Dr Herbert Hooi - Cosmetic MD

Dr Herbert Hooi

MBBS

LLB(Hons)

FACEM

FACAM

cosmetic MD

Sydney

PLATELET RICH PLASMA

AND

SKIN REJUVENATION

THE HISTORY AND THE EVIDENCE

SPEAKER’S DECLARATION OF INTEREST

POTENTIAL CONFLICTS OF INTEREST

Air fares or accommodation expenses supplied by organization or company related to

presentation

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Shareholder or director in company associated with presentation NO

Direct or indirect payment received from company or organization associated with presentation NO

Direct or indirect payment received from outside organization or entity to perform investigation

being presented

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Past payment for services by company or organization associated with presentation NO

Basic Science

Introduction to PRP

The theory of the effect of PRP on the skin

History of the use of PRP for skin rejuvenation

Clinical evidence

PRP – the small print

Problems

Unresolved debates

References

PLATELET RICH PLASMA

Platelets

and

PRPBASIC SCIENCE

PRP is an autologous product of whole blood,

characterised by higher than physiological

platelet concentrations, platelet Growth

Factors and plasma proteins in a small

volume of plasma

In the literature, there are a number of

different preparations of “PRP”, the names

are used interchangeably but they are not all

equivalent functionally or practically

PLATELET RICH PLASMA (PRP)

The platelet fraction of blood is basically derived

from centrifugation of anti -coagulated whole blood

PRODUCTION OF PRP

Source: http://www.medical-labs.net/blood-plasma-and-buffy-coat-318/

Spinning non-anticoagulated blood produces platelet -rich

fibrin (PRF) (Choukroun 2001)

Small anuclear circulating

cell fragments of the

megakaryocyte in bone

marrow

Secrete numerous Growth

Factors on “activation’

Two main functions –

haemostasis

wound healing

Complex internal structure

WHAT ARE PLATELETS?

Surface Outer glycocalyx with

glycoprotein receptors (1)

Inner lipid bilayer membrane

Subsurface membrane contractile system Actin-myosin systems

Circumferential microtubular coil (2)

Open canalicular system

Organelles α granules (3)

dense granules (4)

lysosomes

Other components Glycogen (5)

Endoplasmic reticulum

Mitochondria

PLATELET STRUCTURE

White JG. Platelet structure. Ch 7, fig 7-24 in Michelson A (ed). Platelets (3e)

Academic Press London

1

2

3

4

5

Platelet α granules contain > 100 dif ferent biologically active

molecules

Coagulation factors and mediators

Fibrinogen and VWF, Factors V, XI, XIa, XIIa, XIII

Prothrombin, HMW kininogens (intrinsic)

Plasminogen and Plasmin inhibitors

Growth factors

PDGF – platelet-derived growth factor

FGF – fibroblast growth factor

VEGF – vascular endothelial growth factor

TGFα, TGFβ1 – transforming growth factors

EGF – epidermal growth factor

PLATELET GROWTH FACTORS

Platelet-derived Growth Factors act as stimulators and

regulators of multiple cellular processes in the wound healing

process such as

mitogenesis (cell division)

chemotaxis (cell migration)

differentiation (stem cells)

increased metabolism

The targets are cells such as fibroblasts, macrophages,

neutrophils, immune cells and mesenchymal stem cells which

all have interacting and cooperative roles in wound healing

PLATELET GROWTH FACTORS

WOUND HEALING

Mendes JJ, Neves J. Diabetic Foot Infections: Diagnosis and Treatment. Jnl Diabetic Foot Infections 2012;4(2): 256-45

Why is “wound healing” important in

cosmetic medicine?

WOUND HEALING

Wound healing is the pathway by which

we achieve (most of, if not all) our

results in cosmetic medicine

Collagen

Hyaluronic acid

New tissue growth (skin, blood vessels, fat)

WOUND HEALING

Fundamental intention of introducing platelets

into tissues is to stimulate a tissue

regeneration or “wound-healing” response, by

inducing

neocollagenesis

angiogenesis

production of extra-cellular matrix (hyaluronic acid)

regeneration of epidermis

regulation of MMPs and their inhibitors and

new tissue formation (skin, blood vessels, fat, bone)

THE BASIC PREMISE OF PRP

Haemostasis Inflammation Tissue regeneration Tissue remodeling

1. Formation

of 3D mesh

& platelets

cohesion

2. Platelets and

leukocytes release

growth factors

3. Migration of

macrophages and

stem cells (cell

adhesion

molecules)

