Matching TGF-β1 Activation With Stress-Responsive Charge-Reversal Hydrogel Microspheres for the Treatment of Osteoarthritis.

The abnormal activation of transforming growth factor-β1 (TGF-β1) is closely associated with the occurrence and progression of diseases. However, how to make the regulatory means match the pathological mechanical microenvironment-dependent activation of TGF-β1 to promote lesion repair still faces challenges. In this study, based on force-charge conversion technology, we developed the stress-responsive charge-reversal hydrogel microsphere system. Weakly cross-linked disulfide bonds in the microfluidic-synthesized microspheres break under mechanical stress, interacting with charge-reversal messenger to induce nanoparticle charge reversal (negative to positive). This mode is in line with the activation mechanism of TGF-β1 in the mechanical microenvironment, which can match the appropriate regulatory intensity and thus achieve high efficiency and low toxicity in OA treatment. Experimental results show that this hydrogel microsphere system has a 41.96% improvement in the repair effect of OA cartilage lesions compared to traditional microspheres, and more importantly, the impact on healthy cartilage is reduced by 96.89%. This study provides a new idea for the development of biomaterial regulatory systems that match the pathological microenvironment.