SBIR Phase I: Manufacturing and Characterization of a Synthetic Platelet (SynthoPlateTM) Technology

SBIR 第一阶段：合成血小板 (SynthoPlateTM) 技术的制造和表征

• 批准号: 1745881
• 负责人: Michael Bruckman
• 金额: $ 22.5万
• 依托单位: Haima Therapeutics, LLC
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1745881&HistoricalAwards=false
• 关键词: SBIR; Phase; Manufacturing; Characterization; Synthetic

This SBIR Phase I project aims to further the development a novel nanoparticle-based synthetic platelet technology for the treatment of internal, non-compressible hemorrhage after traumatic injury. Trauma is the leading killer of people aged 1-46, and uncontrollable hemorrhage after injury is the cause of 35% of pre-hospital trauma deaths and 90% of military combat casualties. This is because there are currently no pre-hospital treatment options for internal, non-compressible hemorrhage. If the patient reaches a medical treatment facility in time, the current standard of care is transfusion with blood products, including platelets. However, natural platelet products suffer from shortage in supply (due to donor shortage), difficulty in portability, high risk of bacterial contamination, very short shelf life (3-5 days), requirement of blood typing and cross matching, and multiple biologic side effects (e.g. immune response). Therefore, there exists a significant clinical need for a synthetic platelet surrogate that can address the above limitations and can be administered at point-of-injury or during en route care to stop the bleeding earlier and potentially save lives. Beyond the potential clinical and commercial impact, the proposed research will also provide multi-disciplinary educational and research opportunities in major STEM areas at undergraduate level to create future scientists and engineers.A synthetic platelet technology has been developed that can simulate the hemostatic mechanisms and capabilities of natural platelets while allowing large-scale manufacturing, sterilization, long shelf-life and portability. The technology consists of a platelet-mimetic lipid-based nanoparticle, heteromultivalently surface-decorated with three types of small synthetic peptide ligands that render cooperative mechanisms of binding to von Willebrand Factor (vWF) and collagen (platelet-mimetic injury site-selective adhesion mechanisms) and binding to stimulated form of GPIIb-IIIa on active platelets (platelet-mimetic injury site-directed aggregation mechanism). This patented design is unique in that it is currently the only design that combines these adhesion and aggregation properties of natural platelets on a single synthetic platform. Preliminary studies have established the platelet-mimetic functional mechanisms in vitro as well as its significant hemostatic therapy capability in vivo in small (mouse) and large (pig) animal models of hemorrhage in both prophylactic and emergency administration frameworks. Building on these promising results, this project aims to conduct translationally-directed studies to address technical hurdles associated with manufacturing the synthetic platelets with batch-to-batch consistency and long shelf life (1 year) at a range of storage conditions (widely varying temperatures, altitudes, etc), which would be highly relevant in austere civilian and military applications.

该SBIR I期项目旨在进一步开发一种新型的基于纳米颗粒的合成血小板技术，用于治疗创伤性损伤后的内部不可压缩出血。创伤是1-46岁人群的头号杀手，伤后无法控制的出血是35%院前创伤死亡和90%军事战斗伤亡的原因。这是因为目前没有针对内部不可压缩出血的院前治疗选择。如果患者及时到达医疗机构，目前的护理标准是输注血液制品，包括血小板。然而，天然血小板产品存在供应短缺（由于供体短缺）、便携性困难、细菌污染的高风险、非常短的保质期（3-5天）、需要血型和交叉配血以及多种生物副作用（例如免疫应答）。因此，存在对合成血小板替代物的显著临床需求，所述合成血小板替代物可以解决上述限制，并且可以在损伤点或途中护理期间施用，以更早地止血并可能挽救生命。除了潜在的临床和商业影响外，拟议的研究还将在本科阶段提供主要STEM领域的多学科教育和研究机会，以培养未来的科学家和工程师。已经开发出一种合成血小板技术，可以模拟天然血小板的止血机制和能力，同时允许大规模制造，灭菌，长保质期和便携性。该技术由基于血小板模拟脂质的纳米颗粒组成，该纳米颗粒用三种类型的小合成肽配体进行异多价表面修饰，这些配体提供与血管性血友病因子（vWF）和胶原蛋白结合的协同机制（血小板模拟损伤位点选择性粘附机制）以及与活性血小板上GPIIb-IIIa的刺激形式结合的协同机制（血小板模拟损伤位点定向聚集机制）。这项专利设计是独一无二的，因为它是目前唯一的设计，结合了天然血小板的这些粘附和聚集特性在一个单一的合成平台。初步研究已经在预防性和紧急给药框架中建立了体外血小板模拟功能机制以及其在小型（小鼠）和大型（猪）出血动物模型中的体内显著止血治疗能力。在这些有希望的结果的基础上，该项目旨在进行预防性研究，以解决与在一系列储存条件（广泛变化的温度，海拔等）下制造具有批次间一致性和长保质期（1年）的合成血小板相关的技术障碍，这将在严峻的民用和军事应用中高度相关。