A prospective randomized multicenter phase I/II clinical trial to evaluate safety and efficacy of NOVOCART disk plus autologous disk chondrocyte transplantation in the treatment of nucleotomized and degenerative lumbar disks to avoid secondary disease: safety results of Phase I-a short report.

NOVOCART® Disk plus, an autologous cell compound for autologous disk chondrocyte transplantation, was developed to reduce the degenerative sequel after lumbar disk surgery or to prophylactically avoid degeneration in adjacent disks, if present. The NDisc trial is an ongoing multi-center, randomized study with a sequential phase I study within the combined phase I/II trial with close monitoring of tolerability and safety. Twenty-four adult patients were randomized and treated with the investigational medicinal product NDisc plus or the carrier material only. Rates of adverse events in Phase I of this trial were comparable with those expected in the early time course after elective disk surgery. There was one reherniation 7 months after transplantation, which corresponds to an expected reherniation rate. Immunological markers like CRP and IL-6 were not significantly elevated and there were no imaging abnormalities. No indications of harmful material extrusion or immunological consequences due to the investigational medicinal product NDplus were observed. Therefore, the study appears to be safe and feasible. Safety analyses of Phase I of this trial indicate a relatively low risk considering the benefits that patients with debilitating degenerative disk disease may gain.

Pedicle-Based Non-fusion Stabilization Devices: A Critical Review and Appraisal of Current Evidence.

Over the last decades, spinal fusion has become one of the most important principles in surgical treatment of spinal pathologies. Despite the undoubted benefits of fusion surgery, there are several drawbacks associated with this technique, including adjacent segment degeneration and pseudoarthrosis. Based on biomechanical data, dynamic stabilization of the spine is intended to ameliorate adjacent level degeneration by stabilizing vertebral motion in defined planes and mimicking natural spine movements.In this paper, we review the literature and discuss past and present pedicle-based non-fusion dynamic stabilization devices. Although there is a paucity of high-quality prospective trials, studies have indicated both promising and disappointing results. In comparison to 360° fusion surgery, the perioperative risk seems to be lower. Other complications like screw loosening, however, have been reported with various systems, while a reduction of adjacent segment disease has not yet been demonstrated. The necessary degree of restabilization to achieve pain-free motion seems to vary greatly between patients and current systems are far from perfection. If these problems can be solved, dynamic stabilization may nevertheless be an important option of spinal surgery in the future.

Axial T2 mapping in intervertebral discs: a new technique for assessment of intervertebral disc degeneration.

OBJECTIVES: To demonstrate the potential benefits of biochemical axial T2 mapping of intervertebral discs (IVDs) regarding the detection and grading of early stages of degenerative disc disease using 1.5-Tesla magnetic resonance imaging (MRI) in a clinical setting. METHODS: Ninety-three patients suffering from lumbar spine problems were examined using standard MRI protocols including an axial T2 mapping protocol. All discs were classified morphologically and grouped as "healthy" or "abnormal". Differences between groups were analysed regarding to the specific T2 pattern at different regions of interest (ROIs). RESULTS: Healthy intervertebral discs revealed a distinct cross-sectional T2 value profile: T2 values were significantly lower in the annulus fibrosus compared with the nucleus pulposus (P = 0.01). In abnormal IVDs, T2 values were significantly lower, especially towards the centre of the disc representing the expected decreased water content of the nucleus (P = 0.01). In herniated discs, ROIs within the nucleus pulposus and ROIs covering the annulus fibrosus showed decreased T2 values. CONCLUSIONS: Axial T2 mapping is effective to detect early stages of degenerative disc disease. There is a potential benefit of axial T2 mapping as a diagnostic tool, allowing the quantitative assessment of intervertebral disc degeneration.

Quantitative T2 mapping of knee cartilage: differentiation of healthy control cartilage and cartilage repair tissue in the knee with unloading--initial results.

