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201241 https://hdl.handle.net/2286/R.2.N.201241 http://rightsstatements.org/vocab/InC/1.0/ All Rights Reserved 2025 2027-05-01T11:17:47 129 pages Doctoral Dissertation Academic theses en Schwarz, Grace Caroline Holloway, Julianne L. Stabenfeldt, Sarah E. Nikkhah, Mehdi Arizona State University Partial requirement for: Ph.D., Arizona State University, 2025 Field of study: Biological Design Approximately 14 million fibrous connective tissue injuries occur each year. These are highly organized tissues where the extracellular matrix (ECM) undergoes spatial and temporal physical changes during healthy healing that cannot be replicated with current biomaterials. Electrospinning is a well-established technique to produce fibrous biomaterials that mimic the ECM. Cell morphology and gene expression are highly dependent on fiber alignment and mechanical loading. New tissue engineering approaches that are capable of mimicking these dynamic fibrous structures are needed to better understand the role of these physical cues on cell behavior. Herein, I develop innovative biomaterial platforms which can mimic the three-dimensional (3D) spatial and temporal complexity of fibrous tissues, where such systems can improve our understanding of the spatiotemporal role of 3D fiber organization during development, wound healing, and disease progression. Objective 1: Evaluate the role of fiber alignment and cyclic tensile stress on cell behavior using electrospun fibrous mats. Cells were cultured on aligned and unaligned fibrous mats with and without applied cyclic tensile stress. Cells on aligned fibrous scaffolds were elongated and oriented in the direction of the aligned fibers, where cells on unaligned fibrous scaffolds were spread with no preferential elongation in a specific direction. Scleraxis gene expression was slightly upregulated for aligned scaffolds undergoing cyclic tensile stress at Day 7, emphasizing the combined importance of fiber alignment and applied stress. Objective 2: Spatially and temporally control 3D fiber alignment using magneto-responsive, fiber-hydrogel composites for tissue engineering applications. Fibers were encapsulated within covalently crosslinked hydrogels and layer-by-layer stacking was used to spatially control fiber orientation. For temporal control, fibers were encapsulated within non-covalently crosslinked, guest-host hydrogels and fiber orientation could be controlled in situ at any user-defined time point. Fiber alignment kinetics and maximum alignment percent were dependent on hydrogel crosslinking, fiber length, SPION content, and magnetic field exposure. Cells were encapsulated within these composites and remained viable after 3 days, demonstrating the biocompatibility of this system to be used as a platform for studying the spatiotemporal role of fiber alignment on cell behavior. Bioengineering Composite Electrospinning Fiber Alignment Hydrogel Magnetic Control Spatiotemporal The Role of Dynamic Physical Cues on Mesenchymal Stem Cell Behavior