Adipose-Derived Stem Cell Products and Combination Therapies for the Treatment of Pathological Scars: A Review of Current Preclinical and Clinical Studies

Introduction

Pathological Scar

Scar formation restores tissue integrity after injury and is influenced by factors such as age, gender, wound location, and tension.^1–3 It is a complex process that is strictly controlled by biological mechanisms that require the cooperation of numerous cell types, growth factors, cytokines, and extracellular matrix (ECM).¹ Scars can be classified as normal or pathological. Normal scars undergo a structured healing process, while pathological scars—such as hypertrophic, keloid, and atrophic scars—result from dysregulated wound healing. A normal scar consists of loose, fibrous connective tissue that progressively strengthens and becomes more rigid throughout the healing process. This process involves four key stages: hematoma formation, inflammation, proliferation, and remodeling.⁴ On the other hand, abnormal scars can be classified into hypertrophic scars (HS), keloid scars (KS), and atrophic scars (AS).^3,5,6 Pathological scars result from imbalances in ECM remodeling, inflammatory response, and fibroblast regulation, leading to excessive or insufficient collagen deposition.^3,7

Fibroproliferative scars include hypertrophic and keloid scars.⁶ Hypertrophic scars form within wound margins, expanding for 4–8 weeks before stabilizing. Excessive ECM deposition by fibroblasts prolongs inflammation and fibrosis, leading to red, stiff, elevated, itchy, and painful scars.^4,8–10 In contrast, keloid scars may develop months to years after injury, expanding beyond wound margins due to excessive ECM deposition. Collagen production in keloids is up to 20 times higher than in normal skin with fibronectin (FN) biosynthesis and is four times greater than normal scars.¹¹ Unlike hypertrophic scars, keloids are influenced by genetic factors and have high recurrence rates, often causing skin contraction and functional impairment.^6,8 Clinically, keloids present as raised, hard-textured lumps or bands on the skin’s surface.¹² In fibro-proliferative scars, another contributing mechanism is the involvement of myofibroblasts, which express alpha-smooth muscle actin (α-SMA). These cells play a critical role in excessive collagen accumulation, resulting in an ECM imbalance.^4,7

Occasionally, a scar may become depressed or thinned as it matures into an atrophic scar. This occurs when collagen synthesis diminishes and inflammation falls below normal.⁶ Another source reports that prolonged inflammation significantly reduces both elastic and collagen fibers, and the decrease in epidermal proliferation is closely linked to the development of atrophic scars.¹³ Atrophic scars are among the most challenging and persistent conditions to treat.⁶ These factors make atrophic scars a particularly difficult target for effective therapeutic intervention.

Pathological scars can lead to irritation, restricted mobility, functional and aesthetic alterations, and significant psychological distress.^3,6 Consequently, the search for the most effective therapy for these scars continues. Researchers have established various experimental models to advance therapeutic development, including in-vitro, ex-vivo, and in-vivo systems using both animal and human skin.^14,15 The most commonly utilized in-vitro models are human fibroblast cell (HFC) and keloid fibroblast cell (KFC) cultures, which are derived from human tissue biopsies.^15,16 Additional in vitro methods involve inducing myofibroblast differentiation with TGF-β1 and developing tissue-engineered human hypertrophic scar models.^7,10,17 Ex-vivo techniques utilize explant models to investigate scar formation in tissue samples.¹⁸ In-vivo research often employs rodent and rabbit ear models, where full-thickness wounds are created down to the cartilage, and samples are examined four weeks after wounding to assess scar development.^19,20 Additionally, human hypertrophic or keloid skin grafts are frequently used in animal models, typically involving nude mice.^14,21