PURPOSE: To prospectively determine on T2 cartilage maps the effect of unloading during a clinical magnetic resonance (MR) examination in the postoperative follow-up of patients after matrix-associated autologous chondrocyte transplantation (MACT) of the knee joint. MATERIALS AND METHODS: Ethical approval for this study was provided by the local ethics commission, and written informed consent was obtained. Thirty patients (mean age, 35.4 years +/- 10.5) with a mean postoperative follow-up period of 29.1 months +/- 24.4 were enrolled. A multiecho spin-echo T2-weighted sequence was performed at the beginning (early unloading) and end (late unloading) of the MR examination, with an interval of 45 minutes. Mean and zonal region of interest T2 measurements were obtained in control cartilage and cartilage repair tissue. Statistical analysis of variance was performed. RESULTS: The change in T2 values of control cartilage (early unloading, 50.2 msec +/- 8.4; late unloading, 51.3 msec +/- 8.5) was less pronounced than the change in T2 values of cartilage repair tissue (early unloading, 51.8 msec +/- 11.7; late unloading, 56.1 msec +/- 14.4) (P = .024). The difference between control cartilage and cartilage repair tissue was not significant for early unloading (P = .314) but was significant for late unloading (P = .036). Zonal T2 measurements revealed a higher dependency on unloading for the superficial cartilage layer. CONCLUSION: Our results suggest that T2 relaxation can be used to assess early and late unloading values of articular cartilage in a clinical setting and that the time point of the quantitative T2 measurement affects the differentiation between native and abnormal articular cartilage. (c) RSNA, 2010.

Delayed gadolinium-enhanced MRI of cartilage in the ankle at 3 T: feasibility and preliminary results after matrix-associated autologous chondrocyte implantation.

PURPOSE: To demonstrate the feasibility of delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) in the ankle at 3 T and to obtain preliminary data on matrix associated autologous chondrocyte (MACI) repair tissue. MATERIALS AND METHODS: A 3D dual flip angle sequence was used with an eight-channel multipurpose coil at 3 T to obtain T1 maps both pre- and postintravenous contrast agent (Magnevist, 0.2 mM/kg). Postcontrast T1 over time was evaluated in three volunteers; a modified dGEMRIC protocol was then used to assess 10 cases after MACI in the ankle. RESULTS: Forty-five minutes were found sufficient for maximum T1 decrease. MACI cases had a precontrast mean T1 of 1050 +/- 148.4 msec in reference cartilage (RC) and 1080 +/- 165.6 msec in repair tissue (RT). Postcontrast T1 decreased to 590 +/- 134.0 msec in RC and 554 +/- 133.0 msec in RT. There was no significant difference between the delta relaxation rates in RT (9.44 x 10(-4) s(-1)) and RC (8.04 x 10(-4) s(-1), P = 0.487). The mean relative delta relaxation rate was 1.34 +/- 0.83. CONCLUSION: It is feasible to assess the thin cartilage layers of the ankle with dGEMRIC at 3 T; MACI can yield RT with properties similar to articular cartilage.

T2 and T2* mapping in patients after matrix-associated autologous chondrocyte transplantation: initial results on clinical use with 3.0-Tesla MRI.

OBJECTIVES: To use T2 and T2* mapping in patients after matrix-associated autologous chondrocyte transplantation (MACT) of the knee, and to compare and correlate both methodologies. METHODS: 3.0-Tesla MRI was performed on 30 patients (34.6 +/- 9.9 years) with a follow-up period of 28.1 +/- 18.8 months after MACT. Multi-echo, spin-echo-based T2 mapping using six echoes and gradient-echo-based T2* mapping using six echoes were prepared. T2 and T2* maps were obtained using a pixel-wise, mono-exponential, non-negative least-squares fit analysis. Region-of-interest analysis was performed for mean (full-thickness) as well as deep and superficial aspects of the cartilage repair tissue and control cartilage sites. RESULTS: Mean T2 values (ms) were comparable for the control cartilage (53.4 +/- 11.7) and the repair tissue (55.5 +/- 11.6) (p > 0.05). Mean T2* values (ms) for control cartilage (30.9 +/- 6.6) were significantly higher than those of the repair tissue (24.5 +/- 8.1) (p < 0.001). Zonal stratification was more pronounced for T2* than for T2. The correlation between T2 and T2* was highly significant (p < 0.001), with a Pearson coefficient between 0.276 and 0.433. CONCLUSION: T2 and T2* relaxation time measurements in the evaluation of cartilage repair tissue and its zonal variation show promising results, although the properties visualised by T2 and T2* may differ.

