Platelet-Rich Plasma in Facial Rejuvenation: A Systematic Appraisal of the Available Clinical Evidence

Introduction

The main purpose of facial rejuvenation is to reverse the aging process either by surgical or noninvasive modalities.¹ In recent years, despite the increase in the number of facial rejuvenation cosmetic procedures, there is a decrease in the number of patients opting for surgical facial rejuvenation procedures.² This emphasizes the importance of noninvasive procedures in improving cosmetic outcomes. Among the noninvasive facial rejuvenation methods, platelet-rich plasma (PRP), which is a platelet concentrate obtained from autologous plasma, has been used in wide dermatological applications including facial rejuvenation.³

PRP concentrate consists of various growth factors that perform diverse functions including but not limited to mitogenic and chemotactic functions. The growth factors in PRP include platelet-derived growth factors (PDGFs), transforming growth factor-β1 (TGF-β1), TGF-β2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and epithelial growth factor (EGF).³ Although the exact mechanism of action of PRP in bringing about facial rejuvenation is not yet elucidated, it is hypothesized that the growth factors may mediate tissue repair and regulate cellular proliferation and differentiation genes thereby leading to angiogenesis.¹ These growth factors facilitate rejuvenation at the cellular level, which may lead to better long-term effects in comparison with invasive procedures.⁴ The most suitable PRP preparation method is not yet clear. PRP can be prepared by single and double spin systems. The double spin kits have the potential to yield highly concentrated PRP, while single spin designs result in a serum with less platelets than whole blood (platelet poor plasma).⁵ The use of PRP was further fine-tuned by the introduction of platelet-rich fibrin, which is a modified concentrate of PDGFs extracted from autologous plasma,⁶ and is prepared by procedure similar to PRP preparation.⁷

Despite the availability of different extraction procedures for PRP, there is no consensus on the effectiveness of the extraction procedures. Further, clinically PRP is used both as topical and intradermal injectables. This has further complicated the assessment of effectiveness. Due to the lack of high-quality clinical evidence, the usage of PRP is currently governed by the treating physicians’ clinical judgment and discretion. The clinical evidence landscape is also further complicated by the usage of multiple patients- and physician-reported outcomes of qualitative nature. In this context, the main purpose of this systematic literature review is to appraise the available clinical evidence to provide insights and to assist the treating physicians in clinical decision-making.

Methodology

Data Sources and Searches

The systematic literature review was performed according to the Synthesis Without Meta-analysis (SWiM) guidelines. PubMed and Embase were searched from inception to September 14, 2021. The search was performed with the keywords “platelet-rich plasma AND facial rejuvenation.” A literature search was performed in the databases with a general search string to retrieve all possible studies (clinical trials, observational studies). Additionally, search strings relevant to each query were also used to retrieve any study that could have been missed with a general search string.

Study Selection

Two reviewers independently screened the abstracts and full texts for eligibility for inclusion. Literature from PubMed and Embase were exported into excel to a single master data document. Reviews, meta-analyses, duplicated publications from the same patient population, in vitro studies, and non-English articles were excluded. Any disagreements regarding study inclusion were resolved by a third independent reviewer. Various study attributes including study design, number of patients, treatment arms, study outcomes, end points, and salient results were extracted for appraisal. The PRISMA guidelines were followed for the development of this review (Figure 1). The qualitative assessment of the included studies was performed by the New Castle Ottawa scale for observational studies and JADAD scale for randomized control studies. The study was prospectively registered on the PROSPERO website (ID:CRD42018112733).

