Progress in the Use of Platelet-Rich Plasma to Treat Vitiligo and Melasma

Xian Ding and Sheng-Xiu Liu

Department of Dermatology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.

Abstract There have been numerous therapeutic innovations in the field of dermatology during the past decade.Of these,platelet-rich plasma(PRP)has recently aroused significant interest,particularly in treating acne scars and alopecia,and in skin rejuvenation.In contrast,less attention has been paid to the use of PRP as a treatment for other dermatologic conditions,such as vitiligo and melasma.The objective of this literature review was to focus on conditions of pigmented dermatosis and consolidate the available evidence regarding PRP usage for the practicing dermatologist.We reviewed the relevant literature on PRP treatment on vitiligo and melasma,and concluded that PRP has a significant improvement in pigmented dermatosis.Although numerous studies support the use of PRP,more research is needed to standardize the protocols for obtaining,processing,and applying PRP,as well as to determine the biological and molecular bases of its function.

Keywords: melanocyte, melasma, platelet-rich plasma, vitiligo

Introduction

Platelet-rich plasma(PRP)is a high-concentration autologous plasma solution prepared from blood.The platelets contained in PRP release a variety of growth factors,adhesion molecules, and chemokines.1Recently, PRP has been used to treat various skin diseases (including acne scarring and alopecia) and for skin rejuvenation,including pigmented skin diseases such as vitiligo and melasma.

PRP has been used as a new treatment for vitiligo and melasma,and has achieved satisfactory results in combination with other treatments.2Although the exact mechanism of PRP has not been fully elucidated,the evidence suggests that PRP increases the release of growth factors,adhesion molecules, and chemokines that interact with the local environment and regulate cell differentiation,proliferation,and regeneration(Fig.1).3-4

Figure 1. Effects of PRP on growth factors,adhesion molecules,and chemokines.EGF: epidermal growth factor;FGF: fibroblast growth factor;IFN: interferon;IGF: insulinlike growth factor;IL: interleukin;MITF: microphthalmia-associated transcription factor;PAX: Paired Box;PDGF:platelet-derived growth factor;PRP:platelet-rich plasma;TYR: tyrosinase;TGF: transforming growth factor;TNF: tumor necrosis factor;VEGF: vascular endothelial growth factor.

The purpose of this review was to discuss the mechanism of PRP in the treatment of vitiligo and melasma, and to examine the evidence regarding the effectiveness of PRP in treating vitiligo and melasma to determine the potential application and best practice of PRP usage.This review evaluates the literature up to March 15,2021,and a search was conducted in the PubMed database for “platelet-rich plasma”or“platelet gel”or“PRP”and“dermatology”or“skin”or“melasma”or“vilitigo”or“melanocyte.”Thirtyfour articles met the inclusion criteria for this review.

Function of PRP

PRP is an autologous plasma solution with a higher concentration of platelets than whole blood, usually comprising a three-to seven-fold increase.Once the platelets contained in PRP are activated,the α particles release a large amount of growth factors, adhesion molecules, and chemokines.The main platelet growth factors released are platelet-derived growth factor, insulin-like growth factor,vascular endothelial growth factor, epidermal growth factor,transforming growth factor(TGF-β),and fibroblast growth factor.5-6These growth factors play an important role in the regulation of cell differentiation, proliferation,and regeneration.In addition,PRP releases numerous antiinflammatory cytokines,such as interleukin(IL)-1 receptor antagonist, soluble tumor necrosis factor receptor I, IL-4,IL-10,IL-13,and interferon γ.7

Preparation of PRP

The basic steps of PRP preparation are blood collection,centrifugation, plasma suction, potential secondary centrifugation, selective supernatant removal, mixing/resuscitation of platelets, activation, and application.8-9The final PRP product is affected by several factors in the preparation process, including the centrifugation time,force,and temperature,centrifugation order and quantity,anticoagulation usage, and activation mechanism.10The preparation of PRP is generally divided into single centrifugation and double centrifugation.Although the single centrifugation method is simple to operate,it has an insufficient platelet recovery rate that limits its application.The double centrifugal method involves a complicated procedure that enables the extraction of purer PRP, but also leads to a decline in the platelet recovery rate.11The classic double centrifugation methods include the Petrungaro method(first centrifugation at 1500gfor 6 minutes,second centrifugation at 1000gfor 6 minutes), Landesberg method (two lots of centrifugation at 200gfor 10 minutes), and Aghaloo method (first centrifugation at 215gfor 10 minutes,second centrifugation at 863gfor 10 minutes).12–14There is no clear consensus regarding the best PRP preparation method, and there is no unified worldwide standard at present.

