscosity of Evolence, Evolence Breeze and Zyplast is similar when

injected through the appropriate needles.

46 Chapter 5

Duration and c linical e ffi cacy A preclinical trial of Evolence - 30 versus bovine collagen (Zyplast) in the

nasolabial folds of 12 patients revealed similar effi cacy in the fi rst few

months, but ultimately a longer - lasting correction; in an average follow -

up of 18 months, Evolence - 30 was superior in 9 of 11 patients treated

( p = 0.022). 14 In a double - blind, randomized, multicenter, within - individ-

ual bilateral facial comparison, Narins and colleagues investigated the

effi cacy, safety, and longevity of Evolence versus hyaluronic acid (HA;

Restylane) in 149 patients. 15 Individuals were selected with moderate - to -

deep nasolabial folds on the modifi ed Fitzpatrick wrinkle scale (a score of

2 or more), and up to two injections were used to correct both folds: one

with Evolence, the other with Restylane. Patients were followed for 6

months initially, and then for a year for effi cacy and safety. 13 Skin tests

and sequential antibody levels were performed and followed throughout

the study. The results from immunoglobulin titers and skin tests indicated

no potential for allergic reactions. Data from the initial 6 months of the

study indicated no meaningful difference between the Evolence - or

Restylane - treated nasolabial folds at any point. Patient evaluation also

indicated a 90% improvement over baseline at 6 months on both sides.

Out of the 148 individuals followed for 6 months, 145 were followed for

effi cacy and safety for an additional 6 months, a total of 12 months. 13 Filler

persistence or a wrinkle severity score of 1 over baseline was maintained

at 12 months in 75% of the individuals.

Safety Evolence has been used successfully in Europe for over 5 years as a

facial wrinkle and groove fi ller, with few reported side effects or com-

plications. 11 Preclinical studies of Evolence show no evidence of cyto-

toxicity, delayed dermal contact sensitization, intracutaneous reactivity,

systemic toxicity, mutagenicity, or genotoxicity. 13,16 A biopsy study in an

animal model confi rms the good tissue integration and host response

with demonstrable evidence of fi broblastic activity and neocollagenesis. 17

Intradermal skin testing before the use of Evolence appears unnecessary;

multiple studies have found no histopathological signs or clinical symp-

toms of hypersensitivity. 12 – 15 Shoshani and colleagues investigated the

incidence of hypersensitivity of Evolence in a group of 530 patients who

received intradermal injections of 0.1 mL Evolence in the left forearm,

and a second injection in the right after 2 weeks. 12 Clinical assessments

and serum anticollagen antibody tests in 519 patients detected no

signifi cant erythematous reactions or changes in porcine type I

collagen antibodies at any time. Moreover, Evolence is nonhydrophilic

and hemostatic, minimizing the incidence of swelling, bruising, and

bleeding. 14

Evolence and Evolence Breeze 47

Complications As with all fi llers, minor adverse events (AEs) associated with Evolence

and Evolence Breeze include pain on injection, erythema, edema, ecchy-

mosis, and urticaria. 18,19 When injecting Evolence or Evolence Breeze,

knowledge of anatomy is crucial; embolism, ulceration, and necrosis can

occur with injection in an artery. In addition, Evolence should not be

injected into the glabellar region, following restrictions in that area for use

of other crosslinked collagen fi llers.

Clinical experience to date has demonstrated a high level of safety and

only minor side effects. A small pilot study using a preparation containing

a lower concentration of crosslinked porcine collagen (Evolence - 30) in 12

patients revealed no serious side effects. 14 A pivotal trial of Evolence and

HA (Restylane) in 149 patients with moderate - to - deep nasolabial folds

showed similar safety profi les for both products, with no signifi cant AEs

(indeed, induration, swelling, bruising, and pain were higher in patients

treated with HA). 15 A long - term assessment of the same patients ( n = 145)

noted only mild skin reactions in three individuals (mild erythema in two,

and mild nodule formation in one) at 9 and 12 months after injection; no

side effects were considered serious or severe, and there were no reports

of delayed granuloma or infection. 13

Evolence should not be injected into the lips or infraorbital region due

to the high incidence of nodule formation. Braun and Braun report on 16

of 20 women injected with Evolence for lip augmentation who experi-

enced multiple lip nodules, many of which required treatment; some

nodules were visible in six patients 1 year after injection. 20 However,

Evolence Breeze can be used in the lips, particularly together with botu-

linum toxin type A (BTX - A); Landau found only transient lumpiness

which disappeared spontaneously by week 4 in 15 women. 21 In addition,

a recent study by De Boulle and colleagues report a very low incidence of

nodules or bumps after the injection of Evolence Breeze in 57 individuals

for lip border and volume enhancement. 22

Clinical u se of Evolence/Evolence Breeze

Opaque gels comprising collagen at a concentration of 35 mg/mL are sup-

plied in 0.5 - and 1 - mL prefi lled syringes that can be stored at room tem-

perature; Evolence and Evolence Breeze are third - generation, purifi ed

porcine collagens crosslinked with D - ribose and suspended in phosphate -

buffered physiological saline. The production processes are slightly differ-

ent for Evolence and Evolence Breeze, with modifi ed shearing, fi ltration,

and homogenization practices. The modifi cations to the production line

results in a product (Evolence Breeze) that it is softer, lighter, and less

48 Chapter 5

viscous, with collagen fi bers of shorter lengths, allowing the product to

fl ow through a smaller lumen needle (30G) in a more fi nely textured

consistency. 21

Evolence was approved by the FDA in 2008 for the correction of mod-

erate - to - deep facial wrinkles and folds (Figure 5.3 ), and has been available

in Canada, western and eastern Europe, Israel, South Korea, and Russia

since 2004. Evolence is used to treat a variety of pronounced rhytids, often

in combination with other procedures, such as BTX - A (Figure 5.4 ), and is

ideal for three - dimensional volumizing in the cheeks, malar area, chin,

nasolabial folds, and temples (Figure 5.5 ). Evolence is not indicated for

the lips or periorbital regions.

Figure 5.3 Evolence treatment areas.

(a) (b)

Figure 5.4 Nasolabial folds and perioral region (a) before and (b) after treatment

with Evolence and Evolence Breeze.

Evolence and Evolence Breeze 49

Evolence Breeze has not been approved by the FDA but is available in

Canada and Europe for the treatment of fi ne - to - moderate wrinkles and

folds (Figure 5.6 ). The lower viscosity of Evolence Breeze makes it ideal

for use in the lips (Figure 5.7 ), superfi cial lines and scars, and in infraor-

bital hollows, and it is indicated as a low - volume, intradermal injection

for deep, resting, glabellar folds in tandem with BTX - A treatment of the

dynamic component of the glabellar frown (Figure 5.8 ).

Evolence and Evolence Breeze are contraindicated in patients with

known hypersensitivity reactions to any collagen product, a history of

anaphylactic reactions or serious reactions, bleeding disorders, or compro-

mised immune function (e.g. collagen vascular disease). 18,19 Neither for-

mulation should be injected into blood vessels, as collagen can initiate

(a) (b)

Figure 5.5 Cheek volume (a) before and (b) after augmentation with Evolence.

Figure 5.6 Evolence Breeze treatment

areas.

50 Chapter 5

platelet aggregation and cause vascular occlusion and localized infarction

or embolism. Overfi lling intradermal bovine collagen injections in the

glabella has been associated with dermal necrosis. 18,19 Evolence should not

be injected in the infraorbital hollows or the lips due to long - lasting lumps

(see “ Complications ” ), although the lower viscosity Evolence Breeze can

be useful in those areas.

Injection t echniques Evolence contains no lidocaine. For pain relief, we apply topical 15%

lidocaine and 5% prilocaine in a petroleum jelly base to a clean face free

of make - up for 10 – 15 min before injection. If required, we use regional

and nerve blocks (4% articaine with 1 : 200 000 epinephrine). In most

cases, however, we simply add lidocaine (10 – 20% by volume with

1:100 000 epinephrine) to the Evolence or Evolence Breeze using a sterile

(a) (b)

Figure 5.7 The lips (a) before and (b) after augmentation with Evolence Breeze.

(b)

(a)

Figure 5.8 Evolence Breeze is

indicated as a low - volume, intradermal

injection for deep, resting, glabellar

folds in tandem with botulinum type A

(BTX - A) treatment. (a) Before and (b)

after combination therapy.

Evolence and Evolence Breeze 51

disposable female - to - female double Luer - Lok. Ten passes of the material

back and forth will ensure adequate mixing of the product with the local

anesthetic. Slow antegrade injection of the mixed product will reduce any

discomfort to easily manageable levels. In our experience, most patients

prefer the combination of lidocaine plus Evolence/Evolence Breeze for

pain control over the blocks that we used to use when injecting the lips.

In accordance with the gate control theory of pain, 23 we also use a mas-

sager on the chin (the HT - 1220 Acuvibe) during injection to minimize

pain.

As both Evolence and Evolence Breeze differ from their bovine collagen

predecessors, the technique of injection is therefore different. Evolence is

injected into the deep tissues using the supplied 1 - mL syringe with a 27G

needle or the Excel needle (27G inside bore, 28G outside bore). The less

viscous Evolence Breeze is injected through a 30G needle more superfi -

cially. It can be injected into the mid - dermis for lines or into scars to

elevate them. The recommended treatment protocol for Evolence is a deep

injection using an antero - or retro - grade tunneling technique. We use a

linear threading technique with a slow, steady injection and no overcor-

rection. The slow, continuous fl ow of the product – which requires less

pressure on the plunger than is necessary with HA injections – will produce

an even distribution of implant through the area to be corrected. We can

use this technique with Evolence Breeze in the lips and infraorbital

hollows, but we may also use a very superfi cial, multiple - stab technique

for superfi cial lines and scars.

After and during injection, the implant should be massaged to ensure

even correction with no papules or nodules. Lumps should be massaged

fl at immediately. It is important to note that immediate massage is required

to remodel and sculpt the injected area; the product sets quickly but does

not move from the injected area, unlike HA. Indeed, the biggest novice

mistake is not to massage completely as soon as the nodule or lump is

noted. Nodules persisting after 24 hours can be treated with saline injec-

tion to break up the collagen fi bers, or conservative use of diluted triam-

cinolone acetamide (2.5% in saline).

Conclusion

Evolence and Evolence Breeze are newly approved, third - generation

collagen fi llers that provide immediate results, which last for up to 12

months and require no skin testing. Evolence is used for the correction of

moderate - to - deep nasolabial wrinkles and folds, contour defi ciencies, and

soft - tissue defects, and has been available in Canada, Europe, Israel, South

Korea, and Russia since 2004. Evolence Breeze is also approved by Health

52 Chapter 5

Canada for the correction of fi ne - to - moderate wrinkles and folds.

Although other fi lling agents had begun to replace the fi rst two genera-

tions of collagen as ideal volumizers, the advent of the more viscous

Evolence and Evolence Breeze – longer - lasting collagens delivering good

correction, immediate results, and few side effects – has challenged that

replacement.

Johnson and Johnson in early November 2009 informed its ’ customers

that it would no longer be distributing Evolence in the US, citing apparent

market forces. At the time this book goes to press the product is not

available. However, there is always a possibility that he product will be

available in the future through a new distributor.

References

1. Sclafani AP , Romo T III . Collagen, human collagen, and fat: The search for a three -

dimensional soft tissue fi ller . Facial Plast Surg 2001 ; 17 : 79 – 85 .

2. Murray CA , Zloty D , Warshawski L . The evolution of soft - tissue fi llers in clinical

practice . Dermatol Clin 2005 ; 23 : 343 – 63 .

3. Baumann L. CosmoDerm/CosmoPlast (human bioengineered collagen) for the aging

face . Facial Plast Surg 2004 ; 20 : 125 – 8 .

4. Gross J , Kirk D . The heat precipitation of collagen from neutral salt solutions: Some

rate - regulating factors . J Biol Chem 1958 ; 233 : 355 – 60 .

5. McPherson JM , Ledger PW , Sawamura S , et al. The preparation and physiochemical

characterization of an injectable form of reconstituted, glutaraldehyde cross - linked,

bovine corium collagen . J Biomed Meter Res 1986 ; 20 : 79 – 92 .

6. Dzubow LM , Goldman G . Introduction to soft - tissue augmentation: A historical

perspective . In: Klein AW (ed.), Tissue Augmentation in Clinical Practice: Procedures and

techniques . New York : Marcel Dekker , 1998 ; 1 – 7 .

7. Knapp TR , Luck E , Daniels JR . Behavior of a solubilized collagen as a bioimplant .

J Surg Res 1977 ; 23 : 96 – 105 .

8. Knapp TR , Kaplan EN , Daniels JR . Injectable collagen for soft tissue augmentation .

Plast Reconstr Surg 1977 ; 60 : 398 – 405 .

9. Stegman SJ , Tromovitch TA . Implantation of collagen for depressed scars . J Dermatol

Surg Oncol 1980 ; 6 : 450 – 3 .

10. Watson W , Ray RL , Klein AW , Stegman S . Collagen: A clinical overview . Cutis

1983 ; 31 : 543 – 6 .

11. Matarasso SL , Sadick NS . Soft tissue augmentation . In: Bolognia J , Jorizzo JL , Rapini

RV , Horn T (eds), Dermatology . London : Mosby, Harcourt Health Sciences , 2003 :

2439 – 49 .

12. Shoshani D , Markovitz E , Cohen Y , et al. A skin test hypersensitivity study of a

cross - linked porcine collagen implant for aesthetic surgery . Dermatol Surg 2007 ;

33 : S152 – 8 .

13. Narins RS , Brandt FS , Lorenc P , et al. Twelve - month persistency of a novel Ribose -

cross - linked collagen dermal fi ller . Dermatol Surg 2008 ; 34 : S31 – 9 .

14. Monstrey SJ , Pitrau S , Hamdi M , et al. A two stage phase I trial of Evolence collagen

for soft tissue contour correction . Plast Reconstr Surg 2007 ; 120 : 303 – 11 .

Evolence and Evolence Breeze 53

15. Narins RS , Brandt FS , Lorenc ZP , et al. A randomized, multicenter study of the

safety and effi cacy of Dermicol - P35 and non - animal - stabilized hyaluronic acid gel

for the correction of nasolabial folds . Dermatol Surg 2007 ; 33 ( suppl 2 ): S213 – 21 .

16. Nir E , Azachi M , Shoshani D , Goldlust A . Long - term in vivo evaluation of the safety

and effi cacy of a new procine collagen dermal fi ller cross - linked with ribose . Poster

presented at the American Academy of Dermatology 66th Annual Meeting, San

Antonio, TX, February, 2008 .

17. Pitrau S , Noff M , Blok L , et al. Long term effi cacy of a novel ribose - cross - linked

collagen dermal fi ller: a histologic and histomorphometric study in an animal model .

Dermatol Surg 2007 ; 53 : 1 – 10 .

18. ColBar Life Science Ltd . Evolence Instructions for Use . Herzeliya, Israel : ColBar Life

Science , 2007 .

19. ColBar Life Science Ltd . Evolence Breeze Instructions for Use . Herzeliya, Israel : ColBar

Life Science , 2007 .

20. Braun M , Braun S . Nodule formation following lip augmentation using porcine

collagen - derived fi ller . J Drugs Dermatol 2008 ; 7 : 579 – 81 .

21. Landau M. Lip augmentation and rejuvenation using a novel, porcine collagen -

derived fi ller . J Drugs Dermatol 2008 ; 7 : 236 – 40 .

22. De Boulle K , Swingberghe S , Engman M , et al. Lip augmentation and contour cor-

rection with a ribose cross - linked collagen dermal fi ller . J Drugs Dermatol 2009 ; 8

( 3 suppl): 1 – 8 .

23. Melzack R , Wall PD . Pain mechanisms: A new theory . Science 1965 ; 150 : 171 – 9 .

Poly - L - Lactic Acid Rebecca Fitzgerald Dermatology Private Practice and David Geffen School of Medicine, University of California, Los Angeles, USA

Danny Vleggaar Centre Dermato-Cosmetique ‘ Roseraie ’ , Geneva, Switzerland

CHAPTER 6

Introduction

The purpose of this chapter is to discuss current techniques used with poly -

L - lactic acid (PLLA) to effectively and safely address changes observed in

the aging face. Two simple, yet critically important points should be

observed in order to use this product to its best advantage. First, this

unique agent is not a fi ller, but a stimulator of the host ’ s own collagen

which then acts to volumize tissues in a gradual, progressive manner.

This mechanism of action has important clinical implications in the

manner in which it is used. Biostimulatory agents work through employ-

ment of the host response and their biocompatibility is contingent on the

ability of the material to perform with an appropriate host response in a

specifi c application. 1 As experience has been gained with this product over

the last decade, and our techniques adjusted accordingly, we have found

it to be a very safe and versatile agent that can be used in a manner that

is both predictable and reproducible. Currently recommended prepara-

tion and placement techniques will be addressed in detail.

The second point is to recognize that changes in different tissue

layers of the face within a single individual occur interdependently, as

an interlocking three - dimensional puzzle. Therefore, where to place

the product to optimize results is enhanced by looking at the face as a

whole, rather than focusing on the nasolabial folds or marionette lines,

for example, as isolated entities. Seemingly small changes in shape, topog-

raphy, proportions, balance, and symmetry can have a large impact on

the face. This is a large part of the learning curve with this product and

for this reason much of this chapter is devoted to analyzing and mapping

the face.

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

54

Poly-L-Lactic Acid 55

History

Poly - L - lactic acid (PLLA) was fi rst synthesized in the 1950 ’ s and has a

long history of safe use in medical applications including suture material,

plates, screws, fracture fi xation devices and drug delivery systems

(fi gure 6.1 ). Studies carried out almost a decade ago to evaluate the

use of PLLA in the treatment of facial lipoatrophy associated with

the human immunodefi ciency virus (HIV) showed it to be a safe and

effective product capable of replacing signifi cant amounts of volume.

Initial reports of a relatively high number of palpable, nonvisible sub-

cutaneous papules in these HIV patients, as well as subsequent isolated

case reports of granulomas in the cosmetic population, resulted in early

skepticism among physicians. 2 – 4 It should be noted that the early HIV

studies were carried out with 3 – 4 cc dilutions, little or no hydration time,

and superfi cial (as well as large bolus) injections of product in multiple

treatment sessions spaced only 2 weeks apart. 2 Dramatic decreases in the

number of PLLA device related adverse events with adjustments in tech-

nique have been documented in the literature over the last decade with

safety and effi cacy now well established. 3 Additionally, granulomatous

reactions are now widely recognized to occur with all commercially avail-

able fi ller products. Fortunately this is a rare (and usually self resolving)

complication with all agents, as their seemingly unpredictable appearance

is still poorly understood. 4

Figure 6.1 Historical timeline.

56 Chapter 6

The currently commercially available formulation of injectable PLLA

(Sculptra and Sculptra Aesthetic, Sanofi - Aventis Bridgewater, New Jersey)

received Federal Food and Drug Administration (FDA) approval in the

United States (US) for the restoration and/or correction of the signs

of facial fat loss in patients with HIV associated facial lipoatrophy in

2004. Approval for aesthetic use was gained in 2009, based on the results

of a randomized, evaluator - blinded, parallel - group, multicenter study of

233 immunocompetent patients designed at the time of HIV approval

using a 5cc dilution, a 2 hour hydration time, and a deep dermal grid

pattern injection technique to place product in the nasolabial fold in mul-

tiple treatment sessions placed 3 weeks apart. Collagen was used as the

comparator in order to adhere to a precedent already familiar to the FDA

(from previous fi ller studies). Although refi nements in methodology con-

tinue to evolve and it is currently commonplace to use an 8 – 9 cc dilu-

tion, > 24 hour hydration time, and subdermal placement, the current

aesthetic label refl ects this early study design. Particularly useful informa-

tion from this study is it ’ s documentation of effects lasting 25 months (the

cut off time in the study) with high patient satisfaction (80% at 25

months). 5

Mechanism of a ction of PLLA

PLLA is a synthetic polymer of l - lactic acid linked by ester bonds. Polyesters

such as PLLA are both biocompatible and biodegradable and are

desirable biomaterials because of lack of toxicity in the human host

(they degrade to lactic acid which is then metabolized via the citrate

cycle). 6

The currently commercially available injectable PLLA product (Sculptra,

Sculptra Aesthetic, Sanofi - Aventis Bridgewater, New Jersey) is composed

of nonpyrogenic mannitol (to enhance lyophilization), sodium car-

boxymethylcellulose (an emulsifi er) and PLLA microparticles. It is sup-

plied as a lyophilized powder in a sterile glass vial which must then

be reconstituted with H 2 O prior to use. A particle size of 40 – 63 μ m

in diameter ensures that they are large enough to avoid phagocytosis

by dermal macrophages (heterogeneity in size as well as phagocytosis

of smaller particles could lead to a more intense infl ammatory response)

or passage through capillary walls (which could lead to vascular com-

promise), but small enough to be easily injected by needles as fi ne as

26G. 6

The mechanism of action of injectable PLLA is thought to involve the

initiation of a desired subclinical infl ammatory tissue response to the

polylactides leading to encapsulation of the microparticles and subsequent

Poly-L-Lactic Acid 57

fi broplasia. Over time, the product degrades, the infl ammatory response

wanes, and the ensuing collagen deposition increases providing a gradual

and progressive increase in tissue volume. 6

The infl ammatory response against an implanted polymeric biomaterial

is determined by many factors – some having largely to do with the host,

such as the implantation site and the concentration of material; some

having largely to do with the implant, such as the physical (shape, size,

surface area) and chemical (pH, charge, hydrophilic vs. hydrophobic)

properties of the biomaterial. 7 As this holds true for both the initial and

degraded forms of the product, predictable degradation kinetics is an

important factor in ensuring a predictable host response. 7 A word about

biocompatibility is warranted here, as an understanding of this concept is

key to successful use of this product. Although the initial concept of bio-

compatibility was simply inertness, biomaterials are now used in clinical

medicine to purposely harness a desired host response for a specifi c

purpose.

Simply put, the effect of a biomaterial on the host is to stimulate an

infl ammatory/immune response and the response of the host on the bio-

material is to attempt to eliminate or encapsulate the foreign material. 7

This is taken into account by the widely accepted “ William ’ s defi nition ”

of biocompatibility as the ability of a material to perform with an appropriate

host response in a specifi c application. 1 It is critical to note that the mechanism

of action of PLLA links biocompatibility of the product to the manner

in which it is used i.e., how, where, and how much of the product is

used may greatly infl uence the type and intensity of the host response.

Again, a subclinical infl ammatory response followed by encapsulation

and fi broplasia is the desired end - point for application of this agent as

a soft - tissue augmentation device. Understanding the role of the degra-

dation kinetics of the PLLA polymer in it ’ s ultimate biocompatibility

may help explain the importance of avoiding overcorrection in achieving

this desired endpoint. PLLA primarily degrades through hydrolysis of

ester bonds (although enzymatic metabolism may play a very minor role).

The polymer is a very hydrophobic molecule and this hydrolysis is noted

to occur in stages. The fi rst and longest stage is hydration of the polymer.

The time required is proportional to the molecular weight of the polymer -

PLLA is a high molecular weight polymer taking months to hydrate. 8,9

The fi nal and shortest stage is dissolution into degradation fragments -

largely monomers, dimers, and oligomers of lactic acid. At this fi nal stage

the product becomes progressively more hydrophilic and the rate of chain

scission, and therefore production of degradation fragments, acceler-

ates. 8 – 11 Phagocytosis of small degradation particles by macrophages and

foreign body giant cells then occurs as an expected ‘ next step ’ in the host

response to the biomaterial. This ‘ intracellular ’ phase of degradation in

58 Chapter 6

vivo correlates with an observed change in the type and/or intensity of

a preexisting infl ammatory response which seems to correlate with the

concentration of material present. 12 While small volumes of material

do not reach toxic concentrations in the host, high initial concentrations

or rapid sustained release of degradation products may do so. Large

volumes of material, both initially, and at this late phase of degradation

may lead to an undesired amount of infl ammation resulting in an inap-

propriate host response for the specifi c application for which it was

intended. 12 This physiologic response to overcorrection was observed in

early orthopedic applications where implants with considerable size were

used. Newer processing methods as well as copolymers have addressed

these concerns. 13

These factors may all play a role in why overcorrection should be

avoided with PLLA in the application of soft tissue augmentation. It is

interesting to speculate that overcorrection could conceivably cause

an adverse event for the life of the product (up to 2 years), perhaps

accounting for occasional reports of adverse reactions 12 – 18 months

after treatment. On a positive note, this would also imply that the occur-

rence of these reactions – both early and late – are preventable by

adhering to the currently recommended guidelines for use (designed to

avoid overcorrection).

Product p reparation and i njection t echnique: o ptimizing o utcomes

The manner in which a biostimulatory agent is used determines it ’ s bio-

compatibility in a specifi c application. Experience has taught us that “ too

much, too soon ” with collagen stimulators may lead to overcorrection,

where an overabundance of stimulating microparticles may lead to an

undesired host reaction in the specifi c application of these devices in tissue

augmentation. It is for this reason that it is recommended that patients

are brought to a gradual progressive correction with multiple treatment

sessions with these agents. Important technical considerations of which

the practitioner should be aware all relate to avoiding overcorrection and

include the following.

Product r econstitution Sculptra is composed of PLLA microparticles, nonpyrogenic mannitol,

and sodium carboxymethylcellulose, and is supplied as a lyophilized

powder. The product insert recommends that Sculptra be reconstituted

with 3 – 5 mL of sterile water for injection and then left to hydrate > 2 h

Poly-L-Lactic Acid 59

to disperse the particles. The vial can then be shaken to suspend the

microparticles. Lidocaine may be added to the suspension immediately

before injection. Much literature now strongly supports a fi nal dilution

of at least 5 mL left to hydrate overnight. 2 – 4,6,10 Adequate hydration

time avoids the risk of injecting dry microclumps of material which may

then hydrate in vivo. Experience over the last several years has shown us

that a dilution of 8 – 9ml provides more product while still maintaining

the ability to stimulate a clinically relevant response.

Product a mount The amount of product used at any single treatment session should be

determined solely and completely by the amount of surface area to be

treated at that session using approximately 0.2 – 0.3 mL/cm. The fi nal volu-

metric correction is addressed by the number of treatment sessions. The

novice injector should be aware that it is initially diffi cult to resist the

temptation to treat to full correction at any one session (although this may

be possible with patients needing minimal treatment.) The endpoint is

‘ blanketing ’ the surface area to be treated at that session. The appropriate

volume of product to be used at each session is therefore easily predeter-

mined, i.e. a large atrophic cheek in a male HIV - positive lipoatrophy

patient measuring 6 × 8 cm could require as much as an entire vial of

product, whereas a 2 × 2 cm cheek hollow in a typical 50 - year - old woman

may require only 2 – 4 mL. 11

Product p lacement This can be done with a 1 - mL or 3 - mL syringe and a 25G (long or short)

or 26G (short) needle. Depth of placement varies with location.

The product is placed in the subcutaneous layer in the cheeks, preau-

ricular area, nasolabial folds, and lower face using the crosshatch or

fanning technique. Superfi cial placement should be avoided. 3,4,6

• Slow injections in a crosshatch pattern facilitate careful control of injec-

tion amounts when becoming familiar with the product.

• Fanning has the advantage of fewer needle sticks, but the novice

injector should be vigilant to avoid multiple deposits at the apex of the

fan.

• It may be placed as depot injections supraperiosteally along the zygoma,

maxilla, canine fossa/pyriform aperture, and mandible.

• Be aware that deep subcutaneous or supraperiosteal treatments in

the area of the canine fossa/pyriform aperture with bulking agents

has led to ischemia and necrosis. 14 It is unclear whether this vascular

60 Chapter 6

compromise is the result of occlusion of a vessel or vascular compression

from adjacent swelling. The low viscosity of this product eliminates the

risk of compression in this area; however, a refl ux maneuver should be

done routinely to avoid intravascular injection of product.

• Temple injections are placed deeply, under the temporalis fascia.

Manufacturer ’ s instructions are to place 0.05 - mL depots in the temple;

however, it is common practice among experienced users to place

a 0.3 – 0.6 mL depot in this area, followed by fi rm pressure and massage

to distribute the product evenly. If the product has been placed

in the correct plane, there should be virtually no resistance to the

spread of the product. Again, a routine refl ux maneuver before injec-

tion of product will eradicate any risk of inadvertent intravascular

injection.

• Bear in mind that this product is mixed in water, making for a very low

viscosity solution when compared with a hyaluronic acid gel. The novice

injector must be vigilant to ration the product carefully to avoid inad-

vertent overcorrection.

Product p lacement p recaution Positional stability of a biostimulatory implant is critical to its safe use.

Avoid placement in or through areas of dynamic muscle movement.

Frequent reports of ‘ lip lumps ’ led to recommendations against the use of

all collagen - stimulating devices, including polymethylmethacrylate

(PMMA), PLLA, and calcium hydroxylapatite, in this area. It is assumed

that the perioral muscle movement in this area leads to a clumping of

particles, which in turn leads to localized overcorrection and lumps.

Injections in the modiolus or depressor anguli oris muscle may behave in

a similar fashion. In addition, periorbital supraperiosteal injections

approached through the orbicularis oculi muscle have resulted in papules

shown to be clumps of product embedded in muscle on histopathology. 15

It may be that the path of the needle leaves a tract through which more

deeply placed material may be extruded during muscular contraction

resulting in clumping in the muscle.

Treat, w ait, a ssess • Remember that this product is not a fi ller, but a stimulator of the host ’ s

collagen.

• Allow time for that response to develop before retreatment.

• Wait a minimum of 4 weeks between treatments.

• Be aware that, although the majority of the response will be clinically

apparent approximately 4 weeks after treatment, it may continue to

improve for some time. If there is any question in your mind about the

need for an additional treatment, don ’ t do it. This is especially important

Poly-L-Lactic Acid 61

in young patients who need very little volume. An additional treatment

in this case may result in an overvolumized face.

Aftercare Massage after every two to three injections and again at the end of the

treatment. Have the patient massage over the next few days using the

“ rule of 5s ” (5 min/5 times daily/5 days). This massage may increase cir-

culation during the initial infl ammatory response and has been shown to

reduce the incidence of papules. 2 – 4,6,10

Predicting and p lanning o utcomes/Patient s election and p reparation

Predicting o utcomes We have observed what seems to be a common perception that very

volume depleted patients are the “ optimal candidates ” for PLLA treat-

ments. PLLA can certainly be used in these patients with pleasing results,

but it will likely require a sizable investment of product, time, and money.

Very volume - depleted patients are in fact diffi cult patients to “ fi ll ” regard-

less of product choice. Keep in mind that with any product, revolumizing

is more expensive than recontouring and reshaping. Be aware that this is

patient selection at play here, not product choice. In a younger or fuller

face, a very pleasing, cost - effective, and durable result can be achieved

with a very conservative amount of product.

Successfully predicting outcomes for patients depends on many factors;

however, a few generalizations can be made:

• Very volume depleted faces (usually secondary to HIV lipoatrophy or

endurance exercise) often require a lot of product and a lot of treat-

ment sessions to fi ll, and it is often diffi cult to sustain the fi ll without

relatively frequent ( < 1 year) touchups. 16 Figure 6.2 shows an extremely

lipoatrophic face. The loss of underlying volume is most extreme in the

Figure 6.2 A 48 - year - old HIV - positive man: three vials/treatment, three treatments

(nine vials in total).

62 Chapter 6

Figure 6.3 A 42 year old: two vials/treatment, three treatments (six vials in total).

temples, the mid and lower cheek, and the preauricular area. Loss of

fat in the midface leaves the face with a muscular prominence in the

same location as a “ marionette ” fold. This prominence is likely in the

same location that it has usually occupied – it is just made visible by

the loss of tissue both above and below it. This is improved therefore

not by fi lling the fold, but by replacing the missing volume superior

and inferior to the prominence. Note also that the volume loss in this

face, combined with solar elastosis, has resulted in an outer skin enve-

lope slightly too large for its now “ smaller ” face, and in this case has led

to skin redundancy along the mandible and under the chin. This

redundancy improves after volume replacement in the preauricular

area, mid and lateral cheek.

• Severely lipoatrophic patients such as seen in Figure 6.2 , offer a “ road

map ” of how to effectively treat younger faces, or even plumper faces,

with similar, but less obvious, changes. All of the faces pictured in

fi gures 6.3 – 6.6 , show volume loss and defl ation in the temples, mid

and lower cheek, and preauricular area similar to that seen in Figure

6.2 . It is just less obvious in these faces because it is not as extreme

and is in fact, even obscured, by the folds that it has created. Note,

however, that in all cases replacement of volume done in a fashion

similar to that used in the patient in Figure 6.2 resulted in an improve-

ment. This improvement is seen even in areas not directly treated

including an in increase in brow elevation (from temporal injections),

a decrease in infraorbital shadowing (from refi lling the mid cheek) as

well as a lifting of redundant skin along the mandible. (from refi lling

the mid and lateral cheek, as well as the preauricular area). Also,

note that the more volume the patient had to start with, the less

product was required to achieve the same result. The very volume

depleted patient in Figure 6.2 required 9 vials, the patients in their

40 ’ s in Figure 6.3 and 6.4 required 5 – 6 vials each, while the younger

face in Figure 6.5 and the plumper face in Figure 6.6 required only 2

vials each.

