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

该SBIR第一阶段项目旨在进一步开发一种新的基于纳米颗粒的合成血小板技术，用于治疗创伤后不可压缩的内部出血。创伤是1-46岁人群的头号杀手，伤后失控出血是35%的院前创伤死亡和90%的军事战斗伤亡的原因。这是因为目前还没有院前治疗不可压缩的内部出血的选择。如果患者及时到达医疗设施，目前的护理标准是输血产品，包括血小板。然而，天然血小板制品存在供体短缺、携带困难、细菌污染风险高、保质期短(3-5天)、血型和交叉配型要求以及多种生物副作用(如免疫反应)等问题。因此，临床上非常需要一种能够解决上述限制的合成血小板替代品，这种替代品可以在受伤时或途中给药，以更早止血，并有可能挽救生命。除了潜在的临床和商业影响，拟议的研究还将在本科水平的主要STEM领域提供多学科的教育和研究机会，以培养未来的科学家和工程师。一种合成血小板技术已经开发出来，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。该技术包括一种模拟血小板的脂质纳米颗粒，表面修饰有三种类型的合成小肽配体，这三种配体可以协同结合von Willebrand因子(VWF)和胶原(模拟血小板损伤的定点选择性黏附机制)以及与活性血小板上刺激形式的GPIIb-IIIa结合(模拟血小板损伤的定点定向聚集机制)。这一专利设计是独一无二的，因为它是目前唯一在单一合成平台上结合天然血小板的粘附性和聚集性的设计。初步研究已经在预防和紧急给药框架下，在小(小鼠)和大(猪)动物模型中建立了体外模拟血小板的作用机制以及在体内显著的止血治疗能力。在这些有希望的成果的基础上，该项目旨在进行翻译指导的研究，以解决在一系列储存条件(温度、海拔等变化很大)下生产具有批次间一致性和长保质期(1年)的合成小片的相关技术障碍，这些条件在严酷的民用和军事应用中将具有高度相关性。

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.