Localized delivery of miRNAs targets cyclooxygenases and reduces flexor tendon adhesions

Abstract

The formation of adhesions during healing of an injured tendon remains a difficult problem in clinical practice. Local anti-inflammation gene delivery provides high local gene concentration, reduces the inflammatory response of the injured tendon microenvironment, and decreases systemic side effects to enhance in vivo efficacy. In this study, we designed a novel local sustained gene delivery system by using cyclooxygenase (COX-1 and COX-2)-engineered miRNA plasmid/nanoparticles embedded in hyaluronic acid (HA) hydrogel to reduce flexor tendon adhesions. The local sustained gene delivery system significantly downregulates COX-1 and COX-2 expression in the tendon tissue and the surrounding subcutaneous tissue. More importantly, this plasmid/nanoparticle hydrogel system significantly reduced tissue adhesion formation. This approach offers an effective therapeutic strategy to reduce tendon adhesions by directly targeting the down-regulation of COX-1 and COX-2 expression within the microenvironment of the injured tendon.

Statement of significance: A local sustained gene delivery system was developed to regulate the expression of targeted genes in the specific time and location for tendon adhesion treatment. The engineered miRNA plasmid/nanoparticles embedded in hyaluronic acid hydrogel were synthesized to downregulate the expression of cyclooxygenases in the tendon tissue during the early stage of tendon healing with inflammatory response. This plasmid/nanoparticle hydrogel system offers an effective therapeutic strategy to attenuate the formation of tendon adhesion through direct downregulation of COX-1 and COX-2 expression within the microenvironment of the injured tendon.

Keywords: Cyclooxygenase; Injectable hydrogel; Localized; Reducing flexor tendon adhesions; miRNA delivery.