Reduction of arthrofibrosis utilizing a collagen membrane drug‐eluting scaffold with celecoxib and subcutaneous injections with ketotifen

Abstract

The dense formation of abnormal scar tissue after total knee arthroplasty results in arthrofibrosis, an unfortunate sequela of inflammation. The purpose of this study was to use a validated rabbit model to assess the effects on surgically-induced knee joint contractures of two combined pharmacological interventions: celecoxib (CXB) loaded on an implanted collagen membrane, and subcutaneously (SQ) injected ketotifen. Thirty rabbits were randomly divided into five groups. The first group received no intervention after the index surgery. The remaining four groups underwent intra-articular implantation of collagen membranes loaded with or without CXB at the time of the index surgery; two of which were also treated with SQ ketotifen. Biomechanical joint contracture data were collected at 8, 10, 16, and 24 weeks. At the time of necropsy (24 weeks), posterior capsule tissue was collected for messenger RNA and histopathologic analyses. At 24 weeks, there was a statistically significant increase in passive extension among rabbits in all groups treated with CXB and/or ketotifen compared to those in the contracture control group. There was a statistically significant decrease in COL3A1, COL6A1, and ACTA2 gene expression in the treatment groups compared to the contracture control group (P < .001). Histopathologic data also demonstrated a trend towards decreased fibrous tissue density in the CXB membrane group compared to the vehicle membrane group. The present data suggest that intra-articular placement of a treated collagen membrane blunts the severity of contracture development in a rabbit model of arthrofibrosis, and that ketotifen and CXB may independently contribute to the prevention of arthrofibrosis. Statement of clinical significance: Current literature has demonstrated that arthrofibrosis may affect up to 5% of primary total knee arthroplasty patients. For that reason, novel pharmacologic prophylaxis and treatment modalities are critical to

Biomechanical, histological, and molecular characterization of a new posttraumatic model of arthrofibrosis in rats

“…However, gene expression is highly time-dependent and the terminal time points evaluated in our study may not reflect the optimal time points to determine expression differences between groups. Previous studies in rabbits demonstrated significant differences at both early 34 and late 35 experimental time points. Future investigations evaluating these time points in rats are required to better characterize the molecular basis for contracture in the rat model.…”

Intra-articular celecoxib improves knee extension regardless of surgical release in a rabbit model of arthrofibrosis

“…Although consecutive daily IA injections for two weeks may have limited translatability into clinical practice, our findings are promising in pointing future research into the direction of more clinically relevant drug delivery – potentially a single large-dose injection, oral celecoxib, or drug-eluting scaffolds placed near or within joint at time of capsular release. 46 …”

“…Several studies point to the activation of periarticular myofibroblasts from mesenchymal stem cells as the primary driver of arthrofibrosis. 2 , 22 - 24 Salib et al 25 discussed the ability of celecoxib to prevent arthrofibrosis through the disruption of post-inflammatory cytokines and subsequent interruption of myofibroblast activation. Based on this proposed mechanism, we posit that the celecoxib in our study disrupted the activation of periarticular myofibroblasts from mesenchymal stem cells and interrupted the formation of new scar tissue after the remobilization surgery.…”

“… 22 - 26 Several studies have shown the effectiveness of celecoxib, a selective cyclooxygenase-2 inhibitor, in preventing the formation of scar tissue in our animal model of arthrofibrosis. 24 , 25 , 27 Additionally, Barlow et al 28 previously developed a modified rabbit model with a limited surgical release of an established contracture. In that investigation, authors showed a significant improvement in passive extension angles (PEAs) in the surgically treated contractures.…”

Arthroscopic management of elbow stiffness

“…Basic science investigations from our laboratory indicate that use of nonsteroidal anti-inflammatory drugs (in particular celecoxib) may be beneficial in the prevention and treatment of arthrofibrosis [ 15 ]. Since indomethacin has also been reported to decrease ectopic bone formation in other conditions, we typically recommend indomethacin for 6 weeks to all patients who undergo arthroscopic contracture release.…”