Combining platelet rich plasma with ablative laser for post acne scars: A review

Introduction

Acne vulgaris is a common dermatosis of pilosebaceous unit affecting up to 80% of adolescents and young adults.¹ Acne scarring as a complication of acne vulgaris is reported to affect up to 14% of them, which may lead to low self-esteem, social withdrawal, psychological depression and reduced quality of life.² Acne scars are classified into three primary types: atrophic, hypertrophic and keloidal. Atrophic scars are by far the most common type which can also be sub-classified into ice-pick, rolling and boxcar scars.³ Many acne scar scoring systems have been proposed amongst which Goodman and Baron’s quantitative scoring based on type, number and severity is most commonly used.⁴ They also added a qualitative global grading system, which is a simpler scoring system classifying acne scars as macular, mild, moderate or severe.⁵ Several treatment options are available like chemical peels, chemical reconstruction of skin scars (CROSS) using trichloro acetic acid, dermabrasion, micro-needling, punch floatation, dermal grafting, ablative and non-ablative lasers, intralesional corticosteroids, silicone gels and tissue augmentation using fillers.⁶ Ablative laser resurfacing has been the most effective and has been elevated to the status of gold standard.⁷ However, in addition to significant downtime, resurfacing by ablative laser causes additional cutaneous adverse effects such as erythema, edema, post-inflammatory hyperpigmentation, milia, scarring, secondary infections and acneiform eruptions. The introduction of fractional laser therapy has reduced the severity of these adverse effects, but they remain nonetheless.^8,9 Fractional laser resurfacing relies on producing small zones of micro-damage separated by zones of non-damaged tissue that favour a rapid healing process by promoting formation of new collagen. Platelet-rich plasma is a concentrate of patients’ own platelets with growth factors such as platelet-derived growth factor, vascular endothelial growth factor, epidermal growth factor and transforming growth factor beta, which possess immune-modulating properties and promote tissue healing.¹⁰ Thus, platelet-rich plasma has the potential to mitigate the adverse effects caused by lasers in the treatment of acne scarring.^11,12 Although there are numerous randomised controlled trials (RCTs) and comparative studies proving the efficacy of combining the above two modalities in post acne and other scars, there is only one systematic review and meta-analysis by Chang et al.¹³ (2019) and another meta-analysis by Wu et al.¹⁴ (2020) that analyzed four and nine studies, respectively. We present a broader review including more studies consisting of higher levels of evidence, that is systematic review, meta-analysis and comparative studies, on combination of the platelet-rich plasma and laser therapy in post-acne scars.

Material and Methods

Statistical Analysis and Results

Sixteen studies comprising randomised controlled trials as well as split-face comparative studies fulfilled our selection criteria and were included in our review. [Table 1].

The first split-face randomised controlled trial evaluating the combination of fractional CO₂ laser and platelet-rich plasma was conducted by Lee et al.¹⁵ in 14 patients. Fractional CO₂ laser was performed a month apart followed by either platelet-rich plasma or normal saline injections on the randomised halves of the face and found significant improvement in physician-assessed quartile grading scale on the platelet-rich plasma side when compared to normal saline side (P = 0.03). There was also a significantly less intensity and duration of erythema on the platelet-rich plasma side than the control side, P = 0.01 and 0.047, respectively. The duration of post-treatment edema and crusting was also significantly less (P = 0.04 each).

Gawdat et al.¹⁶ compared the results of three monthly sittings of fractional CO₂ laser followed by intradermal and topical platelet-rich plasma against intradermal normal saline (NS) in 30 patients through a split-face randomised control trial and found significant improvement in physician assessment scale in FCL + PRP groups (topical as well as intradermal) as compared to intradermal normal saline group (P = 0.03). There was no significant difference in the grades of clinical improvement between intradermal and topical platelet-rich plasma. There was significantly shorter duration of erythema, edema, crusting, post-inflammatory hyperpigmentation (PIH) and acneiform eruption in FCL + PRP groups (P = 0.02) and the total downtime was shorter in FCL + PRP groups (P = 0.02). Pain was significantly greater in FCL + intra dermal PRP groups (P = 0.005) as compared to topical platelet-rich plasma with fractional CO₂ laser.

