Recent advances in burns management by Dr. Sunil Keswani, National Burns Centre, Airoli

Recent Advances in Burns ManagementRecent Advances in Burns Management

Dr. Sunil KeswaniDr. Sunil Keswani

National Burns CentreNational Burns Centre

Dr.Sunil Keswani, National Burns Centre, Dr.Sunil Keswani, National Burns Centre, www.burns-india.com, [email protected], [email protected]

Dr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-

india.com, india.com, [email protected]@gmail.com

Factors Affecting Wound Healing

Systemic Local

Age Mechanical injury

Nutrition Infection

Trauma Edema

Metabolic diseases Ischemia/necrotic tissue

Immunosuppression Topical agents

Connective tissue disorders Ionizing radiation

Smoking Low oxygen tension

Foreign bodiesDr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


AGE

•Aging produces intrinsic physiologic changes that result in delayed or

impaired wound healing.

•Dermal collagen content decreases with aging and aging collagen fibers

show distorted architecture and organization.

•The increased incidence of cardiovascular disease, metabolic diseases

(diabetes mellitus, malnutrition, and vitamin deficiencies), cancer all

contribute to the higher incidence of wound problems in the elderly

•Non collagenous protein accumulation at wounded sites is decreased

with aging, which may impair the mechanical properties of scarring in

elderly patients



HYPOXIA, ANEMIA, AND HYPOPERFUSION

•Low oxygen tension has a profoundly deleterious effect on all aspects of

wound healing.

•Fibroplasia, although stimulated initially by the hypoxic wound

environment, is significantly impaired by local hypoxia.

•Optimal collagen synthesis requires oxygen as a cofactor, for the

hydroxylation steps.

•Increasing subcutaneous oxygen tension levels for brief periods during

and immediately after surgery results in enhanced collagen deposition and

in decreased rates of wound infection after elective surgery.



STEROIDS

•Large doses or chronic usage of glucocorticoids reduce collagen

synthesis and wound strength.

•Inhibit the inflammatory phase of wound healing (angiogenesis,

neutrophil and macrophage migration, and fibroblast proliferation) and

the release of lysosomal enzymes.

•Steroids used after the first 3 to 4 days postinjury do not affect wound

healing as severely as when they are used in the immediate

postoperative period.

•Steroid-delayed healing of cutaneous wounds can be stimulated to

epithelialize by topical application of vitamin A



METABOLIC DISORDERS

•Uncontrolled diabetes results in reduced inflammation, angiogenesis,

and collagen synthesis.

•Defects in granulocyte function, capillary ingrowth, and fibroblast

proliferation all have been described in diabetes

•Obesity, insulin resistance, hyperglycemia, and diabetic renal failure

contribute significantly and independently to the impaired wound healing

observed in diabetics.

•Diabetic wound appears to be lacking in sufficient growth factor levels,

which signal normal healing.

•Uremia also has been associated with disordered wound healing.Dr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


NUTRITION

•Not fully understood

•Efforts are being made to develop wound-specific nutritional

interventions and the pharmacologic use of individual nutrients as

modulators of wound outcomes.

•Malnourished patients have diminished hydroxyproline accumulation

(an index of collagen deposition)

•It reflects impaired healing response as well as reduced cell-mediated

immunity, phagocytosis, and intracellular killing of bacteria by

macrophages and neutrophils.Dr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


• The main effect of Arginine on wound healing is to enhance wound

collagen deposition.

• Arginine deficiency results in decreased wound-breaking strength and

wound collagen accumulation.

• Vitamins most closely involved with wound healing are vitamin C and

vitamin A.

• vitamin C deficiency, leads to a defect in wound healing, particularly

via a failure in collagen synthesis and cross-linking.

• Biochemically, vitamin C is required for the conversion of proline and

lysine to hydroxyproline and hydroxylysine, respectively.

• Vitamin C deficiency has also been associated with an increased

incidence of wound infectionDr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


• Vitamin A deficiency impairs wound healing, whereas supplemental

vitamin A benefits wound healing.

• Vitamin A increases the inflammatory response in wound healing,

probably by increasing the lability of lysosomal membranes.

• Vitamin A directly increases collagen production and epidermal growth

factor receptors when it is added in vitro to cultured fibroblasts.

• Supplemental vitamin A can reverse the inhibitory effects of

corticosteroids on wound healing.

