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OBJECTIVE: The use of thiazolidinediones (TZDs) as insulin sensitizers has been shown to have side effects including increased accumulation of bone marrow adipocytes (BMAds) associated with a higher fracture risk and bone loss. A novel TZD analog MSDC-0602K with low affinity to PPARγ has been developed to reduce adverse effects of TZD therapy. However, the effect of MSDC-0602K on bone phenotype and bone marrow mesenchymal stem cells (BM-MSCs) in relation to obesity has not been intensively studied yet. METHODS: Here, we investigated whether 8-week treatment with MSDC-0602K has a less detrimental effect on bone loss and BM-MSC properties in obese mice in comparison to first generation of TZDs, pioglitazone. Bone parameters (bone microstructure, bone marrow adiposity, bone strength) were examined by μCT and 3-point bending test. Primary BM-MSCs were isolated and measured for osteoblast and adipocyte differentiation. Cellular senescence, bioenergetic profiling, nutrient consumption and insulin signaling were also determined. RESULTS: The findings demonstrate that MSDC-0602K improved bone parameters along with increased proportion of smaller BMAds in tibia of obese mice when compared to pioglitazone. Further, primary BM-MSCs isolated from treated mice and human BM-MSCs revealed decreased adipocyte and higher osteoblast differentiation accompanied with less inflammatory and senescent phenotype induced by MSDC-0602K vs. pioglitazone. These changes were further reflected by increased glycolytic activity differently affecting glutamine and glucose cellular metabolism in MSDC-0602K-treated cells compared to pioglitazone, associated with higher osteogenesis. CONCLUSION: Our study provides novel insights into the action of MSDC-0602K in obese mice, characterized by the absence of detrimental effects on bone quality and BM-MSC metabolism when compared to classical TZDs and thus suggesting a potential therapeutical use of MSDC-0602K in both metabolic and bone diseases. ispartof: Molecular Metabolism vol:65 ispartof: location:Germany status: published

The thumb has played a key role in primate evolution due to its involvement in grasping and manipulation. A large component of this wide functionality is by virtue of the uniquely shaped trapeziometacarpal (TMC) joint. This TMC joint allows for a broad range of functional positions, but how its bone structure is adapted to withstand such a large variety of loading regimes is poorly understood. Here, we outline a novel, integrated finite element - micro finite element (FE-µFE) workflow to analyse strain distributions across the internal bony architecture. We have applied this modelling approach to study functional adaptation in the bonobo thumb. More specifically, the approach allows us to evaluate how strain is distributed through the trapezium upon loading of its distal articular facet. As loading conditions, we use pressure distributions for different types of grasping that were estimated in a previous study. Model evaluation shows that the simulated strain values fall within realistic boundaries of the mechanical response of bone. The results show that the strain distributions between the simulated grasps are highly similar, with dissipation towards the proximo-ulnar cluster of trabeculae regardless of trapezial bone architecture. This study presents an innovative FE-µFE approach to simulating strain distributions, and yields insight in the functional adaptation of the TMC joint in bonobos.

A series of N -{ para -(ferrocenyl) ethynyl benzoyl} amino acid and dipeptide methyl and ethyl esters 4–18 were prepared by coupling para -(ferrocenyl) ethynyl benzoic acid 3 to the amino acids GABA(OMe), GABA(OEt) and the dipeptide esters GlyGly(OMe), GlyGly(OEt), Gly-L-Ala(OMe), Gly-L-Ala(OEt), Gly-D-Ala(OMe), Gly-D-Ala(OEt), Gly-L-Leu(OEt), Gly-L-Phe(OEt), SarGly(OMe), SarGly(OEt), Sar-L-Ala(OEt), L-ProGly(OEt) and L-Pro-L-Ala(OEt) using the standard N -(3-dimethylaminopropyl)- N’ -ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. All the compounds were fully characterized using a combination of I.R., UV-Vis, 1 H NMR, 13 C NMR, DEPT-135, 1 H- 13 C COSY (HMQC) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Selected compounds 5 , 7 , 9, 11, 16, 17 and 18 showed micromolar activity in the H1299 NSCLC cell line, with IC 50 values in the range of 3.8–8.3 μM.

