Cartilage Repair and Joint Preservation

Medical and Surgical Treatment Options

Background: Articular cartilage defects are most often caused by trauma and osteoarthritis and less commonly by metabolic disorders of the subchondral bone, such as osteonecrosis and osteochondritis dissecans. Such defects do not heal spontaneously in adults and can lead to secondary osteoarthritis. Medications are indicated for symptomatic relief. Slow-acting drugs in osteoarthritis (SADOA), such as glucosamine and chondroitin, are thought to prevent cartilage degeneration. Reconstructive surgical treatment strategies aim to form a repair tissue or to unload compartments of the joint with articular cartilage damage.

Methods: In this article, we selectively review the pertinent literature, focusing on original publications of the past 5 years and older standard texts. Particular attention is paid to guidelines and clinical studies with a high level of evidence, along with review articles, clinical trials, and book chapters.

Results: There have been only a few randomized trials of medical versus surgical treatments. Pharmacological therapies are now available that are intended to treat the cartilage defect per se, rather than the associated symptoms, yet none of them has yet been shown to slow or reverse the progression of cartilage destruction. Surgical débridement of cartilage does not prevent the progression of osteoarthritis and is thus not recommended as the sole treatment. Marrow-stimulating procedures and osteochondral grafts are indicated for small focal articular cartilage defects, while autologous chondrocyte implantationis mainly indicated for larger cartilage defects. These surgical reconstructive techniques play a lesser role in the treatment of osteoarthritis. Osteotomy near the knee joint is indicated for axial realignment when unilateral osteoarthritis of the knee causes axis deviation.

Conclusion: Surgical reconstructive techniques can improve joint function and thereby postpone the need for replacement of the articular surface with an artificial joint.

Hyaline articular cartilage enables the physiological functioning of joints (e1–e3). Osteoarthritis, trauma, and disorders of the subchondral bone—such as osteochondritis dissecans (OCD) or osteonecrosis, which secondarily affect the articular cartilage—may cause defects of the cartilage (e4–e7). In spite of their different etiology, the clinical end stage is identical: reduced articular function, manifesting as pain and impaired movement. After complete loss of the articular cartilage, endoprosthetic surface replacement is often the only remaining therapeutic option (e8). Reconstructive joint-preserving treatments are therefore of high clinical relevance (e9).

This article provides an overview of medical and surgical approaches to cartilage reconstruction, which are indicated if cartilage defects remain symptomatic in spite of conservative and medical treatment. Since several different disorders result in cartilage loss, we will not exclusively be focusing on the topic of osteoarthritis (e10). This article will neither reflect on aspects of prevention (e11), nor the wide range of physical-physiotherapeutic measures (e12)—which constitute essential components within the multimodal therapeutic approach—nor rheumatic disorders (e13–e16), owing to the complexity of these areas. Neither will we discuss current topics—such as the application of chondrogenic factors as proteins (e17) or genes (e18), tissue engineering of cartilage in bioreactors (e19), testing of biocomposites with improved scaffolds (e20), or preclinical pharmacological therapies (e21).

Definitions

Chondral defects are limited to the cartilage (1, e5, e9). Osteochondral defects extend into the subchondral bone (1, e5, e9). Since regeneration means the identical reconstruction of the original articular cartilage, repair results in a distinct, potentially inferior, form of cartilage (1, e5, e9).

Epidemiology

Osteoarthritis is the most common articular disorder: some 10% of men older than 60 develop osteoarthritis (e22–e24). A prospective study of 1000 arthroscopies of the knee joint found cartilage defects in 61% of cases, 44% of these due to osteoarthritis, 28% due to focal cartilage defects, and 2% due to OCD (e25). In 3% of all patients over the age of 50, knee pain is due to osteonecrosis (e26).

