Platelet rich plasma use for treatment of acne scars: an overview of systematic reviews

Abstract

Background

A reappraisal of the conclusions of systematic reviews (SRs) and meta-analyses validity related to Platelet-rich plasma (PRP), alone or in combination with other treatments, compared to regimens PRP-free for the treatment of acne scars.

Materials and methods

An overview of SRs. The methodological quality of the reviews was assessed using AMSTAR-2 checklist; quality of the evidence of primary studies was appraised following the GRADE approach.

Results

Fifteen SRs were included in this overview. Data were from 124 overlapping reports, based on 34 individual primary studies (10 parallel arm randomized trials, 21 split-face studies, and 3 uncontrolled studies). Most of the studies evaluated combination of PRP with microneedling or with laser therapy compared to microneedling or laser therapy without PRP. Clinical improvement (reported as degree of improvement or improvement score) and patient’s satisfaction rate were significantly higher in PRP recipients compared to controls. Crusting time and duration of erythema were significantly shorter in PRP recipients compared to controls. Most of the reviews considered in this overview can be considered of low methodological quality due to the fact that several critical methodological requirements of AMSTAR-2 checklist were unmet or partially met; only 6 of the 15 reviews incorporated study quality in their conclusions, and no GRADE assessment was performed for the reported outcomes in any of the SRs. With the GRADE approach, the quality of the evidence for the outcomes analysed ranged from very low to low due to risk of bias in the primary studies, inconsistency between the studies, and imprecision.

Discussion

The low or very low certainty of evidence does not support clear clinical decision about the PRP use in combination with microneedling or laser therapy for the treatment of acne scars. Further well-designed studies are required to improve the evidence base for PRP combination therapy for acne scars.

INTRODUCTION

Acne vulgaris is a chronic inflammatory disorder of the pilosebaceous unit that affects all ethnicities and races^1,2. The burden of the condition and the related clinical and psychological sequelae is considerable. Although there are many methods of treatment available, a large percentage of patients remain undertreated or non-compliant with treatment. Ineffective treatment results in the formation of acne scars, which has a major impact on the well-being and quality of life of the patients³. In the past few years, several novel therapeutics have been developed for acne scars management, and among them Platelet-Rich Plasma (PRP)^4–6. PRP is a mixture of highly concentrated platelets and associated growth factors, obtained from whole blood through a two-phase centrifugation process; currently there are more than 40 commercial systems developed to concentrate autologous whole blood into a platelet-rich substance⁷. Besides platelets, PRP contains some inflammatory cells (i.e., monocytes and polymorphonuclear neutrophils) and large amounts of proteins, including platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), epithelial growth factor (EGF) and adhesion molecules (i.e., fibrin, fibronectin and vitronectin)^7–9. Such growth factors and cells have been shown to promote cell recruitment, proliferation and angiogenesis, which may be implicated in tissue regeneration and healing^10,11. Due to these biological regenerative properties, a number of investigators have studied the potential clinical benefit of PRP, also from human umbilical cord blood, in a wide array of conditions ranging from dermatologic disorders to oro-maxillofacial surgery and orthopedics^12–15.

In the last few years, a number of controlled clinical trials have been conducted in order to evaluate the efficacy and safety of PRP for treatment of acne scars, and these primary studies have been the object of a variety of systematic reviews (SRs) and meta-analyses. Their conclusions are, however, quite inconsistent and reflect the wide heterogeneity between different studies in terms of design, conduct, and reporting. The current study is an overview of SRs, also called umbrella review¹⁶, and is aimed to reappraise the validity of the conclusions of the SRs and meta-analyses of PRP for the treatment of acne scars.

MATERIALS AND METHODS

The protocol of the review is registered on the International Prospective Register of Systematic Reviews (PROSPERO registration number CRD42023403149, “Platelet-rich plasma treatment for acne scars: an overview of systematic reviews and meta-analyses”).

Review question/objective

The aim of this umbrella review is to compare the efficacy and safety of PRP, alone or in combination with other treatments, to that of comparator regimens PRP-free for the treatment of acne scars.

Inclusion and exclusion criteria

We considered for inclusion SRs comprising randomized controlled trials (RCTs, parallel arm or split-face design) and controlled non-RCTs (e.g., split-face studies, cohort studies), evaluating the safety and efficacy of PRP in acne scars. Traditional reviews with no clear methodological approach were excluded from this umbrella review. SRs evaluating other dermatologic conditions were excluded unless they also contained data on PRP treatment that could be evaluated separately.

Clinical setting and participants

For this umbrella review, we considered SRs on acne scars at any stage of severity.

Intervention and outcomes

Treatment with PRP, alone or in combination with other treatment (e.g., microneedling, Fractional laser) at any dose, timing and frequency was compared to comparator regimens not containing PRP. We included the following outcomes: clinical improvement (e.g., rate of clinical improvement, change in improvement score, patients’ satisfaction rate, and adverse reactions. Where available, we reported also results of subgroup analyses based on the design of the studies included in the SRs.