Poly-L-Lactic Acid 63

Figure 6.4 A 48 year old: two vials/ treatment × 2, one vial/treatment × 1 (fi ve vials

in total).

Figure 6.5 A 32 year old: one vial/treatment, two treatments (two vials in total)

baseline, 1 month after last treatment and 6 months after last treatment.

• As one would predict, older faces with poor skin quality, fat loss,

and a lack of craniofacial support need a large amount of product

and several treatments to obtain a satisfactory result (Figure 6.7 ). Some

patients prefer this choice over a surgical procedure regardless of

the investment in time and money, although the combination of

surgery and volume replacement would be the most ideal in this sort

of patient. Take the time to sort this out together before treating a

patient who may otherwise become frustrated.

64 Chapter 6

Figure 6.7 A 57 year old: two vials/treatment, four treatments (eight vials in total).

Figure 6.6 A 46 year old: one vial/treatment, two treatments (two vials in total).

Poly-L-Lactic Acid 65

• Before and after photographs of the subtle and natural results attainable

are useful in discussing the product with new patients. They should be

aware that the ultimate treatment plan and result are contingent on the

quality and volume of tissue with which they start. Patient satisfaction

is generally very high when the patient understands the process. Word

of mouth from satisfi ed patients has been a powerful ally in our practices

and accounts for the vast majority of our patients.

Patient s election Patient education is important as with any procedure. The durability of

this product underscores this need. Obtain a true informed consent. As

with all procedures, there is no guarantee of a specifi c or perfect result.

• As with any procedure the patient must demonstrate suffi cient “ psy-

chosocial maturity ” to weather any potential complications.

• Anxious or demanding patients are poor candidates.

• Manage expectations. Be sure that the patient ’ s goals are realistic and

attainable. PLLA offers a natural and durable, but not an immediate,

result. It is not an “ event ” fi ller and may not be the best choice for

someone with an upcoming wedding or reunion.

• A careful and thorough medical history should be taken before treat-

ment. Granuloma formation has been described in isolated case reports

in patients with autoimmune diseases (especially collagen vascular

disease), and in those with poor dental hygiene and dental caries. 17,18

• Although there are no established absolute contraindications, caution

is advised in treating a patient who has received a permanent fi ller

(silicone, polymethylmethacrylate, polyalkylmide gel, acrylic hydrogel

particles (hydroxy - ethylmethacrylate and ethyl methacrylate)) because

confusion would ensue about the source of a complication should this

occur.

• As with all fi ller procedures, the patient should expect some swelling

and bruising. Bruising is exacerbated if the patient is on anticoagulants.

• Avoid any elective procedure in pregnant or nursing women.

Patient p reparation • Photographs document baseline and allow patients to follow their

progress.

• Place the patient in an upright position to take into account the effect

of gravity on facial contours before marking for injection.

• The facial skin should be cleaned with a bacteriostatic wash and sterile

water followed by alcohol (cases of Mycobacterium chelonei infection with

injectable procedures have been traced to tap water). 19

• A topical anesthetic is optional. Ice is helpful.

66 Chapter 6

Understanding the a ging f ace and the e ffects of v olume l oss

It is now widely recognized by the medical community that volume

changes in the skin and soft tissue, as well as in their underlying skeletal

support, contribute greatly to the changes observed in facial aging.

Although gravity was once thought to be the main culprit in this process,

we are now realizing that it is simply our vulnerability to gravity that

changes as our tissues “ defl ate ” with age. In addition, although the

sequence of changes observed as we age is somewhat predictable, the pace

of these changes is unique to each individual. As no two faces age identi-

cally, there is no one algorithm of what every face needs. Most of us lose

a little volume in all structures of the face; others clearly lose more in one

structure than the other. These structural changes then lead to changes in

the morphology of the face in terms of both the three - dimensional con-

tours that dictate how we refl ect or shadow light, and in the shape,

balance, and proportions of our face.

One way that this information can be used in order to evaluate the face

is to look at the integrity of all the structural tissues individually – skin,

fat, muscle, and bone – and then evaluate the subsequent morphology in

this context. Train your eye to look at the face as an inter locking three -

dimensional puzzle, rather than focusing on lines and folds.

Skin Both intrinsic and extrinsic aging in the skin impact its ability to adjust

well to underlying volume loss. Voorhees recently presented research 20,21

showing that as the extracellular collagen matrix is progressively frag-

mented with time and extrinsic insults, the fi broblasts produce less col-

lagen and more collagenase, leading to a deleterious self - perpetuating

cycle. This landmark research reveals that the deteriorating extracellular

collagen matrix both contributes to and fuels loss of skin integrity. The

collagen stimulation reported with hyaluronic acid fi llers by Wang et al. 22

was thought to work through mechanical stretch of the fi broblast. An

improvement in the texture and tone of the skin is a common fi nding

after PLLA treatments. It is interesting to speculate that since collagen

stimulation may produce both direct (through fi broplasia) and indirect

(through increased extracellular matrix and stretch effect) stimulation of

fi broblasts, that repeat treatments with these agents could both replace

signifi cant amounts of collagen and slow it ’ s loss.

Fat The youthful face has an ample amount of volume evenly distributed,

which displays a smooth transition from one area to another and

Poly-L-Lactic Acid 67

Figure 6.8 A youthful face represents a point in time when a particular set of skeletal

proportions are ideal for their soft - tissue envelope. (Reproduced from Stuzin J.

Restoring facial shape in face lifting. Plast Reconstr Surg 2007;119:362 – 76 with

permission.)

confers a well - rounded three - dimensional topography delineated by

a series of arcs and convexities. As we age, these smooth transitions

give way to sharper delineations where different areas seem to become

their own isolated entities (Figure 6.8 ). Rohrich and Pessa 23 recently dem-

onstrated that subcutaneous fat is partitioned into discrete compartments

and that these compartments each age independently of each other. In

addition, the loss or gain of volume in one compartment may have a great

infl uence on surrounding areas. 24 Figure 6.9 demonstrates how treatment

of fat loss in the temple and preauricular area serves to “ lift ” redundant

skin along the jawline. Figure 6.10 demonstrates how refi lling the deep

medical cheek fat pad serves to indirectly efface the lid – cheek junction

and nasolabial fold. Pessa 25 recently noted that creases and folds occur at

a transition point between two areas of varying thickness of subcutaneous

fat as seen in the lid – cheek junction, and the nasolabial, labiomental,

preauricular, and submental creases.

Muscle LeLouarn et al. 26 used MRI (magnetic resonance imaging) to show that

the facial mimetic muscles in youth have a curvilinear contour, and thus

present an anterior surface convexity, due to the presence of underlying

68 Chapter 6

Figure 6.9 Treatment in the area of the temporal and preauricular fat pads:

lift sagging skin in a 60 year old – two vials/treatment, two treatments.

Final photograph taken 8 months after treatment (Photo courtesy of Rhonda

Baldone.)

deep fat pads. The authors speculate that this fat may redistribute over

lifetime of repeated animations. This may have practical clinical signifi -

cance, informing the depth of placement of fi llers and the areas of conco-

mittant use of toxins.

Bone Shaw et al. 27 utilizing computed tomography (CT) in 60 patients from 3

age ranges, concluded that the bony elements of the face change dra-

matically with age. This remodeling leaves less underlying surface support

(the “ table ” ) for the outer soft - tissue envelope (the “ tablecloth ” ), causing

it to fold or sag. There is some evidence that this bony platform changes

most between young and mid - adulthood which may be refl ected in soft -

tissue changes (as fat shifts over the changing underlying support). 28 This

may be one of the reasons why we have observed that supraperiosteal

injections seem to have additional value in the younger patient popu-

lation. In Figure 6.11 sup raperiosteal injections in the temple and along

the supraorbital rim elevate the brow. Treatment around the pyriform

Poly-L-Lactic Acid 69

Figure 6.10 A 58 year old: two vials/treatment, three treatments (six vials in total).

Botulinum toxin type A was used in the mentalis and bilateral depressor anguli oris

muscles at the start of treatment. The last photograph was taken > 4 months after the

fi nal treatment. Treatment in the deep medial cheek fat pad indirectly effaces the lid

cheek junction and the nasolabial fold.

Figure 6.11 A 38 year old: two vials/treatment, two treatments (four vials in total).

Last photograph taken 6 months after fi nal treatment. The patient received no other

treatment. Note brow elevation and changing position (increased curl) of upper lip with

supraperiosteal treatment above the supraorbital rim and along the medial maxilla.

70 Chapter 6

aperture in the canine fossa, and in Ristow ’ s space (a distinct region for

augmentation of the midface lying directly above the central maxilla 24 )

increase the anterior projection of the cheek which then “ smoothes out ”

the skin in the infraorbital area. Interestingly, these injections also seem

to “ push ” the soft tissue forward resulting in increased eversion of

the lips.

Finally, Figure 6.12 shows a young patient with good skin texture

and ample soft tissue, but lacking adequate craniofacial support for

the overlying soft - tissue envelope. Note the change in shape and pro-

portions of the face with supraperiosteal treatments. A closer look

highlights the subtle, but signifi cant changes achieved in the perioral

area with supraperiosteal treatments along the maxilla and mandible. Note

the increased upper lip eversion obtained without direct treatment of

the lip, and the change in position of the base of the nose.

Facial a nalysis and m apping

A youthful face represents a point in time when a particular set of skeletal

proportions is ideal for their soft - tissue envelope. 29 We grow into this from

infancy and then lose it with age. 30 As mentioned previously, although

the sequence of changes as we age is somewhat predictable, the pace is

not. In addition, the changes in each structural layer of the face do not

occur independently, but interdependently, as an interlocking three -

Figure 6.12 A 30 year old: two vials/treatment, two treatments (four vials in total).

The patient received no other treatment. Note the brow elevation and change in the

perioral area with supraperiosteal injections along the supraorbital rim, zygoma,

maxilla, and mandible.

Poly-L-Lactic Acid 71

dimensional puzzle. Subsequently, there is no one algorithm to address

facial aging. Facial analysis is a process of observation and palpation/

provocation that allows us to determine the nature and extent of the

structural tissue changes aging the face in front of us at that particular

point in time, and to then plan a treatment accordingly. It is not a “ recipe, ”

it is a “ read. ” What you choose to address depends on the extent of the

changes noted in each layer and the parity of these changes between

layers, i.e. if there is a great deal of disparity, try to blend them all back

to a more similar place (i.e. we have likely all experienced at some point

the undesirability of putting a pair of young lips on an old face). If there

is just a little change in all layers, almost any interventional approach will

work. If there is a lot of loss of integrity in multiple layers, then multiple

interventions may be needed to obtain optimal results.

PLLA is a versatile agent to use to address these changes because it

can be used to strengthen the dermis, or to mimic volume elsewhere

with “ space - occupying ” collagen: i.e. it mimics fat if placed in fat, or

bone if placed supraperiosteally – allowing the practitioner to tailor

the treatment according to the specifi c aging changes manifested in

that individual face. 31 Deep supraperiosteal injections are done wherever

possible, and subcutaneous injections are carried out where there is

no underlying skeletal support as outlined above in the section on

technique.

Complications

Overall, PLLA injections are associated with low complication rates.

As with all injectable procedures, short - term complications such as

bruising and edema may occur, but are self - limiting. Careful scrutiny

of the available literature reveals the vast majority of complications

to be secondary to technical errors in product preparation or place-

ment. 4,6,32 Granulomatous reactions, sometimes occurring months to

years after administration, have been reported with all currently

available commercial devices, including collagen, hyaluronic acid, PLLA,

silicone, calcium hydroxyl apatite, polymethylmethacrylate, hydrox-

yethylmethacrylate, and polyacrylamide gel; 32 in fact, this list seems to

grow with every newly introduced product. True infl ammatory granu-

lomas are rare and unpredictable, and the events leading to their

appearance are not yet clearly understood. Fortunately, the rate of

clinically detectable granuloma formation is very low (reported to

vary between 0.01 and 0.1%) and most resolve with or without

treatment. 32

72 Chapter 6

Summary

PLLA is a versatile agent that may be used to effectively address facial

aging. Its relatively unique mechanism of action allows the product to

be used to provide gradual, natural and subtle results. It is now widely

recognized by the medical community that volume changes in the skin

and soft tissue, as well as in their underlying skeletal support, greatly

contribute to the changes observed in the aging face. This appreciation,

accompanied by an ever - evolving understanding of the facial aging

process (including the relatively early occurrence of changes in the

craniofacial platform), focus the use of injectable PLLA basically on two

levels (which are most often done in concert with each other): soft -

tissue injections to provide volume, as well as strengthening and support

to these tissues, and supraperiosteal placement to address facial contours

and ratios. 31 Its safety, effi cacy, and durability have been consistently

demonstrated. 2,3,4,6,31,32

Optimizing outcomes, and minimizing adverse events, with this

product are not diffi cult, but do require awareness of and attention

to its specifi c and evolved injection methodology, and are enhanced by

a careful facial analysis before treatment. Performed correctly, PLLA

injections are associated with low complication rates and high patient

satisfaction.

References

1. Williams D. On the mechanisms of biocompatibility . Biomaterials 2008 ; 29 :

2941 – 53 .

2. Butterwick K , Lowe NJ . Injectable poly - l - lactic for cosmetic enhancement: Learning

from the European experience . J Amer Acad Derm 2009 ; 61 ( 2 ); 281 – 93 .

3. Burgess CM , Lowe NJ. NewFill ® for skin augmentation: a new fi ller or failure?

Dermatol Surg 2006 ; 32 : 1530 – 32 .

4. Lowe NJ. Dispelling the myth: appropriate use of poly - l - lactic acid and clinical

considerations . J Eur Acad Dermatol Venereol 2006 ; 20 (suppl 1 ): 2 – 6 .

5. Dermik Laboratories . Sculptra Aesthetic Product Information . Bridgewater, NJ : Dermik

Laboratories , 2009 .

6. Vleggaar D. Facial volumetric correction with injectable poly - l - lactic acid . Dermatol

Surg 2005 ; 31 ( 2 ): 1511 – 17 .

7. Ratner B , Bryant S . Biomaterials: Where we have been and where we are going .

Annu Rev Biomed Eng 2004 ; 6 : 41 – 75 .

8. Gunatillake PA , Adhikari R . Biodegradable synthetic polymers for tissue engineer-

ing . Eur Cells Materials 2003 ; 5 : 1 – 16 .

9. Mainil - Varlet P. Rahn B , Gogolewski S. Long - term in vivo degradation and bone

reaction to various polyactides One - year results . Biomaterials 1997 ; 18 : 257 – 66 .

10. Tokiwa Y , Calabia BP . Biodegradability and biodegradation of poly(lactide) .

Appl Microbio Biotechnol 2006 ; 72 : 244 – 51.

Poly-L-Lactic Acid 73

11. Ishii D , Ying TH , Mahara A et al. ( 2009 ). In vivo tissue response and degradation

behavior of PLLA and stereocomplexed PLA nanofi bers . Biomacromolecules .

http://pubs.acs.org . Downloaded February 7, 2009.

12. Lam KH , Schakenraad JM , Esselbrugge H , Feijen J , Nieuwenhuis P . The effect of

phagocytosis of poly (L - lactic acid) fragments on cellular morphology and viability .

J Biomed Mat Res 1993 ; 27 : 1569 – 77 .

13. Ashammakhi N , Serio W . Refl ections on complications to Bioabsorbable osteofi xa-

tion devices J Cranio Surg 2007 ; 18 ( 5 ): 1242 – 43 .

14. Kinoue K , Sato D , Matsumoto K et al. Arterial embolization and skin necrosis of

the nasal ala following injection of dermal fi llers . Plast Reconstr Surg 2008 ;

121 : 127e – 28e .

15. Stewart DB , Morganroth GS , Mooney MA et al. Management of visible granulomas

following periorbital injection of poly - l - lactic acid . Ophthomal Plast Reconstr Surg

2007 ; 23 : 298 – 301 .

16. Mest DR , Humble GM . Retreatment with injectable poly - L - lactic acid for HIV -

associated facial lipoatrophy 24 - month extension of the Blue Pacifi c Study . Dermatol

Surg 2009 ; 35 : 350 – 59 .

17. Reszko AE , Sadick NE , Magro CM , Farber J . Late - onset subcutaneous nodules after

poly - L - lactic acid injection . Dermatol Surg 2009 ; 35 (Suppl 1 ): 380 – 84 .

18. Lemperle G , Rullan PP , Gauthier - Hazan N. Avoiding and treating dermal fi ller

complications . Plast and Reconst Surg 2006 ; 118 (suppl 3 ): 92S – 107S .

19. Narins RS , Jewell M , Rubin M et al. Clinical conference: Management of rare events

following dermal fi llers - focal necrosis and angry red bumps . Dermatol Surg

2006 ; 32 ( 3 ): 426 – 34 .

20. Fisher GJ , Quan T , Purohit T , et al. Collagen fragmentation promotes oxidative stress

and elevates matrix metalloproteinase - 1 in fi broblasts in aged human skin . Am J

Pathol. 2009 ; 174 ( 1 ); 101 – 14 .

21. Fisher GJ , Varani J , Voorhees JJ . Looking older: Fibroblast collapse and therapeutic

implications . Arch Dermatol. 2008 ; 144 ( 5 ): 666 – 72 .

22. Wang F , Garza LA , Kang S , et al. In vivo stimulation of de novo collagen production

caused by cross - linked hyaluronic acid dermal fi ller injections in photodamaged

human skin . Arch Dermatol. 2007 ; 143 ( 2 ): 155 – 63 .

23. Rohrich RJ , Pessa JE . The fat compartments of the face: Anatomyand clinical impli-

cations fro consmetic surgery . Plast Reconstr Surg. 2007 ; 119 : 2219 – 27 .

24. Rohrich RJ , Pessa JE , Ristow B . The youthful cheek and the deep medial fat com-

partment . Plast Reconstr Surg. 2008 ; 121 ( 6 ): 2107 – 12 .

25. Pessa J. Discussion: The tear trough and lid/cheek junction: anatomy and implica-

tions for surgical correction . Plast Reconstr Surg 2009 ; 123 : 1341 – 42 .

26. Le Louarn CL , Buthiau D , Buis J. Structural aging: The facial recurve concept .

Aesthetic Plast Surg. 2007 ; 31 : 213 – 18 .

27. Shaw RB Jr , Kahn DM . Aging of the midface bony elements: A three - dimensional

computed tomographic study . Plast Reconstr Surg. 2007 ; 119 : 675 – 81 .

28. Pecora NG , McNamara JA. The aging craniofacial complex: A longitudinal

cephalometric study from late adolescence to late adulthood . Am J Orthod Dentofacial

Orthop. 2008 ; 134 ( 4 ): 496 – 505 .

29. Stuzin JM. Restoring facial shape in face lifting: The role of skeletal support in

facial analysis and midface soft - tissue repositioning . Plast Reconstr Surg. 2007 ;

119 ( 1 ): 362 – 76 .

30. Pessa JE , Zadoo VP , Yuan C , et al. Concertina effect and facialaging: nonlinear

aspects of youthfulness and skeletal remodeling, and why, perhaps, infants have

jowls . Plast Reconstr Surg. 1999 ; 103 ( 2 ): 635 – 44 .

74 Chapter 6

31. Fitzgerald R , Vleggaar D. Using Poly - l - lactic acid to mimic volume in multiple tissue

layers . J Drugs Derm. 2009 ; 8 ( s10 ): s5 – 14 .

32. Lemperle G , Gauthier - Hazan N , Wolters M. Foreign Body Granulomas after

all injectable dermal fi llers: Part I. Possible causes . Plast Reconstr Surg 2009 ;

123 ( 6 ): 1842 – 63 .

Liquid Injectable Silicone Chad L. Prather Department of Dermatology, Louisiana State University, New Orleans and Dermasurgery Center, Baton Rouge, Louisiana, USA

CHAPTER 7

In the age of minimally invasive aesthetic improvement, practitioners and

patients continue to strive for the “ ideal fi ller. ” The theoretical ideal fi ller

would be versatile and biocompatible, achieve consistent results, have a

natural feel in vivo, remain safe, and be affordable. Furthermore, it would

be easy to inject, have minimal side effects, and not require allergy testing.

The ideal fi ller would also achieve some degree of longevity and, arguably,

permanence. In the modern era, one existing augmenting agent retains

many attributes of the ideal fi ller: liquid injectable silicone (LIS). LIS is the

original, permanent, synthetic, soft - tissue - augmenting agent that may

correct a variety of cutaneous and subcutaneous atrophies. It uniquely

meets most the ideal fi ller criteria, including versatility, reliability of

results, a natural feel, and an excellent cost – benefi t ratio. Although its use

has historically met with some controversy, when LIS is appropriately

administered with the microdroplet serial puncture technique, patients

may obtain enduring correction of scars, rhytids, and depressions, as well

as lasting augmentation of lips and other facial contour atrophies and

deformities.

Yet the permanent nature of LIS in vivo is ambiguous. Although it is

an attribute when the fi ller is placed correctly, it may also be a liability

when the product is placed incorrectly, results in undesired augmentation,

or serves as a nidus for infl ammation and infection. For this reason, sili-

cone and other permanent fi llers are much less forgiving than temporary

fi llers: overcorrection or undesired augmentation will also persist. Hence,

experience and precise technique are prerequisites to favorable patient

outcomes. Physicians should use LIS only after extensive training in the

proper technique, and in the appropriate patient. Candidates for treatment

should have clear treatment objectives and suffi cient insight into the goal

of gradual augmentation over multiple treatment sessions. Patients who

desire immediate correction or are uncertain of treatment aims are better

treated with shorter - duration, temporary fi llers rather than LIS.

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

75

76 Chapter 7

Basic s cience

Silicon (Si) is second only to oxygen as the most abundant element of the

earth ’ s crust. 1 It is a relatively inert element that is essential to humans in

small amounts. “ Silicone ” (SI) describes the group of synthetic polymers

containing elemental silicon. Polymers in the silicone family may exist in

solid (elastomer), liquid, and gel states, with various chemical, physical,

mechanical, and thermal properties. Synthetic polymers also vary with

regard to purity, sterility, and biocompatibility. 2,3 Although various silicone

polymers are employed for medical use, polydimethylsiloxane is the liquid

injectable silicone used for soft - tissue augmentation. The molecular struc-

ture of this colorless, odorless, nonvolatile oil consists of repeating dimeth-

ylsiloxane units with terminal trimethylsiloxane ends (Figure 7.1 ).

The viscosity of a given LIS product is dependent on the mean chain

length of the dimethylsiloxane molecular units of which it is composed.

Longer - chain molecules have a higher viscosity, and individual polymers

are formulated to a set viscosity dependent on mean chain length. Silicone

viscosity is measured in centistokes (cs), where 1 cs equals the viscosity of

water. Practically, those LIS products employed for injection into the

human body have a viscosity of 350 cs (similar to mineral oil), 1000 cs

(similar to honey), or 5000 cs. 3

LIS has not been found to be carcinogenic, and has demonstrated “ an

enviable record of safety ” according to a 1998 National Science Panel

investigating its use. 4 Importantly, viscosity remains stable after tissue

implantation. Pure LIS is not altered in vivo, although small amounts may

be phagocytosed and enter the reticuloendothelial system. 5,6

Mechanism of a ction

LIS is the original fi broplastic fi ller, and its mechanism of augmentation

is twofold: it causes both the gross displacement of dermal and subcutane-

ous tissue and the deposition of new collagen via fi broplasia. After a local-

ized infl ammatory reaction consisting of neutrophil migration and some

degree of macrophage phagocytic activity, fi broblasts deposit a thin - walled

Figure 7.1 Chemical structure of

polydimethylsiloxane with repeating

trimethylsiloxane units.

Liquid Injectable Silicone 77

collagen capsule around the silicone microdroplet. 7 This capsule effectively

anchors the microdroplet in place and prevents migration. Although

the process of fi broplasia is classically conceptualized in wound healing,

several fi ller products, both temporary and permanent, are now known

to induce collagen fi broplasia as their mechanism of action for aesthetic

improvement. 8

Fibroplasia accounts for signifi cant tissue augmentation over time, and

the practitioner ’ s approach to volume enhancement differs when using

products such as LIS that work by this mechanism. Rather than attempting

to reach the fi nal treatment endpoint in a single session, as is often done

with fi llers that work mostly by tissue displacement, fi broplastic fi llers

require smaller amounts of product broken up into several sessions ade-

quately spaced over time. Appropriate spacing of treatment sessions 1 – 2

months apart allows the fi broplastic process adequate time to occur before

subsequent treatment sessions and avoids overcorrection and undesired

augmentation.

History

Dow Corning (DC) introduced the fi rst commercially available silicone for

industrial use during World War II. Soon after, however, reports of its use

for soft - tissue augmentation began to surface in Japan, Germany, and

Switzerland. The US medical experience with silicone began in the 1950s,

when physicians and nonphysicians alike began injecting silicone oil into

the human body for soft - tissue augmentation. 9 Large boluses of silicone

were found to result in migration of the product along tissue planes to

distant body sites, which led some injectors to add known tissue irritants,

such as vegetable fatty acids, to the silicone products in the hope of pro-

ducing implant - site fi brous reactions to limit product migration. However,

granulomatous reactions at implantation sites of the adulterated products

frequently occurred.

Over the subsequent decades, the widespread use of various silicone oils

for augmentation continued, unfortunately without common standards

with regard to sterility, purity, injection protocol, injection site, or injec-

tion volume. The silicones intended for industrial and medical device use

were later joined by products that were to be investigated for soft - tissue

augmentation, yet no controlled product source existed. In 1965, DC

gained US Food and Drug Administration (FDA) approval for investigation

of a sterilized, highly purifi ed silicone oil specifi cally intended for

soft - tissue augmentation. Over 1300 patients were treated, with only 1

report of a severe complication in a patient treated with a large volume

of silicone in a single injection. However, study protocol was not rigorously

78 Chapter 7

controlled with respect to patient eligibility, injection technique, or treat-

ment volume and interval, and DC stopped investigation due to poor study

control and inability to prevent product misuse.

Before the introduction of bovine collagen in the early 1980s, liquid

silicone was indeed the most popular injectable fi ller due to its natural

texture and long - lasting results. But continued reports of complications,

such as granuloma formation and migration, brought mounting negative

publicity and the passage of a 1975 Nevada law criminalizing the use of

injectable silicone in that state. Nationwide, its use declined as collagen

quickly became the fi ller of choice.

Although the FDA banned the use of LIS for cosmetic implantation in

the early 1990s, its legal use as a fi ller was restored in 1997 with the

passage of the US Modernization Act, which reaffi rmed the physician ’ s

right to employ approved medical devices in an off - label manner. 10 That

same year, Silikon - 1000 (Alcon, Fort Worth, TX), a 1000 cs, highly puri-

fi ed silicone, was approved for intraocular retinal detachment. Thus, with

an approved product on the US market, LIS could be legally used off - label

for soft - tissue augmentation. The FDA has since affi rmed that off - label

injection of approved products is legal as long as it is based on the unique

needs of the patient and is not advertised or marketed for that purpose. 3,5

In 2001 and 2003, the FDA also agreed to allow limited clinical studies

investigating the use of approved LIS for the cosmetic improvement of

nasolabial folds, labiomental folds, mid - malar depressions, and HIV -

associated facial lipoatrophy. These studies are currently ongoing. 11

Controversy

Although the effi cacy of LIS is seldom challenged, the past few decades

have seen debate about its safety, with both critics and advocates basing

their positions largely on anecdotal data rather than rigorously controlled

trials. 12 Well - controlled, long - term studies of LIS for soft - tissue augmenta-

tion have, until recently, been lacking, and the number of patients who

have historically experienced treatment success versus the number who

have experienced signifi cant complications is simply unknown.

A further diffi culty in historically analyzing the safety of “ silicone ” as

an augmenting agent is that, outside of the modern, FDA - approved prod-

ucts available since 1997, an unknown number of products claiming to

be silicone have likely been adulterated, impure, or other substances

altogether. Although highly purifi ed, 350 cs and 1000 cs products intended

for injection into the human body were not introduced until the late

1960s and 1990s respectively, various substances masquerading as “ sili-

cone ” have been injected for the past 60 years, at times with signifi cant

Liquid Injectable Silicone 79

complications. 13 – 16 Even products labeled as “ medical - grade ” silicone have

not historically been regulated or authenticated. A 1989 analysis of six

“ medical - grade ” silicone oils commonly used for injection revealed six

different products of variable viscosity, each with signifi cant amounts of

elemental impurities and low - molecular - weight adulterants. 17

Critics argue that LIS in an inherently unpredictable implant, fraught

with potential complications. Several anecdotal reports and series of com-

plications such as cellulitis, nodules, granulomatous reactions, and migra-

tion have been described, 13 – 15 although variables such as product purity,

volume, and injection technique could not be established with certainty.

Furthermore, complications have been reported to occur as long as 36

years after treatment. 16 Migration of product to other areas of the body

may occur when large boluses of LIS are injected, but this has never been

reported when using the microdroplet serial puncture technique. 18,19

Advocates, on the other hand, maintain that the product is extremely

safe and benefi cial when three tenets of treatment are strictly adhered to:

(1) only FDA - approved products intended for injection into the human

body should be used; (2) the microdroplet serial puncture technique must

be exclusively employed; and (3) a protocol must be followed involving

limited per - session injection volumes, spaced over multiple injection ses-

sions, with adequate intersession spacing.

Several authors have published excellent safety records after prolonged

LIS use. Balkin reported long - term follow - up over 41 years using LIS as

a soft - tissue substitute for plantar fat loss in over 1500 patients, with

25 000 recorded silicone injections. He found that the host response to

injections consisted of a “ banal and stable fi brous tissue formation ” . 7,20

Advocates such as Orentreich, Carruthers, and Jones have also published

multiple reports of their extensive and successful experience with LIS, and

reiterate that the three principles of product purity, appropriate technique,

and proper protocol are imperative for success. 11,21 – 23 Duffy, who has

written extensively on the subject, gathers that LIS has been used for soft -

tissue augmentation worldwide for at least 40 years, and in at least 200 000

patients in the USA. 24,25 He pragmatically cautions that, although pure LIS

may be a superior fi ller for the permanent correction of certain defects,

physicians who use it must realize that its misuse, or the use of other

materials masquerading as LIS, have created “ a pervasive climate of

distrust and a veritable minefi eld of extraordinarily unpleasant medico -

legal possibilities. ” Such perceptions reiterate the importance of ongoing

trials as they replace anecdotal reports with rigorously controlled data.

Despite 60 years of use, only within the past 8 years have well - controlled

trials, with the newer generation of standardized, highly purifi ed pro-

ducts injected according to strict protocol, begun. These studies have so

far demonstrated an excellent profi le of safety and effi cacy. The ongoing

80 Chapter 7

collection of objective data and longer - term follow - up are necessary to

provide clarity into the true risks and benefi ts of soft - tissue augmentation

with the modern silicones.

Indications and p atient s election

Although there are currently no FDA - approved cosmetic indications for

LIS, it has been effectively employed off - label for the augmentation

nasolabial folds (Figure 7.2 ), labiomental folds, mid - malar depressions, lip

atrophy 26 (Figures 7.3 and 7.4 ), hemifacial atrophy, acne and other

atrophic scarring 27 (Figure 7.5 ), age - related atrophy of the hands, corns

and calluses of the feet, and healed diabetic neuropathic foot ulcers. 20

It is most practical for the correction of HIV facial lipoatrophy and some

acne scarring (Figures 7.6 and 7.7 ). Many of the above atrophies are

also well served by modern, temporary fi llers, but, with HIV lipoatrophy,

(a) (b)

Figure 7.2 (a) Pre - and (b) post - treatment of marionette lines and nasolabial folds.

(Courtesy of Doris Hexsel.)

(a) (b)

Figure 7.3 (a) Pre - and (b) post - treatment of lip and vertical lip rhytids. (Courtesy of

Doris Hexsel.)

Liquid Injectable Silicone 81

(a) (b)

Figure 7.4 (a) Pre - and (b) post - treatment of atrophic lip scarring. (Courtesy of Doris

Hexsel.)

(a) (b)

Figure 7.5 Long - term correction of facial acne scarring with LIS. (a) Pre - treatment

and (b) 30 - year follow - up. (Courtesy of Jay G. Barnett and Channing R. Barnett.)