PRP in the treatment of vitiligo

Mechanism of PRP in the treatment of vitiligo

Vitiligo is an acquired, idiopathic disorder clinically characterized by amelanotic skin lesions due to the destruction of melanocytes.Skin pigmentation is controlled by complex interactions between melanocytes, keratinocytes, and fibroblasts.Growth factor/receptor signaling in patients with vitiligo decreases the transmission function,resulting in damaged keratinocyte and fibroblast paracrine activity,leading to the loss of melanocytes.PRP stimulates the paracrine pathway of fibroblasts and keratinocytes through these growth factors to improve their interactions with melanocytes and stabilize melanocytes.15Studies have shown that melanocytes in patients with vitiligo have defects in the Wnt/β-catenin signal pathway,which promotes the differentiation of melanocytes precursors in the skin.Growth factors released by PRP stimulate protein kinase B (Akt) by binding to growth factor receptors on the cell membrane.Akt prevents melanocyte apoptosis by inhibiting B-cell lymphoma 2, and inhibits glycogen synthase kinase-3 (an enzyme that degrades β-catenin) to promote β-catenin accumulation in the cytoplasm, leading to the survival and proliferation of melanocytes.16In addition,PRP has anti-inflammatory effects and inhibits the release of cytokines,which play a role in the pathogenesis of vitiligo.

PRP in the treatment of vitiligo

Our review of published clinical trials shows that vitiligo is effectively improved by PRP combined with excimer laser therapy,NB-UVB phototherapy,and fractional CO2laser therapy.Table 1 summarizes the findings of studies using PRP for vitiligo treatment.

Table 1Studies using PRP for vitiligo treatment.

An intra-patient-controlled study of 17 patients with stable vitiligo treated with autologous miniature punch grafting and subsequent exposure to phototherapy with and without enhancementviaPRP concluded that PRP speeds the repigmentation response to the miniature punch grafting/phototherapy procedure, without having any significant effect on the final outcome.17In addition,Garget al.18reported that PRP-enriched epidermal suspension transplantation has the potential to improve the rate of healing and repigmentation in vitiligo patches.Some studies have reported that PRP combined with excimer laser therapy has a significantly better effect on stable vitiligo than PRP alone and excimer laser alone;furthermore, this combination is well tolerated,shortens the time of excimer laser treatment, and improves patient compliance.19-20A prospective randomized trial reported that fractional CO2laser combined with PRP achieved superior repigmentation than intradermal PRP alone in the treatment of stable nonsegmental vitiligo lesions.21Another prospective, randomized,comparative trial assessed the effect of combined treatment with fractional CO2laser, PRP injection, and narrow-band ultraviolet B (NB-UVB) for stable nonsegmental vitiligo regarding repigmentation grade, patient satisfaction,and adverse effects.22The results showed that fractional CO2laser combined with PRP injection is a promising treatment for vitiligo,followed by combination of fractional CO2laser with NB-UVB phototherapy poor results were obtained after fractional CO2laser alone and PRP injection alone.However, the latest research by Afifyet al.23obtained different conclusions.Their study aimed to evaluate and compare the efficacy and safety of fractional CO2laser,PRP,and NB-UVBeitheraloneorincombination in the treatment of vitiligo.They reported a significant improvement in all treatment groups.However, the percentage of reduction in the affected surface area did not significantly differ between treatment groups.

