Showing papers in "Annals of Biomedical Engineering in 2005"

A model of the upper extremity for simulating musculoskeletal surgery and analyzing neuromuscular control

Abstract: Biomechanical models of the musculoskeletal system are frequently used to study neuromuscular control and simulate surgical procedures. To be broadly applicable, a model must be accessible to users, provide accurate representations of muscles and joints, and capture important interactions between joints. We have developed a model of the upper extremity that includes 15 degrees of freedom representing the shoulder, elbow, forearm, wrist, thumb, and index finger, and 50 muscle compartments crossing these joints. The kinematics of each joint and the force-generating parameters for each muscle were derived from experimental data. The model estimates the muscle-tendon lengths and moment arms for each of the muscles over a wide range of postures. Given a pattern of muscle activations, the model also estimates muscle forces and joint moments. The moment arms and maximum moment-generating capacity of each muscle group (e.g., elbow flexors) were compared to experimental data to assess the accuracy of the model. These comparisons showed that moment arms and joint moments estimated using the model captured important features of upper extremity geometry and mechanics. The model also revealed coupling between joints, such as increased passive finger flexion moment with wrist extension. The computer model is available to researchers at http://nmbl.stanford.edu.

Mechanobiology in the third dimension.

Abstract: Cells are mechanically coupled to their extracellular environments, which play critical roles in both communicating the state of the mechanical environment to the cell as well as in mediating cellular response to a variety of stimuli. Along with the molecular composition and mechanical properties of the extracellular matrix (ECM), recent work has demonstrated the importance of dimensionality in cell-ECM associations for controlling the sensitive communication between cells and the ECM. Matrix forces are generally transmitted to cells differently when the cells are on two-dimensional (2D) vs. within three-dimensional (3D) matrices, and cells in 3D environments may experience mechanical signaling that is unique vis-a-vis cells in 2D environments, such as the recently described 3D-matrix adhesion assemblies. This review examines how the dimensionality of the extracellular environment can affect in vitro cell mechanobiology, focusing on collagen and fibrin systems.

Three-dimensional representation of complex muscle architectures and geometries.

Abstract: Almost all computer models of the musculoskeletal system represent muscle geometry using a series of line segments. This simplification (i) limits the ability of models to accurately represent the paths of muscles with complex geometry and (ii) assumes that moment arms are equivalent for all fibers within a muscle (or muscle compartment). The goal of this work was to develop and evaluate a new method for creating three-dimensional (3D) finite-element models that represent complex muscle geometry and the variation in moment arms across fibers within a muscle. We created 3D models of the psoas, iliacus, gluteus maximus, and gluteus medius muscles from magnetic resonance (MR) images. Peak fiber moment arms varied substantially among fibers within each muscle (e.g., for the psoas the peak fiber hip flexion moment arms varied from 2 to 3 cm, and for the gluteus maximus the peak fiber hip extension moment arms varied from 1 to 7 cm). Moment arms from the literature were generally within the range of fiber moment arms predicted by the 3D models. The models accurately predicted changes in muscle surface geometry over a 55 degrees range of hip flexion, as compared to changes in shape predicted from MR images (average errors between the model and measured surfaces were between 1.7 and 5.2 mm). This new framework for representing muscle will enhance the accuracy of computer models of the musculoskeletal system.

Contactless multiple wavelength photoplethysmographic imaging: a first step toward "SpO2 camera" technology.

Abstract: We describe a route toward contactless imaging of arterial oxygen saturation (SpO2) distribution within tissue, based upon detection of a two-dimensional matrix of spatially resolved optical plethysmographic signals at different wavelengths. As a first step toward SpO 2-imaging we built a monochrome CMOS-camera with apochromatic lens and 3λ-LED-ringlight (λ1 = 660 nm, λ 2 = 810 nm, λ3 = 940 nm; 100 LEDs λ -1). We acquired movies at three wavelengths while simultaneously recording ECG and respiration for seven volunteers. We repeated this experiment for one volunteer at increased frame rate, additionally recording the pulse wave of a pulse oximeter. Movies were processed by dividing each image frame into discrete Regions of Interest (ROIs), averaging 10 × 10 raw pixels each. For each ROI, pulsatile variation over time was assigned to a matrix of ROI-pixel time traces with individual Fourier spectra. Photoplethysmograms correlated well with respiration reference traces at three wavelengths. Increased frame rates revealed weaker pulsations (main frequency components 0. 95 and 1.9 Hz) superimposed upon respiration-correlated photoplethysmograms, which were heartbeat-related at three wavelengths. We acquired spatially resolved heartbeat-related photoplethysmograms at multiple wavelengths using a remote camera. This feasibility study shows potential for non-contact 2-D imaging reflection-mode pulse oximetry. Clinical devices, however, require further development.

