Platelet-like particles for augmenting hemostasis

项目摘要 不受控制的出血是普外科、创伤和急诊的一个重大临床挑战 药失血（出血）是创伤性损伤（约40%）和出血导致死亡的主要原因。 在诸如心肺分流术的侵入性手术之后与显著的发病率相关， mortality.在正常的凝血级联反应中，凝血酶蛋白酶被激活，进而激活 休眠的循环血小板和凝血蛋白前体纤维蛋白原。活化血小板形成a 在受伤部位止血，阻止失血。简单的说，就足以实现短期的 止血，并通过其在纤维蛋白募集中的活性对稳定的基于纤维蛋白的凝块的成熟至关重要 和血块收缩因此，它们在出血或活性期间的大量稀释并不奇怪。 手术期间的抑制导致凝血系统的故障。目前的止血技术包括 局部密封剂、放热沸石和重组凝血因子。这些方法中的每一种都具有 这些方法都取得了一定的成功，但都有明显的缺点，如缺乏伤口特异性;没有一个是 与天然伤口响应止血系统一样“进化”。因此，最近的努力集中在 血小板的合成类似物的产生。重要的血小板功能，人们想概括包括 损伤触发纤维蛋白凝块形成和凝块收缩/稳定的增强。迄今为止， 血小板方法仅以非触发（即组成性）和非特异性的方式概括凝块/血小板结合。 时尚和缺乏其他关键的血小板功能。在这里，我们提出了一种新颖而简单的方法， 通过合成生物学的应用创造血小板样结构。我们提出两个目标。 第一个目的是了解我们的血小板样颗粒如何与凝血的各个阶段相互作用 级联，并了解我们的血小板样颗粒在增强 止血。第二个目的是探索血小板样颗粒的体内功能，特别是在 在多种创伤相关凝血病模型中加强止血。

Project Abstract Uncontrolled bleeding represents a significant clinical challenge in general surgery, trauma, and emergency medicine. Exsanguination (bleeding) is the major cause of death from traumatic injury (~ 40%) and bleeding following invasive surgeries such as cardiopulmonary bypass is associated with significant morbidity and mortality. During the normal clotting cascade, the protease thrombin is activated, which in turn activates dormant circulating platelets and the clotting protein precursor, fibrinogen. Activated platelets form a hemostatic plug at the site of injury, stemming blood loss. Platelets are sufficient to achieve short-term hemostasis and are critical to the maturation of stable fibrin-based clots via their activity in fibrin recruitment and clot contraction. Thus, it is not surprising that their massive dilution during hemorrhage or active inhibition during surgery results in a failure of the clotting system. Current hemostasis technologies include topical sealants, exothermic zeolites and recombinant clotting factors. Each of these approaches has demonstrated modest successes, yet all have significant drawbacks such as a lack of wound specificity; none are as “evolved” as the natural wound-responsive hemostasis system. Thus, more recent efforts have focused on creation of synthetic analogs of platelets. The vital platelet functions that one would like to recapitulate include injury-triggered enhancement of fibrin clot formation and clot contraction/stabilization. To date, artificial platelet approaches only recapitulate clot/platelet binding in a non-triggered (i.e. constitutive) and non-specific fashion and lack the other critical platelet functions. Here we propose a novel and simple approach to the creation of platelet-like structures through the application of synthetic biology. We are proposing two aims. The first aim is to understand how our platelet-like particles interact with various stages of the coagulation cascade and to understand the fundamental mechanism of action of our platelet-like particles in augmenting hemostasis. The second aim is to explore the in vivo function of the platelet-like particles, specifically in the augmentation of hemostasis in multiple models of trauma-associated coagulopathy.