Chemical Strategies for Multistimuli Responsive Dynamic Covalent Materials in Regenerative Medicine

Regenerative medicine requires biomaterials that can function within complex and dynamically changing biological environments. Dynamic covalent chemistry provides a compelling foundation for such materials by combining covalent stability with reversible bond exchange, enabling adaptability, self-healing, and stimulus-responsive behavior. Dynamic covalent biomaterials have therefore emerged as promising platforms for tissue scaffolds, wound healing, and controlled delivery applications. Although many existing systems respond to a single stimulus, such as pH, redox conditions, or enzymatic activity, biological environments are inherently multiresponsive, integrating mechanical, chemical, and biochemical cues simultaneously. As a result, single-stimulus dynamic materials often fail to achieve predictable performance in vivo. This review focuses on chemical strategies for engineering multistimuli responsive dynamic covalent materials that more closely reflect the complexity of native regenerative processes. We discuss key reversible covalent motifs, their thermodynamic and kinetic characteristics, and how these can be combined through orthogonal chemistries, multicomponent networks, and hierarchical architectures to achieve tunable mechanics, stress relaxation, degradation, and biofunctionality. Finally, we outline current challenges and opportunities, emphasizing the need for expanded biocompatible chemistries and rational design principles to advance multistimuli responsive dynamic covalent materials toward translational regenerative medicine.