A theoretical model for the margination of particles within blood vessels.

Abstract: The margination of a particle circulating in the blood stream has been analyzed. The contribution of buoyancy, hemodynamic forces, van der Waals, electrostatic and steric interactions between the circulating particle and the endothelium lining the vasculature has been considered. For practical applications, the contribution of buoyancy, hemodynamic forces and van der Waals interactions should be only taken into account, whilst the effect of electrostatic and steric repulsion becomes important only at very short distances from the endothelium (1–10 nm). The margination speed and the time for margination t s have been estimated as a function of the density of the particle relative to blood Δ ρ, the Hamaker constant A and radius R of the particle. A critical radius R c exists for which the margination time t s has a maximum, which is influenced by both Δ ρ and A: the critical radius decreases as the relative density increases and the Hamaker constant decreases. Therefore, particles used for drug delivery should have a radius smaller than the critical value (in the range of 100 nm) to facilitate margination and interaction with the endothelium. While particles used as nanoharvesting agents in proteomics or genomics analysis should have a radius close to the critical value to minimize margination and increase their circulation time.

Tissue engineering of human heart valve leaflets: a novel bioreactor for a strain-based conditioning approach.

Abstract: Current mechanical conditioning approaches for heart valve tissue engineering concentrate on mimicking the opening and closing behavior of the leaflets, either or not in combination with tissue straining. This study describes a novel approach by mimicking only the diastolic phase of the cardiac cycle, resulting in tissue straining. A novel, yet simplified, bioreactor system was developed for this purpose by applying a dynamic pressure difference over a closed tissue engineered valve, thereby inducing dynamic strains within the leaflets. Besides the use of dynamic strains, the developing leaflet tissues were exposed to pre-strain induced by the use of a stented geometry. To demonstrate the feasibility of this strain-based conditioning approach, human heart valve leaflets were engineered and their mechanical behavior evaluated. The actual dynamic strain magnitude in the leaflets over time was estimated using numerical analyses. Preliminary results showed superior tissue formation and non-linear tissue-like mechanical properties in the strained valves when compared to non-loaded tissue strips. In conclusion, the strain-based conditioning approach, using both pre-strain and dynamic strains, offers new possibilities for bioreactor design and optimization of tissue properties towards a tissue-engineered aortic human heart valve replacement.

Shear stress biology of the endothelium

Abstract: The relationships between blood flow, mechanotransduction, and the localization of arterial lesions can now be advanced by the incorporation of new technologies and the refinement of existing methods in imaging modalities, computational modeling, fluid dynamics, and high throughput genomics and proteomics. When combined with traditional cell and molecular technologies, a powerful palette of investigative approaches is available to address shear stress biology of the endothelium at levels extending from nanoscale subcellular detailed mechanistic responses through to higher organizational levels of regional endothelial phenotypes and heterogeneous vascular beds.

Laser printing of single cells: statistical analysis, cell viability, and stress.

Abstract: Methods to print patterns of mammalian cells to various substrates with high resolution offer unique possibilities to contribute to a wide range of fields including tissue engineering, cell separation, and functional genomics. This manuscript details experiments demonstrating that BioLP TM Biological Laser Printing, can be used to rapidly and accurately print patterns of single cells in a noncontact manner. Human osteosarcoma cells were deposited into a biopolymer matrix, and after 6 days of incubation, the printed cells are shown to be 100% viable. Printing low numbers of cells per spot by BioLPTM is shown to follow a Poisson distribution, indicating that the reproducibility for the number of cells per spot is therefore determined not by the variance in printed volume per drop but by random sampling statistics. Potential cell damage during the laser printing process is also investigated via immunocytochemical studies that demonstrate minimal expression of heat shock proteins by printed cells. Overall, we find that BioLPTM is able to print patterns of osteosarcoma cells with high viability, little to no heat or shear damage to the cells, and at the ultimate single cell resolution.

