Islet dosing and loading density in injection molded macroencapsulation devices

注塑宏观封装装置中的胰岛剂量和装载密度

• 批准号: 10716174
• 负责人: Oren Snir
• 金额: $ 29.84万
• 依托单位: IMMUNOSHIELD THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2024-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10716174
• 关键词: Address; Adverse event; Alginates; Allogenic; Alternative Therapies; American; Animal Model; Animals; Antigens; Area; Benchmarking; Biocompatible Materials; Cadaver; Cell Therapy; Cell Transplantation; Cells; Chronic; Clinic; Clinical; Clinical Research; Complication; Complications of Diabetes Mellitus; Computer Models; Device Designs; Devices; Diabetes Mellitus; Dose; Eligibility Determination; Encapsulated; Engraftment; Fibrosis; Geometry; Graft Rejection; Graft Survival; Hepatic; Histologic; Human; Hydrogels; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Longevity; Methods; Microcapsules drug delivery system; Mission; Modeling; Molds; Morphology; Omentum; Outcome; Oxygen; Pancreas; Patients; Phase; Population; Portal vein structure; Public Health; Rattus; Regimen; Reproducibility; Research; Risk Reduction; Safety; Site; Small Business Innovation Research Grant; Surface; Surgeon; Techniques; Translating; Translations; Transplantation; United States National Institutes of Health; Vascularization; Work; clinical translation; density; design; diabetic; diabetic rat; dosage; euglycemia; experimental study; graft function; high risk; improved; in vivo; insulin signaling; islet; oxygen transport; patient population; phase 2 study; pre-clinical; preclinical study; preservation; prevent; success; transplant model

PROJECT SUMMARY/ABSTRACT: Clinical islet transplantation is a promising alternative therapy for the treatment of type 1 diabetes, with the potential to reduce or eliminate secondary complications and adverse events. The potent immune response to islets remains the greatest challenge to long-term engraftment and function, which necessitates large numbers of islets and typically multiple pancreatic donors to achieve euglycemia, a complication further exacerbated by donor shortages. Methods to eliminate graft rejection in the absence of chronic systemic immunosuppression will vastly expand the eligible patient population and reduce risks associated with cell therapy. Islet encapsulation within a nondegradable biomaterial has long been proposed as a means for reducing immune response to transplanted grafts via a physical barrier to direct antigen recognition by immune cells, with decades of promising research in preclinical studies; however, translation of this technique has been hampered by poor clinical outcomes and safety concerns. As such, macroencapsulation devices for islet encapsulation have been explored in preclinical and clinical studies, and though they confer the safety benefit of a single, retrievable device, functional success of these devices has been limited due in large part to poor oxygen transport. Addressing these specific limitations facing macroencapsulation devices, we use computational modeling-guided device design for improved oxygen transport, and degradable hydrogel-guided enhanced vascularization at the device surface to further maximize oxygen access and mitigate fibrosis. We recently developed a hydrogel injection molding-based method to generate high surface area to volume hydrogel macroencapsulation geometries, a method that enables surgeons to generate encapsulated islets in the clinic upon receipt of cadaveric primary islet isolations. This method is highly reproducible, works with diverse hydrogels, and simple to implement. In this Phase I SBIR application, we will investigate the optimal islet density within macroencapsulation devices in syngeneic studies and identify the optimal allogeneic islet dosage required for diabetes reversal to inform Phase II studies in preclinical large animal allogeneic studies. This will be addressed in the experiments of the following Specific Aims: (1) Syngeneic islet density optimization in a macroencapsulated diabetic rat omentum transplant model, and (2) Allogeneic islet dose optimization in a macroencapsulated diabetic rat omentum transplant model. The expected outcome is that these studies investigating islet density and dosage within high surface area to volume macroencapsulation designs will identify the appropriate configuration to advance to phase II preclinical large animal models.

项目摘要/摘要： 临床胰岛移植是治疗1型糖尿病的有前途的替代疗法， 减少或消除次要并发症和不良事件的潜力。有效的免疫反应 胰岛仍然是长期植入和功能的最大挑战，这需要大量 胰岛，通常是多个胰腺供体来实现尤利西亚的供体，这一并发症进一步加剧了 捐助者短缺。在没有慢性全身免疫抑制的情况下消除移植物排斥的方法 将大大扩大符合条件的患者人群，并降低与细胞疗法有关的风险。胰岛封装 长期以来，在不可核能的生物材料中长期以来，作为减少对免疫反应的一种手段 通过物理屏障移植移植的移植物，以直接通过免疫细胞识别抗原识别，数十年有前途 临床前研究的研究；但是，这种技术的翻译受到临床不良的阻碍 结果和安全问题。因此，已经探索了用于胰岛封装的宏观废包设备 在临床前和临床研究中，尽管它们赋予了单个可检索设备的安全益处，但 这些设备的功能成功在很大程度上是由于氧气运输差而受到限制。寻址 这些特定的限制面临宏观塑料设备，我们使用计算建模引导的设备 设计改进的氧气传输，并在设备上降解的水凝胶引导增强的血管化 表面进一步最大化氧气获取并减轻纤维化。我们最近开发了水凝胶注入 基于成型的方法，以产生高表面积到体积水凝胶宏观塑料几何，A 使外科医生在收到尸体初级后能够在诊所中产生封装的胰岛的方法 胰岛隔离。该方法具有高度可重现的，可与多种水凝胶一起使用，并且易于实施。 在此I阶段I SBIR应用程序中，我们将研究宏观囊泡中的最佳胰岛密度 合成研究中的设备，并确定糖尿病逆转所需的最佳同种异体胰岛剂量 在临床前大动物同种异体研究中为II期研究提供了信息。这将在实验中解决 在以下特定目的中：（1）宏观化糖尿病大鼠中的同步胰岛密度优化 大脑移植模型和（2）在大型糖尿病大鼠中优化的同种异体胰岛剂量优化 omentum移植模型。预期的结果是这些研究胰岛密度和剂量 在高表面积到卷宏观塑料设计中，将确定适当的配置 前进到II期临床前大动物模型。