Cartilage Defects Of Knee Joint Research Articles

Morphohistological study of regeneration of knee joint cartilage defects in an experimental model under the influence of nuclear magnetic resonance therapy

Despite the variety of modern methods of treatment, the problem of hyaline cartilage regeneration is still relevant. Purpose of the study: to determine the effect of nuclear magnetic resonance therapy on the regenerative ability of simulated defects in the cartilage tissue of the knee joint in rats, to assess the dynamics of microscopic changes in articular cartilage in the main and control groups. The study was performed on 60 sex-mature rats. The defects were created in the area of the articular surfaces of the left knee joint – 30 defects in the main group and 30 defects in the control group. The right knee joint of both study groups was used as the norm. Medical (antibiotics, anti-inflammatory, analgesic) therapy was carried out for 3 days after the surgery. On the 4th day after surgery, rats of the main group were given nuclear magnetic resonance therapy for 60 minutes, for 7 days. After 7, 14, 21, 28 days after therapy, histological analysis of cartilage regenerate was performed. 28 days after the use of nuclear magnetic resonance therapy, the height of cartilage regenerate in rats was 82.12±8.89 μm in the intervention group and 56.34±7.82 μm in the control group. Cartilage regenerate in rats after nuclear magnetic resonance therapy was close to the structure of intact hyaline cartilage. However, complete regeneration did not occur, as evidenced by the smaller thickness of the articular cartilage compared to that in the right knee joint. In the control group, the formation of the regeneration had pronounced signs of dysregeneration. The cartilage tissue in the area of the defect, was predominantly fibrous in the nature with areas of necrosis. Nuclear magnetic resonance therapy contributes to the formation of articular cartilage in the defect – cartilage regenerate, which in its histological structure approaches hyaline cartilage.

Enhancing the potential of aged human articular chondrocytes for high-quality cartilage regeneration.

Autologous chondrocyte implantation (ACI) is a regenerative procedure used to treat focal articular cartilage defects in knee joints. However, age has been considered as a limiting factor and ACI is not recommended for patients older than 40-50years of age. One reason for this may be due to the reduced capacity of aged chondrocytes in generating new cartilage. Currently, the underlying mechanism contributing to aging-associated functional decline in chondrocytes is not clear and no proven approach exists to reverse chondrocyte aging. Given that chondrocytes in healthy hyaline cartilage typically display a spherical shape, believed to be essential for chondrocyte phenotype stability, we hypothesize that maintaining aged chondrocytes in a suspension culture that forces the cells to adopt a round morphology may help to "rejuvenate" them to a younger state, thus, leading to enhanced cartilage regeneration. Chondrocytes isolated from aged donors displayed reduced proliferation potential and impaired capacity in generating hyaline cartilage, compared to cells isolated from young donors, indicated by increased hypertrophy and cellular senescence. To test our hypothesis, the "old" chondrocytes were seeded as a suspension onto an agarose-based substratum, where they maintained a round morphology. After the 3-day suspension culture, aged chondrocytes displayed enhanced replicative capacity, compared to those grown adherent to tissue culture plastic. Moreover, chondrocytes subjected to suspension culture formed new cartilage in vitro with higher quality and quantity, with enhanced cartilage matrix deposition, concomitant with lower levels of hypertrophy and cellular senescence markers. Mechanistic analysis suggested the involvement of the RhoA and ERK1/2 signaling pathways in the "rejuvenation" process. In summary, our study presents a robust and straightforward method to enhance the function of aged human chondrocytes, which can be conveniently used to generate a large number of high-quality chondrocytes for ACI application in the elderly.

Silk fibroin hydrogel scaffolds incorporated with chitosan nanoparticles repair articular cartilage defects by regulating TGF-\u03b21 and BMP-2

Cartilage defects frequently occur around the knee joint yet cartilage has limited self-repair abilities. Hydrogel scaffolds have excellent potential for use in tissue engineering. Therefore, the aim of the present study was to assess the ability of silk fibroin (SF) hydrogel scaffolds incorporated with chitosan (CS) nanoparticles (NPs) to repair knee joint cartilage defects. In the present study, composite systems of CS NPs incorporated with transforming growth factor-β1 (TGF-β1; TGF-β1@CS) and SF incorporated with bone morphogenetic protein-2 (BMP-2; TGF-β1@CS/BMP-2@SF) were developed and characterized with respect to their size distribution, zeta potential, morphology, and release of TGF-β1 and BMP-2. Bone marrow stromal cells (BMSCs) were co-cultured with TGF-β1@CS/BMP-2@SF extracts to assess chondrogenesis in vitro using a cell counting kit-8 assay, which was followed by in vivo evaluations in a rabbit model of knee joint cartilage defects. The constructed TGF-β1@CS/BMP-2@SF composite system was successfully characterized and showed favorable biocompatibility. In the presence of TGF-β1@CS/BMP-2@SF extracts, BMSCs exhibited normal cell morphology and enhanced chondrogenic ability both in vitro and in vivo, as evidenced by the promotion of cell viability and the alleviation of cartilage defects. Thus, the TGF-β1@CS/BMP-2@SF hydrogel developed in the present study promoted chondrogenic ability of BMSCs both in vivo and in vitro by releasing TGF-β1 and BMP-2, thereby offering a novel therapeutic strategy for repairing articular cartilage defects in knee joints.

