An elemental correlation study in cancerous breast tissue by total reflection x-ray fluorescence

The total reflection x-ray fluorescence method (TRXRF) has been employed to determine of P, S, K, Ca, Cr, Mn, Fe, Ni, Cu, Zn, Se, Rb, Sr, and Pb concentration in the benign breast tumor tissue from 68 women and in the cancerous breast tissue from 26 women. Concentrations of most of elements show enhancement in cancerous breast tissue. Examined elements compete for binding sites in the cell, change its enzymatic activity, and exert direct or indirect action on the carcinogenic process accelerating the growth of rumors. Inhibition of enzymatic activity caused by variation in trace element concentrations results in immunological breakdown of the body system. An attempt has been made to correlate measured trace element concentrations with the clinical stage of cancer. Physical bases of used analytical method, experimental setup, and the procedure of sample preparation are described.     

An augmented Lagrangian finite element formulation for 3D contact of biphasic tissues

Biphasic contact analysis is essential to obtain a complete understanding of soft tissue biomechanics, and the importance of physiological structure on the joint biomechanics has long been recognised; however, up to date, there are no successful developments of biphasic finite element contact analysis for three-dimensional (3D) geometries of physiological joints. The aim of this study was to develop a finite element formulation for biphasic contact of 3D physiological joints. The augmented Lagrangian method was used to enforce the continuity of contact traction and fluid pressure across the contact interface. The biphasic contact method was implemented in the commercial software COMSOL Multiphysics 4.2^® (COMSOL, Inc., Burlington, MA). The accuracy of the implementation was verified using 3D biphasic contact problems, including indentation with a flat-ended indenter and contact of glenohumeral cartilage layers. The ability of the method to model multibody biphasic contact of physiological joints was proved by a 3D knee model. The 3D biphasic finite element contact method developed in this study can be used to study the biphasic behaviours of the physiological joints.     

Increase in the calcium content of cardiac tissue after postfixation with osmium tetroxide

The concentration of osmium has been measured by destructive chemical analysis in glutaraldehyde fixed heart tissue postfixed with osmium tetroxide and embedded in epoxy resin. After such treatment, the mean atomic number of the specimen (Z) is close to 10, which permits a quantitative analysis of calcium (Ca) by the continuum method, using Z2/A as a correcting factor (A: atomic weight). Wavelength-dispersive X-ray microanalysis has been used to determine the Ca concentration of frog cardiac tissue fixed in glutaraldehyde and embedded in resin. These measurements have been repeated on tissue postfixed in osmium tetroxide; contrary to expectations, the apparent Ca concentration is much higher in osmium treated than in nontreated tissue. However, this result is observed with OsO4 solutions prepared in glass, not with solutions prepared in plastic. It is shown by energy dispersive X-ray analysis of droplets that OsO4 solutions prepared in glass contain large amounts of calcium, potassium and silicon. Care must be taken in preparing OsO4 fixatives when the fixed tissues are to be subjected to X-ray microanalysis of such elements as Ca or Si.     

Elemental composition changes between breast tissue with and without silicone gel sheeting and hypertrophic scar tissue

Hypertrophic scars occur after dermal trauma and are characterized by being elevated above normal skin level as a result of an abundance of collagen. The application of silicone gel sheeting (SGS) has been found to be an effective method of treatment, causing them to regress much quicker than they would do naturally. Normal skin and hypertrophic scar tissue were characterized using proton-induced X-ray emission (PIXE). Skin tissue that had been covered in SGS was also analyzed. For each element and sample type, the concentrations in the epidermis were plotted against the dermis. By considering the concentrations of breast tissue with and without SGS, it could be seen if the SGS changed the compositional structure of the skin. It was found that for the elements P, S, Cl, and K the SGS has no effect on the structure of the skin, as both breast types (with and without SGS) have regression lines that overlap. However, this work shows that there are significant differences for P in the dermis and Cl in the epidermis between the breast tissue with SGS and its control. Therefore, this work shows that the effect the SGS has on concentration occurs similarly for both the epidermis and dermis.     

