Meniscal cartilage is an integral structural component of the human knee, functioning to absorb shocks and providing load sharing, joint stability, congruity, proprioception, and lubrication and nutrition of the cartilage surfaces. Total and partial meniscectomy frequently result in degenerative osteoarthritis. The integrity of the menisci is particularly important in knees in which the anterior cruciate ligament has been damaged. In these situations, the menisci act as secondary stabilizers of anteroposterior and varus-valgus translation.

Treatment

Meniscal allograft transplantation (MAT) is considered a salvage procedure, reserved for patients with disabling knee pain following meniscectomy who are considered too young to undergo total knee arthroplasty or in patients who require a total or near total meniscectomy for irreparable tears. As a result, the population intended to receive these transplants is relatively limited. Using a large database of privately insured non-Medicare patients, Cvetanovich et al (2015) estimated an annual incidence of MAT in the U. S. of 0.24 per 100000.^1, It is not expected that clinical trials will be conducted to compare meniscal allografts with other orthopedic procedures, although trials comparing allograft transplant with medical therapy are possible.

There are three general groups of patients who have been treated with MAT:

• young patients with a history of meniscectomy who have symptoms of pain and discomfort associated with early osteoarthritis that is localized to the meniscus-deficient compartment
• patients undergoing anterior cruciate ligament reconstruction in whom a concomitant meniscal transplant is intended to provide increased stability
• young athletes with few symptoms in whom the allograft transplantation is intended to deter the development of osteoarthritis. Due to the risks associated with this surgical procedure, prophylactic treatment for this purpose is not frequently recommended.

There are several techniques for MAT; most are arthroscopically assisted or all-arthroscopic. Broadly, the techniques are either all-suture fixation or bone fixation. Within the bone fixation category, the surgeon may use either bone plugs or a bone bridge. Types of bone bridges include keyhole, trough, dove-tail, and bridge-in-slot. The technique used depends on laterality and the need for concomitant procedures. Patients with malalignment, focal chondral defects, and/or ligamentous insufficiency may need concomitant procedures (osteotomy, cartilage restoration, and/or ligament reconstruction, respectively).^3,

Tissue engineering that grows new replacement host tissue is also being investigated. For example, the Collagen Meniscus Implant (Ivy Sports Medicine, formerly the ReGen Collagen Scaffold by ReGen Biologics), is a resorbable collagen matrix composed primarily of type I collagen from bovine Achilles tendons. The implant is provided in a semilunar shape and trimmed to size for suturing to the remaining meniscal rim. The implant provides an absorbable collagen scaffold that is replaced by the patient's soft tissue; it is not intended to replace normal body structure. Because it requires a meniscal rim for attachment, it is intended to fill meniscus defects after a partial meniscectomy. Other scaffold materials and cell-seeding techniques are being investigated. Nonabsorbable and nonporous synthetic implants for total meniscus replacement are in development. One total meniscus replacement that is in early phase clinical testing is NUsurface® (Active Implants); it is composed of a polyethylene reinforced polycarbonate urethane.

Outcome Measures

The outcomes of this treatment (ie, pain, functional status) are subjective, patient-reported outcomes that are prone to placebo effects. On the other hand, the natural history of a severely damaged meniscus is predictable, with progressive joint damage, pain, and loss of function.

Regulatory Status
Collagen Meniscus Implants

In 2008, the ReGen Collagen Scaffold was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. The FDA determined that this device was substantially equivalent to existing absorbable surgical mesh devices. The ReGen Collagen Scaffold (also known as MenaFlex^TM CMI) was the only collagen meniscus implant with the FDA clearance at that time. Amid controversy about this 510(k) clearance decision, the FDA reviewed its decision. In October 2010, the FDA rescinded the approval, stating that MenaFlex^TM is intended for different purposes and is technologically dissimilar from the predicate devices identified in the approval process. The manufacturer appealed the rescission and won its appeal in 2014. The product, now called CMIÒ, is manufactured by Ivy Sports Medicine. CMIÒ is the only FDA approved collagen meniscus product currently on the market. FDA product code: OLC.

Related Policies

• Autologous Chondrocyte Implantation for Focal Articular Cartilage Lesions (Policy #013 in the Surgery Section)
• Autografts and Allografts in the Treatment of Focal Articular Cartilage Lesions (Policy #064 in the Surgery Section)

1. Meniscal allograft transplantation is considered medically necessary in members who have had a prior meniscectomy and have symptoms related to the affected side, when all of the following criteria are met:

