温度响应性细胞移植体系改善下肢缺血的疗效及机制研究

Diabetic peripheral vascular disease leading to foot gangrene and amputation, is one of the most serious complications of diabetes. Stem cell transplantation is one of the most promising therapies at present, but it is confronted with the great challenge of low transplantation efficiency. The key reasons include the low survival rate and retention of stem cells during transplantation. A major hurdle in improving the efficacy of current stem cell therapy is lack of suitable cell carriers. At present, injectable materials can improve cell retention and survival, but there are still many problems: 1) the existing hydrogels are often not suitable mechanical strength, elasticity and moisture, it is difficult to load stem cells or rupture during transportation, causing cell injury; 2) They cannot form gel at normal body temperature and change into sol at low temperature, which is difficult to achieve the requirement of releasing the stem cells where needed. Although the injection of stem cells to a certain extent can reduce the rate of cell injury, but it cannot effectively overcome the mechanical damage of stem cells during transplantation..The goal of this project is to create a new class of hydrogel-based cell carriers that address the above limitations in order to significantly improve the efficacy of current stem cell therapy. The specific objective of this proposal is to create a novel temperature-responsive hydrogel microsphere for the loading and release of stem cells. We have successfully constructed the temperature-responsive hydrogel microspheres which possess certain mechanical strength and temperature response characteristics, namely, formation of a certain strength, elasticity and moisture gel system induced by temperature at normal body temperature, and change into sol in the condition of low temperature resulted from lower limb ischemia. Therefore, we speculate that the system can provide some mechanical support and protection for the transplanted stem cells, and then release them under the condition of pathological changes. This project aims to build a new system of cell transplantation, significantly improve the survival rate of transplanted cells, and release to the lesion in response to temperature, improve the effect of cell transplantation in the treatment of lower limb ischemia. Furthermore, the molecular mechanism of stem cell therapy will be explored. The results will provide a theoretical basis and new science foundation for stem cell therapy.

糖尿病外周血管病变导致足部坏疽、截肢，是糖尿病最严重的并发症之一。干细胞移植是目前最有潜力的疗法之一，但面临着移植效率极低的巨大挑战。移植过程中的机械损伤和不能按照机体病变需求归巢，是导致移植干细胞生存率低的重要原因，是制约干细胞疗效的重要瓶颈，目前无理想的解决方案。我们前期成功构建出了温度响应性水凝胶微球干细胞移植体系。该体系不仅具有一定的力学强度，可以减少移植过程中的机械损伤；而且具有温度响应性的特征，即在正常体温下，以凝胶态干细胞体系存在，而在糖尿病下肢血管缺血病变的低温部位，转变为可流动性溶胶态，响应性地释放干细胞。因此本项目旨在探讨温度响应性水凝胶微球干细胞移植体系能否提高移植细胞生存率，并按需释放到病变部位，改善目前细胞移植治疗下肢缺血的疗效，并进一步探讨干细胞治疗的分子信号机制。研究结果将为干细胞治疗提供新的理论依据和方法学基础。

糖尿病外周血管病变是糖尿病最严重的并发症之一。干细胞移植是目前最有潜力的疗法之一，但在移植过程中的机械损伤和无法按照机体病变需求归巢，导致移植干细胞生存率低，制约干细胞疗效。我们通过研究研制了可注射可逆温度响应的水凝胶体系，不仅具有适合的力学强度，对所负载的干细胞具有保护作用；而且该体系对干细胞实现了温度可控释放，即在正常体温下水凝胶体系稳定，而在糖尿病下肢血管缺血病变导致的低温部位，水凝胶转变为溶胶，可控释放干细胞到病变部位，从而提高了干细胞在病变部位的滞留和生存率。研究结果表明水凝胶和干细胞系统联合移植可有效抑制下肢缺血的纤维化和肌萎缩，加速下肢血流恢复，促进血管生成，促进血管修复，明显改善了细胞移植治疗下肢缺血的疗效。我们进一步通过干细胞提取外泌体，采用可注射自愈合水凝胶对其进行高效负载，对糖尿病导致的研制皮肤、血管等病变、损伤进行治疗。研究发现该水凝胶复合体系能够在伤口部位实现对负载外泌体的长效可控释放，延长了外泌体的半衰期、提高了其滞留效率，从而更好地发挥干细胞外泌体对组织、血管的修复功能。此外，我们对水凝胶的组成、结构进行了深入的研究探讨，制备了一系列具有独特结构与功能的自愈合水凝胶、纳米复合水凝胶以及智能水凝胶等体系，用于生物医学领域的血管病变治疗、糖尿病导致的严重皮肤损伤修复、健康监测甚至肿瘤治疗，为功能水凝胶的应用开展了新的方向，为干细胞治疗提供了新的理论依据和方法学基础。

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