Stimuli-responsive Hydrogels for Targeted Antibiotic Delivery in Bone Tissue Engineering

Bone tissue engineering (BTE) faces critical challenges in managing infections such as osteomyelitis, which complicate healing and compromise implant success. Conventional antibiotic therapies often fail to achieve effective localized drug concentrations without systemic toxicity. Stimuli-responsive hydrogels have emerged as a transformative solution, offering spatiotemporally controlled, on-demand antibiotic release triggered by environmental cues such as pH, temperature, enzymatic activity, and redox conditions. This review comprehensively analyzes hydrogel classification, design strategies, and their integration within BTE scaffolds. It highlights the synergistic benefits of smart hydrogels in supporting osteogenic differentiation, enhancing vascularization, and combating infection. Key antibiotic delivery mechanisms-from enzyme-sensitive nanocomposites to dual-stimuli systems-are critically examined alongside their pharmacokinetic advantages and limitations. The article also discusses current translational barriers, including mechanical stability, biocompatibility, and regulatory hurdles, while presenting future directions such as biosensing-enabled, 3D-bioprinted, and AI-assisted platforms. Overall, stimuli-responsive hydrogels represent a promising paradigm in precision antibiotic delivery and regenerative bone therapy.