Finite element method (FEM), mechanobiology and biomimetic scaffolds in bone tissue engineering

Techniques of bone reconstructive surgery are largely based on conventional, non-cell-based therapies that rely on the use of durable materials from outside the patient's body. In contrast to conventional materials, bone tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences towards the development of biological substitutes that restore, maintain, or improve bone tissue function. Bone tissue engineering has led to great expectations for clinical surgery or various diseases that cannot be solved with traditional devices. For example, critical-sized defects in bone, whether induced by primary tumor resection, trauma, or selective surgery have in many cases presented insurmountable challenges to the current gold standard treatment for bone repair. The primary purpose of bone tissue engineering is to apply engineering principles to incite and promote the natural healing process of bone which does not occur in critical-sized defects. The total market for bone tissue regeneration and repair was valued at $1.1 billion in 2007 and is projected to increase to nearly $1.6 billion by 2014.Usually, temporary biomimetic scaffolds are utilized for accommodating cell growth and bone tissue genesis. The scaffold has to promote biological processes such as the production of extra-cellular matrix and vascularisation, furthermore the scaffold has to withstand the mechanical loads acting on it and to transfer them to the natural tissues located in the vicinity. The design of a scaffold for the guided regeneration of a bony tissue requires a multidisciplinary approach. Finite element method and mechanobiology can be used in an integrated approach to find the optimal parameters governing bone scaffold performance.In this paper, a review of the studies that through a combined use of finite element method and mechano-regulation algorithms described the possible patterns of tissue differentiation in biomimetic scaffolds for bone tissue engineering is given. Firstly, the generalities of the finite element method of structural analysis are outlined; second, the issues related to the generation of a finite element model of a given anatomical site or of a bone scaffold are discussed; thirdly, the principles on which mechanobiology is based, the principal theories as well as the main applications of mechano-regulation models in bone tissue engineering are described; finally, the limitations of the mechanobiological models and the future perspectives are indicated.     

A numerical approach to the biomechanical analysis of bone fracture healing

Investigations are reported in the literature, by means of experimental, analytical and numerical methods, concerning the biomechanical properties of bone. However, the evolutionary phenomena of bone fracture healing does not have a large reference literature. This work investigates and describes the behaviour of inclined human femur fractures with external fixation up to complete healing. A numerical formulation based on the finite element method has been adopted. Geometric configuration is defined using data from a magnetic resonance process applied to a femur in vivo. A three dimensional model has been developed by adopting an orthotropic material law for cortical bone and an isotropic law for the fracture gap zone. Stress and strain reponses of the bone and fixation device are investigated with reference to the evolutionary behaviour of the healing tissue.     

Modelling heat transfer in a bone-cement-prosthesis system

The heat transfer in a general bone-cement-prosthesis system was modelled. A quantitative understanding of the heat transfer and the polymerization kinetics in the system is necessary because injury of the bone tissue and the mechanical properties of the cement have been suggested to be effected by the thermal and chemical history of the system. The mathematical model of the heat transfer was based on first principles from polymerization kinetics and heat transfer, rather than certain in vitro observed properties, which has been the common approach. Our model was valid for general three-dimensional geometries and an arbitrary bone cement consisting of an initiator and monomer. The model was simulated for a cross-section of a hip with a potential femoral stem prosthesis and for a cement similar to Palacos R. The simulations were conducted by using the finite element method. These simulations showed that this general model described an auto accelerating heat production and a residual monomer concentration, which are two phenomena suggested to cause bone tissue damage and effect the mechanical properties of the cement.     

