用于胰岛移植的类细胞外基质微凝胶及其治疗糖尿病的研究

The absolute insufficiency of insulin secretion due to the decrease of islet beta cell number is the common pathogenesis of type 1 diabete and advanced type 2 diabete. Islet transplantation is the best way to treat these two types of diabetes. However, the survival rate of the transplanted islet cells is very low owing to immune rejection reactions, which restricts the wide application of this technique. To solve this problem, we design and synthesize hyaluronic acid materials that can be single and double crosslinking, combine droplet-microfluidics to in-situ fabricate islet-laden microgels with different mechanical and degradation properties. Our purpose is to construct ECM-like microenvironment for islet cells, eliminate negative impact on the activity of islet cells caused by the shear forces during islet cell transplantation, reduce the immune rejection, improve the long-term survival rate of transplanted islet cell in vivo, and maintain the continuous secretion of insulin and high response function on blood sugar. As a result, the high blood glucose can be restricted and finally the long-term effective control of blood glucose can be realized if such a strategy is proven to be effective.

因胰岛β细胞数量减少而导致的胰岛素分泌绝对不足是1型糖尿病与晚期2型糖尿病的共同发病机制。胰岛移植是目前治疗这两类糖尿病的最佳方案。然而，由于免疫排斥反应等因素致使移植后的胰岛细胞成活率较低，限制了该技术的广泛应用。针对这一问题，本项目拟通过设计和合成室温下可发生快速单交联和双交联的透明质酸材料，结合液滴微流控技术制备具有不同力学性能和降解性能的微凝胶，同时实现胰岛细胞的原位包载。其目的在于构建适合胰岛细胞生存的类细胞外基质微环境，消除胰岛移植过程中剪切应力对胰岛细胞活性的负面影响，降低移植引发的机体免疫排斥反应，提高胰岛细胞在体内的长期存活率，并保持其连续分泌胰岛素及对血糖的高响应性能，进而达到逆转体内高血糖值，最终实现血糖长期有效控制的目的。

因胰岛β细胞数量减少而导致的胰岛素分泌绝对不足是1型糖尿病与晚期2型糖尿病的共同发病机制。胰岛移植是目前治疗这两类糖尿病的终极方案。然而，强烈的机体免疫排斥反应会导致移植后的胰岛细胞成活率较低，限制了该技术在临床上的广泛应用。针对这一问题，本项目首先设计和合成了室温下可快速交联的明胶和透明质酸单体材料，结合液滴微流控技术制备了载大鼠胰岛细胞的微凝胶，既为胰岛细胞提供适合其生存的类细胞外基质微环境，又在移植的外源性胰岛细胞和机体之间建立物理屏障从而缓解机体产生的免疫排斥反应。而后，构建糖尿病小鼠模型，将载胰岛细胞的类细胞外基质微凝胶异种移植到小鼠的附睾脂肪垫，结果显示，胰岛细胞在体内的长期存活率显著提升，且能保持其连续分泌胰岛素及对血糖的高响应性能，最终实现了长达90天的胰岛素自主分泌。本工作的开展为临床长期胰岛移植提供了新的解决思路和理论依据。