For atrophic scars, there is currently no ideal preclinical model. However, extensive clinical research has been conducted on therapies for atrophic skin. Human skin biopsies from atrophic scars can be used to elucidate the underlying molecular mechanisms.¹³ Although numerous therapeutic techniques for pathological scars exist, it is widely recognized that current treatments still need to be improved.¹⁰ Conventional therapies, such as corticosteroids, have high recurrence rates and side effects.^22,23 Current treatments improve atrophic scars but do not completely eliminate them, highlighting the need for alternative approaches like mesenchymal stem cell (MSC) therapy.⁶

Adipose-Derived Stem Cell Products

MSC has emerged as a popular therapeutic option for scars.²⁴ MSC can be harvested from various tissues, including bone marrow, adipose tissue, and umbilical cord.^25,26 Compared to bone marrow-derived MSC, adipose-derived stem cells (ADSC) are more accessible to harvest and yield a richer supply of stem cells.²²

Various therapies containing ADSC and their derivatives (hereafter referred to as ADSC products) are commonly used in regenerative medicine, particularly for treating pathological scars.^22,27 Previous studies have shown that they are beneficial and safe in monotherapy or combined with other treatment methods.²⁴ Generally, these therapies can be categorized into cell-based and cell-free therapies.²⁸ Cell-based therapy includes stromal vascular fraction (SVF) and ADSCs, while cell-free therapy encompasses adipose tissue extract (ATE), secretomes, exosomes (ADSC-Exo), and extracellular vesicles (ADSC-EV) (Figure 1).^27,29 These products can be extracted from human adipose tissue through liposuction, followed by a series of procedures to produce either cell-based or cell-free therapies.²²

Figure 1 ADSC products.

Stromal vascular fractions can be harvested from human adipose tissue obtained via liposuction from various regions such as the abdomen, thighs, and buttocks.³⁰ SVF contains a heterogeneous cell population, including MSC, pericytes, other progenitor cells, and nucleated cells. These cells exhibit multi-lineage differentiation potential and are considered a rich source of adult stem cells.²² SVF can be characterized by the expression of MSC surface markers (CD44, CD90, CD73) and precursor cell markers (CD146, CD31, CD34).³¹ There are several types of SVF commonly used in therapy, including SVF-gel and SVF-cells.³² To generate SVF-gel, lipoaspirates are mechanically processed to remove lipids and fluids, leaving only SVF cells and fractionated extracellular matrix (ECM). The process involves emulsification and centrifugation of the lipoaspirate, yielding three layers: oil (top), SVF-gel (middle), and blood (bottom), with the middle layer isolated to obtain SVF.^20,23 This product is enriched in adipose-derived stem cells (ASCs), vascular endothelial cells (ECs), and native adipose ECM.³² SVF cells are further isolated through collagenase digestion, and the cell pellet is filtered using a 100 μm mesh to obtain the final product.³²

Adipose derived stem cells can be isolated through lipoaspirate samples and SVF culture.³⁰ ADSCs exhibit a fibroblast-like morphology and have the capability for trilineage differentiation into adipogenic, osteogenic, and chondrogenic lineages.^11,32 They express mesenchymal cell surface markers including CD29, CD44, CD73, CD90, and CD105.^18,33

Adipose tissue extracts can be obtained through physical methods by isolating the middle-fat layer after centrifugation, followed by mechanical emulsification. Subsequent repeated centrifugation separates the fat into four layers. The liquid from the third layer, ATE, is then collected. ATE has a high concentration of cytokines and extracellular vesicles.^19,27

Secretomes are products that are secreted by ADSCs within the conditioned medium (ADSC-CM) that regulate various biological processes.²⁶ Secretomes contain numerous molecules responsible for cell signaling, including cytokines, growth factors, chemokines, EV, and other active substances.² According to a study by Zhang et al, ADSC-derived secretomes secreted 12,221 peptides and 2349 proteins. Some molecules were involved in tissue repair, such as heat shock protein 90 kDa α (HSP90 α) for wound closure, tubulin alpha chain (TAC) for apoptosis of hypertrophic scar fibroblasts, and elongation factor 1-α 1 (EF-1α) for scarless healing.³⁴ Research has demonstrated that mature adipocytes may transform to a more primitive phenotype and recover proliferative capacity using in vitro dedifferentiation procedures, known as dedifferentiated adipocytes (DAs).³⁵ Secretomes derived from differentiated adipocytes (DA-CM) have also been reported as potential therapeutic agents.⁷ Differentiated adipocytes can be characterized by Oil Red O staining.⁷ According to a study by Hoerst et al, differentiated adipocytes secreted 288 proteins. Some were involved in wound healing and regeneration.⁷

