Tetrandrine-loaded electrospun scaffold modulates inflammation and fibroblast activity to promote tendon regeneration

• Knitted scaffolds had better mechanical properties than nanofiber yarns. The UTS and Young's modulus of knitted scaffolds were within the range of the corresponding values of human tendinous tissues, which indicated that knitted scaffolds may be more suitable for tendon repair . • Tetrandrine-loaded knitted scaffold suppressed overproliferation of NIH-3T3 fibroblasts as well as regulated macrophages polarization from an inflammatory M1 phenotype into anti-inflammatory M2 phenotypes. Since an excessive proliferation of myofibroblasts and prolonged inflammatory response are linked to the fibrosis , anti-inflammatory and anti-fibrotic characteristics of the scaffolds may have implications for the treatment of peritendinous adhesions. • The PS-T4 knitted scaffolds not only inhibited migration and proliferation of NIH-3T3 fibroblasts, but also enhanced the preferential migration and growth of tenocytes . Therefore, the scaffolds may offer a promising platform to balance the proliferation of tenocytes and myofibroblasts . • Transplantation of PS-T4 knitted scaffolds in a rat model constricted the clearance area at the scaffold-tissue interface alongside increased collagen deposition, as well as inhibited inflammation, which made the scaffolds play an important role in long-term tendon repair. The effectiveness of tendon regeneration is impeded by an excessive inflammatory response as well as uncontrolled proliferation of fibroblasts. Transplantation of tendon substitutes which can balance inflammatory response while constrict aberrant proliferation of fibroblasts is a key to promote functional tendon regeneration. The objective of this study was to design electrospun tetrandrine-loaded polylactic acid/silk fibroin (PLLA/SF) nanofibers and then fabricate them into knitted scaffolds. Briefly PLLA micron yarns were coated with PLLA/SF nanofibers and processed into knitted scaffolds. The incorporation of tetrandrine into fibers resulted in a significant suppression of fibroblast proliferation ( p < 0.05) and promoted macrophage polarization into anti-inflammatory phenotypes, with a CD206/CD68 ratio increase of 2.5-fold compared to the control. Additionally, knitted scaffolds delayed the inflammatory response and enhanced collagen production at the repair site in vivo . Taken together, our approach of simultaneously harnessing structural and biological cues in the form of an antiproliferative and anti-inflammatory therapeutic alongside PLLA/SF-coated nanoyarns afforded knitted scaffolds. The bifunctional regulation of tetrandrine simultaneously addressing inflammation resolution and fibrotic inhibition represents a strategic advance over existing mono-functional drug-loaded scaffolds.