The Journal of Bone and Joint Surgery

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Commentary & Perspective

Commentary & Perspective on
"Autologous Chondrocyte Implantation Compared with Microfracture in the Knee: A Randomized Trial"
by Gunnar Knutsen, MD, et al.

Commentary & Perspective by
Scott A. Rodeo, MD*,
The Hospital for Special Surgery, New York, NY

This is an important article in which the authors have performed a randomized trial of autologous chondrocyte implantation compared with microfracture treatment for chondral lesions in the knee. To my knowledge, this is the first study to compare these two commonly used cartilage-resurfacing procedures in a prospective, randomized trial. Microfracture is a marrow-stimulation technique in which the lesion is exposed to marrow-derived mesenchymal stem cells. These cells presumably populate the fibrin clot that forms at the defect site following the microfracture procedure. There may also be a contribution from synovial cells. In contrast, in the autologous chondrocyte transplantation technique, chondrocytes are isolated from a cartilage biopsy, expanded in number in tissue culture, and then directly implanted into the site of chondral injury. Although the autologous chondrocyte implantation technique requires two separate procedures, the rationale is that the direct implantation of mature chondrocytes will result in a reparative tissue that more closely resembles hyaline cartilage.

Importantly, the authors have objectively evaluated the reparative tissues after two years of follow-up by way of both arthroscopic inspection and histological analysis of the reparative tissue. Furthermore, the histological examinations were performed by independent observers. Patients in both groups were treated with identical rehabilitation programs, and the patient groups were similar in terms of demographic characteristics and the size of the chondral lesions treated.

The principle finding in this study is that there were no significant differences in outcomes based on subjective scores, arthroscopic inspection, or histological analysis of reparative tissues. Of note, the authors found that patients in the microfracture group had a significantly greater improvement in the SF-36 physical component score than patients in the autologous chondrocyte group. The authors found slightly better results in the microfracture group for patients with smaller lesions, whereas there were no differences in the results by lesion size in the autologous chondrocyte group. Overall, the Lysholm scores were modest at follow-up in both groups, reflecting the difficult clinical problem of chondral injury. Despite the significant improvement in the outcome scores in both groups, we certainly do not yet have the ideal treatment for chondral lesions. Of note, there was a 25% rate of reoperation in the autologous chondrocyte implantation group. These procedures were typically performed to débride hypertrophic tissue at the repair site. Other authors have noted this problem as well.

This article also provides valuable information about the histological appearance of reparative tissue. It is intriguing that there were no differences in the histological appearances of the two groups. I would have hypothesized that the reparative tissue would be more hyaline in the autologous chondrocyte group because that method involves the direct implantation of chondrocytes into the lesion, whereas microfracture and other marrow-stimulation procedures rely on marrow-derived mesenchymal stem cells in addition to a possible contribution from synovial cells. Previous studies have demonstrated that the reparative tissue remodels very gradually over a long period of time, and thus it is possible that, at a later time, the autologous chondrocyte group may perform better^1,2. Longer-term follow-up will be necessary. In the future, additional valuable information may be gained by the use of immunohistochemical techniques on biopsy samples to identify specific cartilage matrix molecules, such as type-II collagen and aggrecan. In-situ hybridization techniques may also be used to define gene-expression patterns in the cells in the reparative tissue. These types of analyses could provide important information about the biochemical and molecular signals that control the healing response.

The finding that many of the lesions into which autologous chondrocytes were implanted contained fibrocartilage suggests that the chondrocytes undergo some degree of dedifferentiation after implantation. It is likely that the absence of a supportive matrix contributes to the loss of the mature chondrocyte phenotype. Future improvements in the autologous chondrocyte implantation technique may be possible by suspending the implanted cells in a matrix that is known to maintain the chondrocyte phenotype (such as alginate gel).

Like any good study, this manuscript identifies several areas for additional study. The patch that is used to cover the defect and contain the implanted cells can be improved. Several investigators have reported hypertrophy of the periosteal membrane. The use of a type-II collagen membrane may reduce this problem. The ability to transplant the chondrocytes in a supportive matrix, such as alginate gel, may entirely eliminate the need for a periosteal patch. The use of such a matrix may also allow maintenance of the chondrocyte phenotype and could potentially make the procedure simpler to perform. Additional study of the molecular signals that regulate the production of critical cartilage matrix components may eventually yield information that can be translated to the autologous chondrocyte implantation technique. For example, the implanted cells could be genetically modified to improve expression of these genes.

Clinical questions remain as well. Additional clinical studies should identify the influence of axial alignment of the limb and the status of the meniscus on the clinical results. As patients with these issues often have multiple problems in the knee and have usually undergone previous surgery (including meniscectomy), such information will assist clinicians in identifying the appropriate patient candidate for these procedures. It is possible that the results of cartilage resurfacing procedures will be improved if limb alignment is corrected or if concomitant meniscus transplantation is carried out in meniscus-deficient patients.

On the basis of the results of this study, consideration should be given to microfracture as the recommended treatment for isolated chondral defects on the femoral condyles. In particular, microfracture appears to be especially indicated for lesions that are smaller than 4 cm². Autologous chondrocyte implantation may be a better technique for larger or uncontained defects. The results of this study will be helpful to us as we counsel patients and impart the information that, even with direct implantation of chondrocytes, the reparative tissue is not completely normal cartilage. I would encourage the authors of this study to continue to follow their patients so that the results at the five-year follow-up can be reported. I would also recommend that future studies of cartilage resurfacing techniques include both standardized clinical outcome scales as well as objective evaluation of the reparative tissue. The repair tissue should be evaluated either with the use of magnetic resonance imaging or by direct arthroscopic inspection. Histological evaluation of the reparative tissue will provide valuable insight into the basic biology of cartilage repair, and immunohistochemistry and in situ hybridization techniques can be used to gain a more detailed insight into the molecular and biochemical characteristics of the repair tissue.

*The author did not receive grants or outside funding in support of his research or preparation of this manuscript. He did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.

References

1. Breinan HA, Minas T, Hsu HP, Nehrer S, Sledge CB, Spector M. Effect of cultured autologous chondrocytes on repair of chondral defects in a canine model. J Bone Joint Surg Am. 1997;79:1439-51.
2. Horas U, Pelinkovic D, Herr G, Aigner T, Schnettler R. Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint. A prospective, comparative trial. J Bone Joint Surg Am. 2003;85:185-92.