• Skeletally mature member less than 50 years of age.
• Disabling knee pain with activity that is refractory to conservative treatment.
  [NOTE: Members should exhibit symptoms of persistent disabling knee pain that has not shown an adequate response to physical therapy and analgesic medications.]
• Absence or near absence (more than 50%) of the meniscus, established by imaging or prior surgery.
• Documented minimal to absent diffuse degenerative changes in the surrounding articular cartilage (e.g., Outerbridge grade II or less, < 50% joint space narrowing)
  [NOTE: The Outerbridge Classification is the most commonly used classification system to objectively assess chondral and osteochondral injuries of the knee:
  Grade 0 = normal cartilage;
  Grade I = cartilage with softening and swelling;
  Grade II = a partial-thickness defect with fissures on the surface that do not reach subchondral bone or exceed 1.5 cm in diameter;
  Grade III = fissuring to the level of subchondral bone in an area with a diameter more than 1.5 cm;
  Grade IV = exposed subchondral bone.]
• Normal knee biomechanics, or alignment and stability achieved concurrently with meniscal transplantation.
  [NOTE: Uncorrected misalignment and instability of the joint are contraindications. Therefore additional procedures, such as repair of ligaments or tendons or creation of an osteotomy for realignment of the joint, may be performed at the same time.]
• Member does not have any of the following contraindications:
  • presence of arthrofibrosis
  • significant muscle atrophy
  • synovial disease, inflammatory arthritis or infection
  • BMI >30 kg/m².

• autologous chondrocyte implantation, or
• osteochondral allografting, or
• osteochondral autografting.

4. Use of other meniscal implants incorporating materials such as collagen and polyurethane are considered investigational.


Medicare Coverage:
Per National Coverage Determination (NCD) 150.12 for Collagen Meniscus Implant, CMS has determined that Collagen Meniscus Implant is noncovered. For additional information refer to National Coverage Determination (NCD) for Collagen Meniscus Implant (150.12). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx. There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for meniscal allograft transplantation. Therefore, Medicare Advantage will follow the Horizon BCBSNJ Medical Policy for meniscal allograft transplantation CPT code 29868.

Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE-SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE:
The most recent literature update was performed through May 13, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The primary literature consists of retrospective case series and systematic reviews of these case series. Two main issues are investigated: (1) Does meniscal allograft transplantation (MAT) reduce pain and improve function? and (2) Does this procedure reduce joint degeneration?

Meniscal Allograft Transplantation

Clinical Context and Therapy Purpose

The purpose of MAT is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as partial meniscectomy without MAT, in patients who are undergoing partial meniscectomy.

The question addressed in this policy is: What is the net health outcome when meniscal allografts are used to treat patients with disabling knee pain following meniscectomy who are too young for total knee arthroplasty?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals who are undergoing partial meniscectomy.

Interventions

The therapy being considered is MAT. Meniscal allografts and other meniscal implants (eg, collagen) are intended to improve symptoms and reduce joint degeneration in patients who have had a total or partial meniscus resection.

MAT is performed by orthopedic surgeons in an inpatient clinical setting.

Comparators

Comparators of interest include partial meniscectomy without MAT.

Partial meniscectomy without MAT is performed by an orthopedic surgeon in an inpatient clinical setting.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, and QOL.

Table 1. Outcomes of Interest for Individuals Undergoing Partial Meniscectomy

Outcomes	Details	Timing
Symptoms	Outcomes of interest include pain measured using various scales and questionnaires	1-10 years
Functional outcomes	Outcomes of interest include knee function and range of motion	1-10 years

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.

Several systematic reviews of available case series have reported reductions in pain and improvements in function at mid-term follow-up, with failure rates at the time of follow-up ranging from 7% to 35% (see Table 2). Elattar et al (2011) published a large systematic review with a total of 1136 allografts.^4, Twelve different clinical scoring systems were described, which generally showed reductions in pain and improvements in function. Hergan et al (2011) conducted a systematic review of the literature to evaluate the characteristics of patients, graft survival, and clinical outcomes.^5,The analysis found that patients with Outerbridge scores of II or less in any area had significantly improved posttreatment Lysholm Knee Score (LKS) and Tegner Activity Scale (TAS) scores, whereas patients with Outerbridge grade III or more in any area (not repaired) did not. Studies that analyzed patients undergoing concomitant procedures did not detect a difference between subgroups compared with MAT alone. Functional outcomes were considered generally good where reported. Rosso et al (2015) published a systematic review evaluating 55 studies (total n=1623 patients).^6, Data from 37 studies were included in demographic and outcome analyses. Collectively, these systematic reviews, which are based primarily on level IV evidence, summarize the short- to medium-term outcomes of MAT (see Table 1).

Table 2. Summary of Key Systematic Reviews of MAT

Variables	Elattar et al (2011)4,	Herganet al (2011)5,	Rosso et al (2015)6,
No. and study type	44 cohort and case series	14 cohort and case series with minimum 2-y follow-up	55 (2 level II, 7 level III, 46 level IV)
Population	1136 knees (1068 patients)	196 knees	1623 patients
Follow-up (range)	4.6 y (8 mo to 20 y)	53.8 mo (24-167 mo)	53.6 mo (12-168 mo)
Outcome measures	Pain and function	Pain and function	Pain and function
Review synthesis
Pain and function	All showed clinical improvement	Alleviation of knee pain and improvement in function noted	Weighted pre-/postmeasuresa: •  VAS pain score decreased from 6.4 to 2.4 •  LKS increased from 55.5 to 82.7
Failure rate	10.6%	7%-35%	Fresh frozen: 9.9% Cryopreserved: 18.2%
Complication rate	21.3%		10.6%
Review conclusion	MAT improves pain and function	Improvements in objective and subjective outcome measures shown in relatively young patients without significant chondromalacia who underwent concomitant repair for cartilage defects, limb malalignment, and/or limb instability	Agreement in literature on MAT indications: •  All studies showed clinical improvement at short- and mid-term follow-ups •  Complication and failure rates acceptable •  Potential chondro-protective effect of MAT remains unclear
Review limitations	Based primarily on case series	Based primarily on case series and qualitative review only	Based primarily on case series

LKS: Lysholm Knee Score; MAT: meniscal allograft transplantation; VAS: visual analog scale.