Faghihi et al.¹⁷ in a two-session, randomised split-face study on 16 participants found higher overall clinical improvement on FCL + PRP side when compared to FCL + NS side, but the difference was not statistically significant by physician-assessed quartile grading scale either 1 month after the first session (P = 0.15) or 4 months after the second (P = 0.23). The patient-assessed 4-point clinical satisfaction scale also showed similar greater but insignificant clinical improvement on FCL + PRP side at 1 or 4 months (P = 0.18 and P = 0.12, respectively). However, significant erythema was seen on FCL + PRP side than the control side on Days 0, 2 and 4 (P = 0.003, P = 0.007 and P = 0.03, respectively). Likewise, significant edema was seen on the FCL + PRP side as compared to control on Days 0, 2 and 8 (P = 0.003, P = 0.004 and P = 0.004, respectively). Similar to intensity, the mean duration of both erythema and edema were greater on the FCL + PRP side but was not statistically significant.

Shah et al.¹⁸ in 2017 performed a randomised split-face study on 30 patients who underwent four monthly sessions of fractional CO₂ laser followed by either platelet-rich plasma or normal saline injections on the two halves of the face and concluded that there was a significant reduction in Goodman and Baron grading in both platelet-rich plasma (mean was 14.83 at baseline and 4.2 at 4 months) and normal saline injection sites (mean Goodman and Baron grading was 15.23 at baseline and 7.5 at 4 months). Fourteen treatment sites (23.3%) showed excellent response to treatment, out of which 10 belonged to platelet-rich plasma sites and four belonged to normal saline site. Good improvement was seen in 19 treatment sites (31.7%) of which 12 were treated with platelet-rich plasma and seven were treated with normal saline. Significantly higher proportion of patients in the normal saline group had persistent erythema, edema and pain as compared to the platelet-rich plasma group (P = 0.0453, 0.008829 and 0.0076, respectively).

Kar et al.¹⁹ in a comparative split-face study performed fractional CO₂ laser at monthly intervals followed by application of topical platelet-rich plasma, and no intervention on left and right sides of their faces, respectively, in 30 patients inferred that although significant improvement was seen on both sides of the face as compared to the baseline, there was no significant difference in improvement between the right and the left sides of the face (P = 0.2891). However, adverse effects such as redness, swelling and pain experienced by each patient were significantly lesser on the side treated with FCL + PRP (left side) than that on the FCL-only side (P < 0.05).

Min et al.²⁰ through a randomised split face study studied platelet-rich plasma–induced collagen production and modulation of laser-induced inflammation after fractional CO₂ laser sessions correlating with increased clinical efficacy in acne scars. They used fractional CO₂ laser a month apart, followed by either intradermal platelet-rich plasma or intradermal normal saline injections on the randomised halves of the face. Skin biopsy specimens for molecular analysis were sent on days 0, 1, 3, 7 and 28 after the first treatment session. They found that the mean 5-point investigator’s global assessment (IGA) score on FCL + PRP side was significantly greater than FCL + NS (P < 0.001). Skin recovery rates after treatment as assessed using epithelization scale showed a significant difference between the two treatment modalities on day 1 (P = 0.01). Patients reported significantly higher scores for improvement on FCL + PRP side as compared to NS + PRP side on days 7 (P = 0.03) and 84 (P = 0.02). Immunohistochemistry showed significantly increased expression of TGFβ1, TGFβ3, c-myc, TIMP, HGF, collagen-1 and collagen-3 on FCL + PRP side. Both erythema index and colorimetric measurements revealed consistently less erythema of the platelet-rich plasma–treated side compared to the control side.

