Total disc replacement for chronic back pain in the presence of disc degeneration.

BACKGROUND: In the search for better surgical treatment of chronic low-back pain (LBP) in the presence of disc degeneration, total disc replacement has received increasing attention in recent years. A possible advantage of total disc replacement compared with fusion is maintained mobility at the operated level, which has been suggested to reduce the chance of adjacent segment degeneration. OBJECTIVES: The aim of this systematic review was to assess the effect of total disc replacement for chronic low-back pain in the presence of lumbar disc degeneration compared with other treatment options in terms of patient-centred improvement, motion preservation and adjacent segment degeneration. SEARCH METHODS: A comprehensive search in Cochrane Back Review Group (CBRG) trials register, CENTRAL, MEDLINE, EMBASE, BIOSIS, ISI, and the FDA register was conducted. We also checked the reference lists and performed citation tracking of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing total disc replacement with any other intervention for degenerative disc disease. DATA COLLECTION AND ANALYSIS: We assessed risk of bias per study using the criteria of the CBRG. Quality of evidence was graded according to the GRADE approach. Two review authors independently selected studies and assessed risk of bias of the studies. Results and upper bounds of confidence intervals were compared against predefined clinically relevant differences. MAIN RESULTS: We included 40 publications, describing seven unique RCT's. The follow-up of the studies was 24 months, with only one extended to five years. Five studies had a low risk of bias, although there is a risk of bias in the included studies due to sponsoring and absence of any kind of blinding. One study compared disc replacement against rehabilitation and found a statistically significant advantage in favour of surgery, which, however, did not reach the predefined threshold for clinical relevance. Six studies compared disc replacement against fusion and found that the mean improvement in VAS back pain was 5.2 mm (of 100 mm) higher (two studies, 676 patients; 95% confidence interval (CI) 0.18 to 10.26) with a low quality of evidence while from the same studies leg pain showed no difference. The improvement of Oswestry score at 24 months in the disc replacement group was 4.27 points more than in the fusion group (five studies; 1207 patients; 95% CI 1.85 to 6.68) with a low quality of evidence. Both upper bounds of the confidence intervals for VAS back pain and Oswestry score were below the predefined clinically relevant difference. Choice of control group (circumferential or anterior fusion) did not appear to result in different outcomes. AUTHORS' CONCLUSIONS: Although statistically significant, the differences between disc replacement and conventional fusion surgery for degenerative disc disease were not beyond the generally accepted clinical important differences with respect to short-term pain relief, disability and Quality of Life. Moreover, these analyses only represent a highly selected population. The primary goal of prevention of adjacent level disease and facet joint degeneration by using total disc replacement, as noted by the manufacturers and distributors, was not properly assessed and not a research question at all. Unfortunately, evidence from observational studies could not be used because of the high risk of bias, while these could have improved external validity assessment of complications in less selected patient groups. Non-randomised studies should however be very clear about patient selection and should incorporate independent, blinded outcome assessment, which was not the case in the excluded studies. Therefore, because we believe that harm and complications may occur after years, we believe that the spine surgery community should be prudent about adopting this technology on a large scale, despite the fact that total disc replacement seems to be effective in treating low-back pain in selected patients, and in the short term is at least equivalent to fusion surgery.

Micro-CT quantification of subchondral endplate changes in intervertebral disc degeneration.

BACKGROUND: The intervertebral disc (IVD) is dependent on nutrient provision through a cartilage layer with underlying subchondral bone, analogous to joint cartilage. In the joint, subchondral bone remodeling has been associated with osteoarthritis (OA) progression due to compromised nutrient and gas diffusion and reduced structural support of the overlaying cartilage. However, subchondral bone changes in IVD degeneration have never been quantified before. OBJECTIVE: The aim of this study is to determine the subchondral bone changes at different stages of IVD degeneration by micro-CT. METHODS: Twenty-seven IVDs including the adjacent vertebral endplates were obtained at autopsy. Midsagittal slices, graded according the Thompson score, were scanned. Per scan 12 standardized cylindrical volumes of interest (VOI) were selected. Six VOIs contained the bony endplate and trabeculae (endplate VOIs) and six accompanying VOIs only contained trabecular bone (vertebral VOIs). Bone volume as percentage of the total volume (BV/TV) of the VOI, trabecular thickness (TrTh) and connectivity density (CD) were determined. RESULTS: An increase in BV/TV and TrTh was found in endplate VOIs of IVDs with higher Thompson score whereas these values remained stable or decreased in the vertebral VOIs. CONCLUSION: The increase in bone volume combined with the increase in TrTh in endplate VOIs strongly suggest that the subchondral endplate condenses to a more dense structure in degenerated IVDs. This may negatively influence the diffusion and nutrition of the IVD. The endplate differences between intact and mild degenerative IVDs (grade II) indicate an early association of subchondral endplate changes with IVD degeneration.