^a Data from 37 of the 55 studies in the systematic review.

Randomized Controlled Trials

Smith et al (2018) reported on the results of a small RCT that randomized 21 patients with a symptomatic meniscal deficient knee to MAT (n=10) or personalized physical therapy (n=11).^7, Another 15 patients who were screened for the RCT decided instead to choose their treatment (referred to as preference group) received MAT (n=6) or personalized physical therapy (n=9). The Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee score, Lysholm Knee Scoring Scale score, and complications were collected at baseline, four and eight months, and one year after the interventions. Trialists reported pooled results from the RCT and preference group, with statistically significant differences in favor of MAT group for KOOS composite score (mean difference, 12; p=0.03) and KOOS subscales of pain (mean difference, 15; p=0.02) and activities of daily living (mean difference, 18; p=0.005). However, pooling data from the RCT and preference group precluded a meaningful interpretation of data.

Case Series

The characteristics and results of several case series with longer-term follow-up are provided in Tables 3 and 4. Verdonk et al (2005) published a large case series with long-term follow-up from 95% of their first 105 fresh cultured (viable) meniscal allografts.^8, The indication for transplantation was moderate-to-severe pain in patients who had undergone previous total meniscectomy, not old enough to be considered for a knee joint replacement, and with good alignment of the lower limb and a stable joint (some were corrected concomitantly). In the study by Hommen et al (2007), concomitant procedures were performed in 75% of the patients, including anterior cruciate ligament reconstruction or revision (n=10), high tibial osteotomy (n=2), and lateral retinaculum release (n=3).^9,

At a mean follow-up of 16 years, van der Wal et al (2009)^10, reported graft survival decreased to 52.5%, while most failures in the study by Vundelinckx et al (2010)^11, occurred approximately 10 years postoperatively. That said, at an average of 105 months of follow-up, the 34 remaining patients assessed in the Vundelinckx et al (2010) study showed significant reductions in pain and improvements in function relative to preoperative levels. Radiographic evidence reported by van der Wal et al (2009) also showed a slight or moderate increase in osteoarthritis in 42% of patients (1 or 2 points) and no increase in the other 58%. Of 15 patients with follow-up radiographs in the Hommen et al (2007) study, 10 (67%) had joint space narrowing, and 12 (80%) had a progression of the Fairbank degenerative joint disease score in the transplanted tibiofemoral compartment.

Table 3. Summary of Key Case Series Characteristics for MAT

Variables	Verdonk et al (2005)8,	Van der Wal et al (2009)10,	Vundelinckxet al (2010)11,
Sample size	105	57	34/49
Mean age (range), y	35 (16-50)	39 (26-55)	33 (14-47)
Population	Previous total meniscectomy	Previous total meniscectomy	Patients with intact allograft
Intervention	MAT	MAT	MAT
Control	None	None	None
Length of FU (range)	3-15 y	14 y (9-18 y)	105 mo

FU: follow-up; MAT: meniscal allograft transplantation.

Table 4. Summary of Key Case Series Outcomes for Meniscal Allograft Transplantation

Outcomes	Verdonk et al (2005)8,			Van der Wal et al (2009)10,			Vundelinckx et al (2010)11,
	Base	FU	p	Base	FU	p	Base	FU	p
VAS score							7.0	3.4	<0.001
LKS score				36	61	<0.05	39.7	71.8	<0.001
KOOS score							35.8	60.2	<0.001
Graft survival rate		70%			•  11 y: 71% •  16 y: 52.5%			90%
Mean survival		11.6 y

Base: baseline; FU: follow-up; KOOS: Knee Injury and Osteoarthritis Outcome Score; LKS: Lysholm Knee Score; VAS: visual analog scale.

Section Summary: MAT

Evidence for the use of MAT in patients with disabling knee pain and a prior meniscectomy consists of systematic reviews of a large number of case series and an RCT. The reviews have found that MAT is associated with reductions in pain and improvements in function. Longer-term studies have indicated that these improvements are maintained in a substantial percentage of patients, up to ten years and beyond. Because the results of a single RCT, which enrolled a very small number of patients, pooled data from randomized and nonrandomized groups, results cannot be interpreted in a meaningful way. Adverse events, such as graft failure and the need for additional procedures, occur frequently. The strength of the evidence, including accurate estimates of the magnitude of benefit and the complication rates, are limited by the type of data available (case series and systematic reviews of these case series) as well as the heterogeneity in surgical techniques and patient characteristics across the studies.

MAT Plus Articular Cartilage Repair

Clinical Context and Therapy Purpose

The purpose of MAT is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as partial meniscectomy without MAT, in patients who are undergoing partial meniscectomy and repair of malalignment, focal chondral defects and/or ligamentous insufficiency.

