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Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2019., Chronic wounds are a major public health burden affecting 6.5 million adults in the United States alone, with healthcare costs upwards of $25 billion annually. Regenerative medicine approaches, including the use of tissue-engineered biomaterials, are a promising strategy to reinitiate healing in these patients. Engineered biomaterials rely on scaffolding structures, often extracellular matrix (ECM) glycoproteins, to provide structural support and biological cues. Of these, type I collagen has proved a valuable starting material due to its ability to self-assemble into 3D structures in vitro, as well its high abundance in a variety of tissues including the skin. Collagen achieves this versatility through a cell-mediated hierarchical assembly process that imparts tissue-specific characteristics including collagen fibril conformation, organization and interactions with other ECM components such as fibronectin. Therefore, strategies to control collagen structure and organization in vitro will facilitate development of improved biomaterials that can direct the behavior of cells within engineered constructs. The work reported in this thesis developed an ultrasound (US) technique to manipulate the structure and function of collagen within 3D hydrogels. US exposure during hydrogel polymerization produced localized changes in collagen and fibronectin fiber organization via both thermal and non-thermal acoustic mechanisms. Acoustically-modified hydrogels in turn modified cellular behaviors essential to wound healing, including adhesion, migration, ECM remodeling, and cellular self-assembly. Together, these studies demonstrate that ultrasound can be used to modify the structure and function of ECM-based biomaterials both site-specifically and non-invasively. These findings suggest that therapeutic ultrasound will be a promising addition to the expanding toolbox of strategies to design therapeutic materials of greater complexity and biological compatibility.