Abdel-Maguid et al.²¹ through a split-face randomised study evaluated the efficacy of stem cell-conditioned medium (SC-CM) versus platelet-rich plasma as an adjuvant to fractional CO₂ laser resurfacing for acne scars in 33 patients. After each fractional CO₂ laser session, group I received either topical stem cell-conditioned medium or topical normal saline (NS) on randomised halves of the face, whereas group II- received either topical platelet-rich plasma or topical normal saline (NS) on the randomised halves. In group I, difference in two sides showed no statistically significant results; on the other hand, group II showed greater reduction on the sides treated with FCL + PRP compared to the FCL + SC-CM sides (P = 0.006). In blinded physician assessment, the difference between FCL + SC-CM and FCL-only treated sides was insignificant in group I (P = 0.245). While in group II, there was significantly better improvement on the FCL + PRP side, which showed excellent marked improvement in 83% of patients, compared to 39% of patients on the FCL + SC-CM side (P = 0.033). Marked increase in organised collagen deposition was noted in FCL + PRP and FCL + SC-CM compared to fractional CO₂ laser alone. Both FCL + PRP treated sides and the FCL+SC-CM sides had more up-regulation of type I pro-collagen compared to the sides treated by fractional CO₂ laser only (P = 0.001 and P = 0.041, respectively). There was no significant difference in the duration of erythema, edema, crusting or post-inflammatory hyperpigmentation between the two sides in either group (P > 0.05).

Abdel Aal et al.²² in a comparative split-face study in 30 patients using fractional CO₂ laser followed by intra dermal platelet-rich plasma and no intervention on right and left sides of the face, respectively, for two sessions found that the overall improvement of the FCL + PRP side was better than the control with a statistically significant difference (P < 0.001). Clearance of erythema was significantly faster on FCL + PRP side than that of the control (P = 0.0052). There was no post-inflammatory hyperpigmentation (PIH) on FCL + PRP side in any of the patients, while it was seen in five patients on the control side (16.6%). Acneiform eruptions too were significantly reduced on the FCL + PRP side as compared to the control. Patients were satisfied with the outcome on their FCL + PRP side more than their control with a statistically significant difference (P < 0.001).

Taweel et al.²³ in 2018 performed a comparative non-split-face study in 40 patients who were divided into two groups: group A received three sessions of FCL + intradermal platelet-rich plasma each a month apart; group B received three sessions of intradermal platelet-rich plasma followed by intradermal carbon dioxide (CO₂) gas injections into the scars with a flow rate at 80 cc/min using 30G needle (carboxy therapy). Physician-assessed quartile grading scale showed significant improvement of acne scars in group A compared to group B (P = 0.039); with no statistically significant differences between the two groups in patients’ satisfaction. A significant increase in the incidence of edema was present in 90% of group A patients, while it was seen in only 50% of the patients in group B. There was no statistically significant difference between the two groups in terms of pain and post-inflammatory hyperpigmentation.

In line with studies with similar protocol by Kar et al.¹⁹ and Abdel Aal et al.,²² Galal et al.²⁴ performed a randomised split-face study on 21 patients who received fractional CO₂ laser at monthly intervals followed by topical fractional CO₂ laser and no intervention on the randomised halves of the face. The quantitative global acne scar grading system showed a statistically significant reduction for both sides of the face (P < 0.0001); however, greater reduction was found on the sides of the face that was treated with combined laser and PRP. FCL + PRP side showed significantly greater improvement in redness and pigmentation too (P < 0.0001). On assessment by Antera scoring system of scar depth, 70% of patients on the FCL + PRP side showed good or excellent improvement as compared to 30% of patients on the fractional CO₂ laser–only side. Improvement in scar appearance and skin texture, as well as decreased pores and pigmentation, were reported by the patients. Patient satisfaction score on reduction of scar, pigmentation and redness was higher for the sides that were treated with combined laser and platelet-rich plasma.

A non-split-faced study by El-Taieb et al.²⁵ was the only randomised control trial combining fractional erbium-yag (Frac Er:Yag) laser and platelet-rich plasma. Totally, 75 subjects were enrolled into three groups of 25 each. Group A received 12 sessions of intradermal injection of platelet-rich plasma at 2-week intervals; group B received six sessions of fractional Frac Er:Yag laser at 4-weeks interval; and group C received a combination of the two treatment modalities. Patients treated with Frac Er:Yag laser + PRP showed significant improvement compared with those treated with Frac Er:Yag laser or platelet-rich plasma alone (P = 0.007 and P = 0.001, respectively). Also, patients treated with Frac Er:Yag laser showed significantly greater improvement than those treated with platelet-rich plasma (P = 0.001). According to the clinical satisfaction of patients on a 4-point scale, patients in group C were more satisfied with their results than those in group A or B (P = 0.001 and P = 0.005, respectively). Likewise, patients treated with Frac Er:Yag laser were markedly more satisfied than those treated with platelet-rich plasma (P = 0.009). There was no statistically significant difference between the study groups regarding any of the post-treatment erythema, post-inflammatory hyperpigmentation or acneiform eruptions.

