Biofluid modeling of the coupled eye-brain system and insights into simulated microgravity conditions.

This work aims at investigating the interactions between the flow of fluids in the eyes and the brain and their potential implications in structural and functional changes in the eyes of astronauts, a condition also known as spaceflight associated neuro-ocular syndrome (SANS). To this end, we propose a reduced (0-dimensional) mathematical model of fluid flow in the eyes and brain, which is embedded into a simplified whole-body circulation model. In particular, the model accounts for: (i) the flows of blood and aqueous humor in the eyes; (ii) the flows of blood, cerebrospinal fluid and interstitial fluid in the brain; and (iii) their interactions. The model is used to simulate variations in intraocular pressure, intracranial pressure and blood flow due to microgravity conditions, which are thought to be critical factors in SANS. Specifically, the model predicts that both intracranial and intraocular pressures increase in microgravity, even though their respective trends may be different. In such conditions, ocular blood flow is predicted to decrease in the choroid and ciliary body circulations, whereas retinal circulation is found to be less susceptible to microgravity-induced alterations, owing to a purely mechanical component in perfusion control associated with the venous segments. These findings indicate that the particular anatomical architecture of venous drainage in the retina may be one of the reasons why most of the SANS alterations are not observed in the retina but, rather, in other vascular beds, particularly the choroid. Thus, clinical assessment of ocular venous function may be considered as a determinant SANS factor, for which astronauts could be screened on earth and in-flight.

A Mathematical Model of Corneal Metabolism in the Presence of an Iris-Fixated Phakic Intraocular Lens.

Purpose: Corneal endothelial cell loss is one of the possible complications associated with phakic iris-fixated intraocular lens (PIOL) implantation. We postulate that this might be connected to the alteration of corneal metabolism secondary to the lens implantation. Methods: A mathematical model of transport and consumption/production of metabolic species in the cornea is proposed, coupled with a model of aqueous flow and transport of metabolic species in the anterior chamber. Results: Results are presented both for open and closed eyelids. We showed that, in the presence of a PIOL, glucose availability at the corneal endothelium decreases significantly during sleeping. Conclusions: Implantation of a PIOL significantly affects nutrient transport processes to the corneal endothelium especially during sleep. It must still be verified whether this finding has a clinical relevance.

A structural model for the in vivo human cornea including collagen-swelling interaction.

A structural model of the in vivo cornea, which accounts for tissue swelling behaviour, for the three-dimensional organization of stromal fibres and for collagen-swelling interaction, is proposed. Modelled as a binary electrolyte gel in thermodynamic equilibrium, the stromal electrostatic free energy is based on the mean-field approximation. To account for active endothelial ionic transport in the in vivo cornea, which modulates osmotic pressure and hydration, stromal mobile ions are shown to satisfy a modified Boltzmann distribution. The elasticity of the stromal collagen network is modelled based on three-dimensional collagen orientation probability distributions for every point in the stroma obtained by synthesizing X-ray diffraction data for azimuthal angle distributions and second harmonic-generated image processing for inclination angle distributions. The model is implemented in a finite-element framework and employed to predict free and confined swelling of stroma in an ionic bath. For the in vivo cornea, the model is used to predict corneal swelling due to increasing intraocular pressure (IOP) and is adapted to model swelling in Fuchs' corneal dystrophy. The biomechanical response of the in vivo cornea to a typical LASIK surgery for myopia is analysed, including tissue fluid pressure and swelling responses. The model provides a new interpretation of the corneal active hydration control (pump-leak) mechanism based on osmotic pressure modulation. The results also illustrate the structural necessity of fibre inclination in stabilizing the corneal refractive surface with respect to changes in tissue hydration and IOP.

The Balance of Fluid and Osmotic Pressures across Active Biological Membranes with Application to the Corneal Endothelium.

