1. Aetna considers autologous chondrocyte implants medically necessary for repairing cartilage defects of the knee in members who meet the following selection criteria:

   Member has symptoms of disabling knee pain related to a full thickness, focal chondral defect with all of the following:

   1. Age 15 - 60 years; and  
   2. BMI less than or equal to 35 (see appendix); and  
   3. Presence of disabling pain and/or knee locking; and   
   4. Focal articular cartilage defect down to but not through the subchondral bone on a load bearing surface of the femoral condyle (medial, lateral, trochlear) (not in the patella); and   
   5. Size of defect measures less than 7 mm in depth, less than 6.0 cm in length, and area ranging from 1.6 - 10 square cm; and  
   6. Stable knee with intact meniscus and normal joint space on X-ray; and  
   7. No active inflammatory or other arthritis, clinically and by X-ray; and 
   8. Procedure is not being done for treatment of degenerative arthritis (osteoarthritis); and  
   9. Failure of conservative therapy (minimum of 2 months of physical therapy) as well as established surgical interventions (i.e., microfraction, drilling, abrasion) (diagnostic arthroscopy, lavage, or debridement is not considered adequate to meet this criterion); and  
   10. Cooperative person for post-operative weight bearing restrictions and activity restrictions together with a potential for completion of post-operative rehabilitation; and  

   11. Informed consent with realistic expectations. 

2. Aetna considers autologous chondrocyte implants experimental and investigational for patellar or talar lesions, or lesions of other joints and all other indications because the effectiveness of autologous chondrocyte implants for these lesions has not been established.

3. Aetna considers the use of Bio-Gide (resorbable bilayer membrane made of porcine collagen) for autologous chondrocyte implantation experimental and investigational.

See also CPB 637 - Osteochondral Autografts (Mosaicplasty, OATS). 

Articular cartilage damaged through acute or chronic trauma or osteochondritis dessicans, has limited ability to regenerate, leading to the symptoms of pain, restricted mobility and locking.  Current treatment methods to stimulate repair of the cartilage include shaving the margins of the damaged cartilage to remove mechanical obstructions or irritants (abrasion or debridement) or drilling through the cartilage through the underlying bone into the vascular marrow in order to permit the ingrowth of fibrocartilage from the marrow.  Long standing severe damage to the articular cartilage can lead to debilitating osteoarthritis, which ultimately may require a total knee arthroplasty.

Autologous chondrocyte implants (autologous chondrocyte transplant) (Carticel, Genzyme Inc., Cambridge, MA) has been investigated as a means of a three-step treatment for repairing cartilage defects in the knee.  First, normal cartilage is harvested from a joint margin during an arthroscopic biopsy procedure.  This biopsy of an articular surface serves as the source of cultured chondrocytes.  This specimen of live articular cartilage is placed into a culture medium. Under a strictly controlled environment the cells are separated from the cartilage.  These cells are then multiplied using a cell-culture technique.  They are stored in the frozen state and are thawed and have a final culturing process before they are shipped to the operating room on the day of the implantation.  It takes about six weeks to culture chondrocytes for implantation.  Approximately 12 million cartilage cells are present in the 0.4ml medium that is ultimately implanted into the defect.  The cultured chondrocytes are implanted into the cartilage defect in a second open arthrotomy procedure.

Patients are referred for autologous chondrocyte implantation after already having had surgery for an articular cartilage problem. If the patient remains symptomatic, and the patient and the surgeon decide that autologous chondrocyte implant is the best option, then an arthroscopic biopsy is planned.

Ideally, candidates for autologous chondrocyte implant should be between 15 and 60 years of age, have full thickness localized defects of the femoral condyles, have intact menisci, have no generalized chondromalacia, have no limb misalignment and are willing and able to undergo vigorous rehabilitation.  This procedure is not recommended for patients who have an unstable knee and for patients sensitive to materials of bovine origins. It is also not recommended for use in children, and not yet in any joint other than the knee.

There is a paucity of evidence on the comparative efficacy of autologous chondrocyte implants to established surgical procedures for articular cartilage defects.  An assessment by the BlueCross BlueShield Association Technology Evaluation Center (TEC, 2003) stated that there was insufficient evidence that the unique components of autologous chondrocyte implantation -- the implantation of cultured chondrocytes -- improves clinical outcomes.  The TEC assessment noted that autologous chondrocyte implantation has four components -- debridement of the injured area, coverage of the injured area with a periosteal tissue flap, implantation of cultured chondrocytes, and physical rehabilitation.  The TEC assessment noted that three of the four components of autologous chondrocyte implantation -- use of a periosteal flap, debridement and rehabilitation – are not unique to autologous chondrocyte implantation, and these components of the procedure may account for some or all of the clinical improvements noted in uncontrolled studies of this procedure.  The TEC assessment stated: "The available evidence is not sufficient to permit conclusions about the independent effect of the novel components of [autologous chondrocyte transplantation] ACT on health outcomes.  The available evidence reports that ACT for the treatment of clinically significant, focal defects of the femoral condyle is associated with improved health outcomes such as diminished pain and improved joint function over the short term.  However, the available evidence is not sufficient to determine if the improvements are caused by the use of autologous chondrocytes (the defining feature of ACT) or how the outcomes achieved with ACT compare with the outcomes achievable simply by use of debridement with rehabilitation."