Scaffolds with a standardized macro-architecture fabricated from several calcium phosphate ceramics using an indirect rapid prototyping technique.

Calcium phosphate ceramics, commonly applied as bone graft substitutes, are a natural choice of scaffolding material for bone tissue engineering. Evidence shows that the chemical composition, macroporosity and microporosity of these ceramics influences their behavior as bone graft substitutes and bone tissue engineering scaffolds but little has been done to optimize these parameters. One method of optimization is to place focus on a particular parameter by normalizing the influence, as much as possible, of confounding parameters. This is difficult to accomplish with traditional fabrication techniques. In this study we describe a design based rapid prototyping method of manufacturing scaffolds with virtually identical macroporous architectures from different calcium phosphate ceramic compositions. Beta-tricalcium phosphate, hydroxyapatite (at two sintering temperatures) and biphasic calcium phosphate scaffolds were manufactured. The macro- and micro-architectures of the scaffolds were characterized as well as the influence of the manufacturing method on the chemistries of the calcium phosphate compositions. The structural characteristics of the resulting scaffolds were remarkably similar. The manufacturing process had little influence on the composition of the materials except for the consistent but small addition of, or increase in, a beta-tricalcium phosphate phase. Among other applications, scaffolds produced by the method described provide a means of examining the influence of different calcium phosphate compositions while confidently excluding the influence of the macroporous structure of the scaffolds.

Hypertrophic differentiation and calcification during intervertebral disc degeneration.

BACKGROUND: In degenerative intervertebral discs (IVDs) collagen type X expression and calcifications have been demonstrated, resembling advanced osteoarthritis (OA), which is associated with hypertrophic differentiation, characterized by the production of collagen type X, Runt-related transcription factor 2 (Runx2), osteoprotegerin (OPG), alkaline phosphatase (ALP) and calcifications. OBJECTIVE: The aim of this study was to determine if hypertrophic differentiation occurs during IVD degeneration. METHODS: IVDs from all Thompson degeneration grades were prepared for histology, extraction of nucleus pulposus (NP) and annulus fibrosis (AF) tissue (N=50) and micro-CT (N=27). The presence of collagen type X, OPG and Runx2 was determined by immunohistochemistry, with OPG levels also determined by Enzyme-linked immunosorbent assay (ELISA). The presence of calcification was determined by micro-CT, von Kossa and Alizarin Red staining. RESULTS: Immunohistochemical staining for collagen type X, OPG, Runx2 appeared more intense in the NP of degenerative compared to healthy IVD samples. OPG levels correlated significantly with degeneration grade (NP: P<0.000; AF: P=0.002) and the number of microscopic calcifications (NP: P=0.002; AF: P=0.008). The extent of calcifications on micro-CT also correlated with degeneration grade (NP: P<0.001, AF: P=0.001) as did von Kossa staining (NP: P=0.015, AF: P=0.016). ALP staining was only incidentally seen in the transition zone of grades IV and V degenerated IVDs. CONCLUSION: This study for the first time demonstrates that hypertrophic differentiation occurs during IVD degeneration, as shown by an increase in OPG levels, the presence of ALP activity, increased immunopositivity of Runx2 and collagen type X.

The presence of extracellular matrix degrading metalloproteinases during fetal development of the intervertebral disc.

