Showing papers by "Georg N. Duda published in 2014"

Standardized Loads Acting in Hip Implants

Abstract: The loads acting in knee joints must be known for improving joint replacement, surgical procedures, physiotherapy, biomechanical computer simulations, and to advise patients with osteoarthritis or fractures about what activities to avoid. Such data would also allow verification of test standards for knee implants. This work analyzes data from 8 subjects with instrumented knee implants, which allowed measuring the contact forces and moments acting in the joint. The implants were powered inductively and the loads transmitted at radio frequency. The time courses of forces and moments during walking, stair climbing, and 6 more activities were averaged for subjects with I) average body weight and average load levels and II) high body weight and high load levels. During all investigated activities except jogging, the high force levels reached 3,372–4,218N. During slow jogging, they were up to 5,165N. The peak torque around the implant stem during walking was 10.5 Nm, which was higher than during all other activities including jogging. The transverse forces and the moments varied greatly between the subjects, especially during non-cyclic activities. The high load levels measured were mostly above those defined in the wear test ISO 14243. The loads defined in the ISO test standard should be adapted to the levels reported here. The new data will allow realistic investigations and improvements of joint replacement, surgical procedures for tendon repair, treatment of fractures, and others. Computer models of the load conditions in the lower extremities will become more realistic if the new data is used as a gold standard. However, due to the extreme individual variations of some load components, even the reported average load profiles can most likely not explain every failure of an implant or a surgical procedure.

Initial immune reaction and angiogenesis in bone healing

Abstract: During hematoma formation following injury, an inflammatory reaction ensues as an initial step in the healing process. As granulation tissue matures, revascularization is a prerequisite for successful healing. The hypothesis of this study was that scarless tissue reconstitution in the regenerative bone healing process is dependent on a balanced immune reaction that initiates revasculatory steps. To test this hypothesis, cellular composition and expression profiles of a bone hematoma (regenerative, scarless) was compared with a muscle soft tissue hematoma (healing with a scar) in a sheep model. Upregulation of regulatory T helper cells and anti-inflammatory cytokine expression (IL-10) coincided with an upregulation of angiogenic factors (HIF1α and HIF1α regulated genes) in the regenerative bone hematoma but not in the soft tissue hematoma. These results indicate that the timely termination of inflammation and early onset of revascularization are interdependent and essential for a regenerative healing process. Prolonged pro-inflammatory signaling occurring in a delayed bone-healing model supports the finding that timely termination of inflammation furthers the regenerative process. Differing cellular compositions are due to different cell sources invading the hematoma, determining the ensuing cytokine expression profile and thus paving the path for regenerative healing in bone or the formation of scar tissue in muscle injury.

Initiation and early control of tissue regeneration – bone healing as a model system for tissue regeneration

Abstract: Introduction: Tissue regeneration in itself is a fascinating process that promises repeated renewal of tissue and organs. Areas covered: This article aims to illustrate the different strategies available to control tissue regeneration at a very early stage, using bone as an exemplary tissue. The aspects of a controlled inflammatory cascade to achieve a balanced immune response, cell therapeutic approaches for improved tissue formation and angiogenesis, guiding the organization of newly formed extracellular matrix by biomaterials, the relevance of mechanical signals for tissue regeneration processes, and the chances and limitations of growth factor treatments are discussed. Expert opinion: The currently available knowledge is reviewed and perspectives for potential new targets are given. This is done under the assumption that early identification of risk patients as well as the application of early intervention strategies is possible.

Age-related loss of lumbar spinal lordosis and mobility--a study of 323 asymptomatic volunteers.

Abstract: Background The understanding of the individual shape and mobility of the lumbar spine are key factors for the prevention and treatment of low back pain. The influence of age and sex on the total lumbar lordosis and the range of motion as well as on different lumbar sub-regions (lower, middle and upper lordosis) in asymptomatic subjects still merits discussion, since it is essential for patient-specific treatment and evidence-based distinction between painful degenerative pathologies and asymptomatic aging.

Changing the Mindset in Life Sciences Toward Translation: A Consensus

Abstract: Participants at the recent Translate! 2014 meeting in Berlin, Germany, reached a consensus on the rate-limiting factor for advancing translational medicine.

