From Fat to Healing: How Adipose‐Derived Stem Cells Are Changing the Game for Diabetic Foot Ulcers—A Perspective

ABSTRACT

Background and Aim

Diabetic foot ulcers (DFUs) pose a significant challenge in the management of chronic wounds, characterized by a high risk of infection and severe complications, including potential limb amputation. The limitations of conventional treatments have sparked interest in regenerative therapies, particularly the use of adipose‐derived stem cells (ADSCs). which possess significant potential across various medical fields for enhancing tissue repair and modulating immune responses. This perspective critically evaluates the potential of ADSCs for treating DFUs while exploring their broader implications in regenerative medicine.

Methods

This perspective incorporates insights from a comprehensive literature review, with searches conducted on platforms such as Google Scholar, PubMed, and Scopus. The selected studies focus on the regenerative efficacy, safety, and clinical applications of ADSCs in wound healing, emphasizing rigorous methodologies that support reliable conclusions.

Results

ADSCs exhibit significant promise in promoting tissue regeneration, stimulating angiogenesis, and modulating immune function—mechanisms that are beneficial not only for patients with DFUs but also for those with other chronic and non‐healing wounds. Nevertheless, challenges persist, including the risk of tumorigenesis, particularly in patients with a history of cancer, as well as variability in therapeutic outcomes due to donor characteristics and processing techniques.

Conclusion

While ADSCs represent a promising therapeutic option for DFUs and provide valuable insights for a wider array of chronic wound therapies, their clinical application requires careful consideration of safety concerns, including risks of tumor formation and immune response issues. Future advancements in cell processing and well‐structured clinical trials will be essential to ensuring efficacy across diverse populations in the broader context of regenerative medicine.

1. Introduction

Diabetic foot ulcers (DFUs) represent a significant challenge in chronic wound care, often resulting in severe complications, including infection, tissue necrosis, and in extreme cases, amputation [1]. Current treatment approaches, including wound debridement and antibiotic therapy, frequently fail to provide lasting healing, highlighting the urgent need for more effective therapeutic solutions [2]. In this context, adipose‐derived stem cells (ADSCs) have emerged as a potential game changer for DFUs due to their unique regenerative properties, which include promoting tissue repair, stimulating angiogenesis, and modulating immune responses [3]. Recent studies underscore their potential in significantly accelerating wound healing and reducing scar formation, attributes that could revolutionize DFU management [4]. ADSCs, which can be quickly isolated from adipose tissue, offer practical benefits such as ease of collection, scalable manufacturing potential, and a reduced risk of immune rejection in autologous applications [5]. These practical advantages of ADSCs make them an attractive and promising option for treating DFUs. Furthermore, ADSCs exhibit immunomodulatory and anti‐inflammatory properties that may foster a supportive environment for tissue regeneration in chronic wounds [6].

Despite the promising potential of ADSCs, for treating DFUs, several critical challenges persist. One major concern is the risk of tumorigenesis, particularly in patients with a history of cancer, which raises significant safety concerns [7, 8]. Additionally, variability in therapeutic outcomes, often linked to differences in donor characteristics such as age, obesity, and comorbidities, as well as variations in ADSC processing techniques, complicates their widespread clinical application [7, 8]. While existing reviews have explored the general potential of ADSCs in wound healing, they often overlook a focused analysis of their specific application to DFUs. This perspective addresses the complex balance between efficacy and safety, particularly for DFUS patients with underlying health conditions. This represents a significant research gap, as current reviews often do not adequately confront DFU‐specific challenges, particularly the balance of efficacy and safety for patients with complex conditions.

To strengthen the case for ADSCs, it is essential to highlight the limitations of conventional stem cell therapies. For example, while bone marrow‐derived mesenchymal stem cells (MSCs) show promise, they face challenges such as invasive harvesting procedures, lower cell yields, and prolonged processing times, making them less practical compared to ADSCs [9]. These limitations emphasize why ADSCs are a more feasible and scalable option, particularly for treating DFUs [10]. Moreover, ADSCs can be processed more quickly and have a minimal risk of immune rejection, especially when derived from autologous sources, which enhances their clinical applicability [5, 10].

Recent advancements in gene editing and biomaterial scaffolds offer promising strategies to improve the functional efficacy of ADSCs, reduce variability in patients' responses, and enhance the safety profile of ADSC‐based therapies. When combined with these innovations, ADSC therapy has the potential to significantly optimize the therapeutic outcomes in chronic wound healing [11].