Matrix metalloproteinases (MMPs) regulate connective tissue architecture and cell migration through extracellular matrix (ECM) degradation and are associated with both physiological and pathological processes. Although they are known to play a role in skeletal development, little is known about the role of MMPs in intervertebral disc (IVD) development. Sixteen fetal human lumbar spine segments, obtained at autopsy, were compared with five normal, non-fetal L4-L5 IVDs. Intensity and/or localization of immunohistochemical staining for MMP-1, -2, -3 and -14 were evaluated by three independent observers. MMP-2 production and activation was quantified by gelatin zymography. MMP-1 and -14 were abundantly present in the nucleus pulposus (NP) and notochordal (NC) cells of the fetal IVDs. In non-fetal IVDs, MMP-1 and -14 staining was significantly less intense (p = 0.001 and p < 0.001, respectively). MMP-3 was found in almost the entire IVD with no significant difference from non-fetal IVDs. MMP-2 staining in the NC and NP cells of the fetal IVD was moderate, but weak in the non-fetal IVD. Gelatin zymography showed a negative correlation of age with MMP-2 activity (p < 0.001). MMP-14 immunostaining correlated positively with MMP-2 activity (p = 0.001). For the first time, the presence of MMP-1, -2, -3 and -14 in the fetal human IVD is shown and the high levels of MMP-1, -2 and -14 suggest a role in the development of the IVD. In particular, the gradual decrease in MMP-2 activation during gestation pinpoints this enzyme as key player in fetal development, possibly through activation by MMP-1 and -14.

Cartilage degeneration in the goat knee caused by treating localized cartilage defects with metal implants.

OBJECTIVE: The purpose of the current study was to investigate the feasibility of applying defect-size femoral implants for the treatment of localized cartilage defects in a 1-year follow-up model. METHODS: In 13 goats, a medial femoral condyle defect was created in both knees. Defects were randomly treated by immediate placement of an oxidized zirconium (OxZr) (n=9) or cobalt-chromium (CoCr) implant (n=9) or left untreated (n=8). Six un-operated knee joints served as a control. Animals were sacrificed at 52 weeks. Joints were evaluated macroscopically. Cartilage quality was analyzed macroscopically and microscopically and cartilage repair of untreated defects was scored microscopically. Glycosaminoglycan (GAG) content, release and synthesis were measured in tissue and medium. Implant osseointegration was measured by automated histomorphometry. RESULTS: Cartilage repair score of the defects was 13.3+/-3.0 out of 24 points (0=no repair, 24=maximal repair). Articular evaluation scores decreased (indicative of degeneration) in untreated defects and in defects treated with either implant (P<0.05). Macroscopical, microscopical and biochemical analysis showed that the presence of untreated defects and the implants caused considerable degeneration of medial tibial plateau, and to a lesser extent of the lateral compartment. Mean bone-implant contact was extensive and not different between materials (39.5+/-28.1% for OxZr and 42.3+/-31.5% for CoCr) (P=0.873). CONCLUSIONS: Considerable cartilage degeneration was induced in the articulating cartilage of the medial tibial plateau 1 year after creating an osteochondral defect in the medial femoral condyle. Treating this defect with a small metal implant, made of either OxZr or CoCr, could not prevent this degeneration. Further optimization of defect-size implants and their placement is required to make this the therapy of choice for the treatment of local cartilage defects.

Articular cartilage degeneration following the treatment of focal cartilage defects with ceramic metal implants and compared with microfracture.

BACKGROUND: Localized cartilage defects are frequently associated with joint pain, reduced function, and a predisposition to the development of osteoarthritis. The purposes of the current study were to investigate the feasibility of the application of defect-sized femoral implants for the treatment of localized cartilage defects and to compare this treatment, in terms of joint degeneration, with the use of microfracture in a goat model of established cartilage defects. METHODS: In nine Dutch milk goats, a defect in the medial femoral condyle was created in both knees. After ten weeks, the knees were randomly treated by microfracture or by placement of an oxidized zirconium implant. At twenty-six weeks after surgery, the animals were killed. The joints were evaluated macroscopically. Implant osseointegration was measured by automated histomorphometry, and cartilage repair (after microfracture) was scored histologically. Cartilage quality was analyzed macroscopically and histologically. Glycosaminoglycan content and release were measured by alcian blue assay, and the synthesis and release of newly formed glycosaminoglycans were measured by liquid scintillation analysis of the incorporation of 35SO4(2-) in tissue and medium. RESULTS: The mean bone-implant contact (and standard error) was appropriate (14.6%+/-5.4%), and the amount of bone surrounding the implant was extensive (mean, 40.3%+/-4.0%). The healing of the microfracture-treated defects was extensive, although not complete (mean, 18.38+/-0.43 points of a maximum possible score of 24 points). The macroscopic cartilage evaluation did not show any significant differences between the treatments. On histologic evaluation, the cartilage of the medial tibial plateau articulating directly against the treated defects demonstrated significantly more degeneration in the microfracture-treated knees than in the implant-treated knees (p<0.05). This was in accordance with a significantly higher glycosaminoglycan content, higher synthetic activity, and decreased glycosaminoglycan release of the medial tibial plateau cartilage of the implant-treated knees (p<0.05 for all). On histological analysis, degeneration was also found in the cartilage of the lateral tibial plateau and condyle, but no significant difference was found between the treatments. CONCLUSIONS: Both microfracture and the use of implants as a treatment for established localized cartilage defects in the medial femoral condyle caused considerable (p < 0.05) degeneration of the directly articulating cartilage as well as in more remote sites in the knee. However, in the medial tibial plateau, the metal implants caused less damage than the microfracture technique.

