Optimizing macroencapsulation devices for islet transplantation via magnetic resonance oximetry

项目总结/摘要： 临床胰岛移植是治疗胰岛素依赖型糖尿病的一种有前途的方法， 通过恢复天然胰岛素信号传导消除长期继发性并发症的潜力。虽然临床 成功证明了通过胰岛替代实现胰岛素非依赖性的可行性 然而，长期免疫抑制方案的必要性限制了这种疗法的广泛适用性。 由于与慢性免疫抑制相关的实质性风险超过糖尿病风险， 相关疾病因此，许多研究探索了大胶囊化的发展 从受体免疫系统中分离移植细胞的设备。迄今为止，这些设备证明 有限的临床功效，这在很大程度上是由于向包封的细胞输送的氧气有限。 在以前的工作中，我们证明了使用血管生成可降解水凝胶来增强 在大囊化装置的表面处的血管化和因此的氧合。尽管改善了 血管化，非理想的装置几何形状限制了体内包封的细胞活力和功能，如 器械氧合的计算机建模。因此，我们寻求使用以下方法来实现宏封装器件设计： 在制造和测试之前优化器件氧分布的计算建模，并评估 通过一种新型的基于硅氧烷探针的磁共振（MR）血氧测定法进行体外和体内器械氧合 该技术最初由共同研究者Vikram Kodibagkar博士开发，用于癌症应用。 我们假设，通过硅氧烷核心探针器械标记的MR血氧饱和度测定将实现首次精确测量。 以时空方式跟踪和评价宏包封装置氧合。我们预计 磁共振成像将验证在不同范围内的氧分布的计算机有限元建模预测， 宏包封装置设计，并实现非侵入性，实时跟踪宏包封装置 体内氧合水平。 这些假设将在以下具体目的的实验中得到解决：（1）验证 通过体外MR血氧测定法进行硅优化的宏包封装置氧梯度;（2）使用非侵入性 MR血氧定量法，用于真实的实时评估大囊化细胞移植物的体内氧合;以及（3）使用MR 血氧测定法，以评价按比例缩放至较大啮齿动物模型的大囊化装置。我们预计这项研究 将使得能够设计改进的宏包封装置， 存活和功能。这种装置设计、确认和体内评价的方法也可以促进 设备放大的过程，可能简化宏封装设备转换的过程， 诊所

PROJECT SUMMARY/ABSTRACT: Clinical islet transplantation is a promising treatment for insulin-dependent diabetic patients, with the potential to eliminate long-term secondary complications by restoring native insulin signaling. While clinical successes have demonstrated the feasibility of achieving insulin independence through islet replacement therapy, the necessity of a long term immunosuppressive regimen limits the widespread applicability of this procedure, as the substantial risk associated with chronic immunosuppression outweighs the risk of diabetes associated morbidities. As a result, much research has explored the development of macroencapsulation devices to isolate transplanted cells from the recipient immune system. To date, these devices demonstrate limited clinical efficacy, due in large part to limited oxygen delivery to encapsulated cells. In previous work, we demonstrated the use of vasculogenic degradable hydrogels to enhance vascularization, and therefore oxygenation, at the surface of macroencapsulation devices. Despite improved vascularization, non-ideal device geometry limits encapsulated cell viability and function in vivo, as indicated by in silico modeling of device oxygenation. As such, we seek to approach macroencapsulation device design using computational modeling to optimize device oxygen distribution prior to fabrication and testing, and evaluate device oxygenation in vitro and in vivo via a novel, siloxane probe-based magnetic resonance (MR) oximetry technique, originally developed by co-PI Dr. Vikram Kodibagkar for cancer applications. We hypothesize that MR oximetry, via siloxane core probe device labelling, will enable the first precise tracking and evaluation of macroencapsulation device oxygenation in a spatiotemporal manner. We anticipate that MR imaging will validate in silico finite element modeling predictions of oxygen distribution within varied macroencapsulation device designs, and enable non-invasive, real-time tracking of macroencapsulation device oxygenation levels in vivo. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) to validate in silico-optimized macroencapsulation device oxygen gradients via MR oximetry in vitro; (2) to use non-invasive MR oximetry to evaluate in vivo oxygenation of macroencapsulated cell grafts in real time; and (3) use MR oximetry to evaluate macroencapsulation devices scaled to a larger rodent model. We anticipate that this study will enable the design of improved macroencapsulation devices that significantly enhance encapsulated cell survival and function in vivo. This approach to device design, validation, and in vivo evaluation may also facilitate the process of device scale-up, potentially streamlining the process of macroencapsulation device translation to the clinic.