Repair effects of bone marrow mesenchymal stem cells modified by adenovirus mediated bcl-xL gene on the cartilage defect of knee joint in rats

Objective To observe the repair effects of bone marrow mesenchymal stem cells (BMSCs) modified by adenovirus mediated B cell lymphoma/leukemia-xL (bcl-xL) gene on the cartilage defect of knee joint in rats. Methods The adenovirus-mediated bcl-xL gene overexpression vector pAdTrack-bcl-xL was constructed. BMSCs were isolated, cultured and amplified, pAdTrack-bcl-xL and blank vector were transfected, and the bcl-xL expression level was detected by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR). Fifty SD rats were randomly divided into five groups (n=10 each). The control group received no treatment, and the remaining four groups (model group, BMSCs treatment group, BMSCs treatment group transfected with empty vector and bcl-xL overexpressed BMSCs treatment group) were all used to make models of cartilage defect of the knee joint. Three days after surgery, the animals were treated accordingly. Rats in each group were sacrificed at 6th and 12th week after treatment, and the knee joints were collected and paraffin sections were made. Then the cartilage tissues of the knee joints were stained and observed by hematoxylin and eosin (HE), Masson and saffron-O methods. Results As compared with the empty vector group, the relative mRNA expression of bcl-xL gene in BMSCs of pAdTrack-bcl-xL group was significantly increased (1.07±0.08 vs. 8.15±0.31, t=-52.893, P<0.01), suggesting that BMSCs with stable over-expression of bcl-xL gene were successfully constructed. Pathological staining results showed that, after 6 weeks of treatment, as compared with the model group, in the BMSCs group and the BMSCs treatment group transfected with empty vector, a large amount of chondrogenesis was seen, the arrangement of chondrocytes tended to be orderly, and the number of chondrocytes significantly increased. However, the bcl-xL over-expressed BMSCs treatment group had more chondrogenesis, more orderly arrangement of chondrocytes and significantly greater number of chondrocytes than the BMSCs treatment group transfected with empty vector. As compared with the same group at 6th week, chondrogenesis was significantly increased in each treatment group at 12th week, especially in BMSCs treatment group with bcl-xL overexpression. Conclusion Bcl-xL over-expressed BMSCs can significantly promote the repair of cartilage defect of knee joints in rats, which will lay a theoretical foundation for the clinical treatment of articular cartilage defect. Key words: Bone marrow mesenchymal stem cells; B cell lymphoma/leukemia-xL over-expression; Knee joint; Cartilage defect

Follow-up study on autogenous osteochondral transplantation for cartilage defect of knee joint

To evaluate clinical effect of autologous osteochondral transplantation in treating localized knee cartilage defects. Fifteen patients with knee cartilage defects were treated by autologous osteochondral transplantation from January 2007 to January 2008, including 8 females and 7 males, aged from 23 to 45 years old. Preoperative and postoperative KSS score at 10 years were compared. All patients were followed up for 10.0 to 10.7 years, with an average of(10.2±0.3) years. Clinical score of KSS was improved from 38.86±4.09 to 85.07±2.19 at 10 years after operation(P<0.05), functional score increased from 3.33±4.88 to 82.67±4.58 at 10 years after operation(P<0.05), KSS score was improved form 42.20±7.84 befor operation to 167.73±6.29 at 10 years after operation, and had statistical differences before and after operation. While there was no statistical difference in stability of knee joint(P>0.05). All patients had no other complications. Through long-term follow-up of patients with cartilage defect in knee treated by autologous bone cartilage transplantation showed that this method could effectively improve function of knee joint and alleviate pain. So it is an effective method for repair of osteochondral defect.

