Injectable Fillers for Atrophic Acne Scars: A Systematic Review of Mechanisms, Evidence, and Clinical Algorithms

Introduction

Acne, a prevalent dermatological condition affecting 9.4% of the global population,¹ primarily emerges during adolescence, with a notable impact on males. It significantly affects functional status, interpersonal relationships, social functioning, and mental health.² An estimated 95% of patients with acne develop scars, predominantly atrophic scars, subdivided into rolling, boxcar, and icepick types.^3–6 The uneven texture of these scars significantly impairs facial aesthetics, profoundly affecting patients’ psychological well-being.⁷ Furthermore, acne scars reduce quality of life and increase the likelihood of depression and suicidal thoughts.^2,8

In acne lesions, inflammation primarily occurs in the infundibulum of the hair follicle, leading to scar formation below the skin surface.⁹ This depth difference causes surface contraction and a depressed appearance.¹⁰ Studies propose that susceptible individuals in the initial stages of acne exhibit increased transforming growth factor-β1 expression, resulting in enhanced extracellular matrix degradation and reduced keratinocyte proliferation¹¹ The severity and duration of the inflammatory response are linked to the development of Atrophic Acne Scars (AAS).¹² Prolonged inflammation can lead to breakdown of the sebaceous gland structure, culminating in the formation of AAS.

A range of interventions has been investigated, including surgical procedures, radiofrequency therapy, microneedling, laser treatment, and autologous platelet-rich plasma (PRP) therapy.^13–16 Some AAS with thin bases respond poorly to multiple sessions of fractional laser or radiofrequency treatment (such as radiofrequency microneedling). Injectable filler therapy can rapidly correct tissue defects and stimulate collagen production, opening new possibilities for treating depressed scars. Accordingly, this review systematically evaluates the clinical utility of dermal fillers for treating AAS, synthesizes the latest evidence on mechanisms, safety and efficacy, and explores future diagnostic and therapeutic approaches for this condition.

New Hopes from Filler Applications

The management of AAS remains a significant challenge for plastic surgeons. Although numerous treatment approaches are available, no standardized, most effective treatment protocol has been established (Figure 1). Nevertheless, these approaches have inherent limitations, with outcomes frequently falling short in terms of cost-effectiveness, treatment duration, recurrence rates, and associated complications. For example, laser therapy can induce considerable discomfort, microneedling necessitates multiple sessions, and PRP therapy is characterized by a delayed onset of action and requires repeated injections. Patients often encounter difficulties in achieving noticeable improvements during the initial phases of treatment.

Figure 1 Treatment approaches for AAS.

Injectable aesthetic treatments are crucial in plastic surgery, with dermal fillers gaining widespread use in cosmetic procedures. Various filler materials have been applied to the treatment of AAS. Filler therapy offers immediate volume restoration, aesthetic enhancement, long-term collagen stimulation, minimal invasiveness, and a favorable safety profile. Advancements in technology and new materials provide promising prospects for patients. This paper presents a detailed review of tissue filler treatments for AAS (Figure 2).

Figure 2 Injection Therapy for AAS.

Methods

We conducted a comprehensive literature search using PubMed and Web of Science to identify relevant studies published between January 1, 2015 and January 31, 2025. Search terms combined keywords such as “Acne Scars”, “Atrophic Scars”, “Collagen”, “autologous fat”, and “Dermal Fillers” using Boolean operators to ensure thorough coverage. Titles and abstracts of retrieved records underwent initial screening, followed by full-text assessment of potentially eligible studies against predefined inclusion and exclusion criteria. We included studies involving patients of any age or gender with any type of acne scar treated with synthetic dermal fillers (eg autologous fat, calcium hydroxylapatite, collagen, hyaluronic acid, poly-L-lactic acid, polycaprolactone, or polymethylmethacrylate); only studies published in English were included. Eligible studies reported treatment efficacy, adverse events, or safety outcomes. Studies not using injectable fillers as the primary intervention or treating unrelated conditions were excluded. We also excluded studies with very small sample sizes, which was pre-defined as single-arm studies with fewer than 10 participants or comparative studies with fewer than 5 participants per group. During full-text screening, a total of 17 studies were excluded based on this criterion. In total, 24 studies met all criteria and were included in the qualitative synthesis.

