| Coverage Policy Manual | |
| Policy #: | 1997014 |
| Category: | Surgery |
| Initiated: | February 1996 |
| Last Review: | May 2023 |
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| Autologous Chondrocyte Implantation for Focal Articular Cartilage Lesions | |
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| Description: |
A variety of procedures are being developed to resurface articular cartilage defects. Autologous chondrocyte implantation involves harvesting chondrocytes from healthy tissue, expanding the cells in vitro, and implanting the expanded cells into the chondral defect. Second- and third-generation techniques include combinations of autologous chondrocytes, scaffolds, and growth factors.
ARTICULAR CARTILAGE LESIONS
Damaged articular cartilage typically fails to heal on its own and can be associated with pain, loss of function, and disability and may lead to debilitating osteoarthritis over time (Makris, 2015). These manifestations can severely impair a patient’s activities of daily living and adversely affect quality of life.
Treatment
Conventional treatment options include débridement, subchondral drilling, microfracture, and abrasion arthroplasty (Simon, 2018). Débridement involves the removal of synovial membrane, osteophytes, loose articular debris, and diseased cartilage and is capable of producing symptomatic relief. Subchondral drilling, microfracture, and abrasion arthroplasty attempt to restore the articular surface by inducing the growth of fibrocartilage into the chondral defect. Compared with the original hyaline cartilage, fibrocartilage has less capability to withstand shock or shearing force and can degenerate over time, often resulting in the return of clinical symptoms. Osteochondral grafts and autologous chondrocyte implantation (ACI) attempt to regenerate hyaline-like cartilage and thereby restore durable function. Osteochondral grafts for the treatment of articular cartilage defects are discussed in Policy 1998142.
With ACI, a region of healthy articular cartilage is identified and biopsied through arthroscopy. The tissue is sent to a facility licensed by the U.S. Food and Drug Administration (FDA) where it is minced and enzymatically digested, and the chondrocytes are separated by filtration. The isolated chondrocytes are cultured for 11 to 21 days to expand the cell population, tested, and then shipped back for implantation. With the patient under general anesthesia, an arthrotomy is performed, and the chondral lesion is excised up to the normal surrounding cartilage. Methods to improve the first-generation ACI procedure have been developed, including the use of a scaffold or matrix-induced autologous chondrocyte implantation (MACI) composed of biocompatible carbohydrates, protein polymers, or synthetics. The only FDA-approved MACI product to date is supplied in a sheet, which is cut to size and fixed with fibrin glue. This procedure is considered technically easier and less time consuming than the first-generation technique, which required suturing of a periosteal or collagen patch and injection of chondrocytes under the patch.
Desired features of articular cartilage repair procedures are the ability (1) to be implanted easily, (2) to reduce surgical morbidity, (3) not to require harvesting of other tissues, (4) to enhance cell proliferation and maturation, (5) to maintain the phenotype, and (6) to integrate with the surrounding articular tissue. In addition to the potential to improve the formation and distribution of hyaline cartilage, use of a scaffold with MACI eliminates the need for harvesting and suture of a periosteal or collagen patch. A scaffold without cells may also support chondrocyte growth.
REGULATORY STATUS
The culturing of chondrocytes is considered by the U.S. Food and Drug Administration (FDA) to fall into the category of manipulated autologous structural cells, which are subject to a biologic licensing requirement. In 1997, Carticel® (Genzyme; now Vericel) received FDA approval for the repair of clinically significant, “...symptomatic cartilaginous defects of the femoral condyle (medial lateral or trochlear) caused by acute or repetitive trauma.…”
In December 2016, MACI® (Vericel) received FDA approval for “the repair of symptomatic, single or multiple full-thickness cartilage defects of the knee with or without bone involvement in adults” (FDA, 2021). MACI® consists of autologous chondrocytes which are cultured onto a bioresorbable porcine-derived collagen membrane. In 2017, production of Carticel was phased out and MACI® is the only ACI product that is available in the United States.
A number of other second-generation methods for implanting autologous chondrocytes in a biodegradable matrix are currently in development or testing or are available outside of the United States. They include Atelocollagen (Koken), a collagen gel; Bioseed® C (BioTissue Technologies), a polymer scaffold; CaReS (Ars Arthro), collagen gel; Cartilix (Biomet), a polymer hydrogel; Chondron (Sewon Cellontech), a fibrin gel; Hyalograft C (Fidia Advanced Polymers), a hyaluronic acid-based scaffold; NeoCart (Histogenics), an autologous chondrocyte implantation (ACI) with a 3-dimensional chondromatrix in a phase 3 trial; and Novocart®3D (Aesculap Biologics), a collagen-chondroitin sulfate scaffold in a phase 3 trial. ChondroCelect® (TiGenix), a characterized chondrocyte implantation with a completed phase 3 trial, uses a gene marker profile to determine in vivo cartilage-forming potential and thereby optimizes the phenotype (e.g., hyaline cartilage vs fibrocartilage) of the tissue produced with each ACI cell batch. Each batch of chondrocytes is graded based on the quantitative gene expression of a selection of positive and negative markers for hyaline cartilage formation. Both Hyalograft C and ChondroCelect have been withdrawn from the market in Europe. In 2020, the FDA granted breakthrough status to Agili-C (CartiHeal, Ltd.), a proprietary biocompatible and biodegradable tapered-shape implant for the treatment of cartilage lesions in arthritic and non-arthritic joints that, when implanted into a pre-prepared osteochondral hole, acts as a 3-dimensional scaffold that potentially supports and promotes the regeneration of the articular cartilage and its underlying subchondral bone. Agili-C was FDA-approved in 2021 for treatment of knee-joint surface lesions with a treatable area of 1 to 7 cm2 without severe osteoarthritis (FDA, 2022).
Coding
There is a specific CPT category I code for ACI of the knee:
27412: Autologous chondrocyte implantation, knee.
Arthroscopic harvesting of chondrocytes from the knee is reported using CPT code 29870. There is a HCPCS code for the autologous cultured chondrocyte implant - J7330.
Related policies:
1998142 Osteochondral Autograft Transfer (OATS) and/or Mosaicplasty for Osteochondral Defects of the Knee
2006006 Osteochondral Allograft and/or Mosaicplasty for Osteochondral Defects of the Knee
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Policy/ Coverage: |
Effective November 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of disabling full-thickness articular cartilage defects of the knee (limited to patella, femoral condyles and trochlea) caused by acute or repetitive trauma, when ALL of the following criteria are met:
Note: This service is limited to 1 matrix/membrane (unit) per knee per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes
For member benefit contracts without primary coverage criteria, autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Simultaneous bilateral or repeat autologous chondrocyte implantation for defects of the knee in any circumstance does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, simultaneous bilateral or repeat autologous chondrocyte implantation for defects of the knee in any circumstance is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective June 2021 through October 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of disabling full-thickness articular cartilage defects of the knee (limited to patella, femoral condyles and trochlea) caused by acute or repetitive trauma, when ALL of the following criteria are met:
Note: This service is limited to 1 matrix/membrane (unit) per knee per lifetime.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes
For member benefit contracts without primary coverage criteria, autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Simultaneous bilateral or repeat autologous chondrocyte implantation for defects of the knee in any circumstance does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, simultaneous bilateral or repeat autologous chondrocyte implantation for defects of the knee in any circumstance is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective September 2018 through May 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation meet member benefit certificate primary coverage criteria for the treatment of disabling full-thickness articular cartilage defects of the knee (limited to patella, femoral condyles and trochlea) caused by acute or repetitive trauma, when all of the following criteria are met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes
For member benefit contracts without Primary Coverage Criteria, autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Simultaneous bilateral or repeat autologous chondrocyte implantation for defects of the knee in any circumstance does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, simultaneous bilateral or repeat autologous chondrocyte implantation for defects of the knee in any circumstance is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to September 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation meet member benefit certificate primary coverage criteria for the treatment of disabling full-thickness articular cartilage defects of the knee (including patella, femoral condyles and trochlea) caused by acute or repetitive trauma, when all of the following criteria are met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes
For member benefit contracts without Primary Coverage Criteria, autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Simultaneous bilateral or repeat autologous chondrocyte implantation for defects of the knee in any circumstance does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, simultaneous bilateral or repeat autologous chondrocyte implantation for defects of the knee in any circumstance is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective July 2017- January 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation meet member benefit certificate primary coverage criteria for the treatment of disabling full-thickness articular cartilage defects of the knee (including patella, femoral condyles and trochlea) caused by acute or repetitive trauma, when all of the following criteria are met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes
For member benefit contracts without Primary Coverage Criteria, autologous chondrocyte implantation for all other joints, including talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Effective July 2013 – June 2017
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Autologous Chondrocyte Implantation (AC I) is indicated for the repair of symptomatic, cartilaginous defects of the femoral condyle caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior surgical procedure when the following criteria are met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Autologous Chondrocyte Implantation (ACI) for all other joints, including patellar and talar, and any indications other than those listed above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes. ACI for patella was studied in a single, observational clinical trial which did not show improved outcomes. ACI for ankle joints is under study in NCT01050816; ACI for hip joints is under study in NCT01500811; ACI for patellofemoral joint is under study in NCT00212849.
