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Background
The menisci of the knee are semi-lunar fibrocartilaginous structures critical in load bearing, shock absorption, stability, and lubrication. Loss of meniscal tissue can lead to pain, decreased function and activity. Current methods of treating repairable meniscal tears include standard suture, meniscal tacks, darts, and arrow devices. Patients with meniscal tears that can not be repaired by these methods typically receive partial or total meniscectomy. However, several investigators believe that degenerative processes in adjacent articular cartilage surfaces may be associated with partial or total meniscectomy and could influence knee function over time (Hede et al, 1992; Schimmer et al, 1998).
Allografts or synthetic meniscus scaffolds have been used for meniscus tears to prevent early degenerative joint disease with varying success, although problems related to reduced initial and long-term stability, as well as immunological reactions prevent wide-spread clinical use (Sandmann et al, 2009).
In December 2008, Menaflex (ReGen Biologics, Inc., Hackensack, NJ), previously known as CMI, received U.S. Food and Drug Administration (FDA) 510(k) marketing clearance as a collagen scaffold for repair and reinforcement of the medial meniscus of the knee. It is a synthetic resorbable collagen matrix implant comprised of bovine type I collagen and is intended for the reinforcement and repair of soft tissue injuries of the medial meniscus where weakness exists, such as defects that result from prior surgeries to the involved meniscus (e.g., partial meniscectomy). The implant is a crescent-shaped device that can be trimmed to fit the defect in the meniscal tissue and is sutured to the remaining native meniscus during arthroscopic surgery. The device provides a sponge-like scaffold that is replaced by the patient's own meniscal tissue over time.
In its 510(k) submission, the manufacturer provided the FDA with data from a prospective, randomized, controlled, multi-center study that compared the Menaflex with partial meniscectomy. Patients (n = 311) with an irreparable injury of the medial meniscus or a previous partial medial meniscectomy were enrolled in the study. There were 2 study arms: (i) patients (n = 157) with no prior surgery on the involved meniscus (the "acute" arm of the study), and (ii) patients (n = 154) with prior (1 to 3) meniscal surgical procedures (the "chronic" arm). Patients were randomized either to receive the collagen meniscus implant or to serve as a control subject treated with a partial meniscectomy only. Subjects underwent frequent clinical follow-up examinations over 2 years and completed validated outcomes questionnaires over 7 years. Patients who had received a collagen meniscus implant were required by protocol to have second-look arthroscopy at 1 year to determine the amount of new tissue growth and to perform a biopsy to assess tissue quality. Re-operation and survival rates were determined. In the acute group, 75 patients received a collagen meniscus implant and 82 were controls. In the chronic group, 85 patients received the implant and 69 were controls. The mean duration of follow-up was 59 months (range of 16 to 92 months). The 141 repeat arthroscopies done at 1 year showed that the collagen meniscus implants had resulted in significantly (p = 0.001) increased meniscal tissue compared with that seen after the original index partial meniscectomy. The implant supported meniscus-like matrix production and integration as it was assimilated and resorbed. In the chronic group, patients who had received an implant regained significantly more of their lost activity than did controls (p = 0.02) and they underwent significantly fewer non-protocol re-operations (p = 0.04). No differences were detected between the 2 treatment groups in the acute arm of the study. Of the 12 documented serious complications in patients with the Menaflex, 7 were classified as probably or at least possibly related to the Menaflex. In 1 patient, a skin infection developed at a portal site requiring joint irrigation and debridement and the Menaflex was removed. Pain scores, Lysholm scores, and patient self-assessment scores improved between the pre-operative and latest follow-up evaluations in all treatment groups and were similar regardless of treatment or chronicity. The authors concluded that the Menaflex device supports new tissue ingrowth and that the new tissue ingrowth is adequate to enhance meniscal function in patients with a chronic meniscal injury; however, it does not have any benefit for patients with an acute injury (Rodkey et al, 2008).