MALDI imaging mass spectrometry: Discrimination of pathophysiological regions in traumatized skeletal muscle by characteristic peptide signatures

Abstract: Due to formation of fibrosis and the loss of contractile muscle tissue, severe muscle injuries often result in insufficient healing marked by a significant reduction of muscle force and motor activity. Our previous studies demonstrated that the local transplantation of mesenchymal stromal cells into an injured skeletal muscle of the rat improves the functional outcome of the healing process. Since, due to the lack of sufficient markers, the accurate discrimination of pathophysiological regions in injured skeletal muscle is inadequate, underlying mechanisms of the beneficial effects of mesenchymal stromal cell transplantation on primary trauma and trauma adjacent muscle area remain elusive. For discrimination of these pathophysiological regions, formalin-fixed injured skeletal muscle tissue was analyzed by MALDI imaging MS. By using two computational evaluation strategies, a supervised approach (ClinProTools) and unsupervised segmentation (SCiLS Lab), characteristic m/z species could be assigned to primary trauma and trauma adjacent muscle regions. Using "bottom-up" MS for protein identification and validation of results by immunohistochemistry, we could identify two proteins, skeletal muscle alpha actin and carbonic anhydrase III, which discriminate between the secondary damage on adjacent tissue and the primary traumatized muscle area. Our results underscore the high potential of MALDI imaging MS to describe the spatial characteristics of pathophysiological changes in muscle.

Evidence of imbalanced adaptation between muscle and tendon in adolescent athletes.

Abstract: Adolescence may be regarded as a critical phase of tissue plasticity in young growing athletes, as the adaptation process of muscle-tendon unit is affected by both environmental mechanical stimuli and maturation The present study investigated potential imbalances of knee extensor muscle strength and patellar tendon properties in adolescent compared with middle-aged athletes featuring long-term musculotendinous adaptations Nineteen adolescent elite volleyball athletes [(A), 159 ± 06 years] and 18 middle-aged competitively active former elite volleyball athletes [(MA), 469 ± 06 years] participated in magnetic resonance imaging and ultrasound-dynamometry sessions to determine quadriceps femoris muscle strength, vastus lateralis morphology and patellar tendon mechanical and morphological properties There was no significant age effect on the physiological cross-sectional area of the vastus lateralis and maximum knee extension moment (P > 005) during voluntary isometric contractions However, the patellar tendon cross-sectional area was significantly smaller (A: 1074 ± 275 mm(2) ; MA: 1217 ± 398 mm(2) ) and the tendon stress during the maximal contractions was significantly higher in adolescent compared with the middle-aged athletes (A: 500 ± 101 MPa; MA: 400 ± 95 MPa) These findings provide evidence of an imbalanced development of muscle strength and tendon mechanical and morphological properties in adolescent athletes, which may have implications for the risk of tendon overuse injuries

Notch pathway inhibition controls myeloma bone disease in the murine MOPC315.BM model

Abstract: Despite evidence that deregulated Notch signalling is a master regulator of multiple myeloma (MM) pathogenesis, its contribution to myeloma bone disease remains to be resolved. Notch promotes survival of human MM cells and triggers human osteoclast activity in vitro. Here, we show that inhibition of Notch through the γ-secretase inhibitor XII (GSI XII) induces apoptosis of murine MOPC315.BM myeloma cells with high Notch activity. GSI XII impairs murine osteoclast differentiation of receptor activator of NF-κB ligand (RANKL)-stimulated RAW264.7 cells in vitro. In the murine MOPC315.BM myeloma model GSI XII has potent anti-MM activity and reduces osteolytic lesions as evidenced by diminished myeloma-specific monoclonal immunoglobulin (Ig)-A serum levels and quantitative assessment of bone structure changes via high-resolution microcomputed tomography scans. Thus, we suggest that Notch inhibition through GSI XII controls myeloma bone disease mainly by targeting Notch in MM cells and possibly in osteoclasts in their microenvironment. We conclude that Notch inhibition is a valid therapeutic strategy in MM.

Measurement of the number of lumbar spinal movements in the sagittal plane in a 24-hour period

Abstract: Purpose Little is known about the number of spinal movements in the sagittal plane in daily life, mainly due to the lack of adequate techniques to assess these movements. Our aim was to measure these movements in asymptomatic volunteers.

Interaction of Age and Mechanical Stability on Bone Defect Healing: An Early Transcriptional Analysis of Fracture Hematoma in Rat

