Topical management of acne scars: The uncharted terrain

Scarring is a common but difficult to manage consequence of acne vulgaris. The intricate balance between the degradation of collagen and its inhibition is disturbed during the formation of acne scars. We mostly rely on invasive, non‐topical modalities for the treatment of acne scars which may not be indicated in all patients. There is also a need for maintainence therapies after these procedures.


| INTRODUC TI ON
Majority (80%-90%) of patients who develop acne scars have atrophic scars associated with loss of collagen compared to a minority who show hypertrophic scars and keloids. 1  The various topical agents that have been tried in the management of acne scars as enumerated in Table 1 are described as follows along with their levels of evidence according to the Oxford Centre for Evidence Based Medicine.

| Tretinoin (level of evidence: 4)
Tretinoin 0.05% is used in the treatment of keloid scars, but there have been scarcity of reports of its use in the less aggressive acne scars. It has proven benefits on cutaneous photoaging. Within the epidermis, there is hyperplasia with a concomitant increase in the mean thickness. Dermal effects include an increase in papillary dermal collagen and elasticity leading to improvement of dermal architecture and skin firmness. 3 D W Harris et al. 3 reported a patient in whom the daily application of tretinoin 0.05% for 4 months resulted in a marked improvement in the superficial acne scars.

| Topical low strength glycolic acid (level of evidence: 1b)
Glycolic acid (GA) peeling is an effective modality for the treatment of atrophic acne scars, but repetitive peels are necessary to obtain evident improvement.
In a randomized comparative study in women with atrophic acne scars which compared the efficacy of biweekly glycolic acid peels versus daily use of topical low-strength (15%) glycolic acid cream, 70% glycolic acid peels provided significantly superior results compared with the topical regimen. Daily home-based application of low-strength glycolic acid was better tolerated and had less sideeffects than glycolic acid peels. 4 Long-term daily use of 15% GA is moderately effective in atrophic acne scars and therefore may be advised for persons who cannot tolerate the peeling procedure.

| Adapalene (level of evidence: 2b)
Use of topical retinoids has been approved for the treatment of acne and photo-damaged skin. Topical retinoids activate dermal fibroblasts to increase the production of procollagen in photoaged skin.
As photodamaged skin and atrophic acne scars share the feature of dermal matrix loss, adapalene 0.3% may potentially exert a beneficial effect in the treatment of atrophic acne scars.
In a phase II study, subjects with moderate to severe facial atrophic acne scars received daily adapalene 0.3% gel. Investigator and subject assessments reported improvement in skin texture/atrophic scars in 50% and 80% of subjects, respectively. 7

| Tazarotene (level of evidence: 1b)
Tazarotene cream, 0.1%, has been found to significantly improve macular acne scars compared with adapalene gel, 0.3%. 8 Retinoids decrease collagenase, which can lead to an accumulation of collagen in scar tissue, apart from their action on fibroblasts to increase collagen synthesis.
In a randomized clinical trial, both halves of each participant's face were randomized to receive either microneedling or topical 0.1% tazarotene gel therapy. The median quantitative score for acne scar severity (Goodman and Baron) at the 6-month follow-up visit following treatment with either tazarotene or microneedling TA B L E 1 Topical agents for acne scars along with their levels of evidence a when used as individual agents, combination therapies or through assisted delivery

| Vitamin C derivatives (level of evidence: 2b)
Vitamin C promotes wound healing through novel pleiotropic modulations in collagen metabolism and can improve atrophic scars (AS) in acne. Vitamin C induces the expression of self-renewal, cell cycle progression, and fibroblast motility genes in dermal fibroblasts. It also attenuates mediators of inflammation through interleukin-1β and tumor necrosis factorα. It improves hyperpigmentation by inhibiting melanin synthesis, tyrosinase, and reactive oxygen species.
Effective treatment with iontophoresis using ascorbyl 2-phosphate 6-palmitate (APP) and DLα-tocopherol phosphate (TP) has been reported. Glyceryl-octyl-ascorbic acid (GOVC), an innovated vitamin C derivative, is capable of a stable, antioxidative, antiacne, antimelanin synthesis gradient in vitro. 10 In an attempt to evaluate the efficacy of a GOVC/APP/TP com- In a split-face study, which enrolled participants with facial acne scars on isotretinoin therapy, one half of the face were treated with tranilast 8% liposomal gel and the other half with a placebo.
The mean GAIS (Global Aesthetic Improvement Scale) scores were significantly lower (better result) for the tranilast treated side than the placebo-treated side in patients concomitantly treated with isotretinoin. 15 Hence, combined topical application of tranilast 8% gel twice daily with oral isotretinoin treatment in the active phase of acne vulgaris may result in fewer scars, finer skin texture, and enhanced appearance.

