Takahiro Ogura

A 20-Year Follow-up After First-Generation Autologous Chondrocyte Implantation

Background: Treating articular cartilage defects is a demanding problem. Although several studies have reported durable and improved clinical outcomes after autologous chondrocyte implantation (ACI) over a long-term period, there is no report with over 20 years’ follow-up. Purpose: To evaluate clinical outcomes after first-generation ACI for the treatment of knees with disabling, large single and multiple cartilage defects for which patients wished to avoid prosthetic arthroplasty, with a minimum of 20 years’ follow-up. Study Design: Case series; Level of evidence, 4. Methods: The authors reviewed prospectively collected data from 23 patients (24 knees; mean age, 35.4 years [range, 13-52 years]) undergoing ACI for the treatment of symptomatic, full-thickness articular cartilage lesions. A mean of 2.1 lesions per knee were treated over a mean total surface area of 11.8 cm2 (range, 2.4-30.5 cm2) per knee. Kaplan-Meier survival analysis and functional outcome scores, including the modified Cincinnati Knee Rating System, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Short Form–36 (SF-36), were used. Patients also self-reported an improvement in pain with a visual analog scale and a satisfaction survey. Results: The 20-year survival rate was 63% (95% CI, 40%-78%). The evaluation of the 15 knees with retained grafts demonstrated that all clinical scores except the WOMAC subscore for stiffness and SF-36 mental component summary score improved significantly and were sustained to 20 years postoperatively. Ninety-three percent of these patients rated knee-specific outcomes as good or excellent. The outcomes for 9 of 24 knees were considered failures, including 5 undergoing revision ACI and 4 being converted to arthroplasty at a mean of 1.7 and 5.9 years, respectively. Only 1 of 5 knees that underwent revision ACI was converted to arthroplasty at 1.9 years after the index surgery, and the other 4 patients were able to maintain their biological knee. Overall, 20 years later, 79% of patients maintained their native knee, for which they initially sought treatment, and were satisfied when evaluated. Conclusion: First-generation ACI provided satisfactory survival rates and significant clinical improvements over a 20-year follow-up, which offers an important standard for comparison with newer-generation ACI technologies of the future.

Long-term Outcomes of Autologous Chondrocyte Implantation in Adolescent Patients

Background: Treating symptomatic articular cartilage lesions is challenging, especially in adolescent patients, because of longer life expectancies and higher levels of functional activity. For this population, long-term outcomes after autologous chondrocyte implantation (ACI) remain to be determined. Purpose: To evaluate long-term outcomes in adolescents after ACI using survival analyses, validated outcome questionnaires, and standard radiographs. Study Design: Case series; Level of evidence, 4. Methods: We performed a review of prospectively collected data from patients who underwent ACI between 1996 and 2013. We evaluated 27 patients aged <18 years old (29 knees; mean age, 15.9 years) who were treated by a single surgeon for symptomatic, full-thickness articular cartilage lesions over a mean 9.6-year follow-up (median, 13 years; range, 2-19 years). A mean of 1.5 lesions per knee were treated over a mean total surface area of 6.2 cm2 (range, 2.0-23.4 cm2) per knee. Survival analysis was performed using the Kaplan-Meier method, with graft failure as the end point. The modified Cincinnati Knee Rating Scale, Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale, and Short Form 36 scores were used to evaluate clinical outcomes. Patients also self-reported knee function and satisfaction. Standard radiographs were evaluated using Kellgren-Lawrence grades. Results: Both 5- and 10-year survival rates were 89%. All clinical scores improved significantly postoperatively. A total of 96% of patients rated knee function as better after surgery, and all patients indicated that they would undergo the same surgery again. Approximately 90% rated knee-specific outcomes as good or excellent and were satisfied with the procedure. At last follow-up, 12 of 26 successful knees were radiographically assessed (mean, 5.6 years postoperatively), with no significant osteoarthritis progression. Three knees were considered failures, which were managed by autologous bone grafting or osteochondral autologous transplantation. Twenty knees required subsequent surgical procedures. These were primarily associated with periosteum and were arthroscopically performed. Conclusion: ACI resulted in satisfactory survival rates and significant improvements in function, pain, and mental health for adolescent patients over a long-term follow-up. ACI was associated with very high satisfaction postoperatively, despite the subsequent procedure rate being relatively high primarily because of the use of periosteum. If periosteum is used, this rate should be a consideration when discussing ACI with patients and their parents.