Shape-memory collagen scaffold for enhanced cartilage regeneration: native collagen versus denatured collagen

Nowadays, it is still questionable whether denatured collagen (DCol) can replace the native collagen (Col) as a bioactive protein in cartilage engineering. We sought to study the advantages of Col with a triple-helical structure in the collagen-based composite materials for cartilage engineering. We presented new three-dimensional (3D) Col and DCol scaffolds with shape memory properties. The effects of Col and DCol scaffolds on rabbit chondrocytes' proliferation, adhesion, differentiation and interaction with matrix were investigated. Tissue compatibility was performed in a subcutaneous Sprague Dawley (SD) rat model. The repair ability of different scaffolds with chondrocytes for full-thickness articular cartilage defects in knee joints of New Zealand white rabbits were investigated. The results indicated that the Col scaffolds (with concentration 1.6wt% and 0.8wt%, respectively) promoted the proliferation, adhesion and redifferentiation of chondrocytes, as well as chondrocyte-matrix interaction, to a greater degree than the DCol scaffolds. In the animal experiment, the Col scaffolds filled in the defect hole significantly maintained chondrocytes function, promoted cartilage and subchondral bone regeneration, compared with the DCol scaffolds, and the scaffolds loaded with chondrocytes were better than the cell-free scaffolds, especially in the case of the Col scaffolds (1.6 wt%). Taken together, these insights suggest that the better proliferation, adhesion and redifferentiation of chondrocytes in Col scaffolds with the triple-helical structure may contribute to the greater cartilage repair ability. Col scaffolds may be more appropriate for repairing cartilage defects than DCol scaffolds, and DCol cannot as an alternative when using collagen-based materials for cartilage engineering applications.

Correction: Effects of collagen matrix and bioreactor cultivation on cartilage regeneration of a full-thickness critical-size knee joint cartilage defects with subchondral bone damage in a rabbit model.

[This corrects the article DOI: 10.1371/journal.pone.0196779.].

Effects of collagen matrix and bioreactor cultivation on cartilage regeneration of a full-thickness critical-size knee joint cartilage defects with subchondral bone damage in a rabbit model.

Cartilage has limited self-repair ability. The purpose of this study was to investigate the effects of different species of collagen-engineered neocartilage for the treatment of critical-size defects in the articular joint in a rabbit model. Type II and I collagen obtained from rabbits and rats was mixed to form a scaffold. The type II/I collagen scaffold was then mixed with rabbit chondrocytes to biofabricate neocartilage constructs using a rotating cell culture system [three-dimensional (3D)-bioreactor]. The rabbit chondrocytes were mixed with rabbit collagen scaffold and rat collagen scaffold to form neoRBT (neo-rabbit cartilage) and neoRAT (neo-rat cartilage) constructs, respectively. The neocartilage matrix constructs were implanted into surgically created defects in rabbit knee chondyles, and histological examinations were performed after 2 and 3 months. Cartilage-like lacunae formation surrounding the chondrocytes was noted in the cell cultures. After 3 months, both the neoRBT and neoRAT groups showed cartilage-like repair tissue covering the 5-mm circular, 4-mm-deep defects that were created in the rabbit condyle and filled with neocartilage plugs. Reparative chondrocytes were aligned as apparent clusters in both the neoRAT and neoRBT groups. Both neoRBT and neoRAT cartilage repair demonstrated integration with healthy adjacent tissue; however, more integration was obtained using the neoRAT cartilage. Our data indicate that different species of type II/I collagen matrix and 3D bioreactor cultivation can facilitate cartilage engineering in vitro for the repair of critical-size defect.

The study of leucocyte and platelet-rich plasma combined with rabbit synovial stem cells for the repair of knee joint cartilage injury

Objective To investigate the effect of platelet-rich plasma (L-PRP) combined with rabbit synovium-derived mesenchymal stem cells (SMSCs) on cartilage repair in knee-joint injured. Methods 60 healthy New Zealand white rabbits were used to establish models of knee-joint cartilage defects, SMSCs were separated, purified and identified, and then L-PRP was prepared using two step centrifugation. The levels of platelet derived growth factor-BB (PDGF-BB), transforming growth factor-β1 (TGF-β1), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) in whole blood and L-PRP were determined using enzyme linked immunosorbent assay (ELISA). After 12 weeks of modeling, the injured cartilage was grossly observed, and hematoxylin-eosin (HE) staining was used to observe cartilage repair under light microscope; histological examination was performed according to the O’Driscoll histologic standard. Results The levels of platelet in L-PRP increased to (135.77±50.56)×104/μl were more 6 times than whole blood [(22.38±3.20)×104/μl, P=0.001], and the levels of PDGF-BB, TGF-β1, bFGF, VEGF in L-PRP were increased as (32.50±5.10) ng/ml, (124.26±32.30) ng/ml, (87.14±12.50) pg/ml, (174.50±31.22) pg/ml significantly higher than whole blood as [(6.28±1.11) ng/ml, (21.72±3.70) ng/ml, (25.85±4.52) pg/ml, (37.87±5.33) pg/ml], the differences were statistically significant (P=0.005, 0.003, 0.008, 0.002). Post-operation 12 weeks, the results from grossly observation, HE staining and histological examination indicated that the repair effect in L-PRP group, SMSCs group, L-PRP combined with SMSCs group was significantly better than in normal saline group, L-PRP and SMSCs group, respectively. Conclusion Both L-PRP and SMSCs be able to promote cartilage repair of knee-joint injured, and L-PRP combined with SMSCs group was be superior to L-PRP and SMSCs group respectively. Key words: Knee-joint; Cartilage injury; Platelet-rich plasma; Rabbit synovium-derived mesenchymal stem cells; Stem cells