Similar to the protocol followed by Abdel Aal et al.,²² Kar et al.¹⁹ and Galal et al.²⁴; Arsiwala et al.²⁶ in a non-split-faced randomised clinical trial in 25 patients compared three monthly sessions of fractional CO₂ laser + topical platelet-rich plasma (group A) with fractional CO₂ laser monotherapy (group B). Although the mean change in Goodman and Baron quantitative global acne scar grading system scores reduced significantly in both groups A and B (P < 0.0001), the head-to-head comparison was statistically insignificant (P = 0.129). Both immediate as wells as long-term adverse effects were more in group B, but the difference from group A was statistically insignificant.

Mahamoud et al.²⁷ (2020) performed a randomised split-face study consisting of 30 subjects who received fractional CO₂ laser sessions 4-weeks apart followed by either intradermal hyaluronic acid (HA) injections or platelet-rich plasma injections on randomised halves of the face. Both FCL + PRP and FCL + HA sides achieved statistically significant differences by Goodman and Baron quantitative as well as qualitative scores (P < 0.001). When compared against one another, the qualitative score showed no statistically significant difference (P = 0.921).

Sujana et al.²⁸ in a randomised non-split-face study in 80 subjects evaluated the efficacy and safety of fractional CO₂ laser alone and in combination with intradermal platelet-rich plasma. Group A was treated with fractional CO₂ laser alone, while Group B was treated with FCL + PRP for 6 months. By Goodman and Baron’s global acne scarring scoring system, patients treated with FCL + PRP responded better to treatment than those treated with fractional CO₂ laser alone. Photographic assessment revealed improvement of skin texture and decreased downtime in FCL + PRP group. Patient’s subjective assessment was also consistent with the results of Goodman and Baron’s objective scoring system. Duration of erythema, edema and crusting was less in FCL + PRP group. Smaller number of patients experienced post-inflammatory hyperpigmentation in the FCL + PRP group too. However, more patients experienced pain in the FCL + PRP group.

El-Hawary et al.²⁹ conducted a randomised non-split-face study in 60 patients in which they were divided into three groups: Group 1 – platelet-rich plasma injections only, Group 2 – fractional CO₂ laser only, and Group 3 – FCL + intradermal platelet-rich plasma injections. They reported significantly higher improvement in group 2 compared to group 1 (P = 0.028) and significantly higher improvement in group 3 than in group 1 (P = 0.002). However, no significant difference was noted between groups 2 and 3 (P = 0.657). There was a similar pattern of outcomes in patient-assessed scale in skin texture, scar appearance and overall satisfaction. There was a significant increase in epidermal thickness, percentage of collagen fibres and number of proliferating epidermal cells (Ki‐67 expression) in all three groups before and 1 month after the last treatment session. Pain was more severe in group 3, while erythema, edema and crust formation were more severe and of longer duration in group 2. The total downtime was shorter in group 3 (4.60 ± 0.84) than in group 2 (5.40 ± 1.07).

Sharma et al.³⁰ (2021) in a split-face study, comprising 30 patients, compared right half (FCL + PRP injections) with left (FCL + NS injections) over four treatment sessions 4-weeks apart. Significant improvement in Goodman and Baron’s qualitative acne scar grading system scale on both sides were reported (P = 0.000). Most common side effects reported were erythema and burning followed by edema, which was seen in 63.3% patients on the study side and in 90% patients on the control side.

