Leveraging cell-instructive hydrogels to understand microenvironmental impact on wound healing processes

Abstract: Wound healing after injury is accomplished by the coordinated action of several cell types that migrate to the injury region and participate in tissue repair. Interactions between invading cells and the surrounding microen- vironment are critical for the healing outcome. Current in vitro studies focus on comparing cell behavior in con- ditions mimicking healthy tissue or fully fibrosed scar and mostly ignore the complex and dynamic properties of the provisional matrix that plays a critical role in instructing cell processes during wound healing. The goal of my research program is to develop cell-instructive biomaterials to support endogenous tissue repair after criti- cal injury. My lab is at the forefront of designing injectable and microporous granular hydrogels with tunable properties to support endogenous cell infiltration and tissue repair. While this approach presents intriguing pos- sibilities for clinical translation, progress is severely hindered by a lack of knowledge on how endogenous cells process the complex biophysical and biochemical properties of the provisional wound matrix and the implanted hydrogels. A major aspect of our lab’s approach is the creation of in vitro platforms to model cellular interac- tions, which serve the dual purpose of improving fundamental understanding of cell behavior in wound-mimick- ing environments and rationalizing biomaterials design to elicit specific cellular behaviors. Over the next five years, our lab will develop or advance in vitro models of endothelial sprouting, mesenchymal stromal cell para- crine signaling, and fibroblast-driven matrix deposition, using synthetically designed modular hydrogels with tunable porosity, ligand density, mechanics, and degradability. These hydrogel platforms will enable us to ad- dress questions not easily answerable with traditional 2D coatings on plastic substrates or naturally derived materials such as Matrigel that cannot be modified to recapitulate wound properties. Outcomes of projects in these thematic areas will ultimately serve our overarching goal of leveraging the fundamental understanding of cellular processes to design therapeutic biomaterials for effective wound healing in diverse tissue and organ systems. Projects across all three themes have the potential to present several intriguing questions that can be addressed with new hypotheses, experimental designs, and increasingly sophisticated biomaterial platforms over the course of this funding period and beyond, making this proposal a perfect fit for the Maximizing Investi- gators Research Award mechanism.