Three-dimensional micro-level computational study of Wolff's law via trabecular bone remodeling in the human proximal femur using design space topology optimization

The law of bone remodeling, commonly referred to as Wolff's Law, asserts that the internal trabecular bone adapts to external loadings, reorienting with the principal stress trajectories to maximize mechanical efficiency creating a naturally optimum structure. The goal of the current study was to utilize an advanced structural optimization algorithm, called design space optimization (DSO), to perform a micro-level three-dimensional finite element bone remodeling simulation on the human proximal femur and analyse the results to determine the validity of Wolff's hypothesis. DSO optimizes the layout of material by iteratively distributing it into the areas of highest loading, while simultaneously changing the design domain to increase computational efficiency. The result is a "fully stressed" structure with minimized compliance and increased stiffness. The large-scale computational simulation utilized a 175 μm mesh resolution and the routine daily loading activities of walking and stair climbing. The resulting anisotropic trabecular architecture was compared to both Wolff's trajectory hypothesis and natural femur samples from literature using a variety of visualization techniques, including radiography and computed tomography (CT). The results qualitatively revealed several anisotropic trabecular regions, that were comparable to the natural human femurs. Quantitatively, the various regional bone volume fractions from the computational results were consistent with quantitative CT analyses. The global strain energy proceeded to become more uniform during optimization; implying increased mechanical efficiency was achieved. The realistic simulated trabecular geometry suggests that the DSO method can accurately predict bone adaptation due to mechanical loading and that the proximal femur is an optimum structure as the Wolff hypothesized.     

Computational simulation of simultaneous cortical and trabecular bone change in human proximal femur during bone remodeling

In this study, we developed a numerical framework that computationally determines simultaneous and interactive structural changes of cortical and trabecular bone types during bone remodeling, and we investigated the structural correlation between the two bone types in human proximal femur. We implemented a surface remodeling technique that performs bone remodeling in the exterior layer of the cortical bone while keeping its interior area unchanged. A micro-finite element (μFE) model was constructed that represents the entire cortical bone and full trabecular architecture in human proximal femur. This study simulated and compared the bone adaptation processes of two different structures: (1) femoral bone that has normal cortical bone shape and (2) perturbed femoral bone that has an artificial bone lump in the inferomedial cortex. Using the proposed numerical method in conjunction with design space optimization, we successfully obtained numerical results that resemble actual human proximal femur. The results revealed that actual cortical bone, as well as the trabecular bone, in human proximal femur has structurally optimal shapes, and it was also shown that a bone abnormality that has little contribution to bone structural integrity tends to disappear. This study also quantitatively determined the structural contribution of each bone: when the trabecular adaptation was complete, the trabecular bone supported 54% of the total load in the human proximal femur while the cortical bone carried 46%.     

Computational simulation of trabecular adaptation progress in human proximal femur during growth

There are a large number of clinical and experimental studies that analyzed trabecular architecture as a result of bone adaptation. However, only a limited amount of quantitative data is currently available on the progress of trabecular adaptation during growth. In this paper, we proposed a two-step numerical simulation method that predicts trabecular adaptation progress during growth using a recently developed topology optimization algorithm, design space optimization (DSO), under the hypothesis that the mechanisms of DSO are functionally equivalent to those of bone adaptation. We applied the proposed scheme to trabecular adaptation simulation in human proximal femur. For the simulation, the full trabecular architecture in human proximal femur was represented by a two-dimensional μFE model with 50 μm resolution. In Step 1, we determined a reference value that regulates trabecular adaptation in human proximal femur. In Step 2, we simulated trabecular adaptation in human proximal femur during growth with the reference value derived in Step 1. We analyzed the architectural and mechanical properties of trabecular patterns through iterations. From the comparison with experimental data in the literature, we showed that in the early growth stage trabecular adaptation was achieved mainly by increasing bone volume fraction (or trabecular thickness), while in the later stage of the development the trabecular architecture gained higher structural efficiency by increasing structural anisotropy with a relatively low level of bone volume fraction (or trabecular thickness). We demonstrated that the proposed numerical framework predicted the growing progress of trabecular bone that has a close correlation with experimental data.     

