Hybrid Hydrogels for Controlled Drug Delivery in Regenerative Therapies

Multifunctional hybrid hydrogel systems have emerged as a paradigm-shifting platform for improving and modeling physiological tissue conditions, enabling regulated drug delivery in regenerative treatments. They can be three-dimensional, hydrophilic networks synthesized by combining natural and synthetic polymers with nanoparticles or bioactive molecules, which imbue them with tunable physicochemical properties, increased mechanical stability, and responsive degradation kinetics, features necessary to deliver precise, site-specific therapeutic intervention. When stimulated at 45°C, photothermal hybrid dressings accelerate wound closure and increase collagen deposition, reactive oxygen species scavenging, and secretion of proregenerative cytokines, as measured by RNA sequencing and histological analysis. This review comprehensively examines the design principles, classification, and functional mechanisms of hybrid hydrogel systems, including natural synthetic composites, nanocomposite hydrogels, and interpenetrating polymer networks. Particular emphasis is placed on drug loading strategies, diffusion- and stimulus-mediated release mechanisms, and approaches to minimize burst release while achieving near-zero-order kinetics. The applications of hybrid hydrogels in regenerative medicine are critically discussed, with detailed insights into bone and cartilage repair, skin and wound healing, cardiovascular regeneration, and neural tissue engineering. These platforms demonstrate enhanced bioactivity, immunomodulation, angiogenesis, and electrical conductivity, supporting their utility across diverse therapeutic contexts.