A computational remodeling approach to predict the physiological architecture of the collagen fibril network in corneo-scleral shells

Organized collagen fibrils form complex networks that introduce strong anisotropic and highly nonlinear attributes into the constitutive response of human eye tissues. Physiological adaptation of the collagen network and the mechanical condition within biological tissues are complex and mutually dependent phenomena. In this contribution, a computational model is presented to investigate the interaction between the collagen fibril architecture and mechanical loading conditions in the corneo-scleral shell. The biomechanical properties of eye tissues are derived from the single crimped fibril at the micro-scale via the collagen network of distributed fibrils at the meso-scale to the incompressible and anisotropic soft tissue at the macro-scale. Biomechanically induced remodeling of the collagen network is captured on the meso-scale by allowing for a continuous re-orientation of preferred fibril orientations and a continuous adaptation of the fibril dispersion. The presented approach is applied to a numerical human eye model considering the cornea and sclera. The predicted fibril morphology correlates well with experimental observations from X-ray scattering data.     

The kinetics of chemically induced nonequilibrium swelling of articular cartilage and corneal stroma

An electromechanical model for charged, hydrated tissues is developed to predict the kinetics of changes in swelling and isometric compressive stress induced by changes in bath salt concentration. The model focuses on ionic transport as the rate limiting step in chemically modulating electrical interactions between the charged macromolecules of the extracellular matrix. The swelling response to such changes in local interaction forces is determined by the relative rates of chemical diffusion and fluid redistribution in the tissue sample. We have tested the model by comparing the experimentally observed salt-induced stress relaxation response in bovine articular cartilage and corneal stroma to the response predicted by the model using constitutive relations for the concentration dependent material properties of the tissues reported in a related study. The qualitatively good agreement between our experimental measurements and the predictions of the model supports the physical basis of the model and demonstrates the model's ability to discriminate between the two soft connective tissues that were examined.     

An anisotropic constitutive model for immersogeometric fluid–structure interaction analysis of bioprosthetic heart valves

This paper considers an anisotropic hyperelastic soft tissue model, originally proposed for native valve tissue and referred to herein as the Lee–Sacks model, in an isogeometric thin shell analysis framework that can be readily combined with immersogeometric fluid–structure interaction (FSI) analysis for high-fidelity simulations of bioprosthetic heart valves (BHVs) interacting with blood flow. We find that the Lee–Sacks model is well-suited to reproduce the anisotropic stress–strain behavior of the cross-linked bovine pericardial tissues that are commonly used in BHVs. An automated procedure for parameter selection leads to an instance of the Lee–Sacks model that matches biaxial stress–strain data from the literature more closely, over a wider range of strains, than other soft tissue models. The relative simplicity of the Lee–Sacks model is attractive for computationally-demanding applications such as FSI analysis and we use the model to demonstrate how the presence and direction of material anisotropy affect the FSI dynamics of BHV leaflets.     

Large deformation shear properties of liver tissue

Characterization of the mechanical properties of soft biological tissues is important for establishing the mechanical tolerances of the tissues, and for input to computational models. In this work, the viscoelastic properties of bovine liver tissue in shear loading have been measured using relaxation and constant shear rate loading. The tissue is nonlinearly viscoelastic for strains greater than 0.2%, has a yield strain of approximately 10, and shows moderate strain-rate sensitivity. The response can be modelled using a nonlinear viscoelastic differential model previously developed for brain tissue.     

Viscoelastic properties of bovine orbital connective tissue and fat: constitutive models