Articular cartilage covers the temporomandibular joint (TMJ) and provides smooth and nearly frictionless articulation while distributing mechanical loads to the subchondral bone. The thickness of the cartilage is considered to be an indicator of the stage of development, maturation, aging, loading history, and disease. The aim of our study was to develop a method for ex vivo assessment of the thickness of the cartilage that covers the TMJ and to compare that with two other existing methods. Eight porcine TMJ condyles were used to measure cartilage thickness. Three different methods were employed: needle penetration, micro-computed tomography (micro-CT), and histology; the latter was considered the gold standard. Histology and micro-CT scanning results showed no significant differences between thicknesses throughout the condyle. Needle penetration produced significantly higher values than histology, in the lateral and anterior regions. All three methods showed the anterior region to be thinner than the other regions. We concluded that overestimated thickness by the needle penetration is caused by the penetration of the needle through the first layer of subchondral bone, in which mineralization is less than in deeper layers. Micro-CT scanning method was found to be a valid method to quantify the thickness of the cartilage, and has the advantage of being non-destructive.

1-Alkyl-1′- N - meta -(ferrocenyl) benzoyl dipeptide esters 7–18 and 1-alkyl-1′- N - ortho -(ferrocenyl) benzoyl dipeptide esters 19–30 were prepared by coupling the alkyl ferrocenyl benzoic acids 1–6 to the dipeptide ethyl esters Gly-Gly(OEt), Gly-L-Ala(OEt), Gly-L-Leu(OEt) and Gly-L-Phe(OEt) using the standard N -(3-dimethylaminopropyl)- N' -ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. The alkyl groups employed in the synthesis were methyl, ethyl and propyl. The compounds were characterized using a combination of 1 H NMR, 13 C NMR, DEPT-135 and 1 H- 13 C COSY (HMQC) spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Selected compounds showed micromolar activity in the H1299 NSCLC cell line, with IC 50 values in the range of 2.6–20.1 μM.

The aim of this study was to quantify the effects of understuffing and overstuffing UKA on bone stresses, load distribution and ligament strains. For that purpose, a numerical knee model of a cadaveric knee was developed and was validated against experimental measurements on that same knee. Good agreement was found among the numerical and experimental results. This study showed that, even if a medial UKA is well-aligned with normal soft tissue tension and with correct thickness of the tibia component, it induces a stiffness modification in the joint that alters the load distribution between the medial and lateral compartments, the bone stress and the ligament strain potentially leading to an osteoarthritic progression. publisher: Elsevier articletitle: Load Sharing and Ligament Strains in Balanced, Overstuffed and Understuffed UKA. A Validated Finite Element Analysis journaltitle: The Journal of Arthroplasty articlelink: http://dx.doi.org/10.1016/j.arth.2014.01.020 content_type: article copyright: Copyright © 2014 Elsevier Inc. All rights reserved. ispartof: Journal of Arthroplasty vol:29 issue:7 pages:1491-8 ispartof: location:United States status: published

1-Alkyl-1′- N - para -(ferrocenyl) benzoyl dipeptide esters 4 – 12 were prepared by coupling the alkyl ferrocenyl benzoic acids 1 – 3 to the dipeptide ethyl esters Gly- L -Ala(OEt), Gly- L -Leu(OEt) and Gly- L -Phe(OEt) using the standard N -(3-dimethylaminopropyl)- N’ -ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. All the compounds were fully characterized using a combination of 1 H NMR, 13 C NMR, DEPT-135 and 1 H– 13 C COSY (HMQC) spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and cyclic voltammetry (CV). Selected compounds showed micromolar activity in the H1299 NSCLC cell line, with IC 50 values in the range of 4.5–6.6 μM.

