Sustainable chondroitin sulfate hydrogels for controlled and environmentally safe drug release: synthesis, characterization, and pH-responsiveness

Abstract

Sustainable chondroitin sulfate (CS) hydrogels have emerged as promising platforms for controlled drug release due to their biocompatibility, biodegradability, and potential to reduce environmental impacts. The combination of CS with natural or synthetic polymers enables the development of intelligent, pH-responsive matrices capable of modulating drug release in specific physiological environments. This systematic review of 50 studies demonstrated that CS-based hydrogels offer favorable safety profiles and tunable performance. Their synthesis occurs predominantly through free radical polymerization, using crosslinking agents such as ethylene glycol dimethacrylate (EGDMA) and N,N?-methylenebisacrylamide (MBA). These hydrogels exhibit consistent pH responsiveness, with greater swelling and drug release at physiological pH (7.4) than under acidic conditions (1.2), a behavior attributed to the protonation and deprotonation of carboxyl and sulfate groups that modulate charge density and electrostatic repulsion. Drug release durations range from 36–72 hours for anti-inflammatory agents to more than six weeks for cationic oncology therapies, with kinetics primarily described by non-Fickian diffusion mechanisms. Evidence regarding environmental safety remains limited. Cytotoxicity assays (MTT, CCK-8) report cell viability above 94 percent, and in vivo studies in rabbits indicate low toxicity. Complexation with CS enhances the biocompatibility of synthetic polymeric components, and biodegradation studies show slow degradation under physiological buffer conditions. Nevertheless, comprehensive environmental impact assessments, green chemistry metrics, and explicit sustainability indicators were not reported, representing an important gap for more conclusive evaluations of the environmental sustainability of these hydrogels.