Has Deep Brain Stimulation Changed the Very Long-Term Outcome of Parkinson's Disease? A Controlled Longitudinal Study.

BACKGROUND: The long-term impact of deep brain stimulation (DBS) on Parkinson's disease (PD) is difficult to assess and has not yet been rigorously evaluated in comparison to its natural history. OBJECTIVE: Comparison of key disability milestones (recurrent falls, psychosis, dementia, and institutionalization) and death in patients with PD with versus without DBS. METHODS: We collected retrospective information from clinical notes of patients with PD at our center that were implanted with subthalamic DBS >8 years ago (1999-2010) and a control group of PD patients without DBS similar in age at onset, age at baseline, sex distribution, and number of comorbidities at baseline (extracted from a registry study performed in 2004). Cox regression models were used to calculate hazard ratios, adjusted for potential baseline confounding variables (age, sex, disease duration, disease severity, and number of comorbidities). RESULTS: A total of 74 DBS-treated and 61 control patients with PD were included. For a median observational period of 14 years, patients treated with DBS were at lower risk of experiencing recurrent falls (hazard ratio = 0.57; 95% confidence interval, 0.37-0.90; P = 0.015) and psychosis (hazard ratio = 0.26; 95% confidence interval, 0.12-0.59; P = 0.001) compared with control patients. There was no significant difference in risk for dementia, institutionalization, or death. Disease progression as assessed by Hoehn and Yahr scores was not slower in DBS-treated patients. CONCLUSIONS: Treatment with chronic subthalamic DBS was associated with lower risk for recurrent falls and psychotic symptoms, effects that may be mediated through improved motor symptom control and reduction in dopaminergic therapies, respectively. There was no evidence for DBS effects on underlying disease progression.

Evaluation and comparison of cartilage repair tissue of the patella and medial femoral condyle by using morphological MRI and biochemical zonal T2 mapping.

The objective of this study was to use advanced MR techniques to evaluate and compare cartilage repair tissue after matrix-associated autologous chondrocyte transplantation (MACT) in the patella and medial femoral condyle (MFC). Thirty-four patients treated with MACT underwent 3-T MRI of the knee. Patients were treated on either patella (n = 17) or MFC (n = 17) cartilage and were matched by age and postoperative interval. For morphological evaluation, the MR observation of cartilage repair tissue (MOCART) score was used, with a 3D-True-FISP sequence. For biochemical assessment, T2 mapping was prepared by using a multiecho spin-echo approach with particular attention to the cartilage zonal structure. Statistical evaluation was done by analyses of variance. The MOCART score showed no significant differences between the patella and MFC (p > or = 0.05). With regard to biochemical T2 relaxation, higher T2 values were found throughout the MFC (p < 0.05). The zonal increase in T2 values from deep to superficial was significant for control cartilage (p < 0.001) and cartilage repair tissue (p < 0.05), with an earlier onset in the repair tissue of the patella. The assessment of cartilage repair tissue of the patella and MFC afforded comparable morphological results, whereas biochemical T2 values showed differences, possibly due to dissimilar biomechanical loading conditions.

Initial results of in vivo high-resolution morphological and biochemical cartilage imaging of patients after matrix-associated autologous chondrocyte transplantation (MACT) of the ankle.