Collagen-Based Fillers

Collagen-based fillers are among the earliest biomaterials used for skin repair and are categorized as animal-derived or recombinant humanized collagen. Animal-derived collagen, sourced from bovine, porcine, or fish skin, has a complex composition and can trigger immunogenic responses.¹⁷ Concerns about immunogenicity, hypersensitivity reactions, and prion infection have limited its use.^18,19 Recombinant humanized collagen, produced by inserting human collagen genes into host cells, offers high purity, consistency, absence of animal-derived risks, and enhanced biocompatibility.²⁰ Clinicians have effectively treated AAS with various collagen preparations, with filling effects lasting approximately 6 months.^21–24

Hyaluronic Acid Fillers

Hyaluronic acid (HA) is a naturally occurring acidic mucopolysaccharide with consistent composition across species. About half of the HA in the human body resides in the skin.²⁵ HA is characterized by excellent biocompatibility, lack of immunogenicity, and high water-binding capacity. Upon hydration, it forms a flexible, viscous matrix. When introduced into the dermis, HA promptly enhances skin thickness and moisture content, resulting in immediate aesthetic improvement. It also displays anti-inflammatory properties and promotes collagen production.^3,26 These attributes have led to widespread use of HA in facial aesthetic procedures in recent years. Sipperstein et al²⁷ conducted a randomized, placebo-controlled trial involving 15 patients with AAS, demonstrating a notable decrease in Global Scar Grading System (QGSGS) scores from baseline in the HA group. A subsequent 2-year follow-up²⁸ showed sustained efficacy without significant diminution, affirming the enduring reparative benefits of HA injection. Mehrabi et al²⁹ reported that formulations combining high-molecular-weight HA and low-molecular-weight HA produce more effective long-term outcomes than traditional crosslinked dermal fillers. This increased effectiveness may reflect the capacity of HA complexes of different sizes to interact with multiple cell-surface receptors and regulate cellular functions, thereby decreasing HA degradation and continuously promoting collagen regeneration.^30,31 Sparavigna et al³² demonstrated notable therapeutic outcomes in individuals with AAS using a high-concentration (4.5%) hybrid cooperative complex of hyaluronans in conjunction with a biplane injection method. Needle-free, spring-loaded jet-injection technology has been used for transdermal delivery of vaccines and insulin for an extended period.³³ Kaminaka et al³⁴ applied needle-free electronic pneumatic HA injection for facial AAS. The EPIHA method showed substantial effectiveness, with rolling scars improving more than boxcar and icepick scars.

Collagen Stimulator Fillers

To address the limitations of HA fillers, such as short lifespan and restricted capabilities, the aesthetic medicine field has introduced a class of fillers with collagen-stimulating properties. These agents trigger the natural collagen production process of the skin, leading to prolonged tissue rejuvenation and volume enhancement. Commonly used collagen stimulators include polycaprolactone (PCL), poly-L-lactic acid (PLLA), poly-D, L-lactic acid (PDLLA), and calcium hydroxylapatite (CaHA).

CaHA Fillers

Calcium hydroxylapatite (CaHA) is a naturally occurring mineral present in human bones and teeth and can be produced artificially using various deposition methods.³⁵ Owing to excellent biocompatibility and biodegradability, CaHA has been widely used in non-surgical cosmetic procedures and is the second most commonly used dermal filler, representing 5.9% of all fillers.³⁶ Facial injections of CaHA have been shown to significantly improve aesthetic outcomes.³⁷ CaHA formulations typically comprise microspheres 25–45 μm in diameter dispersed in a gel carrier.³⁸ The gel component offers immediate or short-term volumetric support, whereas the porous structure of the microspheres attracts nearby fibroblasts and promotes continuous collagen production.^39–41 Antonino et al⁴² studied women with moderate to severe AAS, assessing outcomes with digital macro photography, Vectra H2, and Antera 3D. The clinical efficacy of CaHA injection was superior to that of placebo, whereas combining CaHA with high-intensity focused ultrasound (HIFU) did not enhance efficacy compared with monotherapy. Goldberg et al⁴³ treated 10 patients with different AAS types using CaHA fillers, finding substantial improvement in rolling scars and limited effectiveness for icepick scars.

