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In regenerative medicine, a synthetic extracellular matrix is crucial for supporting stem cells during its differentiation process to integrate into surrounding tissues. Hydrogels are used extensively in biomaterials as synthetic matrices to support the cells. However, to mimic the biological niche of a functional tissue, various chemical functionalities are necessary. We present here, a method of functionalizing a highly porous hydrogel with functional groups by mixing the hydrogel with a plant virus, tobacco mosaic virus (TMV), and its mutant. The implication of this process resides with the three important features of TMV: its well-defined genetic/chemical modularity, its multivalency (TMV capsid is composed of 2130 copies of identical subunits), and its well-defined structural features. Previous studies utilizing the native TMV on two-dimensional supports accelerated mesenchymal stem cell differentiation, and surfaces modified with genetically modified viral particles further enhanced cell attachment and differentiation. Herein we demonstrate that functionalization of a porous alginate scaffold can be achieved by the addition of viral particles with minimal processing and downstream purifications, and the cell attachment and differentiation within the macroporous scaffold can be effectively manipulated by altering the peptide or small molecule displayed on the viral particles.

This study focuses on the development of injectable hydrogels to mimic the cartilage microenvironment using hyaluronic acid (HA) derivatives as starting materials. Cysteine-inserted Tobacco mosaic virus (TMV) mutants (TMV1cys) could be cross-linked to methacrylated hyaluronic acid (MeHA) polymers by thiol-ene "click" chemistry and form hydrogels under physiological condition. The resulting hydrogels could promote in vitro chondrogenesis of bone marrow mesenchymal stem cells (BMSCs) significantly higher than that in the TMV-free HA hydrogels by upregulating bone morphogenetic protein-2 (BMP-2) expression and enhancing collagen accumulation.