An Innovative Delivery System of Oxygen-Releasing Nanospheres and Self-Healing Hydrogels Enhances the Therapeutic Effectiveness of Bone Marrow Mesenchymal Stem Cells for Chronic Limb-Threatening Ischemia

Abstract

Moyan Zhao,1 Zixuan Zhou,2 Amir Sherchan,1 Weizhong Yuan,2 Xiaoyun Xie,3 Maoquan Li1,3 1Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 2Key Laboratory of Advanced Civil Materials of Ministry of Education, School of Materials Science and Engineering, Tongji University, Shanghai, 201804, People’s Republic of China; 3Department of Intervention and Vascular Surgery, Shanghai Tenth People’s Hospital, Shanghai, 200092, People’s Republic of ChinaCorrespondence: Maoquan Li, Department of Intervention and Vascular Surgery, Shanghai Tenth People’s Hospital, Shanghai, 200092, People’s Republic of China, Email [email protected]: Bone marrow mesenchymal stem cells (BMSCs) have emerged as promising candidate for postoperative therapeutics in chronic limb-threatening ischemia (CLTI). Nevertheless, their effectiveness is limited by their low survival rate and impaired functionality in the ischemic microenvironment. To overcome these challenges, we have devised an innovative delivery approach to support the utilization of BMSCs in CLTI therapy.Methods: We synthesized oxygen-releasing nanospheres and self-healing hydrogels. The in vivo functionality of the hydrogel-nanosphere delivery system was evaluated via a multimodality animal live imaging system. A unilateral lower limb ischemia model was established in mice, and a delivery system loaded with BMSCs was administered. The experimental groups included normal mice, ischemic mice, ischemic mice treated with BMSCs in PBS, and ischemic mice treated with BMSCs in the delivery system. Blood perfusion was quantitatively measured via a laser doppler flowmeter (LDF). Immunofluorescence, Masson’s trichrome staining, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) were also used.Results: For cell viability analysis 80 μg.mL− 1 was considered the optimal concentration for cell survival. In vivo, 18 days after injection, the cell membrane fluorescence signal in the delivery system was significantly greater (5.65510± 8.2268) p/s/cm²/sr than that in the other groups (p=0.043). Ischemic mice treated with BMSCs in the delivery system presented an improved limb salvage rate (0.926± 0.12)% compared with that of ischemic mice treated with BMSCs in PBS (0.841± 0.029)% at the 5th week after ischemia establishment (p=0.0033).Conclusion: Our findings suggest that the survival time of BMSCs is prolonged in this innovative delivery system. The combination of nanospheres and hydrogels effectively restored vascular blood perfusion while exerting minimal toxicity on BMSCs. This novel approach combining oxygen-releasing nanospheres and self-healing hydrogels as a delivery system represents an advancement in enhancing the functionality of BMSCs to treat CLTI. Keywords: nanoscale microsphere, stem cell therapy, delivery system, chronic vascular disease, revascularization, tissue recovery

Keywords

• nanoscale microsphere
• stem cell therapy
• revascularization
• tissue repair.