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1.  Treatment of focal degenerative cartilage defects with polymer-based autologous chondrocyte grafts: four-year clinical results 
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.
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.
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.
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.
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.
PMCID: PMC2795849  PMID: 19653049
3.  Autologous chondrocyte implantation (ACI) for the treatment of large and complex cartilage lesions of the knee 
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.
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
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.
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.
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).
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).
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.
We demonstrate, for the first time, that 3D-ACI is effective in repairing cartilage defects in a rat model of ACLT-induced OA.
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 
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.
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.
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.
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).
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.
PMCID: PMC3889462  PMID: 23979923
6.  Current Treatments of Isolated Articular Cartilage Lesions of the Knee Achieve Similar Outcomes 
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.
We compared postoperative functional outcomes, followup MRI appearance, and arthroscopic examination after microfracture (MF), osteochondral autograft transplantation (OAT), or autologous chondrocyte implantation (ACI).
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.
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.
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.
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.
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.
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.
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.
PMCID: PMC4209503  PMID: 25352927
Bone marrow stimulation; cartilage repair; drilling; microfracture; platelet-rich plasma; polyglycolic acid-hyaluronan scaffold; polymer-based implant.
11.  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.
PMCID: PMC2911921  PMID: 20697474
Cartilage injuries; cartilage repair; cartilage regeneration; autologous chondrocyte implantation
12.  Arthroscopic cartilage regeneration facilitating procedure for osteoarthritic knee 
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.
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).
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.
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.
PMCID: PMC3583133  PMID: 23171074
Osteoarthritis; Knee; Medial plica; Arthroscopy; Cartilage; Regeneration
13.  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.
PMCID: PMC2254665  PMID: 16320051
14.  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.
PMCID: PMC2584266  PMID: 18528742
15.  Association between expression of the Bone morphogenetic proteins 2 and 7 in the repair of circumscribed cartilage lesions with clinical outcome 
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.
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.
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.
BMP-2 seems to play an important role in surgically induced cartilage repair; synovial expression correlates with the clinical outcome.
PMCID: PMC2920860  PMID: 20670444
16.  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.
PMCID: PMC3068953  PMID: 21418566
17.  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.
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.
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.
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).
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.
PMCID: PMC3674617  PMID: 23206933
18.  Knee chondral lesions treated with autologous chondrocyte transplantation in a tridimensional matrix: clinical evaluation at 1-year follow-up 
Despite the many studies on chondral injury repair, no outcomes have been evaluated with the Western Ontario and McMaster (WOMAC) Universities osteoarthritis index, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Oxford Knee Score, all of which are specific for evaluating the presence of osteoarthritis.
Materials and methods
We evaluated the clinical progress of patients following autologous chondrocyte implantation (ACI) performed by our Bone and Tissue Bank using a technique in which cells, instead of being introduced to the articular defect in a liquid form, are implanted into a tridimensional matrix of semisolid collagen (Condrograft®). A total of 22 patients underwent the procedure, 15 of whom were available for a 1-year follow-up that included clinical evaluation by WOMAC score before and after surgery and KOOS and the Oxford Knee Score after surgery.
The results were improved WOMAC score from 56.4 before surgery to 16.2 after surgery (P < 0.002), average KOOS score of 83.6, and average Oxford Knee Score of 18.8.
These results indicate that our tridimensional matrix technique effectively improved patients’ quality of life, at least in the short term, and delayed any subsequent procedure. Long-term assessment is necessary to determine the true value of this technique.
PMCID: PMC2784059  PMID: 19936886
Tridimensional matrix; WOMAC score; Clinical evaluation; Oxford Knee Score; KOOS
19.  Knee chondral lesions treated with autologous chondrocyte transplantation in a tridimensional matrix: clinical evaluation at 1-year follow-up 
Despite the many studies on chondral injury repair, no outcomes have been evaluated with the Western Ontario and McMaster (WOMAC) Universities osteoarthritis index, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Oxford Knee Score, all of which are specific for evaluating the presence of osteoarthritis.