4. Stem cell

proliferation

/ Stimulation

of fibroblasts

5. Stem cell

differentiation /

Proliferation

fibroblasts /

Increased

expression MMPs

RegenLab Switzerland

MECHANISM OF ACTION OF PRP IN VIVO

In practical terms, PRP

Accelerates healing in injured tissue (adjuvant

therapy)

Rejuvenates ageing (but otherwise uninjured)

skin as a consequence of the wound healing

response (primary therapy)

Stimulation of a natural process

Takes time

Individual variation in response

THE BASIC PREMISE OF PRP

HISTORY OF PLATELET

PREPARATIONS AND

SKIN REJUVENATION

1975 - first reference to platelets being used as a healing agent -mixture of autologous platelets, fibrinogen and thrombin was studied as a corneal adhesive (Rosenthal et al 1975)

1976 – platelet factors stimulate fibroblasts (Rutherford 1976)

1982 – wound healing properties of platelets demonstrated in vivo – angiogenesis, neocollagenesis (Knighton 1982)

1986 – platelet-derived growth factors used to treat chronic non-healing wounds (Knighton 1986)

1987 – PRP could be used as part of the process of blood salvage during surgery to reduce the need for blood transfusions (Ferrari et al 1987)

1990 – PRP used to accelerate healing of chronic diabetic lower l imb ulcers (Margolis 2001)

1990 onwards– expanded use of PRP in various fields such as dentistry, maxillofacial surgery, vascular surgery, plastic surgery

1990 onwards – expanding use of “platelet gel” (platelet -r ich fibrin) in tissue healing and bone regeneration in oral and M -F surgery, wound care and cosmetic surgery (Marx 1998, Everts 2006)

HISTORY OF PLATELET USE

2008 – PRP first used on otherwise normal skin to improve skin texture (Radaelli 2010) (Regenlab)

2008 – Kakudo reported that PRP / PPP can stimulate proliferation of human mesenchymal stem cells and fibroblasts in vitro

2009 – PRFM reported as a dermal fil l ing agent (Sclafani 2009) (activated PRP - Selphyl)

2011 – In vivo histological evidence of PRP effect on human skin (Sclafani 2011) (Selphyl)

2011 – PRP used as adjuvant therapy to accelerate wound healing after laser skin resurfacing (Lee 2011 and Zhu 2013)

2014 – PRP combined with microneedling to improve acne scarring (Nofal 2014, Chawla 2014)

2015 – PRP improves photodamaged skin (Diaz-Ley 2015)

HISTORY OF PRP USE

PRP AND SKIN

THE CLINICAL EVIDENCE

PRP in cosmetic medicine started around 9 years ago

Gaining popularity worldwide – notably via celebrity endorsement!

“Vampire” Facials, Face LiftTM

PRP – COSMETIC MEDICINE

PubMed search (“platelet” “rich” “plasma” “skin”)

337 English language results (Feb 2017)

54 papers identified dealing with PRP and skin rejuvenation

No published clinical in vivo studies until 2008

Radaelli 2010 JDD

Sclafani 2011 AFPS

Diaz-Ley 2015 DT

Abuaf 2016 AD

PRP – COSMETIC MEDICINE

RADAELLI 2010

JDD 2010

Case series

23 patients, age 28-70

3 sessions of Regenlab PRP every month

4ml distributed over the forehead, cheek, NLF and neck

RADAELLI 2010

Subjective grading system – patient and doctor

Improvements in look (87%), wrinkles (52%), tone (83%) at 4 months after initial session

AfterBefore

Archives Facial Plastic Surgery Oct 2011

Method

4 healthy adult volunteers

PRP injected into deep dermis of upper arms (Selphyl)

Serial FT skin biopsies over 10 weeks

Histologic examination

SCLAFANI 2011

SCLAFANI 2011

Minimal inflammation

noted at day 7

Activated fibroblasts

New collagen

Angiogenesis in mid to

deep dermis

Clinically, swelling in

treated area had

resolved but noted

presence of persistent

“fullness” in the skin

SCLAFANI 2011

Fibroblast response

tapering by day 70

Extensive areas of new

collagen and new blood

vessels

Dermal adipocytes

persisted

Patients reported a

“softer” texture of the

treated skin

DIAZ-LEY 2015

Dermatologic Therapy Oct 2015

PRGF-Endoret

3 sessions at 3 week intervals

10 healthy subjects aged 34-59

Punch biopsies done at baseline and at week 12

Subjective grading system

Histological analysis

Increased skin thickness (45%)

