Rapid Reconstitution of a Lyophilized, Bio-inspired, Artificial Red Blood Cell

项目总结 需要一种人造氧(O2)载体来替代储存的血液制品，后者有时是 无法获得(院前护理、严峻的环境、资源有限的国家)、不受欢迎(免疫风险 响应)，或供不应求(大规模伤亡事件)。此外，输注晶体或 仅胶体溶液就会导致血液成分如红细胞(RBCs)的稀释不足， 它们对向各种组织输送氧气(O2)至关重要。KaloCyte的重点是开发ErythroMer (EM)，一种冷冻干燥的、受生物启发的人造红细胞，它将改变需要输血的患者的方式 储存红细胞或全血时不能进行治疗。以前的氧气载体产品有两个 阻止它们模仿红细胞生理的主要设计缺陷：(1)无法适当地将氧气释放到 在肺中捕获后的组织和(2)一氧化氮(NO)的隔离导致血管收缩。EM是 设计成不仅携带氧气，而且还克服了以前氧气载体遇到的障碍(目的是 红血球替代品)。EM通过模拟生理性的RBC O2捕获和传递来实现这一点 与血管系统良性互动。这些关键的仿生设计特征将EM与 之前的尝试。此外，EM是为无菌冷冻干燥而设计的，因此，易于方便、快速 在环境条件下长时间干燥储存后重建。EM提供了一种实用的方法来处理复杂的 需要，并且专为规模化的成本效益生产而设计。我们的原型已经通过了严格的体外实验和 活体“概念验证”测试。KaloCyte的成立是为了让我们可以将EM创新转化为 务实的治疗，以及认识到颠覆性地引入输血的商业潜力 医药。我们的项目目标是实现快速、简便的重建并建立最佳的胶体(白蛋白 和冻干血浆)和结晶(生理盐水、乳酸林格氏、血浆溶血素A)比率 再悬浮，同时不破坏血液的渗透压和肿胀压。新兴市场知识产权稳健 并由KaloCyte确保，KaloCyte由坚实的研究团队支持，我们的首席执行官拥有强大的治疗性 行业背景和科学顾问，具有开发基于血红蛋白的氧气载体的经验， 冷冻干燥、输血医学、出血和复苏、临床前开发和试验设计。丁苯橡胶 资金将使KaloCyte能够在EM生产方面进行关键的临床前开发，并启动基础工作 IND授权所必需的。值得注意的是，我们最初的研究和这里的方法符合出版的FDA 对血液替代品的期望。考虑到巨大的需求和市场潜力，我们有失血性休克 作为FDA批准的第一个适应症。在失血性休克试验成功后，我们将扩大EM 进入其他环境，并利用该设计将效力扩展到储存血液之外。

PROJECT SUMMARY There is need for an artificial oxygen (O2) carrier to substitute for stored blood products, which at times are unavailable (pre-hospital care, austere environments, resource-limited countries), undesirable (risk of immune response), or in short supply to meet demand (mass casualty event). Moreover, transfusion of a crystalloid or colloid solution alone will lead to dilutional deficiencies of blood components such as red blood cells (RBCs), which are critical for delivering oxygen (O2) to the various tissues. KaloCyte's focus is to develop ErythroMer (EM), a lyophilized, bio-inspired, artificial RBC, which will transform how patients who need a transfusion are treated when stored RBCs or whole blood are not an option. Previous oxygen carrier products have had two major design flaws preventing them from mimicking RBC physiology: (1) inability to appropriately release O2 to tissues after capture in the lungs and (2) sequestration of nitric oxide (NO) resulting in vasoconstriction. EM is designed to not only carry O2 but also surmount the barriers encountered by prior oxygen carriers (intended as red blood cell substitutes). EM accomplishes this by emulating physiologic RBC O2 capture and delivery along with benign interaction with the vasculature. These key bio-inspired design features differentiate EM from previous attempts. Moreover, EM is designed for sterile lyophilization and so, is amenable to facile, rapid reconstitution after extended dry storage under ambient conditions. EM offers a pragmatic approach to a complex need and is designed for cost-effective production at scale. Our prototype has passed rigorous initial ex vivo and in vivo “proof of concept” testing. KaloCyte was founded so that we may translate EM innovations into a pragmatic therapeutic and as well as realize the commercial potential of a disruptive introduction into transfusion medicine. Our project goals are to enable rapid, facile reconstitution and establish the optimal colloid (albumin and freeze-dried plasma), and crystalloid (normal saline, lactated ringers, PlasmaLyte A) ratios for EM resuspension, while not disrupting the osmolality and oncotic pressure of blood. EM intellectual property is robust and secured by KaloCyte, which is supported by a solid research team, our CEO with a strong therapeutic industry background and scientific advisors, with experience in hemoglobin-based oxygen carrier development, lyophilization, transfusion medicine, hemorrhage & resuscitation, pre-clinical development and trial design. SBIR funding will enable KaloCyte to critical pre-clinical development in EM production and initiate groundwork required for IND authorization. Of note, our initial studies and the approach herein meet published FDA expectations for blood substitutes. Given the significant need and market potential we have hemorrhagic shock as the first indication for FDA approval. Following a successful trial for hemorrhagic shock, we would expand EM into other settings and exploit the design to extend efficacies beyond that of stored blood.