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1.  Can consistent benchmarking within a standardized pain management concept decrease postoperative pain after total hip arthroplasty? A prospective cohort study including 367 patients 
Journal of Pain Research  2016;9:1205-1213.
The number of total hip replacement surgeries has steadily increased over recent years. Reduction in postoperative pain increases patient satisfaction and enables better mobilization. Thus, pain management needs to be continuously improved. Problems are often caused not only by medical issues but also by organization and hospital structure. The present study shows how the quality of pain management can be increased by implementing a standardized pain concept and simple, consistent, benchmarking.
All patients included in the study had undergone total hip arthroplasty (THA). Outcome parameters were analyzed 24 hours after surgery by means of the questionnaires from the German-wide project “Quality Improvement in Postoperative Pain Management” (QUIPS). A pain nurse interviewed patients and continuously assessed outcome quality parameters. A multidisciplinary team of anesthetists, orthopedic surgeons, and nurses implemented a regular procedure of data analysis and internal benchmarking. The health care team was informed of any results, and suggested improvements. Every staff member involved in pain management participated in educational lessons, and a special pain nurse was trained in each ward.
From 2014 to 2015, 367 patients were included. The mean maximal pain score 24 hours after surgery was 4.0 (±3.0) on an 11-point numeric rating scale, and patient satisfaction was 9.0 (±1.2). Over time, the maximum pain score decreased (mean 3.0, ±2.0), whereas patient satisfaction significantly increased (mean 9.8, ±0.4; p<0.05). Among 49 anonymized hospitals, our clinic stayed on first rank in terms of lowest maximum pain and patient satisfaction over the period.
Results were already acceptable at the beginning of benchmarking a standardized pain management concept. But regular benchmarking, implementation of feedback mechanisms, and staff education made the pain management concept even more successful. Multidisciplinary teamwork and flexibility in adapting processes seem to be highly important for successful pain management.
PMCID: PMC5179212  PMID: 28031727
postoperative pain; total hip arthroplasty; pain management concept; benchmarking
2.  Native femoral anteversion should not be used as reference in cementless total hip arthroplasty with a straight, tapered stem: a retrospective clinical study 
Improper femoral and acetabular component positioning can be associated with instability, impingement, component wear and finally patient dissatisfaction in total hip arthroplasty (THA). The concept of “femur first”/“combined anteversion”, incorporates various aspects of performing a functional optimization of the prosthetic stem and cup position of the stem relative to the cup intraoperatively.
In the present study we asked two questions: (1) Do native femoral anteversion and anteversion of the implant correlate? (2) Do anteversion of the final broach and implant anteversion correlate?
In a secondary analysis of a prospective controlled trial, a subgroup of 55 patients, who underwent computer-assisted, cementless THA with a straight, tapered stem through an anterolateral, minimally invasive (MIS) approach in a lateral decubitus position were examined retrospectivly. Intraoperative fluoroscopy was used to verify a “best-fit” position of the final broach. An image-free navigation system was used for measurement of the native femoral version, version of the final broach and the final implant. Femoral neck resection height was measured in postoperative CT-scans. This investigation was approved by the local Ethics Commission (No.10-121-0263) and is a secondary analysis of a larger project (DRKS00000739, German Clinical Trials Register May-02–2011).
The mean difference between native femoral version and final implant was 1.9° (+/− 9.5), with a range from −20.7° to 21.5° and a Spearman’s correlation coefficient of 0.39 (p < 0.003). In contrast, we observed a mean difference between final broach and implant version of −1.9° (+/− 3.5), with a range from −12.7° to 8.7° and a Spearman’s correlation coefficient of 0.89 (p < 0.001). In 83.6 % (46/55) final stem version was outside the normal range as defined by Tönnis (15-20°). The mean femoral neck resection height was 7.3 mm (+/− 5.6). There was no correlation between resection height and version of the implant (Spearman’s correlation coefficient 0.14).
Native femoral version significantly differs from the final anteversion of a cementless, straight, tapered stem and therefore is not a reliable reference in cementless THA. Measuring anteversion of the final “fit and fill” broach is a feasible assistance in order to predict final stem anteversion intraoperatively. There is no correlation between femoral neck resection height and version of the implant.
PMCID: PMC5028956  PMID: 27646313
Hip arthroplasty; Stem version; Combined anteversion; Imageless navigation
3.  Visual intraoperative estimation of cup and stem position is not reliable in minimally invasive hip arthroplasty 
Acta Orthopaedica  2016;87(3):225-230.
Background and purpose
In hip arthroplasty, acetabular inclination and anteversion—and also femoral stem torsion—are generally assessed by eye intraoperatively. We assessed whether visual estimation of cup and stem position is reliable.
Patients and methods
In the course of a subgroup analysis of a prospective clinical trial, 65 patients underwent cementless hip arthroplasty using a minimally invasive anterolateral approach in lateral decubitus position. Altogether, 4 experienced surgeons assessed cup position intraoperatively according to the operative definition by Murray in the anterior pelvic plane and stem torsion in relation to the femoral condylar plane. Inclination, anteversion, and stem torsion were measured blind postoperatively on 3D-CT and compared to intraoperative results.
The mean difference between the 3D-CT results and intraoperative estimations by eye was −4.9° (−18 to 8.7) for inclination, 9.7° (−16 to 41) for anteversion, and −7.3° (−34 to 15) for stem torsion. We found an overestimation of > 5° for cup inclination in 32 hips, an overestimation of > 5° for stem torsion in 40 hips, and an underestimation < 5° for cup anteversion in 42 hips. The level of professional experience and patient characteristics had no clinically relevant effect on the accuracy of estimation by eye. Altogether, 46 stems were located outside the native norm of 10–20° as defined by Tönnis, measured on 3D-CT.
