John Sanderson, MD

Topical Human Growth Factors and Cytokinesin Skin Rejuvenation

and Procedure Recovery

RECOMMENDED TO OPTIMIZE AND STIMULATE SKIN HEALTH

HUMAN GROWTH FACTORS & CYTOKINES GO MAINSTREAM

Guide you on a deep but brief dive into the rapidly evolving science of growth factors and stem cells as applied to clinical aesthetics.

MY 20 MINUTE CHALLENGE:

The Evidence is UNDERWHELMING.

EFFICACY OF CURRENT GENERATION OF TOPICAL ACTIVE INGREDIENTS

DERMATOLOGIC CONDITIONS REJUVENATION / AESTHETICS

THE NEW SCIENCE OF STEM CELLS IS CHANGING EVERYTHING.

stem cells cytokines

growth factors

aesthetic modalities

regeneration

paracrine

autocrine

biosignals

rejuvenation miRNA

WHAT ARE STEM CELLS?

Stem cells, cytokines & growth factors make life possible. They control growth and development by regulating cell division and differentiation. They orchestrate the healing

process of all injured tissues, including the skin.

FROM CONCEPTION ‘TIL DEATH…

• Signaling proteins

• Local and distant effects

• Circulate in picomolar quantities

• Peptides, proteins, glycoprotein,

• Picogram dose response curves

• Cellular communications

• Embryogenesis

• Immune function

Growth factors are one of the several classes of cytokines.

Some cytokines are pro-inflammatory.Some cytokines are anti-inflammatory.

WHAT ARE CYTOKINES?

• Cell-to-cell signaling molecules• Alter gene expression• Promote cell division – proliferation• May inhibit apoptosis• Morphogenesis• Angiogenesis• Cell differentiation – maturation• Tissue homeostasis• Wound healing

If unregulated –growth factors and receptors implicated in cancers

WHAT ARE GROWTH FACTORS?

• Biosignaling

• Receptor chemistry

• Highly efficient

CELL TO CELL COMMUNICATION

One molecule - chain reaction –many cells

Don’t get with your botanical “actives”

Dosing advantage for human GF’s!

PARACRINE AMPLIFICATION

95% of the effect is due to paracrine chemical release

5% is due to engraftment & differentiation into host tissue cell type

Conditioned medium of culture of stem cells equivalent effects

STEM CELL THERAPY

TGF-b1TGF-b3

TGF-b2

Inflammatory - acute Inflammatory - chronic Growth factors- neutral Anti-inflammatory

Products with TGF-b1 create inflammation- BUT inflammation is the enemyProducts that induce TGF-b1 e.g. “PLOD-2 gene” mimicsProducts that just say TGF-b Do they not know the difference?

The TGF-β Family of Growth Factors

CYTOKINES, GROWTH FACTORS AND HEALING

Don’t get stuck here!

Optimalaesthetic outcomes

STAGES OF WOUND HEALING

COLLAGENESIS DURING WOUND HEALING

NATURE HEALS THEM …IN AN ORDERLY FASHION (BUT NOT ALWAYS)

DEVICES CREATE CONTROLLED WOUNDS

Major contributor to skin aging & most skin maladies

Often responsible for suboptimal outcomes in skin

rejuvenation and energy based skin treatments

Positive aesthetic outcomes can be enhanced/engineered by controlling inflammation.

INFLAMMATION: THE PRIMARY CULPRIT IN POOR AESTHETIC RESULTS

• During first and second trimesters, fetal skin heals rapidly without scars.

• Inflammation is absent or extremely brief.

• Anti-inflammatory cytokines are abundant.

• During the third trimester, cutaneous wounds heal more slowly, with adult-like inflammation.

• Results in scars with over-production of densely packed, disorganized collagen.

FETAL SKIN HEALS SCAR FREE

GOAL: EMULATE SCAR-FREE FETAL WOUND HEALING

Inflammation is the major contributory factor in hyperpigmentation and

hypopigmentation.

INFLAMMATION AND PIGMENTATION

Inflammation is the major contributory factor in fibrosis.

FIBROTIC ACNE SCARRING HYPERTROPHIC SCARS SCLERODERMA

COLLAGENESIS: DESIREDFIBROSIS: DEFINITELY NOT

INFLAMMATION FIBROSIS CANCER

• Common aesthetic medical procedures involve the delivery of energy or controlled trauma to the skin.

• The first phase of healing in response to any acute insult is inflammation.

• The more swiftly the inflammatory phase can be exited, and proliferation and remodeling phases begin, the better the aesthetic result.

• Selection of appropriate topical growth factors and cytokines can modulate and facilitate resolution of inflammation.

