Biotransport in nervous tissues is complicated by the existence of neural fibers. These axonal fibers result in inhomogeneous and anisotropic extracellular transport, which complicates the prediction of local drug delivery such as convection-enhanced delivery [1]. Previous studies by our group [4] have shown that by using diffusion tensor imaging (DTI) [2, 3], anisotropic transport in rat spinal cord can be modeled using computational models, and consequently extracellular flows which influence drug transport can be well predicted. In previous studies, DTI-based models used data from an excised and fixed rat spinal cord. In the current study, we extend our DTI study to in vivo measures, and report the in vivo characterization of transport anisotropy in rat spinal cord. The MR imaging method is presented and the DTI data is discussed.

Many preservation methods have utilized sugars such as trehalose as protectants against injury during cell preservation processing, especially during drying (1–5). As mammalian cells do not synthesize trehalose, research in the mammalian cell desiccation field has focused on the development of strategies to enable trehalose delivery into the intracellular milieu. Numerous techniques have been explored ranging from microinjection (2) to the creation or utilization of membrane pores (1,3). Fluid phase endocytosis has shown great promise as an effective strategy for non-invasively delivering water-soluble materials into the intracellular space (4, 5). In this technique trehalose is transported across the cell membrane in membrane-bound cellular compartments called endosomes. Cells incubated in cell culture medium containing trehalose have been shown to take up considerable amounts of trehalose by this technique (4, 5). How much of this trehalose actually become available for protection of biomolecules during the dehydration process has yet to be determined.

Direct infusion of therapeutic agents into the spinal cord provides a promising way to treat traumatic injury and intrinsic diseases of the spinal cord, which may cause paralysis and other neurological deficits. Direct infusion into the spinal cord involves complex invasive surgery since the spinal cord is well protected by the vertebral bone. Instead, infusion directly into peripheral nerves is of interest since it provides a remote delivery site to the spinal cord, requiring less invasive surgery and reducing the risk of spinal cord injury during surgery. It may also allow targeting of specific neurons at nerve root entry. Previous studies have shown [1, 2] that transport in peripheral nerves is anisotropic with a preferred direction parallel to the fiber tracts. A large-scale longitudinal spread of molecular agents may be obtained and spread of molecular agents into the spinal cord may be possible.

Over the last few years, research interest in tissue engineering as an alternative for current treatment and replacement strategies for cardiovascular and heart valve diseases has significantly increased. In vitro mechanical conditioning is an essential tool for engineering strong implantable tissues [1]. Detailed knowledge of the mechanical properties of the native tissue as well as the properties of the developing engineered constructs is vital for a better understanding and control of the mechanical conditioning process. The nonlinear and anisotropic behavior of soft tissues puts high demands on their mechanical characterization. Current standards in mechanical testing of soft tissues include (multiaxial) tensile testing and indentation tests. Uniaxial tensile tests do not provide sufficient information for characterizing the full anisotropic material behavior, while biaxial tensile tests are difficult to perform, and boundary effects limit the test region to a small central portion of the tissue. In addition, characterization of the local tissue properties from a tensile test is non-trivial. Indentation tests may be used to overcome some of these limitations. Indentation tests are easy to perform and when indenter size is small relative to the tissue dimensions, local characterization is possible. We have demonstrated that by recording deformation gradients and indentation force during a spherical indentation test the anisotropic mechanical behavior of engineered cardiovascular constructs can be characterized [2]. In the current study this combined numerical-experimental approach is used on Tissue Engineered Heart Valves (TEHV).

The prevalence of AAA is growing along with population age and according to different studies AAA rupture is the 13 th most common cause of death in the U.S., causing an estimated 15,000 deaths per year. In biomechanical terms, AAA rupture is a phenomenon that occurs when the developing mechanical stresses within the aneurysm inner wall, as a result of the exerted intraluminal pressure, exceed the failure strength of the aortic tissue. To obtain a reliable estimation of wall stress, it is necessary to perform an accurate three-dimensional reconstruction of the AAA geometry and model an appropriate constitutive law for the aneurysmal tissue material characterization. In this regard, a recent study on the biaxial mechanical behavior of human AAA tissue specimens [1] demonstrates that aneurysmal arterial tissue behaves mechanically anisotropic. The objectives of the present work are to determine the effect of material anisotropy of the aneurysmal abdominal aorta on wall stress distribution and to establish a comparison of wall mechanics between ruptured and unruptured aneurysms.

