INTRODUCTION

Signs of facial aging include the appearance of wrinkles, deepening of expression lines, and altered skin pigmentation, texture, and elasticity. Skin youthfulness relies on a fine-tuned equilibrium between anabolism and catabolism, and aging reflects a progressive metabolic imbalance, that includes increased collagen and elastin degradation, accompanied by reduced and disorganized fiber production.[1] A therapeutic agent able to reverse these deleterious processes could, in theory, exhibit an antiaging effect and promote a facial esthetic regeneration. Platelet-rich plasma (PRP) is defined as autologous plasma with a platelet concentration above the baseline (150,000/μL to 400,000/μL), usually four to seven times higher.[23] The healing role of platelets in response to injury is well known, with clinical effects partially relying on the release of alpha granules, rich in growth factors such as platelet-derived growth factor, transforming growth factor-β1 and -β2 (TGF-β1 and TGF-β2), vascular endothelial growth factor, basic fibroblast growth factor (bFGF), and epithelial growth factor (EGF).[4] As wound healing and tissue rejuvenation share some common metabolic features, it was hypothesized that PRP could act on both pathways.[5] PRP has been traditionally used in regenerative treatments in oral and maxillofacial surgery[67] and orthopedic surgery,[8] but in recent years, its potential rejuvenating properties have also sparked the interest of reproductive medicine[9] and dermatology.[10] When applied in skin, PRP could potentially recycle the damaged extracellular matrix through the activation of leukocyte matrix metalloproteases, stimulation of fibroblast proliferation, and increased collagen production via increased expression of G1 cell cycle regulators.[1112] In the last decade, case reports, prospective studies, and a few clinical trials have addressed theskin-rejuvenating properties of PRP.[131415] Each publication usually describes its own method of preparation and application of PRP and evaluation of final results. This lack of uniformity between authors may help explain why some excitingly describe PRP as the new “fountain of youth,” whereas others simply do not find any differences compared to placebo. In this work, the author aims to systematically review the latest evidence available on the use of PRP for facial skin rejuvenating.

MATERIALS AND METHODS

MEDLINE (PubMed) was searched for articles focusing on the use of PRP for facial skin rejuvenation. Search terms were ([platelet-rich plasma OR PRP] AND [face, aging, wrinkles, or rejuvenation]). Inclusion criteria were (1) peer-reviewed original clinical trials, (2) written in English language, (3) published from January 1, 2017 through July 31, 2022, (4) focusing of facial skin rejuvenation, and (5) treatment with PRP alone or in association with other procedures. Exclusion criteria were (1) studies other than clinical trials (e.g., case reports, meta-analysis), (2) use of PRP to treat anatomical structures other than facial skin (e.g., joints, ovaries), and (3) treatments not focusing on facial aging (e.g., alopecia, acne scars).

RESULTS

Initial search retrieved 539 articles and from these, 523 were excluded based on title, abstract and exclusion criteria. A total of 16 articles were included in the review,[16171819202122232425262728293031] with an aggregate of 586 participants [Table 1]. Among the 16 articles, in 10 studies (62.5%), PRP was injected in monotherapy, in five studies (31.2%), PRP was topically applied following ablative laser treatment (CO₂ or erbium), microneedling or electroporation and in one study (6.3%) PRP was injected in conjunction with autologous fat. Eight studies (50.0%) were split-face comparative clinical trials, with PRP being compared to placebo (four articles, 25.0%), platelet-poor plasma (PPP) gel (two articles, 12.5%), trichloroacetic acid (TCA) (one article, 6.3%), and readymade growth factors (one article, 6.3%). One study (6.3%) compared groups of participants treated with ablative CO₂ laser and PRP versus ablative CO₂ laser alone and in seven studies (43.8%) participants acted as their own controls in a before- versus after-treatment assessment.