Functional adaptation of cancellous bone in human proximal femur predicted by trabecular surface remodeling simulation toward uniform stress state

Two-dimensional simulation of trabecular surface remodeling was conducted for a human proximal femur to investigate the structural change of cancellous bone toward a uniform stress state. Considering that a local mechanical stimulus plays an important role in cellular activities in bone remodeling, local stress nonuniformity was assumed to drive trabecular structural change to seek a uniform stress state. A large-scale pixel-based finite element model was used to simulate structural changes of individual trabeculae over the entire bone. As a result, the initial structure of trabeculae changed from isotropic to anisotropic due to trabecular microstructural changes caused by surface remodeling according to the mechanical environment in the proximal femur. Under a single-loading condition, it was shown that the apparent structural property evaluated by fabric ellipses corresponded to the apparent stress state in cancellous bone. As is observed in the actual bone, a distributed trabecular structure was obtained under a multiple-loading condition. Through these studies, it was concluded that trabecular surface remodeling toward a local uniform stress state at the trabecular level could naturally bring about functional adaptation phenomenon at the apparent tissue level. The proposed simulation model would be capable of providing insight into the hierarchical mechanism of trabecular surface remodeling at the microstructural level up to the apparent tissue level.     

Computer simulation of orthodontic tooth movement using CT image-based voxel finite element models with the level set method

Orthodontic tooth movement (OTM) is an adaptive biomechanical response of dentoalveolar components to orthodontic forces, in which remodeling of the alveolar bone occurs in response to changes in the surrounding mechanical environment. In this study, we developed a framework for OTM simulation by combining an image-based voxel finite element method, with a surface-tracking level set method using three-dimensional computer models. For a case study to demonstrate its capability of expressing clinical tooth movement, we observed displacement and rotation of the tooth under three types of force conditions. The simulation results demonstrate that the proposed simulation method has the potential to predict clinical OTM.     

Mathematical analysis of trabecular 'trajectories' in apparent trajectorial structures: the unfortunate historical emphasis on the human proximal femur

Wolff's "law" of the functional adaptation of bone is rooted in the trajectory hypothesis of cancellous bone architecture. Wolff often used the human proximal femur as an example of a trajectorial structure (i.e. arched trabecular patterns appear to be aligned along tension/compression stress trajectories). We examined two tenets of the trajectory hypothesis; namely, that the trabecular tracts from the tension- and compression-loaded sides of a bending environment will: (1) follow 'lines' (trajectories) of tension/compression stress that resemble an arch with its apex on a neutral axis, and (2) form orthogonal (90 degrees ) intersections. These predictions were analysed in proximal femora of chimpanzees and modern humans, and in calcanei of sheep and deer. Compared to complex loading of the human femoral neck, the chimpanzee femoral neck reputedly receives relatively simpler loading (i.e. temporally/spatially more consistent bending), and the artiodactyl calcaneus is even more simply loaded in bending. In order to directly consider Wolff's observations, measurements were also made on two-dimensional, cantilevered beams and curved beams, each with intersecting compression/tension stress trajectories. Results in the calcanei showed: (1) the same nonlinear equation best described the dorsal ("compression") and plantar ("tension") trabecular tracts, (2) these tracts could be exactly superimposed on the corresponding compression/tension stress trajectories of the cantilevered beams, and (3) trabecular tracts typically formed orthogonal intersections. In contrast, trabecular tracts in human and chimpanzee femoral necks were non-orthogonal (mean approximately 70 degrees ), with shapes differing from trabecular tracts in calcanei and stress trajectories in the beams. Although often being described by the same equations, the trajectories in the curved beams had lower r(2) values than calcaneal tracts. These results suggest that the trabecular patterns in the calcanei and stress trajectories in short beams are consistent with basic tenets of the trajectory hypothesis while those in human and chimpanzee femoral necks are not. Compared to calcanei, the more complexly loaded human and chimpanzee femoral necks probably receive more prevalent/predominant shear, which is best accommodated by non-orthogonal, asymmetric trabecular tracts. The asymmetrical trabecular patterns in the proximal femora may also reflect the different developmental 'fields' (trochanteric vs. neck/head) that formed these regions, of which there is no parallel in the calcanei.     

