Advanced hydrogels for tissue engineering and regenerative medicine: from material design to clinical translation
Hydrogels have emerged as one of the most versatile classes of biomaterials for tissue engineering and regenerative medicine (TERM) due to their striking structural and functional similarities to the native extracellular matrix high water content, tunable physicochemical properties, and excellent biocompatibility. This comprehensive review provides a systematic synthesis of hydrogel-based biomaterials, examining their evolving role in regenerative medicine through a critical analysis of literature published between 2020 and 2026. The fundamental design requirements for regenerative scaffolds, namely biocompatibility, biodegradability, mechanical tunability, and extracellular matrix (ECM) biomimicry, are first established. Subsequently, natural polymers (alginate, chitosan, collagen, gelatin, and hyaluronic acid (HA) and synthetic polymers (polyethylene glycol, PLA, polycaprolactone, PNIPAM) are critically evaluated as hydrogel building blocks, with their advantages, limitations, and representative applications systematically compared. Recent advances in hydrogel fabrication technologies including injectable systems, nanocomposite hydrogels, stimuli-responsive “smart” hydrogels, self-healing formulations, and conductive platforms, are systematically reviewed with specific focus on applications in bone, cartilage, skin, cardiac, neural, and oral tissue engineering. We then examine emerging therapeutic applications beyond traditional scaffolding, including controlled drug/gene delivery, biosensing, and personalized medicine. A critical analysis of translational barriers addresses preclinical model relevance, scalability challenges, sterilization requirements, and evolving regulatory frameworks including the FDA Modernization Act 2.0. Finally, we explore future directions including AI-assisted hydrogel design, patient-specific biofabrication, and “living” hydrogel systems incorporating engineered cells. By identifying evidence-based design principles and persistent knowledge gaps, this review provides a roadmap for accelerating the clinical adoption of next-generation hydrogel-based regenerative therapies.