High Cell Density Bioartificial Pancreas Enabled by Implantable Oxygen Generator

描述（由申请人提供）：该拟议SBIR项目的总体目标是开发一种小型化植入式氧气发生器，该发生器将持续向免疫隔离细胞植入装置内的细胞供氧。这将在高细胞密度下保持细胞活力和功能，从而最大限度地减少整体植入物尺寸。氧气发生器将由远程充电电池供电。该平台技术的第一个拟议应用是用于治疗1型糖尿病（T1 D）的胰岛植入物。氧合器与特征良好的免疫隔离装置的组合被称为具有植入式供氧的生物人工胰腺（BAPIOS）。植入式氧气发生器也是一种平台技术，可以与其他细胞植入装置和其他治疗性细胞类型组合，用于其他细胞疗法，用于肝衰竭， 帕金森病、甲状腺（帕拉）疾病和血友病。胰岛同种异体移植正在美国进行临床试验。也有来自领先中心的结果表明，50%的接受者的胰岛素依赖性超过5年。然而，T1 D的广泛临床应用受到两个关键障碍的阻碍：1）目前门静脉内肝移植部位需要全身免疫抑制; 2）人胰岛组织的有限和低供应（每年几千个合适的供体）。使用生物相容性的、可回收的细胞分离装置可以通过使得能够更有效和高效地使用同种异体胰岛而没有免疫抑制以及最终使用干细胞衍生的或异种胰岛而具有最小或没有免疫抑制来解决这些关键障碍。自体移植（用于胰腺炎患者和癌前诊断）也可以受益于具有可回收性和细胞免疫隔离的简单植入程序。目前的细胞植入装置具有不足的氧气（即使装置预血管化）来提供实际尺寸的临床植入物所需的高细胞密度。拟议的技术将包括第一个可植入的，连续的氧气供应与集成的可充电电池。为期12个月的第一阶段项目的具体目标是：目标1：设计和制造微型氧气发生器（氧合器）;目标2：I期微型氧合器和氧合植入器械的体外评价;目标3：糖尿病裸大鼠模型中的初步体内试验;目标4：II期实施的具有植入式供氧的完整生物人工胰腺（BAPIOS）的设计。该目标包括完全植入式氧合器以及针对该应用的细胞植入装置的定制。这个I期可行性研究将为最终设计和制造完全植入式氧合电池提供基础 在II期和大型动物研究中植入，最终导致人类T1 D的治疗。

DESCRIPTION (provided by applicant): The overall goal of this proposed SBIR project is to develop a miniaturized implantable oxygen generator that will continuously supply oxygen to cells within an immunoisolation cell implant device. This will maintain cellular viability and function at high cell densities thus minimizing overall implant size. The oxygen generator will be powered by a remotely rechargeable battery. The first proposed application of this platform technology is pancreatic islet implant for the treatment of Type 1 diabetes (T1D). The combination of the oxygenator with a well-characterized immunoisolation device is termed a bioartificial pancreas with implantable oxygen supply (BAPIOS). The implantable oxygen generator is also a platform technology that could be combined with other cell implant devices and other therapeutic cell types for other cellular therapies for conditions such as liver failure, Parkinson's disease, (para)thyroid disease and hemophilia. Pancreatic islet allotransplantation is in U.S. clinical trials. There are also results from leading centers demonstrating insulin independence for more than 5 years for 50% of the recipients. However, widespread clinical application of for T1D is hindered by two critical barriers: 1) the need for systemic immunosuppression for the current intraportal liver transplant site; and 2) by the finite and low supply of human islet tissue (a few thousand suitable donors per year). The use of biocompatible, retrievable, cell isolating devices may address these critical barriers by enabling the more effective and efficient use of allogeneic islets without immunosuppression and the eventual use of stem cell-derived or xenogeneic islets with minimum or no immunosuppression. Autotransplantation (for pancreatitis patients and pre-cancer diagnosis) could also benefit from a simple implant procedure with retrievability and cellular immunoisolation. Current cell implant devices have insufficient oxygen (even with prevascularization of the device) to provide the high cellular densities required for practically-sized clinical implants. The proposed technology would include the first implantable, continuous oxygen supply with integrated rechargeable battery. The Specific Aims of the 12 month Phase I project are: Aim 1: Design and fabrication of a miniature oxygen generator (oxygenator); Aim 2: In vitro evaluation of the Ph I miniature oxygenator and the oxygenated implant device; Aim 3: Preliminary in vivo testing in a diabetic nude rat model; and Aim 4: Design of complete bioartificial pancreas with implantable oxygen supply (BAPIOS) for implementation in Ph II. This aim includes a fully implantable oxygenator as well as customization of the cell implant device for this application. This Ph I feasibility stuy will provide the groundwork for final design and fabrication of a fully implantable oxygenated cell implant in Phase II and large animal studies ultimately leading to the treatment of T1D in humans.