Assessment of the effect of mesh density on the material property discretisation within QCT based FE models: a practical example using the implanted proximal tibia

A three-dimensional, quantitative computed tomography based finite element model of a proximal implanted tibia was analysed in order to assess the effect of mesh density on material property discretisation and the resulting influence on the predicted stress distribution. The mesh was refined on the contact surfaces (matched meshes) with element sizes of 3, 2, 1.4, 1 and 0.8 mm. The same loading conditions were used in all models (bi-condylar load: 60% medial, 40% lateral). Significant variations were observed in the modulus distributions between the coarsest and finest mesh densities. Poor discretisation of the material properties also resulted in poor correlations of the stresses and risk ratios between the coarsest and finest meshes. Little difference in Young's modulus, von Mises stress and risk ratio distributions were observed between the three finest models; hence, it was concluded that for this particular case an element size of 1.4 mm on the contact surfaces was enough to properly describe the stiffness, stress and risk ratio distributions within the bone. Poor convergence of the material property distribution occurred when the element size was significantly larger than the pixel size of the source CT data. It was concluded that unless there is convergence in the Young's modulus distribution, convergence of the stress field or of other parameters of interest will not occur either.     

Effects of obesity on occupant responses in frontal crashes: a simulation analysis using human body models

The objective of this study is to investigate the effects of obesity on occupant responses in frontal crashes using whole-body human finite element (FE) models representing occupants with different obesity levels. In this study, the geometry of THUMS 4 midsize male model was varied using mesh morphing techniques with target geometries defined by statistical models of external body contour and exterior ribcage geometry. Models with different body mass indices (BMIs) were calibrated against cadaver test data under high-speed abdomen loading and frontal crash conditions. A parametric analysis was performed to investigate the effects of BMI on occupant injuries in frontal crashes based on the Taguchi method while controlling for several vehicle design parameters. Simulations of obese occupants predicted significantly higher risks of injuries to the thorax and lower extremities in frontal crashes compared with non-obese occupants, which is consistent with previous field data analyses. These higher injury risks are mainly due to the increased body mass and relatively poor belt fit caused by soft tissues for obese occupants. This study demonstrated the feasibility of using a parametric human FE model to investigate the obesity effects on occupant responses in frontal crashes.     

A mechanistic approach to understanding conjugated linoleic acid's role in inflammation using murine models of rheumatoid arthritis

A naturally occurring fatty acid, conjugated linoleic acid (CLA), reduces immune-induced TNF and inducible cyclooxygenase (COX-2) expression; key mediators of inflammation in rheumatoid arthritis (RA). On the basis of previous work, it was hypothesized that dietary CLA would act as an anti-inflammatory agent in select animal models of RA. In the collagen antibody-induced arthritis (CAIA) model, mice fed CLA (mixed isomers of c9, t11, and t10, c12-CLA) for 3 wk before anticollagen antibody injection had reduced lipopolysaccharide-induced plasma TNF levels and had arthritic scores that were 60% of mice fed corn oil (CO). In the collagen-induced arthritis (CIA) model, mice fed mixed isomers of CLA for 21 days before immunization had lower IgG(1) titers, earlier signs of joint inflammation, but similar arthritis scores compared with CO fed mice during the remaining 70-day post-injection period. Beginning on day 80 to 133, CLA-fed mice had arthritic scores 70% that of the CO-fed mice. In a second CIA experiment, CLA was fed only after the booster injection. Plasma IgG(1) levels were not reduced and arthritis onset was delayed 4 days in CLA-fed mice compared with the CO-fed mice. Peak arthritis score was similar between CLA and CO-fed mice from day 35 to 56. Because CLA reduced inflammation in the CAIA model, delayed onset of arthritis in the CIA model (CIA experiment 2) and reduced arthritis score after day 80 in the CIA model (CIA experiment 1), we concluded that dietary CLA exhibited anti-inflammatory activity that was dependent on antibody.     

