Harnessing protein conformational changes to control the timing of growth factor release from dynamic hydrogels

Dynamic hydrogels have emerged as an important class of materials for controlled drug delivery applications. Here we describe an approach to develop dynamic, drug-releasing materials based on a ligand-induced protein conformational change. Specifically, when calmodulin (CaM) was incorporated as a functional unit in hydrogel networks, its nanometer scale conformational change translated to macroscopic hydrogel volume changes. The magnitude of the hydrogels' volume changes was tuned by varying their initial composition and processing techniques. After characterizing the hydrogels' dynamic properties, we encapsulated an important bioactive protein, vascular endothelial growth factor (VEGF), in the hydrogels and characterized how their dynamic properties controlled VEGF release. The mass of VEGF encapsulated in CaM-based hydrogels was tuned by varying the VEGF encapsulation technique and the hydrogels' initial composition. Significantly, CaM's ligand-induced conformational change triggered hydrogel volume decreases, fluid exclusion, and VEGF release at predetermined times. The VEGF release rate was modulated by varying the size of the hydrogels and their dynamic properties. There are over 200 proteins that undergo well characterized ligand-induced conformational changes. Therefore, the approach demonstrated here could provide a broadly applicable mechanism to control the release of therapeutic proteins from hydrogels in response to an extensive range of specific biochemical ligands.