Articular cartilage is a flexible, elastic tissue that covers the surface of the tibia, femur, and the underside of the patella. It allows for smooth articulation of joints. Damaged articular cartilage and osteochondral defects (OCD) of the knee often fail to heal on their own. They are frequently associated with pain, disability, loss of function, and long-term complications of osteoarthritis. Various methods of cartilage resurfacing have been investigated, including marrow-stimulation techniques such as subchondral drilling, microfracture (MF), and abrasion arthroplasty. These procedures are considered standard therapies and attempt to restore the articular surface by including the growth of fibrocartilage into the chondral defect. However, fibrocartilage does not share the same biochemical properties as hyaline cartilage. Compared to the original hyaline cartilage, fibrocartilage has less capability to withstand shock or shearing force. It can also degenerate over time, which results in symptom recurrence. Therefore, various treatment strategies for chondral resurfacing with hyaline cartilage have been investigated.
Autologous chondrocyte implantation (ACI) attempts to regenerate hyaline-like cartilage and restore durable function. A healthy area of articular cartilage is identified and biopsied through arthroscopy. The tissue is minced and enzymatically digested, and the chondrocytes are separated by filtration. After the cells are expanded in vitro, they are implanted into the chondral defect. Second-generation techniques include combinations of autologous or allogeneic chondrocytes, minced cartilage, and growth factors. Third-generation techniques embed chondrocytes into three-dimensionally constructed scaffolds for cell growth, which may not need a periosteal cover or fixing stitches as they can be trimmed to fit exactly into the cartilage defect with fibrin glue.
The entire ACI procedure consists of four steps. The first step involves the initial arthroscopy and biopsy of normal cartilage. Second, culturing of chondrocytes can take up to 11-21 days. Third, a separate arthrotomy is performed to create a periosteal flap and implant the chondrocytes. Finally, after the implant, the individual will participate in a postoperative rehabilitation protocol.
Based on the available peer-reviewed literature, the general consensus is that ACI is best utilized in individuals who have reached skeletal maturity up through 55 years of age, and who were not responsive to previous arthroscopic or other surgical repair. ACI is indicated for the repair of symptomatic, isolated, full-thickness cartilaginous defects of the femoral condyle that are caused by pain and/or joint locking and that are at least 1.5 cm2 in size. The procedure is not indicated when osteoarthritis or joint instability is present. The available published peer-reviewed literature is inadequate to support the use of ACI in joints other than the knee.
According to the American Academy of Orthopaedic Surgeons (AAOS), most candidates eligible for articular cartilage restoration are young adults with a single injury or lesion. Older individuals, or those with many lesions in one joint, are less likely to benefit from articular cartilage restoration surgery. ACI is most useful for younger individuals who have single defects larger than 2 cm in diameter. It has the advantage of using the treated individual's own cells, so there is no danger of tissue rejection, but the disadvantage of being a two-stage procedure, which requires an open incision and takes several weeks to complete.
FDA-approved matrix-induced chondrocyte implantation (i.e., MACI® (Vericel) autologous cultured chondrocytes on porcine collagen membrane) is an equally acceptable alternative to autologous cultured chondrocytes.
Several other second-generation methods for implanting autologous chondrocytes in a biodegradable matrix are currently in development and testing. These include ChondroCelect (characterized chondrocyte implantation; TiGenex, Phase III trial), BioCart II (ProChon Biotech, Phase II trial), Cartilix (polymer hydrogel; Cartilix), Cartipatch (solid scaffold with an agarose-alginate matrix; TBF Tissue Engineering, Phase III trial), NeoCart (ACI with a 3-dimensional chondromatrix; Histogenics, Phase II trial), Hyalograft C (ACI with a hyaluronic acid-based scaffold; Fidia Advanced Polymers), and CAIS (Cartilage Autograft Implantation System, which harvests cartilage and disperses chondrocytes on a scaffold in a single-stage treatment; Johnson & Johnson). Although these second-generation ACI products have been used clinically in Europe, but none, other than MACI®, are FDA-approved for use in the US at this time.
DeNovo NT Graft consists of particulated natural articular cartilage with living cells. The tissues are recovered from juvenile donor joints. DeNovo NT consists of tissue fragments that are mixed intra-operatively with fibrin glue before implantation in the prepared lesion. It is proposed that mincing the tissue helps both with cell migration from the extracellular matrix and with fixation. Because there is no use of chemicals and there is minimal manipulation, the allograft tissue does not require FDA approval for marketing.