Extracellular vesicles (EVs) are particles found within secretomes and are isolated from conditioned media through ultracentrifugation.³⁶ EVs are characterized by their circular shape, bilayer membrane structure, and a size range of 50–200 nm.^36,37 EVs express markers such as CD9, CD63, TSG101, and Alix while showing minimal expression of VEGFA, PDGFB, and TGFβ1.^36,37 Small extracellular vesicles exocytosed into the extracellular space are called exosomes.²⁶ Exosomes are molecules that participate in cell-to-cell communication, presenting genetic material such as mRNAs, miRNAs, proteins, and lipids.³⁸ Exosomes are characterized by their cup-shaped structure, with a size of 30–150 nm in diameter.^27,39,40 They also express markers like CD9, CD63, CD81, and TSG101.^38–40 Additionally, miRNAs, which serve as critical mediators in intercellular communication, have been detected in exosomes, including miR-21, miR-23a, miR-125b, miR-29a, miR-145, miR-125b-5p, miR-10a-5p, miR-23a-3p, miR-21-5p, and miR-92a-3p.^40,41

ADSC products offer advantages over conventional treatments for pathological scars.²³ Therefore, we explore the potential use of ADSC products in the treatment of pathological scars, summarizing current research trends, mechanisms, and clinical applications. We aim to bridge the gap between preclinical and clinical studies and evaluate ADSC products as monotherapies or combination therapies to identify optimal therapeutic strategies for managing pathological scars.

Methods

A comprehensive literature search was conducted, guided by the PICO framework: population (cellular, animal, and clinical models of hypertrophic, keloid, and atrophic scars); intervention (ADSC products and derivatives, either as single or combination therapies); comparison (control groups/standard treatment (corticosteroid/other treatments); and outcome (effects related to scar modifications). The literature sources utilized were electronic databases, namely PubMed and Scopus. The search keywords are provided in supplementary file 1. The selected articles were original research articles (preclinical and clinical trials) published in English or Indonesian until July 19, 2024. We excluded the following types of articles: (1) Reviews, study protocols, conference papers, letters, and case reports; (2) Stem cell therapies derived from non-adipose tissue sources; (3) Studies focused on typical wound healing phases, acute wounds, infected wounds, diabetic wounds, or acute burn injuries. Specifically, we excluded articles published before January 20, 2023, for clinical trials on hypertrophic and keloid scars. The search results were screened by two independent reviewers (NMA and YC) using the Rayyan application. The selection process of the articles is detailed in the PRISMA flow diagram (Figure 2).

Figure 2 Prisma flow diagram. Notes: PRISMA figure adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. Published online March 29, 2021:n71.42

Results

A total of 737 studies were identified from the electronic databases. Among these, 176 duplicates were removed, and 170 studies were excluded after the initial screening. A total of 479 articles were screened using Rayyan, resulting in 43 studies that met the inclusion criteria (Figure 2). Our systematic search identified current research trends focusing on adipose-derived products, including ADSC, adipose subcutaneous tissue (ADT), ATE, SVF, DA-CM, ADSC-CM, and exosomes or extracellular vesicles derived from ADSC (ADSC-exo/EVs). With advancements in technology, various methods were being investigated to enhance the effectiveness of these therapies, such as modifying stem cells with TGFβ3, IL10, miRNAs, and electrospun membranes.