For member benefit contracts without Primary Coverage Criteria, Autologous Chondrocyte Implantation for all other joints, including patellar and talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Matrix-induced autologous chondrocyte implantation (MACI) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. MACI is under study in NCT01458782 and NCT007179561.
For contracts without primary coverage criteria, matrix-induced autologous chondrocyte implantation is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.
Effective July 2011- June 2013
Autologous Chondrocyte Implantation (AC I) is indicated for the repair of symptomatic, cartilaginous defects of the femoral condyle caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior surgical procedure when the following criteria are met:
Carticel should only be used in conjunction with debridement, placement of a periosteal flap and rehabilitation.
Autologous Chondrocyte Implantation (ACI) for all other joints, including patellar and talar, and any indications other than those listed above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes. ACI for patella was studied in a single, observational clinical trial which did not show improved outcomes. ACI for ankle joints is under study in NCT01050816; ACI for hip joints is under study in NCT01500811; ACI for patellofemoral joint is under study in NCT00212849.
For member benefit contracts without Primary Coverage Criteria, Autologous Chondrocyte Implantation for all other joints, including patellar and talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Matrix-induced autologous chondrocyte implantation (MACI) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. MACI is under study in NCT01458782 and NCT007179561.
For contracts without primary coverage criteria, matrix-induced autologous chondrocyte implantation is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.
Treatment of focal articular cartilage lesions with autologous minced cartilage or allogeneic minced cartilage or cartilage cells does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, treatment of focal articular cartilage lesions with autologous minced cartilage or allogeneic minced cartilage or cartilage cells is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.
Effective, March 2010 – June 2011
Autologous Chondrocyte Implantation (AC I) is indicated for the repair of symptomatic, cartilaginous defects of the femoral condyle caused by acute or repetitive trauma, in patients who have had an inadequate response to prior abrasion arthroplasty, mosaicplasty or osteochondral autograft transfer procedures when the following criteria are met:
Carticel should only be used in conjunction with debridement, placement of a periosteal flap and rehabilitation.
Autologous Chondrocyte Implantation for all other joints, including patellar and talar, and any indications other than those listed above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For member benefit contracts without Primary Coverage Criteria, Autologous Chondrocyte Implantation for all other joints, including patellar and talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Matrix-induced autologous chondrocyte implantation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, matrix-induced autologous chondrocyte implantation is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.
Treatment of focal articular cartilage lesions with autologous minced cartilage or allogeneic minced cartilage or cartilage cells does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For contracts without primary coverage criteria, treatment of focal articular cartilage lesions with autologous minced cartilage or allogeneic minced cartilage or cartilage cells is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.
Effective, December 2009 - February 2010
Autologous Chondrocyte Implantation (AC I) is indicated for the repair of symptomatic, cartilaginous defects of the femoral condyle caused by acute or repetitive trauma, in patients who have had an inadequate response to prior abrasion arthroplasty, mosaicplasty or osteochondral autograft transfer procedures when the following criteria are met:
Carticel should only be used in conjunction with debridement, placement of a periosteal flap and rehabilitation.
Autologous Chondrocyte Implantation for all other joints, including patellar and talar, and any indications other than those listed above does not meet Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For member benefit contracts without Primary Coverage Criteria, Autologous Chondrocyte Implantation for all other joints, including patellar and talar, and any indications other than those listed above is considered investigational. Investigational services are exclusions in the member benefit certificate of coverage.
Effective February 1996 – November 2009
Autologous Chondrocyte Implantation (AC I) is indicated for the repair of symptomatic, cartilaginous defects of the femoral condyle caused by acute or repetitive trauma, in patients who have had an inadequate response to prior abrasion arthroplasty, mosaicplasty or osteochondral autograft transfer procedures when the following criteria are met:
Carticel should only be used in conjunction with debridement, placement of a periosteal flap and rehabilitation.
For Member Benefit Contracts or Plans with Primary Coverage Criteria, ACI for the treatment of osteoarthritis, is not covered because it fails to meet the Primary Coverage Criteria (“The Criteria”) of the applicable benefit certificate or health plan. (The Criteria require, among other things, that there be scientific evidence of effectiveness, as defined in The Criteria. The Criteria exclude coverage of treatments, such as ACI for the treatment of osteoarthritis, for which there is lack of scientific evidence).
For Member Benefit Contracts or Plans with explicit exclusion language for experimental or investigational services, ACI for the treatment of osteoarthritis, is not covered because it is considered experimental or investigational treatment, as defined in the applicable benefit contract or health plan, which excludes coverage of experimental or investigational treatment or services.
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| Rationale: |
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
Autologous Chondrocyte Transplant as a First-Line Therapy
The published clinical data on autologous chondrocyte transplantation of the knee are largely derived from 2 patient cohorts: (1) the Swedish series and (2) the Cartilage Repair Registry. Results of patients treated by Dr. Tom Minas are also reported separately with additional outcome measures in the published literature. Abstract reports of several studies comparing ACT with an alternative treatment are also available. Notably, a randomized controlled trial is being conducted in Norway comparing ACT with microfracture, but final results have not yet been published in the peer-reviewed medical literature.
The publications and reports that have been added since the prior update include:
As of 2003, the current body of evidence has improved in several regards: more of the original data have been published; the reported data contain more complete follow-up; outcome results are available at longer follow-up; some comparative studies are being conducted though results are not yet published outside of abstract reports. Nevertheless, the primary deficiency in the available evidence remains unchanged in that there are no published controlled studies that compare the outcomes of ACT with the outcomes of other treatments or even with the natural progression of the disease.
Small/Medium-Sized Cartilage Defects (approximately <3 cm2)
The main deficiency of the existing evidence is that there are no controlled studies that actually compare the outcomes of ACT with any other treatment or even with the natural progression of the disease. The available studies report the proportions of patients treated with ACT who achieved various levels of outcomes, but there is no way to determine if those outcomes are better than, the same as, or worse than, the outcomes that would have occurred with other treatments. Although the unique feature of ACT is the transplantation of cultured chondrocytes, the fact is that ACT is given in conjunction with 3 other interventions; i.e., debridement of the injured area, placement of a periosteal flap, and rehabilitation. Given that any outcomes seen after ACT could be due, in whole or in part, to the other components of ACT, at present, there is no way to determine whether the inclusion of autologous cultured chondrocytes has any independent effect on outcomes, or how large the effect may be.
Large Cartilage Defects (Approximately >3 cm2)
Analysis of the Cartilage Registry stratified according to lesion size shows that improvement can be achieved after ACT in a substantial portion of patients with large chondral injuries over 4 cm2. More than 70% of 163 patients at 12 months and 65% of 50 patients at 24 months were rated as improved. The number of patients in the 36 months’ analysis (n<10) was too small to provide reliable subgroup analysis. However, interpretation of the clinical significance of reported “improvement” is limited by the lack of information regarding the magnitude of improvement in these large lesion subgroups. The 2001 and 2002 registry reports do not provide results stratified by lesion size.
Autologous Chondrocyte Transplant as a Second-Line Therapy
A substantial portion of patients treated with ACT that are included in the Swedish series or in the Cartilage Registry have had a prior surgical procedure that presumably yielded an inadequate response. However, the available evidence rarely describes the outcomes of ACT separately for the second-line group of patients in a manner that permits a within-subjects controlled comparison.