It is interesting to note that the FDA (2008) made the following observations during their analysis of the Rodkey study data: (i) the majority of the Menaflex devices were firmly attached to the host rim, however, 16 % were not firmly attached and 18 % of knee compartments were determined to be worse than during the operative procedure at the time of the re-look arthroscopic procedure, (ii) the investigators reported that 5 years after receiving a Menaflex implant, 22.7 % of control patients required further meniscal surgery, compared to only 9.5 % of the Menaflex recipients, however, if additional operations that were performed during the second arthroscopy are included, the re-operation rate among Menaflex recipients was 19.7 %, and (iii) the Tegner Index is meant to complement other functional scores (e.g., the Lysholm knee score) for patients with ligamentous injuries, however, the investigators reported the Tegner Index in isolation and there was no pre-specified hypothesis for its use in the study design, thus, it is unclear how this endpoint should be interpreted given that there is no defined clinical significance for the Tegner Score when used in isolation. In addition, there is a noted difference in the rehabilitation necessary for individuals receiving the Menaflex implant versus partial meniscectomy. During the first 6 months following implantation, the patient's activity level is restricted to reduce the stress on the mesh-reinforced meniscus, allowing tissue in-growth and maturation to take place. In contrast, the rehabilitation program for a partial meniscectomy is to return to full activities by 2 to 3 weeks post-operatively since there is no period of meniscal healing required.
At the 75th annual meeting of the American Academy of Orthopaedic Surgeons in March 2008, histologic findings were presented from patients who had received the Menaflex implant (n = 128). Biopsies taken 1 year after implantation found residual implant material in 63 % of cases and all cases showed infiltration of the implant matrix with new meniscal tissue. Inflammation was noted around the implant in 9 % of patients (Choi, 2008).
Systematic evidence reviews have not evaluated the Menaflex device. A Cochrane review (Howell and Handoll, 2000) on the effects of common surgical interventions in the treatment of meniscal injuries of the knee concluded, "[t]he lack of randomised trials means that no conclusions can be drawn on the issue of surgical versus non-surgical treatment of meniscal injuries, nor meniscal tear repair versus excision. In randomised trials so far reported, there is no evidence of difference in radiological or long term clinical outcomes between arthroscopic and open meniscal surgery, or between total and partial meniscectomy. Partial meniscectomy seems preferable to the total removal of the meniscus in terms of recovery and overall functional outcome in the short term."
Although some clinical studies have demonstrated improvement with the collagen meniscus implant, the number of patients have been small in all studies and the positive effect on the prevention of progression of osteoarthritis was not compared with control groups (Bumam, 2007).
An assessment by the California Technology Assessment Forum (Tice, 2010) concluded that the collagen meniscus implant does not meet CTAF criteria. The CTAF assessment found that the pivotal randomized clinical trial (citing Rodkey et al, 2008) failed to demonstrate any improvement in pain or symptoms in either arm of the trial and the trial has substantial risk for selection bias, confounding, and reporting bias because of the large number of patients lost to follow-up after randomization and the lack of blinding for subjective outcomes. In addition, no data on osteoarthritis were presented. The CTAF assessment concluded that the trial "presents evidence that the collagen meniscus implant offers no important clinical benefits, requires longer and more intensive post-operative rehabilitation, and some uncertainty remains about the potential for long-term harm from the device."
The Centers for Medicare and Medicaid Services (CMS, 2010) has concluded that the collagen meniscus implant does not improve health outcomes in the Medicare population. Therefore, CMS has determined that the collagen meniscus implant is not reasonable and necessary for the treatment of meniscal injury/tear. Furthermore, on October 14, 2010, the FDA announced that the Menaflex Collagen Scaffold should not have been cleared for marketing in the United States. The FDA has now concluded that the Menaflex device is intended to be used for different purposes and is technologically dissimilar from devices already on the market known as “predicate devices”. These differences can affect the safety and effectiveness of the Menaflex device. For example, instead of simply repairing or reinforcing damaged tissue like predicate devices, Menaflex is intended to stimulate the growth of new tissue to replace tissue that was surgically removed. Because of these differences, the Menaflex device should not have been cleared by the agency. The announcement follows a re-evaluation of the scientific evidence that was undertaken after a September 2009 agency report identified problems in the agency’s review of the device. To correct this error, the agency will begin the process to rescind the product’s marketing clearance.