Figure 1 PRISMA flow chart. Notes: PRISMA figure adapted from Moher D, Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.60

Results

The systematic search yielded a total of 161 articles that were subjected to preliminary screening based on the title and abstract. A total of 36 studies were included for the evidence synthesis, of which, 18 studies were interventional, whereas 17 were observational studies; the remaining 1 study was a case report. The baseline trial characteristics of the studies included in the analysis are represented in Table 1. Among the 36 studies, 9 (25%) studies used PRP as monotherapy and 23 (80%) studies used PRP in combination with other techniques such as micro-needling, CO₂ laser treatment, or hyaluronic acid, growth factors, and Botox. PRP was used for treating acne scars in 17 studies (47.22%), facial aging in 17 studies (48.44%), and loss of tissue volume in 2 studies.

Table 1 Baseline Characteristics of the Included Studies

Except for 7 studies (19.44%), all studies reported a significant improvement after PRP application either as monotherapy or combination therapy in various conditions of facial rejuvenation including facial wrinkles, aging, pigmentation, nasolabial folds, acne scars, and tissue volume.

Administration of PRP

Due to the non-specific nature of autologous PRP, the dose of administration of PRP is not standardized in clinical practice. Since the active component of PRP is the growth promoters released by the platelets upon activation, it may not be feasible to standardize the same. Among the 36 studies, 20 studies reported the volume of PRP administered in the respective cohort of patients, and it ranged from 0.1 to 4 mL (Table 2). Although the purpose and desired outcome in each study were different, the rationale for using a particular volume of platelet concentrate was not explained in any of the studies. Further, platelet counts and leukocyte cell counts were provided only in 7 and 1 studies, respectively, which suggests a lack of a rational approach in determining the PRP administration volume. Because PRP is the first generation of platelet concentrate and other blood-derived platelet concentrates like the platelet-rich fibrin is also used in clinical practice, it is essential to use a surrogate marker for determining the amount of growth factors in the PRP.

Table 2 Components of Platelet-Rich Plasma Preparation in 36 Included Studies

Outcomes and End Point of Interest in PRP Treatment

Apart from the administration dose of PRP, the lack of uniform assessment of efficacy is another important aspect of PRP treatment. The end points for determining efficacy were based on the desired treatment outcome. Among the included studies, the end points of efficacy ranged from the usage of the FACE Q questionnaire to an independent photographic assessment of wrinkles and acne (Table 3). The findings of combination therapy are presented in Table 4. A qualitative assessment of the included studies is provided in Table 5.

Table 3 Studies with Platelet-Rich Monotherapy for Facial Rejuvenation

Table 4 Studies with Platelet-Rich Combination Therapy for Facial Rejuvenation

Table 5 Evidence Grading of the Studies Included in the Literature Review

Application of PRP in Facial Rejuvenation

Among the studies that used PRP monotherapy, the mode of administration of PRP was an intradermal injection in all the studies except for one study in which it was used as a topical application. All studies reported significant improvement after PRP application although there is a lack of uniformity in assessment and reporting of the outcome measures. This makes it difficult to draw definitive conclusions based on the results reported in these studies. Results in 7 studies were assessed based on the photographs obtained at baseline and follow-up (Table 3).

PRP has several benefits in facial rejuvenation and due to its enormous benefits, it is being used in several conditions such as atrophic acne scars, pigmentation, facial wrinkles, facial folds, loss of elasticity, and loss of tissue volume.⁸