Search strategy

Relevant studies in four bibliographic databases (Embase, PubMed, Web of Science, and Cochrane central) were searched as of January 2023. The searches were carried-out without languages restriction using Medical Subjects Heading: “Platelet rich plasma/PRP” AND “acne scars” AND “systematic review” OR “meta-analysis”. In addition to the electronic search, we checked the reference lists of the most relevant items (original studies and reviews) to identify potentially eligible studies not captured by the initial literature search.

Study selection and data extraction

All titles were screened by two independent assessors (MC and FM). Eligibility assessment was based on the title or abstract and on the full text if required. Full texts of possibly eligible articles were obtained and assessed independently by two reviewers (MC and FM). Both reviewers compared the articles identified. The two assessors also independently extracted quantitative and qualitative data from each selected study, with disagreements resolved through discussion and on the basis of the opinion of a third reviewer (IP). Findings are presented in tabular format with supporting text (Table I). Quantitative tabulation of results included: first author name and year of publication, study design, the experimental treatment and controls, number of included studies and number of participants, the outcomes assessed, and the main conclusion of the review as reported by authors.

Table I.

Main characteristics of included studies

Study, year [reference]	Design	Intervention	Control	No. studies (no. pts)	Outcome/s assessed	Main conclusions
Leo, 2015 [19]	SR in aesthetic dermatology, including acne scars (3 studies) and other conditions	PRP (injection or topical) alone or in combination with other treatments (FCL)	No treatment, saline	3 studies, 66 participants	Clinical appearance of acne scars, clinical improvement. No meta-analytical pooling performed	The PRP-treated side showed significant improvements in the overall clinical appearance of acne scars compared to the control group. There were no significant differences between the topical and intradermal PRP treatment groups, but the topical PRP was better tolerated
Kravvas, 2017 [20]	SR of various treatment for acne scars (PRP in two trial)	MN+PRP injection	MN + saline, MN with Vit C	2 studies (split face design) with 50 and 27 participants	Improvement of scars; adverse events. No meta-analytical pooling performed; only rates of events provided and p value for chi-square	After treatment, the mean score (Goodman’s Quantitative scores) of PRP treated face was 7.08, with a 62.20% improvement in acne scars. The other half of the face had a mean score of 10.42, with 45.84% improvement of acne scars following treatment (p<0.00001)
Motosko, 2018 [21]	A SR of clinical studies and case reports that addressed PRP alone and/or in combination with fat grafting for facial rejuvenation, acne scarring (2 studies), or androgenic alopecia were included	MN+PRP, PRP injection	MN with vit. C, trichloroacetic acid	2 studies, 57 participants	Acne scars appearance, patient satisfaction. No meta-analytical pooling performed	The procedure is limited by the lack of a standardized method for preparation and application of PRP. PRP Improved acne scars and increased patient satisfaction
Alser, 2018 [22]	A SR of PRP in scar management. Atrophic, keloid, surgical and traumatic scars were considered	PRP alone; PRP with FCL, or MN	MN, saline, vit. C	7 controlled studies with various design (RCTs, split face, quasi experimental study) and 4 case series for a total of 375 participants (175 pts from case series)	Acne scars appearance, patient satisfaction, adverse events. No meta-analytical pooling performed	PRP can improve the quality of atrophic acne scars treated with laser therapy and decrease the duration of laser-related side effects including oedema and erythema. Manuscripts were classified according to the Joanna Briggs Institute Levels of evidence
Hesseler, 2018 [23]	A SR and meta-analysis	PRP with MN/dermaroller (6 trials) or with FCL (7 studies)	Dermaroller, MN, FCL	13 trial (696 participants)	Due to the heterogeneity of studies and widely variable outcome measures, statistical analysis could not be performed.	PRP in combination with FCL treatment, administered in 2–3 sequential sessions 1 month apart, improves the appearance of acne scars. The evidence for the use of PRP with MN is less supportive. Levels of evidence reported according to 2009 Oxford center for evidence-based medicine
Hsiek, 2019 [24]	A SR and meta-analysis of PRP for anthropic acne scars	Assisted therapy with PRP in combination with MN, or FCL	MN, FCL	7 studies (363 participants), 6 included in the quantitative synthesis.	Degree of improvement using an improvement score; adverse events. Meta-analytical pooling performed.	Results of the meta-analysis show a significantly higher degree of improvement in the PRP group compared to the control group (OR=8.19; 95% CI 4.32–15.52: 5 studies, 249 cases), as well as better mean improvement score (WMD=23.7; 95% CI 18.6–28.8, 4 studies, 200 pts). No information on the methodological quality of included studies provided
Huang, 2019 [25]	A SR and meta-analysis	PRP with MN/dermaroller (5 trials) or with FCL (6 studies)	Dermaroller, MN, FCL	11 studies (633 participants)	Improvement and satisfaction evaluation. Meta-analytical forest plots of clinical improvement (≥50% or 75%) in PRP recipients and controls (MN, FCL) provided	PRP in combination with MN or FCL resulted in higher efficacy and patient satisfaction than the same therapy without PRP