Intermediate- to Long-Term Results of Combined Anterior Cruciate Ligament Reconstruction and Autologous Chondrocyte Implantation

Background: Cartilage injury associated with anterior cruciate ligament (ACL) ruptures is common; however, relatively few reports exist on concurrent cartilage repair with ACL reconstruction. Autologous chondrocyte implantation (ACI) has been utilized successfully for treatment of moderate to large chondral defects. Hypothesis: ACL insufficiency with relatively large chondral defects may be effectively managed with concurrent ACL reconstruction and ACI. Study Design: Case series; Level of evidence, 4. Methods: Patients undergoing concurrent ACL primary or revision reconstruction with ACI of single or multiple cartilage defects were prospectively evaluated for a minimum 2 years. Pre- and postoperative outcome measures included the modified Cincinnati Rating Scale (MCRS), Western Ontario and McMaster Universities Osteoarthritis Index, visual analog pain scales, and postsurgery satisfaction surveys. ACI graft failure or persistent pain without functional improvement were considered treatment failures. Results: Twenty-six patients were included, with 13 primary and 13 revision ACL reconstructions performed. Mean defect total surface area was 8.4 cm2, with a mean follow-up of 95 months (range, 24-240 months). MCRS improved from 3.62 ± 1.42 to 5.54 ± 2.32, Western Ontario and McMaster Universities Osteoarthritis Index from 45.31 ± 17.27 to 26.54 ± 17.71, and visual analog pain scale from 6.19 ± 1.27 to 3.65 ± 1.77 (all Ps <.001). Eight patients were clinical failures, 69% of patients were improved at final follow-up, and 92% stated they would likely undergo the procedure again. No outcome correlation was found with regard to age, body mass index, sex, defect size/number, follow-up time, or primary versus revision ACL reconstruction. In subanalysis, revision ACL reconstructions had worse preoperative MCRS scores and greater defect surface areas. However, revision MCRS score improvements were greater, resulting in similar final functional scores when compared with primary reconstructions. Conclusion: Challenging cases of ACL tears with large chondral defects treated with concurrent ACL reconstruction and ACI can lead to moderately improved pain and function at long-term follow-up. Factors associated with clinical failure are not clear. When combined with ACI, patients undergoing revision ACL reconstructions have worse function preoperatively compared with those undergoing primary reconstructions but have similar final outcomes.

Autologous Chondrocyte Implantation

Introduction Autologous chondrocyte implantation (ACI) for the treatment of articular cartilage lesions of the knee joint provides successful and durable long-term outcomes. Indications & Contraindications Step 1 Preoperative Planning Video 1 Obtain standing radiographs and magnetic resonance imaging (MRI) scans to identify all associated abnormalities (background factors). Step 2 Arthroscopic Assessment and Cartilage Biopsy Video 2 Evaluate the knee joint systematically and harvest cartilage tissue from the non-weight-bearing area. Step 3 Make the Incision for the Arthrotomy Video 3 Use a medial or lateral parapatellar arthrotomy and expose the lesion adequately. Step 4 Prepare the Defect Video 4 Debride all fissured and unstable articular cartilage surrounding the full-thickness chondral injury down to healthy contained cartilage. Step 5 Address Associated Abnormalities Address associated abnormalities (predisposing background factors) to optimize recovery and a successful outcome. Step 6 Prepare and Fix the Collagen Membranes Video 5 Orient the membrane patch with the rough surface to the subchondral bone and the smooth surface toward the articular surface; then sew it, tying the sutures knots on the membrane and not the cartilage, to tension it adequately throughout the entire defect. Step 7 Chondrocyte Implantation Video 6 Gently deliver the cells and fill the defect. Step 8 Postoperative Care (1) Initiate range-of-motion exercises to enhance chondrocyte regeneration and decrease the likelihood of intra-articular adhesion, (2) protect the graft from loading for 6 to 12 weeks after surgery to prevent graft overload and central degeneration or delamination of the graft, and (3) initiate isometric muscle exercises to regain muscle tone and prevent atrophy. Results ACI provided durable outcomes in 210 patients followed prospectively for 10 to 17 years after treatment with the first-generation ACI-periosteum technique6. Pitfalls & ChallengesRationale for the treatment of cartilage damage in younger patients depends on a thorough understanding of the predisposing factors for the chondrosis and the stage of disease. Implantation with autologous cultured chondrocytes allows for resurfacing of larger defect areas with reproducibly good/excellent results in 90% of patients with isolated lesions of the femoral condyle. Patellar lesions also may be successfully treated (approximately 75% improved) but strict attention must be given to correction of malalignment. Results in patients with tibial and salvage lesions are encouraging; however, these results should be viewed with caution due to the small number of patients with 2-year follow-up. Autologous chondrocyte implantation involves an open technique with the inherent disadvantages of adhesions and a more prolonged recovery. However, these disadvantages must be weighed against the procedures ability to produce a hyaline-type tissue with greater durability than fibrocartilage repairs produced by traditional marrow-stimulation techniques. We recommended matching the treatment procedure to patient expectations and lesion/demographic characteristics. Based on the available literature. algorithms have been published that recommend autologous chondrocyte implantation be reserved as first-line treatment for high-demand patients with large lesions (>2 cm2) and as revision therapy in patients with lesions of all sizes, regardless of patient demand, who have failed alternative marrow stimulation techniques.