Even an experienced surgeon’s intraoperative estimation of cup and stem position by eye is not reliable compared to 3D-CT in minimally invasive THA. The use of mechanical insertion jigs, intraoperative fluoroscopy, or imageless navigation is recommended for correct implant insertion.
PMCID: PMC4900086  PMID: 26848628
4.  Predominance of synovial sensory nerve fibers in arthrofibrosis following total knee arthroplasty compared to osteoarthritis of the knee 
So far, there exists no golden standard for the treatment of arthrofibrosis (AF) following total knee arthroplasty (TKA). Although pain is a hallmark of AF, nociceptive nerve fibers have never been investigated in affected joint tissue.
A total of 24 patients with osteoarthritis (OA) of the knee (n = 12) and post-TKA AF of the knee (n = 12) were included. Along evaluation of typical clinical signs and symptoms by using the Knee Society Clinical Rating System (KSS), the Knee Injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC index), the innervation of joint tissue was studied by semiquantitative immunofluorescence of nerve fibers.
Patients with AF compared to OA had a lower KSS and lower KOOS. In all compartments (anterior, medial, and lateral recesses), the density of synovial sympathetic nerve fibers was significantly higher in OA compared to AF, which was also true for the density of sensory nerve fibers in the medial and lateral recesses. In synovial tissue of the anterior recess of patients with AF compared to OA, the density of nociceptive sensory nerve fibers was significantly higher relative to sympathetic nerve fibers. This was similarly observed in the neighboring infrapatellar fat pad of the knee.
Similar as in many painful musculoskeletal diseases, this study indicates that patients with arthrofibrosis of the knee after TKA demonstrate a preponderance of profibrotic sensory nerve fibers over antifibrotic sympathetic nerve fibers. This could serve as a starting point for AF therapy with specific antifibrotic pain medication or regional anesthetic techniques.
PMCID: PMC4758104  PMID: 26888574
Arthrofibrosis; Knee; Osteoarthritis; Arthroplasty; Nerve fibers
5.  Does Computer-Assisted Femur First THR Improve Musculoskeletal Loading Conditions? 
BioMed Research International  2015;2015:625317.
We have developed a novel, computer-assisted operation method for minimal-invasive total hip replacement (THR) following the concept of “femur first/combined anteversion,” which incorporates various aspects of performing a functional optimization of the prosthetic stem and cup position (CAS FF). The purpose of this study is to assess whether the hip joint reaction forces and patient's gait parameters are being improved by CAS FF in relation to conventional THR (CON). We enrolled 60 patients (28 CAS FF/32 CON) and invited them for gait analysis at three time points (preoperatively, postop six months, and postop 12 months). Data retrieved from gait analysis was processed using patient-specific musculoskeletal models. The target parameters were hip reaction force magnitude (hrf), symmetries, and orientation with respect to the cup. Hrf in the CAS FF group were closer to a young healthy normal. Phase-shift symmetry showed an increase in the CAS FF group. Hrf orientation in the CAS FF group was closer to optimum, though no edge or rim-loading occurred in the CON group as well. The CAS FF group showed an improved hrf orientation in an early stage and a trend to an improved long-term outcome.
PMCID: PMC4637031  PMID: 26582355
6.  Current therapeutic strategies of heterotopic ossification – a survey amongst orthopaedic and trauma departments in Germany 
Heterotopic ossification (HO) is a complication after tissue trauma, fracture and surgery (i.e. total hip arthroplasty). Prophylaxis is the most effective therapy. If HO formations become symptomatic and limit patients’ quality of life, revision surgery is indicated and is usually combined with a perioperative oral prophylaxis (NSAIDs) and/or irradiation. However, a long-term use of NSAIDs can induce gastro-intestinal or cardiac side-effects and possible bony non-unions during fracture healing. Subject of this study was to assess the current status of HO prophylaxis after injuries or fractures and to evaluate current indications and strategies for excision of symptomatic HO.
Between 2013 and 2014, a questionnaire was sent to 119 orthopaedic and trauma surgery departments in Germany. Participation was voluntary and all acquired data was given anonymously.
The cumulative feedback rate was 71 %. Trauma and orthopaedic surgery departments in Germany recommend oral HO prophylaxis after acetabulum and femoral neck fractures, elbow dislocation, and fracture or dislocation of the radial head. Pain upon movement and an increasing loss of range of motion in the affected joint are considered to be clear indications for HO surgery. A partial removal of ROM-limiting HO formations was also considered important. The vast majority of all departments include perioperative oral HO prophylaxis and/or irradiation if surgical HO removal is planned. The choice and duration of NSAIDs is highly variable.
HO is of clinical significance in current traumatology and orthopaedics. Certain fractures and injuries are prone to HO, and prophylactic measures should be taken. The respondents in this survey assessed current therapeutic strategies for HO formations similarly. These concepts are in line with the literature. However, the duration of perioperative oral HO prophylaxis varied greatly among the specialist centres. This is significant as a long-term use of NSAIDs fosters a potential risk for the patients’ safety and could influence the clinical outcome. National and international guidelines need to be developed to further reduce HO rates and improve patients’ safety in trauma and orthopaedic surgery.
PMCID: PMC4619196  PMID: 26494270
Heterotopic ossification; Trauma; Therapy; Fracture; Prophylaxis
7.  Fluoroscopy and Imageless Navigation Enable an Equivalent Reconstruction of Leg Length and Global and Femoral Offset in THA 
Restoration of biomechanics is a major goal in THA. Imageless navigation enables intraoperative control of leg length equalization and offset reconstruction. However, the effect of navigation compared with intraoperative fluoroscopy is unclear.