Surgeon equipoise as an inclusion criterion for the evaluation of nonoperative versus operative treatment of thoracolumbar spinal injuries.

BACKGROUND CONTEXT: Prospective studies have failed to demonstrate the superiority of either operative or nonoperative treatment of thoracolumbar fractures. Similar to other surgical fields, research has been limited by the variability in surgical interventions, difficult recruitment, infrequent pathology, and the urgency of interventions. PURPOSE: To outline factors precluding randomized controlled trials in spinal fractures research, and describe a novel methodology that seeks to improve on the design of observational studies. STUDY DESIGN/SETTING: A preliminary report describing an observational study design with clinical equipoise as an inclusion criterion. The proposed methodology is a cohort study with head-to-head comparison of operative and nonoperative treatment regimens in an expertise-based trial fashion. Patients are selected retrospectively by an expert panel and clinical outcomes are assessed to compare competing treatment regimens. Surgeon equipoise served as an inclusion criterion. PATIENT SAMPLE: Patients with closed or open thoracolumbar spinal fracture with or without neurological impairment, presenting to one of two different trauma centers between 1991 and 2005 (N = 760). OUTCOME MEASURES: Homogeneity of baseline clinical and demographic data and distribution of prognostic risk factors between the operative and the nonoperative cohort. METHODS: Patients treated for spine fractures at two University hospitals practicing opposing methods of fracture intervention were identified by medical diagnosis code searches (n = 760). A panel of spine treatment experts, blinded to the treatment received clinically has assessed each case retrospectively. Patients were included in the study when there was disagreement on the preferred treatment, that is, operative or nonoperative treatment of the injury. Baseline and initial data of a study evaluating nonoperative versus operative spinal fracture treatment are presented. RESULTS: One hundred and ninety patients were included in the study accounting for a panel discordance rate of 29%. The distribution of baseline characteristics and demographics of the study populations were equal across the parallel cohorts enrolled in the study, that is, no differences in prognostic factors were observed. CONCLUSIONS: The use of clinical equipoise as an inclusion criterion in comparative studies may be used to avoid selection bias. Using multivariate analysis of retrospectively assembled parallel cohorts, a valid comparison of operative and nonoperative spine fracture treatment strategies and their outcomes is possible.

Increased MMP-2 activity during intervertebral disc degeneration is correlated to MMP-14 levels.

Intervertebral disc (IVD) degeneration is associated with the increased expression of several matrix metalloproteinases (MMPs), in particular MMP-2. However, little is known about the actual activity of MMP-2 in healthy and degenerated discs, or what mechanisms are involved in its activation. A major activation pathway involves complex formation with MMP-14 and a tissue inhibitor of metalloproteinases-2 (TIMP-2). In a series of 56 human IVDs, obtained at autopsy and graded according to the Thompson score (I-V), we analysed whether MMP-2 activity was increased in different stages of IVD degeneration and to what extent activation was related to the production of MMP-14 and TIMP-2. MMP-2 activation and production were quantified by gelatin zymography. Immunohistochemical staining of MMP-14 and TIMP-2 was quantified with a video overlay-based system. A positive correlation was observed between the amount of active MMP-2 and pro-MMP-2 and degeneration grade (p < 0.001, correlation coefficient (CC) 0.557; and p < 0.001, CC 0.556, respectively). MMP-2 activity correlated positively with MMP-14 and less strongly with TIMP-2 (p = 0.001, CC 0.436; and p = 0.03, CC 0.288, respectively). Moreover, immunopositivity for MMP-14 correlated to degeneration grade (p = 0.002, CC 0.398). IVD degeneration was associated with the activity of MMP-2 and the correlation of its activation with MMP-14 production suggests MMP-14 activates MMP-2 during degeneration. As MMP-14 is capable of activating several other enzymes that are also thought to be involved in IVD degeneration, it may be a key mediator of the degenerative process.

Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial.

INTRODUCTION: Incubation of blood with CrSO(4)-coated glass beads stimulates the synthesis of anti-inflammatory cytokines, such as interleukin-1 receptor antagonist (IL-1ra), IL-4, IL-10, and IL-13. As IL-1beta is thought to play a key role in the development of osteoarthritis (OA), this product, also known as Orthokin, might be a viable treatment for symptomatic knee OA. The aim of the current study was to evaluate the efficacy of Orthokin for treatment of symptomatic knee OA in a randomized, multicentre, double-blind, placebo-controlled trial. PATIENTS AND METHODS: One hundred and sixty-seven patients received six intra-articular injections either with Orthokin or physiological saline. The primary efficacy objective consisted of 30% superiority on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 3, 6, 9, and 12 months post-treatment. Additionally, the patients completed the visual analogue scale for pain, the Knee injury and Osteoarthritis Outcome Score (KOOS) and Knee Society Clinical Rating System. RESULTS: Orthokin and placebo treatment resulted in similar improvements on the WOMAC (16.8% vs 16.5%, respectively; n.s.). Orthokin resulted in significantly more improvement for KOOS symptom (P = 0.002) and KOOS sport (P = 0.042) parameters as compared to placebo treatment. For most other outcome parameters, Orthokin-treated patients consistently showed higher improvement compared to placebo-treated patients, although none of these differences were statistically significant. Two serious adverse events were observed in the Orthokin group: one patient with repeated severe inflammatory reactions of the knee joint within hours after the injection and one patient with septic arthritis which was attributed to the injection procedure rather than the product. CONCLUSION: The statistically significant improvement of KOOS symptom and sport parameters together with the consistently higher, though non-statistically significant, improvement of most other parameters demonstrates that Orthokin clearly induces a biological response different from placebo treatment and warrant future investigations into the possible chondroprotective effect of Orthokin. However, in the current study the primary efficacy objective was not met and, therefore, the use of Orthokin currently cannot yet be recommended for the treatment of OA.

[Congenital pain-insensitivity syndrome; a rare indication of the benefit of pain]. / Congenitaal pijnongevoeligheidssyndroom; een zeldzame aanwijzing voor het nut van pijn.

A 34-year-old woman with a known congenital pain-insensitivity syndrome presented because of increasing weakness and sensory loss in her right leg. The cause was a rapidly progressive partial caudal compression syndrome in the absence ofknown prior trauma. Radiology revealed a lumbar Charcot spine, i.e. total destruction of the spine with compression of the dural sac. Emergency surgery included opening of the lumbar canal and spondylodesis. Postoperatively, there was almost full neurological recovery. In the pathogenesis the absence of protective pain sensation combined with trophic degeneration due to neurovascular dysregulation may play a role.

[Findings in 67 patients with recurrent or persistent symptoms after implantation of a disc prosthesis for low back pain]. / Bevindingen bij 67 patiënten met recidiverende of persisterende klachten na het plaatsen van een discusprothese wegens lage rugpijn.

OBJECTIVE: To determine the symptoms in patients who presented with persistent or recurrent backache or leg pain after implantation of an artificial disc prosthesis. DESIGN: Descriptive. METHOD: During the past II years in the Maastricht University Hospital (n=65) and the Utrecht University Medical Centre (n=2), 67 patients were seen with persistent or recurrent backache or leg pain in whom, an average of 53 months previously, one or more SB Charité-III lumbar-disc prostheses had been implanted elsewhere. The results were evaluated. RESULTS: The most prominent findings were: migration of the prosthesis (n=6); subsidence into the vertebra (n=35); disc degeneration at one or more neighbouring levels (n=34) and arthrosis of facet joints (n=24). In 9 cases, rupture of the metal wire around the polyethylene core was observed and in 5 cases there were radiological signs of polyethylene wear. Re-operation (spondylodesis) was generally unsatisfactory if the prosthesis was left in place. In 21 patients, the prosthesis was removed; all specimens showed polyethylene wear or rupture. CONCLUSION: Published results are mostly case series and suffer from observer bias; moreover, the benefits are moderate. Given the uncertain role ofdisc degeneration in patients with chronic backache, the real risk of complications and the uncertain advantages, the implantation ofa disc prosthesis is difficult to defend.

