Modulation of Short-Term Delivery of Proteins from Hydrogels

For modulation of cellular behavior, systems that can provide controlled delivery of proteins (soluble signals) over a few hours to a few days are highly desirable. Conventional erosion-controlled systems are inadequate as their degradation spans days to months. Conversely, hydrogels offer quicker release but are limited by a high burst release that can lead to cytotoxicity and rapid depletion of the permeant. To avoid burst release and achieve controlled diffusion of proteins, we propose exploiting electrostatic interactions between the hydrogel matrix and proteins. Here we demonstrate this concept using two disparate hydrogel systems: (1) a chemically cross-linked protein (gelatin) matrix and (2) a physically cross-linked polysaccharide (agarose) matrix and three proteins having different isoelectric points. By introducing fixed charges into the hydrogel matrix using carboxylated agarose (CA), the precise and controlled release of BSA, lactoferrin, and FGF2 over a few hours to days is demonstrated. Using electroendosmosis, we further provide evidence for a clear role for CA in modulating the release. Our findings suggest that the paradigm presented herein has the potential to significantly enhance the design of hydrogel systems for the delivery of proteins and RNA therapeutics for vaccines and biomedical applications ranging from tissue engineering to functional coatings for medical devices.