The main deficiency of the existing evidence is that there are no published controlled studies that actually compare the outcomes of ACT with any other treatments or even with the natural progression of the disease.  The available studies do 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.

Other published structured evidence reviews have reached similar conclusions about the paucity of comparative studies of autologous chondrocyte implantation.  The National Institute for Clinical Excellence (2005) reviewed the evidence supporting the use of autologous chondrocyte implantation for full-thickness cartilage defects in knee joints.  The assessment noted the paucity of prospective controlled clinical studies comparing the outcomes of autologous chondrocyte implantation to alternative treatment modalities.  The assessment noted that most of the available evidence for autologous chondrocyte implant is from uncontrolled case series, and that this literature is subject to bias because of the inherent weakness of case series.  The assessment also noted that the long-term impact of autologous chondrocyte implantation is poorly documented.  The assessment concluded that it is not possible to draw definitive conclusions about the clinical effectiveness of this technology based on available literature. Quality Improvement Scotland (NHS QIS, 2005) concurred with the conclusions of the NICE assessment.

A evidence review prepared for the Cochrane Collaboration by Wasiak, et al. (2006) concluded that "[t]he use of ACI and other chondral resurfacing techniques is becoming increasingly widespread. However, there is at present no evidence of significant difference between ACI and other interventions." Four randomized controlled trials including 266 participants met inclusion criteria. One trial of ACI versus mosaicplasty (citing Bentley, et al., 2003) reported statistically significant results for ACI at one year, but only in a post-hoc subgroup analysis of participants with medial condylar defects;  when taking into account all participants, no significant differences were noted. A second trial of ACI versus mosaicplasty found no statistically significant difference in clinical outcomes at two years (citing Horas, et al., 2003). There was no statistically significant difference in outcomes at two years in a trial comparing ACI with microfracture (citing Knutsen, et al., 2004). In addition, one trial of matrix-guided ACI (MACI) versus microfracture did not contain enough long-term results to reach definitive conclusions (citing Basad, et al., 2004). The review concluded that "[a]dditional good quality randomised controlled trials with long-term functional outcomes are required."

An assessment by the National Coordinating Centre for Health Technology Assessment (NCCHTA) (Jobanputra, et al., 2001) concluded that "autologous chondrocyte transplantation should be regarded as an experimental therapy." More recently, a cost-effectiveness analysis from NCCHTA (Clar, et al., 2005) concluded that "[t]here is insufficient evidence at present to say that ACI is cost-effective compared with microfracture or mosaicplasty." 

An assessment of autologous chondrocyte transplantation by the French National Authority for Health (HAS, 2005) concluded: "It is difficult to determine either the benefit/risk ratio or the role of the technique in managing isolated chondral tissue defects in young subjects, as there are insufficient comparative trials of a good level of evidence or long-term follow-up.  ACI is an emerging technique which is still very much in the development stage." 

A systematic evidence review of autologous chondrocyte transplantation by the Galacian Agency for Health Technology Assessment (AVALIA-T, 2005) found that "[t]here is no evidence showing that ACI is better than other procedures on the treatment of chondral lesions of the knee." A reassessment of ACI by the Galacian Agency for Health Technology Assessment (AVALIA-T, 2006) reached similar conclusions: "Most of the articles are poor-quality case series; and cohort studies do not improve existing evidence. Clinical trials do not suggest better outcomes when comparing ACI against other procedures (mosaicplasty); but they point MACI [matrix-guided ACI] to be safer than ACI, mainly due to a decrease on the risk of periosteal hypertrophy." The assessment concluded that ACI has yet to be proven superior to other procedures for osteochondral lesions of the knee, and that randomized controlled clinical trials of ACI and MACI of the knee and ankle are needed.

