Abstract: Wound dressing based on mesenchymal stem cells (MSC) is promising for the treatment of diabetic foot ulcer (DFU). However, the unfavorable microenvironment of the DFU including hyperglycemia, ischemia, hypoxia, hyper-oxidation, infection, and the resultant chronic inflammation confers challenges to the survival and efficacy of transplanted MSC. We have previously demonstrated that spheroids (Sp) formed by MSC differentiated from human embryonic stem cells (E-MSC) were more effective than dissociated E-MSCs to promote wound healing in non-diabetic mice. However, reduced efficacy was observed in diabetic mice in the present study. We hypothesize that improvement can be achieved by strengthening the E-MSC Sp efficacy with strategies to tackle the diabetic environment. To this end, we encapsulated E-MSC Sp with gelatin methacryloyl (GelMA) doped with polydopamine nanoparticles (nPDA) to generate a living dressing (named GnP-Sp). First, GelMA combined with nPDA (GnP) manifested excellent features of shape adaptation, adhesion, pore structure and degradation, and biocompatibility. E-MSC Sp combined with nPDA also demonstrated stronger antioxidant ability and induced higher M2/M1 macrophage ratio in vitro compared to E-MSC Sp alone. Upon application in a mouse DFU model, the GnP-Sp dressing repressed the local inflammation, expedited angiogenesis and collagen deposition, and accelerated wound repair. Furthermore, E-MSCs Sp outperformed dissociated MSCs in stimulating regenerative cytokines, chemokines, and angiogenesis factors associated with elevated hypoxic signaling. These findings suggest that GnP enhance the therapeutic efficacy of E-MSC Sp by improving the diabetic conditions and the new living dressing may serve as a more effective therapy for DFU than E-MSC Sp alone.
Funding Source: Macau Science and Technology Development Fund (FDCT) Key grant #0002/2021/AKP, National Science Foundation China General Grant #32270842, and National Key R&D grant of the Ministry of Science & Technology of China #2022YFA1105000
