Pressure Management Technologies for Oxygenation of Implanted Insulin Secreting Cells

项目总结 移植胰岛素分泌细胞充氧的压力管理技术 SBIR项目的总体目标是开发一种先进的、微型化的植入式电化学 氧气发生器，以良好调节的剂量和浓度向细胞供应氧气 免疫隔离装置，以确保它们在高密度下的生存和功能，并最大限度地减少整体植入 尺码。拟议的第二阶段计划解决了NIDDK特别RFA中的几个关键重点领域。 核心创新是一种正在申请专利的自我调节电化学气体发生器(SREGG)，它 本质上管理产生的氧气的压力；这允许仔细控制氧气剂量， 设备简单性和可靠性。SREGG将成为Giner的最终制氧模块 植入供氧的生物人工胰腺(BAPIOS™)系统。全植入型BAPIOS™ 系统包括SREGG、装满葡萄糖调节细胞的细胞胶囊和电源/控制电子设备； 系统充电是在晚上通过无线经皮能量转移。BAPIOS™系统 开发是在单独的Giner和NIDDK(R44DK100999)资金下进行的。 移植细胞的氧合对于在高细胞密度下维持活性和功能至关重要， 将植入物的整体尺寸降至最小。Giner BAPIOS™系统的第一个提出的应用是人类 胰岛移植治疗1型糖尿病(T1D)，未来将应用于2型糖尿病。这个 SREGG也是一种平台技术，可以与各种细胞植入设备和治疗相结合 用于额外细胞疗法的细胞类型。BAPIOS™系统包括一个细胞植入胶囊，带有临床 测试和证明的安全记录，并将被完全植入皮下，不容易感染 经皮管/导联。此方法优于同种异体胰腺移植或门脉内胰岛移植。 因为它将涉及简单的手术，并避免长期系统性的成本和健康风险 免疫抑制。吉纳的最终解决方案将利用干细胞来源细胞的最新进展 来源，消除了通过捐赠和隔离来获取同种异体胰岛的需要。BAPIOS的™治疗 将消除标准胰岛素药物疗法的累积压力(即蛋白质的糖基化和 由于频繁的高血糖造成的后遗症)通过给予自然的血糖控制；以及没有磨损 泵、频繁的血液检测和注射为T1D患者带来了新的自由和积极的生活方式。 在第一阶段项目中，在材料选择和优化工艺方面取得了重大进展 SREGG电池的设计和建造。出色的压力调节、电池效率和长期性能 在几个SREGG细胞原型的台架测试中得到了演示。开发一部小说， 采用互补型电流控制芯片组，该电路具有高效、可靠的特点 以及对未来植入物应用的实质性小型化的适应性。详细的SREGG设计是 产生了将细胞过渡到第二阶段的植入测试的可行性之外。 第二阶段的工作将进一步开发SREGG电池，用于集成和植入、设计和制造 支持临床前试验的电子控制和压力监测设备，并显示压力 在小动物模型中使用SREGG细胞和相关的生物人工胰腺成分进行对照， 在糖尿病大鼠模型中实现30天血糖控制的目标。吉纳将转包给一家医疗机构 设备制造商指定、测试和制造符合ISO 13485设计的先进临床前系统 控制力。吉纳还将组建一个协作团队，以支持和进行动物研究，开发 临床前/临床实施方案，并进行体内和移植后评估 植入的装置。该计划还将有助于科学工作的主体，以了解 高纯度人胰岛在低氧条件下的代谢和胰岛素分泌行为 大胶囊。

PROJECT SUMMARY Pressure Management Technologies for Oxygenation of Implanted Insulin-Secreting Cells The overall goal of the SBIR project is to develop an advanced, miniaturized implantable electrochemical oxygen generator that supplies oxygen at well-regulated dose and concentration to cells within an immunoisolation device, so as to ensure their viability and function at high density and minimize overall implant size. The proposed Phase II program addresses several key areas of emphasis in this NIDDK special RFA. The core innovation is a patent-pending, self-regulating electrochemical gas generator (SREGG), which intrinsically manages the pressure of oxygen generated; this allows for careful control over oxygen dose, device simplicity and dependability. The SREGG will be the definitive oxygen generation module of the Giner bioartificial pancreas with implanted oxygen supply (BAPIOS™) system. The fully implantable BAPIOS™ system includes the SREGG, cell capsule filled with glucose-regulating cells and power/control electronics; system recharging is via wireless transcutaneous energy transfer in the evenings. The BAPIOS™ system development is taking place under separate Giner and NIDDK (R44DK100999) funding. Oxygenation of implanted cells is critical to maintaining viability and function at high cellular densities, minimizing overall implant size. The first proposed application of the Giner BAPIOS™ system is a human pancreatic islet implant for treatment of type 1 diabetes (T1D), with future application to type 2 diabetes. The SREGG is also a platform technology that may be combined with various cell implant devices and therapeutic cell types for additional cell therapies. The BAPIOS™ system includes a cell implant capsule with clinical testing and proven safety records, and will be fully implanted subcutaneously without infection-prone percutaneous tubes/leads. This approach is superior to allogenic pancreas or intraportal islet transplantation because it will involve simple surgery and avoids the cost and health hazards of long term systemic immunosuppression. Giner’s ultimate solution will leverage the most recent progress in stem cell-derived cell sourcing, obviating the need to procure allogeneic islets by donation and isolation. The BAPIOS™ treatment will eliminate accumulated strain of standard insulin drug therapy (i.e., glycosylation of proteins and risk of sequelae due to frequent high blood sugar) by imparting natural glucose control; and the absence of worn pumps, frequent blood testing and injections promises renewed freedom and active lifestyles for T1D sufferers. In the Phase I project, significant progress was achieved in selection of materials and optimization of the SREGG cell design and construction. Excellent pressure regulation, cell efficiency and long-term performance were demonstrated in bench testing of several SREGG cell prototypes. Development of a novel, complementary current control chipset was also undertaken, and this circuitry showed high efficiency, reliability and amenability to substantial future miniaturization for implant applications. A detailed SREGG design was generated to transition the cell beyond feasibility toward implant testing in Phase II. The Phase II effort will further develop the SREGG cell for integration and implantation, design and fabricate electronic controls and pressure monitoring devices in support of preclinical tests, and demonstrate pressure control using the SREGG cell and associated bioartificial pancreas components in a small animal model, with the goal of achieving 30 days of glucose control in a diabetic rat model. Giner will subcontract with a medical device manufacturer to specify, derisk and fabricate advanced preclinical systems under ISO 13485 design control. Giner will additionally assemble a collaborative team to support and conduct animal studies, develop protocols for preclinical/clinical implementation, and perform in vivo and post-explant evaluations of the implanted devices. The program will also contribute to the body of scientific work toward the understanding of the metabolic and insulin secretion behavior of high purity human islets under the conditions of macroencapsulation.