DeNovo ET Live Chondral Engineered Tissue Graft (Neocartilage®) is produced by ISTO Technologies with exclusive distribution rights by Zimmer. In June 2006, the (FDA) approved ISTO’s Investigational New Drug (IND) application for Neocartilage®, a tissue-engineered living tissue graft designed to repair cartilage defects, restore joint function, and relieve pain in the knee.
PEER-REVIEWED LITERATURE
OSTEOCHONDRAL DEFECTS OF THE KNEE
In a prospective, randomized, controlled trial, Bentley et al. (2003) evaluated 100 individuals with a symptomatic lesion of the articular cartilage in the knee who were randomized to undergo either osteochondral autograft transplantation (OAT; n=42) or ACI (n=58). The mean age of the study participants was 31.3 years (16 to 49). The mean duration of symptoms was 7.2 years with a mean follow-up of 19 months (12 to 26). Outcome measurements included objective clinical assessment and function assessment using modified Cincinatti and Stanmore scores. Eighty-eight percent of individuals had excellent or good results after ACI compared with 69% of individuals after OAT. Arthroscopy at one-year follow-up demonstrated excellent or good results in 82% of individuals after ACI and in 34% of individuals after OAT. All five patellar OAT mosaicplasties failed. The authors concluded that ACI was superior to OAT for the repair of articular defects in the knee. The study is limited in its small sample size and relatively short follow-up period.
In a systematic review, Magnussen et al. (2008) evaluated ACI and OAT for the treatment of isolated articular cartilage defects in the knee, while considering the effect of lesion size on clinical outcomes. The authors included five randomized, controlled trials and one prospective comparative study, representing 421 individuals. The surgical procedures included ACI, OAT, matrix-induced ACI, and MF. The minimum follow-up was 1 year (mean of 1.7 years; range of 1 to 3 years). All included studies that documented greater than 95% follow-up for clinical outcome measurements. No surgical technique consistently demonstrated superior results when compared with the others. In larger lesions, the outcomes for MF tended to be worse, however. All studies reported improvement in clinical outcome measurements postoperatively in all treatment groups when compared with preoperative assessment. However, there were no non-operative comparative groups included in any of the studies. The authors concluded that MF may be used as a first-line treatment for articular cartilage defects discovered at arthroscopy because it does not preclude later treatment with ACI or OAT. No single surgical technique produced superior clinical results for the treatment of full-thickness articular cartilage defects. The study is limited in its lack of an appropriate non-surgical control group, heterogeneous study designs, and short-term follow-up periods.
In a systematic review, Bekkers et al. (2009) identified the parameters for valid treatment selection in the repair of articular cartilage lesions of the knee. The authors included a total of 4 randomized controlled trials in their review and found that lesion size, activity level, and age were the influencing parameters for the outcome of articular cartilage repair surgery. Lesions greater than 2.5 cm2 should be treated with either ACI or OAT, while MF is a good first-line treatment option for smaller lesions. Active individuals showed better results after ACI or OAT when compared to MF. Younger individuals under 30 years of age seemed to benefit more from any form of cartilage repair surgery than those over 30 years of age. The authors concluded that the influencing parameters for the outcome of articular cartilage repair surgery should direct surgeons toward evidence-based treatment of articular cartilage lesions of the knee.
In a systematic review, Harris et al. (2010) examined the safety and effectiveness of ACI for the treatment of cartilage defects in the knee. Thirteen level I and II studies (e.g., systematic reviews, meta-analyses, randomized controlled trials) representing 917 individuals were included in this review. Modified Coleman Methodology Score (MCMS) was 54 out of 100. Patients underwent ACI (n=604), MF (n=271), or OAT (n=42). Three of the 7 studies indicated better clinical outcomes after ACI when compared to MF after 1 to 3 years of follow-up. Three other studies indicated no difference in these treatments after 1 to 5 years of follow-up. ACI and OAT demonstrated similar short-term outcomes, although two studies indicated that individuals undergoing OAT recovered more quickly. Although outcomes were equivalent between first- and second-generation ACI and between open and arthroscopic ACI, four studies indicated that complication rates were higher with open periosteal cover, first-generation ACI. Younger individuals with shorter pre-operative duration of symptoms and fewer prior surgical procedures had the best outcomes after both ACI and MF. A defect size greater than 4 cm2 was the only predictor of better outcomes when ACI was compared with a non-ACI surgical technique. The authors concluded that ACI, MF, and OAT provided short-term success for the treatment of cartilage defects. The study is limited in its relatively short-term follow-up period and heterogeneous study designs.