Autologous Chondrocyte Implantation “Sandwich” Technique Compared With Autologous Bone Grafting for Deep Osteochondral Lesions in the Knee

Background: Treating symptomatic osteochondral defects is challenging, especially in young adults with deep (>8-10 mm) empty defects after osteochondritis dissecans (OCD) or collapsed condyles secondary to avascular necrosis (AVN). For this population, osteoarthritis (OA) is inevitable if articular congruence is not restored. Purpose: To describe the autologous chondrocyte implantation (ACI) “sandwich” technique with autologous bone grafting (ABG) and compare it with ABG alone for restoration of the osteochondral unit. The midterm to long-term outcomes in patients after the treatment for OCD and AVN will be reported and compared. Study Design: Cohort study; Level of evidence, 3. Methods: The outcomes for a consecutive cohort of 24 patients who underwent combined ABG with the ACI sandwich technique between 2001 and 2013 (ACI sandwich group) was compared with a historical control group of 17 consecutive patients who underwent ABG alone between 1995 and 2002 (ABG group) by a single surgeon for symptomatic deep (>8 mm) osteochondral lesions. Patients who were followed up with a minimum of 2 years were included in this study. The modified Cincinnati Knee Rating System, the Western Ontario and McMaster Universities Osteoarthritis Index, a visual analog scale (VAS), the Short Form–36, and a patient satisfaction survey were used to evaluate clinical outcomes. Survival analysis was performed using the Kaplan-Meier method, with no clinical improvement, graft failure, or conversion to prosthetic arthroplasty as the endpoint (failure). Kellgren-Lawrence (K-L) grading to assess OA progression was also performed. Results: In the ABG group, 13 of 17 patients (76%) were available with a mean follow-up of 15.7 years postoperatively (range, 5-21 years). In the ACI sandwich group, all 24 patients were available with a mean follow-up of 7.8 years postoperatively (range, 2-15 years). No significant differences were observed between the groups in terms of age, sex, side of the operated knee, body mass index, lesion type, lesion size, lesion depth, lesion location, or the need for realignment osteotomy. Eight patients (62%) were considered failures in the ABG group, while 3 patients (13%) were considered failures in the ACI sandwich group. The survival rate was significantly better in the ACI sandwich group than the ABG group (87% vs 54% at 5 years, respectively; P = .0025). All functional scores in patients with retained grafts significantly improved in the ACI sandwich group, whereas only the VAS score showed significant improvement in the ABG group. The patient satisfaction survey showed a very high satisfaction rate in the ACI sandwich group, with over 90% of patients reporting their knees as good or excellent and being satisfied with the procedure. In the ACI sandwich group, K-L grading demonstrated no significant OA progression from preoperatively to a mean 5.1 years postoperatively. Conclusion: Our study showed that the ACI sandwich technique provided excellent and superior survival rates compared to ABG alone and significant improvements over midterm to long-term follow-up. This unique treatment offers native joint preservation for conditions that naturally will progress to OA and eventually require prosthetic arthroplasty.

