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Cartilage Regeneration
and Repair, Where Are We?

A Review of the Proceedings of the International Cartilage Repair Society's Second Symposium

Geoffrey B. Higgs, MD Arthur L. Boland, MD
Sports Medicine and Shoulder Service
Massachusetts General Hospital and Harvard University

          The treatment of hyaline cartilage injury and degeneration is a challenge for orthopaedic surgeons. Hyaline cartilage pathology accounts for a large portion of office practice and operative procedures, but treatment remains unpredictable. The actual regeneration of hyaline cartilage is probably beyond our current reach. Ideally, the treatment of articular surface defects should be based on sound basic science principles and well performed clinical studies.

          With this goal in mind, the International Cartilage Repair Society (ICRS) was formed to encourage and facilitate communication and collaboration among international investigators interested in the treatment of articular surface degeneration.

The society is unusual in that it includes equal representation from both practicing orthopaedic surgeons as well as laboratory researchers interested in hyaline cartilage. The presidency alternates between clinical and laboratory representatives.

          Under the direction of faculty from the Harvard Combined Orthopaedic Program and the Massachusetts Institute of Technology, including Drs. Arthur Boland, Jim Herndon, Tom Minas, Myron Spector, and Alan Grodzinsky, the ICRS convened in Boston, from November 16 to 18, 1998 for its Second International Symposium. The meeting provided a forum for discussion of the basic science of cartilage repair and the results of treatment of cartilage injury. The format included podium and poster presentations, symposia, and live surgical demonstrations, with ample time for discussion.

          This article is a review of the proceedings of the ICRS in the context of currently accepted diagnosis and treatment alternatives for articular cartilage injury, degeneration, and repair. A large number of individuals and institutions made significant contributions to the conference and this short review cannot adequately recognize more than a small number of them. Based upon the data presented at the symposium, one reasonable treatment algorithm for hyaline cartilage injury and degeneration will be presented.


          The meeting kicked off with the presentation of ICRS honorary memberships to three of the greatest contributors to articular cartilage research: Drs. Robert Salter, Henry Mankin, and Clement Sledge. Dr. Joseph Buckwalter from the University of Iowa presented a comprehensive overview of hyaline cartilage injury, degeneration, and repair. Chondral injuries tend to vary with age and respond differently to treatment. The etiology of focal articular surface defects is debated. Acute trauma, repetitive micro-trauma, and interruption of blood supply (osteonecrosis) have all been considered as possible causative factors. We also need to clarify the natural history of these lesions. It remains unclear which lesions will cause symptoms and which will progress.

          Patients less than 20 years of age tend to have osteochondral lesions; patients aged 20 to 40 years develop chondral lesions; and older patients develop degenerative chondral pathology. Dr. Buckwalter's list of operative treatment options for hyaline cartilage injury currently utilized by orthopaedic surgeons included microfracture, chondral abrasionplasty, osteochondral autograft transplantation (OATS or mosaicplasty), autologous chondrocyte implantation (ACI), fresh or frozen osteochondral allografts, autologous perichondral or periosteal transplantation, and transplantation of bioabsorbable or non-bioabsorbable matrices. Emphasis was placed upon the need to correct any mechanical axis deviation or articular instability. If these abnormalities are not addressed, the chosen cartilage procedure is destined to fail. The ultimate alternative is, of course, partial or total replacement of the joint with a prosthesis.

          Dr. Buckwalter commented on the limitations of both basic science and clinical research efforts. Experiments performed in animals may help us to better understand the composition and the structural and biomechanical properties of the articular surface; however, the animal model cannot precisely mimic the variability of chondral lesions and the unique anatomy and loading conditions encountered in humans. Experimental models for focal cartilage defects have been more easily produced than models for degenerative articular surface injury. Degenerative lesions tend to be diffuse, variegated, and associated with more generalized cartilage degeneration. Furthermore, it is very difficult to account for the variability encountered in human patients with regard to the origin of the problem, the stability of the knee, genetic predisposition, mechanical alignment, and overall activity level.

