Programming Hydrogel Release Kinetics to Tissue Healing Phases: From Network Design to Therapeutic Synchronization

Abstract

The sequential phases of tissue healing—inflammation, proliferation, and remodeling—demand distinct pharmacokinetic profiles that conventional drug delivery systems fail to provide, creating a “chronotherapy gap” that contributes to chronic wound pathologies. Hydrogels, with their highly tunable network structures, offer a unique platform to program release kinetics in synchrony with these healing timelines. This review systematically examines design strategies for phase-synchronized hydrogel systems, categorized into three hierarchical paradigms: intrinsic network control (crosslinking density, degradation kinetics, and architectural engineering) that pre-programs release profiles; extrinsic/responsive control (endogenous pH/ROS/MMP/glucose and exogenous NIR/ultrasound/electro/magnetic triggers) that enables on-demand phase-shifting; and integrated systems that combine passive spatial compartmentalization with active responsiveness. We survey representative applications across cutaneous wounds, bone defects, cartilage, tendon, myocardial, and neural tissues, highlighting both common design principles and tissue-specific adaptations. Key translational bottlenecks—including in vivo–in vitro discrepancies, cargo stability, sterilization challenges, and regulatory complexity—are critically examined, alongside emerging frontiers such as closed-loop biosensing, artificial intelligence-driven design, and four-dimensional printing. We conclude that the field is evolving from passive drug depots toward active therapeutic synchronizers, where material programming is set to the body’s biological clock, offering a transformative paradigm for regenerative medicine.