A postmarketing analysis of the Cartilage Registry data examining results of ACT in patients who had an inadequate response to prior treatment was requested by the FDA and has reportedly been submitted to the FDA in June 2000 (personal communication Dr. David Levine, Genzyme Tissue Repair, June 2000), but is not available for review by TEC. In addition, Genzyme Tissue Repair is conducting an ongoing prospective Study of the Treatment of Articular Repair (STAR), comparing the effect of alternative knee surgery to the effect of Carticel treatment (protocol of STAR study). In this study, patients will serve as their own controls and time to failure after ACT will be compared with time to failure after previous alternative knee surgery. Results from this study are expected in 2006.
Patients with Prior Debridement and Rehabilitation with Initial Improvement Followed by Symptom Recurrence
The analysis conducted by the FDA as part of the approval process is the only report that specifically evaluated the outcomes in patients who received a prior debridement that subsequently failed and then underwent ACT. This analysis included 22 patients. The analysis is not adequate to compare the results of ACT with debridement and does not provide sufficient information to demonstrate the effectiveness of ACT after a failed prior debridement.
Patients with Prior Debridement and Rehabilitation with No Initial Improvement
No published studies were identified that reported the outcome of ACT specifically in patients who had no improvement following debridement and rehabilitation.
Patients with a Prior Marrow-Stimulation Technique with Initial Improvement Followed by Symptom Recurrence
No published studies were identified that reported the outcome of ACT specifically in patients who had initial improvement with recurrence at a later time following a marrow-stimulation technique.
Patients with a Prior Marrow-Stimulation Technique without Initial Improvement
No published studies were identified that reported the outcome of ACT specifically in patients who did not have initial improvement following a marrow-stimulation technique.
Autologous Chondrocyte Transplantation for Ankle Osteochondral Defects
There has been interest in applying ACT to cartilage defects in the ankle. However, the literature on ACT for ankle osteochondral defects share the same limitations as ACT for knee osteochondral defects. There are no published controlled studies that compare the outcomes of ACT with the outcomes of other treatments or with the natural progression of ankle osteochondral defects. The published literature is inadequate to permit conclusions regarding the use of ACT for ankle osteochondral defects.
Only 2 small case series involving a total of 16 patients with ankle osteochondral defects were identified. One case series 5 of 8 patients studied the use of ACT for osteochondritis dissecans of the talus. Measured outcomes included the arthroscopic and radiologic evidence of cartilage like tissue with coverage of the osteochondral defects 6 months after treatment. Another case series 6 of 8 patients with osteochondritis due to trauma were treated with ACT and an ankle fixation device for 1 year. Outcomes measured were improved American Foot and Ankle Society scores in 1 study with an average score of 32 of 100 points preoperatively, which improved to an average of 91/ 100 points at 24 months’ follow-up. In the second study, clinical scores for all patients improved on Finsen scale from “bad” preoperatively (score 3 or 4) to “excellent” (score of 0) or “good” (scores of 1-2) at postoperative follow-up. Average preop score was 3-4 and average postop score was .6. Histologic appearance of reconstructed cartilage with chondrocytes and expression of collagen II, characteristic of hyaline cartilage was noted in those cases that underwent follow-up arthroscopy and biopsy.
2009 Update
A literature search through November 2009 identified the following published literature.
Results from the Study of the Treatment of Articular Repair (STAR) trial have been published (Cole, 2007). STAR was a prospective, open-label 4-year study in 154 patients from 29 clinical centers. Each patient served as his or her own control, undergoing ACI after having failed or experienced an inadequate response to a prior cartilage repair procedure (for example, 78% underwent debridement, 29% microfracture, 12% subchondral drilling) on a distal femur index lesion (109 medial femoral condyle, 32 lateral femoral condyle, 46 trochlea). The median lesion size was 4.6 cm 2 with 26% involving osteochondritis dissecans. Fifty patients had multiple lesions in the reference knee and 29 received multiple cellular implants. Prior treatment inadequacy was defined as both patient and surgeon agreement that the patient’s symptoms or function required surgical retreatment of the defect and a patient’s rating of overall condition of the knee was a score of 5 or less, using the Modified Cincinnati Knee Rating System (MCKRS). In this group, the median time to meet the failure criteria was 3.4 months for the prior index procedure, with more than 90% of patients having failed within 10.3 months. Patients who met these criteria were treated with ACI and assessed every 6 months for up to 4 years.
The primary outcome, treatment failure for ACI, was defined as any of the following: 1) a patient underwent surgical retreatment that violated the subchondral bone or repeated ACI for the same index defect; 2) complete delamination or removal of the graft; or 3) a patient’s rating of the overall condition of the knee using the MCKRS failed to improve from the baseline knee score over 3 consecutive 6-month time intervals. Withdrawals from the study were considered as failures at the last follow-up. The mean overall MCKRS for the entire patient population at baseline was 3.3 (n=154), and 126 (82%) completed 4-year follow-up. Thirty-seven patients were considered failures. Most of the 37 failures occurred within 30 months. At 48 months, three fourths of all patients in the study showed good to excellent results with a mean MCKRS score of 6.3 (n=115). Secondary outcome measures also showed improvement, including pain, symptoms, sports and recreation, knee -related quality of life, and activities of daily living. There was no relationship between the size of the lesion at baseline and treatment outcomes with ACI.
Over half of the population experienced at least one serious adverse event secondary to ACI, and 40% of patients underwent subsequent surgical procedures on the index knee related to ACI. Adverse events included arthrofibrosis , graft overgrowth, chondromalacia or chondrosis, graft complications (i.e., fraying or fibrillation), graft delamination, and joint adhesion. Subsequent surgical procedures (regardless of relationship to ACI) included debridement of cartilage lesion, lysis of adhesions, other debridement, meniscectomy, loose body removal, microfracture of the index lesion, and scar tissue removal. The most common cause for a subsequent surgical procedure was periosteal patch hypertrophy. A majority of patients who had a subsequent surgical procedure went on to have successful results, while 39% were eventually considered treatment failures. The results of the STAR trial suggest that ACI may improve knee symptoms and function in some patients with severe, debilitating, previously treated cartilage lesions of the distal femur for at least 4 years after the procedure. Additional surgical procedures may be expected.
Three systematic reviews on ACI for chondral defects of the knee were identified. The reviews concur that existing randomized clinical trials show some promising results for ACI in the treatment of focal cartilage lesions, but additional study of this technique is warranted to establish its place among cartilage restoration approaches. A 2008 systematic review by Magnussen et al assessed whether “advanced” cartilage repair techniques (osteochondral transplantation or autologous chondrocyte transplantation) showed superior outcomes in comparison with traditional abrasive techniques for the treatment of isolated articular cartilage defects (Magnussen, 2008). Finding a total of 5 randomized controlled trials and 1 prospective comparative trial that met their selection criteria, Magnussen and colleagues concluded that no one technique had been shown to produce superior clinical results for treatment of articular cartilage defects with the available follow-up. They stated that, “any differences in outcome based on the formation of articular rather than fibrocartilage in the defect may be quite subtle and only reveal themselves after many years of follow-up.“ Efficacy of the microfracture technique alone was examined in a 2009 systematic review (Mithoefer, 2009). Twenty-eight studies describing 3122 patients were included in the review, 6 of the studies were randomized controlled trials. Microfracture was found to improve knee function in all studies during the first 24 months after the procedure, but the reports on durability were conflicting.
ACI versus Marrow Stimulating Techniques
In an RCT of 80 patients randomized to either ACI or microfracture of the knee (an arthroscopic marrow stimulation procedure), Knutsen and colleagues reported no significant differences in the treatment groups at 2-year follow-up in macroscopic and histologic findings (Knutsen, 2004). The Lysholm and pain scores were also not significantly different at 1 and 2 years. The physical component score of the SF -36 was worse in the ACI group, which the authors suggest may be related to the greater surgical involvement. Five -year follow -up on all 80 patients revealed 9 failures for both groups.(Knutsen, 2007) There was a trend for earlier failure in the ACI group with no difference in subjective measures of pain or function between the ACI and microfracture groups. Thus, the more invasive ACI open surgical procedure was not associated with any added clinical benefit.