Materials and methods
We evaluated the clinical progress of patients following autologous chondrocyte implantation (ACI) performed by our Bone and Tissue Bank using a technique in which cells, instead of being introduced to the articular defect in a liquid form, are implanted into a tridimensional matrix of semisolid collagen (Condrograft®). A total of 22 patients underwent the procedure, 15 of whom were available for a 1-year follow-up that included clinical evaluation by WOMAC score before and after surgery and KOOS and the Oxford Knee Score after surgery.
The results were improved WOMAC score from 56.4 before surgery to 16.2 after surgery (P < 0.002), average KOOS score of 83.6, and average Oxford Knee Score of 18.8.
These results indicate that our tridimensional matrix technique effectively improved patients’ quality of life, at least in the short term, and delayed any subsequent procedure. Long-term assessment is necessary to determine the true value of this technique.
PMCID: PMC2784059  PMID: 19936886
Tridimensional matrix; WOMAC score; Clinical evaluation; Oxford Knee Score; KOOS
20.  Matrix-induced autologous chondrocyte implantation for a large chondral defect in a professional football player: a case report 
Matrix-assisted autologous chondrocyte implantation is a well-known procedure for the treatment of cartilage defects, which aims to establish a regenerative milieu and restore hyaline cartilage. However, much less is known about third-generation autologous chondrocyte implantation application in high-level athletes. We report on the two-year follow-up outcome after matrix-assisted autologous chondrocyte implantation to treat a large cartilage lesion of the lateral femoral condyle in a male Caucasian professional football player.
Case presentation
A 27-year-old male Caucasian professional football player was previously treated for cartilage problems of his left knee with two failed microfracture procedures resulting in a 9 cm2 Outerbridge Grade 4 chondral lesion at his lateral femoral condyle. Preoperative Tegner-Lysholm and Brittberg-Peterson scores were 64 and 58, and by the second year they were 91 and 6. An evaluation with magnetic resonance imaging demonstrated filling of the defect with the signal intensity of the repair tissue resembling healthy cartilage. Second-look arthroscopy revealed robust, smooth cartilage covering his lateral femoral condyle. He returned to his former competitive level without restrictions or complaints one year after the procedure.
This case illustrates that robust cartilage tissue can be obtained with a matrix-assisted autologous chondrocyte implantation procedure even after two failed microfracture procedures in a large (9 cm2) cartilage defect. To the best of our knowledge, this is the first case report on the application of the third-generation cell therapy treatment technique, matrix-assisted autologous chondrocyte implantation, in a professional football player.
PMCID: PMC3404975  PMID: 22742735
21.  Repair of a chondral defect using a cell free scaffold in a young patient - a case report of successful scaffold transformation and colonisation 
BMC Surgery  2013;13:11.
Chondral defects of the articular surface are a common condition that can lead to osteoarthritis if not treated. Therapy of this condition is a topic of constant debate and a variety of chondral repair strategies are currently used. One strategy involves implantation of a cell-free matrix of type I collagen (COL1), to provide a scaffold for chondrocyte migration and proliferation and extracellular matrix production. Although several studies have suggested that chondrocytes can move, to the best of our knowledge there is still no proof of chondrocyte occurrence in a former cell-free scaffold for articular cartilage repair in humans.
Case presentation
An 18-year-old male patient underwent arthroscopic surgery of the knee for patellar instability and a chondral defect of the femoral condyle. Clinical outcome scores were recorded pre-operatively, after 6 weeks and after 6, 12, 24 and 36 months. MRI was recorded after 6 weeks and after 6, 12, 24 and 36 months postoperatively. At 42 months after implantation of a cell-free type I collagen matrix and reconstruction of the medial patellofemoral ligament, the patient was again treated arthroscopically for a tear of the medial meniscus of the same knee. A biopsy of the previous chondral defect was taken during arthroscopy for histological examination.
