Islet dosing and loading density in injection molded macroencapsulation devices

项目总结/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， 可能减少或消除继发性并发症和不良事件。免疫系统对 胰岛仍然是长期植入和功能的最大挑战，这需要大量的胰岛细胞。 胰岛和典型的多个胰腺供体来实现功能正常化， 捐助者短缺。在无慢性全身免疫抑制的情况下消除移植物排斥反应的方法 这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。胰岛包裹 在不可降解的生物材料中，长期以来一直被提出作为减少免疫反应的手段， 移植移植物通过物理屏障直接识别免疫细胞的抗原，几十年来， 临床前研究中的研究;然而，该技术的转化受到不良临床研究的阻碍， 结果和安全问题。因此，已经探索了用于胰岛包封的宏包封装置 在临床前和临床研究中，尽管它们提供了单个可回收器械的安全性受益， 这些装置的功能成功受到限制，这在很大程度上是由于氧气输送不良。解决 这些具体的限制，面对宏封装设备，我们使用计算建模引导设备 设计用于改善氧气输送，以及可降解水凝胶引导的器械血管化增强 表面以进一步最大化氧气获取并减轻纤维化。我们最近开发了一种水凝胶注射剂 本发明涉及一种用于产生高表面积比体积的水凝胶宏观包封几何形状的基于模制的方法， 一种使外科医生能够在收到尸体原代胰岛细胞后在临床上生成包膜胰岛的方法 孤立的小岛该方法具有高度可重复性，适用于各种水凝胶，并且易于实施。 在第一阶段SBIR应用中，我们将研究巨囊内的最佳胰岛密度 设备在同基因研究，并确定最佳的同种异体胰岛剂量所需的糖尿病逆转， 为临床前大型动物同种异体研究中的II期研究提供信息。这将在实验中得到解决 具体目的如下：（1）在大囊化糖尿病大鼠中优化同基因胰岛密度 大网膜移植模型，和（2）大囊化糖尿病大鼠中同种异体胰岛剂量优化 大网膜移植模型。预期的结果是，这些研究胰岛密度和剂量 在高表面积体积比的宏包封设计中， 进入II期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.