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Tuning the Biophysical and Biochemical Cues of Fibrin Microthread Scaffolds Towards the Treatment of Volumetric Muscle Loss Public

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65.8 million Americans suffer from musculoskeletal injuries annually, with treatment costs exceeding 176 billion dollars. These injuries can cause volumetric muscle loss (VML), where severe musculoskeletal injury results in poor functional recovery. Due to the severity of VML injuries, the extracellular matrix (ECM) surrounding myofibers is destroyed. This normally provides mechanical support, topographic alignment cues, and bioactive signaling molecules, such as fibroblast growth factor 2 (FGF2), to orchestrate regeneration. The current standard of care for treating VML is autologous tissue transfer, but this procedure is unable to restore function and can result in complications including infection and graft failure. Thus, an unmet clinical need remains to develop a treatment that restores function to VML injuries. Towards this, tissue engineered scaffolds are being developed to enhance functional muscle regeneration by incorporating biophysical and biochemical cues that mimic native skeletal muscle tissue composition, architecture, mechanics, and bioactive signaling. In this thesis, we developed strategies to tune the biophysical and biochemical cues of fibrin microthreads, a cylindrical fibrous scaffold that mimics the structure of a muscle fiber. The goal of this project was to develop fibrin microthreads with anisotropic surface features, robust mechanical properties, and physiologically relevant, sustained release of FGF2 to direct the cellular processes that will ultimately enhance functional skeletal muscle regeneration in VML injuries. We developed a method to etch microthreads in an acidic buffer, and found this created aligned, sub-micron surface features on microthreads while maintaining microthread bulk mechanical properties. Microthreads etched in acidic buffer enhanced myoblast alignment and filamentous stress fiber organization compared to control microthreads. Next, we developed enzymatic crosslinking strategies using horseradish peroxidase (HRP) by either incorporating crosslinkers during microthread production or in a post-processing bath. Varying incorporation strategies enabled the development of HRP crosslinked microthreads with enhanced tensile strengths and a decreased rate of plasmin-mediated degradation, while maintaining myoblast viability. Finally, we evaluated the effect of co-incorporating FGF2 within microthreads or passively adsorbing FGF2 to heparin-conjugated microthreads, mimicking FGF2 sequestration in ECM. Fibrin microthreads demonstrated sustained release of FGF2 over one week and enhanced myoblast proliferation and outgrowth in vitro. We expect the strategic engineering of biophysical and biochemical cues through the development of aligned topographic features, enzymatic crosslinking, and sustained FGF2 delivery will further develop fibrin microthread scaffolds towards the goal of creating a treatment that restores function following VML injuries.

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  • 02/01/2021
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  • etd-4326
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  • 2020
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  • 2020-09-29
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