In a prospective, randomized, controlled trial, Van Assche et al. (2010) evaluated the functional performance of ACI in an open knee procedure when compared to MF for the treatment of OCD of the knee. Sixty-seven individuals with local cartilage defect with a mean size of 2.4 cm2 of the femoral condyle of the knee were included in the study. Identical rehabilitation protocols were implemented for both the ACI and MF groups. Study participants were followed over a 2-year period. Active knee flexion and extension range, anterior laxity, knee extension strength (concentric at 60 degrees), and single leg hop performance were evaluated pre-surgery and at 6, 9, 12, and 24 months post-surgery. The change in outcome measurements was comparable between the two treatment arms over the course of the 2-year period. Of the 54 individuals that were followed until the 24-month end-point, 70% (n=38) returned to > 85% in overall functional performance. A decrease in functional performance at 6 months following ACI resulted in slower recovery at 9 and 12 months compared to MF. The authors concluded that ACI individuals had similar overall functional outcomes when compared to MF individuals. The study is limited in its small sample size and short-term follow-up period.
In a randomized controlled trial, Zeifang et al. (2010) evaluated the safety and effectiveness of matrix-associated ACI when compared to traditional periosteal flap ACI. Twenty-one individuals with symptomatic isolated full-thickness cartilage defects were randomized. The main outcome measurement was the postoperative change in knee function as assessed by International Knee Documentation Committee (IKDC) score at 12 months. Secondary outcomes included postoperative changes in health-related quality of life and knee functionality assessed by Lysholm and Gillquist scores. While there was a significant improvement in knee functionality in the traditional ACI group, as assessed by Lysholm and Gillquist scores at 12 months and 24 months, there was no significant improvement in the matrix group. Additionally, there was no difference in the effectiveness between the original and matrix groups at 12 and 24 months with respect to IKDC scores. The study is limited in its small sample size and short-term follow-up period.
In a systematic review, Harris et al. (2011) compared the failure, re-operation, and complication rates of all generations and techniques of ACI for the treatment of knee OCD. MCMS were calculated for all studies. Eight-two studies were identified for inclusion, representing 5,276 individuals and 6,080 defects. Ninety percent of the studies in this review were rated poor according to the MCMS. There were 305 failures overall, representing 5.8% of study participants. Individuals undergoing third-generation ACI were precluded from this systematic review due to low numbers. The mean time to failure was 22 months. Failure rates were highest with periosteal ACI (PACI). Failure rates for PACI, collagen-membrane cover ACI (CACI), second-generation, and all-arthroscopic second-generation ACI were 7.7%, 1.5%, 3.3%, and 0.83%, respectively. The failure rate of arthrotomy-based ACI was 6.1% vs. 0.83% for all-arthroscopic ACI. The overall rate of re-operation was 33%. Re-operation rates after PACI, CACI, and second-generation ACI were 36%, 40%, and 18%, respectively. Unplanned re-operation rates after PACI, CACI, second-generation, and all-arthroscopic second-generation ACI were 27%, 5%, 5%, and 1.4%, respectively. The authors concluded that while the use of a collagen-membrane cover, second-generation techniques, and all-arthroscopic second-generation approaches have reduced the failure, complication, and re-operation rates after ACI, failure rates are highest with PACI. The study is limited in its heterogeneity of study designs and study populations.
