Enhanced Islet Transplantation with Tunable, Protein-Delivering Scaffolds

描述(由申请人提供)： 胰岛移植有可能成为第一个真正治愈1型糖尿病的方法。埃德蒙顿议定书在2000年的成功极大地激起了社区的兴奋，但随后证明其局限性和失败的工作缓和了这种情绪。胰岛在隔离后很脆弱，目前的移植方法会导致多达2/3的胰岛在几天内丢失。这导致对每个接受者都有大量的小岛需求。细胞凋亡和不充分的血管重建是造成这种损失的主要原因，肝移植部位的有效性一再受到质疑。这项建议的目的是研究微孔蛋白支架作为一种新的基于生物材料的肝外胰岛移植方法，以及如何使用它们来最小化胰岛损失和最大限度地提高移植成功率。与迄今为止大多数基于生物材料的方法利用胰岛包裹形成鲜明对比的是，这些支架促进了胰岛植入、组织渗透和血运重建。它们提供了可调的3D支持架构，最值得注意的是，随着时间的推移，可以将蛋白质因子局部输送到胰岛微环境中。这些支架可以探索一系列的胰岛支持结构，并提供几种蛋白质来操纵胰岛微环境。体外实验将研究这些变量对胰岛功能、存活和凋亡的影响，不依赖于宿主组织的影响。在1型糖尿病小鼠模型的体内移植将被用来在宿主组织的背景下研究支架结构和蛋白输送对胰岛功能、存活、细胞凋亡和血运重建的影响，其中渗透和血运重建在揭示过程限制和移植成功的机制方面发挥着重要作用。未来的研究可以利用这些发现和优化来促进较大动物或非人类灵长类动物的胰岛移植，为将这一新方法转化为临床提供基础。 1型糖尿病是一种终生疾病，几乎不可避免地会出现并发症，导致严重的发病率和死亡率。目前胰岛移植方案的缺陷阻碍了对绝大多数糖尿病患者的应用。拟议的目标有可能在两个方面显著改善胰岛移植：通过提供一个平台，对移植环境中对胰岛重要的物理和化学线索进行基础研究，并通过展示一种新的肝外移植模式，使胰岛损失最小化，胰岛功能最大化。

DESCRIPTION (provided by applicant): Islet transplantation has the potential to be the first real cure for type-1 diabetes. The Edmonton Protocol's success in 2000 excited the community immensely, but follow-up work demonstrating its limitations and failures tempered those feelings. Islets are vulnerable post-isolation and current transplantation methods cause the loss of up to 2/3 of islets within days. This has lead to a massive islet requirement for every recipient. Apoptosis and inadequate revascularization are major contributors to this loss and the effectiveness of a hepatic transplant site has been repeatedly questioned. The aims of this proposal will investigate microporous protein-delivering scaffolds as a novel biomaterials-based approach to extrahepatic islet transplantation and how they can be used to minimize islet loss and maximize transplant success. In distinct contrast with the majority of biomaterials-based approaches to date, which have utilized islet encapsulation, these scaffolds encourage islet engraftment, tissue infiltration and revascularization. They provide a tunable 3D support architecture and most notably, can locally deliver protein factors to the islet microenvironment over time. These scaffolds enable the exploration of a range of islet support architectures and the delivery of several proteins for manipulating the islet microenvironment. In vitro experiments will study the impact of these variables on islet function, survival and apoptosis independent of host tissue effects. In vivo transplantation in a murine model of type-1 diabetes will be used to investigate the effects of scaffold architecture and protein delivery on islet function, survival, apoptosis and revascularization in the context of host tissue, where infiltration and revascularization play important roles to reveal processes limiting, and mechanisms underiying transplant success. Future studies can utilize these findings and optimizations to promote islet transplantation in larger animals or non-human primates, providing the basis for translating this novel approach to the clinic. Type-1 diabetes is a life-long disease with near-inevitable complications that are responsible for significant morbidity and mortality. The shortcomings of current islet transplantation protocols prevent application to the vast majority of diabetes patients. The proposed aims have the potential to significantly improve islet transplantation in two ways; by providing a platform for fundamental studies of the physical and chemical cues important to islets in a transplant setting, and by demonstrating a new extrahepatic transplantation model that minimizes islet loss and maximizes islet function.