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This hydrogel demonstrated superior performance compared to a previously reported hydrogel designed for intra-articular drug delivery, which, in our study, neither recovered its structure nor maintained drug release under mechanical loading. When injected into mouse knee joints, the hydrogel provided consistent release kinetics of the encapsulated drug in both treadmill-running and nonrunning mice. In a mouse model of severe PTOA exacerbated by treadmill-running, the L-006235 hydrogel significantly reduced cartilage degeneration, whereas the free drug did not. 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