Islet dosing and loading density in injection molded macroencapsulation devices

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，具有 有可能减少或消除继发性并发症和不良事件。强效的免疫反应 胰岛仍然是长期植入和发挥作用的最大挑战，这需要大量的 胰岛和通常是多个胰腺供体以实现正常血糖，这一并发症因 捐赠者短缺。在没有慢性全身免疫抑制的情况下消除移植物排斥反应的方法 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 在不可降解的生物材料内，长期以来一直被认为是降低免疫反应的一种手段 移植的移植物通过物理屏障引导免疫细胞识别抗原，几十年来前景看好 临床前研究；然而，这项技术的翻译因糟糕的临床而受阻 结果和安全问题。因此，已经探索了用于胰岛封装的大胶囊装置 在临床前和临床研究中，尽管它们提供了单一的、可回收的设备的安全益处， 这些设备的功能成功在很大程度上是由于氧气运输不力所致。寻址 面对这些宏胶囊设备的具体限制，我们使用了计算建模引导的设备 改善氧气传输的设计，以及可降解的水凝胶引导的增强设备中的血管形成 表面，以进一步最大限度地获得氧气和减轻纤维化。我们最近开发了一种水凝胶注射剂 基于模塑的产生高表面积到体积的水凝胶大胶囊几何形状的方法， 一种方法，使外科医生能够在临床上接收到主要身体时产生被包裹的胰岛 胰岛隔离。该方法重复性强，适用于多种水凝胶，且易于实现。 在这个第一阶段的SBIR应用中，我们将研究大胶囊内的最佳胰岛密度 同基因研究中的装置并确定糖尿病逆转所需的最佳同种异体胰岛剂量 通知临床前大型动物同种异体研究的第二阶段研究。这个问题将在实验中解决。 具体目的如下：(1)大囊化糖尿病大鼠同基因胰岛密度优化 大网膜移植模型；(2)大胶囊糖尿病大鼠同种异体胰岛剂量的优化 大网膜移植模型。预期的结果是，这些调查胰岛密度和剂量的研究 在高表面积到体积的情况下，大胶囊设计将确定适当的配置，以 进展到第二阶段临床前大型动物模型。

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.