Reported mechanical properties of orbital connective tissue and fat have been too sparse to model strain–stress relationships underlying biomechanical interactions in strabismus. We performed rheological tests to develop a multi-mode upper convected Maxwell (UCM) model of these tissues under shear loading. From 20 fresh bovine orbits, 30 samples of connective tissue were taken from rectus pulley regions and 30 samples of fatty tissues from the posterior orbit. Additional samples were defatted to determine connective tissue weight proportion, which was verified histologically. Mechanical testing in shear employed a triborheometer to perform: strain sweeps at 0.5–2.0 Hz; shear stress relaxation with 1% strain; viscometry at 0.01−0.5 s⁻¹ strain rate; and shear oscillation at 1% strain. Average connective tissue weight proportion was 98% for predominantly connective tissue and 76% for fatty tissue. Connective tissue specimens reached a long-term relaxation modulus of 668 Pa after 1,500 s, while corresponding values for fatty tissue specimens were 290 Pa and 1,100 s. Shear stress magnitude for connective tissue exceeded that of fatty tissue by five-fold. Based on these data, we developed a multi-mode UCM model with variable viscosities and time constants, and a damped hyperelastic response that accurately described measured properties of both connective and fatty tissues. Model parameters differed significantly between the two tissues. Viscoelastic properties of predominantly connective orbital tissues under shear loading differ markedly from properties of orbital fat, but both are accurately reflected using UCM models. These viscoelastic models will facilitate realistic global modeling of EOM behavior in binocular alignment and strabismus.     

Inertia effects on characterization of dynamic response of brain tissue

Modeling and simulation of traumatic brain injury (TBI) resulted from collision or blast loading requires characterization of mechanical response over a wide range of loading rates under valid testing conditions. In this study, mechanical response of fresh bovine brain tissue was studied using the two modified Kolsky bar techniques. Radial deformation behavior of annular specimens, which are typically used to characterize the dynamic uniaxial compressive response of biological tissues, was examined using a modified Kolsky bar and a high speed camera to collect images while the specimen deforms at an axial strain rate of 2000s(-1). The high-speed images revealed inhomogeneous specimen deformation possibly brought about by radial inertia and causing a multi-axial stress state. To acquire valid stress-strain results that can be used to produce constitutive behavior of the soft materials, a novel torsion technique was developed to obtain pure shear response at dynamic loading rates. Experimental results show clear differences in the material response using the two methods. These results indicate that the previously demonstrated annular specimen geometry aimed at reducing inertia induced stress components for high rate soft materials uniaxial-compressive testing may still possess a significant component of radial inertia induced radial stress which consequently caused the observed inhomogeneous deformation in brain tissue test samples.     

Simulation of planar soft tissues using a structural constitutive model: Finite element implementation and validation

Computational implementation of physical and physiologically realistic constitutive models is critical for numerical simulation of soft biological tissues in a variety of biomedical applications. It is well established that the highly nonlinear and anisotropic mechanical behaviors of soft tissues are an emergent behavior of the underlying tissue microstructure. In the present study, we have implemented a structural constitutive model into a finite element framework specialized for membrane tissues. We noted that starting with a single element subjected to uniaxial tension, the non-fibrous tissue matrix must be present to prevent unrealistic tissue deformations. Flexural simulations were used to set the non-fibrous matrix modulus because fibers have little effects on tissue deformation under three-point bending. Multiple deformation modes were simulated, including strip biaxial, planar biaxial with two attachment methods, and membrane inflation. Detailed comparisons with experimental data were undertaken to insure faithful simulations of both the macro-level stress–strain insights into adaptations of the fiber architecture under stress, such as fiber reorientation and fiber recruitment. Results indicated a high degree of fidelity and demonstrated interesting microstructural adaptions to stress and the important role of the underlying tissue matrix. Moreover, we apparently resolve a discrepancy in our 1997 study (Billiar and Sacks, 1997. J. Biomech. 30 (7), 753–756) where we observed that under strip biaxial stretch the simulated fiber splay responses were not in good agreement with the experimental results, suggesting non-affine deformations may have occurred. However, by correctly accounting for the isotropic phase of the measured fiber splay, good agreement was obtained. While not the final word, these simulations suggest that affine fiber kinematics for planar collagenous tissues is a reasonable assumption at the macro level. Simulation tools such as these are imperative in the design and simulation of native and engineered tissues.     

