A bioactive hydrogel regulates chondrocyte fate with hypoxia-mimetic chondrogenic induction and vascular invasion suppression for full-thickness cartilage repair.

Abstract

Chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is always compromised by hypertrophic maturation, rendering long-term phenotype maintenance a key challenge. While hypoxia drives chondrogenic commitment, sustained hypoxic stimulation within the injured joint paradoxically accelerates hypertrophy via subchondral vascular invasion and inflammatory imbalance. To resolve this dilemma, we developed a photocross-linkable hydrogel composed of N-acryloyl aspartic acid (AASP) and asiatic acid-grafted gelatin (Gel-AA) for full-thickness cartilage repair. Mechanistically, the carboxyl groups of AASP chelate iron ions and stabilize HIF-1α, sustaining its activity under normoxic conditions to establish a hypoxia-mimicking microenvironment that promotes BMSC chondrogenesis. Of note, AA curbs vascular invasion, reduces oxidative stress, and prevents hypertrophic drift by suppressing VEGF-driven angiogenic signaling and reshaping the immune microenvironment toward a regenerative state. Consequently, this hydrogel fine-tunes chondrocyte fate by coupling the initiation of chondrogenic differentiation with the inhibition of subsequent phenotypic deterioration. In vivo results further verified that this dual-regulatory strategy achieves structurally and phenotypically stable hyaline-like cartilage regeneration, offering a promising therapeutic paradigm for cartilage repair.