Cerebral malaria: the contribution of studies in animal models to our understanding of immunopathogenesis

Cerebral malaria is a serious and often fatal complication of Plasmodium falciparum infections. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances and host immune responses are all thought to be involved. This review outlines the current state of knowledge of cerebral disease in humans, and discusses the contribution of studies of animal models to elucidation of the underlying mechanisms.     

Computer simulation of metal ion equilibria in biofluids. IV. Plutonium speciation in human blood plasma and chelation therapy using polyaminopolycarboxylic acids

An investigation by computer simulation into the nature of Pu(IV) binding to low-molecular ligands in human blood plasma is described. Particular consideration is given to the interactions of various chelating agents which have been or might be used for treating plutonium intoxication. Formation constants of EDTA and DTPA with Cu(II), Mg(II), Mn(II), Zn(II), and Cd(II) have been measured under biologic conditions of temperature and background electrolyte. The relative ability of these and other chelating agents to cause excretion of plutonium and the concomitant loss of certain essential trace metals has thus been assessed.     

Computer simulation of organogenesis: An approach to the analysis of shape changes in epithelial organs

Embryonic development of epithelial organ primordia often involves changes in several parameters, such as cell height, cell width, cell volume, amount of extracellular space, and cell number. Since these changes often occur simultaneously, it becomes difficult to “separate out” the role that each plays in the developmental process. A computer program has been written that allows the shape of epithelial organs to be reproduced based upon measurements of the primordium. A developmental sequence can be simulated by changing the dimensions of the primordium based upon either measurements of the developmental stages or theoretical projections of changes. The primordium is divided into blocks representing groups of cells, based upon characteristics of the different cell groups. The program allows differences in cell height and circular and spiral curvatures of the primordium to be simulated. Analysis of the optic primordium using this method has allowed recognition of several regional changes during optic cup formation. These are sequential constriction of cell apices at the margin of the optic cup, expansion of the apical surface toward the center of the retinal disc, and spreading of the future pigmented layer. Simulation of other organs permits regions of morphogenetic activity to be identified.     

The science of visitor management in parks and protected areas: from verbal reports to simulation models

Visitor management in parks, wilderness and other protected areas requires information about visitor-environment interactions and, particularly, the distribution and flow of visitors in space and time. Such information is usually sketchy and based largely on the verbal reports of visitors. A review of recent psychological and neurological research and theory suggests that traditional verbal survey methods cannot in principle provide an adequate basis for models of human landscape navigation. We argue for more use of direct observation of visitor movements and the utility of travel simulation models. Simulation modelling of visitor flow can be helpful in making monitoring programs more efficient, in fine-tuning existing management programs, and in assessing the likely consequences of alternative future scenarios We review early efforts to simulate the flow of recreation use, describe several current modelling efforts and conclude with suggestions for a research and development effort.     

Application of the biogenetic law to behavioral ontogeny: a test using nest architecture in paper wasps

General principles derived from studies of morphological ontogeny are useful in ethology. Behavioral ontogeny may be interpreted from an holistic view in which a series of behaviors is treated as an ontogeny toward a larger, complex, behavioral product. If the component behaviors are defined broadly, many taxa may be compared to find general principles that are not evident when behaviors are dissected to their smallest recognizable units. Flow charts can illustrate such general ontogenetic sequences in a manner that shows what sorts of modifications have evolved from the general pattern. Certain changes may illustrate forms of ontogenetic evolution that are well known for morphological development, such as addition or embellishment of terminal ontogenetic steps, or compression of ontogeny by acceleration or deletion of early steps. The major modifications in nest construction behavior of 28 genera of paper wasps are presented to test the predictions of the biogenetic rule with respect to character polarity. Cladistic analyses of separate morphological and behavioral data sets show that polarity is accurately inferred with respect to the five major patterns of nest construction in paper wasps.     

