Therapeutic Potential of Ultrasound‐Controlled BMP ‐2 Release From Thermoresponsive Hydrogels in a Rat Knee Osteoarthritis Model

This study aimed to develop and validate an injectable thermosensitive hydrogel as an ultrasound-responsive depot for transiently enhanced BMP-2 release to promote functional and structural recovery in a rat model of osteoarthritis. A BMP-2-loaded mPEG-PLGA-BOX thermosensitive hydrogel was developed and characterized in vitro for its rheological properties, degradation behavior, and drug-release kinetics. The feasibility of ultrasound-triggered release was assessed using various duty cycles. Subsequently, therapeutic efficacy was evaluated in a monoiodoacetate-induced rat model of osteoarthritis. Treatment groups included untreated control (MIA), free BMP-2 (MB), passive BMP-2-hydrogel (MHB), and BMP-2-loaded hydrogel with ultrasound stimulation (MHBU). Outcomes were assessed up to day 49 using functional gait analysis (CatWalk), histopathology (H&E, Toluidine Blue), and immunohistochemistry for Collagen II, Collagen X, and Sox 9. The in vitro analysis supported the selection of a non-thermal 5% ultrasound duty cycle, which produced an approximately 550-fold ultrasound-enhanced release ratio without a detectable temperature increase while limiting residual-volume loss relative to the higher-duty-cycle conditions. In vivo, the MHBU therapy was uniquely effective. It was the only intervention to significantly restore articular cartilage thickness (212.8 ± 42.0 μm vs. 124.3 ± 12.7 μm, p < 0.01), achieving a level statistically indistinguishable from healthy controls. This structural repair was directly correlated with normalized dynamic gait parameters (print area, stance) and a restored tissue-level profile, characterized by enhanced Collagen II matrix, suppressed pathological Collagen X expression, and recovered chondrogenic Sox 9 expression. This study demonstrates that an ultrasound-responsive hydrogel platform successfully overcomes the limitations of both conventional growth factor delivery (rapid clearance) and passive hydrogel encapsulation (slow release). This synergistic, ultrasound-triggered system promotes significant functional and structural cartilage restoration, representing a promising translatable strategy for osteoarthritis therapy.