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The biological treatment of focal articular cartilage lesions in the knee: future trends?
Instructional Course 206
The Biological Treatment of Focal Articular Cartilage Lesions in the Knee: Future Trends? Nicholas A. Sgaglione, M.D.
T
he current interest in biological repair and resurfacing of articular cartilage defects of the knee continues to rapidly expand as more procedures become available and accepted as mainstream techniques. Despite the progress that has been achieved, significant challenges and controversies remain when considering many of the available approaches to treat symptomatic focal lesions. There are numerous factors that contribute to these clinical challenges and controversies.1-3 First, there is no one current technique that stands out as an optimal surgical method and there are few available methods that restore zoned hyaline cartilage and consistently produce histomorphologically similar and biomechanically durable articular tissue. The exquisitely unique structural and functional characteristics of articular cartilage impart properties that permit it to respond to complex compressive loading in a mobile, fluid-filled environment. That specific structure has yet to be surgically reproduced in a predictable manner. Furthermore, variable lesion pathoetiologies, including chondral and osteochondral fractures, osteochondritis dissecans and early degenerative lesions, limit the classification of articular defects and interpretation of treatment outcomes. Second, the tendency for articular cartilage to respond to injury in a disordered manner as well as the potential for unpredictable symptomatology results in a poorly understood natural history, which is compounded by the biolatency of chondrocytes. That biolatency requires more comprehensive and extended
Address correspondence to Nicholas A. Sgaglione, M.D., Division of Sports Medicine, Department of Orthopaedic Surgery, North Shore University Hospital, 800 Community Dr, Manhasset, NY 11030, U.S.A. E-mail: [email protected] © 2003 by the Arthroscopy Association of North America 0749-8063/03/1910-0124$30.00/0 doi:10.1016/j.arthro.2003.09.042
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outcomes assessments and dictates that traditional outcome follow-up parameters be reconsidered before concluding whether a treatment is truly efficacious. Study designs are further potentially biased by the fact that chondral trauma frequently presents in association with other knee pathology (anterior cruciate ligament and meniscal tears) making it difficult to determine which pathologic entity is responsible for which symptom and to what extent. At the current time, published peer-reviewed literature lacks controlled comparison studies that identify an optimal treatment method.4-9 Clearly, many of these controversial issues remain unsolved and consensus regarding what to do and what not to do when symptomatic articular cartilage lesions are diagnosed in the knee has not been reached. This has only served to generate greater interest in the restoration of hyaline cartilage as the search for the “Holy Grail” continues. Increasingly, our society places a premium on remaining active and the heightened emphasis on physical fitness and restoring function has also expanded clinical interest. This has increased the spotlight on successful biological resurfacing techniques as well as all other methods of addressing and reconstructing combined knee pathology including ligament deficiency, meniscal attrition, and axial malalignment. As the demand for viable treatment alternatives expands, there continues to be an explosion in basic science and novel technologies that are being developed to promote neochondrogenesis.10,11 The advances in molecular biology, polymer science, biomaterials, and tissue engineering have all resulted in numerous technology platforms that have accelerated the interest in the development of clinical solutions. Buzz words such as stem cells, gene therapy, or genetic engineering have captured the attention of the media and the public alike. Many of these potential technologies and procedures remain in their inception but hold great promise in the future. This
Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 19, No 10 (December, Suppl 1), 2003: pp 154-160
FOCAL ARTICULAR CARTILAGE LESIONS article serves to present a review of where we are and where we may be going in the approach to the treatment of articular cartilage defects in the knee. The purpose is to help to better define the clinical challenge and serve to enable the treating orthopaedist to sort out what to do and what not to do and when to do it.12,13
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restore hyaline or hyaline-like articular cartilage tissue. Most would agree that obtaining a more complex histologic tissue to repair chondral lesions may be associated with a more durable response to loading over time.15-19 PROCEDURES: WHERE ARE WE?
TRENDS More recently, several trends in orthopaedics and medicine in general have been recognized and appear to be driving the development of newer treatment methods and technologies. Considerable concern for cost-effective techniques has become a significant reality as government and third-party insurers ratchet down on health care spending and cap certain procedures as well as seek to define clinical treatment guidelines. Another clear trend is the increased emphasis on minimally invasive procedures which has captured the imagination of patients even when certain miniaturized techniques can represent technology beyond reason. In addition, as patients seek minimally invasive alternatives to traditional procedures, they in part expect faster healing, quicker recoveries, and “accelerated rehabilitation protocols.” These demands are magnified by the media as well as patients and physicians alike and can contribute to unrealistic expectations regarding the manipulation of healing and biology. These trends of cost containment, demand for minimally invasive procedures and accelerated recovery may continue to drive or at least impact future consideration of articular cartilage treatments.1,14 GOALS The goals of surgical treatment of articular cartilage defects specifically biological resurfacing, include finding a method that restores zoned hyaline cartilage through a practical and minimally invasive approach that is preferably arthroscopic and associated with minimal morbidity. In particular, that relates to not compromising the ability to effectively perform established procedures such as knee arthroplasty if biological resurfacing attempts fail. In addition, optimal treatment should be cost effective, ultimately reimbursable and most importantly, successful not only in the short term, but also in the long term and as far as the development of osteoarthritis is concerned. Traditional surgical methods such as debridement and drilling have come under greater scrutiny as the recognition that a long-term successful outcome may not be associated with procedures that do not predictably
Certainly, restoration of hyaline cartilage seems feasible and it is established that ex vivo chondrogenesis and cell culture expansion as well as chondrocyte viability after transfer can be realized and carried out. Numerous studies have reported on a 70% to 85% successful outcome of articular cartilage lesions treated with autologous chondrocyte implantation (ACI).20-22 Concerns however, remain over the precise histomorphometry and extent of “hyaline-like” repair tissue associated with ACI as well as the need for staged surgery including an arthrotomy and periosteal patch suturing. These issues in addition to reimbursement inconsistencies have limited the widespread acceptance of this technique. More practical methods used to treat chondral defects have included marrow stimulation and osteochondral tissue transfer techniques. Arthroscopic debridement and microfracture of the subchondral bone has been reported with 73% to 82% success in active athletic patients.23-25 Although clinical outcomes have been favorable, questions remain as to whether a mosaic of fibrous or fibrocartilage, which has been reported to result from marrow stimulation, will ultimately respond favorably to the compressive loads that are seen by articular cartilage. This is of particular concern when treating larger lesions in the weight-bearing zones.16,26 The transfer of osteochondral autograft or allograft plugs to resurface chondral defects has gained wider acceptance with successful outcomes reported in up to 92% of selected cases.27 Using a whole-tissue graft that includes a viable hyaline tissue cap as well as fully layered zoned articular cartilage and subchondral bone remains promising and addresses several of the goals of restoring hyaline tissue with a less invasive procedure and relatively shorter recovery time. Advantages also include a single-stage procedure and the potential for arthroscopic delivery. Nonetheless, unresolved shortcomings include concerns over harvest site morbidity with the use of autografts and availability, immunologic, infectious disease and procurement issues associated with the use of allografts.28-35 The current surgical options all have advantages and disadvantages and most certainly represent first generation approaches to biological resurfacing of focal defects.
