Safety and efficacy of human platelet extract in skin recovery after fractional CO2 laser resurfacing of the face: A randomized, controlled, evaluator‐blinded pilot study

Fractional carbon dioxide (CO2) laser resurfacing is used successfully for facial rejuvenation. Post procedure skincare is a variable that influences downtime caused by pain/tenderness, erythema, crusting, and bruising.


| INTRODUC TI ON
The face is one of the first anatomical regions noticed and evaluated by others. 1 Premature facial photoaging can lead to an unwanted aesthetic appearance, which may cause some subjects to have psychological distress. Damage caused by free radicals and environmental toxicities, such as UV radiation to exposed areas, is a common problem leading to the appearance of skin laxity, wrinkles, and brown spots. 2 Commonly exposed areas include the face, neck, hands, and decolletage. Beauty, being a multidimensional concept, undoubtedly has a central influence on our lives, 3 leading individuals to seek a variety of cosmetic treatments. Fractional laser resurfacing procedures are commonly used to treat adverse effects of photoaging. In 2020, nearly 1 million Americans sought minimally invasive laser skin resurfacing procedures to ameliorate these problems. 4 Fractional photo thermolysis generates an array of intended microscopic areas of thermal injury to the skin. 5 Proper post-laser skincare is vital to helping improve recovery while minimizing downtime and infection risk. 6 Side effects such as discomfort, erythema, and irritation can be prolonged in some patients after laser resurfacing. Identification of topical treatments to accelerate skin recovery is therefore a key priority. Ideally, topical dressings following ablative laser procedures should improve and optimize the wound healing microenvironment. 7 Studies have been conducted to evaluate application of many products after laser resurfacing, including platelet-rich plasma (PRP), 8 mesenchymal stem cell media, 9,10 oxygen emulsions, 11 fusidic acid cream, 12 Cryptomphalus aspersa, 13 and skin care regimens containing β-glucan. 14,15 Posttreatment topical steroids have also been shown to reduce downtime but remains controversial as they may increase other side effects and potentially impact long-term benefits of thermolysis. 6,15 Recovery agents such as Aquaphor, Vaseline, and Vanicream Moisturizing Ointment are commonly used in the early post-laser recovery period to create an occlusive barrier to hold moisture and provide protection to the skin from pollutants in the air as the skin heals.
One of the latest developments in aesthetic regenerative medicine is the use of human platelet extract (HPE). Platelets are considered an ideal source due to their high propensity for wound/ skin healing, with high hemocompatibility and low immunogenicity profile. 16 HPE suspended in a carrier gel for topical cosmetic application has been successfully used to address skin problems related to aging and environmental damage. 17 Topical human platelet extract (plated)™ CALM Serum (Rion Aesthetics, Rochester, MN), with Renewosome™ technology, exosomes sourced from sterile U.S. sourced pooled human apheresed platelets, has the potential to induce maximal effects on skin regeneration and recovery. HPE CALM Serum is produced with consistent batch quality, purity, and potency. 17 It is an off-the-shelf cosmetic product for skin rejuvenation that has demonstrated induction to normalized skin health at 4-6 weeks, with improved clinical measures of facial photodamage and cutaneous aging. 17 CALM is designed for post-laser recovery and contains methyl to create a cooling sensation. This study examines evidence-based outcomes for accelerated skin recovery after fractional carbon dioxide (CO 2 ) laser resurfacing of the full-face utilizing CALM Serum (human platelet extract) in a topical cosmetic application compared to our standard of care, Stratacel® silicone gel (Stratpharm AG, Basel, Switzerland) 2 weeks after daily use.

| Trial design and population
This prospective, single-center, randomized, controlled, evaluatorblinded study of the safety and efficacy of (plated)™ CALM Serum Helsinki. The study was approved by the Advarra IRB. All subjects gave informed consent before any study procedures were performed.
This pilot study was conducted to assess the safety, tolerability, and accelerated renewing impact of the topical CALM Serum in nine experimental group participants compared to nine participants treated with standard of care alone (silicone gel) following CO 2 ablative laser therapy to the full face.
Subjects who met all inclusion criteria and no exclusion criteria were enrolled and randomized in a 1:1 fashion to treatment with HPE or standard of care. The main criteria for inclusion were male and female adults 18 years or older with Fitzpatrick skin phototypes I-III who were desiring CO 2 laser resurfacing of the full face. Major exclusion criteria included subjects with multiple medical comorbidities, those who were pregnant or nursing, and subjects with Fitzpatrick skin phototypes IV-VI. Dermatological exclusion criteria included, but were not limited to, the use of retinoids 7 days prior to the procedure, active cutaneous infections in the treatment area, diseases that could inhibit healing, such as scleroderma, or other cutaneous conditions that could confound study results.
The study was supervised by a board-certified plastic surgeon.
The study team included aesthetic registered nurses with laser certifications who conducted the procedures, and a research study coordinator.

