Platelet-like particles for augmenting hemostasis

用于增强止血的类血小板颗粒

基本信息

批准号：
9288212
负责人：
Thomas Harrison Barker
金额：
$ 66.21万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9288212
关键词：
Advanced Development Adverse effects Affinity Alpha Particles Antibodies Binding Biocompatible Materials Biomedical Engineering Biophysics Biotechnology Bleeding time procedure Blood Coagulation Disorders Blood Coagulation Factor Blood Platelets Blood Tests Blood Vessels Cardiopulmonary Bypass Cause of Death Cells Chemistry Clinical Clinical Medicine Clinical Trials Coagulants Coagulation Process Consumption Contracts Coupled Development Discipline Emergency Medicine Ensure Failure Fiber Fibrin Fibrinogen Formulation Functional disorder Goals Growth Hemorrhage Hemostatic Agents Hemostatic function Human Hydrogels In Vitro Injury Lead Life Microfluidics Modeling Molecular Molecular Evolution Morbidity - disease rate Nature Operative Surgical Procedures Peptide Hydrolases Physical Chemistry Physics Plasma Platelet Transfusion Polymers Pre-hospital setting Process Protein Engineering Protein Precursors Publishing Recombinants Records Recruitment Activity Regulation Research Research Personnel Risk Rodent Science Site Source Specificity Structure System Techniques Technology Testing Thrombin Thrombosis Trauma Traumatic injury Work Zeolites analog antibody engineering base crosslink design effective therapy in vivo innovation mimetics mortality mouse model novel particle poly-N-isopropylacrylamide polymerization spatiotemporal stem success synthetic biology wound

项目摘要

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.

项目摘要不受控制的出血是普通外科、创伤和急诊领域的重大临床挑战失血（出血）是跌打损伤（约 40%）和出血导致死亡的主要原因。体外循环等侵入性手术后与显着的发病率相关在正常的凝血级联过程中，蛋白酶凝血酶被激活，凝血酶又被激活。活化的血小板形成在受伤部位进行止血栓塞，血小板足以达到短期止血的目的。止血，并且通过纤维蛋白募集活性对稳定的基于纤维蛋白的凝块的成熟至关重要因此，它们在出血或活动期间大量稀释也就不足为奇了。手术期间的抑制会导致凝血系统失效，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都有各自的用途。取得了一定的成功，但都显示出明显的缺点，例如缺乏伤口特异性；与自然伤口反应性止血系统一样“进化”，因此，最近的努力集中在这一点上。人们想要重述的重要血小板功能包括创建血小板的合成类似物。损伤引发的纤维蛋白凝块形成和凝块收缩/稳定的增强迄今为止，是人工的。血小板方法仅以非触发（即组成性）和非特异性方式重现凝块/血小板结合时尚且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来解决这一问题。我们提出了两个目标：通过应用合成生物学创建血小板样结构。第一个目标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中的基本作用机制第二个目的是探索血小板样颗粒的体内功能，特别是在止血方面。在多种创伤相关凝血病模型中增强止血作用。