Degradative polylactide nanofibers promote M2 macrophage polarization via STAT6 pathway in peritendinous adhesion

Biodegradability has been considered a future trend in the development of medical biomaterials, with polylactide (PLA) and its derivatives regarded as the essential representatives. However, along with post-implantation degradation, the complications, such as in-stent restenosis and postoperative adhesion, are increasingly evident, which can significantly hamper its clinical application. With high plasticity and heterogeneity, macrophages can switch from the pro-inflammatory to the anti-inflammatory microenvironment. Macrophage M2 polarization is closely related to postoperative adhesion and occurs mainly in the late stages of injury, which overlaps with the period of PLA degradation. The STAT6 pathway plays a regulatory role in this process. Therefore, we speculated that STAT6 participates in M2 polarization caused by PLA degradation. Macrophages were grown on esterase-degraded PLA membranes to mimic in vivo degradation. We identified that PLA degradation promotes STAT6 phosphorylation-mediated excessive M2 polarization in macrophages, resulting in a pro-adhesion microenvironment. Furthermore, the in vivo results revealed the dynamic changes in the macrophage status mediated by PLA degradation from proliferation to the remodeling phase. Consistent with the in vitro results, we demonstrated that STAT6 phosphorylation is the vital promoter of peritendinous M2 macrophages polarization promoted by PLA degradation. The released pro-adhesion cytokines, such as TGF-β, accelerate the myofibroblast state transition from rest-state to activation-state. Together with MMP2 and Col III release, they lead to peritendinous adhesion. Our study reveals the regulatory mechanisms underlying PLA degradation and reduced anti-adhesion efficacy and provides a novel direction for optimizing PLA anti-adhesion membranes.