A modified lap test to more accurately estimate interfacial shear strength for bonded tissues

Effective attachment to relevant anatomical surfaces has long been a critical issue for tissue replacement or repair. This is especially true for cartilage repair where adequate, reliable initial fixation to surrounding tissue and joint surfaces has been a dominant factor affecting clinical outcomes. Due to ease of application and ability to replicate dimensions and rates across multiple experiments, the single-lap test in tension has become a common method to assess interfacial strength for cartilage and other tissues in apposition. The standard single-lap configuration does not, however, provide a true measure of shear strength. The presence of a bending moment and resulting bond rotation create an uneven stress environment; specimens typically fail due to peel stresses at the edges of the interface. This report describes finite element analysis of variations to the single-lap method in which supports were added to either side of the bond interface. These results were then experimentally validated using photochemically bonded articular cartilage. Both the finite element and experimental results show that the addition of supports helps mitigate edge stresses and produces a more uniform stress distribution across the bond interface. Adding supports to prevent bond rotation, even for specimens not fixed to the supports, still produces a better estimate of shear strength than the traditional, non-supported configuration. These findings allow selection of a single-lap approach to more closely approximate shear strength even in those situations where it is not feasible or otherwise desirable to fix the tissue specimens to supports.     

Steady-state analysis of self-heated thermistors using finite elements

The purpose of this work is to validate, using numerical, finite element methods, the thermal assumptions made in the analytical analysis of a coupled thermistor probe-tissue model upon which a thermal conductivity measurement scheme has been based. Analytic, closed form temperature profiles generated by the self-heated thermistors can be found if three simplifying assumptions are made: the thermistor is spherical; heat is generated in all regions of the bead; and heat is generated uniformly in the bead. This analytic solution is used to derive a linear relationship between tissue thermal conductivity and the ratio of thermistor temperature rise over electrical power required to maintain that temperature rise. This derived, linear relationship is used to determine thermal conductivity from the observed experimental data. However, in reality, the thermistor bead is a prolate spheroid surrounded by a passive shell, and the heating pattern in the bead is highly nonuniform. In the physical system, the exact relationship between the tissue thermal conductivity and parameters measured by the thermistor is not known. The finite element method was used to calculate the steady-state temperature profiles generated by thermistor beads with realistic geometry and heating patterns. The results of the finite element analysis show that the empirical, linear relationship remains valid when all three simplified assumptions are significantly relaxed.     

Human males and females body thermoregulation: Perfusion effect analysis

Skin temperature is a common physiological parameter that reflects thermal responses. Blood perfusion is an important part of the physiological processes that the human body undergoes in order to maintain homeostasis. This study focuses on the effect of perfusion on the temperature distribution in human males and females body in different thermal environment. The study has been carried out for one dimensional steady cases using finite element method. The input parameter of the model is the blood perfusion or volumetric flow rate within the tissue. The appropriate physical and physiological parameters together with suitable boundary conditions that affect the heat regulations have been incorporated in the model. The study is to have a better understanding that how does thermoregulation change in human males and females skin layered due to perfusion.     

Finite element simulation of skeletal muscular structures obtained from images of histological serial sections

In this study, we present a method for the three-dimensional reconstruction of objects obtained from histological serial sections (exemplified by those of a pennate striated skeletal muscle) and its application to the finite element method. A hyperelastic material model is used for modeling biological soft tissue. The reconstruction process relies on the direct construction of a volumetric mesh using an octree approach which leads to a stable finite element method. Stability can be expressed in the spectral matrix condition number. To visualize stress patterns within the underlying anatomy the simulation results are projected onto images of the histological scenario.     

A stress compatible finite element for implant/cement interface analyses

A new finite element has been developed to enforce normal and shear stress continuity at bimaterial interface points in order to alleviate the problem of high stress discontinuity predictions by the conventional displacement finite element method. The proposed element is based on a five node isoparametric quadrilateral element where the fifth node is located at the interface boundary of the element. A series of validation tests have been carried out to assess the correctness of the stress distribution obtained by the new element at interfaces of highly dissimilar materials. The results of the tests are compared to analytical solutions and to results from convergence studies performed by the conventional finite element method (SAP-IV). Overall, the proposed element has been demonstrated to have a very satisfactory degree of reliability, especially in view of the observed inability of the conventional method to yield interpretable interface stress values for most cases analyzed. Finally, the new interface element has been applied to the analysis of an axisymmetric model of the knee tibial implant. The superiority of the proposed element over the conventional one has been demonstrated in this case by a convergence study.     