Chang, 2019 [26]	A SR and MA of MN combined with PRP for acne scars	PRP +MN	MN + saline, or vit C, or thrichloracetic acid	5 trials, 226 participants	Meta-analytical pooled estimates of clinical improvement, patient satisfaction, adverse events available	The addition of PRP to MN for the treatment of acne scars not only improves objective cosmetic outcomes but also enhances subjective patient satisfaction. ROB not assessed
Chang, 2019 [27]	A SR and meta-analysis of PRP Combined with Ablative FCL for Acne Scars	PRP+ FCL	Dermaroller, MN	4 studies, 104 participants	Meta-analytical pooled estimates of clinical improvement, patient satisfaction, adverse events available	Clinical improvement after combination therapy was significantly higher than that after laser alone (odds ratio [OR]=2.992, p=0.001). Regarding major side effects, patients undergoing combination therapy experienced significantly shorter duration of crust compared with CO2 laser alone (standard mean difference= −1.140, p<0.001). ROB according to ROB-2 tool for 3 split-face randomized trials (some concern reported for outcome assessment), and not assessed for a split-face non-randomized trial.
Gupta, 2019 [28]	A SR and MA of PRP in the Field of Hair Restoration and Facial Aesthetics	PRP+ MN or PRP +FCL	MN, FCL	8 trials in acne scars (7 controlled trial), 220 participants, 115 split-face	No meta-analytical pooling of acne scars data provided	Controlled studies suggest that 2 to 4 sessions of PRP combined with traditional therapies can help minimize acne scarring. Levels of evidence reported according to 2009 Oxford center for evidence-based medicine
Long, 2019 [29]	A SR and MA of MN combined with PRP for acne scars	PRP +MN	MN + saline, or vit C, or thrichloracetic acid	8 trials. A total of 311 participants (153 whole-face participants and 158 split-face participants)	Changes in a mean difference of Goodman and Baron qualitative scores,	Combination therapy with intradermal or topical PRP was significantly more effective than monotherapy alone and combination therapy with an adjunct other than PRP. All the included studies (9) were at high or unclear risk of bias in several items of the ROB-2 tool
Wu, 2020 [30]	A SR and MA of FCL combined with PRP in the treatment of acne scars	PRP+ FCL	FCL	9 studies, randomized and not, for a total of 357 participants, 145 split-face	Clinical Improvement score and rate, patient satisfaction, adverse events (edema, crusting time). Meta-analytical pooling performed	FCL combined with PRP treatment group showed significantly better results than the FCL control group in terms of clinical improvement score, clinical improvement rate, patient satisfaction, and crusting period. RoB 2.0 tool was used to assess the quality of 10 included studies, although some of these studies were not randomized. Moreover, only 5 studies were judged at unclear risk of bias in 1–2 domains, despite the fact that lack or inadequate randomization and lack of blinding were common among the selected studies
Kang, 2022 [31]	A SR and MA of MN combined with PRP for acne scarring	PRP+ MN	MN+ saline, or vit C, or trichloracetic acid	14 trials (4 randomized and 10 split-face non-randomized controlled studies) with 442 participants were included	Pooled data of: rate of significant clinical improvement; difference of changes in Goodman Baron scores QS after treatment; rate of patient satisfaction; adverse events. Subgroup analyses according to trials design (RCTs vs non-RCTs)	Combined treatment with MN with PRP is more effective than MN without PRP for patients with acne scars. ROB according to Newcastle-Ottawa scale for the 10 non-RCT, and ROB-2 for 4 RCTs- The RCTs were at high or unclear risk of bias in many items of the ROB-2 tool, particularly those related to the random sequence generation, the allocation concealment and blinding of participants and outcome assessors. By contrast, for the non-RCTs the Ottawa-Newcastle scale was applied and the authors calculated a summary score (from 8 to 9)
Ebrahimi, 2020 [32]	A SR and MA of FCL or MN combined with PRP for atrophic acne scars and other scars	PRP+FCL, or PRP+MN. Also, PRP alone evaluated	FCL, or MN	13 clinical trials were included in the meta-analysis, and 10 more in the systematic review	Clinical improvement (overall, excellent, marked, moderate, poor)	When used alone, moderate improvement was the most frequently observed degree of response with PRP (36%) whereas, when added to laser or micro-needling, most patients experienced marked (33%, 43%, respectively) or excellent (32% and 23%, respectively) results. Quality assessment performed with a 27 items checklist (Downs and Black, modified)
Aljefri, 2022 [33]	A SR and MA of FCL combined with PRP for atrophic acne scars	PRP+ FCL	FCL	11 trials, 313 participants (240 split-face participants)	Clinical improvement, patient satisfaction, Goodman and Baron qualitative scores, duration of erythema and edema	The combined use of laser and PRP showed a statistically significant clinical improvement and patient satisfaction compared to the use of laser alone. Also, a significant improvement in Goodman and Baron's score was achieved by combining PRP with laser. The combined treatment of laser and PRP was highly synergistic, effective, and safe in treating moderate to severe atrophic acne scars. ROB-2 tool used for all the included studies, including those not randomized

PRP: platelet-rich plasma; SR: systematic review; MA: meta-analysis; ROB: risk of bias; MN, microneedling; FCL, fractional carbon dioxide laser.

