Screw-Thread Needle Mediated In Situ Delivery of Tangeretin @β -Cyclodextrin Sulfated Sodium Salt Complexes for the Therapy of Achilles Tendinitis

Abstract

Achilles tendinitis (AT) has posed as an intractable clinical problem, for which there is currently a lack of satisfactory treatment approaches. Local drug delivery has proven to be effective for AT therapy, but suitable drugs and local/sustained drug delivery technique for superior therapeutic effects are still in urgent need. In this work, screw-thread needle acupuncture-mediated in situ delivery of tangeretin@β-cyclodextrin sulfated sodium salt (TAN@CDs) complexes was developed for AT therapy. Briefly, TAN was firstly encapsulated into the cavity of CDs with a TAN loading rate of 4.6%. Then, a trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride-modified screw-thread needle (TMSTN) was immersed into the TAN@CDs solution to fasten the TAN@CDs complexes to the grooves of the TMSTN through electrostatic interaction. The biosafe concentration of TAN@CDs solution was controlled at 30 mg/mL through hemolysis assay, H&E staining, and blood biochemical analyses. TAN@CDs could release TAN in a sustained manner for over 8 h in a simulated Achilles tendon microenvironment. TAN delivery amount of single acupuncture (sequential clockwise/anticlockwise rotation) of the TAN@CDs/TMSTN was determined to be 1.28 μg, and an Achilles tendon defect model of rat was applied to evaluate its therapeutic effects against AT. Gross appearance observation of the Achilles tendon, H&E staining, Masson staining, and biomechanical testing proved that through periodic acupuncture of the TAN@CDs/TMSTN, AT could nearly be cured. The superior therapeutic outcomes of TAN@CDs/TMSTN‑mediated acupuncture against AT are likely attributable to the synergistic interplay between the acupuncture intervention and the in situ release of TAN. Immunohistochemical staining demonstrated that the released TAN molecules treat AT through downregulating inflammatory cytokines and upregulating tendon repair-related factors, therefore promoting collagen synthesis and tenogenic differentiation throughout healing. In sum, this work reported an efficient strategy for AT therapy.