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

Conventional synthetic hydrogels often lack the load-bearing capacity and mechanical properties of native biopolymers found in tissue, such as cartilage. In natural tissues, like cartilage, toughness is often imparted via the combination of fibrous non-covalent self-assembly with key covalent bond formation. The controlled combination of supramolecular fibers and covalent interactions remains difficult to engineer, yet could 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 in many native tissues. A benzene-1,3,5-tricarboxamide (BTA) based hydrogelator was developed with synthetically addressable norbornene handles, which self-assembled across multiple length scales to form a fibrillar and viscoelastic hydrogel. Inspired by collagen's covalent cross-linking of fibrils, we fine-tuned the mechanical properties such as toughness, stiffness, and strength of the hydrogels by covalent intra- and inter-fiber cross-links. At over 90% water, the hydrogels withstood up to 550% tensile strain, 90% compressive strain, and dissipated energy with recoverable hysteresis. The norbornene BTA hydrogels were shear-thinning and could be 3D bioprinted with good shape fidelity, and the fabricated structures were further toughened by introducing covalent cross-linking. These materials enabled the bioprinting of hMSC spheroids and differentiation/maturation into chondrogenic tissue. Collectively, our findings highlight that the conjunction of self-assembly and covalent cross-linking of supramolecular fibers offers a potentially powerful strategy for the bottom-up design of dynamic, yet tough, synthetic hydrogels and bioinks. This article is protected by copyright. All rights reserved.