The question addressed in this policy is: What is the net health outcome when meniscal allografts are used to treat patients with disabling knee pain following meniscectomy who are too young for total knee arthroplasty?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals who are undergoing partial meniscectomy and repair of malalignment, focal chondral defects and/or ligamentous insufficiency.

Interventions

The therapy being considered is MAT.

Comparators

Comparators of interest include partial meniscectomy without MAT.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, and QOL.

Patients with malalignment, focal chondral defects, and/or ligamentous insufficiency may require additional surgery combined with MAT. When MAT is combined with osteotomy or articular cartilage repair in a single procedure, MAT should be performed first.

The evidence available for the efficacy of MAT in knees with chondral damage consists of one prospective comparative study, case series, most of which are retrospective, and systematic reviews of case series.

Systematic Reviews

Harris et al (2011) published a systematic review of MAT plus cartilage repair or restoration (see Table 5).^12, Patients underwent MAT with autologous chondrocyte implantation (n=73), osteochondral allograft (n=20), osteochondral autograft (n=17), or microfracture (n=3). All studies showed improvement in clinical outcomes at final follow-up compared with the preoperative condition. Outcomes were similar to historical outcomes, extracted from mid-term and long-term follow-up studies, of procedures performed in isolation. Additional surgeries are common (nearly 50%) after MAT plus cartilage repair or restoration procedures.

Table 5. Summary of Key Systematic Reviews

Variables	Harris et al (2011)12,
No. and study type	6 case series
Population	110
Intervention	MAT combined with cartilage repair or restoration
Control	•  Baseline to posttreatment •  Historical controls of procedures performed in isolation
Outcome measures	Pain and function
Review synthesis	•  Outcomes improved from baseline to posttreatment •  4/6 studies found outcomes equivalent to procedures performed in isolation •  2/6 studies found combined surgery not as good as historical controls
Review conclusion	MAT can improve pain and function when combined with cartilage repair or restoration procedures
Review limitations	Based on case series with historical controls

MAT: meniscal allograft transplantation.

The largest and longest study to report on MAT in patients with significant (grade III and IV) chondral damage is that by Stone et al (2010) who reported mean allograft survival of 9.9 years (see Table 5).^13, Other prospective studies have reported on graft survival and functional outcomes when MAT has been combined with articular cartilage repair.^14,15,

Case Series

The following studies were published subsequent to the systematic review (see Table 6). Kempshall et al (2015) looked at MAT concomitant with cartilage repair procedures on (1) patients with more knee cartilage damage (grade 3b >1 cm² ) and (2) patients with less knee cartilage damage (grade 3b <1 cm²).^16, Functional outcomes following the procedures were similar between the two groups. However, implant survival (using graft failure as an endpoint) was lower among those with greater cartilage damage.

Ogura et al (2016) retrospectively reviewed patients who had undergone autologous chondrocyte implantation and MAT.^17, Seventeen patients were followed for a mean of 7.9 years. Significant improvements in clinical outcomes (visual analog scale for pain, Western Ontario and McMaster Universities Arthritis Index, 36-Item Short-Form Health Survey, and modified Cincinnati Knee Rating Scale scores) were reported in 65% of the patients. Of the six procedures considered failures, four underwent TKA and two underwent revision surgery.

Zaffagnini et al (2016) reviewed 147 patients undergoing arthroscopic bone plug-free MAT, with 48% of patients having concomitant procedures (mostly high tibial osteotomy and anterior cruciate ligament reconstruction).^18, Two survival analyses were conducted, one with the endpoint of surgical failure (need for revision procedures related to initial MAT) and the other with the endpoint of clinical failure (same revision procedures as a surgical failure or LKS less than 65 at final follow-up). Mean overall survival time with the surgical failure endpoint was 9.7 years (95% confidence interval, 9.1 to 10.3 years) and mean overall survival with the clinical failure endpoint was 8.0 years (95% confidence interval, 7.1 to 8.8 years). Logistic regression analysis did not reveal any variables (including concomitant procedures) affecting the surgical or clinical failure endpoints.

Table 6. Series of MAT with Articular Cartilage Repair

Variables	Stone et al (2010)13,	Kempshall et al (2015)16,	Ogura et al (2016)17,	Zaffagnini et al (2016)18,
Sample size	115	99	17	147
Population	Consecutive patients with grade III-IV chondral damage	Prospective series •   Grade 3b <1 cm2 •   Grade 3b >1 cm2	Retrospective series	Retrospective series
Intervention	MAT	MACI and microfracture more common if chondral damage was 3c >1 cm2	ACI with MAT	MAT
Control	None	None	None	None
Outcome measures	MAT survival	•   MAT survival •   KOOS, TAS, LKS, IKDC scores	•   MAT survival •   MCKRS, WOMAC, VAS, SF-36	•   MAT survival •   KOOS, LKS, VAS
Length of FU	5.8 y	2 y	5-10 y	4 y
Results	•   Mean MAT survival, 9.9 y •    47% required additional surgery	•   Similar outcomes on KOOS, TAS, LKS, IKDC scores for 2 groups •   MAT survival 97.9% if 3b <1 cm2 and 78% if 3c >1 cm2	•   Mean MAT survival rate, 75% at 5- and 10-y follow-up •   67% (12/18) required additional surgery	•   Mean MAT survival range, 8-9.7 y •   17% required additional surgery