A new point of view for mosaicplasty in the treatment of focal cartilage defects of knee joint: honeycomb pattern.

Background A focal full thickness cartilage lesion of knee joint is one of the commonly seen intraarticular pathologies among the joint cartilage problems. Osteochondral autograft transfer mosaicplasty is a method which has satisfactory outcomes among the treatment preferences of cartilage defects. In spite of the favorable clinical results there are some pitfalls of mosaicplasty treatment especially in cases of large defects. One of the major problems of the classical OAT mosaicplasty is the gap spaces between the plugs. The objective of the present study is to report the early clinical and radiological outcomes and to evaluate the clinical application of a new hexagonal osteochondral graft system (HOGS) with the hypothesis of improvement of the OAT mosaicplasty method with the use of hexagonally shaped plugs. The study has intended to answer two questions. (1) Does mosaicplasty with the new HOGS has favorable early clinical outcomes? (2) Is it possible to arrange the osteochondral autografts without leaving gap spaces by using hexagonal pattern in OAT mosaicplasty?Patients and methodsWe designed a retrospective study to report analysis of early outcomes of the initial case series of OAT mosaicplasty by using a new HOGS. Six male individuals with the diagnosis of osteochondral defect and treated with HOGS and reached sixth month follow-up formed the basis of the study. The clinical status of the patients were evaluated with IKDC score. The radiological evaluations were carried out with direct X-rays and magnetic resonance imaging (MRI) studies. The mosaicplasty procedures were carried out via standard surgical method of classical OAT mosaicplasty by using the HOGS following a diagnostic arthroscopy in the same session. The inclusion criteria was a full thickness osteochondral lesion of femoral condyle between 1.5 and 6 cm2 and completion of 6 month follow-ups. The patients having deformities around the knee or major ligament lesions were excluded. MOCART scoring system was used for the evaluation of follow-up MRI findings. The clinical status of the patients were evaluated with IKDC scores.ResultsThe mean age of the patients was 40.8 (±5.2) years and the mean duration of the symptoms on presentation was 16 (±4.3) months. On the initial MRI studies mean defect area was measured 3.7 cm2 (±0.9) which was compatible with arthroscopic findings. During the surgical procedures it was possible to fill the defect area completely. The mean number of plugs in this series was 4.8 (±1.1). We did not faced with insufficient donor reserve problem in any of the cases. On the sixth month follow-up physical examination there was no limitation of the knee joint range of motion in the cases. All patients were able to bear weight on to their operated extremities without pain. The mean postoperative IKDC score improvement was 70.2 (±3.5) which shows significant improvement compared to preoperative scores. On the control MRI studies the bone integration of the hexagonal plugs were complete the cartilage continuity of the articular surfaces were intact and the grafts were well incorporated in all cases. The mean MOCART score on the 6th month MRI studies was 65.8 (±4.1).ConclusionThe early outcomes of OAT mosaicplasty with HOGS are comparable to studies on the classical mosaicplasty. According to our observations in this study we can say that the gap space left between the cylindrical plugs can be solved by using hexagonal prism shaped plugs.