• Vitamin A also can restore wound healing that has been impaired by

diabetes, tumor formation, cyclophosphamide, and radiation.

• Doses ranging from 25,000 to 100,000 IU per day



ZINC •In deficiency states there is decreased fibroblast proliferation,

decreased collagen synthesis, impaired overall wound strength, and

delayed epithelialization.



INFECTION•If the wound is contaminated with >105 microorganisms, the risk of

wound infection is markedly increased, but this threshold may be much

lower in the presence of foreign materials.

•The most common organisms responsible for wound infections, in

order of frequency, are Staphylococcus species, coagulase-negative

Streptococcus, enterococci, and Pseudomonas.

•Bacteria prolong the inflammatory phase and interfere with

epithelialization, contraction, and collagen deposition.

•Bacteria may accelerate expression or increase concentrations of

MMPs, growth factors, and cytokines in chronic-type wounds



DRESSING•The main purpose of wound dressings is to provide the ideal

environment for wound healing.

•Ideal dressing – not a clinical reality.

DESIRED CHARACTERISTICS OF WOUND DRESSINGS

Promote wound healing (maintain moist environment)

Conformability

Pain control

Odor control

Nonallergenic and nonirritating

Permeability to gas

Safety

Nontraumatic removal

Cost-effectiveness

Convenience



• Occlusion also helps in dermal collagen synthesis and epithelial cell

migration and limits tissue desiccation.

• As it may enhance bacterial growth, occlusion is contraindicated in

infected and highly exudative wounds.

• Dressings can be classified as primary or secondary.

• A primary dressing is placed directly on the wound and may provide

absorption of fluids and prevent desiccation, infection, and adhesion

of a secondary dressing.

• A secondary dressing is one that is placed on the primary dressing

for further protection, absorption, compression, and occlusion.



Absorbent Dressings

•Absorb without getting soaked through, as this would permit bacteria

from the outside to enter the wound.

• sponge.

Non adherent Dressings

•Dressings impregnated with paraffin, petroleum jelly, or water-soluble

jelly for use as non adherent coverage.

•A secondary dressing must be placed on top to

seal the edges and prevent desiccation and infection.Dr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


Occlusive and Semiocclusive Dressings

•Good environment for clean & minimally exudative wounds.

•Waterproof and impervious to microbes,

•Permeable to water vapour and oxygen.



Alginates

•Brown algae and contain long chains of polysaccharides containing

mannuronic and glucuronic acid.

•Processed as the calcium form, alginates turn into soluble sodium

alginate through ion exchange in the presence of wound exudates.

•The polymers gel, swell, and absorb a great deal of fluid.

•Used when there is skin loss, in open surgical wounds with medium

exudation, and on full-thickness chronic wounds.



• Type of dressing to be used depends on the amount of wound drainage

• Nondraining Wound - with a semiocclusive dressing.

• Mild Drainage (1 to 2 mL/d) - semiocclusive or absorbent nonadherent

dressing.

• Moderately draining wounds (3 to 5 mL/d) - dressed with a nonadherent

primary layer plus an absorbent secondary layer plus an occlusive

dressing to protect normal tissue.

• Heavily draining wounds (>5 mL/d) require a similar dressing to

moderately draining wounds, but with the addition of a highly absorbent

secondary layer.Dr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


• Vacuum-assisted closure system assists in wound closure by applying

localized negative pressure to the surface and margins of the wound.

• Found to be effective for chronic open wounds (diabetic ulcers and stages 3

and 4 pressure ulcers), acute and traumatic wounds, flaps and grafts,

dehisced incisions.

Mechanism of action

Problems – Pain, fluid loss, especially in large wounds, and risk of bleeding. It is

contraindicated in patients with frail, thin or easily bruised skin, and in those

with neoplasms forming part of the wound floor.



Hyperbaric oxygen

•As adjunct in the management of nonhealing wounds.

•Most non-healing tissues are hypoxic

Mechanism of action of hyperbaric oxygen

•Hyperoxygenation causes

1. Immune stimulation by restoring WBC function and enhancing their

phagocytic capabilities and

2. Neo-vascularization in hypoxic areas by augmenting fibroblastic

activity and capillary growth.

•Vasoconstriction reduces edema and tissue swelling while ensuring

adequate Oxygen delivery.

•Bactericidal for anaerobic organisms & inhibits growth of aerobic bacteria.