Increased numbers of fibroblasts in deep dermis

Increased collagen volume

Decreased areas of solar elastosis

Subjective rating of satisfaction

grading scale 0-4

7/9 were satisfied or very satisfied

All patients with photodamagereported improvement whereas no patient without photodamagereported improvement

DIAZ-LEY 2015

Single session of PRP on one side and saline on the other

side, nappage-microneedle technique

Measured increase in dermal collagen with punch biopsies at

28 days

Saline – 46% (attributed to the microneedling effect)

PRP – 88%

PRP:saline ratio 1.93:1

ABUAF 2016

Annals Dermatology Dec

2016

Regenlab, activated with

calcium

20 randomly chosen

volunteers, aged 40-49,

skin types I -III

ABUAF 2016

ABUAF 2016

PRP – THE SMALL PRINT

“Oils ain’t oils” – not all PRP are created equal

Terminology (Davis et al 2014)

PRP - platelet-rich plasma

PRF - platelet-rich fibrin

P-PRP - pure platelet-rich plasma

L-PRP - leukocyte- and platelet-rich plasma

PRGF, plasma rich in growth factors or preparation rich in growth factors

PRFM - platelet-rich fibrin matrix

PC - platelet concentrate

PRC - platelet-rich concentrate

cPRP - concentrated platelet-rich plasma

PG - platelet gel

PRG - platelet-rich gel

PLG - platelet-leukocyte gel

BC-PRP - buffy coat platelet-rich plasma

PRP - THE SMALL PRINT

Problems with PRP for skin rejuvenation in the l iterature

1. There were no clinical studies to start with Initial justification of effects extrapolated from in vitro studies and

studies in other tissues – bone, joint -> practice preceded the evidence!

2. First studies Case studies; lack of controls, patient selection

Subjective grading of effect – confirmation bias

3. Standardisation PRP preparation – PRP / PRF / other?

PRP platelet counts – usually not checked and not reported

Activators

Protocol variation – single session v multiple sessions

4. Other factors Platelet concentration

White cell counts

What about PPP? (Kakudo 2008, Kim 2011)


In an attempt to overcome dif ferent terminology and the lack

of standardisation of studies with respect to platelet

concentration, the manner of activation and the number of

remaining white and red blood cells, a number of

classification systems were proposed

Dohan Ehrenfest 2009 [Oral and M-F Surgery]

Mishra 2012 [Sports medicine]

DeLong (PAW) 2012 [Orthopaedics]

POSEIDO 2013 [Oral and M-F Surgery]

Magalon (DEPA) 2015 [Sports medicine]

Mautner (PLRA) 2015 [Orthopaedics]

No currently accepted single classification system, whether in

orthopaedics, sports medicine, surgery or cosmetic medicine


DOHAN EHRENFEST CLASSIFICATION

Type Form White Cells Example

Systems

P-PRP (Pure PRP) Unactivated – liquid

Activated - gel

Almost none Vivostat PRF

PRGF/Endoret

L-PRP (Leukocyte- and

Platelet-Rich Plasma)

Unactivated – liquid

Activated - gel

Varies SmartPReP

Magellan

Angel / Arthrex

GPS III

Regen

Selphyl

P-PRF (Pure Platelet-

Rich Fibrin)

Activated - gel Minimal Fibrinet*

L-PRF (Leukocyte- and

Platelet-Rich

Fibrin)

Activated - gel Varies Intra-Spin*

• In cosmetic medicine, primary application technique is liquid form

• Majority of available systems on the market produce L-PRP

Definition of Platelet -Rich Plasma

Autologous plasma with platelet concentration above baseline (Marx 2001)

Too Simplistic!

Problems

Whose baseline?

Normal platelet count range is wide (150K -400K/μL)

How much above baseline?

Marx / Everts count >1000K/μL or 5 x baseline

5 x 150K = 750K; 5 x 400K = 2000K (750K < 2x)

Platelet counts often not reported in studies

Other factors involved in therapeutic effect (or lack of)

Platelet poor plasma

Residual white cells

Residual red cells

Manner of activation, if any


Two major types of PRP preparation systems (De Long 2012)

plasma (Regen, Selphyl, Endoret)

buffy coat (Angel, GPS, Harvest, Emcyte)

PLATELET CONCENTRATION

Plasma systems

Intention is to exclude WC –shorter and slower spin times and rates

Platelet concentrations ~ <2x-3x baseline

Buffy coat systems

Intention is to capture as many platelets as possible –also will capture WCs and RCs – longer and higher spin times and rates

Harvest 3-7x

Emcyte 7-10x

Davis 2014

Does this matter?