Diffusivity and solubility of nitric oxide in water and saline

Abstract: Aqueous diffusivities and solubilities of NO were determined by using a chemiluminescence detector to measure time-dependent fluxes across stagnant liquid films confined between polydimethylsiloxane membranes. The NO diffusivities in pure water and PBS at 25 degrees C were found to be (2.21+/-0.02) x 10(-5) cm2 s(-1) and (2.21+/-0.04) x 10(-5) cm2 s(-1), respectively. Although lower than most previous values for NO at room temperature, these diffusivities are very similar to those for O2, as one would expect. Extrapolation to 37 degrees C yielded a value of 3.0 x 10(-5) cm2 s(-1). The solubility of NO in water at 25 degrees C was (1.94+/-0.03) x 10(-6) mol cm(-3) atm(-1), in agreement with the literature. This agreement, along with the excellent fits obtained to the transient flux data (<4% rms error in each experiment), supports the validity of the simultaneously measured diffusivity. The solubility of NO in PBS at 25 degrees C was (1.75+/-0.02) x 10(-6) mol cm(-3) atm(-1). The modest (10%) reduction in solubility relative to that in pure water is consistent with the usual effects of salts on gas solubilities.

Flow in prosthetic heart valves: state-of-the-art and future directions.

Abstract: Since the first successful implantation of a prosthetic heart valve four decades ago, over 50 different designs have been developed including both mechanical and bioprosthetic valves. Today, the most widely implanted design is the mechanical bileaflet, with over 170,000 implants worldwide each year. Several different mechanical valves are currently available and many of them have good bulk forward flow hemodynamics, with lower transvalvular pressure drops, larger effective orifice areas, and fewer regions of forward flow stasis than their earlier-generation counterparts such as the ball-and-cage and tilting-disc valves. However, mechanical valve implants suffer from complications resulting from thrombus deposition and patients implanted with these valves need to be under long-term anti-coagulant therapy. In general, blood thinners are not needed with bioprosthetic implants, but tissue valves suffer from structural failure with, an average life-time of 10-12 years, before replacement is needed. Flow-induced stresses on the formed elements in blood have been implicated in thrombus initiation within the mechanical valve prostheses. Regions of stress concentration on the leaflets during the complex motion of the leaflets have been implicated with structural failure of the leaflets with bioprosthetic valves. In vivo and in vitro experimental studies have yielded valuable information on the relationship between hemodynamic stresses and the problems associated with the implants. More recently, Computational Fluid Dynamics (CFD) has emerged as a promising tool, which, alongside experimentation, can yield insights of unprecedented detail into the hemodynamics of prosthetic heart valves. For CFD to realize its full potential, however, it must rely on numerical techniques that can handle the enormous geometrical complexities of prosthetic devices with spatial and temporal resolution sufficiently high to accurately capture all hemodynamically relevant scales of motion. Such algorithms do not exist today and their development should be a major research priority. For CFD to further gain the confidence of valve designers and medical practitioners it must also undergo comprehensive validation with experimental data. Such validation requires the use of high-resolution flow measuring tools and techniques and the integration of experimental studies with CFD modeling.

Flow Perfusion Enhances the Calcified Matrix Deposition of Marrow Stromal Cells in Biodegradable Nonwoven Fiber Mesh Scaffolds

Abstract: In this study, we report on the ability of resorbable poly(L-lactic acid) (PLLA) nonwoven scaffolds to support the attachment, growth, and differentiation of marrow stromal cells (MSCs) under fluid flow. Rat MSCs were isolated from young male Wistar rats and expanded using established methods. The cells were then seeded on PLLA nonwoven fiber meshes. The PLLA nonwoven fiber meshes had 99% porosity, 17 μm fiber diameter, 10 mm scaffold diameter, and 1.7-mm thickness. The nonwoven PLLA meshes were seeded with a cell suspension of 5 × 105 cells in 300 μl, and cultured in a flow perfusion bioreactor and under static conditions. Cell/polymer nonwoven scaffolds cultured under flow perfusion had significantly higher amounts of calcified matrix deposited on them after 16 days of culture. Microcomputed tomography revealed that the in vitro generated extracellular matrix in the scaffolds cultured under static conditions was denser at the periphery of the scaffold while in the scaffolds cultured in the perfusion bioreactor the extracellular matrix demonstrated a more homogeneous distribution. These results show that flow perfusion accelerates the proliferation and differentiation of MSCs, seeded on nonwoven PLLA scaffolds, toward the osteoblastic phenotype, and improves the distribution of the in vitro generated calcified extracellular matrix.

Osteoblast elastic modulus measured by atomic force microscopy is substrate dependent.