HCMV大小鼠眼组织损伤模型的初步研究

目的探讨接种人巨细胞病毒(Humancytomegalovirus,HCMV)是否引起Wistar大鼠、昆明种小鼠眼组织损伤.方法将HCMVAD169毒株经静脉接种Wistar大鼠和昆明种小鼠,观察动物眼部发病情况,原位杂交检测动物眼组织中的HCMVDNA片段.结果接种病毒后部分动物缓慢出现眼部发病,局部分泌物增多、浑浊甚至失明;经原位杂交于视锥、视杆细胞和角膜内皮细胞中检出HCMVDNA片段.结论HCMV可以感染动物眼组织,并引起动物发生眼病.     

Mechanical properties of brain tissue in tension

This paper contains experimental results of in vitro, uniaxial tension of swine brain tissue in finite deformation as well as proposes a new hyper-viscoelastic constitutive model for the brain tissue. The experimental results obtained for two loading velocities, corresponding to strain rates of 0.64 and 0.64 x 10(-2)s(-1), are presented. We believe that these are the first ever experiments of this kind. The applied strain rates were similar to those applied in our previous study, focused on explaining brain tissue properties in compression. The stress-strain curves are convex downward for all extension rates. The tissue response stiffened as the loading speed increased, indicating a strong stress-strain rate dependence. Swine brain tissue was found to be considerably softer in extension than in compression. Previously proposed in the literature brain tissue constitutive models, developed based on experimental data collected in compression are shown to be inadequate to explain tissue behaviour in tension. A new, non-linear, viscoelastic model based on the generalisation of the Ogden strain energy hyper-elastic constitutive equation is proposed. The new model accounts well for brain tissue deformation behaviour in both tension and compression (natural strain in <-0.3,0.2>) for strain rates ranging over five orders of magnitude.     

Incorporation of experimentally-derived fiber orientation into a structural constitutive model for planar collagenous tissues

Structural constitutive models integrate information on tissue composition and structure, avoiding ambiguities in material characterization. However, critical structural information (such as fiber orientation) must be modeled using assumed statistical distributions, with the distribution parameters estimated from fits to the mechanical test data. Thus, full realization of structural approaches continues to be limited without direct quantitative structural information for direct implementation or to validate model predictions. In the present study, fiber orientation information obtained using small angle light scattering (SALS) was directly incorporated into a structural constitutive model based on work by Lanir (J. Biomech., v. 16, pp. 1-12, 1983). Demonstration of the model was performed using existing biaxial mechanical and fiber orientation data for native bovine pericardium (Sacks and Chuong, ABME, v.26, pp. 892-902, 1998). The structural constitutive model accurately predicted the complete measured biaxial mechanical response. An important aspect of this approach is that only a single equibiaxial test to determine the effective fiber stress-strain response and the SALS-derived fiber orientation distribution were required to determine the complete planar biaxial mechanical response. Changes in collagen fiber crimp under equibiaxial strain suggest that, at the meso-scale, fiber deformations follow the global tissue strains. This result supports the assumption of affine strain to estimate the fiber strains. However, future evaluations will have to be performed for tissue subjected to a wider range of strain to more fully validate the current approach.     

Environmental light and endogenous antioxidants as the main determinants of non-cancer ocular diseases

The human eye is constantly exposed to sunlight and artificial lighting. Exogenous sources of reactive oxygen species (ROS) such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins contribute to oxidative damage in ocular tissues. Long-term exposure to these insults places the aging eye at considerable risk for pathological consequences of oxidative stress. Furthermore, in eye tissues, mitochondria are an important endogenous source of ROS. Over time, all ocular structures, from the tear film to the retina, undergo oxidative stress, and therefore, the antioxidant defenses of each tissue assume the role of a safeguard against degenerative ocular pathologies. The ocular surface and cornea protect the other ocular tissues and are significantly exposed to oxidative stress of environmental origin. Overwhelming of antioxidant defenses in these tissues clinically manifests as pathologies including pterygium, corneal dystrophies, and endothelial Fuch's dystrophy. The crystalline lens is highly susceptible to oxidative damage in aging because its cells and their intracellular proteins are not turned over or replaced, thus providing the basis for cataractogenesis. The trabecular meshwork, which is the anterior chamber tissue devoted to aqueous humor drainage, has a particular susceptibility to mitochondrial oxidative injury that affects its endothelium and leads to an intraocular pressure increase that marks the beginning of glaucoma. Photo-oxidative stress can cause acute or chronic retinal damage. The pathogenesis of age-related macular degeneration involves oxidative stress and death of the retinal pigment epithelium followed by death of the overlying photoreceptors. Accordingly, converging evidence indicates that mutagenic mechanisms of environmental and endogenous sources play a fundamental pathogenic role in degenerative eye diseases.     