If some is good, is more always better?

Concept of Therapeutic Index

In context of bone regeneration, concentration of > 1M (1000K or 3 -

6x baseline) required (Marx 2001, Weibrich 2004); however,

concentrations > 6-11x inhibited osteoblast activity (Weibrich 2004)

In vitro evidence suggests that fibroblast proliferation, collagen

production and mesenchymal stem cell proliferation are dose

dependent (Haynesworth 2002, Liu 2002, Everts 2006)

Graziani (2006) studied effect of PRP on osteoblasts and fibroblasts

in vitro, concluded that 2.5x was optimal


Issues

Absolute counts not considered

Even if absolute counts reported, the count does not necessarily

indicate a higher GF end-product (especially if comparing individuals

– Cho 2011)

Concentrations (as compared with total platelet yield) can be

manipulated by the end user (by taking off PPP)

Currently, no study of PRP for skin rejuvenation that used

systems yielding higher platelet concentrations

Thus, no direct comparison comparing macroscopic (visible)

effects of lower platelet concentrations v higher platelet

concentrations for skin rejuvenation in vivo has been

performed

No evidence, at present, to suggest that higher platelet counts

are better in the context of skin rejuvenation


Effect of including WC in end-product is contestable (esp in

orthopaedic literature)

Neutrophils contain pro-inflammatory molecules such as

MMPs, TNF-α, IL -1β is it logical to think that excluding

neutrophils may lead to better tissue healing?

Higher than baseline WC counts (esp. neutrophils) leads to more

inflammation may be beneficial in situations of open wounds

and infection (Frykberg 2010, Saad Setta 2011, Rappl 2011)

Recall that Platelet GFs are chemotactic – neutrophils will be

attracted to the area anyway in the first phase of wound healing!

Kawazoe (2012) showed that WC-containing PRP enhanced

tissue thickness in a mice auricle model over PRP alone

Dohan Ehrenfest (2012) demonstrated that L -PRF membranes

are more robust than P-PRF membranes and release more GFs

WHITE CELLS (WC)

Published papers have used plasma-type PRP preparations (that

is, with a lower than baseline WC)

Recall that Radaelli, Sclafani, Diaz-Ley, Abuaf all used WC-poor (and

moderate platelet concentration) PRP systems

Sclafani showed histologically that at day 7, there was minimal

inflammation (but … may be end stage of inflammatory phase)

No clinical papers for skin rejuvenation in vivo for the higher

platelet count and white cell -rich buffy coat systems

Superiority of one type of system over another (in regard to

white cell counts and skin rejuvenation) lacks proof at present

WHITE CELLS (WC)

Platelets must be “activated” to release GFs ADP, thrombin, collagen, fibrinogen VWF

Early PRP preparations used bovine thrombin as an activator issues of antigenicity

Current systems use calcium (usually chloride salt) as this is a natural trigger for the clotting cascade autologous thrombin

Rationale– ensures formation of a fibrin network virtually total platelet activation accelerated delivery of growth factors to treated area (all GFs secreted by 4-8 hours)

Does this make a difference? Platelet activation occurs in vivo

“Natural” activation gradual growth factor release over 5-7 days v “activated” release over 4 -8 hours (Harrison 2011)

Exceptions – wounds, fat grafting, ?emphasising angiogenesis, PPP

All published studies use calcium as an activator

ACTIVATION

PPP is often discarded during the process of harvesting PRP –

assumption is that this fraction contributes little, if any,

tissue effect this assumption is likely incorrect

In vitro studies of activated PPP demonstrated mitogenic

effects of human MSCs (hMSCs), fibroblasts and adipocytes

(Koellensperger 2006, Kocaoemer 2007, Kakudo 2008, Cho

2011)

These studies suggest that there are other factors within

plasma (or other cells) that also play a significant part in the

wound healing process apart from platelets

Note that the PPP must be “activated” with calcium chloride,

unactivated PPP has not been shown to have any tissue

effects (Kakudo)

PLATELET POOR PLASMA

PRP is a viable procedure for skin rejuvenation

Simple to use, quick, effective with minimal downtimes but …

Results take time

Set expectations

Clinical evidence demonstrating effectiveness is building

(slowly)

Doesn’t matter what system you use

Platelet concentrations

White cell counts

Don’t discard PPP

SUMMARY

THANK YOU!

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Dr Herbert Hooi - Cosmetic MD

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