Fibrinogen-Triggered Matrix Assembly from Designed Peptide-Polymer Conjugates

描述(由申请人提供)：在外科、创伤和紧急反应医学领域，控制出血和绑定受损组织的需要代表着迫切而重要的临床需求。失血仍然是第二大死因(27%-39%)，原因是创伤和多发创伤，其中34%的死亡发生在院前(如门诊)环境中。尽管在开发和部署快速止血的合成系统方面做出了大量努力，但这些数字仍然存在。天然止血系统(纤维蛋白原/纤维蛋白)虽然在进化上高度保守并在轻微损伤情况下成功，但在严重出血创伤和多发创伤情况下严重失败，部分原因是大量稀释效应，无法集中关键因素，以及在聚合过程中未能产生组织压缩力。在这项提案中，我们的目标是将两项使能技术结合在一起，i)合理设计的多价纤维蛋白旋钮多肽，它结合凝血因子纤维蛋白原；ii)刺激响应微凝胶，显示触发组装成膨胀的水凝胶组件，并探索这些高度新颖的纤维蛋白原(即创伤)触发的微凝胶组件的动态范围。我们的中心假设是，显示节肽的刺激反应微凝胶将在纤维蛋白原的启动下组装成由微凝胶的组成控制的网络(即。多肽密度、链长、交联度)和多肽(即亲和力和多价性)。为了验证这一假设，我们将首先量化工程合成纤维蛋白结肽与纤维蛋白原的结合亲和力(特定目标1)。然后，在所述纤维蛋白结肽与刺激反应微凝胶偶联后，进行微流变学研究以表征生物合成杂化基质组件(特定目标2)。将我们的节肽与刺激响应型微凝胶相结合，前者能够“感应”纤维蛋白原和纤维蛋白，后者能够通过快速自组装成凝胶基质来“做出反应”，这代表着一种治疗创伤出血的高度创新的方法。作为这项研究的结果而开发的技术的好处是创建了一种止血系统，该系统既能够集中凝血因子，又能够通过触发肿胀产生压缩力，从而为创伤和多发性创伤后需要彻底控制出血的患者提供服务。 公共卫生相关性：该提案中的实验将导致用于止血的新的和强大的伤口反应生物材料的开发。根据这一提议开发的技术将使创伤受害者的治疗能够防止他们的失血性死亡，即失血致死，这是创伤死亡的主要原因之一。

DESCRIPTION (provided by applicant): The need to control bleeding and bind damaged tissues represents a pressing and significant clinical need in the arenas of surgery, trauma, and emergency response medicine. Exsanguination remains the second most prevalent cause of death (27-39%) due to traumatic and polytrauma injury, with 34% of these deaths in the prehospital (e.g. ambulatory) setting. These numbers have persisted despite substantial efforts to develop and deploy synthetic systems that rapidly stem blood loss. The natural hemostatic system (fibrinogen/fibrin), while highly evolutionarily conserved and successful in modest injury situations, critically fails in situations of major hemorrhaging trauma and polytrauma, in part due massive dilution effects, inability to concentrate critical factors, and failure to generate tissue compressive forces during polymerization. In this proposal, our objective is to couple two enabling technologies, i) rationally designed, multivalent fibrin knob peptides, which bind the clotting factor fibrinogen and ii) stimuli-responsive microgels that display triggered assembly into swelling hydrogel assemblies, and to explore the dynamic range of these highly novel fibrinogen (i.e. wound) -triggered microgel assemblies. Our central hypothesis is that stimuli-responsive microgels displaying knob peptides will undergo fibrinogen-initiated assembly into networks that are controlled by the composition of the microgel (ie. peptide density, chain length, crosslinking) and peptide (ie. affinity and multivalency) constituents. To test this hypothesis we will first quantify the binding affinities of engineered synthetic fibrin knob peptides to fibrinogen (Specific Aim 1). Then, following the coupling of said fibrin knob peptides to stimuli-responsive microgels, perform micro-rheological studies to characterize the bio-synthetic hybrid matrix assembly (Specific Aim 2). Coupling our knob peptides, which are capable of "sensing" fibrinogen and fibrin, with stimuli-responsive microgels, which are capable of "responding" via rapid self-assembly into gel matrices, represents a highly innovative approach to hemorrhaging traumatic wounds. The benefit of the technology developed as a consequence of this study is the creation of a hemostatic system that is capable of both concentrating clotting factors and generating compressive forces through triggered swelling, thus serving patients in need of radical hemorrhage control following trauma and polytrauma. PUBLIC HEALTH RELEVANCE: The experiments in this proposal will lead to the development of new and powerful wound-responsive biomaterials for hemostasis. The technology developed as a result of this proposal will enable the treatment of trauma victims to prevent their hemorrhagic death, i.e. bleeding to death, one of the primary causes of death due to trauma.