Evolving transport properties of dynamic hydrogels enable self-tuning of short- and long-term cargo delivery

Abstract

Hydrogels are crosslinked polymer networks with high water content, widely employed in biomedical applications such as drug delivery, tissue engineering, and regenerative medicine. Injectable, depot-forming hydrogels enable sustained release of therapeutic agents by modulating macromolecular diffusion through dynamic polymer networks. However, achieving reliable control over release kinetics remains a challenge, as the injection process induces shear-mediated disruption of transient crosslinks, leading to an initial burst release that can cause local toxicity and compromise therapeutic efficacy. Here, we present a hydrogel formulation strategy designed to restore network structure post-injection through rapid reformation of dynamic crosslinks, enabling time-dependent regulation of diffusion properties. By tuning viscoelastic parameters, including stress relaxation time and network recovery rate, we reduced the extent of burst release without compromising sustained delivery. Using model protein cargo, we demonstrate in both $in~vitro$ and $in~vivo$ settings that hydrogels with faster crosslink reformation kinetics exhibit significantly lower early-phase release while maintaining long-term delivery comparable to unmodified formulations. These results establish a mechanistic framework for decoupling short- and long-term release behavior, offering a broadly applicable strategy for precise drug delivery in soft tissue environments.