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1.  Treatment of focal degenerative cartilage defects with polymer-based autologous chondrocyte grafts: four-year clinical results 
Introduction
Second-generation autologous chondrocyte implantation with scaffolds stabilizing the grafts is a clinically effective procedure for cartilage repair. In this ongoing prospective observational case report study, we evaluated the effectiveness of BioSeed®-C, a cell-based cartilage graft based on autologous chondrocytes embedded in fibrin and a stable resorbable polymer scaffold, for the treatment of clinical symptomatic focal degenerative defects of the knee.
Methods
Clinical outcome after 4-year clinical follow-up was assessed in 19 patients with preoperatively radiologically confirmed osteoarthritis and a Kellgren-Lawrence score of 2 or more. Clinical scoring was performed before implantation of the graft and 6, 12, and 48 months after implantation using the Lysholm score, the Knee injury and Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee (IKDC) score, and the International Cartilage Repair Society (ICRS) score. Cartilage regeneration and articular resurfacing were assessed by magnetic resonance imaging (MRI) 4 years after implantation of the autologous cartilage graft.
Results
Significant improvement (P < 0.05) of the Lysholm and ICRS scores was observed as early as 6 months after implantation of BioSeed®-C and remained stable during follow-up. The IKDC score showed significant improvement compared with the preoperative situation at 12 and 48 months (P < 0.05). The KOOS showed significant improvement in the subclasses pain, activities of daily living, and knee-related quality of life 6 months as well as 1 and 4 years after implantation of BioSeed®-C in osteoarthritic defects (P < 0.05). MRI analysis showed moderate to complete defect filling with a normal to incidentally hyperintense signal in 16 out of 19 patients treated with BioSeed®-C. Two patients without improvement in the clinical and MRI scores received a total knee endoprosthesis after 4 years.
Conclusions
The results show that the good clinical outcome achieved 1 year after implantation of BioSeed®-C remains stable over the course of a period of 4 years and suggest that implanting BioSeed®-C is a promising treatment option for the repair of focal degenerative defects of the knee.
doi:10.1186/ar2638
PMCID: PMC2688178  PMID: 19265548
2.  Autologous Chondrocyte Implantation for Joint Preservation in Patients with Early Osteoarthritis 
Young patients with early osteoarthritis wishing to remain functionally active have limited treatment options. Existing studies examining the use of autologous chondrocyte implantation (ACI) have included patients with early degenerative changes; however, none specifically investigated the outcome of ACI with this challenging problem. We prospectively followed 153 patients (155 knees) for up to 11 years after treatment with ACI for early-stage osteoarthritis. Patient pain and function was assessed using WOMAC, modified Cincinnati, SF-36, Knee Society score, and a satisfaction questionnaire. Mean patient age was 38.3 years. On average, 2.1 defects were treated per knee; the mean defect size was 4.9 cm2 and total area per knee was 10.4 cm2. Eight percent of joints were considered treatment failures that went on to arthroplasty and the remaining patients experienced 50% to 75% improvement in WOMAC subscales. Our data suggest that ACI in patients with early osteoarthritis results in clinically relevant reductions in pain and improvement in function. At 5 years postoperatively, 92% of patients were functioning well and were able to delay the need for joint replacement. Given the limited number of treatment options for this subset of patients, autologous chondrocyte implantation may offer improved quality of life for young osteoarthritic patients.
Level of Evidence: Level IV, case series. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-009-0998-0
PMCID: PMC2795849  PMID: 19653049
3.  Autologous chondrocyte implantation (ACI) for the treatment of large and complex cartilage lesions of the knee 
Background
Complex cartilage lesions of the knee including large cartilage defects, kissing lesions, and osteoarthritis (OA) represent a common problem in orthopaedic surgery and a challenging task for the orthopaedic surgeon. As there is only limited data, we performed a prospective clinical study to investigate the benefit of autologous chondrocyte implantation (ACI) for this demanding patient population.
Methods
Fifty-one patients displaying at least one of the criteria were included in the present retrospective study: (1.) defect size larger than 10 cm2; (2.) multiple lesions; (3.) kissing lesions, cartilage lesions Outerbridge grade III-IV, and/or (4.) mild/moderate osteoarthritis (OA). For outcome measurements, the International Cartilage Society's International Knee Documentation Committee's (IKDC) questionnaire, as well as the Cincinnati, Tegner, Lysholm and Noyes scores were used. Radiographic evaluation for OA was done using the Kellgren score.
Results and Discussion
Patient's age was 36 years (13-61), defects size 7.25 (3-17.5) cm2, previous surgical procedures 1.94 (0-8), and follow-up 30 (12-63) months. Instruments for outcome measurement indicated significant improvement in activity, working ability, and sports. Mean ICRS grade improved from 3.8 preoperatively to grade 3 postoperatively, Tegner grade 1.4 enhanced to grade 3.39. The Cincinnati score enhanced from 25.65 to 66.33, the Lysholm score from 33.26 to 64.68, the Larson score from 43.59 to 79.31, and Noyes score from 12.5 to 46.67, representing an improvement from Cincinnati grade 3.65 to grade 2.1. Lysholm grade 4 improved to grade 3.33, and Larson grade 3.96 to 2.78 (Table 1), (p < 0.001). Patients with kissing cartilage lesions had similar results as patients with single cartilage lesions.