The movement of fluid and solutes across biological membranes facilitates the transport of nutrients for living organisms and maintains the fluid and osmotic pressures in biological systems. Understanding the pressure balances across membranes is crucial for studying fluid and electrolyte homeostasis in living systems, and is an area of active research. In this study, a set of enhanced Kedem-Katchalsky (KK) equations is proposed to describe fluxes of water and solutes across biological membranes, and is applied to analyze the relationship between fluid and osmotic pressures, accounting for active transport mechanisms that propel substances against their concentration gradients and for fixed charges that alter ionic distributions in separated environments. The equilibrium analysis demonstrates that the proposed theory recovers the Donnan osmotic pressure and can predict the correct fluid pressure difference across membranes, a result which cannot be achieved by existing KK theories due to the neglect of fixed charges. The steady-state analysis on active membranes suggests a new pressure mechanism which balances the fluid pressure together with the osmotic pressure. The source of this pressure arises from active ionic fluxes and from interactions between solvent and solutes in membrane transport. We apply the proposed theory to study the transendothelial fluid pressure in the in vivo cornea, which is a crucial factor maintaining the hydration and transparency of the tissue. The results show the importance of the proposed pressure mechanism in mediating stromal fluid pressure and provide a new interpretation of the pressure modulation mechanism in the in vivo cornea.

Three-dimensional modeling of metabolic species transport in the cornea with a hydrogel intrastromal inlay.

PURPOSE: Intrastromal inlays for refractive correction of presbyopia are being adopted into clinical practice. An important concern is the effect of the inlay on the long-term health of the cornea due to disturbances in the concentration profiles of metabolic species. A three-dimensional metabolic model for the cornea is employed to investigate oxygen, glucose, and lactate ion transport in the cornea and to estimate changes in species concentrations induced by the introduction of a hydrogel inlay. METHODS: A reaction-diffusion metabolic model, appropriate for highly oxygen-permeable hydrogel inlays, is used to describe cellular consumption of oxygen and glucose and production of lactic acid. A three-layer corneal geometry (epithelium, stroma, endothelium) is employed with a hydrogel inlay placed under a lamellar flap. The model is solved numerically by the finite element method. RESULTS: For a commercially available hydrogel material with a relative inlay diffusivity of 43.5%, maximum glucose depletion and lactate ion accumulation occur anterior to the inlay and both are less than 3%. Below 20% relative diffusivity, glucose depletion and lactate ion accumulation increase exponentially. Glucose depletion increases slightly with increasing depth of inlay placement. CONCLUSIONS: The flux of metabolic species is modified by an inlay, depending on the inlay relative diffusivity. For commercially available hydrogel materials and a typical inlay design, predicted changes in species concentrations are small when compared to the variation of concentrations across the normal cornea. In general, glucose depletion and lactate ion accumulation are highly sensitive to inlay diffusivity and somewhat insensitive to inlay depth.

THREE-DIMENSIONAL MODELING OF METABOLIC SPECIES TRANSPORT IN THE CORNEA WITH A HYDROGEL INTRASTROMAL INLAY.

Purpose: Intrastromal inlays for refractive correction of presbyopia are being adopted into clinical practice. An important concern is the effect of the inlay on the long-term health of the cornea due to disturbances in the concentration profiles of metabolic species. A 3-D metabolic model for the cornea is employed to investigate oxygen, glucose and lactate ion transport in the cornea and to estimate changes in species concentrations induced by the introduction of a hydrogel inlay. Methods: A reaction-diffusion metabolic model, appropriate for highly oxygen-permeable hydrogel inlays, is used to describe cellular consumption of oxygen and glucose and production of lactic acid. A three-layer corneal geometry (epithelium, stroma, endothelium) is employed with a hydrogel inlay placed under a lamellar flap. The model is solved numerically by the finite element method. Results: For a commercially available hydrogel material with a relative inlay diffusivity of 43.5%, maximum glucose depletion and lactate ion accumulation occur anterior to the inlay and both are less than 3%. Below 20% relative diffusivity, glucose depletion and lactate ion accumulation increase exponentially. Glucose depletion increases slightly with increasing depth of inlay placement. Conclusions: The flux of metabolic species is modified by an inlay, depending on the inlay relative diffusivity. For commercially available hydrogel materials and a typical inlay design, predicted changes in species concentrations are small when compared to the variation of concentrations across the normal cornea. In general, glucose depletion and lactate ion accumulation are highly sensitive to inlay diffusivity and somewhat insensitive to inlay depth.

