Previous literature assessments conclude that there was insufficient evidence to permit conclusions concerning the health outcomes associated with ACI for the following reasons:
- The available studies do not consistently report all the information needed to assess the results and efficacy of ACI;
- The available data are based on two single-arm series with incomplete follow-up and no concurrent control groups; and
- The lack of controls for prior surgical management, adjunctive procedures, intensity of rehabilitation, and prognosis for improvement further confound the determination of treatment effect.
The FDA reported approval of Carticel primarily on case reports of 153 patients treated in Sweden. Of patients who were followed for at least 18-months after the treatment, about 70% showed improvement. Biopsies were done on 22 patients with Carticel. Fifteen showed hyaline cartilage development post therapy. Over one half of the patients who had failed to benefit from earlier surgical intervention without Carticel, had longer lasting improved outcomes when Carticel was included in the procedure.
While ACI appears to be a promising alternative to the standard approaches for cartilage defects of the knee, the efficacy and long-term outcomes remain unknown. Well-designed RCTs are required to prove the efficacy, continue to define patient selection criteria, and document the long-term outcomes when compared to alternative therapies. At the present time, ACI is a treatment plan ONLY for carefully selected patients.
This is a listing of the Patient Selection Criteria with the corresponding Rationale:
- Between the ages of 15- to 55-years old at the time of surgery. RATIONALE: Bone maturity is incomplete for patients younger than 15-years of age; implanting cartilage cells may affect bone growth and the results of the procedure. With age, the quality of the cartilage in the knee worsens; implanting poor-quality cartilage cells may affect results of the procedure.
- Body mass index of < 35. RATIONALE: Increased body weight increases strain and stress of the knee resulting in inadequate rehabilitation following the procedure and decreasing the durability of the procedure.
- Knee must be stable and aligned with normal joint spacing. RATIONALE: If the knee is not stable (ligaments and other structures) it is not possible to determine whether the symptoms are related to the knee’s instability or to cartilage defects. Unstable knees may affect the results of the procedure.
- The cartilage defect must be < six cm in length, < seven mm in depth, and total area size ranged from lower limit of three to upper limit of ten cm2. RATIONALE: Small cartilage defects are not likely to cause significant problems and symptoms may improve without surgical intervention.
- Full thickness cartilaginous, not the bone, defects found on the load bearing surface of the distal femur (medial or lateral femoral condyle lesions or trochlear lesions). RATIONALE: If more than cartilage is involved, adding back more cartilage may not solve the problem. The bone underneath the problem cartilage must be adequate since cartilage cannot directly replace missing bone.
- The cartilage defect(s) involve the weight-bearing surface of the knee called the femoral condyles. Other parts of the knee, including the area underneath the kneecap (patellofemoral joint) and the lower part of the knee joint (tibial articular cartilage) are normal. These areas including opposing surface lesions (known as kissing lesions) located on either side of the tibial surface of the femoral condyle and/or patellar surface. RATIONALE: There is less scientific data regarding other joints in the knee to determine whether health outcomes would be improved with ACI. The FDA has only approved the Carticel product for use on the femoral condyle (medial, lateral or trochlear aspects). If other parts of the knee are abnormal, the results of ACI on the femoral condyle may be affected.
- Operative site is infection-free. RATIONALE: Cultured chondrocytes introduced into a compromised infectious operative site can affect the integrity of new articular cartilage.
- Osteochondritis dissecans which involves both cartilage and bone is not suitable for ACI and is not covered. RATIONALE: If the osteochondritis dissecans has happened in the past and the bone is now normal, this exclusion does not apply.
- Degenerative joint disease (osteoarthritis [OA]) or inflammatory disease(s) (rheumatoid arthritis) is not suitable for ACI and is not covered. RATIONALE: These types of conditions may not respond to this procedure and the FDA has not approved the Carticel product for these indications.
- No evidence of cartilage defects in areas, other than the knee, such as the ankle. RATIONALE: The FDA has only approved the Carticel product for used on the femoral condyle (medial, lateral or trochlear aspects).
- No history of malignancy in bones, cartilage, fat, or muscle in the treated leg. RATIONALE: Prior malignancies of the treated leg may not facilitate new articular cartilage development and the FDA has not approved the Carticel product when given following a malignancy diagnosis.
- No history of sensitivities or allergies to gentamicin or anaphylactic response to bovine originated materials. RATIONALE: The FDA approved labeled approval warns that the Carticel product should not be given to patients with a known history of anaphylaxis to gentamicin or known sensitivities to materials of bovine origin.
- The patient must be capable of following the rigorous post-procedure rehabilitation protocol and should cease participation in those activities that resulted in the cartilage damage. RATIONALE: The outcome of the procedure may be affected by inadequate rehabilitation following the procedure and the durability of the procedure may be adversely affected by continued, avoidable, repetitive trauma. Coverage for a second or additional ACI procedure will not be allowed when there is evidence of persistence of continued, avoidable, repetitive trauma. This procedure limitation is in place whether or not the previous procedure was covered under the current benefit plan.