In a case series, Monllau et al (2011) evaluated the clinical outcome of a collagen meniscus implant (CMI) in an injured medial meniscus after a minimum of 10 years' follow-up. A total of 25 patients underwent arthroscopic CMI. They had either persistent compartmental joint line pain due to a previous medial meniscus resection (5 cases) or a large irreparable meniscus tear at arthroscopy (20 cases). Implant failure was defined as infection due to the implant or mechanical failure of the device. Twenty-two patients returned for clinical, functional, and radiographic evaluation. Magnetic resonance imaging was also performed and was analyzed with the criteria of Genovese et al (where type 3 indicates normal and type 1 indicates completely abnormal). All the afore-mentioned evaluations were carried out at a minimum of 10 years (range of 10.1 to 12.5 years) after the procedure. The mean Lysholm score improved from 59.9 pre-operatively to 89.6 at 1 year (p < 0.001), and it was 87.5 at final follow-up (p < 0.001). The results were good or excellent in 83 % of the population. No differences were observed between the Lysholm score at 1 year of follow-up with the score at final follow-up (p > 0.05). The mean pain score on a visual analog scale (VAS) improved by 3.5 points at final follow-up. Patient satisfaction with the procedure was 3.4 of 4 points. Radiographic evaluation showed either minimal or no narrowing of the joint line. Magnetic resonance imaging showed type 2 in 64 % of cases and type 3 in 21 %. All cases showed less volume than expected (size type 2 in 89 %). The failure rate in the patient population was 8 % (2 of 25). There were no complications related to the device. The authors concluded that although there were several different types of patients and acute and chronic tears were treated in a limited number of patients, meniscal substitution with CMI provides significant pain relief and functional improvement after a minimum of 10 years' follow-up. The implant generally diminished in size, but the procedure proved to be safe and had a low rate of implant failure on a long-term basis. No development or progression of degenerative knee joint disease was observed in most cases (Level IV evidence).
In a cohort study, Zaffagnini et al (2011) compared the long-term outcomes of the medial collagen meniscus implant (MCMI) versus partial medial meniscectomy (PMM). A total of 33 non-consecutive patients (men; mean age of 40 years) with meniscal injuries were enrolled in the study to receive MCMI or to serve as a control patient treated with PMM. The choice of treatment was decided by the patient. All patients were clinically evaluated at time 0 and at 5 years and a minimum of 10 years after surgery (mean follow-up of 133 months) by Lysholm, VAS for pain, objective International Knee Documentation Committee (IKDC) knee form, and Tegner activity level scores. The SF-36 score was performed pre-operatively and at final follow-up. Bilateral weight-bearing radiographs were completed before the index surgery and at final follow-up. Minimum 10-year follow-up MRI images were compared with pre-operative MRI images by means of the Yulish score. The Genovese score was also used to evalute MCMI MRI survivorship. The MCMI group, compared with the PMM group, showed significantly lower VAS for pain (1.2 +/- 0.9 versus 3.3 +/- 1.8; p = 0.004) and higher objective IKDC (7A and 10B for MCMI, 4B and 12C for PMM; p = 0.0001), Teger index (75 +/- 27.5 versus 50 +/- 11.67; p = 0.026), and SF-36 (53.9 +/- 4.0 versus 44.1 +/- 9.2; p = 0.026 for Physical Health Index; 54.7 +/- 3.8 versus 43.8 +/- 6.5; p = 0.004 for Mental Health Index) scores. Radiographic evaluation showed significantly less medial joint space narrowing in the MCMI group than in the PMM group (0.48 +/- 0.63 mm versus 2.13 +/- 0.79 mm; p = 0.0003). No significant differences between groups were reported regarding Lysholm (p = 0.062) and Yulish (p = 0.122) scores. Genovese score remained constant between 5 and 10 years after surgery (p = 0.5). The MRI evaluation of the MCMI patients revealed 11 cases of myxoid degeneration signal: 4 had a normal signal with reduced size, and 2 had no recognizable implant. The authors concluded that pain, activity level, and radiological outcomes are significantly improved with use of the MCMI at a minimum 10-year follow-up compared with PMM alone. Moreover, they stated that randomized controlled trials on a larger population are needed to confirm MCMI benefits at long-term.
