(720f) Programmable Protein Delivery from Microgel/Hydrogel Composites (MHCs) Via Discrete Combinations of Multi-State Protein-Loaded Unit Ingredients

Therapeutic proteins have drawn increasing attention in the development of advanced therapies and biomedical devices, yet there are outstanding challenges for the delivery of multiple-protein therapies with customizable release profiles due to intrinsic complexity of pharmacokinetics as well as difficulties in post-fabrication modification of the drug delivery systems (DDSs). Hydrogels, a class of soft materials, have been widely investigated as DDSs in the current field of drug delivery. The crosslinked network microstructure of hydrogels enables the encapsulation or immobilization of drugs, based on the hydrogel mesh size (size of the voids in network) relative to the hydrodynamic diameter of the drug entity. However, once a particular hydrogel fabrication formulation is selected, the mesh size is effectively “locked in”, and cannot be varied in a fine-tuned way to enable the programmable release of multiple drugs of distinct sizes.

In pursuit of more customizable multi-protein release mechanisms from hydrogel, recent research has delved into formulation strategies that exploits various intermolecular interactions between proteins and the hydrogel network or associated excipients, such as coacervation, PEGylation, crystallization, covalent conjugation, etc., via chemistry and engineering approaches. Here we propose an 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 post-fabrication modifications on the DDS. Firstly, we load model proteins in distinct physical states into dextran-based “thiol-ene” click crosslinkable hydrogel matrices and fabricate into various types of hydrogel microparticles (microgels) via microfluidic techniques. Next, simple discrete combinations of these microgel “unit ingredients” are packaged into a poly(ethylene glycol) matrices serving as a bulk carrier hydrogel to formulate the MHC DDS. With different discrete combinations of unit ingredients, we demonstrate, in vitro, how these MHC DDSs can achieve both tunable release for a single low-molecular-weight model protein (and ideally, highly similar proteins) with a spectrum of available release profiles ranging from burst release to sustained release, and a counterintuitive rate-reversed release of two model proteins where a larger protein initially released faster than a smaller protein, by simply changing the types and tuning the ratio of unit ingredients. Quantitatively, we present that the drug releasing behavior can be described by the classic Korsmeyer-Peppas kinetic model, and the model parameters can be correlated as functions of the discrete combinations packaged, thus highlighting the quantitative tunability of release behaviors.

These MHC DDSs can be used as topically applied wound dressings or implantable protein-releasing depots that allow scheduled and programmable multi-protein delivery in biomedical and clinical applications. We also envision this idea of using distinct types of microgels as “unit ingredients” to be broadly generalizable and, crucially, expandable to a “library” of release behavior that eventually can serve to customize, tune, and program release profiles for clinical applications.