Three-dimensional distribution of transverse collagen fibers in the anterior human corneal stroma.

PURPOSE: Recent investigations of human corneal structure and biomechanics have shown that stromal collagen fibers (lamellae) are organized into a complex, highly intertwined three-dimensional meshwork of transverse oriented fibers that increases stromal stiffness and controls corneal shape. The purpose of this study was to characterize the three-dimensional distribution of transverse collagen fibers along the major meridians of the cornea using an automated method to rapidly quantify the collagen fibers' angular orientation. METHODS: Three eyes from three donors were perfusion-fixed under pressure, excised, and cut into four quadrants. Quadrants were physically sectioned using a vibratome and scanned using nonlinear optical high-resolution macroscopy. Planes were analyzed numerically using software to identify collagen fiber angles relative to the corneal surface, stromal depth, and radial position within the anterior 250 µm of the stroma. RESULTS: The range of fiber angles and the fiber percentage having an angular displacement greater than ±3.5° relative to the corneal surface ("transverse fibers") was highest in the anterior stroma and decreased with depth. Numerical analysis showed no significant differences in fiber angles and transverse fibers between quadrants, meridians, and radial position. CONCLUSIONS: These results match our previous observation of a depth-dependent gradient in stromal collagen interconnectivity in the central cornea, and show that this gradient extends from the central cornea to the limbus. The lack of a preferred distribution of angled fibers with regard to corneal quadrant or radial position likely serves to evenly distribute loads and to avoid the formation of areas of stress concentration.

Mechanisms of self-organization for the collagen fibril lattice in the human cornea.

The transparency of the human cornea depends on the regular lattice arrangement of the collagen fibrils and on the maintenance of an optimal hydration--the achievement of both depends on the presence of stromal proteoglycans (PGs) and their linear sidechains of negatively charged glycosaminoglycans (GAGs). Although the GAGs produce osmotic pressure by the Donnan effect, the means by which they exert positional control of the lattice is less clear. In this study, a theoretical model based on equilibrium thermodynamics is used to describe restoring force mechanisms that may control and maintain the fibril lattice and underlie corneal transparency. Electrostatic-based restoring forces that result from local charge density changes induced by fibril motion, and entropic elastic restoring forces that arise from duplexed GAG structures that bridge neighbouring fibrils, are described. The model allows for the possibility that fibrils have a GAG-dense coating that adds an additional fibril force mechanism preventing fibril aggregation. Swelling pressure predictions are used to validate the model with results showing excellent agreement with experimental data over a range of hydration from 30 to 200% of normal. The model suggests that the electrostatic restoring force is dominant, with the entropic forces from GAG duplexes being an order or more smaller. The effect of a random GAG organization, as observed in recent imaging, is considered in a dynamic model of the lattice that incorporates randomness in both the spatial distribution of GAG charge and the topology of the GAG duplexes. A striking result is that the electrostatic restoring forces alone are able to reproduce the image-based lattice distribution function for the human cornea, and thus dynamically maintain the short-range order of the lattice.

The role of 3-D collagen organization in stromal elasticity: a model based on X-ray diffraction data and second harmonic-generated images.

Examining the cross-section of the human cornea with second harmonic-generated (SHG) imaging shows that many lamellae do not lie parallel to the cornea's anterior surface but have inclined trajectories that take them through the corneal thickness with a depth-dependent distribution. A continuum mechanics-based model of stromal elasticity is developed based on orientation information extracted and synthesized from both X-ray scattering studies and SHG imaging. The model describes the effects of inclined lamella orientation by introducing a probability function that varies with depth through the stroma, which characterizes the range and distribution of lamellae at inclined angles. When combined with the preferred lamellar orientations found from X-ray scattering experiments, a fully 3-D representation of lamella orientation is achieved. Stromal elasticity is calculated by a weighted average of individual lamella properties based on the spatially varying 3-D orientation distribution. The model is calibrated with in vitro torsional shear experiments and in vivo indentation data and then validated with an in vitro inflation study. A quantitative explanation of the experimentally measured depth dependence of mechanical properties emerges from the model. The significance of the 3-D lamella orientation in the mechanics of the human cornea is demonstrated by investigating and contrasting the effects of previous modeling assumptions made on lamella orientation.