OBJECTIVE: The aim of this study was to use morphological as well as biochemical (T2 and T2* relaxation times and diffusion-weighted imaging (DWI)) magnetic resonance imaging (MRI) for the evaluation of healthy cartilage and cartilage repair tissue after matrix-associated autologous chondrocyte transplantation (MACT) of the ankle joint. MATERIALS AND METHODS: Ten healthy volunteers (mean age, 32.4 years) and 12 patients who underwent MACT of the ankle joint (mean age, 32.8 years) were included. In order to evaluate possible maturation effects, patients were separated into short-term (6-13 months) and long-term (20-54 months) follow-up cohorts. MRI was performed on a 3.0-T magnetic resonance (MR) scanner using a new dedicated eight-channel foot-and-ankle coil. Using high-resolution morphological MRI, the magnetic resonance observation of cartilage repair tissue (MOCART) score was assessed. For biochemical MRI, T2 mapping, T2* mapping, and DWI were obtained. Region-of-interest analysis was performed within native cartilage of the volunteers and control cartilage as well as cartilage repair tissue in the patients subsequent to MACT. RESULTS: The overall MOCART score in patients after MACT was 73.8. T2 relaxation times (approximately 50 ms), T2* relaxation times (approximately 16 ms), and the diffusion constant for DWI (approximately 1.3) were comparable for the healthy volunteers and the control cartilage in the patients after MACT. The cartilage repair tissue showed no significant difference in T2 and T2* relaxation times (p > or = 0.05) compared to the control cartilage; however, a significantly higher diffusivity (approximately 1.5; p < 0.05) was noted in the cartilage repair tissue. CONCLUSION: The obtained results suggest that besides morphological MRI and biochemical MR techniques, such as T2 and T2* mapping, DWI may also deliver additional information about the ultrastructure of cartilage and cartilage repair tissue in the ankle joint using high-field MRI, a dedicated multichannel coil, and sophisticated sequences.

Improved accuracy of component alignment with the implementation of image-free navigation in total knee arthroplasty.

Accuracy of implant positioning and reconstruction of the mechanical leg axis are major requirements for achieving good long-term results in total knee arthroplasty (TKA). The purpose of the present study was to determine whether image-free computer navigation technology has the potential to improve the accuracy of component alignment in TKA cohorts of experienced surgeons immediately and constantly. One hundred patients with primary arthritis of the knee underwent the unilateral total knee arthroplasty. The cohort of 50 TKAs implanted with conventional instrumentation was directly followed by the cohort of the very first 50 computer-assisted TKAs. All surgeries were performed by two senior surgeons. All patients received the Zimmer NexGen total knee prosthesis (Zimmer Inc., Warsaw, IN, USA). There was no variability regarding surgeons or surgical technique, except for the use of the navigation system (StealthStation) Treon plus Medtronic Inc., Minnesota, MI, USA). Accuracy of implant positioning was measured on postoperative long-leg standing radiographs and standard lateral X-rays with regard to the valgus angle and the coronal and sagittal component angles. In addition, preoperative deformities of the mechanical leg axis, tourniquet time, age, and gender were correlated. Statistical analyses were performed using the SPSS 15.0 (SPSS Inc., Chicago, IL, USA) software package. Independent t-tests were used, with significance set at P < 0.05 (two-tailed) to compare differences in mean angular values and frontal mechanical alignment between the two cohorts. To compute the rate of optimally implanted prostheses between the two groups we used the chi(2) test. The average postoperative radiological frontal mechanical alignment was 1.88 degrees of varus (range 6.1 degrees of valgus-10.1 degrees of varus; SD 3.68 degrees ) in the conventional cohort and 0.28 degrees of varus (range 3.7 degrees -6.0 degrees of varus; SD 1.97 degrees ) in the navigated cohort. Including all criteria for optimal implant alignment, 16 cases (32%) in the conventional cohort and 31 cases (62%) in the navigated cohort have been implanted optimally. The average difference in tourniquet time was modest with additional 12.9 min in the navigated cohort compared to the conventional cohort. Our findings suggest that the experienced knee surgeons can improve immediately and constantly the accuracy of component orientation using an image-free computer-assisted navigation system in TKA. The computer-assisted technology has shown to be easy to use, safe, and efficient in routine knee replacement surgery. We believe that navigation is a key technology for various current and future surgical alignment topics and minimal-invasive lower limb surgery.