PRP with Micro-Needling Applications

PRP in conjunction with the micro-needling procedure was explored in 5 studies reporting significant effects in treating acne scars and facial aging.^9–13 Ibrahim et al compared the efficacy and safety of micro-needling with PRP and micro-needling alone in 35 patients with atrophic acne scars. Although significant improvement was observed after both the treatment modalities there was no significant difference between the 2 modalities as assessed by Goodman and Baron’s global acne scarring system. However, regarding safety, PRP with micro-needling had significantly lesser erythema and edema than micro-needling alone, which could plausibly be attributed to the healing and tissue repair properties of PRP.¹³ A randomized study evaluated the effects of micro-needling and PRP both, alone and in combination, in 90 patients. There was a statistically significant improvement in the PRP and micro-needling group compared with PRP and micro-needling alone. Moreover, the patient satisfaction was also statistically significant in the combination group compared with PRP and micro-needling groups alone. The authors suggest that the combination therapy is efficacious and safe in treating atrophic scars of different etiologies with minimal downtime and affordable cost.⁹ Asif et al assessed the combination efficacy of PRP with micro-needling in managing atrophic acne scars in 50 patients. Goodman’s qualitative and quantitative scales showed significant improvement by micro-needling alone and a combination of PRP and micro-needling. There was a significant difference between the 2 treatments modalities. Patient satisfaction scores were also significantly different between PRP and micro-needling and micro-needling alone. The authors propose a hypothesis that in combination therapy of micro-needling and PRP, the damage caused due to micro-needling is cured by the healing mechanism of the activated platelets, cytokines, and the growth factors from PRP.¹² Another study compared a combination of PRP and micro-needling with micro-needling and trichloroacetic acid (TCA) peeling in 24 subjects with atrophic acne scars. Both the combinations showed significant improvement in acne scars, however, there was no significant difference by histometric evaluation of epidermal thickness. Although both the combination techniques were efficacious, micro-needling with TCA was preferred by the subjects over micro-needling with PRP for acne scars.¹¹ A similar study of combination techniques for photoaging and facial wrinkles showed a significant increase in evaluation scores of PRP and micro-needling compared with micro-needling and TCA. Additionally, histological results also revealed improvement of dermal structures in micro-needling and PRP combination compared with micro-needling and TCA.¹⁰ In a recent randomized trial, Alam et al showed that PRP therapy improved the visual appearance in individuals with photoaged skin, the results showed that both fine and coarse texture improved significantly more with a single treatment of PRP than the individuals treated with normal saline.¹⁴

PRP with Laser Applications

Laser treatment with PRP has been reported to produce superior results in treating acne scars and facial aging. Seven studies reported the efficacy of CO₂ laser treatment in conjunction with PRP. Min et al evaluated the molecular mechanism of increased clinical efficacy of PRP combined with CO2 laser treatment in 25 subjects with acne scars. PRP in combination with CO₂ laser treatment showed significant improvement as assessed by the investigator global assessment scale. Patient satisfaction scores were also significantly higher in PRP and CO₂ laser treatment than CO₂ treatment alone. Immunohistochemical results suggest that there was increased TGFβ1 and C-myc levels, and collagen 1 expression was significantly higher in combination treatment suggestive of the clinical efficacy of the combination therapy.¹⁵ Similar results were reported in other studies,^16–19 Kar et al reported significant improvement on both sides of the face with combination treatment of fractional CO₂ laser treatment along with PRP and treatment with CO₂ for atrophic acne scars as assessed by Goodman and Barons quantitative global acne scar grading system, but there was no significant difference between right and left sides of the face. The authors conclude that in the PRP treatment there is a significant reduction in the downtime and the inflammation caused by laser treatment.²⁰ AI Taweel et al investigated the efficacy of PRP combined with carboxytherapy compared with PRP with fractional CO₂ laser treatment in 40 patients with atrophic acne scars. PRP combined with CO₂ laser treatment significantly improved acne scars compared with PRP combined with carboxytherapy treatment. However, it was observed that carboxytherapy had fewer side effects than CO₂ treatment and could be a beneficial treatment option for acne scars.²¹ Zhu et al evaluated the efficacy and safety of erbium fractional laser treatment combined with PRP in treating acne scars. Combination therapy was given to 22 subjects and 90.9% of the patients showed an improvement of >50%, and 91% of the patients were satisfied with the treatment. The assessment was performed by comparing pre- and post-treatment photographs of the patients. The results suggest the efficacy and safety of the combination therapy in producing synergic benefits in the treatment of acne scars.²² Another recent clinical trial conducted by El-Taieb showed that combination treatment of PRP with the addition of erbium laser showed superior efficacy as compared with 12 sessions of single plasma-rich therapy over the same period. The clinical trial participants were assessed by acne scar grading, photography, and subjective evaluation.²³

