Engineering Hydrogels for Affinity-Based Release of Therapeutic Proteins

Therapeutic proteins can treat a myriad of diseases; however, their effectiveness is limited by short half-lives. Controlled release systems are advantageous because they prolong the action of protein drugs, minimize transient surges, and keep concentrations within a therapeutic range. Hydrogels are amenable to chemical modifications and comprise a versatile platform for controlled release, enabling minimally invasive injections at the injury site and acting as a depot to sustain the delivery of therapeutic proteins therefrom. Affinity-based release strategies have binding partners immobilized within the hydrogel to release proteins through noncovalent interactions and under mild conditions that maintain their three-dimensional architecture required for bioactivity. Naturally occurring binding interactions between therapeutic proteins and extracellular matrix components were advanced first but are inherently limited. Computational and experimental tools have emerged to enable high-specificity and moderate-affinity binding interactions to candidate therapeutic proteins. Directed evolution has enabled the development of novel peptide-, protein-, and aptamer-binding partners that modulate release from hydrogel delivery vehicles. With these tools, affinity-based systems that enable specific and tunable rates of release are being developed for diverse applications, including tissue regeneration and cancer treatment. These systems can now be tuned for the controlled release of multiple bioactive proteins. In this review, we examine the tools required to design novel binding partners for affinity-controlled release from hydrogels and provide insights into their formulations for specific applications.