(a) (b)

Figure 7.6 (a) Pre - and (b) post - treatment of HIV - associated facial lipoatrophy: 22 mL

of LIS were injected over 12 monthly sessions. (Courtesy of Derek Jones.)

82 Chapter 7

LIS retains several advantages over other fi llers for patients requiring a

signifi cant degree of durable correction. In HIV - related facial lipoatrophy,

LIS presents a highly cost - effective, durable, natural feeling, effi cacious

treatment option that results in sustained improvement to help combat

the social and professional stigmas routinely experienced with this condi-

tion. For these reasons, LIS remains an incredibly useful fi ller in the

experienced injector ’ s armamentarium.

In contrast, LIS is specifi cally contraindicated for injection into the

breasts, eyelids, bound - down scars, or an actively infl amed site, and its

safety has not been studied in pregnant women. Nor should it be injected

into patients with dental carries, chronic bacterial sinusitis, or other active

bacterial infection, or in those who may predisposed to facial trauma

through contact sports due to an increased risk for chronic infection associ-

ated with an implant in such patients. In addition, LIS is not a substitute

for surgical re - draping, chemical or mechanical resurfacing, or improve-

ment of dynamic rhytids with botulinum toxin.

Rather, the ideal patient is one with appropriate insight into the per-

manent and off - label nature of LIS, a realistic attitude regarding achievable

results, in good physical health, and compliant with recommendations.

Those who seek immediate correction or temporary augmentation are best

served by temporary fi llers. Serious consideration by both the physician

and the patient must be given to the longevity of results obtained with

LIS. Although permanent fi llers such as LIS might refl exively seem pre-

ferred to temporary fi llers due to their longevity, one must contemplate

the possibility that both societal and personal aesthetic goals may change

over time. Furthermore, an undesirable outcome will be unlikely to dimin-

ish with time and may be diffi cult to correct.

(a) (b)

Figure 7.7 (a) Pre - and (b) post - treatment of HIV - associated facial lipoatrophy:

12.5 mL of LIS were injected over 8 monthly treatments (photograph b was taken 6

months after the last silicone injection). (Courtesy of Derek Jones.)

Liquid Injectable Silicone 83

Instrumentation Although 350 cs LIS is approved in Europe, in the USA the most appro-

priate LIS for off - label soft - tissue augmentation is Silikon - 1000 (Alcon,

Fort Worth, TX) (Figure 7.8 ). Adatosil 5000 cs (Bausch & Lomb, Rochester,

NY) may also be used off - label, but proves to be rather viscous as a soft -

tissue fi ller; 0.5 mL LIS is drawn through a 16G Nokor needle into a 1 - mL

Becton Dickinson (BD) Luer - Lok syringe using sterile technique

(Figure 7.9 ). As molecules from the rubber stopper of the syringe could

theoretically contaminate the LIS after a long exposure period, LIS should

be drawn into the injecting syringe immediately before treatment, and

should never be stored in the syringe. LIS is most easily injected through

a 27G, ½ - inch Kendall Monoject aluminum - hubbed needle. Plastic -

hubbed needles tend to pop off with the higher injection pressures

needed for injection through smaller gauge needles. To increase injector

comfort, ½ - inch inner diameter rubber electrical bushings purchased

from a hardware store may be autoclaved and placed over the barrel of

the syringe to cushion the physician ’ s second and third fi nger during

Figure 7.8 Silikon - 1000. (Courtesy of

Derek Jones.)

Figure 7.9 Instrumentation. (Courtesy

of Derek Jones.)

84 Chapter 7

injection (Figure 7.10 ). A BD 3/10 mL insulin syringe, similar to that

often used for botulinum toxin, may also be used for injection of LIS,

but these syringes must be backloaded. 28

Patient p reparation As with all fi llers, patients should avoid aspirin, non - steroidal anti - infl am-

matory drugs (NSAIDs), and anticoagulants for 7 – 10 days before injection.

Perhaps more than with any other minimally invasive procedure, a thor-

ough discussion about the risks, benefi ts, and alternative treatments to LIS

should occur and be documented before injecting LIS. Patients must

understand that LIS is a permanent fi ller and that it is being used off - label.

Written informed consent must be obtained.

Furthermore, high - quality pre - treatment photographs should be taken.

Make - up is removed, and the skin is washed with an antibacterial cleanser

and prepped with a povidone – iodine antiseptic or other surgical prepara-

tory solution. Areas to be injected are outlined under good lighting with

the patient in a sitting position, using a fi ne - tip marking pen (Figure 7.11 ).

Target areas for volume restoration should be marked in both the smiling

and the resting position, as these often change remarkably with facial

activity. When treating HIV facial lipoatrophy, mid - malar depressions

Figure 7.10 Assembled

instrumentation. (Courtesy of Derek

Jones.)

Figure 7.11 Patient marking: the

patient should be marked in both the

smiling and the resting positions.

(Courtesy of Derek Jones.)

Liquid Injectable Silicone 85

often become slightly elevated on smiling, and overcorrection of this area

may result in a “ chipmunk ” appearance when the patient smiles. A topical

anesthetic such as lidocaine or other topical amide mixture is then placed

on the treatment area and wiped off after 30 min with clean gauze.

Injection t echnique Although temporary fi llers may be injected by varied techniques, LIS

should be injected only by the microdroplet serial puncture technique

originally described by Orentreich. 5 Other injection techniques risk unde-

sirable consequences, including pooling or beading of silicone macrodro-

plets in the injection tract and possible migration via escape from the

anchoring fi broplastic capsules. A microdroplet is defi ned as 0.005 – 0.01 mL

of product, an amount that possesses a very large surface area compared

with volume. A larger surface area:volume ratio effectively allows the

microdroplet to be anchored into place by the ensuing fi broplasia that

occurs around it. With larger macrodroplets, defi ned as > 0.01 mL, encap-

sulation may not be suffi cient to prevent product migration. A larger

surface area:volume ratio also allows for a greater amount of fi broplasia

– and thus augmentation – per unit volume, since a given volume of LIS

dispersed into many microdroplets provides a greater total surface area

than would be provided by fewer, larger droplets. Maximizing the total

surface area of injected product effectively maximizes the degree of

augmentation.

Injections are made into the immediate subdermal plane or deeper.

Often, as the needle enters the subdermal plane, there is a slight give in

the tissue resistance to the needle. Intradermal injection should be dili-

gently avoided, because it may result in dermal erythema and ridging

(Figure 7.12 ). Care should be taken to make sure that the needle is in the

subdermal plane before depressing the plunger. Furthermore, the injec-

tor ’ s thumb should be removed from the plunger before removing the

needle. Injections should be placed at 2 - to 5 - mm intervals along the skin

Figure 7.12 Dermal erythema and

ridging secondary to intradermal

injection. (Courtesy of Derek Jones.)

86 Chapter 7

surface at the optimal angle for penetration and deposition into the sub-

dermal plane. The optimal angle varies with the intended depth of LIS

placement. For areas where deeper placement is desired, a more oblique

(approaching perpendicular to the skin surface) angle of insertion is best,

whereas a more acute (approaching parallel to the skin surface) angle of

insertion works best for more superfi cial deposition.

As a rule, multiple passes over the same treatment area in a single

session should be avoided, although experienced injectors may sometimes

make a second pass at a different subcutaneous level. Importantly, greater

correction should be accomplished over a longer period of time rather than

with a larger per - session volume. Per session treatment volumes should

be limited to 0.5 mL for smaller surface areas such as the nasolabial fold,

and no more than 2.0 mL for larger surface areas such as facial lipoatrophy.

Such per - session volumes allow around 100 – 200 individual injections

with microdroplet deposition at 2 - to 5 - mm intervals, allowing a large

treatment area to be covered in a single session if necessary.

Moreover, injection sessions should be spaced at least 1 month apart,

or longer, to allow for a limited fi brous tissue reaction to occur around

each silicone microdroplet. As with all fi llers working mainly by fi bropla-

sia, intentional overcorrection immediately after injection should be

avoided. As optimal correction approaches, treatment intervals should be

extended to allow complete deposition of fi brous tissue before the next

injection. Intervals on the order of every 2 – 6 months are appropriate in

the late treatment period in order to allow for delayed fi broplasia, during

which continued treatment could result in overcorrection.

Side and e ffects and m anaging c omplications

The immediate injection - related side effects commonly seen with all fi llers

occur with LIS as well. The mild pain of needle insertion is usually well

controlled with pretreatment topical lidocaine anesthetics. Occasionally,

pre - treatment with oral analgesics (i.e. 0.5 mg alprazolam and two tablets

of acetaminophen/hydrocodone 5/500 mg) 1 hour before treatment may

be necessary in the pain - intolerant patient. Post - injection edema and ery-

thema are common, usually mild, and resolve within a few days. The

transient edema may even be representative of what optimal correction

may look like after several treatments. Ecchymosis, when it occurs, also

usually resolves within a few days.

When injected with the appropriate technique, LIS is remarkably similar

in texture and sensation to natural soft tissue. However, when larger

cumulative volumes are employed, such as in HIV facial lipoatrophy, the

treated area may occasionally feel slightly rubbery and fi rmer than natural

Liquid Injectable Silicone 87

soft tissue. Migration of LIS is an often - mentioned and undesired side

effect of LIS. Using small volumes over multiple treatment sessions with

the microdroplet technique avoids this problem, because microdroplets of

silicone are anchored to the surrounding soft tissue by fi broplasia. However,

LIS may track along tissue planes in the path of least resistance when

injected in large boluses all at once.

Skin dyschromia is a rare side effect of LIS, occurring most often when

LIS is inadvertently injected into the dermis. When the infl ammatory

response to LIS extends into the dermis, postinfl ammatory erythema,

postinfl ammatory hyperpigmentation, and telangiectasias may occur.

Often, dermal ridging occurs in conjunction with the dyschromia.

Erythema and telangiectasia may be treated with a pulsed dye laser or

intense pulsed light device. Hyperpigmentation may be treated with hyd-

roquinone and sun protection. And dermal ridging may improve with

intralesional steroid injection, but the response is often incomplete and

the problem persistent.

A more concerning potential adverse event to LIS is granuloma forma-

tion, presenting as edematous, infl amed, indurated nodules or plaques in

the subcutis or dermis. Such reactions have been described with LIS as

well as a variety of other permanent or longer - lasting fi llers such as

polymethylmethacrylate and polylactic acid. 21 These reactions are thought

to be immune mediated, yet the basis of the immune mechanism remains

unclear. It has been postulated that granulomatous reactions may be a

result of infection at a distant site, as granulomatous reactions to LIS have

been noted with acute bacterial dental abscesses or sinusitis to resolve

upon treatment of the infection. Another leading, and perhaps comple-

mentary, theory is that bacterial biofi lm formation around the LIS micro-

droplet may serve as a nidus for a chronic infection and resultant

infl ammatory host response. 29 Biofi lms may occur if bacterial organisms

are introduced upon fi ller injection or seed the fi ller later during bacter-

emic episodes, and once present may remain dormant for months or years

on foreign body surfaces such as implanted LIS. Biofi lms may serve as a

target of a delayed immune response by the patient when organisms

convert back to a planktonic state, explaining the potential for granuloma

formation years after LIS injection. In theory, immune restoration in HIV

might also then predispose the patient to granuloma formation years

later, 25 but this has not been frequently observed by experienced injec-

tors. 21,27 It is estimated that some fraction of 1% of patients correctly

treated with injectable grade LIS may eventually develop such granulo-

matous reactions. 5 Should granulomatous reactions develop, they may

be treated with high concentrations of intralesional triamcinolone (20 –

40 mg/mL) at 2 - to 4 - week intervals. However, based on the biofi lm

hypothesis, institution of a full - dose, broad - spectrum antibiotic such as

88 Chapter 7

minocycline once or twice daily should also occur. Isotretinoin, etanercept,

and topical imiquimod have also been used successfully to treat LIS granu-

lomas. 30 – 33 Ultimately, however, granulomas that fail to resolve may

require surgical removal.

Summary

In an era of expanding soft - tissue augmenting agents, liquid injectable

silicone remains a unique and effective fi ller when appropriately employed

by experienced injectors using the microdroplet serial puncture technique.

Although LIS is effective for the correction of a variety of facial atrophies

and deformities, currently its greatest application is for the permanent

correction of HIV - associated facial lipoatrophy. Although LIS has gener-

ated controversy in the past, the modern, highly purifi ed silicone oils

studied in controlled clinical settings have so far proven to be extremely

safe agents that warrant distinction from their predecessors. Yet, as with

any procedure, complications may still occur, and may be more diffi cult

to treat due to the permanent nature of the product. For this reason, LIS

should be considered only in appropriate patients who have had full dis-

closure as to the off - label nature of its use and adequate informed consent.

When all criteria are met, LIS may be one of the most cost - effective and

natural fi llers available, and continued studies are ongoing to further

examine both long - term safety and effi cacy.

References

1. Turekian KK , Wedepohl KH . ( Distribution of the elements in some major units of

the earth ’ s crust . Bull Geol Soc Am 1961 ; 72 : 175 – 92 .

2. Spanoudis S , Koski G. Sci.polymers. Available at www.plasnet.com.au/

index.php?option=com_content&view=article&id=89:polymer-faq&catid=118:

FAQ&Itemid=258 (accessed January 31, 2009).

3. Orentreich DS , Jones DH . Liquid injectable silicone . In: Carruthers J , Carruthers A

(eds), Soft Tissue Augmentation , 1st edn . New York : Elsevier , 2005 : 77 – 91 .

4. Diamond B , Hulka B , Kerkvliet N , Tugwell P . Summary of report of national science

panel: silicone breast implants in relation to connective tissue diseases and

immunologic dysfunction, 1998 . Available at: www.fjc.gov/BREIMLIT/SCIENCE/

summary.htm (accessed January 31, 2009).

5. Orentreich DS. Liquid injectable silicone: techniques for soft tissue augmentation .

Clinics Plast Surg 2000 ; 27 : 595 – 612 .

6. Selmanowitz VJ , Orentreich N . Medical grade fl uid silicone: a monographic review .

J Dermatol Surg Oncol 1977 ; 3 : 597 – 611 .

7. Wallace WD , Balkin SW , Kaplan L , Nelson SD . The histological host response of

liquid silicone injections for prevention of pressure - related ulcers of the foot: a 38 -

year study . J Am Pod Med Assocn 2004 ; 94 , 550 - 557 .

Liquid Injectable Silicone 89

8. Carruthers J , Carruthers A , Mandy SH , Lowe NJ , Prather CL , Jones DH . Fillers

working by fi broplasia . In: Carruthers J , Carruthers A (eds), Soft Tissue Augmentation ,

2nd edn . New York : Elsevier , 2008 : 90 – 100 .

9. Klein AW. Skin fi lling: collagen and other injectables of the skin . Dermatol Clinics

2001 ; 19 : 491 – 508 .

10. Food and Drug Administration . Physicians to stop injecting silicone for cosmetic

treatment of wrinkles , Press Release P92 - 5, 1992. Available at: www.fda.gov/bbs/

topics/NEWS/NEW00267.html (accessed January 31, 2009).

11. Jones DH , Carruthers A , Orentreich D , et al. Highly purifi ed 1000 - cSt silicone oil

for treatment of human immunodefi ciency virus - associated facial lipoatrophy: an

open pilot trial . Dermatol Surg 2004 ; 30 : 1279 – 86 .

12. Duffy DM. ( 2002 ) The silicone conundrum: a battle of anecdotes . Dermatologic

Surgery 28 , 590 .

13. Delage C , Shane JJ , Johnson FB . Mammary silicone granuloma: Migration of sili-

cone fl uid to abdominal wall and inguinal region . Arch Dermatol 1973 ; 108 ( 1 ):

105 – 7 .

14. Baselga E , Pujol R . Indurated plaques and persistent ulcers in an HIV - 1 seropositive

man . Arch Dermatol 1994 ; 130 : 785 – 9 .

15. Rapaport MJ , Vinnik C , Zarem H . Injectable silicone: cause of facial nodules,

cellulitis, ulceration, and migration . Aesthet Plast Surg 1996 ; 20 : 267 – 76 .

16. Rapaport MR. Silicone injections revisited . Dermatol Surg 2002 ; 28 : 594 – 5 .

17. Parel JM. Silicone oils: physiochemical properties . In: Glaser BM , Michels RG (eds),

Retina , Vol 3. St Louis, MI : Mosby , 1989 : 261 – 77 .

18. Duffy DM. Liquid silicone for soft tissue augmentation . Dermatol Surg 2005 ; 31 ( 11 Pt

2): 1530 – 51 .

19. Price EA , Schueler H , Perper JA . Massive systemic silicone embolism: a case report

and review of literature . Am J Forensic Med Pathol 2006 ; 27 ( 2 ): 97 – 102 .

20. Balkin SW. Injectable silicone and the foot: a 41 - year clinical and histologic history .

Dermatol Surg 2005 ; 31 ( 11 Pt 2): 1555 – 9 .

21. Jones D. HIV facial lipoatrophy: causes and treatment options . Dermatol Surg

2005 ; 31 ( 11 Pt 2): 1519 – 29 .

22. Jones DH. Injectable silicone for facial lipoatrophy . Cosmet Dermatol 2002 ;

15 : 13 – 15 .

23. Orentreich D , Leone AS . A case of HIV - associated facial lipoatrophy treated with

1000 - cs liquid injectable silicone . Dermatol Surg 2004 ; 30 : 548 – 51 .

24. Duffy DM. Tissue injectable liquid silicone: new perspectives . In: Klein AW (ed.),

Augmentation in Clinical Practice: Procedures and techniques . New York : Marcel Dekker ,

1998 : 237 – 63 .

25. Duffy DM. Liquid silicone for soft tissue augmentation: histological, clinical, and

molecular perspectives . In: Klein A (ed.), Tissue Augmentation in Clinical Practice , 2nd

edn . New York : Taylor & Francis , 2006 : 141 – 237 .

26. Fulton JE Jr , Porumb S , Caruso JC , Shitabata PK . Lip augmentation with liquid

silicone . Dermatol Surg 2005 ; 31 ( 11 Pt 2): 1577 – 86 .

27. Barnett JG , Barnett CR . Treatment of acne scars with liquid silicone injections:

30 - year perspective . Dermatol Surg 2005 ; 31 ( 11 Pt 2): 1542 – 9 .

28. Benedetto AV , Lewis AT . Injecting 1000 centistoke liquid silicone with ease and

precision . Dermatol Surg 2003 ; 29 : 211 – 14 .

29. Christensen L. Normal and pathologic tissue reactions to soft tissue gel fi llers .

Dermatol Surg 2007 ; 33 : S168 – 75 .

30. Desai AM , Browning J , Rosen T . Etanercept therapy for silicone granuloma . J Drugs

Dermatol 2006 ; 5 : 894 – 6 .

90 Chapter 7

31. Baumann LS , Halem ML . Lip silicone granulomatous foreign body reaction treated

with aldara (imiquimod 5%) . Dermatol Surg 2003 ; 29 : 429 – 32 .

32. Lloret P , Espana A , Leache A , et al. Successful treatment of granulomatous reactions

secondary to injection of esthetic implants . Dermatol Surg 2005 ; 31 : 486 – 90 .

33. Pasternack FR , Fox LP , Engler DE . Silicone granulomas treated with etanercept .

Arch Dermatol 2005 ; 141 : 13 – 15 .

Hydrogel Polymers Naissan O. Wesley Skin Care and Laser Physicians of Beverly Hills, Los Angeles, USA

CHAPTER 8

History and s cience

Hydrogel polymers are hydrophilic substances that are made up of poly-

acrylamide subunits. 1 Acrylamide is a highly water - soluble vinyl monomer

formed from the hydration of acrylonitrile. As a monomer, acrylamide has

been shown to be neurotoxic and teratogenic. 2,3 However, when the

monomers are crosslinked to the polymer form, the potential neurotoxic-

ity and teratogenicity effects cease. 3 Most commercial uses of acrylamide

are available in the form of polymers. Polyacrylamide can hold between

300 and 400 times its weight in water and has been used for many years

in medical applications, drug delivery, intraocular lenses and soft contact

lenses, water purifi cation, paper processing, mining and mineral process-

ing, food packaging, and agriculture. 3,4 Their use for aesthetic procedures

was fi rst reported in 2001.

Soft - tissue hydrogel polymer fi llers are gels that are permanent, nonbio-

degradable, and hydrophilic. 1 They have a high degree of elasticity. With

regard to Bio - Alcamid, its oxidizability is < 1, its spontaneous pH is 6.9 and

there is no monomer (PPM 0). 5 When used as soft - tissue fi llers, hydrogel

polymers are classifi ed as class IIB medical devices (Box 8.1 ).

Hydrogel polymers used for soft - tissue augmentation include Aquamid

(Contura International A/S, Soborg, Denmark), Bio - Alcamid (Polymekon,

Milan, Italy), Argiform (Bioform, Moscow, Russia), and Interfall (Interfall

Co. Ltd, Ukraine). Former hydrogel fi llers Bioformacryl, Formacryl,

Royamid, Amazing - gel, Evolution, and Outline were available in Europe,

Russia, and China but are no longer on the market. 6

Aquamid is a 5% polyacrylamide polymer with 97.5% water. 7 Bio -

Alcamid is composed of a backbone of 2.5 – 5% crosslinked polyalkylimide

and 95 – 97.5% water. It does not contain free acrylamide monomers. 8

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

91

92 Chapter 8

Polyalkylimide is a subtype of polyacrylamide. In the past, the manufac-

turer ’ s website has referred to the product ’ s composition as polyacryla-

mide. Recently, the information on the website has changed to state

that the gel is composed of polyalkylimide (see www.ascentemedical.

com/content/view/27/206 and www.purmedical.com/bioAlcamid.htm ).

Argiform is a second - generation polyacrylamide gel made up to 95%

polyacrylamide, with 0.03% residual unpolymerized acrylamide monomer

and 5% water. It is identical in composition to its predecessor Formacryl,

except that a silver ion has been added to the manufacturing process to

help repel bacteria (see www.bioform.ru ). Interfall is 3.5 – 6% crosslinked

polyacrylamide with water; it also contains crosslinking agents, such as

methylene - bisacrylamide, and a mixture of ammonium persulfate and

tetramethylethylenediamine as the initiator of polymerization (see www.

bpg.bg/interfall/index.htm ).

After injection in to tissue, the polymer becomes an “ endoprosthesis ”

due to fi broblast activity around the substance, which forms a thin approx-

imately 0.2 - mm fi brous capsule. 5,9 – 12 After approximately 2 months, the

fi broblast activity within and around the capsule ceases and the capsule

remains 0.2 mm thick without further thickening or sclerosis. 13 The thin

capsule contrasts with thicker capsules found surrounding silicone, which

is a hydrophobic permanent fi ller. 8,12

Indications

Bio - Alcamid received the CE (Conformiti é Europ é ene) certifi cate in

October 2001, and has been used in Europe as a permanent fi ller substance

for age - related volume loss and for HIV - and highly active antiretroviral

therapy (HAART) - associated lipodystrophy 9 (Figure 8.1 ). In Canada, Bio -

Alcamid is approved only for the treatment of HIV - and HAART - associated

facial lipoatrophy (see www.purmedical.com/bioAlcamid.htm ). Aquamid

has been used outside the USA since 1993, but was fi rst reported to be

used for cosmetic procedures in Europe in 2001. 14 Since 2001, approxi-

mately 150 000 patients have received more than 250 000 injections with

Box 8.1 Properties of hydrogel polymer fi llers Permanent Nonbiodegradable Radiolucent gel Hydrophilic High degree of elasticity Class IIB medical device

Hydrogel Polymers 93

Aquamid for aesthetic purposes and for HIV - associated lipoatrophy. 15

A US - based double - masked, randomized, multi - center study of 315 sub-

jects comparing Aquamid versus Restylane found that Aquamid was as

effective as Restylane in the aesthetic enhancement of nasolabial folds,

and that the effectiveness of Aquamid was maintained at 12 months. 16

Argiform is available in Russia and is marketed and used for lip enhance-

ment. Interfall is a volume fi ller manufactured in the Ukraine. None of

these products currently have approval by the US Food and Drug

Administration (FDA) for use in the USA.

Although not approved in every country, these hydrogel polymers are

used worldwide for aesthetic purposes. In addition to facial volume cor-

rection, both Bio - Alcamid and Aquamid have also been used for breast,

calf, and buttock augmentation, often combined with liposculpture. 5

Technique

Bio - Alcamid Bio - Alcamid is available in 1 - mL, 3 - mL and 5 - mL Luer - Lok syringes.

Injections are made with an 18G 1.5 - inch needle or 2 – 3 mm diameter

(a) (b)

Figure 8.1 (a) Patient with HIV - associated lipoatrophy pre - Bio - Alcamid injection. (b)

Two months post Bio - Alcamid injection. (Photograph courtesy of Derek Jones.)

94 Chapter 8

cannula. Smaller 21 – 23G needles may be used to fi ll facial rhytids. Bio -

Alcamid 1 – 3 mL of is typically injected into each nasolabial fold, cheek,

chin, or jawline for aesthetic purposes. For HIV - associated lipoatrophy, a

total of 10 – 30 mL is typically injected, depending on degree of volume

loss. 1 For breast augmentation or pectus excavatum 40 – 120 mL may be

injected into the breasts or chest. For buttock augmentation, 100 – 500 mL

may be injected. 5

Sterile preparation is recommended before injection. Local anesthesia is

typically obtained with lidocaine with epinephrine either by nerve block

or directly infi ltrated into the treatment area. A skin incision is made with

a sharp scalpel blade. Then the 18G needle or 2 - to 3 - mm cannula is

introduced into the incised skin and Bio - Alcamid is injected retrograde

with one single lodging. Most authors recommend placing a new parallel

lodging with a separate puncture point in the event of irregularities or

insuffi ciency. 5

Aquamid Aquamid is available in Europe in pre - fi lled 1 - mL syringes and is injected

as a clear gel with a 27G needle (see www.aquamid.info/ifs.htm ). The

product may be stored at room temperature. Similar to Bio - Alcamid,

Aquamid should be injected under sterile conditions, under local

anesthesia, and in a retrograde manner. Approximately 1 – 4 mL are typi-

cally injected into the nasolabial folds, 1 – 4 mL into the lips, and 1 mL

into the glabella. 15

Argiform Argiform is used for lip enhancement. The gel is injected with a 25G

5/8 - inch (0.50 × 16 mm) needle into the vermillion border and lip

body in a retrograde manner. Similar to Bio - Alcamid and Aquamid,

Argiform is laid down in a parallel array. The manufacturer reports

that the gel does not extrude via puncture sites after injection; however,

they do recommend light pressure at puncture sites to prevent extru-

sion from occurring. The amount of gel injected depends on the

amount of volume desired to achieve a fuller lip, but typically does

not exceed 0.5 mL into each lip (1.0 mL total). If more than 1 mL is

injected, there is a higher risk of nodule formation during lip move-

ment. Immediately after injection, the gel is molded into place by

grasping the lip between the thumb and index fi ngers and smoothing

out any irregularities. Over the next 2 – 4 weeks after injection, some

reduction in tissue volume may be expected. Thus, patients should be

informed about the possibility of additional future injection(s) (see

www.bioform.ru ).

Hydrogel Polymers 95

Interfall Interfall is available in the Ukraine and was called Amazing - gel when

produced by a Chinese manufacturer (Fuhua Co., China) until it was

banned in China in April, 2006 (see www.physorg.com/news68374349.

html ). According to the manufacturer ’ s website, Interfall is available in

sterile vials of 20 mL, 50 mL, and 250 mL volume for use in the face, body,

breasts, genitals, vocal folds, and scars. 12 It should be stored at room tem-

perature and has a shelf - life of 2 years. Further information about Interfall

is not available at the time of writing.

Potential a dverse r eactions

Although the permanent nature of the hydrogel fi llers is often considered

an advantage, there are numerous reports of adverse events. Common

reactions seen immediately after injection include erythema, edema,

and bruising that may last up to 1 week, as with any soft - tissue fi ller.

However, adverse reactions unique to hydrogel polymers also occur.

Complications related to hydrogel fi ller therapy can be early and late

occurring and include infection, nodule formation, product migration,

and sterile infl ammatory abscesses. 1,6,7,14,17 – 20 Capsular contraction may

also occur, changing the shape of the endoprosthesis, and causing the

depot to feel unnaturally hard to touch. Although complications do not

occur in every case of hydrogel polymer injection, an analysis of 2000

cases of Bio - Alcamid treatments for a variety of aesthetic purposes over

3 years revealed that 12 of 2000 implants were infected with Staphylococcus

aureus , requiring incision and drainage of the implant and antibiotic

therapy in all 12 cases. 21 Late - occurring reactions can occur months to

years after injection and can be recurrent (Figure 8.2 ). In one report

of 25 patients with late - occurring adverse effects due to polyalkylimide

fi llers, the mean latency between injection and symptoms was 13.4

months. 8

Late - occurring complications can be spontaneous. However, many are

often preceded by disruption of the fi brocellular layer surrounding

the product after invasive procedures such as injection of additional fi ller

material, blepharoplasty, and dental work. The most common presen-

tation is that of an infl ammatory abscess where patients present with

pain and edema at or near the site of prior fi ller placement 1,6,7,14,17 – 20

(Figure 8.3 ).

Serologies most commonly reveal elevated acute phase reactants, but

increased angiotensin - converting enzyme or ACE (with normal calcium

levels), lactate dehydrogenase (LDH), positive ANAs (anti - neutrophil anti-

bodies), and abnormal electrophoresis abnormalities may be found. 8,9

96 Chapter 8

(a) (b)

(c) (d)

Figure 8.2 (a) Presentation of acute infl ammatory reaction 3 years after Bio - Alcamid

injection. Cultures of the exudates grew α - hemolytic streptococci of the viridians

group. (b) Ten days after incision and drainage, intravenous vancomycin and

subsequent oral clindamycin were given. (c) Nine months later, presentation of

recurrent, chronic infl ammatory reaction of 5 months ’ duration. (d) Appearance

1 week after incision and drainage and cephalexin 500 mg orally four times a day for

7 days. (Reprinted with permission from Jones DH, Carruthers A, Fitzgerald R,

Sarantopoulos GP, Binder S. Late - appearing abscesses after injections of

nonabsorbable hydrogel polymer for HIV - associated facial lipoatrophy. Dermatol Surg

2007; 33 (suppl 2):S193 – 8.)

Hydrogel Polymers 97

Negative cultures of aspirated material from infl ammatory reactions are

the norm, but Gram stains of the exudates have shown Gram - positive

cocci in singlets, doublets, and chains. 19 In the rare instance that positive

cultures are obtained, Streptococcus viridians has been the most common

organism identifi ed. 18 – 20 Several cases of cultures growing Propionibacterium

acnes , coagulase - negative staphylococci, meticillin - resistant Staphylococcus

(a) (b)

(c) (d)

Figure 8.3 (a,b) Acute infl ammatory reaction with nondrainable rock hard nodules

in the glabella and nasolabial fold after a dental visit, 2 years after Bio - Alcamid

injection. (c,d) Resolution of the nodules 1 month after 1.0 mL intralesional

triamcinolone 40 mg/mL to the subcutis of the glabella and 1.0 mL intralesional

triamcinolone 20 mg/mL into the nasolabial fold, and 6 weeks of oral minocycline

135 mg daily (Solodyn, Medicis, Scottsdale, AZ). (Photograph courtesy of Derek

Jones)

98 Chapter 8

aureus , group G streptococci, and Candida species have also been reported. 19

Nonspecifi c foreign body granulomas are seen on histopathological

examination. 7,19 The fi ller can also be visualized on T2 - weighted magnetic

resonance imaging (MRI) with fat - suppressing spectro - presaturation

inversion recovery (SPIR). 1

In most cases, patients are given antibiotics while cultures are pending.

Patients with an infl ammatory response to hydrogel polymers usually

improve with a combination of antibiotics, drainage, and steroid injec-

tions, but improvement is usually not achieved with antibiotics alone.

One hypothesis for the cause of infl ammation is that puncture of

the capsule by a needle from dental work or injection of a secondary

fi ller may introduce bacteria that are not detectable in culture, but

may stimulate chronic infl ammation. 6 Therefore, the implant of tem-

porary or permanent fi llers may serve as a growth medium for biofi lm

formation. It has recently been shown that Staph. aureus forms a bacte-

rial biofi lm on hydrophilic substances, whereas Escherichia coli prefers

hydrophobic substances. 22 The introduction of a staphylococcal, strep-

tococcal, or other bacterial species through skin and implant puncture

could explain biofi lm formation. Once a bacterial biofi lm is established,

elimination of the bacteria stimulating the infl ammation is extremely

diffi cult. Removal of all of the fi ller material plus long - term broad -

spectrum antibiotics that are able to penetrate the implant capsule is

advocated.

