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.
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.
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|Bryksin, Anton V; Brown, Ashley C; Baksh, Michael M et al. (2014) Learning from nature - novel synthetic biology approaches for biomaterial design. Acta Biomater 10:1761-9|
|Brown, Ashley C; Stabenfeldt, Sarah E; Ahn, Byungwook et al. (2014) Ultrasoft microgels displaying emergent platelet-like behaviours. Nat Mater 13:1108-14|
|Brown, Ashley C; Barker, Thomas H (2014) Fibrin-based biomaterials: modulation of macroscopic properties through rational design at the molecular level. Acta Biomater 10:1502-14|