The immediate effect of navigation on implant accuracy in primary mini-invasive unicompartmental knee arthroplasty.

The success of unicompartmental knee arthroplasty (UKA) is highly dependent on the accuracy of the component alignment. Objective of the present study was to evaluate the immediate effect of image-free computer navigation technology on implant accuracy in primary mini-invasive UKA. This study reviews 40 patients with primary isolated arthritis of the medial compartment of the knee that underwent unicompartmental knee arthroplasty through a minimally invasive approach. A cohort of the 20 most recent consecutive UKA's implanted with standard instrumentation was followed by a cohort of the very first 20 consecutive cases after conversion to the navigated technique. There was no variability regarding implant (Oxford meniscal unicompartmental knee system--Biomet Orthopedics, Inc., Warsaw, Indiana 46580, USA), surgeons and surgical technique, except for the use of the navigation system (Treon plus--Medtronic Inc., Minnesota, MI, USA). The axis alignment and accuracy of implant positioning was measured on postoperative long-leg standing radiographs and standard lateral X-rays with regard to the valgus angle and the coronal and sagittal component angle. In addition, preoperative deformities of the mechanical leg axis, tourniquet time, age, gender, and body mass index were correlated. Statistical analyses were performed using the SPSS 14.0 (SPSS Inc., Chicago, IL, USA) software package. Optimal implant alignment including all measurements in the desired angular range was significantly (P=0.041) higher in the navigated cohort. Navigation eliminated outliers in the frontal mechanical alignment and coronal orientation of the femoral component totally and significantly (P<0.02). Furthermore, navigation narrowed the range of outliers in all other planes of component orientation. There were no statistically significant differences in the mean numerical values between the cohorts, except for the frontal mechanical alignment (P<0.009) and coronal tibial alignment (P<0.037). The average tourniquet time was increased by 10.95 min in the navigated cohort. Our results indicate that navigation immediately improves accuracy of bone cuts and reduces the number of outliers with implementation in UKA.

In vivo biochemical 7.0 Tesla magnetic resonance: preliminary results of dGEMRIC, zonal T2, and T2* mapping of articular cartilage.