Depth-dependent transverse shear properties of the human corneal stroma.

PURPOSE: To measure the transverse shear modulus of the human corneal stroma and its profile through the depth by mechanical testing, and to assess the validity of the hypothesis that the shear modulus will be greater in the anterior third due to increased interweaving of lamellae. METHODS: Torsional rheometry was used to measure the transverse shear properties of 6 mm diameter buttons of matched human cadaver cornea pairs. One cornea from each pair was cut into thirds through the thickness with a femtosecond laser and each stromal third was tested individually. The remaining intact corneas were tested to measure full stroma shear modulus. The shear modulus from a 1% shear strain oscillatory test was measured at various levels of axial compression for all samples. RESULTS: After controlling for axial compression, the transverse shear moduli of isolated anterior layers were significantly higher than central and posterior layers. Mean modulus values at 0% axial strain were 7.71 ± 6.34 kPa in the anterior, 1.99 ± 0.45 kPa in the center, 1.31 ± 1.01 kPa in the posterior, and 9.48 ± 2.92 kPa for full thickness samples. A mean equilibrium compressive modulus of 38.7 ± 8.6 kPa at 0% axial strain was calculated from axial compression measured during the shear tests. CONCLUSIONS: Transverse shear moduli are two to three orders of magnitude lower than tensile moduli reported in the literature. The profile of shear moduli through the depth displayed a significant increase from posterior to anterior. This gradient supports the hypothesis and corresponds to the gradient of interwoven lamellae seen in imaging of stromal cross-sections.

Multiscale modeling framework of transdermal drug delivery.

This study addresses the modeling of transdermal diffusion of drugs to better understand the permeation of molecules through the skin, especially the stratum corneum, which forms the main permeation barrier to percutaneous permeation. In order to ensure reproducibility and predictability of drug permeation through the skin and into the body, a quantitative understanding of the permeation barrier properties of the stratum corneum (SC) is crucial. We propose a multiscale framework of modeling the multicomponent transdermal diffusion of molecules. The problem is divided into subproblems of increasing length scale: microscopic, mesoscopic, and macroscopic. First, the microscopic diffusion coefficient in the lipid bilayers of the SC is found through molecular dynamics (MD) simulations. Then, a homogenization procedure is performed over a model unit cell of the heterogeneous SC, resulting in effective diffusion parameters. These effective parameters are the macroscopic diffusion coefficients for the homogeneous medium that is "equivalent" to the heterogeneous SC, and thus can be used in finite element simulations of the macroscopic diffusion process. The resulting drug flux through the skin shows very reasonable agreement to experimental data.

Finite element modeling of acousto-mechanical coupling in the cat middle ear.

The function of the middle ear is to transfer acoustic energy from the ear canal to the cochlea. An essential component of this system is the tympanic membrane. In this paper, a new finite element model of the middle ear of the domestic cat is presented, generated in part from cadaver anatomy via microcomputed tomographic imaging. This model includes a layered composite model of the eardrum, fully coupled with the acoustics in the ear canal and middle-ear cavities. Obtaining the frequency response from 100 Hz to 20 kHz is a computationally challenging task, which has been accomplished by using a new adaptive implementation of the reduced-order matrix Padé-via-Lanczos algorithm. The results are compared to established physiological data. The fully coupled model is applied to study the role of the collagen fiber sublayers of the eardrum and to investigate the relationship between the structure of the middle-ear cavities and its function. Three applications of this model are presented, demonstrating the shift in the middle-ear resonance due to the presence of the septum that divides the middle-ear cavity space, the significance of the radial fiber layer on high frequency transmission, and the importance of the transverse shear modulus in the eardrum microstructure.

Simulating and interpreting Kelvin probe force microscopy images on dielectrics with boundary integral equations.