Mean scores and grades at surgery (Tx) and at follow-up
Conclusion
Our results suggest that ACI provides mid-term results in patients with complex cartilage lesions of the knee. If long term results will confirm our findings, ACI may be a considered as a valuable tool for the treatment of complex cartilage lesions of the knee.
doi:10.1186/1758-2555-3-11
PMCID: PMC3114778  PMID: 21599992
4.  Therapeutic strategy of third-generation autologous chondrocyte implantation for osteoarthritis 
Upsala Journal of Medical Sciences  2011;116(2):107-114.
Background
Autologous chondrocyte implantation (ACI) is considered a promising choice for the treatment of cartilage defects. However, the application of ACI to osteoarthritic patients is, in general, contraindicated. The purpose of this study is to evaluate the efficiency of three-dimensionallystructured ACI (3D-ACI; CaReS) in a rat model of knee osteoarthritis (OA).
Methods
OA-like degenerative changes in the articular cartilage were created by transecting the anterior cruciate ligament (ACLT) in athymic nude rats. Two weeks later, CaReS was transplanted at the cartilage injury sites created by micro-drilling in the patella groove (Chondrocyte-implanted (CI) group: CaReS collagen with human chondrocytes; Collagen group: CaReS collagen without cells; and Sham group: sham operation; n = 15/group).
Results
Reverse Transcription Polymerase Chain Reaction (RT-PCR) analysis demonstrated the expression of human-specific type 2 collagen and Sry-type high-mobility-group box 9 (SOX9) in the CI group—not in the other groups—throughout the study period. Double immunohistochemistry for human-specific type 2 collagen and human leukocyte antigen-abacavir (HLA-ABC) at week 4 showed positive staining in the CI group only. Macroscopic assessment showed better repair at the cartilage defect sites in the CI group, compared to the other groups. Histological assessment with toluidine blue staining showed that the thickness of the articular cartilage and semi-quantitative histological scores were higher in the CI group than in the other groups up to week 20.
Conclusions
We demonstrate, for the first time, that 3D-ACI is effective in repairing cartilage defects in a rat model of ACLT-induced OA.
doi:10.3109/03009734.2011.552812
PMCID: PMC3078539  PMID: 21352090
Chondrocyte implantation; geriatrics; knee osteoarthritis; orthopedics
5.  The John Insall Award: A Minimum 10-year Outcome Study of Autologous Chondrocyte Implantation 
Background
Autologous chondrocyte implantation (ACI) has demonstrated good and excellent results in over 75% of patients up to 10 years after surgery. Reports of longer-term outcomes, however, remain limited.
Questions/purposes
The purposes of this study were to describe the (1) survivorship of ACI grafts; (2) the long-term functional outcomes using validated scoring tools after ACI; and (3) to provide an analysis of potential predictors for failure.
Methods
Two hundred ten patients treated with ACI were followed for more than 10 years. Indications for the procedure included symptomatic cartilage defects in all compartments of the knee unresponsive to nonoperative measures. Mean age at surgery was 36 ± 9 years; mean defect size measured 8.4 ± 5.5 cm2. Outcome scores were prospectively collected pre- and postoperatively at the last followup.
Results
At a mean of 12 ± 2 years followup, 53 of 210 patients (25%) had at least one failed ACI graft. Nineteen of these patients went on to arthroplasty, 27 patients were salvaged with revision cartilage repair, and seven patients declined further treatment; three patients were lost to followup. The modified Cincinnati increased from 3.9 ± 1.5 to 6.4 ± 1.5, WOMAC improved from 39 ± 21 to 23 ± 16, Knee Society Score (KSS) knee score rose from 54 ± 18 to 79 ± 19, and KSS function from 65 ± 23 to 78 ± 17 (all p < 0.0001). The Physical Component of the SF-36 score increased from 33 ± 14 to 49 ± 18, whereas the Mental Component improved from 46 ± 14 to 52 ± 15 (both p < 0.001). Survivorship was higher in patients with complex versus salvage-type lesions (p = 0.03) with primary ACI versus ACI after prior marrow stimulation (p = 0.004) and with concomitant high tibial osteotomy (HTO) versus no HTO (p = 0.01).
Conclusions
ACI provided durable outcomes with a survivorship of 71% at 10 years and improved function in 75% of patients with symptomatic cartilage defects of the knee at a minimum of 10 years after surgery. A history of prior marrow stimulation as well as the treatment of very large defects was associated with an increased risk of failure.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-013-3146-9
PMCID: PMC3889462  PMID: 23979923
6.  Current Treatments of Isolated Articular Cartilage Lesions of the Knee Achieve Similar Outcomes 
Background
Many surgical techniques, including microfracture, periosteal and perichondral grafts, chondrocyte transplantation, and osteochondral grafts, have been studied in an attempt to restore damaged articular cartilage. However, there is no consensus regarding the best method to repair isolated articular cartilage defects of the knee.
Questions/purposes
We compared postoperative functional outcomes, followup MRI appearance, and arthroscopic examination after microfracture (MF), osteochondral autograft transplantation (OAT), or autologous chondrocyte implantation (ACI).
Methods
We prospectively investigated 30 knees with MF, 22 with OAT, and 18 with ACI. Minimum followup was 3 years (mean, 5 years; range, 3–10 years). We included only patients with isolated cartilage defects and without other knee injuries. The three procedures were compared in terms of function using the Lysholm knee evaluation scale, Tegner activity scale, and Hospital for Special Surgery (HSS) score; modified Outerbridge cartilage grades using MRI; and International Cartilage Repair Society (ICRS) repair grade using arthroscopy.