INTRODUCTION: Ultra-high-field whole-body systems (7.0 T) have a high potential for future human in vivo magnetic resonance imaging (MRI). In musculoskeletal MRI, biochemical imaging of articular cartilage may benefit, in particular. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and T2 mapping have shown potential at 3.0 T. Although dGEMRIC, allows the determination of the glycosaminoglycan content of articular cartilage, T2 mapping is a promising tool for the evaluation of water and collagen content. In addition, the evaluation of zonal variation, based on tissue anisotropy, provides an indicator of the nature of cartilage ie, hyaline or hyaline-like articular cartilage.Thus, the aim of our study was to show the feasibility of in vivo dGEMRIC, and T2 and T2* relaxation measurements, at 7.0 T MRI; and to evaluate the potential of T2 and T2* measurements in an initial patient study after matrix-associated autologous chondrocyte transplantation (MACT) in the knee. MATERIALS AND METHODS: MRI was performed on a whole-body 7.0 T MR scanner using a dedicated circular polarization knee coil. The protocol consisted of an inversion recovery sequence for dGEMRIC, a multiecho spin-echo sequence for standard T2 mapping, a gradient-echo sequence for T2* mapping and a morphologic PD SPACE sequence. Twelve healthy volunteers (mean age, 26.7 +/- 3.4 years) and 4 patients (mean age, 38.0 +/- 14.0 years) were enrolled 29.5 +/- 15.1 months after MACT. For dGEMRIC, 5 healthy volunteers (mean age, 32.4 +/- 11.2 years) were included. T1 maps were calculated using a nonlinear, 2-parameter, least squares fit analysis. Using a region-of-interest analysis, mean cartilage relaxation rate was determined as T1 (0) for precontrast measurements and T1 (Gd) for postcontrast gadopentate dimeglumine [Gd-DTPA(2-)] measurements. T2 and T2* maps were obtained using a pixelwise, monoexponential, non-negative least squares fit analysis; region-of-interest analysis was carried out for deep and superficial cartilage aspects. Statistical evaluation was performed by analyses of variance. RESULTS: Mean T1 (dGEMRIC) values for healthy volunteers showed slightly different results for femoral [T1 (0): 1259 +/- 277 ms; T1 (Gd): 683 +/- 141 ms] compared with tibial cartilage [T1 (0): 1093 +/- 281 ms; T1 (Gd): 769 +/- 150 ms]. Global mean T2 relaxation for healthy volunteers showed comparable results for femoral (T2: 56.3 +/- 15.2 ms; T2*: 19.7 +/- 6.4 ms) and patellar (T2: 54.6 +/- 13.0 ms; T2*: 19.6 +/- 5.2 ms) cartilage, but lower values for tibial cartilage (T2: 43.6 +/- 8.5 ms; T2*: 16.6 +/- 5.6 ms). All healthy cartilage sites showed a significant increase from deep to superficial cartilage (P < 0.001). Within healthy cartilage sites in MACT patients, adequate values could be found for T2 (56.6 +/- 13.2 ms) and T2* (18.6 +/- 5.3 ms), which also showed a significant stratification. Within cartilage repair tissue, global mean values showed no difference, with 55.9 +/- 4.9 ms for T2 and 16.2 +/- 6.3 ms for T2*. However, zonal assessment showed only a slight and not significant increase from deep to superficial cartilage (T2: P = 0.174; T2*: P = 0.150). CONCLUSION: In vivo T1 dGEMRIC assessment in healthy cartilage, and T2 and T2* mapping in healthy and reparative articular cartilage, seems to be possible at 7.0 T MRI. For T2 and T2*, zonal variation of articular cartilage could also be evaluated at 7.0 T. This zonal assessment of deep and superficial cartilage aspects shows promising results for the differentiation of healthy and affected articular cartilage. In future studies, optimized protocol selection, and sophisticated coil technology, together with increased signal at ultra-high-field MRI, may lead to advanced biochemical cartilage imaging.

Magnetization transfer contrast and T2 mapping in the evaluation of cartilage repair tissue with 3T MRI.

PURPOSE: To use magnetization transfer (MT) imaging in the visualization of healthy articular cartilage and cartilage repair tissue after different cartilage repair procedures, and to assess global as well as zonal values and compare the results to T2-relaxation. MATERIALS AND METHODS: Thirty-four patients (17 after microfracture [MFX] and 17 after matrix-associated autologous cartilage transplantation [MACT]) were examined with 3T MRI. The MT ratio (MTR) was calculated from measurements with and without MT contrast. T2-values were evaluated using a multiecho, spin-echo approach. Global (full thickness of cartilage) and zonal (deep and superficial aspect) region-of-interest assessment of cartilage repair tissue and normal-appearing cartilage was performed. RESULTS: In patients after MFX and MACT, the global MTR of cartilage repair tissue was significantly lower compared to healthy cartilage. In contrast, using T2, cartilage repair tissue showed significantly lower T2 values only after MFX, whereas after MACT, global T2 values were comparable to healthy cartilage. For zonal evaluation, MTR and T2 showed a significant stratification within healthy cartilage, and T2 additionally within cartilage repair tissue after MACT. CONCLUSION: MT imaging is capable and sensitive in the detection of differences between healthy cartilage and areas of cartilage repair and might be an additional tool in biochemical cartilage imaging. For both MTR and T2 mapping, zonal assessment is desirable.