Distinguishing infl ammation due to a bacterial biofi lm from a low - grade

sensitivity reaction is diffi cult. Most fi ller substances have been reported

to have immunogenicity, including hyaluronic acid (HA). A study of

delayed immune - mediated effects from HA and HA combined with

polymethylmethacrylate included 25 cases of patients with symptoms

starting 1 – 60 months after injection. The adverse effects were infl amma-

tory nodules, cutaneous leukocytoclastic vasculitis, sarcoid - like reaction,

and labial granulomas, and serum abnormalities were present in all of

those tested. 23 Although rare, hypersensitivity should always be consid-

ered in the differential diagnosis of a patient presenting with an infl am-

matory reaction after receiving an injection of a fi ller. Intradermal skin

testing with a fi ller substance before treatment may be helpful in suscep-

tible individuals. 24

Migration of hydrogel fi llers has also been reported. 6,14 It has been

speculated that the thin capsule formed around these hydrogel polymers

may be fl accid in subcutaneous and mammary tissue, which could result

in capsular rupture with force, muscle activity, or vigorous massage, espe-

cially in patients with a thin subcutaneous layer. 25 An incomplete or

absence of capsule in or near muscle has also been reported. 6 The pumping

Hydrogel Polymers 99

action of the muscles may therefore result in gel migration, especially

years after injection.

Although complications with hydrogel fi llers can be severe and diffi cult

to manage, their use can still signifi cantly impact quality of life. In a

prospective study of 17 patients in the Netherlands with signifi cant HIV -

associated lipoatrophy, 4 of 17 patients suffered complications including

infection requiring drainage, gel migration, and hardened capsule forma-

tion after one session of polyalkylimide injection. In this study all patients

demonstrated decreased subjective severity of lipoatrophy and improved

quality of life, even in the four patients who had complications. 25 In

addition, larger amounts of Bio - Alcamid and Aquamid can be injected

in one session compared with other long - lasting soft - tissue fi llers such as

silicone and polylactic acid (Sculptra, Newfi ll), making it more desirable

for some patients with severe lipoatrophy who desire a single - stage

procedure. 13,24

Management of a dverse r eactions

Complications have been managed with antibiotics, incision and drai-

nage, oral or intralesional steroids, nonsteroidal antiinfl ammatory drugs

(NSAIDs), hydroxychloroquine, and removal of the product, with varying

results. 1,6,7,17 – 20 Despite resolution with these methods, patients may have

recurrent symptoms. Removal of the product has been performed via inci-

sion with a large - gauge needle and squeezing the gel out. However, the

fi ller substance may not be easily removed with puncturing and squeezing;

thus, surgery with complete excision may be required to remove all of the

injected material. Gel that has migrated in the breasts or calves must

usually be managed by surgical excision.

For small, infl amed nodules, intralesional corticosteroids should be

attempted fi rst. When intralesional corticosteroids have failed or for

larger abscesses, an attempt at incision and drainage with culture and

pathology of the expressed material is recommended. Although cultures

are often negative, starting broad - spectrum antibiotics in addition to inci-

sion and drainage may still be useful for their antiinfl ammatory properties.

Amoxicillin/clavulanate potassium (Augmentin), clarithromycin, clin-

damycin, and minocycline, among others, have been tried with some

success. 19,24

A novel approach using an irrigation system to remove the hydrogel

polymer has recently been published. 18 Under sterile conditions and ultra-

sound guidance, a 14 – 16G intravenous cannula is inserted into the site of

fi ller placement. The cannula is secured in place with a suture. Frequent

100 Chapter 8

irrigation, up to eight times a day, is performed by injecting and aspirating

solutions such as Hartmann ’ s, saline, or 10% povidone – iodine solution.

Irrigation has been reported to be slightly painful in some patients.

Complete implant removal can be achieved; however, in cases where

removal was not complete, the amount of fi ller was reduced considerably

and symptoms were alleviated. In this report, this approach was performed

in patients who were concerned about having larger scars as a result of

incision and drainage or excision. However, patients were hospitalized for

several days for this procedure, which may not always be feasible in most

US healthcare settings.

If hydrogel fi llers are to be utilized, strict antiseptic precautions should

be taken to ensure that they are injected in a sterile fashion. Once injected,

caution must also be taken when additional fi llers are injected at a later

date so as not to puncture the endoprosthesis for risk of infl ammatory

reaction or biofi lm formation. Prophylactic antibiotics may be warranted

before initial injection and before repeat soft - tissue fi ller injections, surgery

in the affected area, or dental procedures. One study recommends that

patients should be instructed not to touch the injected sites for 4 hours

after the procedure and to avoid high pressure at the site for 3 weeks. 25

Conclusion

Hydrogel polymers are permanent volume fi llers available outside the

United States. They are useful for patients with severe volume loss or

lipoatrophy as large amounts of product may be injected in one session.

Although infrequent, diffi cult - to - manage complications have been

reported with these products.

With the explosion of new substances coming on to the market for soft -

tissue augmentation, it is essential that physicians be aware of both short -

and long - term effects of new materials. Industry must also recognize the

potential complications and problems with products, and disclose reported

complications in their literature. 24 Globalization of the cosmetic surgery

market presents unique challenges to physicians. It is important for physi-

cians to be aware of potential presentations and complications of new and

less commonly used cosmetic treatments, including those used primarily

outside the United States. 23

References

1. Karim RB , Hage JJ , Van Rozelaar L , Lange CAH , Raaijmakers J. Complications of

polyalkylimide 4% injections (Bio - Alcamid ™ ): a report of 18 cases . J Plast Recontruct

Aesthetic Surg 2006 ; 59 : 1409 – 14 .

Hydrogel Polymers 101

2. Exon JH. A review of the toxicology of acrylamide . J Toxicol Environ Health B Crit Rev

2006 ; 9 : 397 – 412 .

3. Smith EA , Oehme FW . Acrylamide and polyacrylamide: a review of production, use,

environmental fate and neurotoxicity . Rev Environ Health 1991 ; 9 : 215 – 28 .

4. Shaw I , Thomson B . Acrylamide food risk . Lancet 2003 ; 361 : 434 .

5. Claoue BL , Rabineau P . The polyalkylimide gel: experience with Bio - Alcamid . Semin

Cutan Med Surg 2004 ; 23 : 236 – 40 .

6. Cheng NX , Xu SL , Deng H , et al. Migration of implants: a problem with injectable

polyacrylamide gel in aesthetic plastic surgery . Aesth Plast Surg 2006 ; 30 : 215 – 25 .

7. Amin SP , Marmur ES , Goldberg DJ . Complications from injectable polyacrylamide

gel, a new nonbiodegradable soft tissue fi ller . Dermatol Surg 2004 ; 30 ( 12 Pt 2):

1507 – 9 .

8. Alijotas - Reig J , Garcia - Gimenez V , Miro - Mur F , Vilardell - Tarres M. Delayed

immune - mediated adverse effects related to polyacrylamide dermal fi llers: clinical

fi ndings, management and follow - up . Arch Dermatol 2009 ; 35 : 360 – 6 .

9. Honig JF. Cheek augmentation with bio - alcamid in facial lipoatrophy in HIV sero-

positive patients . Journal Craniofac Surg 2008 ; 19 : 1085 – 8 .

10. Formigli L , Zecchi S , Protopapa C , et al. Bio - Alcamid: an electron microscopic study

after skin implantation . Plast Reconstr Surg 2005 ; 113 : 1104 – 6 .

11. Lemperle G , Morhenn V , Charrier U . Human histology and persistence of various

injectable fi ller substances for soft tissue augmentation . Aesth Plast Surg 2003 ; 115 :

337 – 8 .

12. Christensen LH , Nielsen JB , Mouritsen L , Sorensen M , Lose G . Tissue integration

of polyacrylamide hydrogel: an experimental study of periurethral, perivesical, and

mammary gland tissue in the pig . Dermatol Surg 2008 ; 34 : S68 – 77 .

13. Lotti T , Cammarota N , Protopapa C . Immunohistochemical and ultrastructural

evaluation of human tissue after subcutaneous injection of new fi ller Bio - Alcamid .

Polymekon Science Dosier 2001 ; 1 : 28 – 31 .

14. Goldman MP. Pressure - induced migration of a permanent soft tissue fi ller . Dermatol

Surg 2009 ; 35 ( suppl 1 ): 403 – 6 .

15. Wolters M , Lampe H . Prospective multicenter study for evaluation of safety, effi cacy,

and esthetic results of cross - linked polyacrylamide hydrogel in 81 patients . Dermatol

Surg 2009 ; 35 ( suppl 1 ): 338 – 43 .

16. Narins R. A 12 - month Controlled Study in the United States of the Safety and

Effi cacy of Hydrogel, A Permanent Soft - Tissue Filler . [Abstract]. American Society

of Dermatologic Surgery Meeting, October 1 – 4, 2009 .

17. El - Sayed Ibrahim El - Shafey. Complications from repeated injection or puncture of

old polyacrylamide gel implant sites: case reports . Aesth Plast Surg 2008 ; 32 : 162 – 5 .

18. Goldan O , Georgiou I , Grabov - Nardini G , et al. Early and late complications after

a nonabsorbable hydrogel polymer injection: a series of 14 patients and novel

management . Dermatol Surg 2007 ; 33 ; S199 – 206 .

19. Jones DH , Carruthers A , Fitzgerald R , Sarantopoulos P , Binder S . Late - appearing

abscesses after injections of nonabsorbable hydrogel polymer for HIV - associated

facial lipoatrophy . Dermatol Surg 2007 ; 33 : S193 – 8 .

20. Gomez - de la Fuente E , Alvarez - Fernandez JG , Pinedo F , et al. Cutaneous adverse

reaction to Bio - Alcamid Implant . Acta Dermosifi liogr 2007 ; 98 : 271 – 5 .

21. Pacini S , Ruggiero M , Morucci G , et al. Bio - Alcamid: a novelty for reconstructive

and cosmetic surgery . Ital J Anat Embryol 2002 ; 107 : 209 – 14 .

22. Ji J , Zhang W . Bacterial behaviors on polymer surfaces with organic and inorganic

antimicrobial compounds . J Biomed Mater Res A 2009 ; 88 : 448 – 53 .

102 Chapter 8

23. Alijotas - Reig J , Garcia Gimenez V. Delayed immune - mediated adverse effects

related to hyaluronic acid and acrylic hydrogel dermal fi llers: clinical fi ndings, long -

term follow - up and review of the literature . J Eur Acad Dermatol Venereol 2008 ;

22 : 150 – 61 .

24. LaTowsky BC , Wesley NO , MacGregor JL , Kaminer MS , Arndt KA. Delayed infl am-

matory reaction to 4% polyacrylamide gel (Bio - Alcamid) used for soft tissue aug-

mentation . Arch Dermatol in press (December 2009).

25. Karim RB , de Lint CA , van Galen SR , et al. Long - term effect of polyalkylamide gel

injections on severity of facial lipoatrophy and quality of life of HIV - positive patients .

Aesthetic Plast Surg 2008 ; 32 : 873 – 8 .

Artefi ll: the First to Last Adam M. Rotunda Division of Dermatology, David Geffen School of Medicine, University of California, Los Angeles, USA

Rhoda S. Narins Division of Dermatology, New York University School of Medicine, New York, USA

CHAPTER 9

Conventional approaches to facial folds are surgical augmentation or mini-

mally invasive injectables, which until recently have been limited to resorb-

able fi llers. Although medical - grade silicone has been used as a dermal fi ller

for years, widespread acceptance has been limited primarily due to its

nonapproval for this indication. Artefi ll, smartly marketed with the tagline,

“ The First to Last, ” is the fi rst to break conventions. It is the only soft - tissue

fi ller cleared by the US Food and Drug Administration (FDA) in 2006 to

address the unmet need for a nonresorbable fi ller indicated for the correc-

tion of nasolabial folds. Artefi ll is composed of polymethylmethacrylate

(PMMA) microspheres suspended in bovine collagen containing lidocaine.

The unique durability of the product presents safety concerns that are not

germane to the conventional, nonpermanent products discussed in this

textbook. We wish to examine Artefi ll ’ s history and evolution, pivotal trial

effi cacy and safety data, and its uses and limitations in clinical practice.

History

Since Judet introduced PMMA in 1947 as the fi rst hip prosthesis, 1 the

chemical inertness and biocompatibility of the material has been well

accepted. Methylmethacrylate polymers are nontoxic, noncarcinogenic,

and have a melting temperature of 101 ° C. 2 Further investigation in animals

revealed that a key factor of the biocompatibility of dermally implanted

PMMA is the round, smooth shape and size of the microspheres. 3

Dr Gottfreid Lemperle of Germany developed PMMA microsphere tech-

nology for permanent soft - tissue dermal augmentation that was fi rst used in

clinical trials in 1989. 4, 5 Arteplast, the original formulation, was composed

of 32 – 42 μ m PMMA beads suspended in a rapidly resorbed gelatin vehicle,

which was thought to promote intradermal clumping after injection. In

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

103

104 Chapter 9

Figure 9.1 Erythema and atrophy

demonstrated at the site of PMMA

(polymethylmethacrylate) microsphere

granuloma due to intralesional

triamcinolone injections. (Reproduced

from Gelfer A, Carruthers A,

Carruthers J, Jang F, Bernstein SC. The

natural history of

polymethylmethacrylate microspheres

granulomas. Dermatol Surg

2007; 33 :614 – 20 with permission of

Blackwell Publishing.)

1994, Artecoll was developed using a new purifi cation process that reduced

the irregular particle surface contours and disparate PMMA particle size

originally evident in Arteplast. Moreover, the reformulation was intended

to eliminate nanoparticle elements and electrical surface charges found on

the beads by implementing a novel sieving process during manufacturing.

A high rate of Arteplast granulomas (up to 2.5% of the 400 individuals

injected with the original formulation) was likely due to these irregulari-

ties. 4 Non - resorbable particles less than 20 μ m can be phagocytosed and not

degraded, leading histologically 3 to a collection of infl ammatory cells, col-

lagen and “ frustrated macrophages ” (giant cells), which may give rise clini-

cally to infl amed nodules at the site of product placement (Figure 9.1 ).

Since 1994, Artecoll was marketed in Europe by Rofi l Medical

International (Breda, the Netherlands) and has subsequently been used in

more than 200 000 patients. 4 The reported complication rate of that

product was < 0.1%. 4 In 2001, Artecoll was modifi ed so that bovine col-

lagen sourced from a restricted, closed cattle herd in the USA could be

used to reduce risks of prion contamination. Initial investigations of

Artecoll revealed that PMMA particle size with a diameter less than 20 μ m

was < 1% of the formulation. 4 However, subsequent testing by Artes

Medical revealed that particle size with a diameter less than 20 μ m in the

Artecoll distributed in Canada was actually > 30%. 6 These particles are the

most likely reason for numerous reports of Artecoll granulomas reported

in Canada, 6 where the product has been approved since 1998. Therefore,

in 2003, despite previous failed attempts aimed at eliminating nanosized

particles, a second - generation Artecoll was produced to ensure that par-

ticles smaller than 20 μ m were < 1% of the PMMA in the formulation. The

proportion of particles smaller than 20 μ m is considered undetectable in

the Artefi ll available in the USA. 7

In addition to a history of reformulations and product refi nements, all

of which had not inspired confi dence in this fi ller technology, over a

Artefi ll: the First to Last 105

period of about 6 years multiple versions of PMMA (with similar sounding

names) have been manufactured. 8 PMMA bead suspensions have been

available for use at various locations across the globe for about a decade.

Numerous manufacturers, producing slightly different products, have sold

to licensed practitioners most commonly in Brazil, the European Union

(EU), Canada and the USA.

A study sponsored by Artes Medical using scanning electron micros-

copy (SEM) demonstrated the varied particle shapes, surface fi nishes,

particle size anomalies and gross size distributions of related PMMA prod-

ucts available worldwide at different time points. 8 Table 9.1 summarizes

their fi ndings.

Table 9.1 Summary of scanning electron microscopy ( SEM ) fi ndings

Product Country of Origin

SEM Analysis (Particle shape, surface fi nish,

size, gross size distribution, and anomalies)

ArteFill (Year 2007) USA • Size: 30 to 50 microns, with negligible

small sizes.

• Shape: Smooth surfaced microspheres with

scant if any sediment.

Artecoll (Year 2005) Canada • Size: 30 to 50 microns, with negligible

small sizes.

• Shape: Smooth surfaced microspheres with

slight surface irregularity, scant if any

sediment.

Artecoll (circa 2001) Europe • Size: 32 to 40 microns, but with larger

variation in particle sizes.

• Shape: presence of nanoparticles on the

surface of mincrospheres.

• There are sub - 20 micron particles and some

sub 5 micron particles noted with some

sediment.

Metacrill (circa 2006) Brazil • Size: 0.2 to 60 microns. Many sub - 20

micron particles exist, and many are sub - 5

micron.

• Shape: Many irregular shapes, some non

spherical, jagged edges, poor surface.

NewPlastic (circa 2006) Brazil • Size: 0.2 to 70 microns. Some large spheres

over 70 microns and some very small

particles.

• Shape: Some are non spherical, and

conjoined, may small spheres and particles

exist.

Reproduced from Piacquadio D, Smith S, Anderson R. A comparison of commercially available

polymethylmethacrylate - based soft tissue fi llers. Dermatol Surg 2008; 34 :S48 – 52 with permission

of Blackwell Publishing.

106 Chapter 9

It is apparent that the diversity and inconsistency of the PMMA beads

synthesized over the past decade could induce marked differences in safety

profi les and performance of these products. Although the nonuniformity

in the non - US products has been documented to adversely impact bio-

compatibility and migration, 3 the direct impact of the PMMA characteris-

tics in one specifi c version of the product has not been compared with

those of another version in well - controlled clinical trials.

The PMMA available in Brazil as Metacrill and NewPlastic has a

signifi cantly varied particle size and surface characteristics relative to

the 2007 Artefi ll now available in the USA. 8 A survey of SEM fi ndings

reveal the progressively uniform particle size and surface regularity

as one contrasts PMMA products from Brazil (Figure 9.2 ), Artecoll

and Artefi ll from Canada (Figure 9.3 ), and, lastly, Artefi ll available in

Figure 9.2 Upper two images: SEM (scanning electron microscopy) fi ndings of

PMMA (polymethylmethacrylate) from Brazil, circa 2006 (Metacrill). Lower two

images: SEM fi ndings of PMMA from Brazil, circa 2006 (NewPlastic). (Reproduced

from Piacquadio D, Smith S, Anderson R. A comparison of commercially available

polymethylmethacrylate - based soft tissue fi llers. Dermatol Surg 2008; 34 :S48 – 52 with

permission of Blackwell Publishing.)

Artefi ll: the First to Last 107

Figure 9.3 Upper two images: SEM fi ndings of PMMA (polymethylmethacrylate)

from Canada, year 2005 (Artecoll). Lower two images: SEM fi ndings of PMMA from

Canada, year 2007 (Artefi ll). (Reproduced from Piacquadio D, Smith S, Anderson R.

A comparison of commercially available polymethylmethacrylate - based soft tissue

fi llers. Dermatol Surg 2008; 34 :S48 – 52 with permission of Blackwell Publishing.)

the USA (Figure 9.4 ). The pivotal trial submitted to review by the

FDA used Artecoll, with differences from Artefi ll that are highlighted in

Table 9.2 .

It is likely that a history of reformulations, name changes and varied

manufacturers have led to great confusion and skepticism about the

safety of Artefi ll among clinicians already wary of permanent fi llers.

Unfortunately, the disrepute of non - US PMMA deriving primarily from

reports of granulomas 6,9 – 13 has led to a similar sentiment towards

PMMA manufactured in the USA. However, potentially positive out-

comes from a large (1000 patient), long - term, prospective study inves-

tigating the safety and effi cacy of Artefi ll, initiated in August 2008,

may reinvigorate interest in the product and provide momentum for

108 Chapter 9

Figure 9.4 SEM (scanning electron microscopy) images of PMMA

(polymethylmethacrylate) from the USA, year 2007 (Artefi ll). (Reproduced from

Piacquadio D, Smith S, Anderson R. A comparison of commercially available

polymethylmethacrylate - based soft tissue fi llers. Dermatol Surg 2008; 34 :S48 – 52 with

permission of Blackwell Publishing.)

Table 9.2 Third - generation PMMA enhancements compared with second - generation

ones

3rd Generation 2nd Generation

Distributor/Manufacturer Artes Medical Dedicated U.S. GMP

manufacturing facility

Rofi l Medical (Netherlands) European Medical Contract

Manufacturing

Composition 20% PMMA suspended in 80% bovine collagen gel, 0.3% lidocaine

PMMA

Characteristics

Round & smooth surface

Uniform size

Removal of PMMA microsphers < 20 microns

Round & smooth surface

Non-uniform size

Regulatory Status FDA approved (October 2003)

Not FDA approved, not in U.S. clinical trials

Reproduced from Cohen SR, Berner CF, Busso M, et al. Five - year safety and effi cacy of a novel

polymethylmethacrylate aesthetic soft tissue fi ller for the correction of nasolabial folds.

Dermatol Surg 2007; 33 :S222 – 30 with permission of Blackwell Publishing.

Artefi ll: the First to Last 109

manufacture and use in the USA in the future. Artes Medical, Inc.

(San Diego, CA) fi led for Chapter 7 Bankruptcy on December 1, 2008,

yet Artefi ll was recently acquired by Suneva Medical, Inc. (San Diego,

CA). We anticipate that the company will rejuvenate Artefi ll and in

doing so seek additional data to alleviate safety concerns and support

the effi cacy of its product.

Mechanism

Artefi ll consists of a 20% (by vol) semisolid blend of smooth - surfaced

PMMA microspheres ranging in size from 30 μ m to 50 μ m suspended in

an 80% (by vol) gel matrix of partially denatured bovine collagen gel, with

0.3% lidocaine hydrochloride. In accordance with FDA requirements,

< 1% of the PMMA particles are < 20 μ m, with the rest consisting of 32 - to

40 - μ m beads. 7

The proposed mechanism of action of the device is based on the PMMA

microsphere ’ s ability to stimulate the host ’ s immune response to induce

fi broblast neocollagenesis on and in between the microspheres. Over a

period of 1 – 3 months, new collagen serves to replace the short - lived

bovine collagen composing most of the injected material. This sequence

of events leads, in turn, to a composite of the patient ’ s own collagen

interspersed with the nonresorbable PMMA microspheres, thereby pre-

venting bead migration. 3 Therefore, tissue augmentation is expected to be

permanent, consisting of 80% (by vol) host connective tissue. Correction

of volume defi cits occurs gradually, over the two or three injection

sessions spanning several months, rather than after one injection session

typical of most resorbable fi llers. This stepwise treatment avoids perma-

nent overcorrection. In all cases of injection, the material is injected into

the deep, reticular dermis in order to avoid the nodularity and irregularity

commonly seen with superfi cial placement.

Safety and e ffi cacy

Effi cacy The pivotal trial submitted to the FDA using the second - generation pred-

ecessor to Artefi ll, named Artecoll, was completed in September 2001. 4

It was a randomized, double - blind, controlled study at eight US treat-

ment centers which included 251 individuals using PMMA ( n = 128)

compared with a collagen control (Zyderm II/Zyplast, Inamed Aesthetics,

Santa Barbara, CA, n = 123). Product effi cacy was determined using a

validated six - point, facial fold assessment (FFA), photonumeric grading

110 Chapter 9

scale at four anatomical sites. Either a control substance or Artecoll

was injected in the glabellar folds, nasolabial folds, vertical lip lines,

and marionette lines (corner of the mouth). The FFA, a photometric

index rating wrinkle severity ranging from 0 (none) to 5 (severe), was

determined in a randomized manner and raters were not informed

of the evaluation period (pre - or post - treatment). The mean score of

the FFA of all the facial sites, graded by three blinded, independent

graders using standardized photographs, was designated as the primary

endpoint. At all times, for those patients treated bilaterally, such as in

the nasolabial folds, scores were averaged yielding one score per patient

used for analysis.

At the end of the study, the number of patients receiving treatment to

each of the facial areas was not signifi cantly different between the Artecoll

and the control group. Most patients (108 vs 104 of the Artecoll and col-

lagen groups, respectively) received treatment to the nasolabial folds.

At 1 month, there were no signifi cant differences for any site except

for the control group, where the glabellar wrinkles appeared more

improved compared with Artecoll. However, at 3 months, nasolabial fold

and marionette lines were signifi cantly better than for the controls, but

the overall FFA was not signifi cant between the two treatments. At 6

months, Artecoll was signifi cantly better than the control substance at the

nasolabial folds and overall.

Individuals receiving the PMMA fi ller displayed signifi cant nasolabial

fold correction at 3, 6, and 12 months relative to the collagen control at

similar time points ( p < 0.001). This was observed despite smaller quanti-

ties of the fi ller utilized than in the collagen controls patients (0.82 mL/

fold vs 1.46 mL/fold, p < 0.001, respectively). In fact, the effi cacy of the

collagen fi ller disappeared by 6 months. Further, the PMMA fi ller dem-

onstrated nasolabial fold correction for both the primary and secondary

measures at 12 months ( p < 0.001).

Given the underlying long - term safety concern for this novel fi ller, of

interest is a 5 - year safety study conducted by the sponsor, Artes Medical,

to better defi ne product safety. 7 Using the cohort of patients treated in

the original pivotal trial, the primary objective of this study was to

determine effi cacy for nasolabial folds based on the blinded FFA evalu-

ations, as well as safety using unanticipated event evaluations. Study

candidates were those patients initially treated with PMMA ( n = 128)

plus those in the collagen control group who elected at 6 months to

crossover into the PMMA fi ller therapy ( n = 106) for a total of 234

potential participants.

The eight original investigators contacted these individuals 5 years from

their last treatment by telephone or certifi ed letter who were asked to

participate in a single follow - up visit, where numerous assessments were

Artefi ll: the First to Last 111

performed. Although the photos at 6 months were previously evaluated

at the time of the clinical trial, they were graded once again by three

independent physicians (dermatologists or plastic surgeons) to minimize

drift bias. Photographs used for the FFA at the 6 - month time point were

evaluated and compared with photos of the nasolabial folds at the new

5 - year follow - up (performed under similar conditions) and provided in

random order to the assessing physicians in the same session. These

evaluations were performed blinded to the time point and treatment of

the participants and averaged. Change from pre - treatment to 6 months

was computed using the original (pivotal trial) set of 6 - month photograph

ratings. Change from 6 months to 5 years was computed using the new

set of 6 - month photograph ratings and the cumulative improvement was

computed by summing these two changes. Investigators were asked at

the visit to determine on a 5 - point scale the success of the PMMA fi ller

treatment, using an ordinal scale ranging from “ not at all successful ” to

“ completely successful. ” In addition, patients were requested to rate

themselves as “ very dissatisfi ed ” to “ very satisfi ed. ”

From the original study, 62% or 145 individuals responded to the

inquiries for their participation, of whom 142 were eligible for evaluation

(15 men, 127 women, mean age 52.4 years). Most individuals were from

their original PMMA treatment group (82) and 60 from the crossover

group. The mean follow - up period was 5.4 years from their last treatment

(range 4.5 – 6.3 [excluded from analysis] years). Although multiple

anatomical sites were treated during the original pivotal trial, this long -

term study focused only on the nasolabial folds, for which 124 of the 142

participants had treated. Most treatments were bilateral.

This long - term effi cacy study determined convincingly that PMMA

fi ller is indeed permanent (Figures 9.5 and 9.6 ). The mean clinical

Figure 9.5 Male patient, before and after photos – baseline to year 5. This man had

no additional cosmetic procedure during the 5 - year follow - up period. (Reproduced

from Cohen SR, Berner CF, Busso M, et al. Five - year safety and effi cacy of a novel

polymethylmethacrylate aesthetic soft tissue fi ller for the correction of nasolabial

folds. Dermatol Surg 2007; 33 :S222 – 30 with permission of Blackwell Publishing.)

112 Chapter 9

VerySuccessful N=50

Satisfied N=31

ModeratelySuccessful N=8

SomewhatSatisfied N=9

SomewhatSuccessful N=3

Dissatisfied N=3

Not at AllSuccessful N=1

Very Dissatisfied N=0

CompletelySuccessful N=61

Very Satisfied N=80

Investigators’ Ratings N=123 Subjects’ Ratings N=123

Figure 9.7 Investigators ’ success ratings at Year 5 (left) and Subjects ’ satisfaction

ratings at year 5 (right). (Reproduced from Cohen SR, Berner CF, Busso M, et al.

Five - year safety and effi cacy of a novel polymethylmethacrylate aesthetic soft tissue

fi ller for the correction of nasolabial folds. Dermatol Surg 2007; 33 :S222 – 30 with

permission of Blackwell Publishing.)

Figure 9.6 Female patient, before and after photos – baseline to year 5. This woman

had no additional cosmetic procedure during the 5 - year follow - up period.

(Reproduced from Cohen SR, Berner CF, Busso M, et al. Five - year safety and effi cacy

of a novel polymethylmethacrylate aesthetic soft tissue fi ller for the correction of

nasolabial folds. Dermatol Surg 2007; 33 :S222 – 30 with permission of Blackwell

Publishing.)

improvement, as graded by live assessment by the live (unblinded) inves-

tigator, was 1.67 (on the 5 - point FFA scale) and 1.01 by the blinded

evaluations of the photographs. The PMMA maintained signifi cant

improvement in all evaluated patients ( n = 119) at 5 years compared

with baseline (note that fi ve patients were excluded due to missing

photographs). Ninety percent of the investigators reported “ completely

successful ” or “ very successful ” and, similarly, 90% of patients were “ very

satisfi ed ” or “ satisfi ed ” with the treatment (Figure 9.7 ).

Artefi ll: the First to Last 113

There is evidence that, over time, the fi ller improves in performance

(Figure 9.8 ). Blinded observer improvement in the FFA was 0.2 point

higher at the 5 - year photograph assessments than at the 6 - month FFA

assessments of the nasolabial folds ( p < 0.002).

Safety It is generally agreed that permanent fi llers expose patients to certain

potential long - term risks that are not encountered with the use of resorb-

able fi llers. Artes Medical has investigated the product characteristics of

nonstandardized, less stringently regulated products containing PMMA,

and it has acknowledged that these disparities from the current US -

produced Artefi ll are likely responsible for the generally unfavorable

opinion that clinicians have for its product. 8 As is true for pharmaceutical

drugs, devices such as fi llers are subject to varied regulatory standards and

requirements across the globe. The most stringent preclinical, clinical, and

manufacturing standards are upheld in the USA. In the EU, on the other

hand, referenced data and relatively small human safety and effi cacy trials

are required for device approval and, in countries outside the EU and the

USA, the pathway to drug and/or device approval is generally less

stringent.

1.2

1

0.8

0.6

0.4

0.2

0

Mas

ked

Obs

erve

r R

ated

FFA

Sca

le Im

prov

emen

tA

B

PMMAControl

1 m

onth

1 Yea

r

5 Yea

rs

3 m

onth

s

5 m

onth

s

⎫⎪⎬⎪⎭

⎫⎪⎪⎪⎪⎬⎪⎪⎪⎪⎭

Figure 9.8 (a) PMMA (polymethylmethacrylate) fi ller shows marked improvements

over collagen control at 6 months ( p < 0.001). (b) Continuous improvement of

PMMA fi ller ratings between 6 months (0.71) and 5 years (1.01, p < 0.001).

(Reproduced from Cohen SR, Berner CF, Busso M, et al. Five - year safety and effi cacy

of a novel polymethylmethacrylate aesthetic soft tissue fi ller for the correction of

nasolabial folds. Dermatol Surg 2007; 33 :S222 – 30 with permission of Blackwell

Publishing.)

114 Chapter 9

Granulomas can occur after any injectable fi ller, 12 and their incidence

been estimated to be 1:100 – 1:5000 injected patients. 9 The time period

between injection and granulomas reported with Artecoll has ranged

anywhere between 6 months and 10 years. 9 They are characterized by

rapid - onset, swollen, erythematous, typically tender nodules at one or

more of the injected sites. These should be distinguished clinically from

true lumps and nodularity, which may occur at sites injected “ overenthu-

siastically ” 6 (too much volume) or too superfi cially. The development of

a biofi lm should also be considered with any injectable, and an antibiotic

should be tried as the fi rst line of treatment. The lips are particularly prone

to nodules and perhaps granulomas 6,13 (Figure 9.9 ). This may be due to

the intense power of the lip muscle which forces the material into lumps.

Impurities and irregularities in the fi ller are thought to be responsible for

noninfectious PMMA granulomas.

The pivotal trial submitted to the FDA cited above revealed a compara-

ble, statistically insignifi cant , adverse event profi le between the collagen

control and Artecoll. 4 There were a total of 27 adverse events (of 128

individuals) in the Artecoll groups versus 38 events (of 123 individuals)

in the control group. In general, there was more redness, lumpiness, and

swelling in the control group. Serum immunoglobin G levels, used to

detect allergy to the bovine collagen in both products, was elevated in one

person using Artecoll after 1 month only, and in one person in the col-

lagen control after 1, 3, and 6 months.

