This prospective randomized study compares multiple endpoints after treatment of cartilage defects of the weight-bearing femoral condyles with either autologous chondrocyte implantation or microfracture. This methodologically sound study confirms the difficulty of treating articular cartilage defects and the progressive osteoarthritis that can ensue despite treatment with cartilage repair techniques. The results demonstrated good clinical improvement in 77% of patients in both groups and equal failure rates of 23% in both groups at five years. More alarming was the radiographic progression of osteoarthritis in one-third of patients in this young patient cohort by five years after treatment, which correlates with poorer clinical outcome and persistent pain.
There were forty patients in each treatment group, which was the number that the original sample-size estimation had shown was required to demonstrate a difference in the Lysholm and SF-36 scores between the groups of at least 0.75 standard deviation from the mean, with an alpha level of 0.05. The patients were independently evaluated at two years and evaluated by the author at five years with complete follow-up on all patients (although some were only contacted by telephone and/or mail).
The characteristics of the patients were similar between the autologous chondrocyte implantation and the microfracture group with regard to age (mean, 33.3 and 31.1 years, respectively), defect size (mean, 5.1 and 4.5 cm2, respectively), prior surgery (mean, 1.6 and 1.4 procedures, respectively), and body weight (mean, 81 and 82.1 kg, respectively). Eighty-nine percent of lesions were located on the medial femoral condyle, and 11% were located on the lateral femoral condyle.
The outcome measures included the validated Short Form 36 [SF-36] as well as nonvalidated joint-specific scores, such as the Lysholm score, the International Cartilage Repair Society (ICRS) form, the Tegner score, and a visual analog scale. Secondary end points included a histological evaluation of biopsy specimens at two years (as assessed with a semiquantitative four-point grading system) and a radiographic evaluation with use of the classification system of Kellgren and Lawrence.
The pain sensitive scores (the SF-36 physical component score and the visual analog scores) demonstrated the greatest clinical and statistical improvements. This result is not surprising considering that patients present with painful chondral lesions and that relief of pain is the primary objective of the treating surgeon, with a secondary objective of halting osteoarthritic progression of disease in a chondral defect. Although the SF-36 physical component score was superior in the microfracture group at two years, no difference in those scores was seen between the two groups at five years. There was significant clinical improvement (p < 0.05) in both groups at five years (72% of the patients had less pain, and 80% had improvement in the Lysholm score). Both groups had substantial improvement in the SF-36 and Tegner scores, although, with the numbers available for study, the differences were not significant. The autologous chondrocyte implantation group showed an initial slow improvement (understandably so, as the implantation procedure involves open arthrotomy) and scored lower than the microfracture group at two years but then "caught up" and had equal scores at five years.
Subsequent surgical procedures were common after both autologous chondrocyte implantation (25%) and microfracture (10%). Autologous chondrocyte implantation is known to have periosteal-related problems of overgrowth, and 25% matches the results obtained in my own series. The 10% reoperation rate in the microfracture group, however, included surgery for adhesions and overgrowth, which is somewhat surprising.
Both treatments had a prevalence of failure of 23% (nine of forty patients). Failure was defined as requiring reoperation because of symptoms due to a lack of healing of the chondral defect. Autologous chondrocyte implantation failure occurred earlier (26.2 months after the implantation), and microfracture failure occurred later (37.8 months after treatment). The modes of failure (graft edge, total delamination, or central degeneration) were not elucidated. Were the failures in the largest defect sizes, and did this pattern differ between the microfracture and autologous chondrocyte implantation groups? Failures were treated with repeat cartilage repair by microfracture, autologous chondrocyte implantation and osteochondral grafting, high tibial valgus osteotomy, and, for one failure in each group, total knee arthroplasty.
The best histological quality at the two-year assessment was found in knees that did not fail. This is not surprising and validates our efforts to produce hyaline articular cartilage and fill the defect with hard, smooth tissue that is well integrated to adjacent native cartilage and underlying bone, thereby stabilizing the defect and maintaining a congruent joint.
The 23% failure rate in both groups is high, and the 33% prevalence of osteoarthritis should be assessed further. Axial alignment radiographs were not mentioned in the index article1 and are presumed not to have been made. Clinical assessment of mechanical alignment is difficult, with mild hip varus and tibial genu varum possibly accounting for a substantial amount of mechanical varus. As little as 2° of mechanical varus or valgus malalignment could predispose patients in either group to premature graft failure and progression of disease2.We perform osteotomies in one-third of our patients with tibiofemoral disease, thereby restoring the mechanical axis to neutral, and neither we nor the Gothenburg group (personal communication) have seen joint-space narrowing.