PRP with Fat Grafting/Lipofilling Applications

Fat grafting or lipofilling has gained importance as a surgical alternative due to its long-term results in treating acne scars.²⁴ A study comparing the efficacy of nano fat and PRP with or without fractional CO₂ laser in treating atrophic scars revealed that both the combination treatments were efficacious in improving scars by increasing skin and subcutaneous tissue thickness with no significant difference between the 2 types of combinations.²⁵ A double-blind, placebo-controlled, randomized trial on the efficacy of PRP with lipofilling in patients with loss of skin elasticity and tissue volume revealed no improvement in the outcome about skin elasticity, graft volume maintenance, and patient satisfaction, however, the recovery time was significantly reduced due to addition of PRP.²⁶ A retrospective study evaluated the effects of PRP on the recovery time and aesthetic outcome in treating loss of tissue volume, significant ptosis, and the subsequent descent of tissues. The patients were divided into 4 groups consisting of fat grafts only, fat grafting and PRP, minimal access cranial suspension (MACS) lift and fat grafting, and MACS-lift, fat grafting, and PRP. It was observed that there was a significant drop in the recovery days after the addition of PRP to lipofilling and additionally the aesthetic outcome was also better in fat grafting and PRP group. The results of the assessment were based on pre- and post-photographs evaluated by plastic surgeons.²⁷ A study by Rigotti et al²⁸ demonstrated that treatment with expanded adipose-derived stem cells or stromal vascular fraction (SVF) enriched fat modified the pattern of the subcutaneous dermis and thus producing a skin rejuvenation effect. SVF represents a rich reservoir of regenerative precursor cells.²⁹ However, the PRP therapy did not have any significant advantages in producing any skin rejuvenation effect over the adipose-derived stem cells or enriched fat. However, another study conducted by Van Dongen showed that PRP supplemented lipofilling did not improve the facial skin quality or patient satisfaction in a population consisting of healthy individuals. Concerning the safety profile, the investigators concluded that PRP supplemented lipofilling supplemented with a SVF could be considered a safe procedure. Additionally, in a study conducted by Sasaki et al, fat grafting techniques combined with PRP therapy showed improvement in the average percent change in mean volume assessments at the fat/PRP sites from baseline values, as profiled by 3D Vectra Analysis, demonstrated a higher, but statistically nonsignificant value over 1 year than the percent value changes at the fat/normal saline sites in the opposing face or hand.³⁰ The large variation in the outcomes of fat grafting when PRP was added might be attributed to the presence or absence of inflammatory leukocytes or reactive oxygen species in erythrocytes.³¹

PRP with Thread-Lifting Applications

Ali et al evaluated the 2-year outcome of thread lifting with absorbable barbed polydioxanone (PDO) threads with or without PRP in the treatment of facial aging. Thread lifting had significant effects on skin lifting and patient satisfaction. Significant results were also seen with thread lifting combined with PRP.³²

PRP with Hyaluronic Acid Applications

Research studies have shown that by combining hyaluronic acid (HA) and PRP, the synergic effect of the treatment would be associated with the enhanced function of dermal fibrosis, thus providing better outcomes in facial rejuvenation.^33,34 Ulusal et al studied the effect of HA with PRP in facial aging. Significant improvement was observed regarding the general appearance as graded by the physicians on the 5-grade wrinkle severity rating scale and by patient satisfaction scores. However, there was no significant difference in the aesthetic improvement scores provided by patients and physicians after treatment.³⁵