In the included preclinical studies, six studies used ADSC products derived from animals, and 28 studies used ADSC products derived from humans as interventions on keloid or hypertrophic cell or tissue models (Table 1 and Table 2). No studies using atrophic scar models were identified in the preclinical trials. We also included six clinical trials consisting of 43 subjects with hypertrophic scars, eight subjects with keloid scars, and 73 subjects with atrophic scars (Table 3).

Table 1 In-vitro/ex-vivo Results

Table 2 In vivo Results

Table 3 Clinical Results

To identify the best therapy for pathological scars, we explored the potential of ADSC products and derivatives in combination with other treatments. We found seven articles investigating combination therapies involving fractional CO₂ laser, platelet-rich plasma (PRP), botulinum toxin (BTA), or photo-modulation therapy. Among these, four preclinical studies used keloid and hypertrophic scar models with fractional CO₂ laser, BTA, or photo-modulation therapy combinations. At the clinical level, four studies involving 32 patients with atrophic scars used a combination of fractional CO₂ laser and PRP. However, no combination therapies for keloid or hypertrophic scars were identified in the clinical studies (Table 4).

Table 4 Combination Therapy

Discussion

Different types of ADSC are likely to influence their effectiveness. For instance, research by Domergue et al compared the effects of SVF versus ADSC, finding that ADSC yielded superior results overall.⁵⁶ Zhang et al compared ADSC with ADSC-CM, further confirming the efficacy of ADSC and finding that ADSC continued to provide superior outcomes.⁵⁷ Other research comparing SVF-gel and SVF-cells demonstrated that SVF-gel yielded superior results overall.³² Additionally, higher therapy concentrations in ADSC-CM and ADSC-exo may lead to better results, as indicated by several previous studies.^34,49,53 However, comparative studies on the effectiveness of ADSC products based on type or concentration are still limited and require further exploration.

ADSC Products for Hypertrophic and Keloid Scar

The therapeutic potential of ADSC products in treating hypertrophic and keloid scars arises from their ability to modulate molecular pathways. ADSC products exhibited distinct effects on normal and hypertrophic/ keloid fibroblasts. ADSC products reduced migration, proliferation, and collagen expression in hypertrophic/ keloid fibroblasts, whereas these parameters were increased in normal fibroblasts.⁴⁷ This review outlined the mechanisms of ADSC products in keloid and hypertrophic scars, focusing on ECM remodeling, cell density regulation, adipogenesis, angiogenesis, antioxidant regulation, mechanical properties, and anti-inflammatory effects. Furthermore, ADSC products improve scar structure and function, promoting tissue regeneration. At the clinical level, these effects translated to improvements in itch symptoms and scar texture, including size, color, texture, and thickness of the scar. No serious adverse effects were reported^22,31 (Figure 3)

Figure 3 Molecular to clinical changes of hypertrophic or keloid scar with ADSC products intervention. Notes: ↑ indicates an upregulation of molecular expression or an increase in clinical parameters, while ↓ indicates a downregulation of molecular expression or a decrease in clinical parameters.

ECM Remodeling

ECM significantly influenced the development and persistence of hypertrophic and keloid scars. The balance of ECM components was maintained by normal fibroblasts, which regulated collagen synthesis and degradation. However, this balance was disrupted in hypertrophic and keloid scars, leading to fibrosis and excessive collagen deposition.^11,43,52

ADSC products were shown to modulate fibroblast differentiation into myofibroblasts, thereby reducing fibrosis.^7,44 The studies we reviewed, we identified several molecules targeted by ADSC products, including the inhibition of pro-fibrotic signaling pathways such as P38/MAPK, TGFβ1/SMAD3, SMAD7, pAKT/ERK1/2, and NOTCH1/JAG1.^{7,16,18,33,46,49,53} This modulation led to downregulating fibrotic markers like α-SMA, αSM22, CTGF, CXCL1, CCL2, and LIF.^16,43,47,48 Additionally, ADSC enhanced anti-fibrotic pathways, including BMP4/SMAD1,5,9 and PPARγ, which counterbalanced the pro-fibrotic signals.⁷

