Abstract
ABSTRACT
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.