The 5 - year safety study revealed no serious or unanticipated adverse

events, yet 28 cases of adverse events (in 21 individuals) among the 145

participants were recorded. 7 Of these, 20 treatment - related events were

experienced by 15 participants. Most events (80%) were mild in nature

and consisted of “ lumpiness ” in 10 of the 15 treatment - related adverse

events. Most notable were two cases of “ granuloma or enlargement of the

implant ” based on clinical, not histological, observation. One of these cases

Figure 9.9 PMMA

(polymethylmethacrylate) microsphere

granulomas in the upper lip.

(Reproduced from Gelfer A, Carruthers

A, Carruthers J, Jang F, Bernstein SC.

The natural history of

polymethylmethacrylate microspheres

granulomas. Dermatol Surg

2007; 33 :614 – 20 with permission of

Blackwell Publishing.)

Artefi ll: the First to Last 115

was someone who reported both moderate severe lumps in the melolabial

fold and lip 6 months after the last injection. Excision was required for

fi nal resolution. In another patient, who had a nodule in each of the

nasolabial folds 5 years after PMMA injection, intralesional steroid injec-

tion was only moderately effective at reducing these “ severely ” infl amed

reactions. However, we do not know the concentration of triamcinolone

used. The concentration of intralesional steroid needed to treat these

lumps is usually high (40 mg/mL triamcinolone). The patient has to be

warned of possible temporary atrophy which can then be treated with a

temporary fi ller.

In sum, the short - and long - term data available from well - controlled

clinical trials do not suggest any prevailing safety concern. Nevertheless,

it may be some time before clinicians are comfortable with the fact that

Artefi ll represents a new class of durable, permanent fi llers that satisfi es

an unmet need, rather than a source of needless, potentially permanent

adverse events.

The safety data reviewed reveal that Artefi ll shares a comparable safety

profi le with that of the other soft - tissue dermal fi llers (i.e. specifi cally

hyaluronic acids and calcium hydroxylapatite). Moreover, granulomatous

and localized infl ammatory nodules have been documented with these

other nonpermanent fi llers. 9,12 The caveat to this discussion, however, is

that experience with Artefi ll in the USA is relatively limited. With contin-

ued use, the refi ned, third - generation PMMA product (Artefi ll) may reveal

an even lower risk profi le than that observed in the long - term studies with

Artecoll. Nevertheless, as with the other fi llers, resorbable or not, and the

broadened use to other anatomical sites and to a diverse injector popula-

tion (presenting varied training and techniques), we may perhaps learn

of additional adverse events anecdotally and in the peer - reviewed scien-

tifi c literature.

Practical a pplications

Although the FDA has approved Artefi ll for correction of nasolabial folds,

unlike some of the other resorbable fi llers, the pivotal trial submitted to

the FDA has demonstrated that Artefi ll can also be used safely and effec-

tively in other locations, yet these anatomical areas are still considered

off - label. Clinicians are using Artefi ll to augment volume defi cits in the

malar and submalar areas as a result of HIV or senescence, as well as

placing Artefi ll in acne scars and along the nasal dorsum as a minimally

invasive means to shape the nasal profi le. Truth be told, Artefi ll is being

used in a manner similar to other dermal fi llers; however, it is prudent to

avoid injecting the product in the tear troughs and vermillion lip.

116 Chapter 9

Ideal patients are those who have used dermal fi llers in the past. In our

experience, patients who are very comfortable conceptually with facial

augmentation, and those who have experienced localized reactions

common to all injectables, are the most suitable for permanent fi llers.

Otherwise, the concern about any local response may be compounded

with an additional fear resulting from the fi ller ’ s permanence. Whether

there are localized anticipated reactions such as transient redness and

swelling common to all fi llers, or a more serious problem as a result of

treatment, the ‘ experienced ’ fi ller patient will generally be better equipped

to manage the situation with the physician. Furthermore, the authors

believe that Artefi ll is best used by experienced physician injectors only,

such as those who have previously treated several hundreds of patients

with nonpermanent fi llers.

Although the approach to injection with Artefi ll is similar to other

dermal fi llers, unlike the more “ forgiving ” collagen - based, or even

hyaluronic acid - based, fi llers for that matter, it is particularly technique

sensitive. Before treatment with the currently available product, patients

should be tested for allergy to bovine collagen, although, in the future,

additional product refi nements may eliminate the need for allergy testing

in the product. Localized redness and swelling after placement of the

product on the volar aspect of the forearm, or other easily visualized site,

2 weeks before facial injection will determine pre - existing allergy. If the

patient is not allergic, the following steps are used:

1. The facial site is fi rst gently cleansed with isopropyl alcohol or hydrogen

peroxide.

2. A topical anesthetic, such as EMLA (2.5% lidocaine and 2.5% prilo-

caine, AstraZeneca, Wilmington, Delaware) or other topical anesthetic

formulation can be applied to the skin for 20 – 30 minutes. This will be

wiped off immediately before injection only into the facial side to be

treated. The other side can be left covered until immediately before

injection. Some clinicians prefer the use of an icepack directly on the

skin for several seconds before injection. Should the white roll (where

the vermillion [red] lip meets the cutaneous upper lip) be treated, local

mental and infraorbital nerve block may be used. The red part (vermil-

lion) or body of the lips, as well as the tear troughs, should not be

injected.

3. The desired depth is deep dermis (reticular dermis)/upper subcutane-

ous fat layer (Figure 9.10 ) using a tunneling method, where the product

is continuously injected while the needle is moved back and

forth beneath the wrinkle at a fi xed level (Figure 9.11 ). Injection

technique preferences vary between clinicians, but in general the

tunneling method, rather than serial injection or the depot technique,

Artefi ll: the First to Last 117

is recommended. Crosshatching and fanning, common techniques used

with the other fi llers, are employed.

4. As the viscosity of Artefi ll is several times higher than collagen and

other hyaluronic acid fi llers used for dermal fold augmentation, a 27G

or even a 26G half - inch needle is used. Some clinicians test the patency

of the needle by injecting a small quantity of product from the tip

before implantation.

5. As with other fi llers, blanching of the skin means that injection was

too superfi cial and therefore the needle should be withdrawn and the

blanched area immediately massaged. Deep placement at the subcuta-

neous/deep dermal junction appears to avert lumps and other surface

irregularities seen using more superfi cial placement.

6. At the end of the injection, the skin should be gently massaged. Patients

are advised not to massage the area at home, but they can be instructed

Figure 9.10 The recommended

method of Artefi ll injection. The

product is placed in the deep dermis/

subcutaneous fat interface and

tunneled proximally. (Reproduced with

permission from Artes Medical.)

Figure 9.11 Before and after Artefi ll placement. Tunneling rather than serial

injection or depot injection is recommended for facial lines. (Reproduced with

permission from Artes Medical.)

118 Chapter 9

to apply a cold pack on the injected sites for 10 minutes every hour for

several hours at home.

7. Mild - to - moderate swelling will be apparent for 12 – 24 hours and mild

erythema or pink color will be present for up to 5 days after injection.

Bruising is variable (and may occur more often and with greater sever-

ity in patients who use over - the - counter herbal products, NSAIDs, fi sh

oil, vitamin E, and aspirin or other blood thinners), but patients should

be forewarned. The bruising is certainly less than with hyaluronic acid

and more similar to that seen with collagen products.

8. Patients are best seen at 4 weeks after the initial treatment (some clini-

cians recommend a 2 - week follow - up) to allow for additional adjust-

ments and fi lling. Additional follow - up and treatment may occur over

a span of several months to allow for gradual fi lling and correction as

the patient ’ s collagen scaffolds the PMMA bead.

Approach to g ranulomas

Numerous techniques have been described to treat PMMA - induced, non -

infectious granulomas, 9 – 13 a testament to the fact that none of these

methods has been deemed most effective, although high - dose intralesional

steroids appear to be the most reasonable fi rst - line therapy. Steroids such

as triamcinolone acetonide (Kenalog), methylprednisolone acetonide

(Depo - Medrol), and betamethasone diproprionate (Diprosone) have been

used. Dermal and fat atrophy (see Figure 9.1 ) after intralesional steroid

injection is a treatment risk that should be discussed, but atrophy risk can

be mitigated by relatively deep injection (should the granuloma similarly

appear deep) along with using low volumes of high - dose steroids. It is our

experience that very high doses if triamcinolone acetonide, as noted above

– up to 40 mg/mL – are most effective.

Other injectable therapy consists of combinations of steroids, Diprosone

and 5 - fl uorouracil (5FU), and lidocaine. 10 Alternatively, intralesional bleo-

mycin is a theoretical therapy, 6 and intralesional allopurinol has been

reported to be effective for Arteplast granulomas. 11 Systemic use of NSAIDs

such as ibuprofen, antibiotics such as minocycline or cephalexin, and

corticosteroids have also been used, as have tacrolimus, imiquimod, and

antihistamine creams. 6 A recent report describes resolution of Metacrill -

induced lip and hand nodules after melting them with a high - frequency

100 - watt probe, but this has not been met with enthusiasm. 13 Multiple

hard nodules of Metacrill treated by one of the authors (RN) responded

only to 40 mg/mL triamcinolone, suggesting that indeed perhaps small

aliquots of high - dose intralesional steroids could be considered the most

effective fi rst - line therapy for PMMA - induced granulomas.

Artefi ll: the First to Last 119

Although PMMA granulomas are relatively uncommon, it is a major

concern for both clinicians and patients. It has been conjectured that these

reactions are self - limited and eventually self - resolving. 6 It is not agreed

whether excision causes more harm (scarring) than good (removal). 6,13

Regardless, close follow - up is a prudent and ethical medical practice,

as careful attention and involvement by the physician to the care of a

dissatisfi ed aesthetic patient build trust and reassurance, and avert medi-

colegal consequences in most cases.

Summary

There is an increasing desire for facial augmentation with injectable dermal

soft - tissue fi llers. With this interest is a vocal minority of patients who

express desire for permanent tissue augmentation. Artefi ll currently fi lls

this need and delivers an overwhelmingly satisfactory outcome for patients

willing to use it, and physicians trained to inject it. Nevertheless, the rela-

tively limited experience with Artefi ll in the USA and its permanence

mandate meticulous technique and an experienced hand. Despite a rela-

tively tarnished past, one complicated by reports of granulomas and vari-

able manufacturing standards, the FDA - approved product has met rigorous

safety standards and has thus far delivered on its promise of a safe and

effi cacious permanent fi ller. Over time, we feel that clinicians and patients

will feel more comfortable with the concept of “ permanence. ” And further,

we will come to appreciate that aging will not leave these or any other

permanent “ implants ” apparent for the world to see. Although the future

of Artefi ll ’ s availability in the USA is ambiguous, it may prove, in the long

run, the benchmark standard in this novel class of fi llers.

References

1. Judet J. Prostheses en resins acrylic . Mem Acad Chir 1997 ; 73 : 561 .

2. Polymers and Monomers . Material safety data sheet (MSDS) Poly(methylmethacrylate)

MW6000 to MX 350000 . Obtained online at www.polymersciences.com/shop/

product/asp?dept%5Fid=300107&pf%5Fid=04552

3. Lemperle G , Morhenn VB , Pestonjamasp V , Gallo RL . Migration studies and histol-

ogy of injectable microspheres of different sizes in mice . Plast Reconstr Surg

2004 ; 113 : 1380 – 90

4. Cohen SR , Holmes RE . Artecoll: a long - lasting injectable wrinkle fi ller material:

Report of a controlled, randomized, multicenter clinical trial of 251 subjects . Plast

Reconstr Surg 2004 ; 114 : 964 – 76 .

5. Lemperle G , Romano JJ , Busso M . Soft tissue augmentation with Artecoll: 10 - year

history, indications, techniques, and complications . Dermatol Surg 2003 ; 29 : 573 – 87 .

120 Chapter 9

6. Gelfer A , Carruthers A , Carruthers J , Jang F , Bernstein SC . The natural history of

polymethylmethacrylate microspheres granulomas . Dermatol Surg 2007 ; 33 : 614 – 20 .

7. Cohen SR , Berner CF , Busso M , et al. Five - year safety and effi cacy of a novel

polymethylmethacrylate aesthetic soft tissue fi ller for the correction of nasolabial

folds . Dermatol Surg 2007 ; 33 : S222 – 30 .

8. Piacquadio D , Smith S , Anderson R . A comparison of commercially available

polymethylmethacrylate - based soft tissue fi llers . Dermatol Surg 2008 ; 34 : S48 – 52 .

9. Lemperle G , Rullan PP , Gauthier - Hazan N. Avoiding and treating dermal fi ller

complications . Plast Reconstr Surg 2006 ; 118 : 92S – 107S .

10. Conejo - Mir JS , Sanz Guirado S , Angel Mu ñ oz M. Adverse granulomatous reaction

to Artecoll treated by intralesional 5 - fl uorouracil and triamcinolone injections .

Dermatol Surg 2006 ; 32 : 1079 – 81

11. Reisberger EM , Landthaler M , Wiest L , Schr ö der J , Stolz W . Foreign body granulo-

mas caused by polymethylmethacrylate microspheres: successful treatment with

allopurinol . Arch Dermatol 2003 ; 139 : 17 – 20 .

12. Carruthers A , Carruthers JD . Polymethylmethacrylate microspheres/collagen as a

tissue augmenting agent: personal experience over 5 years . Dermatol Surg

2005 ; 31 : 1561 – 4 .

13. Odo MEY , Odo LM , Nemoto NCF , Cuc è LC . Treatment of nodules caused by

polymethylmethacrylate. A pilot study . Dermatol Surg 2008 ; 34 : 1746 – 9 .

Complications from Soft - Tissue Augmentation of the Face: A Guide to Understanding, Avoiding, and Managing Periprocedural Issues Marc D. Glashofer Island Dermatology, Long Beach, New York, USA

Joel L. Cohen AboutSkin Dermatology and DermSurgery, and Department of Dermatology, University of Colorado, Englewood, Colorado, USA

CHAPTER 10

The use of soft - tissue augmentation agents has increased in popularity as

more individuals are seeking nonsurgical procedures for age - related reju-

venation. This has been driven by an aging population looking for aes-

thetic results that are minimally invasive and with little down time. It has

been over 20 years since the approval of the fi rst dermal fi ller, with the

majority of the currently marketed fi ller agents approved in the last 5 – 18

years. According to a survey conducted in 2007 by the American Society

for Dermatologic Surgery, over 1 million injections of dermal fi llers were

administered in 2007, representing a signifi cant increase over previous

years. 1 These agents are increasingly being utilized in our practices due in

large part to their effectiveness and versatility, and the availability of mul-

tiple new options. Their favorable safety profi les also contribute to the

popularity of these products. 2,3 Despite their impressive safety record,

complications and adverse events can occur. The number of complications

is likely to increase as new products become available, more people begin

seeking this type of intervention, and more injectors begin providing these

services. In particular, there has recently been an alarming trend of

increasing numbers of untrained physicians and practitioners who do not

have an MD using these products. 4

In November 2008 an executive summary from the Food and

Administration ’ s (FDA ’ s) Offi ce of Device Evaluation expressed their

concern over growing reports being fi led to their offi ce about “ adverse

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

121

122 Chapter 10

events with dermal fi ller agents, with a number that are serious and unex-

pected. ” Some of these adverse events included facial, lip, and eye palsy,

disfi gurement, retinal vascular occlusion, as well as rare, but life - threaten-

ing, events such as severe allergic reactions and anaphylactic shock. 5 One of

the reasons why the FDA is concerned about an increase in complications

is as a result of consumer demand for fi llers that are being used outside of

approved indications. The exact incidence of complications is unclear to the

FDA, as clinical trials are usually designed to continue for only 6 months,

whereas some adverse events, which typically occur and resolve shortly

after injection, were found to have a delayed onset and long - lasting serious

effects. As a result, the FDA is considering that warnings on product labels

for dermal fi llers be strengthened, and require manufacturers to conduct

longer and larger studies to be submitted as part of product approval appli-

cation. Another concern that dermatologists need to be aware of is the use

of counterfeit fi ller agents. It cannot be emphasized enough that acquiring

these agents from sources outside their approved US distributors can lead

to an adulterated product with the potential for serious complications. To

ensure the best possible outcomes and greatest patient satisfaction, the aes-

thetic physician who injects dermal fi llers must have proper training in

their use, be aware of the types of complications, be able to anticipate

adverse effects, and know how to treat them if they do occur. When a fi ller

is being used in an off - label manner, it is of even greater signifi cance that

this be disclosed and associated risks discussed with the patient.

The types of materials approved as soft - tissue augmentation agents

vary from biologic to synthetic materials. Currently available fi ller prod-

ucts can be categorized by duration of effect: temporary (approximately

4 – 9 months), temporary - plus (duration up to 18 months), and permanent

options (Box 10.1 ).

All fi llers are associated with the risk of both early and late complica-

tions (Box 10.2 ). The treating physician and patient need to be aware of

these before their implementation.

Injection s ite r eactions

The most common adverse events associated with fi llers are local injection

site reactions. These are usually manifested by pain, erythema, and edema.

In one study comparing hyaluronic acid (Restylane) with collagen (Zyplast)

for the treatment of nasolabial folds on contralateral sides, injection

site reactions occurred at 93.5% and 90.6% of the hyaluronic acid - and

collagen - treated sites, respectively. 6 These reactions were predominantly

mild or moderate in intensity, lasted less than 7 days, and were generally

similar between treatments.

Complications from Soft-Tissue Augmentation of the Face 123

Box 10.2 Onset of adverse events Early (occurring up to several days post treatment)

• Injection site reactions: erythema, edema, ecchymosis , pruritus, tenderness

• Skin discoloration: erythema, blue appearing papules, blanching of skin

• Infection: erythema, edema, pain, fl uctuant masses, possible systemic symptoms

• Hypersensitivity: erythema, angioedema, nonfl uctuant nodules

• Nodularities: caused by inappropriate placement of product

• Tissue necrosis and venous congestion: secondary to vascular compromise

Delayed (occurring from weeks to years post - treatment)

• Infection: erythema, edema, pain, systemic symptoms

• Granuloma formation: persistent palpable or visible nodules

• Migration of product or product clumping

• Aseptic abscess or biofi lm reaction

• Persistent discoloration and hyperpigmentation

• Persistent scarring

Adapted from Lowe, NJ, et al. Adverse reactions to dermal fi llers: Review. Dermatol Surg

2005; 31 :1616 – 25.

Pain is often one of the commonly reported adverse events associated

with fi ller agents. Certain anatomical sites such as the lips, perioral region,

and infraorbital skin are more sensitive as a result of increased sensory

innervation of these sites. There are a variety of techniques that can be

Box 10.1 Common dermal fi llers Temporary Bovine collagen (Zyderm, Zyplast, Allergan, Inc., Santa Barbara, CA) Human collagen (CosmoDerm, CosmoPlast, Allergan, Inc., Santa Barbara, CA) Porcine collagen (Evolence) Hyaluronic acid (Restylane, Medicis Aesthetics, Inc., Scottsdale, AZ; Juv é derm,

Allergan, Inc., Santa Barbara, CA; Prevelle Silk, Genzyme, Inc., Ridgefi eld, NJ) Calcium hydroxylapatite (Radiesse, BioForm Medical, Inc., San Mateo, CA) Autologous fat

Temporary - Plus Poly - L - lactic acid (Sculptra, Dermik Laboratories, Berwyn, PA)

Permanent Collagen + polymethylmethacrylate (Artecoll/ArteFill, Suneva Medical, Inc., San Diego, CA) Silicone (Adatosil 5000, Bausch & Lomb, Rochester, NY; Silikon 1000, Alcon

Laboratories, Fort Worth, TX)

124 Chapter 10

used to minimize pain associated with injections. These include the use of

topical anesthetics, application of ice before and after the injection, local

nerve blocks, and vibratory distraction. 7 In addition, it is known that larger

needles cause more tissue injury and thus cause a greater degree of injec-

tion discomfort. Utilizing the smallest diameter needle recommended in

the product insert (usually a 30G for many products) to properly place the

product is advocated. When writing this chapter, Prevelle Silk had recently

been introduced to the US market with the goal of minimizing the pain

associated with injection because it has been formulated with a local anes-

thetic. Several other products that contain anesthetic are likely coming to

the USA, including Juv é derm plus lidocaine.

As these injection site reactions are fairly common and somewhat pre-

dictable, patients should be informed of them in consultation so that they

can plan their treatments in advance. Most fi llers often result in some

degree of injection site reactions, which may last for 4 – 7 days. There are

some measures that can be taken before and after treatment to reduce the

amount of ecchymosis that patients may experience. In general, bruising

can be minimized by choosing the injectable fi ller least likely to cause this

problem, e.g. it is believed that collagen - containing fi llers are less likely to

cause ecchymosis compared with hyaluronic fi llers, although they have

been found to have a shorter duration of effect. This is secondary to the

platelet - aggregating effects of collagen. 8 Within the hyaluronic acid cate-

gory of products, some experts believe that some products result in less

swelling than others related to several factors, including extrusion forces,

particulate matter, and equilibrium hydration. Swelling and bruising can

also often be minimized by avoidance of agents that inhibit coagulation,

such as aspirin and nonsteroidal antiinfl ammatory drugs. Vitamin supple-

ments such as garlic and ginkgo biloba are also known for their inhibitory

effects on platelets. 9 Other supplements such as vitamin E, St John ’ s wort,

ginger, ginseng, green tea, kava - kava, celery root, and fi sh oil can inhibit

coagulation pathways and further increase bleeding and bruising. 10 It is

best to withhold these exogenous substances 7 – 10 days before the proce-

dure. With respect to aspirin specifi cally, although preventive daily dosing

can usually be avoided during this timeframe, the use of “ therapeutic ”

aspirin for patients who have had a history of a heart attack, stroke, or

blood clot should not be discontinued.

Some practitioners advocate the role of homeopathic medications

such as bromelain and arnica in reducing post - treatment ecchymosis.

Bromelain is a substance naturally present in mature pineapple stems

( Ananas comosus ). It has been shown to decrease vascular permeability

in animal models by lowering the levels of bradykinin, thereby poten-

tially resulting in less edema, pain, and infl ammation. 11 Some clinical

studies with bromelain were performed over 30 years ago, and have

Complications from Soft-Tissue Augmentation of the Face 125

shown confl icting results. One study of 53 patients undergoing rhinoplasty

revealed decreased swelling and ecchymosis associated with bromelain

use. 12 However, a further study of 154 plastic surgery patients demon-

strated no statistically signifi cant difference in edema between the bro-

melain and the placebo groups. 13

Arnica , Arnica montana, is an extract derived from several mountain

plants. The exact mechanism of action of arnica in the treatment of bruises

remains unknown; however, it is thought that a compound derived from

the extract contains helenalin, a molecule that has been shown to posses

antiinfl ammatory effects. 14 In addition, it has been proposed that arnica

inhibits platelet function in vitro. 15 There have been confl icting results

derived from clinical trials of both topical and oral arnica formulations for

the treatment of ecchymosis, with some revealing a decrease in post -

treatment bruising, whereas others show no statistical difference. Further

investigations are needed to substantiate this effect.

Nodules and p apules

Most subcutaneous nodules and papules, as manifested by palpable and/

or visible bumps under the skin, are frequently a result of inappropriate

placement of product. Injecting too superfi cially can lead to lumps of

visible product, or bluish bumps under the skin, specifi cally with hyaluronic

acid fi llers (Tyndall ’ s effect) (Figure 10.1 ). Such reactions can, for the most

part, be prevented by use of the correct technique. Papules and nodules

related to superfi cial placement can sometimes be treated simply by digital

pressure, aspiration, or incision and drainage. 16,17 Their occurrence can,

however, result in anxiety and dissatisfaction for patients.

Injection of a fi ller product too superfi cially may result in a persistent

nodule. Correction of visible papules and nodules can often be accom-

plished by puncturing the site with a 25G or 27G needle and expressing

Figure 10.1 Inappropriate placement of

fi llers can lead to product visibility under

the skin.

126 Chapter 10

the product. When lumps and nodules are secondary to the use of

a hyaluronic acid fi ller, the enzyme hyaluronidase can be utilized to

treat them. 17 A preliminary skin test should be performed before its

use because there have been reports of sensitivity to animal - derived

hyaluronidase. 18

The incidence of injection site nodules appears to be higher in patients

receiving poly - L - lactic acid (PLLA, Sculptra), particularly in the human

immunodefi ciency virus (HIV) - infected population. In clinical studies,

subcutaneous papules, defi ned as lesions ≤ 5 mm, typically palpable,

asymptomatic, and nonvisible, were seen in 52% and 31% of patients in

two separate European HIV - related lipoatrophy studies, each with a 2 - year

follow - up period. Nodule onset occurred at an average of 7 months post -

treatment (range 0.3 – 25 months) and resolved spontaneously over the

course of the study in 23% of the patients. Lower incidences of PLLA

nodules were seen in two American HIV - related lipoatrophy studies and

in an immunocompetent patient study with 1 - year follow - up periods. 21,22

In the American HIV - related lipoatrophy studies, nodules occurred in

6 – 13% of patients.19,20 In a more recent study, comparing PLLA with col-

lagen for the correction of nasolabial fold rhytids in non - HIV - infected

patients, nodules < 5 mm in diameter occurred in 8.6% of patients receiv-

ing PLLA and 3.4% of those receiving collagen. Nodules > 5 mm diameter

occurred in 6.9% of individuals receiving PLLA and 6.0% receiving col-

lagen. 20 It is believed that modifi cations to the initial European injection

protocol and improvements in technique helped minimize the occurrence

of subcutaneous papules seen in these later studies. It is important to note

that differences in regional thickness of skin can increase chances of injec-

tion site nodules, e.g. superfi cial placement in the infraorbital hollow may

result from inexperienced injectors not realizing the change in thickness

of the skin between the cheek and lower lid, thus increasing the possibility

of noticeable papules 23 (Figure 10.2 ).

Figure 10.2 Noticeable papules of the

infraorbital region.

Complications from Soft-Tissue Augmentation of the Face 127

It is now known that the effi cacy and safety of PLLA can be infl uenced

by correct product reconstitution, dilution, and administration. Recent

reports by experts in the fi eld provide insight to how administration of

PLLA with optimal techniques can help enhance treatment effect while

simultaneously minimizing undesired events 24 (NJ Lowe and CA Maxwell,

personal observations, 2002 – 2005) (Box 10.3 ).

Collagen plus polymethylmethacrylate (Artecoll/ArteFill, Suneva

Medical, San Diego, CA), is categorized as a permanent fi ller and as

such is less for giving of complications. Indeed, the most common issues

seen with Artecoll involved superfi cial placement. There have been

reports of long - lasting itching and persistent erythema. This may be

permanent, but responds to topical or intralesional corticosteroids. 26

In addition, the use of this product is contraindicated in certain areas

such as the lips, as there may be nodularities and uneven distribution as

a result of product migration secondary to the action of the orbicularis

oris muscle. 25

If calcium hydroxylapatite (Radiesse) is placed too superfi cially in the

mid - or papillary dermis, visible white nodules may occur. These can

usually be treated by puncturing the nodules with a number 11 blade or

needle, and then expressing the contents. 26 A higher incidence of nodule

formation may occur when treating the nasojugal sulcus. As a result of

the thin skin in the tear trough, injection of calcium hydroxylapatite too

superfi cially in this area can result in visibility of the fi ller. Rejuvenation

of this region should be attempted only by those with considerable

Box 10.3 Minimizing adverse events associated with poly - L - lactic acid injection • Product should be reconstituted with at least 5 mL of sterile water for injection,

with 1 mL lidocaine added before injection

• Allow reconstituted poly - L - lactic acid to stand for ≥ 24 hours (preferentially 72 hours) before use

• Do not refrigerate or freeze; keep at room temperature before injection

• Use a needle with a large enough bore (25 – 26G) so that it does not clog. Care should also be taken not to inject the precipitate at the end of the syringe

• Inject into the upper subcutis in a crosshatch manner

• Massage the injected area after treatment and instruct the patient do this twice daily for approximately 1 week

Adapted from Narins, RS. Minimizing adverse events associated with poly - L - lactic acid injection.

Dermatol Surg 2008; 34 ,:S100 – 4.

128 Chapter 10

experience. As with Artecoll, superfi cial migration of product may occur

when this is used in the lips so it is thus not recommended.

Fat transplantation is a relatively safe procedure with a low complication

rate. The most common complication of fat transplantation is overcorrec-

tion, which may result in visible nodules, especially in the infraorbital

region. Superfi cial nodules can also result from the injection of an

extremely large bolus of fat too superfi cially. Overcorrection may be dif-

fi cult to treat. Low - dose intralesional steroids, local massage, and excision

have been attempted as treatments with variable success. 27

Granulomas

Granulomatous foreign body reactions, manifested as persistent nodules,

are usually seen as a later complication of fi ller agents. These granulomas

are secondary to an infl ammatory response to a specifi c product. There is

speculation that the composition and size of the fi ller agent can be associ-

ated with the risk of developing this type of reaction. As collagen is usually

resorbed in approximately 3 – 4 months, the risk of delayed or persistent

granulomas is quite low.

Hyaluronic acid products have been rarely associated with granuloma

formation, as evidenced by delayed erythema and either painful or non-

tender swollen lumps. 16 Based on the collective experience of several

well - known aesthetic physicians, an algorithm was designed to help

manage these infl ammatory nodules, which were informally characterized

as delayed - onset “ angry red bumps ” (Figures 10.3 ).

In a specifi c case, a patient received a hyaluronic acid product in the

vermillion and subsequently developed discrete nodules initially associ-

ated with eczematous changes in the overlying skin 6 weeks after injec-

tion. 28 Histological analysis revealed the presence of a sharply demarcated

nodule in the subcutaneous fat which was consistent with a granuloma-

tous foreign body reaction to the fi ller. These granulomas have been

shown to sometimes respond to intralesional steroids and calcineurin

inhibitors (Protopic, Astellas Pharma US, Inc., Deerfi eld, IL). In cases of

hyaluronic acid - related granulomatous foreign body reactions that do not

respond to initial treatment with topical antiinfl ammatory drugs, hyaluro-

nidase can be employed to resolve the problem. 17

There have been reports of foreign body reactions to PLLA as well. One

paper reported three cases with signifi cant visible deformity as a result

of foreign body - induced giant - cell granulomatous reactions after skin

augmentation. These reactions were attributed to the aberrant reactivity

of the recipient to the material. 29 Treatment with intralesional steroids

and 5% imiquimod cream (Aldara), Graceway Pharmaceuticals Exton PA,

Complications from Soft-Tissue Augmentation of the Face 129

Delayed Onset Angry Red Bumps

Yes

No

Is the lesionfluctuant?

Needle aspiration or incision and drainage;gram /acid-fast stain; culture and sensitivity

(aerobic, anaerobic, AFSB)Antibiotics; BIAXIN Rx*

Antibiotics with coveragefor acid-fast bacteria for 7 days

BIAXIN Rx*

Re-evaluate for fluctuance. Results of stainsand C&S. Improvement or worsening.

Continue for antibiotics for total of 14 days

Intralesional steroids?Yes/No

Day 14Re-evaluate of fluctuance

(Improvement or worsening)Fluctuant:

YES

NO

Nonfluctuant:YES

Consider a calcineurininhibitor

Consider biopsy forpathological confirmation

Worse/Fluctuant?

Continue Rx toresolution

May need chronic antibiotic suppression andintralesional steroids p.r.n. until NASHA is

resorbedDiscourage hyaluronidase injection

Figure 10.3 Algorithm for the management of angry red bumps. Asterisk

indicates Biaxin (clarithromycin, Abbott Laboratories, Abbott Park, IL). AFB, acid -

fast bacilli; C & S, culture and sensitivity; NASHA, nonanimal - stabilized hyaluronic

acid. (Reprinted from Narins RS, Jewell M, Rubin M, Cohen J, Strobos J. Clinical

conference: management of rare events following dermal fi llers – focal necrosis and

angry red bumps. Dermatol Surg 2006; 32 :426 – 34.)

Northridge, CA) resulted in no visible clinical improvement. Treatment in

one of the cases involved excision of the largest nodules, with a “ satisfac-

tory ” result (Figures 10.4 ). The physicians recommend that, if feasible,

surgical excision is the best option for this type of reaction; however, this

would result in at least some degree of clinical scarring.