We asked whether intraoperative use of imageless navigation (1) improves the relative accuracy of leg length and global and femoral offset restoration; (2) increases the absolute precision of leg length and global and femoral offset equalization; and (3) reduces outliers in a reconstruction zone of ± 5 mm for leg length and global and femoral offset restoration compared with intraoperative fluoroscopy during minimally invasive (MIS) THA with the patient in a lateral decubitus position.
In this prospective study a consecutive series of 125 patients were randomized to either navigation-guided or fluoroscopy-controlled THA using sealed, opaque envelopes. All patients received the same cementless prosthetic components through an anterolateral MIS approach while they were in a lateral decubitus position. Leg length, global or total offset (representing the combination of femoral and acetabular offset), and femoral offset differences were restored using either navigation or fluoroscopy. Postoperatively, residual leg length and global and femoral offset discrepancies were analyzed on magnification-corrected radiographs of the pelvis by an independent and blinded examiner using digital planning software. Accuracy was defined as the relative postoperative difference between the surgically treated and the unaffected contralateral side for leg length and offset, respectively; precision was defined as the absolute postoperative deviation of leg length and global and femoral offset regardless of lengthening or shortening of leg length and offset throughout the THA. All analyses were performed per intention-to-treat.
Analyzing the relative accuracy of leg length restoration we found a mean difference of 0.2 mm (95% CI, −1.0 to +1.4 mm; p = 0.729) between fluoroscopy and navigation, 0.2 mm (95 % CI, −0.9 to +1.3 mm; p = 0.740) for global offset and 1.7 mm (95 % CI, +0.4 to +2.9 mm; p = 0.008) for femoral offset. For the absolute precision of leg length and global and femoral offset equalization, there was a mean difference of 1.7 ± 0.3 mm (p < 0.001) between fluoroscopy and navigation. The biomechanical reconstruction with a residual leg length and global and femoral offset discrepancy less than 5 mm and less than 8 mm, respectively, succeeded in 93% and 98%, respectively, in the navigation group and in 54% and 95%, respectively, in the fluoroscopy group.
Intraoperative fluoroscopy and imageless navigation seem equivalent in accuracy and precision to reconstruct leg length and global and femoral offset during MIS THA with the patient in the lateral decubitus position.
Level of Evidence
Level I, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC4160474  PMID: 24964886
8.  The influence of component alignment on patellar kinematics in total knee arthroplasty 
Acta Orthopaedica  2015;86(4):444-450.
Background and purpose
Postoperative anterior knee pain is one of the most frequent complications after total knee arthroplasty (TKA). Changes in patellar kinematics after TKA relative to the preoperative arthritic knee are not well understood. We compared the patellar kinematics preoperatively with the kinematics after ligament-balanced navigated TKA.
Patients and methods
We measured patellar tracking before and after ligament-balanced TKA in 40 consecutive patients using computer navigation. Furthermore, the influences of different femoral and tibial component alignment on patellar kinematics were analyzed using generalized linear models.
After TKA, the patellae shifted statistically significantly more laterally between 30° and 60°. The lateral tilt increased at 90° of flexion whereas the epicondylar distance decreased between 45° and 75° of flexion. Sagittal component alignment, but not rotational component alignment, had a significant influence on patellar kinematics.
There are major differences in patellar kinematics between the preoperative arthritic knee and the knee after TKA. Combined sagittal component alignment in particular appears to have a major effect on patellar kinematics. Surgeons should be especially aware of altering preoperative sagittal alignment until the possible clinical relevance has been investigated.
PMCID: PMC4513599  PMID: 25582349
9.  Reactivity of rat bone marrow-derived macrophages to neurotransmitter stimulation in the context of collagen II-induced arthritis 
Numerous observations indicate that rheumatoid arthritis (RA) has a bone marrow component. In parallel, local synovial changes depend on neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze whether collagen II-induced arthritis (CIA) has an impact on number, adhesion, apoptosis, and proliferation of the macrophage subset of bone marrow cells and how alterations in neurotransmitter microenvironment affect these properties.
Bone marrow-derived macrophages (BMMs) were isolated from Dark Agouti rats at different stages of CIA, and number, adhesion, caspase 3/7 activity, and proliferation were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA), and vasoactive intestinal peptide (VIP).
Opposed to enhanced CD11b+ (cluster of differentiation 11b-positive) and EMR1+ (epidermal growth factor-like module-containing mucin-like hormone receptor-like 1-positive) cells, characterizing the macrophage subset, in native bone marrow of rats with acute inflammatory arthritis, we found decreased numbers of CIA macrophages after enrichment and culture in comparison with healthy (control) animals. Adhesion studies revealed significantly reduced attachment to plastic in acute arthritis and collagen type I and fibronectin in chronic arthritis. Additionally, we found a strong reduction in proliferation of BMMs at CIA onset and in the chronic phase of CIA. Apoptosis remained unaffected. Neurotransmitter stimulation profoundly affected proliferation, adhesion, and apoptosis of BMMs from CIA and control rats, depending on disease time point. Cultured BMMs from CIA and control animals expressed neurotransmitter receptors for ACh, VIP and NA, but the expression profile seemed not to be affected by CIA.
Induction of CIA distinctly inhibits proliferation of BMMs in low- and non-inflammatory phases and reduces attachment to plastic at the acute inflammatory arthritis stage and adhesion to collagen I and fibronectin at the chronic stage. Influence of neurotransmitter stimulation on adhesion, apoptosis, and proliferation is altered by CIA depending on disease stage. We suggest an altered reactivity of BMMs to neurotransmitter stimulation caused by CIA and maybe also by aging.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0684-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4496866  PMID: 26104678
10.  Accuracy of bony landmarks for restoring the natural joint line in revision knee surgery: an MRI study 
International Orthopaedics  2014;38(6):1173-1181.