PLLA Fillers

PLLA, a biodegradable synthetic polymer within the polylactic acid (PLA) family, demonstrates exceptional biocompatibility and typically does not elicit significant immune or allergic reactions.⁴⁴ PLLA fillers are supplied as microspheres 40–63 μm in diameter, which inhibits phagocytosis by macrophages.^45,46 Soft-tissue enhancement can persist for up to 2 years.⁴⁷ Sadick et al⁴⁸ reported the use of PLLA injections in a 60-year-old Caucasian female patient with a history of CO2 laser therapy, dermabrasion, and trichloroacetic acid peels for AAS, all of which had yielded unsatisfactory results; PLLA injection therapy resulted in high patient satisfaction. Several studies^49–51 have shown that PLLA effectively improves AAS, particularly in individuals with thin dermis, with therapeutic benefits lasting as long as 4 years.

PDLLA Fillers

PDLLA, a synthetic polymer produced by random copolymerization of D-lactic acid and L-lactic acid monomers, exhibits an amorphous structure that results in accelerated degradation and enhanced flexibility.⁵² PDLLA microspheres sized 30–50 μm can induce fibroblast activation via nonspecific inflammatory reactions, thereby facilitating deposition of type I collagen. However, its biostimulatory effect is comparatively short-lived relative to PLLA. Combining PDLLA with fillers such as HA can extend therapeutic effectiveness. Unlike PLLA, the reduced crystallinity of PDLLA lowers the likelihood of post-injection nodules, making it more suitable for superficial scar treatment or combination therapy. A South Korean study included five patients treated with laser-assisted, needle-free microjet injection of poly-D,L-lactic acid. After five treatment sessions, improvements in AAS and skin texture were observed, with high patient satisfaction.⁵³

PCL Fillers

PCL is an aliphatic organic polymer recognized for its excellent biocompatibility, biodegradability, and absorbability. It is employed as a collagen stimulator in a novel filler that contains synthetic PCL microspheres (20–50 μm in diameter) suspended in a carboxymethyl cellulose (CMC) gel. The CMC gel serves as a carrier, provides an immediate filling effect, and is gradually absorbed by macrophages over 2–3 months. As the gel resorbs, the PCL microspheres become exposed within the tissue and biologically stimulate type I collagen⁵⁴ production, resulting in durable contouring effects. Lotfi et al¹⁵ evaluated PCL combined with radiofrequency-assisted subcutaneous isolation for AAS and observed significant improvement across all AAS appearance categories. Khattab et al⁵⁵ treated 24 patients with AAS using either PCL thread engraving or microneedling combined with PRP; both approaches produced marked clinical improvement, although patient satisfaction was higher with PCL thread engraving.

PMMA Fillers

Polymethylmethacrylate (PMMA) is a long-lasting synthetic filler consisting of methyl methacrylate microspheres (30–120 μm in diameter) suspended in a bovine collagen carrier. It is FDA-approved for AAS treatment and is often used in facial rejuvenation procedures targeting regions such as the jawline and temples.⁵⁶ PMMA microspheres provide immediate structural support to deep dermal or subcutaneous deficits and induce a controlled inflammatory response that leads to fibroblast encapsulation and collagen deposition, promoting sustained tissue restoration.⁵⁷ In 42 patients, Joseph et al⁵⁸ reported a ≥1-point improvement in ASAS score at 4 and 7 months after PMMA injection; both clinicians and participants noted significant aesthetic enhancement on the GAIS. Solomon⁵⁹ reviewed PMMA use for AAS and found that most patients experienced substantial improvement and exceptionally high satisfaction.

Autologous Fat

Autologous fat serves as an optimal filler due to complete biocompatibility, ample availability in the body, seamless integration into host tissue, favorable plasticity, and potential for long-lasting effects.⁶⁰ Although adipocytes were traditionally regarded as inert energy storage units, numerous studies have highlighted their notable capacity for proliferation and regeneration.^61,62 Comprising mature adipocytes and a stromal vascular component (SVF), adipose tissue consists of these two primary constituents.⁶³ The pivotal characteristic of SVF cells is exceptional reparative capability, facilitated by stem cells that synergize with growth factors to stimulate angiogenesis, collagen remodeling, and skin barrier restoration.⁶⁴ Shetty et al⁶⁵ evaluated the effectiveness of a single autologous fat graft combined with three PRP injections in patients with AAS. After a three-month follow-up, both groups showed significant improvement in scars, and no statistically significant difference was observed between the two treatment groups. Nilforoushzadeh et al⁶⁶ used autologous fat to treat facial AAS in a cohort of 9 adult patients and reported significant improvements in pore size, hyperpigmentation, skin tone, melanin levels, skin elasticity, and transepidermal water loss (TEWL) after a 6-month follow-up. Vingan et al⁶⁷ employed microparticle fat aspiration injection for the treatment of AAS. Evaluation at 3 and 6 months revealed enhanced clinical outcomes based on clinician and patient Global Aesthetic Improvement Scale (GAIS) scores. Moreover, an elevated decay coefficient at the 6-month follow-up suggests remodeling and recombination of collagen during the study period.