ACI: autologous chondrocyte implantation; FU: follow-up; IKDC: International Knee Documentation Committee; KOOS: Knee Injury and Osteoarthritis Outcome Score; LSK: Lysholm Knee Score; MACI: matrix-assisted autologous chondrocyte implantation; MAT: meniscal allograft transplantation; MCKRS: modified Cincinnati Knee Rating Scale; SF-36: 36-Item Short-Form Health Survey; TAS: Tegner Activity Scale; VAS: visual analog scale; WOMAC: Western Ontario and McMaster Universities Arthritis Index.

Section Summary: MAT Plus Articular Cartilage Repair

There is a limited amount of low-quality evidence on combined MAT and articular cartilage repair. The available literature has reported reductions in pain and improvements in functioning following these procedures, though studies have reported graft failures and the need for additional surgeries.

Collagen Meniscus Implants

Clinical Context and Therapy Purpose

The purpose of CMIs is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as partial meniscectomy without a meniscal implant, in patients with who are undergoing partial meniscectomy.

The question addressed in this policy is: What is the net health outcome when meniscal allografts are used to treat patients with disabling knee pain following meniscectomy who are too young for total knee arthroplasty?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals who are undergoing partial meniscectomy.

Interventions

The therapy being considered is CMIs .

CMIs are performed by an orthopedic surgeon in an inpatient clinical setting.

Comparators

Comparators of interest include partial meniscectomy without a meniscal implant.

Partial meniscectomy without a meniscal implant is performed by an orthopedic surgeon in an inpatient clinical setting.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, and QOL.

ACMI is sutured into place on a meniscal rim and is intended for use with a partial meniscectomy. Therefore, the literature search focused on controlled trials comparing health outcomes for CMI with partial meniscectomy alone. The literature to date consists of case series, a large RCT sponsored by a CMI manufacturer, a smaller RCT from Germany, and a small prospective comparative cohort study.

Systematic Reviews

Two systematic reviews, one by Harston et al (2012)^19, and the other by Warth et al (2015),^20,are summarized in Table 7. A third, by Zaffagnini et al (2015),^21, focused only on studies assessing postoperative magnetic resonance imaging evaluations, which included 6 studies, none of which was an RCT and all of which were included in the Warth et al (2015) review. We do not discuss the Zaffagnini et al (2015) review further. Houck et al (2018) published the results of a systematic review that included multiple scaffold implantations including CMI.^22, No studies in addition to those previously summarized by Warth et al (2015)^20,were cited in this systematic review and Houck et al (2018)are not discussed further.

Table 7. Summary of Key Systematic Reviews for CMI

Variables	Harston et al (2012)19,	Warth et al (2015)20,
Search date	May 2011	March 2014
No. of studies	11	13
Population	520	674
Intervention	•  321 patients received a CMI •  41.1% patients had concomitant procedures	•  439 patients received CMI •  32.3% patients had concomitant procedures
Control	Partial meniscectomy alone
Outcome measures	•  LKS, TAS, pain scales •  8/11 studies provided postoperative imaging data	•  LKS, TAS, pain scales •  11/13 studies provided postoperative imaging data
Length of FU	6-135 mo	3-152 mo
Review synthesis	•  66%-70% patients receiving CMI had satisfactory outcomes •  Outcomes in studies with control or comparison groups reported improvements in both groups •  Reduced CMI size at last follow-up reported in 6 (54.5%) of 11 studies	•  CMI showed superior clinical outcomes vs partial meniscectomy alone •  Several studies reported that meniscus scaffold decreased in volume over time •  Second-look arthroscopy showed presence of newly formed meniscus-like tissue in area of the scaffold
Review limitations	•  Based on low-quality evidence	•  Mostly level IV evidence •  No meta-analysis due to differing methodologies and data reporting across studies

CMI: collagen meniscus implant; FU: follow-up; LSK: Lysholm Knee Score; TAS: Tegner Activity Scale.

The quality of the studies included in the systematic reviews was generally rated as low. Tables 7 and 8 summarize select studies (two RCTs, two cohorts) included in the systematic reviews. A large RCT from the manufacturers of MenaFlex (Rodkey et al [2008]^23,) was conducted under a Food and Drug Administration investigational device exemption. Only TAS scores in the chronic arm (but not the acute arm) differed significantly between the CMI and partial meniscectomy only groups. Kaplan-Meier analysis suggested a modest 10% increase in survival in the chronic CMI group.

Randomized Controlled Trials

An independent research group published results from an RCT, reported by Linke et al (2006), comparing high tibial valgus osteotomy alone with osteotomy plus CMI.^24, Arthroscopy in the CMI group showed 35% complete healing, 30% partial healing requiring resection of the posterior part of the implant, and 35% with only small remains of the CMI left. Complications included implantation in insufficiently vascularized tissue, sutures cutting into the implant, inadequate fixation to the rim, destruction of the implant in an unstable knee joint or with premature loading postoperatively, allergic reaction to the xenogenic collagen implant, avulsion of the implant with joint blocking, and infection. Pain and function scores did not differ significantly between the CMI and control groups.