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N. A. SGAGLIONE FUTURE APPROACHES: WHAT IS REQUIRED?
Repair Versus Regeneration Versus Replacement If what we have currently available can be considered first-generation techniques, what then is the next generation of biological solutions to treating focal chondral defects? Does it build on methods that are now available or do we seek out novel techniques and technologies that have yet to be considered? It is important to first organize resurfacing methods into repair, regeneration, and or replacement. Repair, by definition can be considered an injury response mechanism that may be completed in a shorter defined time period. Regeneration defines a more lengthy process that may recapitulate the developmental cascade. Replacement would be defined by the use of a biological prosthesis or polymer. Repair and regeneration would require a cell source for replication, biologic turnover, and most importantly matrix production. Current cell sources include differentiated chondrocytes (ACI) while in the laboratory, chondroprogenitor cell lines including mesenchymal stem cells and juvenile chondrocytes have been selected. Stem cell populations may be harvested from bone marrow elements, muscle and periosteum. Furthermore, studies have also reported on the use of undifferentiated skin fibroblasts and adipose tissue as sources of chondral precursor cells. Beyond actual anatomic cell sources, autogenous versus allogeneic cell lines can also be considered and categorized depending on availability, costeffectiveness, and compatibility. The advantages of using autogenous cell lines and tissue include reduced cost and negligible disease transmission and immunologic issues. The advantages of allogeneic sources include availability and reduced harvest site issues and morbidity.2,36-39 Once a cell line is selected, it would serve to effectively produce a matrix that would proliferate and remodel. That articular cartilage matrix is the essential substance that is subtended by the cell line and is comprised of a complex lattice of type II collagen fibrils and proteoglycan macromolecules that are responsible for the biomechanical function of the new tissue. The immature composite tissue would require an organizational architecture and temporary scaffold in order to provide a 3-dimensional structure for all components to fill the defect during the proliferative and maturation phases of healing and regeneration. This scaffold would impart volume stability, initial mechanical strength, porosity for cell seeding, and
migration and biocompatibility within the surrounding host tissue. The tissue construct including the scaffold would require a method of attachment to the underlying bone tissue and adjacent native articular cartilage. Numerous scaffolds have been reported on, including collagen gels, marine proteins and alginate, xenografts, esterified hyaluronic acids, ceramics and mineral substitutes, and poly-alpha-hydroxyacids, including polylactides (PLA) and polyglycolides (PGA).40,41 Once a cell source and scaffold are selected, bioactive factors that regulate cell and tissue behavior could be utilized. These proteins can be classified according to their actions as anabolic agents or morphogens and growth factors that function to amplify chondrocyte phenotype and differentiation, improve the quality of the matrix expression and thereby produce a purer and more optimal and durable hyaline tissue. Other bioactive proteins can be classified as catabolic inhibitors that act to control and limit degradative processes, tissue breakdown, and cell death or apoptosis. Bioactive polypeptides can have numerous functions that permit manipulation and control of biological processes including healing, repair and regeneration.42-44 The requirements for successful tissue repair mechanisms would then include cells, scaffold, and bioactive factors; however, the ingredients must be coordinated to produce a zoned hyaline structure that can intimately integrate within the surrounding native tissue including the adjacent site specific host articular cartilage (condyle, trochlea, patella, or plateau) and underlying bone. Even more challenging, the repair construct must be able to function under load and over time and maintain its biological order and integrity. How does this repair process proceed? Laboratory and basic science work requires the multidisciplinary coordination of molecular biologists, bioengineers, polymer and biomaterial chemists, and clinical orthopaedists. Experimental protocols must be designed to meet the challenges of appropriate animal model selection and study, valid demonstration of safety and efficacy, and satisfying regulatory hurdles. They must also gain industry, clinical, and patient acceptance.45
FUTURE APPROACHES: SPECIFIC PROJECTS Exogenous Methods to Augment Repair Several projects are currently being investigated and represent early potential methods for a new generation of articular cartilage repair and regeneration.