          The results of operative treatments for chondral lesions will be measured largely in terms of subjective factors, at least in the short term. There is no good means of physically examining or objectively measuring the quality of reparative articular tissues on a routine basis. Therefore, experimental trials in humans must include objective measurement of patient oriented factors such as daily function, pain, and return to work or sport in addition to the traditional objective measurement of range of motion, stability, and alignment.

          The short-term success of a procedure does not necessarily equate with long-term repair. The reparative tissue produced after most cartilage repair techniques can appear normal grossly and even under light microscopy, but cannot withstand the demands required of an articular surface and quickly degenerate. As Dr. Buckwalter noted, the cells appear to produce the correct components, but they can't seem to put them together correctly to produce hyaline cartilage.

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Basic Science

          Dr. Klaus Kuettner from Rush-Presbyterian Medical Center in Chicago noted several peculiarities of articular cartilage that hinder researchers. He suggested that chondral articular surface composition, metabolism, and structural properties vary not only between different joints, but also between different locations within a given joint. For example, degenerative disease is more easily induced in the knee as compared with the ankle. These differences may correlate with the density of receptors for Interluekin-1 (IL-1) present on the chondrocytes in these areas. Attempts to study these theories in animals are confounded by the fact that IL-1 seems to affect human tissue differently than animal articular cartilage: in animals, IL-1 inhibits hyaline cartilage repair and synthesis; in humans, it increases cartilage degradation.

          The superficial cartilage layer is morphologically and biochemically distinct from deeper layers and there are a number of different chondral phenotypes within a given organism. Based on these observations, Dr. Myron Spector raised the question of whether or not we should harvest full thickness hyaline cartilage when performing ACI, and process cells from the different layers separately. There was also concern that tissue harvested from a low demand site would not function well when transplanted into a high demand site.

          Dr. Bjorn Olsen from Harvard University emphasized the importance of an adequate family history and presented data to suggest a genetic basis for some cases of osteoarthritis. His lab has demonstrated that subtle gene mutations can affect collagen structure and function, ultimately influencing the incidence of osteoarthritis. Dr. Olsen pointed out that basic science techniques should focus on clinically applicable questions.

          In a section discussing cartilage behavior in various mechanical environments, Dr. Alan Grozinsky from the Massachusetts Institute of Technology (MIT) emphasized that static compression inhibits cartilage matrix synthesis, while physiologic dynamic compression and shear stimulate matrix synthesis. High compression forces cause cartilage cell apoptosis (programmed cell death). Later in the meeting Dr. M.E. Levenston, also from MIT, presented data suggesting that compressive load at a force below that which would cause gross abnormality of articular cartilage resulted in 60% apoptosis of chondrocytes. This observation raises the concern that articular cartilage might be injured during mosaicplasty (OATS) when the osteochondral plugs are malleted into place.

          As is the quandary in most aspects of orthopaedics, the group emphasized the need for a universal system for the classification of cartilage injuries. All participants were in agreement that we are, as of yet, unable to regenerate hyaline articular cartilage. Some of the speakers questioned whether this was necessary, suggesting that other types of repair cartilage might prove adequate.

Imaging of Cartilage

          One symposium addressed the use of Magnetic Resonance Imaging (MRI) to evaluate hyaline cartilage. Most of the participants agreed that current MRI cartilage evaluation techniques are inadequate. Even so, Dr. G.A. Paletta, Jr. from the Hospital for Special Surgery described a correlation between the MRI appearance of transplanted osteochondral plugs (OATS) and their histological and biomechanical characteristics in a dog model. Dr. A. Georgoulis and co-workers from the University of Ioannina in Greece found MRI useful for confirming defect filling in Autologous Chondrocyte Implantation (ACI). In contrast, Dr. C. Erggelet and colleagues from the University of Freiburg in Germany found no correlation between clinical results and MRI results. Attempts to improve MR imaging of cartilage focus on the need for faster sequences and greater resolution. Dr. Vladimir Bobic from Broadgreen Hospital in Liverpool, England will head a subcommittee to develop an ICRS protocol for advancing MR imaging for the evaluation of hyaline cartilage injury and articular cartilage repair techniques.