Published controlled clinical trials have compared autologous chondrocyte implant to established procedures.  Although results of available clinical studies have not been consistent, the strongest available evidence suggests that outcomes of microfracture may be superior to autologous chondrocyte implant. Knutsen, et al. (2004) compared short-term clinical outcomes of autologous chondrocyte implantation and microfracture in a randomized controlled clinical trial involving 80 persons with a single large symptomatic cartilage defect on the femoral condyle.  At two-years follow-up, the investigators reported significantly better improvement in functional status (according to the SF-36 physical component score) in the microfracture group than in the autologous chondrocyte implantation group. Knutsen, et al. (2007) reported on the results of 5-year follow up. The investigators found no significant difference in the clinical and radiographic results between the ACI group and the microfracture group. At the five-year follow-up interval, there were nine failures (23 percent) in both groups.  

A study reported in abstract form by Anderson et al. (2003) compared autologous chondrocyte implantation with microfracture in 46 patients with full-thickness cartilage lesions greater than 2 cm in size.  The investigators reported a mean improvement in the Cincinnati score was 3.1 for autologous chondrocyte implantation and 1.3 for microfracture.  The investigators reported that the reduction in pain was also better with autologous chondrocyte implantation compared with microfracture.  Although this study was prospective, there was no random assignment to treatment groups; thus this study is of weaker design than the previously reported studies by Knutsen, et al. (2004, 2007).  In addition, this study has been criticized for having a high percentage of worker's compensation patients, and 5 of the 23 patients treated with microfracture were lost to follow-up.

There is inadequate evidence that the prior performance of marrow stimulation techniques affect the outcome of subsequent autologous chondrocyte implantation. Evidence from the Study of Treatment of Articular Repair (STAR) clinical trial found no significant difference in outcome of ACI between subjects whose prior surgery had been a marrow stimulation technique and subjects whose prior surgery had been a debridement. In this multicenter clinical study, 154 patients with failed treatment for articular cartilage defects of the knee received autologous chondrocyte implantation and were followed for four years. Outcomes included change from baseline in knee function, knee pain, quality of life, and overall health. The investigators reported that 126 patients (82%) completed the protocol; 76 percent of patients were treatment successes at study end, while 24 percent were deemed treatment failures. Mean improvements were observed from baseline to all time points for all outcome measures. The investigators reported that results did not differ between patients whose primary surgery had been a marrow-stimulating procedure and those whose primary procedure had been a debridement alone.

Minas, et al. (2009) reported on a single institution study of 321 consecutive patients treated with autologous chondrocyte implantation for full-thickness cartilage defects that reached more than 2 years of follow-up. Patients were grouped based on whether they had undergone prior treatment with a marrow stimulation technique. Outcomes were classified as complete failure if more than 25% of a grafted defect area had to be removed in later procedures because of persistent symptoms. The investigators reported that there were 522 defects in 321 patients (325 joints) treated with autologous chondrocyte implantation. On average, there were 1.7 lesions per patient. Of these joints, 111 had previously undergone surgery that penetrated the subchondral bone; 214 joints had no prior treatment that affected the subchondral bone and served as controls. Within the marrow stimulation group, there were 29 (26%) failures, compared with 17 (8%) failures in the control group. 

Both of these studies are limited by their cohort nature. In addition, the study by Minas, et al. (2009) is subject to bias as all of the ACIs were treated by a single investigator, and the investigator's assessments and subsequent treatment decisions may have been influenced by the investigator's knowledge of the patients' prior procedures. Randomized controlled clinical trials are needed to better assess whether marrow-stimulation techniques reduce the likelihood of success of subsequent ACI, or whether patients who fail marrow stimulation techniques would be more likely to fail ACI regardless of whether they had a prior marrow stimulation.

Two controlled clinical trials comparing autologous chondrocyte implantation with osteochondral transplant procedures have been published in recent years, with inconsistent results.  Bentley, et al. (2003) reported on the results of a randomized controlled clinical trial comparing autologous chondrocyte implantation to mosaicplasty in 100 patients with symptomatic defects of the articular cartilage of the knee.  After a mean follow-up of 19 months, functional assessment using the modified Cincinnati and Stanmore scores and objective clinical assessment showed that 88% had excellent or good results after autologous chondrocyte implantation compared with 69% after mosaicplasty.  Horas, et al. (2003) reported on the results of a randomized clinical study comparing transplantation of an osteochondral cylinder to autologous chondrocyte implantation in forty patients with an articular cartilage lesion of the femoral condyle.  The investigators reported that the improvements in function in subjects receiving autologous chondrocyte implantation lagged behind subjects receiving osteochondral cylinder transplantation.  In addition, the investigators reported that the defects treated with autologous chondrocyte implantation were primarily filled with fibrocartilage rather than hyaline cartilage.  These studies have been criticized for the short duration of follow up.  LaPrade (2003) commented that "[f]urther study with a minimum follow-up of 5 years as well as a complete and thorough histologic analysis is needed to determine which technique, [autologous chondrocyte implantation] or autogenous osteocartilaginous transfer, is best."

