Optimizing macroencapsulation devices for islet transplantation via magnetic resonance oximetry

通过磁共振血氧测定法优化胰岛移植的宏观封装装置

基本信息

批准号：
10276561
负责人：
Vikram D. Kodibagkar
金额：
$ 34.67万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-16 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10276561
关键词：
Address Allogenic American Cell Density Cell Survival Cell Transplantation Cell physiology Cells Chronic Clinic Clinical Complications of Diabetes Mellitus Computer Models Containment Coupled Development Device Designs Device or Instrument Development Devices Diffusion Elements Encapsulated Evaluation Finite Element Analysis Geometry Graft Survival Health Hydrogels Immune system Immunosuppression In Vitro Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Label Location Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Measures Mission Modeling Monitor Morbidity - disease rate Mus Organoids Oxygen Oxygen saturation measurement Patients Performance Population Procedures Process Protocols documentation Protons Public Health Rattus Regimen Replacement Therapy Reporter Research Risk Rodent Model Safety Siloxanes Site Spatial Distribution Surface Techniques Testing Time Tissues Translating Translations Transplantation United States National Institutes of Health Validation Vascularization Work base clinical efficacy design diabetes risk diabetic diabetic patient diabetic rat experimental study graft function improved in silico in vitro testing in vivo in vivo Model in vivo evaluation infection risk insulin signaling islet mouse model non-invasive monitor novel preclinical efficacy predictive modeling scale up spatiotemporal success tissue oxygenation tool type I diabetic vasculogenesis

项目摘要

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.

项目概要/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传导来消除长期继发并发症的潜力。同时临床成功证明了通过胰岛替代实现胰岛素独立的可行性治疗中，长期免疫抑制疗法的必要性限制了该疗法的广泛应用程序，因为与慢性免疫抑制相关的重大风险超过了糖尿病的风险相关的疾病。因此，许多研究探索了宏观封装的发展将移植细胞与受体免疫系统分离的装置。迄今为止，这些设备表明临床疗效有限，很大程度上是由于向封装细胞输送的氧气有限。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宏观封装装置表面的血管化，以及因此的氧合。尽管有所改善血管化、非理想的装置几何形状限制了封装细胞的活力和体内功能，如装置氧合的计算机模拟。因此，我们寻求使用宏封装器件设计在制造和测试之前优化设备氧气分布的计算模型，并评估通过基于硅氧烷探针的新型磁共振 (MR) 血氧测定法进行体外和体内氧合装置技术最初由联合 PI Vikram Kodibagkar 博士开发用于癌症应用。我们假设 MR 血氧测定法，通过硅氧烷核心探针装置标记，将能够实现第一个精确的血氧饱和度测定。以时空方式跟踪和评估宏观封装装置氧合。我们预计 MR 成像将在硅片有限元建模中验证不同范围内氧气分布的预测宏封装器件设计，并实现宏封装器件的非侵入式实时跟踪体内氧合水平。这些假设将在以下具体目标的实验中得到解决：（1）验证通过体外 MR 血氧测定法进行计算机优化的宏观封装装置氧梯度； (2)采用非侵入式 MR 血氧测定法实时评估大封装细胞移植物的体内氧合作用； (3) 使用 MR 血氧测定法评估宏观封装装置缩放到更大的啮齿动物模型。我们预计这项研究将能够设计改进的宏观封装装置，从而显着增强封装的电池体内的生存和功能。这种设备设计、验证和体内评估方法也可能有助于器件放大的过程，有可能简化宏封装器件转换的过程诊所。