Hypoxia‐preconditioned adipose‐derived stem cells with injectable small intestinal submucosa for enhanced cartilage repair in osteoarthritis

Abstract Osteoarthritis (OA) is a widespread degenerative condition marked by inflammation‐induced damage to chondrocytes and gradual breakdown of the cartilage extracellular matrix. Adipose‐derived mesenchymal stem cells (ADSCs) hold potential for treating OA due to their capacity to differentiate into various cell types and their paracrine signaling functions. However, the inflammatory environment in OA reduces ADSC viability post‐injection, while the absence of a supportive carrier causes significant cell loss, impairing their capacity for cartilage repair. To address these challenges, we improved the stemness and paracrine activity of ADSCs through hypoxia preconditioning and integrated them into an injectable small intestinal submucosa (SIS) tissue repair scaffold. This resulted in an SIS + ADSC composite material, designed for intra‐articular injection to enhance cartilage repair in arthritis. Our findings revealed that exposing ADSCs to 2% oxygen during hypoxia preconditioning and incorporating them into injectable SIS significantly increased the secretion of growth factors (VEGF, bFGF, EGF) and upregulated key hypoxia and stem cell markers (HIF‐1α, NANOG, SOX‐2, Oct‐4). In a rat OA model, hypoxia‐preconditioned SIS + ADSC composites markedly enhanced cartilage repair by stimulating anabolic activity, suppressing catabolic pathways, and reducing inflammation, thereby exhibiting strong protective and reparative effects. In summary, combining hypoxia preconditioning with injectable SIS offers an innovative and effective approach to optimize OA treatment by enhancing paracrine signaling, paving the way for new insights and technologies in cartilage repair within regenerative medicine.