Analysis of human abnormal walking using a multi-body model: joint models for abnormal walking and walking aids to reduce compensatory action

This paper proposes new models of diseased joints and evaluates the effectiveness of walking aids such as a cane and a brace for compensating for lost functions due to joint disorders. The ZMJ concept described in the previous work (Yamashita and Tagawa, 1988. In: Radharaman (Ed.), Robotics and Factories of the Future'87. Springer, New York, pp. 670-677) is modified into three joint models as follows: a passive element joint (PEJ) which has a spring at the diseased joint; a constrained range joint (CRJ), the motion of which stays within some constrained relative angle; a partial moment joint (PMJ) which can produce a partial amount of the moment produced about the joint in normal walking. A cane can enlarge a supporting area and adjust the posture of the upper torso to be upright. An ischial weight-bearing brace is effective for conservative management of hip disorders by reducing a load to the joint (Shiba et al., 1998. Clinical Orthopaedics and Related Research 351, 149-157). Walking aids like a cane or brace have been conveniently used by the handicapped. Abnormal walking was simulated for each joint model. Dynamic effects of a cane and a brace on abnormal walking were examined by the multi-body walking model.     

Modeling of the deformation of flexible tubes using a single law: application to veins of the lower limb in man

The topic of this study mainly concerns a representative model of the behavior of flexible ducts such as elastic tubes or veins. This model is based on a phenomenological approach of the inflation and collapse of the tube. It leads to a single "universal" analytical expression of the tube law, valid fir a wide range of' positive and negative transmural pressures, which presents a significant improvement compared to previous theoretical studies defined with different expressions on restricted ranges of pressure. Moreover, the theoretical approaches most often require simplif'ing hypotheses--no longitudinal tension, no surrounding tissues--which are quite unrealistic both in the physiological case and in the experimental setup. These theoretical models can therefore be expected only roughly to describe the actual behavior of such vessels. The representative model, on the contrary, allows one to account for the deformation--inflating as well as collapse--of elastic tubes or veins with better accuracy. The tube law is a function of six parameters chosen in order to fit the experimental data. A comparison between results obtained in our laboratory using silicone tubes and representative models is presented. The model is then applied to physiological data obtained in vivo on human leg veins.     

Identification of staphylococcal enterotoxin B domains involved in binding to cultured human kidney proximal tubular cells: imparting proliferation and death

Studies suggest that staphylococcal enterotoxin B (SEB) is initially harbored in the kidney by binding to digalactosylceramide molecules in the proximal tubular cells. However, little is known in regard to the peptide motif within SEB that binds to these cells and imparts toxic effects. Herein, using human kidney proximal tubular cells (PTs) we have performed a systematic study on the binding of various peptides and peptide analogs of SEB and demonstrate a structure-functional relationship. Using [(125)I]labeled SEB peptides, we show a high affinity and displaceable binding of SEB 191-220 to human PT cells. Binding was mitigated by the use of antibody against SEB, by digalactosylceramide (the putative receptor), and by the use of endoglycoceramidase, which selectively removes the oligosaccharide backbones from glycosphingolipids. Our structure/ functional studies revealed that peptide 130-160 induces a concentration-dependent increase in programmed cell death/ apoptosis in human proximal tubular cells. Mechanistic studies further suggest that SEB/SEB peptide (130-160) impart apoptosis via the activation of neutral sphingomyelinase, which hydrolizes sphingomyelin to ceramide and phosphocholine. SEB 130-160 mediated apoptosis was mitigated by preincubation of cells with antibody against SEB and an SEB 130-160 antibody.