Programmed drug delivering Janus hydrogel adapted to the spatio-temporal therapeutic window for Achilles tendon repair.

Abstract

Peritendinous adhesion formation and tendon re-rupture are prevalent clinical complications following tendon repair surgery. The key to reducing adhesions and enhancing the biomechanical strength of injured tendons lies in suppressing inflammation and extrinsic fibroblast activation while promoting intrinsic tenocyte proliferation. However, as tenocytes are inherently a type of fibroblast, it remains challenging for a single drug to reduce adhesion and improve tendon strength simultaneously. To address this challenge, a Janus hydrogel was designed for spatiotemporal programmed drug delivery specifically tailored to Achilles tendon repair. The outer layer of the Janus hydrogel rapidly releases melatonin (MT) via poly(N-acryloyl alaninamide) (PNAAA), effectively suppressing inflammation and extrinsic fibroblast activation. The inner layer gel, formed by thiol-modified gelatin (GelSH) and norbornene-modified hyaluronic acid (HANB), incorporates protein-binding AAc-NHS and gradually releases platelet-derived growth factor-BB (PDGF-BB), thereby promoting tenocyte proliferation. In the rat Achilles tendon injury model, the spatiotemporal programmed drug delivery Janus hydrogel successfully reduced adhesion while enhancing tendon healing strength. This work promoted Achilles tendon repair by meeting the distinct spatiotemporal therapeutic needs. STATEMENT OF SIGNIFICANCE: Melatonin may inhibit fibroblast proliferation and differentiation via the PI3K/AKT pathway, whereas PDGF-BB promotes tenocyte proliferation and differentiation through the same pathway. Consequently, the effects of these two drugs on fibroblasts and tenocytes may be conflicting. In this study, the programmed drug delivery Janus hydrogel was designed to match the different stages of tendon repair and achieved staggered release of melatonin and PDGF-BB. Melatonin@PNAAA primarily targets the extrinsic healing pathway, focusing on inflammatory cells during the inflammatory phase and fibroblasts during the proliferative phase. PDGF-BB@SHNB mainly targets intrinsic healing pathway, focusing on tenocytes during the proliferative phase and collagen synthesis during the remodeling phase. This spatiotemporal delivery system alleviates adhesion while promoting tendon healing.