Observational Studies

Zaffagnini et al (2011) compared outcomes of 18 patients who chose CMI with 18 patients who chose partial medial meniscectomy, with a minimum 10-year follow-up.^25, The two groups were comparable at baseline. No significant differences were found in the LKS and Yulish scores. Independent and blinded radiographic evaluation showed significantly less medial joint space narrowing in the CMI group (0.48 mm) than in the partial meniscectomy group (2.13 mm). This study had the potential for selection bias.

A retrospective review by Bulgheroni et al (2015) of 34 patients (17 CMI, 17 partial medial meniscectomies) found no significant differences between the groups for pain and function scores at an average of 9.6 years of follow-up.^26,

Table 8. Summary of Key Study Characteristics for CMI

Variables	Rodkey et al (2008)23,	Linke et al (2006)24,	Zaffagnini et al (2011)25,	Bulgheroni et al 2015)26,
Study design	RCT	RCT	Controlled cohort	Retrospective cohorts
Sample size	311	60	36	34
Population	Acute and chronic partial meniscectomy		Patient choice	Matched controls
Intervention	CMI	Osteotomy plus CMI	CMI	CMI
Control	Partial meniscectomy alone	Osteotomy alone	Partial meniscectomy alone	Partial meniscectomy alone
Length of FU (range)	59 mo (16-92 mo)	8-18 mo	133 mo (120-152 mo)	9.6 y

CMI: collagen meniscus implant; FU: follow-up; RCT: randomized controlled trial.

Table 9. Summary of Key Study Results for CMI

Outcomes

Rodkey et al (2008)23,

Linke et al  (2006)24,

Zaffagnini et al  (2011)25,

Bulgheroni et al  (2015)26,

CMI

Ctrl

p

CMI

Ctrl

p

CMI

Ctrl

p

CMI

Ctrl

p

Survival rate

90%a

80% a

65%

89%

VAS pain

19/100a

21/100a

2.2/10

1.5/10

NS

1.2/10

3.3/10

<0.004

14.7/100

13.5/100

NS

LKS score

79a

78a

NS

93.6

91.0

NS

»86

»80

NS

94.1

95.5

NS

IKDC score

NS

<0.001b

85.7

88.1

NS

TAS score

42%a

29%a

<0.02

75

50

<0.026

6 5-6

6 5-6

NS

CMI: collagen meniscus implant; Ctrl: control; IKDC: International Knee Documentation Committee; LSK: Lysholm Knee Score; TAS: Tegner Activity Scale; VAS: visual analog scale.

^a Chronic only.

^b Higher scores reported by CMI group vs control group.

Section Summary: CMI

Evidence for the use of CMI in patients undergoing partial meniscectomies consists of 2 systematic reviews, the most recent including 674 patients. The reviews reported overall positive results with CMI, but the quality of the included studies (RCTs and observational studies) was low. Radiologic evaluation showed destruction and/or absorption of the implant in a very large portion of patients.

Summary of Evidence

For individuals who are undergoing partial meniscectomy who receive MAT, the evidence includes systematic reviews of mostly case series and an RCT. The relevant outcomes are symptoms, functional outcomes, and QOL. The systematic reviews concluded that most studies have shown statistically significant improvements in pain and function following the procedure. The benefits have also been shown to have a long-term effect (>10 years). Reviews have also reported acceptable complication and failure rates. There remains no evidence that MAT can delay or prevent the development of knee osteoarthritis. A limitation of the evidence is its reliance primarily on case series. Because of the single RCT, which enrolled a very small number of patients, pooled data from randomized and nonrandomized groups, results cannot be interpreted in a meaningful way. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are undergoing partial meniscectomy and concomitant repair of malalignment, focal chondral defects, and/or ligamentous insufficiency who receive MAT, the evidence includes a systematic review of case series as well as case series published after the systematic review. The relevant outcomes are symptoms, functional outcomes, and QOL. The systematic review concluded that pain and function improved following the procedure. One of the series published after the review showed that patients with more severe cartilage damage experienced favorable outcomes similar to patients with less cartilage damage. Another series published subsequently reported an overall 9.7-year survival of the implant. A limitation of the evidence is its reliance primarily on case series. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are undergoing partial meniscectomy who receive CMIs , the evidence includes two systematic reviews primarily of case series. The relevant outcomes are symptoms, functional outcomes, and QOL. The reviews reported overall positive results with the CMI, but the quality of the selected studies (RCTs, observational studies) was low. Radiologic evaluations have shown reductions in the size of the implant in a large portion of patients. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2011 Input

In response to requests, input was received from 1 physician specialty society (3 reviewers) and 3 academic medical centers while this policy was under review in 2011. Input considered combined meniscal allograft transplantation (MAT) and focal cartilage repair procedures to be medically necessary for patients younger than 55 years of age who have failed conservative treatment. Reviewers agreed that the collagen meniscus implant is investigational, although some considered it to be both investigational and medically necessary for some patients.