FOCAL ARTICULAR CARTILAGE LESIONS Citing current methods to promote tissue repair and in an attempt to improve on current practical arthroscopic marrow stimulation techniques, microfracture chondroplasty may be augmented by the use of exogenous methods. Adjunct modalities may help to promote and stimulate a more optimal hyaline tissue repair response that functions better and more predictably than fibrous or fibrocartilage tissue. Currently, a phase II multicenter clinical study is underway using low-intensity pulsed ultrasound applied with an external coil 20 minutes twice a day after a microfracture procedure in order to enhance the repair tissue response. The clinical study is based on a small and large animal study that showed significant improvement in the tissue repair response seen with drilling and ultrasonic stimulation compared to drilling alone (J. Huckle, personal communication, 2002).46 Another method of improving on the repair response may be to use current approved intraoperative techniques to concentrate autogenous platelet-rich plasma (PRP) to produce a fibrin matrix theoretically loaded with growth factors and then insert it within the drilled lesion to amplify the “superclot” that forms. The use of ready-to-mix concentrates of the patient’s own blood products prepared at the time of the surgical procedure may represent the first example of the introduction of clinically practical application of bioactive factors to the surgical site. In addition, centrifuged and intraoperatively prepared PRP may also be used with biocompatible scaffolds to “seed” the constructs. This technology awaits more definitive bioassays for documentation of specific growth factor presence, concentration, stability, expression, and effective action (N. Grippi, personal communication, 2003). New Methods of Cell-Based Therapies Current methods for a cell-based therapy to regenerate articular cartilage include (in the United States) the technique of ACI. The next generation of techniques used for implanting autogenous chondrocytes would seem to be a method of introducing the ex vivo expanded cells using a smaller incision and without requiring a periosteal patch. This would reduce the extent of surgical dissection at implantation and eliminate the technical challenges of harvesting and suturing a watertight patch over the chondral defect. Other advantages may include a reduction in the incidence of periosteal complications such as hypertrophy, delamination, and mounding. There are several novel technologies that are being
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tested that produce expanded sheets of chondrogenic cells and 3-dimensional tissue constructs that move the ACI technique to the next level. These nextgeneration techniques would result in the introduction of preformed tissue rather than cells into the defect. One such technology that is being investigated in large animal models is based on the use of juvenile allogeneic chondrogenic precursor cells that can be cultured and expanded ex vivo using scaffold-independent methodology to produces cartilaginous tissue. Another technology utilizes ex vivo bioreactor systems to apply appropriately calculated external mechanical loads to the expanded chondral tissue explants to promote matrix production, remodeling, and construct maturation. These bioreactor platforms provide an environment that is not only through the use of hydrostatic forces and nutrient-rich culture mediums helpful in “regenerating” a higher quality of mature chondral grafts but also useful for study of tissue response to loads over time. The ability to expand a 3-dimensional graft before implantation is especially attractive in that it may represent a method of introducing a laboratoryproduced graft construct that is zoned tissue and preshaped and may even be combined with underlying bone that is a whole tissue “off the shelf” plug. These ex vivo–produced biological replacement tissue grafts could then be press-fit into defects including those that may be associated with bone and articular cartilage deficiency such as osteochondritis dissecans (J. Huckle, personal communication, 2002). Novel Scaffold Technologies Specific clinical work underway in Europe has been presented on the use of various scaffolds seeded with harvested autologous chondrocytes. Recent initial reports on the use of extracellular xenograft membranes or esterified hyaluronic acid matrices that function as scaffolds for ex vivo seeding of autogenous chondrocytes have been encouraging. Using porcine type I-III collagen small intestinal submucosal 3-dimensional matrices, defects have been treated using both miniarthrotomy and arthroscopic methods for implantation. The technical ability to implant the seeded construct and then either press-fit the chondral defect or attach the matrix using minimally invasive suturing techniques, bioadhesives such as fibrin glue or bioabsorbable anchors is currently under investigation (Marcacci, 2003, and Facchini, 2002, personal communications).47
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Gene Therapy Gene therapy holds great promise in the future approach to the treatment of articular cartilage pathology both in terms of controlling and manipulating repair as well as regenerating tissue. Gene therapy is defined as the ability through gene transfer to deliver a therapeutic protein to a target cell or tissue in order to induce that cell or tissue to engage in repair or regeneration and guide healing. The use of gene therapy techniques in combination with tissue engineering methods provides numerous options as far as musculoskeletal disease is concerned. Various approaches may be taken using human recombinant gene models.37,38,48 In general, one approach would include the following schematic: a candidate gene, target cell, therapeutic protein, and bioactive factor are selected. At first, a candidate gene is chosen that selectively codes for expression of a specific therapeutic protein that would presumably contribute to articular cartilage repair or regeneration through neochondrogenesis. The gene would then be introduced into a selected target cell, such as a chondrocyte, chondrocyte precursor cell, or stem cell, that would be then manufacture and express the therapeutic protein. The introduction of the gene and encoding DNA into the target cell could be carried out using viral transfection or nonviral methods and using ex vivo or in vivo techniques. Once the target cell has been transduced, it would then function as a source of the therapeutic protein and express that protein in order to produce morphogenic anabolic or catabolic effects on itself and adjacent novel and host tissue. The therapeutic proteins or bioactive factors would serve not only to produce a higher quality structural repair tissue but also one that would function under load and integrate and mature properly within the chondral defect. Mechanisms to control the process would be programmed in using genes for promoters, cell line purification, timing, and dosing of the protein production and shutting it down. Specific projects on cell-based therapies that have been reported and continue to be expanded on by Grande et al.49 Their recent study has been on chondrogenesis pathways and regeneration of chondral tissue at levels that are earlier in the developmental cascade of chondrocytes. By selecting out embryonic pathways and reproducing progenitor cell mechanisms, theoretically regenerative processes of neochondrogenesis can be efficiently reproduced and possibly controlled. Recent experiments have been carried out in the New Zealand rabbit model and have used plu-
ripotent mesenchymal stem cells from the periosteum as well as muscle as target cells. Several candidate genes have been selected and used, encoding for therapeutic proteins including bone morphogenic protein-7 (BMP-7), insulin-like growth factor-1 (IGF-1) and sonic hedgehog protein (Shh). Both BMP-7 and IGF-1 have been shown to function as morphogens that improve the quality of the expressed chondral matrix and tissue through stimulation of proteoglycan synthesis and proliferation of chondrocytes. The Shh protein is part of a family of polypeptide regulators that function “upstream” of the traditional chondrocyte-regulating growth factors. Developmental mechanisms that occur earlier in the embryonic cascade may be regulated by certain proteins such as Shh that produce signals for initial patterning of chondrocytes, which may allow for more control of chondrocyte precursor cell proliferation particularly if stem cell lines are used. Experiments have included repair constructs for chondral defects using these gene therapy approaches, expanding the various bioactive factor– producing transfected cell lines in culture ex vivo, and seeding them onto nonwoven polymer scaffolds (using polyglycolic acid materials). Results have been observed with several protocols using both single and bilayer constructs that are seeded with cell line producing IGF-1 in one layer of the defect coupled with cells encoded to produce BMP-7 in the second layer of the defect. These approaches have yielded hyaline cartilage constructs with superior characteristics and further work is being directed along these lines to improve repair tissue and subchondral bone integration as well as potentially zoned repair tissue.43,44,49-51 CONCLUSIONS The future holds much promise and, although many rapid advances and progress has been realized, much work still needs to done. Many questions remain unanswered and many problems remain unsolved. Which cells should be used: mesenchymal stem cells (muscle, periosteum, or marrow derived) versus chondral cells, including chondroprogenitor or differentiated chondrocytes? Which source of cells: autogenous versus allogeneic? What type of scaffold or carrier should be used to fill the defect: biological matrices versus polymer or copolymer prosthetic matrices? The area of bioactive factor expression and delivery is far from solved. What are the most effective soluble regulators and factors and to what extent should the effects control catabolism to limit degradative processes versus anabolic to encourage proliferation?
