April 1996 Bulletin

Cartilage researchers tell progress
Technologies hold promise, but caution is urged

by Joseph A. Buckwalter, MD

Joseph A. Buckwalter, MD, is chairman of the Academy's Council on Research and Scientific Affairs.

Advances in synovial joint imaging and arthroscopic techniques have made it possible for orthopaedic surgeons to diagnose and evaluate articular cartilage defects with great accuracy, yet the treatment of these lesions continues to present challenging problems.

Most isolated articular cartilage defects appear to result from trauma that often leaves the majority of the articular surface intact.1 The defects commonly occur in young adults who wish to maintain a high level of activity, and in some of these individuals cause pain, effusions and mechanical dysfunction of the involved joint. Left untreated, these lesions fail to heal and may progress to symptomatic joint degeneration. Conventional treatment by debridement and various methods of penetrating subchondral bone produces variable results.2 For these reasons, orthopaedic surgeons have sought new treatments for their patients with isolated articular cartilage defects.

Experimental investigations conducted over the last 25 years indicate that a variety of methods, including implantation of artificial matrices, growth factors, perichondrium, periosteum, chondrocytes and mesenchymal stem cells,2, 3, 7-10, 12-14, 17-22 can stimulate formation of new cartilaginous tissue in osteochondral and chondral defects. Encouraging clinical results have been reported following treatment of chondral defects with artificial matrices and perichondrial grafts.2, 4, 11, 16, 20 These experimental and clinical results and their implications for the possibility of regenerating articular cartilage in humans attracted relatively little attention until October 1994 when the New England Journal of Medicine published a report describing the treatment of 23 patients with chondral defects of the knee with autologous chondrocyte transplantation combined with periosteal grafting.5 Two years or more following the procedure, 14 of 16 patients with femoral condylar transplants and two of the seven patients with patellar transplants had good to excellent results. Histologic examination showed that 11 of 15 femoral and one of seven patellar transplants had the appearance of hyaline cartilage. Following publication of this article and subsequent widespread discussion of the procedure in the mass media, patients have been requesting this treatment and orthopaedic surgeons in North America have started offering chondrocyte transplantation to their patients.

Discuss treatments

Because of the great interest on the part of patients and orthopaedic surgeons, the Academy held a symposium at the Annual Meeting on Feb. 23, 1996 in Atlanta to present and discuss current information concerning chondrocyte transplantation as well as other treatments of chondral defects.6 Symposium panel members reviewed the biology of cartilage formation and regeneration, the clinical results of chondrocyte transplantation and periosteal grafting and regulatory issues related to these new strategies for regeneration of the articular surface. Randy Rosier, MD, of Rochester, N.Y., outlined the scientific basis for chondrocyte transplantation and regeneration of articular cartilage. He stressed the complexity of the process and the need to carefully evaluate the composition and function of new tissue produced by any of the approaches to this problem.

Lars Peterson, MD, of Gothenburg, Sweden, one of the authors of the New England Journal of Medicine article and an earlier report describing experimental studies of chondrocyte transplantation,5, 9 presented the most recent results of transplanting autologous chondrocytes and covering them with periosteum in 251 patients with more than 300 chondral defects. The authors performed most of the procedures to treat chondral defects in the knee, but they used the same technique for treatment of shoulder and ankle chondral defects.

Improved function

Preliminary results showed that more than two years after treatment for chondral defects of the knee, 47 of 66 patients had improved knee function and biopsies of the implanted tissue showed hyaline-like cartilage. Dr. Peterson stressed that ongoing experimental work will further refine and improve the technique and that plans for prospective randomized controlled studies have been developed.

Shawn O'Driscoll, MD, of Rochester, Minn., presented the most recent results of his long-term studies of periosteal transplants. He described 12 good or excellent outcomes in the treatment of large chondral defects of the knee, two poor outcomes and six defects in which the outcome is not yet determined. He stressed the importance of basic experimental work and further development of this method, careful selection of patients and exacting surgical technique. He pointed out that small technical differences in the harvest of the periosteum dramatically alter the number of viable cells that are transplanted, and therefore the probability of a good result.

William Tomford, MD, of Massachusetts General Hospital, Boston, reviewed current Food and Drug Administration (FDA) policy concerning autologous chondrocyte transplantation. Dr. Tomford stressed that Genzyme Corp., a company currently developing chondrocyte transplantation, appears to be using appropriate manufacturing processes and that he believes that the FDA feels this is a safe procedure, but that the FDA has not yet considered or reviewed issues related to efficacy. Dr. Tomford also pointed out that the available data on the newer approaches to regeneration of articular surface, including autologous chondrocyte transplantation, are insufficient to determine whether patients should be advised to undergo this procedure.

