Optimizing macroencapsulation devices for islet transplantation via magnetic resonance oximetry

项目摘要/摘要： 临床胰岛移植是治疗胰岛素依赖型糖尿病患者的一种有前途的治疗方法， 通过恢复天然胰岛素信号来消除长期继发性并发症的可能性。在临床上 已有的成功证明了通过胰岛替代实现胰岛素独立的可行性。 治疗上，长期免疫抑制疗法的必要性限制了这种疗法的广泛适用性 程序，因为与慢性免疫抑制相关的实质性风险超过了糖尿病的风险 相关的病症。因此，许多研究对大胶囊的发展进行了探索 从受者免疫系统中分离移植细胞的设备。到目前为止，这些设备展示了 临床疗效有限，很大程度上是由于对被包裹细胞的氧气输送有限。 在之前的工作中，我们演示了使用血管生成可降解水凝胶来增强 在大胶囊化设备的表面形成血管，从而产生氧合作用。尽管情况有所改善 血管化，非理想的装置几何结构限制了被包裹的细胞在体内的活性和功能，如 在设备充氧的计算机模拟中。因此，我们尝试使用以下方法来设计宏封装设备 在制造和测试之前优化设备氧气分布的计算建模，并评估 一种新的基于硅氧烷探头的磁共振血氧仪在体内外的装置氧合 这项技术最初是由与PI合作的Vikram Kodibagkar博士开发的，用于癌症应用。 我们推测，通过标记硅氧烷核心探头装置，磁共振血氧测定仪将能够实现第一个精确的 以时空方式跟踪和评估大胶囊设备的氧合作用。我们期待着 磁共振成像将在电子有限元模拟中验证对不同区域内氧分布的预测 大胶囊设备的设计，并实现对大胶囊设备的非侵入性、实时跟踪 体内的氧合水平。 这些假设将在以下具体目标的实验中得到解决：(1)验证 硅胶优化大胶囊装置体外血氧梯度磁共振血氧测定仪；(2)使用非侵入性 磁共振血氧仪实时评估大胶囊细胞移植物体内的氧合情况；以及(3)使用磁共振 血氧测定仪评估大胶囊设备的规模，以适应更大的啮齿动物模型。我们预计这项研究 将支持改进的宏封装设备的设计，从而显著增强封装的细胞 在体内的存活和功能。这种设备设计、验证和体内评估的方法也可以促进 设备纵向扩展过程，潜在地简化了将宏封装设备转换为 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.