Impact on cartilage repair of the knee: Patient profiling and single-stage regeneration

Abstract

Cartilage defects are considered troublesome injuries, which can cause symptoms as pain, swelling and locking, limit function and impede quality of life, similar to patients with osteoarthritis. Treatment of these defects is a clinical challenge as currently, an ideal strategy is lacking, especially for larger (> 2 cm2) defects. This thesis aimed at improving cartilage repair, both from a patient and societal perspective. Tools were provided for patient profiling as well as a new treatment introduced to allow single-stage cost-effective cartilage repair.

Large and symptomatic defects are frequently treated using autologous chondrocyte implantation (ACI) in which an initial biopsy is followed by a second surgical intervention for re-implantation of cultured cells. While good results up to twenty years have been shown, high treatment costs along with the burden on patients that have to undergo two surgeries with an interval of up to two months, has stimulated the development of an investigator-driven single-stage procedure (IMPACT). This treatment uses mesenchymal stromal/ stem cells (MSCs) to replace the expanded chondrocytes currently used. It is based on a proof of concept that has shown MSCs and cartilage cells can communicate and stimulate cartilage regeneration when cultured together. In this thesis we have shown, for the first time, that this communication takes place through cell-cell contact via gap junctions. In a first in man study, we found the strategy to be safe in the short-term (up to twelve months) and lead to cartilage regeneration. Biopsies taken twelve months after surgery showed the regenerated tissue to completely consist of patient-own cells confirming the stimulatory role of MSCs. This is in contrast with the current view on MSCs as stem cells that can differentiate into chondrocytes. Cost-effectiveness models showed that if IMPACT would achieve within ten percent of the clinical outcome after ACI, it could have a dramatic impact on cost-effectiveness in this patient category. An airbrush system was used in the laboratory to introduce a full arthroscopic application of IMPACT. Cells were found to survive the spraying procedure and a cadaveric study confirmed feasibility of the airbrush technique. Ongoing research continues to search for optimal spraying conditions and applicators to allow clinical application of arthroscopic airbrush-facilitated single-stage cartilage repair in the near future. In this thesis, we have worked on introducing patient profiling for cartilage repair. That is, using prognostic factors to better predict clinical outcome in practice. We found the Knee injury and Osteoarthritis Outcome Score (KOOS) to be a valuable and reliable tool to measure clinical outcome and identify such relevant prognostic factors. For example, the knowledge that treatment delay does not benefit outcome is important to consider when seeing a patient with a cartilage injury. Difficulty in using biomarkers and MRI as means of determining clinical outcome after treatment was emphasized through a cohort study and lsystematic review, respectivelt. Thus although first steps were made, significant challenges remain for patient profiling in daily practice. The safety of allogeneic MSCs found and there stimulatory effect through communication with cartilage cells in humans has been exceptionally encouraging.