In a retrospective study, Panagopoulos et al. (2012) evaluated the early functional outcome and activity levels after ACI in professional soldiers and athletes for the treatment of knee OCD. Nineteen individuals with an average of 32.2 years were treated with ACI and followed for a minimum of 2 years. All individuals, with the exception of 2, had received previous arthroscopic treatment with debridement and/or MF. The mean size of post-debridement defect was 6.54 cm2. The average subjective knee evaluation and Lysholm scores improved from 39.16 and 42.42, respectively, preoperatively to 62.4 and 69.4, respectively, at last follow-up. Second-look arthroscopy was performed in 11 individuals due to persistent pain, decreased range of movement, and mechanical symptoms. Thirty-one percent of the individuals (n=6) returned to pre-injury levels of athletic performance. The authors concluded that mid-term results of ACI in high-performance athletes may not be as good as reports of other similar technologies, including osteochondral grafting. The authors cited numerous issues including prolonged rehabilitation and subsequent surgical interventions and note that participant age and defect size may potentially influence the outcome and overall performance in this select study population. The study is limited in its small sample size, short-term follow-up period, and retrospective nature.
In a systematic review, Kon et al. (2013) reviewed the current state of evidence on matrix-assisted ACI for knee OCD. A total of 51 articles were selected, including 3 randomized controlled trials and 10 comparative studies. The authors reported that matrix-assisted ACI procedures may be a therapeutic option for the treatment of chondral lesions, and that low-quality studies with short- to medium-term follow-up report positive outcomes for specific patient populations. However, high-level studies are lacking; systematic long-term evaluation and randomized controlled trials are needed to confirm the potential of matrix ACI, especially when compared to traditional approaches.
The FDA approval for MACI®, which is an autologous cultured chondrocytes on porcine collagen membrane) (Vericel, Cambridge, MA) was supported by the results of SUMMIT trial (Superiority of MACI implant versus Microfracture Treatment in patients with symptomatic articular cartilage defects in the knee), a Phase 3 two‑year, prospective, multicenter, randomized, open-label, parallel-group study that enrolled a total of 144 patients, ages 18 to 54 years, with at least one symptomatic Outerbridge Grade III or IV focal cartilage defect on the medial femoral condyle, lateral femoral condyle, and/or the trochlea (Saris, et al., 2014; Vericel, 2016). The co-primary efficacy endpoint was change from baseline to Week 104 for the subject's Knee injury and Osteoarthritis Outcome Score (KOOS) in 2 subscales: Pain and Function (Sports and Recreational Activities [SRA]). At Week 104, KOOS pain and function (SRA) had improved from baseline in both treatment groups, but the improvement was statistically significantly (p<0.001) greater in the MACI group compared with the microfracture group. In a responder analysis, the proportion of subjects with at least a 10-point improvement in both KOOS pain and function (SRA) was greater in the MACI group (63/72 = 87.5%; 95% CI [77.6%, 94.6%]) compared with the microfracture group (49/72 = 68.1%; 95% CI [56.0%, 78.6%]). Patients from the two-year SUMMIT study had the option to enroll in a three-year follow-up study (extension study). A majority of the patients who completed the SUMMIT study also participated in a three year extension study. The FDA concluded that the overall efficacy data support a long-term clinical benefit from the use of the Maci implant in patients with cartilage defects of the knee.
The most frequently occurring adverse reactions (≥5%) reported for MACI in the 2-year randomized, controlled clinical trial were arthralgia, tendonitis, back pain, joint swelling, common cold-like symptoms, headache, and joint effusion. Serious adverse reactions reported for MACI were arthralgia, cartilage injury, meniscus injury, treatment failure, and osteoarthritis.
According to the manufacturer, Maci is expected to be a less tedious technical procedure performed via mini-arthrotomy (Vericel, 2016). The seeded cellular membrane is directly implanted to the defect area and secured by a fibrin sealant, which eliminates the need for suturing and testing of water tightness. The Maci procedure is quicker to perform and requires a smaller incision.
MACI is contraindicated in patients with a known history of hypersensitivity to gentamicin, other aminoglycosides, or products of porcine or bovine origin. MACI is also contraindicated for patients with severe osteoarthritis of the knee, inflammatory arthritis, inflammatory joint disease, or uncorrected congenital blood coagulation disorders. MACI is also not indicated for use in patients who have undergone prior knee surgery in the past six months, excluding surgery to procure a biopsy or a concomitant procedure to prepare the knee for a MACI implant. MACI is contraindicated in patients who are unable to follow a physician-prescribed post-surgical rehabilitation program.
The safety of MACI in patients with malignancy in the area of cartilage biopsy or implant is unknown. Expansion of present malignant or dysplastic cells during the culturing process or implantation is possible.
