Summary Biomaterial scaffolds represent a promising approach for material-based tissue regeneration. We previously developed microporous annealed particle (MAP) hydrogels - a flowable, microparticle-based hydrogel in which neighboring hydrogel particles are linked in situ to form a porous scaffold that accelerates wound healing. Recently, we found that a relatively simple modification to the crosslinker peptide from L-enantiomer to D- enantiomer resulted in substantial skin regeneration and that this regeneration only occurs when the adaptive immune system is intact. Further investigation revealed that although D-chiral peptides were poor activators of macrophage innate immune signaling, D-chiral peptides within MAP (D-MAP) elicited significant antigen-specific immunity. In this proposal, we will further investigate the ability of our D-MAP material to activate the adaptive immune system and lead to skin tissue regeneration. Aim 1 will focus on further understanding any role of the innate immune system and the ability of MAP scaffold microstructure to dictate macrophage phenotype. Aim 2 will focus on testing our hypothesis that the adaptive immune system is activated by our material and leads to regenerative wound healing. Aim 3 will investigate other biomaterial approaches to present D-peptides and further control immune system activation.

Project Narrative Wound healing cost the healthcare system billions of dollars and the current cost is set to increase as the population ages. The ability to improve poorly healing wounds would impact the lives of millions of Americans ranging from patients undergoing scheduled surgeries to patients with accidental injuries or wounds caused by other diseases such as diabetes. The goal of this proposal is to develop materials that can use the body’s immune system to promote regenerative wound healing.