Restoring the joint line (JL) improves clinical and functional outcome in total knee arthroplasty (TKA). Therefore, anatomical landmarks to approximate the JL have been published. So far, the natural deviation of the JL 90° to the mechanical tibial axis has not been considered. Thus, we designed this study to: (1) determine the natural JL of knees in healthy persons in respect to the mechanical tibial axis, (2) validate and double-check intra-operative bony landmarks already been published in respect to the natural JL and (3) find possible correlations between distances from bony landmarks to the JL and femoral and tibial width.
Eighty MRI scans of knees of healthy persons were examined by two independent observers. Distances from the tip of the fibular head (FH), the medial (ME) and lateral (LE) epicondyles and the adductor tubercle (AT) to the JL within the medial and lateral compartment were measured. Further, we determined the orientation of the JL in respect to the mechanical axis of the tibia. Interobserver correlations were calculated. Differences were analyzed using Student’s t test. Linear regression models were calculated to analyze correlations.
Interobserver correlation was excellent. Mean JL deviation was 4.2° varus. Distance between the FH, ME, LE and AT to the JL within the medial compartment was 12.2, 33.9, 33.4 and 45.4 mm, respectively. Within in the lateral compartment, distances were 15.3, 31.0, 30.6 and 42.3 mm to the JL. Strong correlation was found between femoral width and distances from the AT, ME and LE to the JL.
In TKA, the JL is usually altered due to the classic resection technique, which does not respect the natural deviation of the JL. Estimating the natural JL by adding absolute values to bony landmarks, as proposed in the literature, is not recommended. According to our data, the JL can be best estimated by adding the calculated value: 6.40 + (width femur [mm] × 0.49) to the AT.
PMCID: PMC4037526  PMID: 24570152
Bony landmarks; Knee revision surgery; MRI measurement; Joint line
11.  Subchondral bone influences chondrogenic differentiation and collagen production of human bone marrow-derived mesenchymal stem cells and articular chondrocytes 
Osteoarthritis (OA) is characterized by an imbalance in cartilage and underlying subchondral bone homeostasis. We hypothesized that signals from the subchondral bone may modulate production of matrix components, alter chondrogenic differentiation potential of cocultured bone marrow-derived mesenchymal stem cells (BMSC) and induce a phenotypic shift in differentiated OA chondrocytes.
We established a novel coculture model between BMSC, mixed cultures (BMSC and chondrocytes) and chondrocytes embedded in fibrin gel with OA and normal subchondral bone explants (OAB and NB). Tissues and cells were either derived from OA or trauma patients. In addition, we used adipose-derived stem cells (ASC) from liposuction. With gene expression analysis, biochemical assays, immunofluorescence and biomechanical tests we characterized the properties of newly generated extracellular matrix (ECM) from chondrocytes and chondrogenically differentiating BMSC cocultured with OAB or NB in comparison with monocultures (cultures without bone explants).
Overall, gene expression of collagens of OAB and NB cocultured cells was reduced compared to monocultures. Concomitantly, we observed significantly lower collagen I, II and III and glycosaminoglycan (GAG) production in OAB cocultured cell lysates. In parallel, we detected increased concentrations of soluble GAGs and basic fibroblast growth factor (bFGF), interleukin (IL)-6 and IL-8 in supernatants of OAB and NB cocultures mainly at early time points. IL-1ß concentration was increased in supernatants of OAB cocultures, but not in NB cocultures. Cell-free NB or OAB explants released different amounts of IL-1ß, bFGF and soluble GAG into cell culture supernatants. In comparison to cocultures, monocultures exhibited higher Young’s modulus and equilibrium modulus. Stimulation of monocultures with IL-1ß led to a downregulation of aggrecan (ACAN) gene expression and in general to induced matrix metalloprotease (MMP)2, MMP3 and MMP-13 gene expression while IL-6 and IL-8 stimulation partly reduced ACAN, MMP3 and MMP-13 gene expression.
Our results suggest an alteration of molecular composition and mechanical properties of the newly formed ECM in subchondral bone cocultures. We suggest that soluble factors, that is interleukins and bFGF, released in cocultures exert inhibitory effects on collagen and temporary effects on proteoglycan production, which finally results in a reduction of mechanical strength of newly formed fibrillar networks.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0453-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4209060  PMID: 25296561
12.  Melanocortin 1 Receptor-Signaling Deficiency Results in an Articular Cartilage Phenotype and Accelerates Pathogenesis of Surgically Induced Murine Osteoarthritis 
PLoS ONE  2014;9(9):e105858.
Proopiomelanocortin-derived peptides exert pleiotropic effects via binding to melanocortin receptors (MCR). MCR-subtypes have been detected in cartilage and bone and mediate an increasing number of effects in diathrodial joints. This study aims to determine the role of MC1-receptors (MC1) in joint physiology and pathogenesis of osteoarthritis (OA) using MC1-signaling deficient mice (Mc1re/e). OA was surgically induced in Mc1re/e and wild-type (WT) mice by transection of the medial meniscotibial ligament. Histomorphometry of Safranin O stained articular cartilage was performed with non-operated controls (11 weeks and 6 months) and 4/8 weeks past surgery. µCT–analysis for assessing epiphyseal bone architecture was performed as a longitudinal study at 4/8 weeks after OA-induction. Collagen II, ICAM-1 and MC1 expression was analysed by immunohistochemistry. Mc1re/e mice display less Safranin O and collagen II stained articular cartilage area compared to WT prior to OA-induction without signs of spontaneous cartilage surface erosion. This MC1-signaling deficiency related cartilage phenotype persisted in 6 month animals. At 4/8 weeks after OA-induction cartilage erosions were increased in Mc1re/e knees paralleled by weaker collagen II staining. Prior to OA-induction, Mc1re/e mice do not differ from WT with respect to bone parameters. During OA, Mc1re/e mice developed more osteophytes and had higher epiphyseal bone density and mass. Trabecular thickness was increased while concomitantly trabecular separation was decreased in Mc1re/e mice. Numbers of ICAM-positive chondrocytes were equal in non-operated 11 weeks Mc1re/e and WT whereas number of positive chondrocytes decreased during OA-progression. Unchallenged Mc1re/e mice display smaller articular cartilage covered area without OA-related surface erosions indicating that MC1-signaling is critical for proper cartilage matrix integrity and formation. When challenged with OA, Mc1re/e mice develop a more severe OA-pathology. Our data suggest that MC1-signaling protects against cartilage degradation and subchondral bone sclerosis in OA indicating a beneficial role of the POMC system in joint pathophysiology.