Saris et al published a multicenter randomized trial of characterized chondrocyte implantation versus microfracture; the average lesion size was 2.8 cm2 (Saris, 2008). Chondrocytes were isolated from a cartilage biopsy specimen and expanded ex vivo (ChondroCelect, TiGenix, Belgium). ChondroCelect is not approved for use in the United States. Each batch of chondrocytes was graded based on the quantitative gene expression of a selection of positive and negative markers for hyaline cartilage formation. Chondrocytes that were predicted to form stable hyaline cartilage in vivo were implanted by arthrotomy approximately 27 days after chondrocyte harvest. Surgical and rehabilitation procedures were standardized, and evaluation of a biopsy specimen at 12 months was conducted by an independent evaluator. Histological analysis showed better results with ACI for some measures of structural repair such as cartilage surface area, safranin O and collagen II ratio, and cell morphology. However, measures of integration (e.g., subchondral bone abnormalities, basal integration, vascularization) and surface architecture were not improved relative to the microfracture group. Self-assessed pain and function with the KOOS questionnaire were similar following ACI or microfracture at 12 or 18 months’ follow-up. Joint swelling and joint crepitation were greater in the ACI group, particularly following the arthrotomy. Thus, although histological results were somewhat improved, in this study characterized chondrocyte implantation did not improve health outcomes in comparison with microfracture at short -term follow -up.
In Visna et al, 50 patients with full-thickness, moderate to large chondral defects of 2.0–10.0 cm 2 of the femoral condyle, trochlea, or patella (43 cases due to injury) were randomized to either Johnson abrasion techniques or ACI of the knee using a preparation of autologous chondrocytes using a fibrin tissue glue rather than a periosteal patch to seal the implanted chondrocytes (Visna, 2004). The study reported improvements after 12 months in the Lysholm, International Knee Documentation Committee, and Tegner activity scores that were significantly better among the 25 ACI patients compared with the 25 patients in the abrasion group. Additional procedures (28 in the ACI group and 20 in the abrasion group) included anterior cruciate ligament replacement, meniscectomy, and lateral release.
ACI versus Osteochondral Autografts
Horas and colleagues reported 2-year follow-up on a study of 40 patients (between 18 and 42 years of age) with an articular lesion of the femoral condyle (range of 3.2 to 5.6 cm2) who were randomly assigned to undergo either autologous chondrocyte transplant or osteochondral autografting (Horas, 2003). Eleven (28%) had received prior surgical treatment. The authors reported that both treatments resulted in an improvement in symptoms (85% of each group), although those in the osteochondral autografting group responded more quickly. Histomorphological evaluation of 5 biopsy specimens at 2 years or less after transplantation indicated that the osteochondral cylinders had retained their hyaline character, although the investigators noted a persistent interface between the transplant and the surrounding original cartilage. Evaluation of autologous chondrocyte implants indicated a rigid, elastic tissue, with partial roughening and the presence of fibrocartilage.
Bentley and colleagues randomized 100 consecutive patients with symptomatic lesions of the knee (average 4.7 cm2, range of 1 to 12 cm2) to ACI or mosaicplasty (Bentley, 2003). Seventy-four percent of lesions were on the femoral condyle, and 25% of lesions were on the patella. Ninety-four patients had undergone previous surgical interventions, and the average duration of symptoms before surgery was 7 years. Clinical assessment at 1 year showed excellent or good results in 98% of the ACI patients and in 69% of the mosaicplasty patients. The mosaicplasty plugs showed incomplete healing of the spaces between the grafts, fibrillation of the repair tissue, and disintegration of the grafts in some patients. This finding may be related to the unusual prominent placement of the plugs in this study, which was intended to allow contact with the opposite articular surface, Arthroscopy at 1 year showed filling of the defects following ACI, but soft tissue was observed in 50% of patients. Biopsies taken from 19 ACI patients revealed a mixture of hyaline and fibrocartilage.
Dozin et al reported results from a multicenter randomized clinical trial in which ACI was compared to osteochondral autografting (Dozin, 2005). Forty-four individuals aged 16-40 years, who had a focal, symptomatic chondral injury of Outerbridge grade III or IV with no previous surgical treatment, were randomly assigned to ACI or mosaicplasty 6 months after undergoing arthroscopic debridement. The average lesion size was 1.9 cm. Only 12 of 22 (54%) in the ACI group and 11 of 22 (50%) of the mosaicplasty group actually underwent the assigned procedure. Dropouts comprised 14 patients (32%) who reported spontaneous improvement following arthroscopy and did not undergo subsequent surgery, 5 who did not show up at the presurgery examination and could not be further traced, and 2 who refused surgery for personal reasons. Because of the substantial dropout rate, the original primary outcome measure, the mean Lysholm Knee Scoring Scale (LKSS) assessed 12 months post-surgery was converted into a scale in which improvement was categorized by proportions of responders. With this scale, and including 10 patients who were cured by debridement (intention-to-treat analysis) the percentages of patients who achieved complete success were 89% (16 of 18 evaluable cases) in the mosaicplasty arm versus 68% (13 of 19 evaluable cases) in the ACI arm (test for trend P = 0.093). The high rate of spontaneous improvement after simple debridement raises questions about the appropriateness of additional surgical intervention in patients similar to those included in this trial. These results are not sufficient to permit conclusions regarding the effect of ACI on health outcomes in comparison with mosaicplasty or to demonstrate an independent effect of the use of ACI versus debridement and exercise rehabilitation.
Other Randomized Trials
Gooding and colleagues randomized 68 patients with osteochondral defects (mean 4.5 cm2, range1-12 cm2) of the femoral condyle (54%), trochlea (6%) or patella (40%) to ACI with either a periosteal or collagen cover (Gooding, 2006). At 2 years, 74% of the patients with the collagen cover had good to excellent results compared with 67% of the patients with the periosteal cover. Hypertrophy required shaving in 36% of patients treated with the periosteal cover. None of the collagen covers required shaving.
Observational Studies
Browne et al published 5-year outcomes from 87 of the first 100 patients (40 centers, 87% follow-up) treated with ACI for lesions on the distal femur from the FDA-regulated Carticel safety registry maintained by Genzyme Biosurgery. (20) Patients were an average of 37 years old, with a mean lesion size of 4.9cm2 (range of 0.8 to 23.5 cm2). Seventy percent of the patients had failed at least one previous cartilage procedure, and the average self-rated overall condition was 3.2 (poor to fair). At 5 years following the index procedure, the average follow -up score was 5.8 (fair to good), a 2.6-point improvement on the 10-point scale. Sixty-two patients (71%) reported improvement, 25 (29%) reported no change or worsening. Thirty-seven patients (42%) had 51 operations after ACI. The most common findings were adhesions (n=6), hypertrophic changes of the graft (n=5), loose bodies (n=4)m loose or delaminated periosteal patch (n=4), and meniscal tears (n=4). Factors associated with failure in 6 patients were non-compliance with the postoperative protocol, additional injury, and uncorrected malalignment. Defect size was not found to be significantly associated with outcome; self-reported outcomes were associated with workers’ compensation claims.
Rosenberger et al reported average 4.7 years’ follow-up (range 2–11 years) on a cohort of 56 patients (45 to 60 years of age) with lesions of the femoral condyle, trochlea, or patella (Rosenerger, 2008). Results were generally similar to those observed in younger patients, with 72% rating themselves as good or excellent but 43% requiring additional arthroscopic procedures for periosteal-related problems and adhesion. A European group reported complications in 309 consecutive patients, 52 of whom (17%) had undergone revision surgery for persistent clinical problems (Niemeyer, 2006). Three different ACI techniques had been used, periosteum-covered, membrane-covered (Chondrogi de Geistlich Biomaterials, Switzerland) and 3-dimensional matrix (BioSeed-C, Biotissue Technologies, Germany). Follow-up at a mean of 4.5 years showed that the highest rate of revision surgery was in patients with periosteum-covered ACI (27% ) in comparison with membrane-covered or matrix-induced ACI (12% and 15%, respectively). There was a trend (p = 0.09) for a higher incidence of hypertrophy with patellar defects in comparison with the femoral condyles or trochlea.
