Treatment Options for Injury to Articular Cartilage
Special Feature
Treatment Options for Injury to Articular Cartilage
By David R. Diduch, MS, MD
Injuries to articular cartilage have a limited ability to heal. Articular cartilage is avascular, relatively hypocellular, and the chondrocytes at the margins of traumatic defects do not replicate or produce new matrix sufficiently for a clinically useful repair. Numerous techniques have been developed to aid in repair of these articular defects, with recent, excellent reviews of treatment options by O’Driscoll,1 Mandelbaum and colleagues,2 and a collection of articles edited by Lonner.3 In general, these techniques include either 1) stimulation of the intrinsic repair mechanism from the subchondral bone; 2) transplants to fill the defect with autografts or allografts; 3) cell-based therapy to regenerate the chondrocytes and surrounding matrix; or 4) combinations of these techniques with growth factors or biologically active carriers to influence the repair process. This review summarizes these options and provides a framework for approaching articular cartilage injuries based on the recent literature.
Stimulation of Repair by Marrow Stromal Cells
Initial attempts at articular cartilage repair involved penetration of the subchondral bone plate to stimulate extrinsic repair by pluripotential marrow stromal cells. These stromal cells have been well demonstrated to be able to differentiate into chondrocytes or osteoblasts. Unfortunately, they also differentiate into fibroblasts, and these techniques result mainly in generation of a fibrocartilage matrix of Type I and Type II collagen with a lower water content that cannot withstand compressive loads and degenerates over time.
Methods to penetrate the subchondral bone include arthroscopic drilling or abrasion, as well as the microfracture technique popularized by Steadman, all of which are combined with debridement of loose cartilage to achieve stable articular cartilage borders. Several investigators have demonstrated that roughly 60-70% of patients improve clinically. Continuous passive motion with protective weight bearing for the first 4-8 weeks postsurgery may improve the clinical outcome. However, all of these repair techniques generate fibrocartilage, and the results deteriorate over time. Currently, penetration of the subchondral bone to stimulate a fibrocartilage repair is probably best suited for lesions smaller than 2 cm2 with stable borders so that the repair tissue will be subjected to minimal compressive loads and wear. This is a reasonable initial approach if the patient has a small lesion that is truly symptomatic. The procedure probably causes no harm and preserves other treatment options.2
Transplantation to Fill a Defect
Larger lesions that will experience compressive loads will be more likely to progress to degenerative arthritis and, thus, may benefit from techniques designed to replace the damaged area. Patches of periosteum have been used in rabbits forming regenerate tissue more closely resembling hyaline articular cartilage. The pluripotential cells of the inner, cambium layer of periosteum appear responsible for the repair, and this layer is placed facing outward. However, no convincing studies exist with human subjects to date that are sufficiently well controlled and peer reviewed to recommend its widespread use.1 Perichondrium has also been used as a graft source but requires harvest from a distant site, such as the ribs, and is less chondrogenic.
Osteochondral autografts have been transplanted from areas less necessary for weight bearing, such as the intercondylar notch or lateral condylar ridge of the femur, to fill cartilage defects just as one would change the hole on a golf green. Multiple plugs of a small diameter or fewer plugs of a larger diameter can be used. Fibrocartilage fills the spaces between the plugs. Stability of the plugs, healing within the defect, and viability of the chondrocytes all appear to be excellent. Because the procedure can be done arthroscopically and early clinical results appear good, the technique has rapidly gained popularity. Limitations include the inability to treat defects greater than 6-8 cm2 due to the limited availability of donor grafts, potential symptoms from the donor sites, and poor integration with the surrounding native cartilage.4 However, for moderate-sized lesions, osteochondral autografts appear to offer an excellent treatment option.
If donor site morbidity or availability is a problem, the osteochondral transplant can be performed with allograft. Fresh, unfrozen allografts have been shown to best preserve chondrocyte viability, which is both time- and temperature-dependent. Ghazavi and associates demonstrated 85% clinical success in 126 knees at a mean of 7.5 years, with a survivorship of 71% at 10 years.5 Because chondrocyte and graft viability decreases with time and there is the potential for disease transmission, allograft transfer is best reserved for large lesions or salvage situations without alternatives.