FOCAL ARTICULAR CARTILAGE LESIONS Dosing, delivery method, timing, and the effects of combination are yet to be worked out. These questions and others will ultimately need to be answered before an effective and reproducible treatment is realized. We are clearly at the dawn of an exciting and new era that joins molecular biologist with polymer chemist and basic scientist with orthopaedic surgeon. As work progresses, realistic goals must be considered and valid data analysis and clinical interpretations must be scrutinized. Ultimately we are moving in the right direction and, although most would agree that the future is now, much remains to be worked out and we are not yet there. REFERENCES 1. Sgaglione N, Miniaci A, Gillogly S, Carter T. Update on advanced surgical techniques in the treatment of traumatic focal articular cartilage lesions of the knee. Arthroscopy 2002; 18:9-32. 2. O’Driscoll S. The healing and regeneration of articular cartilage. J Bone Joint Surg Am 1998;80:1795-1807. 3. Mandelbaum B, Browne J, Fu F, Micheli L, Mosely B, Erggelet C. Current concepts on articular cartilage lesions of the knee. Am J Sports Med 1998;26:853-861. 4. Mankin HJ. The response of articular cartilage to mechanical injury. J Bone Joint Surg Am 1982;64:460-466. 5. Buckwalter JA, Lohmander S. Operative treatment of osteoarthrosis: Current practice and future development. J Bone Joint Surg Am 1994;76:1405-1418. 6. Buckwalter JA, Mankin HJ. Articular cartilage. J Bone Joint Surg Am 1997;79:600-611. 7. Buckwalter JA, Mankin HJ. Articular cartilage. Part II: Degeneration and osteoarthrosis, repair, regeneration, and transplantation. J Bone Joint Surg Am 1997;79:612-632. 8. Sahlstrom A. The natural course of arthrosis of the knee. Clin Orthop 1997;340:152-157. 9. Shelbourne KD, Jari S, Gray T. Outcome of untreated traumatic articular cartilage defects of the knee. J Bone Joint Surg Am 2003;85:8-16 (suppl 2). 10. Jackson DW, Scheer MJ, Simon TM. Cartilage substitutes: Overview of basic science and treatment options. J Am Acad Orthop Surg 2001;9:37-52. 11. Chen F, Frenkel S, DiCesare P. Repair of articular cartilage defects: Treatment options. Am J Orthop 1999;2:88-96. 12. Sandell L, Silva M. What’s new in orthopaedic research. J Bone Joint Surg Am 2001;83:1117-1124. 13. Warren S, Sylvester K, Chen C, Hedrick M, Longaker M. New directions in bioabsorbable technology. Orthopedics 2002;25: 1201-1210. 14. Minas T. Chondrocyte implantation in the repair of chondral lesions of the knee: Economics and quality of life. Am J Orthop 1998;27:739-744. 15. Poole R. What type of cartilage repair are we attempting to attain? J Bone Joint Surg Am 2003;85:40-44 (suppl 2). 16. Nehrer S, Spector M, Minas T. Histologic analysis of tissue after failed cartilage repair procedures. Clin Orthop 1999;365: 149-162. 17. Mitchell N, Shepard N. The resurfacing of adult rabbit articular cartilage by multiple perforations through the subchondral bone. J Bone Joint Surg Am 1976;58:230-233. 18. Johnson L. Arthroscopic abrasion arthroplasty historical and pathologic perspective: Present status. Arthroscopy 1986;2:5469.
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19. Menche D, Frenkel S, Blair B, Watnik N, Toolan B, Yaghoubian R, Pitman M. A comparison of abrasion burr arthroplasty and subchondral drilling in the treatment of full-thickness cartilage lesions in the rabbit. Arthroscopy 1996;12:280286. 20. Peterson L, Brittberg M, Kiviranta I, Akerlund E, Lindahl A. Autologous chondrocyte transplantation: Biomechanics and long-term durability. Am J Sports Med 2002;30:2-12. 21. Minas T, Peterson L. Advanced techniques in autologous chondrocyte transplantation. Clin Sports Med 1999;18:13-44. 22. Peterson L, Minas T, Brittberg M, Lindahl A. Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation. J Bone Joint Surg Am 2003;85:17-24 (suppl 2). 23. Blevins F, Steadman R, Rodrigo J, Silliman J. Treatment of articular cartilage defects in athletes: An analysis of functional outcome and lesion appearance. Orthopedics 1998;21:761768. 24. Steadman JR, Rodkey WG, Singelton SB, Briggs KK. Microfracture technique for full thickness chondral defects: Technique and clinical results. Oper Tech Orthop 1997;7:300-307. 25. Steadman JR, Miller B, Karas S, Schlegel T, Briggs K, Hawkins R. The microfracture technique in the treatment of chondral lesions of the knee in National Football League players. J Knee Surg 2003;2:83-86. 