Injectable pH‐Responsive CI1040 Delayed‐Release Hydrogel for the Treatment of Tendon Adhesion

Abstract Tendon injuries, often leading to debilitating adhesions, pose significant challenges in clinical practice. Conventional treatments have limitations, necessitating novel strategies. Injectable hydrogels, known for their biocompatibility, have shown promise. To enhance their antiadhesive properties, researchers have started incorporating drugs. Existing drug delivery systems often peak in the initial days, falling short during the fibroblast proliferation phase which occurs ≈1 week after injury. In this research, CI1040 is selected as an antiadhesion drug, encapsulated within zeolitic imidazolate framework‐8(ZIF‐8), and incorporated into oxidized hyaluronic acid/N‐carboxyethyl chitosan(OHA/CEC) hydrogel(Gel), resulting in the synthesis of CI1040@ZIF@Gel. This unique pH‐responsive drug release system involves encapsulating CI1040 within ZIF‐8, a substance that degrades under acidic conditions while remaining stable in physiological environments. This system selectively releases the drug during the fibroblast proliferation phase, responding to the localized pH reduction post‐tendon injury. CI1040@ZIF@Gel exerted a 65% inhibition on extracellular signal‐regulated kinase (ERK) phosphorylation, reducing the production of collagen types III (Col III) in the adhesion area by 56%. These results indicate that CI1040@ZIF@Gel can effectively inhibit fibroblast proliferation and adhesion through the interleukin 9 receptor/mitogen‐activated protein kinase/extracellular signal‐regulated kinase(IL9r/MEK/ERK) pathway, while also acting as a physical barrier to prevent the formation of tendon adhesion.