Assessment of methodological quality of systematic reviews

We used the AMSTAR-2 critical appraisal checklist for SRs, a tool that evaluates both quantitative and qualitative reviews¹⁷. The tool is suitable for reviews including randomised and non-randomised studies. It includes 16 domains relating to the research question, review design, search strategy, study selection, data extraction, justification for excluded studies, description of included studies, risk of bias, sources of funding, meta-analysis, heterogeneity, publication bias, and conflicts of interest. Two review authors (MC, FM) independently assessed the quality of evidence in the included reviews and the methodological quality of the SRs. We resolved discrepancies through discussion or, if needed, through a third review author (IP). We did not exclude reviews based on AMSTAR 2 ratings, but considered the ratings in interpretation of our results.

Summary of the evidence and appraisal of the quality of evidence

For the quantitative synthesis, we reported the effect size (odds ratio [OR], risk ratio [RR], risk difference [RD], Mean Difference [MD] or Standardized Mean Difference [SMD) with the 95% confidence intervals [CI]), as reported in individual reviews, and the main conclusions of each SR/meta-analysis.

The quality of evidence was appraised following the GRADE approach (Grades of Recommendation, Assessment, Development, and Evaluation). Whenever available, the grading of the quality of evidence reported in the included reviews was considered to determine the quality of evidence. In a situation in which the grading of evidence was not reported by the authors of the study, the GRADE approach was applied in its five domains (risk of bias, indirectness, imprecision, inconsistency, and publication bias) based on the information available from the study¹⁸.

In addition, a three-color score was used for an immediate visual inspection of the comparison between intervention (PRP based regimens) and controls (not containing PRP) with regards to the main outcomes assessed: clinical improvement, patients’ satisfaction, and more commonly observed adverse events (green color: PRP confers advantage over standard therapy or controls; red color: PRP confers disadvantage over standard therapy or control; yellow color: no clear advantage or disadvantage).

RESULTS

The electronic and manual search retrieved 568 references. The Preferred Reporting Items for SRs and Meta-Analyses (PRISMA) flow diagram is reported in Figure 1. At the first stage of screening titles and abstracts, 80 references were selected. After the full texts were scrutinized against the inclusion and exclusion criteria, 15 SRs were included in the umbrella review^19–33. Five SRs reporting other treatment for acne scars but not PRP were excluded^5,34–37.

Figure 1.

PRISMA flow diagram of study selection

PRISMA flow diagram summarizes the inclusion and exclusion of studies (PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Out of 265 records screened, 15 articles were utilized in quantitative synthesis.

Description of the studies

Of the 15 SRs included in the overview, 11 were focused exclusively on treatment of acne scars, while 4^19,21,22,28 focused also on other dermatologic conditions (e.g., alopecia, aestehetic dermatology, other skin scars). The 15 SRs included 124 overlapping reports, 24 from parallel arms RCTs, 95 from split-face studies (randomized or non-randomized), and 5 from uncontrolled studies. These reports were based on 34 individual primary studies, including 10 parallel arm RCTs, 21 split-face study (4 randomized), and 3 uncontrolled studies (case series); 18 studies evaluated combination of PRP with microneedling compared to microneedling without PRP, and 12 combinations of PRP with fractional laser compared to fractional laser without PRP. While all the SRs focused on PRP injection, three focused also on topical PRP administration ^19,29,32. The main characteristics of the included reviews are summarized in Table I.

Methodological quality

None of the reviews met all the AMSTAR-2 methodological requirements; all the reviews did not report the source of funding for the studies included in the review, and this was the only unmet requirement in 4 reviews ^27,29,30,33. Six reviews had ≥7 unmet requirements, 3 had 4–6 unmet requirement, and two^31,33 had 1–2 unmet requirement (Table II). All but one had 1 or more (from 1 to 6) methodological requirements partially met.

Table II.

Methodological quality of the systematic reviews assessed using the AMSTAR-2 checklist

Author, year [reference]	AMSTAR-2 DOMAIN
	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16
Leo, 2015 [19]
Kravvas, 2017 [20]
Motosko, 2018 [21]
Alser, 2018 [22]
Hesseler, 2018 [23]
Hsiek, 2019 [24]
Huang, 2019 [25]
Chang, 2019 [26]
Chang, 2019 [27]
Gupta, 2019 [28]
Long, 2019 [29]
Wu, 2020 [30]
Kang, 2022 31]
Ebrahimi, 2022 [32]
Aljefri, 2022 [33]
Amstar-2 domains: 1. Did the research questions and inclusion criteria for the review include the components of PICO? 2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol? 3. Did the review authors explain their selection of the study designs for inclusion in the review? 4. Did the review authors use a comprehensive literature search strategy? 5. Did the review authors perform study selection in duplicate? 6. Did the review authors perform data extraction in duplicate? 7. Did the review authors provide a list of excluded studies and justify the exclusions? 8. Did the review authors describe the included studies in adequate detail? 9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? 10. Did the review authors report on the sources of funding for the studies included in the review? 11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? 12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? 13. Did the review authors account for RoB in individual studies when interpreting/discussing the results of the review? 14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity 15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? 16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review? Although AMSTAR 2 consists of 16 items, critical domains include items 2, 4, 7, 9, 11, 13, and 15.

