An Ultrasound-Responsive Bio-Adhesive Piezoelectric Hydrogel for Osteoarthritis Cartilage

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive loss of articular cartilage and an associated decline in its intrinsic mechanoelectrical signaling. Current osteoarthritis treatments relieve symptoms but fail to prevent cartilage degeneration or restore its native biophysical microenvironment. Here, we present an ultrasound-activated, mussel-inspired bio-adhesive hydrogel that addresses these challenges by recreating the cartilage's piezoelectric cues in situ while achieving stable intra-articular retention under synovial conditions. The hydrogel, denoted SFHD-BT@PDA, consists of a silk fibroin (SF) matrix integrated with dopamine-functionalized hyaluronic acid (HADA) and embedded barium titanate nanoparticles coated with polydopamine (BT@PDA). This multi-level design imparts strong interfacial adhesion to wet cartilage (via catechol-mediated bonding to collagen) and piezoelectric sensitivity to external ultrasound. Under ultrasound stimulation, SFHD-BT@PDA generates localized electrical microcurrents that recruit endogenous MSCs via electrotaxis and subsequently promote their chondrogenic differentiation. In vitro, ultrasound-triggered electrical cues upregulated chondrogenic markers (SOX9, collagen II, aggrecan) in MSCs and activated TGF-β signaling, demonstrating restoration of the pro-anabolic bioelectric microenvironment. In a murine DMM model, the adhesive hydrogel exhibited prolonged retention on cartilage surfaces and, with ultrasound, induced robust cartilage regeneration and OA reversal. Treated joints showed preserved proteoglycan and Type II collagen content, inhibited osteophyte formation, and protection of subchondral bone microarchitecture. In summary, this mussel-inspired piezoelectric hydrogel provides an electromechanical stimulation platform that effectively couples physical cues with bio-adhesion to regenerate cartilage.