A Thermoresponsive Biodegradable Polymer with Intrinsic Antioxidant Properties

Oxidative stress in tissue can contribute to chronic inflammation that impairs wound healing and the efficacy of cell-based therapies and medical devices. We describe the synthesis and characterization of a biodegradable, thermoresponsive gel with intrinsic antioxidant properties suitable for the delivery of therapeutics. Citric acid, poly(ethylene glycol) (PEG), and poly-N-isopropylacrylamide (PNIPAAm) were copolymerized by sequential polycondensation and radical polymerization to produce poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN). PPCN was chemically characterized, and the thermoresponsive behavior, antioxidant properties, morphology, potential for protein and cell delivery, and tissue compatibility in vivo were evaluated. The PPCN gel has a lower critical solution temperature (LCST) of 26 degrees C and exhibits intrinsic antioxidant properties based on its ability to scavenge free radicals, chelate metal ions, and inhibit lipid peroxidation. PPCN displays a hierarchical architecture of micropores and nanofibers, and contrary to typical thermoresponsive polymers, such as PNIPAAm, PPCN gel maintains its volume upon formation. PPCN efficiently entrapped and slowly released the chemokine SDF-1 alpha and supported the viability and proliferation of vascular cells. Subcutaneous injections in rats showed that PPCN gels are resorbed over time and new connective tissue formation takes place without signs of significant inflammation. Ultimately, this intrinsically antioxidant, biodegradable, thermoresponsive gel could potentially be used as an injectable biomaterial for applications where oxidative stress in tissue is a concern.