Abstract
Diabetic foot ulcers (DFU) are a severe and recurrent complication of diabetes that significantly increase the risk of infection, amputation, and mortality. Conventional therapies often fail to achieve complete healing due to the complex microenvironment characterized by ischemia, chronic inflammation, neuropathy, and oxidative stress. Stem-cell-based interventions offer a multifaceted therapeutic strategy by promoting angiogenesis, modulating immune responses, reducing oxidative damage, and enhancing extracellular matrix remodeling. This review provides a comprehensive analysis of major stem-cell sources including bone marrow-derived mesenchymal stem cells (BM-MSCs), adipose-derived stem cells (ADSCs), umbilical cord blood mesenchymal stem cells (UCB-MSCs), and induced pluripotent stem cells (iPSCs). Comparative evaluation highlights that ADSCs are advantageous for autologous use and easy harvesting, BM-MSCs have the longest clinical track record, UCB-MSCs offer low immunogenicity for allogeneic applications, and iPSCs provide customizable options but require genomic stability monitoring. Increasing evidence supports the use of cell-free approaches, particularly exosome and secretome-based therapies, which reproduce stem-cell paracrine effects while minimizing ethical and safety concerns. Integration of these biologics with advanced biomaterials and nanoplatforms further enhances local retention, controlled release, and wound microenvironment regulation. Despite encouraging results, challenges remain in standardizing cell preparation, optimizing dosage and delivery, and ensuring long-term safety and cost-effectiveness. Future directions include harmonizing clinical protocols, expanding exosome-based therapeutics, and conducting large multicenter trials to validate their efficacy in real-world DFU management.