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cartilage transplants, autologous chondrocyte transplantation, knee injuries, osteoarthritis

Cartilage transplants: After the media hype - what are the facts about autologous chondrocyte transplantation (ACT)

Getting behind the media hype: what are the practical facts about cartilage transplantation?

Recently several of the popular newspapers reported on cartilage transplantation as a 'miracle cure' for everyone with bad knees, including injured athletes. Here two experts present the scientific reality behind the media hype.

Traumatic articular cartilage injuries (the joint lining as opposed to the shock absorber inside the joint) in the knee are common and are a frequent cause of pain and loss of function leading to poor performance in athletes. When these cartilage injuries are full thickness, the potential long term problems include early osteoarthritis and its associated disability.
Although full-thickness articular cartilage defects constitute only a small portion of all cartilage injuries, their poor capacity for repair makes their treatment a great challenge. This has recently aroused media interest with regard to the use of a relatively new procedure - autologous chondrocyte transplantation (ACT) - which was commented on briefly in issue 12 of Sports Injury Bulletin.
Sports injuries account for 28% of all knee injuries. Chondral damage, including both partial and full thickness defects, has been documented in up to 61.5% of knee arthroscopies for knee symptoms. In the United States 650,000 reparative knee procedures are carried out each year, of which 20,000 to 40,000 could qualify for autologous chondrocyte transplantation.

Background
Articular cartilage consists of chondrocytes (cartilage cells) embedded in a highly specialised extracellular matrix. This matrix which is composed of water (80%), collagen and proteoglycans gives articular cartilage its elasticity and provides resistance to tensile, compressive (up to 65 times body weight) and shear forces as well as a smooth , efficient surface for motion.
However articular cartilage lacks an arterial blood supply, venous and lymphatic drainage and derives its nutrition primarily from the synovial fluid and to some extent from the adjacent bone blood supply. This has implications in healing in that superficial lesions rely solely on chondrocyte mitosis for repair. This is known as intrinsic repair and as a rule is unsatisfactory. Extrinsic repair occurs in lesions which traverse the cartilage/bone region and communi-cate with blood, marrow and pluripotential stem cells in the underlying bone. The repair tissue formed is fibrocartilage, which may look like articular cartilage macroscopically at arthroscopy but does not have the same microscopic arrangement and hence biomechanical properties as articular cartilage. Fibrocartilage is mechanically insufficient as it cannot withstand the normal physiological loading and wear stresses on the knee during work or sports. This problem of poor repair material has led to the move from the more commonplace 'traditional cartilage resurfacing techniques' to the emerging and exciting 'new methods' of cartilage repair.
Traditional resurfacing techniques include knee lavage and debridement, defect drilling and microfracture and periosteal/perichondral grafting. These were described in issue 12 of Sports Injury Bulletin. The newer methods refer to osteochondral autografts where small matchstick-shaped grafts are taken from non-weight-bearing parts of the knee and planted into the predrilled defect, and autologous chondrocyte transplantation.

The procedure
The patient is usually referred for autologous chondrocyte transplantation after already having had surgery for an articular cartilage problem. If the patient remains symptomatic, and the patient and the surgeon decide that autologous chondrocyte transplant is the best option, then an arthroscopic biopsy is planned.
Selection criteria for this procedure have yet to be definitively established. Ideally, the patients are between 15 and 55 years of age, have full thickness localised defects of the femoral condyles, have intact menisci, have no generalised chondrmalacia, have no limb malalignment and are willing and able to undergo vigorous rehabilitation. This procedure is not recommended for patients who have an unstable knee and for patients sensitive to materials of bovine origins or allergic to the antibiotic gentamicin. It is also not recommended for use in children, and not yet in any joint other than the knee.
The arthroscopy allows re-evaluation of the articular cartilage lesion to see if there has been any progression of the lesion, and then to precisely size it. After that, a small biopsy, the size of a raisin, is taken from the margin of the joint surface. This specimen of live articular cartilage is placed into a culture medium, which keeps the cells healthy during their transport to the laboratory. Under a strictly controlled environment the cells are separated from the cartilage. These cells are then multiplied using a cell-culture technique. They are stored in the frozen state and are thawed and have a final culturing process before they are shipped to the operating room on the day of the implantation. The interval period is usually six weeks. Approximately 12 million cartilage cells are present in the 0.4ml medium that is ultimately implanted into the defect.

