RESUMEN
Peritendinous adhesion that forms after tendon injury substantially limits daily life. The pathology of adhesion involves inflammation and the associated proliferation. However, the current studies on this condition are lacking, previous studies reveal that cyclooxygenase-2 (COX2) gene inhibitors have anti-adhesion effects through reducing prostaglandin E2 (PGE2) and the proliferation of fibroblasts, are contrary to the failure in anti-adhesion through deletion of EP4 (prostaglandin E receptor 4) gene in fibroblasts in mice of another study. In this study, single-cell RNA sequencing analysis of human and mouse specimens are combined with eight types of conditional knockout mice and further reveal that deletion of COX2 in myeloid cells and deletion of EP4 gene in sensory nerves decrease adhesion and impair the biomechanical properties of repaired tendons. Furthermore, the COX2 inhibitor parecoxib reduces PGE2 but impairs the biomechanical properties of repaired tendons. Interestingly, PGE2 local treatment improves the biomechanical properties of the repaired tendons. These findings clarify the complex role of PGE2 in peritendinous adhesion formation (PAF) and tendon repair.
RESUMEN
BACKGROUND: Hydrogels are used to provide a barrier against peritendinous adhesion formation, but when implanted intraoperatively, they degrade rapidly and aggravate early inflammatory pain. It is uncertain whether clinical efficacy can be improved by avoiding the inflammatory phase when hydrogels are delivered during adhesion formation. QUESTIONS/PURPOSES: (1) Compared with intraoperative hydrogel application, does ultrasound-guided postoperative application result in better total active motion (TAM) at 12 months after tendon injury? (2) Does ultrasound-guided postoperative application of hydrogels result in lower pain, better function, and better satisfaction? METHODS: This open-label, prospective, single-center, randomized controlled trial was conducted by reparative and reconstructive surgeons at the National Orthopedics Clinical Medical Center, Shanghai, People's Republic of China. Between May 2021 and December 2022, 53% (168 of 317) of patients who met our inclusion criteria were recruited, and 47% (149 of 317) of patients were excluded because of the exclusion criteria. Finally, 84 patients were randomized to the postoperative group to receive ultrasound-guided carboxymethyl chitosan (CMC) hydrogel delayed injection, and 84 patients were randomized to the intraoperative group to receive CMC hydrogel intraoperative application. Another 8% (7 of 84) of patients in the postoperative group and 10% (8 of 84) of patients in the intraoperative group were lost before the minimum study follow-up time of 1 year or had incomplete datasets, leaving 91% (153 of 168) of patients with data for analysis. Data on outcome events were analyzed according to the intention-to-treat principle, which included all patients who underwent randomization. Follow-up visits were completed at 3 weeks, 6 weeks, 3 months, 6 months, and 12 months after tendon repair. The primary outcome was TAM (ie, the sum of the degrees of active metacarpophalangeal joint, proximal interphalangeal joint, and distal interphalangeal joint flexion less the degrees from full extension; minimum clinically important difference [MCID] 20°) at 12 months. Secondary outcomes included pain (measured with a VAS; range 0 to 10, a higher score indicating worse pain; MCID 0.6), Michigan Hand Outcomes Questionnaire activities of daily living (MHQ-ADL) score (range 0 to 100, a higher score indicating better outcomes; MCID 10.1), and MHQ satisfaction (MHQ-SAT) score (range 0 to 100, a higher score indicating better outcomes; MCID 33.0). RESULTS: At 12 months, the ultrasound-guided postoperative injection group had improved TAM (intraoperative 189° [95% CI 179° to 199°] versus postoperative 209° [95% CI 199° to 219°], mean difference 20° [95% CI 6° to 35°]; p = 0.006; the mean difference in the primary outcome fulfilled the MCID value at all time points). At 6 weeks, we found no clinically important difference in VAS pain scores among groups (intraoperative mean ± SD 2.0 ± 1.0 versus postoperative 1.7 ± 1.0, mean difference 0.3 [95% CI 0.1 to 0.7]; p = 0.02); however, at 3 weeks, the VAS pain scores showed clinically important difference among groups (3.6 ± 1.4 versus 2.9 ± 1.2, mean difference 0.7 [95% CI 0.3 to 1.1]; p = 0.001). At 3 months, the ultrasound-guided postoperative injection group had higher MHQ-ADL scores (intraoperative 62 ± 10 versus postoperative 75 ± 10, mean difference 13 [95% CI 11 to 17]; p < 0.001), and the mean difference of MHQ-ADL scores reached the MCID value at all time points. At 3 months, there was no clinically important difference in MHQ-SAT scores between groups (intraoperative 62 ± 8 versus postoperative 70 ± 8, mean difference 8 [95% CI 6 to 11]; p < 0.001). CONCLUSION: Compared with intraoperative CMC hydrogel injection, postoperative ultrasound-guided injection improved the TAM and function of the affected limb, showed a short-term pain control effect, and did not increase the risk of complications. Clinical trials are needed to confirm the safety and efficacy of ultrasound-guided postoperative injection of CMC hydrogels and to determine the most effective dose and the health and economic benefits of treatment. LEVEL OF EVIDENCE: Level I, therapeutic study.