A Thermoresponsive Biodegradable Polymer with Intrinsic Antioxidant Properties

Abstract

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 °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-1α 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.

Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs)

“…Activation of Notch signaling remarkably enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo . Furthermore, using the biodegradable citrate-based thermoresponsive PPCNg scaffold [42, 43, 49] leads to the formation of more mature bone with extensive angiogenesis and vascularization when the MSCs are stimulated by BMP9 and Notch. BMP9 and Notch were shown to up-regulate the expression of the angiogenic regulators in iMAD cells and ectopic bone tissues (Fig.…”

“…The PPCNg is gelatin-containing polyethylene glycolcitrate-co-N-isopropylacrylamide (PPCN) polymer which is biodegradable, biocompatible and intrinsically antioxidant [49]. One of the most prominent features of PPCNg is its hierarchical architecture of micropores and nanofibers with a lower critical solution temperature of 26°C and no significant volume reduction upon gelation [49]. We showed that PPCNg can gel robustly at 30°C at a final concentration as low as 50mg/ml [42, 43].…”

“…PPCN was synthesized by the polycondensation of citric acid, glycerol 1,3-diglycerolate diacrylate, poly (ethylene glycol) (PEG) to form an acrylated pre-polymer, which was then reacted with poly-N-isopropylacrylamide as described [49]. The chemical, biodegradable and thermoresponsive features were characterized for each newly synthesized batch as reported [49].…”

“…The chemical, biodegradable and thermoresponsive features were characterized for each newly synthesized batch as reported [49]. Prior to mixing with cells, PPCN powder was dissolved in PBS (100 mg/ml stock solution), sterilized by syringe filtration using 0.22 µm filters, and kept at 4°C.…”

Synthesis and characterization of rare-earth metal guanidinates stabilized by amine-bridged bis(phenolate) ligands and their application in the controlled polymerization of rac-lactide and rac-β-butyrolactone

“…[1][2][3][4][5][6] The most straightforward route to prepare PLA and PHB is the ring-opening polymerization (ROP) of the corresponding cyclic monomers, promoted by initiators that achieve high activity with controlled molecular weight, polydispersity, and microstructure of resulting polymers. 1,4,7 Among the variety of metal complexes that have been disclosed for these polymerizations, rare-earth metal complexes have been reported to be efficient initiators for the preparation of unique polyesters with controlled features.…”