2. Methods

This perspective is based on a literature review examining the efficacy of adipose‐derived stem cells (ADSCs) in treating diabetic foot ulcers (DFUs). No ethical approval or informed consent was required, as this study involves no human subjects or primary data collection.

2.1. Literature Review

A comprehensive search was conducted across Google Scholar, PubMed, and Scopus to identify relevant peer‐reviewed articles on ADSC therapy for diabetic ulcers. The review specifically and rigorously focused on studies evaluating ADSCs' clinical outcomes, safety, and efficacy in managing DFUs.

Inclusion criteria were established to ensure the relevance and quality of the studies reviewed, while studies that did not explicitly investigate ADSCs in the context of DFUs were excluded. This focused analysis underscores the promising potential of ADSCs in addressing the challenges associated with DFUs.

3. Therapeutic Potential of ADSCS in Diabetic Ulcer Healing

ADSCs, a specialized group of mesenchymal stem cells (MSCs), have emerged as a promising tool in regenerative medicine, particularly for diabetic ulcers, which are often characterized by impaired healing due to poor circulation and tissue necrosis [6]. These cells possess the unique ability to differentiate into various cell types, including endothelial cells, thus facilitating critical tissue repair processes [6].

3.1. Role in Angiogenesis and Immune Modulation

ADSCs stimulate new blood vessel formation, reduce inflammation, and encourage granulation tissue formation, which collectively support wound healing [7, 8]. Though the release of essential growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor‐beta (TGF‐β), and fibroblast growth factor (FGF), ADSCs play a crucial role in promoting angiogenesis and restoring blood flow to ischemic tissues, addressing primary challenges in DFUs [9]. Furthermore, ADSCs possess immunomodulatory properties, which help to create a regenerative microenvironment conducive to wound closure and tissue repair [10].

3.2. Contribution to Extracellular Matrix Remodeling and Collagen Deposition

ADSCs have been shown to promote extracellular matrix (ECM) remodeling, especially by modulating fibroblast activity and enhancing collagen deposition. ADSCs influence the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which regulate ECM turnover. By promoting the secretion of collagen type I and other ECM proteins, ADSCs help to facilitate the formation of a stable and organized ECM, which is critical for wound healing in DFUs [6].

A study by Dong et al. demonstrated that ADSCs enhance collagen deposition in diabetic wound models by increasing the expression of collagen‐producing fibroblasts. This process accelerates tissue repair and contributes to more durable wound healing [11]. Tseng et al. observed that ADSCs promote collagen synthesis in chronic wounds by influencing the TGF‐β signaling pathway, a key mediator of collagen deposition and ECM remodeling [12].

Preclinical studies using animal models of diabetic wounds corroborated these findings [8]. Li et al. demonstrated that ADSCs enhanced ECM remodeling in diabetic rat models by stimulating fibroblast migration and collagen synthesis, contributing to improved wound closure rates [10].

3.3. Clinical Evidence Supporting ADSC Therapy in Diabetic Ulcer Healing

Clinical evidence further confirms that ADSCs outperform conventional treatment in wound healing, positioning them as a compelling alternative for diabetic ulcer management [13]. Cytori Therapeutics Inc. is utilizing adipose‐derived regenerative cells (ADRCs) for chronic DFUs (NCT01253364) [12], with Phase I trials showing 50% faster healing compared to control groups, particularly in patients with critical limb ischemia. Similarly, IntelliCell Biosciences Inc. is investigating stromal vascular fraction (SVF) derived from adipose tissue to promote wound healing in DFUs (NCT02287848) [12], demonstrating improved wound closure rates and accelerated healing times in initial trials.

The integration of complementary therapies like VAC Therapy System by KCI has also shown promising results. This negative pressure wound therapy enhances healing when used in conjunction with ADSC‐based therapies, suggesting a synergistic effect that improves patient outcomes (NCT00224796) [12]. Furthermore, Stampucel by Stampeutics Research Pvt. Ltd. is addressing diabetes‐related vascular complications, further illustrating ADSCs' transformative potential in chronic wound management (NCT01483830) [12].

These studies collectively highlight the robust therapeutic potential of ADSCs in promoting wound healing and reducing complications in chronic wounds, paving the way for more effective interventions in managing diabetic ulcers and related complications.

