Fibrinogen-Triggered Matrix Assembly from Designed Peptide-Polymer Conjugates

由设计的肽-聚合物缀合物进行纤维蛋白原触发的基质组装

• 批准号: 8401133
• 负责人: Thomas Harrison Barker
• 金额: $ 17.43万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401133
• 关键词: Abdomen; Address; Affinity; Architecture; Behavior; Binding; Biocompatible Materials; Biological; Blood Coagulation Factor; Blood Vessels; Cause of Death; Cessation of life; Characteristics; Chest; Clinical; Colloids; Coupling; Cues; Defect; Development; Electrostatics; Emergency Medicine; Emergency Situation; Engineering; Failure; Fibrin; Fibrinogen; Gel; Goals; Hemorrhage; Hemostatic Agents; Hemostatic function; Hybrids; Hydrogels; Injury; Investigation; Lead; Length; Mechanics; Medicine; Methods; Molecular; N-terminal; Operative Surgical Procedures; Patients; Peptides; Polymers; Property; Proteins; Prunella vulgaris; Research; Rheology; Risk; Stimulus; Structure; Surface Plasmon Resonance; Swelling; System; Technology; Testing; Time; Tissues; Trauma; Traumatic Hemorrhage; Variant; base; biosynthetic material; crosslink; density; design; innovation; novel; particle; polymerization; prevent; research study; response; self assembly; stem; wound

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.

描述（由申请人提供）：控制出血并结合受损的组织的需求代表了手术，创伤和应急药物领域的紧迫而巨大的临床需求。由于创伤性和多发性损伤，解血仍然是第二大流行的死亡原因（27-39％），其中34％的死亡人数在院前（例如卧床）中。尽管努力开发和部署迅速阻止失血的合成系统，但这些数字仍然持续。天然止血系统（纤维蛋白原/纤维蛋白）虽然在适度的损伤情况下在高度进化上保持了保守和成功，但在重大出血性创伤和多发肿瘤的情况下，严重失败，部分原因是由于巨大的稀释效应，无法浓缩关键因素以及在聚合过程中未能产生组织压缩力。在该提案中，我们的目标是将两种有能力的技术融合，i）由合理设计的多价纤维蛋白旋钮肽结合结合凝血因子纤维蛋白原和ii）刺激反应性的微凝胶，这些微凝胶显示为溶胀的水凝胶组件中触发的组装，并探索这些高度新颖的纤维纤维（i.ebigrige）的动态范围。我们的中心假设是，表现出旋钮肽的刺激反应性微凝胶将经历纤维蛋白原引发的组装到网络中，这些组件由微凝胶组成（即肽密度，链长，交叉链接）和肽（即，亲和力和多价）组成控制。为了检验该假设，我们将首先量化工程合成纤维蛋白旋钮肽对纤维蛋白原的结合亲和力（特定的目标1）。然后，在将上述纤维蛋白旋钮肽偶联以刺激反应性微凝胶之后，进行微得分研究以表征生物合成杂化基质组件（特定的AIM 2）。将我们的旋钮肽与刺激反应性的微凝胶一起耦合，它们能够通过快速自组装成凝胶矩阵来“响应”纤维蛋白原和纤维蛋白，代表了一种高度创新的出血性创伤性伤口的方法。这项研究的结果开发的技术的好处是，产生了止血系统，该系统能够通过触发肿胀来浓缩凝血因子并产生压缩力，从而为需要在创伤和多发性肿瘤后需要根治性出血控制的患者提供服务。