Reliability, reproducibility and variability of the traditional Histologic/Histochemical Grading System vs the new OARSI Osteoarthritis Cartilage Histopathology Assessment System.

OBJECTIVE: For many years, the Histologic/Histochemical Grading System (HHGS) for osteoarthritis monitoring has been used as a histological scoring system for the quality of cartilage. There are, however, some limitations using this grading system. The goal of the investigation presented in this paper was to examine the hypothesized advantage of the recently introduced Osteoarthritis Research Society International (OARSI) Cartilage Histopathology Assessment System (OOCHAS) as compared to the most frequently used HHGS by means of reliability, reproducibility, and variability evaluation as well as the correlation analysis between the two systems in goat knee articular cartilage. METHODS: Nine hundred and thirty-six sections of Dutch Milk goat articular knee cartilage were scored using light microscopy. Three observers applied the HHGS for all sections and subsequently, the OOCHAS. The same scoring procedure was repeated after a minimum interval of 1 week. For each system the reliability, reproducibility and variability as well as the correlation between both systems were determined. RESULTS: The reliability of the OOCHAS was higher as compared to the HHGS. Both the HHGS as well the OOCHAS have an excellent intra- and inter-observer reproducibility and variability and a good positive correlation between the scores. CONCLUSIONS: Although the HHGS has proven to be an excellent tool for histological scoring of cartilage quality, we recommend the OOCHAS as the premium choice while stressing the importance of further research investigating the correlation of the histological results to macroscopic and biochemical parameters.

Articular damage caused by metal plugs in a rabbit model for treatment of localized cartilage defects.

OBJECTIVE: Currently, the surgical treatment of localized cartilage defects has limitations. Alternatively, localized cartilage defects may be treated with small biocompatible metal cartilage tacks. Our purpose was to investigate the applicability of defect-size femoral implants. Different bearing materials, cobalt-chromium (CoCr) and oxidized zirconium (OxZr), were tested to evaluate the effect on opposing cartilage quality and osseointegration at different insertion depths. METHODS: In 18 adult female New Zealand White rabbits, a medial femoral condyle defect was filled with either an OxZr or a CoCr implant (Ø articulating surface 3.5 mm; fixating pin of 9.1 mm length), placed flush, 1mm deep or 1mm protruding with respect to the level of the surrounding cartilage. Animals were sacrificed after 4 weeks. Tibial cartilage quality was scored microscopically and osseointegration measured by automated histomorphometry. RESULTS: Considerable articulating cartilage erosion was found in all conditions. Tibial cartilage quality was least compromised when both implants were placed flush compared to deep (P=0.01) or protruding position (P=0.004) and was better for OxZr compared to CoCr (P=0.011) when left protruding, while no differences were found when placed deep of flush. Most bone formation around the fixating pin was observed in a protruding position (P=0.01). In deep position, more bone-implant contact was observed with CoCr compared to OxZr (P=0.02). CONCLUSIONS: OxZr and CoCr implants showed good osseointegration when used as a localized cartilage defect treatment in the rabbit knee; however, opposite cartilage damage was observed in all cases. Placement flush to the surrounding cartilage seems essential and when left protruding OxZr may be less erosive. In conclusion, caution is warranted using small metal implants for the treatment of localized cartilage in the human patient.

Validation of the short-form WOMAC function scale for the evaluation of osteoarthritis of the knee.

