John R. Martin
Many different polymeric scaffold materials that exhibit degradability and minimal toxicity have been developed as bone void fillers to promote tissue regeneration in large bone defects, but in general these materials do not intrinsically promote new bone growth. To this end, implants coated with electrostatic layer-by-layer (LbL) assemblies of polyelectrolyte polymers and pro-healing growth factor proteins such as bone morphogenic protein-2 (BMP-2) have been developed. However, current polyelectrolyte-based constructs are engineered to degrade by non-specific hydrolysis to mediate protein release and are minimally-responsive to the rate of tissue repair. This limitation motivates the need for LbL systems that better deliver therapies over the entire lifetime of the bone healing process. Therefore, we have developed stimuli-responsive LbL nanofilms that selectively release drug payloads in response to cell-generated reactive oxygen species (ROS), yielding a system that prolongs the drug efficacy window by conserving therapeutics only until they are needed. Poly(thioketal-β-amino amide) (PTK-BAA) cationic polymers were synthesized by step-growth polymerization; the polymer’s thioketal and amide bonds are hydrolytically inert while thioketals are selectively degraded by ROS. When incorporated into LbL films with anionic poly(acrylic acid) and either the model cationic protein lysozyme or therapeutic protein BMP-2, these coatings experienced minimal protein release when incubated in PBS at 37°C but discharged significantly greater protein amounts when treated with physiological doses of hydrogen peroxide (H2O2). These data highlight the utility of PTK-BAA polymers as environmentally-responsive LbL film constituents and emphasize the potential of “on-demand” drug delivery systems in bone regenerative applications.