Decellularized Matrix Fillers

Decellularized matrix is a novel regenerative material derived from the extracellular matrix (ECM). Obtained through a decellularization process, it maintains biologically active components and structure. A key advantage of decellularized matrix is the ability to preserve the natural three-dimensional architecture and bioactive factors of the ECM. This complex organic entity contains signaling molecules that play a crucial role in inducing and facilitating cellular adhesion, proliferation, differentiation, and tissue formation. Particles of decellularized matrix, typically 50–200 μm in diameter, are injected by minimally invasive techniques to address concave scars. The porous structure of these particles enables recruitment of host stem cells and fibroblasts, thereby promoting angiogenesis and tissue regeneration. Park et al⁶⁸ used microparticulated decellularized dermal matrix in conjunction with PRP injection to address AAS in a cohort of 16 patients. After 3 months, both study groups showed improvement in AAS. Notably, the combined treatment group exhibited significantly reduced ASAS scores and ECCA weight scores compared with the PRP control group. Table 1 summarizes the main results.

Table 1 Results of Included Studies

Discussion

Acne scarring remains a persistent challenge for plastic surgeons, particularly affecting adolescents physically and psychologically. Although various treatments have been developed, many are time-consuming, traumatic, and require multiple sessions for noticeable improvement. Conventional methods often fail to address deep or wide scars effectively. In contrast, filler treatments can provide prompt and substantial improvement in scar depression with a single injection. The minimally invasive nature of this approach is well received by patients, and the reversibility of most fillers allows adjustment through enzymatic degradation. For more profound scars, therapeutic benefit can be achieved with filling injections. Fillers are broadly categorized into two types: volume fillers, such as HA, injected directly into scars to enhance the skin, and biostimulatory fillers PLLA, PMMA, CaHA, and PCL, which increase volume immediately and stimulate natural collagen production.⁷³

In addition to the dermal fillers and autologous cell- and tissue-based regenerative therapies discussed above, autologous platelet concentrates (APCs) have emerged as a promising minimally invasive treatment option for AAS. Their key advantages include an autologous origin, easy accessibility, low immunogenicity, and multitarget regenerative properties.⁷⁴ The current international classification system divides APCs into four main types: pure platelet-rich plasma (P-PRP), leukocyte-rich platelet-rich plasma (L-PRP), pure platelet-rich fibrin (P-PRF), and leukocyte-rich platelet-rich fibrin (L-PRF).⁷⁵ A growing body of evidence suggests that APCs significantly promote wound healing and tissue regeneration, improve graft survival, and reduce the risk of adverse events Notably, they have shown favorable clinical outcomes in the management of skin defects. Therefore, APCs hold promise as a valuable therapeutic approach for the future treatment of refractory AAS.^76–78

In cases with significant dermal loss in deep scars, conventional treatments such as laser therapy and chemical peels may not effectively promote rapid collagen regeneration. Biostimulatory fillers present a more favorable option because they provide immediate filling effects and stimulate collagen regeneration for long-term therapeutic benefit.

Comprehensive Therapy

The management of acne scars frequently presents challenges when relying on a single therapeutic approach. A prevailing treatment paradigm integrates multiple modalities to enhance efficacy.⁷⁹ Koren et al⁷¹ conducted a comparative analysis of EBD alone, CaHA alone, and a combined approach, concluding that CaHA with EBD outperforms either treatment alone. Ebrahim et al⁶⁹ assessed subcutaneous isolation in conjunction with crosslinked HA or PLLA for scarring resulting from AAS. Following surgical intervention alone, 67.3% of patients demonstrated notable clinical enhancement, whereas combination therapy yielded significant clinical improvement in 94.1% and 82.4% of patients, respectively. Abdelwahab et al⁸⁰ compared subcutaneous separation combined with either dotmatrix CO2 laser or crosslinked HA against subcutaneous separation alone and reached a consistent conclusion. Gronovich et al⁷² demonstrated that combining autologous fat grafting with a 154-nanometer, non-stripping erbium laser dot matrix can safely and effectively treat AAS, improving scar appearance and texture.

