An ideal hydrogel for biomedical engineering should mimic the intrinsic properties of natural tissue, especially high toughness and self-healing ability, in order to withstand cyclic loading and repair skin and muscle damage. In addition, excellent cell affinity and tissue adhesiveness enable integration with the surrounding tissue after implantation. Inspired by the natural mussel adhesive mechanism, we designed a polydopamine-polyacrylamide (PDA-PAM) single network hydrogel by preventing the overoxidation of dopamine to maintain enough free catechol groups in the hydrogel. Therefore, the hydrogel possesses super stretchability, high toughness, stimuli-free self-healing ability, cell affinity and tissue adhesiveness. More remarkably, the current hydrogel can repeatedly be adhered on/stripped from a variety of surfaces for many cycles without loss of adhesion strength. Furthermore, the hydrogel can serve as an excellent platform to host various nano-building blocks, in which multiple functionalities are integrated to achieve versatile potential applications, such as magnetic and electrical therapies.

Glycosaminoglycan-based hydrogels are widely used for cartilage repair because glycosaminoglycans are the main component of the cartilage extracellular matrix and can maintain chondrocyte functions. However, most of the glycosaminoglycan-based hydrogels are negatively charged and cell-repellant, and they cannot host cells or favor tissue regeneration. Inspired by mussel chemistry, we designed a polydopamine-chondroitin sulfate-polyacrylamide (PDA-CS-PAM) hydrogel with tissue adhesiveness and super mechanical properties for growth-factor-free cartilage regeneration. Thanks to the abundant reactive catechol groups on the PDA, a cartilage-specific PDA-CS complex was formed by the self-assembly of PDA and CS, and then the PDA-CS complex was homogenously incorporated into an elastic hydrogel network. This catechol-group-enriched PDA-CS complex endowed the hydrogel with good cell affinity and tissue adhesiveness to facilitate cell adhesion and tissue integration. Compared with bare CS, the PDA-CS complex in the hydrogel was more effective in exerting its functions on adhered cells to upregulate chondrogenic differentiation. Because of the synergistic effects of noncovalent interactions caused by the PDA-CS complex and covalently cross-linked PAM network, the hydrogel exhibited super resilience and toughness, meeting the mechanical requirement of cartilage repair. Collectively, this tissue-adhesive and tough PDA-CS-PAM hydrogel with good cell affinity creates a growth-factor-free and biomimetic microenvironment for chondrocyte growth and cartilage regeneration and sheds light on the development of growth-factor-free biomaterials for cartilage repair.

Articular cartilage defect repair is challenging for clinics because it is avascular tissue lack of self-regenerative ability. Gelatin-based hydrogels are widely used in the field of tissue engineering because of their good biodegradability, excellent biocompatibility, and cell/tissue affinity. However, gelatin-based hydrogels exhibit poor thermal stability and low mechanical strength, which limits their applications in cartilage repair. In this study, methacrylic anhydride (MA) was employed to modify gelatin to obtain photo-crosslinkable methacrylated gelatin (GelMA). The GelMA-based natural-synthetic polymer biohybrid hydrogel was prepared by co-polymerizing acrylamide (AM) and GelMA under ultraviolet radiation in the presence of a photo-initiator. The GelMA/PAM biohybrid hydrogel simultaneously possessed the advantages of both PAM hydrogels and GelMA hydrogels. The GelMA block provided specific biological functions for cell adhesion and proliferation, while the flexible PAM chains reinforced the brittle gelatin network and sustain load during deformation. Compared with pure PAM hydrogel and GelMA, the GelMA/PAM biohybrid hydrogels showed enhanced compression strength (0.38 MPa) and improved elasticity (storage modulus of 1000 Pa). The GelMA/PAM biohybrid hydrogel showed a favorable degradation rate and sustained protein release. In vitro cell culture showed that the chondrocytes remained viable and proliferated on the biohybrid hydrogel, demonstrating that the biohybrid hydrogels had good cell adhesion and excellent biocompatibility. In a rabbit knee cartilage defect model, we evaluated the cartilage repair ability of the biohybrid hydrogel in vivo. In summary, this study demonstrated that hybridization of synthetic polymers considerably improves the performance and expands the application of the gelatin-based hydrogels. The biohybrid