Etiology

A multitude of disorders can lead to articular cartilage defects (Table 1 gif ppt). Circumscribed cartilage defects whereby the surrounding cartilage remains in a normal condition often arise as a result of trauma or OCD (e5, e9). Osteoarthritis is characterized by areas of poorly delineated defects. Primary osteoarthritis is a complex pathology in whose genesis genetic, biomechanical, and biochemical factors have a role (e27–e29). It may also be caused by secondary—for example, traumatic—defects to the articular cartilage (e30). OCD is a potentially reversible disorder primarily of the subchondral bone (e4, e5). If it extends to the articular cartilage, then an osteochondral defect may develop (e4, e5, e31, e32). Osteonecrosis arises from bone infarction that causes an osteochondral defect (e33–e38). The important question, why cartilage defects in adults do not regenerate by themselves, has not been answered in spite of many studies. Possible reasons include the lacking blood supply to the bone, aggressive proliferation of synovial cells, and insufficient signals to promote regeneration, and/or early activation of catabolic signaling cascades (e1, e29).

Imaging diagnostics

Diagnosing focal, non-arthritic cartilage defects is difficult. The standard radiograph in two planes does not show chondral defects, while osteochondral defects are only visible after larger osseous fragments have become detached (e9). In order to diagnose osteoarthritis, radiological criteria (e39) and the size of the radiological joint space are used as direct indicators of cartilage thickness (e40, e41). For this purpose, the 45° weight bearing X-ray in the Rosenberg view is used. In this way, a narrowing of the joint space can be detected in those articular areas that are already damaged in the early stages of osteoarthritis and that bear weight when the knee is flexed (this is often undetectable when the knee is straightened in the anterior-posterior radiographic view) (e9, e41–e43).

In order to expose the defect, magnetic resonance imaging (MRI) has become the technique of choice. Increasingly, the high-resolution 3-Tesla MRI is used (e44-e46). Experimentally the cartilage volume is quantifiable, and in moderately severe or severe osteoarthritis it correlates to the narrowing of the joint space (e47). Bone marrow edema—as a sign of contusion—provides an important indirect indication of a cartilage defect. After cartilage reconstruction procedures (e44), MRI imaging protocols help to assess structural (Mocart assessment system) (e48) and biochemical parameters of the repair tissue (dGEMRIC and sodium imaging to assess the proteoglycan content; T2/T1rho(T1ρ) mapping to assess the collagen content and the fiber arrangement) (e44–e51).

These time consuming methods are not yet suitable for routine examinations.

The selection of additional approaches depends on the underlying pathology. Subchondral bone can be assessed by means of computed tomography (CT); CT arthrography enables precise assessments of the stability of the osteochondral fragment in OCD (e52).

Therapeutic principles

Pain reduction is the primary goal of medial therapy for all symptomatic cartilage defects (2, e53) in the context of a stepwise scheme, starting with paracetamol (acetaminophen) in mild pain, non-steroidal anti-inflammatory drugs (NSAIDs) in moderate pain, with opioids added on in case of severe pain. Intra-articular corticoids are indicated in the acute phase. Since their symptomatic effect has been confirmed (2, e53), we will not discuss them any further in this article.

Reconstructive surgical treatment aims to improve articular function and congruence as well as prevent osteoarthritic damage to intact areas of the cartilage. Table 1 shows the—mostly stage dependent—therapeutic options for traumatic cartilage defects (e4, e9), osteoarthritis (e4, e8–e10, e12), OCD (e31, e32, e54–e58), and osteonecrosis (e4, e38).

Medical treatment

Almost all of the treatments mentioned in this review article are used primarily for the treatment of osteoarthritis. The short follow-up periods remain a problem, in view of the slow progression of cartilage degeneration over time.

Causal pharmacological concepts for the treatment of osteoarthritis aim to slow down the degeneration process (2). The group of the slow acting drugs in osteoarthritis (SADOA) is divided into symptomatic slow acting drugs in osteoarthritis (SYSADOA), which have a symptomatic effect (improvement of joint function, pain reduction) and disease modifying osteoarthritis drugs (DMOADs). DMOADs are intended to stop the cartilage degeneration or even reverse it (Table 2 gif ppt). The Osteoarthritis Research Society International has published evidence based recommendations for the treatment of osteoarthritis of the knee and hip (gonarthrosis and coxarthrosis) (evidence level I, meta-analysis of 351 studies) (3).