ADSC products also influenced ECM remodeling by reducing collagen deposition and enhancing collagen degradation. They reduced collagen synthesis by downregulating COL genes (particularly COL1, COL3, COL11, COL12) or interfering with procollagen genes (especially procollagens I and III) responsible for COL formation.^7,16,48 Furthermore, ADSC products modulated enzymes that degrade COLs by upregulating metalloproteinases (MMPs) such as MMP-1, MMP-2, MMP-3, MMP-8, and MMP-12, while downregulating TIMPs, the inhibitors of MMPs.^44,48,56 Moreover, P-4-HB expression was downregulated by ADSC products, a protein that stabilizes the collagen triple helix structure.⁴⁷ ADSC products decrease collagen accumulation by reducing the activity of fibronectin (FN) and PAI-1 while increasing Decorin (DCN), a small leucine-rich proteoglycan that promotes collagen degradation and inhibits excessive collagen formation.^51,52,54 The presence of DCN in fibroblasts further reduced α-SMA activity, contributing to its anti-fibrotic effect.^51,54

Consequently, the molecular-level ECM remodeling induced by ADSC products led to improved scar phenotypes at the tissue level. Previous studies demonstrated that ADSC products decreased collagen density and deposition while improving collagen structure, resulting in more organized collagen fibers within the tissue.^12,20,34 This process contributed to a reduction in dermal thickness.^19,32

Cell Density Regulation

KFC and HFC play a central role in forming fibro-proliferative scars characterized by excessive proliferation and apoptosis resistance.^12,21,37,44 This abnormal cellular behavior is driven by pathways such as the Hedgehog signaling pathway involving NRP2, which regulates SHH, SMO, and GLI1, and is marked by the overexpression of Ki67, a proliferation marker.^12,45

ADSC products mitigated this abnormal proliferation by leading to cell cycle arrest in the G0/G1 phase and reducing progression through the S and G2/M phases, thereby decreasing cell growth.^38,52 Additionally, ADSC products enhanced apoptosis by triggering the BAX/BCL2/Caspase3 pathway.¹² Through inhibition of the JAK2/STAT3 pathway by SOCS1, ADSC products also suppressed autophagy, collagen deposition, cell migration, and cell proliferation.³⁷ By regulating these pathways, ADSCs effectively reduce the density of KFCs and HFCs, therefore reducing collagen density at the tissue level and contributing to decreased dermis thickness.^34,56

Adipogenesis

Restoring the subcutaneous adipose layer is essential to alleviate fibro-proliferative scars. The presence of adipocytes within the scar contributes to these improvements due to their crucial roles in regulating metabolism and immunity and promoting wound repair.^19,32 ADSCs stimulated adipogenesis, as evidenced by the upregulation of subcutaneous regeneration marker perilipin, along with adipoblast differentiation markers such as C/EBPα and PPARγ.^19,32 Following the restoration of the subcutaneous adipose layer and alterations to dermal ECM components, the overall scar texture was enhanced.

Angiogenesis

Fibro-proliferative scars were frequently characterized by abnormal angiogenesis, contributing to their persistence and severity. ADSC products inhibited endothelial cell angiogenesis to suppress scar development.⁴⁵ ADSCs were shown to downregulate key angiogenic markers, including vascular endothelial growth factor (VEGF), which played a central role in promoting angiogenesis and markers such as CD34 and CD31.^11,18,56 This reduction in angiogenesis helped decrease excessive blood vessel formation within the scar tissue, contributing to the normalization of the scar tissue and supporting overall tissue regeneration.