Static indentation of anisotropic biomaterials using axially asymmetric indenters--a computational study

Indentation has historically been used by biomechanicians to extract the small strain elastic or viscoelastic properties of biological tissues. Because of the axisymmetry of indenters used in these studies however, analysis of the results requires the assumption of material isotropy and often yields an "effective" elastic modulus. Since most biological tissues such as bone and myocardium are known to be anisotropic, the use of conventional indentation techniques for estimating material properties is therefore limited. The feasibility of using an axially asymmetric indenter to determine material directions and in-plane material properties for anisotropic tissue is explored here using finite element analysis. The load versus displacement curves as would be measured by an indenter depend on the orientation of the indenter cross section relative to the in-plane material axes, thus suggesting a method for determining the underlying material directions. Additionally, the stiffness of the tissue response to indentation is sensitive to the values of the in-plane anisotropic material properties and prestretches, and thus test results can be used to back out relevant constitutive parameters.     

Characterization of tissue scaffolds for time-dependent biotransport criteria – a novel computational procedure

This study aims to establish a new computational framework that allows modeling transient oxygen diffusion in tissue scaffolds more efficiently. It has been well known that the survival of cells strongly relies on continuous oxygen/nutrient supply and metabolite removal. With optimal design in scaffold architecture, its ability to sustain long distance oxygen supply could be improved considerably. In this study, finite element based homogenization procedure is first used to characterize the initial effective biotransport properties in silico. These initial properties are proper indicators to prediction of the on-going performance of tissue scaffolds over time. The transient model by adopting an edge-based smoothed finite element method with combination of mass-redistributed method is then established to more efficiently simulate the transient oxygen transfer process in tissue scaffolds. The proposed new method allows large time steps to model the oxygen diffusion process without losing numerical accuracy, thereby enhancing the computational efficiency significantly, in particular for the design optimization problems which typically require numerous analysis iterations. A number of different scaffold designs are examined either under net diffusion without cell seeding, or under cellular oxygen/nutrient uptake with or without considering cell viability. The association between the homogenized effective diffusivity of net scaffold microstructures and corresponding transient diffusion and time-dependent cellular activities is divulged. This study provides some insights into scaffold design.     

NACOB presentation to ASB Young Scientist Award: Postdoctoral. The impact of boundary conditions and mesh size on the accuracy of cancellous bone tissue modulus determination using large-scale finite-element modeling. North American Congress on Biomechanics.

The apparent properties of cancellous bone are determined by a combination of both hard tissue properties and microstructural organization. A method is desired to extract the underlying hard tissue properties from simple mechanical tests, free from the complications of microstructure. It has been suggested that microCT voxel-based large-scale finite element models could be employed to accomplish this goal (van Rietbergen et al., 1995, Journal of Biomechanics, 28, 69-81). This approach has recently been implemented and it is becoming increasingly popular as finite element models increase in size and sophistication (Fyhrie et al., 1997, Proceedings of the 43rd Annual Meeting of the Orthopaedic Research Society, San Francisco, CA, p. 815; van Rietbergen et al., 1997, Proceedings of the 43rd Annual Meeting of the Orthopaedic Research Society, San Francisco, CA, p. 62). However, no direct quantitative measurements of the accuracy of this method applied to porous structures such as cancellous bone have been made. This project demonstrates the feasibility of this approach by quantifying its best-case accuracy in determining the trabecular hard tissue modulus of analogues fabricated of a material with known material properties determined independently by direct testing. In addition we were able to assess the impact of mesh size and boundary conditions on accuracy. We found that the assumption of a frictionless boundary condition in the parallel plate compression loading configuration was a significant source of error that could be overcome with the use of rigid end-caps similar to those used by Keaveny et al. (1997 Journal of Orthopaedic Research, 15(1), 101-110). In conclusion, we found that this approach is an effective method for determining the average trabecular hard tissue properties of human cancellous bone with an expected practical accuracy level better than 5%.     

