Next-generation injectable hydrogels: Advanced crosslinking strategies, multi-stimuli responsiveness, and translational advances for precision regenerative medicine
Govindaraj Sabarees, Yobu Sam Jebaraj, Elumalai Ezhilarasan, Yuvaraj Dravid Ragul
Abstract
Injectable hydrogels represent a transformative platform in biomaterials, enabling minimally invasive delivery and precise therapeutic localization with biomimetic structural and functional properties. Recent innovations in chemistry and crosslinking ranging from photopolymerization, click chemistry, and Schiff’s base formation to enzyme-mediated catalysis and supramolecular assemblies allow finely tuned gelation kinetics, mechanical strength, degradation, and responsive bioactivity under physiological conditions. This comprehensive review systematically examines next-generation injectable hydrogels, highlighting chemical and physical crosslinking mechanisms and integration of multi-stimuli responsiveness including temperature, pH, light, and enzymatic triggers to achieve spatiotemporal control of tissue regeneration and drug delivery. We critically evaluate translational advances across diverse tissue engineering domains such as bone, cartilage, cardiac, neural, skin, liver, pancreas, vascular, and periodontal tissues. Challenges in scalability, reproducibility, sterilization, and regulatory approval remain, yet ongoing progress in biofunctionalization and injectable biofabrication underpins their promise for personalized regenerative medicine. Bridging fundamental materials science and clinical translation, injectable hydrogels are poised to revolutionize minimally invasive therapies and precision medicine in the decade ahead. • Review of next-generation injectable hydrogels for precision regenerative medicine. • Overview of advanced crosslinking methods such as photo, click, Schiff base, enzymatic, and supramolecular systems. • Multi-stimuli responsive hydrogels activated by temperature, pH, light, and enzymes for controlled therapy. • Applications of injectable hydrogels in bone, cartilage, cardiac, neural, skin, liver, vascular, and periodontal tissues. • Challenges and future prospects for clinical translation, including scalability, sterilization, and regulatory issues.