Abstract: The actin and microtubule cytoskeleton have been found to contribute to the elastic modulus of cells, which may be modulated by adhesion to extracellular matrix (ECM) proteins and subsequent alterations in the cytoskeleton. In this study, the apparent elastic modulus (Eapp) of osteoblast-like MC3T3-E1 cells adhered to fibronectin (FN), vitronectin (VN), type I collagen (COLI), fetal bovine serum (FBS), or poly-l-lysine (PLL), and bare glass were determined using an atomic force microscope (AFM). The Eapp of osteoblasts adhered to ECM proteins (FN, VN, COLI, and FBS) that bind cells via integrins were higher compared to cells on glass and PLL, which adhere cells through nonspecific binding. Also, osteoblasts adhered to FN, VN, COLI, and FBS had F-actin stress fiber formation, while osteoblasts on glass and PLL showed few F-actin fibers. Disruption of the actin cytoskeleton decreased Eapp of osteoblasts plated on FN to the level of osteoblasts plated on glass, while microtubule disruption had no significant effect. This suggests that the elevated modulus of osteoblasts adhered to FN was due to remodeling of the actin cytoskeleton upon adhesion to ECM proteins. Modulation of cell stiffness upon adhesion to various substrates may influence mechanosignal transduction in osteoblasts.

The air-conditioning capacity of the human nose.

Abstract: The nose is the front line defender of the respiratory system. Unsteady simulations in three-dimensional models have been developed to study transport patterns in the human nose and its overall air-conditioning capacity. The results suggested that the healthy nose can efficiently provide about 90% of the heat and the water fluxes required to condition the ambient inspired air to near alveolar conditions in a variety of environmental conditions and independent of variations in internal structural components. The anatomical replica of the human nose showed the best performance and was able to provide 92% of the heating and 96% of the moisture needed to condition the inspired air to alveolar conditions. A detailed analysis explored the relative contribution of endonasal structural components to the air-conditioning process. During a moderate breathing effort, about 11% reduction in the efficacy of nasal air-conditioning capacity was observed.

Cellular fluid mechanics and mechanotransduction.

Abstract: Mechanotransduction, the transformation of an applied mechanical force into a cellular biomolecular response, is briefly reviewed focusing on fluid shear stress and endothelial cells. Particular emphasis is placed on recent studies of the surface proteoglycan layer (glycocalyx) as a primary sensor of fluid shear stress that can transmit force to apical structures such as the plasma membrane or the actin cortical web where transduction can take place or to more remote regions of the cell such as intercellular junctions and basal adhesion plaques where transduction can also occur. All of these possibilities are reviewed from an integrated perspective.

Numerical simulation of cell motion in tube flow.

Abstract: A theoretical model is presented for describing the motion of a deformable cell encapsulating a Newtonian fluid and enclosed by an elastic membrane in tube flow. In the mathematical formulation, the interior and exterior hydrodynamics are coupled with the membrane mechanics by means of surface equilibrium equations, and the problem is formulated as a system of integral equations for the interfacial velocity, the disturbance tube-wall traction, and the pressure difference across the two ends to the tube due to the presence of the cell. Numerical solutions obtained by a boundary-element method are presented for flow in a cylindrical tube with a circular cross-section, cytoplasm viscosity equal to the ambient fluid viscosity, and cells positioned sufficiently far from the tube wall so that strong lubrication forces do not arise. In the numerical simulations, cells with spherical, oblate ellipsoidal, and biconcave unstressed shapes enclosed by membranes that obey a neo-Hookean constitutive equation are considered. Spherical cells are found to slowly migrate toward the tube centerline at a rate that depends on the mean flow velocity, whereas oblate and biconcave cells are found to develop parachute and slipper-like shapes, respectively, from axisymmetric and more general initial orientations.

Computational study of fluid mechanical disturbance induced by endovascular stents.

Abstract: Arterial restenosis following stent deployment may be influenced by the local flow environment within and around the stent. We have used computational fluid dynamics to investigate the flow field in the vicinity of model stents positioned within straight and curved vessels. Our simulations have revealed the presence of flow separation and recirculation immediately downstream of stents. In steady flow within straight vessels, the extent of flow disturbance downstream of the stent increases with both Reynolds number and stent wire thickness but is relatively insensitive to stent interwire spacing. In curved vessels, flow disturbance downstream of the stent occurs along both the inner and outer vessel walls with the extent of disturbance dependent on the angle of vessel curvature. In pulsatile flow, the regions of flow disturbance periodically increase and decrease in size. Non-Newtonian fluid properties lead to a modest reduction in flow disturbance downstream of the stent. In more realistic stent geometries such as stents modeled as spirals or as intertwined rings, the nature of stent-induced flow disturbance is exquisitely sensitive to stent design. These results provide an understanding of the flow physics in the vicinity of stents and suggest strategies for stent design optimization to minimize flow disturbance.

