Title: Autologous Chondrocyte Implantation in the knee: from animal model to broader clinical practice
Other Titles: Autologe Kraakbeenceltransplantatie in de knie: van dierenmodel naar bredere klinische toepassing
Authors: Vanlauwe, Johan
Issue Date: 19-Sep-2012
Abstract: The treatment of cartilage lesions of the knee, and in extenso other joints remains a huge challenge for the orthopeadic surgeon. For cartilage repair one can rely on several surgical techniques to alleviate the symptoms and try to heal the cartilage lesion. Simple lavage and debridement can help improve symptoms by solving a mechanical problem, but does not address the lesion itself, which has insufficient capacity to heal. One can rely on endogenous repair mechanisms such as marrow stimulation techniques to try and repair the defect. This has been the mainstay for the last 2 decades in cartilage repair. Techniques such as drilling, spongialization, abrasion and more recently microfracture have been developed over the years. All of these techniques rely on the patients’ own repair response by recruiting stem cells from the underlying bone that seep out from the bone marrow cavities into the lesion to form a blood clot that will fill the lesion and remodel into a scarlike coverage of the defect. This scar contains cartilage elements such as collagen type 2 and proteoglycans in various amounts that cannot be predicted. Most probably the repair response resembles the formation of a callus like endochondral repair of a bony lesion that due to the joint environment remains in an intermediate cartilage like phase (delayed union) for a longer period of time. In the end bone formation can take over giving rise to the formation of “intralesional osteofytes” and degradation of the overlying repair tissue due to inadequate restitution of the subchondral bone plate and a non favorable biomechanical environment. Another technique to solve the problem is to immediately transplant a full osteochondral unit of cartilage and bone into the cartilage lesion. In this way one avoids the problem of integration of the cartilage repair tissue into the underlying bone, because this is usually the failure mechanism of any form of cartilage treatment. Major disadvantage here is the fact that these osteochondral plugs have to be taken from elsewhere in the knee, in “so called” lesser weight bearing zones of the articulation, leading to several new problems, such as donor site morbidity, plug breakage, acceptor site mismatch in cartilage thickness and subchondral bone plate, and failure of lateral integration of the plugs in the surrounding healthy cartilage. In addition, true integration of both the bony and cartilage layer in the surrounding tissue has never been seen, and is probably not possibleA more recent technique developed in Scandinavia by Lars Peterson’s group uses Autologous cultured chondrocytes isolated from a small biopsy of cartilage in the knee, that have been propagated and multiplied in culture for several weeks, to get about 40000 cells/µl that are then implanted in the knee under a patch of periost taken from the proximal tibia. This periosteal patch covers the defects and creates a “biological chamber” for the cultured chondrocytes to proliferate further and recreate cartilage matrix to cover the entirety of the defect and finally remodel into hyaline-like cartilage tissue well integrated with the surroundings and with the underlying subchondral bone. Several issues of ACI were unclear at the moment this thesis project was started. First of all, chondrocytes in cultures show the tendency to lose their phenotypic traits, losing their capacity to form stable cartilage in an in vivo setting. This has been very nicely shown in several publications by Franscesco Dell’Accio et al., who also developed a genetic marker score to semi-­‐quantify this phenotypic change to set a threshold after which the cells fail to make hyaline cartilage. On this scientific basis, my thesisproject aimed at showing that well characterized cells with the capacity to make stable ectopic cartilage in vivo, remain in the defect after implantation and contribute in the repair process in a large animal model. Using this characterized cell population, a pivotal clinical trial was developed to test autologous chondrocyte implantation in a randomized setting against the first line treatment of cartilage lesions at that time being Microfracture. A number of issues concerning standardization of surgery and follow-­‐up, clinical and structural scoring were resolved to improve the quality of the data. We could show that ACI with a characterized product (also called CCI) leads to structural superiority of the regenerated tissue at 1 year with clinical outcomes that are similar for both treatments despite the disadvantage of ACI as an open procedure versus an arthroscopic microfracture. At three year follow-­‐up we could show a statistically significant clinical superiority in the cell transplantation group that was clinically relevant in patients with a higher molecular score and a shorter time to treatment since symptom onset (early onset group= less than 3 years of symptoms). At five years the statistical significance was lost in the whole group but again in the early onset group the difference remained statistically significant and clinically relevant. Female gender was more at risk for failure as was the presence of subchondral bone changes at one year. Next to the use in a randomized trial, which is generally restricted to a limited and selected population rendering the data less applicable to the general population, CCI was also used in a population of 38 patients with patellofemoral lesions. This population will be almost 40% of the general population treated by orthopeadic surgeon today according to several papers presenting epidemiological data on knee cartilage lesions.In this patient group we could show that clinical data are equal to other groups using this technique in the same group with a follow up of 4 years. We tried to link the clinical data to radiological features and lesions characteristics to find one or more predictors of response but probably because of lack of sufficient numbers of patients, we did not succeed. The only interesting feature was the distalizing effect of a Fulkerson osteotomy on the patella by an amount of about 10%, partly solving the patellar height problem in patella alta. Fact remains that in the treatment of a patellofemoral cartilage lesion, one has to consider all clinical and radiological parameters, requiring an “a la carte” treatment. A second group of patients treated outside the randomized setting, was the compassionate use group consisting of 370 patients in 7 centers. Safety data were collected from 334 patients (90.3%), and effectiveness data were from 282 (76.2%) of the 370 patients treated. This is a cross sectional analysis. Again here we were able to show that this treatment is perfectly applicable to the general population. Indeed in an RCT one looks at a comparison of a specific item of a technique or a product, whereas so called “level 2” data are more relevant to clinical practice because they create the ability to possibly find features in a patient group that become prognosticators for future patients to be treated. This treatment has now been applied in over 500 cases with a reliable and well characterized product, showing robust and predictable clinical outcome and an excellent safety profile. To date is is still not possible to have robust predictors of response, but these data have provided new insights on the position of CCI and ACI in general as a first line approach in the treatment algorithm of cartilage lesions. Were initially ACI was merely seen as a second line after failure of microfracture, we know now that in a specific patient group with an early onset of symptoms, ACI with characterized chondrocytes appears to outperform microfracture histologically and clinically. We learned that microfracture as a “quick” fix is not as harmless as it seems and can even preclude good results of future treatments due to the disturbance of the subchondral plate. It becomes generally accepted that the reconstitution of the “osteochondral unit” is one of the pillars of not only cartilage repair but prevention of osteoarthritis in general.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Cell and Gene Therapy Applications (-)
Biomechanics, -implants and Tissue Engineering (-)

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