Results
All three procedures showed improvement in functional scores. There were no differences in functional scores and postoperative MRI grades among the groups. Arthroscopy at 1 year showed excellent or good results in 80% after MF, 82% after OAT, and 80% after ACI. Our study did not show a clear benefit of either ACI or OAT over MF.
Conclusions
Owing to a lack of superiority of any one treatment, we believe MF is a reasonable option as a first-line therapy given its ease and affordability relative to ACI or OAT.
Level of Evidence
Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-012-2304-9
PMCID: PMC3392395  PMID: 22422593
7.  Evolution of Autologous Chondrocyte Repair and Comparison to Other Cartilage Repair Techniques 
BioMed Research International  2014;2014:272481.
Articular cartilage defects have been addressed using microfracture, abrasion chondroplasty, or osteochondral grafting, but these strategies do not generate tissue that adequately recapitulates native cartilage. During the past 25 years, promising new strategies using assorted scaffolds and cell sources to induce chondrocyte expansion have emerged. We reviewed the evolution of autologous chondrocyte implantation and compared it to other cartilage repair techniques. Methods. We searched PubMed from 1949 to 2014 for the keywords “autologous chondrocyte implantation” (ACI) and “cartilage repair” in clinical trials, meta-analyses, and review articles. We analyzed these articles, their bibliographies, our experience, and cartilage regeneration textbooks. Results. Microfracture, abrasion chondroplasty, osteochondral grafting, ACI, and autologous matrix-induced chondrogenesis are distinguishable by cell source (including chondrocytes and stem cells) and associated scaffolds (natural or synthetic, hydrogels or membranes). ACI seems to be as good as, if not better than, microfracture for repairing large chondral defects in a young patient's knee as evaluated by multiple clinical indices and the quality of regenerated tissue. Conclusion. Although there is not enough evidence to determine the best repair technique, ACI is the most established cell-based treatment for full-thickness chondral defects in young patients.
doi:10.1155/2014/272481
PMCID: PMC4151850  PMID: 25210707
8.  Matrix-induced autologous chondrocyte implantation for the treatment of chondral defects of the knees in Chinese patients 
Articular cartilage injury is the most common type of damage seen in clinical orthopedic practice. The matrix-induced autologous chondrocyte implant (MACI) was developed to repair articular cartilage with an advance on the autologous chondrocyte implant procedure. This study aimed to evaluate whether MACI is a safe and efficacious cartilage repair treatment for patients with knee cartilage lesions. The primary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS) domains and magnetic resonance imaging (MRI) results, compared between baseline and postoperative months 3, 6, 12, and 24. A total of 15 patients (20 knees), with an average age of 33.9 years, had a mean defect size of 4.01 cm2. By 6-month follow-up, KOOS results demonstrated significant improvements in symptoms and knee-related quality of life. MRI showed significant improvements in four individual graft scoring parameters at 24 months postoperatively. At 24 months, 90% of MACI grafts had filled completely and 10% had good-to-excellent filling of the chondral defect. Most (95%) of the MACI grafts were isointense and 5% were slightly hyperintense. Histologic evaluation at 15 and 24 months showed predominantly hyaline cartilage in newly generated tissue. There were no postoperative complications in any patients and no adverse events related to the MACI operation. This 2-year study has confirmed that MACI is safe and effective with the advantages of a simple technique and significant clinical improvements. Further functional and mechanistic studies with longer follow-up are needed to validate the efficacy and safety of MACI in patients with articular cartilage injuries.
doi:10.2147/DDDT.S71356
PMCID: PMC4266264  PMID: 25525334
articular cartilage lesion; Knee Injury and Osteoarthritis Outcome Score; KOOS; magnetic resonance imaging; MRI
9.  Reconstruction of Osteochondral Defects by Combined Bone Grafting and a Bilayer Collagen Membrane as a Sandwich Technique 
Orthopedic Reviews  2013;5(4):e36.
Treatment of osteochondral lesions of the knee remains a major challenge in orthopedic surgery. Recently established procedures like autologous chondrocyte implantation or matrix-associated chondrocyte implantation yield good results, but include the disadvantage of two-step procedures. The purpose of this study was to evaluate the clinical and magnetic resonance imaging outcome of repairs of osteochondral defects of the knee by a combined procedure of bone grafting and covering with a bilayer collagen membrane in a sandwich technique. Seven male patients with a mean age of 42 (range 30-55) years and symptomatic focal osteochondral lesions of the knee grade IV according to the International Cartilage Repair Society classification were included. The mean diameter of defects was 28.6 (range 15-40) mm. Results were evaluated at a minimum of 24 months after surgery by International Knee Documentation Committee score, Lysholm-score, visual analogue scale, and magnetic resonance imaging with specific cartilage sequences, evaluating the ICRS score and the Magnetic Observation of Cartilage Repair Tissue (MOCART) score. All patients judged the operation as successful. Among the patients available for the long-term follow-up, mean visual analogue scale value was 1.3 (range 0-3) out of 10 points. Mean International Knee Documentation Committee score was 80.8 (range 63.2-88.5) out of 100 points. Mean Lysholm score was 85 (range 55-95) out of 100 points. None of the patients had to be reoperated until today. Evaluation of magnetic resonance imaging using the MOCART score revealed a good correlation to the clinical outcome. This is the first study reporting results after reconstruction of osteochondral defects of the knee joint by bone grafting and a bilayer collagen membrane. This new method offers the advantage of a one-step-procedure and yields both good clinical and magnetic resonance findings. We conclude that this procedure can be a valuable tool to improve joint function after osteochondral defects, trauma, and in joints with local arthritic lesions.
