Contemporary thinking related to the meniscus focuses on preservation, restoration, and reconstruction24,25. The literature is replete with studies that cite the important biomechanical roles that the menisci play in shock absorption, force transmission, and load distribution across the knee in addition to contributing to stability, joint congruence, nutrition of the articular cartilage, protection of the articular cartilage, joint lubrication, and proprioception6,26-31. Published data support the theory that meniscal attrition after partial or subtotal meniscectomy may be associated with degenerative processes in adjacent articular cartilage surfaces30,32-36. Despite this extensive fund of knowledge about the potential negative effects of removing part or all of the meniscus, arthroscopic partial meniscectomy remains the most commonly performed orthopaedic procedure in the United States. The development of a more sophisticated and scientific understanding and approach to knee problems and, in particular, the natural history of the meniscectomized knee has raised substantial concern about the risk of late degenerative osteoarthritis24,25. Hence, it seems more logical to repair or reconstruct injured menisci whenever possible rather than just resecting the damaged portion.
Many different materials, including artificial materials, autogenous tissue, and allograft tissue, have been evaluated for replacement of the meniscus. Our work with the collagen meniscus implant has confirmed that this device supports the growth of new repair tissue15,17. The new tissue replaces the collagen meniscus implant as it is resorbed, or the collagen meniscus implant is assimilated into the new tissue over time15-17. We hypothesized that this form of meniscus replacement would meet the body's need and, compared with partial meniscectomy, lead to better clinical knee function, without causing any harm and while potentially protecting the articular cartilage in the involved compartment.
This randomized clinical trial is unique in that all patients who received the collagen meniscus implant were required by protocol to undergo second-look arthroscopy and biopsy of the new tissue at one year.
A recent cadaver study confirmed that the greater the amount of meniscus that is retained, the more normal are the biomechanical stresses experienced by the knee joint31. In our study, patients who received the collagen meniscus implant had significantly more tissue, and thus more tissue surface area, at one year than they had immediately after the meniscectomy. Although we could not measure in situ joint forces in our patients, this finding of an increased amount of tissue surface area suggests that it is possible that a joint with new tissue generated by the collagen meniscus implant will experience biomechanical forces that are closer to normal than those experienced by a joint following partial meniscectomy.
Pain scores, Lysholm scores, and patient self-assessment scores improved between the preoperative and latest follow-up evaluations in all treatment groups, and they were similar regardless of treatment or chronicity. These outcome measures may not be sensitive enough to detect differences in a meniscus treatment study of this type, or it is possible that any differences between treatment groups in the acute arm of the study may not have been great enough to matter clinically. Alternatively, it is possible that the follow-up time, although it was about five years, was insufficient for significant changes to develop. Limited follow-up may have been more of a factor in the acute group than in the chronic group. Long-term follow-up of all patients in this study is necessary to determine if treatment with the collagen meniscus implant will eventually prove superior to partial meniscectomy alone or if both treatments will remain equivalent.
One of the goals of meniscal replacement is to permit patients to regain activity levels that they had lost as a result of the meniscal injury and/or partial meniscectomy. As demonstrated by the Tegner index, patients with a chronic meniscal injury treated with the collagen meniscus implant regained significantly more of their lost activity than did controls, thus returning more closely to their preinjury activity levels. It therefore appears that the control patients in the chronic group had to reduce their activity levels in order to maintain pain levels similar to those in the patients in the chronic group who had received a collagen meniscus implant. In the acute arm of the study, the patients in the two treatment groups regained equal amounts of their lost activity and essentially the same amount as the patients in the chronic arm who had received a collagen meniscus implant. Thus, the new tissue generated by the collagen meniscus implant allowed the patients with a chronic injury that had been treated with multiple operations to regain as much of their preinjury activity level as the patients with an acute injury, who had lost much less of the meniscus at the time of the index surgery (63% loss in the chronically injured patients who received the collagen meniscus implant compared with 41% and 49% loss in the acutely injured controls and patients who had received a collagen meniscus implant, respectively, as noted in Table II).
Patient satisfaction has gained important attention in recent years as a major outcome measure of the success of orthopaedic procedures, especially those involving the knee37,38. In this study, we cannot draw any firm conclusions with regard to patient satisfaction. The limited follow-up time of five years might be a factor, especially for the patients in the acute group. Only longer follow-up will determine if there is a true clinical difference between the outcomes of the two treatments studied.
The ultimate goal of any knee treatment is to prevent, or at least delay, further degenerative joint disease and, hence, the necessity for additional surgical procedures. In this study, patients in the chronic group who had received a collagen meniscus implant had about half as many unplanned reoperations on the involved knee for the treatment of disability or persistent pain and/or mechanical meniscus symptoms as did the controls. The odds of such a reoperation being performed were 2.7 times greater for the controls than for the patients in the chronic group who had received a collagen meniscus implant. Although the patients who had received a collagen meniscus implant were required to have second-look arthroscopy with a biopsy at one year, the reported nonprotocol reoperations for the patients who had received a collagen meniscus implant were a result of clinically relevant pathological conditions (Table V); hence, we do not believe that the repeat arthroscopic procedures required by the protocol biased the overall survival and reoperation rates. These findings suggest that, in the patients in the chronic group, the new tissue generated by the collagen meniscus implant appears to have replaced or reproduced at least some of the functions of the original meniscal tissue. Thus, we speculate that the new tissue, the function of which was similar to that of the native meniscal tissue, may slow the progression of degenerative joint changes that otherwise would lead to decreased functional capacity and require additional surgical intervention. We were unable to demonstrate any differences between the acutely injured patients who had received the collagen meniscus implant and those treated with partial meniscectomy alone.