2008 Input

In response to requests, input was received from 1 physician specialty society and 3 academic medical centers while this policy was under review in 2008. Although long-term effects on joint space narrowing were unknown, all reviewers considered MAT to be beneficial in selected patients, with evidence of short to intermediate pain relief when performed in younger patients who had a prior meniscectomy and disabling knee pain. Contraindications noted were uncorrected instability, uncorrected malalignment, and the presence of significant articular disease.

Practice Guidelines and Position Statements

International Meniscus Reconstruction Experts Forum

The International Meniscus Reconstruction Experts Forum (2015) published consensus statements on the practice of MAT (see Table 10).^2, The Forum's statements included guidance on indications, graft procurement and preparation, surgical technique, and rehabilitation.

Table 10. Select Consensus Statements on the Practice of MAT

Statements

Indications for MAT: Unicompartmental pain post-meniscectomy In combination with anterior cruciate ligament reconstruction when meniscus deficient In combination with articular cartilage repair if meniscus deficient

MAT not recommended for asymptomatic meniscus deficient patient.

Potentially poorer outcomes expected in patients with moderate to severe OA (Kellgren-Lawrence grade ≥3).

Non-irradiated fresh frozen or fresh viable grafts are recommended.

Mechanical axis alignment should be performed prior to MAT; if mechanical axis deviation present, consider realignment osteotomy.

Based on current evidence, the superiority of 1 surgical technique over another (all-suture vs bone) is not established.

Outcome scores should include: Disease-specific: Western Ontario Meniscal Evaluation Tool Region-specific: Knee injury and Osteoarthritis Outcome Score Activity: Marx Activity Rating Scale Quality of life/utility: EuroQoL 5 dimensions questionnaire

MAT: meniscal allograft transplantation; OA: osteoarthritis.

National Institute for Health and Care Excellence

The guidance from the National Institute for Health and Care Excellence (2012) stated that the evidence on "partial replacement of the meniscus of the knee using a biodegradable scaffold raises no major safety concerns," but evidence for any advantage of the procedure over standard surgery was limited.^27,

American Academy of Orthopaedic Surgeons

The American Academy of Orthopaedic Surgeons (2009) updated its position in 2014, still recommending MAT for active people younger than 55 years old, with the goal of replacing the meniscus cushion before the articular cartilage is damaged.^28, The website also notes that "synthetic (artificial) meniscal tissue has been tried, but there is conflicting information at this time."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Currently, ongoing and unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01712191a	Treatment of the Medial Meniscus with the Treatment of the Medial Meniscus with the NUSurface® Meniscus Implant	150	Mar 2016 (completed)
NCT02136901a	The VENUS Clinical Study (Verifying the Effectiveness of the NUSurface® System): A Multi-center, Prospective, Randomized, Interventional Superiority Clinical Study	37	Jun 2020

NCT: national clinical trial.

^a Denotes industry-sponsored or cosponsored trial.]

2. Getgood A, LaPrade RF, Verdonk P, et al. International Meniscus Reconstruction Experts Forum (IMREF) 2015 Consensus Statement on the Practice of Meniscal Allograft Transplantation. Am J Sports Med. May 2017; 45(5): 1195-1205. PMID 27562342

3. Frank RM, Cole BJ. Meniscus transplantation. Curr Rev Musculoskelet Med. Dec 2015; 8(4): 443-50. PMID 26431702

4. Elattar M, Dhollander A, Verdonk R, et al. Twenty-six years of meniscal allograft transplantation: is it still experimental? A meta-analysis of 44 trials. Knee Surg Sports Traumatol Arthrosc. Feb 2011; 19(2): 147-57. PMID 21161170

5. Hergan D, Thut D, Sherman O, et al. Meniscal allograft transplantation. Arthroscopy. Jan 2011; 27(1): 101-12. PMID 20884166

6. Rosso F, Bisicchia S, Bonasia DE, et al. Meniscal allograft transplantation: a systematic review. Am J Sports Med. Apr 2015; 43(4): 998-1007. PMID 24928760

7. Smith NA, Parsons N, Wright D, et al. A pilot randomized trial of meniscal allograft transplantation versus personalized physiotherapy for patients with a symptomatic meniscal deficient knee compartment. Bone Joint J. Jan 2018; 100-B(1): 56-63. PMID 29305451

8. Verdonk PC, Demurie A, Almqvist KF, et al. Transplantation of viable meniscal allograft. Survivorship analysis and clinical outcome of one hundred cases. J Bone Joint Surg Am. Apr 2005; 87(4): 715-24. PMID 15805198

9. Hommen JP, Applegate GR, Del Pizzo W. Meniscus allograft transplantation: ten-year results of cryopreserved allografts. Arthroscopy. Apr 2007; 23(4): 388-93. PMID 17418331

10. van der Wal RJ, Thomassen BJ, van Arkel ER. Long-term clinical outcome of open meniscal allograft transplantation. Am J Sports Med. Nov 2009; 37(11): 2134-9. PMID 19542303

