Kristi Chaewon Lee

Background:  Chronic wounds such as deep burns and diabetic foot ulcers present a significant challenge to patients and the healthcare system due to prolonged healing times, high cost of care, and high risk of infection leading to morbidity and mortality¹. Compared to acute wounds, chronic wounds have impaired progress through the stages of wound healing, often characterized by delayed angiogenesis, excessive inflammation, and prevalence of biofilm proliferation^1,2. Traditional treatment methods such as skin grafts and wound dressings have limitations such as high infection risk, poor graft survivability, and delayed wound bed revascularization^1,2. Due to these limitations, there is increasing interest in research in tissue engineering strategies that can promote the body’s mechanisms of wound healing.

Objective:  This review focused on the therapeutic potential of adipose-derived stem cells (ADSCs) embedded in hydrogels as an alternative to traditional hydrogel dressings, with particular interest in the promotion of macrophage polarization and angiogenesis.

Methods:  A literature search was conducted on Google Scholar to find peer-reviewed articles published between 2018 and 2024, using the key terms: “chronic wound healing”, “adipose-derived stem cells”, “hydrogels”, “VEGF”, and “M2 polarization”.

Results:  Animal model studies showed that ADSCs have promise in enhancing chronic wound healing due to their promotion of the body’s proliferation of growth factors and cytokines. In particular, ADSCs induced the polarization of macrophages from the M1 subtype (inflammatory) to the M2 subtype (anti-inflammatory, tissue regeneration) in wound beds^3,4. Predominance of M2 macrophages promoted angiogenesis through vascular endothelial growth factor (VEGF) pathways, resulting in enhanced vascularization of wound beds and speeding up the process of wound closure^4,5. ADSCs embedded into hydrogels composed of gelatin and hyaluronic acid showed high levels of cell survival and mechanical strength, proving to be a viable method of delivering ADSCs onto wound beds². These initial promising results led to a human clinical trial on ADSC hydrogels used to treat diabetic foot ulcers. This trial showed significantly faster wound closure for patients with ADSC hydrogel treatment (82% full wound closure by trial week 12), versus patients with a traditional hydrogel treatment (53% full wound closure)⁶.

Conclusions:  ADSCs embedded in hydrogels pose a promising strategy for accelerating chronic wound healing by enhancing vascularization, reducing inflammation, and increasing tissue regeneration through M2 macrophage polarization and increasing VEGF pathways. Additionally, they successfully manage the limitations of current chronic wound therapies. Given the high availability and ease of development of ADSC hydrogels, this treatment should be highly considered in future research and large-scale clinical trials for long-term safety evaluations.

Work Cited:

1.  Li Q, Wang D, Jiang Z, et al. Advances of hydrogel combined with stem cells in promoting chronic wound healing. Frontiers in Chemistry. 2022;10. doi:https://doi.org/10.3389/fchem.2022.1038839
2. Eke G, Mangir N, Hasirci N, MacNeil S, Hasirci V. Development of a UV crosslinked biodegradable hydrogel containing adipose derived stem cells to promote vascularization for skin wounds and tissue engineering. Biomaterials. 2017;129:188-198. doi:https://doi.org/10.1016/j.biomaterials.2017.03.021
3. Liu F, Xu X, Sun T. Vascular endothelial growth factor accelerates healing of foot ulcers in diabetic rats via promoting M2 macrophage polarization. Diabetic medicine : a journal of the British Diabetic Association. 2024;41(9):e15388. doi:https://doi.org/10.1111/dme.15388
4. Shi R, Jin Y, Zhao S, Yuan H, Shi J, Zhao H. Hypoxic ADSC-derived exosomes enhance wound healing in diabetic mice via delivery of circ-Snhg11 and induction of M2-like macrophage polarization. Biomedicine & Pharmacotherapy. 2022;153:113463. doi:https://doi.org/10.1016/j.biopha.2022.113463
5. Chen L, Zheng Q, Liu Y, et al. Adipose-derived stem cells promote diabetic wound healing via the recruitment and differentiation of endothelial progenitor cells into endothelial cells mediated by the VEGF-PLCγ-ERK pathway. Archives of Biochemistry and Biophysics. 2020;692:108531. doi:https://doi.org/10.1016/j.abb.2020.108531
6. Moon KC, Suh HS, Kim KB, Han SK, Young KW, Lee JW. Potential of Allogeneic Adipose-Derived Stem Cell – Hydrogel Complex for Treating Diabetic Foot Ulcers. Diabetes. Published online January 24, 2019:db180699. doi:https://doi.org/10.2337/db18-0699