Abstract: Among other stressors, age and mechanical constraints significantly influence regeneration cascades in bone healing. Here, our aim was to identify genes and, through their functional annotation, related biological processes that are influenced by an interaction between the effects of mechanical fixation stability and age. Therefore, at day three post-osteotomy, chip-based whole-genome gene expression analyses of fracture hematoma tissue were performed for four groups of Sprague-Dawley rats with a 1.5-mm osteotomy gap in the femora with varying age (12 vs. 52 weeks - biologically challenging) and external fixator stiffness (mechanically challenging). From 31099 analysed genes, 1103 genes were differentially expressed between the six possible combinations of the four groups and from those 144 genes were identified as statistically significantly influenced by the interaction between age and fixation stability. Functional annotation of these differentially expressed genes revealed an association with extracellular space, cell migration or vasculature development. The chip-based whole-genome gene expression data was validated by q-RT-PCR at days three and seven post-osteotomy for MMP-9 and MMP-13, members of the mechanosensitive matrix metalloproteinase family and key players in cell migration and angiogenesis. Furthermore, we observed an interaction of age and mechanical stimuli in vitro on cell migration of mesenchymal stromal cells. These cells are a subpopulation of the fracture hematoma and are known to be key players in bone regeneration. In summary, these data correspond to and might explain our previously described biomechanical healing outcome after six weeks in response to fixation stiffness variation. In conclusion, our data highlight the importance of analysing the influence of risk factors of fracture healing (e.g. advanced age, suboptimal fixator stability) in combination rather than alone.

Amino-polyvinyl alcohol coated superparamagnetic iron oxide nanoparticles are suitable for monitoring of human mesenchymal stromal cells in vivo.

Abstract: Mesenchymal stromal cells (MSCs) are promising candidates in regenerative cell-therapies. However, optimizing their number and route of delivery remains a critical issue, which can be addressed by monitoring the MSCs' bio-distribution in vivo using super-paramagnetic iron-oxide nanoparticles (SPIONs). In this study, amino-polyvinyl alcohol coated (A-PVA) SPIONs are introduced for cell-labeling and visualization by magnetic resonance imaging (MRI) of human MSCs. Size and surface charge of A-PVA-SPIONs differ depending on their solvent. Under MSC-labeling conditions, A-PVA-SPIONs have a hydrodynamic diameter of 42 ± 2 nm and a negative Zeta potential of 25 ± 5 mV, which enable efficient internalization by MSCs without the need to use transfection agents. Transmission X-ray microscopy localizes A-PVA-SPIONs in intracellular vesicles and as cytosolic single particles. After identifying non-interfering cell-assays and determining the delivered and cellular dose, in addition to the administered dose, A-PVA-SPIONs are found to be non-toxic to MSCs and non-destructive towards their multi-lineage differentiation potential. Surprisingly, MSC migration is increased. In MRI, A-PVA-SPION-labeled MSCs are successfully visualized in vitro and in vivo. In conclusion, A-PVA-SPIONs have no unfavorable influences on MSCs, although it becomes evident how sensitive their functional behavior is towards SPION-labeling. And A-PVA-SPIONs allow MSC-monitoring in vivo.

Multiscale, Converging Defects of Macro-Porosity, Microstructure and Matrix Mineralization Impact Long Bone Fragility in NF1

Abstract: Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro-porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro-porotic bone lesions.

European musculoskeletal health and mobility in Horizon 2020: Setting priorities for musculoskeletal research and innovation.

Abstract: We have entered the second decade of the new millennium and societies in industrialised countries are facing tremendous challenges from demographic, environmental and lifestyle factors. The European ‘age quake’ has not reached its highest magnitude. This will have an impact on musculoskeletal

Longitudinal change in femorotibial cartilage thickness and subchondral bone plate area in male and female adolescent vs. mature athletes.

Abstract: Summary Little is known about changes in human cartilage thickness and subchondral bone plate area (tAB) during growth. The objective of this study was to explore longitudinal change in femorotibial cartilage thickness and tAB in adolescent athletes, and to compare these data with those of mature former athletes. Twenty young (baseline age 16.0 ± 0.6 years) and 20 mature (46.3 ± 4.7 years) volleyball athletes were studied (10 men and 10 women in each group). Magnetic resonance images were acquired at baseline and at year 2-follow-up, and longitudinal changes in cartilage thickness and tAB were determined quantitatively after segmentation. The yearly increase in total femorotibial cartilage thickness was 0.8% (95% confidence interval [CI]: −0.5; 2.1%) in young men and 1.4% (95% CI: 0.7; 2.2%) in young women; the gain in tAB was 0.4% (95% CI: −0.1; 0.8%) and 0.7% (95% CI: 0.2; 1.2%), respectively (no significant difference between sexes). The cartilage thickness increase was greatest in the medial femur, and was not significantly associated with the variability in tAB growth (r = −0.19). Mature athletes showed smaller gains in tAB, and lost >1% of femorotibial cartilage per annum, with the greatest loss observed in the lateral tibia. In conclusion, we find an increase in cartilage thickness (and some in tAB) in young athletes toward the end of adolescence. This increase appeared somewhat greater in women than men, but the differences between both sexes did not reach statistical significance. Mature (former) athletes displayed high rates of (lateral) femorotibial cartilage loss, potentially due to a high prevalence of knee injuries.