26. Frisbie D, Oxford J, Southwood L, et al. Early events in cartilage repair after subchondral bone microfracture. Clin Orthop 2003;407:215-227. 27. Hangody L, Fules P. Autologous osteochondral mosaicplasty for the treatment of full thickness defects of weight-bearing joints: Ten years of experimental and clinical experience. J Bone Joint Surg Am 2003;85:25-32 (suppl 2). 28. Hangody L, Kish G, Karpati Z, Udvarhelyi I, Szigeti I, Bely M. Mosaicplasty for the treatment of articular cartilage defects: Application in clinical practice. Orthopedics 1998;21: 751-755. 29. Simonian P, Sussman P, Wickiewicz T, Paletta G, Warren R. Contact pressures at osteochondral donor sites in the knee. Am J Sports Med 1998;26:491-494. 30. Tomford WW. Current concepts review: Transmission of disease through transplantation of musculoskeletal allografts. J Bone Joint Surg Am 1995;77:1742-1754. 31. Convery RF, Akeson WH, Meyers MH. The operative technique of fresh osteochondral allografting of the knee. Oper Tech Orthop 1997;7:340-344. 32. Ghazavi MT, Pritzker KP, Davis AM, Gross A. Fresh osteochondral allografts for post-traumatic osteochondral defects of the knee. J Bone Joint Surg Br 1997;79:1008-1013. 33. Chu CR, Convery FR, Akeson WH, Meyers M, Amiel D. Articular cartilage transplantation: Clinical results in the knee. Clin Orthop 1999;360:159-168. 34. Strong DM, Friedlaender GE, Tomford WW, Springfield DS, Shives TC, Burchardt H, Enneking WF, Mankin HJ. Immunologic responses in human recipients of osseous and osteochondral allografts. Clin Orthop 1996;326:107-114. 35. Shasha N, Krywulak S, Backstein D, Pressman A, Gross A. Long-term follow-up of fresh tibial osteochondral allografts for failed tibial plateau fractures. J Bone Joint Surg Am 2003; 85:33-39 (suppl 2). 36. Jackson D, Simon T. Tissue engineering principles in orthopaedic surgery. Clin Orthop 1999;367:S31-S45 (suppl). 37. Hannallah D, Peterson B, Lieberman J, Fu F, Huard J. Gene therapy in orthopaedic surgery. J Bone Joint Surg Am 2002; 84:1046-1061. 38. Musgrave D, Fu F, Huard J. Gene therapy and tissue engineering in orthopaedic surgery. J Am Acad Orthop Surg 2002;10: 6-15. 39. Bruder S. Current and emerging technologies in orthopaedic tissue engineering. Clin Orthop 1999;376:S406-S409 (suppl).
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40. Grande D, Halberstadt C, Naughton G, Schwartz R. Evaluation of matrix scaffolds for tissue engineering of articular cartilage grafts. J Biomed Mater Res 1997;34:211-220. 41. Diduch D, Jordan L, Mierisch C, Balian G. Marrow stromal cells embedded in alginate for repair of osteochondral defects. Arthroscopy 2000;16:571-577. 42. Hickey D, Frenkel S, Di Cesare. Clinical applications of growth factors for articular cartilage repair. Am J Orthop 2003;2:70-76. 43. Mason J, Grande D, Barcia M, Grant R, Pergolizzi R, Brietbart A. Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: Potential utility in gene therapy for osteochondral repair. Gene Ther 1998;5:1098-1104. 44. Fortier L, Balkman C, Sandell L, Ratcliffe A, Nixon A. Insulin-like growth factor-1 gene expression patterns during spontaneous repair of acute articular cartilage injury. J Orthop Res 2000;19:720-728. 45. Grande D, Breidbart A, Mason J, Paulino C, Laser J, Schwartz R. Cartilage tissue engineering: Current limitations and solutions. Clin Orthop 1999;367:S176-S185 (suppl).
46. Cook S, Salkeld S, Popich, Patron L, Ryaby J, Jone D, Barrack R. Improved cartilage repair after treatment with low-intensity pulsed ultrasound. Clin Orthop 2001;391:S231S243 (suppl). 47. Cherubino P, Ronga M, Grassi F, Bulgheroni P. Autologous chondrocyte implantation with a collagen membrane. J Orthop Surg 2002;1:169-177. 48. Mason J, Brietbart A, Barcia M, Porti D, Pergolizzi R, Grande D. Cartilage and bone regeneration using gene-enhanced tissue engineering. Clin Orthop 2000;379:S171-S178 (suppl). 49. Grande D, Mason J, Dines D. Stem cells as platforms for delivery of genes to enhance cartilage repair. J Bone Joint Surg Am 2003;85:111-116 (suppl 2). 50. Riddle R, Johnson R, Laufer E, Tabin C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 1993;75: 1401-1416. 51. Sellars R, Zhang R, Glasson S, Kim H, Peluso D, D’Augusta D, Morris E. Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2). J Bone Joint Surg Am 1997;79:1452-1463.
The Biological Treatment of Focal Articular Cartilage Lesions in the Knee: Future Trends? Nicholas A. Sgaglione, M.D.