Patients undergoing procedures associated with MACI are not routinely tested for transmissible infectious diseases. A cartilage biopsy and MACI implant may carry the risk of transmitting infectious diseases to healthcare providers handling the tissue. Universal precautions should be employed when handling the biopsy samples and the MACI product.
To create a favorable environment for healing, concomitant pathologies that include meniscal pathology, cruciate ligament instability and joint misalignment, must be addressed prior to or concurrent with the implantation of MACI.
Treatment guidelines regarding the use of thromboprophylaxis and antibiotic prophylaxis around orthopaedic surgery should be followed. Use in patients with local inflammations or active infections in the bone, joint, and surrounding soft tissue should be temporarily deferred until documented recovery.
The MACI implant is not recommended during pregnancy. For implantations post-pregnancy, the safety of breast feeding to infant has not been determined. Use of MACI in pediatric patients or patients over 55 years of age has not been assessed.
OSTEOCHONDRAL DEFECTS OF THE TALUS
The available peer-reviewed literature with respect to ACI for the treatment of osteochondral lesions of the ankle is of low quality (e.g., retrospective case series) and quantity. In a meta-analysis, Niemeyer et al. (2012) evaluated the efficiency and effectiveness of ACI for talar lesions. Of the 16 studies included in this meta-analysis representing 213 cases, all studies represented retrospective case series. Osteochondral and chondral defects were a mean size of 2.3 ± 0.6 cm2. The mean study size was 13 individuals (2 to 46) with a mean follow-up of 32 ± 27 months (6 to 120). A total of 9 different scores were used as outcome parameters, including overall clinical success rate. The mean Coleman Methodology score, which assessed the quality of studies reporting outcomes, was 65 out of a 100 point scale. The overall clinical success rate was 89.9%. The authors concluded that the evidence concerning the use of ACI for osteochondral and chondral defects of the talus was still elusive. Although clinical outcomes are promising, a lack of controlled studies does not allow for superiority or inferiority to other techniques such as MF to be determined. The study is limited in its heterogeneity and inclusion of retrospective studies.
SUMMARY
A variety of procedures are being developed to resurface articular cartilage defects. Autologous chondrocyte implantation (ACI) 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.
For individuals who have focal articular cartilage lesion(s) of the weight-bearing surface of the femoral condyles, trochlea, or patella who receive ACI, the evidence includes systematic reviews, randomized controlled trials, and prospective observational studies. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, and quality of life. There is a large body of evidence on ACI for the treatment of focal articular cartilage lesions of the knee. For large lesions, ACI results in better outcomes than microfracture, particularly in the long term. In addition, there is a limit to the size of lesions that can be treated with osteochondral autograft transfer, due to a limit on the number of osteochondral cores that can be safely harvested. As a result, ACI has become the established treatment for large articular cartilage lesions in the knee. In 2017, first-generation ACI with a collagen cover was phased out and replaced with an ACI preparation that seeds the chondrocytes onto a bioresorbable collagen sponge. Although the implantation procedure for this second-generation ACI is less technically demanding, studies to date have not shown improved outcomes compared with first-generation ACI. Some evidence has suggested an increase in hypertrophy (overgrowth) of the new implant that may exceed that of the collagen membrane covered implant. Long-term studies with a larger number of patients will be needed to determine whether this hypertrophy impacts graft survival. Based on mid-term outcomes that approximate those of first-generation ACI and the lack of alternatives, second-generation ACI may be considered an option for large disabling full-thickness cartilage lesions of the knee. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
For individuals who have focal articular cartilage lesions of joints other than the knee who receive ACI, the evidence includes systematic reviews of case series. Relevant outcomes are symptoms, change in disease status, morbid events, functional outcomes, and quality of life. The greatest amount of literature is for ACI of the talus. Comparative trials are needed to determine whether ACI improves outcomes for lesions in joints other than the knee. The evidence is insufficient to determine the effects of the technology on health outcomes.
MACI for patellar lesions has been evaluated in a systematic review and a nonrandomized comparative study. The included studies reported outcomes that did not differ substantially from those using MACI for tibiofemoral lesions. Observational studies have indicated that a prior cartilage procedure may negatively impact the success of ACI, realignment procedures improve the success of ACI for patellar lesions, and ACI combined with meniscal allograft results in outcomes similar to either procedure performed alone.