Early efficacy study of matrix induced autologous chondrocyte implantation repairing knee joint cartilage injury

Objective To study the feasibility and early efficacy of matrix-induced autologous chondrocyte implantation repairing knee joint cartilage injury. Methods The Matrix-induced autologous chondrocyte implantation was used to repair knee joint cartilage injury in 13 cases (11 males and 2 females) with knee joint cartilage injury from April 2012 to March 2013. The average age was 27.5 years old. All cases were suffering from unilateral focal cartilage defect of knee joint with International Cartilage Repair Society (ICRS) chondral defect classification system grade III or IV, visual analogue scale (VAS) >3, and all of which had corresponding pain symptoms. The average defect area was 4.2 cm2. Standardized rehabilitation exercise was carried out after matrix-induced autologous chondrocyte implantation. Patients were followed up for 1 years, and knee injury and use osteoarthritis outcome score (KOOS), International Knee Documentation Committee (IKDC), subjective knee form and Lysholm score were collected to assess the function. Meanwhile, magnetic resonance observation of cartilage repair tissue (MOCART) score was used to assess the magnetic resonance imaging. Results All patients had been followed-up for 1 year. One patient had meniscus repair under arthroscopy for the meniscus injury caused by downstairs sprain in 6.5 months postoperative, so the score of 12 months postoperative was excluded. The knee range of motion was decreased in 3 months postoperative (123.1°±8.0°) compared to preoperative one (135.4°±5.7°), and has no difference in 6 months (136.1°±6.1°) and 12 months postoperative (135.1°±3.6°) compared to preoperative one. The 5 subsets of KOOS score were decreased in 3 months compared to preoperative one, and were significantly increased in 6 months and 12 months. The IKDC has no difference in 3 months (26.1±3.9) compared to preoperative one (43.5± 6.5), and were significantly increased in 6 months (53.3±5.8) and 12 months (62.8±7.2) compared to preoperative one. The magnetic resonance observation of cartilage repair tissue (MOCART) score was increased in 12 month (73.3±17.9) compared to preoperative one (51.5±12.6). Conclusion MACI is a good technology for knee joint cartilage injury. It has a good clinical effect on re- pairing cartilage injury effectively and restoring the function of knee joint. Key words: Chondrocytes; Transplantation, autologous; knee joint

Priority of surgical treatment techniques of full cartilage defects of knee joint

Aim. Surgical treatment of chondromalacia of knee joint cartilage is an actual problem of the modern orthopedics because the means of conservative therapy can be realized at an initial stage only and almost exhausted at the further ones. Imperfections of palliative surgical techniques are the short-term clinical effect and pathogenetic baselessness because surgical procedure is not directed on reparation of cartilaginous tissue. For today there are a lot of transplantation techniques that are used for biological renewal of articular surface with formation of hyaline or at least hyaline-like cartilage. The deep forage of cartilage defect bottom to the medullary canal is a perspective and priority technique. Methods. The results of treatment of 61 patients with chondromalacia of knee joint of 3-4 degree according to R. Outerbridge are the base of the work. 20 patients of every group underwent microfracturization of cartilage defect bottom and subchondral forage of defect zone. 21 patients underwent the deep forage of defect zone of knee joint according to an offered technique. Result. The results of treatment with microfracturization, subchondral forage and deep forage of defect zone indicate the more strong clinical effect especially in the last clinical group where good and satisfactory results ratios in the term of observation 18 and 24 month remain stable. Conclusions. Deep forage of cartilage defects zone is the most adequate reparative technique of the surgical treatment of local knee joint cartilage defects. Owing to this procedure the number of cells of reparative chondrogenesis predecessors is realized

Microfracture for Treatment of Knee Cartilage Defects in Children and Adolescents

Even though operative microfracture is the most frequent method for treatment of limited knee joint cartilage lesions among adults, data about ouctome in children and adolescents are rare. We performed a retrospective chart review and telephone interview to analyze for the clinical outcome following knee joint cartilage defect microfracturing among 10 children. Mean postoperative Lysholm was 92.1±9.9 and Tegner was 7.0±1.9. Clinical outcome differed across knee joint regions, as well as in dependence of varying pre-operative symptom duration, although this was not significant. Regression analysis did not reveal a significant impact of patient or defect characteristics on clinical outcome. Arthroscopic microfracturing for treatment of limited size symptomatic knee joint cartilage defects among children and adolescents is considered a reasonable surgical option. However, long-term outcome and larger patient cohorts are required.

Comparing the Chondrogenic Potential in vivo of Autogeneic Mesenchymal Stem Cells Derived from Different Tissues

