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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.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  Knee chondral lesions treated with autologous chondrocyte transplantation in a tridimensional matrix: clinical evaluation at 1-year follow-up 
Background
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.
Results
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.
Conclusions
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.
doi:10.1007/s10195-009-0069-z
PMCID: PMC2784059  PMID: 19936886
Tridimensional matrix; WOMAC score; Clinical evaluation; Oxford Knee Score; KOOS
15.  Knee chondral lesions treated with autologous chondrocyte transplantation in a tridimensional matrix: clinical evaluation at 1-year follow-up 
Background
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.
Results
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.
Conclusions
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.
doi:10.1007/s10195-009-0069-z
PMCID: PMC2784059  PMID: 19936886
Tridimensional matrix; WOMAC score; Clinical evaluation; Oxford Knee Score; KOOS
16.  Matrix-induced autologous chondrocyte implantation for a large chondral defect in a professional football player: a case report 
Introduction
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.
Conclusions
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.
doi:10.1186/1752-1947-6-173
PMCID: PMC3404975  PMID: 22742735
17.  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.
doi:10.1186/ar1710
PMCID: PMC1174952  PMID: 15899042
18.  A retrospective analysis of medial opening wedge high tibial osteotomy for varus osteoarthritic knee 
Indian Journal of Orthopaedics  2012;46(4):455-461.
Background:
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.
Results:
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.
Conclusion:
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.
doi:10.4103/0019-5413.98833
PMCID: PMC3421937  PMID: 22912522
Medial; high tibial osteotomy; locking compression plate; T-buttress plate; bone graft
19.  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.
doi:10.1186/ar2218
PMCID: PMC2206334  PMID: 17596264
20.  Platelet-Rich Plasma Treatment in Symptomatic Patients With Knee Osteoarthritis 
Sports Health  2012;4(2):162-172.
Background:
With increasing frequency, platelet-rich plasma (PRP) preparations have been used to treat cartilage lesions to regenerate tissue homeostasis and retard the progression of knee osteoarthritis (OA).
Purpose:
To determine the effectiveness of intra-articular PRP injections in active patients with knee OA and to evaluate clinical outcomes in patients with and without previous surgical treatment for cartilage lesions.
Study Design:
Case series.
Materials and Methods:
Fifty patients with knee OA were followed for a minimum of 12 months. All were treated with 2 intra-articular injections of autologous PRP. Twenty-five patients had undergone a previous operative intervention for cartilage lesions, whereas 25 had not. Operated patients had undergone either cartilage shaving or microfracture. Multiple evaluative scores were collected at pretreatment and at 6 and 12 months posttreatment. The required sample of patients was determined beforehand by using statistical power analysis; International Knee Documentation Committee (subjective) score was defined as the primary parameter. A P value of less than 0.05 was considered statistically significant. General linear model–repeated measure test evaluated within-time improvement for each variable for all patients. Post hoc test with Bonferroni adjustment for multiple comparisons was performed to investigate the significance in improvement within time evaluations for each variable for the total sample. The differences in improvement between operated and nonoperated patients were also investigated, as were those between sexes.
Results:
All patients showed significant improvement in all scores at 6 and 12 months (P < 0.01) and returned to previous activities. No significant difference in improvement was found between the evaluated subgroups (P < 0.01).
Conclusions:
The PRP treatment showed positive effects in patients with knee OA. Operated and nonoperated patients showed significant improvement by means of diminishing pain and improved symptoms and quality of life.
Clinical Relevance:
There are only a few studies of PRP treatment for cartilage on osteoarthritic knees. Different PRP products might be more or less appropriate to treat different types of tissues and pathologies. The clinical efficacy of PRP remains under debate, and a standardized protocol has not yet been established.
doi:10.1177/1941738111431801
PMCID: PMC3435904  PMID: 23016084
knee; cartilage; osteoarthritis; platelet-rich plasma; microfracture; cartilage shaving
21.  Sequential outcome following autologous chondrocyte implantation of the knee: A six-year follow-up 
International Orthopaedics  2009;34(7):959-964.