Although some US physicians report success with PLLA using the

modifi cations mentioned previously, many physicians still have concerns

when using this product, especially in patients with an intact immune

system. The concern of a vigorous granulomatous response to this product

has been evidenced in patients who have had immune reconstitution,

130 Chapter 10

where a previously immunodefi cient patient became relatively immu-

nocompetent while being treated for HIV. The hypothesis is that these

patients may develop an overactive response to infectious or foreign

substances. At present, the risk of immune response to PLLA among

immunocompetent patients is still an unresolved concern of several key

opinion leaders. 30

Bovine collagen plus polymethylmethacrylate (PMMA; Artecoll,

ArteFill) can also be associated with the formation of delayed granulomas,

although the rate is low. Between 1995 and 2000, these complications

occurred in just 0.01% (15/200 000) of Artecoll patients. 25 Granulomas in

those receiving bovine collagen plus PMMA have generally occurred 6 – 24

months post - treatment. These enlarging granulomas often appeared after

the second or third implantation of the product. The specifi c cause of these

reactions is unknown; however, half the patients experiencing them

reported an associated severe infection (infl uenza) or some type of facial

injury. Treatment usually consists of intralesional injections of corti-

costeroids. It is important to note that the ArteFill is not the same as the

Artecoll. ArteFill is derived from a closed US bovine herd, and has a

smaller particle size, so there is believed to be a signifi cantly lower risk of

immunogenicity.

Granulomas seen after silicone gel injections can occur years after injec-

tion. It is not yet completely understood why delayed granuloma forma-

tions occur. 31 Treatment of these is usually accomplished with intralesional

steroids and/or excision when possible. Successful amelioration of these

granulomas has been reported with the use of the immunomodulatory

cream Aldara. 32

Hypertrophic s carring

Excessive scar formation is a rare complication that can be encountered

when injecting fi ller agents. This is usually as a result of too superfi cial a

Figure 10.4 Sterile abscess after

incision and drainage of angry red

bump three weeks after hyaluronic acid

fi ller injections.

Complications from Soft-Tissue Augmentation of the Face 131

placement of the fi ller in the upper dermis. African – American individuals

have an inherently higher incidence of developing hypertrophic scars and

keloids after trauma. There had been concern that this population was at

increased risk of developing excessive scarring after augmentation with

fi ller agents. This speculation was recently dispelled by a study revealing

that the use of hyaluronic acid in people with darker skin was as safe and

effective as in people with fair skin. 33 It is noted, however, that it is of

importance to minimize the number of needle punctures, in order to limit

the risk of hyperpigmentation in patients with Fitzpatrick types IV – VI.

When hypertrophic scars do occur they can often be successfully managed

with intralesional triamcinolone injections, 10 - 40 mg/mL at 1 - month

intervals. The use of the pulse - dye laser has also been successful in treating

post - injection hypertrophic scars. Ultimately, the most critical point in

minimizing this potential event is to place the product in the proper plane,

which is not too superfi cial.

Infection

As the skin is pierced during injections, infection after soft - tissue augmen-

tation can occur. The injecting physician needs to screen for, and if neces-

sary treat, active, chronic, or recurrent regional infections before any

injections. Potential infectious etiologies may be bacterial or viral in nature.

It is possible that fi llers may trigger recurrent herpetic (herpes simplex

virus or HSV) lesions. 16 Therefore, in patients with a history of herpes

outbreaks, prophylactic antiviral treatment is often recommended if the

fi ller is to be used for the purpose of lip augmentation. In patients with

active herpes lesions, facial injections should not be performed until the

lesions have completely resolved.

To minimize the risk of infection, appropriate skin preparation with

either isopropyl alcohol or chlorhexidine should be performed. Commonly

recovered bacterial microorganisms associated with injections of dermal

fi llers include staphylococci and streptococci. When an infection is sus-

pected, as manifested by single or multiple erythematous and/or fl uctuant

nodules, it is best to culture the exudate and initiate empirical treatment

with an antibiotic such as clarithromycin for at least 2 weeks until

the more specifi c culture results become available. 16 There have also

been reports of infections from mycobacteria after facial augmentation

using autologous fat. 34 When a new lesion appears at the site of injection

more than 2 weeks post - procedure, it may be suggestive of an atypical

infection, such as a mycobacterial organism. 35 In this setting patients

usually present with a fi rm, mildly tender nodule, and may have systemic

132 Chapter 10

symptoms such as fever and fatigue. When suspected, the lesion should

be cultured or biopsied, and the specimens sent for bacterial, fungal, and

acid - fast stains.

Biofi lm reactions are a new concern regarding culture negative infec-

tions (so - called sterile abscesses) at the sites of prior fi ller injections. 36

Some of these reactions have been reported years after injection of

the product. Biofi lm reactions have been reported more frequently

when a permanent nondegradable gel such as silicone or polyacrylamide

gel is injected. It is hypothesized that a low - grade chronic infection

can occur and thrive in a biofi lm – a fi lm comprising bacteria, their nutri-

ents, and their waste products. As silicone does not interact with

host tissue, the biofi lm serves as a barrier to infl ammatory cells and

cytokines that would normally be able to quell this infection. 30 The use

of intralesional corticosteroids in this setting is contraindicated. If this

infection is treated initially with steroids, intralesionally or systemically,

NSAIDs, a weak antibiotic, or a broad - spectrum antibiotic in a low

dosage, then these measures can actually aggravate and prolong the

infectious process. This type of biofi lm infection requires treatment

with a broad - spectrum antibiotic in high dose for an extended treatment

period. 37 – 39

Contamination of fi ller agents is another concern, especially when there

are individuals who may utilize non - FDA - approved products or illegally

import products outside of approved US distributors. Specifi cally, in 2002,

there was an outbreak of Mycobacterium abscessus infection in New York

after soft - tissue augmentation with an unapproved hyaluronic acid

product, Hyacell, which was performed by a nonphysician in a New York

City hotel room. 40 Empirical treatment with clarithromycin and pred-

nisone resulted in clearance of these infections. With the increase in

nonphysicians and untrained personnel performing aesthetic procedures,

and with the possibility that non - FDA - approved agents or even counterfeit

products are being used, it is possible that we may see an increase in these

types of complications.

Hypersensitivity r eactions All soft - tissue augmentation agents, with the exception of autologous fat,

are composed of foreign body material. As a result, varying degrees of

immune system reactivity can occur. Severe reactions are rare, but can have

important medical and aesthetic implications. In addition to product -

specifi c sensitivity reactions, the introduction of a foreign substance other

than the fi ller, such as residual lipstick incompletely removed from the

patient ’ s lips before injection, could potentially cause an immunologic

reaction.

Complications from Soft-Tissue Augmentation of the Face 133

Given its animal source, bovine collagen, in the form of Zyderm I,

Zyderm II, and Zyplast, can be immunogenic, resulting in allergic

reactions. The incidence of foreign body reactions reaches 1.3% in some

series. 6 Before bovine collagen injection, two skin tests are recom-

mended to test for sensitivity. As a result of the availability of newer

fi ller agents that are not engineered from an animal source, bovine

collagen has fallen out of favor. A new porcine - derived collagen, Evolence

(OrthoNuetorgena), was FDA approved in the summer of 2008 for use

in the correction of rhytids of the nasolabial folds. Porcine - derived

collagen is very genetically similar to human collagen. 41 In addition,

this specifi c product has been engineered with the goal of eliminating

crossantigenic portions of the collagen molecule which could elicit an

immune response. 42 Therefore, no skin test is needed. The availability of

human collagen as a fi ller agent several years ago (Cosmoderm and

Cosmoplast) signifi cantly reduced concerns about the risk of hyper-

sensitivity reactions to the collagen class of fi llers, after so many years of

there simply being bovine collagen on the market. However, one must be

aware that a sensitivity - type reaction with human collagen may still rarely

be possible. 43

Hypersensitivity has also been very rarely reported with hyaluronic acid

products. Injectable hyaluronic acid has been derived either from avian

sources or via fermentation using streptococci, but the latter nonanimal -

sourced bacterial fermentation processing has prevailed in acceptance. It

has been postulated that residual proteins resulting from the manufactur-

ing process can potentially lead to hypersensitivity reactions in certain

patients. One rare, but dramatic, type of reaction was an angioedema - type

hypersensitivity to a nonanimal - stabilized hyaluronic acid gel after injec-

tion into the upper lip. 44 In this case, the patient received 1 mL of Restylane

for lip augmentation. One hour after injection, the patient returned to the

treating physician with an angioedema - type swelling of the upper lip

(Figure 10.5 ), without systemic complaints. The patient was treated with

Figure 10.5 Angioedema - type swelling

and early vertical and horizontal

fi ssures 1 hour post - procedure in a

patient treated with 1 mL hyaluronic

acid per side. (Photograph courtesy of

Naomi Lawrence, MD .)

134 Chapter 10

8 mg dexamethasone intramuscularly and was observed for 2 hours.

Stabilization of swelling occurred, and she was subsequently treated with

an oral steroid taper with complete resolution of edema within 5 days.

Protocols in the manufacturing of Restylane were instituted in 2000 to

reduce the amount of trace protein present. Safety data of the product

used before 1999 revealed a rate of adverse events 5.9 times greater com-

pared with use of the product after this date. 45 Similar modifi cations have

been implemented with other fi ller agents in this class to further decrease

rates of hypersensitivity reactions.

Necrosis

Judicious injection of fi llers requires an appreciation of normal facial

anatomy, with consideration given to location and course of major arteries

and nerves, and differences between regional properties and thickness.

Injection necrosis is a rare but important complication associated with

dermal fi llers. 46 Inadvertent injection of fi ller product directly into a vessel

or placing too much volume around a vessel can lead to an immediate

reticulated violaceous discoloration of the skin, which can be a sign of

impending necrosis such as along the course of the angular artery (Figure

10.6 ) (nasolabial fold area) or supratrochlear artery (glabellar area)

(Figure 10.7 ). Necrosis can be attributed to one of two factors: an inter-

ruption of vascular supply due to compression, or frank obstruction, of

vessels by direct injection of the material into a vessel itself. This can

manifest clinically as a violaceous bluish - grey discoloration, pain, erosion,

and/or ulceration (Figure 10.8 ). The glabellar region is the injection site

commonly believed to be at greater risk, as small - caliber vessels branch

from the supratrochlear arteries to supply this watershed region with

minimal collateral circulation. 47

Figure 10.6 The anatomic location of

the angular artery giving rise to the

lateral nasal artery at the level of the

alar groove (intra - operative photo

during Mohs surgery).

Complications from Soft-Tissue Augmentation of the Face 135

According to a recent treatment algorithm, a number of precautions can

be taken to avoid necrosis. 48 In the glabella, these precautions include:

injecting superfi cially and medially (away from the eye); aspirating before

injecting; and injecting slowly, avoiding overcorrection, and using only a

small amount of product divided over multiple treatment sessions. Selection

Figure 10.8 Impending necrosis.

Figure 10.7 Necrosis of the glabella.

136 Chapter 10

of appropriate agents that are small in particle size and intended for super-

fi cial use is vital. If impending necrosis is suspected, treatment options

include immediately applying warm gauze and tapping the area to facilitate

vasodilation and blood fl ow. The application of nitroglycerin paste to

further promote vasodilation is also believed to be of potential benefi t. For

cases in which a hyaluronic acid fi ller is used, there have recently been

two reports of impending necrosis where hyaluronidase was successfully

used along the distribution of the underlying vessel and the adjacent patchy

violaceous skin to remove some of the product and seemingly decompress

the vessel. 48,49 For more severe or unresponsive cases of necrosis, Schanz

and colleagues described their success using deep subcutaneous injections

of low - molecular - weight heparin into the affected area. 50

Development of emboli are serious complications that have not been

seen with hyaluronic acids, but have been seen in association with fat

transplantation and earlier forms of collagen. 51 A rare case of occlusion of

the middle cerebral artery and ocular fat embolism with blindness has

occurred after the use of autologous fat for augmentation of the senescent

face. 52,53 There has even been a report in the literature of an acute fatal

stroke immediately after injection of autologous fat. 54

Conclusion

Injectable fi lling agents offer the promise of facial rejuvenation while offer-

ing reduced risks compared with more invasive procedures. The use of

fi llers for cosmetic dermatology indications is increasing rapidly, and will

likely continue to do so in the foreseeable future. Although usually safe

as a class, complications can and do occur. To ensure the best possible

outcomes and greatest patient satisfaction, the physician who injects soft -

tissue augmentation agents must have proper training in their use. A

thorough understanding of facial anatomy, as well as proper product selec-

tion and injection techniques, is required to minimize avoidable adverse

events. A detailed understanding of the potential pitfalls, and how best to

avoid and manage them when they occur, is of paramount importance to

all those who utilize these agents.

References

1. Physician Practice Survey . American Society for Dermatologic Surgery, Rolling

Meadows, Illinois. 2007 .

2. Andre P. Evaluation of the safety of a non - animal stabilized hyaluronic acid

(NASHA — Q - Medical, Sweden) in European countries: a retrospective study from

1997 to 2001 . J Eur Acad Dermatol Venereol 2004 ; 18 : 422 – 5 .

Complications from Soft-Tissue Augmentation of the Face 137

3. Godin MS , Majmundar MV , Chrzanowski DS , Dodson KM . Use of Radiesse in com-

bination with Restylane for facial augmentation . Arch Facial Plast Surg 2006 ; 8 : 92 – 7 .

4. Brody HJ , Geronemus R , Farris P. Beauty Versus Medicine: The Nonphysician

Practice of Dermatologic Surgery . Dermatol Surg 2003 ; 29 : 319 – 24 .

5. Executive Summary Dermal Filler Devices General and Plastic Surgery Devices

Panel, Food and Drug Administration. November 2008 . ( www.fda.gov/OHRMS/

DOCKETS/ac/08/briefing/2008-4391b1-01%20-%20FDA%20Executive%20

Summary%20Dermal%20Fillers.pdf )

6. Narins RS , Brandt F , Leyden J , et al. A randomized, double - blind, multicenter com-

parison of the effi cacy and tolerability of Restylane versus Zyplast for the correction

of nasolabial folds . Dermatol Surg 2003 ; 29 : 588 – 95 .

7. Niamtu J , Smith K , Carruthers J . Pain control in cosmetic facial surgery . In: Dover

JS , Alam , M , eds. Procedures in Cosmetic Dermatology . Philadelphia : Saunders Elsevier ,

2008 : pp. 127 – 41

8. Bauman , L. Minimizing bruising . Skin Aging 2007 ; 15 ( 10 ): 48 – 9 .

9. Ang - Lee MK , Moss J , Yuan CS. Herbal medicines and perioperative care . JAMA

2000 ; 286 : 208 – 16 .

10. Dinehart SM , Henry L . Dietary supplements: altered coagulation and effects on

bruising . Dermatol Surg 2005 ; 31 : 819 – 26 .

11. Kumakura S , Yamashita M , Tsurufuji S . Effect of bromelain on kaolin - induced

infl ammation in rats . Eur J Pharmacol 1988 ; 150 : 295 – 301 .

12. Seltzer AP. Minimizing post - operative edema and ecchymosis by the use of an oral

enzyme preparation (bromelain). A controlled study of 53 rhinoplasty cases . Eye Ear

Nose Throat Mon 1962 ; 41 : 813 – 7

13. Gylling U , Rintala A , Taipale S , et al. The effect of a proteolytic enzyme combinate

(bromelain) on the postoperative edema by oral application. A clinical and experi-

mental study . Acta Chir Scand 1966 ; 131 : 193 – 6 .

14. Lyss G , Schmidt TJ , Merfort I , Pahl HL . Helenalin, an anti - infl ammatory sesquiter-

pene lactone from Arnica, selectively inhibits transcription factor NF - κ B . Biol Chem

1997 ; 378 : 951 – 61 .

15. Schroder H , Losche W , Strobach H , et al. Helenalin and 11alpha,13 - dihydrohelen-

alin, two constituents from Arnica montana L., inhibit human platelet function via

thiol - dependent pathways . Thromb Res 1990 ; 57 : 839 – 45 .

16. Narins RS , Jewell M , Rubin M , et al. Clinical conference: management of rare events

following dermal fi llers – focal necrosis and angry red bumps . Dermatol Surg

2006 ; 32 : 426 – 34 .

17. Brody HJ. Use of hyaluronidase in the treatment of granulomatous hyaluronic acid

reactions or unwanted hyaluronic acid misplacement . Dermatol Surg

2005 ; 31 : 893 – 7 .

18. Hirsch RJ , Cohen JL . Surgical insights: challenge: correcting superfi cially placed

hyaluronic acid . Skin Aging 2007 ; 15 : 36 – 8 .

19. Sculptra . Prescribing information . Bridgewater, NJ : Dermik Laboratories , 2006 .

20. Werschler P. The Cosmetic Study Investigator Group. Effi cacy of injectable poly - L -

lactic acid versus human collagen for the correction of nasolabial fold wrinkles .

Presented at the American Society for Dermatologic Surgery. October 28, 2006;

Palm Desert, CA, Abstract CS359.

21. Burgess CM , Quiroga RM . Assessment of the safety and effi cacy of poly - L - lactic acid

for the treatment of HIV - associated facial lipoatrophy . J Am Acad Dermatol

2005 ; 52 : 233 – 9 .

22. Engelhard P , Knies M . Safety and effi cacy of New - Fill ® (polylactic acid) in the

treatment of HIV - associated lipoatrophy of the face (HALF) . XIV International AIDS

Conference; 2002 Jul 7 – 12 ; Barcelona, Spain.

138 Chapter 10

23. Stewart D , Gladstone H , Mooney M , et al. Visible papules after periorbital injection

of poly - L - lactic acid . Ophthal Plast Reconstr Surg 2007 ; 23 : 298 – 301 .

24. Narins , RS. Minimizing adverse events associated with poly - L - lactic acid injection .

Dermatol Surg 2008 ; 34 ( suppl 1 ): S100 – 4 .

25. Lemperle G , Romano JJ , Busso M . Soft tissue augmentation with Artecoll: 10 - year

history, indications, techniques, and complications . Dermatol Surg 2003 ; 29 : 573 – 87 .

26. Berlin A , Cohen JL , Goldberg DJ . Calcium hydroxylapatite for facial rejuvenation .

Semin Cutan Med Surg 2006 ; 25 : 132 – 7 .

27. Donofrio L. Technique of periorbital lipoaugmentation . Dermatol Surg

2003 ; 29 : 92 – 98 .

28. Fern á ndez - Ace ñ ero MJ , Zamora E , Borbujo J. Granulomatous foreign body reaction

against hyaluronic acid: report of a case after lip augmentation . Dermatol Surg

2003 ; 29 : 1225 – 6 .

29. Beljaards RC , de Roos K - P , Bruins FG. NewFill for skin augmentation: A new fi ller

or failure? Dermatol Surg 2005 ; 31 : 772 – 6 .

30. Newburger AE. Cosmetic medical devices and their FDA regulation . Arch Dermatol

2006 ; 142 : 225 – 8 .

31. Christensen , L. Normal and pathologic tissue reactions to soft tissue gel fi llers .

Dermatol Surg 2007 ; 33 ( suppl 2 ): S168 – 75 .

32. Baumann LS , Halem ML . Lip silicone granulomatous foreign body reaction treated

with aldara (imiquimod 5%) . Dermatol Surg 2003 ; 29 : 429 – 32 .

33. Odunze M , Cohn A , Few JW . Restylane and people of color . Plast Reconstr Surg

2007 ; 120 : 2011 – 16 .

34. Obagi S. Autologous fat augmentation and periorbital laser resurfacing complicated

by abscess formation . Am J Cosmet Surg 2003 ; 20 : 155 – 7 .

35. Klein AW. Injectable bovine collagen . In: Klein AW , ed. Tissue Augmentation in

Clinical Practice: Procedures and techniques . New York : Marcel Dekker , 1998 : pp.

269 – 91 .

36. Narins RS , Monheit G. Editorial Comment . Dermatol Surg 2008 ; 34 : S1 .

37. Christensen L , Breiting V , Vuust J , Hogdall E . Adverse reactions following injection

with a permanent facial fi ller polyacrylamide hydrogel (Aquamid): causes and treat-

ment . Eur J Plast Surg 2006 ; 28 : 464 – 71 .

38. Lowe NJ , Maxwell CA , Patnaik R . Adverse reactions to dermal fi llers: review .

Dermatol Surg 2005 ; 31 : 1616 – 25 .

39. Zarini E , Supino R , Pratesi G , et al. Biocompatibility and tissue interactions of a new

fi ller material for medical use . Plast Reconstr Surg 2004 ; 15 : 934 – 42 .

40. Toy BR , Frank PJ . Outbreak of Mycobacterium abscessus infection after soft tissue

augmentation . Dermatol Surg 2003 ; 29 : 971 – 3 .

41. Shoshani D , Markovitz E , Cohen Y , et al. Skin test hypersensitivity study of a cross -

linked, porcine collagen implant for aesthetic surgery . Dermatol Surg 2007 ; 33 :

S152 – 8 .

42. Narins R , Monheit G . Evolence – a new collagen fi ller . Presentation at the World

Congress of Dermatology, Buenos Aires, October 2, 2007

43. Stolman LP. To the editor: human collagen reactions . Dermatol Surg 2005 ; 31 :

1634 .

44. Leonhardt JM , Lawrence N , Narins RS . Angioedema acute hypersensitivity reaction

to injectable hyaluronic acid . Dermatol Surg 2005 ; 31 : 577 – 9 .

45. Friedman PM , Mafong EA , Kauvar AN , et al. Safety data of injectable nonanimal

stabilized hyaluronic acid gel for soft tissue augmentation . Dermatol Surg 2002 ; 28 :

491 – 4 .

Complications from Soft-Tissue Augmentation of the Face 139

46. Glaich AS , Cohen JL , Goldberg LH . Injection necrosis of the glabella: protocol for

prevention and treatment after use of dermal fi llers . Dermatol Surg 2006 ; 32 :

276 – 81 .

47. Hanke CW , Hingley R , Jolivette DM , et al. Abscess formation and local necrosis after

treatment with Zyderm ® or Zyplast ® collagen implant . J Am Acad Dermatol 1991 ; 25 :

319 – 26 .

48. Hirsch RJ , Cohen JL , Carruthers JD . Successful management of an unusual presen-

tation of impending necrosis following a hyaluronic acid injection embolus and a

proposed algorithm for management with hyaluronidase . Dermatol Surg 2007 ; 33 :

357 – 60 .

49. Hirsch RJ , Lupo M , Cohen JL , Duffy D . Delayed presentation of impending necrosis

following soft tissue augmentation with hyaluronic acid and successful management

with hyaluronidase . J Drugs Dermatol 2007 ; 6 : 325 – 8 .

50. Schanz S , Schippert W , Ulmer A , et al. Arterial embolization caused by injection of

hyaluronic acid (Restylane) . Br J Dermatol 2002 ; 146 : 928 – 9 .

51. Hanke CW. Adverse reactions to bovine collagen . In: Klein A , ed. Augmentation in

Clinical Practice: Procedures and techniques . New York : Marcel Dekker , 1998 : p. 145 .

52. Dreizen NG , Framm L . Sudden unilateral visual loss after autologous fat injection

into the glabellar area . Am J Opthalmol 1989 ; 107 : 85 – 87 .

53. Feinendegen D , Baumgartner R , Schroth G , Mattle H , Tschopp H . Middle cerebral

artery occlusion and ocular fat embolism after autologous fat injection in the face .

J Neurol 2009 ; 245 : 53 – 4 .

54. Yoon SS , Chang DI , Chung KC . Acute fatal stroke immediately following autologous

fat injection into the face . Neurology 2003 ; 61 : 1151 – 2 .

The Mathematics of Facial Beauty: A Cheek Enhancement Guide for the Aesthetic Injector Arthur Swift Westmount Institute of Plastic Surgery, and Victoria Park Medical Spa, Montreal, Canada and McGill University, Montreal, Canada

CHAPTER 11

All beauty is mathematics.

(Ancient Greek saying)

The recent availability of safe volumizing fi llers has provided cosmetic

physicians the tools necessary to contour facial features nonsurgically.

To this end, it is imperative to have a good understanding of the aes-

thetic goals necessary to achieve a beautiful and natural result. What

should be the preferred facial volume and feature shape? What is the

ideal beautiful normal for each individual face, and is there a code to

unlock the patient ’ s potential? Is it unreasonable to have lofty aesthetic

goals, or should we be less principled and more moderate? “ A thing

moderately good is not as good as it ought to be. Moderation in temper

is always a virtue; but moderation in principle is always a vice ” (Thomas

Paine 1737 – 1809).

This chapter focuses on trying to decipher objective parameters in creat-

ing a template to maximize each individual ’ s facial beauty. The technique

offered is personal and, as is evidenced below, not a unique concept. It in

no way represents the best or sole method to nonsurgically release the

patient ’ s facial beauty potential. Rather the intent is to encourage aesthetic

injectors to always be result oriented, to develop methodical and compre-

hensive approaches to facial enhancement, and to push creativity beyond

rejuvenation into the realm of beauty maximization.

Facial beauty

A thing of beauty is a joy forever: Its loveliness increases: it will never pass into

nothingness.

John Keats

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

140

The Mathematics of Facial Beauty 141

St Thomas Aquinas, known as the “ angelic doctor, ” was one of the

great philosophers of the Catholic Church in the thirteenth century. He

proclaimed beauty to be “ integras, proportio, et claritas ” – harmony, propor-

tion, and clarity. True facial beauty arouses the senses to an emotional

level of pleasure and “ evokes in the perceiver a high degree of attraction ”

(Stephen Marquardt, personal communication).

It would seem essential that the injection specialist have a deep under-

standing and a well - cultivated taste for beauty. Otherwise he would be

satisfi ed with a low and common goal rather than the maximization of

beauty potential in his patient. Although certain individuals may be

endowed with an innate aesthetic sense, it can be learned at least in part

by the ardent study of art and the constant observation of facial and body

proportions and relationships. 1

Regardless of nationality, age, or ethnic background, for the most part

people universally share a sense of what is attractive. 2 When British

researchers asked women from England, China, and India to rate pictures

of various Greek men, their choices were identical. When asked to select

attractive faces from a diverse collection, whites, Asians and Latinos from

a dozen countries also shared the same choices. 3 Studies have shown

that even babies demonstrate a sense of what is attractive: 3 - and 6 - month -

old infants will gaze longer at a nice - looking face than at one that is not

attractive. 4

In a large research project on facial attractiveness at several German

universities, digitally composed faces were created using a specialized

software algorithm based on people ’ s perception of beauty (see www.

beautycheck.de ). Using a 7 - point Likert scale (1 = very unattractive to

7 = very attractive), results proved that in fact most people, regardless of

ethnicity, seem to have similar subjective ideas about what constitutes an

attractive face (Figure 11.1 ).

Finding objective answers, however, as to why we regard one face as being

more beautiful than another is actually not as easy as it seems. Review of

numerous articles on facial beauty has led this author to identify seven key

facial features that appear to be subconsciously assessed when determining

facial beauty (Figure 11.2 ). It is interesting to note that four features of these

“ Magnifi cent Seven ” – facial shape, eyebrow shape, nose and lips – are

amenable to injection contouring with fi llers (e.g. hyaluronic acids) and

neuromodulators (e.g. botulinum toxin A). Skin clarity, texture, and color

can be markedly improved with topical agents, present - day energy device

technology, and judicial use of make - up; forehead height can be accentu-

ated or camoufl aged by hair style; and inter - eye distance can be disguised

by creative shadowing when applying eye make - up. All this emphasizes

the importance of working closely with skilled aestheticians and experi-

enced hairdressers when offering patients global facial beautifi cation.

142 Chapter 11

1 32

654

Figure 11.1 Using a morphing software, German researchers created gradually

changing images. Images 5 and 6 consistently scored highest on the seven - point

attractive scale when exposed to different large volume cohorts.

distanceV. Nose shape

I. Facial shape (cheeks & chin)II. Forehead heightIII. Eyebrow shapeIV. Eye size and inter-eye

VI. Lips (length and height)VII. Skin clarity/texture/color

Figure 11.2 The “ Magnifi cent Seven ”

facial features that infl uence our

perception of facial beauty.

The Mathematics of Facial Beauty 143

Figure 11.3 Artist ’ s rendition of an

attractive face scaled to fi ve eyewidths ’

across.

The story of phi I know not what beauty is, but I know that it touches many things.

D ü rer

The attractiveness of the female fi gure is often described in measured

numbers (e.g. 36 – 24 – 36), so why not the face? The ancient Greeks

maintained that all beauty is mathematics. The idea of a mathematical

code, formula, relationship, or even a number that can describe facial

beauty is not a modern concept. Medieval artists were impressed by

the magical number 7. For them, the perfect face was neatly divisible

into horizontal sevenths: the hair the top seventh, forehead two - sevenths,

nose another two - sevenths, a seventh between nose and mouth, and the

fi nal seventh from mouth to chin. Novice artists are often taught that the

simplest way to approximate the relative width of facial features is to

divide the face into vertical fi fths with each fi fth being equal to one eye

width (Figure 11.3 ).

Only one mathematical relationship has been consistently and repeat-

edly reported to be present in beautiful things, both living (Figure 11.4 )

and synthetic (Figure 11.5 ) – the “ Golden Ratio ” (also known as the

“ Divine Proportion ” ).

The Golden Ratio is a mathematical ratio of 1.618:1, and the number

1.618 is called phi ( Φ ) , because it was regularly used by the Greek sculptor

144 Chapter 11

A

E

CB

FD

Figure 11.4 The divine proportion in living things: (a) nautilus shell; (b) sunfl ower;

(c) tiger ’ s head; (d) phalanges of the hand; (e) human body; (f) butterfl y.

A CB

ED

Figure 11.5 The Golden Ratio in architecture, music and art. (a) Venus de Milo; (b)

Stradivarius violin; (c) Notre Dame Cathedral; (d) Parthenon; (e) Leonardo da Vinci ’ s

Vitruvian Man.

The Mathematics of Facial Beauty 145

a

a+ba+b is to a as a is to b

b

⎧ ⎪ ⎪ ⎨ ⎪ ⎪ ⎩

Figure 11.6 The Golden Section is the only point in line ab

that divides line ab in a ratio of 1.618 ( a ) to 1 ( b ); 1 ( a ) to

0.618 ( b ); and 1 ( a ) to 1.618 ( a + b ).

Phidias. 5 Phi with an upper case “ P ” is 1.6180339887 … , whereas phi with

a lower case “ p ” is 0.6180339887 … , the reciprocal of phi and also phi − 1.

This irrational number is the only one in mathematics that, when sub-

tracted by units (1.0), yields its own reciprocal.

Employed since the time of the Egyptians, the Golden Ratio was formu-

lated as one of Euclid ’ s elements, one of the most beautiful and infl uential

works of science in the history of humankind. This ratio was known to

the Greeks as the “ Golden Section ” and to the Renaissance artists as the

“ Divine Proportion ” . In geometry, it is a linear relationship in which the

smaller length is to the larger part as the larger part is to the complete line

(Figure 11.6 ).

RM Ricketts noted that the golden calipers applied to the human hand

reveals that each phalanx of each fi nger is golden to the next in all fi ve

fi ngers 6 (see Figure 11.4 d).

Stephen Marquardt, a California - based oral and maxillofacial surgeon,

has conducted extensive research on human facial attractiveness. 7 His

pioneering work on the mathematical construction of facial form led to

his controversial (see www.beautyanalysis.com ) 8 “ Golden Mask, ” derived

from the Golden Ratio (Figure 11.7 ). Marquardt maintains that the evi-

dence shows that our perception of physical beauty is hardwired into our

being and based on how closely one ’ s features refl ect phi in their propor-

tions. His modifi cation of Hungerford ’ s classic quote that “ beauty is in the

phi [eye] of the beholder ” is quite convincing.

Since January 2007, the author has employed the application of

the Golden Ratio in his facial injection technique in an attempt to maxi-

mize the results obtained (beauti ” phi ” cation). This was achieved initially

by the use of a golden mean caliper – a tool based on an articulated

pentagon for dynamically measuring the phi proportion (Figure 11.8 ).

The calipers were fi rst used by Renaissance artists to determine the

“ divine ” proportions for their compositions in stone and on canvas. The

calipers initially help the aesthetic injector see phi more as a relationship

than as a number. Eventually, a geometric familiarity with the Golden

Ratio develops which leads to its intuitive expression in the injection

technique.

In the absence of disease, the medial canthi remain a constant cuta-

neous landmark with age for each individual adult face. Measuring the

146 Chapter 11

intercanthal distance ( x ) to establish the unit length on which Phi

(1.618 x ) and phi (0.618 x ) are created, aesthetic goals can now be defi ned

in order to maximize each patient ’ s “ phi ” beauty potential. The following

sections describe the author ’ s personal technique for beauti ” phi ” cation.

The math to the beautiful cheek … beauty ’ s ensign yet

Is crimson in thy lips and in thy cheeks

William Shakespeare, Romeo and Juliet

Figure 11.7 Marquardt ’ s female and male golden masks ( www.beautyanalysis.com ).

The Mathematics of Facial Beauty 147

Figure 11.8 Golden mean caliper: when the gauge is adjusted, the middle arm will

always show the golden section or phi ratio point between the two outer arms.