Glucosamine, a component of the cartilage matrix, has a mild anti-inflammatory effect when taken orally. Independent placebo controlled trials did not find any effect (e59); other studies showed a symptomatic effect (2). Two randomized controlled studies showed a mild, significant reduction in the joint space narrowing of the knee (e60, e61), but not in the hip joint (e62). The GAIT multicenter study found neither a reduction in the narrowing of the joint space nor any clinical improvement in pain and articular function after two years in patients with gonarthrosis (evidence level I) (4, 5).

The effects of chondroitin sulfate (component of cartilage matrix) regarding pain reduction, functional improvement, and cartilage preservation remain unclear. In patients with osteoarthritis of the knee, an improvement in symptoms and a reduction in the narrowing of the joint space on radiography were described after two years (6, e63), but the GAIT Study did not find any differences between the verum and placebo groups (evidence level I for both) (4, 5, e64).

The orally administered drug diacerin (1,8-diacetoxy-3-carboxy anthraquinone, not licensed in Germany) inhibits the proinflammatory cytokine interleukin-1 (IL-1). It seems unlikely that it affects the degeneration of the cartilage (2). A meta-analysis showed a mild symptomatic (anti-inflammatory) effect within the first six months (evidence level I) (7).

Intra-articular injection of hyaluronic acid (main component of the synovia) improves articular function and reduces pain compared with placebo (8). Clinically, its effect sets in later than that of intra-articular corticosteroids (which provide better pain reduction within the first two weeks) (e65). The symptomatic effect of hyaluronic acid is strongest 13 weeks after application (8). Although a better effectiveness has been suggested for hyaluronic acid preparations with a higher molecular weight (e66), no randomized clinical studies have so far confirmed this assumption. Moreover, when higher molecular weights were used, adverse effects were more common (swelling, pain) (e67). Confirmed data regarding the progression of osteoarthritis are lacking.

Fibroblast growth factor 18 (FGF-18) was found to stimulate the proliferation of chondrocytes and proteoglycan synthesis (e68) and to lead to improved cartilage repair in an animal model of osteoarthritis (e69). Current phase I and phase II studies are investigating intra-articular injection of recombinant FGF-18 for the treatment of osteoarthritis (e70) and trauma induced cartilage defects (e71).

Regarding causal therapy for osteoarthritis, further interesting therapeutic approaches exist (2), such as:

• The selective inhibition of catabolic enzymes (for example, matrix metalloproteinases)
• The selective inhibition of IL-1 and different signal transduction pathways (among others, MAPKinase -, NF-κB- signaling pathway), and
• The intra-articular administration of thrombocyte-rich plasma (PRP)(e72).

It is also hypothesized that bisphosphonates, calcitonin, and estrogens may lead to a reduction of cartilage degeneration (2, e73).

For the treatment of osteonecrosis, osteoanabolic drugs—for example, the prostaglandin analogue iloprost—are under discussion, but thus far they do not have licensing approval. Clinically they may achieve pain reduction and functional improvement in the early stages (e74, e75) (evidence level IV). Randomized studies are lacking.

Surgical methods

Reconstructive surgical approaches are indicated for cartilage defects that remain symptomatic in spite of sufficient conservative and medical treatment (Figure 1 gif ppt). Since they aim to prevent secondary processes they should be used at an early symptomatic stage. In selecting a suitable treatment method, the following parameters are important::

• Etiology
• Patient specific objectives (pain reduction, functional improvement)
• Patient’s age
• Body mass index (BMI)
• Level of physical activity
• Mechanical leg axis
• Comorbidities (ligament injuries, meniscal injuries)
• Size and location of defect
• “Kissing” lesions.

Surgical options for focal cartilage defects include in particular marrow-stimulating procedures, osteochondral transplants, and autologous chondrocyte implantation(ACI). Osteotomy around the knee joint is indicated primarily in patients with unicompartmental gonarthrosis. Because of this multiplicity of approaches it is often difficult to compare the success rates of each surgical procedure with one another as well as with untreated defects. Equally unsatisfactory are the existing options for collecting quantitative data, since clinical assessment systems do not provide information on the biomechanical functionality of the repair tissue, as re-arthroscopy to collect a biopsy specimen from the repair tissue is controversial, and the correlation of histology and clinical symptoms is unclear. For this reason, more case studies (9–18, e76, e77) have been reported than randomized controlled studies (18–20, e78).

