2.1 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.

2.2 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 side-effects 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.

2.3 Topical adapalene/benzoyl peroxide gel (level of evidence: 1b)

Atrophic acne scars evolve primarily from inflammatory and post-inflammatory acne lesions. Topical A 0.3/BPO2.5 (Adapalene 0.3%/Benzoyl Peroxide 2.5%) gel has efficacy in the treatment of moderate or severe inflammatory acne vulgaris.⁵

In the randomized split face study by Dreno et al, reductions in atrophic acne scars and acne lesions observed after 24 weeks of treatment with A0.3/BPO2.5 gel were maintained with treatment up to 48 weeks. The additional improvement in atrophic scar count with 48 weeks' A0.3/ BPO2.5 treatment, compared to delayed application at 24 weeks, highlighted the importance of early initiation of effective acne treatment to prevent and reduce the formation of acne scars.⁶

2.4 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

2.5 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 indicated significant improvement that was comparable for both treatments.⁹

2.6 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 factor-α. It improves hyperpigmentation by inhibiting melanin synthesis, tyrosinase, and reactive oxygen species.

Effective treatment with iontophoresis using ascorbyl 2-phosphate 6-palmitate (APP) and DL-α-tocopherol phosphate (TP) has been reported. Glyceryl-octyl-ascorbic acid (GOVC), an innovated vitamin C derivative, is capable of a stable, antioxidative, anti-acne, antimelanin synthesis gradient in vitro.¹⁰

In an attempt to evaluate the efficacy of a GOVC/APP/TP complex lotion for the treatment of post-inflammatory hyperpigmentation (PIH), erythema(PIE), and atrophic scars in acne vulgaris, a split-face comparative clinical trial using a GOVC/APP/TP complex lotion was performed. Remarkable improvement in PIH, PIE, and AS was observed on the right side of the face with application of the GOVC/APP/TP complex lotion.¹¹

2.7 Topical tacrolimus (level of evidence: 4)

Macular erythema which is one of the dreaded sequelae of acne is considered a sign of ongoing inflammation which either persists or culminates in atrophic scarring. It results from acne-induced inflammatory cascade and neovascularization.

Topical tacrolimus, a macrolide calcineurin inhibitor, is used in inflammatory conditions due to its inhibition of T cells. It also antagonizes VEGF (vascular endothelial growth factor) causing anti-angiogenic potential, thus targeting both the components of macular erythema. Tacrolimus 0.1% ointment monotherapy in patients with acne-related macular erythema caused a visible reduction in erythema in 5–7 weeks, and there was no sign of relapse after 14 weeks.¹² Topical tacrolimus is therefore a promising treatment for macular erythema, thereby preventing atrophic acne scarring.

3.1 Silicone gel (level of evidence: 1b)

Silicone gel is used as an early scar prevention measure. It increases wound moisturization by its water vapor permeability. It also results in rearrangements of collagen fibers by decreasing fibrogenic cytokines, especially transforming growth factor-β, improving electrostatic property, increasing oxygen tension, and reducing tissue inhibitor of metalloproteinase 2, which are increased in acne scar-prone patients.

In a randomized, comparative trial where patients were treated with three sessions of ablative Er:YAG laser at 1-month intervals and silicone gel or placebo was applied in split-face manner, topical silicone gel resulted in significantly less roughness compared with placebo.¹³

3.2 Tranilast (level of evidence: 1b)

Tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, is used as an anti-allergy drug and in treatment for fibrotic conditions, keloids, and hypertrophic scars.

It inhibits the release of chemical mediators from mast cells and also inhibits collagen synthesis in human fibroblasts, through inhibition of transforming growth factor (TGF)-β1 release from scar fibroblasts.¹⁴

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.

3.3 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 gel contains inflammatory proteins like chemokine ligand 5 which enhances the migration of the skin-derived stem cells for regeneration.

Although in much less concentrations than PRP (platelet rich plasma), PPP (platelet poor plasma) contains growth factors that promote tissue healing. Moreover, it contains much larger amount of fibrinogen than PRP. Upon activation, fibrinogen is converted into fibrin bundles which trap platelets providing a prolonged source of growth factors.

In a study that compared the efficacy of (A) fractional CO2 laser (FCL) combined with intradermal injection of plasma gel, (B) FCL combined with topical application of plasma gel, and (C) FCL monotherapy in the treatment of atrophic post-acne scars, the reductions in quantitative GSGS (global scarring grading system) scores in group A and group B were comparable, and both were significantly better than that in group C.¹⁶ So, topical application of plasma gel may be as effective as intralesional plasma gel. Plasma gel preparation: ten milliliters of venous blood was collected in tubes containing sodium citrate solution. The tubes were then centrifuged at 1500 revolutions per minute (rpm) for 10 min. The upper plasma and buffy coat layers were aspirated and centrifuged again for 10 min at 3500 rpm. The whole plasma (PRP and PPP) was then aspirated leaving behind the erythrocyte pellet and activated by calcium chloride in a proportion of 0.1 ml per 1 ml of plasma. The activated plasma was heated in a hot water bath (70–100°C) for 3 min and then in a cold bath (5–0°C) for 3 min to obtain the viscous gel. (Centrifuge used: Low speed, Electric centrifuge, model 80–1, CGOLDENWALL, Max. speed: 4000 rpm, Maximum Relative centrifugal force: 1790 × g, timer: 1 to 30 min, Power supply: 220 V 50 Hz).

3.4 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.¹⁷

3.5 Amniotic fluid derived mesenchymal stem cell products (level of evidence: 2b)

Amniotic fluid-derived mesenchymal stem cells (AF-MSC) produce cytokines and chemokines, which enhance wound healing, including interleukin (IL)-8, IL-6, transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF).¹⁸ However, these growth factors are large hydrophilic molecules that penetrate the epidermis in low quantities. Accordingly, it needs an assisted form of delivery.

In a split face study by El Domyati et al, AF-MSC was topically applied to right side of the face after microneedling. There was significant increase in the improvement percentage of acne scars on right side vs left side of face.¹⁹

3.6 Topical prp with microneedling (level of evidence: 2a)

Topical PRP and microneedling (35 split-face participants and 55 whole-face participants) showed significantly better results in Goodman and Baron qualitative scores than microneedling alone.²⁰

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.

3.7 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 non-invasive nature merit the use of TI over PRP.

3.8 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 on one side of the face before MFRF treatment. The other side was treated with MFRF and normal saline. Both acne scar assessment scores and patient satisfaction were better with combination therapy than with monotherapy.²³

3.9 Retinoic acid plus glycolic acid (level of evidence:4)

Retinoic acid (RA) can attenuate acne scars and reduce post-acne hyperpigmentation while the keratolytic activity of glycolic acid (GA) can reduce atrophic acne scars. The synergistic effect of retinaldehyde and GA has been well studied with positive results. In a retrospective assessment of 35 patients using topical RAGA combination on acne scars, significant improvement in acne scars was noticed in majority of the patients .²⁴

4.1 Iontophoresis: estriol and tretinoin (level of evidence: 4)

Estrogens are known to inhibit sebaceous gland function. An increase in vascularization and of acid mucopolysaccharides and hyaluronic acid are responsible for the increase in dermal water content. 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.