Identifying a minimal rheological configuration: a tool for effective and efficient constitutive modeling of soft tissues

We describe a modeling methodology intended as a preliminary step in the identification of appropriate constitutive frameworks for the time-dependent response of biological tissues. The modeling approach comprises a customizable rheological network of viscous and elastic elements governed by user-defined 1D constitutive relationships. The model parameters are identified by iterative nonlinear optimization, minimizing the error between experimental and model-predicted structural (load-displacement) tissue response under a specific mode of deformation. We demonstrate the use of this methodology by determining the minimal rheological arrangement, constitutive relationships, and model parameters for the structural response of various soft tissues, including ex vivo perfused porcine liver in indentation, ex vivo porcine brain cortical tissue in indentation, and ex vivo human cervical tissue in unconfined compression. Our results indicate that the identified rheological configurations provide good agreement with experimental data, including multiple constant strain rate load/unload tests and stress relaxation tests. Our experience suggests that the described modeling framework is an efficient tool for exploring a wide array of constitutive relationships and rheological arrangements, which can subsequently serve as a basis for 3D constitutive model development and finite-element implementations. The proposed approach can also be employed as a self-contained tool to obtain simplified 1D phenomenological models of the structural response of biological tissue to single-axis manipulations for applications in haptic technologies.     

Isoelectric focusing studies of aldehyde dehydrogenases, alcohol dehydrogenases and oxidases from mammalian anterior eye tissues

1. Isoelectric focusing (IEF) and zymogram methods were used to examine the tissue distribution, multiplicity and substrate specificities of alcohol dehydrogenases (ADHs), aldehyde dehydrogenases (ALDHs) and ocular oxidases (EOXs) from mammalian anterior eye tissues. 2. Baboon, cattle, pig and sheep corneal extracts exhibited high ALDH activities; the corneal ALDHs were distinct from the major liver ALDHs and distinguished by their preference for medium-chain aldehydes. 3. Baboon and pig corneal extracts also showed high ADH activities, by comparison with ovine and bovine samples. Moreover, the ADHs were distinct from the major liver isozymes in pI value and substrate specificity. 4. Mammalian lens extracts exhibited significant ALDH activity of a form corresponding to the major liver cytosolic isozyme. Minor activity of the corneal enzyme was also observed in some species. 5. Lens ADH phenotypes were species-specific, and consisted of either Class II activity (baboon and sheep), Class III ADH activity (pig), or activities of both ADH classes (cattle). 6. Lens extracts also exhibited a complex pattern of ocular oxidase (EOX) activities following IEF. 7. A role in peroxidatic aldehyde detoxification is proposed for these enzymes in anterior eye tissues.     

Ocular Lesions Induced by the Trachoma Agent in Rabbits

Injection of the T'ang strain of trachoma agent into the anterior chamber of the rabbit eye caused corneal opacity, characteristic microscopic lesions of the corneal endothelium, varying degrees of neovascularization of the cornea, and uveitis. These ocular changes were agent-specific. The experimental data showed that the microorganism developed in the ocular tissues. The results of this study suggest the possibility of using the rabbit eye as an experimental model for the study of trachoma.     

A closed-form structural model of planar fibrous tissue mechanics

Structural models of tissue mechanics, in which the tissue is represented as a sum or integral of fiber contributions for a distribution of fiber orientations, are a popular tool to represent the complex mechanical behavior of soft tissues. A significant practical challenge, however, is evaluation of the integral that defines the stress. Numerical integration is accurate but computationally demanding, posing an impediment to incorporation of structural models into large-scale finite-element simulations. In this paper, a closed-form analytic evaluation of the integral is derived for fibers distributed according to a von Mises distribution and an exponential fiber stress–strain law.     

