Fibrinogen-Triggered Matrix Assembly from Designed Peptide-Polymer Conjugates

描述（由申请人提供）：控制出血和结合受损组织的需求代表了外科、创伤和应急医学领域的迫切和重要的临床需求。由于创伤和多发性创伤，失血仍然是第二大最常见的死亡原因（27-39%），其中34%的死亡发生在院前（例如门诊）环境中。尽管在开发和部署快速阻止失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）虽然在中度损伤情况下高度进化保守和成功，但在严重创伤和多发性创伤的情况下严重失败，部分原因是大量稀释效应，无法集中关键因素，以及在聚合过程中无法产生组织压缩力。在该提案中，我们的目标是将两种使能技术结合，i）合理设计的多价纤维蛋白结肽，其结合凝血因子纤维蛋白原，和ii）刺激响应性微凝胶，其显示触发组装成溶胀水凝胶组装体，并探索这些高度新颖的纤维蛋白原（即伤口）触发的微凝胶组装体的动态范围。我们的中心假设是，显示旋钮肽的刺激响应性微凝胶将经历纤维蛋白原启动的组装成由微凝胶组成控制的网络（即，肽密度、链长、交联）和肽（即，亲和性和多价性）成分。为了检验这一假设，我们将首先定量工程化合成纤维蛋白球肽与纤维蛋白原的结合亲和力（特异性目标1）。然后，在将所述纤维蛋白结肽偶联至刺激响应性微凝胶之后，进行微流变学研究以表征生物合成杂合基质组装体（具体目标2）。将我们的能够“感应”纤维蛋白原和纤维蛋白的结肽与能够通过快速自组装成凝胶基质“响应”的刺激响应性微凝胶偶联，代表了一种高度创新的创伤性伤口愈合方法。本研究开发的技术的受益是创建了一种止血系统，该系统能够浓缩凝血因子并通过触发肿胀产生压缩力，从而为创伤和多发创伤后需要彻底控制出血的患者提供服务。

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.