Effects of friction on the unconfined compressive response of articular cartilage: a finite element analysis

A finite element analysis is used to study a previously unresolved issue of the effects of platen-specimen friction on the response of the unconfined compression test; effects of platen permeability are also determined. The finite element formulation is based on the linear KLM biphasic model for articular cartilage and other hydrated soft tissues. A Galerkin weighted residual method is applied to both the solid phase and the fluid phase, and the continuity equation for the intrinsically incompressible binary mixture is introduced via a penalty method. The solid phase displacements and fluid phase velocities are interpolated for each element in terms of unknown nodal values, producing a system of first order differential equations which are solved using a standard numerical finite difference technique. An axisymmetric element of quadrilateral cross-section is developed and applied to the mechanical test problem of a cylindrical specimen of soft tissue in unconfined compression. These studies show that interfacial friction plays a major role in the unconfined compression response of articular cartilage specimens with small thickness to diameter ratios.     

Analysis of effects of friction on the deformation behavior of soft tissues in unconfined compression tests

Frictionless specimen/platen contact in unconfined compression tests has traditionally been assumed in determining material properties of soft tissues via an analytical solution. In the present study, the suitability of this assumption was examined using a finite element method. The effect of the specimen/platen friction on the mechanical characteristics of soft tissues in unconfined compression was analyzed based on the published experimental data of three different materials (pigskin, pig brain, and human calcaneal fat). The soft tissues were considered to be nonlinear and viscoelastic; the friction coefficient at the contact interface between the specimens and platens was assumed to vary from 0.0 to 0.5. Our numerical simulations show that the tissue specimens are, due to the specimen/platen friction, not compressed in a uniform stress/strain state, as has been traditionally assumed in analytical analysis. The stress of the specimens obtained with the specimen/platen friction can be greater than those with the frictionless specimen/platen contact by more than 50%, even in well-controlled test conditions.     

The preprotachykinin A promoter interacts with a sequence specific single stranded DNA binding protein.

An element within the Preprotachykinin A (PPT) promoter is highly homologous to an element from the rat type II Na channel promoter. This Na Channel element has been previously proposed to be common to a number of neuronal genes. We demonstrate that the PPT element binds a sequence specific DNA binding protein. The protein binds to only one strand of the PPT element and has little or no specificity for the double stranded DNA species. Gel retardation analysis indicates that the protein is found in both rat neuronal tissue and adult dorsal root ganglia neurons in culture but not in established tissue culture cell lines. Using the PPT element linked to magnetic beads we have been able to demonstrate the enrichment of a protein with a molecular weight of 40k with that of the binding activity. A mechanism for protein binding to the DNA is proposed based on the fact that the region binding the protein is the loop of a larger stem-loop structure in the DNA.     

Implementation of controlling strategy in a biomechanical lower limb model with active muscles for coupling multibody dynamics and finite element analysis

Computational biomechanics for human body modeling has generally been categorized into two separated domains: finite element analysis and multibody dynamics. Combining the advantages of both domains is necessary when tissue stress and physical body motion are both of interest. However, the method for this topic is still in exploration. The aim of this study is to implement unique controlling strategies in finite element model for simultaneously simulating musculoskeletal body dynamics and in vivo stress inside human tissues. A finite element lower limb model with 3D active muscles was selected for the implementation of controlling strategies, which was further validated against in-vivo human motion experiments. A unique feedback control strategy that couples together a basic Proportion-Integration-Differentiation (PID) controller and generic active signals from Computed Muscle Control (CMC) method of the musculoskeletal model or normalized EMG singles was proposed and applied in the present model. The results show that the new proposed controlling strategy show a good correlation with experimental test data of the normal gait considering joint kinematics, while stress distribution of local lower limb tissue can be also detected in real-time with lower limb motion. In summary, the present work is the first step for the application of active controlling strategy in the finite element model for concurrent simulation of both body dynamics and tissue stress. In the future, the present method can be further developed to apply it in various fields for human biomechanical analysis to monitor local stress and strain distribution by simultaneously simulating human locomotion.