ACI for patellar cartilage defects is typically reported as less effective than ACI for lesions of the femoral condyles, and some studies have reported biomechanical alignment procedures and unloading to improve outcomes for retropatellar ACI (Henderson, 2006) (Farr, 2007). A 2008 study from Europe described clinical results from 70 of 95 patients (74%) treated with ACI or MACI for full-thickness defects of the patella (Niemeyer, 2008). The average defect was 4.4 cm2. Depending on surgeon preference, patients received ACI with a periosteal patch, Chondroglide membrane, or MACI. Fourteen patients were lost to follow -up and 11 patients were excluded from the follow-up study due to dysplasia of the femoropatellar joint and significant (more than 5 degrees) varus or valgus deformity. In addition to patient responses for the Cincinnati Sports Activity scale, Lysholm score and International Knee Documentation Committee (IKDC ) score, a physical examination was performed by an independent examiner who was blinded to data obtained at the time of surgery, including defec t size and location. Objective evaluation at an average follow-up of 38 months showed normal or nearly normal results in 47 patients (67%). Results were classified as abnormal in 14 patients (20%), and 9 patients (13%) were considered failures . Results were not divided according to the type of implant (ACI or MACI), although it was reported that 2 patients with hypertrophy of the implant were from the group treated with periosteal patch covered ACI. In addition, these results are limited by the retrospective design and loss to follow-up, and would be applicable only to those patients without varus or valgus deformity. Other studies from Europe report patellofemoral cartilage defects treated with second generation MACI implants (26, 27) These products are not approved in the U.S. and are therefore considered investigational.
Combined meniscus transplantation and articular cartilage repair has been reported. Farr et al. described outcomes from a prospective series of 36 patients who underwent autologous chondrocyte implantation (ACI) together with meniscal transplantation in the same compartment (Farr, 2007). Lesions ranged from 1.5 to 12.1 cm2. Patients identified with advanced chondrosis during staging arthroscopy were excluded from the study. Four patients received treatment for bipolar lesions, while 16 of the procedures were done concomitant with another procedure such as osteotomy, patellar realignment, or anterior cruciate ligament (ACL) reconstruction. Four patients were considered failures before 2 years, and 3 were lost to follow-up, resulting in 29 evaluable patients at an average of 4.5 years after surgery. The Lysholm score improved from an average score of 58 to 78; maximum pain decreased an average 33%. Excluding the 4 failures, 68% of their patients required additional surgeries; 52% had 1 additional surgery, and 16% required 2 or more additional surgeries. The most common procedures were trimming of periosteal overgrowth or degenerative rims of the transplanted meniscus. Another report described average 3.1 years of follow-up from a prospective series of 30 patients (31 procedures) who had undergone combined meniscal allograft transplantation with ACI (52%) or osteochondral allograft transplantation (OA; 48%)(Rue, 2008). The Lysholm score improved in both the ACI (from 55 to 79) and OA (from 42 to 68) groups; 48% of patients (60% ACI and 36% OA) were considered to be normal or nearly normal at the latest follow-up. Patients treated with OA were on average older (average 37 vs. 23 years) and with larger lesions (5.5 cm2 vs. 3.9 cm2). Two patients were considered failures and 5 underwent subsequent surgery. Although results seem promising, evidence is currently insufficient to permit conclusions regarding the effect of combined transplantation-implantation procedures on health outcomes.
A 3-fold increased failure of ACI after previous treatment with marrow stimulation techniques was found in a cohort of 321 patients with more than 2 years follow-up (out of 332 treated) (Minas, 2009). The average lesion was 8 cm2, and the indications for treatment of cartilage defects with ACI included 1 or more full-thickness chondral defects of the knee with consistent history, physical examination, imaging, and arthroscopy; no or correctable ligamentous instability, malalignment, or meniscal deficiency; and not more than 50% loss of joint space on weight-bearing radiographs. Independent analysis showed a failure rate of 8% of joints that did not have prior marrow stimulation of the lesion, compared with 26% that had previously been treated with marrow stimulation.
Joints other than the Knee
There has been interest in applying ACI to cartilage defects in other joints. For example, 1 case series of 8 patients studied the use of ACI for osteochondritis dissecans of the talus (Koulalis, 2002). Outcome measures included arthroscopic and radiologic evidence of cartilage-like tissue with coverage of the osteochondral defects 6 months after treatment. Another case series of 8 patients with osteochondritis due to trauma were treated with ACI and an ankle fixation device for 1 year (Giannini, 2001). Outcomes were improved American Foot and Ankle Society scores in 1 study with an average score of 32 of 100 points preoperatively, which improved to an average of 91 of 100 points at 24 months' follow-up. Clinical scores for all patients improved on a Finsen scale from “bad” preoperatively (score 3 or 4) to “excellent” (score of 0) or “good” (scores of 1-2) at postoperative follow -up. Histologic appearance of reconstructed cartilage with chondrocytes and expression of collagen II, characteristic of hyaline cartilage, was noted in those cases that underwent follow-up arthroscopy and biopsy.
In 2009, Nam and colleagues published a report that they described as the first US prospective study of ACI of the talus (Nam, 2009). The 11 patients described had failed non-surgical and prior surgical management, with a mean of 1.9 prior surgical procedures including debridement, drilling, pinning, or abrasion arthroplasty. Osteotomy was performed in order to access the mean 2.7 cm2 talar lesions. Six of the patients also underwent cyst excavation and bone grafting for extensive subchondral cystic involvement, and the chondrocytes were injected between a sandwich of 2 periosteal grafts. Following treatment of the cartilage lesion with ACI, the osteotomy was reattached with screws. Rehabilitation consisted of physician-monitored gradual advancement in weight -bearing over 6 weeks, as indicated by radiographic healing of the osteotomy. This was followed by 3 phases of formal physical therapy, termed transitional, remodeling, and maturation phases. Ten of the patients underwent second-look arthroscopy and hardware removal at a mean of 14 months and 9 underwent MRI evaluation at a mean of 31 months. At a mean 38 -month clinical evaluation, 3 patients were classified as excellent (no pain, swelling, or locking with strenuous activity), 6 were classified as good, 2 as fair, with none classified as poor. Ten of the 11 patients (91%) were considered to be improved by the procedure. Significant improvements were obtained with the Tegner activity scale, Finsen score, and the American Orthopaedic Foot and Ankle Society (AOFAS) ankle hindfoot score. Second-look arthroscopy showed smooth repair tissue with a line of demarcation between normal cartilage and the graft, with overgrowth of repair tissue requiring debridement in 2 patients. The repair tissue was softer to probing than the adjacent cartilage, although an increase in firmness was noted from the 9- to 24-month observations. Use of MACI for osteochondral lesions of the talus has also been reported from overseas (Schneider, 2009).
A search of the clinical trials database in January 2010 identified one company-sponsored study on DeNovo NT, Natural Tissue Graft (www.clinicaltrials.gov: NCT00791245). The study is an observational case series with a total of 25 patients recruited from 4 sites in the U.S. The anticipated completion date, including 2-year follow-up, is December 2013. A review by investigators involved in the company sponsored clinical trial indicates that 70 cases with DeNovo NT had been performed at the time of publication in 2008 (McCormick, 2008). Although the author’s anecdotal experience suggests that the hyaline-like tissue produced by minced cartilage techniques may be superior to that formed after microfracture, “the technology is still in its infancy and no long-term or randomized human studies have been concluded.”
In 2005, the National Institute for Health and Clinical Excellence (NICE) issued an updated Technology Appraisal Guidance on the use of autologous chondrocyte implantation. The NICE guidance cited insufficient evidence to determine the benefits of autologous chondrocyte implantation and indicated this technology “should not be used for the treatment of articular cartilage defects except where the treatment is part of a clinical study.” The guidance noted many limitations in available trial data including length of follow-up, comparison to conservative treatment, assessment of the quality of cartilage produced, and the impact of cartilage produced on functional outcomes and health-related quality of life.
Summary
Although long-term studies are lacking, evidence indicates that ACI can improve symptoms in some patients with lesions of the articular cartilage of the knee who have failed prior surgical treatment. These patients, who are too young for total knee replacement, have limited options. Therefore, based on the clinical input, highly suggestive evidence from randomized controlled trials and prospective observational studies, it is concluded that ACI may be considered an option for disabling full-thickness chondral lesions of the knee caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior marrow stimulation procedure. Additional studies are needed to evaluate whether marrow stimulation at the time of biopsy affects implant success. Evidence is currently insufficient to evaluate the efficacy of ACI in comparison with other surgical repair procedures as a primary treatment of large lesions, or to evaluate the efficacy of ACI for joints other than the knee.