doi:10.4081/or.2013.e36
PMCID: PMC3883077  PMID: 24416480
knee; osteochondral defects; cartilage repair; regenerative joint surgery; magnetic resonance imaging; MOCART score
10.  A 5-Year Follow-Up After Cartilage Repair in the Knee Using a Platelet-Rich Plasma-Immersed Polymer-Based Implant 
The aim of our study was to analyze the clinical outcome after repair of cartilage defects of the knee with subchondral drilling and resorbable polymer-based implants immersed with autologous platelet-rich plasma (PRP). Fifty-two patients with focal chondral defects were treated with subchondral drilling, followed by covering with a polyglycolic acid - hyaluronan (PGA-HA) implant (chondrotissue®) immersed with autologous PRP. At 5-year follow-up, patients’ situation was assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) and compared to the pre-operative situation. The KOOS showed clinically meaningful and significant (p < 0.05) improvement in all subcategories compared to baseline. Subgroup analysis showed that there were no differences in the clinical outcome regarding defect size and localization as well as degenerative condition of the knee. Cartilage repair was complete in 20 out of 21 patients at 4-year follow-up as shown by magnetic resonance observation of cartilage repair tissue (MOCART) scoring. Covering of focal cartilage defects with the PGA-HA implant and PRP after bone marrow stimulation leads to a lasting improvement of the patients’ situation.
doi:10.2174/1874325001408010346
PMCID: PMC4209503  PMID: 25352927
Bone marrow stimulation; cartilage repair; drilling; microfracture; platelet-rich plasma; polyglycolic acid-hyaluronan scaffold; polymer-based implant.
11.  Autologous Matrix-Induced Chondrogenesis in the Knee 
Cartilage  2014;5(3):145-153.
Objective:
Autologous matrix-induced chondrogenesis (AMIC) is a 1-step cartilage restoration technique that combines microfracture with the use of an exogenous scaffold. This matrix covers and mechanically stabilizes the clot. There have been an increasing number of studies performed related to the AMIC technique and an update of its use and results is warranted.
Design and methods:
Using the PubMed database, a literature search was performed using the terms “AMIC” or “Autologous Matrix Induced Chondrogenesis.” A total of 19 basic science and clinical articles were identified.
Results:
Ten studies that were published on the use of AMIC for knee chondral defects were identified and the results of 219 patients were analyzed. The improvements in Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee Subjective, Lysholm and Tegner scores at 2 years were comparable to the published results from autologous chondrocyte implantation (ACI) and matrix ACI techniques for cartilage repair.
Conclusions:
Our systematic review of the current state of the AMIC technique suggests that it is a promising 1-stage cartilage repair technique. The short-term clinical outcomes and magnetic resonance imaging results are comparable to other cell-based methods. Further studies with AMIC in randomized studies versus other repair techniques such as ACI are needed in the future.
doi:10.1177/1947603514529445
PMCID: PMC4297179  PMID: 26069694
cartilage; microfracture; autologous matrix-induced chondrogenesis (AMIC)
12.  Cartilage repair: A review of Stanmore experience in the treatment of osteochondral defects in the knee with various surgical techniques 
Indian Journal of Orthopaedics  2010;44(3):238-245.
Articular cartilage damage in the young adult knee, if left untreated, it may proceed to degenerative osteoarthritis and is a serious cause of disability and loss of function. Surgical cartilage repair of an osteochondral defect can give the patient significant relief from symptoms and preserve the functional life of the joint. Several techniques including bone marrow stimulation, cartilage tissue based therapy, cartilage cell seeded therapies and osteotomies have been described in the literature with varying results. Established techniques rely mainly on the formation of fibro-cartilage, which has been shown to degenerate over time due to shear forces. The implantation of autologous cultured chondrocytes into an osteochondral defect, may replace damaged cartilage with hyaline or hyaline-like cartilage. This clinical review assesses current surgical techniques and makes recommendations on the most appropriate method of cartilage repair when managing symptomatic osteochondral defects of the knee. We also discuss the experience with the technique of autologous chondrocyte implantation at our institution over the past 11 years.
doi:10.4103/0019-5413.65136
PMCID: PMC2911921  PMID: 20697474
Cartilage injuries; cartilage repair; cartilage regeneration; autologous chondrocyte implantation
13.  In Vivo Evaluation of Different Surgical Procedures for Autologous Chondrocyte Implantation 
Cartilage  2013;4(1):83-90.
Objective:
Autologous chondrocyte implantation (ACI) involves the application of a chondrocyte suspension into a membrane-sealed cartilage defect. Recently, “cell-seeded collagen matrix-supported” ACI has been developed wherein chondrocytes are seeded on a biomembrane. This study aimed at preclinically comparing 4 variant ACI techniques in a refined goat model: 2 traditional procedures, whereby the defect is sealed by a periosteal flap or collagen membrane, and 2 cell-seeding methods, with the collagen membrane either sutured or glued into the defect.
Design:
The efficacy of the surgical techniques was evaluated in an acute critical size chondral defect in the medial condyle of 32 skeletally mature goats, randomly assigned to 1 of the 4 aforementioned treatment groups. After 10 weeks in vivo, the quality of the repair was graded histologically by 2 independent, blinded readers using the “modified O’Driscoll” score.
Results:
The cell-seeding procedure whereby the membrane is sutured into the defect has a similar structural repair capacity than traditional ACI techniques. However, when the cell-seeded membrane was glued into the defect, the outcome appeared inferior.
