High Cell Density Bioartificial Pancreas Enabled by Implantable Oxygen Generator

 SBIR项目的总体目标是开发和测试具有植入式氧气供应的人类规模生物人工胰腺（BAPIOS（tm））。这包括一个小型化的植入式电化学氧气发生器（EOG），它将连续供应氧气给免疫隔离细胞植入装置内的胰岛或胰岛细胞。氧合在高细胞密度下维持细胞活力和功能，从而最大限度地减小植入物的总体尺寸。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）的人类胰岛植入物。植入式EOG也是一种平台技术，可以与各种细胞植入装置和治疗性细胞类型组合，用于针对肝衰竭、帕金森病、（帕拉）甲状腺疾病和胰腺切除术等适应症的额外细胞疗法。Giner BAPIOS（TM）系统包括一个细胞植入胶囊，具有临床测试和经证实的安全记录。BAPIOS（tm）系统将完全皮下植入，无易感染的经皮导管/电极导线。门静脉内胰岛同种异体移植（IPIATx）肝脏正在成为选定T1 D患者的一种有前途的治疗方法。来自领先中心的结果表明，50%的受者的胰岛素依赖性超过5年;这接近复杂的全胰腺移植的成功率，但IPIATx目前需要2-3个供体的胰岛。胰岛移植用于T1 D的广泛临床应用受到关键障碍的阻碍，包括：1）当前移植部位需要全身免疫抑制;和2）人胰岛组织的有限供应（每年<5，000名美国胰腺供体）。生物相容性、可回收的细胞分离装置的使用通过使得能够更有效和高效地使用同种异体胰岛而无需免疫抑制以及最终使用葡萄糖响应性、胰岛素分泌细胞的替代来源来解决这些关键障碍。在PhI项目中，在大鼠模型中明确证明，氧气对于高密度植入物（8，000人胰岛当量（IE）/cm 2）的活力和功能是必要的。结果还表明，皮下包封的含氧植入物逆转了糖尿病，与该动物模型中肝脏或肾脏包膜部位的文献结果相比，胰岛更少（边缘质量更低）。 设计并制造了微型EOG;测试证明了超过足够的氧气来支持预期用于人体植入的胰岛剂量。PhII项目的成果将是第一个具有植入式氧气供应的生物人工胰腺。Ph II Giner BAPIOS（tm）系统将采用模块化设计，包括：a）具有生物相容性和进入体液的新规定的可植入人体规模EOG; B）利用经皮能量转移的动力系统;以及c）为氧气输送定制的已建立细胞胶囊（TheraCyte（tm））。该方案的结论是：1）临床前试验测试完全植入式PhI系统;和2）完整设计Giner BAPIOS（tm）系统的人体临床模型，用于未来的实施和临床测试。

 DESCRIPTION (provided by applicant): High Cell Density Bioartificial Pancreas Enabled by Implantable Oxygen Generator The overall goal of the SBIR project is to develop and test a human scale BioArtificial Pancreas with Implantable Oxygen Supply (BAPIOS(tm)). This consists of a miniaturized implantable electrochemical oxygen generator (EOG) that will continuously supply oxygen to islets or ß-cells within an immunoisolation cell implant device. Oxygenation maintains cell viability and function at high cellular densities, minimizing overall implant size. The first proposed application of this platform technology is a human pancreatic islet implant for the treatment of Type 1 diabetes (T1D). The implantable EOG is also a platform technology that may be combined with various cell implant devices and therapeutic cell types for additional cell therapies for indications such as liver failure, Parkinson's disease, (para)thyroid disease and pancreatectomy. The Giner BAPIOS(tm) system includes a cell implant capsule with clinical testing and proven safety records. The BAPIOS(tm) system will be fully implanted subcutaneously without infection-prone percutaneous tubes/leads. Intraportal Pancreatic Islet Allogeneic Transplantation (IPIATx) liver is emerging as a promising treatment for select T1D patients. Results from leading centers demonstrate insulin independence for more than 5 years for 50% of the recipients; this approaches the success rate of a complex whole pancreas transplant, but IPIATx currently requires islets from 2-3 donors. Widespread clinical application of islet transplantation for T1D is hindered by critical barriers including: 1) the need for systemic immunosuppression for the current transplant site; and 2) the limited supply of human islet tissue (<5,000 U.S. pancreas donors per year). The use of biocompatible, retrievable, cell isolating devices addresses these critical barriers by enabling the more effective and efficient use of allogeneic islets without immunosuppression and the eventual use of alternative sources of glucose-responsive, insulin-secreting cells. In the PhI project, it was definitively demonstrate in a rat model that oxygen is necessary to allow the viability and function of a high density implant (8,000 human islet equivalents (IE) per cm2). The results also showed that subcutaneous encapsulated oxygenated implants reversed diabetes with fewer islets (lower marginal mass) than literature results for the liver or kidney capsule sites in this animal model. miniature EOG was designed and fabricated; testing demonstrated more than sufficient oxygen for supporting the islet dose anticipated for human implant. The outcome of the PhII project will be the first bioartificial pancreas with implantable oxygen supply. The Ph II Giner BAPIOS(tm) system will have a modular design including: a) an implantable human scale EOG with novel provisions for biocompatibility and access to body water; b) a power system utilizing transcutaneous energy transfer; and c) an established cell capsule (TheraCyte(tm)) tailored for oxygen delivery. The program concludes with: 1) preclinical trial testing the fully implantable PhI system; and 2) complete design for the human clinical model of the Giner BAPIOS(tm) system for future implementation and clinical testing.