to compare the chondrogenic ability of mesenchymal stem cells (MSCs) derived from different tissues in rabbits' full-thickness articular cartilage defects. sixty New Zealand white rabbits of ordinary grade with a body weight of 2.5 approximately 3.5kg were selected for this study. Six were sacrificed for preparation of deminerized bone matrix (DBM) as scaffold. Fifty-four were used for cartilage defects model. Full-thickness cartilage defect of knee joint was created on trochlear groove at two sides of the femur with a diameter of 4 mm and thickness of 3 mm. All 54 rabbits were randomly divided into 6 groups and treated by autogeneic MSCs isolated from bone marrow, periosteum, synovium, adipose tissue and muscle, respectively. The 6th group was a control group with nothing plugged into the defects. Every three rabbits were killed at three time points, which were 4, 8, and 12 weeks after the operation in each group. The reparative tissue samples were evaluated grossly, histologically, immunohistochemically, and graded according to gross and histological scales 12 weeks postoperatively. We input the scores into SPSS 11.5 software and the analysis of variance (one-way-ANOVA) and student-newman-keuls (SNK-q) test were used to process statistical analysis and find out if the differences between each group had statistical significance. fifty-four rabbits are included in the final analysis. The defects are all repaired by hyaline-like tissue except the control group. The bone-marrow-MSCs produced much more cartilage matrix than that of other groups. Gross and histological grading scale indicates that the defects repaired by MSCs isolated from bone marrow are superior to that repaired by MSCs isolated from periosteum, synovium, adipose tissue, and muscle (p < 0.05). In adipose-MSCs and muscle-MSCs group, some defects are even repaired by fibrous tissue. bone-marrow-MSCs have greater in vivo chondrogenic potential than periosteum-, synovium-, adipose- and muscle-MSCs.

Prognosis for the result of treatment of damages in the knee joint cartilage

The problem of prediction of an effective restoration of a cartilage defect has not been solved yet. The purpose of the study was to reveal the factors which essentially influence treatment results in the knee joint cartilage defects. Remote (from 8 to 14 years) treatment results of 176 patients with knee osteoarthritis were analyzed. Seventy-nine patients had cartilage lesions of the internal condyle of the femur, whereas the rest of these patients had defects of both the articular surface of the internal condyle of the femur and of the articular cartilage of the tibial plateau. Only cartilage defects and lesions of degree III by Outerbridge were taken into account. The used surgical techniques were as follows: microfracture in 142 cases and mosaic plasty in 34 ones. The age factor proved to be statistically significant for predicting osteoarthrosis progress. The best treatment results were received in patients under 40. In the age group of 40-55 years the results were satisfactory. The influence of the lesion area on the treatment results was not significant, as it was shown by absence of any correlation between the lesion area and the remote results. The initial condition of the knee joint was an important significant predictor for the treatment results. A high correlation was revealed between a preoperative narrowing of the articular space and treatment results. The medial tibial angle was the most significant parameter for predicting treatment of the knee joint. When its value was 86° or less, no positive results of treatment of the cartilage defects were received. The geometry of the distal femur did not produce any significant influence on the treatment results. Results of restoration of the condyle cartilage lesions in the knee joints mostly depended on the initial knee joint status and biomechanical relations in the joint, rather than on the lesion area.

Long-term effects of chondrospheres on cartilage lesions in an autologous chondrocyte implantation model as investigated in the SCID mouse model

Microtraumata often lead to articular cartilage lesions. Due to the bradytrophic character of hyaline cartilage, these lesions are hardly repaired by the organism. Autologous chondrocyte implantation (ACI) was established for restoring isolated structural cartilage defects in knee joints. However, results are not always convincing. Human chondrocytes from patients undergoing total knee arthroplasty were cultured in monolayer followed by condensing single chondrocytes to spheroids (chondrospheres). The integrative capacity of chondrospheres was examined by implanting them into lesions in human articular cartilage specimens and co-implanting them into SCID mice. Mice were sacrificed after 4, 12 and 24 weeks. HE and safranin O staining as well as immunohistochemistry using anti-S100, anti-collagen I and II antibodies were performed and analyzed using semiquantitative scores. Integration of the chondrospheres with the (native) cartilage matrix was analyzed by determining the percentage of adhering surface. With respect to long-term stability, the chondrocytes within chondrospheres showed a typical chondrocytic morphology. Immunohistochemically, a high collagen II production was detected. Over a time period of 24 weeks, an increasing content of collagen type II, glycosaminoglycans and collagenous fibers were found. Importantly, the newly synthesized cartilaginous matrix integrated continuously with the native cartilage lesion border. In conclusion, the presented data demonstrate that chondrospheres are able to restore and conserve their phenotype for at least 24 weeks under in vivo conditions. Moreover, chondrospheres adhere to full-thickness cartilage defects and appear to produce a cartilaginous extracellular matrix which fuses with native cartilage thus generating an autologous cartilage-like repair tissue.