Implantation and rehab
Currently, the implantation technique requires an open (rather than keyhole) approach to the knee. The first step of the surgery is to trim the defect to a stable rim and clear the bony base. A copy of the defect is made from sterile paper and used to trace out the desired cut for harvesting a periosteal patch from the proximal tibia. The periosteum is the living tissue on the outside of bone. It can be gently separated from the bone and has the consistency of a wet paper bag. The patch is then transferred to the defect and sutured such that it forms a water-tight seal. It is further sealed with fibrin (biologic) glue. The cultured chondrocytes are then injected under the patch and a final seal of the patch is performed. Newer techniques that use an artificial mesh rather than harvesting the patient's own periosteum are now becoming available.
The rehabilitation is long and demanding. Individual regimes vary with some centres recomm-ending early motion while others immobilise the knee in plaster for three weeks. Patients are typically allowed to put weight on their operated leg after eight weeks. Physiotherapy is continued for up to 12 months, and sporting activities are curtailed during this time.

Results
Autologous chondrocyte transplants were introduced in Sweden in 1987 with the first results of clinical trials published in 1994. The original results were encouraging with an excellent outcome in 88% of patients (with isolated femoral defects) at 32 months. This fuelled interest in this procedure and further published trials at the end of the 90s gave similar results.
At present the two main groups publishing results are the Swedish group led by one of the pioneers, M. Britberg, and the U.S.A.-based Genzyme group.
The Swedish published their two to nine year follow up of over 100 patients last year. They evaluated outcome on based patient and physician clinical outcome scales, appearance at arthroscopy and microscopic analysis. The clinical results were good to excellent in a different proportion depending on the indications:

Isolated femoral condyle defects 92%
Ostoechondritis dissecans 89%
Patella 65%
Femoral condyle defects with A.C.L. repair 75%

At arthroscopy good 'repair tissue fill' could be seen with good adherence to bone, hardness to probing and seamless integration. Microscopy of selected grafts showed a hyaline-like matrix lacking a fibrous component. There were 7 graft failures in this group.
The Genzyme group results show that 70% of patients improved, with 28% of patients 'resuming all activities' and 42% reporting 'some improvement'. 83% of patients with osteochond-ritis dissecans reported some improvement. The arthroscopic findings correlated very well with clinical outcome. There is still no apparent association of clinical outcomes with lesion size or cell dose administered.
In the UK results of this procedure are starting to emerge. At the Royal National Orthopaedic Hospital in Stanmore, George Bentley's group report a short-term success rate of 80%. Moreover, patients treated with this type of cartilage cell transplant apparently show a greater improvement than those treated with osteochondral autografts (the other popular modern technique).
The efficacy of this treatment has recently been evaluated, and the National Institute for Clinical Excellence has published a guidance report. ACT raises a number of health economics issues as it appears to be rapidly gaining in popularity but costs between £5000 and £8000 per patient. On the other hand, these are typically young patients who present early in their sporting / working careers. Knee scores and quality of life scores show a dramatic enhancement of function which is maintained from 12 to 24 months after surgery.

Complications
The overall failure rate is at present quoted as being 10%. The two most common complications include loosening of the transplant tissue, formation of fibrous tissue at the repair site and adhesions with return of pain and locking. Neither of these complications usually leaves the patient in a worse condition than his/her pre-transplantation state. Other adverse events include post-op haematoma (big blood clot), hypertrophic synovitis (angry knee) and superficial wound infection.

Conclusion
At present there is no single, well-proven technique for repairing articular cartilage defects. Given the population group which is affected by such injuries, the concern is that patients who damage their articular cartilage in their teens or 20s will be facing knee-replacement surgery at a young age.
Autologous chondrocyte transplantation appears to be a promising technique for managing such defects. The results available thus far from well-controlled clinical trials are encouraging. This is not a first- line technique, is not applicable to everyone and is expensive. Patient selection criteria for ACT are still not clearly defined and long-term functional outcomes and benefits relative to alternative strategies remain unknown. Only well-designed, randomised, controlled trials will answer these questions and until such data is available, autologous chondrocyte transplantation will continue to be restricted to selected centres where patients are carefully followed-up.

Joseph Borg and Fares Haddad



References
Brittberg M, Lindahl A, Nilsson A, et al. 'Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation.' N Engl J Med 1994; 331:889-895.
Gillogly S, Voight M, Blackburn T. 'Treatment of articular cartilage defects of the knee with autologous chondrocyte implantation.' Jour of Orthop and Sports Physical Ther 1998; 28:241-251
Mont MA, Jones LC, Vogelstein BN, Hungerford DS. 'Evidence of inappropriate application of autologous cartilage transplantation therapy in an uncontrolled environment.' Am J Sports Med. 1999 Sep-Oct;27(5):617-20.
Minas T. 'Chondrocyte implantation in the repair of chondral lesions of the knee: economics and quality of life.' Am J Orthop. 1998 Nov;27(11):739-44
Bentley G, Minas T. 'Treating joint damage in young people.' BMJ. 2000 Jun 10;320(7249):1585-8.



cartilage transplants, autologous chondrocyte transplantation, knee injuries, osteoarthritis