Injectable Silk Fibroin/Tannic Acid Hydrogel with Dual Factors for Meniscus Repair

Despite advances in tissue engineering, the clinical application of scaffolds for meniscal repair remains limited by implantation challenges and the difficulty of directing stem cells toward a stable meniscal phenotype. Here, we present an injectable hydrogel composed of silk fibroin (SF) and tannic acid (TA), codelivering transforming growth factor-β₃ (TGF-β₃) and the transcription factor Mohawk (MKX). TA enhanced the β-sheet content of SF, yielding a hydrogel with superior rheological stability and shear-thinning behavior suitable for minimally invasive administration. The ST hydrogel provided sustained release of both bioactive factors over 35 days, with cumulative release below 16%. MKX attenuated TGF-β₃-induced hypertrophic differentiation of adipose-derived mesenchymal stem cells, promoting a fibrochondrocyte-like phenotype characterized by elevated expression of COL1A1, COL2A1, and aggrecan. Inflammatory stimulation assays demonstrated downregulation of osteoarthritis-related genes (e.g., MMP13, IL-6, and RUNX2) in the ST-TM group. In a rabbit meniscus tear model, ST hydrogels loaded with TGF-β₃ and MKX significantly enhanced extracellular matrix deposition, promoted structural repair of the meniscus, and improved biomechanical properties at 10 weeks postimplantation. These findings support the potential of this dual-factor hydrogel system as a cell-free therapeutic strategy for functional meniscus regeneration, with potential relevance to the modulation of OA-related degeneration.Impact StatementThis study presents a novel injectable silk fibroin/tannic acid hydrogel codelivering transforming growth factor-β₃ and Mohawk, which synergistically promotes fibrochondrocyte differentiation and inhibits hypertrophy of stem cells. Demonstrating injectable handling characteristics, controlled release, and in vivo efficacy, this cell-free platform offers a clinically translatable strategy for functional meniscus repair, with potential protective effects against osteoarthritis-related degeneration.