Following the formal presentations, members of the audience discussed their experience with chondrocyte transplantation and posed questions about the technique. Bertram Zarins, MD, of Massachusetts General Hospital, indicated that he had not been able to confirm the efficacy of the procedure, and Thomas Minas, MD, The Brigham and Women's Hospital, Boston, stated that his experience suggested that orthopaedic surgeons should "look at the procedure positively, but with skepticism and caution." Professor Ernst Hunziker, Bern, Switzerland, suggested comparing the technique of transplanting autologous chondrocytes and covering them with periosteum with periosteal grafts alone or with periosteal grafts covering a synthetic matrix.

Urges caution

The Academy symposium and published reports show that the newer approaches to articular cartilage restoration, including cell transplantation, synthetic matrices, periosteal grafts, perichondrial grafts and others, appear to have promise; but orthopaedic surgeons should exercise caution in recommending these procedures for their patients. Thus far, none of the methods of treating chondral defects have been shown to stimulate formation of tissue that duplicates the structure, composition, mechanical properties and durability of articular cartilage and none of them have been evaluated in controlled prospective clinical studies.15 For example, chondrocyte transplantation combined with periosteal grafting has not been compared in prospective studies with periosteal grafting alone, implantation of a synthetic matrix or debridement and penetration of subchondral bone. Both the experimental and the clinical studies have focused on isolated articular surface defects. Osteoarthritic joints present far more complex problems than localized cartilage defects in otherwise normal joints, and it is not clear that stimulating formation of a new articular surface in limited regions of an osteoarthritic joint will produce long lasting clinical benefits.2 For these reasons, before physicians accept the newer approaches to treatment of chondral defects, careful controlled prospective clinical studies are needed to determine the clinical efficacy of these approaches.

Over the next five years, orthopaedic surgeons will see a wide variety of exciting new treatments for musculoskeletal diseases and injuries. Chondrocyte transplantation, periosteal grafting, synthetic matrices, growth factors and other methods of stimulating formation of articular cartilage represent only a small fraction of the spectrum of new treatments of musculoskeletal diseases and injuries that are currently being developed. Other remarkable biotechnologies that have the potential to stimulate healing and tissue regeneration include combining growth factors with synthetic matrices and cell transplants, and use of electromagnetic fields, ultrasound and controlled loading and motion.

At the same time these new technologies become available, increasing societal concerns for the cost and quality of health care will hold all medical and surgical treatments to higher standards of safety, efficacy and cost-efficiency. Orthopaedic surgeons must therefore carefully evaluate new technologies and expect the highest quality of scientific evidence before recommending new technologies to their patients. Judgments concerning the value of new technologies should be based on critical assessment of well-designed rigorous basic and clinical studies, not on press releases, descriptions of the results in small numbers of patients or advertisements.

To assist fellows, the Academy is developing educational programs as well as guidelines concerning application of new biotechnologies in clinical practice. As a result of the great interest in the 1996 symposium on chondrocyte transplantation and other new approaches to regeneration of articular cartilage,6 the Academy will hold a symposium at the 1997 Annual Meeting in San Francisco to provide the most recent information concerning these technologies, including clinical results, basic investigations and the status of these procedures as viewed by regulatory agencies.

A standing-room-only crowd of hundreds of orthopaedic researchers and other interested parties attended the Academy's Annual Meeting symposium on chondrocyte transplantation.

References

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2. Buckwalter JA, Lohmander S: Operative treatment of osteoarthritis: Current practice and future development. J Bone Joint Surg 1994; 76A:1405-1418.
3. Bentley G, Greer RB: Homotrans-
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5. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L: Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. New Eng J Med 1994;331:889-895.
6. American Academy of Orthopaedic Surgeons, Chondrocyte transplantation, Academy News, 1996: Atlanta, Ga. pp. 1,7.
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12. Homminga GN, Buma P, Koot HW, van der Kraan PM, van den Berg WB: Chondrocyte behavior in fibrin glue in-vitro. Acta Orthop Scan 1993;64:441-445.
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18. Noguchi T, Oka M, Fujino M, Neo M, Yamamuro T: Repair of osteochondral defects with grafts of cultured chondrocytes: Comparison of allografts and isografts. Clin Orthop Rel Res 1994;302:251-258.
19. Robinson D, Halperin N, Nevo Z: Regenerating hyaline cartilage in articular defects of old chickens using implants of embryonal chick chondrocytes embedded in a new natural delivery substance. Calcif Tissue Int 1990;46:246-253.
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Audiotapes of the 1996 symposium on Chondrocyte Transplantation are available from National Audio Video, Inc., 4465 Washington St., Denver, Colo. 80216, (800) 373-2952.