Antioxidant Regulation

Elevated reactive oxygen species (ROS) levels were detected in HFCs and KFCs.¹² ADSC facilitated regeneration by inhibiting antioxidant defense mechanisms within the scar tissue through the downregulation of NRF2, a crucial protein in antioxidant signaling¹² This suppression resulted in reduced activity of antioxidant enzymes, including superoxide dismutase (SOD), NAD(P)H: quinone oxidoreductase 1 (NQO1), and heme oxygenase 1 (HO-1). Consequently, the accumulation of ROS increased, leading to enhanced cell apoptosis within the fibro-proliferative scar.¹²

Mechanical Properties Modulation

The mechanical properties of scar tissue, including cell migration and contraction, are crucial to the formation and persistence of hypertrophic and keloid scars. ADSC products have been shown to reduce the migration rate of KFCs and HFCs.³⁷ In contrast, they enhanced cell migration in normal fibroblasts, which is essential for wound healing.⁴⁷ These differential effects on cell migration were likely influenced by the PI3K/AKT, MAPK, and SOCS1/JAK2/STAT3 pathways.^12,37

Previous studies also indicated that myofibroblasts exhibited high contractile activity, contributing to scar contracture.⁴³ Wound contraction occurs after skin damage, marked by skin tightness.⁴⁸ ADSCs inhibited this contractile activity, which was associated with reduced scar contracture at the tissue level.^43,48,52 These phenomena were likely due to the changes in cell morphology observed with ADSC therapy, where cells exhibited a more regular shape and narrower intracellular spaces, in contrast to the wider morphology seen in cells without ADSC treatment.⁵⁵

Anti-Inflammatory Effects

Inflammation influenced scar formation, particularly in the development of hypertrophic scars associated with excessive wound repair. This process resulted from a combination of local inflammation and abnormal cytokine secretion.^46,48 IL-10, a multifunctional cytokine known for regulating cell growth and differentiation, played a pivotal role in inflammatory and immune responses and was recognized as an inflammation and immunosuppressive factor.^44,46 In studies where ADSC was modified with IL-10, it was demonstrated that ADSC significantly reduced the expression of macrophage inflammatory protein (MIP), MIP-1β, IL-1β, and IL-6, all of which are critical mediators of inflammation.^46,48

Additionally, ADSC-treated cells exhibited a decrease in other immune markers, including CD45 and C31, a marker for white blood cells, CD3 for T lymphocytes, CXCL1 for neutrophils, MCP-1 (CCL2) for monocytes, and CD68 and CD206 for macrophages, indicating reduced immune cell infiltration at the site of inflammation.^32,44,54

ADSC also suppressed the NFκB inflammatory pathway by regulating the levels of p-IκBα/IκBα and p-p65/p65, critical indicators of NFκB activity, which led to decreased levels of pro-inflammatory cytokines, such as IL-1β and IL-6.⁴⁶ Furthermore, ADSC was shown to modulate arachidonic acid (AA) and prostaglandin E2 (PGE2), both of which are essential mediators in the inflammatory process.²¹ This modulation contributed to the overall anti-inflammatory effects of ADSC in the hypertrophic and keloid scar, thus promoting tissue regeneration.

ADSC Products for Atrophic Scar

Our systematic search has identified several clinical-level studies on atrophic scars. We identified that current studies research atrophic scars at the clinical level using SVF and microfat therapies. The results of SVF treatments involving 30 patients include improvements in scar severity index, scar area percentage, scar depression, and texture. Increases in epidermis thickness and collagen density were also noted.⁵⁸ Biophysical and histological examinations further revealed improved epidermal thickness, enhanced collagen density, a better dermal-epidermal junction, and indications of collagen remodeling.^58,60 Skin hydration also improved and patients reported good satisfaction with the treatment.^30,60 In studies involving microfat with 43 patients, the treatment was associated with good satisfaction outcomes.⁵⁹ Overall, ADSC products at the clinical level did not show adverse effects or exhibited only expected minimal side effects such as minor pain, brief edema, and erythema.

