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

基本信息

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
项目类别：
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

项目摘要

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 型糖尿病的一种有前途的替代疗法，减少或消除继发并发症和不良事件的潜力。强大的免疫反应胰岛仍然是长期植入和功能的最大挑战，这需要大量的胰岛和通常多个胰腺供体以实现血糖正常，这种并发症进一步加剧捐助者短缺。在没有慢性全身免疫抑制的情况下消除移植排斥的方法将极大地扩大符合条件的患者群体并降低与细胞治疗相关的风险。胰岛封装长期以来，人们一直提出将不可降解的生物材料作为减少免疫反应的一种手段。移植的移植物通过物理屏障直接被免疫细胞识别抗原，具有数十年的前景临床前研究；然而，由于临床效果不佳，该技术的转化受到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封装装置在临床前和临床研究中，尽管它们具有单一可回收装置的安全优势，这些设备的功能成功在很大程度上是由于氧气输送不良而受到限制。寻址这些宏观封装设备面临的具体限制，我们使用计算建模引导设备改善氧气输送的设计，以及可降解水凝胶引导的增强设备血管化表面以进一步最大化氧气进入并减轻纤维化。我们最近开发了一种水凝胶注射剂基于成型的方法来生成高表面积体积水凝胶宏观封装几何形状，使外科医生能够在收到尸体原代细胞后在诊所生成封装胰岛的方法胰岛隔离。该方法具有高度重复性，适用于多种水凝胶，并且易于实施。在此 I 期 SBIR 应用中，我们将研究宏观封装内的最佳胰岛密度同基因研究中的设备，并确定糖尿病逆转所需的最佳同种异体胰岛剂量为临床前大型动物同种异体研究的 II 期研究提供信息。这将在实验中解决以下具体目标： (1) 大囊糖尿病大鼠的同基因胰岛密度优化大网膜移植模型，以及 (2) 大囊糖尿病大鼠的同种异体胰岛剂量优化大网膜移植模型。预期结果是这些研究调查胰岛密度和剂量在高表面积体积宏观封装设计中，将确定适当的配置进入II期临床前大型动物模型。