This study validates the short-form WOMAC function scale for assessment of conservative treatment of osteoarthritis of the knee. Data were collected before treatment and six and nine months later, from 100 patients with osteoarthritis of the knee to determine the validity, internal consistency, test-retest reliability, floor and ceiling effects, and responsiveness of the short-form WOMAC function scale. The scale showed high correlation with the traditional WOMAC and other measures. The internal consistency was good (Cronbach alpha: 0.88 to 0.95) and an excellent test-retest reliability was found (Lin's concordance correlation coefficient (rho(c)): 0.85 to 0.94). The responsiveness was adequate and comparable to that of the traditional WOMAC (standardised response mean 0.56 to 0.44 and effect size 0.64 to 0.57) and appeared not to be significantly affected by floor or ceiling effects (0% and 7%, respectively). The short-form WOMAC function scale is a valid, reliable and responsive alternative to the traditional WOMAC in the evaluation of patients with osteoarthritis of the knee managed conservatively. It is simple to use in daily practice and is therefore less of a burden for patients in clinical trials.

Impact of expansion and redifferentiation conditions on chondrogenic capacity of cultured chondrocytes.

Cartilage regeneration based on isolated and culture-expanded chondrocytes is studied in a variety of in vitro models, but with varying morphological quality of tissue synthesized. The goal of the present study was to investigate the extent of the influence of expansion and redifferentiation conditions on final tissue morphology by comparing 2 expansion and redifferentiation methods. Chondrocytes from 9 human donors were expanded in medium without growth factor supplementation (basic expansion condition [BEC]) or in medium with basic fibroblast growth factor (bFGF) supplementation (growth factor supplemented expansion condition [GFSEC]). After expansion, cells were either redifferentiated in pellet culture or seeded on collagen type II-coated filters. Post-expansion mRNA levels of collagen type I and II and Sox-5, -6, and 9, measured by semiquantitative real-time polymerase chain reaction (PCR), suggested that expansion in GFSEC results in increased dedifferentiation compared to BEC. However, after 28 days of redifferentiation culture, morphology of tissue synthesized by GFSEC-expanded chondrocytes scored significantly higher on the Bern scale compared to BEC (6.4 +/- 0.3 points vs. 4.5 +/- 0.3 points in pellet culture and 6.0 +/- 0.4 points vs. 4.5 +/- 0.3 points on collagen-coated filters; p < 0.05). Expansion in GFSEC compared to BEC increased proteoglycan (PG) synthesis rate at day 9 (4.0-fold in pellet culture and 1.9-fold on collagen-coated filters; p < 0.01), PG release (6.7-fold in pellet culture and 3.2-fold on collagen-coated filters; p < 0.001), and final PG content at day 28 (1.6-fold in pellet culture and 1.5-fold on collagen-coated filters; p < 0.05). Redifferentiation on collagen-coated filters compared to pellet culture increased PG synthesis rate at day 9 (5.2-fold in BEC-expanded chondrocytes and 2.6-fold in GFSEC-expanded chondrocytes; p < 0.01), PG release (4.2-fold in BEC-expanded chondrocytes and 3.1-fold in GFSECexpanded chondrocytes; p < 0.01), and final PG content (1.3-fold in BEC-expanded chondrocytes and 1.9- fold in GFSEC-expanded chondrocytes; p < 0.01). Moreover, as visualized via electron microscopy, chondrocytes and organization of extracellular matrix cultured on filters was more similar to those found for hyaline cartilage. In conclusion, chondrocyte expansion in GFSEC and redifferentiation on collagen-coated filters resulted in most optimal chondrogenesis.

Altered in vitro chondrogenic properties of chondrocytes harvested from unaffected cartilage in osteoarthritic joints.

OBJECTIVE: In vitro models of chondrogenesis often depart from chondrocytes harvested from less-affected areas of osteoarthritic joints. However, there are indications that these chondrocytes are phenotypically different from chondrocytes from healthy joints and thus might differ in their capacity to generate hyaline cartilage. The goal of this study was to compare the chondrogenic capacity of chondrocytes from healthy and OA joints. DESIGN: Chondrocytes isolated from nine healthy and nine OA knee joints were expanded in monolayer for two passages. Chondrocytes from passages 1 and 2 were analyzed for expression of (de)differentiation and hypertrophy markers and were seeded at passage 2 on collagen-coated filters for redifferentiation culture to study cartilage matrix formation. RESULTS: The collagen II/I mRNA ratio, reflecting differentiation, decreased from passage 1 to 2 in both chondrocytes from OA joints and chondrocytes from healthy joints (P<0.05), without a significant difference between the two donor types. At passage 1, levels of the cartilage transcription factors Sox-5, Sox-6 and Sox-9 appeared to be higher in chondrocytes from OA joints (n.s.), but this was not seen at passage 2. However, a clear difference was observed in collagen type X expression, which was high in chondrocytes from OA joints at both passages, while undetectable in chondrocytes from healthy joints (P<0.01). Tissue generated by chondrocytes from healthy joints redifferentiated for 28 days, showed a significantly better morphology, as assessed by histological scoring (P<0.01) and higher proteoglycan content (P<0.05), compared to chondrocytes from OA joints. Matrix turnover parameters, i.e., proteoglycan synthesis and degradation rate, were not significantly affected by donor tissue origin. CONCLUSIONS: These results suggest that clear differences between chondrocytes from healthy and OA joints exist and that these are not completely abolished during the process of de- and redifferentiation. Therefore, in vitro cartilage regeneration models, which use chondrocytes from OA joints, should be interpreted with care.