There are no adequate prospective clinical studies of the effectiveness of autologous chondrocyte implantation on defects of the patella or talus.  Prospective, randomized clinical studies are needed to assess the impact on functional status, disability, and pain.  In addition, studies need to compare the effectiveness of autologous chondrocyte implantation to established methods of treatment of patellar or talus defects.

Mont, et al. (1999) reported on the use of autologous chondrocyte implantation for indications not supported by adequate clinical data, including the use of autologous chondrocyte implantation for patellar lesions.  The investigators concluded: "The results of this study underscore the importance of controlled, application-limited experience before the release of new procedures for widespread clinical applications.  The uncontrolled use of this procedure may negatively skew the overall results for this technique, prejudicing a procedure that may be successful for the correct indications."

Mandelbaum et al (2007) stated that the treatment of trochlear cartilage lesions is challenging given the likely presence of other patellofemoral joint pathologies, the topography of the area, and the limited available treatment options.  Only 1 other study has examined the effectiveness of ACI for lesions of the patellofemoral joint.  These researchers hypothesized that patients treated with ACI for moderate-to-large isolated lesions located on the trochlea will report improvement in the modified overall condition scale score of the Cincinnati Knee Rating System at a minimum 2-year follow-up.  Using modified scales of the Cincinnati Knee Rating System, a total of 40 Cartilage Repair Registry patients rated their overall condition and symptoms at baseline and at a mean follow-up of 59 +/- 18 months were studied.  Factors likely to affect outcomes also were analyzed.  At baseline, patients were between the age of 16 to 48 years, had a mean total defect size of 4.5 cm(2), and reported an overall condition score of 3.1 points (poor).  Many failed a prior marrow-stimulation procedure (48 %).  Other procedures performed before baseline included tibio-femoral osteotomy in 23 % and lateral release or Fulkerson for patella mal-tracking in 13 %.  A total of 43 % of the patients were receiving workers' compensation at baseline.  Patients reported statistically significant improvement in their mean overall condition (3.1 points pre-operatively to 6.4 points post-operatively), pain (2.6 to 6.2 points), and swelling (3.9 to 6.3 points) scores.  Eleven patients experienced 17 subsequent procedures, and no patients had a failed implantation.  The authors concluded that ACI appears to improve function and reduce symptoms in young-to-middle aged patients with symptomatic, full-thickness articular cartilage lesions of the trochlea.

Farr (2007) noted that many patients with patellofemoral pain have multiple knee disorders, such as chondral defects, mal-alignment, and ligament insufficiency.  This investigator reviewed a treatment approach that included ACI and biomechanical altering procedures to reduce impairment and symptoms in patients with patello-femoral lesions and biomechanical disorders.  Thirty-eight patients (39 knees; mean age of 31.2 years) had large isolated (trochlear, 4.3 cm2; patellar, 5.4 cm2) or bipolar (mean total surface area of 8.8 cm2) patello-femoral lesions.  The minimum follow-up was 0.5 years (median of 3.1 years; range of 0.5 to 5.1 years).  The author observed a median improvement for the following patient and physician scores: modified Cincinnati Knee Rating System scores (3 points each), Lysholm score (31 points), and visual analog scale scores for resting (2 points) and maximum pain (3 points).  At a mean follow-up of 1.2 years in the 22 patients (23 knees) undergoing second-look arthroscopy, ACI-repaired tissue scored a median of 11 of 12 points using the International Cartilage Repair Society cartilage repair assessment.  Twenty-five patients had 32 subsequent surgeries, including 14 to remove hardware from a prior osteotomy; ACI failed in 3 patients.  The authors stated that despite the high rate of re-operation, the data suggested that combined treatment of ACI and biomechanical altering procedures may be a reasonable option for selected patients with co-existing patello-femoral lesions and mechanical disorders.

The Bio-Gide, a resorbable bilayer membrane, consists of highly purified collagen types I and III (porcine origin).  The membrane is highly biocompatible and supports wound healing.  The 3-dimensional, natural fiber structure promotes cell adhesion, serves as a matrix for soft tissue support and provides a barrier to the ingrowth of overlying soft tissue into underlying bony defects.  According to the product labeling, the Bio-Gide is used in dental surgery.  There is a lack of evidence in the peer-reviewed literature on the use of Bio-Gide for ACT procedures.

Appendix

*BMI is calculated by dividing the person's weight (in kilograms) by height (in meters) squared:

BMI = weight (kg) * [height (m)]²

Note: To convert pounds to kilograms, multiply pounds by 0.45. To convert inches to meters, multiply inches by 0.0254

or

For a simple and rapid calculation of BMI, please click below and it will take you to the Obesity Education Initiative.

*BMI = weight (kg) * [height (m)]²