Present status of and future direction for articular cartilage repair

Articular cartilage defects are a major clinical problem for orthopedic surgeons. About 10 years ago, autologous chondrocyte implantation (ACI) was explored [1], approved by the U.S. Food and Drug Administration (FDA), and performed in more than 20 000 patients worldwide. However, the effectiveness of ACI remains controversial because of the lack of evidence of effi cacy from randomized controlled trials. There is currently no satisfactory clinical technique that is widely accepted for the regenerative repair of these lesions. Current clinical practice usually involves a bone marrow stimulation technique, which involves subchondral bone breaking to facilitate cartilage repair from bone marrow-derived cells and cytokines. However, with this procedure, cartilage defects are repaired with fi brocartilage [2]. Almost 15 years ago, mosaicplasty [3,4] was explored in addition to ACI. Using this technique, we can repair small articular cartilage defects with hyaline cartilage, but there are still a number of problems that remain unsolved, such as donor site morbidity. In attempts to develop better methods, different cell sources and delivery vehicles, the addition of growth factors, and transduction of some genes have all been investigated. We have been interested in the use of bone marrow mesenchymal cells (BMMC) because they have a number of suitable properties [5–8]. First, it is easy to obtain autologous cells: this can be achieved by aspiration of blood from the bone marrow using local anesthesia, without major side effects. Another reason for our interest in using these cells is that because we can cause them to proliferate without their capacity for differentiation being lost, this technique can be applied in large articular cartilage defects. Therefore, this procedure can be performed clinically with relative ease. Thus, we performed BMMC transplantation in human articular cartilage defects in knee joints. In this article, we explain the articular cartilage repair procedure with cell transplantation, mainly focusing on those with BMMC transplantation.

Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation

To support a review of the guidance issued by the National Institute for Health and Clinical Excellence (NICE) in December 2000 by examining the current clinical and cost-effectiveness evidence on autologous cartilage transplantation. Electronic databases. Evidence on clinical effectiveness was obtained from randomised trials, supplemented by data from selected observational studies for longer term results, and for the natural history of chondral lesions. Because of a lack of long-term results on outcomes such as later osteoarthritis and knee replacement, only illustrative modelling was done, using a range of assumptions that seemed reasonable, but were not evidence based. Four randomised controlled trials were included, as well as observational data from case series. The trials studied a total of 266 patients and the observational studies up to 101 patients. Two studies compared autologous chondrocyte implantation (ACI) with mosaicplasty, the third compared ACI with microfracture, and the fourth compared matrix-guided ACI (MACI) with microfracture. Follow-up was 1 year in one study, and up to 3 years in the remaining three studies. The first trial of ACI versus mosaicplasty found that ACI gave better results than mosaicplasty at 1 year. Overall, 88% had excellent or good results with ACI versus 69% with mosaicplasty. About half of the biopsies after ACI showed hyaline cartilage. The second trial of ACI versus mosaicplasty found little difference in clinical outcomes at 2 years. Disappointingly, biopsies from the ACI group showed fibrocartilage rather than hyaline cartilage. The trial of ACI versus microfracture also found only small differences in outcomes at 2 years. Finally, the trial of MACI versus microfracture contained insufficient long-term results at present, but the study does show the feasibility of doing ACI by the MACI technique. It also suggested that after ACI, it takes 2 years for full-thickness cartilage to be produced. Reliable costs per quality-adjusted life-year (QALY) could not be calculated owing to the absence of necessary data. Simple short-term modelling suggests that the quality of life gain from ACI versus microfracture would have to be between 70 and 100% greater over 2 years for it to be more cost-effective within the 20,000--30,000 pounds sterling per QALY cost-effectiveness thresholds. However, if the quality of life gains could be maintained for a decade, increments relative to microfracture would only have to be 10--20% greater to justify additional treatment costs within the cost-effectiveness band indicated above. Follow-up from the trials so far has only been up to 2 years, with longer term outcomes being uncertain. There is insufficient evidence at present to say that ACI is cost-effective compared with microfracture or mosaicplasty. Longer term outcomes are required. Economic modelling using some assumptions about long-term outcomes that seem reasonable suggests that ACI would be cost-effective because it is more likely to produce hyaline cartilage, which is more likely to be durable and to prevent osteoarthritis in the longer term (e.g. 20 years). Further research is needed into earlier methods of predicting long-term results. Basic science research is also needed into factors that influence stem cells to become chondrocytes and to produce high-quality cartilage, as it may be possible to have more patients developing hyaline cartilage after microfracture. Study is also needed into cost-effective methods of rehabilitation and the effect of early mobilisation on cartilage growth.

Repairing large porcine full-thickness defects of articular cartilage using autologous chondrocyte-engineered cartilage.