4. Adipose‐Derived Stem Cells in Diabetic Ulcer Healing: A Comprehensive Approach to Wound Regeneration

Adipose‐derived stem cells (ADSCs) offer a transformative strategy in regenerative medicine, particularly for the treatment of diabetic foot ulcers (DFUs). Diabetic ulcers present a significant clinical challenge due to their slow healing and high susceptibility to complications, including infection and limb amputation. ADSCs address critical barriers to effective wound repair, providing a multi‐faceted therapeutic solution to enhance the healing process in diabetic patients [13].

One of the key mechanisms by which ADSCs promote healing is through neovascularization, which is essential for restoring adequate blood flow to ischemic tissues in the wound area [14]. ADSCs release various angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF), all of which stimulate endothelial cell proliferation and migration to form new blood vessels [11]. Additionally, ADSCs possess the ability to differentiate into endothelial‐like cells, contributing directly to vascular regeneration and improving blood supply in the wound bed [15].

Another pivotal aspect of ADSCs' therapeutic potential is their immunomodulatory function. Chronic inflammation, driven by prolonged hyperglycemia, is a major barrier to effective wound healing in diabetic ulcers [16]. ADSCs address this by secreting anti‐inflammatory cytokines like interleukin‐10 (IL‐10) and transforming growth factor‐beta (TGF‐β), which suppress the activation of pro‐inflammatory immune cells, particularly macrophages. Moreover, ADSCs facilitate the transition of macrophages from a pro‐inflammatory (M1) to an anti‐inflammatory (M2) phenotype, fostering an environment conducive to tissue repair and regeneration [17].

In addition to their anti‐inflammatory effects, ADSCs play a crucial role in tissue regeneration and extracellular matrix (ECM) remodeling [17]. ADSCs differentiate into dermal fibroblasts, which are essential for collagen synthesis and ECM formation—key components in wound healing. Diabetic ulcers often suffer from impaired collagen deposition, resulting in weak and unstable tissue. By stimulating fibroblast activity, ADSCs promote collagen production and restore the structural integrity of the wound tissue [18]. ADSCs also release chemotactic factors, such as stromal cell‐derived factor‐1 (SDF‐1), which attract endogenous stem cells and progenitor cells to the wound site, accelerating reepithelialization and supporting wound closure [17]. The underlying molecular and cellular functions of ADSCs in these processes are summarized in Table 1, illustrating the biological basis of their therapeutic potential. As clinical research continues to advance, integrating ADSC‐based therapies into diabetic ulcer management is becoming increasingly promising. By addressing critical challenges such as impaired circulation, chronic inflammation, and tissue regeneration, ADSCs offer a comprehensive solution for chronic wound care. Their unique ability to promote not only wound closure but also sustainable tissue regeneration could significantly enhance patient outcomes and redefine the future of diabetic ulcer treatment.

Table 1.

Cellular and molecular biological basis of ADSCs in the healing of diabetic ulcer.

Aspect	Mechanism/function	Impact on diabetic ulcer healing	Reference
IL‐10 secretion	ADSCs release IL‐10, which inhibits pro‐inflammatory cytokines such as INF‐γ and TNF‐α.	Reduces chronic inflammation, promotes healing by switching macrophages from M1 to M2.	[19]
Transforming growth factor (TGF‐β)	ADSCs secrete TGF‐β, facilitating the suppression of inflammation and promoting extracellular matrix remodeling.	Enhances tissue repair and regeneration, aiding wound closure.	[20]
Macrophage polarization (M1 to M2)	ADSCs induce the shift of macrophages from a pro‐inflammatory M1 phenotype to a reparative M2 phenotype.	Accelerates tissue repair and angiogenesis, critical for wound healing in diabetic ulcers.	[19]
Extracellular vesicles (EVs)	ADSCs‐derived EVs carry miRNAs and proteins that regulate immune responses by modulating cytokine production.	Improves cellular communication, leading to enhanced immune response regulation.	[21]
MicroRNA (miRNA‐146a)	ADSC‐derived exosomes contain miRNA‐146a, which downregulates NF‐κB signaling pathways.	Reduces inflammation and protects against excessive immune responses in diabetic wounds.	[4]
Nuclear factor kappa B (NF‐κB) pathway	Inhibition of the NF‐κB pathway by ADSCs, reducing pro‐inflammatory gene expression.	Lowers inflammatory responses, enhancing wound healing speed and quality.	[21]
Heme oxygenase‐1 (HO‐1) expression	ADSCs upregulate HO‐1, an enzyme with anti‐inflammatory properties that helps in reducing oxidative stress.	Protects tissues from further damage by reducing oxidative stress in chronic diabetic ulcers.	[22]
Arginase‐1 expression	M2 macrophages, induced by ADSCs, express Arginase‐1, which competes with iNOS, reducing nitric oxide production.	Lowers inflammation and promotes wound healing through enhanced tissue regeneration.	[6]
Fibroblast growth factor (FGF)	ADSCs stimulate the production of FGF, enhancing fibroblast proliferation and collagen production.	Promotes tissue regeneration and speeds up wound closure in chronic ulcers.	[12]
CXCR4 expression on ADSCs	ADSCs express CXCR4, which enhances homing to injury sites and mediates immune‐modulatory effects.	Improves ADSCs' migration to the wound site, contributing to enhanced wound healing outcomes.	[23]