T
he current interest in biological repair and resurfacing of articular cartilage defects of the knee continues to rapidly expand as more procedures become available and accepted as mainstream techniques. Despite the progress that has been achieved, significant challenges and controversies remain when considering many of the available approaches to treat symptomatic focal lesions. There are numerous factors that contribute to these clinical challenges and controversies.1-3 First, there is no one current technique that stands out as an optimal surgical method and there are few available methods that restore zoned hyaline cartilage and consistently produce histomorphologically similar and biomechanically durable articular tissue. The exquisitely unique structural and functional characteristics of articular cartilage impart properties that permit it to respond to complex compressive loading in a mobile, fluid-filled environment. That specific structure has yet to be surgically reproduced in a predictable manner. Furthermore, variable lesion pathoetiologies, including chondral and osteochondral fractures, osteochondritis dissecans and early degenerative lesions, limit the classification of articular defects and interpretation of treatment outcomes. Second, the tendency for articular cartilage to respond to injury in a disordered manner as well as the potential for unpredictable symptomatology results in a poorly understood natural history, which is compounded by the biolatency of chondrocytes. That biolatency requires more comprehensive and extended
Address correspondence to Nicholas A. Sgaglione, M.D., Division of Sports Medicine, Department of Orthopaedic Surgery, North Shore University Hospital, 800 Community Dr, Manhasset, NY 11030, U.S.A. E-mail: [email protected] © 2003 by the Arthroscopy Association of North America 0749-8063/03/1910-0124$30.00/0 doi:10.1016/j.arthro.2003.09.042
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outcomes assessments and dictates that traditional outcome follow-up parameters be reconsidered before concluding whether a treatment is truly efficacious. Study designs are further potentially biased by the fact that chondral trauma frequently presents in association with other knee pathology (anterior cruciate ligament and meniscal tears) making it difficult to determine which pathologic entity is responsible for which symptom and to what extent. At the current time, published peer-reviewed literature lacks controlled comparison studies that identify an optimal treatment method.4-9 Clearly, many of these controversial issues remain unsolved and consensus regarding what to do and what not to do when symptomatic articular cartilage lesions are diagnosed in the knee has not been reached. This has only served to generate greater interest in the restoration of hyaline cartilage as the search for the “Holy Grail” continues. Increasingly, our society places a premium on remaining active and the heightened emphasis on physical fitness and restoring function has also expanded clinical interest. This has increased the spotlight on successful biological resurfacing techniques as well as all other methods of addressing and reconstructing combined knee pathology including ligament deficiency, meniscal attrition, and axial malalignment. As the demand for viable treatment alternatives expands, there continues to be an explosion in basic science and novel technologies that are being developed to promote neochondrogenesis.10,11 The advances in molecular biology, polymer science, biomaterials, and tissue engineering have all resulted in numerous technology platforms that have accelerated the interest in the development of clinical solutions. Buzz words such as stem cells, gene therapy, or genetic engineering have captured the attention of the media and the public alike. Many of these potential technologies and procedures remain in their inception but hold great promise in the future. This
Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 19, No 10 (December, Suppl 1), 2003: pp 154-160
FOCAL ARTICULAR CARTILAGE LESIONS article serves to present a review of where we are and where we may be going in the approach to the treatment of articular cartilage defects in the knee. The purpose is to help to better define the clinical challenge and serve to enable the treating orthopaedist to sort out what to do and what not to do and when to do it.12,13
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restore hyaline or hyaline-like articular cartilage tissue. Most would agree that obtaining a more complex histologic tissue to repair chondral lesions may be associated with a more durable response to loading over time.15-19 PROCEDURES: WHERE ARE WE?
TRENDS More recently, several trends in orthopaedics and medicine in general have been recognized and appear to be driving the development of newer treatment methods and technologies. Considerable concern for cost-effective techniques has become a significant reality as government and third-party insurers ratchet down on health care spending and cap certain procedures as well as seek to define clinical treatment guidelines. Another clear trend is the increased emphasis on minimally invasive procedures which has captured the imagination of patients even when certain miniaturized techniques can represent technology beyond reason. In addition, as patients seek minimally invasive alternatives to traditional procedures, they in part expect faster healing, quicker recoveries, and “accelerated rehabilitation protocols.” These demands are magnified by the media as well as patients and physicians alike and can contribute to unrealistic expectations regarding the manipulation of healing and biology. These trends of cost containment, demand for minimally invasive procedures and accelerated recovery may continue to drive or at least impact future consideration of articular cartilage treatments.1,14 GOALS The goals of surgical treatment of articular cartilage defects specifically biological resurfacing, include finding a method that restores zoned hyaline cartilage through a practical and minimally invasive approach that is preferably arthroscopic and associated with minimal morbidity. In particular, that relates to not compromising the ability to effectively perform established procedures such as knee arthroplasty if biological resurfacing attempts fail. In addition, optimal treatment should be cost effective, ultimately reimbursable and most importantly, successful not only in the short term, but also in the long term and as far as the development of osteoarthritis is concerned. Traditional surgical methods such as debridement and drilling have come under greater scrutiny as the recognition that a long-term successful outcome may not be associated with procedures that do not predictably
Certainly, restoration of hyaline cartilage seems feasible and it is established that ex vivo chondrogenesis and cell culture expansion as well as chondrocyte viability after transfer can be realized and carried out. Numerous studies have reported on a 70% to 85% successful outcome of articular cartilage lesions treated with autologous chondrocyte implantation (ACI).20-22 Concerns however, remain over the precise histomorphometry and extent of “hyaline-like” repair tissue associated with ACI as well as the need for staged surgery including an arthrotomy and periosteal patch suturing. These issues in addition to reimbursement inconsistencies have limited the widespread acceptance of this technique. More practical methods used to treat chondral defects have included marrow stimulation and osteochondral tissue transfer techniques. Arthroscopic debridement and microfracture of the subchondral bone has been reported with 73% to 82% success in active athletic patients.23-25 Although clinical outcomes have been favorable, questions remain as to whether a mosaic of fibrous or fibrocartilage, which has been reported to result from marrow stimulation, will ultimately respond favorably to the compressive loads that are seen by articular cartilage. This is of particular concern when treating larger lesions in the weight-bearing zones.16,26 The transfer of osteochondral autograft or allograft plugs to resurface chondral defects has gained wider acceptance with successful outcomes reported in up to 92% of selected cases.27 Using a whole-tissue graft that includes a viable hyaline tissue cap as well as fully layered zoned articular cartilage and subchondral bone remains promising and addresses several of the goals of restoring hyaline tissue with a less invasive procedure and relatively shorter recovery time. Advantages also include a single-stage procedure and the potential for arthroscopic delivery. Nonetheless, unresolved shortcomings include concerns over harvest site morbidity with the use of autografts and availability, immunologic, infectious disease and procurement issues associated with the use of allografts.28-35 The current surgical options all have advantages and disadvantages and most certainly represent first generation approaches to biological resurfacing of focal defects.
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N. A. SGAGLIONE FUTURE APPROACHES: WHAT IS REQUIRED?