Reliable computer models are needed for a better understanding of the physical mechanisms of skull fracture in accidental hits, falls, bicycle - motor vehicle & car accidents and assaults. The performance and biofidelity of these models depend on the correct anatomical representation and material description of these structures. In literature, a strain energy criterion has been proposed to predict skull fractures. However, a broad range of values for this criterion has been reported. This study investigates if the impactor orientation, scalp thickness and material model of the skull could provide us with insight in the influencing factors of this criterion. 18 skull fracture experiments previously performed in our research group were reproduced in finite element simulations. Subject-specific skull geometries were derived from medical images and used to create high-quality finite element meshes. Based on local Hounsfield units, a subject-specific isotropic material model was assigned. The subject-specific models were able to predict fractures who matched visually with the corresponding experimental fracture patterns and provided detailed fracture patterns. The sensitivity study showed that small variations in impactor positioning as well as variations of the local geometry (frontal-temporal-occipital) strongly influenced the skull strain energy. Subject-specific modelling leads to a more accurate prediction of the force-displacement curve. The average error of the peak fracture force for all the 18 cases is 0.4190 for the subject-specific and 0.4538 for the homogeneous material model, for the displacement; 0.3368 versus 0.3844. But it should be carefully interpreted as small variations in the computational model significantly influence the outcome. ispartof: JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS vol:100 ispartof: location:Netherlands status: published

N -{6-(Ferrocenyl) ethynyl-2-naphthoyl} amino acid and dipeptide ethyl esters 2 – 8 were prepared by coupling 6-(ferrocenyl) ethynyl-2-naphthoic acid 1 to the amino acid ethyl ester GABA(OEt) and the dipeptide ethyl esters GlyGly(OEt), GlyAla(OEt), SarGly(OEt), SarAla(OEt), ProGly(OEt) and ProAla(OEt) using the standard N -(3-dimethylaminopropyl)- N ′-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. All the compounds were fully characterized using a combination of 1 H NMR, 13 C NMR, DEPT-135 and 1 H– 13 C COSY (HMQC) spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and cyclic voltammetry (CV). Compounds, 2 – 8 showed micromolar activity in the H1299 NSCLC cell line, with IC 50 values in the range of 3.2–7.2 μM.

High-resolution in vivo bone micro-architecture assessment, as possible now for the distal forearm, in combination with bone remodelling simulation algorithms could, eventually, predict patient-specific bone morphology changes. To simulate load-adaptive bone remodelling, however, physiological loading conditions must be defined. In this paper we test a previously developed algorithm to estimate such physiological loading conditions from the bone micro-architecture. The aims of this study were to investigate if realistic boundary forces and moments are predicted for the scanned distal radius section and how these predicted forces and moments should be distributed to the scanned section in order to obtain a load transfer similar to that in situ. Images at in vivo resolution were generated for the clinically measured section of nine distal radius cadaver bones, converted to micro-finite element models and used for load estimation. Models of the full distal radius were created to analyse tissue loading distributions of the sections in situ. It was found that predicted forces and moments at the boundaries of the scanned region varied considerably but, when translated to equivalent radiocarpal joint forces, agreed well with values reported in the literature. Bone tissue loading distribution was in best agreement with in situ distributions when loading was applied to an extra layer of material at both ends of the clinical scan region. The agreement of the predicted loading to previous studies and the wide range of predicted loading values indicate that subject-specific bone loading estimation is possible and necessary.