Conclusion:
These findings indicate that optimizing the goat model and the postoperative recovery does allow preclinical evaluation of ACI-based cartilage implants in a load-bearing setting. This preclinical observation provides support to the clinical utilization of the sutured membrane-seeded (ACI-CS) technique, provided sutures, but not fibrin sealants, are used to fix the cell-seeded membrane in the defect bed.
doi:10.1177/1947603512457564
PMCID: PMC4297110  PMID: 26069652
ACI; ACT-CS; membrane seeded; O’Driscoll; goat
14.  Arthroscopic cartilage regeneration facilitating procedure for osteoarthritic knee 
Background
The effectiveness of arthroscopic treatment for osteoarthritic knee is a controversy. This study presents the technique of a novel concept of arthroscopic procedure and investigates its clinical outcome.
Method
An arthroscopic procedure targeted on elimination of focal abrasion phenomenon and regaining soft tissue balance around patello-femoral joint was applied to treat osteoarthritis knees. Five hundred and seventy-one knees of 367 patients with osteoarthritis received this procedure. There were 70 (19%) male and 297 (81%) female and the mean age was 60 years (SD 10). The Knee Society score (KSS) and the knee injury and osteoarthritis outcome score (KOOS) were used for subjective outcome study. The roentgenographic changes of femoral-tibial angle and joint space width were evaluated for objective outcomes. The mean follow-up period was 38 months (SD 3).
Results
There were 505 knees in 326 patients available with more than 3 years follow-up and the mean follow-up period was 38 months (SD 3). The subjective satisfactory rate for the whole series was 85.5%. For 134 knees with comprehensive follow-up evaluation, the KSS and all subscales of the KOOS improved statistically. The femoral-tibial angle improved from 1.57 degrees (SD 3.92) to 1.93 degrees (SD 4.12) (mean difference: 0.35, SD 0.17). The joint space width increased from 2.02 millimeters (SD 1.24) to 2.17 millimeters (SD 1.17) (mean difference: 0.13, SD 0.05). The degeneration process of the medial compartment was found being reversed in 82.1% of these knees by radiographic evaluation.
Conclusions
Based on these observations arthroscopic cartilage regeneration facilitating procedure is an effective treatment for osteoarthritis of the knee joint and can be expected to satisfy the majority of patients and reverse the degenerative process of their knees.
doi:10.1186/1471-2474-13-226
PMCID: PMC3583133  PMID: 23171074
Osteoarthritis; Knee; Medial plica; Arthroscopy; Cartilage; Regeneration
15.  Activity-Related Outcomes of Articular Cartilage Surgery 
Cartilage  2013;4(3):193-203.
Objective: The purpose of this systematic review was to compare activity-based outcomes after microfracture, autologous chondrocyte implantation (ACI), and osteochondral autograft (OAT). Design: Multiple databases were searched with specific inclusion and exclusion criteria for level III and higher studies with activity outcomes after microfracture, OAT, osteochondral allograft, and ACI. Activity-based outcomes included the Knee Injury and Osteoarthritis Outcome Score (KOOS), the Tegner Score, the Cincinnati Knee scores, the International Knee Documentation Committee (IKDC) subjective knee score, the Marx activity score, and/or the rate of return-to-sport. Results: Twenty studies were included (1,375 patients). Although results were heterogeneous, significant advantages were seen for ACI and OAT as compared with microfracture in Tegner scores at 1 year (ACI vs. microfracture, P = 0.0016), IKDC scores at 2 years (ACI vs microfracture, P = 0.046), Lysholm scores at 1 year (OAT vs microfracture, P = 0.032), and Marx scores at 2 years (OAT vs microfracture, P < 0.001). The only score or time point to favor microfracture was Lysholm score at 1 year (ACI vs microfracture, P = 0.037). No other standardized outcome measures or time points were significantly different. Several studies demonstrated significantly earlier return to competition with microfracture. Overall reoperation rates were similar, but of reoperations, a higher proportion of those following ACI were unplanned with the majority of performed for graft delamination or hypertrophy. Conclusions: ACI and OAT may have some benefits over microfracture, although return-to-sport is fastest following microfracture. Heterogeneity in technique, outcome measures, and patient populations hampers systematic comparison within the current literature.
doi:10.1177/1947603513481603
PMCID: PMC4297087  PMID: 26069665
cartilage; microfracture; autologous chondrocyte implantation; osteochondral autograft; athlete
16.  Arthroscopic Transplantation of Synovial Stem Cells Improves Clinical Outcomes in Knees With Cartilage Defects 
Background
Transplantation of mesenchymal stem cells (MSCs) is one possible strategy to achieve articular cartilage repair. We previously reported that synovial MSCs were highly proliferative and able to undergo chondrogenesis. We also found that placing a suspension of synovial MSCs on a cartilage defect for 10 minutes promoted cartilage repair in rabbit and pig models. However, the in vivo efficacy of this approach has not been tested clinically.
Questions/purposes
We asked whether transplantation of synovial MSCs improves (1) MRI features, (2) histologic features, and (3) clinical evaluation scores in patients with cartilage defects in the knee?