It has been documented, however, that chondral defects alone have resulted in early osteoarthritis despite the presence of only mild or no symptoms. Messner and Maletius3 reported on twenty-eight young athletes who received minimal treatment for full-thickness articular defects of the knee. Lesions were traumatic in origin in the majority of these patients. At an average follow-up of fourteen years, twenty-two patients had excellent or good function. Twelve patients (43%) had radiographic evidence of joint-space narrowing, however, which, according to those authors, is a rate "twice as high as in patients with partial meniscectomy with initially intact cartilage and similar follow-up time." Axial alignment was not discussed in their series.
Intralesional osteophyte formation has been reported to occur in up to 25% of knees that have undergone microfracture repairs4,5. This may account for the biopsies that reveal type-4 histology (inadequate biopsy or no repair tissue—predominantly bone).
We are currently reviewing our patients who had failure of autologous chondrocyte implantation after marrow stimulation techniques and comparing them with our patients who had chondral defects that remained untreated. Our unpublished data suggest that the failure rate associated with autologous chondrocyte implantation after marrow stimulation is 2.5 times higher than that seen after autologous chondrocyte implantation without the use of marrow stimulation techniques. Poor attachment and early delamination of well-formed autologous chondrocyte implantation grafts has been observed.
In the current study by Knutsen et al., 93% of patients were previously treated with operative procedures, including débridements (twenty-nine patients), Pridie drilling (three patients), and drillings or fragment fixation for the treatment of osteochondritis dissecans (thirteen patients). These treatments may have altered the subchondral bone, creating unfavorable conditions for autologous chondrocyte implantation or microfracture or both.
The results from the Gothenburg group differed from the results of this study in that those authors achieved good-to-excellent results for 90% of their patients when the problem was with the weight-bearing femoral condyle and for 89% of their patients who had osteochondritis dissecans6. Durability of the weight-bearing femoral condyles was reported to be 96% at ten years7. Is this difference related to technique or to cell culture, which, in the Gothenburg series, was autologous serum with no cryopreservation of the chondrocytes?
Long-term follow-up of the cohort in the series of Knutsen et al. will indeed be interesting. Persistent pain correlated best with Kellgren and Lawrence osteoarthritis changes and visual analog scores. Do chondral defects predispose to osteoarthritis, despite treatment? Does subtle malalignment or genetic predisposition to osteoarthritis determine the eventual outcome? This study does clearly show, however, that hyaline cartilage repairs are durable and that a good repair fill relieves symptoms regardless of the type of treatment. Important questions remain: Can we enhance marrow treatments to form hyaline repair over bone or fibrocartilage? Can we optimize autologous chondrocyte implantation cultures so that they will have no fibrous component and will integrate to underlying bone? Is microfracture a site-specific repair as has been suggested5? Is autologous chondrocyte implantation effective throughout the knee? Does prior microfracture adversely affect autologous chondrocyte implantation?
Additional well-controlled studies are needed. I congratulate the authors for an excellent collaborative study and for setting the standard for future comparative trials to evaluate new techniques. This should continue to be our goal.
*The author did not receive any outside funding or grants in support of his research for or preparation of this work. The author or a member of his immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Genzyme Biosurgery). Also, a commercial entity (Genzyme Biosurgery) paid or directed in any one year, or agreed to pay or direct, benefits in excess of $10,000 to a research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which one or more of the authors, or a member of his or her immediate family, is affiliated or associated.
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2. Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA. 2001;286:188-95.
3. Messner K, Maletius W. The long-term prognosis for severe damage to weight-bearing cartilage in the knee: a 14-year clinical and radiographic follow-up in 28 young athletes. Acta Orthop Scand. 1996;67:165-8.
4. Mithoefer K, Williams RJ 3rd, Warren RF, Potter HG, Spock CR, Jones EC, Wickiewicz TL, Marx RG. The microfracture technique for the treatment of articular cartilage lesions in the knee. A prospective cohort study. J Bone Joint Surg Am. 2005;87:1911-20.
5. Kreuz PC, Steinwachs MR, Erggelet C, Krause SJ, Konrad G, Uhl M, Sudkamp N. Results after microfracture of full-thickness chondral defects in different compartments in the knee. Osteoarthritis Cartilage. 2006;14:1119-25.
6. Peterson L, Minas T, Brittberg M, Nilsson A, Sjögren-Jansson E, Lindahl A. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res. 2000;374:212-34.
7. Peterson L, Brittberg M, Kiviranta I, Akerlund EL, Lindahl A. Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am J Sports Med. 2002;30:2-12.