Small endosseous implants, such as screws, are important components of modern orthopedics and dentistry. Hence they have to reliably fulfill a variety of requirements, which makes the development of such implants challenging. Finite element analysis is a widely used computational tool used to analyze and optimize implant stability in bone. For these purposes, bone is generally modeled as a continuum material. However, bone failure and bone adaptation processes are occurring at the discrete level of individual trabeculae; hence the assessment of stresses and strains at this level is relevant. Therefore, the aim of the present study was to investigate how peri-implant strain distribution and load transfer between implant and bone are affected by the continuum assumption. We performed a computational study in which cancellous screws were inserted in continuum and discrete models of trabecular bone; axial loading was simulated. We found strong differences in bone-implant stiffness between the discrete and continuum bone model. They depended on bone density and applied boundary conditions. Furthermore, load transfer from the screw to the surrounding bone differed strongly between the continuum and discrete models, especially for low-density bone. Based on our findings we conclude that continuum bone models are of limited use for finite element analysis of peri-implant mechanical loading in trabecular bone when a precise quantification of peri-implant stresses and strains is required. Therefore, for the assessment and improvement of trabecular bone implants, finite element models which accurately represent trabecular microarchitecture should be used.

Elastic modulus and strength of trabecular bone are negatively affected by osteoporosis and other metabolic bone diseases. Micro-computed tomography-based beam models have been presented as a fast and accurate way to determine bone competence. However, these models are not accurate for trabecular bone specimens with a high number of plate-like trabeculae. Therefore, the aim of this study was to improve this promising methodology by representing plate-like trabeculae in a way that better reflects their mechanical behavior. Using an optimized skeletonization and meshing algorithm, voxel-based models of trabecular bone samples were simplified into a complex structure of rods and plates. Rod-like and plate-like trabeculae were modeled as beam and shell elements, respectively, using local histomorphometric characteristics. To validate our model, apparent elastic modulus was determined from simulated uniaxial elastic compression of 257 cubic samples of trabecular bone (4mm×4mm×4mm; 30μm voxel size; BIOMED I project) in three orthogonal directions using the beam-shell models and using large-scale voxel models that served as the gold standard. Excellent agreement (R(2)=0.97) was found between the two, with an average CPU-time reduction factor of 49 for the beam-shell models. In contrast to earlier skeleton-based beam models, the novel beam-shell models predicted elastic modulus values equally well for structures from different skeletal sites. It allows performing detailed parametric analyses that cover the entire spectrum of trabecular bone microstructures.

Stem cell-mediated gene therapy for fracture repair, utilizes genetically engineered mesenchymal stem cells (MSCs) for the induction of bone growth and is considered a promising approach in skeletal tissue regeneration. Previous studies have shown that murine nonunion fractures can be repaired by implanting MSCs over-expressing recombinant human bone morphogenetic protein-2 (rhBMP-2). Nanoindentation studies of bone tissue induced by MSCs in a radius fracture site indicated similar elastic modulus compared to intact murine bone, eight weeks post treatment. In the present study we sought to investigate temporal changes in microarchitecture and biomechanical properties of repaired murine radius bones, following the implantation of MSCs. High resolution micro computed tomography (Micro-CT) was performed 10 and 35 weeks post MSC implantation, followed by micro finite element (Micro-FE) analysis. The results have shown that the regenerated bone tissue remodels over time, as indicated by a significant decrease in bone volume, total volume and connectivity density combined with an increase in mineral density. In addition, the axial stiffness of limbs repaired with MSCs was 2 to 1.5 times higher compared to the contralateral intact limbs, at 10 and 35 weeks post treatment. These results could be attributed to the fusion that occurred between in the ulna and radius bones. In conclusion, although MSCs induce bone formation, which exceeds the fracture site, significant remodeling of the repair callus occurs over time. In addition, limbs treated with an MSC graft demonstrated superior biomechanical properties, which could indicate the clinical benefit of future MSC application in nonunion fracture repair.