Results from second generation ACI procedures (MACI) from Europe appear promising. These products utilize a variety of biodegradable scaffolds and have the potential to improve consistent hyaline cartilage formation and reduce complications associated with injection under a periosteal patch. To date no MACI products are approved in the United States. Minced cartilage techniques are in the early stages of development and testing and/or not approved in the United States.
2011 Update
A 2010 systematic review by Harris and colleagues included 13 randomized and non-randomized controlled trials of 917 subjects who underwent ACI (n=604), microfracture (n=271), or osteochondral autograft (n=42). The mean study quality was rated as 54 out of 100, with no studies considered of good or excellent quality, 7 considered fair, and 6 considered poor. Four studies compared different generations of ACI, finding no difference in outcomes but higher complication rates with open, periosteal cover, first-generation ACI. At 1 to 5-year follow-up, 3 of 7 studies showed better clinical outcomes after ACI in comparison with microfracture, 1 study showed better outcomes after microfracture, and 3 studies showed no difference in these treatments. Clinical outcomes after microfracture were found to deteriorate after 18 to 24 months in 3 of 7 studies. Studies comparing ACI and osteochondral autograft showed similar short-term clinical outcomes, with more rapid improvement but an increase in arthrofibrosis and donor site morbidity following osteochondral autograft. Younger patients with a shorter preoperative duration of symptoms and fewer prior surgical procedures had the best outcomes after surgical intervention. A defect size greater than 4 cm2 was the only factor predictive of better outcomes when ACI was compared with other surgical techniques.
Another publication by Harris et al. in 2010 was a systematic review of combined meniscal allograft transplantation and cartilage repair/restoration (Harris, 2011). Six level IV studies (case series) with a total of 110 patients were included in the review. Patients underwent meniscal allograft transplantation with either ACI (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 to the preoperative condition. Outcomes were also compared with historical outcomes of each individual procedure performed in isolation. Four of the 6 studies found outcomes equivalent to procedures performed in isolation, while 2 studies found that outcomes with combined surgery were not as good as the historical controls. Across the 6 studies, 13 failures (12%) were reported; these included 11 isolated meniscal allograft transplantation failures, 1 combined meniscal allograft and ACI failure, and 1 isolated ACI failure. Three knees with failed meniscal allograft transplantation were converted to total knee arthroplasty. Nearly 50% of the patients underwent 1 or more subsequent surgeries after combined meniscal allograft transplantation and cartilage repair/restoration procedures.
In 2009, Saris et al. published 36-month outcomes (100% follow-up) from this randomized trial (Saris, 2008) (Saris, 2009). The mean improvement in the overall KOOS was greater in the ACI group than the microfracture group (21 vs. 16 points, respectively). More ACI than microfracture-treated patients were considered to be treatment responders (83% vs. 62%, respectively), defined as an increase from baseline of at least 10 percentage points in at least 3 of the 4 KOOS subdomains or a decrease of at least 20 percentage points in visual analog scores (VAS) for pain. At 36 months after surgery, 2 ACI (3.9%) and 7 microfracture patients (11.5%) had failed treatment and subsequently underwent reintervention. Magnetic resonance imaging (MRI) showed greater worsening of the subchondral bone reaction with microfracture compared with ACI.
In 2010, this group of investigators published 6 to 10-year follow-up (mean 9.2 years) on 72 patients in the cartilage repair registry (Moseley, 2010). Information on adverse events, treatment failures, and operations after ACI were reported on follow-up questionnaires or came from patient and surgeon reports. Fifty-four patients (75%) met the eligibility criteria of the study, which included ACI treatment of lesions on the distal femur and improvement at the 1 to 5-year follow-up period. Of these 54 patients, 47 (87%) sustained a mean improvement of 3.8 points from baseline to the later follow-up period. During the 6- to 10-year follow-up period, ACI failed in 3 patients at a mean of 8 years after implantation. For the cohort of 72 patients, 69% reported improvement, 17% failed, and 12.5% reported no change from baseline to follow-up. During the study period, 30 patients (42%) had 42 operations after ACI, the majority of which met the study definition of treatment failure.
In 2010, Peterson and colleagues reported on 224 patients who replied to questionnaires at 10 to 20 year follow-up (Peterson, 2010). This represents 38% of a total of 590 patients who underwent ACI at their institution between 1987 and 1998. The average age of the patients was 33 years (range, 14 to 61) at the time of the ACI, and the indication for treatment was any symptomatic full-thickness cartilage lesion up to 16 cm2, including patients with meniscal (34% of patients) or ACL lesions (19%). Fifty-five patients (25%) had multiple lesions, 73 patients (33%) had unipolar or bipolar patellar lesions, and 26 patients (12%) had osteochondritis dissecans. Three hundred and forty-one surveys were mailed to the treated patients; the response rate was 65%. Information about baseline measurements was collected from the patients’ charts or from prior studies and when available, compared with the questionnaire responses at follow-up. At a mean of 12.8 years’ follow-up, 74% of the patients reported their status as better or the same as the previous years, and 92% were satisfied with the operation. The average Lysholm score improved from 60.3 preoperatively to 69.5 postoperatively, the Tegner from 7.2 to 8.2, and the Brittberg-Person from 59.4 to 40.9. At the final measurement, the KOOS score averaged 74.8 for pain, 63 for symptoms, 81 for activities of daily living, 41.5 for sports, and 49.3 for quality of life. The average Noyes score was 5.4. Patients with bipolar lesions had a worse final outcome than patients with multiple unipolar lesions. The presence of meniscal injuries before ACI or history of bone marrow procedures before the implantation did not seem to affect the final outcomes.
In 2009, Pascual-Garrido et al. reported outcomes from 52 patients (83% follow-up) who underwent ACI of the patellofemoral joint (patella or trochlea) (Pascual-Garrido, 2009). The mean defect size was 4.2 cm2. In addition to ACI of the patella, 67% of patients had concomitant procedures performed, including anteromedialization (n=28), lateral release (n=4), lateral meniscal transplant (n=2), and osteochondral autograft (n=1). Questionnaires were administered preoperatively, 6 months and 1 year postoperatively, and then annually. At an average follow-up of 4 years there was significant improvement in the Lysholm, IKDC, KOOS pain, KOOS Symptoms, KOOS Activities of Daily Living, KOOS Sport, Cincinnati, Tegner, and Short Form (SF)-12 Physical. Patients reported the overall condition of their knee as excellent, very good, or good in 71% of the cases; 81% of the patients were satisfied with the procedure. There were 4 failures (8%), defined as poor clinical outcome accompanied by evidence of graft failure or need for conversion to knee arthroplasty or osteochondral allograft.
Minas and colleagues assessed the influence of ACI on the need for joint replacement surgery in 153 patients (155 knees) who had a mean age of 38 years (range, 17 to 60), evidence of early osteoarthritis at the time of surgery (peripheral intra-articular osteophyte formation and/or 0% to 50% joint space narrowing), and equal to or greater than 2 years of follow-up (Minas, 2010). (Patients with more than 50% loss of joint space were not eligible for treatment with ACI.) Patients were also included in the study if they had normal radiographs but evidence of bipolar lesions or generalized chondromalacia noted at the time of surgery. An average of 2.1 defects per knee was treated, with a mean defect size of 4.9 cm2 and a total mean defect area of 10.4 cm2. Defects were located on the femoral condyle (n=150), trochlea (n=85), patella (n=60) and tibial plateau (n=14). There were 42 (27%) bipolar lesions, the majority of which were patellofemoral. Concurrent procedures included correction of tibiofemoral malalignment (31% of knees) and patellar maltracking (28% of knees). At 5 years’ postoperatively (range, 24 to 132 months), 12 knees (8%) were considered treatment failures and underwent arthroplasty due to graft failure (n=3), inadequate pain relief (n=1), and progression of osteoarthritic disease beyond the originally transplanted defect area (n=8). The remaining 92% of patients showed improvements in all scores from baseline to final follow-up. For example, there was 52% improvement in Western Ontario and McMaster Universities Arthritis Index (WOMAC) subscales, and the proportion of patients who experienced severe or extreme pain while walking on a flat surface decreased by 73%. Subsequent surgical procedures after the index implantation were performed in 95 knees (61%), including 52 cases of periosteal hypertrophy, 32 cases of arthrofibrosis, 23 graft complications, and 11 for periosteal delamination.