MORE POSITIVE AESTHETIC OUTCOMES

Early Evidence

WHAT ACTUALLY IS IN THESE CONDITIONED MEDIA PRODUCTS?

• Reside in bone marrow• Patrol the whole body• Search out injury or distress• Attach and set up shop• Local drug store• May engraft • Sense requirements of healing• Release cytokines & GF’s• Orchestrates healing in stages• When work is done – pulls out• Returns to bone marrow

MESENCHYMAL STEM CELLS OF BONE MARROW ORIGIN

• A special kind of adult stem cell controls healing in all tissues, including the skin.

• They originate in the bone marrow and patrol the body via the blood stream.

• Upon finding injury, they remain and act as smart “mini-drugstores” secreting cytokines and growth factors.

• This is the ONLY population of cells that serves this function.

ONE POPULATION OF STEM CELL CONTROLS TISSUE HEALING

“CONDUCTOR” OF THE SYMPHONY

OF HEALING

“WORKER” IN TISSUE REPAIR & RECONSTRUCTION

“FIREFIGHTER” IN QUENCHINGINFLAMMATION

BONE MARROW STEM CELLS PLAY MULTIPLE ROLES

• “Bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds.”

• “This study determined the effects of paracrine signaling from bone marrow mesenchymal stem cells on dermal fibroblasts included proliferation, migration and expression of genes important in wound repair.”

• “Bone marrow mesenchymal stem cells provide an important early signal for dermal fibroblast responses to cutaneous injury.”

Mesenchymal stem cells induce dermal fibroblast responses to injuryExperimental Cell Research Volume 316, Issue 1, 1 January 2010, Pages 48–54

FIBROBLASTS TAKE ORDERS, NOT GIVE THEM.

During cell culture, bone marrow mesenchymal stem cells (MSC) produce many fold the relative concentration of growth factors and cytokines important to the healing process than do fibroblasts.

MESENCHYMAL STEM CELLSVS. FIBROBLASTS

• Skin ages from accumulated damage while cells tasked with repair decline.

• 4% remain at age 30.

• 2.5% at age 50

• Fewer cells means reduced pro-healing anti-inflammatory bio-signals

Topical application of growth factors and cytokines produced in cell cultures of BM-MSC is the physiologic equivalent of turning the skin clock back to a younger time when there were more BM-MSC circulating in the blood and resident within the skin.

BM-MSC NUMBER DECLINES WITH AGE & SIGNALS SENESCENCE

Optimized for MSC growth & harvest of pathway driven paracrine biosignals

We wrote the book

VENUS SKIN SCT

“…evidence shows that administration of bone marrow stem cell conditioned media, the broth the cells were cultured in, produces the same benefits as the cells themselves. This is after all the cells are removed!

This supports the use of topical bio-signals from stem cells as a valuable topical anti-aging technology. The effect of additional topical bio-signals is like having more stem cells, like turning the skin clock back in time.

Bone Marrow Research Vol. 2011, Article ID 207326

KEY POINT

When applying conditioned media

from cell cultures to the skin, clinical

effects result from the “net pattern” of many growth factors

and cytokines.

CYTOKINE & GF CLASSIFICATION

Bone marrow stem cell conditioned media is markedly ANTI-INFLAMMATORY

BIO-SIGNAL PATTERN DETERMINES EFFECT.

• Niche is fixed in fact tissue• Precursors to fat cells• Create adipokines

(inflammatory) • Grow very fast in culture• Little or no cost• By product of liposuction• Average age adult 50’s• Different secretome• Pro-inflammatory balance

ADIPOSE DERIVED STEM CELLS

Adipose (fat) stem cell conditioned media is highly PRO-INFLAMMATORY

BIO-SIGNAL PATTERN DETERMINES EFFECT.

The increased morbidity and mortality of obesity-associated cancers have been attributed to higher levels of hormones, adipokines, and cytokines secreted by the adipose tissue. The increased amount of adipose tissue also results in higher numbers of adipose stromal/stem cells (ASCs). These ASCs have been shown to impact cancer progression directly through several mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma.

The obesity cancer paradigm: exploration of the interactions and crosstalk with adipose stem cellsStem Cells 02/2015

Omental adipose tissue may play crucial roles for tumor promotion through the expression of tumor promoting chemokines. Accordingly, tumor surrounding adipose tissue may be a novel target for immunotherapy of cancer.

Adipose derived stem cell isolated from omentum: A novel source of chemokines for ovarian cancer growthJournal of Caner Research and Therapeutics 01/2014

ADIPOSE STEM CELL CANCER CONCERNS

Our results demonstrated that BMSCs treatment caused a delayed tumor growth and a prolonged survival in both tumor models

[…] in vivo and in vitro results showed that BMSCs have a systemic suppressive effect.