PMCID: PMC4156302  PMID: 25191747
13.  Osteoarthritic cartilage explants affect extracellular matrix production and composition in cocultured bone marrow-derived mesenchymal stem cells and articular chondrocytes 
In the present study, we established a novel in vitro coculture model to evaluate the influence of osteoarthritis (OA) cartilage explants on the composition of newly produced matrix and chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells (BMSCs) and the phenotype of OA chondrocytes. In addition, we included a “tri-culture” model, whereby a mixture of BMSCs and chondrocytes was cultured on the surface of OA cartilage explants.
Gene expression analysis, protein and glycosaminoglycan (GAG) assays, dot-blot, immunofluorescence, and biomechanical tests were used to characterize the properties of newly generated extracellular matrix (ECM) from chondrocytes and chondrogenically differentiated BMSCs and a mix thereof. We compared articular cartilage explant cocultures with BMSCs, chondrocytes, and mixed cultures (chondrocytes and BMSCs 1:1) embedded in fibrin gels with fibrin gel-embedded cells cultured without cartilage explants (monocultures).
In general, co- and tri-cultured cell regimens exhibited reduced mRNA and protein levels of collagens I, II, III, and X in comparison with monocultures, whereas no changes in GAG synthesis were observed. All co- and tri-culture regimens tended to exhibit lower Young’s and equilibrium modulus compared with monocultures. In contrast, aggregate modulus and hydraulic permeability seemed to be higher in co- and tri-cultures. Supernatants of cocultures contained significant higher levels of interleukin-1 beta (IL-1β), IL-6, and IL-8. Stimulation of monocultures with IL-1β and IL-6 reduced collagen gene expression in BMSCs and mixed cultures in general but was often upregulated in chondrocytes at late culture time points. IL-8 stimulation affected BMSCs only.
Our results suggest an inhibitory effect of OA cartilage on the production of collagens. This indicates a distinct modulatory influence that affects the collagen composition of the de novo-produced ECM from co- and tri-cultured cells and leads to impaired mechanical and biochemical properties of the matrix because of an altered fibrillar network. We suggest that soluble factors, including IL-1β and IL-6, released from OA cartilage partly mediate these effects. Thus, neighbored OA cartilage provides inhibitory signals with respect to BMSCs’ chondrogenic differentiation and matrix composition, which need to be accounted for in future cell-based OA treatment strategies.
PMCID: PMC4097830  PMID: 24916039
14.  A minimally invasive approach for total hip arthroplasty does not diminish early post-operative outcome in obese patients: a prospective, randomised trial 
International Orthopaedics  2013;37(6):1013-1018.
The benefits of minimally invasive surgical techniques in total hip arthroplasty (THA) are well known, but concerns about applying those techniques in obese patients are controversial. We prospectively compared patients with increased body mass index (BMI ≥30) undergoing THA with normal weight patients.
A total of 134 patients admitted for unilateral THA were randomised to have surgery through either a transgluteal or a minimally invasive approach (MicroHip). In each group a BMI ≥30 was used to define obese patients. Pre- and early post-operative demographics, intraoperative data, baseline haematological values, hip function (Harris Hip Score, Oxford Hip Score) and quality of life (EQ-5D) were assessed with follow-up at three months.
Duration of surgery, blood loss, C-reactive protein levels, radiographic measurements and complication rates were comparable in all groups. There was a tendency for lower serum creatine kinase levels in the MicroHip group. Intraoperative fluoroscopic time and dose area products were significantly elevated in patients with a BMI exceeding 30 regardless of the approach used. Time points of mobilisation, length of hospital stay and functional outcome measurements were similar in the different weight groups.
Our data suggest that obese patients gain similar benefit from MicroHip THA as do non-obese patients. The results of this study should be further investigated to assess long-term survivorship.
PMCID: PMC3664165  PMID: 23446330
15.  Comparing navigation-based in vivo knee kinematics pre- and postoperatively between a cruciate-retaining and a cruciate-substituting implant 
International Orthopaedics  2013;37(3):407-414.
Individual physiological knee kinematics are highly variable in normal knees and are altered following cruciate-substituting (PS) and cruciate-retaining (CR) total knee arthroplasty (TKA). We wanted to know whether knee kinematics are different choosing two different knee designs, CR and PS TKA, during surgery using computer navigation.
For this purpose, 60 consecutive TKA were randomised, receiving either CR (37 patients) or PS TKA (23 patients). All patients underwent computer navigation, and kinematics were assessed prior to making any cuts or releases and after implantation. Outcome measures were relative rotation between femur and tibia, measured medial and lateral gaps and medial and lateral condylar lift-off.