Methods
Patients with a symptomatic single cartilage lesion of the femoral condyle were indicated for inclusion in our study, and between April 2008 and April 2011, 10 patients were enrolled in this study. All patients completed followups of 3 years or more. The average followup period was 52 months (range, 37–80 months). Synovial MSCs were expanded with 10% autologous human serum for 14 days after digestion. For transplantation, the patient was positioned so that the cartilage defect was facing upward, and synovial MSC suspension was placed on the cartilage defect with a syringe under arthroscopic control. The defect with the applied suspension then was held in the upward position for 10 minutes. Five patients underwent concomitant ACL reconstructions, among whom two had meniscus suturing performed simultaneously. For MRI quantification, the cartilage defect was scored from 0 to 5. Second-look arthroscopy was performed for four patients and biopsy specimens were evaluated histologically. Clinical outcome was assessed using the Lysholm score and Tegner Activity Level Scale at final followup. Comparisons of MRI and Lysholm scores before and after treatment for each patient were analyzed using the Wilcoxon signed-rank test.
Results
MRI score (median ± 95% CI) was 1.0 ± 0.3 before and 5.0 ± 0.7 after, and increased after treatment in each patient (p = 0.005). Second-look arthroscopy in four patients showed that the cartilage defect appeared to be qualitatively better in all cases. Histologic analyses showed hyaline cartilage in three patients and fibrous cartilage in one at the deep zone. The Lysholm score (median ± 95% CI) was 76 ± 7 before and 95 ± 3 after, and increased after treatment in each patient (p = 0.005). The Tegner Activity Level Scale did not decrease after treatment in each patient.
Conclusions
For this small initial case series, transplantation of synovial MSCs was effective in terms of MRI score, qualitative histology, and Lysholm score. The use of synovial MSCs has an advantage in that the cells can be prepared at passage 0 in only 14 days. Transplantation of synovial MSCs may be less invasive than mosaicplasty and autologous chondrocyte implantation. To conclusively show the effectiveness of this treatment requires comparative studies, especially with more established arthroscopic procedures, such as marrow stimulation techniques.
Level of Evidence
Level IV, therapeutic study.
doi:10.1007/s11999-015-4324-8
PMCID: PMC4457765  PMID: 25925939
17.  The Chondrogenic Potential of Mesenchymal Cells and Chondrocytes from Osteoarthritic Subjects 
Cartilage  2011;2(1):40-49.
Objective:
The multipotential nature of stem or progenitor cells apparently makes them the ideal choice for any cell therapy, but this as yet remains to be proven. This study (30 subjects) was designed to compare the potential to repair articular cartilage of chondrocytes taken from different regions in osteoarthritic cartilage with that of mesenchymal stem cells prepared from bone marrow of the same subject.
Design:
Cartilage biopsies, bone marrow, and blood samples were taken from each of 30 individuals with chronic osteoarthritis (aged 62-85 years) undergoing total knee replacement. The chondrogenic potential of chondrocytes isolated from cartilage biopsies taken from different regions of osteoarthritic cartilage was compared with that of mesenchymal cells by quantitative analysis of several chondrocyte specific markers and an ex vivo cartilage differentiation assay.
Results:
Cartilage-derived articular chondrocytes are superior to bone marrow–derived cells when compared for their ex vivo chondrogenic potential. Interestingly, there was marked and significant difference in the expression of chondrocytic markers between chondrocytes derived from adjacent, visually distinct regions of the diseased cartilage. When cultured in the presence of a fibroblast growth factor 2 variant, all cell samples from both tissues showed a high degree of chondrogenic potential.
Conclusions:
Although bone marrow–derived mesenchymal cells, when supplemented with the appropriate chondrogenic factors, are a suitable source for autologous cartilage implantation, adult chondroprogenitor cells, particularly those from moderately affected regions of the osteoarthritic joints, demonstrate superior chondrogenic potential.
doi:10.1177/1947603510380899
PMCID: PMC4300788  PMID: 26069568
autologous chondrocyte implantation; MSCs; cartilage regeneration; osteoarthritis
18.  The use of autologous chondrocyte implantation following and combined with anterior cruciate ligament reconstruction 
International Orthopaedics  2005;30(1):48-53.
We report our experience of using autologous chondrocyte implantation (ACI) to treat osteochondral defects of the knee in combination with anterior cruciate ligament (ACL) reconstruction. The outcome of symptomatic osteochondral lesions treated with ACI following previous successful ACL reconstruction is also reviewed. Patients were followed for a mean of 23 months. Nine patients underwent ACL reconstruction in combination with ACI. Mean modified Cincinnati knee scores improved from 42 to 69 following surgery. Seven patients described their knee as better and two as the same. A second group of nine patients underwent ACI for symptomatic articular cartilage defects following previous ACL reconstruction. In this group, the mean modified Cincinnati knee score improved from 53 to 62 after surgery. Six patients described their knee as better and three as worse. Combined treatment using ACI with ACL reconstruction is technically feasible and resulted in sustained improvement in pain and function. The results following previous ACL reconstruction also resulted in clinical improvement, although results were not as good as following the combined procedure.
doi:10.1007/s00264-005-0025-3
PMCID: PMC2254665  PMID: 16320051
19.  Results of Chondrocyte Implantation with a Fibrin-Hyaluronan Matrix: A Preliminary Study  
Fibrin, a homologous polymer, is the natural scaffold of wound healing and therefore a candidate as a carrier for cell transplantation. We explored a novel matrix-based implant cartilage repair composed of both fibrin and hyaluronan in a defined ratio that takes advantage of the biological and mechanical properties of these two elements. The matrix was seeded with autologous chondrocytes expanded in the presence of a proprietary growth factor variant designed to preserve their chondrogenic potential. We prospectively followed eight patients with symptomatic-chronic cartilage defects treated with this carrier. Patients had arthroscopy to harvest autologous chondrocytes then grown in autologous serum. Chondrocytes were cultured in the presence of the FGF variant and then seeded on the fibrin-hyaluronan matrix. About 4 weeks following biopsy, the patients underwent implantation of the constructs by miniarthrotomy. Three of the eight patients had transient effusion. Clinical performance was measured by Lysholm and IKDC scores, MRI, and the need for secondary surgery. The clinical outcome of a 1-year followup demonstrated increase of clinical scores. The MRI followup showed good filling of the defect with tissue having the imaging appearance of cartilage in all patients. Apart from the transient effusion in three patients we observed no other adverse events during the followup.
Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-008-0322-4
PMCID: PMC2584266  PMID: 18528742
20.  Association between expression of the Bone morphogenetic proteins 2 and 7 in the repair of circumscribed cartilage lesions with clinical outcome 
Background
Although there is much known about the role of BMPs in cartilage metabolism reliable data about the in vivo regulation in natural and surgically induced cartilage repair are still missing.
Methods
Lavage fluids of knee joints of 47 patients were collected during surgical therapy. 5 patients had no cartilage lesion and served as a control group, the other 42 patients with circumscribed cartilage defects were treated by microfracturing (19) or by an Autologous Chondrocyte Implantation (23). The concentrations of BMP-2 and BMP-7 were determined by ELISA. The clinical status was evaluated using the IKDC Score prior to and 1 year following the operation.
Results
High level expression in the control group was found for BMP-2, concentrations of BMP-7 remained below detection levels. No statistical differences could be detected in concentrations of BMP-2 or BMP-7 in the lavage fluids of knees with cartilage lesions compared to the control group. Levels of BMP-7 did not change after surgical cartilage repair, whereas concentrations of BMP-2 statistically significant increased after the intervention (p < 0.001). The clinical outcome following cartilage regenerating surgery increased after 1 year by 29% (p < 0.001). The difference of the IKDC score after 1 year and prior to the operation was used to quantify the degree of improvement following surgery. This difference statistically significant correlated with initial BMP-2 (R = 0.554, p < 0.001) but not BMP-7 (R = 0.031, n.s.) levels in the knee joints.
Conclusions
BMP-2 seems to play an important role in surgically induced cartilage repair; synovial expression correlates with the clinical outcome.
doi:10.1186/1471-2474-11-170
PMCID: PMC2920860  PMID: 20670444
21.  What Patients Expect About Autologous Chondrocyte Implantation (ACI) for Treatment of Cartilage Defects at the Knee Joint 
Cartilage  2012;3(1):13-19.
Objective:
Although autologous chondrocyte implantation (ACI) has become an established surgical treatment for cartilage defects of the knee, little is known about what patients expect about this surgery.
Design:
A total of 150 patients who underwent ACI for cartilage defects at the knee were assigned to the present study and asked about their expectations and estimation concerning the ACI procedure. Patients were asked to answer 4 questions of a web-based questionnaire concerning their expectations on clinical outcome and on factors they considered relevant for clinical outcome.
Results:
A total of 118 (79%) returned questionnaires. Mean patient age was 32.6 years and mean defects size was 4.1 cm2. A proportion of 70% (n = 83) of patients expected pain-free sports participation as a result of the ACI surgery, including 24 patients who expected to return to high-impact sports without any restrictions. Only 12.7% expected a reduction but persistence of pain during everyday activities. Concerning factors that influence outcome, the majority of the patients (55.1%) considered defect characteristics (i.e., size and location) most important for clinical outcome, whereas only a small proportion of patients considered rehabilitation (7.6%), cell quality (10.2%), or prior surgeries (4.2%) more relevant for final outcome.
Conclusion:
The present study illustrates that expectations of ACI patients are demanding and quite high. The ACI technique seems generally considered to be able to restore pain-free sports participation. Patients do not seem to be aware of all factors of possible importance concerning clinical outcome.
doi:10.1177/1947603511415840
PMCID: PMC4297184  PMID: 26069615
autologous chondrocyte implantation; cartilage defect; cartilage repair; expectations; cell transplantation
22.  Combined autologous chondrocyte implantation (ACI) with supra-condylar femoral varus osteotomy, following lateral growth-plate damage in an adolescent knee: 8-year follow-up 
We report the 8-year clinical and radiographic outcome of an adolescent patient with a large osteochondral defect of the lateral femoral condyle, and ipsilateral genu valgum secondary to an epiphyseal injury, managed with autologous chondrocyte implantation (ACI) and supracondylar re-alignment femoral osteotomy. Long-term clinical success was achieved using this method, illustrating the effective use of re-alignment osteotomy in correcting mal-alignment of the knee, protecting the ACI graft site and providing the optimum environment for cartilage repair and regeneration. This is the first report of the combined use of ACI and femoral osteotomy for such a case.
doi:10.1186/1758-2555-3-5
PMCID: PMC3068953  PMID: 21418566
23.  Long-Term Evaluation of Autologous Chondrocyte Implantation 
Cartilage  2012;3(4):342-350.
Purpose:
The purpose of this study was to report the clinical outcomes of autologous chondrocyte implantation (ACI) procedures performed by a single orthopedic surgeon at a minimum of 7 years follow-up.
Methods:
A retrospective review of prospectively collected data was performed on 29 patients who underwent ACI of the knee between the years of 1998 and 2003. Prospective data were collected to assess changes in standardized outcome measures preoperatively and 2, 4, and 7 years postoperatively. All patients enrolled in the study were also recruited to undergo physical examination when possible.