The effect of synovial fluid from injured knee joints on in vitro chondrogenesis.

Various in vivo and in vitro studies suggest that joint homeostasis may have a crucial effect on the quality of regeneration tissue resulting from cartilage tissue engineering techniques. The goal of the current study was to evaluate the effect of synovial fluid (SF) from injured knee joints on in vitro chondrogenesis. Chondrocytes were isolated from a healthy human femoral condyle (post-mortem) and expanded in monolayer for 2 passages. Subsequently, the chondrocytes were redifferentiated for 14 days on collagencoated filters, cultured either in the presence or absence of 10% SF. SF was obtained from 12 injured human knee joints. After 14 days of culture, SF supplementation resulted in a significant downregulation of final proteoglycan (PG) content (7.3 +/- 1.8 mg versus 15.6 +/- 1.3 mg; p = 0.0001), PG content normalized to DNA (0.7 +/- 0.5 mg/microg versus 3.0 +/- 0.6 mg/microg; p < 0.05), relative collagen type II mRNA levels normalized to GAPDH mRNA levels (0.2 +/- 0.3 versus 7.0 +/- 5.6; p < 0.001), and differentiation index (collagen type II/I mRNA ratio; 0.1 +/- 0.2 versus 6.0 +/- 2.9; p < 0.001) as compared to control culture conditions. Additionally, SF-supplemented media resulted in significantly increased cellularity, as reflected by DNA content, compared with control media (1,369 +/- 683 microg versus 514 +/- 72 microg; p < 0.0001). Morphology, and collagen type I, X, and aggrecan mRNA levels were not significantly affected. In conclusion, this study demonstrates that SF from injured human knee joints significantly affects in vitro chondrogenesis and therefore may provide a viable target for future improvement of ACT by refinement of culture techniques, patient selection, or pretreatment of affected joints to restore joint homeostasis.

Patient-reported outcome in total hip replacement. A comparison of five instruments of health status.

Our aim was to define the minimum set of patient-reported outcome measures which are required to assess health status after total hip replacement (THR). In 114 patients, we compared the pre-operative characteristics and sensitivity to change of the Oxford hip score (OHS), the Western Ontario and McMaster Universities osteoarthritis index (WOMAC), the SF-36, the SF-12 (derived from the SF-36), and the Euroqol questionnaire (EQ-5D). At one year after operation, very large effect sizes were found for the disease-specific measures, the physical domains of the SF-12, SF-36 and the EQ-5Dindex (1.3 to 3.0). Patients in Charnley class A showed more change in the OHS, WOMAC pain and function, the physical domains of the SF-36 and the EQ-5Dvas (p < 0.05) compared with those in the Charnley B and C group. In this group, the effect size for the OHS more than doubled the effect sizes of WOMAC pain and physical function. We found high correlations and correlations of change between the OHS, the WOMAC, the physical domains of the SF-12 and the SF-36 and EQ-5Dindex. The SF-36 and EQ-5D scores at one year after operation approached those of the general population. Furthermore, we found a binomial distribution of the pre-operative EQ-5Dindex score and a pre-operative discrepancy and post-operative agreement between the EQ-5Dvas and EQ-5Dindex. We recommend the use of the OHS and SF-12 in the assessment of THR. The SF-36 may be used in circumstances when smaller changes in health status are investigated, for example in the follow-up of THR. The EQ-5D is useful in situations in which utility values are needed in order to calculate cost-effectiveness or quality-adjusted life years (QALYs), such as in the assessment of new techniques in THR.