We were not able to demonstrate a significant difference in femoral external rotation between either group prior to implantation (7.9° CR vs. 7.4° PS) or after implantation (9.0° CR vs. 11.3° PS), both groups showed femoral roll-back. It significantly increased pre- to postoperatively in PS TKA. In the CR group both gaps increased, the change of the medial gap was significantly attributable to medial release. In the PS group both gaps increased and the change of the medial and of the lateral gap was significant. Condylar lift-off was observed in the CR group during 20° and 60° of flexion.
This study did not reveal significant differences in navigation-based knee kinematics between CR and PS implants. Femoral roll-back was observed in both implant designs, but significantly increased pre- to postoperatively in PS TKA. A slight midflexion instability was observed in CR TKA. Intra-operative computer navigation can measure knee kinematics during surgery before and after TKR implantation and may assist surgeons to optimise knee kinematics or identify abnormal knee kinematics that could be corrected with ligament releases to improve the functional result of a TKR, whether it is a CR or PS design. Our intra-operative finding needs to be confirmed using fluoroscopic or radiographic 3D matching after complete recovery from surgery.
PMCID: PMC3580100  PMID: 23361937
16.  Arthrodesis of the talonavicular joint using angle-stable mini-plates: a prospective study 
International Orthopaedics  2012;36(12):2491-2494.
The talonavicular joint is a central connection of the human foot. Symptomatic talonavicular arthritis can be adequately addressed by isolated talonavicular fusion. However, non-union remains a relevant clinical challenge to the orthopaedic surgeon. The aim of this study was to analyse the clinicoradiological outcome of talonavicular fusion using angle-stable mini-plates.
We performed 30 talonavicular fusions in 30 patients (12 male, 18 female) with a mean age of 58.8 years (range, 22–74) between 2005 and 2007. Osseous joint fusion was achieved using mono- and multidirectional angle-stable mini-plates. The patients followed a standardised immobilisation and weight bearing protocol. The mean postoperative follow up was 15.8 months (6.1–23.8).
The American Orthopedic Foot and Ankle Society AOFAS score increased significantly from 31.7 (19–42) to 82.3 points (55–97) (p < 0.001). Neither age at operation nor gender influenced the score results significantly, while the aetiology of talonavicular degeneration showed a significant effect. Mean visual analogue scale (VAS) pain intensity (0–10) reduced from 8.6 to 1.7 (p < 0.001). Good or excellent results were achieved in 26 patients, while two patients reported fair and another two poor results. Complete osseous fusion was observed at a mean of 10.9 weeks (8–13) postoperatively.
For the treatment of talonavicular arthritis, the application of mono- and multidirectional angle-stable mini-plates provided a strong fixation that led to high union rates and good to excellent overall outcome.
PMCID: PMC3508057  PMID: 23052279
17.  Treatment of deep articular talus lesions by matrix associated autologous chondrocyte implantation—results at five years 
International Orthopaedics  2012;36(11):2279-2285.
Treatment of focal full-thickness chondral or osteochondral defects of the talus remains a challenge. The aim of this study was to evaluate the postoperative success and the long-term efficacy of matrix associated autologous chondrocyte implantation in these defects.
Matrix associated autologous chondrocyte implantation (MACI) was applied in 22 consecutive patients (mean age 23.9 years) with full-thickness chondral or osteochondral lesions of the talus. The average defect-size was 1.94 cm² (range 1–6). In case of osteochondritis dissecans (n = 13) an autologous bone graft was performed simultaneously. Follow-ups were routinely scheduled up to 63.5 (±7.4) months, consisting of clinical evaluation and magnetic resonance imaging.
The AOFAS score improved significantly from 70.1 to 87.9/92.6/93.5/95.0/95.5 and 95.3 points at three, six, 12, 24, 36 and 63.5 months, respectively. On a visual analogue scale, pain intensity decreased from 5.7 (±2.6) to 0.9 (±0.8) while subjective function increased from 5.3 (±2.3) to 8.9 (±0.9) at final follow-up (each p < 0.001). The Tegner score rose significantly from 2.4 (±1.2) to 4.7 (±0.6). The MOCART score improved from 62.6 (±19.4) at three months to 83.8 (±9.4) at final follow-up. No significant differences were found between lesions caused by osteochondritis dissecans or trauma and between first- or second-line treatments. For all scores, the most benefit was seen within the first 12 months with stable results afterwards. No major complications were noted.
Matrix associated autologous chondrocyte implantation is capable of significant and stable long-term improvement of pain and functional impairment caused by focal full-thickness chondral and osteochondral talus lesions.
PMCID: PMC3479272  PMID: 22885840
18.  Fluoroscopy-guided retrograde core drilling and cancellous bone grafting in osteochondral defects of the talus 
International Orthopaedics  2012;36(8):1635-1640.
In undetached osteochondral lesions (OCL) of the talus both revitalisation of the subchondral necrosis and cartilage preservation are essential. For these cases, we assess the results of minimally invasive retrograde core drilling and cancellous bone grafting.
Forty-one osteochondral lesions of the talus (12x grade I, 22x grade II and 7x grade III according to the Pritsch classification, defect sizes 7–14 mm) in 38 patients (mean age 33.2 years) treated by fluoroscopy-guided retrograde core drilling and autologous cancellous bone grafting were evaluated by clinical scores and MRI. The mean follow-up was 29.0 (±13) months.
The AOFAS score increased significantly from 47.3 (±15.3) to 80.8 (±18.6) points. Lesions with intact cartilage (grades I and II) had a tendency to superior results than grade III lesions (83.1 ± 17.3 vs. 69.4 ± 22.2 points, p = 0.07). First-line treatments and open distal tibial growth plates led to significantly better outcomes (each p < 0.05). Age, gender, BMI, time to follow-up, defect localisation or a traumatic origin did not influence the score results. On a visual analogue scale pain intensity reduced from 7.5 (±1.5) to 3.7 (±2.6) while subjective function increased from 4.6 (±2.0) to 8.2 (±2.3) (each p < 0.001). In MRI follow-ups, five of the 41 patients showed a complete bone remodelling. In two cases demarcation was detectable.
