Advanced treatment for articular cartilage lesions: Development of an injectable glucosinolate-releasing hyaluronic acid

Intra-articular injection of hyaluronic acid (HA) is commonly used to treat early-stage articular cartilage lesions (ACLs). While effective in restoring mechanical function, its long-term efficacy is limited by short stability and modest chondroprotective activity. A promising approach to enhance clinical outcomes is to combine HA with bioactive compounds. Here, we developed a novel microstructured HA (HA-MPHA-BGL) that releases benzylglucosinolate (BGL), a glucosinolate (GLS) derived from the Brassicaceae family. HA-MPHA-BGL was designed to fulfil two essential requirements for cartilage repair: (i) improving the physicochemical properties of HA to prolong its stability through the incorporation of HA crosslinked microparticles, and (ii) boosting its chondroprotective potential by exploiting the bioactivity of BGL. Additionally, HA-MPHA-BGL was designed for targeting GLS directly to the articular site, thus overcoming the limitations associated with oral supplementation. HA-MPHA-BGL demonstrated good rheological characteristics and exhibited resistance to enzymatic degradation in vitro. Biological assays demonstrated its cytocompatibility and chondroprotective effects on human joint cells: HA-MPHA-BGL increased the expression of type 2 collagen, the major component of cartilage matrix, and reduced the expression of degenerative markers such as type 1 and 10 collagens, matrix metalloproteinase-13 (MMP-13), and A Disintegrin and Metalloproteinase with Thrombospondin motifs 5 (ADAMTS-5) in mesenchymal stromal cells. Furthermore, HA-MPHA-BGL mitigated inflammation by reducing the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkβ) pathway in a co-culture of chondrocytes and synoviocytes. As a prototype of GLS-releasing HA, HA-MPHA-BGL represents a significant advancement in infiltrative therapies and lays the ground for further research on GLS-based treatments for ACLs.