Flow Imaging and Computing: Large Artery Hemodynamics

Abstract: The objective of our session at the International Bio-Fluid Mechanics Symposium and Workshop was at the International Bio-Fluid Mechanics Symposium and Workshop to review the state-of-the-art in, and identify future directions for, imaging and computational modeling of blood flow in the large arteries and the microcirculation. Naturally, talks in other sessions of the workshop overlapped this broad topic, and so here we summarize progress within the last decade in terms of the technical development and application of flow imaging and computing, rather than the knowledge derived from specific studies. We then briefly discuss ways in these tools may be extended, and their application broadened, in the next decade. Furthermore, owing to the conceptual division between the hemodynamics of large arteries, and those within the microcirculation, we review these regimes separately: The former here by Steinman and Taylor; and the latter in a separate paper by Cristini.

Fluid-Structure Coupled CFD Simulation of the Left Ventricular Flow During Filling Phase

Abstract: The fluid-structure coupled simulation of the heart, though at its developing stage, has shown great prospect in heart function investigations and clinical applications. The purpose of this paper is to verify a commercial software based fluid-structure interaction scheme for the left ventricular filling. The scheme applies the finite volume method to discretize the arbitrary Lagrangian-Eulerian formulation of the Navier-Stokes equations for the fluid while using the nonlinear finite element method to model the structure. The coupling of the fluid and structure is implemented by combining the fluid and structure equations as a unified system and solving it simultaneously at every time step. The left ventricular filling flow in a three-dimensional ellipsoidal thin-wall model geometry of the human heart is simulated, based on a prescribed time-varying Young's modulus. The coupling converges smoothly though the deformation is very large. The pressure-volume relation of the model ventricle, the spatial and temporal distributions of pressure, transient velocity vectors as well as vortex patterns are analyzed, and they agree qualitatively and quantitatively well with the existing data. This preliminary study has verified the feasibility of the scheme and shown the possibility to simulate the left ventricular flow in a more realistic way by adding a myocardial constitutive law into the model and using a more realistic heart geometry.

Electromyography: Physiology, Engineering and Non-Invasive Applications

Abstract: It is now almost a century since Piper used a string galvanometer to study muscle activity and initiated the first studies in electromyography (EMG). But not many volumes have emerged since then to describe the fascinating developments in the field of muscle physiology and diagnostics. Such a synthesis is long overdue, and to accomplish this goal, Merletti and Parker have elicited contributions from an internationally famed group of EMG research experts. As a result, Electromyography: Physiology, Engineering and Non-Invasive Applications has materialized as a pioneering volume that captures the remarkable revolution in the field of skeletal muscle electrodiagnostics and research. Most of the book’s 18 chapters are very good or outstanding. Repetitions are present, but they appear to be didactic rather than distracting. The introductory chapter offers superb reading on the basic biophysical and (electro)physiological aspects of EMG signal generation. The chapters on EMG methodologies, decomposition techniques, surface biophysical issues, signal conditioning and extraction, simulation/modeling, and myoelectric manifestations, written by senior authors, are superlative. The book concludes with the description of various advancements and relevant clinical applications in the areas ranging from neurology and ergonomics to exercise physiology, from rehabilitation medicine to biofeedback and prostheses control. The chapters are succinct and contain numerous clinical pearls of wisdom. A few exceptions are the chapters on signal extraction, EMG modeling and simulation, and myoelectric manifestations, which are wordy and, though informative, not as authoritative as the others. Applications are generally well covered, but the depth of the practical information useful to busy researchers varies from excellent, as in the instances of ergonomics, movement and gait analysis, and rehabilitation medicine, to brittle, as in the instance of exercise physiology. One criticism of the book is that little attention is focused on the beguiling issue of mechanomyography (vibromyography), which is developing as a contestant with superior muscle diagnostic potential against EMG. Overall, this textbook is a harmonious work that can certainly be appreciated by graduate students and researchers from different backgrounds such as bioengineering, life sciences, exercise sciences, sports health, neuro(physio)logy, and occupational medicine. Electromyography is certainly the best single reference book currently available in the field and more importantly, this book comes with the assurance that what is presented is reliable, objective, and up to date.

Local maximal stress hypothesis and computational plaque vulnerability index for atherosclerotic plaque assessment.