Biological Knee Reconstruction With Concomitant Autologous Chondrocyte Implantation and Meniscal Allograft Transplantation: Mid- to Long-term Outcomes

Background: Treating articular cartilage defects and meniscal deficiency is challenging. Although some short- to mid-term follow-up studies report good clinical outcomes after concurrent autologous chondrocyte implantation (ACI) and meniscal allograft transplantation (MAT), longer follow-up is needed. Purpose: To evaluate mid- to long-term outcomes after combined ACI with MAT. Study Design: Case series; Level of evidence, 4. Methods: We performed a retrospective review of prospectively gathered data from patients who had undergone ACI with MAT between 1999 and 2013. A single surgeon treated 18 patients for symptomatic full-thickness chondral defects with meniscal deficiency. One patient was lost to follow-up. Thus, 17 patients (18 knees; mean age, 31.7 years) were evaluated over a mean 7.9-year follow-up (range, 2-16 years). A mean 1.8 lesions per knee were treated over a total surface area of 7.6 cm2 (range, 2.3-21 cm2) per knee. Seventeen lateral and 1 medial MATs were performed. Survival was analyzed using the Kaplan-Meier method. The modified Cincinnati Knee Rating Scale, Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale, and Short Form–36 were used to evaluate clinical outcomes. Patients also self-reported knee function and satisfaction. Standard radiographs were scored for Kellgren-Lawrence (K-L) grade. Results: Both 5- and 10-year survival rates were 75%. Outcomes for 6 knees were considered failures. Of the 6 failures, 4 knees were converted to arthroplasty and the other 2 knees underwent biological revision surgery. Of the 12 successfully operated knees, all clinical measures significantly improved postoperatively. Ten patients representing 11 of the 12 knees rated outcomes for their knees as good or excellent, and 1 rated their outcome as fair. Eight patients representing 9 of the 12 knees were satisfied with the procedure. There was no significant osteoarthritis progression based on K-L grading from preoperatively to a mean 5.9 years after surgery. Seven of the 12 knees (58%) required subsequent surgical procedures (5 arthroscopic alone, 2 both arthroscopic and open). Conclusion: Combined ACI with MAT provided significant improvement in 65% of the operated knees over a mid- to long-term follow-up. This procedure can allow patients to retain their biological knees, delay or prevent rapid degeneration to osteoarthritis, and could be recognized as a bridge procedure before artificial knee replacement. However, careful discussion between the patient and surgeon is necessary before surgery to ensure realistic expectations.

Methods of high integrity RNA extraction from cell/agarose construct.

BackgroundAgarose hydrogels are widely used for three-dimensional cell scaffolding in tissue engineering and cell biology. Recently, molecular profiles have been obtained with extraction of a minimal volume of RNA using fluorescent-tagged quantitative polymerase chain reaction (qPCR), which requires high integrity RNA. However, the agarose interferes considerably with the quantity and quality of the extracted RNA. Moreover, little is known about RNA integrity when the RNA is extracted from cell/agarose construct. Thus, in order to obtain RNA of sufficient integrity, we examined various extraction methods and addressed reproducible methodologies for RNA extraction from cell/agarose constructs using spectrophotometry and microfluidic capillary electrophoresis.ResultsWith various extraction methods using a mono-phasic solution of phenol and guanidine isothiocyanate, we evaluated quantity and quality of total RNA from cell/agarose construct. Extraction with solution of phenol and guanidine isothiocyanate followed by a silica based membrane filter column gave sufficient RNA integrity number, which allowed us to proceed to fluorescent-tagged qPCR for evaluating various cellular activities.ConclusionsThe RNA extraction methods using phenol and guanidine isothiocyanate solution and a silica membrane column can be useful for obtaining high integrity RNA from cell/agarose constructs rich in polysaccharide and extracellular matrix. Our study contributes to further investigation using agarose hydrogels and other materials rich in polysaccharide in the field of cellular and tissue engineering.