Discussion

The randomised control trials included in this review combined FCL/Frac Er:Yag and platelet-rich plasma and most of them compared it with normal saline as control. The method of delivery of platelet-rich plasma was broadly of two types, intradermal injection or topical application. The efficacy of FCL/Frac Er:Yag + PRP injections when compared with FCL/Frac Er:Yag + normal saline injections in improvement of scars were statistically significant in studies by Lee et al.,¹⁵ Gawdat et al.,¹⁶ Shah et al.,¹⁸ Min et al.²⁰ and El-Taieb et al.²⁵ Abdel al et al.²² and El-Hawary et al.²⁹ observed significant improvement in FCL + PRP group as compared to platelet-rich plasma alone. But, El-Hawary et al.²⁹ did not find a significant difference between FCL + PRP group as compared to the fractional CO₂ laser alone. Taweel et al.²³ compared the FCL + PRP injections with FCL+ CO₂ gas injections (carboxy therapy) and found significant improvement in facial halves treated with FCL + PRP injections. Only one randomised control trial by Faghihi et al.¹⁷ found no differences in improvement of acne scars in FCL + PRP injections as compared to FCL + NS injections. A randomised control trial by Mahamoud et al.²⁷ compared FCL + PRP injections with FCL + hyaluronic acid injections and found no statistically significant difference between the two. Comparing the adverse effects of platelet-rich plasma injections as compared to normal saline controls, most studies (Lee et al.,¹⁵ Gawdat et al.,¹⁶ Shah et al.,¹⁸ Min et al.,²⁰ Abdel Aal et al.²² and El-Hawary et al.²⁹) reported significantly less intensity of erythema, edema, crusting, downtime and post-inflammatory hyperpigmentation. However, two studies Gawdat et al.¹⁶ and El-Hawary et al.,²⁹ reported significantly increased pain in the FCL + PRP group as compared to FCL + NS. Taweel et al.²³ too found significantly more edema in the intradermal platelet-rich plasma group as compared to the intradermal CO₂ group. Lastly, Faghihi et al.¹⁷ observed significantly greater intensity of erythema and edema in FCL+ PRP side as compared to the control side.

Comparing the studies using topical platelet-rich plasma in fractional CO₂ laser and comparing it with topical normal saline, only one randomised control trial by Abdel-Maguid et al.²¹ showed significant improvement on comparing FCL + topical PRP and FCL + topical NS. Galal et al.²⁴ reported improved outcome on FCL + topical PRP side but did not mention whether it was statistically significant as compared to FCL + topical NS side. Two randomised control trials, by Kar et al.¹⁹ and Arsiwala et al.,²⁶ found no significant difference in improvement comparing FCL + topical PRP and FCL + topical NS. On analysing the adverse effects in combination of fractional CO₂ laser and topical platelet-rich plasma, Kar et al.¹⁹ found significantly less erythema, swelling and pain on FCL + topical PRP side than that on the fractional CO₂ laser–only side. Galal et al.²⁴ concluded that patient satisfaction scores on reduction of erythema and pigmentation were higher for the sides that were treated with FCL + PRP as compared to fractional CO₂ laser alone. Arsiwala et al.²⁶ also concluded that immediate adverse effects (erythema, edema and pain), as well as long-term adverse effects (post-inflammatory hyperpigmentation, pain, erythema, acne. and secondary infection), were less in the subjects treated with FCL + topical PRP, but the difference was not statistically significant. Abdel-Maguid et al²¹ who compared FCL + PRP on one side with FCL + NS on the other observed no significant difference in the duration of erythema, edema, crusting or post-inflammatory hyperpigmentation between the two sides.

Despite acne scars being a common condition, the number of studies qualifying for this review was low (16), as we included only the studies with higher levels of evidence. The studies analysed are heterogeneous in nature with differences in study protocols, number of sessions of platelet-rich plasma and/or lasers, type of lasers used and durations of follow-up.

Conclusion

Through this review, we analysed 16 randomised control trials and spilt-face studies where most reported statistically significant improvement in acne scars combining fractional lasers and intradermal platelet-rich plasma. While most of these studies also reported significantly less adverse effects in terms of erythema, edema, downtime and post-inflammatory hyperpigmentation on fractional laser + PRP side, some reported increased incidence of pain and edema. Comparing topical platelet-rich plasma with intradermal injections, there is only one study with significant improvement while two others observed no improvements as compared to topical normal saline. However, when compared to injectable platelet-rich plasma, topical platelet-rich plasma caused much less incidence as well as severity of adverse effects. We recommend combining fractional ablative lasers and intradermal platelet-rich plasma in the management of acne scars for increased efficacy and to reduce the incidence of procedure related erythema, post-inflammatory hyperpigmentation and downtime.