Multiscale structural and functional biomechanics of contracting platelet-fibrin based biomaterials and blood clots in oral microenvironment

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Project Summary Platelet-rich plasma clots are a unique biomaterial used for oral and dental surgical procedures to promote wound healing and tissue regeneration in the oral cavity. While aspects of platelet biochemical regenerative potential have been previously studied, the biomechanical function of platelets resulting in contraction of fibrin matrix and blood clots at injury sites in the oral environment has not been addressed. Blood clot contraction is a result of the biomechanical interactions between activated platelets and polymerized fibrin, the two major components of hemostatic clots at oral injury sites, other than red blood cells and fewer leukocytes. The biomedical importance of clot contraction in vivo is evident from promoting wound healing around teeth and implants by approximating the edges of the wound and formation of impermeable physical barriers against bacterial invasion and toxin propagation in oral wounds. Despite the importance of the platelet contractile function for remodeling of blood clots at oral injury sites and clots comprising platelet-rich fibrin surgical hemostatic sealants, the relation between clot contraction dynamics and metabolic and structural changes in activated platelets in oral wounds remains largely unknown. Thus, the main objective of the proposed research is to discover multiscale and time-dependent biomechanical and structural mechanisms of platelet-induced clot contraction in the oral microenvironment and its functional consequences, including modulations of clot mechanical properties and stability. We will focus on the following Aims: Aim 1. Determine structural mechanisms of platelet-induced clot contraction studied at the cellular and subcellular levels. Aim 2. Define the impact of salivary extracellular vesicles on structural properties and viscoelasticity of contracting platelet-rich plasma clots. Aim 3. Identify late-stage structural, metabolic, and functional consequences of platelet activation and contraction in the oral microenvironment. To reach our goals, we will apply state-of-the-art biophysical and biochemical methods with quantitative characterization and structural details from the molecular and cellular levels up to the scale of the entire clot. By applying a combination of different techniques, including high- resolution light microscopy, rheometry, and biochemical assays, our project will bridge the gap between different spatial scales and will establish relations between the molecular, single-cell and single-fiber levels to global structural and mechanical modulations of the entire blood clot. The proposed study will establish a mechanistic basis for platelet-driven clot contraction in the presence of salivary extracellular vesicles, which will yield insights into the structure and function of activated platelets as well as variations of viscoelastic properties and architecture of platelet-fibrin scaffolds at oral injury sites. The acquired knowledge will improve our understanding of hemostasis in the oral microenvironment, inform design of new treatment modalities and assist in development of platelet-fibrin-based biomaterials for oral cavities with modulated mechanical properties to improve patient recovery and oral health.