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Operative Treatment


Advantages: Cost-effective; technically feasible; supportive clinical data; does not preclude the subsequent use of other techniques.

Disadvantages: Does not reliably produce hyaline cartilage.

Clinical Data: Dr.Steadman reported clinical trials of microfracture in humans documenting improvement of symptoms and function in 364 of 485 patients (75%) followed prospectively for an average of 7 years.

Laboratory Data: Dr. Myron Spector reported that chondral defects treated with microfracture fill completely with fibrocartilage at 3 months in an animal model. Dr. Steadman and colleagues at the Steadman and Hawkins clinic in Vail, Colorado used microfracture to treat full thickness cartilage defects in horses. At 4 weeks the defects were 90-100% filled, with histology indicating 30% hyaline cartilage at 8 months and 42% at 12 months.

Recommended Technique: The surgeon should debride the chondral defect to a stable articular margin. The base of the defect should be debrided through the calcified cartilage layer. Three to four perforations per square centimeter should be made, starting with circumferential perforations at the perimeter of the defect. Postoperatively, the patient should be treated with early controlled motion and limited weight bearing for six weeks.

Osteochondral Autograft Transplantation (OATS or Mosaicplasty)

Advantages: Potentially high survival-rate of articular chondrocytes; appears to maintain hyaline cartilage characteristics.

Disadvantages: Donor site morbidity, limited supply of grafts, and long rehabilitation. The results of this method of treatment may be very technique dependent. The technique is most suitable for smaller defects. There is no truly non-weight-bearing portion of the articular surface. Malleting the plug in to place may cause articular surface injury.

Clinical Data: Dr. R.A. Gambardella from the Kerlan-Jobe Orthopaedic Clinic reported 43% good results at 18 months, noting that outcomes were adversely affected by patella-femoral chondromalacia and uncorrected mechanical axis. L. Hangody reported an HSS knee score of 82 in 168 patients at 18 month to 5 year follow-up. Repeat arthroscopy with biopsy and histological analysis in 33 patients showed donor sites filled with fibrocartilage. The transplanted cartilage appeared to retain its hyaline cartilage characteristics and showed deep matrix integration. Other investigators reported satisfactory results in upwards of 86% in the short term: Imhoff and colleagues from the University of Munich, Germany reported 90% satisfactory results with 3-20 month follow-up; Gautier and Jakob from the Kantonsspital, Fribourg, Switzerland, 86% at 2 years; and Magnani from Bologna, Italy, 94% with 3-12 month follow-up. Complications included fracture or folding of the trephine tip, fracture of the osteochondral plug, anterior knee pain, and postoperative hematoma.

Laboratory Data: Dr. G.A. Paletta Jr. evaluated the OATS procedure in a dog model with histological and biomechanical evaluation at 24 weeks follow-up. The hyaline cartilage did not integrate with the surrounding tissue, a tidemark was present and there was surface irregularity. The plugs showed decreased viable chondrocytes and increased stiffness. H.U. Staubli from the Tiefenauspital, Bern, Switzerland and co-workers assessed patella-femoral contact zones and concluded that the best site for harvest of osteochondral plugs is the superior medial margin of the femoral notch. They recommend avoiding the superior lateral aspect of the femoral trochlea.

Recommended Technique: Drs. Gautier and Jakob recommend this technique for chondral lesions between 1.5 and 3.0 square centimeters in size; Drs. Hangody and Imhoff use the technique for lesions as large as 8.5 and 7.0 square centimeters respectively.

Autologous Chondrocyte Implantation (ACI)

Advantages: Potential for restoration of normal hyaline cartilage.

Disadvantages: Two procedures required including an arthrotomy; expensive; laboratory support required; highly technique dependent; unpredictable results for the patella-femoral joint.