An accurate prediction of bone strength in the human radius is of major interest because distal radius fractures are amongst the most common in humans. The objective of this study was to determine gender and age-related changes in bone morphometry at the radius and how these relate to bone strength. Specifically, our aims were to (i) analyze gender differences to get an insight into different bone quantities and qualities between women and men, (ii) to determine which microarchitectural bone parameters would best correlate with strength, (iii) to find the region of interest for the best assessment of bone strength, and (iv) to determine how loss of bone quality depends on age. Intact right forearms of 164 formalin-fixed cadavers from a high-risk elderly population were imaged with a new generation high-resolution pQCT scanner (HR-pQCT). Morphometric indices were derived for six different regions and were related to failure load as assessed by experimental uniaxial compression testing. Significant gender differences in bone quantity and quality were found that correlated well with measured failure load. The most relevant region to determine failure load based on morphometric indices assessed in this study was located just below the proximal end of the subchondral plate; this region differed from the one measured clinically today. Trends in bone changes with increasing age were found, even though for all morphometric indices the variation between subjects was large in comparison to the observed age-related changes. We conclude that HR-pQCT systems can determine how gender and age-related changes in morphometric parameters relate to bone strength, and that HR-pQCT is a promising tool for the assessment of bone quality in patient populations.

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength. Bone strength depends, among others, on bone density, bone geometry and its internal architecture. With the recent introduction of a new generation high-resolution 3D peripheral quantitative computed tomography (HR-pQCT) system, direct quantification of structural bone parameters has become feasible. Furthermore, it has recently been demonstrated that bone mechanical competence can be derived from HR-pQCT based micro-finite element modeling (microFE). However, reproducibility data for HR-pQCT-derived mechanical indices is not well-known. Therefore, the aim of this study was to quantify reproducibility of HR-pQCT-derived indices. We measured 14 distal formalin-fixed cadaveric forearms three times and analyzed three different regions for each measurement. For each region cortical and trabecular parameters were determined. Reproducibility was assessed with respect to precision error (PE) and intraclass correlation coefficient (ICC). Reproducibility values were found to be best in all three regions for the full bone compartment with an average PE of 0.79%, followed by the cortical compartment (PE=1.19%) and the trabecular compartment with an average PE of 2.31%. The mechanical parameters showed similar reproducibility (PE=0.48%-2.93% for bone strength and stiffness, respectively). ICC showed a very high reproducibility of subject-specific measurements, ranging from 0.982 to 1.000, allowing secure identification of individual donors ranging from healthy to severely osteoporotic subjects. From these in vitro results we conclude that HR-pQCT derived morphometric and mechanical parameters are highly reproducible such that differences in bone structure and strength can be detected with a reproducibility error smaller than 3%; hence, the technique has a high potential to become a tool for detecting bone quality and bone competence of individual subjects.

Current practice to determine bone tissue modulus of murine cortical bone is to estimate it from three-point bending tests, using Euler-Bernoulli beam theory. However, murine femora are not perfect beams; hence, results can be inaccurate. Our aim was to assess the accuracy of beam theory, which we tested for two commonly used inbred strains of mice, C57BL/6 (B6) and C3H/He (C3H). We measured the three-dimensional structure of male and female B6 and C3H femora (N=20/group) by means of micro-computed tomography. For each femur five micro-finite element (micro-FE) models were created that simulated three-point bending tests with varying distances between the supports. Tissue modulus was calculated from beam theory using micro-FE results. The accuracy of beam theory was assessed by comparing the beam theory-derived moduli with the modulus as used in the micro-FE analyses. An additional set of fresh-frozen femora (10 B6 and 12 C3H) was biomechanically tested and subjected to the same micro-FE analyses. These combined experimental-computational analyses enabled an unbiased assessment of specimen-specific tissue modulus. We found that by using beam theory, tissue modulus was underestimated for all femora. Femoral geometry and size had strong effects on beam theory-derived tissue moduli. Owing to their relatively thin cortex, underestimation was markedly higher for B6 than for C3H. Underestimation was dependent on support width in a strain-specific manner. From our combined experimental-computational approach we calculated tissue moduli of 12.0+/-1.3 GPa and 13.4+/-2.1 GPa for B6 and C3H, respectively. We conclude that tissue moduli in murine femora are strongly underestimated when calculated from beam theory. Using image-based micro-FE analyses we could precisely quantify this underestimation. We showed that previously reported murine inbred strain-specific differences in tissue modulus are largely an effect of geometric differences, not accounted for by beam theory. We suggest a re-evaluation of the tissue properties obtained from three-point bending tests, especially in mouse genetics.

