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Hydrogels are three-dimensional platforms that serve as substitutes for native extracellular matrix. These materials are starting to play important roles in regenerative medicine because of their similarities to native matrix in water content and flexibility. It would be very advantagoues for researchers to be able to regulate cell behavior and fate with specific hydrogels that have tunable mechanical properties as biophysical cues. Recent developments in dynamic chemistry have yielded designs of adaptable hydrogels that mimic dynamic nature of extracellular matrix. The current review provides a comprehensive overview for adaptable hydrogel in regenerative medicine as follows. First, we outline strategies to design adaptable hydrogel network with reversible linkages according to previous findings in supramolecular chemistry and dynamic covalent chemistry. Next, we describe the mechanism of dynamic mechanical microenvironment influence cell behaviors and fate, including how stress relaxation influences on cell behavior and how mechanosignals regulate matrix remodeling. Finally, we highlight techniques such as bioprinting which utilize adaptable hydrogel in regenerative medicine. We conclude by discussing the limitations and challenges for adaptable hydrogel, and we present perspectives for future studies.

[Display omitted] • A dynamic IPN hydrogel is fabricated via photopolymerization and oxidation of GelMA and HASH. • The dynamic IPN hydrogel exhibits tunable physical and mechanical properties. • The dynamic IPN hydrogel mimics the viscoelasticity and adaptability of the ECM. • A bilayer tissue-engineered skin is constructed based on dynamic IPN hydrogels. • The bilayer tissue-engineered skin can promote healing of full-thickness skin defects. Tissue engineering scaffolds with tunable viscoelasticity and adaptability for cell behavior and fate regulation are highly desired. Here a dynamic interpenetrating polymer network (IPN) hydrogel was fabricated via photopolymerization and oxidation of methacryloyl gelatin (GelMA) and hyaluronic acid (HASH). The permanent GelMA network formed by C C bonds provides stable support for cells while the dynamic HASH network formed by disulfide bonds provides an adaptable microenvironment for cell growth. The proposed IPN hydrogel exhibits extensive and tunable porosity, swelling, degradation, and mechanical properties. Remarkably, the dynamic IPN hydrogel mimics the viscoelasticity and adaptability of the extracellular matrix (ECM), which can regulate cellular behaviors such as morphogenesis, alignment, proliferation, migration while offering resistance to cell mediated shrinkage and enzymatic digestion, maintaining the structural integrity of the scaffold. Our results suggest that dynamic IPN 3/7 (HASH/GelMA) hydrogels had more similar physical properties to human skin and were more favorable for human skin fibroblasts (HSF) and human immortalized keratinocytes (HaCaT) growth. Moreover, bilayer tissue-engineered skin prepared using the dynamic IPN hydrogel exhibited satisfactory mechanical stability, dermal-epidermal stratification, matrix secretion, structural differentiation, and barrier functions. In addition, the bilayer tissue-engineered skin can significantly promote healing of full-thickness skin defects through accelerated wound re-epithelialization, collagen deposition, and angiogenesis, without causing non-specific or specific immune rejection. This work based on the novel dynamic IPN hydrogel with biomimetic viscoelasticity and adaptability demonstrates the promising application in tissue engineering. [ABSTRACT FROM AUTHOR]

Hydrogels are three-dimensional platforms that serve as substitutes for native extracellular matrix. These materials are starting to play important roles in regenerative medicine because of their similarities to native matrix in water content and flexibility. It would be very advantagoues for researchers to be able to regulate cell behavior and fate with specific hydrogels that have tunable mechanical properties as biophysical cues. Recent developments in dynamic chemistry have yielded designs of adaptable hydrogels that mimic dynamic nature of extracellular matrix. The current review provides a comprehensive overview for adaptable hydrogel in regenerative medicine as follows. First, we outline strategies to design adaptable hydrogel network with reversible linkages according to previous findings in supramolecular chemistry and dynamic covalent chemistry. Next, we describe the mechanism of dynamic mechanical microenvironment influence cell behaviors and fate, including how stress relaxation influences on cell behavior and how mechanosignals regulate matrix remodeling. Finally, we highlight techniques such as bioprinting which utilize adaptable hydrogel in regenerative medicine. We conclude by discussing the limitations and challenges for adaptable hydrogel, and we present perspectives for future studies., Competing Interests: The authors declare no conflict of interest., (© 2020 [The Author/The Authors].)

Reversibly cross-linked adaptable hydrogels show great advantages in tissue engineering. The dynamic adaptable networks can overcome three-dimensional (3D) physical restrictions to enable normal cellular functions without hydrogel degradation. However, because of the dynamic reversibility, adaptable hydrogels typically exhibit weak mechanical properties and rapid erosion behaviors. Herein, we develop a facile strategy to prepare stable adaptable hydrogels using dynamic covalent chemistry, stable covalent chemistry, and the interpenetrating polymeric network (IPN) strategy. The developed IPN HA/γ-PGA adaptable hydrogels have stable structures, good mechanical properties, enzymatic degradability, and injectability. Compression test indicates that although containing 95% water, the IPN HA/γ-PGA adaptable hydrogels can suffer more than 85% compressive strain and show a fast shape recovery capacity and good antifatigue ability. Benefitting from the good cytocompatibility of functionalized HA and γ-PGA and the mild preparation process of IPN HA/γ-PGA adaptable hydrogels, NIH 3T3 cells can tolerate the 3D encapsulation process and show high cell viability. Therefore, owing to their desirable properties, the developed HA/γ-PGA adaptable hydrogels have great potential applications for load-bearing tissue engineering.