5. Therapeutic Promise and Safety Challenges of ADSCs in Diabetic Ulcer Healing

Adipose‐derived stem cells (ADSCs) hold significant promise for healing diabetic ulcers due to their strong regenerative capabilities. However, several risks and limitations must be thoroughly evaluated to ensure these therapies are safe and effective in clinical applications. ADSCs can rapidly proliferate and differentiate, which is beneficial for tissue repair. However, this rapid growth increases the risk of tumor formation, a major concern in therapeutic contexts [24]. Studies on animal models indicate that ADSCs may promote tumor growth by releasing proangiogenic factors, such as vascular endothelial growth factor (VEGF). This raises particular concerns for patients with latent or precancerous conditions [25].

Moreover, the in vitro expansion of ADSCs introduces additional risks. Extended culture conditions and specific growth factors can lead to chromosomal abnormalities, increasing the likelihood of malignant transformation [26]. This risk becomes apparent when mesenchymal stem cells, including ADSCs, undergo extensive population doublings. Therefore, it is critical to maintain stringent monitoring and control of culture conditions to preserve cell integrity [27].

Another significant concern in therapies involving ADSCs is donor‐related factors' impact on the cells' therapeutic quality [28]. For example, the age and metabolic health of donors are crucial considerations. ADSCs sourced from older individuals or those with metabolic issues may show reduced functionality, limiting their regenerative efficacy in clinical applications. It is essential to carefully assess the source and condition of ADSCs to optimize therapeutic outcomes [29].

The immune response is an additional primary concern with ADSC‐based therapies, while allogeneic ADSCs are generally viewed as immune‐privileged, they can still evoke immune rejection, especially in inflammatory environments such as chronic wounds [30]. This immune reaction could potentially diminish their effectiveness or even lead to adverse effects [31]. Strategies to mitigate this issue include autologous ADSC transplantation, immune modulation therapies, and genetic engineering of cells designed to reduce immune responses and enhance therapeutic compatibility [32].

Current research explores genetic modifications that incorporate tumor‐suppressive properties or promote antitumor activity to increase the safety of ADSCs. This approach aims to maintain their regenerative capabilities while minimizing oncogenic risks [28]. As ADSCs' research advances, rigorous safety assessments and standardized protocols will be crucial. Genetic engineering and advanced cell modification provide promising strategies to address safety challenges, making ADSCs a viable therapeutic option for healing diabetic ulcers and other regenerative applications [6].

5.1. ADSCs in Extracellular Matrix Remodeling and Collagen Deposition

ADSCs play a significant role in enhancing wound healing by promoting the remodeling of the extracellular matrix and the deposition of collagen, as well as serving angiogenic and immune‐modulatory functions [33]. The ECM provides structural support, facilitating cellular migration and tissue organization during the healing process. ADSCs secrete key factors such as fibroblast growth factor and transforming growth factor‐beta, which stimulate fibroblasts to produce collagen and organize ECM components. These processes are essential for wound closure and maintaining tissue integrity [34].

ADSC‐conditioned media has been shown to enhance collagen synthesis in fibroblasts, thereby aiding in ECM remodeling. Additionally, ADSCs produce matrix metalloproteinase, such as MMP‐2 and MMP‐9, which degrade damaged ECM, facilitating the proper arrangement of new collagen fibers and ensuring effective tissue regeneration and structural integration [35]. Furthermore, ADSCs promote the maturation of collagen fibers, which improves wound tensile strength, as shown in studies involving diabetic rats models, these findings underscore the potential of ADSCs in regenerative therapies, particularly for treating diabetic ulcers [36].