It Inhibits production of alpha-toxin by C Welchii and is synergistic with

Aminoglycosides and Quinolones. Thus it is life saving in gas gangrene and

severe necrotising infections.



Skin Replacements

•All wounds require coverage in order to prevent evaporative losses and

infection and to provide an environment that promotes healing.

Conventional Skin Grafts

•Split thickness grafts

•Full-thickness grafts

•Autologous grafts

•Allogeneic grafts

•Xenogeneic grafts (e.g., porcine).



Current Skin EngineeringCurrent Skin Engineering

• Tissue-engineered skin exists as cells grown in vitro and subsequently seeded onto a scaffold or some porous material which is then placed in vivo at the site of injury.

• Three categories of skin substitutes:– Epidermal Substitutes– Dermal Substitutes– Dermo-epidermal SubstitutesDr.Sunil Keswani, National Dr.Sunil Keswani, National

Burns Centre, www.burns-Burns Centre, www.burns-india.com, india.com,

[email protected]@gmail.com

NEED FOR ARTIFICIAL SKIN Drawbacks of conventional treatment

In severe burns like 3rd degree burns, normal wound healing is slow and larger area is involved

Natural skin has limited options to recover, hence need for synthetic skin

Use of patient’s own skin - costly, hospitalization, anesthesia, pain, immobilization etc.

Solution to skin grafting is artificial skin transplants



EVOLUTION OF BURN WOUND CARE

Burn wounds were occluded with dressings

Animal and reptile skin used as a "skin substitute"

Pig skin became popularized in the 1960’s

Human tissue used as a skin substitute

(cadaver skin & human amnion)



First Cultivation of Human Epidermal Cells (1960’s)

(autologous keratinocytes)

Use of allogenic keratinocyte grafts

Bilayered Artificial Skin

Contn…



ProcessProcess



COMMERCIALLY AVAILABLE SKIN SUBSTITUTESWith advancing technology, a host of both permanent and temporary biologically active skin substitutes are available to replace allograft and xenografts.-

I. Naturally occurring tissues

- Cutaneous allografts - Cutaneous xenografts - Amniotic membranes

II. Skin substitutes- Synthetic bilaminate- Collagen based composites

Biobrane TransCyte Integra Dr.Sunil Keswani, National Dr.Sunil Keswani, National

Burns Centre, www.burns-Burns Centre, www.burns-india.com, india.com,

[email protected]@gmail.com

III. Collagen based dermal analogs- De-epithelized allograft- Alloderm

IV. Cell Culture -derived - Keratinocyte Cells Sprays

-Bilayer human tissue (Apligraf)

- Cultured autologous keratinocytes- Fibroblast seeded dermal analogs- Collagen-glycosaminoglycan matrix- Polyglycolic or acid mesh (Dermagraft)- Epithelial seeded dermal analog



Application of cells spray along with autograft for extensive burns

Case StudyQueen Victoria hospital, UK- 90% TBSA FT Successful Treatment with meek micro graft+ cell spray



Before Cell Spray

Control arm

During Cell Spray

Preliminary Safety-Study on application of autologous keratinocytes cell spray

No sign of any adverse reaction on day 4 after surgery



GMP cell culture facility @ NBCGMP cell culture facility @ NBC

Change Room Class 1lakh HEPA

Clean room 2 Class 10 000 HEPAClean room 3 class 1000 HEPA

GMP cell culture facility @ NBCGMP cell culture facility @ NBC



Cell Spray making processCell Spray making process



Primary cell culturePrimary cell culture



Secondary Culture of keratinocytesSecondary Culture of keratinocytes



PREPARATION OF SKIN COMPOSITE PREPARATION OF SKIN COMPOSITE

FUNCTIONAL EPIDERMIS



BIOBRANE

Biobrane is a bilayer synthetic skin substitute

Outer epidermal analog constructed of a thin silicone film with

barrier functions

Small pores present in silicone to allow for exudates removal

and permeability to topical antibiotics

Inner dermal analog composed of nylon filament weave upon

which is bonded type I collagen peptides



BIOBRANE



BIOBRANE APPLIED TO WOUNDS



PROCESS OF HEALING

A superficial partial thickness burn

The zone of necrosis is confined to the upper dermis & is usually separated by a layer of edema from the viable wound surface



Viable wound bed showing fibrin and collagenDr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


Bilayer BIOBRANE placed on clean woundDr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