11. Vundelinckx B, Bellemans J, Vanlauwe J. Arthroscopically assisted meniscal allograft transplantation in the knee: a medium-term subjective, clinical, and radiographical outcome evaluation. Am J Sports Med. Nov 2010; 38(11): 2240-7. PMID 20724642

12. Harris JD, Cavo M, Brophy R, et al. Biological knee reconstruction: a systematic review of combined meniscal allograft transplantation and cartilage repair or restoration. Arthroscopy. Mar 2011; 27(3): 409-18. PMID 21030203

13. Stone KR, Adelson WS, Pelsis JR, et al. Long-term survival of concurrent meniscus allograft transplantation and repair of the articular cartilage: a prospective two- to 12-year follow-up report. J Bone Joint Surg Br. Jul 2010; 92(7): 941-8. PMID 20595111

14. Farr J, Rawal A, Marberry KM. Concomitant meniscal allograft transplantation and autologous chondrocyte implantation: minimum 2-year follow-up. Am J Sports Med. Sep 2007; 35(9): 1459-66. PMID 17435058

15. Rue JP, Yanke AB, Busam ML, et al. Prospective evaluation of concurrent meniscus transplantation and articular cartilage repair: minimum 2-year follow-up. Am J Sports Med. Sep 2008; 36(9): 1770-8. PMID 18483199

16. Kempshall PJ, Parkinson B, Thomas M, et al. Outcome of meniscal allograft transplantation related to articular cartilage status: advanced chondral damage should not be a contraindication. Knee Surg Sports Traumatol Arthrosc. Jan 2015; 23(1): 280-9. PMID 25432522

17. Ogura T, Bryant T, Minas T. Biological Knee Reconstruction With Concomitant Autologous Chondrocyte Implantation and Meniscal Allograft Transplantation: Mid- to Long-term Outcomes. Orthop J Sports Med. Oct 2016; 4(10): 2325967116668490. PMID 27803938

18. Zaffagnini S, Grassi A, Marcheggiani Muccioli GM, et al. Survivorship and clinical outcomes of 147 consecutive isolated or combined arthroscopic bone plug free meniscal allograft transplantation. Knee Surg Sports Traumatol Arthrosc. May 2016; 24(5): 1432-9. PMID 26860105

19. Harston A, Nyland J, Brand E, et al. Collagen meniscus implantation: a systematic review including rehabilitation and return to sports activity. Knee Surg Sports Traumatol Arthrosc. Jan 2012; 20(1): 135-46. PMID 21695465

20. Warth RJ, Rodkey WG. Resorbable collagen scaffolds for the treatment of meniscus defects: a systematic review. Arthroscopy. May 2015; 31(5): 927-41. PMID 25595693

21. Zaffagnini S, Grassi A, Marcheggiani Muccioli GM, et al. MRI evaluation of a collagen meniscus implant: a systematic review. Knee Surg Sports Traumatol Arthrosc. Nov 2015; 23(11): 3228-37. PMID 24993568

22. Houck DA, Kraeutler MJ, Belk JW, et al. Similar clinical outcomes following collagen or polyurethane meniscal scaffold implantation: a systematic review. Knee Surg Sports Traumatol Arthrosc. Aug 2018; 26(8): 2259-2269. PMID 29340746

23. Rodkey WG, DeHaven KE, Montgomery WH, et al. Comparison of the collagen meniscus implant with partial meniscectomy. A prospective randomized trial. J Bone Joint Surg Am. Jul 2008; 90(7): 1413-26. PMID 18594088

24. Linke RD, Ulmer M, Imhoff AB. [Replacement of the meniscus with a collagen implant (CMI)]. Oper Orthop Traumatol. Dec 2006; 18(5-6): 453-62. PMID 17171330

25. Zaffagnini S, Marcheggiani Muccioli GM, Lopomo N, et al. Prospective long-term outcomes of the medial collagen meniscus implant versus partial medial meniscectomy: a minimum 10-year follow-up study. Am J Sports Med. May 2011; 39(5): 977-85. PMID 21297005

26. Bulgheroni E, Grassi A, Bulgheroni P, et al. Long-term outcomes of medial CMI implant versus partial medial meniscectomy in patients with concomitant ACL reconstruction. Knee Surg Sports Traumatol Arthrosc. Nov 2015; 23(11): 3221-7. PMID 24990662

27. National Institute for Health and Care Excellence (NICE). Partial replacement of the meniscus of the knee using a biodegradable scaffold: guidance [IPG430]. 2012; https://www.nice.org.uk/guidance/IPG430. Accessed May 2020.

28. American Academy of Orthopaedic Surgeons. OrthoInfo: Meniscal transplant surgery. 2014; https://orthoinfo.aaos.org/en/treatment/meniscal-transplant-surgery/. Accessed March 16, 2018.

29. Centers for Medicare and Medicaid Services (CMS). Decision Memo for COLLAGEN MENISCUS IMPLANT (CAG-00414N). 2010; https://www.cms.gov/medicare-coverage-database/details/nca-decision- memo.aspx?NCAId=235&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=All&KeyWord=Collage n+Meniscus+Implant&KeyWordLookUp=Title&KeyWordSearchType=And&id=235&bc=gAAAACAACAAAAA%3d %3d&. Accessed March 16, 2018.

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