gms | German Medical Science

Objectives/Interrogation: The objective is to deliver anti-inflammation gene to the healing digital flexor tendon to ensure high local gene concentration and to reduce the inflammatory responses of the injured tendon microenvironment to reduce adhesions and improve the healing strengths.

Methods: We designed a novel local sustained gene delivery system by using cyclooxygenases (COX-1 and COX-2) engineered miRNA plasmid/nanoparticles embedded in hyaluronic acid (HA) hydrogel. 64 completely transected digital flexor tendons of the long toes of both feet of 32 white Leghorn chickens were equally randomized into four groups: non-treated; hydrogel; hydrogel containing nanoparticle/negative plasmid complexes and hydrogel containing nanoparticle/COX-1 and COX-2 miRNA plasmid complexes group. At 6 weeks after surgery and gene therapy, severity of adhesions were scored. Gliding excursions, work of digital flexion and ultimate strengths of the healing tendons were tested in an Instron testing machine. We used two-way analysis of variance followed by post hoc Dunnett's t-test to analyze the differences in adhesion scores, gliding excursions, work of flexion and ultimate strengths.

Results and Conclusions: This local sustained gene delivery approach down-regulated COX-1 and COX-2 gene expression in tendons and surrounding subcutaneous tissues. At 6 weeks after treatment, adhesion scores in the COX-1 and COX-2 miRNA plasmid/nanoparticle group were significantly smaller than in the negative plasmid/nanoparticle group (p=0.028), unloaded hydrogel group (p=0.006) and non-treatment group (p=0.038). The gliding excursions were significantly increased in the COX-1 and COX-2 miRNA plasmid/nanoparticle group than in the negative plasmid/nanoparticle group (p=0.027), unloaded hydrogel group (p=0.028) and non-treatment group (p=0.009). However, there were no significant differences in the work of flexion among four groups. More importantly, the healing strengths in the COX-1 and COX-2 miRNA plasmid/nanoparticle group was significantly greater than that of negative miRNA plasmid/nanoparticle group (p=0.002), unloaded hydrogel (p=0.001) and non-treatment group (p=0.039).

Inhibition of the cyclooxygenases COX-1 and COX-2 was found to have remarkably increased the tendon healing strengths to 160% of the control and decreased adhesions in term of adhesion severity and gliding excursions. This approach may offer an effective therapeutic strategy to increase tendon healing strength and reduce adhesions.