Minimal Clinically Important Differences and Substantial Clinical Benefit in Patient-Reported Outcome Measures after Autologous Chondrocyte Implantation

Objective We sought to determine the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) associated with the Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Lysholm, and Short Form–12 (SF-12) after autologous chondrocyte implantation (ACI). Design Ninety-two patients with satisfaction surveys at a minimum of 2 years postoperatively and at least 1 repeated patient-reported outcome measure (PROM) were analysed. The MCID was determined using 4 anchor-based methods: average change, mean change, minimally detectable change, and the optimal cutoff point for receiver operating characteristic (ROC) curves. If an anchor-based method was not applicable, standard deviation–based and effect size–based estimates were used. SCB was determined using ROC curve analysis. Results The 4 anchor-based methods provided a range of MCID values for each PROM (11-18.8 for the KOOS pain, 9.2-17.3 for the KOOS activities of daily living, 12.5-18.6 for the KOOS sport/recreation, 12.8-19.6 for the KOOS quality of life, 10.8-16.4 for the IKDC, and 6.2-8.2 for the SF-12 physical component summary). Using the 2 distribution-based methods, the following MCID value ranges were obtained: KOOS symptom, 3.6 to 8.4; the Lysholm, 4.2 to 10.5; and the SF-12 mental component summary, 1.9 to 4.6. SCB was 30 for the KOOS sport/recreation and 34.4 for the IKDC, which most accurately predict substantial improvement. No significant association was noted between SCB achievement and the baseline PROMs. Conclusion The MCID and SCB determined in our study will allow interpretation of the effects of treatment in clinical practice and trials. Given the varied MCID values in this study, standardisation of the most appropriate calculation methods is warranted.

Preoperative Mental Health Has a Stronger Association with Baseline Self-Assessed Knee Scores than Defect Morphology in Patients Undergoing Cartilage Repair

Objective The purpose of this study was to assess potential correlations between the mental component summary of the Short Form–12 (SF-12 MCS), patient characteristics or lesion morphology, and preoperative self-assessed pain and function scores in patients undergoing autologous chondrocyte implantation (ACI). Design A total of 290 patients underwent ACI for symptomatic cartilage lesions in the knee. One hundred and seventy-eight patients were included in this study as they completed preoperative SF-12, Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner, Lysholm, and International Knee Documentation Committee (IKDC) scores. Age, sex, smoker status, body mass index, Worker’s Compensation, previous surgeries, concomitant surgeries, number of defects, lesion location in the patella, and total defect size were recorded for each patient. Pearson’s correlation and multivariate regression models were used to distinguish associations between these factors and preoperative knee scores. Results The SF-12 MCS showed the strongest bivariate correlation with all KOOS subgroups (P < 0.001) (except KOOS Symptom; P = 0.557), Tegner (P = 0.005), Lysholm (P < 0.001), and IKDC scores (P < 0.001). In the multivariate regression models, the SF-12 MCS showed the strongest association with all KOOS subgroups (P < 0.001) (except KOOS Symptom; P = 0.91), Lysholm (P = 0.001), Tegner (P = 0.017), and IKDC (P < 0.001). Conclusion In patients with symptomatic cartilage defects of the knee, preoperative patient mental health has a strong association with self-assessed pain and functional knee scores. Further studies are needed to determine if preoperative mental health management can improve preoperative symptoms and postoperative outcomes.

Validation of the Oswestry Risk of Knee Arthroplasty Index (ORKA-1) for Patients Undergoing Autologous Chondrocyte Implantation

Objective The purpose of this study was first to externally validate the Oswestry Risk of Knee Arthroplasty index (ORKA-1) by applying it to an autologous chondrocyte implantation (ACI) patient cohort in the United States with a broader definition of failure than only arthroplasty, and second, to determine predictive factors for the risk of ACI failure as defined by the senior author. Design A total of 171 patients that underwent ACI were included to validate the ORKA-1 as all factors needed for calculation and outcomes were recorded. For Cox regression analysis, 154 patients were included as they completed preoperative Knee Injury and Osteoarthritis Outcome Score (KOOS), Tegner, Lysholm, International Knee Documentation Committee (IKDC), and 12-item Shor Form (SF-12) scores. Patient- and lesion-associated parameters were recorded for each patient. Results At final follow-up (maximum of 10 years post-ACI), a total of 27 patients (15.8%) were considered a failure by senior author’s definition. With ACI failure as endpoint, the mean survival was 7.96 years in risk group 1 and 5.4 years in risk group 5. Cox regression analysis identified preoperative KOOS Sport/Recreation as the only significant predictive factor for ACI failure (P = 0.007). Conclusion The ORKA-1 is a helpful tool for surgeons to estimate an individual patient’s likelihood of ACI survival. Further studies with larger patient cohorts as well as a consensus definition of failure are needed to further refine predictors of ACI failure.