The exact mechanisms by which ADSC affected atrophic scars are not fully understood. However, existing studies emphasized the significant role of TGF-β1 signaling and inflammation in the development of atrophic scars.¹³ Atrophic scars occur due to severe collagen and elastic fiber degradation in the dermis, followed by incomplete healing. This mechanism was related to a marked decrease in epidermal proliferation and elevated inflammation, fueled by T-helper cells and innate immunity.¹³ The marked elevation of TGF-β1 further implicated it in these pathological processes. By regulating ECM, TGF-β1 signaling, and inflammation differently from normal fibroblasts, ADSC products have been demonstrated to alleviate scarring in hypertrophic and keloid scar models.¹³ ADSC products also prevent collagen degradation by reducing MMP expression, which results in increased collagen density.⁵⁸ This suggested that ADSC may, presumably in the opposite effect, similarly regulate these variables in atrophic scars. Further research was crucial to explore and confirm these mechanisms (Figure 4).

Figure 4 Molecular to clinical changes of atrophic scar with ADSC products intervention. Notes: ↑ indicates an upregulation of molecular expression or an increase in clinical parameters, while ↓ indicates a downregulation of molecular expression or a decrease in clinical parameters.

Combination and Comparison to Other Treatments

Research has increasingly focused on combination therapies involving ADSC products and other therapeutic modalities to improve clinical efficacy. Combinations with fractional CO₂ laser or botulinum toxin A have been explored for hypertrophic scars. Cai et al reported that combining ATE injections with fractional CO₂ laser significantly outperformed the individual therapies in a rabbit ear model. However, ATE alone was more effective than laser therapy, and the combination therapy did not show a significant difference in adipogenesis expression compared to ATE alone, indicating that ATE monotherapy could be sufficiently effective in treating hypertrophic scars.¹⁹ In contrast, a study by Xiao et al demonstrated that SVF-gel combined with fractional CO₂ laser yielded superior results in animal and human studies, improving scar texture, quantitative assessment, and reducing itch symptoms. This combination therapy was also found to be more effective than the standard treatment of triamcinolone acetate injection with laser therapy. However, in terms of adipogenesis, SVF gel monotherapy outperformed laser monotherapy.²³ Additionally, Qian et al found that combining SVF-gel injection with Botulinum Toxin A produced better outcomes than SVF monotherapy, even though the difference between combination therapy and SVF monotherapy was insignificant. Nevertheless, it was discovered that botulinum toxin A monotherapy produced the best results.²⁰ These findings suggest that Botulinum Toxin A as a therapy for hypertrophic scars warrants further clinical exploration to understand its potential fully. Moreover, another combination therapy using photo-modulation therapy and ADSC-CM has shown promising results. This combination was safe and yielded superior outcomes in keloid and hypertrophic scar models compared to monotherapy.¹⁶ However, this study was conducted in vitro, indicating that further exploration and validation in clinical settings are necessary to confirm its effectiveness. Based on these findings, combination therapies for hypertrophic scars can lead to varying outcomes, highlighting the need for further exploration, particularly at the clinical level.

Combination therapies involving ADSC products have been investigated at the clinical level for atrophic scars, particularly with fractional CO₂ laser and PRP combined with autologous fat grafting. Roohaninasab et al observed that combining SVF injections with fractional CO₂ laser in post-burn atrophic scars significantly improved skin density, epidermal thickness, and overall patient satisfaction.⁶¹ These findings were further supported by Zhou et al highlighting that ADSC-CM after fractional CO₂ laser treatment in patients with atrophic scars improved scar severity and skin elasticity and increased collagen density, all with minimal adverse effects.⁶³ Additionally, Nilforoushzadeh et al extended these findings by demonstrating that the combination of SVF injection with PRP and autologous fat grafting enhanced skin quality, including improvements in elasticity and melanin content, along with high levels of patient satisfaction.⁶² Overall, these results suggest that combination therapies for atrophic scars show promising outcomes. Nevertheless, other results by Eitta et al showed that ADSC monotherapy was as effective as three sessions of fractional CO₂ laser treatment based on improvements in scar severity, decreases in scar area percentage, enhanced skin hydration, and overall treatment satisfaction.³⁰ In addition, the findings by Elkakhy et al revealed that PRP monotherapy was superior to SVF monotherapy⁶⁰ (Table 4).