Bone marrow mesenchymal stem cells suppress metastatic tumor development in mouse by modulating immune system. Stem Cell Res Ther. 2015 Mar.

• Red face for decades with flare ups TNTC

• Tx with daily doxycline, topical metronidazole, and steroid prn

• 7.1.2011 – all meds dc’d and topical containing BM-MSC CM started twice daily

• Reduced redness without a flare up in > 4 years

PROOF OF CONCEPT IN PATIENT #1

Pilot trial: 24 days durationFourteen subjects (12f/1m)36 to 72 yrs. of age

Measured: Coarse lines, fine lines, reflectivity, texture, tone, coloration

Results:All subjects improved in at least one criterion.11 of 14 (86%) observed improvement in four criteria.

PILOT TRIAL BONE MARROW STEM CELL CONDITIONED MEDIA

First generation bone marrow derived mesenchymal stem cell conditioned medium as active

50 SUBJECT CLINICAL TRIAL

• Chronic red face for years

• Applied topical containing BM-MSC CM twice daily

• Reduced redness and more even skin tone at end of first month

REDUCED INFLAMMATION IN ONE MONTH

• Faster recovery • Up to 40% less downtime• Reduced inflammation• Less edema• Less discomfort

FACILITATED HEALING POSTFRACTIONAL CO2 LASER RESURFACING

• 10 p.m. – called saying “my face is on fire. Do you think your product will help?”

• Advised to take “before” photos and immediately apply product containing BM-MSC conditioned media.

• 7:30 a.m. – called saying “it was amazing. My skin calmed very quickly. When I woke up I had to call to let you know.” Sent “after” photos taken while still in her pajamas.

RESOLUTION OF INFLAMMATIONAFTER ERBIUM LASER

Four ablative treatments, each a month part using a BM-MSC cell culture derived topical at time of treatment, and another formulated for twice daily anti-aging skin care.

POST ABLATIVE RESULTS ON A 74 YEAR OLD WOMAN

• Used product for 8 weeks b.i.d.

• Two episodes of cosmetic microneedling with .25 mm device three weeks apart

RF ABLATIVE: ACNE & PIH

• Actually defensins – glycoproteins snails secrete when stressed.

• Humans make their own defensins.

• Defensins are highly inflammatory.

• Snail antigens cross react with house dust mite proteins IgE.

• Dust mites are one of the most common human allergens.

• A case of allergic dermatitis in context of using a snail “growth factor” product as part of a microneedling session

“GROWTH FACTORS” FROM SNAILS

• Take a culture of fibroblasts, add a substance, then measure collagen synthesis by cells.

• Simple minded logic: If it increases collagen then it must be a growth factor.

• Truth: fibroblasts make collagen defensively. You only need to perturb the cell a bit.

• Consequence: collagen made in the presence of inflammation is gnarly, fibrotic, stiff, and not aesthetically pleasing.

“GROWTH FACTORS” IN NAME ONLY

• Growth Factors (GF’s) & Cytokines are signaling molecules that mediate human growth, healing and regeneration.

• Real human GF’s have real human growth factor receptors to match.

• They are 100% natural (to humans). Plant and animal GF’s are not natural. Any salubrious effect is an accident of nature.

• Real human GF’s communicate in a paracrine fashion with signal amplification in human tissues – a big deal in terms of dosing.

• Growth factors work in concert, not in isolation.

SUMMARY

• Stem cells make GF’s in abundance. 95% of the miracle of stem cells is due to paracrine (chemical) effects.

• The stem cell secretome is different for each stem cell niche, and can be coaxed to change under controlled lab conditions

• Bone marrow-derived stem cells are unique in that their whole function is regenerative, not committed precursors to a single tissue.

• They are recognized throughout regenerative medicine as the master stem cells. When they are used up … end game.

SUMMARY

• Adipose stem cells have become a popular choice as paracrine factories in aesthetics.

• Where inflammation is helpful in the short term, they are quite valuable (orthopedics, fat transfers, etc.) In a single dose fashion.

• The presence of inflammation and potent adipokines like leptin raises red flags about cancer risk.

• Recent literature abounds with examples.

SUMMARY

• The Venus Skin platform capitalizes on the advantages of

BM-MSC’s and adds an accumulated knowledge base of stem cell secretomes.

• Custom cocktails means that specific skin conditions or aesthetic concerns can be targeted.

• Anti-inflammatory GF admixtures can augment the effect of various energy delivering modalities by employing specific cocktails of growth factors matched to a specific clinical effect

• Inflammation is not necessary for healing! It is something that accompanies aging. But doesn’t have to.

SUMMARY