Large full-thickness defects of articular cartilage remain a major challenge to orthopedic surgeons because of unsatisfactory results of current therapy. Many methods, such as chondrectomy, drilling, cartilage scraping, arthroplasty, transplantation of chondrocytes, periosteum, perichondrium, as well as cartilage and bone, have been tried to repair articular cartilage defects. However, the results are far from satisfactory. In this study, we applied a tissue-engineering approach to the repair of articular cartilage defects of knee joints in a porcine model. Using isolated autologous chondrocytes, polyglycolic acid (PGA), and Pluronic, we have successfully in vivo-engineered hyaline cartilage and repaired articular cartilage defects. The surface of the repaired defects appeared smooth at 24 weeks postrepair. Histological examination demonstrated a typical hyaline cartilage structure with ideal interface healing between the engineered cartilage and the adjacent normal cartilage and underlying cancellous bone. In addition, glycosaminoglycan (GAG) levels in the engineered cartilage reached 80% of that found in native cartilage at 24 weeks postrepair. Biomechanical analysis at 24 weeks demonstrated that the biomechanical properties of the tissue-engineered cartilage were improved compared with those at an earlier stage. Thus, the results of this study may provide insight into the clinical repair of articular cartilage defects.

Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

Background Proposed service Autologous chondrocyte transplantation (ACT) is a novel surgical approach used to treat full-thickness cartilage defects in knee joints. Small grafts of normal cartilage removed from the patient’s diseased joint are treated in a laboratory to obtain cartilage cells. These cells are cultured to expand the cell population and reimplanted a few weeks later into areas where cartilage is denuded by disease. The aim of this procedure is to restore normal cartilage to the ends of bones and thereby restore normal joint function. Epidemiology There are no reliable estimates of the prevalence of cartilage defects in the knee. Lesions are most likely to arise in sportsmen and women as a result of injury. Up to 20% of individuals sustaining a haemarthrosis following a knee injury may have cartilage damage. Objectives This systematic review of the available evidence was performed to: 1. Describe the types of knee disease for which ACT has been applied, the natural history and epidemiology of these conditions, and alternative treatment options 2. Determine long-term clinical outcomes following ACT and other surgical procedures for knee cartilage defects 3. Examine the economic evidence and consider the economic gains resulting from ACT. Methods To analyse the effectiveness of treatment and the resultant economic impact, a systematic review of the literature, involving a range of databases, was performed. In addition, contact was made with leading researchers and industry. Full details are described in the main report. Results Number and quality of studies and direction of evidence Of 46 identified reports, 17 met the criteria for inclusion in this review. Eight of the included reports were available as abstracts only. At least 2600 patients appear to have been treated with ACT. All included reports were case series with a variable length of follow-up. With one exception, all the studies reported improvement in patient status, usually over a follow-up period of less than 2 years. Summary of benefits The outcome of ACT surgery was rated as ‘good’ or ‘excellent’ by approximately 70% of patients 2 years after treatment. Approximately 16% of patients required further arthroscopic surgical procedures during follow-up, and treatment was judged to have failed in 3–7% of patients. For comparator treatments, the outcome was rated as ‘good’ or ‘excellent’ in 10–95% of patients 2 years after treatment. Economic review The reports of two studies, one based in the USA and the other in Sweden, included economic data. Neither study compared ACT with other treatments. Using data from these studies and other sources, it was estimated that ACT performed in the UK would cost £4667 or £8167 for cell culture and surgery, depending on which service provider was used for cell culture. Incremental cost over 2 years, when set against comparator treatments, was estimated to be £3771 or £7271 (base case) for cell culture, surgery and rehabilitation. Using the OsCell facility for cell culture (Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust), this figure would be £3167. Conclusions The reported literature on ACT and comparators is subject to bias because of the inherent weaknesses of case series. In addition, the long-term impact of conventional surgical treatments or no surgical treatment is poorly documented. The cost-effectiveness analysis is similarly limited by the poverty of the effectiveness data on both ACT and comparators, the lack of long-term follow-up and the lack of empirical data for some of the parameters in the model used. Recommendations for research Further studies are required to: 1. Provide more accurate data on the occurrence of hyaline cartilage defects, including defects that arise acutely and those that are secondary to other types of knee injuries 2. Clarify the relationship of cartilage defects to clinical symptoms 3. Evaluate in detail the natural history of cartilage defects diagnosed by modern arthroscopic methods 4. Compare ACT with other treatments deemed appropriate, based on randomised trials currently in progress or planned 5. Examine, in prospective randomised trials, issues such as differences in outcome in patient subgroups (e.g. the suggested poor outcomes in patients with patellar defects), with patients followed for as long as possible 6. Address the deficiencies in evaluating the clinical outcomes of knee injury and incorporate measures of general health status 7. Consider study designs, other than randomised trials, that might be used to assess complex interventions such as those required in complex knee injuries.