Cartilage repair: using autologous chondrocyte implantation techniques.
All our joints are covered with an almost translucent, shiny and extremely slippery white surface, which is described as hyaline cartilage. The word stems from the Greek hyalos = glass, and the Latin cartilage = gristle. It should not be mistaken for the meniscus, a crescent shaped structure lying between femur and tibia, and made of much softer, pliable fibrous tissue. It is often referred to as the 'soft cartilage', but erroneously called 'the cartilage' by most people. Its function is to stabilise the round shaped femur on the rather flat shaped tibia, just like a cup on a saucer. In addition it provides shock absorption to the knee and, as we all know, it may get damaged through violent twisting and turning activities.
In 1743 the British surgeon William Hunter made the now famous statement that 'From Hippocrates to the present age it is universally allowed that ulcerated cartilage is a troublesome thing and that once destroyed it is not repaired' (Hunter 1743). Hunter's observation that damage to mature cartilage does not heal has united clinicians in the desperate attempt to find ways to facilitate durable cartilage repair. It is a well known fact that any joint surface damage, if left untreated, will invariably deteriorate and eventually spread to surrounding areas (Mankin 1982). The end result of such a process is often the development of osteoarthritis (Bentley 1980, Buckwalter et al 2000).
The treatment of articular cartilage defects in the knee has been at the centre of attention over the last few years, as the number of young adults suffering joint injuries continues to grow. It has been estimated that, in the UK, 10,000 patients each year may suffer cartilage damage, most often caused through sporting activities, which is warranting repair (NICE 2008). In a high proportion of these patients the treatment opportunity is lost either through delay in diagnosis or failure to recognize the condition altogether (NICE 2008).
Damage to articular cartilage may be related to acute trauma, overuse, ligament instability, leg mal-alignment (bowed or knocked knees), menisectomy (removal of shock absorber cartilage) or osteochondritis dissecans (Schindler 2007). Acute cartilage defects may arise from a fall or a direct blow, but more often occur as a result of a twisting injury whilst the knee is exposed to full load-bearing. In such an environment shear forces combined with joint compression forces create a build-up in tension between the surface cartilage and the underlying bone. As a result the surface cartilage may delaminate from its undersurface, break off and create a 'full-thickness' cartilage defect (Figure 1). Symptoms may be apparent immediately but often do not occur for many months or even years after the primary insult. If the damage to the articular surface remains untreated it will invariably lead to an increased incidence of cartilage degeneration and osteoarthritis (Buckwalter et al 2000).
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Physiology of articular cartilage
Articular cartilage, otherwise known as hyaline cartilage, is the tissue that lines joint surfaces (surface cartilage). Due to its unique structure it allows for frictionless and painless movement throughout life. It also acts as a shock absorber, cushioning the bone from forces of more than five times the body's weight. Cartilage is mainly composed of water (75%) and carries only small amount of structural elements. These elements consist of relatively few highly specialised cells the so-called chondrocytes (cartilage cells), which are embedded within a matrix of collagen, proteins and sugar components (proteoglycans and glucosaminoglycans) (Mankin et al 2007). This matrix protects the cells from injury through normal joint use and provides a lubrication system for frictionless movement (Bentley 1980). Throughout life chondrocytes renew matrix molecules lost through degradation and hence maintain physiological joint function. Under normal circumstances, and in the absence of joint trauma or deformity, articular cartilage is well designed to tolerate a lifetime of use.
Healing and repair of any tissue requires an inflammatory response which is dependent on the tissue's blood supply. As the surface cartilage has neither blood supply nor lymphatic drainage, it remains ineffective in responding to injury and has very limited potential for self-repair (Bentley 1980, Mankin 1982, Buckwalter et al 2000). Even if healing occurs the repair tissue is often of inferior mechanical quality and liable to early degeneration (Mankin et al 2007). Ultimately, however, any mechanical damage to the joint surface invariably increases the risk of developing osteoarthritis.
Patients frequently complain of acute stabbing pain immediately after injury, whilst swelling may occur with some delay within 12 to 24 hours. If swelling develops immediately, damage to internal ligaments such as the anterior cruciate ligament is likely, and needs to be ruled out. Weight bearing may be painful and difficult during the first few days. Thereafter some patients may suffer from locking or giving way of the knee particular on twisting and turning or on descending stairs. Symptoms may, however, not be present initially (silent event) and may only become apparent weeks or months later. This is due to a cartilage flap being torn off the bony surface and becoming impinged in the joint. A toothache type pain on load bearing in a specific knee location is the most prominent complaint under those circumstances.
Although a thorough examination by the clinician is valuable, it is by no means reliable in diagnosing a cartilage injury as no specific tests exist. MRI (magnetic resonance imaging) has become the investigation of choice in diagnosing cartilage injuries as it allows visualisation of soft tissue structures including ligaments, menisci and surface cartilage with high accuracy (Teller et al. 2001). Radiographs thereagainst do not allow the visualisation of soft tissues and are therefore unhelpful in the diagnostic process. If, despite MRI, uncertainty about cartilage integrity remains and the clinical suspicion is high, a diagnostic arthroscopy is to be considered.