Débridement

Débridement of the articular cartilage entails smoothing the lesion and removing loose fragments in order to avoid the transmission of shear forces on intact layers of the cartilage. Since débridement does not avert the progression of osteoarthritis it is not recommended as the sole treatment (20, e78). It does, however, have a justifiable position in the therapy of activated osteoarthritis when mechanical symptoms (such as locking) are present, in clinically symptomatic meniscal lesions, and in synovialitis that is detritus-induced, which can lead to further degeneration of the joint (e8).

Marrow-stimulating procedures

After perforation of the subchondral medullary cavity by means of microfracture surgery, Pridie drilling, or abrasion arthroplasty (e79–e81), a blood clot forms from bone marrow, on the basis of which the cartilage defect is filled with a repair tissue consisting of fibrocartilage (structurally and biomechanically inferior to hyaline articular cartilage) (Figure 2 jpg ppt). Marrow-stimulating procedures are the first-line approach in circumscribed chondral defects (covering an area of less than 2–3 cm²) (e82). An independent prospective controlled study found improved clinical results after five years in 77% of patients (17). The size and number of defects (21), the patient’s level of physical activity, and the patient’s age are prognostically important (e82). Physically active patients younger than 30–40 years have better results than older, physically inactive patients (e83–e86). A case series in which, in addition to the microfracture surgery, a collagen membrane was inserted yielded better clinical results after three years compared with baseline (size of the lesion: 4.2 cm²) (e87). Randomized controlled studies are lacking. In addition to marrow-stimulating procedures, increased subchondral bone formation with subsequent thinning of the repair cartilage covering it has been described, as has the formation of intralesional osteophytes (e88-e90).

Autologous chondrocyte transplantation

In classic autologous chondrocyte implantation (ACI), chondrocytes are isolated by means of cartilage biopsy, grown in cell culture, and then implanted into the defect, which has been covered with a periosteal flap (22). In the newer, matrix-associated transplantation methods, the chondrocytes are seeded in scaffolds as carrier substances (Figure 3 jpg ppt) (e91–e93)—applying principles of tissue engineering. Their exact contribution to the repair tissue remains unknown. Full-thickness symptomatic cartilage defects (3–10 cm²) in the knee joint constitute the main indication (13, 23, e86, e94, e95). Cartilage defects in which other approaches have failed are a further indication (e9, e96–e98). ACI is not indicated to treat osteoarthritis (13, e98, e99).

Compared with microfracture surgery (defect sizes 5.1 cm² and 4.5 cm²) similar clinical and histological results were found after five years (18) (evidence level I). Younger patients in whom symptoms are of short duration and who had few prior surgical interventions showed the best results (e86, e100). A multicenter clinical observational study found after 10 years an improvement after ACI in 69% of all patients (12). A randomized study (evidence level II) comparing classic and matrix-associated ACI found no clinical differences two years postoperatively (24). Current studies give rise to the assumption that ACI compared with marrow-stimulating procedures results in better histological repair, although the clinical results are similar (14, 15, 19, e101). For large osteochondral defects (for example, in OCD), matrix-associated ACI with autologous bone graft (“sandwich technique”) is the procedure of choice (9, e4, e101, e102). Hypertrophy of the repair tissue and delamination of the periosteal flap—as has been observed in classic ACI—have become extremely rare (<1%) as a result of applying matrix-associated transplantation procedures (e103, e104).

Transplantation of adult mesenchymal stem cells

A recent cohort study (evidence level III) reported similar clinical results two years postoperatively for transplantation of autologous bone marrow-derived mesenchymal stem cells (MSC) as for ACI (lesion sizes 4.6 cm² and 3.6 cm²) (e105). Case reports have shown fibrocartilaginous repair tissue (e106, e107). Intra-articular administration of MSC is under discussion for the treatment of osteoarthritis (e108). Clinical studies with higher evidence levels are needed before its use can be recommended.