Repair Versus Regeneration Versus Replacement If what we have currently available can be considered first-generation techniques, what then is the next generation of biological solutions to treating focal chondral defects? Does it build on methods that are now available or do we seek out novel techniques and technologies that have yet to be considered? It is important to first organize resurfacing methods into repair, regeneration, and or replacement. Repair, by definition can be considered an injury response mechanism that may be completed in a shorter defined time period. Regeneration defines a more lengthy process that may recapitulate the developmental cascade. Replacement would be defined by the use of a biological prosthesis or polymer. Repair and regeneration would require a cell source for replication, biologic turnover, and most importantly matrix production. Current cell sources include differentiated chondrocytes (ACI) while in the laboratory, chondroprogenitor cell lines including mesenchymal stem cells and juvenile chondrocytes have been selected. Stem cell populations may be harvested from bone marrow elements, muscle and periosteum. Furthermore, studies have also reported on the use of undifferentiated skin fibroblasts and adipose tissue as sources of chondral precursor cells. Beyond actual anatomic cell sources, autogenous versus allogeneic cell lines can also be considered and categorized depending on availability, costeffectiveness, and compatibility. The advantages of using autogenous cell lines and tissue include reduced cost and negligible disease transmission and immunologic issues. The advantages of allogeneic sources include availability and reduced harvest site issues and morbidity.2,36-39 Once a cell line is selected, it would serve to effectively produce a matrix that would proliferate and remodel. That articular cartilage matrix is the essential substance that is subtended by the cell line and is comprised of a complex lattice of type II collagen fibrils and proteoglycan macromolecules that are responsible for the biomechanical function of the new tissue. The immature composite tissue would require an organizational architecture and temporary scaffold in order to provide a 3-dimensional structure for all components to fill the defect during the proliferative and maturation phases of healing and regeneration. This scaffold would impart volume stability, initial mechanical strength, porosity for cell seeding, and
migration and biocompatibility within the surrounding host tissue. The tissue construct including the scaffold would require a method of attachment to the underlying bone tissue and adjacent native articular cartilage. Numerous scaffolds have been reported on, including collagen gels, marine proteins and alginate, xenografts, esterified hyaluronic acids, ceramics and mineral substitutes, and poly-alpha-hydroxyacids, including polylactides (PLA) and polyglycolides (PGA).40,41 Once a cell source and scaffold are selected, bioactive factors that regulate cell and tissue behavior could be utilized. These proteins can be classified according to their actions as anabolic agents or morphogens and growth factors that function to amplify chondrocyte phenotype and differentiation, improve the quality of the matrix expression and thereby produce a purer and more optimal and durable hyaline tissue. Other bioactive proteins can be classified as catabolic inhibitors that act to control and limit degradative processes, tissue breakdown, and cell death or apoptosis. Bioactive polypeptides can have numerous functions that permit manipulation and control of biological processes including healing, repair and regeneration.42-44 The requirements for successful tissue repair mechanisms would then include cells, scaffold, and bioactive factors; however, the ingredients must be coordinated to produce a zoned hyaline structure that can intimately integrate within the surrounding native tissue including the adjacent site specific host articular cartilage (condyle, trochlea, patella, or plateau) and underlying bone. Even more challenging, the repair construct must be able to function under load and over time and maintain its biological order and integrity. How does this repair process proceed? Laboratory and basic science work requires the multidisciplinary coordination of molecular biologists, bioengineers, polymer and biomaterial chemists, and clinical orthopaedists. Experimental protocols must be designed to meet the challenges of appropriate animal model selection and study, valid demonstration of safety and efficacy, and satisfying regulatory hurdles. They must also gain industry, clinical, and patient acceptance.45
FUTURE APPROACHES: SPECIFIC PROJECTS Exogenous Methods to Augment Repair Several projects are currently being investigated and represent early potential methods for a new generation of articular cartilage repair and regeneration.
FOCAL ARTICULAR CARTILAGE LESIONS Citing current methods to promote tissue repair and in an attempt to improve on current practical arthroscopic marrow stimulation techniques, microfracture chondroplasty may be augmented by the use of exogenous methods. Adjunct modalities may help to promote and stimulate a more optimal hyaline tissue repair response that functions better and more predictably than fibrous or fibrocartilage tissue. Currently, a phase II multicenter clinical study is underway using low-intensity pulsed ultrasound applied with an external coil 20 minutes twice a day after a microfracture procedure in order to enhance the repair tissue response. The clinical study is based on a small and large animal study that showed significant improvement in the tissue repair response seen with drilling and ultrasonic stimulation compared to drilling alone (J. Huckle, personal communication, 2002).46 Another method of improving on the repair response may be to use current approved intraoperative techniques to concentrate autogenous platelet-rich plasma (PRP) to produce a fibrin matrix theoretically loaded with growth factors and then insert it within the drilled lesion to amplify the “superclot” that forms. The use of ready-to-mix concentrates of the patient’s own blood products prepared at the time of the surgical procedure may represent the first example of the introduction of clinically practical application of bioactive factors to the surgical site. In addition, centrifuged and intraoperatively prepared PRP may also be used with biocompatible scaffolds to “seed” the constructs. This technology awaits more definitive bioassays for documentation of specific growth factor presence, concentration, stability, expression, and effective action (N. Grippi, personal communication, 2003). New Methods of Cell-Based Therapies Current methods for a cell-based therapy to regenerate articular cartilage include (in the United States) the technique of ACI. The next generation of techniques used for implanting autogenous chondrocytes would seem to be a method of introducing the ex vivo expanded cells using a smaller incision and without requiring a periosteal patch. This would reduce the extent of surgical dissection at implantation and eliminate the technical challenges of harvesting and suturing a watertight patch over the chondral defect. Other advantages may include a reduction in the incidence of periosteal complications such as hypertrophy, delamination, and mounding. There are several novel technologies that are being