Relationship between nanoscale mineral properties and calcein labeling in mineralizing bone surfaces.

Abstract: Bone's mineral properties, such as particle thickness and degree of alignment have been associated with bone quality. Bone formation, remodeling, aging of the tissue and mineral homeostasis influence mineral particle properties leading to specific patterns across bone. Scanning small angle X-ray scattering (sSAXS) with synchrotron radiation is a powerful tool, which allows us to study bone's nanoscale mineral properties in a position-resolved way. We used sSAXS, fluorescence light microscopy and backscattered electron (BSE) imaging to study bone's mineral properties at the tibial midshaft of in vivo-loaded mice. By combining these techniques, we could detect local changes in mineral properties. Regions labeled with calcein fluorochrome have lower mean mineral thickness and degree of mineral alignment. We also observed thinner and less aligned mineral particles near blood vessels. We conclude that mineral properties (i) are altered by fluorochrome labeling and (ii) depend on the proximity to blood vessels.

A finite element model of in vivo mouse tibial compression loading: influence of boundary conditions

Abstract: Though bone is known to adapt to its mechanical challenges, the relationship between the local mechanical stimuli and the adaptive tissue response seems so far unclear. A major challenge appears to be a proper characterization of the local mechanical stimuli of the bones (e.g. strains). The finite element modeling is a powerful tool to characterize these mechanical stimuli not only on the bone surface but across the tissue. However, generating a predictive finite element model of biological tissue strains (e.g., physiological-like loading) encounters aspects that are inevitably unclear or vague and thus might significantly influence the predicted findings. We aimed at investigating the influence of variations in bone alignment, joint contact surfaces and displacement constraints on the predicted strains in an in vivo mouse tibial compression experiment. We found that the general strain state within the mouse tibia under compressive loading was not affected by these uncertain factors. However, strain magnitudes at various tibial regions were highly influenced by specific modeling assumptions. The displacement constraints to control the joint contact sites appeared to be the most influential factor on the predicted strains in the mouse tibia. Strains could vary up to 150% by modifying the displacement constraints. To a lesser degree, bone misalignment (from 0 to 20°) also resulted in a change of strain (+300 µe = 40%). The definition of joint contact surfaces could lead to up to 6% variation. Our findings demonstrate the relevance of the specific boundary conditions in the in vivo mouse tibia loading experiment for the prediction of local mechanical strain values using finite element modeling.

Bone morphogenetic protein (bmp) variants with highly reduced antagonist sensitivity and enhanced specific biological activity

Abstract: Instant invention refers to peptides having the biological activity of a BMP molecule comprising or consisting of an amino acid sequence having an amino acid identity of at least 50% of SEQ ID No. 1, wherein a first amino acid substitution is at position N59 of SEQ ID No. 1 and a second amino acid substitution is at position N102 of SEQ ID No. 1, nucleic acids encoding for the said peptides, vectors comprising the said nucleic acid, transgenic host cells or organisms, a process for the manufacturing of the peptide of the invention, pharmaceutical compositions, research tools or diagnostic tools and kits comprising the molecules, vectors or cells of the invention, the use of the molecules of the invention for the manufacturing of a research tool or diagnostic tool, or for the prevention, treatment or diagnosis of a BMP-related disease or condition.

A finite element model of in vivo mouse tibial compression loading: influence of boundary conditions udc (531.2+519.6):617.3

Abstract: Though bone is known to adapt to its mechanical challenges, the relationship between the local mechanical stimuli and the adaptive tissue response seems so far unclear. A major challenge appears to be a proper characterization of the local mechanical stimuli of the bones (e.g. strains). The finite element modeling is a powerful tool to characterize these mechanical stimuli not only on the bone surface but across the tissue. However, generating a predictive finite element model of biological tissue strains (e.g., physiological-like loading) encounters aspects that are inevitably unclear or vague and thus might significantly influence the predicted findings. We aimed at investigating the influence of variations in bone alignment, joint contact surfaces and displacement constraints on the predicted strains in an in vivo mouse tibial compression experiment. We found that the general strain state within the mouse tibia under compressive loading was not affected by these uncertain factors. However, strain magnitudes at various tibial regions were highly influenced by specific modeling assumptions. The displacement constraints to control the joint contact sites appeared to be the most influential factor on the predicted strains in the mouse tibia. Strains could vary up to 150% by modifying the displacement constraints. To a lesser degree, bone misalignment (from 0 to 20°) also resulted in a change of strain (+300 µe = 40%). The definition of joint contact surfaces could lead to up to 6% variation. Our findings demonstrate the relevance of the specific boundary conditions in the in vivo mouse tibia loading experiment for the prediction of local mechanical strain values using finite element modeling.