Breakthrough dual-drug hydrogel promotes cartilage repair in osteoarthritis

A research team from Northwest University, China, has developed a breakthrough nano-composite hydrogel system to address the dual challenges of inflammation and cartilage damage in osteoarthritis (OA), a leading cause of joint disability worldwide. Published in Engineering, the study confirms that the dual-drug-loaded hydrogel promotes cartilage repair through synergistic immune regulation and chondrocyte differentiation, offering a novel therapeutic strategy for OA.

OA is characterized by persistent inflammation and impaired cartilage regeneration, with existing treatments failing to effectively target both mechanisms. The newly developed HLC(Dex)–SPNs–KGN hydrogel combines two natural proteins-human-like collagen (HLC) and silk protein nanoparticles (SPNs)-to deliver two key molecules: dexamethasone (Dex), an anti-inflammatory glucocorticoid, which suppresses early inflammation and polarizes pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages; and kartogenin (KGN), which induces human mesenchymal stem cells (hMSCs) to differentiate into chondrocytes and maintains chondrocyte stability in later stages.

The hydrogel design enables spatiotemporal control of drug release: Dex is rapidly released early to combat inflammation, while KGN is sustained for weeks to promote cartilage regeneration. This dual mechanism creates a microenvironment conducive to tissue repair, mimicking natural cartilage healing stages. The hydrogel's porous structure (10–30 μm pore size) supports cell adhesion and nutrient supply, with a gelation efficiency of 95%. Release profiles show an early burst of Dex (80% released within 40 days) and sustained release of KGN (40% released within 40 days).

Inflammatory RAW264.7 macrophages treated with the hydrogel showed a 75% reduction in pro-inflammatory TNF-α and a 6-fold increase in anti-inflammatory IL-10 compared to controls. hMSCs co-cultured with the hydrogel exhibited significantly higher expression of cartilage-specific proteins (COMP, Col II, aggrecan, and SOX-9) and genes, with RUNX1, a key regulator of chondrocyte survival, showing the highest expression.

In rabbit knee defect models, the hydrogel completely filled defects with new cartilage tissue, featuring a smooth surface and good integration with surrounding tissue (ICRS grade II), whereas controls showed predominantly fibrous tissue (grade III). Micro-CT and histological analyses revealed significantly improved bone mineral density (BMD) and bone volume/total volume ratio (BV/TV) in the hydrogel group, along with reduced levels of inflammatory factors (TNF-α, IL-6, and ADAMTS5).

The authors note that combining immune regulation with controlled cartilage induction via a biocompatible hydrogel overcomes limitations of traditional OA treatments. The dual-drug delivery system not only alleviates inflammation but also actively promotes cartilage regeneration, offering a holistic solution for joint repair. The use of natural proteins like collagen and silk ensures biodegradability and safety, while the nano-composite structure allows precise modulation of drug release. This platform may be adapted for other degenerative diseases requiring spatiotemporal therapeutic control.

The team plans to optimize hydrogel purification processes for clinical translation and study long-term safety in larger animal models. Additionally, they are exploring the system's applicability to other musculoskeletal injuries, such as tendon or bone defects.

This research highlights the potential of biomaterial-based therapies to revolutionize OA treatment, offering hope to millions affected by this disabling disease. By addressing both inflammation and tissue damage simultaneously.