Damaged articular cartilage and its limited capacity for natural healing present major challenges to the healthcare professional dealing with young and active individuals who want to regain normal knee function. An array of different repair techniques have emerged over the past 50 years, all of which have shown various degrees of success (Pridie 1959, Friedman 1984, O'Driscoll & Salter 1986, Stone 2000, Clarke & Scott 2006). The most commonly known is microfracture, a marrow stimulation technique designed to create a temporary blood supply to the bone surface, which as we know is essential for the healing process (Friedman 1984, Steadman et al 2003). Unfortunately the repair cartilage (fibrous cartilage) created through this technique is somewhat similar to a scar which forms on the skin surface. It has inferior structural qualities to hyaline cartilage and hence is somewhat more likely to wear.
In the early 1970s Bentley and Greer were able to show that chondrocytes transplanted into articular cartilage defects of rabbits enhance cartilage healing (Bentley & Greer 1971). The first human application of cartilage cell transplantation or otherwise known as autologous chondrocyte implantation (ACI) was performed in 1994 by Lars Peterson and Matts Brittberg from the University of Gothenburg in Sweden (Figures 2 and 3) (Brittberg et al 1994). The aim of this treatment is to enable the regeneration of hyaline or hyaline-like cartilage, thereby restoring normal joint function. The basic technique has undergone considerable development since its inception and is likely to become an established form of treatment for symptomatic osteochondral defects in the knee (Minas & Peterson 1999, Peterson et al 2000, Micheli et al 2001, Gillogly 2002, Bentley et al 2003, Haddo et al 2004).
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The technique requires the patient to undergo two surgical procedures. At first a small sample of surface cartilage, often harvested from the defect margin, is obtained through a key-hole procedure (arthroscopy) (Figure 2). The chondrocytes within the received tissue sample are then isolated and cultured in the laboratory over a period of 4 to 6 weeks. During this period the number of cells increases by 50 fold to reach approximately 2 to 5 million (Brittberg et al 1994). In a second surgical procedure, the damaged area is cleared of all remaining cartilage and the cultured chondrocytes implanted. Traditionally this is facilitated by injecting the cells under a collagen membrane or periosteal flap which is carefully sutured onto the defect (Figure 3). Technical difficulties with fixation of the membrane and problems with graft delamination and overgrowth (hypertrophy) however have been reported (Minas and Peterson 1999, Peterson et al 2000, Micheli et al 2001, Ueno et al 2001, Sohn et al 2002).
The implantation of cultured chondrocytes in suspension has also led to concerns about the uneven distribution of chondrocytes within the defect and the potential for cell leakage (Sohn et al 2002).
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In order to overcome such problems, biodegradable scaffolds seeded with chondrocytes have been developed (2nd generation ACI).
The second generation technique allows chondrocytes to be cultured within a solid collagen matrix, which is then glued directly into the defect, simplifying the implantation process significantly (matrix-guided autologous chondrocyte implantation or MACI) (Figure 4) (Bentley et al 2003, Briggs et al 2003, Zheng & Wood 2003, Haddo et al 2004). A further advantage of this method of cell delivery is that the scaffold may act as a barrier to invasion of the graft by fibroblasts, which may otherwise induce fibrous repair (Frankel et al 1997). Because MACI implantation is essentially 'suturefree', it is quicker to perform than ACI and requires a less extensive exposure, which is of particular advantage when combining the technique with other interventions such as ligamentous reconstruction, bone grafting, or high tibial osteotomy (Figure 5).
Neither form of chondrocyte implantation is suitable in cases of joint instability (eg: cruciate ligament tears) unless ligament reconstruction can be performed simultaneously, or in situations of significant joint mal-alignment (bowed or knocked knees). In these situations the joint is exposed to shear forces and uneven load distribution which would invariably damage of the newly grown cartilage. By far the best results have been achieved in localised and confined defects, which are surrounded by otherwise healthy surface cartilage. The success is reduced in so called bipolar lesions where defects are present on opposing surfaces, and those located in the patello-femoral joint (area behind the knee cap).
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Many people are still under the misapprehension that ACI or MACI may facilitate the reconstruction of joints affected by osteoarthritis. Unfortunately however, this is not yet feasible with currently available technologies. This is primarily due to the fact that in osteoarthritis the whole joint is affected by changes in biomechanics, biochemistry and surface biology, creating an environment unsuitable for cartilage implantation (Mankin et al 2007).