Biobrane adhered to surface by nylon-collagen mesh. Preservation of thin water layer on surface to allow epithelial migration along inner layer



Biobrane peeled back from surface to demonstrate rapid migration of new epithelium along nylon-collagen mesh



Biobrane removed with re-epithelializationDr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


BIOBRANE REMOVAL

APPLICATION OF BIOBRANE



TRANSCYTE Trancyte is a bilayer skin substitute

Outer epidermal analog is a thin nonporous silicone film with barrier functions

Inner dermal analog is layered with human fibroblast products mainly collagen type 1, fibronectin and Glycosaminoglycan

Subsequent cryo-preservation destroys fibroblasts but preserves activity of fibroblast-derived products

Thin water layer at surface is maintained for epidermal cell migration

It is removed after re-epithelialization



TRANSCYTE



TRANCYTE IN PLACE



TRANSCYTE



ALLODERM AlloDerm is an acellular dermal matrix designed to serve as a biologic scaffold for normal tissue remodeling

It is a donated human tissue processed to remove all epidermal and dermal cells while preserving the remaining biological dermal matrix

It directs normal revascularization and cell repopulation as blood vessels, collagens, proteoglycans and elastin are preserved

This extracelullar matrix contains the blood vessel channels which serve as conduits for revascularization

Collagens, proteoglycans and elastin provide structure and information for cell repopulation

The preserved proteoglycans and proteins direct the patient's own cells to initiate revascularization and cell repopulation



NORMAL DERMIS ALLODERM



Day 1: Biologic Scaffold



Day 7-10

• Host fibroblast cells and blood vessels respond to the transplantation of the AlloDerm matrix • Initiation of the revascularization and normal tissue remodeling process



Day 45 Replacement and revascularization of the transplant continues as normal connective tissue



Day 90 AlloDerm repopulated with the patient's own cells Fibroblasts continue to lay down autologous collagen



INTEGRA INTEGRA is a bilayer membrane system for skin replacement

The dermal replacement layer - porous matrix of fibers of cross-linked bovine tendon collagen and a glycosaminoglycan (chondroitin-6-sulfate)

The temporary epidermal substitute layer - synthetic polysiloxane polymer (silicone) and functions to control moisture loss from the wound

The collagen dermal replacement layer serves as a matrix for the infiltration of fibroblasts, macrophages, lymphocytes, and capillaries derived from the wound bed

As healing progresses an endogenous collagen matrix is deposited by fibroblasts



Upon adequate vascularization of the dermal layer and availability of donor autograft tissue, the temporary silicone layer is removed

A thin, meshed layer of epidermal autograft is placed over the "neodermis"(usually 14-21 days after application)

Cells from the epidermal autograft grow and form a confluent stratum corneum, thereby closing the wound reconstituting a functional dermis and epidermis

After final healing of the wound, the neodermis tissue histologically and functionally is similar to normal dermis

used for child limb injuries (Violas et al., 2005)

Contn…



HEALING WITH INTEGRA



IntegraIntegra



ActicoatActicoat



Fascial ExcisionFascial Excision



Integra appliedIntegra applied



Covered with ActicoatCovered with Acticoat



MATERIALS & METHODSMATERIALS & METHODSSurplus cuttingSurplus cutting



MATERIALS & METHODSMATERIALS & METHODSPositioning on plate.Positioning on plate.



MATERIALS & METHODSMATERIALS & METHODSDermatome cut throughDermatome cut through



MATERIALS & METHODSMATERIALS & METHODSAdhesive SprayingAdhesive Spraying



MATERIALS & METHODSMATERIALS & METHODSCork removing.Cork removing.



MATERIALS & METHODSMATERIALS & METHODSGauze expansionGauze expansion



MATERIALS & METHODSMATERIALS & METHODSGauze expanded.Gauze expanded.



MATERIALS & METHODSMATERIALS & METHODSMicrograft positioningMicrograft positioning



MATERIALS & METHODSMATERIALS & METHODSAfter gauze removal. 7th day.After gauze removal. 7th day.



MATERIALS & METHODSMATERIALS & METHODS10th day wound care.10th day wound care.



MATERIALS & METHODSMATERIALS & METHODSLong term control.Long term control.