The technique reported is a highly effective therapeutic option in OCL of the talus with intact cartilage grades I and II. However, second-line treatments and grade III lesions with cracked cartilage surface can not be generally recommended for this procedure.
PMCID: PMC3535023  PMID: 22491802
19.  Accuracy of acetabular cup placement in computer-assisted, minimally-invasive THR in a lateral decubitus position 
International Orthopaedics  2010;35(6):809-815.
In a prospective and randomised clinical study, we implanted acetabular cups either by means of an image-free computer-navigation system (navigated group, n = 32) or by free-hand technique (freehand group n = 32, two drop-outs). Total hip replacement was conducted in the lateral position and through a minimally invasive anterior approach (MicroHip). The position of the component was determined postoperatively on CT scans of the pelvis using CT-planning software. We found an average inclination of 42.3° (range 32.7–50.6°; SD±3.8°) and an average anteversion of 24.5° (range 12.0–33.3°; SD±6.0°) in the computer-assisted study group and an average inclination of 37.9° (range 25.6–50.2°; SD±6.3°) and an average anteversion of 23.8° (range 5.6–46.9°; SD±10.1°) in the freehand group. The higher precision of computer navigation was indicated by the lower standard deviations. For both measurements we found a significant heterogeneity of variances (p < 0.05, Levene's test). The mean difference between the cup inclination/anteversion values displayed by computer navigation and the true cup position (CT control) was 0.37° (SD 3.26) and −5.61° (SD 6.48), respectively. We found a bias (underestimation) with regard to anteversion determined by the imageless computer navigation system. A bias for inclination was not found. Registration of the landmarks of the anterior pelvic plane in lateral position with undraped percutaneous methods leads to an error in cup anteversion, but not to an error in cup inclination. The bias we found is consistent with a correct registration of the anterosuperior iliac spine (ASIS) and with a registration of the symphysis 1 cm above the bone, corresponding to the less compressible overlying soft tissue in this region. There was no significant correlation between the bias and the thickness of soft tissue above the pubic tubercles. We suggest use of a percutaneous registration of ASIS and an invasive registration above the pubic tubercles when computer-assisted navigation is performed in minimally invasive THR in a lateral position.
PMCID: PMC3103965  PMID: 20495801
20.  The association between Femoral Tilt and impingement-free range-of-motion in total hip arthroplasty 
There is a complex interaction among acetabular component position and antetorsion of the femoral stem in determining the maximum, impingement-free prosthetic range-of-motion (ROM) in total hip arthroplasty (THA). By insertion into the femoral canal, stems of any geometry follow the natural anterior bow of the proximal femur, creating a sagittal Femoral Tilt (FT). We sought to study the incidence of FT as measured on postoperative computed tomography scans and its influence on impingement-free ROM in THA.
The incidence of the postoperative FT was evaluated on 40 computed tomography scans after cementless THA. With the help of a three-dimensional computer model of the hip, we then systematically analyzed the effects of FT on femoral antetorsion and its influence on calculations for a ROM maximized and impingement-free compliant stem/cup orientation.
The mean postoperative FT on CT scans was 5.7° ± 1.8°. In all tests, FT significantly influenced the antetorsion values. Re-calculating the compliant component positions according to the concept of combined anteversion with and without the influence of FT revealed that the zone of compliance could differ by more than 200%. For a 7° change in FT, the impingement-free cup position differed by 4° for inclination when the same antetorsion was used.
A range-of-motion optimized cup position in THA cannot be calculated based on antetorsion values alone. The FT has a significant impact on recommended cup positions within the concept of “femur first” or “combined anteversion”. Ignoring FT may pose an increased risk of impingement as well as dislocation.
PMCID: PMC3416712  PMID: 22559740
21.  Minimally invasive computer-navigated total hip arthroplasty, following the concept of femur first and combined anteversion: design of a blinded randomized controlled trial 
Impingement can be a serious complication after total hip arthroplasty (THA), and is one of the major causes of postoperative pain, dislocation, aseptic loosening, and implant breakage. Minimally invasive THA and computer-navigated surgery were introduced several years ago. We have developed a novel, computer-assisted operation method for THA following the concept of "femur first"/"combined anteversion", which incorporates various aspects of performing a functional optimization of the cup position, and comprehensively addresses range of motion (ROM) as well as cup containment and alignment parameters. Hence, the purpose of this study is to assess whether the artificial joint's ROM can be improved by this computer-assisted operation method. Second, the clinical and radiological outcome will be evaluated.
A registered patient- and observer-blinded randomized controlled trial will be conducted. Patients between the ages of 50 and 75 admitted for primary unilateral THA will be included. Patients will be randomly allocated to either receive minimally invasive computer-navigated "femur first" THA or the conventional minimally invasive THA procedure. Self-reported functional status and health-related quality of life (questionnaires) will be assessed both preoperatively and postoperatively. Perioperative complications will be registered. Radiographic evaluation will take place up to 6 weeks postoperatively with a computed tomography (CT) scan. Component position will be evaluated by an independent external institute on a 3D reconstruction of the femur/pelvis using image-processing software. Postoperative ROM will be calculated by an algorithm which automatically determines bony and prosthetic impingements.
In the past, computer navigation has improved the accuracy of component positioning. So far, there are only few objective data quantifying the risks and benefits of computer navigated THA. Therefore, this study has been designed to compare minimally invasive computer-navigated "femur first" THA with a conventional technique for minimally invasive THA. The results of this trial will be presented as soon as they become available.
