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实的治愈1型糖尿病的方法。《埃德蒙顿议定书》在2000年的成功使社区大为兴奋，但随后的工作表明了其局限性和失败，缓和了这种情绪。胰岛在隔离后是脆弱的，目前的移植方法在几天内导致多达2/3的胰岛损失。这导致每个接受者都需要大量的胰岛。细胞凋亡和血运重建不足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。本提案的目的是研究微孔蛋白质递送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大限度地减少胰岛损失和最大限度地提高移植成功率。与迄今为止大多数利用胰岛包封的基于生物材料的方法形成鲜明对比，这些支架促进胰岛植入、组织浸润和血管重建。它们提供了一个可调的3D支持架构，最值得注意的是，可以随着时间的推移将蛋白质因子局部递送到胰岛微环境。这些支架使得能够探索一系列胰岛支持结构和递送用于操纵胰岛微环境的几种蛋白质。体外实验将研究这些变量对胰岛功能、存活和凋亡的影响，而不依赖于宿主组织的影响。在1型糖尿病的鼠模型中的体内移植将用于研究支架结构和蛋白质递送对宿主组织背景下的胰岛功能、存活、凋亡和血管重建的影响，其中浸润和血管重建在揭示过程限制和移植成功的机制方面发挥重要作用。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灵长类动物的胰岛移植，为将这种新方法转化为临床提供基础。 1型糖尿病是一种终身疾病，具有几乎不可避免的并发症，这些并发症是导致显著发病率和死亡率的原因。目前胰岛移植方案的缺点阻碍了对绝大多数糖尿病患者的应用。提出的目标有可能显着改善胰岛移植在两个方面：通过提供一个平台的基础研究的物理和化学线索重要的胰岛移植设置，并通过展示一个新的肝外移植模型，最大限度地减少胰岛损失和胰岛功能最大化。

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.