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tested that produce expanded sheets of chondrogenic cells and 3-dimensional tissue constructs that move the ACI technique to the next level. These nextgeneration techniques would result in the introduction of preformed tissue rather than cells into the defect. One such technology that is being investigated in large animal models is based on the use of juvenile allogeneic chondrogenic precursor cells that can be cultured and expanded ex vivo using scaffold-independent methodology to produces cartilaginous tissue. Another technology utilizes ex vivo bioreactor systems to apply appropriately calculated external mechanical loads to the expanded chondral tissue explants to promote matrix production, remodeling, and construct maturation. These bioreactor platforms provide an environment that is not only through the use of hydrostatic forces and nutrient-rich culture mediums helpful in “regenerating” a higher quality of mature chondral grafts but also useful for study of tissue response to loads over time. The ability to expand a 3-dimensional graft before implantation is especially attractive in that it may represent a method of introducing a laboratoryproduced graft construct that is zoned tissue and preshaped and may even be combined with underlying bone that is a whole tissue “off the shelf” plug. These ex vivo–produced biological replacement tissue grafts could then be press-fit into defects including those that may be associated with bone and articular cartilage deficiency such as osteochondritis dissecans (J. Huckle, personal communication, 2002). Novel Scaffold Technologies Specific clinical work underway in Europe has been presented on the use of various scaffolds seeded with harvested autologous chondrocytes. Recent initial reports on the use of extracellular xenograft membranes or esterified hyaluronic acid matrices that function as scaffolds for ex vivo seeding of autogenous chondrocytes have been encouraging. Using porcine type I-III collagen small intestinal submucosal 3-dimensional matrices, defects have been treated using both miniarthrotomy and arthroscopic methods for implantation. The technical ability to implant the seeded construct and then either press-fit the chondral defect or attach the matrix using minimally invasive suturing techniques, bioadhesives such as fibrin glue or bioabsorbable anchors is currently under investigation (Marcacci, 2003, and Facchini, 2002, personal communications).47
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Gene Therapy Gene therapy holds great promise in the future approach to the treatment of articular cartilage pathology both in terms of controlling and manipulating repair as well as regenerating tissue. Gene therapy is defined as the ability through gene transfer to deliver a therapeutic protein to a target cell or tissue in order to induce that cell or tissue to engage in repair or regeneration and guide healing. The use of gene therapy techniques in combination with tissue engineering methods provides numerous options as far as musculoskeletal disease is concerned. Various approaches may be taken using human recombinant gene models.37,38,48 In general, one approach would include the following schematic: a candidate gene, target cell, therapeutic protein, and bioactive factor are selected. At first, a candidate gene is chosen that selectively codes for expression of a specific therapeutic protein that would presumably contribute to articular cartilage repair or regeneration through neochondrogenesis. The gene would then be introduced into a selected target cell, such as a chondrocyte, chondrocyte precursor cell, or stem cell, that would be then manufacture and express the therapeutic protein. The introduction of the gene and encoding DNA into the target cell could be carried out using viral transfection or nonviral methods and using ex vivo or in vivo techniques. Once the target cell has been transduced, it would then function as a source of the therapeutic protein and express that protein in order to produce morphogenic anabolic or catabolic effects on itself and adjacent novel and host tissue. The therapeutic proteins or bioactive factors would serve not only to produce a higher quality structural repair tissue but also one that would function under load and integrate and mature properly within the chondral defect. Mechanisms to control the process would be programmed in using genes for promoters, cell line purification, timing, and dosing of the protein production and shutting it down. Specific projects on cell-based therapies that have been reported and continue to be expanded on by Grande et al.49 Their recent study has been on chondrogenesis pathways and regeneration of chondral tissue at levels that are earlier in the developmental cascade of chondrocytes. By selecting out embryonic pathways and reproducing progenitor cell mechanisms, theoretically regenerative processes of neochondrogenesis can be efficiently reproduced and possibly controlled. Recent experiments have been carried out in the New Zealand rabbit model and have used plu-
ripotent mesenchymal stem cells from the periosteum as well as muscle as target cells. Several candidate genes have been selected and used, encoding for therapeutic proteins including bone morphogenic protein-7 (BMP-7), insulin-like growth factor-1 (IGF-1) and sonic hedgehog protein (Shh). Both BMP-7 and IGF-1 have been shown to function as morphogens that improve the quality of the expressed chondral matrix and tissue through stimulation of proteoglycan synthesis and proliferation of chondrocytes. The Shh protein is part of a family of polypeptide regulators that function “upstream” of the traditional chondrocyte-regulating growth factors. Developmental mechanisms that occur earlier in the embryonic cascade may be regulated by certain proteins such as Shh that produce signals for initial patterning of chondrocytes, which may allow for more control of chondrocyte precursor cell proliferation particularly if stem cell lines are used. Experiments have included repair constructs for chondral defects using these gene therapy approaches, expanding the various bioactive factor– producing transfected cell lines in culture ex vivo, and seeding them onto nonwoven polymer scaffolds (using polyglycolic acid materials). Results have been observed with several protocols using both single and bilayer constructs that are seeded with cell line producing IGF-1 in one layer of the defect coupled with cells encoded to produce BMP-7 in the second layer of the defect. These approaches have yielded hyaline cartilage constructs with superior characteristics and further work is being directed along these lines to improve repair tissue and subchondral bone integration as well as potentially zoned repair tissue.43,44,49-51 CONCLUSIONS The future holds much promise and, although many rapid advances and progress has been realized, much work still needs to done. Many questions remain unanswered and many problems remain unsolved. Which cells should be used: mesenchymal stem cells (muscle, periosteum, or marrow derived) versus chondral cells, including chondroprogenitor or differentiated chondrocytes? Which source of cells: autogenous versus allogeneic? What type of scaffold or carrier should be used to fill the defect: biological matrices versus polymer or copolymer prosthetic matrices? The area of bioactive factor expression and delivery is far from solved. What are the most effective soluble regulators and factors and to what extent should the effects control catabolism to limit degradative processes versus anabolic to encourage proliferation?
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46. Cook S, Salkeld S, Popich, Patron L, Ryaby J, Jone D, Barrack R. Improved cartilage repair after treatment with low-intensity pulsed ultrasound. Clin Orthop 2001;391:S231S243 (suppl). 47. Cherubino P, Ronga M, Grassi F, Bulgheroni P. Autologous chondrocyte implantation with a collagen membrane. J Orthop Surg 2002;1:169-177. 48. Mason J, Brietbart A, Barcia M, Porti D, Pergolizzi R, Grande D. Cartilage and bone regeneration using gene-enhanced tissue engineering. Clin Orthop 2000;379:S171-S178 (suppl). 49. Grande D, Mason J, Dines D. Stem cells as platforms for delivery of genes to enhance cartilage repair. J Bone Joint Surg Am 2003;85:111-116 (suppl 2). 50. Riddle R, Johnson R, Laufer E, Tabin C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 1993;75: 1401-1416. 51. Sellars R, Zhang R, Glasson S, Kim H, Peluso D, D’Augusta D, Morris E. Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2). J Bone Joint Surg Am 1997;79:1452-1463.