As demonstrated by the Outerbridge scores, the status of the chondral surfaces in the patients in either the acute or the chronic group who had received a collagen meniscus implant did not change significantly during the first year. Thus, it appears that the collagen meniscus implant and the new tissue did not damage the chondral surfaces during the first year after implantation in either the acute or the chronic group. We are unable to speculate on whether there were further changes of the chondral surfaces beyond one year in the patients who had received a collagen meniscus implant.
The rates of serious complications were essentially equal for the patients treated with the collagen meniscus implant and the control patients. Although seven of the twelve complications in the group with the collagen meniscus implant were classified as being probably or at least possibly related to the implant, it appears that placement of the collagen meniscus implant did not lead to any more serious complications than did partial meniscectomy, the current standard of care. We believe that this finding is noteworthy especially because the patients who had received a collagen meniscus implant were required to undergo a second surgical procedure with a biopsy of the meniscal tissue but the controls were not.
One of the major strengths of this study is the relatively high percentage of second-look arthroscopic procedures and biopsies performed in the patients with the collagen meniscus implant. Theoretically, the tissue replacing the lost meniscal tissue does not have to recapitulate the normal meniscus exactly. It must, however, function enough like normal meniscal tissue so that patients will regain their lost activity level and it will not cause damage to the joint, and hopefully it will function biomechanically so that further degenerative changes are lessened. The histological analysis confirmed that the collagen meniscus implant supports the growth of a new hybrid repair tissue—that is, not pure fibrocartilage like the normal meniscus, but rather a composite of repair tissues. The new tissue is meniscus-like, fills the meniscal defect, and remains stable and survives for at least one year as demonstrated by direct observation in this study. Because approximately 10% to 25% of the collagen meniscus implant scaffold was still present at one year, presumably the maturation process was ongoing. It is noteworthy that, in the Phase-II feasibility study, no remnants of the collagen meniscus implant were observed in the biopsy specimens taken at five to six years and the new tissue appeared to be mature and had survived in place17. There was no arthroscopic or histological evidence that the collagen meniscus implant or the new tissue had any significant untoward effects on the joints; thus, it appears safe.
As noted, one of the covariates in the data analysis was the presence or absence of a concurrent anterior cruciate ligament reconstruction. In no instance did we observe such a reconstruction to have an apparent effect on clinical outcomes at the latest (five-year) follow-up evaluation, regardless of whether the patient had been treated with the collagen meniscus implant or partial meniscectomy alone. This finding suggests that all effects observed at the latest follow-up evaluations were likely a result of the meniscal procedure, not the secondary procedure of anterior cruciate ligament reconstruction.
A weakness of our study is that it could not be blinded, and lack of blinding could lead to patient reporting bias. The postoperative rehabilitation protocols were very different between the collagen meniscus implant and control groups, but we speculate that those differences would not have any profound effects on the five-year outcomes. Additionally, the control patients did not have second-look arthroscopy to confirm that they had not regenerated competent meniscal tissue. However, on the basis of the literature and historical controls, we are confident that there was no meaningful spontaneous regeneration of meniscal tissue in the patients treated with partial meniscectomy alone1-6,28-36. Another weakness of the study is that the follow-up period may have been insufficient to observe some of the chronic or long-term changes known to occur following meniscectomy. A follow-up period of only five years may have been more important in the acute group since significant changes and diminished clinical results would not be expected that soon in that group2,32,34-36. Alternatively, it may be that the collagen meniscus implant does not provide any positive benefits over partial meniscectomy in acutely injured patients.
An additional weakness of this study is the possibility of recall bias in the scoring of preinjury activity levels to calculate the Tegner index. However, if patients overestimated their preinjury activity level, in most instances this overestimation would have resulted in an underestimation of the Tegner index. Another weakness is that, although radiographs were made at one and two years in most cases, there was so much variability in the views and techniques used at the sixteen different study sites that the consulting radiologist was unable to make any definitive statements. Finally, the duration of follow-up for seventeen patients (5.5% of the original enrollment) was less than two years.
In conclusion, the collagen meniscus implant supports new tissue ingrowth that appears to be adequate to enhance meniscal function as evidenced by improved clinical outcomes in patients with a chronic meniscal injury. This new tissue generated by the collagen meniscus implant is stable and appears safe and biomechanically competent. Consistent with our study hypothesis, we believe that the collagen meniscus implant has the utility to be used to replace irreparable or lost meniscal tissue and improve the quality of life in patients with a chronic meniscal injury.
NOTE: The collagen meniscus implant is classified by the U.S. Food and Drug Administration as an investigational device and it is not currently available for sale or distribution in the United States. The authors gratefully acknowledge the following orthopaedic surgeon-investigators who contributed cases to this study. Alphabetically, they are Jack Andrish, Bernard Bach, Robert Bronstein, Charles Bush-Joseph, Jerald Cooper, Marc Friedman, John Garrett, Peter Indelicato, Kurt Jacobson, Warren King, Michael Maloney, Thomas Rosenburg, David Schmidt, James Smith, John Uribe, James Williams, and Richard Zorn. The authors also acknowledge Dr. Edward F. DiCarlo and Dr. Vincent J. Vigorita, who provided expertise as independent pathologists and analyzed all of the biopsy specimens.
Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from ReGen Biologics. In addition, one or more of the authors or a member of his or her 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 (ReGen Biologics). Also, a commercial entity (ReGen Biologics) 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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Investigation performed at the Steadman Hawkins Research Foundation, Vail, Colorado
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