Synthetic Hydrogels for Islet Vascularization and Engraftment

用于胰岛血管化和移植的合成水凝胶

• 批准号: 10607152
• 负责人: Michelle Quizon
• 金额: $ 4.77万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-08-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607152
• 关键词: Affect; Allogenic; Animal Model; Animals; Autoimmune Diseases; Beta Cell; Biocompatible Materials; Blood; Blood Coagulation Factor; Blood Glucose; Blood Vessels; Calcium Signaling; Cardiovascular Diseases; Cell Therapy; Cells; Cessation of life; Chronic; Clinical; Collagen; Data; Development; Devices; Diabetes Mellitus; Disease; Dose; Encapsulated; Endothelial Cells; Engineering; Engraftment; Extrahepatic; Family suidae; Fatty acid glycerol esters; Formulation; Foundations; Functional disorder; Future; Gel; Glucose; Glucose tolerance test; Growth; Healthcare; Hepatic; Hour; Hydrogels; Hypoxia; Immunosuppression; Implant; In Vitro; Inflammatory; Infusion procedures; Injectable; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Islets of Langerhans Transplantation; Kinetics; Maleimides; Mediating; Metabolic; Microfluidic Microchips; Modeling; Monitor; Neonatal; Neuropathy; Newly Diagnosed; Nutrient; Omentum; Organ; Outcome; Patients; Perfusion; Persons; Platelet Activation; Portal vein structure; Prevalence; Procedures; Rattus; Reaction; Research; Retrieval; Rodent; Rodent Model; Site; Solid; Technology; Testing; Time; Tissues; Transplant Recipients; Transplantation; Validation; Vascular Endothelial Growth Factors; Vascularization; Work; arm; autoimmune pathogenesis; blood glucose regulation; complement system; delivery vehicle; diabetic; diabetic rat; ethylene glycol; glycemic control; graft function; immunomodulatory strategy; in vivo; innovation; intrahepatic; islet; neovascularization; non-diabetic; novel; novel strategies; release factor; scaffold; screening; subcutaneous; vascular bed

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.

项目摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，在美国，影响了160万人， 每年的医疗费用为160亿美元，每年的患病率增加64，000个新诊断。临床 胰岛移植（CIT），即通过肝门静脉输注胰岛，已显示出作为一种有希望的治疗方法。 T1 D治疗然而，只有50%的接受者在五年内保持胰岛素独立性， 目前仅限于T1 D患者的边缘子集，部分原因是两个主要限制：即时血液- 介导的炎症反应和延迟的胰岛血管化（>14天）。的显著损失 在肝内部位移植后的数小时至数天内，递送的胰岛（60-80%）发生。 因此，非常需要建立一种替代的移植部位，以避免即时出血- 介导的炎症反应，并支持胰岛的长期植入。皮下 该部位是一个有吸引力的肝外部位，在可及性、便利性、 重新给药（如有必要）、易于监测和易于检索（如有必要）。然而，未经修改的 皮下部位由于血管灌注不足而在临床上受到限制， 动力学和低氧。一个优雅的，容易的策略，以促进新血管形成是生物材料- 促血管生成因子如血管内皮生长因子（VEGF）的介导递送。VEGF 促进内皮细胞的生长，并且是天然胰岛血管形成和发育的主要调节剂。 本项目的目标是设计可注射的VEGF递送合成聚乙二醇[PEG] 促进胰岛血管化、植入和在皮下空间中发挥功能的水凝胶。我们有 先前工程化的含有VEGF的水凝胶，其促进胰岛存活、血管形成和功能， 啮齿动物性腺脂肪垫和网膜，具有高度固有血管化的部位。我的核心假设是 VEGF-递送凝胶可进一步优化以促进胰岛血管化、植入和 在皮下空间发挥作用，这是一个具有高临床潜力的部位。我的初步数据支持这一点 为该应用提供了强有力的科学前提和可行性。总体目标将 1）鉴定最佳支持VEGF-PEG水凝胶制剂， 使用血管化胰岛芯片平台的胰岛血管化; 2）评价VEGF-PEG水凝胶的能力 促进糖尿病大鼠同种异体胰岛血管化、植入和功能;和3）检查 VEGF-水凝胶促进同种异体胰岛血管化和植入皮下空间 非糖尿病猪该项目的预期成果包括：1）用于胰岛的可注射递送载体， 促进胰岛血管化、植入和皮下空间的功能，以及2）验证结果 这是一个大型动物模型，将为未来的转化型糖尿病大型动物模型研究提供信息。