In a straightforward attempt to understand how PRP can enhance facial rejuvenation several studies were design to directly compare PRP with placebo. Cameli et al.[20] and Elnehrawy et al.[25] evaluated the effect of PRP on facial skin rejuvenation. The former performed three sessions of PRP injection at one-month intervals while the later designed a study using a single PRP injection. Using both subjective (clinical and participants evaluation) and objective (by means of instrumental noninvasive devices) evaluations, Cameli et al.[20] concluded that PRP improved skin texture, elasticity and smoothness, skin barrier function, and capacitance. Elnehrawy et al.[25] described a significant improvement of wrinkles, notably the nasolabial fold, after treatment with PRP. In the following year, Alam et al.[16] published their results using a split-face model to evaluate the effect of a single injection of PRP to the cheek. Again, evaluation was performed by both physicians (two dermatologists) and participants. No significant improvement was assessed by physicians. In contrast, participants considered that the PRP-treated side was significantly improved in both texture and wrinkles, leading to an increased overall satisfaction. Everts et al.[26] and Lee et al.[29] published their studies using pretreatment photographs of participants as controls. In the former, participants received PRP injections in three sessions at one-month intervals, while in the later participants received only a single PRP injection. Everts et al.[26] described that wrinkle count significantly decreased and skin firmness improved right after the first PRP injection, with these effects being sustained throughout the six-month follow-up period. At the end of this period, a decrease in erythema was also noted. Overall patient satisfaction was above 90%. In contrast, Lee et al.[29] reported that only 45% of participants showed any type of esthetic improvement according to physician assessment, although most participants were satisfied with the results. Draelos et al.[22] designed a split-face study in which PRP was not directly injected in the skin as in the previously presented articles, but mixed with a serum and applied as a mask following electroporation, twice daily for 8 weeks. No significantly differences were recorded, although results suggested that PRP mixed with serum could improve skin radiance, luminosity, firmness, and softness. Skin biopsies performed on four patients at the end of the evaluation period revealed that PRP mixed with serum was able to improve the architecture of rete peg and upregulate collagen gene expression. Du and Lei[23] an interesting study where they not only designed a split-face study to evaluate PRP versus phosphate-buffered saline (PBS) injected in three sessions with 2-week intervals but also irradiated a human organotypic skin model with ultraviolet-B light before injecting it with PRP to evaluate effect on gene expression.[23] Results showed that PRP improved the skin quality of participants. Multispectral imaging also revealed that PRP decreased wrinkles, texture, and pores when compared with the PBS treatment. The in vitro study suggested that PRP ameliorated skin photoaging through regulation of MMP-1, tyrosinase, fibrillin, and tropoelastin gene expression. Finally, Banihashemi et al.[18] demonstrated that injections with PRP in two sessions with 3-month interval, at 3- and 6-month follow-ups were associated with moderate to excellent improvement of periorbital dark circles and wrinkles, nasolabial folds, and skin stiffness (although only dark circles and nasolabial folds were statistically significant).

Another set of studies focused on comparing the effects of PRP versus other substances on facial rejuvenation. Gawdat et al.[27] proposed to compare PRP with a readymade growth factor solution (mesotherapy) using a split-face model and administrations every 2 weeks for a period of 3 months. Although both procedures improved skin turgor, overall vitality, epidermal and dermal thickness, patient satisfaction, and effect longevity were significantly higher with PRP. El-Domyati et al.[24] published a split-face study comparing the effect of microneedling alone, combined with PRP or with TCA at 15%. Outcomes focused on visual appearance and histological characterization. According to the authors, combining the minimally invasive techniques microneedling with PRP or TCA 15% improved wrinkle appearance and skin texture more than microneedling alone. Moreover, PRP had a better effect on the external cellular matrix of the skin. Neinaa et al.[21] and Diab et al.[30] published their results in 2020 and 2021, respectively, comparing PRP with PPP gel using a split-face approach. Studies were aimed at the periorbital area, focusing on wrinkle and hyperpigmentation improvement. While both authors described that PPP and PRP reduced tear through, a lighting effect on periorbital dark circles was only noticed by Neinaa et al.[21] In both studies, the direct comparison between the visual impact of PPP and PRP seemed to favor the former. Treatment with PPP was associated with 10% severe and 17.5% moderate complications. No severe complications were associated with PRP, with only 2.5% of participants experiencing moderate complications, favoring, in this particular aspect, the use of PRP.

Finally, a few authors have evaluated the association of PRP with other esthetic procedures. Hui et al.[28] and Araco[17] proposed to study the synergy between PRP and CO₂ laser skin resurfacing. Both authors design split-face experiments, applying PRP immediately after skin ablation with laser. In addition, Araco[17] developed a medical device that was able to embed, preserve, and topically deliver PRP at home, twice a day, during 12 weeks. The association between PRP and CO₂ laser rendered a better improvement of skin wrinkles, texture, moisture, and tightness. Regarding recovery, Hui et al. noted a decreased erythema, edema, and crusting when compared to CO₂ laser therapy alone. Cai et al.[19] irradiated facial skin with fractional erbium laser (2940 nm), followed by PRP coating. Both participants and physicians noted a clear improvement of signs of skin age, mainly color, pore expansion, and skin texture. Finally, Willemsen et al.[31] evaluated the effect of adding PRP to facial lipofilling versus lipofilling alone. According to the authors, adding PRP to the lipograft did not improve skin elasticity, volume retention nor overall patient satisfaction. Nevertheless, combining both substances significantly reduced the recovery time reported by participants.

DISCUSSION

Throughout the process of analysis of each article, the first feature that popped to the eye was heterogeneity. PRP preparation methods, administration protocols, and results assessment were highly variable among the selected studies. Nevertheless, generically, PRP seemed to improve signs of facial aging.

