Synthetic Hydrogels for Islet Vascularization and Engraftment

项目摘要 1型糖尿病(T1D)是一种自身免疫性疾病，在美国，影响着160万人 每年的医疗费用为160亿美元，患病率每年增加6.4万例新诊断。临床 胰岛移植(CIT)，即通过肝门静脉输注胰岛，已显示出作为一种 T1D治疗。然而，只有50%的受者在五年后保持胰岛素独立，而且这一过程 目前仅限于T1D患者的边缘子集，部分原因是两大限制：即时血液- 介导炎症反应和胰岛血管形成延迟(&gt；14天)。重大损失 交付的胰岛--60%-80%--发生在肝内移植后的几小时到几天内。 因此，有必要建立一个替代的移植地点，以避免瞬间血液- 介导炎症反应，支持胰岛的长期植入。皮下组织 网站是一个有吸引力的肝外网站，具有很高的临床潜力，可访问性，便利性，能力 重新给药(如有必要)、易于监测和易于检索(如有必要)。但是，未修改的 临床上皮下部位受限是由于血管灌流不足，结果是代谢不足。 动力学和低氧。促进新生血管的一种优雅、便捷的策略是生物材料- 介导性传递促血管生成因子，如血管内皮生长因子(VEGF)。血管内皮生长因子 促进内皮细胞的生长，是天然胰岛血管形成和发育的主要调节因子。 该项目的目标是设计可注射的血管内皮生长因子传递合成聚乙二醇[聚乙二醇]。 促进胰岛血管化、植入和在皮下空间发挥作用的水凝胶。我们有 先前设计的含有血管内皮生长因子的水凝胶可以促进胰岛的存活、血管形成和功能 啮齿类动物的性腺脂肪垫和大网膜，是固有的高度血管化的部位。我的中心假设是 可以进一步优化血管内皮生长因子传递凝胶以促进胰岛血管形成、植入和 皮下腔的功能，这是一个具有很高临床潜力的部位。我的初步数据支持这一点 为本研究的应用提供了较强的科学前提和可行性。总的目标是 要通过三个具体目标来实现：1)确定以最佳方式支持 利用带血管的芯片上胰岛平台进行胰岛血管化；2)评估血管内皮生长因子-聚乙二醇水凝胶的能力 促进糖尿病大鼠同种异体胰岛的血管化、植入和功能；3)检测 血管内皮生长因子水凝胶促进同种异体胰岛血管化和皮下植入 非糖尿病猪。该项目的预期成果包括：1)一种可注射的胰岛递送工具， 促进胰岛在皮下空间的血管化、植入和功能，2)验证结果 一种大型动物模型，将为未来在转化型糖尿病大型动物模型中的研究提供参考。

Project Summary Type 1 diabetes (T1D) is an autoimmune disease that, in the U.S., affects 1.6 million people, amasses $16 billion in annual healthcare expenses, and annually rises in prevalence by 64,000 new diagnoses. Clinical islet transplantation (CIT), which is infusion of islets through the hepatic portal vein, has shown promise as a T1D treatment. However, only 50% of recipients maintain insulin independence at five years and the procedure is currently limited to a marginal subset of T1D patients, in part due to two major limitations: instant blood- mediated inflammatory reaction and delayed vascularization of islets (>14 days). A significant loss of delivered islets – 60-80% – occurs within hours to days following transplantation in the intrahepatic site. Therefore, there is a significant need to establish an alternative transplant site that avoids instant blood- mediated inflammatory reaction and supports the long-term engraftment of islets. The subcutaneous site is an attractive extrahepatic site with high clinical potential in terms of accessibility, convenience, ability to re-dose (if necessary), ease of monitoring, and ease of retrieval (if necessary). However, the unmodified subcutaneous site is clinically limited due to inadequate vascular perfusion and, as a result, inadequate metabolic kinetics and low oxygenation. An elegant, facile strategy to promote neovascularization is the biomaterial- mediated delivery of proangiogenic factors such as vascular endothelial growth factor (VEGF). VEGF promotes the growth of endothelial cells and is a major regulator of native islet vascularization and development. The objective of this project is to engineer injectable VEGF-delivering synthetic poly(ethylene glycol) [PEG] hydrogels that promote islet vascularization, engraftment, and function in the subcutaneous space. We have previously engineered VEGF-containing hydrogels that promote islet survival, vascularization, and function in the rodent gonadal fat pad and omentum, sites with high inherent vascularization. My central hypothesis is that the VEGF-delivering gel can be further optimized to promote islet vascularization, engraftment, and function in the subcutaneous space, a site with high clinical potential. My preliminary data support this hypothesis and provide strong scientific premise and feasibility for this application. The overall objective will be accomplished across three specific aims: 1) Identify VEGF-PEG hydrogel formulations that optimally support islet vascularization using a vascularized islet-on-a-chip platform; 2) Evaluate the ability of VEGF-PEG hydrogels to promote allogeneic islet vascularization, engraftment, and function in diabetic rats; and 3) Examine the ability of VEGF-hydrogels to promote allogeneic islet vascularization and engraftment in the subcutaneous space of non-diabetic pigs. Expected outcomes for this project include: 1) An injectable delivery vehicle for islets that promotes islet vascularization, engraftment, and function in the subcutaneous space and 2) Validation results in a large animal model that will inform future studies in a translational diabetic large animal model.