Autologous osteochondral transplants

For this procedure, cartilage-bone cylinders from non-weight bearing areas are transplanted into a small osteochondral defect. In mosaicplasty, a larger lesion is filled in with multiple cylinders; it is also possible to transfer the posterior femoral condyle (e109–e112). In the medium term the results after single osteochondral transplantation have been good in 80–80% of cases; with regard to the knee, they were more successful for the femorotibial joint than the femoropatellar joint (e113, e114). A prospective randomized study showed better clinical-functional and MRI results after three years for osteochondral transplants than for microfracture surgery (e114). In a case series, transfer of the condyle bone showed an improvement after 5.5 years compared with baseline (evidence level IV) (e115). Osteochondral transplants are useful for small focal defects (less than 1.5 cm diameter), whereas for large lesions matrix-associated ACI with autologous bone graft is preferable to mosaicplasty because of the higher rate of complications associated with this technique (uneven surface, dislocation) and the multiple donor sites (9, e4, e102).

Redistribution of pathological loads by means of osteotomies

Osteotomies around the knee joint correct malalignment of the leg axis and are intended to prevent further cartilage degeneration by locally reducing pressure in the damaged joint compartment (e116–e120). The correction is usually performed on the frontal plane, however, any of the three planes can be corrected. The classical indication is the correction of genu varus deformity in cases of symptomatic early medial femoro-tibial osteoarthritis in the knee with an intact lateral femoro-tibial joint. In this scenario, open-wedge high tibial osteotomy performed in a biplanar technique and fixated with an internal plate fixator is increasingly gaining in importance (25) (Figure 4 jpg ppt). Review articles have reported pain reduction and functional improvement in 90% of cases after correct patient selection (e121, e122). The ideal candidate is a younger patient (<50 years) with stable ligaments without a higher-degree of axial malalignment, a good range of motion, and optimal BMI (e121, e123, e124).

If the implantation of an endoprosthetic surface replacement is defined as an end point, the survival rates are 73% after five years and 52% after 10 years, a according to a meta-analysis (e124). A retrospective study (follow-up period 16.5 years) showed only a slight radiological progression of the medial gonarthrosis after high tibial osteotomy (e125). In the context of reconstructive cartilage surgery for focal defects, osteotomies are also performed during primary interventions to unload the affected compartment when axial malalignment is present or in case of revision surgery (with the aim to protect the repair tissue) (23, e97, e126).

Conclusion and outlook

The aim of medical therapy is to maintain joint function and delay the need for surgical measures. Medical therapy is—at least temporarily—able to maintain articular function in osteoarthritis while controlling the pain, independent of the stage of disease and at least temporarily. For DMOADs it has thus far not been shown whether they slow down osteoarthritic cartilage degeneration or even stop it.

Reconstructive surgical therapies result in cartilage repair. Marrow-stimulating procedures and osteochondral transplants are the first-line treatments for the clinically common small focal articular cartilage defects. ACI is unrivalled for the primary treatment of larger focal cartilage defects, and a secondary option after other reconstructive therapies have failed. ACI and marrow-stimulating procedures are therefore not competing with each other; rather, they complement each other. They have shown particularly good results in active patients younger than 40 years.

For the treatment of osteoarthritic cartilage defects, reconstructive surgical therapeutic approaches are of lesser importance. Osteotomies around the knee play a significant role in this setting as they remove weight of osteoarthritic areas of the joint and delay the need for endoprosthetic joint replacement. Orthopedic surgeons and trauma surgeons thus have a wide range of useful therapeutic options at their disposal (22, e127, e128).

Further controlled randomized clinical studies with longer follow-up periods that investigate the development of osteoarthritis as the ultimate parameter will result in improved cartilage reconstruction and joint preservation (e129).

Conflict of interest statement

Professor Madry is a clinical investigator in the randomized, double blind, placebo controlled, international, multicenter, clinical phase II study “AS902330 in Cartilage Injury Repair,” which studies the intraarticular effects of FGF-18 in cartilage defects and is funded by Merck Serono.

Dr Grün has shares in Orthogenics.

Professor Knutsen declares that no conflict of interest exists.

Manuscript received on 2 March 2011, revised version accepted on 31 May 2011.

Translated from the original German by Dr Birte Twisselmann.

Corresponding author
Prof. Dr. med. Henning Madry
Lehrstuhl für Experimentelle Orthopädie und Arthroseforschung
Universität des Saarlandes
Gebäude 37
Kirrbergerstr. 1
66421 Homburg, Germany

@For eReferences please refer to:
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