PRP with Growth Factor Applications

A combination of growth factors with PRP has shown to be an effective treatment in facial rejuvenation. Kamakura et al studied the efficacy and safety of PRP with growth factors for treating wrinkles and depressed areas of the skin of 2005 patients. Patient and investigator satisfaction was 97.3% and 98.4%, respectively, as assessed by the global aesthetic improvement scale. Ratings by wrinkle severity rating scale also showed improvement in the grade with PRP and growth factor combination suggesting that this is an effective and safe treatment of wrinkles with minimal complications.³⁶ A recent prospective clinical trial conducted by Abdel-Maguid et al in a head-to-head trial to determine the efficacy of stem cell-conditioned medium after fractional CO₂ laser (FCL) compared with combined FCL and PRP, the results showed better and faster improvement with FCL plus PRP than FCL. In 33 patients dermal collagen and procollagen type 1 was increased after PRP therapy in 3 sessions.³⁷

PRP with Subcision Applications

Subcutaneous incision-less surgery (subcision) is also a widely used technique for treating acne scars.³⁸ Deshmukh et al studied the effect of subcision adjunct to PRP in treating atrophic acne scars in 44 patients. Significant improvement was observed in PRP plus subcision compared with subcision alone. Goodman and Baron’s qualitative acne scar grading system revealed statistically significant improvement with PRP plus subcision compared with subcision alone (32.08% vs 8.33%, P = 0.04). Patients’ objective scores also increased significantly in combination therapy suggestive of the synergic effect of the treatment. However, post-inflammatory pigmentation was reported as a side effect of the treatment.³⁹

Implementation of the Standard Classification System for PRP

The optimal PRP platelet concentration is unclear; however, the current methods^40,41 by which PRP is prepared reported >1×10⁶ platelets/µL having 300% to 700% enrichment.⁴² In most cosmetic procedures for dermatological conditions such as acne scar, facial rejuvenation, and graft survival in hair transplantation, higher concentrations of platelet-derived growth factors are appropriate to use for obtaining better results.^43,44 Even though there is enormous evidence of the benefits of PRP in facial rejuvenation, conflicting results are reported in the literature. Moreover, there is no standard reporting system for PRP to deduce and replicate the results of the published literature. PRP preparation includes various steps such as platelet concentration, white blood cells, red blood cells, and use of activators. Details of these along with the volume delivered are not reported in all the published literature evaluating the efficacy and safety of PRP. Although there are a few recommendations and classifications proposed for the adoption of reporting important characteristics of the PRP preparation in the scientific literature,^45–47 as evident from our systematic review, none of these are implemented at large. Additionally, following a standard method to measure the outcomes is also an important factor for clinicians and researchers for interpretation and reproduction of the published literature to obtain the optimal results of PRP as the need for its use continues to grow in facial rejuvenation. Similar interpretations were made by Hausauer and Humphrey in a two-part systematic review and expert analysis where they performed an in-depth analysis of PRP in hair restoration, soft-tissue remodeling, resurfacing, and rejuvenation. They found a wide variation in study methodologies with different protocols and differences in outcomes measured in different studies for indication of PRP in facial rejuvenation.^48,49 Hence, in the future, it is of utmost importance to standardize the methods of PRP preparation and optimize treatment methods in order to further improve its usefulness.

There are a few limitations in this systematic review, firstly most of the studies included were of observational design with very few being RCTs. The reporting of the PRP preparation was improper and a few of the studies did not include a standard outcome measurement tool and hence statistical synthesis of the outcomes could not be performed.

Conclusion

PRP has beneficial effects on facial rejuvenation either alone or in combination with other treatment modalities such as laser treatment, fat grafting, subcision, growth factors, and thread lifting. This systematic literature review reveals the high potential of PRP in generating growth factors combined with platelets that render healing effect is essentially a minimally invasive technique for the treatment of skin acne scars and aging. However, due to the lack of uniformity in reporting PRP preparation and employing standard valid assessment methods to report outcomes, there is paucity in proving the therapeutic benefits of PRP using meta-analysis with the available data. Large scale, randomized, control studies employing standard PRP preparation protocols and standard reporting systems are warranted to further validate the use of PRP in facial rejuvenation.