The post-operative rehabilitation program varies depending on the location of the chondrocyte implantation. Patients are encouraged to use a so-called CPM machine (continuous passive motion) for several hours during the first four to six weeks O'Driscoll & Salter 1986). The gentle motion is hoped to prevent the proliferating cartilage from overgrowing, a problem which, if it occurs, may require arthroscopic shaving. Defects on the weight bearing surface (tibio-femoral joint) need to be offloaded, and patients usually stay on crutches for up to 3 months (Figure 1). Physiotherapy is particularly important during the initial post operative period and should focus on maintaining muscle function and joint flexibility. Hydrotherapy including underwater jogging has proved to be very popular at this stage. The patient is then gradually introduced back to normal daily activities and allowed light sporting activities (cycling, swimming etc.). At 6 to 9 months the activity level may be stepped-up introducing rowing, cross-trainer and gentle weight training. Cutting, twisting and turning activities are usually avoided for at least 12 to 15 months or until the surgeon is happy with the progress and confident that the cartilage graft has taken. Most surgeons verify cartilage integrity by obtaining MRI scans during the rehabilitation period. In some cases a second-look arthroscopy may be necessary especially if the patient complains of mechanical symptoms such as locking or clicking. Return to full level sporting activities is not desirable much before 15 to 18 months post surgery.
Patients where the treated defect is located in the front of the knee (patello-femoral joint) require a different regime. Load-bearing in those patients is generally permissible whilst active bending of the knee (patella-femoral loading) needs to be restricted. This is best achieved through wearing of a locked hinge brace or cricket splint, whilst passive mobilisation on the CPM can be continued with. The brace is gradually unlocked, and most patients regain a full active range of motion by 3 months. Squatting and kneeling however are to be avoided for longer periods depending on the size of the lesion and its exact location.
Patients need to be aware that the technique may not be successful in everyone for a variety of reasons. It is generally expected that 80 to 90% of patients undergoing either ACI or MACI will experience significant functional improvements (Peterson et al 2000, Brittberg et al 2001). The relative effectiveness, quality of life gain and durability of ACI compared to other cartilage repair techniques however remain unclear as comparative long-term follow-up studies are scarce (Bentley et al 2003, Knutsen et al 2004). Poor pre-operative function and a long history of symptoms with numerous earlier surgical procedures have shown to be poor prognostic indicators. It is thus essential that these factors together with properties of the chondral lesion are taken into account during patient selection and counselling.
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A limited number of long-term studies with up to 9 year follow-up have however confirmed good or excellent results in 82% to 92% of patients (Peterson et al 2000, Brittberg et al 2001, NICE 2008). Complications included superficial wound infection, postoperative haematoma, intra-articular adhesion, and periosteal hypertrophy, whilst complete graft failure was reported in up to 16% of cases. Minas reported on a group of 169 patients with large cartilage lesions of up to 12 [cm.sup.2] treated with ACI. Overall 87% of patients showed significant improvement after a minimum follow-up of 24 months, whilst 13% were considered failures (Minas 2001). Similarly good results have also been reported using second generation MACI techniques (Figure 6) (Behrens et al 2006, Ronga et al 2006).
The field of cartilage repair has witnessed significant changes over the past two decades. Autologous chondrocyte implantation techniques represent exciting new developments geared towards reconstitution of damaged joint surfaces and the prevention of arthritis. Advances in tissue engineering have helped to refine the technique and overcome some of the problems associated with the 1st generation of autologous cartilage cell implantation. With 2nd generation techniques collagen membranes saturated with cultured cartilage cells are glued directly into the defect simplifying the procedure significantly without adversely affecting outcome.
Although the treatment of arthritic joints remains out of our realm, we are now in a position to restore localised cartilage defects successfully, empowering many people to regain physical fitness and return to high levels of sporting activities.
The National Institute of Health Clinical Excellence has expressed that ACI should be reserved for patients in whom earlier treatments for defects of the articular cartilage have failed, and that such treatment should be conducted as part of ongoing or new clinical study designed to generate robust and relevant outcome data, including the measurement of health-related quality of life and long-term follow-up (NICE 2008). Despite these restrictions both ACI and MACI are available to patients through private health care providers and at very few selected centres in the NHS.
Biotechnology companies and clinicians are investigating alternative sources of stem cells, hoping to create ready-to-implant materials containing matrix and cells produced in vitro. Such materials could further reduce morbidity by avoiding the need for a cartilage biopsy and possibly allowing for direct arthroscopic implantation. Despite the general enthusiasm about new technologies, one should however exercise caution and patience whilst major advances in cartilage repair and arthritis prevention are under development.
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Provenance and Peer review: Commissioned by the Editor; Peer reviewed
by Oliver S Schindler
Correspondence address: Mr Oliver Schindler, Droitwich Knee Clinic, St Andrews Road, Droitwich, Worcestershire, WR9 8YX. Email: email@example.com
Oliver S Schindler MD, MFSEM(UK), OFD(Orth), FRCS(Orth)
Consultant Orthopaedic Surgeon with a special interest in Sports Medicine / Clinical Director of the Droitwich Knee Clinic Ltd at the BMI Droitwich Spa Hospital
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|Title Annotation:||CLINICAL FEATURE|
|Author:||Schindler, Oliver S.|
|Publication:||Journal of Perioperative Practice|
|Date:||Feb 1, 2009|
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