A polyphenol-functionalized cartilage matrix bioink protects cell-laden organoid constructs under oxidative stress

Cartilage repair in osteoarthritis is limited not only by structural defects in articular cartilage but also by the chronic redox and immune dysregulation in the microenvironment. Acellular cartilage matrix (ACM) replicates tissue-specific extracellular matrix (ECM) characteristics, but lacks the capacity to counteract oxidative stress and secondary inflammation in the tissue microenvironment. In this research, we incorporated tannic acid (TA) into methacrylated ACM (ACMMA) to develop a dynamic dual-crosslinked network bioink for cartilage organoid constructs. TA remodeled precursor assembly behavior, altered the interfacial charge, and promoted the formation of a denser hydrogel microstructure. ACMMA-TA exhibited enhanced chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) equivalent to ACMMA. However, under oxidative stress, it significantly reduced intracellular and mitochondrial reactive oxygen species (ROS) levels, preserved mitochondrial membrane potential, suppressed the expression of pro-inflammatory cytokines, and promoted anti-inflammatory macrophage polarization. Transcriptomic analysis of ACMMA-TA based organoid constructs revealed enhanced ECM preservation and glutathione metabolism, along with the inhibition of IL-17 and NF-κB signaling. In a rat articular cartilage defect model, the ACMMA and ACMMA-TA groups showed comparable moderate improvement, while TA functionalized cell-laden organoid constructs achieved the highest ICRS scores with hyaline-like cartilage formation. These results indicate that TA functions as a conditional microenvironment stabilizer, suggesting that biomaterial design for cartilage repair may prioritize maintaining cell function under pathological stress over structural optimization or robust chondrogenic capacity alone.