Abstract: It is believed that atherosclerotic plaque rupture may be related to maximal stress conditions in the plaque. More careful examination of stress distributions in plaques reveals that it may be the local stress/strain behaviors at critical sites such as very thin plaque cap and locations with plaque cap weakness that are more closely related to plaque rupture risk. A “local maximal stress hypothesis” and a stress-based computational plaque vulnerability index (CPVI) are proposed to assess plaque vulnerability. A critical site selection (CSS) method is proposed to identify critical sites in the plaque and critical stress conditions which are be used to determine CPVI values. Our initial results based on 34 2D MRI slices from 14 human coronary plaque samples indicate that CPVI plaque assessment has an 85% agreement rate (91% if the square root of stress values is used) with assessment given by histopathological analysis. Large-scale and long-term patient studies are needed to further validate our findings for more accurate quantitative plaque vulnerability assessment.

Substrate curvature influences the direction of nerve outgrowth.

Abstract: Nerve outgrowth in the developing nervous system utilizes a variety of attractive and repulsive molecules found in the extracellular environment. In addition, physical cues may play an important regulatory role in determining directional outgrowth of nervous tissue. Here, by culturing nerve cells on filamentous surfaces and measuring directional growth, we tested the hypothesis that substrate curvature is sufficient to influence the directional outgrowth of nerve cells. We found that the mean direction of neurite outgrowth aligned with the direction of minimum principle curvature, and the spatial variance in outgrowth direction was directly related to the maximum principle curvature. As substrate size approached the size of an axon, adherent neurons extended processes that followed the direction of the long axis of the substrate similar to what occurs during development along pioneering axons and radial glial fibers. A simple Boltzmann model describing the interplay between adhesion and bending stiffness of the nerve process was found to be in close agreement with the data suggesting that cell stiffness and substrate curvature can act together in a manner that is sufficient to direct nerve outgrowth in the absence of contrasting molecular cues. The study highlights the potential importance of cellular level geometry as a fidelity-enhancing cue in the developing and regenerating nervous system.

The Influence of Noncollagenous Matrix Components on the Micromechanical Environment of Tendon Fascicles

Abstract: Tendon is composed of type I collagen fibers, interspersed with proteoglycan matrix and cells. Glycosaminoglycans may play a role in maintaining the structural integrity of tendon, preventing excessive shearing between collagen components. This study tests the hypothesis that tendon extension mechanisms can be altered by modifying the composition of noncollagenous matrix. Tendon explants were treated with phosphate buffered saline (PBS) or PBS + 0.5 U ml(-1) chondroitinase ABC. Structural changes were examined using TEM and biochemical analysis, while strain response was examined using confocal microscopy and gross mechanical characterization. Chondroitinase ABC removed 90% of glycosaminoglycans from the matrix. Results demonstrated significant swelling of fibrils and surrounding matrix when incubated in either solution. In response to applied strain, PBS incubated samples demonstrated significantly less sliding between adjacent fibers than nonincubated, and a 33% reduction in maximum force. By contrast, fascicles incubated in chondroitinase ABC demonstrated a similar strain response to nonincubated. Data indicate that collagen-proteoglycan binding characteristics can be influenced by incubation and this, in turn, can influence the preferred extension mechanisms adopted by fascicles. This highlights the importance of maintaining fascicles within their natural environment to prevent structural or mechanical changes prior to subsequent analysis.

A Predictive Model of Therapeutic Monoclonal Antibody Dynamics and Regulation by the Neonatal Fc Receptor (FcRn)

Abstract: We constructed a novel physiologically-based pharmacokinetic (PBPK) model for predicting interactions between the neonatal Fc receptor (FcRn) and anti-carcinoembryonic antigen (CEA) monoclonal antibodies (mAbs) with varying affinity for FcRn. Our new model, an integration and extension of several previously published models, includes aspects of mAb-FcRn dynamics within intracellular compartments not represented in previous PBPK models. We added mechanistic structure that details internalization of class G immunoglobulins by endothelial cells, subsequent FcRn binding, recycling into plasma of FcRn-bound IgG and degradation of free endosomal IgG. Degradation in liver is explicitly represented along with the FcRn submodel in skin and muscle. A variable tumor mass submodel is also included, used to estimate the growth of an avascular, necrotic tumor core, providing a more realistic picture of mAb uptake by tumor. We fitted the new multiscale model to published anti-CEA mAb biodistribution data, i.e. concentration-time profiles in tumor and various healthy tissues in mice, providing new estimates of mAb-FcRn related kinetic parameters. The model was further validated by successful prediction of F(ab')2 mAb fragment biodistribution, providing additional evidence of its potential value in optimizing intact mAb and mAb fragment dosing for clinical imaging and immunotherapy applications.

Computer-based detection and analysis of heart sound and murmur.