- Documentation is required for review of medical necessity, which includes patient chart notes confirming injury and prior treatments and therapies, x-ray reports documenting normal alignment and absence of OA, and photographs showing the presence of the cartilage defect and normal cartilage surrounding the knee. RATIONALE: Documentation confirms prior conservative and/or surgical treatments/therapies and current knee anatomy. Normal cartilage surrounding the defect is critical to carry the increasing weight bearing load during rehabilitation. The cartilage defect must be clearly visible and distinctly measurable. The photodocumentation should occur at the time of the arthroscopy to harvest chondrocytes.
NOTE: Additional procedures may be done during the second operative session; arthrotomy, such as repair of ligaments or tendons, or recreation of osteotomy for realignment of the joint. Therefore it may be difficult to attribute the outcomes entirely to the chondrocyte transplant procedure.
Inasmuch, as there are currently no generally agreed upon patient selection criteria, these patient selection criteria are based on the best available evidence on the efficacy and durability of ACI. They were developed to allow rational coverage determinations for individual cases, even though the published evidence of efficacy and durability is incomplete. Three FDA-required studies in-progress (a registry-based study, the Study of the Treatment of Articular Repair (STAR) and the periosteal study) have not yet concluded, nor been peer-reviewed, nor published in the scientific literature.
A search of the literature was completed through MedLine database for the period of July 2003 through May 2008. No additional published studies were identified that would prompt reconsideration of the policy statement, which remains unchanged.
A search of peer reviewed literature through May 2010 identified the following studies.
Results from the STAR trial have been published; these were previously available in the Carticel package insert and from a meeting presentation in July 2007. STAR was a prospective, open-label four-year study in 154 patients (mean age: 35-years; 69% male) 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 (e.g., 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 cm2 (range of 1-30 cm2), with 26% involving osteochondritis dissecans. Fifty patients (32%) had multiple lesions in the reference knee and 29 (19%) 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 five 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 six-months for up to four-years.
The primary outcome, treatment failure for ACI, was defined as any of the following:
- a patient underwent surgical retreatment that violated the subchondral bone or repeated ACI for the same index defect; or
- a complete delamination or removal of the graft; or
- a patient’s rating of the overall condition of the knee using the MCKRS failed to improve from the baseline knee score over three consecutive six-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 four-year follow-up. Thirty-seven patients (24%) were considered failures; 11 failed based on the surgical failure criterion and 26 failed based on the MCKRS criterion. Most of the 37 failures (92%) occurred within 30-months. At 48-months, three-fourths of all patients in the study (76%) 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 (54%) 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 (16%), graft overgrowth (15%), chondromalacia or chondrosis (12%), graft complications (i.e., fraying or fibrillation, 10%), graft delamination (6%), and joint adhesion (5%). Subsequent surgical procedures (regardless of relationship to ACI) included debridement of cartilage lesion (31%), lysis of adhesions (14%), other debridement (10%), meniscectomy (6%), loose body removal (5%), microfracture of the index lesion (5%), and scar tissue removal (5%). The most common cause for a subsequent surgical procedure was periosteal patch hypertrophy. A majority (61%) 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 four-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 RCTs 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. Finding a total of five RCTs and one 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. Twenty-eight studies describing 3,122 patients were included in the review; six of the studies were 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.
ACI versus Marrow-Stimulating Techniques
In a RCT of 80 patients randomized to ACI or microfracture of the knee (an arthroscopic marrow-stimulation procedure), Knutsen and colleagues reported no significant differences in the treatment groups at the two-year follow-up in macroscopic and histologic findings. The Lysholm and pain scores were also not significantly different at one- and two-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. A five-year follow-up on all 80 patients revealed 9 failures (23%) for both groups. There was a trend (p=0.10) for earlier failure in the ACI group (26- vs. 38-months) 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 ACI (n=57) versus microfracture (n=61); the average lesion size was 2.8 cm2. Chondrocytes were isolated from a cartilage biopsy specimen and expanded ex vivo (ChondroCelect, TiGenix of Belgium). ChondroCelect is not approved for use in the U.S. 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, and vascularization) and surface architecture were not improved relative to the microfracture group. Self-assessed pain and function with the Knee Injury and Osteoarthritis Outcome Score (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 cm2 of the femoral condyle, trochlea, or patella (43 cases due to injury) were randomized to 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. 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 a two-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: 3.2 to 5.6 cm2) who were randomly assigned to undergo ACI or osteochondral autografting. 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 five biopsy specimens at two-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 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: 1 to 12 cm2) to ACI or mosaicplasty. 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 seven-years. Clinical assessment at one-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 one-year showed filling of the defects following ACI, but soft tissue was observed in 50% of patients. Biopsy specimens taken from 19 ACI patients revealed a mixture of hyaline and fibrocartilage.
