Streptavidin functionalized hyaluronic acid hydrogels for controlled and customizable drug delivery

Hyaluronic acid (HA)-based hydrogels have emerged as promising materials for tissue repair given their ability to rapidly gel in situ to precisely fill tissue defects, their mechanical tunability and customizable degradation kinetics, and their capacity to deliver therapeutic agents to the site of injury. HA hydrogels can also be used to encapsulate therapeutics for local delivery; however, release through diffusion may be too rapid to achieve a therapeutic window for many applications. To overcome this limitation, we functionalized norbornene-modified HA (NorHA) hydrogels with streptavidin using thiol-ene click chemistry, enabling efficient tethering of biotin-modified agents (i.e., fluorophores, liposomes) to the hydrogel. We first confirmed that streptavidin functionalization increased the retention of encapsulated agents both in vitro and in vivo and did not impact hydrogel properties (including rapid gelation or mechanical tunability). Next, we incorporated matrix metalloproteinase (MMP) degradable crosslinks to further tune hydrogel degradation, permitting increased cellular invasion in vivo without disrupting retention and delivery of biotin-modified fluorophores. Lastly, streptavidin functionalized hydrogels were used to encapsulate and control the release of liposomes, with customizable release of model therapeutics within the liposome core and membrane. Overall, these findings support a promising material to control the release of therapeutics that could be useful in a variety of biomedical applications. STATEMENT OF SIGNIFICANCE: Soft tissue injuries are ubiquitous and a significant cause of disability in society. Functionalized hydrogels enable controlled delivery of therapeutics to promote tissue repair. In this study we demonstrated that streptavidin functionalization of hyaluronic acid-based hydrogels successfully tethers biotin-modified agents, prolonging their localized delivery. Functionalization did not impact hydrogel gelation, mechanical tunability, or the ability to tailor hydrogel degradation. Further, the tethering of biotin-modified liposome nanocarriers enabled staged delivery of multiple agents. Altogether, our results highlight streptavidin functionalized hydrogels as a promising platform to promote endogenous healing and tissue regeneration through controlled spatiotemporal delivery.