The 2011 literature update identified two additional reports on MACI for articular defects of the ankle. A prospective investigation of MACI was performed on 10 patients with focal lesions of the talus that had failed arthroscopic debridement/curettage (average of 1.7 previous procedures) (Giza, 2010). Chondrocytes were harvested from the talus (without malleolar osteotomy) and implanted into defects that averaged 1.3 cm2. The AOFAS ankle-hindfoot score improved from 61.2 at baseline to 74.7 1 year postoperatively but did not reach statistical significance 2 years postoperatively (score of 73.3, range 42 to 90). At both 1 and 2 years’ follow-up, there was significant improvement in the SF-36 for Physical Functioning and Bodily Pain. Another study evaluated outcomes of MACI in 18 patients (19 ankles) at a mean follow-up of 24.5 months (Aurich, 2011). Significant improvements, averaging 50%, were obtained for all clinical scores in the 14 cases with greater than 16 months’ follow-up. According to the AOFAS Hindfoot score, 64% were rated as excellent and good, whereas 36% were rated fair and poor. These results correlated moderately with the age of the patient and the duration of symptoms but not with the size of the lesion. In general, there was no relation between MRI scores and clinical outcome, although the filling of the defect showed some correlation (r=-.48) with the American Academy of Orthopaedic Surgeons Lower Limb Outcomes Assessment Instruments.
Zengerink et al. published a systematic review of treatment of osteochondral lesions of the talus in 2010 (Zengerink, 2010). Fifty-one nonrandomized and 1 randomized trial were included in the review. Success rates were 85% for bone marrow stimulation, 87% for osteochondral autografting, and 76% for ACI. Because of the high cost of ACI and the knee morbidity seen with osteochondral autografting, the authors concluded that bone marrow stimulation is the treatment of choice for primary osteochondral talar lesions. A 2009 report examined the association between defect size and outcomes following marrow stimulation techniques in 120 ankles (Choi, 2009). Eight ankles subsequently underwent osteochondral transplantation, and 22 ankles were considered clinical failures (AOFAS Ankle-Hindfoot score <80). Linear regression suggested a cutoff defect size of 1.5 cm2 for marrow stimulation techniques, with an 80% failure rate compared to a 10.5% failure rate for ankles with a defect size of less than 1.5 cm2. Three of 58 ankles (5.2%) with a defect area of less than 1 cm2 showed clinical failure, while 7 of 37 ankles (18.9%) with a defect area between 1.0 and 1.5 cm2 failed.
In a 2010 clinical practice guideline on the diagnosis and treatment of osteochondritis dissecans (OCD), the American Academy of Orthopaedic Surgeons (AAOS) was unable to recommend for or against a specific cartilage repair technique in symptomatic skeletally immature or mature patients with an unsalvageable osteochondritis dissecans lesion. This recommendation of insufficient evidence was based on a systematic review that found 4 level IV studies that addressed cartilage repair techniques for an unsalvageable OCD lesion. Since each of the level IV articles utilized different techniques, different outcome measures, and differing lengths of follow-up, the work group deemed that the evidence for any specific technique was inconclusive.
In summary, recent evidence indicates that ACI combined with meniscal allograft results in outcomes similar to either procedure performed alone. Therefore, coverage statement has been revised to remove the criteria requiring an absence of meniscal pathology. No other changes to the coverage statement have been made.
2012 Update
A search of the MEDLINE database through September 2012 did not reveal any new information that would prompt a change in the coverage statement. The key literature identified is summarized as follows:
In 2011, Kon et al. reported a prospective comparative study of second generation ACI (Hyalograft C) versus microfracture in 41 professional or semiprofessional male soccer players (Kon, 2011). This was a pragmatic clinical trial, with treatment allocation based on the center that patients went to; 1 center performed ACI and 2 centers performed microfracture. The 2 patient groups were comparable for age, defect size, location, previous and combined surgery, and follow-up. Patients were evaluated prospectively at 2 years and at a final mean 7.5-year follow-up (minimum, 4 years). The percentage of patients who returned to competition was similar, with 80% in the microfracture group and 86% in the ACI group. Patients treated with microfracture needed a median of 8 months before playing their first official soccer game, whereas the ACI group required a median time of 12.5 months. The International Knee Documentation Committee (IKDC) subjective score showed similar results at 2 years’ follow-up but significantly better results in the ACI group at the final evaluation. In the microfracture group, results decreased over time (from 86.8 at 2 years to 79.0 at final follow-up), whereas the ACI group had stable results between 2 years and final follow-up (90.5 and 91.0, respectively). The IKDC objective score was similar in the 2 groups, with 90-95% of knees considered to be normal or nearly normal. Subjective evaluation of functional level was significantly better in the ACI group at final follow-up (91 vs. 84).
Also, in 2011, Cole et al. reported a multicenter trial with 29 patients (out of 582 screened) randomized in a 1:2 ratio to microfracture or CAIS (Cole, 2011). In the single-stage CAIS procedure, autologous hyaline cartilage was harvested, minced, affixed on a synthetic absorbable scaffold, and then fixed on the lesion site with absorbable staples. There were no significant differences between groups in the duration of symptoms, International Cartilage Repair Society (ICRS) grade, and area and depth of the chondral defect. There was a difference in the gender and work status of the 2 groups. At 3 weeks and 6 months, there were no significant differences in outcomes between the 2 groups. The IKDC score was significantly higher in the CAIS group compared to the microfracture group at both 12 (73.9 vs. 57.8) and 24 (83.0 vs. 59.5) months. All subdomains of the KOOS (Symptoms and Stiffness, Pain, Activities of Daily Living, Sports and Recreation, Knee-related Quality of Life) were significantly increased at 24 months in the CAIS group compared with microfracture patients. Qualitative analysis of magnetic resonance imaging (MRI) at 3 weeks, and 6, 12, and 24 months showed no differences in fill of the graft bed, tissue integration, or presence of subchondral cysts. Adverse events were similar for the 2 groups.
Clinical Trials
Autologous chondrocyte implantation and matrix-induced chondrocyte implantation are currently being studied in the following clinical trials.
NCT01050816- A phase 3 trial to observe the effects of CHONDRON (Autologous Chondrocytes) for 12 months in patients with ankle cartilage defect.
NCT01500811- A phase I trial studying the effects of autologous chondrocyte intra-articular implantation in patients with severe hip osteoarthritis. This study is currently recruiting subjects.
NCT00212849-A phase 4 trial studying the outcomes of patients treated with ACI for articular cartilage lesions in the patellofemoral joint.
NCT01458782- A randomized trial comparing autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation.
2013 Update
The following is a summary of the key literature identified since the last policy update.
Kon et al. published a systematic review of matrix-assisted ACI in 2013 (Kon, 2013). The review identified 51 articles, including 3 randomized controlled trials, 10 comparative studies, 33 case series, and 5 case reports that reported on functional or clinical outcomes. The review found an expanding evidence base that reports good results at short to medium follow-up, although long-term follow-up and randomized controlled trials are needed to compare MACI with other available treatments.
Basad et al. reported a small randomized trial that compared MACI® (n=40) to microfracture (n=20) in patients with a single post-traumatic chondral defect between 4 and 10 cm2 (Basad, 2010). Both groups improved at the 2 year follow-up, with a significant advantage of MACI over microfracture on the Lysholm (92 vs. 69), Tegner (4 vs. 3), and International Cartilage Repair Society (ICRS) patient (a higher percentage of patients with an ICRS score of I) and ICRS surgeon scores.
In 2012, Crawford et al. reported results of an industry-sponsored, FDA-regulated, multi-center randomized Phase II trial (Crawford, 2012). Thirty patients with lesions less than 8 cm2 were randomized to NeoCart (n=21) or to microfracture (n=9). The SF-36, KOOS, IKDC and VAS pain scores were assessed at up to 24 months by intent-to-treat analysis, and patients were classified as responders if they had at least a 12-point improvement in the pain score of the KOOS and a 20-point improvement in the IKDC subjective score. At 24 months, there was no significant difference in the mean KOOS pain scores or IKDC scores. The NeoCart group showed significantly greater improvement in the KOOS pain score, KOOS sports, KOOS QOL, IKCD, and VAS pain scores compared to microfracture. There was a trend for a greater number of responders in the NeoCart group (p=0.097); 79% of NeoCart patients were considered to be responders, compared to 44% of the microfracture group.