Among the 15 studies, 4 did not report clearly if guidelines or protocols were used to perform the review. Six reviews (40%) did not perform a quantitative synthesis (=meta-analysis) ^19–23,28. Six reviews did not assess ROB, and in 5 reviews we deemed the technique to assess ROB unsatisfactory (for example, the ROB-2 tool was applied to non-randomized split-face studies, or there was inconsistency in some ROB items assessment among the different reviews); also, some reviews used summary scores, which have been shown to be unreliable assessments of validity³⁸, and are explicitly discouraged by the Cochrane organization³⁹. Ninereviews (60%) did not account for ROB when interpreting/discussing the results of the review, 3 reviews did it partially, and only 2 satisfactorily. Six reviews (40 %) did not include investigation of heterogeneity.

Seven reviews (46.6%) did not mention publication bias in material and methods and results, and failed to discuss the possible impact of publication bias on review findings. In 6 reviews we judged the search strategy not comprehensive, mostly because did not include EMBASE but only PUBMED and Cochrane central. Study selection and screening was performed in duplicate by 40% (6 reviews) and 53.3% (8 reviews) of authors team, respectively. Other unmet domains were related to the list of excluded studies and reasons (9 reviews, 60%).

No GRADE assessment was performed for the reported outcomes in any of the SRs.

Summary of the effect of PRP on the main outcomes

Outcome “Clinical improvement”

Clinical improvement was the most common reported outcome, and in 9 SRs a quantitative synthesis for this outcome was conducted. The outcome was assessed and reported as degree of improvement (for example, mean difference in degree of improvement, rate of improvement ≥50 or ≥75%) ^{24–27,30,31,33}, and/or as improvement score (for example, change in Godman and Baron score) ^29–31,33;; one review reported overall, excellent, marked, moderate and poor rate of improvement³². All the reviews showed significant advantages with PRP in combination with microneedling or fractional laser treatment compared to controls without PRP, although rate of marked response was similar among PRP+laser therapy and laser therapy recipients in one comparison³². The effect size of the comparisons (OR, RR or MD) is summarized in Table III.

Table III.

Summary of findings table. Effects of PRP treatment of acne scars on more commonly reported outcomes