This prospective six-year longitudinal study reviews the clinical outcome of patients undergoing autologous chondrocyte implantation (ACI) and a porcine type I/III collagen membrane cover for deep chondral defects of the knee. We present 57 patients (31 male, 26 female) with a mean age of 31.6 years (range 15–51 years) that have undergone ACI since July 1998. The mean size of the defect was 3.14 cm2 (range 1.0–7.0 cm2). All patients were assessed annually using seven independent validated clinical rating scores with the data analysed using ANOVA. ACI using a porcine type I/III collagen membrane cover produced statistically significant improvements (p < 0.001), maintained for up to six years, in knee symptoms compared to pre-operative levels. This study provides evidence of the medium-term benefit achieved by transplanting autologous chondrocytes to osteochondral defects.
doi:10.1007/s00264-009-0842-x
PMCID: PMC2989043  PMID: 19669763
22.  Gel-type autologous chondrocyte (Chondron™) implantation for treatment of articular cartilage defects of the knee 
Background
Gel-type autologous chondrocyte (Chondron™) implantations have been used for several years without using periosteum or membrane. This study involves evaluations of the clinical results of Chondron™ at many clinical centers at various time points during the postoperative patient follow-up.
Methods
Data from 98 patients with articular cartilage injury of the knee joint and who underwent Chondron™ implantation at ten Korean hospitals between January 2005 and November 2008, were included and were divided into two groups based on the patient follow-up period, i.e. 13~24-month follow-up and greater than 25-month follow-up. The telephone Knee Society Score obtained during telephone interviews with patients, was used as the evaluation tool.
Results
On the tKSS-A (telephone Knee Society Score-A), the score improved from 43.52 ± 20.20 to 89.71 ± 13.69 (P < 0.05), and on the tKSS-B (telephone Knee Society Score-B), the score improved from 50.66 ± 20.05 to 89.38 ± 15.76 (P < 0.05). The total improvement was from 94.18 ± 31.43 to 179.10 ± 24.69 (P < 0.05).
Conclusion
Gel-type autologous chondrocyte implantation for chondral knee defects appears to be a safe and effective method for both decreasing pain and improving knee function.
doi:10.1186/1471-2474-11-103
PMCID: PMC2894009  PMID: 20507640
23.  Glycosaminoglycan profiles of repair tissue formed following autologous chondrocyte implantation differ from control cartilage 
Currently, autologous chondrocyte implantation (ACI) is the most commonly used cell-based therapy for the treatment of isolated femoral condyle lesions of the knee. A small number of centres performing ACI have reported encouraging long-term clinical results, but there is currently a lack of quantitative and qualitative biochemical data regarding the nature of the repair tissue. Glycosaminoglycan (GAG) structure influences physiological function and is likely to be important in the long-term stability of the repair tissue. The objective of this study was to use fluorophore-assisted carbohydrate electrophoresis (FACE) to both quantitatively and qualitatively analyse the GAG composition of repair tissue biopsies and compare them with age-matched cadaveric controls. We used immunohistochemistry to provide a baseline reference for comparison. Biopsies were taken from eight patients (22 to 52 years old) 1 year after ACI treatment and from four cadavers (20 to 50 years old). FACE quantitatively profiled the GAGs in as little as 5 μg of cartilage. The pattern and intensity of immunostaining were generally comparable with the data obtained with FACE. In the ACI repair tissue, there was a twofold reduction in chondroitin sulphate and keratan sulphate compared with age-matched control cartilage. By contrast, there was an increase in hyaluronan with significantly shorter chondroitin sulphate chains and less chondroitin 6-sulphate in repair tissue than control cartilage. The composition of the repair tissue thus is not identical to mature articular cartilage.