In addition to good clinical and radiological results reported for cell-free scaffolds for cartilage repair in several other studies, transformation of the scaffold could be observed during re-arthroscopy for the meniscal tear. Histological examination of the specimen revealed articular cartilage with vital chondrocytes and a strong staining reaction for type II collagen (COL II), but no reaction for type I collagen staining. This might indicate a complete transformation of the scaffold and supports the theory that cell free scaffolds could support cell migration. Although the cell source remains unclear, migrating chondrocytes from the periphery remain a possibility.
PMCID: PMC3637466  PMID: 23590134
Vital chondrocyte; Cell-free scaffold; Histological examination; Chondrocyte migration
22.  Quantitative ultrasound can assess the regeneration process of tissue-engineered cartilage using a complex between adherent bone marrow cells and a three-dimensional scaffold 
Arthritis Research & Therapy  2005;7(3):R552-R559.
Articular cartilage (hyaline cartilage) defects resulting from traumatic injury or degenerative joint disease do not repair themselves spontaneously. Therefore, such defects may require novel regenerative strategies to restore biologically and biomechanically functional tissue. Recently, tissue engineering using a complex of cells and scaffold has emerged as a new approach for repairing cartilage defects and restoring cartilage function. With the advent of this new technology, accurate methods for evaluating articular cartilage have become important. In particular, in vivo evaluation is essential for determining the best treatment. However, without a biopsy, which causes damage, articular cartilage cannot be accurately evaluated in a clinical context. We have developed a novel system for evaluating articular cartilage, in which the acoustic properties of the cartilage are measured by introducing an ultrasonic probe during arthroscopy of the knee joint. The purpose of the current study was to determine the efficacy of this ultrasound system for evaluating tissue-engineered cartilage in an experimental model involving implantation of a cell/scaffold complex into rabbit knee joint defects. Ultrasonic echoes from the articular cartilage were converted into a wavelet map by wavelet transformation. On the wavelet map, the percentage maximum magnitude (the maximum magnitude of the measurement area of the operated knee divided by that of the intact cartilage of the opposite, nonoperated knee; %MM) was used as a quantitative index of cartilage regeneration. Using this index, the tissue-engineered cartilage was examined to elucidate the relations between ultrasonic analysis and biochemical and histological analyses. The %MM increased over the time course of the implant and all the hyaline-like cartilage samples from the histological findings had a high %MM. Correlations were observed between the %MM and the semiquantitative histologic grading scale scores from the histological findings. In the biochemical findings, the chondroitin sulfate content increased over the time course of the implant, whereas the hydroxyproline content remained constant. The chondroitin sulfate content showed a similarity to the results of the %MM values. Ultrasonic measurements were found to predict the regeneration process of the tissue-engineered cartilage as a minimally invasive method. Therefore, ultrasonic evaluation using a wavelet map can support the evaluation of tissue-engineered cartilage using cell/scaffold complexes.
PMCID: PMC1174952  PMID: 15899042
23.  A retrospective analysis of medial opening wedge high tibial osteotomy for varus osteoarthritic knee 
Indian Journal of Orthopaedics  2012;46(4):455-461.
Medial opening wedge high tibial osteotomy (MOWHTO) has proven to be an effective treatment for varus osteoarthritic knees. Various methods of fixation with different implant types and using either bone grafts or bone substitutes have been reported. We performed non-locking T-buttress plate fixation with autologous iliac bone graft augmentation, which is defined here as the traditional method, and locking compression plate fixation without any bone graft or bone substitute. We aimed to compare bone union and complications of these two MOWHTO techniques.
Materials and Methods:
Between June 2005 and December 2007, 50 patients who underwent MOWHTO (a total of 60 knees) were retrospectively reviewed and classified into two groups: group A, which consisted of 26 patients (30 knees) was treated using T-buttress plate fixation with autologous iliac bone graft augmentation and group B, which consisted of 24 patients (30 knees) was operated upon using a medial high tibial locking compression plate without any augmentation. Demographic characteristics and radiographic outcomes, including union rate, time to union, medial osteotomy defects, and complications, were collected and compared between the two groups. The progress of all patients was followed for at least 2 years.