Review [reference]	Outcome	Interventions and controls	Effect size (RR, OR or RD) and 95% CIs	GRA DE assessment (reason/s for downgrading)	Comment	Effect direction
Clinical Improvement
Hsiek, 2019 [24]	Degree of improvement - 5 studies (249 participants)	PRP+MN, or FCL vs MN or FCL	OR 8.19 (4.32/15.52). p=0.00001; I2=54	⊕⊖⊖⊖ Very low (ROB, inconsistency, imprecision)	PRP in combination with MN or FCL increases clinical improvement compared to MN or FCL without PRP, but the certainty of the evidence is very-low
	Mean difference in degree of improvement - 4 studies (200 participants)		MD 23.7 (18.6/28.8). p=0.00001; I2=54
Huang, 2029 [25]	Rate of improvement ≥75%	PRP+MN vs MN, 3 studies (172 participants)	RR 3.8 (1.07/14.0)	⊕⊕⊖⊖ Low (ROB, imprecision)	PRP in combination with MN or FCL resulted in higher efficacy than the same therapy without PRP. Low certainty of evidence
		PRP+FCL vs FCL, 3 studies (165 participants)	RR 3.2 (1.5/7.0)
Chang, 2019 [27]	Overall rate of improvement - 4 studies (120 participants)	PRP+FCL vs FCL	OR 2.9 (1.5/5.8), p=0.001	⊕⊕⊖⊖ Low (ROB, imprecision)	PRP in combination with FCL resulted in higher efficacy than the same therapy without PRP. Low certainty of evidence
Wu, 2020 [30]	Clinical improvement score - 5 studies (225 participants)	PRP+FCL vs FCL	MD, 0.51 (0.30/0.72); p<0.00001	⊕⊕⊖⊖ Low (ROB, imprecision)	PRP in combination with FCL resulted in higher efficacy than the same therapy without PRP. Low certainty of evidence. Both injected and topical PRP showed higher efficacy compared to controls in in clinical improvement score and rate of improvement ≥75%. However no significant differences were seen in topical PRP and controls in terms of improvement ≥50%. (OR=2.47, 95% CI [0.99, 6.16], p=0.05)
	Rate of improvement ≥75% - 3 studies (165 participants)		OR 4.69 (1.92/11.45); p=0007
	Rate improvement ≥50%	PRP injection-4 studies (197 participants)	OR 2.78 (1.51/5.12); p=0.001	⊕⊕⊖⊖ Low (ROB, imprecision)	PRP injection in combination resulted in higher efficacy than the same therapy without PRP
		PRP topical - 2 studies (87 participants)	OR 2.47 (0.99/6.16); p=0.05	⊕⊖⊖⊖ Very low (ROB, serious imprecision due to low number of pts. and CIs cross the unit)	PRP topical in combination has not clear advantages over the same therapy without PRP
Chang, 2019 [26]	Rate improvement ≥50% - 4 studies (226 participants, 113 split-face)	PRP+MN vs MN	RR 4.5 (2.5/7.9); p=0.000	⊕⊕⊖⊖ Low (ROB, imprecision)	PRP in combination with MN resulted in higher efficacy than the same therapy without PRP. Low certainty of evidence
Long, 2019 [29]	Change in qualitative score (Goodman and Baron)	Combination therapy with or without PRP - 4 studies (186 participants)	MD −16.34 (−17.6/−15.3); p<0.00001; I2=97	⊕⊖⊖⊖ Very-low (ROB, serious inconsystency)	PRP in combination w resulted in higher efficacy than combination therapy without PRP. Very-low certainty of evidence
		Topical PRP+MN vs MN - 3 studies (90 participants, 35 split-face)	MD −11.3 (−12.1/−9.8); p<0.00001	⊕⊕⊖⊖ Low (ROB, imprecision)	Combination therapy with PRP, either topical or intradermal, resulted in higher efficacy compared with combination therapy without PRP. Subgroups differences favours intradermal injection compared to local PRP administration (p<0.001
		Combination therapy with intradermal PRP vs combination therapy without PRP - (2 studies (96 participants, 40 split-face)	MD −23.3 (−25.1/−21.5); p<0.00001	⊕⊕⊖⊖ Low (ROB, imprecision)
		PRP+MN vs MN monotherapy (2 studies, 80 split-face pts)	MD −0.34 (−0.49/−0.18); p<0.0001	⊕⊕⊖⊖ Low (ROB, imprecision)	Combination therapy with PRP and MN resulted in higher efficacy compared to monotherapy with MN
Kang, 2022 [31]	Rate of significant improvement-10 studies, 538 participants (422 split-face)	PRP+MN vs MN	OR 2.97 (1.96/4.51); p<0.00001; I2=81	⊕⊕⊖⊖ Low (ROB, inconsistency)	Combination therapy with PRP and MN resulted in higher efficacy compared to MN without PRP. Low-level of certainty
	Change in qualitative score (Goodman and Baron) - 6 studies, 333 participants (178 split-face)		MD −0.32 (−0.44/−0.20); p<0.0001	⊕⊕⊕⊖ Moderate (ROB)	Combination therapy with PRP and MN resulted in higher efficacy compared to MN without PRP. Moderate-level of certainty
Aljefri, 2022 [33]	Rate of improvement - 7 trias, 205 participants	PRP+FCL vs FCL	OR 2.56 (95% CIs, 1.37/4.78)	⊕⊕⊖⊖ Low (ROB, imprecision)	Combination therapy with PRP and FCL resulted in higher efficacy compared to FCL without PRP. Low-level of certainty
	Change in qualitative score (Goodman and Baron) - 6 trials, 168 participants		SMD, −0.40 (95% CIs, −0.65/−0.14)