Dozin et al. reported results from a multicenter RCT in which ACI was compared to osteochondral autografting. Forty-four individuals (61% male, 39% female) aged 16- to 40-years (mean 28.7 +/- 7.8), 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 six-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, five who did not show up at the pre-surgery examination and could not be further traced, and two 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 (LKSS <60, LKSS 60–90, LKSS 90–100). With this scale, and including ten 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; range: 1–12 cm2) of the femoral condyle (54%), trochlea (6%), or patella (40%) to ACI with either a periosteal or collagen cover. At two-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.
Browne et al. published five-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. Patients were an average of 37-years old, with a mean lesion size of 4.9 cm2 (range: 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 five-years following the index procedure, the average follow-up score was 5.8 (fair to good), a 2.6-point improvement on the ten-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), loose or delaminated periosteal patch (n=4), and meniscal tears (n=4). Factors associated with failure in six patients were nonadherence 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- to 11-years) on a cohort of 56 patients (45- to 60-years of age) with lesions of the femoral condyle (49%), trochlea (29%), or patella (22%). 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. Three different ACI techniques had been used, periosteum-covered, membrane-covered (Chondrogide Geistlich Biomaterials, Switzerland), and three-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. 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. The average defect was 4.4 cm2. Depending on surgeon preference, patients received ACI with a periosteal patch, Chondroglide membrane, or MACI. Fourteen patients (15%) were lost to follow-up and 11 patients (12%) 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, LKSS, and International Knee Documentation Committee score, a physical examination was performed by an independent examiner who was blinded to data obtained at the time of surgery, including defect 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 nine patients (13%) were considered failures. Results were not divided according to the type of implant (ACI or MACI), although it was reported that two 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. 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 ACI together with meniscal transplantation in the same compartment. 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 (11%) were considered failures before two-years, and three were lost to follow-up (8%), resulting in 29 evaluable patients at an average of 4.5-years after surgery. The LKSS improved from an average score of 58 to 78; maximum pain decreased an average 33% (from 7.6 to 5.1). Excluding the four failures, 68% of their patients required additional surgeries; 52% had one additional surgery, and 16% required two 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%). The LKSS 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 (7%) and five (17%) underwent subsequent surgery. Although results seemed promising, evidence is insufficient to permit conclusions regarding the effect of combined transplantation-implantation procedures on health outcomes.
A threefold increased failure of ACI after previous treatment with marrow stimulation techniques was found in a cohort of 321 patients with more than two-years of follow-up (of 332 treated). The average lesion was eight cm2, and the indications for treatment of cartilage defects with ACI included one 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 (17 of 214) that did not have prior marrow stimulation of the lesion, compared with 26% (29 of 11 joints) 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, one case series of eight patients studied the use of ACI for osteochondritis dissecans of the talus. Outcome measures included arthroscopic and radiologic evidence of cartilage-like tissue with coverage of the osteochondral defects six-months after treatment. Another case series of eight patients with osteochondritis due to trauma were treated with ACI and an ankle fixation device for one-year. Outcomes were improved American Foot and Ankle Society scores in one 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 U.S. prospective study of ACI of the talus. The 11 patients described had failed nonsurgical and prior surgical management, with a mean of 1.9 prior surgical procedures including debridement, drilling, pinning, or abrasion arthroplasty. Osteotomy was performed 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 two 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 six weeks, as indicated by radiographic healing of the osteotomy. This was followed by three 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 (range: 9- to 24-months) and nine underwent magnetic resonance imaging evaluation at a mean of 31-months (range: 16- to 4-months). At a mean 38-month clinical evaluation (range: 24- to 60-months), three patients were classified as excellent (no pain, swelling, or locking with strenuous activity), six were classified as good, two 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 (from 1.3 to 4.0), Finsen score, and the American Orthopaedic Foot and Ankle Society ankle hindfoot score (from 47 to 84). 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 two patients (20%). The repair tissue was softer to probing than the adjacent cartilage, although an increase in firmness was noted from the nine to 24-month observations. Use of MACI for osteochondral lesions of the talus has also been reported from overseas.
A search of the clinical trials database 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 four sites in the U.S. The anticipated completion date, including two-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. 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 ACI. 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.
Stem Cells Used For Cartilage Lesion Treatment
Due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature, the use of stem cells to treat focal articular cartilage lesions is considered investigational.
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 RCTs 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 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 use 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 U.S.; therefore, these are considered investigational. Minced cartilage techniques are in the early stages of development and testing and/or not approved in the U.S.; these are considered investigational.