In Situ Covalent Reinforcement of a Benzene‐1,3,5‐Tricarboxamide Supramolecular Polymer Enables Biomimetic, Tough, and Fibrous Hydrogels and Bioinks

Abstract Synthetic hydrogels often lack the load‐bearing capacity and mechanical properties of native biopolymers found in tissue, such as cartilage. In natural tissues, toughness is often imparted via the combination of fibrous noncovalent self‐assembly with key covalent bond formation. This controlled combination of supramolecular and covalent interactions remains difficult to engineer, yet can provide a clear strategy for advanced biomaterials. Here, a synthetic supramolecular/covalent strategy is investigated for creating a tough hydrogel that embodies the hierarchical fibrous architecture of the extracellular matrix (ECM). A benzene‐1,3,5‐tricarboxamide (BTA) hydrogelator is developed with synthetically addressable norbornene handles that self‐assembles to form a and viscoelastic hydrogel. Inspired by collagen's covalent cross‐linking of fibrils, the mechanical properties are reinforced by covalent intra‐ and interfiber cross‐links. At over 90% water, the hydrogels withstand up to 550% tensile strain, 90% compressive strain, and dissipated energy with recoverable hysteresis. The hydrogels are shear‐thinning, can be 3D bioprinted with good shape fidelity, and can be toughened via covalent cross‐linking. These materials enable the bioprinting of human mesenchymal stromal cell (hMSC) spheroids and subsequent differentiation into chondrogenic tissue. Collectively, these findings highlight the power of covalent reinforcement of supramolecular fibers, offering a strategy for the bottom‐up design of dynamic, yet tough, hydrogels and bioinks.