Clinical Data: An update on the largest ongoing series by Dr. L. Peterson and colleagues from Gothenburg, Sweden included clinical, arthroscopic, and histological evaluation. They subcategorized their results by lesion location, type, and instability. Satisfactory results at 2 to 9 years follow-up were achieved in 80% of patients overall: 90% for femoral condyle lesions; 74% for femoral condyle lesions with simultaneous ACL reconstruction; 84% for osteochondral defects; 69% for patellar lesions; 58% for trochlear lesions; and 75% for multiple defects. On follow-up arthroscopic evaluation, they used a 12 point system to grade healing of the lesion: they allotted 4 points each for defect fill, integration of the border, and macroscopic appearance. They reported a score of 10.3 in isolated lesions, 10.9 in ACL reconstructed knees, and 10.5 in osteochondral defects. Biopsies of the repair tissue were obtained in 37 patients. The presence of hyaline-like repair tissue correlated with a satisfactory clinical result. They reported a 19% failure rate based upon histological criteria.

Dr. Tom Minas reported his results in subsets of simple and complex lesions with satisfactory results of 63% at 1-year follow-up and 100% at 2-year follow-up in a small cohort of complex lesions. In salvage procedures, the rate of satisfactory results was 78% at one year and 100% at two years. Specific complications reported by Dr. Minas included detachment of the periosteal graft (11%), adhesions (10%), hypertrophic periosteal patch (10%), treatment failure (7%), and DVT (1.4%).

Dr. B.P. McKeon from the New England Baptist Hospital in Boston reported satisfactory results in 100% of patients at 13 months; Dr. A. Lindahl and colleagues from Gothenburg University in Sweden, 100% at 52 months; Drs. Hart and Paddle-Ledinek from Monash University in Melbourne Australia, 100% at 9 months. Dr. Georgoulis and co-workers reported pain relief in all patients. Dr. D.R. Turgeon from Presbyterian Hospital in Dallas, Texas reported 80% clinical improvement and 75% patient satisfaction at 1-year follow-up. The only dissenting data were from Koh and colleagues at the Hospital for Special Surgery who reported failure in 8 of 14 patients.

Laboratory Data: Dr. Myron Spector reported 50% filling of a focal defect at 3 months in an animal model. Histologic and gross results deteriorated at 12-18 months. Dr. A. Lindahl reported hyaline-like tissue in 73% of specimens 52 months following ACI.

Technique Recommendations: The technique is not indicated in osteoarthritis, and should be used with caution in the patello-femoral joint. It may be best to reserve this technique for patients in whom conventional techniques have failed. The following lesion size specifications were recommended: A. Georgoulis: 3.0 to 8.0 square centimeters; B.P. McKeon: 1.2 to 18.0 square centimeters; Sandelin from Helsinki, Finland: 2.0 to 20.0 square centimeters; and A. Scorrano from Belluno Hosptial in Italy, 2.2 to 21.0 square centimeters.

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Other Techniques
Carbon Fiber Matrix Implant

Dr. G. Bentley reported 8 year follow-up of carbon fiber matrix implants, noting satisfactory results in 77% of patients overall, with 93% satisfactory results in the treatment of medial femoral condyle lesions.

Periosteal and Perichondral Grafts

Sandelin and colleagues reported 77% satisfactory results at 4 to 13 years follow-up in the treatment of patellar defects with periosteal grafts, but reported that the results deteriorated with longer follow-up periods. Dr. Angermann and colleagues from Naestred, Denmark compared their follow-up at 8 years with earlier 1-year follow-up in the treatment of osteochondral defects with periosteal grafts, and noted that the results had deteriorated. Only 49% of patients treated for patellar lesions still had a satisfactory result at the later follow-up. Dr. Bruns and co-workers from the University of Hamburg in Hamburg, Germany used autogenous rib perichondrial grafts to treat osteochondral defects (OCD). All of the patients followed for more than one year had improvement in the Lysholm and HSS scores.

Laboratory data presented by Dr. S.W. O'Driscoll from the Mayo Clinic in Rochester, Minnesota demonstrated an age-related decline in the chondrogenic potential of periosteum with a parallel decline in both the proliferative activity as well as the number of cells in the cambium layer. The animal data presented by Bruns suggested that hyaline cartilage-like tissue grew in all defects treated with perichondral grafts. There was no graft calcification.