Zeifang et al. conducted a small (n=21) randomized trial comparing MACI and ACI (Zeifang, 2010). The average size of the cartilage defects was 4.3 cm2, and patients had undergone an average of 2 prior surgeries on the affected knee. Postoperatively, there was no significant difference between the 2 groups on the IKDC score at either 12 months (72.0 for MACI and 76.7 for ACI), or 24 months (70.1 for MACI and 77.1 for ACI). Exploratory analysis found a significant inverse correlation with age (r = -0.52 at 12 months and r = - 0.49 at 24 months) indicating that better results were observed in younger patients. There was no significant difference between the groups in the SF-36. The Lysholm score showed a significant improvement only in the ACI group (from 61.3 at baseline to 86.3 at 12 months and 84.0 at 24 months). The Tegner activity score did not change significantly in either group.
2014 Update
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
Minas et al prospectively followed 210 ACI-treated patients (362 grafts) for at least 10 years (Minas, 2014). Malalignment, patellar maltracking and meniscal or ligamentous deficiency had also been corrected as needed. At a mean of 12 years’ follow-up, 53 patients (25%) had graft failure. Nineteen of these patients (9%) went on to arthroplasty, 27 patients (13%) were salvaged with revision cartilage repair, and 7 patients declined further treatment. For the 157 patients who had successful grafts, functional outcomes were significantly improved from baseline to follow-up, as measured by the Western Ontario & McMaster Universities Index (WOMAC), Knee Society Score (KSS) for knee and function, and SF-36 (all p<0.001). Survival of the graft was significantly higher in patients with complex versus salvage-type lesions (p=0.03), with concomitant high tibial osteotomy (HTO) versus no HTO (p=0.01), and with primary ACI versus ACI after a prior marrow stimulation procedure (p=0.004). For example, ACI graft survival was 79% compared with 44% for knees with defects that had been previously treated with microfracture.
In 2014, Gomoll et al reported a multicenter registry study of the treatment of mono or bipolar patellar defects with ACI in 110 patients with a minimum of 4 years’ follow-up (mean, 90 months; range, 48-192 months) (Gomoll. 2014). Concurrent surgical procedures included tibial tubercle osteotomy in 69% of patients, lateral release in 41%, vastus medialis advancement in 20%, and trocleoplasty in 5%. At the latest follow-up, statistically and clinically significant improvements in pain and function were obtained on the IKDC, Cincinnati Rating Scale, WOMAC and KSSs, although it was noted that results were inferior to ACI for cartilage lesions of the femoral condyles. Excluding repeat arthroscopy for graft hypertrophy or lysis of adhesions, 9 patients were considered treatment failures. Pascual-Garrido et al reported outcomes from 52 patients (83% follow-up) who underwent ACI of the patellofemoral joint (patella or trochlea).(30) In addition to ACI of the patella, 67% of patients had concomitant procedures performed, including anteromedialization (n=28), lateral release (n=4), lateral meniscal transplant (n=2), and OA (n=1). Questionnaires were administered preoperatively, 6 months and 1 year postoperatively, and then annually. At an average follow-up of 4 years (range, 2-7), there was significant improvement in the Lysholm, IKDC, KOOS Pain, KOOS Symptoms, KOOS Activities of Daily Living, KOOS Sport, Cincinnati, Tegner, and SF-12 Physical. Patients reported the overall condition of their knee as excellent, very good, or good in 71% of the cases. There were 4 failures (8%), defined as poor clinical outcome accompanied by evidence of graft failure or need for conversion to knee arthroplasty or OA.
Second Generation ACI Products
SUMMIT was an industry-sponsored multicenter randomized open-label trial (NCT00719576) comparing MACI® with microfracture for larger cartilage defects (≥3 cm2), which typically fare worse than smaller lesions when treated with microfracture (Saris, 2014). Patients (n=144) were included who had at least 1 symptomatic grade III or IV focal cartilage defect on the femoral condyles or trochlea, a stable knee, an intact or partial meniscus, and a moderate to severe KOOS pain value (<55). The average lesion size was 4.8 cm2 (range, 3-20 cm2); 34.6% of patients had undergone a prior marrow stimulation procedure. At 2-year follow-up, the MACI® group had significantly better subscores for KOOS pain (coprimary outcome, difference of 11.76, p<0.001) and function (coprimary outcome, difference of 11.41, p=0.16) as well as the other KOOS subscales (Activities of Daily Living, Knee-Related Quality of Life, Other Symptoms). With response to treatment defined as a 10-point improvement in both the KOOS pain and function subscales, significantly more patients in the MACI group responded to treatment compared with the microfracture group (87.5% vs 68.1%, p=0.016). There were no significant differences between the groups for cartilage repair, as measured by second look arthroscopy, biopsy, or MRI. The lack of blinding in this study reduces the validity of the patient-reported outcome measures.
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Marrow Stimulation Procedures
Montgomery and colleagues reported a study of articular cartilage procedures of the knee from a national database of insurance billing records (Montgomery, 2014). There were 216 million orthopedic procedures identified over a 6-year period. For the 163,448 articular cartilage procedure codes reported over this period, 98% were microfracture (n=36,095) or chondroplasty (n=125,245). Efficacy of the microfracture technique was examined in a 2009 systematic review.6 Twenty-eight studies describing 3122 patients were included in the review; 6 of the studies were randomized controlled trials (RCTs). Microfracture was found to improve knee function in all studies during the first 24 months after the procedure, but the reports on durability were conflicting. A prospective longitudinal study of 110 patients by Solheim and colleagues found that at a mean of 12 years (range, 10 to 14) after microfracture, 45.5% of patients had poor outcomes, including 43 patients who required additional surgery (Solheim, 2014).
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this policy are listed below:
Ongoing
NCT01066702 (industry-sponsored or co-sponsored trial) A Randomized Comparison of NeoCart to Microfracture for the Repair of Articular Cartilage Injuries in the Knee; planned enrollment 245; projected completion date July 2017.
NCT01656902 (industry-sponsored or co-sponsored trial) A Prospective Randomized Controlled Multicenter Phase-III Clinical Study to Evaluate the Safety and Effectiveness of NOVOCART® 3D Plus Compared to the Standard Procedure Microfracture in the Treatment of Articular Cartilage Defects of the Knee; planned enrollment 261; projected completion date June 2019.
NCT01957722 (industry-sponsored or co-sponsored trial); A Phase 3, Prospective, Randomized, Partially Blinded Multi-Center Study to Measure the Safety and Efficacy of NOVOCART 3D Compared to Microfracture in the Treatment of Articular Cartilage Defects; planned enrollment 233; projected completion date August 2021.
2020 Update
A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A systematic review by Sacolick et al examined the patient-reported outcomes, complication rates, and failure rates of autologous chondrocyte implantation and matrix-induced autologous chondrocyte implantation for osteochondritis dissecans in adults (Sacolick, 2019). Nine clinical studies were assessed (type not specified), with 179 (>200 lesions) patients aged 18-49 years (mean=27.6 y). Follow-up ranged from 6.5 months to 10 years. Results of patient-reported outcomes showed that 85% of patients reported excellent or good outcomes. All patient-reported outcome measures used across the studies, International Knee Documentation Committee Form, Lysholm Knee Questionnaire, EuroQol Visual Analog Scale, Cincinnati Rating System, and the Tegner Activity Scale—reported statistically significant improvements from preoperative to final follow-up (p-values not reported). Of the studies that reported complication and failure rates for autologous chondrocyte implantation/matrix-induced autologous chondrocyte implantation, 23 (15.7%) of 146 patients reported complications, and failure rate was 8.2%. Unplanned reoperations were necessary for 20.5% of patients. The study results showed that autologous chondrocyte implantation/matrix-induced autologous chondrocyte implantation had the best outcomes for active young males with small lesions. Older adults and less active individuals, as well as those with lesions >6 cm2, did not fare as well. A limitation of this review was its lack of randomized trials with controls to compare to autologous chondrocyte implantation/matrix-induced autologous chondrocyte implantation.
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