| Plasma gel (level of evidence: 1b)
Liquid plasma when transformed into a viscous gel maintains its shape due to the effective cross-linking giving a filling effect. Plasma

| Lyophilized growth factors (level of evidence: 2b)
Lyophilized growth factors (L-GFs) are considered a PRP product that are standardized in terms of growth factor concentrations. It is derived from multiple platelets concentrates, after stages of protection, vacuum freeze-drying, and gamma ray sterilization which facilitate platelets storage, reduces contamination, and increases viability. It allows physicians to apply a standard amount of growth factors and ensure their rapid release and access to the target tissue.
In a study where fractional CO2 laser was performed on both sides of the face followed by topical application of L-GFs on one side and conventional PRP on the other side, the degree of clinical improvement and patients' satisfaction were significantly higher with shorter downtime in response to fractional CO2 laser combined with L-GFs rather than its combination with PRP. The effect of an intradermal injection of distilled water with microneedling does not achieve that of PRP and microneedling further supporting PRP's efficacy. Topical PRP surpassed topical vitamin C in atrophic acne scar reduction. Thus, topical or intradermal PRP alongside microneedling shows superior results when compared to vitamin C or distilled water, respectively.

| Topical insulin (level of evidence: 2b)
Following microneedling, collagen is deposited in the normal lattice pattern, while growth factors of PRP augment the healing of PAS.
Topical insulin (TI) activates the PI3K/AKT pathways to increase VEGF. Following TI, increased synthesis and maturation of collagen fibers, chiefly type III, occur in a basket weave like organization (normal skin), rather than crisscross manner (scar). 21 In a split-face comparative study of microneedling with 1-2 ml topical PRP and microneedling with 1-2 ml topical insulin (Human actrapid® insulin 40 IU/ml solution: bio synthetic rDNA human insulin), there was significant and comparable improvements with the two modalities. 22 However, easy accessibility, low cost, and noninvasive nature merit the use of TI over PRP.

| Poly lactic acid (level of evidence: 2b)
Filler injections with poly-lactic acid (PLA) have been reported as effective treatments for volumetric deficiency. It acts as a biostimulator to induce collagen production and vascularization of existing collagen.
PLA has a high molecular weight of 140 kDa. It also has an irregular crystalline shape, which slows its physiological absorption and therefore needs assisted delivery. Microneedle fractional radiofrequency (MFRF) transmits thermal energy to the dermis without epidermal and dermoepidermal junction damage, with less risk of hyperpigmentation.
In a split face study, poly-lactic acid was applied to the acne scars Also, structural improvement of elastic fibers has been described in women after topical application.
Using iontophoresis, either tretinoin or estriol, can be administered to the scarred skin. In a study by Schmidt et al., 25 improvement of acne scars was observed in 93% of patients treated with 0.025% tretinoin-gel iontophoresis and in 100% of the group treated with estriol (0.3% acid aqueous solution) iontophoresis. Side effects appeared in the tretinoin group and consisted of increased dryness and of retinoid dermatitis.

| CON CLUS ION
A home-based topical treatment that is well tolerated would be a useful addition in the armamentarium of acne scar management.
Such a home-based treatment option for acne scars will relieve physician dependence and healthcare expenses for patients. As acne and scarring can be an ongoing and a recurrent process, device based approaches may need some form of maintenance therapy to maintain the attained outcome and to prevent further scarring.
The use of a modality such as tazarotene that prevents acne flares while addressing acne scarring is also a reasonable addition to clinical practice. Finding effective, non-procedural medical treatments has proven challenging, and there is a dearth of evidence to support their use by clinicians. Therefore, we recommend further studies to unearth these hidden tools.

CO N FLI C T O F I NTE R E S T
This article has no funding source, and none of the authors have relevant conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.