Human-derived hemoglobin based oxygen carrier for utilization in organ and tissue preservation

基于人源血红蛋白的氧载体用于器官和组织保存

• 批准号: 9254282
• 负责人: William Richard Light
• 金额: $ 23.9万
• 依托单位: VIRTECH BIO, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-24 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254282
• 关键词: Address; Anions; Biological Preservation; Biotechnology; Blood; Buffers; Carbon Dioxide; Cattle; Cell Survival; Clinical; Colloids; Complex; Contracts; Coupled; Cytolysis; Development; Devices; Equilibrium; Equipment; Erythrocytes; Excipients; Excision; Filtration; Fluid Shifts; Formulation; Gases; Generations; Glutaral; Hemoglobin; Hour; Human; Hydrogen; Length of Stay; Light; Measures; Medical Device; Membrane; Methods; Molecular Weight; Morbidity - disease rate; Organ; Organ Preservation; Organ Preservation Solutions; Organ Viability; Osmotic Pressure; Osmotic Shocks; Outcome; Oxygen; Perfusion; Phase; Postoperative Period; Process; Production; Property; Reducing Agents; Reporting; Research; Schiff Bases; Series; Small Business Innovation Research Grant; Source; System; TNFRSF5 gene; Temperature; Testing; Time; Tissue Viability; Tissues; Toxic effect; Transfusion; Transplantation; Ultrafiltration; Universities; Variant; Waiting Lists; Wisconsin; Work; base; biomarker discovery; biophysical properties; cost; cost effective; design; drug discovery; experience; improved; in vivo; liver preservation; manufacturing process; member; microchip; mortality; novel strategies; oxygen transport; polymerization; pre-clinical; pressure; prototype; research study; sodium borohydride; stability testing; tissue/organ preservation

This project aims to develop a human derived Hemoglobin-Based Oxygen Carrier (HBOC) solution (Phase I) to be utilized in numerous ex-vivo applications (Phase II) where an oxygen delivery solution is required: 1) machine perfusion (MP) systems for organ and tissue preservation, 2) MP systems for the discovery of biomarkers, and 3) perfusate in human microchips for drug discovery. This is the first HBOC to be developed specifically for ex-vivo applications with the novel approach being an excipient that balances for ex-vivo fluid shifts. Furthermore, this new product will be developed within a streamlined, highly efficient commercial process that will allow a seamless transition to cost-effective Contract Manufacturing Organizations (CMO). VirTech Bio's HBOC and manufacturing process were conceived following successful proof-of-concept ex-vivo studies 1 with an HBOC (Hemopure®). Unfortunately, the company (OPK Biotech) went bankrupt in 2014. Hemopure had a complex and expensive manufacturing process 2,3 that precluded the use of any CMO. The main issues were related to bovine contamination, hydrogen gas toxicity and the need for expensive and specialized equipment. VirTech Bio's's new process developed for this SBIR Phase I proposal addresses all these concerns while creating a more cost-effective commercial production of this component. The initial source of human hemoglobin molecules will be expired human blood obtained through a process 4 already approved by regulatory bodies. The outdated human red blood cells will be `washed' via ultrafiltration, lysed by osmotic shock and purified by a three-step tangential flow filtration system to remove cellular impurities. Subsequently, polymerization will be with glutaraldehyde, followed by Schiff-base stabilization. The Specific aims include: 1) biophysical characterization to demonstrate similarity with the original HBOC, 2) stability testing of the molecular weight and storage parameters and 3) compatibility testing with machine perfusion (without the organs) for 12 hours at relevant conditions. This product once developed and validated will be coupled with a machine perfusion device in Phase II and utilized for liver preservation according to our previous experience. The new HBOC for utilization in organ preservation should have a significant positive impact in clinical transplantation. Effective organ oxygenation ex-vivo will enhance the current standards of organ preservation and increase the number of transplants 5. It should have additional positive downstream effects by decreasing the morbidity and the mortality on the transplant waiting list 6, improving post-operative outcomes and decreasing the length-of-stay 7. All these benefits should have a direct impact in the ability to decrease the overall costs in clinical transplantation 8. !

该项目旨在开发一种人源血红蛋白载氧体（HBOC）解决方案（第一阶段） 可用于需要氧气输送解决方案的众多离体应用（第二阶段）：1) 用于保存器官和组织的机器灌注 (MP) 系统，2) 用于发现 生物标记物，3) 灌注到人体微芯片中用于药物发现。这是第一个开发的HBOC 专门针对离体应用，新方法是平衡离体液体的赋形剂 轮班。此外，该新产品将在精简、高效的商业模式内开发 该流程将允许无缝过渡到具有成本效益的合同制造组织 (CMO)。 VirTech Bio 的 HBOC 和制造工艺是在成功的体外概念验证后构思的 研究 1 使用 HBOC (Hemopure®)。不幸的是，该公司（OPK Biotech）于2014年破产。 Hemopure 的制造工艺复杂且昂贵 2,3，无法使用任何 CMO。这 主要问题涉及牛污染、氢气毒性以及需要昂贵且可靠的技术。 专业设备。 VirTech Bio 为 SBIR 第一阶段提案开发的新工艺解决了所有问题 这些问题同时创造了该组件更具成本效益的商业生产。 人类血红蛋白分子的最初来源将是通过过程4获得的过期人类血液 已经获得监管机构的批准。过时的人类红细胞将通过超滤被“清洗”， 通过渗透压休克裂解并通过三步切向流过滤系统纯化以去除细胞 杂质。随后，用戊二醛进行聚合，然后进行希夫碱稳定化。这 具体目标包括：1) 生物物理表征，以证明与原始 HBOC 的相似性，2) 分子量和储存参数的稳定性测试以及3）与机器的兼容性测试 在相关条件下灌注（无器官）12小时。 该产品一旦开发和验证，将与第二阶段的机器灌注装置结合使用 根据我们以往的经验，用于肝脏保存。用于器官应用的新型 HBOC 保存应该会对临床移植产生显着的积极影响。有效的器官氧合 离体将提高目前的器官保存标准并增加移植数量5。 应该通过降低发病率和死亡率来产生额外的积极下游影响 移植等候名单 6、改善术后效果并缩短住院时间 7. 所有这些 效益应该对降低临床移植总体成本的能力产生直接影响 8. ！