6. Complications Related to ADSC Delivery

The delivery of ADSCs is crucial for their therapeutic effectiveness. Topical transplantation, which is often used for treating diabetic ulcers, can lead to complications such as inflammation, infection, or tissue necrosis if not performed under aseptic conditions [37]. While intravenous (IV) infusion allows for systemic distribution of ADSCs, it carries the risk of pulmonary embolism due to microvascular obstruction in the lungs [37]. Additionally, uneven cell distribution during direct injection poses challenges that may affect clinical outcomes. When ADSCs are used as cell‐based wound dressings, they are at risk of desiccation, infection, and mechanical pressure, all of which can compromise their viability [38]. More research is needed to optimize ADSC delivery methods and dosages, particularly in the context of managing chronic wounds.

7. Strengths and Limitations

7.1. Strengths

ADSC provides a minimally invasive approach for tissue regeneration, with the ability to differentiate into various cell types, such as endothelial and fibroblasts. This versatility allows them to promote angiogenesis (the formation of new blood vessels), enhance collagen deposition, and accelerate wound healing. The ease of isolating ADSCs from adipose tissue, combined with their autologous potential and immunomodulatory properties, makes them a promising treatment option for chronic diabetic ulcers. Additionally, compared to other types of stem cells, ADSCs are more accessible and relatively easy to expand, further enhancing their appeal in clinical applications.

7.2. Limitations

Despite their potential, the current evidence on ADSCs is limited and derived from studies with inconsistent methodologies and small sample sizes. This variability, coupled with differences in ADSC processing techniques and patient characteristics, makes it difficult to draw definitive conclusions. Furthermore, concerns regarding tumorigenesis and immune rejection remain, highlighting the need for more standardized and long‐term clinical trials to fully evaluate the safety and efficacy of ADSCs. Additionally, ADSC therapy may need to be combined with other treatments to optimize healing outcomes.

8. Recommendations

To establish ADSC therapy as a standard treatment, comprehensive clinical trials must be conducted to evaluate safety and efficacy across diverse patient populations while monitoring potential risks, including tumorigenesis. It is vital to develop standardized protocols for processing ADSCs. Additionally, combining ADSCs with scaffolds or growth factors may enhance their therapeutic potential. Long‐term monitoring and regulatory oversight are critical to ensuring the safe implementation of ADSC therapies in clinical practice.

9. Conclusion

ADSCs show significant promise for treating diabetic ulcers due to their healing and anti‐inflammatory properties. These cells enhance wound healing by stimulating angiogenesis, modulating immune responses, and promoting tissue regeneration. ADSCs are relatively easy to isolate and apply, making them a viable option for clinical use. However, concerns about potential tumor growth and variability in cell quality based on donor factors such as age, health status, and metabolic condition still need to be addressed. While early research is promising, robust, large‐scale clinical trials are essential to confirm the long‐term safety and efficacy of ADSC‐based therapies.

Future research should explore emerging technologies, such as gene‐editing tools like CRISPR/Cas 9, to optimize ADSCs' regenerative potential and reduce treatment variability. Additionally, combination therapies, including biomaterials scaffolds or growth factors, could improve therapeutic outcomes. Standardizing ADSC processing methods and personalizing treatments based on patients' characteristics will be key in optimizing treatment efficacy. While the future of ADSCs therapy for diabetic ulcers appears promising, it is crucial to balance therapeutic benefits with safety precautions, and it is essential to ensure successful clinical implementation of these innovative therapies.

Author Contributions

Prithiviraj Nagarajan: conceptualization, writing – original draft, writing – review and editing. Mani Rajarathinam: conceptualization, data curation, resources, writing – review and editing. Arun Daniel Jayakumar: visualization and validation. Prasad Thirumal: investigation and validation. Kumar Rangarajalu: validation and formal analysis. Nisha Perumal: writing – review and editing. Pavithra Muthiah: validation and resources. Anusheela Howlader: methodology, formal analysis, supervision, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The lead author, Prithiviraj Nagarajan, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Nagarajan P., Rajarathinam M., Jayakumar A. D., et al., “From Fat to Healing: How Adipose‐Derived Stem Cells Are Changing the Game for Diabetic Foot Ulcers—A Perspective,” Health Science Reports 8 (2025): 1‐7, 10.1002/hsr2.71385.

Data Availability Statement

The authors have nothing to report.