All osteotomies united within 12 weeks after surgery. Group B had slightly longer time to union than group A (10.3 weeks and 9.5 weeks, respectively; P = 0.125). A significantly higher incidence of medial defects after osteotomy was reported in the locking compression plate group (P = 0.001). A total of 5 (8.3%) knees had complications. In group A, one knee had a superficial wound infection and another knee had a lateral tibial plateau fracture without significant loss of correction. In group B, one knee had screw penetration into the knee joint and two knees had local irritation that required the removal of the hardware.
Locking compression plate fixation without the use of bone grafts or bone substitutes provides a satisfactory union rate and an acceptable complication rate when compared to the traditional MOWHTO technique. Thus, we recommend using this technique for treating unicompartmental medial knee osteoarthritis.
PMCID: PMC3421937  PMID: 22912522
Medial; high tibial osteotomy; locking compression plate; T-buttress plate; bone graft
24.  Imaging of cartilage repair procedures 
The rationale for cartilage repair is to prevent precocious osteoarthritis in untreated focal cartilage injuries in the young and middle-aged population. The gamut of surgical techniques, normal postoperative radiological appearances, and possible complications have been described. An objective method of recording the quality of repair tissue is with the magnetic resonance observation of cartilage repair tissue (MOCART) score. This scoring system evaluates nine parameters that include the extent of defect filling, border zone integration, signal intensity, quality of structure and surface, subchondral bone, subchondral lamina, and records presence or absence of synovitis and adhesions. The five common techniques of cartilage repair currently offered include bone marrow stimulation (microfracture or drilling), mosaicplasty, synthetic resorbable scaffold grafts, osteochondral allograft transplants, and autologous chondrocyte implantation (ACI). Complications of cartilage repair procedures that may be demonstrated on magnetic resonance imaging (MRI) include plug loosening, graft protuberance, graft depression, and collapse in mosaicplasty, graft hypertrophy in ACI, and immune response leading to graft rejection, which is more common with synthetic grafts and cadaveric allografts.
PMCID: PMC4126139  PMID: 25114387
Cartilage; repair; magnetic resonance imaging
25.  Comparison of marker gene expression in chondrocytes from patients receiving autologous chondrocyte transplantation versus osteoarthritis patients 
Currently, autologous chondrocyte transplantation (ACT) is used to treat traumatic cartilage damage or osteochondrosis dissecans, but not degenerative arthritis. Since substantial refinements in the isolation, expansion and transplantation of chondrocytes have been made in recent years, the treatment of early stage osteoarthritic lesions using ACT might now be feasible. In this study, we determined the gene expression patterns of osteoarthritic (OA) chondrocytes ex vivo after primary culture and subculture and compared these with healthy chondrocytes ex vivo and with articular chondrocytes expanded for treatment of patients by ACT. Gene expression profiles were determined using quantitative RT-PCR for type I, II and X collagen, aggrecan, IL-1β and activin-like kinase-1. Furthermore, we tested the capability of osteoarthritic chondrocytes to generate hyaline-like cartilage by implanting chondrocyte-seeded collagen scaffolds into immunodeficient (SCID) mice. OA chondrocytes ex vivo showed highly elevated levels of IL-1β mRNA, but type I and II collagen levels were comparable to those of healthy chondrocytes. After primary culture, IL-1β levels decreased to baseline levels, while the type II and type I collagen mRNA levels matched those found in chondrocytes used for ACT. OA chondrocytes generated type II collagen and proteoglycan-rich cartilage transplants in SCID mice. We conclude that after expansion under suitable conditions, the cartilage of OA patients contains cells that are not significantly different from those from healthy donors prepared for ACT. OA chondrocytes are also capable of producing a cartilage-like tissue in the in vivo SCID mouse model. Thus, such chondrocytes seem to fulfil the prerequisites for use in ACT treatment.
PMCID: PMC2206334  PMID: 17596264

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