Ebrahimi, 2022 [32]	Rate of improvement (defined as overall, excellent, marked, moderate, poor)	PRP+FCL	When added to FCL, PRP increased rate of excellent response from 0 to 32% (95% CIs, 10/36).	⊕⊕⊖⊖ Low (ROB,including publication bias, and inconsistency)	Combination therapy with PRP and FCL resulted in higher rate of excellent response compared to FCL without PRP. Low level of certainty
			Rates of marked improvement were similar among FCL recipients (34%) and PRP+FCL recipients (33%, 95%CIs, 11/53)	⊕⊖⊖⊖ Very-low (ROB, imprecision, inconsystency)	Rate of marked response were similar among PRP+FCL and FCL recipients. Very-low-level of certainty
		PRP+MN	When added to MN, PRP increased rate of excellent response from 3 to 23% (95 % CIs, 10/36), and of marked improvement from 19 to 43% (95% CIs, 28/57)	⊕⊕⊖⊖ Low (ROB,including publication bias, and inconsistency)	Combination therapy with PRP and MN resulted in higher efficacy compared to MN without PRP. Low level of certainty
Outcome	Adverse events
Hsiek, [24]	Edema	3 studies (105 participants)	MD, −0.53 (−1.73/0.67); p=0.39	⊕⊖⊖⊖ Very-low (ROB, imprecision, inconsystency)	Unclear differences between groups
	Erythema		MD, −1.07 (−2.39/0.25); p=0.11	⊕⊖⊖⊖ Very-low (ROB, imprecision, inconsystency)	Unclear differences between groups
Chang, 2019 [27]	Edema	3 studies (90 participants)	SMD −0.6 (−1.9/0.6); p=0.35; I2=89	⊕⊖⊖⊖ Very-low (ROB, imprecision, inconsystency)	Unclear differences between groups
	Erythema	3 studies (90 participants)	SMD −0.6 (−1.6/0.3); p=0.2; I2=83	Very-low (ROB, imprecision, inconsystency)	Unclear differences between groups
	Crusting time	2 studies (58 participants)	SMD −1.14 (−0.6/−4.3)	Low (ROB, imprecision)	Crusting time significantly shorter in PRP + FCL recipients compared to FCL recipients
Adverse events
Wu, 2020 [30]	Edema	2 studies (121 participants)	OR 0.24 (0.06/0.92); p=0.04	⊕⊕⊖⊖ Low (ROB, imprecision)	The number of edema cases was significantly lower in the experimental group compared to the control group
	Erythema	2 studies (121 participants)	OR 0.21 (0.05/0.80); p=0.02		The number of erythema cases was significantly lower in the experimental group compared to the control group
	Crusting time	2 studies (73 participants)	MD, −1.04 (−1.56/−0.52); p<0.0001		Crusting time significantly shorter in PRP recipients
Kang, 2022 [31]	Edema (severe)	2 studies (136 participants, 40 split-face)	OR 1.14 (0.47/2.76); p=0.77	⊕⊕⊖⊖ Low (ROB, imprecision)	Unclear differences between groups
	Erythema (severe)	3 studies (171 participants, 58 split-face)	OR 1.59 (0.73/3.46); p=0.24		Unclear differences between groups
Aljefri, 2022 [33]	Duration of erithema	8 trials (174 participants)	SMd, −0.67 (95% CIs, −1.32/−0.01); p=0.05. I2=75	⊕⊕⊖⊖ Low (ROB, inconsistency)	Shorter duration of erythema in PRP recipients
Outcome	Patient satisfaction
Huang, 2020 [25]		PRP +FCL or +MN vs FCL or MN	MD 2.54 (1.44/4.49)		Only MD favouring combination group provided
Chang, 2019 [27]	3 studies (106 articipants)	PRP + FCL vs FCL	OR 3.1 (1.5/6.6); p=0.002	⊕⊕⊖⊖ Low (ROB, imprecision)	Patients who underwent combination therapy (PRP+FCL) had significantly highersatisfaction rates than did patients who underwent FCL alone; low level of certainty
Wu, 2020 [30]	4 studies (191 participants)	PRP+FCL vs FCL	OR 3.31 (1.75/6.26); p=0.0002	⊕⊕⊖⊖ Low (ROB, imprecision)	Patients who underwent combination therapy (PRP+FCL) had significantly higher satisfaction rates than did patients who underwent FCL alone; low level of certainty
Chang, 2019 [26]	4 studies (280 participants)	PRP+MN vs MN	RR 1.8 (1.1/2.8); p=0.01; I2=69	⊕⊖⊖⊖ Very-low (ROB, inconsistency, imprecision)	Patients who underwent combination therapy(PRP+MN) had significantly higher satisfaction rates than did patients who underwentMN alone; very-low level of certainty
Long, 2019 [29]	4 studies (215 participants)	PRP+MN vs MN	SMD 0.87 (−0.01/1.75); p=0.05	⊕⊕⊖⊖ Low (ROB, imprecision)	No statistically significant benefit of PRP+MN vs MN without PRP. Low level of certainty
Kang 2022 [31]	6 studies (396 participants)	PRP+MN vs MN	OR 4.15 (2.3/8.9); p<0.00001; I2=53	⊕⊕⊖⊖ Low (ROB, inconsistency)	Patients who underwent combination therapy (PRP+MN) had significantly higher satisfaction rates than did patients who underwent MN without PRP; low level of certainty
Aljefri, 2022 [33]	6 studies (191 participants)	PRP+FCL vs FCL	OR 3.38 (95% CIs, 1.80/6.34); p=0.0001	⊕⊕⊖⊖ Low (ROB, imprecision)	Patients who underwent combination therapy (PRP+FCL) had significantly higher satisfaction rates than did patients who underwent FCL without PRP; low level of certainty