Kelvin probe force microscopy (KPFM) is designed for measuring the tip-sample contact potential differences by probing the sample surface, measuring the electrostatic interaction, and adjusting a feedback circuit. However, for the case of a dielectric (insulating) sample, the contact potential difference may be ill defined, and the KPFM probe may be sensing electrostatic interactions with a certain distribution of sample trapped charges or dipoles, leading to difficulty in interpreting the images. We have proposed a general framework based on boundary integral equations for simulating the KPFM image based on the knowledge about the sample charge distributions (forward problem) and a deconvolution algorithm solving for the trapped charges on the surface from an image (inverse problem). The forward problem is a classical potential problem, which can be efficiently solved using the boundary element method. Nevertheless, the inverse problem is ill posed due to data incompleteness. For some special cases, we have developed deconvolution algorithms based on the forward problem solution. As an example, this algorithm is applied to process the KPFM image of a gadolinia-doped ceria thin film to solve for its surface charge density, which is a more relevant quantity for samples of this kind than the contact potential difference (normally only defined for conductive samples) values contained in the raw image.

Using the method of homogenization to calculate the effective diffusivity of the stratum corneum with permeable corneocytes.

The stratum corneum is the outermost layer of the skin, which acts as a barrier membrane against the penetration of molecules into and out of the body. It has a biphasic structure consisting of keratinized cells (corneocytes) that are embedded in a lipid matrix. The macroscopic transport properties of the stratum corneum are functions of its microstructure and the transport properties of the corneocytes and the lipid matrix, and are of considerable interest in the context of transdermal drug delivery and quantifying exposure to toxins, as well as for determining the relation of skin disorders to disruption of the stratum corneum barrier. Due to the complexity of the tissue and the difference in length scales involved in its microstructure, a direct analysis of the mass transport properties of the stratum corneum is not feasible. In this study, we undertake an approach where the macroscopic diffusion tensor of the stratum corneum is obtained through homogenization using the method of asymptotic expansions. The biphasic structure of the stratum corneum is fully accounted for by allowing the corneocytes to be permeable and considering the partitioning between the corneocytes and the lipid phases. By systematically exploring the effect of permeable corneocytes on the macroscopic transport properties of the stratum corneum, we show that solute properties such as lipophilicity and relative permeabilities in the two phases have large effects on its transdermal diffusion behavior.

A resolution study for electrostatic force microscopy on bimetallic samples using the boundary element method.

Electrostatic force microscopy (EFM) is a special design of non-contact atomic force microscopy used for detecting electrostatic interactions between the probe tip and the sample. Its resolution is limited by the finite probe size and the long-range characteristics of electrostatic forces. Therefore, quantitative analysis is crucial to understanding the relationship between the actual local surface potential distribution and the quantities obtained from EFM measurements. To study EFM measurements on bimetallic samples with surface potential inhomogeneities as a special case, we have simulated such measurements using the boundary element method and calculated the force component and force gradient component that would be measured by amplitude modulation (AM) EFM and frequency modulation (FM) EFM, respectively. Such analyses have been performed for inhomogeneities of various shapes and sizes, for different tip-sample separations and tip geometries, for different applied voltages, and for different media (e.g., vacuum or water) in which the experiment is performed. For a sample with a surface potential discontinuity, the FM-EFM resolution expression agrees with the literature; however, the simulation for AM-EFM suggests the existence of an optimal tip radius of curvature in terms of resolution. On the other hand, for samples with strip- and disk-shaped surface potential inhomogeneities, we have obtained quantitative expressions for the detectability size requirements as a function of experimental conditions for both AM- and FM-EFMs, which suggest that a larger tip radius of curvature is moderately favored for detecting the presence of such inhomogeneities.

Finite element modeling of coupled diffusion with partitioning in transdermal drug delivery.