POST-PHYSICAL REHABILITATION OUTCOME



Case 1- day of admissionCase 1- day of admission



Day 3-PreopDay 3-Preop



Day 3-Early excison and homografting-postopDay 3-Early excison and homografting-postop



Day 5Day 5



Day 7Day 7



Day 9Day 9



Day 15Day 15



Case 2- Case 2- day of admissionday of admission



Day 3Day 3 Preop Postop Preop Postop



Day 7Day 7



Day 12Day 12



Day 21Day 21



Admission DischargeAdmission Discharge



Early excison and graftingEarly excison and grafting

Pre-Op wound

Application of Homograft Day 3

Complete healing Day 21



Pre-Op WoundPre-Op Wound



Progressive healing of WoundProgressive healing of Wound



On DischargeOn Discharge



Case 5- Case 5- day of Admissionday of Admission



Before and After HomograftingBefore and After Homografting



Progressive healingProgressive healing



Progressive HealingProgressive Healing



Progressive healing of RIGHT HAND Progressive healing of RIGHT HAND



Progressive Healing of LEFT HANDProgressive Healing of LEFT HAND



Day 15Day 15 Homograft Application post opHomograft Application post op



Case 7-Chemical Burns on admissionCase 7-Chemical Burns on admission



Progressive healing-Autografting Progressive healing-Autografting



End Result-AutograftingEnd Result-Autografting



DERMAGRAFT

is an example of a synthetic matrix combined with allogenic fibroblasts and has good resistance to tearing (Bello et al., 2001)

Dermal fibroblasts are seeded onto biocompatible Vicryl scaffold to form a living tissue

The scaffold Vicryl is a blend of polylactic and polyglycolic acids (synthetic absorbable surgical sutures)

Vicryl is inert, non-antigenic, non-pyrogenic and elicit only a mild tissue reaction during absorption

Dermagraft is a total skin replacement for

• full thickness burns and

• chronic wounds like diabetic foot ulcersDr.Sunil Keswani, National Dr.Sunil Keswani, National Burns Centre, www.burns-Burns Centre, www.burns-


Dermagraft cassettes ready for patient use

DERMAGRAFT



APLIGRAF is supplied as a living, bi-layered skin substitute

The lower dermal layer combines bovine type 1 collagen and human fibroblasts (dermal cells), which produce additional matrix proteins

The upper epidermal layer is formed by promoting human keratinocytes (epidermal cells) first to multiply and then to differentiate to replicate the architecture of the human epidermis

APLIGRAF does not contain melanocytes, Langerhans' cells, macrophages, and lymphocytes, or other structures such as blood vessels, hair follicles or sweat glands

approved by the FDA to treat patients exhibiting venous leg ulcers & for diabetic foot ulcer treatment



SOME CASE STUDIES FOR APLIGRAF APPLICATION

1 2

3 4



Traditional Skin GraftTraditional Skin Graft Artificial skinArtificial skin

• Skin graft from the patient applied to wound

• Grafted dermis does not regenerate, resulting in scars that contract

• Larger donor sites are needed to compensate for graft shrinkage

• Harvested donor sites are painful, itchy and red

• Stiffness of graft area

• Two-layer template composed of a porous matrix inner layer and a silicone outer layer applied to the wound

• Dermis is regenerated and grows

Regenerated dermis maintains shape and strength

Thin epidermal graft does not create lasting donor site wound

• Pliable skin



Current Research and ChallengesCurrent Research and Challenges Role of Stem cells in wound healing (e.g- MSCs) Role of Gene Therapy to stimulate wound healing Development of autologous cell based skin substitutes

• Methods to evaluate safety and efficacy of the products in vivo.

• Challenges: Cost related concerns

• Variable clinical study data



Future Directions More effective cell preservation techniques could enhance shelf life and minimize issues related to storage

Simplified thawing and rinsing of cryopreserved products would make such products more user-friendly

A more complete understanding of the mechanism of therapeutic action of bioengineered skin could lead to even more efficacious products

eg) genetic modification of the cells to overproduce specific cytokines like growth factors might be

feasible and productive



Efforts by manufacturers to further reduce the cost of cellular skin substitute wound therapy could change the role of this approach dramatically

Lower cost could also allow for multiple applications and possibly increase the efficacy of the course of treatment

Contn…





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Recent advances in burns management by Dr. Sunil Keswani, National Burns Centre, Airoli

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Transcript of Recent advances in burns management by Dr. Sunil Keswani, National Burns Centre, Airoli