the effect size favours PRP compared to controls in a significant way; no significant differences between groups; the effect size favours controls compared to PRP in a significant way. PRP: Platelet-rich plasma; OR: odds ratio; RR: risk ratio; RD: risk difference; SMD: standardized mean difference; FCL: Fractional carbon dioxide laser; MN: microneedling; ROB: risk of bias.

One review performed subgroup analysis of according to study design: the effect size favouring PRP was consistent among RCTs and split-face studies³¹. Three of the SRs evaluated also the use of topical PRP ^29,30,32. Two of these reviews ^29,30 concluded that the use of injectable preparation is more consistently effective compared to topical preparations.

A suitable and consistent ROB assessment (for example, ROB-2 for RCTs, or Newcastle-Ottawa score for non-RCTs) was performed in only 4 reviews ^27,29–31. Our assessment of the quality of the evidence showed from low to very-low levels of certainty. The main reasons for evidence being low or very low quality were the ROB, the small number of participants in some studies, and or the inconsistency.

Outcome “Adverse events”

A quantitative synthesis of the occurrence of adverse events (edema and erythema) were reported in 4 SRs^24,27,30,31. Two reviews^{27, 30} reported also crusting time, and one review³³ duration of erythema. Edema and erythema cases were reported with similar frequency among the intervention group and controls in 3 reviews ^24,26,31; one review³⁰ reported significantly lower rate of adverse events among PRP recipients compared to controls. Crusting time and duration of erythema was significantly shorter in PRP recipients compared to controls. The quality of the evidence was graded from low to very-low, mostly because of ROB, imprecision and/or inconsistency. The effect size of the comparisons (OR, MD, or SMD) are summarized in Table III.

Outcome “Patient satisfaction”

Patient satisfaction was reported in 7 SRs (Table III)^{25–27,29–31,33}. In six reviews, the effect size favoured combination therapy with PRP compared to controls (from very-low to low certainty of evidence); in one review²⁹ a trend toward benefit of PRP+ microneedling over microneedling alone was observed, but the difference was of borderline significance (p=0.05; low-level of certainty). The quality of the evidence was graded from low to very-low, mostly because of ROB, imprecision and/or inconsistency.

GRADE assessment

For the 3 outcomes considered, a total of 38 comparison between PRP recipients and controls were performed in the included SRs, as summarized in Table III (Summary of findings table). Overall, the quality of the evidence was limited by lack of high-quality studies in the included reviews. The quality of the evidence according to the GRADE assessment was very-low in 10 comparisons, low in 27, and moderate in one of these comparisons. Reasons for downgrading were ROB, imprecision and/or inconsistency. The ROB was mostly related to ascertainment bias or detection bias, since in most of the primary studies patients were not masked to the assigned treatment, and in several trials outcome assessors were not masked (or it was unclear if they were masked) to the assigned treatment. Masking is of particular relevance when the outcomes are subjective, as for patient satisfaction, pattern recognition of images, and clinical scores³⁹. Imprecision was also commonly encountered, and was related to either the low number of participants or to the CIs crossing the clinical decision threshold between recommending and not recommending treatment (for the outcome adverse events). Inconsistency refers to an unexplained heterogeneity of results, mostly related to the high I² levels in some of the comparisons.

DISCUSSION

Umbrella reviews assemble together several SRs on the same condition and allow to consider for inclusion the highest level of evidence available, namely other SRs and meta-analyses⁴⁰. In this umbrella review we have reappraised the results of 15 SRs published between 2015 and 2022 on the clinical use of PRP for the treatment of acne scars. The reviews included in this overview present data from 124 overlapping reports, based on 34 individual primary studies (10 parallel-arm RCTs, 21 split-face studies (4 randomized), and 3 uncontrolled studies). We believe that this makes the current overview the largest review to date within this subject area, and hope this will make it particularly helpful to decision makers.

The main findings of this umbrella review can be summarized as follows:

1. the use of PRP in combination with microneedling or laser therapy showed significant advantages compared to microneedling or laser therapy without PRP, but the level of evidence available was in the vast majority low or very-low.

2. self-reported patient’s satisfaction rate was significantly higher in participants receiving combination therapy with PRP, but again the levels of evidence were low or very-low.

3. the occurrence of adverse events (edema, erythema) was similar among participants receiving combination therapy with PRP and controls in 3 of the 4 reviews reporting this outcome, while duration of erythema and crusting time was shorter in PRP recipients (low or very-low level of evidence).

It makes intuitive sense to take into account information on indispensable components of every SR, such as those related to the quality of included studies³⁸. Nonetheless, six of the SRs (40%) included in this overview did not assess ROB at all, while in 5 reviews (33.3%) we deemed the technique to assess ROB inadequate (for example, ROB-2 tool applied to non-randomized split-face studies, inconsistency in some ROB items assessment among the different reviews, use of summary scores often resulting in overestimation of methodological quality of non-RCTs). Consequently, only in 4 reviews (26.6%) the authors used a satisfactory technique for assessing ROB in individual studies, and only 6 of the 15 reviews incorporated study quality in their conclusions. As a consequence, many of the SRs considered in this overview can be considered of “low quality” due to insufficiency in critical domains, as demonstrated by the AMSTAR-2 evaluation.

GRADE assessment is a well recognized approach for making recommendations, but it was not applied by the authors in any of the included reviews. Therefore, as specified in the PROSPERO protocol, we applied the GRADE approach in its five domains (ROB, indirectness, imprecision, inconsistency, and publication bias) basing on the information available from the studies. With the GRADE approach, the quality of the evidence for the outcomes analysed ranged from very low to low due to risk of bias in the primary studies, inconsistency between the studies, and imprecision. With low levels or very-low levels of evidence our confidence in the effect estimates is limited or insufficient, and the true effect may be substantially different from the estimates of the effects.

An important barrier to interpreting PRP research for acne scars is lack of standardization of PRP preparation protocols, administration schedules, and inconsistency in baseline severity of acne scores and in clinical endpoints. Finally, no studies have assessed long-term results of PRP on acne scars, as the follow-up was commonly of 3–6 months, and even shorter.

CONCLUSIONS

It is difficult to make recommendations based on low or very-low quality of evidence. PRP holds promise for acne scars, but further research is required to establish its role in combination with other treatments.