Cell-Based Therapy
A cell-based approach to repair potentially offers the ability to restore the cells and surrounding matrix in a progressive, permanent fashion. Brittberg and colleagues have developed a technique for autologous chondrocyte transplantation.6 Cells are obtained from an arthroscopic biopsy, released from the matrix and culture expanded, then delivered to the defect under a periosteal patch. Their results were good or excellent in 14 of 16 femoral lesions, but only two of seven patellar defects did well. Their results improved with the addition of osteotomies to correct malalignment or patellar maltracking. In a national registry for all surgeons doing the procedure, the results are roughly 85% successful now at three years. Early second-look biopsies of the original series revealed normal-appearing hyaline cartilage. Although the numbers were small and there was no control group, the technique appears to have a definite benefit over techniques that generate fibrocartilage. Disadvantages of this method include the need for two surgical procedures (biopsy and implantation), potential damage to surrounding cartilage when the periosteal patch is sewn in place, and expense. The expense to culture expand the cells has limited the clinical application of the technique. Indeed, it is not clear what role the cells play (vs the periosteum) in the generation of new hyaline cartilage. However, given that the early histology and clinical results are better than those of any other existing technique, chondrocyte autotransplantation may be appropriate, especially for larger defects.
Marrow stromal cells have also been used in animal studies with good results.7 They offer the possibility of regeneration of both bone and cartilage. This may be especially useful for osteochondritis dissecans lesions that are not repairable by other means, and may prove to be an advantage over chondrocytes.
Growth Factors and Carriers
Numerous growth factors, including transforming growth factor-beta, insulin-like growth factor-1, and bone morphogenetic proteins, have been proposed to influence intrinsic healing or the formation of regenerate tissue. Delivery seems to be the problem. Local injections of growth factors into a joint result in arthritic degeneration.1,8 Various resorbable carriers are being explored, but problems exist with controlling the amount and speed at which the growth factors are released. Polymers such as polyglycolic or polylactic acid, alginate, and hyaluronic acid sponges, as well as collagen gels and even nonresorbable matrices have been tested.1,3,7 The matrix can be used for delivery of growth factors and/or cells, and may directly have chondrogenic effects as well.
Another way to deliver growth factors is by transfecting cells with the gene encoding that factor so that the cell then makes the growth factor locally. This technique of gene therapy allows one to manipulate the repair process at the defect while avoiding potential side effects of systemic or injected delivery. These techniques remain experimental but hold a great deal of promise as new techniques to treat articular cartilage injuries.
Compared to just a few years ago, many more options are now available to treat articular cartilage injuries with good clinical results. It is anticipated that this will be an extremely active and productive area of orthopedic research in the near future.
References
1. O’Driscoll SW. The healing and regeneration of articular cartilage. J Bone Joint Surg Am 1998;80:1795-1812.
2. Mandelbaum BR, et al. Articular cartilage lesions of the knee. Am J Sports Med 1998;26(6):853-861.
3. Lonner JH, guest editor. Treatment alternatives for focal osteochondral defects of the knee. In: William GR, Fitzgerald RH, eds. Seminars in Arthroplasty, Orlando, FL: WB Saunders; 1999:10(1).
4. Bobic V. Osteochondral autologous graft transplantation in the treatment of focal articular cartilage lesion. Semin Arthroplasty 1999;10(1):21-30.
5. Ghazavi MT, et al. Fresh osteochondral allografts for post-traumatic osteochondral defects of the knee. J Bone Joint Surg Br 1997;79(6):1008-1013.
6. Brittberg M, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994;331:889-895.
7. Wakitani S, et al. Mesenchymal cell-based repair of large, full-thickness defects of articular cartilage. J Bone Joint Surg Am 1994;76:579-592.
8. van Beuningen HM, et al. Transforming growth factor beta 1 stimulates articular chondrocyteproteoglycan synthesis and induces osteophyte formation in the murine knee joint. Lab Invest 1994;71:279-290.
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For osteochondral autograft plug transfer, the area between the plugs:
a. fills with fibrocartilage.
b. heals with articular cartilage over time.
c. incorporates into the chondral surface with the plug.
d. remains empty.
In chondrocyte autotransplantation:
a. the chondrocytes have been shown to be directly responsible for the repair rather than the periosteum.
b. the chondrocytes have been shown to differentiate into osteoblasts as well as chondrocytes to fill osteochondral defects.
c. the defect shows progressive filling with time, rather than wear, consistent with matrix production.
d. results were independent of the need for other procedures to
correct malalignment or patella maltracking.
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