Autologous Chondrocyte Transplantation / Implantation Versus Existing treatments


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CHONDRAL DEFECTS

What is a chondral defect?

A chondral defect is a defect in the articular (hyaline) cartilage at the end of the bones. The defect is often on the femoral condyle (the rounded end of the thigh bone) and can result from an injury where there is a direct blow to the bent knee. Sometimes the damage involves bone loss resulting in osteochondral defects. The ACTIVE trial includes patients with isolated chondral or osteochondral defects. Candidates for the trial tend to be relatively young and must not have advanced osteoarthritis.

What does articular cartilage do?

Articular cartilage is a tough, smooth, elastic tissue which covers the ends of bones that form joints. It enables the bones to move smoothly over one another and acts as a shock absorber, cushioning the bone from forces of more than five times the body's weight. Damaged articular cartilage in knees can cause the joint to be painful, swollen and difficult to move.

Why doesn't it mend itself?

Cartilage is not like skin, it doesn't have the ability to repair itself properly. Instead, the damage tends to spread, allowing the bones to rub directly against each other. Any repair tissue that does form is not like normal hyaline cartilage and it doesn't work very well.

What is the best treatment?

Many patients appear to do well from an arthroscopic washout and debridement where any loose bodies of cartilage are removed and the defect is tidied back to healthy cartilage. However, when this treatment fails to relieve symptoms it is unclear what the best treatment is. ACTIVE is being run to help identify the best treatment. Only patients for whom previous treatment has failed are included in the ACTIVE trial.

What treatments are included in the ACTIVE trial?

All ACTIVE patients have a surgical treatment which is either a cell grafting treatment (autologous chondrocyte implantation (ACI) or matrix-assisted ACI (MACI)) or a non-ACI alternative. The surgeon will only recruit patients into the trial if he is undecided about whether ACI/MACI or an alternative might be the most appropriate treatment. There are several alternative, existing treatments available (described below) and the surgeon decides which one would be most appropriate for the patient. Within 3 months before surgery the patient is randomly allocated to have either ACI/MACI or the pre-selected alternative.

Non-ACI treatments

Debridement

Debridement is a rather broad term, but for ACTIVE it involves the removal of all "unstable" cartilage from the edge and base of the defect which is then washed or sucked away. Debridement is done arthroscopically which means it is done using keyhole surgery where a thin 'scope' is pushed into the joint (arthro=joint) to view the cartilage structure.

Abrasion/drilling

Abrasion/drilling involves arthroscopic debridement but in addition the base of the defect is debrided until small bleeding points are seen. The philosophy is that primitive blood cells are recruited from the underlying bone and these reform into joint cartilage cells and cover the damaged area with a new articular surface.

Microfracture

Microfracture is a modification of the drilling technique. Debridement is carried out to form a stable perpendicular edge of healthy cartilage. An arthroscopic awl is then used to make multiple holes in the defect, 3-4 mm apart. Blood from the defect is washed away until a clot forms. This "super clot" is believed to be the optimal environment for tissue to regenerate within the lesion.

Mosaicplasty

Mosaicplasty (also known as Osteochondral Cylinder Transplantation) involves filling the defect with osteochondral plugs to form a "mosaic". The plugs are usually taken from relatively non-weight bearing areas on the peripheries of both femoral condyles. The technique is usually done as an open procedure since care is needed to match the plugs with the size and shape of the defect to produce a smooth surface with the plugs fitting closely together. The main advantage of mosaicplasty is that the defect is filled with mature hyaline cartilage straight away. To avoid symptoms occuring from the donor site, this technique is only used for small defects.

AMIC

Since January 2007 AMIC (Autologous Matrix-Induced Chondrogenesis) has been included as one of the non-ACI treatments available in the trial. This new technique is similar to microfracture but it involves using a collagen membrane patch to stabilise the microfracture clot.

Bone grafting

Since April 2008 patients with osteochondral defects with more than 3 mm of bone loss can be included in ACTIVE. The standard treatment for these defects is bone grafting. Bone grafts may be autologous (the patient's own bone) allogenic (from a donor) or synthetic bone substitute depending on the surgeon's preference. Patients with osteochondral defects randomised to ACI will have bone grafting plus ACI.

Autologous chondrocyte implantation (ACI)

ACI uses the patient's own cells (chondrocytes) which are harvested from healthy articular cartilage, cultivated in a laboratory and implanted over the defect. The cells are held in place either by a periosteal patch which is soft tissue taken from the membrane covering the patient's tibia (shin bone) or by a manufactured collagen membrane patch. ACTIVE patients who are allocated ACI are further randomised to have one of the two types of patches.

In this two-stage procedure surgeons first harvest the cells arthroscopically from a healthy, non-weight bearing area of the knee joint. The chondrocytes are then treated in a laboratory for 3-4 weeks where they will multiple into several million chondrocytes. During the second surgery, the surgeon cleans the defect site, and removes a piece of periosteum (if using the periosteum patch). The patch (either periosteum or manufactured collegen membrane) is stitched and secured over the defect, and the cultured chondrocytes are then injected beneath the patch. There, the chondrocytes should eventually produce a form of cartilage very much like the original hyaline cartilage.

ACI Procedure

Rehabilitation following ACI is likely to be slower than the other treatments because the cells need time to generate repair tissue. Patients are given a physiotherapy programme to follow and should be prepared to give up driving for 7 weeks and avoid very strenuous activities for several months.

The Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Trust has its own laboratory where cells are prepared for ACI. For more information on ACI please visit the Oscell website.

Matrix-induced ACI

MACI is a variant of ACI which has become an option in the trial (since March 2007) and can be used as an alternative to traditional ACI. With MACI the cells are cultured on collagen membrane in the laboratory before being attached over the defect. MACI does not normally require any stitching to the cartilage and is therefore a quicker procedure.

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ACTIVE is being carried out by the Robert Jones & Agnes Hunt Orthopaedic & District Hospital NHS Trust in collaboration with the University of Birmingham Clinical Trials Unit and Health Economics Facility. The trial is funded by the Medical Research Council and administrated by Keele University.