Programmable protein delivery from microgel/hydrogel composites (MHCs) via discrete combinations of multi-state protein-loaded unit ingredients

Abstract

Therapeutic proteins have drawn increasing attention in the development of advanced drugs and biomedical devices, yet there are outstanding challenges for the delivery of multiple-protein therapies with customized release profiles. Hydrogel-based drug delivery systems (DDS) have been widely investigated, primarily via highly specific chemical modification routes, for programmable topical, injectable, and depot-based protein delivery. In this paper, we propose a microgel/hydrogel composite (MHC) DDS for tunable and programmable multi-protein delivery, which leverages different physical states of proteins (freely dissolved or coacervated) and completely avoids bespoke chemical modifications on the hydrogels. We load model proteins in distinct physical states into dextran-based hydrogel microparticles (microgels) fabricated using microfluidics, after which simple discrete combinations of these microgel ‘unit ingredients’ are packaged into poly(ethylene glycol) hydrogel matrices to formulate the MHC DDS. With discrete combinations of unit ingredients, we demonstrate how these MHC DDSs can achieve both tunable release for a single low-molecular-weight model protein (and ideally, highly similar proteins) and a counterintuitive rate-reversed release of two model proteins that are vastly different in size. Moreover, we show that these MHCs follow Korsmeyer-Peppas kinetic behavior as a function of the discrete combinations packaged, thus highlighting the quantitative tunability of release behaviors. We envision the use of these MHC DDSs as topically applied wound dressings or implantable protein-releasing depots that allow scheduled and programmable multi-protein delivery in biomedical and clinical applications.