Harston et al (2012) examined CMI effectiveness for improving patient function, symptoms, and activity level. Study methodologies, rehabilitation, and return to sports guidelines were also reviewed. MedLine, EMBASE, CINAHL, Life Science Citations, and Cochrane Central Register of Controlled Trials databases were searched from January 1995 to May 2011 using the term collagen meniscal or meniscus implant. Only human studies with English language abstracts that reported patient outcomes were included. Modified Coleman Methodology criteria were used to score research quality. A total of 11 studies with 520 subjects (men = 428; women = 92; 17.7 % women) of 38.2 +/- 3.7 years of age met the inclusion criteria. Of these subjects, 321 (men = 263, women = 58; 18.1 % women) received a CMI. Based primarily on Lysholm Knee Score, Tegner Activity Scale, pain scales and self-assessment measurements knee function, symptoms, and activity level generally improved by 46.6 +/- 39.9 months post-surgery. Rehabilitation was described in 9/11 (81.8 %) studies and 4 released patients to full activities at 6 months post-surgery. No study described how advanced rehabilitation or function testing contributed to return to activity decision-making. Research quality was generally low (67.1 +/- 18.6) with widely ranging (29 to 97) scores. Reduced CMI size at last follow-up was reported in 6/11 (54.5 %) studies, but the significance of this finding is unknown. The authors concluded that knee function, symptoms, and activity level generally improved following CMI use, but poor research report quality was common. They stated that additional well-designed long-term prospective studies are needed to better determine knee osteoarthrosis prevention efficacy and appropriate patient selection.
Furthermore, the Work Loss Data Institute's guideline on "Knee and leg (acute and chronic)" (2011) does not recommend the use of CMI/Menaflex.
Spencer et al (2012) presented their early experience on meniscal scaffolds and performed a review of the literature. A total of 23 patients underwent meniscal scaffold implantation (14 medial, 9 lateral) with either the Menaflex (ReGen Biologics) (n = 12) or Actifit (Orteq) (n = 11) scaffolds. Minimum follow-up was 1 year with a mean of 24.1 months (18 to 27) for the Menaflex and 14.7 months (12 to 18) for the Actifit groups. Mean age at surgery was 35years (17 to 47) with a mean Outerbridge grade of 1.9 in the affected compartment. Eight (36 %) underwent concurrent osteotomy, ligament reconstruction or microfracture of the tibial plateau. KOOS, Lysholm, Tegner activity and IKDC scores were collected pre-operatively and at 6-month interval post-surgery. Assessment of the reconstruction was obtained with MRI scanning and arthroscopy. One scaffold tore and was revised at 19 months post-operatively. A total of 21 out of 23 (91.3 %) had a significant improvement in knee scores when compared to pre-surgery levels at latest follow-up. Second-look arthroscopy in 14 at 1-year post-implantation showed variable amounts of regenerative tissue. There was no progression in chondral wear noted on repeat MRI scanning. The authors concluded that treatment with meniscal scaffold implants can provide good pain relief for the post-meniscectomy knee following partial meniscectomy. Moreover, they stated that longer follow-up is needed to examine if they also prevent the progressive chondral wear associated with a post-meniscectomy knee.
The National Institute for Health and Clinical Excellence's guideline on "Partial replacement of the meniscus of the knee using a biodegradable scaffold" (NICE, 2012) states that "Current evidence on partial replacement of the meniscus of the knee using a biodegradable scaffold raises no major safety concerns. Evidence for any advantage of the procedure over standard surgery, for symptom relief in the short-term, or for any reduction in further operations in the long-term, is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research".
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