The single feature that matters time and again in studies on facial beauty

is symmetry. 9 Many papers have discussed attractiveness in terms of sym-

metry, balance, and harmony. 10 – 13 Although often referred to as the “ fi rst

feature of beauty, ” symmetry is not absolute. 14 Kent Remington, a pioneer

in the fi eld of aesthetic dermatology, has eloquently (and rightfully) stated

that the left and right sides of the face should be considered more as sisters

than as twins.

Consensus guidelines point to “ an evolving paradigm ” in facial rejuve-

nation with a shift from the two - dimensional approach (focus on correct-

ing dynamic facial lines) to the three - dimensional one including loss of

facial volume. 15 Youth and beauty are exemplifi ed by a full and wide

midface, referred to as the “ triangle of youth ” (Figure 11.9 ). Aging changes

the three - dimensional topography of the underlying facial structures,

resulting in defl ation and ptosis of the midface skin and soft tissue 16

(Table 11.1 ). Conventional face lifting without volume replacement

is unable to restore facial fullness and fails to address the issue of

deteriorating facial shape secondary to facial soft - tissue atrophy. Reasonable

goals in both midface rejuvenation and cheek enhancement should involve

adequate volume restoration and contouring in the aesthetically appropriate

locations . 17,18

148 Chapter 11

Figure 11.10 A female model

demonstrating an ovoid, angular cheek

mound with eccentric apex (star) as

well as the ogee curve of the right

cheek contour.

Figure 11.9 The “ triangle of youth ” . Youth is typifi ed by a full and wide midface.

Aging results in defl ation of midface structures and support, tissue deterioration and

subsequent descent of the facial envelope, causing a reversal of the triangle.

Table 11.1 Volume loss staging in the midface

Stage 1 Stage 2 Stage 3 Stage 4

Normal Evidence of early soft - tissue

ptosis or atrophy

Slightly visible

Visible depression

or descent

Severe depression

or atrophy

The female cheek mound is ovoid or egg shaped, not circular, and should

not extend higher than the limbus of the lower eyelid (Figure 11.10 ). The

cheek axis is not vertical but angled from the lateral commissure to the base

of the ear helix. Most importantly, each malar prominence has a defi ned

The Mathematics of Facial Beauty 149

Figure 11.11 Top models demonstrating Phi facial width proportion (i.e. medial

canthus to medial canthus measure x ; medial canthus to ipsilateral cheek apex

measures 1.618 x ).

apex, located high on the midface, below and lateral to the lateral canthus,

and eccentrically located within the cheek oval.

Proportion and harmony are paramount in the midface, so great care

should be taken to avoid overjudicious use of fi ller product in this region

in the attempt to reinfl ate. As a rule of thumb, ideal facial width, for most

ethnicities, falls approximately Phi from the medial canthus for each cheek

(Figure 11.11 ).

Technique The technique for midface contour volumization and cheek enhance-

ment should involve a minimum of needle punctures in order to achieve

the desired result. A fi ller product with a high G ′ (stiffness factor) or

high cohesivity is chosen in order to maximize lifting capacity of the

overlying tissue (tentpole effect). Placement of the product is done sub-

muscularly (supraperiosteally) via vertical puncture, and subcutaneously

via angulated percutaneous technique, always injecting ante grade.

Injection aliquots are usually limited to no more than 0.5 mL and

150 Chapter 11

negative pressure on the syringe is recommended to check for intra-

vascular needle location in high - risk regions. Depending on the type of

product selected for the lift effect, feathering of the cheek contour in

a more superfi cial subdermal plane may be indicated using a softer

(lower G ′ ) product to avoid any step - off areas. Massage with ultrasound

gel is always performed after treatment to mold and blend the product

as discerned by tactile fi ngertip touch rather than relying on visual

observation.

A two - step marking approach is used to create the “ Faberg é egg ” appear-

ance to the cheek along with its eccentric apex. This process can be likened

to giving the face what it wants (its volume), and then giving it what it

needs (the proper apogee).

Step 1: giving the cheek what it wants (restoring the ogee curve) Ogee is an architectural shape consisting of a concave arc fl owing into a

convex arc, creating an S - shaped curve. In aesthetic facial surgery, the

term is used to describe the malar or cheekbone prominence transitioning

into the midcheek hollow (Figure 11.11 ). The aim of cheek enhancement

is to restore (or in some cases create) a gentle ogee curve and subtly defi ne

the malar prominence ’ s zenith.

Using an eyebrow pencil, the depleted and concave (negative vector)

areas of the cheek are marked overlying the anterior cheek, malar –

zygomatic and submalar regions (Figure 11.12 ). The inferior border of

the body of the maxilla is outlined to demarcate supraperiosteal and

subcutaneous placement of product. Injections overlying the body of

the maxilla are layered supraperiosteally (submuscularly) as well as

subcutaneously (if necessary to correct any resistant contour irregulari-

ties), while those overlying the parotid (preauricular), submalar region,

and lower anterior cheek are performed purely in the subcutaneous

plane. Any pre - existing irregularities in the skin are addressed by direct

intradermal injection of an appropriate lower G ′ product. Injections

are performed from superior to inferior on the face, as higher placed

product will infl uence the lower zones by lifting the adjacent inferior

tissue. This is evidenced by the softening of the nasolabial fold and jowl

on the treated side after the cheek mound has been restored. Quite

often less product is required for direct correction of whatever deformity

may remain along the upper nasolabial fold triangle and prejowl sulcus

(Figure 11.13 ).

Step 2: giving the cheek what it needs (the proper apogee) Once the previous step 1 markings have been wiped away and the gel

massage completed, the cheek is now ready for the beauti ” phi ” cation

The Mathematics of Facial Beauty 151

Parotid line

Body of MaxillaLine

1

23

Figure 11.12 The depleted region of the right cheek is outlined (black dashed line).

Injections overlying the body of the maxilla (zone 1 above the body of maxilla line)

are placed supraperiosteally and if necessary subcutaneously. Depth of volume

injections for zones 2 and 3 are limited to the subcutaneous plane.

Cheek apex defined subtly

Softening of N/L fold and

marionette

Treated Side

Persistent Jowl

Deflated peau d’orange skin

Blunted malar region

Untreated Side

Softening of jowl

Pre-auricular hollow

Positive contour

Figure 11.13 Injections of the upper midface affecting lower zones (nasolabial fold

and jowl).

152 Chapter 11

markings to delineate the ovoid appearance and defi ne the cheek apex

(Figure 11.14 ). A line is drawn from the lateral commissure to the

lateral canthus of the ipsilateral eye. This will establish the anterior

extent of the malar prominence (Hinderer ’ s line). A second line is

drawn from the lateral commissure to the inferior tragus of the ipsilat-

eral ear, denoting the lateral and inferior boundaries of the malar prom-

inence (base of the triangle). The highpoint of the cheek is marked by

a horizontal line at the level of the limbus of the lower eyelid. The

cheek oval is drawn within these boundaries and tangential to the lines

drawn. Feathering of the edges of the oval with subcutaneous fi ller

product is done as necessary to create a smooth egg - shaped mound.

Lastly, a line is drawn down from the lateral canthus to the base of the

triangle, perpendicular to the latter (the height of the triangle). The

cheek apex lies Φ (about a third of the way) from the lateral canthus

along this line. Note that this defi ned point is in an eccentric position

within the cheek oval. This same apex injection point can be obtained

by the intersection of a line drawn from the nasal alar groove ( Φ of the

nose) to the upper tragus, and a line drawn down vertically from the

midpoint of the lateral orbital rim (Figure 11.15 ). The fi nal injection

(between 0.25 and 0.5 mL of product placed on bone by vertical punc-

ture) is performed at this precise point to give the cheek what it needs

– a beauti ” phi ” ed apex. Molding and blending of this apogee are done

with ultrasound gel to provide a smooth contour. Facial width can be

confi rmed with the golden ratio calipers and fi ller added at this location

to “ idealize ” the facial width proportion.

Figure 11.14 Beauti “ phi ” cation: the

oval cheek mound lies within the

triangular markings (see text) with the

malar apex located as depicted (star).

The Mathematics of Facial Beauty 153

Figure 11.15 Beauti “ phi ” cation: cheek

apex (star) defi ned by the intersection

of a line drawn from the nasal alar

groove to the upper tragus and a line

drawn vertically down from the

midpoint of the lateral orbital rim.

Modifi cations for the male cheek

The male cheek has more anteromedial fullness, a broader - based malar

prominence, and an apex that is more medial and subtly defi ned. The

following modifi cations of the markings are noted:

• Hinderer ’ s line (anteromedial border) is drawn from the lateral commis-

sure towards the ipsilateral lateral iris, stopping at the infraorbital rim.

• Due to the lower jaw angle and stronger jaw, the line denoting

the inferolateral border of the cheek (base of the triangle) is drawn

from the lateral commissure to the base of the ipsilateral infratragal

notch.

• The apex is modest and more medially located at one - third of the distance

along a line drawn from the lateral canthus to the base of the triangle,

intersecting the latter at a right angle.

• Finally, the Ogee created should be fl atter in its lower S curve.

Learn to think in combineese (the language of combination therapy)

The doctrine of beauti ” phi ” cation, or any nonsurgical facial enhan-

cement, is that it be individualized, minimally invasive, result oriented,

cost - effective, synergistic, and associated with minimal downtime, anxiety

(for both the patient and physician), and pain. The art of bundling prod-

ucts with procedures – of combining fi llers, neurotoxin, skin creams,

lasers, and energy devices – is where technology and creativity meet.

154 Chapter 11

Pre 1 yr.6 mos.

Figure 11.17 Beauti “ phi ” cation: results at 6 months and 1 year follow - up, no

additional treatment.

Pre

Pre

6 mos.

6 mos.

Figure 11.16 Beauti “ phi ” cation: 6 - month result with hyaluronic acid fi ller for tear

troughs, lateral brows, cheek, and chin enhancement.

The Mathematics of Facial Beauty 155

1 yr.

1 yr.

Pre

Pre

Figure 11.18 Beauti “ phi ” cation: results at 1 year, single treatment with hyaluronic

acid (tear troughs, cheeks, prejowl sulci, chin) and porcine collagen for lip phi

proportion. Neuromodulator (botulinum toxin A or BTX - A) given at 18 - week

intervals for browlift, periorbital dynamic lines, and chin.

Phi relationships can be approached for all facial features, including

the nose, chin, lips, and brows, but are beyond the scope of this

chapter. The point must be emphasized that having a plan and using

pre - treatment markings to achieve desired results are the critical element

to volumization in the face. Once goals have been determined and a

budget established, a logical syntax is used to create an algorithm for

selecting products and procedures. The methodology will lead to consist-

ent and pleasing results with a high rate of patient satisfaction (Figures

11.16 – 11.20 ).

156 Chapter 11

1 yr.Pre

Figure 11.19 Beauti “ phi ” cation: combination therapy result at 1 year. Hyaluronic

acid fi ller (midface, superior and inferior orbital rims, nasolabial folds, prejowl sulci),

panfacial neuromodulator (browlift, forehead, glabella, crow ’ s feet, chin, depressor

angulae oris), microdermabrasion, and ALA - aminolevulinic acid/IPL - intense pulsed

light therapy, home skincare regimen.

18 mos.Pre

Figure 11.20 Beauti “ phi ” cation: results at 18 months. Hyaluronic acid fi ller (cheeks,

tear troughs, nose, prejowl sulci, mental crease, lips, philtral columns) and

neuromodulator (browlift, glabella, forehead, crow ’ s feet, chin).

The Mathematics of Facial Beauty 157

References

1. Millard DR. Principalization of Plastic Surgery . Baltimore, MD : Lippincott Williams &

Wilkins , 1987 .

2. Cunningham MR , Roberts AR , Wu C - H , Barbee A , Druen PB. “ Their ideas of

beauty are, on the whole, the same as ours ” : Consistency and variability in the cross -

cultural perception of female physical attractiveness . J Personality Social Psychol

1995 ; 68 : 261 – 79 .

3. Jones D , Hill K . Criteria of facial attractiveness in fi ve populations . Human Nature

1993 ; 4 : 271 – 96 .

4. Langlois JH , Roggman LA , Casey RJ , Ritter JM , Rieser - Danner LA , Jenkins VY.

Infant preferences for attractive faces: Rudiments of a stereotype? Dev Psychol

1987 ; 23 : 363 – 9 .

5. Livio M. The Golden Ratio: The story of phi, the world ’ s most astonishing number . Broadway

Books , 2002 .

6. Ricketts R. The biologic signifi cance of the divine proportion and Fibonacci series .

Am J Orthod 1982 ; 81 : 351 – 70 .

7. Bashour , Mounir. Is an Objective Measuring System for Facial Attractiveness Possible?

Dissertation.com, 06/28/2007 .

8. Safran B. The Mathematics of Beauty: The divine proportion ’ s effect on facial attractiveness ,

Brown University , 2007 .

9. Rhodes G , Proffi tt F , Grady JM , Sumich A . Facial symmetry and the perception of

beauty . Psychonomic Bull Rev 1998 ; 5 : 659 – 69 .

10. Brooks M , Pomiankowski A . Symmetry is in the eye of the beholder . Trends Ecol

Evol 1994 ; 9 : 201 – 2 .

11. Concar D. Sex and the symmetrical body . New Scientist 1995 ; 146 : 40 – 4 .

12. Enquist M , Arak A . Symmetry, beauty and evolution . Nature 1994 ; 372 , 169 – 72 .

13. Grammer K , Thornhill R. Human ( Homo sapiens ) facial attractiveness and sexual

selection: The role of symmetry and averageness . J Compar Psychol 1994 ; 108 :

233 – 42 .

14. Swaddle JP , Cuthill IC . Asymmetry and human facial attractiveness: Symmetry may

not always be beautiful . Proc R Soc Lond: Series B 1995 ; 261 , 111 – 16 .

15. Carruthers J , Glogau RG , Blitzer A . Advances in facial rejuvenation: botulinum

toxin type a, hyaluronic acid dermal fi llers, and combination therapies – consensus

recommendations . Plast Reconstr Surg 2008 ; 121 ( suppl 5 ) 5S – 30S .

16. Raspaldo H. Volumizing effect of a new hyaluronic acid sub - dermal facial fi ller: A

retrospective analysis based on 102 cases . J Cosmet Laser Ther 2008 ; 10 , 134 – 42 .

17. Coleman SR. Structural Fat Grafting . Quality Medical Publishing , 2004 .

18. Donafrio LM. Fat distribution: A morphologic study of the aging face . Dermatol Surg

2000 ; 26 : 1107 – 12 .

Hyaluronic Acids: Clinical Applications Derek Jones Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, USA

Timothy C. Flynn Cary Skin Center, Cary, and Department of Dermatology, University of North Carolina, Chapel Hill, North Carolina, USA

CHAPTER 12

In the year 2007 alone, approximately 1.5 million reported fi ller proce-

dures were performed in the USA, 1 with the hyaluronic acid (HA)

products Juv é derm and Restylane sharing the top sales in this market.

These treatments are effective because, as a person ages, the amount of

hyaluronic acid in the skin is reduced, which decreases the skin ’ s water -

binding capacity and tissue turgor, leading to visible wrinkles and droop-

ing skin. The signs of aging are accelerated with sun exposure, specifi cally

ultraviolet - B (UVB) radiation. A 2007 study reported that UVB radiation

decreases the amount of HA in the dermis and upregulates the number

of HA degradation products (such as hyaluronidase). 2 HA fi llers are

designed to restore the appearance of youth to the skin by replacing HA

and binding water, thus reducing the aged appearance of sagging skin

and skin folds.

In Chapter 3 we learned that several variables affect the performance

of individual HA fi llers, including the concentration of HA, degree of

crosslinking, cohesivity, G ′ , and particle size, which all interact to create

the unique properties of a particular HA product. Each of these factors

may be determined and compared, allowing the physician to have a better

appreciation of how to use the various HA products to obtain optimal

patient outcomes.

At the time of writing there are six FDA - approved HA fi llers: Juv é derm

Ultra and Ultra Plus (Allergan, Irvine, CA), Restylane/Perlane (Medicis,

Scottsdale, AZ), Prevelle Silk (Mentor, Irving, TX), and Hydrelle (Anika

Therapeutics, Woburn, MA). The pivotal trial data leading to FDA approval

for each fi ller are reviewed below.

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

158

Hyaluronic Acids: Clinical Applications 159

HA fi llers

Restylane Restylane is a particle HA product consisting of 100 000 gel particles per

milliliter derived from bacterial fermentation. The pivotal trial for

Restylane, as performed and reported by Narins et al., 3 randomized 138

patients with prominent nasolabial folds to receive Restylane in one

nasolabial fold and bovine collagen (Zyplast) in the contralateral fold.

Treatments were repeated at 2 - week intervals until optimal cosmetic

results were obtained. A blinded investigator evaluated outcomes at 2,

4, and 6 months after baseline. Results proved that less injection volume

of Restylane was required to reach optimal cosmetic result compared

with Zyplast, and that patients and investigators judged Restylane to be

more effective in maintaining the cosmetic correction. The investigator -

based Wrinkle Severity Rating Scale (WRSR) and Global Aesthetic

Improvement Scale assessments at 6 months after baseline indicated that

Restylane was superior in 56.9% and 62.0% of patients, respectively,

whereas Zyplast was superior in 9.5% and 8.0% of patients, respectively.

The frequency, intensity, and duration of injection site reactions were

similar for the two products. It was concluded that Restylane provides

a more durable aesthetic improvement than Zyplast and is well tolerated.

A recent study has shown that improvements seen after initial treatment

with Restylane persisted for up to 18 months with one retreatment. 4

Reasons for persistence after reinjection include the increased production

of native collagen which has been shown to be promoted by fi broblast

stretching. 5

Perlane Perlane, a more viscous form of Restylane containing larger - sized particles

of gel, received the approval of the Food and Drug Administration (FDA)

in 2007 based on four prospective, randomized clinical studies enrolling

559 patients. 6 The largest study enrolled 283 patients who were rand-

omized to receive Restylane in one nasolabial fold and Perlane in the

contralateral fold, with the primary effi cacy endpoint being the difference

in WSRS scores compared with baseline at 12 weeks, with secondary

endpoints at 2, 6, and 24 weeks. At 12 weeks, 122 (87%) of the patients

in the Perlane group and 108 (77%) in the Restylane group maintained

at least a 1 - point improvement in the WSRS score. At 24 weeks, 63% of

the Perlane patients maintained at least a 1 - point improvement, compared

with 74% of Restylane patients. The differences between the two products

were not statistically signifi cant and therefore Perlane is considered “ non-

inferior ” to Restylane.

160 Chapter 12

Juv é derm Juv é derm, compared with Restylane, is a higher concentration HA (24 mg/

mL), has a higher concentration of crosslinked HA, contains less uncross-

linked HA, and utilizes homogenization in preparation of the fi nal

product, which gives the gel a comparatively smoother consistency.

Proponents of Juv é derm argue that Juv é derm promotes a smoother

result after injection compared with Restylane. However, this has never

been proven in well - designed head - to - head trials. The Juv é derm pivotal

FDA trial, as studied and reported by Baumann et al., enrolled 439

subjects who were randomized to receive one of three formulations of

Juv é derm in one nasolabial fold and Zyplast collagen in the contralateral

fold. 7 At 24 weeks, all three preparations achieved considerably longer -

lasting clinical correction than bovine collagen with 81 – 90% of Juv é derm -

treated patients maintaining a clinically signifi cant improvement from

baseline for 6 months or longer (Figure 12.1 ). 7 Up to 88% of subjects

preferred Juv é derm over bovine collagen. All fi llers were similarly well

tolerated. Currently, Juv é derm and Juv é derm Ultra Plus are available in

the USA. Juv é derm Ultra Plus is a robust fi ller with a higher degree of

crosslinking and is indicated where more robust fi lling is needed (i.e.

deeper nasolabial folds). Similar to Restylane, longer - term follow - up has

shown persistence of the product for up to a year or longer after repeat

treatments. 8 Therefore, both Restylane and Juv é derm may be considered

semi - permanent fi llers.

Prevelle Silk Prevelle Silk is a 5.5 mg/mL HA particle gel containing lidocaine which

decreases pain on injection. With the exception of the addition of lido-

caine, it is identical to Captique, which is no longer available in the USA.

Compared with Restylane and Juv é derm, it contains a much lower con-

centration of HA, and is considered a “ softer ” HA fi ller with less lift capac-

ity. It has a shorter duration of correction (3 months or less). The FDA

pivotal trial was a prospective, single - blind, randomized, single - center,

split - face study conducted in 45 individuals to evaluate the safety and

injection pain during and after the injection procedure with dermal injec-

tion with and without lidocaine into contralateral nasolabial folds. 9 Pain

assessments for the Prevelle Silk - treated sides were lower during injection

and for up to 1 hour post - treatment. The majority of patients preferred

the Prevelle Silk - treated side because it was less painful. Prevelle Silk is

manufactured in the same manner as Hylan B gel (previously available in

the USA as Hylaform), except that the HA in Prevelle Silk is derived from

a bacterial source rather than from an avian source and includes the addi-

tion of 0.3% lidocaine hydrochloride. The FDA pivotal trial for Hylan B

enrolled 261 patients who were randomized and treated with either

Hyaluronic Acids: Clinical Applications 161

Zyplast or Hylan B in contralateral nasolabial folds. The results showed

that per nasolabial fold more volume of Zyplast was required for correction

(1.1 mL) compared with Hylan B (0.75 mL), and duration of correction

was similar to Zyplast at 12 weeks. Both fi llers were equally tolerated.

Ultra Plus Zyplast

2 weeks

24 weeks post Repeat Treatment 48 weeks post Repeat Treatment

24 weeksBaseline

Complimentary Repeat Treatment with Juvéderm

Ultra Plus ZyplastZyplast

Ultra Plus Ultra Plus Ultra Plus Ultra Plus

DBA FEC

G H I J

Ultra Plus

Ultra Plus

2 weeks

24 weeks post Repeat Treatment 48 weeks post Repeat Treatment

24 weeksBaseline

Ultra Plus ZyplastZyplast

Ultra Plus

A

G

Complimentary Repeat Treatment with Juvéderm

FE

Ultra Plus

DCB

Zyplast

JUltra PlusUltra Plus

IUltra Plus

H

Figure 12.1 Effectiveness of Juv é derm Ultra Plus dermal fi ller in the treatment of

severe nasolabial folds. (From Lupo MP, Smith SR, Thomas JA, Murphy DK,

Beddingfi eld FC 3rd. Plast Reconstr Surg 2008; 121 :289 – 97.)

162 Chapter 12

Hydrelle Hydrelle (formally Elevess) is a 28 mg/mL HA fi ller and, like all the other

currently FDA - approved fi llers, it is derived from bacterial fermentation.

Similar to Prevelle Silk, it contains 0.3% lidocaine hydrochloride. It also

contains sodium metabisulfi te as an antioxidant and is contraindicated in

those with sulfi te allergies. The FDA pivotal trial was a prospective, ran-

domized, controlled, double - blinded, multi - center study using Hydrelle in

one nasolabial fold and Cosmoplast human collagen in the contralateral

fold. 10 Up to three treatments at 2 - week intervals were allowed until

optimal correction was achieved. Visits occurred at 1, 4, 6, 9 and 12

months to establish safety and effectiveness. The primary effi cacy endpoint

was the change in the 6 - point wrinkle severity scale (Lemperle Scale) as

rated by a blinded, non - treating evaluator. The study randomized and

enrolled 141 patients. Results proved that compared to Cosmoplast, less

Hydrelle was required to reach optimal correction. Compared with

Cosmoplast, Hydrelle achieved a statistically signifi cant greater improve-

ment in correction at 4 months but not at 6 months. Adverse events were

similar except that more bruising and swelling occurred with Hydrelle

compared to Cosmoplast. The authors have been informed of numerous

anecdotal cases of infl ammatory reactions after injection of Hydrelle. This

may be due to excessive crosslinking of the product or excessive levels of

sodium metabisulfi te. Further studies are warranted.

Indications

It should be noted that all currently FDA - approved HAs have been studied

only in nasolabial folds and carry the specifi c indication on package inserts

that they are approved for dermal injection for correction of moderate - to -

severe facial wrinkles and folds, such as nasolabial folds. Although not

specifi cally FDA approved, available HAs have been studied off - label for

correction of glabellar rhytids, oral commissures (meilolabial folds), lips,

midface volumizing, infraorbital, or nasojugal grooves (tear troughs), and

augmentation of the dorsal hand. Each off - label indication is considered

separately below.

Glabellar r hytids Botulinum toxin A (BTX - A) is the standard treatment for glabellar

furrows. However, some individuals have resting glabellar rhytids that

are suffi ciently deep or “ etched - in ” that they respond poorly to BTX - A.

Carruthers and Carruthers performed a study to retrospec tively

compare the effi cacy of BTX - A combined with intradermal Hylan B with

the effi cacy of BTX - A alone in 16 individuals with moderate - to - severe

glabellar rhytids. 11 Their response to Hylan B plus BTX - A was compared

Hyaluronic Acids: Clinical Applications 163

clinically and photographically to their response with BTX - A alone.

Results showed that all subjects had moderate or severe glabellar rhy tids

at rest before treatment. After BTX - A alone, none (0%) had achieved

no or mild rhytids. After BTX - A and Hylan B injection, only 1 of 16

(6%) had moderate glabellar rhytids, with the remainder (94%) being

mild. The authors concluded that moderate - to - severe glabellar rhytids

were better treated by BTX - A with Hylan B than with BTX - A injection

alone.

In the author ’ s opinion, BTX - A works best when combined with about

0.4 mL on average of Restylane or Juv é derm, which contains the ideal

volume to achieve optimal correction for most patients with deep etched -

in glabellar lines who are unlikely to respond to BTX - A alone. Furthermore,

learning to identify patients at baseline who will respond better to a com-

bination of HA and BTX - A will often result in higher patient satisfaction

if the patient is informed of that before any treatment is administered.

In the glabellar area, HA should be injected into the mid - to deep dermis,

using a slow, linear retrograde technique, with small amounts with each

linear pass. Caution should be noted with glabellar injections in that the

supratrochlear artery runs in the immediate subdermal plane. Inadvertent

injection into this artery may cause tissue ischemia and severe tissue

necrosis. 12 Impending necrosis, manifested as a sudden blanching of tissue

in the watershed distribution of the supratrochlear artery, followed by a

reticulated purple to blue mottled discoloration of the skin, may be imme-

diately reversed by injection of hyaluronidase into the area. 13

Lips and o ral c ommissures Loss of volume and vermillion defi nition of the lips, combined with loss

of the supporting volume of the oral commissures, represent common and

signifi cant components of the aging process in the perioral region. Options

for approved, lip - enhancement agents are limited, although off - label use

of hyaluronic acid - based dermal fi llers is frequently employed.

A recent multi - center feasibility study for lip enhancement using Juv é -

derm Ultra was conducted under an Investigational Device Exemption. 14

The study was a prospective, open - label, multicenter study treating lips

and perioral areas with touch - up treatments allowed at 2 weeks after

initial treatment if needed to reach optimal correction. The primary effec-

tiveness analysis was performed by determining “ responders, ” as defi ned

as the individuals who at 12 weeks increased their lip fullness greater or

equal to 1 point on a 4 - point - validated lip fullness scale (as rated by a

blinded noninjecting expert physician) and who also met their lip fullness

scale treatment goals. The primary study phase was 6 months, with addi-

tional visits at 6 - week intervals for up to an additional 6 months until lip

fullness returned to baseline score.

164 Chapter 12

Fifty individuals were enrolled, and these participants served as their

own controls. For eligibility, participants were required to be at least 18

years old, desire enhancement of the lips (vermillion borders, vermilion

mucosa, Cupid ’ s bow, philtral columns, oral commissures), and judged by

the evaluating investigator as having attainable treatment goals and a pre -

treatment lip fullness score of minimal or mild on the 4 - point lip fullness

scale. Lip fullness goals were established by the treating investigator and

participant before treatment. Assessments were made by the participant,

treating investigator and an evaluating investigator blinded to the volume,

location of treatment, and previous assessment scores.

At each visit lip fullness, perioral lines, and oral commissures were

assessed using validated photometric scales, and standardized three -

dimensional images were obtained for measurement of lip changes. Safety

evaluations included common treatment site reactions as well as lip sensa-

tion and functionality assessments.

Results showed that the average treatment volume was 1.6 mL total

of Juv é derm Ultra for the upper and lower lip and oral commissures

(Figure 12.2 ). 6 Touch - ups were required for 18 of 50 patients at 2 weeks

with an average volume of 0.6 mL. At the 12 - week primary endpoint, 71%

Figure 12.2 Baseline and weeks 2, 12, and 36: poster presentation at the American

Society of Aesthetic Plastic Surgery, Las Vegas, NV. May 2009. (From Fagien et al., 13

with permission of Allergan.)

Hyaluronic Acids: Clinical Applications 165

( p < 0.0001) of participants achieved their lip fullness goals and improved

greater or equal to 1 point on the lip fullness scale. The agreed endpoint

was pre - established as 40% of the cohort being defi ned as responders at

12 weeks, so clinical effectiveness was established.

Participant assessments showed that the vast majority were not adver-

sely affected by treatment in terms of lip function or sensation, whereas

investigator assessments demonstrated little change from baseline in

lip functionality, both in repose and in animation. The most common

treatment reactions were transient swelling (94%), bruising (92%), and

tenderness (88%). Aside from these treatment reactions, there were no

adverse events related to the Juv é derm injection. The conclusion was that

the results of 50 patients demonstrate the utility of Juv é derm Ultra for lip

enhancement and improvement of perioral lines and oral commissures

with an acceptable safety profi le.

Both the authors prefer Juv é derm for perioral treatments. When inject-

ing lips with Juv é derm, the author DJ employs an intraoral sulcus block

with 2% lidocaine without epinephrine for anesthesia and employs a

linear retrograde technique with a 30G 1 - inch needle. In addition, a small

amount of 1% lidocaine may be mixed with the Juv é derm Ultra just

before injection using the female - to - female Luer - Lok transfer technique

described below. A demonstration of lip injections performed by this

author may be found in the DVD that accompanies this book.

Cheek v olumizing Many signs of aging are due to loss of subcutaneous fat in the malar

and submalar cheek regions. Fillers, including HAs, may successfully

volumize this area when injected appropriately (Figure 12.3 ). Chapter 12 ,

entitled “ The mathematics of facial beauty: a cheek enhancement guide

(a) (b)

Figure 12.3 Before (a) and 2 weeks after (b) Restylane for treatment of facial

lipoatophy.

166 Chapter 12

for the aesthetic injector ” , specifi cally addresses cheek enhancement

using HA fi llers.

Juv é derm Voluma is a new HA fi ller that is not yet FDA approved,

although FDA studies are underway. It is a 20 mg/mL HA of streptococcal

origin with a higher lift capacity. It has a lower molecular weight and

higher crosslinking ratio than other available HAs. It will be indicated

for subcutaneous/supraperiosteal injection for facial volumizing and con-

touring. It should be noted that fi llers must be injected into the subcutane-

ous or supraperiosteal plane when volumizing the midface. Intradermal

or too superfi cial injection may create persistent dermal contour

irregularities.

A recent study performed by Raspaldo 2 assessed effectiveness and safety

of Voluma in maintaining increased volume in the malar area for up to

18 months post - treatment. Retrospective record data were analyzed for

102 patients (93 women, 9 men; mean age 51.27 years) who received

Voluma injected into the midface. All patients were assessed at baseline,

1 month, and 6 – 18 months post - injection. The Investigator Global

Aesthetic Improvement assessment after 1 month and 6 – 18 months

showed that most patients were “ much ” or “ very much ” improved.

Investigator volume loss assessment confi rmed that most patients were

either stage 1 or 2 (normal or slight midfacial atrophy) 1 month post -

treatment, which was maintained at 6 – 18 months. Patient effi cacy assess-

ment was “ very good ” or “ good ” in most cases. It was concluded that

Voluma provides aesthetic improvements according to investigator and

patient assessment for up to 18 months post - treatment with an excellent

safety profi le.

Dorsal h and v olumizing Most injectable fi ller procedures have concentrated on the face. Many

patients complain of thinning of the skin on the dorsal hand and subse-

quent increased visibility of the subcutaneous veins. Injection of fi llers,

including HA, into the subcutaneous skin of the dorsal hand can restore

dermal thinning.

A recent study compared the use of hyaluronic acid (Restylane, Medicis

Aesthetics Inc.) and collagen (Cosmoplast, INAMED Aesthetics) for soft -

tissue augmentation of the dorsal hands. 15 Ten female patients who dem-

onstrated dermal thinning of the dorsal hands were randomized to receive

1.4 mL of hyaluronic acid or 2.0 cm collagen to alternate interphalangeal

spaces of the dorsal hands. Patients returned at 1 week, 1 month, 3

months, and 6 months for digital photography and completion of a patient/

physician questionnaire. Hands were scored by two separate blinded

Hyaluronic Acids: Clinical Applications 167

physicians on scales of 1 – 5 for clearance of veins. Patients scored both

tolerability and satisfaction on a scale of 1 – 5. Hyaluronic acid proved to

be superior to collagen in effi cacy with analysis showing a mean difference

of 0.95 (0.004) and a median difference of 0.9 (0.008) for clearance. The

satisfaction difference was not signifi cant with a mean difference of 0.80

(0.070) and median difference of 1.0 (0.117). It was concluded that the

use of soft - tissue fi llers is a viable tool in hand rejuvenation with hyaluronic

acid proving to be superior in effi cacy to collagen.