Abstract: To develop a digital algorithm that detects first and second heart sounds, defines the systole and diastole, and characterises the systolic murmur. Heart sounds were recorded in 300 children with a cardiac murmur, using an electronic stethoscope. A Digital algorithm was developed for detection of first and second heart sounds. R-waves and T-waves in the electrocardiography were used as references for detection. The sound signal analysis was carried out using the short-time Fourier transform. The first heart sound detection rate, with reference to the R-wave, was 100% within 0.05–0.2R-R interval. The second heart sound detection rate between the end of the T-wave and the 0.6R-R interval was 97%. The systolic and diastolic phases of the cardiac cycle could be identified. Because of the overlap between heart sounds and murmur a systolic segment between the first and second heart sounds (20–70%) was selected for murmur analysis. The maximum intensity of the systolic murmur, its average frequency, and the mean spectral power were quantified. The frequency at the point with the highest sound intensity in the spectrum and its time from the first heart sound, the highest frequency, and frequency range were also determined. This method will serve as the foundation for computer-based detection of heart sounds and the characterisation of cardiac murmurs.

Roles of hemodynamic forces in vascular cell differentiation.

Abstract: The pulsatile nature of blood flow is a key stimulus for the modulation of vascular cell differentiation. Within the vascular media, physiologic stress is manifested as cyclic strain, while in the lumen, cells are subjected to shear stress. These two respective biomechanical forces influence the phenotype and degree of differentiation or proliferation of smooth muscle cells and endothelial cells within the human vasculature. Elucidation of the effect of these mechanical forces on cellular differentiation has led to a surge of research into this area because of the implications for both the treatment of atherosclerotic disease and the future of vascular tissue engineering. The use of mechanical force to directly control vascular cell differentiation may be utilized as an invaluable engineering tool in the future. However, an understanding of the role of hemodynamics in vascular cell differentiation and proliferation is critical before application can be realized. Thus, this review will provide a current perspective on the latest research and controversy behind the role of hemodynamic forces for vascular cell differentiation and phenotype modulation. Furthermore, this review will illustrate the application of hemodynamic force for vascular tissue engineering and explicate future directions for research.

Physics-driven CFD modeling of complex anatomical cardiovascular flows-a TCPC case study.

Abstract: Recent developments in medical image acquisition combined with the latest advancements in numerical methods for solving the Navier-Stokes equations have created unprecedented opportunities for developing simple and reliable computational fluid dynamics (CFD) tools for meeting patient-specific surgical planning objectives. However, for CFD to reach its full potential and gain the trust and confidence of medical practitioners, physics-driven numerical modeling is required. This study reports on the experience gained from an ongoing integrated CFD modeling effort aimed at developing an advanced numerical simulation tool capable of accurately predicting flow characteristics in an anatomically correct total cavopulmonary connection (TCPC). An anatomical intra-atrial TCPC model is reconstructed from a stack of magnetic resonance (MR) images acquired in vivo. An exact replica of the computational geometry was built using transparent rapid prototyping. Following the same approach as in earlier studies on idealized models, flow structures, pressure drops, and energy losses were assessed both numerically and experimentally, then compared. Numerical studies were performed with both a first-order accurate commercial software and a recently developed, second-order accurate, in-house flow solver. The commercial CFD model could, with reasonable accuracy, capture global flow quantities of interest such as control volume power losses and pressure drops and time-averaged flow patterns. However, for steady inflow conditions, both flow visualization experiments and particle image velocimetry (PIV) measurements revealed unsteady, complex, and highly 3D flow structures, which could not be captured by this numerical model with the available computational resources and additional modeling efforts that are described. Preliminary time-accurate computations with the in-house flow solver were shown to capture for the first time these complex flow features and yielded solutions in good agreement with the experimental observations. Flow fields obtained were similar for the studied total cardiac output range (1–3 l/min); however hydrodynamic power loss increased dramatically with increasing cardiac output, suggesting significant energy demand at exercise conditions. The simulation of cardiovascular flows poses a formidable challenge to even the most advanced CFD tools currently available. A successful prediction requires a two-pronged, physics-based approach, which integrates high-resolution CFD tools and high-resolution laboratory measurements.

Flow perfusion culture of marrow stromal cells seeded on porous biphasic calcium phosphate ceramics.

