Animal models aid study of arthrofibrosis after TKA

Arthrofibrosis is a recognized complication of total knee arthroplasty (TKA) and one of the leading reasons for re-operations and revision surgery. Often defined as flexion less than 90 degrees postoperatively, it is characterized by abnormal scarring leading to restriction of the joint. The scar tissue may form intra-articularly and extra-articularly, and may persist in a subset of patients despite manipulation under anesthesia.

Clinically, patients present with limited knee range of motion. Some may have pain with activities of daily living, such as walking, standing or climbing stairs; others may have unusual postoperative pain and swelling unrelated to deep periprosthetic infection or mechanical failure. In severe cases, the arthrofibrosis may become progressive, with fibrous tissue thickening and tightening the entire capsule, making joint movement nearly impossible.

Mayo Clinic research led by Matthew P. Abdel, M.D., an orthopedic surgeon at Mayo Clinic's campus in Rochester, Minnesota, has shown that despite advances in surgical technique, implant design and pain management, the incidence of arthrofibrosis after primary TKA has remained virtually unchanged for the past two decades.

A review of nearly 10,000 patients who underwent cemented posterior-stabilized TKAs at Mayo Clinic's campus in Minnesota between 2000 and 2012 revealed that 5.8 percent developed limited range of motion, with 2.8 percent requiring manipulation under anesthesia (MUA).

These numbers were relatively unchanged from the previous decade, when the rate of limited motion was 5.4 percent, with 2.9 percent of patients requiring MUA. With contemporary MUA, mean flexion improved from 61 to 109 degrees, but a subset of 14 patients failed to maintain at least 90 degrees of flexion.

Dr. Abdel says there is limited information available to determine which patients will develop arthrofibrosis postoperatively. "Two patients who are kin can have the same surgery with the same surgeon, and one will develop arthrofibrosis, and the other won't," he notes.

Theoretically, the disease process could be prevented by interventions that affect the profibrotic cascade, but because the pathology of arthrofibrosis is not well-understood, finding pharmaceutical and biological targets has been challenging. Myofibroblasts (α-smooth muscle actin-expressing fibroblasts), the chief effector cells in joint fibrosis, are one potential target, as shown by Dr. Abdel and his translational laboratory in a landmark 2012 article published in the Journal of Orthopaedic Research.

While other studies have shown increased myofibroblasts in human elbow contractures and in animal models of arthrofibrosis, the timeline of myofibroblast development wasn't known until recently. That led a team of Mayo Clinic investigators to undertake a study examining the number of myofibroblasts in an animal model of knee contracture over a 24-week period.

The study involved 18 rabbits that underwent a validated surgical procedure on their right limbs that causes a knee joint contracture. Both the animal model and modified procedure were created at Mayo.

The rabbits were then divided into three groups of six:

  • Group I underwent two weeks of postoperative immobilization.
  • Group II underwent eight weeks of immobilization.
  • Group III underwent eight weeks of immobilization plus 16 weeks of remobilization.

The left collateral limbs of the rabbits served as controls, along with five additional rabbits that did not undergo surgery. The percent and number of total myofibroblasts and total cell counts were measured and compared with controls at two, eight and 24 weeks.

Results showed that the relative number of myofibroblasts was significantly elevated in the operated limbs compared with nonoperated limbs at two weeks after surgery. After peaking at two weeks, these numbers declined, with the relative number of myofibroblasts dropping from 19.9 plus or minus 3.1 percent at two weeks to 3.0 plus or minus 2.7 percent at eight weeks.

Indeed, at eight weeks of immobilization and 16 weeks of remobilization — a total of 24 weeks — there were no significant differences in the relative number of myofibroblasts between the operated and control limbs.

Dr. Abdel notes that although it was suspected that myofibroblasts were an early phenomenon, this was the first study to characterize them during the formation of a joint contracture. This further validates the idea that pathology starts early in arthrofibrosis and that interventions to inhibit fibrosis should likely start early in the disease process, too.

A search for such interventions is ongoing at Mayo Clinic. A 2014 study published in Bone & Joint Research found that intra-articular injections of the potential anti-fibrotic agent decorin caused significant alterations in several fibrotic genes, but did not alter the clinical contractures. Dr. Abdel, who was lead study author, says the timing of administration of decorin was likely responsible for the lack of improvement.

Another study looked at the results of surgical capsular release in an animal model of joint contracture. In that study, published in the Journal of Orthopaedic Research in 2013, capsular release decreased extension loss immediately after surgery as well as after 16 weeks of remobilization, echoing clinical experience in the surgical treatment of arthrofibrosis.

"We have published multiple papers on animal models of arthrofibrosis, trying to replicate the clinical scenario identically, in an effort to execute true translational research," Dr. Abdel says. "We have taken this work from the bedside to the bench and then back to the bedside — that is, identifying a clinical problem such as fibrosis, taking it to the lab to test it in novel animal models and then taking it back to study in clinical trials."

For more information

Abdel MP, et al. Myofibroblast cells are preferentially expressed early in a rabbit model of joint contracture. Journal of Orthopaedic Research. 2012;30:713.

Abdel MP, et al. Intra-articular decorin influences the fibrosis genetic expression profile in a rabbit model of joint contracture. Bone & Joint Research. 2014;3:82.

Barlow JD, et al. Surgical capsular release reduces flexion contracture in a rabbit model of arthrofibrosis. Journal of Orthopaedic Research. 2013;31:1529.