The use of PRP versus placebo was assessed in eight studies.[1618,2022,2325,2629] In five out of eight, a significantly positive effect of PRP was observed by both participants and physicians. Improvements were seen in skin texture, wrinkles, and pigmentation. In contrast, Alam et al.[16] and Lee et al.[29] described that improvement was mostly reported by participants, whereas external evaluators relying on photographs assessed a much more discrete effect. Authors theorized that, by knowing their faces intimately and in great detail, participants could perceive differences more clearly and that external reviewers may have not been able to assess some skin details such as texture or smoothness in a photographic evaluation. Despite this explanation, in both studies, the administration protocols described a single PRP injection, as opposed to multisession study designs described in most of the other articles. It is possible that more evident effects could be achieved if more sessions of PRP were attempted. Finally, Draelos et al.[22] tested the effect of the topical application of PRP following electroporation performed at home, by the patient itself. The lack of statistically significant effects was attributed to the shortness of the 8-week follow-up period. It can also be theorized that electroporation did not permeate the skin to a level at which PRP could actually reach the dermal layer of the skin in sufficient concentration.

A second set of studies focused on the comparison between PRP and other active substances.[2124,2730] Gawdat et al.[32] concluded that both PRP and a readymade growth solution were superior to placebo, with PRP showing the best results regarding patient satisfaction, fewer side effects, and sustainability over time. Readymade growth solution contains a mixture of epidermal growth factor (EGF), insulin-like growth factor-1, bFGF, thioredoxin (TRX), copper tripeptide-1, multivitamins, amino acids, and minerals. However, when analyzing the secretome of activated platelets, it is possible to identify more than 300 bioactive proteins. Therefore, a synergic effect between many of these components that are absent from the readymade growth solution could be responsible for the differences reported by the authors. El-Domyati et al. compared the effect of PRP versus chemical peeling with TCA 15%, both following microneedling with a dermaroller. Although both treatments enhanced skin quality, the histological effect of each appeared different. Apparently, while TCA had a more pronounced effect on epidermal thickness, PRP seemed to have a better outcome on the architecture of the extracellular dermal structures, highlighting a more physiological effect. Neinaa et al.[30] and Diab et al.[21] compared PRP versus PPP gel in the treatment of wrinkles and dark circles of the periorbital area. Although both treatments improved the overall satisfaction of participants, PPP, despite having a lower platelet concentration, achieved better scores. Plasma gel is produced by adding activating agents, such as thrombin or calcium chloride to PPP, that induce the formation of a three-dimensional fibrin matrix. Unlike PRP, PPP gel acts as an autologous dermal filler upon injection, immediately stretching the skin, reducing tear through, and enhancing skin lightning. This effect, easily observed by participants, may explain the better outcome of PPP versus PRP and why it is not kept beyond 3 months.[2130]

Three studies focused on the use of PRP in association with CO₂[1728] and erbium[19] fractional lasers. In all three, the use of PRP enhanced the antiaging effect of laser resurfacing, reducing recovery time and side effects. The use of ablative lasers in facial rejuvenation is well described and relies on the physiological response of skin to injury and subsequent renewal of the extracellular matrix.[3334] Fractional lasers promote tissue vaporization in the shape of uniform columns that reach the dermal layer, and it has been shown that these structures can be used to deliver therapeutic substances.[35] By using both fractional lasers and PRP, it seems a synergetic effect is achieved via an initial injury burst and the enhancement of type III and type IV collagen production and dermal stem cells proliferation.[19] The association between PRP and lipofilling was studied by Willemsen et al.[31] Results indicated that the addition of PRP to autologous fat did not increase patient satisfaction compared to lipofilling alone. It is possible that the immediate effect of lipofilling on volumization could be masking any potential effect of PRP on facial rejuvenation.

In order to understand the biological effect of PRP behind facial rejuvenation, some authors evaluated the effect on tissue architecture and molecular profile. Previous studies conducted in hepatocytes and dermal fibroblasts reported that platelet-released factors enhance collagen expression, hyaluronic acid production, and fibroblast proliferation.[1236] In the studies selected for this review addressing this question, PRP improved elasticity not only by increasing the dermal content on collagen and elastin but also by increasing the water retention capacity of the skin.[1720,222324] Gene expression analysis revealed PRP had a positive effect on collagen mRNA upregulation and in the response of skin to ultraviolet-B light, by modulating the expression of metalloproteinase-1 (MMP-1), tyrosinase, fibrillin, and tropoelastin genes.[2223]

In conclusion, the use of PRP on facial rejuvenation remains controversial. The lack of uniformity in PRP preparation methods, administration protocols, and results assessment translate into a wide array of outcomes, ranging from the absence of response to remarkable effects on facial skin quality. In most studies included in this review, PRP seemed to revert to some degree the signs of facial aging, such as wrinkles, hyperpigmentation, and dehydration. This visual enhancement was accompanied by significant histological and molecular responses leading to an improved dermal matrix architecture.