Abstract: Calcium phosphate ceramics have been widely used for filling bone defects to aid in the regeneration of new bone tissue. Addition of osteogenic cells to porous ceramic scaffolds may accelerate the bone repair process. This study demonstrates the feasibility of culturing marrow stromal cells (MSCs) on porous biphasic calcium phosphate ceramic scaffolds in a flow perfusion bioreactor. The flow of medium through the scaffold porosity benefits cell differentiation by enhancing nutrient transport to the scaffold interior and by providing mechanical stimulation to cells in the form of fluid shear. Primary rat MSCs were seeded onto porous ceramic (60% hydroxyapatite, 40% beta-tricalcium phosphate) scaffolds, cultured for up to 16 days in static or flow perfusion conditions, and assessed for osteoblastic differentiation. Cells were distributed throughout the entire scaffold by 16 days of flow perfusion culture whereas they were located only along the scaffold perimeter in static culture. At all culture times, flow perfused constructs demonstrated greater osteoblastic differentiation than statically cultured constructs as evidenced by alkaline phosphatase activity, osteopontin secretion into the culture medium, and histological evaluation. These results demonstrate the feasibility and benefit of culturing cell/ceramic constructs in a flow perfusion bioreactor for bone tissue engineering applications.

Large deformation finite element analysis of micropipette aspiration to determine the mechanical properties of the chondrocyte.

Abstract: Chondrocytes, the cells in articular cartilage, exhibit solid-like viscoelastic behavior in response to mechanical stress. In modeling the creep response of these cells during micropipette aspiration, previous studies have attributed the viscoelastic behavior of chondrocytes to either intrinsic viscoelasticity of the cytoplasm or to biphasic effects arising from fluid–solid interactions within the cell. However, the mechanisms responsible for the viscoelastic behavior of chondrocytes are not fully understood and may involve one or both of these phenomena. In this study, the micropipette aspiration experiment was modeled using a large strain finite element simulation that incorporated contact boundary conditions. The cell was modeled using finite strain incompressible and compressible elastic models, a two-mode compressible viscoelastic model, or a biphasic elastic or viscoelastic model. Comparison of the model to the experimentally measured response of chondrocytes to a step increase in aspiration pressure showed that a two-mode compressible viscoelastic formulation accurately captured the creep response of chondrocytes during micropipette aspiration. Similarly, a biphasic two-mode viscoelastic analysis could predict all aspects of the cell’s creep response to a step aspiration. In contrast, a biphasic elastic formulation was not capable of predicting the complete creep response, suggesting that the creep response of the chondrocytes under micropipette aspiration is predominantly due to intrinsic viscoelastic phenomena and is not due to the biphasic behavior.

Hemodynamics and complications encountered with arteriovenous fistulas and grafts as vascular access for hemodialysis: a review.

Abstract: This review article describes the current state of affairs concerning in vivo, in vitro and in numero studies on the hemodynamics in vascular access for hemodialysis. The use and complications of autogenous and non-autogenous fistulas and catheters and access port devices are explained in the first part. The major hemodynamic complications are stenosis, initiated by intimal hyperplasia development, and thrombosis. The different in literature proposed conceivable causes of intimal hyperplasia development like surgical interventions, compliance mismatch, wall shear stress (WSS) and shear rate, vessel wall thrill and blood pressure are discussed on the basis of in vivo, in vitro and in numero studies.

Zonal uniformity in mechanical properties of the chondrocyte pericellular matrix: micropipette aspiration of canine chondrons isolated by cartilage homogenization.

Abstract: The pericellular matrix (PCM) is a region of tissue that surrounds chondrocytes in articular cartilage and together with the enclosed cells is termed the chondron. Previous studies suggest that the mechanical properties of the PCM, relative to those of the chondrocyte and the extracellular matrix (ECM), may significantly influence the stress-strain, physicochemical, and fluid-flow environments of the cell. The aim of this study was to measure the biomechanical properties of the PCM of mechanically isolated chondrons and to test the hypothesis that the Young's modulus of the PCM varies with zone of origin in articular cartilage (surface vs. middle/deep). Chondrons were extracted from articular cartilage of the canine knee using mechanical homogenization, and the elastic properties of the PCM were determined using micropipette aspiration in combination with theoretical models of the chondron as an elastic incompressible half-space, an elastic compressible bilayer, or an elastic compressible shell. The Young's modulus of the PCM was significantly higher than that reported for isolated chondrocytes but over an order of magnitude lower than that of the cartilage ECM. No significant differences were observed in the Young's modulus of the PCM between surface zone (24.0 +/- 8.9 kPa) and middle/deep zone cartilage (23.2 +/- 7.1 kPa). In combination with previous theoretical biomechanical models of the chondron, these findings suggest that the PCM significantly influences the mechanical environment of the chondrocyte in articular cartilage and therefore may play a role in modulating cellular responses to micromechanical factors.