Trial registration number
PMCID: PMC3180441  PMID: 21854588
22.  The oncofetal gene survivin is re-expressed in osteoarthritis and is required for chondrocyte proliferation in vitro 
Regulation of cell death and cell division are key processes during chondrogenesis and in cartilage homeostasis and pathology. The oncogene survivin is considered to be critical for the coordination of mitosis and maintenance of cell viability during embryonic development and in cancer, and is not detectable in most adult differentiated tissues and cells. We analyzed survivin expression in osteoarthritic cartilage and its function in primary human chondrocytes in vitro.
Survivin expression was analyzed by immunoblotting and quantitative real-time PCR. The localization was visualized by immunofluorescence. Survivin functions in vitro were investigated by transfection of a specific siRNA.
Survivin was expressed in human osteoarthritic cartilage, but was not detectable in macroscopically and microscopically unaffected cartilage of osteoarthritic knee joints. In primary human chondrocyte cultures, survivin was localized to heterogeneous subcellular compartments. Suppression of survivin resulted in inhibition of cell cycle progression and sensitization toward apoptotic stimuli in vitro.
The present study indicates a role for survivin in osteoarthritic cartilage and human chondrocytes. In vitro experiments indicated its involvement in cellular division and viability. Learning more about the functions of survivin in chondrocyte biology might further help toward understanding and modulating the complex processes of cartilage pathology and regeneration.
PMCID: PMC3141611  PMID: 21729321
apoptosis; chondrocyte; osteoarthritis; proliferation; survivin
23.  Leg Length and Offset Measures with a Pinless Femoral Reference Array during THA 
The bony fixation of reference marker arrays used for computer-assisted navigation during total hip arthroplasty (THA) theoretically involves the risk of fracture, infection, and/or pin loosening. We asked whether intraoperative assessment of leg length (LL) and offset (OS) changes would be accurate using a novel pinless femoral reference system in conjunction with an imageless measurement algorithm based on specific realignment of the relationship between a dynamic femoral and pelvis reference array. LL/OS measurements were recorded during THA in 17 cadaver specimen hips. Preoperatively and postoperatively, specimens were scanned using CT. Linear radiographic LL/OS changes were determined by two investigators using visible fiducial landmarks and image processing software. We found a high correlation of repeated measurements within and between (both 0.95 or greater) the two examiners who did the CT assessments. Pinless LL/OS values showed mean differences less than 1 mm and correlations when compared with CT measurements.
PMCID: PMC2882021  PMID: 19768517
24.  The antiapoptotic gene survivin is highly expressed in human chondrosarcoma and promotes drug resistance in chondrosarcoma cells in vitro 
BMC Cancer  2011;11:120.
Chondrosarcoma is virtually resistant to chemotherapy and radiation therapy. Survivin, the smallest member of the inhibitor of apoptosis protein family, is a critical factor for tumor progression and resistance to conventional therapeutic approaches in a wide range of malignancies. However, the role of survivin in chondrosarcoma has not been well studied. We examined the importance of survivin gene expression in chondrosarcoma and analysed its influences on proliferation, apoptosis and resistance to chemotherapy in vitro.
Resected chondrosarcoma specimens from which paraffin-embedded tissues could be extracted were available from 12 patients. In vitro experiments were performed in human chondrosarcoma cell lines SW1353 and Hs819.T. Immunohistochemistry, immunoblot, quantitative PCR, RNA interference, gene-overexpression and analyses of cell proliferation and apoptosis were performed.
Expression of survivin protein was detected in all chondrosarcoma specimens analyzed, while undetectable in adult human cartilage. RNA interference targeting survivin resulted in a G2/M-arrest of the cell cycle and led to increased rates of apoptosis in chondrosarcoma cells in vitro. Overexpression of survivin resulted in pronounced resistance to doxorubicin treatment.
These findings indicate that survivin plays a role in the pathogenesis and pronounced chemoresistance of high grade chondrosarcoma. Survivin antagonizing therapeutic strategies may lead to new treatment options in unresectable and metastasized chondrosarcoma.
PMCID: PMC3076263  PMID: 21457573
25.  Lifestyle factors and lumbar disc disease: results of a German multi-center case-control study (EPILIFT) 
Arthritis Research & Therapy  2010;12(5):R193.
In the large-scale case-control study EPILIFT, we investigated the dose-response relationship between lifestyle factors (weight, smoking amount, cumulative duration of different sports activities) and lumbar disc disease.
In four German study regions (Frankfurt am Main, Freiburg, Halle/Saale, Regensburg), 564 male and female patients with lumbar disc herniation and 351 patients with lumbar disc narrowing (chondrosis) aged 25 to 70 years were prospectively recruited. From the regional population registers, 901 population control subjects were randomly selected. In a structured personal interview, we enquired as to body weight at different ages, body height, cumulative smoking amount and cumulative duration of different sports activities. Confounders were selected according to biological plausibility and to the change-in-estimate criterion. Adjusted, gender-stratified odds ratios with 95% confidence intervals were calculated using unconditional logistic regression analysis.
The results of this case-control study reveal a positive association between weight and lumbar disc herniation as well as lumbar disc narrowing among men and women. A medium amount of pack-years was associated with lumbar disc herniation and narrowing in men and women. A non-significantly lowered risk of lumbar disc disease was found in men with high levels of cumulative body building and strength training.
According to our multi-center case-control study, body weight might be related to lumbar disc herniation as well as to lumbar disc narrowing. Further research should clarify the potential protective role of body building or strength training on lumbar disc disease.
PMCID: PMC2991029  PMID: 20955546

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