The finite element method is employed to simulate two-dimensional (axisymmetric) drug diffusion from a finite drug reservoir into the skin. The numerical formulation is based on a general mathematical model for multicomponent nonlinear diffusion that takes into account the coupling effects between the different components. The presence of several diffusing components is crucial, as many transdermal drug delivery formulations contain one or more permeation enhancers in addition to the drug. The coupling between the drug and permeation enhancer(s) results in nonlinear diffusion with concentration-dependent diffusivities of the various components. The framework is suitable for modeling both linear and nonlinear, single- and multicomponent diffusions, however, as it reduces to the correct formulation simply by setting the relevant parameters to zero. In addition, we show that partitioning of the penetrants from the reservoir into the skin can be treated in a straightforward manner in this framework using the mixed method. Partitioning at interface boundaries poses some difficulty with the standard finite element method as it creates a discontinuity in the concentration variable at the interface. To our knowledge, nonlinear (concentration-dependent) partitioning in diffusion problems has not been treated numerically before, and we demonstrate that nonlinear partitioning may have an important role in the effect of permeation enhancers. The mixed method that we adopt includes the flux at the interface explicitly in the formulation, allowing the modeling of concentration-dependent partitioning of the permeants between the reservoir and the skin as well as constant (linear) partitioning. The result is a versatile finite element framework suitable for modeling both linear and nonlinear diffusions in heterogeneous media where the diffusivities and partition coefficients may vary in each subregion.

A 3D model of muscle reveals the causes of nonuniform strains in the biceps brachii.

Biomechanical models generally assume that muscle fascicles shorten uniformly. However, dynamic magnetic resonance (MR) images of the biceps brachii have recently shown nonuniform shortening along some muscle fascicles during low-load elbow flexion (J. Appl. Physiol. 92 (2002) 2381). The purpose of this study was to uncover the features of the biceps brachii architecture and material properties that could lead to nonuniform shortening. We created a three-dimensional finite-element model of the biceps brachii and compared the tissue strains predicted by the model with experimentally measured tissue strains. The finite-element model predicted strains that were within one standard deviation of the experimentally measured strains. Analysis of the model revealed that the variation in fascicle lengths within the muscle and the curvature of the fascicles were the primary factors contributing to nonuniform strains. Continuum representations of muscle, combined with in vivo image data, are needed to deepen our understanding of how complex geometric arrangements of muscle fibers affect muscle contraction mechanics.

Computational modeling of mechanical anisotropy in the cornea and sclera.

PURPOSE: To determine the biomechanical deformation of the cornea resulting from tissue cutting and removal by use of a new computational model and to investigate the effect of mechanical anisotrophy resulting from the fibrillar architecture. SETTING: Department of Mechanical Engineering, Stanford University, Stanford, California, USA. METHODS: A mathematical model for a typical lamella that explicitly accounts for the strain energy of the collagen fibrils, extrafibrillar matrix, and proteoglycan cross-linking was developed. A stromal model was then obtained by generalized averaging of the lamella properties through the stromal thickness, taking into account the preferred orientations of the collagen fibrils, which were obtained from x-ray scattering data. RESULTS: The model was used to predict astigmatism induced by a tunnel incision in the sclera, such as is used for cataract extraction and intraocular lens implantation. The amount of induced cylinder was in good agreement with published clinical data. Results show it is important for the model to incorporate preexisting corneal physiological stress caused by intraocular pressure. CONCLUSIONS: The mathematical model described appears to provide a framework for further development, capturing the essential features of mechanical anisotropy of the cornea. The tunnel incision simulation indicated the importance of the anisotropy in this case.

Application of Padé via Lanczos approximations for efficient multifrequency solution of Helmholtz problems.

This paper addresses the efficient solution of acoustic problems in which the primary interest is obtaining the solution only on restricted portions of the domain but over a wide range of frequencies. The exterior acoustics boundary value problem is approximated using the finite element method in combination with the Dirichlet-to-Neumann (DtN) map. The restriction domain problem is formally posed in transfer function form based on the finite element solution. In order to obtain the solution over a range of frequencies, a matrix-valued Padé approximation of the transfer function is employed, using a two-sided block Lanczos algorithm. This approach provides a stable and efficient representation of the Padé approximation. In order to apply the algorithm, it is necessary to reformulate the transfer function due to the frequency dependency in the nonreflecting boundary condition. This is illustrated for the case of the DtN boundary condition, but there is no restriction on the approach which can also be applied to other radiation boundary conditions. Numerical tests confirm that the approach offers significant computational speed-up.