Treatment of melasma with PRP

Mechanism of PRP in the treatment of melasma

Melasma is a common form of acquired symmetrical melanosis diagnosed based on the presence of brown or gray plaques on facial areas exposed to ultraviolet light.The pathogenesis of melasma is not completely clear, but may be associated with sunlight exposure, changes in hormone levels, genetic susceptibility, vascular factors,nutritional level, and mental factors.Transcriptional analysis of melasma skin samples shows that numerous genes related to melanin synthesis and melanocyte markers such as microphthalmia-associated transcription factor,tyrosinase (TYR), and TYR-related protein are upregulated in the skin of patients with melasma.24Studies have shown that TGF-β1 binds to the receptors on cell membranes to activate the Smad signal pathway, inhibits melanin synthesis by downregulating the activity of TYR and microphthalmia-associated transcription factor, and promotes the production of TYR-related protein.25TGFβ1 also inhibits the expression of the paired-box homeotic genePaired Box 3,which is a key regulator of UV-induced melanogenesis.26Yunet al.27found that epidermal growth factor reduces melanogenesis by inhibiting prostaglandin E2 and TYR.Recent studies have shown that melasma may be not only a melanocytic disease, but also a photoaging skin disease.28Ultraviolet light exposure increases the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 that degrade type IV and type VI collagen in the skin.The resultant damaged basement membrane promotes the entry of melanocytes and melanin into the dermis.However, TGF-β1 stimulates the expression of laminin,type IV collagen,and tenascin,repairs the basement membrane, and prevents melanocytes and melanin from entering the dermis.Platelet-derived growth factor also stimulates collagen synthesis, increases extracellular components (especially hyaluronic acid), and makes the skin shinier.

PRP in the treatment of melasma

Local decolorant is the main method used to treat melasma.The most popular anti-melanin drug is hydroquinone, which competitively inhibits tyrosinase andinhibits the conversion of dihydroxyphenylalanine to melanin.However, hydroquinone has some safety risks such as exogenous precocity, permanent decolorization,and potential carcinogenesis.In addition, the use of local decolorant alone cannot restore the photoaging skin condition of melasma.Therefore, anti-aging methods should be combined with local decolorants to improve melasma.PRP therapy has prospects for broad application in thetreatmentof melasma.Comparedwith other melasma treatments,PRP therapy has fewer adverse effects and less pigmentation rebound.Table 2 summarizes the findings of seven randomized controlled trials investigating the efficacy of PRP injection for melasma treatment.

Table 2Studies using PRP for melasma treatment.

Tuknayatet al.29reported an average 54.5% reduction in the modified melasma area severity index(MASI)score after three sessions of intralesional PRP with a 1-month interval between sessions.Gameaet al.30compared the efficacy of topical tranexamic acid 5% in liposome base alone versus in combination with intradermal PRP for melasma treatment and reported that PRP is advisable as an autologous safe elixir that boosts the therapeutic effect of tranexamic acid.A recent randomized, clinical trial in which 30 patients received PRP by microneedling every 3 weeks for three sessions showed that 10%, 30%, and 60% of patients achieved improvements of<25%,25%–50%, and 50%–75%, respectively.31Hofnyet al.32compared the therapeutic effects of PRP administeredviamicroneedling or microinjection in the treatment of melasma.PRP was delivered into the melasma skin lesions by microinjections on the left side of the face, and by microneedling on the right side of the face.The MASI scores significantly decreased on each side of the face;however,there was no obvious difference between the two sides.In another randomized clinical trial, the expression of TGF-β protein in the lesional skin of patients with melasma was significantly increased after treatment with PRP.33A randomized,split-face,single-blinded trial found that intralesional injection of PRP significantly improved the modified MASI score in 10 female patients with melasma.34In another therapeutic trial, 20 patients with melasma received five fortnightly sessions of autologous PRP injections in the facial melasma.35After treatment,the response was good in 13.3% of patients,fair in 60%,and poor in 26.7%.None of the patients showed an excellent response.

Conclusions

PRP has prospects for broad application and can be combined with other methods in the clinical treatment of refractory pigmented dermatoses.However,there are still limitations associated with PRP,such as the lack of logical and mechanical proband.For example, it is currently impossible to explain how a treatment that is effective for melasma works on diametrically opposed diseases such as vitiligo.It is necessary to explore the signal pathways of keratinocytes,fibroblasts,adipocytes,and endothelial cells to regulate melanin production.