Despite the development of hydrogels with high mechanical properties, insufficient adhesion between these materials and biological surfaces significantly limits their use in the biomedical field. By controlling toughening processes, we designed a composite double-network hydrogel with ~90% water content, which creates a dissipative interface and robustly adheres to soft tissues such as cartilage and meniscus. A double-network matrix composed of covalently crosslinked poly(ethylene glycol) dimethacrylate and ionically crosslinked alginate was reinforced with nano-fibrillated cellulose. No tissue surface modification was needed to obtain high adhesion properties of the developed hydrogel. Instead, mechanistic principles were used to control interfacial cracks propagation. Comparing to commercial tissue adhesives, the integration of the dissipative polymeric network on the soft tissue surfaces allowed increasing significantly the adhesion strength, such as ~130 kPa for articular cartilage. Our findings highlight the significant role of controlling hydrogel structure and dissipation processes for toughening the interface. This research provides a promising path to the development of highly adhesive hydrogels for tissues repair.

During loading of viscoelastic tissues, part of the mechanical energy is transformed into heat that can locally increase the tissue temperature, a phenomenon known as self-heating. In the framework of mechanobiology, it has been accepted that cells react and adapt to mechanical stimuli. However, the cellular effect of temperature increase as a by-product of loading has been widely neglected. In this work, we focused on cartilage self-heating to present a ‘thermo-mechanobiological’ paradigm, and demonstrate how the coupling of a biomimetic temperature evolution and mechanical loading could influence cell behavior. We thereby developed a customized in vitro system allowing to recapitulate pertinent in vivo physical cues and determined the cells chondrogenic response to thermal and/or mechanical stimuli. Cellular mechanisms of action and potential signaling pathways of thermo-mechanotransduction process were also investigated. We found that co-existence of thermo-mechanical cues had a superior effect on chondrogenic gene expression compared to either signal alone. Specifically, the expression of Sox9 was significantly upregulated by application of the physiological thermo-mechanical stimulus. Multimodal transient receptor potential vanilloid 4 (TRPV4) channels were identified as key mediators of thermo-mechanotransduction process, which becomes ineffective without external calcium sources. We also observed that the isolated temperature evolution, as a by-product of loading, is a contributing factor to the cell response and this could be considered as important as the conventional mechanical loading. Providing an optimal thermo-mechanical environment by synergy of heat and loading portrays new opportunity for development of novel treatments for cartilage regeneration and can furthermore signal key elements for emerging cell-based therapies.

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Development of mechanically durable and biologically inductive hydrogels is a major challenge for load-bearing applications such as engineered cartilage. Dissipative capacity of articular cartilage is central to its functional behavior when submitted to loading. While fluid frictional drag is playing a significant role in this phenomenon, the flow-dependent source of dissipation is mostly overlooked in the design of hydrogel scaffolds. Herein, we propose an original strategy based on the combination of fluidic and polymeric dissipation sources to simultaneously enhance hydrogel mechanical and mechanobiological performances. The nondestructive dissipation processes were carefully designed by hybrid cross-linking of the hydrogel network and low permeability of the porous structure. It was found that intrachain and pore water distribution in the porous hydrogels improves the mechanical properties in high water fractions. In contrast to widely reported tough hydrogels presenting limited load support capability at low strain values, we obtained stiff and dissipative hydrogels with unique fatigue behavior. We showed that the fatigue resistance capability is not a function of morphology, dissipation level, and stiffness of the viscoelastic hydrogels but rather depends on the origin of the dissipation. Moreover, the preserved dissipation source under mechanical stimulation maintained a mechanoinductive niche for enhancing chondrogenesis owing to fluid frictional drag contribution. The proposed strategy can be widely used to design functional scaffolds in high loading demands for enduring physiological stimuli and generating regulatory cues to cells.