As with the cheek, injectable fi llers in the dorsal hands should be into

the subcutaneous plane. Care should be taken to avoid intravascular

injection into the subcutaneous veins, which could lead to pulmonary

embolism.

Infraorbital h ollows ( n asojugal f olds, t ear t roughs) The infraorbital hollow (also termed the ‘ nasojugal ’ groove or tear

trough) is one of the more sought - after indications for HA injection.

Performed correctly, patient satisfaction is high (Figure 12.4 ). However,

it is also the most challenging for the injector to master. In the author

DJ ’ s referral practice, it is the most commonly encountered area

for patients seeking treatment for an adverse event (overvolumizing,

lumpiness, or visible show of material) caused by other injectors.

Thankfully, these adverse events are readily treatable with the injection

of hyaluronidase. 16

In general, only the very experienced injector should attempt correction

of this area. The HA should be injected in the immediate epiperiosteal

plane deep to the orbicularis oculi using small depot injections with a

serial puncture technique. Alternatively linear injection may be used

through a 30G needle. Subdermal injection should be assiduously avoided

because lumpiness, counter irregularities, and the Tyndall effect are

common with subdermal injections. Care should be taken not to damage

the infraorbital nerve, which exits in this area, and not to penetrate

the nasal sidewall arteries. Treatment of the infraorbital hollow often

gives the best results when cheek fi lling is performed concomitantly.

Figure 12.4 Before (left) and after (right) Juv é derm Ultra for prominent tear troughs.

168 Chapter 12

Figure 12.5 Before (a – c) and 2 weeks after (d – e) Juv é derm Ultra and Ultra Plus to

the nasolabial folds, lips, and oral commissures. (Details of this treatment performed

by the author (DJ) can be viewed on the DVD that accompanies this book.)

(a)

(b)

(c)

(d)

(e)

(f)

Hyaluronic Acids: Clinical Applications 169

Two excellent manuscripts – by Bosniak and Sadick 17 and Hirsch et al. 18

have recently been published on proper techniques in this area and

should be considered mandatory reading for all physicians interested in

treating this area.

Safety

The safety profi les of currently FDA - approved HA fi llers are strong. The

most common procedure - or device - related adverse events are injection

site erythema, swelling, pain, and bruising, all of which usually resolve

within a few days. More serious complications can sometimes occur and

most can be avoided with appropriate injection techniques.

Inappropriate or superfi cial placement is one of the most frequent

reasons for patient dissatisfaction. Too superfi cial placement of HA in the

dermis can result in a Tyndall effect, which is a blue discoloration caused

by the refraction of light from the clear gel visible superfi cially in the skin.

Although most physicians believe that they are injecting intradermally in

the nasolabial fold, a recent study documents that most properly injected

HA actually resides in the immediate subcutaneous plane. 19 To avoid

superfi cial injection, care should be taken that, when injecting in a linear

fashion, the metal hub of the needle should not be visible through the

skin in the plane of injection.

True hypersensitivity to injectable HA is rare, and occurs about 1/5000

cases. Infection is quite uncommon as well and can usually be managed

with either antibiotics or antivirals depending on the clinical features.

Injection of HA into the perioral area can potentiate recurrence of herpes

simplex virus (HSV) infection, and patients prone to recurrent perioral

HSV infection should receive appropriate antiviral prophylaxis before

treatment.

The most worrisome complication is cutaneous necrosis, which is most

commonly caused by occlusion of vascular structures by inadvertent injec-

tion of HA intravascularly or by sidewall compression of vascular struc-

tures due to overvolumizing of the surrounding soft tissue. The

supratrochlear artery in the glabellar area and the angular artery in the

superior nasolabial fold are particularly susceptible, and these areas should

be considered “ high risk. ” The injecting physician should have masterful

knowledge of vascular structures in areas of injection (Figure 12.6 ). A

protocol to treat the full spectrum of cutaneous necrosis has recently been

reviewed by Cohen, 12 Hirsch and Carothers. 13

Due to the reversibility of hyaluronic acid, complications from these

fi llers can be easily corrected. The use of ovine testicular hyaluronidase

(Vitrase) can dissolve injected HA, which is highly useful if the product

170 Chapter 12

Figure 12.6 Vascular anatomy of the

midface. The angular artery (a branch

of the facial artery) anastomoses with

the supratrochlear and dorsal nasal

arteries (branches of the ophthalmic

artery), joining the external carotid

artery network with the internal

carotid artery network. Occlusion or

embolic events involving this network

can lead to extensive tissue necrosis.

ST, supratrochlear artery; D, dorsal

nasal artery; A, angular artery; SF,

superior labial artery; F, facial artery.

is misplaced, 4 if there is a complication post - injection (e.g. vascular occlu-

sion or delayed granulomatous reactions), 4 or if there is impending vas-

cular necrosis. 13 Studies are ongoing to determine the proper dosing of

hyaluronidase. In the author DJ ’ s experience, 10 units of hyaluronidase

per 0.1 mL of Juv é derm or 5 units per 0.1 mL of Restylane to be dissolved

is the most appropriate dose. The need for the greater amount of hyaluro-

nidase for Juvederm has been proven with in - vitro studies, and is likely

because the product is more highly crosslinked, has a higher concentration

of HA, and is is non - particulate and more cohesive, allowing for less pen-

etration of hyaluronidase. Further studies are warranted to refi ne in - vivo

dosing recommendations and to determine if this resistance profi le confers

longer in - vivo residence time of Juvederm compared to other HA fi llers. 20

Anesthesia

A new trend with HA fi llers is the addition of lidocaine to the product to

decrease the pain of treatment. although Prevelle Silk and Elevess cur-

rently have lidocaine preincorporated in the fi nal product, Restylane/

Perlane and Juv é derm do not, although they are the most commonly

injected fi llers.

A Juv é derm product with lidocaine is expected to receive FDA

approval in the near future. A recent study has shown that the use of

preincorporated lidocaine in Juv é derm greatly increases patient comfort

during the procedure. 21 This double - blind study at three centers enrolled

60 participants, injected with either Juv é derm with or without lidocaine,

Hyaluronic Acids: Clinical Applications 171

randomly assigned to left or right nasolabial fold. The injecting phy-

sician assessed severity of pain and ease of injection. Participants used

a visual analog scale (0 – 10) for pain assessment. Adverse events were

recorded. Physician assessment of injection pain was none or mild in

81% of HA gel injections with preincorporated lidocaine and 36% of

HA - alone injections ( p < 0.001). Mean pain assessment by participants

was 3.6 for HA plus lidocaine and 5.8 for HA alone ( p < 0.001). Ninety -

fi ve percent of the injections were considered easy or very easy; a

greater percentage of HA plus lidocaine injections was rated very easy.

Mild - to - moderate expected treatment - related adverse events were

reported for both products. Juv é derm with preincorporated lidocaine

increased participant comfort during treatment and improved the

injection expe rience, and does not appear to compromise safety or effec-

tiveness of the product.

Although Juv é derm and Restylane are currently sold without preincor-

porated lidocaine in the USA, these fi llers are often used off - label with

physician - added lidocaine. In the author DJ ’ s experience, it is best to use

a 1 : 10 dilution of 1% lidocaine with epinephrine:HA fi ller. The lidocaine

is mixed with the fi ller using a female - to - female adapter, with the

product pushed back and forth approximately 20 times. This off - label

technique is demonstrated in the DVD that accompanies this book. To

further enhance patient comfort, the authors recommend application of

topical anesthesia such as EMLA to the injection site for at least 15

minutes before the procedure, and the use of an intraoral sulcus block

when injecting the lips.

Injection t echniques

Patients should be clear in their treatment goals and all risks, benefi ts,

indications, and options of treatment should be discussed. Photographs

and written informed consent should be considered mandatory for all

patients. Furthermore, patients should be advised to refrain from anti-

coagulants such as NSAIDs, fi sh oil, and ginko and other sup plements

for 7 days before the procedure to limit the potential for bruising.

A variety of HA injection techniques may be utilized depending on the

indication, including antegrade or retrograde linear threading, serial punc-

ture, crosshatching, and subcutaneous and epiperiosteal injection. Good

results are often technique related, and the initial learning curve is steep.

Likewise, aesthetic artistic talent is necessary; similar to artists, some injec-

tors will achieve better results than others. Great care must be taken not

to inject too superfi cially, too quickly, or intravascularly. It is the author ’ s

belief that the best learning occurs by observing good injection technique

172 Chapter 12

and by accumulating experience by performing injections. The author

DJ ’ s favored injection techniques of nasolabial folds, oral commissures,

and lips are demonstrated in the DVD that accompanies this textbook

(Figure 12.5 ). Novice injectors should begin by injecting the nasolabial

folds, and then progress to off - label areas such as lips and midface volu-

mizing once that has been mastered.

One question associated with dermal fi llers is whether the rate and

variability of local adverse events after treatment are related to injection

technique and needle trauma or to the intrinsic chemical composition.

Glogau and Kane 22 recently performed a study to determine if there is a

relationship between dermal fi ller injection technique and the incidence

of local adverse events. A prospective, blinded, controlled study enrolled

283 patients who were randomized to receive midface volume correction

of the nasolabial folds and oral commissures with Restylane or Perlane.

Data was collected on multiple injection technique variables to assess

adverse events. Injection techniques that increase the dissection of the

subepidermal plane (e.g. fanlike needle use, rapid injection, rapid fl ow

rates, and higher volumes) increased the incidence of local adverse events.

Injection techniques that increase epidermal damage or subcutaneous

exposure (e.g. multiple punctures or deep subcutaneous injection) had no

effect on adverse events. Furthermore, single injection correction, depth

of injection, and Restylane/Perlane injected had no effect on local adverse

events. It was concluded that local adverse events after injection with the

Restylane/Perlane fi llers used in this study were related to investigator

technique and not to differences in the intrinsic properties of the HA

agents.

Helpful tips to decrease adverse events include stopping antiplatelet or

anticoagulant medications before injection as appropriate. This will

decrease the bruising and local reactions in the skin. The use of topical

anesthetics 30 minutes before injection can decrease the pain of the needle

stick. Ice or local skin cooling can help decrease the injection pain and

post - treatment icing may also decrease bruising.

Several other HAs are being used in clinical trials in the USA. They

include Puragen Plus (Mentor Corporation, Santa Barbara, CA), which

contains lidocaine integrated directly into the formula, Belotero Soft and

Belotero Basic (Anteis, Geneva, Switzerland), and Teosyal (Teoxane

Laboratories, Geneva, Switzerland).

In summary, HA fi llers last longer than bovine and human collagen

and in general have better patient satisfaction, longer - lasting correction,

and similar incidence of adverse events. Practitioners are now using

HA fi llers in most areas of the face, and are using them at deep and

midfacial planes to replace lost facial volumes to give a natural, more

beautiful result.

Hyaluronic Acids: Clinical Applications 173

References

1. http://www.surgery.org/media/news-releases/117-cosmetic-procedures-in-2007- ,

accessed December 12, 2009 .

2. Raspaldo H. Volumizing effect of a new hyaluronic acid sub - dermal fi ller: a retro-

spective analysis based on 102 cases . J Cosmet Laser Ther 2008 ; 10 : 134 – 42 .

3. Narins RS , Brandt F , Leyden J , Lorenc ZP , Rubin M , Smith S . A randomized, double -

blind, multicenter comparison of the effi cacy and tolerability of Restylane versus

Zyplast for the correction of nasolabial folds . Dermatol Surg 2003 ; 29 : 588 – 95 .

4. Narins RS , Dayan SH , Brandt FS , Baldwin EK . Persistence and improvement of

nasolabial fold correction with nonanimal - stabilized hyaluronic acid 100,000 gel

particles/ml fi ller on two retreatment schedules: results up to 18 months on two

retreatment schedules . Dermatol Surg 2008 ; 34 ( suppl 1 ): S2 – 8 .

5. Wang F , Garza LA , Kang S , et al. In vivo stimulation of de novo collagen production

caused by cross - linked hyaluronic acid dermal fi ller injections in photodamaged

human skin . Arch Dermatol 2007 ; 143 : 155 – 63 .

6. Perlane Prescribing Information. Medicis Pharmaceutical Corporation . www.

medicis.com/products/pi/pi_perlane.pdf . Accessed December 12, 2009 .

7. Baumann L , Lupo M , Monheit G , Thomas J , Murphy D , Walker P . Comparison of

smooth - gel hyaluronic acid dermal fi llers with cross - linked bovine collagen: a multi-

center, double - masked, randomized, within - subject study . Dermatol Surg 2007 ; 33

( suppl 2 ): S128 – 35 .

8. Smith S , Jones D . Poster presentation: Effi cacy and safety following repeat treatment

for a new family of hyaluronic acid based fi llers . American Academy of Dermatology

Academy 2006 Meeting, San Diego, CA, 2006 .

9. Prevelle Silk . Package insert. Mentor Corporation, 2007 .

10. Elevess . Package insert. Anika Therapeutics, Inc, 2006 .

11. Carruthers J , Carruthers A . A prospective, randomized, parallel group study analyz-

ing the effect of BTX - A (Botox) and nonanimal sourced hyaluronic acid (NASHA,

Restylane) in combination compared with NASHA (Restylane) alone in severe gla-

bellar rhytides in adult female subjects: treatment of severe glabellar rhytides with

a hyaluronic acid derivative compared with the derivative and BTX - A . Dermatol Surg

2003 ; 29 : 802 – 9 .

12. Cohen J. Understanding, avoiding, and managing dermal fi ller complications .

Dermatol Surg 2008 ; 34 ( suppl 1 ): S92 – 9 .

13. Hirsch R , Cohen J , Carruthers J , Carruthers A . Successful management of an

unusual presentation of impending necrosis following a hyaluronic acid injection

embolus and a proposed algorithm for management with hyaluronidase . Dermatol

Surg 2007 ; 33 : 357 – 60 .

14. Fagien S , Mass C , Thomas J , Murphy D , Beddingfi eld F. Juvederm Ultra for lip

enhancement: an open label, multicenter study . Poster presentation at the American

Society of Aesthetic Plastic Surgery, Las Vegas, NV, May 2009.

15. Man J , Rao J , Goldman M . A double - blind, comparative study of nonanimal -

stabilized hyaluronic acid versus human collagen for tissue augmentation of the

dorsal hands . Dermatol Surg 2008 ; 34 : 1026 – 31 .

16. Brody HJ . Use of hyaluronidase in the treatment of granulomatous hyaluronic acid

reactions or unwanted hyaluronic acid misplacement . Dermatol Surg 2005 ; 31 :

893 – 7 .

17. Bosniak S , Sadick N , Cantisano - Zilkha M , Glavis IP , Roy D. The hyaluronic acid

push technique for the nasojugal groove . Dermatol Surg 2008 ; 34 : 127 – 31

174 Chapter 12

18. Hirsch R , Carruthers J , Carruthers A . Infraorbital hollow treatment by dermal fi llers .

Dermatol Surg 2007 ; 33 : 1116 – 19 .

19. Arlette JP , Trotter MJ . Anatomic location of hyaluronic acid fi ller material injected

into naso labial fold: a histologic study . Dermatol Surg 2008 ; 34 ( suppl 1 ): S56 – 63 .

20. Jones D , Borell M , Tezel A . In vitro resistance to degradation of hyaluronic acid

dermal fi llers by ovine testicular hyaluronidase . Dermatologic Surgery , In press.

21. Levy PM , Deboulle K , Raspaldo H . Comparison of injection comfort of a new cat-

egory of cohesive hyaluronic acid fi ller with preincorporated lidocaine and a

hyaluronic acid fi ller alone . Dermatol Surg 2009 ; 35 ( suppl 1) : 332 – 7 .

22. Glogau R , Kane M . Effect of injection techniques on the rate of local adverse events

in patients implanted with nonanimal hyaluronic acid gel dermal fi llers . Dermatol

Surg 2008 ; 34 : S105 – 9

175

Index

abscesses, sterile 132

acetaminophen 86

acrylamide 91

Adatosil 83

adverse effects see complications

aging process 147

Aldara 128, 130

allopurinol 118

alprazolam 86

Amazing-gel 91, 95

amoxicillin 99

analgesia see pain management

anesthesia see local anesthesia

Aquamid 91

indications 92–3, 99

injection technique 94

Aquinas, St Thomas 141

Argiform 91, 92

indications 93

injection technique 94

arnica 124, 125

Artecoll

complications 127, 128, 130

effi cacy 109–13

history 104, 105, 106, 107

safety 114–15

Artefi ll 103, 119

complications 113, 127, 130

granulomas 118–19

history 104–9

mechanism 109

practical applications 115–18

safety 113, 115

and Sculptra 65

Arteplast 103, 104, 118

Artes Medical, Inc. 109

articaine 50

aspirin 124

assessment 7

Augmentin 99

awareness of cosmetic dermatology

practice 3

BCDI (biscarbodi-imide) 21

BDDE (1,4-butanediol diglycidyl ether)

21

beauty 140–3

mathematics 146–9

combination therapy 153–6

phi 143–6

technique 149–53

Belotero Basic 172

Belotero Soft 172

Betacaine 35

betamethasone dipropionate 118

Biaxin 39, 129

Bio-Alcamid

complications 95, 96, 97

indications 92, 93, 99

injection technique 93–4

properties 91

biocompatibility 54

176 Index

biofi lms 132

hydrogel polymers 98, 100

polymethylmethacrylate 114

silicone 87

Bioformacryl 91

biostimulatory agents 54

see also Sculptra

bleomycin 118

bone, and aging process 72

botulinum toxin A (BTX-A) 162–3

and Evolence/Evolence Breeze 47,

48, 49, 50

bovine collagen 43

history 43, 44, 78

hypersensitivity reactions 133

polymethylmethacrylate 103, 104,

109, 116

see also Zyderm; Zyplast

breastfeeding

CaHA microspheres 33–4

Sculptra 64

bromelain 124–5

Caine tips 11

calcium hydroxylapatite (CaHA)

microspheres (Radiesse) 37, 40

anesthetic mixed with 8–10

clinical experience 29–31

complications 127–8

considerations 33–40

contraindications 65

duration 31

effi cacy 29–30

follow-up treatment 40

injection techniques 32

lower face injections 35–40

midface injections 35–7

nodules 31

pain management 34

pivotal trials 28–9

post-treatment procedures 40

properties and mechanism of action

27–8

radiographic properties 32

safety 31–4

cancelled procedures 7

Candida species 98

Captique 160

celery root 124

cephalexin 96, 118

cheek 146–9

augmentation 149–53

chilling 10, 11, 17

hyaluronic acids 172

chlorhexidine 131

clarithromycin 99, 131, 132

clavulanate potassium 99

clindamycin 96, 99

closing room 4

cohesivity of hyaluronic acids 24–5

collagen

bovine 43

history 43, 44, 78

hypersensitivity reactions 133

polymethylmethacrylate 103, 104,

109, 116

see also Zyderm; Zyplast

complications

emboli 136

granulomas 128

hypersensitivity reactions 133

injection site reactions 122, 124

history 43–4, 78

human 43, 133

history 44

trial 28

see also Cosmoplast

porcine see Evolence/Evolence

Breeze

combination therapy 153–5

complications 121–2

granulomas 128–30

hypersensitivity reactions 132–4

hypertrophic scarring 130–1

infection 131–2

injection site reactions 122–5

necrosis 134–6

nodules and papules 125–8

see also under specifi c fi llers

concentration of hyaluronic acids 22

consent 7

hyaluronic acids 171

Sculptra 65

silicone 84

Index 177

consultation see cosmetic patient

consultation

consultation sheets 6

contaminated fi llers 132

cooling 10, 11, 17

hyaluronic acids 172

cosmetic coordinators 6

cosmetic offi ce practice (COP) 1–2

cosmetic patient consultation (CPC) 1

assessment 7

components 2–7

cosmetic offi ce practice 1–2

education 5–7

setting 2–5

Cosmoderm 43, 133

history 44

Cosmoplast 43, 133

effi cacy 162, 166–7

history 44

trial 28

cost issues 6–7

counterfeit fi llers 122, 132

cranial nerve V 12

crosslinking

collagen implants 44, 45

hyaluronic acids 21

Depo-Medrol 118

deposits 6–7

Dermalive 65

dexamethasone 134

Diprosone 118

Divine Proportion 143–6

doxycycline 88

Dürer, Albrecht 143

DVS (divinyl sulfone) 21

education

internal 3, 7

patient 4, 5–7

CaHA microspheres 33–4

Sculptra 65

silicone 84

see also training

effective hyaluronic acid concentration

22

ELA-Max 10

elastic modulus of hyaluronic acids

22–3, 24

Elevess 158, 162

crosslinker 21

lidocaine 162, 170

emboli 136

EMLA cream 10, 11, 116, 171

environmental aids, anesthesia 11

epinephrine 11

CaHA microspheres 33–4

complications 11–12

Evolence/Evolence Breeze 50

hyaluronic acids 171

hydrogel polymers 94

mixed with dermal fi ller 8, 37

tissue infi ltration 16, 17

Escherichia coli 98

etanercept 88

Euclid 145

Evolence/Evolence Breeze 43, 44–5,

51–2, 133

clinical use 47–51

complications 47

contraindications 47, 48, 49–50

duration 46

effi cacy 46

injection techniques 50–1

safety 46

Evolution 91

extrusion force

CaHA microspheres 9

hyaluronic acids 24

facial analysis and mapping 70

facial beauty 140–3

mathematics 146–9

combination therapy 153–6

phi 143–6

technique 149–53

fat, and aging process 72

fat transplantation 128, 136

fi broplasia

hydrogel polymers 92

silicone 76–7, 85, 86, 87

fi nancial issues 6–7

fi sh oil 124, 171

5-fl uorouracil (5FU) 118

178 Index

Food and Drug Administration (FDA)

CaHA microspheres 27, 28, 29, 40

collagen implants 43, 44, 133

Evolence/Evolence Breeze 45, 48,

49

complications 121–2

crosslinkers 21, 45

hyaluronic acids 21, 158, 159, 160,

162, 170

hydrogel polymers 93

polymethylmethacrylate 103, 107,

109, 114, 115, 119

Sculptra 56

silicone 77, 78, 79, 80

Formacryl 91, 92

garlic 124

gel hardness 22–3

ginger 124

ginkgo biloba 124, 171

ginseng 1124

Glymatrix technology 45

Golden Mask 145, 146

golden mean caliper 145, 147

Golden Ratio 143–6

Golden Section 145

granulomas 128–30

polymethylmethacrylate 104, 107,

114, 115, 118–19

silicone 87–8

green tea 124

Gross, J. 43

helenalin 125

heparin 136

herpesvirus infection 131

CaHA microspheres 33

hyaluronic acids 169

Hinderer’s line 152, 153

history taking 34

HIV-associated lipoatrophy

CaHA microspheres 27, 28–9, 30,

33, 35, 37

complications 96, 126, 130

hydrogel polymers 92–3, 94, 96, 99

Sculptra 55

silicone 80–2, 84–5, 86

homeopathic medications 124–5

homogenization 24

human collagen 43, 133

history 44

trial 28

see also Cosmoplast

Hyacell 132

hyaluronic acids (HAs, hyalurons)

19–21, 25, 158

and CaHA microspheres 37, 39

complications 98, 167, 169–70, 172

granulomas 128

hypersensitivity reactions 133–4

hypertrophic scarring 131

infection 132

injection site reactions 122, 124

necrosis 136

nodules and papules 126

concentration 22

crosslinking 21

gel hardness 22–3

indications 162–9

injection techniques 171–2

local anesthesia 170–1

particle size 23–5

safety 169–70

see also Elevess; Juvéderm line;

Perlane; Prevelle Silk; Restylane

hyaluronidase 126, 128, 136, 163,

167, 169–70

hydrocodone 86

hydrogel polymers 100

complications 95–100

history and science 91–2

indications 92–3, 99

injection technique 93–5

properties 91–2

hydroquinone 87

hydroxychloroquine 99

Hylaform 160

Hylan B 160–1, 162–3

hypersensitivity reactions 132–4

hyaluronic acids 169

hypertrophic scarring 130–1

ibuprofen 118

icing 11, 17, 124

Index 179

Artefi ll 116

hyaluronic acids 172

Sculptra 65

imiquimod 88, 118, 128

infection 131–2

infl uenza 130

infraorbital nerve 12, 13

block 12–13, 14

mini-block 13–15

injection site reactions 122–5

Interfall 91, 92

indications 93

injection technique 95

isopropyl alcohol 131

isotretinoin 88

Juvéderm line 158, 160, 161

complications 129, 170

crosslinker 21

indications 163–5, 166, 167, 168

local anesthetic 124, 170–1

particle size 24, 25

kava-kava 124

Keats, John 140

Kefl ex 39

Kenalog 118

Kirk, D. 43

Knapp, T.R. 44

lactation

CaHA microspheres 33

Sculptra 65

Lemperle, Gottfreid 103

lidocaine 11–12

Artefi ll 103, 109, 116, 118

Betacaine 35

Elevess 162, 170

Evolence/Evolence Breeze 50–1

hydrogel polymers 94

infraorbital nerve block 13

Juvéderm 124, 165, 170–1

mixed with fi ller 8, 10

CaHA microspheres 8, 9, 33

Evolence/Evolence Breeze

50–1

Juvéderm 165, 171

Restylane 171

Sculptra 58

Prevelle Silk 160, 170

Puragen Plus 172

silicone 85, 86

tips 11

tissue infi ltration 17

topical anesthetics 10, 11

lidocaine tips 11

lipoatrophy see HIV-associated

lipoatrophy

liquid injectable silicone (LIS) see

silicone

LMX-4 10

local anesthesia

CaHA microspheres 8–10, 33

hyaluronic acids 170–1

hydrogel polymers 94

local tissue infi ltration 16–17

mixed with fi ller

CaHA microspheres 8–10, 33

Evolence/Evolence Breeze 50–1

hyaluronic acids 171

Sculptra 58

pre-treatment 10–11

Sculptra 58, 65

sensory nerve distribution in mid-

and lower face 12–16

silicone 85, 86

see also specifi c anesthetics

local tissue infi ltration 10, 16–17

low-molecular-weight heparin 136

Luer-Lok syringe

CaHA microspheres 8–9, 33

Evolence/Evolence Breeze 51

hydrogel polymers 93

Juvéderm 165

silicone 83

marionette lines 38–9

marketing 2–3

Marquardt, Stephen 141, 145, 146

massage

Artefi ll 117

CaHA microspheres 9, 35, 39

cheek augmentation 150

Evolence/Evolence Breeze 51

180 Index

local tissue infi ltration 17

Sculptra 60, 61

mathematics of facial beauty 146–9

combination therapy 153–6

phi 143–6

technique 149–53

medical records 5

mental nerve 12, 13

block 15–16

Metacrill 105, 106, 118

methylprednisolone acetonide 118

microdroplets 85

minocycline 99, 118

mirrors 4

mucosal swabs 11

muscle, and aging process 67

Mycobacterium abscessus 132

NASHA particles 23

nasolabial folds (NLFs), mini-block

13–15

necrosis 134–6

hyaluronic acids 163, 169, 170

nerve blocks 10, 124

infraorbital 12–15

mental 15–16

mini-block 13–15

nerves 12–16

New-Fill 55

NewPlastic 105, 106

nitroglycerin paste 136

nodules 125–8

CaHA microspheres 31

Evolence/Evolence Breeze 47, 51

hydrogel polymers 94, 99

no-shows 7

nursing mothers

CaHA microspheres 33

Sculptra 65

off-label treatments 122

Artefi ll 115

CaHA microspheres 10, 29

hyaluronic acids 162–9, 171

silicone 78, 82, 83, 84

ogee curve 150, 153

Outline 91

Paine, Thomas 140

pain management 11, 123–4

CaHA microspheres 33

Evolence/Evolence Breeze 50–1

silicone 86

see also local anesthesia

papules 125–8

particle size of hyaluronic acids

23–5

patient assessment 7

penicillin 39

Perlane 158, 159

crosslinker 21

injection techniques 172

local anesthesia 170

particle size 23–4

phi/Phi 143–6, 149

physical aids, anesthesia 11

polyacrylamide 91, 92

complications 132

polyalkylimide 92

complications 95

polydimethylsiloxane 76

poly-L-lactic acid (PLLA, Sculptra)

54–5, 56, 72

aging face and volume loss,

understanding 66–69

complications 71, 126–7, 128

composition and mechanism of

action 56–8

contraindications 59, 65

facial analysis and mapping 70–1

history 55–6

patient preparation 65

patient selection 65

predicting outcomes 61–4

preparation and injection technique

58–61

polymethylmethacrylate (PMMA)

103–7

complications 87, 98, 127, 130

granulomas 104, 107, 114,

118–19

contraindications 60

duration 111–13

effi cacy 109–13

mechanism 109

Index 181

practical applications 115–18

safety 113–15

porcine collagen see Evolence/Evolence

Breeze

prednisone 132

pregnancy

CaHA microspheres 34

Sculptra 64

silicone 82

Prevelle Silk 158, 160–1

crosslinker 21

local anesthesia 124, 160, 170

price issues 6–7

prilocaine 10, 35, 50, 116

Propionibacterium acnes 97

Protopic 128

public awareness of cosmetic

dermatology practice 3

pulse-dye laser 131

Puragen Plus 172

Radiesse (calcium hydroxylapatite

(CaHA) microspheres) 37, 40

anesthetic mixed with 8–10

clinical experience 29–31

complications 127–8

considerations 33–40

contraindications 33, 59

duration 31, 40

effi cacy 29–31

follow-up treatment 40

injection techniques 34

lower face injections 37–40

midface injections 35–7

nodules 31

pain management 34

pivotal trials 28–9

post-treatment procedures 40

properties and mechanism of action

27–8

radiographic properties 32–3

safety 31–3

radiographic properties, CaHA

microspheres 32–3

record keeping 5

refund policy 7

Remington, Kent 147

Restylane 158, 159

complications 122, 133–4, 170

crosslinker 21

duration 46

effi cacy 46

injection techniques 172

local anesthesia 170, 171

particle size 23–4

safety 47

Ricketts, R.M. 145

Royamid 91

St John’s wort 124

S-Caine patch 10

scarring, hypertrophic 130–1

scheduling of consultations 3–4, 5

Sculptra (poly-L-lactic acid, PLLA) 54,

72

aging face and volume loss,

understanding 66–70

complications 71–2, 126–7, 128

composition and mechanism of

action 56–8

contraindications 56, 60, 65

facial analysis and mapping 70–1

history 55–6

patient preparation 65

patient selection 65

predicting outcomes 61–5

preparation and injection technique

58–61

selling, organizational 2–3

sensory nerves 12–16

setting for cosmetic patient

consultation 2–5

Shakespeare, William 146

side effects see complications

silicone 75, 88

basic science 76

complications 86–8, 130, 132

contraindications 82

controversy 78–80

effi cacy 79

history 77–8

indications and patient selection

80–2

injection technique 85–6

182 Index

instrumentation 83–4

mechanism of action 76–7

patient preparation 84–5

safety 78–80

and Sculptra 65

skin aging 66

sodium metabisulfi te 162

Staphylococcus aureus 95, 97–8

sterile abscesses 132

St John’s wort 124

Streptococcus viridians 97

Suneva Medical, Inc. 109

symmetry, facial 147

Synera 10

tacrolimus 118

“talkesthesia” 11

Teosyal 172

tetracaine 10

timing of consultations 4, 5

tissue infi ltration 10, 16–17

topical anesthetics 10–11, 124

Artefi ll 116

CaHA microspheres 33–4

hyaluronic acids 172

Sculptra 66

silicone 85, 86

training 122

organizational 3, 7

Sculptra 56

silicone 75

triamcinolone 87, 97, 115, 118,

131

triangle of youth 147, 148

trigeminal nerve 12

Tyndall effect 125, 167, 169

ultraviolet-B (UVB) radiation 158

vascular anatomy of midface 170

vibration 11, 124

viscosity

Artefi ll 117

CaHA microspheres 9, 35

Evolence and Evolence Breeze 45,

48, 49, 50, 51

hyaluronic acids 24

Sculptra 60

silicone 76

Zyplast 45

vitamin supplements 124

Vitrase 169

Voluma 166

volume loss 66–70, 147–8

xylocaine 11

Zimmer Chiller 11

Zyderm 43

complications 133

history 44

Zyplast

complications 122, 133

effi cacy 46, 159, 160–1

history 44

viscosity 45