Results:
The final cohort consisted of 29 patients with a mean final follow-up time of 8.40 years (range = 7.14-10.88 years). Comparing preoperative scores to 7-year postoperative values, the mean International Knee Documentation Committee (IKDC) score improved from 39.80 to 59.24 (P < 0.001), mean Tegner-Lysholm score increased from 48.07 to 74.17 (P < 0.001), SF-12 physical score improved from 40.38 to 48.66 (P < 0.001), and SF-12 mental score improved from 44.14 to 48.98 (P < 0.05). Significant improvement occurred in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain (56.03 to 80.36), symptoms (54.19 to 74.75), activities of daily living (72.01 to 85.90), sports (23.34 to 55.34), and quality of life (24.56 to 56.03) (P < 0.001). In addition, 7-year postoperative scores were at or near levels seen at 2 years (mean = 2.16; range = 0.94-4.03 years) and 4 years (mean = 4.43; range = 2.16-5.88 years) postoperatively, reflecting durable improvement. Subjectively, on a scale of 1 to 10 (10 being completely satisfied), the mean postoperative satisfaction rate was 8.14. Additionally, 88.9% of the patients would elect to have this surgery again if the same problem was to occur in the contralateral joint.
Conclusions:
The results of ACI in patients who present with symptomatic, full-thickness chondral defects remain durable at a minimum of 7-year follow-up with persistent, high levels of patient satisfaction.
Level of Evidence:
Case series; Level of evidence, IV.
doi:10.1177/1947603512439460
PMCID: PMC4297145  PMID: 26069644
outcome measures; articular cartilage; chondrocytes; knee; autologous chondrocyte implantation
24.  Increased Production of Clusterin in Biopsies of Repair Tissue following Autologous Chondrocyte Implantation 
Cartilage  2013;4(3):227-238.
Objective. To characterize the immunolocalization of clusterin in the repair cartilage of patients having undergone autologous chondrocyte implantation (ACI) and evaluate correlation to clinical outcome. Design. Full-depth core biopsies of repair tissue were obtained from 38 patients who had undergone ACI at an average of 18 ± 13 months previously (range 8-67 months). The biopsies were snap frozen, cryosectioned, and clusterin production immunolocalized using a specific monoclonal clusterin antibody and compared with normal and osteoarthritic cartilage. Clinical outcome was assessed from patients preoperatively, at the time of biopsy, and annually postoperatively. Results. Intensity of immunostaining for clusterin decreased with age in healthy cartilage tissue. Clusterin was detected to a variable degree in 37 of the 38 ACI cartilage biopsies, in single and clustered chondrocytes, in the pericellular capsule and the cartilage extracellular matrix, as well as the osteocytes and osteoid within the bone. Chondrocytes in hyaline repair tissue were significantly more immunopositive than those in fibrocartilage repair tissue. Clinical outcome improved significantly post-ACI, but did not correlate with the presence of clusterin in the repair tissue. Conclusions. These results demonstrate the presence of clusterin in actively repairing human cartilage and indicate a different distribution of clusterin in this tissue compared to normal cartilage. Variability in clusterin staining in the repair tissue could indicate different states of chondrogenic differentiation. The clinical significance of clusterin within repair tissue is difficult to assess, although the ideal functioning repair tissue morphology should resemble that of healthy adult cartilage.
doi:10.1177/1947603513477652
PMCID: PMC4297085  PMID: 26069669
autologous chondrocyte implantation; clusterin; cartilage; repair
25.  Interleukin-6 is elevated in synovial fluid of patients with focal cartilage defects and stimulates cartilage matrix production in an in vitro regeneration model 
Arthritis Research & Therapy  2012;14(6):R262.
Introduction
This study aimed to determine whether, as in osteoarthritis, increased levels of interleukin-6 (IL-6) are present in the synovial fluid of patients with symptomatic cartilage defects and whether this IL-6 affects cartilage regeneration as well as the cartilage in the degenerated knee.
Methods
IL-6 concentrations were determined by ELISA in synovial fluid and in conditioned media of chondrocytes regenerating cartilage. Chondrocytes were obtained from donors with symptomatic cartilage defects, healthy and osteoarthritic donors. The effect of IL-6 on cartilage regeneration and on metabolism of the resident cartilage in the knee was studied by both inhibition of endogenous IL-6 and addition of IL-6, in a regeneration model and in osteoarthritic explants in the presence of synovial fluid, respectively. Readout parameters were DNA and glycosaminoglycan (GAG) content and release. Differences between controls and IL-6 blocked or supplemented samples were determined by univariate analysis of variance using a randomized block design.
Results
Synovial fluid of patients with symptomatic cartilage defects contained more IL-6 than synovial fluid of healthy donors (P = 0.001) and did not differ from osteoarthritic donors. IL-6 production of osteoarthritic chondrocytes during cartilage regeneration was higher than that of healthy and defect chondrocytes (P < 0.001). Adding IL-6 increased GAG production by healthy chondrocytes and decreased GAG release by osteoarthritic chondrocytes (P < 0.05). Inhibition of IL-6 present in osteoarthritic synovial fluid showed a trend towards decreased GAG content of the explants (P = 0.06).
Conclusions
Our results support a modest anabolic role for IL-6 in cartilage matrix production. Targeting multiple cytokines, including IL-6, may be effective in improving cartilage repair in symptomatic cartilage defects and osteoarthritis.
doi:10.1186/ar4107
PMCID: PMC3674617  PMID: 23206933

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