Fresh Osteochondral Allograft Transplantation

Dr. Constance R. Chu, currently an arthroplasty fellow at the Brigham and Women's Hospital, reported the latest data from the Univesity of California at San Diego on the use of fresh osteochondral shell allograft (thin fresh-frozen allografts) resurfacing in the knee. At an average follow-up of 75 months satisfactory results were recorded in 76% of patients overall; 84% in unipolar lesions and 50% in bipolar lesions. Of interest, patello-femoral grafts led to satisfactory results in 75% of both unipolar and bipolar grafts. Dr. S. Takai and co-workers from Kyoto Prefecture University, Kyoto, Japan reported a 7.5-year follow-up in the use of autologous osteochondral shell grafts in the treatment of OCD. None of the patients had pain, an effusion, or diminished motion..

New Techniques for the Objective Evaluation of Repair Tissue

Dr. J-K Suh and co-workers from the University of Pittsburgh are developing an ultrasonic indentation probe which can be used arthroscopically to measure articular cartilage thickness and mechanical properties. Dr. Suh presented data supporting the accuracy and reproducibility of the technique. Dr. S. Treppo from MIT described an electromechanical spectroscope probe that can detect cartilage degradation and may facilitate the evaluation of intrinsic material properties.

Thoughts for the Future

The use of bioabsorbable matrices in the treatment of chondral defects holds promise. One group used Polylactide-co-Glycolide as a scaffold for cartilage matrix integration. In an animal model, at 16 weeks sacrifice, the articular surface was smooth with full integration. Of considerable interest is the fact that they found no difference in integration between those grafts pre-loaded with autologous chondrocytes and those not pre-loaded. Superficial chondral ablation of abnormal superficial tissue using a heat probe with minimal penetration of heat has shown some promise in early trials. There is considerable interest in learning to isolate pleuripotential stem cells from the bone marrow, grow them in-vitro, induce them to grow and differentiate into chondrogenic cells, and then transplant them into a defect. The application of various growth factors to stimulate neogenesis of these pluripotential stem cells holds much promise.

An Algorithm for the Management of Articular Surface Defects

Dr. Tom Minas suggested a practical algorithm for orthopaedic surgeons treating patients with symptomatic full thickness articular surface defects. The presentation of an articular surface injury may mimic a meniscal tear. Symptoms and signs include pain with weight-bearing; mechanical catching, clicking, or locking; and effusion. Since MRI cannot reliably identify cartilage lesions, definitive diagnosis may require direct arthroscopic visualization. Malalignment and instability of the articulation must be identified and addressed. It is appropriate to treat articular surface defects with the simplest, least expensive, lowest risk procedures first, proceeding to more involved procedures as warranted. Most techniques report approximately 70% satisfactory results. For smaller lesions (less than two square centimeters) Dr. Minas recommends simple debridement (or chondroplasty) for low demand patients and a subchondral perforation procedure (e.g. microfracture) for higher demand patients. If these simpler procedures fail, the surgeon can offer autologous chondrocyte implantation (ACI) or mosaicplasty (OATS).

The results of simpler procedures are less predictable for lesions larger than 2 square centimeters in size. The surgeon can try debridement with or without subchondral perforation, but it may be appropriate to proceed to ACI, OATS, or another alternative as initial treatment for larger lesions. In case of failure, it may be appropriate to attempt ACI or OATS again. Alternatively, one might proceed to osteochondral auto- or allograft transplantation. Prosthetic replacement represents the last resort.


Expectations for absolute, clinically applicable answers for the treatment of hyaline cartilage injury went unfulfilled. However, the ICRS Symposium served as an excellent forum for intellectual exchange on the treatment of hyaline cartilage injury and repair. A lesson learned, yet again, is that with greater understanding of a complex process, more questions can be asked than answered. Yet, kudos must go to all those who are asking the difficult questions and making the effort to answer them.

Geoffrey B. Higgs, MD is Sports Medicine and Shoulder Fellow at Massachusetts
General Hospital and Harvard University
Arthur Boland, MD is Chief of Sports Medicine at Harvard University and Assistant
Professor of Orthopaedic Surgery, Harvard Medical School

Address correspondence to: Arthur Boland, MD; Massachusetts General Hospital;
10 Hawthorne Place; Boston, MA 02114

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