Modified ADSC

Technological advancements also enable the enhancement of ADSC therapies through various modifications. Current research includes preclinical models investigating ADSC products enriched with TGFβ3, IL10, and miRNAs or loaded into electrospun membranes for treating hypertrophic or keloid scars. The combination of ADSC-enriched-TGFβ3 & IL10 demonstrated superior outcomes by further reducing cell proliferation, enhancing cell migration, reducing cell viability and increasing apoptosis, reducing cellularity and vascularity, and anti-fibrotic effects by increasing the expression of MMP-1, MMP-8, and MMP-12, while decreasing both COL3A1 and COL1A1 expressions.⁴⁴ Meanwhile, ADSC-enriched-TGFβ3 significantly reduced cell proliferation and viability, enhanced cell migration, diminished cellularity and vascularity, and anti-fibrotic effects by increasing the expression of MMP-1 and MMP-12 expression while decreasing COL3A1 expression.⁴⁴ Conversely, ADSC-enriched-IL10 also reduced cell proliferation and viability; and diminished cellularity and vascularity; but was more effective in inducing apoptosis and an anti-fibrotic effect by elevating MMP-1 while reducing α-SMA expression.⁴⁴ Further studies have demonstrated that ADSC-enriched-IL10 can reduce proliferation and migration, exhibit anti-inflammatory effects via NF-κB pathway suppression, and display anti-fibrotic properties through the TGF-β/Smads pathway.⁴⁶

ADSC-exo enriched with specific miRNAs show promising results. For example, ADSC-exo-miR-125b-5p exhibits anti-fibrotic activity via the miR-125b-5p/SMAD2 pathway, reducing cell migration and proliferation.⁴¹ ADSC-exo-miRNA7846-3p decreases cell viability, proliferation, and apoptosis resistance, suppresses angiogenesis, and inhibits the Hedgehog pathway.⁴⁵ ADSC-exo-miR-192-5p and ADSC-exo-miR29a also reduce migration, proliferation, and viability and show anti-fibrotic effects.^38,40 Moreover, ADSC-conditioned media (ADSC-CM) loaded in electrospun membranes has decreased cell proliferation, migration, and fibrosis.⁵⁰

Research on these approaches in hypertrophic and keloid scar models remains limited, particularly at the clinical level, and to our knowledge, trials have yet to be conducted on atrophic scars. Further exploration of these strategies is necessary to understand their potential and efficacy fully.

Challenges and Limitations

This review discusses the effects of ADSC products on pathological scars in general without specifying the impact based on the type of therapy. It is recognized that the type and concentration of ADSC products may influence their effectiveness; however, the lack of detailed information on these factors highlights the need for further studies. We have yet to identify any preclinical research on atrophic scars, possibly due to the challenges in creating representative preclinical models. Additionally, further exploration of combination therapies or modifications of ADSC products at the clinical level is needed, as treating pathological scars remains challenging and requires significant advancements.

Conclusion

ADSC products can improve hypertrophic and keloid scar texture and severity by remodeling the ECM, regulating cell density, promoting adipogenesis and angiogenesis, modulating mechanical properties, regulating antioxidants, and exerting anti-inflammatory effects. ADSC products have also shown potential in improving atrophic scar texture and severity, as demonstrated by increased scar depth; however, the underlying mechanisms require further exploration. While modifications or combinations of ADSC products may enhance their effectiveness, further exploration at the clinical level is necessary.