BIOACTIVE POLYMERS FOR EFFECTIVE ISLET DELIVERY SYSTEM

本申请的目的是改善功能性（胰岛素分泌速率和模式）并延长免疫保护胰岛的寿命。低功能性（低于胰腺中天然胰岛胰岛素释放率的15%）需要植入物内大量的胰岛，这会导致手术并发症和患者不适。生物杂交人工胰腺（BAP）中胰岛的寿命有限，可能需要频繁的细胞重新接种，并导致胰岛移植中的进一步供应问题。改善胰岛功能和延长寿命将通过减少糖尿病患者达到正常血糖所需的胰岛数量和减少与胰岛供应相关的探针来最大限度地减少BAP的体积。在本研究中假设：1）通过模拟无血管组织中的易化氧转运，免疫保护的胰岛释放更高量的胰岛素，恢复其固有的双相释放模式，并延长其寿命，和2）促胰岛素剂进一步促进胰岛分泌胰岛素。基于这些假设，将设计一种新的BAP系统，该系统包含氧载体（或氧结合囊泡）和磺酰脲化合物的胰岛刺激剂和胰高血糖素样促胰岛素肽-1的水溶性聚合物缀合物，并将胰岛包埋在BAP中。该研究检查了它们对胰岛活力、胰岛素分泌量、胰岛素释放曲线和免疫保护胰岛寿命的影响。特别是，这两个假设的综合协同效应将被强调。在改善免疫保护膜中包埋的胰岛的功能和寿命方面的成功结果可以应用于微囊化治疗性细胞的递送和BAP的小型化。此外，本研究提出的方法将为解决人类细胞或组织来源短缺的问题提供一个潜在的解决方案。

The goals of this application are to improve the functionality (insulin secretion rate and pattern) and to expand the life-span of immunoprotected pancreatic islets. The low functionality (less than 15% of the insulin release rate of native islets in pancreas) required a large number of islets within the implant, which causes complications in surgery and discomfort for patients. The limited life-span of the islets in a biohybrid artificial pancreas (BAP) may require frequent cell reseeding and cause further supply problems in islet transplantation. Improved islet functionality and prolonged life-span will minimize the volume of the BAP by reducing the number of islets needed for diabetic patients to achieve normoglycaemia and reduce probes associated with islet supply. It is hypothesized in this research that 1) my mimicking facilitated oxygen transport in avascular tissues, the immunoprotected islets release a higher amount of insulin, recover their intrinsic biphasic release pattern, and prolong their life-span, and 2) insulinotropic agents further promote insulin secretion from islets. Based on these hypotheses, a new BAP system will be designed which contains the water-soluble polymeric conjugates of oxygen carriers (or oxygen binding vesicles) and islet stimulants of sulfonylurea compounds and glucagon-like insulinotropic peptide-1 with entrapped islets in the BAP. The research examines their effects on islet viability, the amount of insulin secretion, the insulin release profile, and the life-span of immunoprotected pancreatic islets. Especially, the combined synergy effects of both hypotheses will be emphasized. The successful results in improving functionality and life-span of islets entrapped in an immunoprotected membrane can be applied in the delivery of micro-encapsulated therapeutic cells and to the miniaturization of a BAP. In addition, the approaches proposed in this research will provide a potential solution to the shortage problem of human cell or tissue sources.