A 2016 phase I trial explored the safety, efficacy, and practicality of joint cartilage grafts from nasal chondrocytes in the treatment of knee articular cartilage injuries. For the ten injuries treated, five were repaired completely and three were more than 50% repaired two years post-procedure with only two serious adverse events reported during the trial.
In order to resist wear and tear, and resulting conditions such as osteoarthritis, the ends of bones in the joints are covered with a layer of smooth connective tissue known as articular (joint) cartilage. Cartilage is also found in different forms throughout the body, playing roles in organ structure and function, and varying based on composition and the properties of the chondrocytes (cartilage-producing cells) within them. If injury occurs and articular cartilage is damaged, it is often necessary to repair the affected area by grafting chondrocytes. Autografts – cells transplanted from elsewhere in the same patient – are usually preferred in order to avoid graft rejection. As chondrocytes from the typically elastic nasal cartilage are more prolific than articular chondrocytes, yet can mimic them once implanted, producing cartilage with a similar composition, their use as sources of autografts may lead to quick yet reliable recoveries from cartilage-related joint injuries.
A 2016 phase I trial published in the Lancet sought to determine the safety, practicality, and efficacy of nasal chondrocyte-derived autografts in the treatment of articular cartilage injuries of the knee. Ten patients, age 18-55, who suffered articular cartilage injuries 2-6cm2 in size on the femoral condyle or trochlea of the knee joint were recruited from the University Hospital Basel in Switzerland. Chondrocytes were isolated from the nasal septum of each patient and cultured for 2 weeks using media containing growth factors and the patient’s own blood. The chondrocytes were counted and tested for viability before being introduced into a 30 x 40 x 2 mm collagen membrane, which would serve as a scaffold upon which the chondrocytes could build cartilage. Each patient’s cells were tested for bacterial contamination after 1 day, 14 days, and 25 days, and for fungal infection after 1 day, 14 days, and 21 days. Grafts which were contaminated, did not withstand handling with forceps, or did not have at least 70% cell viability were not implanted.
During surgery, the site of injury was cleaned and the graft was cut to size. The unused portions of the grafts were kept for analysis. The grafts were secured to the surrounding cartilage by absorbable stitching and to the bone beneath the cartilage by fibrin glue, which essentially holds the graft and the bone together with a clot.
To determine the procedure’s safety with respect to causing cancer, a scaled-down version of the procedure was first tested in 8-week-old mice using nasal chondrocytes from three healthy human subjects. Mice were euthanized and dissected at 6 months (by which time tumours would have typically manifested). No tumours were found at the implantation sites or elsewhere within the mice.
At 6 and 24 months post-procedure, grafted cartilage was examined using MRI to determine its similarity (composition-wise) and fit with the surrounding cartilage. Safety was measured based on the rate of adverse events reported between the procedure and 24 months afterward. Patients also self-assessed their knee function before and 24 months after the procedure using two scales: the International Knee Documentation Committee (IKDC) subjective knee evaluation form, scoring function from 0 to 100; and the Knee Injury and Osteoarthritis Outcome Score (KOOS), scoring pain, other knee-related symptoms, the ability to perform activities of daily living, the ability to participate in sports and recreation, and quality of life from 0 to 100.
9 of the 10 patients completed the study: 1 was excluded due to independent injuries which required further surgery at various sites, including the graft location. Two of the remaining patients each received autografts for two separate injuries. No adverse reactions occurred at the graft sites. Further surgery was required for a patient who acquired a cartilage injury at another site in the same knee as the graft within 12 months of the procedure, and for another patient with a non-cartilage injury in the opposite knee at 17 months. One patient at 11 months and another at 20 months acquired a non-cartilage injury in the same knee as the graft, though did not require surgery. One patient acquired an injury in a meniscus (a pad of cushion-like cartilage) of the opposite knee to that with the graft, at 11 months. Another’s ankle was twisted at 11 months. The average IKDC and KOOS ratings improved significantly, though scores for the patient who acquired a new cartilage injury in the same knee decreased. Of the 10 injuries autografted, 5 completely filled in the injured area: notably, in 1 of these cases the graft site was filled in at 6 months, and in another, the area was overfilled. Three of the 10 injuries were more than 50% repaired at 24 months, and in another 3 the underlying bone was left partially uncovered by the graft, which may have led to some graft degeneration. The compositional similarity between grafted cartilage and articular cartilage increased significantly between 6 and 24 months. No association was found between a graft’s fit and its composition. For the excluded patient it was found that though the graft had filled in the site, it set unevenly. A biopsy of the uneven graft revealed its composition to be roughly 50% similar to articular cartilage.
The findings of this trial suggest the use of joint cartilage grafts from nasal chondrocytes in the treatment of knee articular cartilage injury is safe and practical. As a phase I trial, the first test of this procedure in humans, these results are preliminary and further trials with a larger sample size will be required to more accurately determine the safety and efficacy of the procedure. With a larger study population, adverse events not noted among the ten participants observed in this trial may appear, and the effect of injury size and type on recovery may become clear. Part of the efficacy in this study was determined by patient self-assessment, which may not have provided as accurate or objective an assessment as clinical tests such as a mechanical stress test performed on the joint. Future trials may also benefit from a longer observation time and more frequent examinations.
Written By: Raishard Haynes, MBS