Scaffolds, also called bioscaffolds, are needed in all tissue engineering applications as carriers for cells and biochemical factors, as constructs providing appropriate mechanical conditions, or as a combination of the two. The aim of this paper is to present recent developments in micro-computed tomography (microCT) analyses of scaffolds. The focus will be on imaging and quantification aspects in bone research, and will deal with the assessment of scaffold architecture and how it interacts with bone tissue. We show that micro-architectural imaging is a nondestructive and noninvasive procedure that allows a precise three-dimensional (3D) measurement of scaffold architecture. Direct microCT-based image analysis allows to accurately quantify scaffold porosity, surface area, and 3D measures such as pore size, pore distribution, and strut thickness; furthermore, it allows for a precise measurement of bone growth into the scaffold and onto its surface. This methodology is useful for quality control of scaffold fabrication processes, to assess scaffold degradation kinetics, and to assess bone tissue response. Even more so, in combination with bioreactors or in vivo animal models, microCT allows to qualitatively and quantitatively assess the spatial and temporal mineralization of bone tissue formation in scaffolds; such longitudinal studies improve the assessment of bone response due to scaffold architecture. Computational models will be helpful in further analyses of these data in order to improve our understanding of mechanical and biochemical stimuli on bone formation, and are likely to provide valuable knowledge to optimize scaffold design.

1,3-bisphenyl-4-methyl-pyrazolo[3,4-b]quinoline (PAQ4) has been found to be an excellent blue emitter in the solid state. High solid state photoluminescent quantum efficiencies have been found when doped in a number of polymer matrices, such as polycarbonate, polystyrene, poly (methyl methacrylate). Photoluminescence and electroluminescence of PAQ4-doped poly (N-vinyl carbazole) were also investigated. Dopant–dopant interaction between PAQ4 molecules was found to favour the production of high fluorescence at high dopant concentrations, which also contributed to a red shift and peak broadening in the emission peaks. Thin- and single-layered electroluminescent devices were also prepared using PAQ4-doped PVK as an emitting layer. Self-absorption was also observed in the devices, which modified emission spectra. It formed a useful tool to monitor the devices. Electroluminescence from the device was shifted slightly to the blue when compared to its photoluminescence. It suggests that the exciton recombination is located close to the polymer–ITO interface in the devices studied.

Finite element analysis ( FEA ) is the method of choice to nondestructively quantify stresses and strains in bones. Moderate to good estimates of bone strength can be obtained from continuum-level FEA. Improved predictive capacity is expected from microstructural FE models that represent the trabecular architecture in detail. With the advent of recently developed high-resolution in vivo bone imaging systems and the steady increase in computational power, such microstructural FE analyses are now becoming available to estimate bone strength in humans in a clinical setting. The procedure can help improve predictions of fracture risk, clarify the pathophysiology of skeletal diseases, and monitor the response to therapy.

Because porosity can affect a wide range of performance attributes in vessels, its measurement has become an important component of ceramic technological studies. To measure ceramic porosity, archaeologists have borrowed well-established methods from the material sciences. However, these methods can have drawbacks for archaeological applications including the potential to damage archaeological residues contained within the sherd, the need for expensive equipment, and/or the use of hazardous materials. In this paper we introduce a new, non-destructive method for measuring porosity based on the infusion of liquid nitrogen into the sherd. A comparison of results obtained from this method with those obtained from other approaches indicates that the technique produces reliable results.