Development of Shear-Thinning and Self-Healing Hydrogels Through Guest-Host Interactions for Biomedical Applications

Hydrogels have emerged as an invaluable class of materials for biomedical applications, owing in part to their utility as structural, bioinstructive, and cell-laden implants that mimic many aspects of native tissues. Despite their many positive attributes, conventional hydrogels face numerous challenges toward translational therapies, including difficulty in delivery (i.e., invasive implantation) as well as limited control over biophysical properties (i.e., porosity, degradation, and strength). To address these challenges, the overall goal of this dissertation was the development of a class of supramolecular hydrogels that can be implanted in vivo by simple injection and that have tunable properties — either innate to the system or achieved through additional modifications. Toward this, we developed guest-host (GH) hydrogels that undergo supramolecular assembly through complexation of hyaluronic acid (HA) separately modified by adamantane (Ad-HA, guest) and β-cyclodextrin (CD-HA, host). Modular modifications were made to GH hydrogels to enable tuning of biophysical properties, including the incorporation of matrix-metalloproteinase cleavable peptides between HA and Ad to form enzymatically degradable assemblies. Additionally, dual-crosslinking (DC) of methacrylated CD-HA (CD-MeHA) and thiolated Ad-HA (Ad-HA-SH) by Michael addition subsequent to GH assembly was explored to stiffen hydrogels in vivo following injection. Finally, injectable and tough double network (DN) hydrogels were fabricated, where GH hydrogels were formed in the presence of an interpenetrating covalent network (methacrylated HA, MeHA) crosslinked by Michael addition with a dithiol under cytocompatible conditions. Both GH and DC hydrogels were further explored in vivo, with application to attenuate the maladaptive left ventricular (LV) remodeling that occurs following myocardial infarction (MI) that can result in heart failure. DC hydrogels reduced stress within the infarct region, prevented early ventricular expansion and thereby ameliorated progressive LV remodeling. Moreover, the preservation of myocardial geometry reduced incidence and severity of ischemic mitral regurgitation — an undesirable and devastating consequence of LV remodeling. Overall, the body of work represents a novel approach to engineer biomaterials with unique properties toward biomedical therapies.