| Treatment
All study participants followed a standardized skin care regimen for the entire 1-month study period. A 7-day pre-procedure facial skincare regimen for subjects randomized to the HPE treatment group included Cetaphil cleanser (or equivalent) twice daily morning and evening, with application of HPE once daily, and EltaMD  Prior to the laser procedure, facial skin was cleansed with alcohol followed by application of a topical anesthetic cream containing 23% lidocaine and 7% tetracaine. After 1 h the anesthetic cream was removed with alcohol and the skin was cleansed with Hibiclens.

| Skin evaluation
Immediately post-procedure, CALM was applied to the skin in the HPE group in a thin layer, using 3-4 pumps. After 15 min a thin layer of silicone gel was then applied. For the control group, a thin layer of silicone gel was applied immediately post-procedure. No other products, masks, or ice were used post-procedure.

| Study endpoints and variables
The primary outcome measure was improvement in the overall ap-  (Table 1)

| Statistical analysis
Mixed models were used to investigate the impact of day, treatment group, and their interaction (including a quadratic term for day) on the ratings for patient reported discomfort across seven items.
Simple t-tests were performed, without correction for multiple tests, at time points indicated by graphical analysis for the outcomes identified with treatment effects by the mixed models. Crusting resolved about 5 days sooner in the HPE group than in the control group (Figure 1). At Day 10, the average crusting discomfort in the HPE group was 0.11 as compared to 0.89 in of the control group (t-test p-value = 0.0193).

| RE SULTS
Itching was experienced by nearly all participants on Days 2-4.
The severity of itching tended to be higher in the control group up through Day 4 with no statistically significant differences on any single day (Figure 2). Similarly, burning-stinging trended higher in the HPE group on the first few days of healing; however, control subjects experienced symptoms of pain/tenderness on more diary days than the HPE group. Nevertheless, the differences on any 1 day were not statistically significant.
The HPE group had statistically significantly less downtime by   There were no reported side effects or adverse events. The products were well tolerated with no reports of contact allergies.

| DISCUSS ION
HPE here was noted to facilitate a post-laser aesthetic recovery with no evidence of complications or safety concern. 17 By delivering renewing factors and antioxidants, 16

| CON CLUS IONS
This study demonstrates that a novel human platelet-derived exosome serum with a unique proprietary formulation technology provides statistically significant post-laser treatment clinical recovery over a silicone-based gel for reducing crusting, and downtime.
Subjects experienced less symptoms of pain/tenderness, redness, crusting/flaking, bruising, and itching in the first 14 days than the control group. HPE also demonstrated statistically significant improvements in brighter and more youthful appearing skin at Day 14.
HPE is safe and well tolerated. It is a potential first-line treatment to facilitate wound healing after laser resurfacing.

AUTH O R CO NTR I B UTI O N S
SD and AB: study design and conceptual development; SD, NG, JW, and EK: study conduct; KC: statistical analysis; LEJ: writing and editing.

ACK N OWLED G M ENTS
Alisa Lask and Emily DeGrazia for conceptual input into study design.

FU N D I N G I N FO R M ATI O N
This study was partially financed by Rion Aesthetics, LLC (Rochester, MN).

CO N FLI C T O F I NTER E S T S TATEM ENT
LEJ is a consultant for Rion Aesthetics, LLC. CP is an employee of Rion, Inc. (Rochester, MN). AB has ownership interest in Rion Inc.
and Rion Aesthetics, LLC.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

E TH I C S S TATEM ENT
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to and the appropriate ethical review committee approval has been received. Approval was obtained from Advarra IRB. Informed consent was obtained from all participants. All participants provided photography consent.