Future research should explore combination approaches, such as integrating fillers with dot-matrix CO₂ laser therapy to enhance scar edge smoothness and using botulinum toxin to relax local muscle tension for the prevention and treatment of depressed scars.⁸¹

Adverse Reactions and Complications

Complications related to filler therapy are influenced by filler type, injection technique, and individual patient characteristics. These events range from mild injection-site reactions to more severe outcomes such as granulomas and allergic reactions.^82,83 Commonly reported complications include petechiae, edema, pain, and bleeding at the injection site; most patients recover quickly. Superficial placement can cause skin discoloration and the Tyndall effect.⁸⁴ Rare but serious complications, such as skin necrosis, vision loss, and paresthesia, are associated with the complex vascular and neural anatomy of the face.⁸⁵

HA demonstrates a favorable safety profile with transient and localized side effects,⁸⁶ which is reversibility and low immunogenicity. Most studies report mild adverse events, including pain, edema, and ecchymosis, rather than severe complications.^27,70 In contrast, other fillers such as CaHA and PLLA may result in small nodules or scars due to microsphere properties.⁸⁷ PMMA, which contains bovine collagen microspheres, is associated with a higher risk of pruritus, allergy, and granuloma formation.⁸⁸ PCL, evaluated by Lin et al⁸⁷ in a retrospective study of 1111 patients, showed minimal complications over 3 years, with few cases of edema, bruising, and lumps. Notably, there were no reports of intravascular injection, nodules, granulomas, or infection. Autologous fat grafting may cause pain during both harvesting and injection, as well as erythema, congestion, edema, and pigmentation at the donor site.⁸⁹

In addition to local injection site reactions, lymphadenopathy from dermal fillers are an underrecognized safety issue.⁹⁰ Lymphadenitis is among the most commonly reported events.⁹¹ Clinical observations indicate that facial filler injections frequently result in regional lymphadenopathy. Microparticles from both biodegradable and non-biodegradable fillers can migrate via lymphatics to cervical and facial nodes, inducing a foreign-body inflammatory response. However, due to the lack of routine lymphatic imaging or histological examination in follow-up, these complications remain unconfirmed by large-scale prospective studies. Another underrecognized complication is non-odontogenic abscess, which can be life-threatening depending on the extent of purulent involvement.⁹²

These abscesses typically occur in the head and neck region—areas that closely overlap with common dermal filler injection sites. Iatrogenic factors, including facial injections and implant procedures, are important triggers. Moreover, infections in this region can progress rapidly and carry high morbidity.⁹³ Therefore, timely diagnosis and intervention—including drainage and anti-infective therapy—are critical to improving clinical outcomes.

The Limitations

This review has several limitations that should be considered when interpreting its findings and clinical recommendations. First, as a narrative review, it did not involve original clinical trials or experimental research. Consequently, it cannot offer causal conclusions derived from primary data and instead aims to synthesize and analyze published clinical evidence on injectable fillers for atrophic acne scars. Second, the literature search was restricted to a 10-year period, which may have excluded seminal early studies and long-term follow-up data, thereby providing an incomplete perspective on the field’s development. Third, only 24 references were included, a limited number that may not fully capture the breadth of relevant clinical evidence, technical advances, or real-world practice data. Fourth, the review included only English-language publications, potentially overlooking high-quality studies, technical reports, and clinical insights reported in other languages—introducing a degree of language selection bias.

In addition, heterogeneity among the included studies limits the generalizability of the findings. Variability in sample sizes, endpoint definitions, and imaging modalities contributed to this issue. There may also be a risk of publication bias, as studies with favorable outcomes are more likely to be published.

To strengthen the evidence base, future research should adopt standardized core outcome measures. These should include validated clinician-reported tools, such as the Quantitative Global Scarring Grading System (QGSGS) and the Global Aesthetic Improvement Scale (GAIS), alongside patient-reported outcome measures (e g PROMIS). Implementing consistent imaging protocols and predefined follow-up durations will also be essential to enhance cross-study comparability.

Conclusion and Future Perspective

The use of fillers for treating AAS offers immediate therapeutic benefit with minimal invasiveness and shows promising potential. Nonetheless, single-filler therapy encounters obstacles, including the need for repeated injections and limited efficacy for deep scars. Furthermore, concurrent use of different filler types may enhance both immediate filling and long-term regenerative effects, thereby extending therapeutic duration. These combined approaches are expected to address limitations of conventional treatments, such as high recurrence rates and prolonged recovery. However, refinement of injection methodologies and dosage ratios is essential to establish uniform clinical application.