doi:10.1186/ar2278
PMCID: PMC2206378  PMID: 17697352
24.  THE ROLE OF REHABILITATION FOLLOWING AUTOLOGOUS CHONDROCYTE IMPLANTATION: A RETROSPECTIVE CHART REVIEW 
Purpose/Background:
Clinical outcomes following autologous chondrocyte implantation (ACI) are influenced by multiple factors, including patient demographics, lesion characteristics, quality of the surgical repair, and post‐operative rehabilitation. However, it is currently unknown what specific characteristics of rehabilitation have the greatest influence on clinical outcomes following ACI. The purpose of this study was to conduct a retrospective chart review of patients undergoing ACI with the intent to describe this patient population’s demographics, clinical outcomes, and rehabilitation practices. This study aimed to assess the consistency of the documentation process relative to post‐operative rehabilitation in order to provide information and guide initiatives for improving the quality of rehabilitation practices following ACI.
Methods:
The medical records of patients treated for chondral defect(s) of the knee who subsequently underwent the ACI procedure were retrospectively reviewed. A systematic review of medical, surgical, and rehabilitation records was performed. In addition, patient‐reported outcome measures (IKDC, WOMAC, Lysholm, SF‐36) recorded pre‐operatively, and 3, 6, and 12 months post‐operatively were extracted from an existing database.
Results:
20 medical charts (35.9 ± 6.8 years; 9 male, 11 female) were systematically reviewed. The average IKDC, WOMAC, Lysholm, and SF‐36 scores all improved from baseline to 3, 6 and 12 months post‐operatively, with the greatest changes occurring at 6 and 12 months. There was inconsistent documentation relative to post‐operative rehabilitation, including CPM use, weight‐bearing progression, home‐exercise compliance, and strength progressions.
Conclusions:
Due to variations in the documentation process, the authors were unable to determine what specific components of rehabilitation influence the recovery process. In order to further understand how rehabilitation practices influence outcomes following ACI, specific components of the rehabilitation process must be consistently and systematically documented over time.
Level of Evidence:
2C
PMCID: PMC3811727  PMID: 24175146
autologous chondrocyte implantation; chart review; clinical outcome; rehabilitation
25.  Treatment of full thickness cartilage defects in human knees with Autologous Chondrocyte Transplantation* 
BACKGROUND:
Although a variety of strategies have been employed for managing articular cartilage defects in the knee, overall outcomes have not been satisfactory. An alternative option may be autologous chondrocyte transplantation (ACT). However, as this method is still under investigation, here we assessed the efficacy of ACT for human knee defect cartilage repair.
METHODS:
In a randomized clinical trial study, eleven patients (mean age 31.09 years) were enrolled in the study with full thickness cartilage defects in the knee. Arthroscopically, healthy cartilage was obtained, chondrocytes expanded for 2-3 weeks and ACT performed. Clinical status was evaluated before ACT, 6 and 12 months after ACT using the Brittberg-Peterson functional assessment and modified Cincinnati rating score. Magnetic resonance imaging (MRI) findings were evaluated based on the scoring systems used by Sally Roberts and by Henderson.
RESULTS:
Modified Cincinnati rating indicated significant improvement of clinical score before ACT compared to 6 (p = 0.000) and 12 (p = 0.000) months after ACT (from 2.73 before ACT to 7.27, 8.36 and 9.5 at 6, 12, and 48 months after ACT, respectively). Brittberg-Peterson functional assessment indicated a decline from 79.27 to 25.82 and 19.27 at 6 and 12 months post ACT. Further, statistical test demonstrated significant differences 6, 12 and 48 months post ACT (p = 0.007). Evaluation of MRI revealed a score of 6.5 for Henderson criteria and a score of 2.5 for Robert criteria.
CONCLUSIONS:
Our study demonstrated that ACT of the knee provides an excellent treatment for full thickness cartilage defects with outstanding clinical and radiological outcomes.
PMCID: PMC3263096  PMID: 22279451
Articular Cartilage; Full Thickness Cartilage Defect; Autologus Chondrocyte Transplantation; Knee

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