Patient-specific modeling of corneal refractive surgery outcomes and inverse estimation of elastic property changes

The purpose of this study is to develop a 3D patient-specific finite element model (FEM) of the cornea and sclera to compare predicted and in vivo refractive outcomes and to estimate the corneal elastic property changes associated with each procedure. Both eyes of a patient who underwent laser-assisted in situ keratomileusis (LASIK) for myopic astigmatism were modeled. Pre- and postoperative Scheimpflug anterior and posterior corneal elevation maps were imported into a 3D corneo-scleral FEM with an unrestrained limbus. Preoperative corneal hyperelastic properties were chosen to account for meridional anisotropy. Inverse FEM was used to determine the undeformed corneal state that produced <0.1% error in anterior elevation between simulated and in vivo preoperative geometries. Case-specific 3D aspheric ablation profiles were simulated, and corneal topography and spherical aberration were compared at clinical intraocular pressure. The magnitude of elastic weakening of the residual corneal bed required to maximize the agreement with clinical axial power was calculated and compared with the changes in ocular response analyzer (ORA) measurements. The models produced curvature maps and spherical aberrations equivalent to in vivo measurements. For the preoperative property values used in this study, predicted elastic weakening with LASIK was as high as 55% for a radially uniform model of residual corneal weakening and 65% at the point of maximum ablation in a spatially varying model of weakening. Reductions in ORA variables were also observed. A patient-specific FEM of corneal refractive surgery is presented, which allows the estimation of surgically induced changes in corneal elastic properties. Significant elastic weakening after LASIK was required to replicate clinical topographic outcomes in this two-eye pilot study.     

Modeling of long-term fatigue damage of soft tissue with stress softening and permanent set effects

One of the major failure modes of bioprosthetic heart valves is non-calcific structural deterioration due to fatigue of the tissue leaflets. Experimental methods to characterize tissue fatigue properties are complex and time-consuming. A constitutive fatigue model that could be calibrated by isolated material tests would be ideal for investigating the effects of more complex loading conditions. However, there is a lack of tissue fatigue damage models in the literature. To address these limitations, in this study, a phenomenological constitutive model was developed to describe the stress softening and permanent set effects of tissue subjected to long-term cyclic loading. The model was used to capture characteristic uniaxial fatigue data for glutaraldehyde-treated bovine pericardium and was then implemented into finite element software. The simulated fatigue response agreed well with the experimental data and thus demonstrates feasibility of this approach.     

Methodology to determine failure characteristics of planar soft tissues using a dynamic tensile test

Predicting the injury risk in automotive collisions requires accurate knowledge of human tissues, more particularly their mechanical properties under dynamic loadings. The present methodology aims to determine the failure characteristics of planar soft tissues such as skin, hollow organs and large vessel walls. This consists of a dynamic tensile test, which implies high-testing velocities close to those in automotive collisions. To proceed, I-shaped tissue samples are subjected to dynamic tensile tests using a customized tensile device based on the drop test principle. Data acquisition has especially been adapted to heterogeneous and soft biological tissues given that standard measurement systems (considered to be global) have been completed with a non-contact and full-field strain measurement (considered to be local). This local measurement technique, called the Image Correlation Method (ICM) provides an accurate strain analysis by revealing strain concentrations and avoids damaging the tissue. The methodology has first been applied to human forehead skin and can be further expanded to other planar soft tissues. The failure characteristics for the skin in terms of ultimate stress are 3 MPa +/- 1.5 MPa. The ultimate global longitudinal strains are equal to 9.5%+/-1.9% (Green-Lagrange strain), which contrasts with the ultimate local longitudinal strain values of 24.0%+/-5.3% (Green-Lagrange strain). This difference is a consequence of the tissue heterogeneity, clearly illustrated by the heterogeneous distribution of the local strain field. All data will assist in developing the tissue constitutive law that will be implemented in finite element models.