Elastography, the imaging of soft tissues on the basis of elastic modulus has been actively studied in the recent years. Since cancerous tissue is often stiffer than normal tissue [1] its response to mechanical stimuli is considerably different. Hence information about the mechanical properties of cancers and tumors can be potentially extracted from imaging. This inverse problem of estimating mechanical properties from imaging and displacement data holds promise for applications in medical diagnostics.

Current Aortic Valve (AV) computational structural models do not explicitly account for the layered leaflet microstructure, i.e. collagen fibers and elastin matrix. Homogenized anisotropic hyperelastic material models are commonly used for the effective mechanical behavior of the leaflets. The later are difficult to calibrate and often unstable in structural simulations. In this study, we introduce a new heterogeneous material micromodeling approach for the porcine leaflet tissue that explicitly recognizes the collagen fiber network (CFN) distribution and integrate it with the elastin matrix into the global structural analysis of the AV system. The proposed multiscale (heterogeneous) material and structural (MMS) models are verified in their ability to predict the overall AV structural response from in-vitro pulsatile and static loops. Sophisticated imagery measurements are used to examine the kinematics and deformations of the leaflets. The proposed MMS framework is computationally effective in predicting the overall mechanical behavior of the AV structure.

Local infusion, i.e., convection-enhanced delivery (CED), is increasingly being considered as a means to deliver therapeutic agents to nervous tissues. These infusion techniques bypass the blood-brain barrier and overcome problems associated with slow diffusion [1, 2]. Predictive models of extracellular fluid flow and transport during and following CED would be useful in treatment optimization and planning. To account for large infusion volumes, such infusion models should incorporate tissue boundaries and anisotropic tissue properties.

Traumatic brain injury (TBI) is a debilitating injury that affects more than 1.4 million people in the United States each year. Of the incidences of TBI, diffuse axonal injury (DAI) accounts for the second largest percentage of deaths. DAI is caused by inertial loads to the head, and it is characterized by damage to neurons. Despite the extensive research on DAI, the injury mechanisms associated with the pathology are still poorly understood. The crucial link between the inertial forces to the head at the macroscale and the resulting damage at the cellular level has yet to be explained. An integral step to understanding this coupling between mechanical forces and the functional damage of neurons is the development of an analytical model that accurately represents the mechanics of brain deformation under inertial loads. It has been noted in clinical and experimental studies that the most common injury location of DAI is within the deep white matter of the brain. Structures such as the splenium of the corpus callosum are cited as being highly susceptible to damage [1]. Although numerous brain tissue models have been proposed, few models account for the anisotropic nature of white matter in the brain. As a first step in developing an anisotropic model for white matter, the effect of the invariant terms in a strain energy function for white matter is analyzed.

Articular cartilage exhibits inhomogeneous, rate-dependent and tension-compression (TC) nonlinear material properties. It is a biphasic material (solid and fluid phases) and its solid phase is stiffer in tension than compression [1]. Despite this complex material behavior, elastic, incompressible material models can be used to predict the short-time loading response of cartilage [2]. To our knowledge, the use of an anisotropic incompressible material to represent cartilage in a finite element (FE) joint model has not been investigated and thus the importance of the TC nonlinearity in the analysis of 3D articular contact models is limited [3]. We have been investigating a TC nonlinear incompressible constitutive model to represent hip cartilage. The objective of this study was to assess the influence of TC nonlinearity on FE predictions of stress and strain as a function of congruency between two spherical cartilage layers. It was hypothesized that the TC nonlinear and neo-Hookean constitutive models would yield a similar response when the cartilage layers were nearly congruent, but as the congruency of the cartilage layers decreased the predicted response from the two materials would be different.

Aligned, electrospun scaffolds are a useful tool for the engineering of fiber-reinforced tissues (such as tendon, meniscus, and muscle) as they mimic the topography and anisotropy of the native tissue extracellular matrix (ECM) [1]. We have shown that fiber-alignment of slow-degrading poly(ε-caprolactone) (PCL) enhances the organization of newly-formed ECM and improves construct properties [2]. However, one significant drawback to these 3D templates is their small pore size, resulting from tight fiber packing, which hampers cell infiltration. To increase scaffold porosity and thereby accelerate cell ingress, we have recently reported on the fabrication of dual polymer composite scaffolds containing both water-soluble poly(ethylene oxide) (PEO) and PCL fibers [3]. Removal of the sacrificial PEO fibers before seeding improved cell infiltration, but did so at the cost of the overall structural integrity. To further expand the potential properties (mechanics and degradation) of these composite scaffolds, this study introduced a third component (50:50 poly(lactic-co-glycolic acid) (PLGA)) using a newly constructed tri-polymer electrospinning device. We evaluated each polymer singly and when combined into a tri-polymer (3P) fibrous network. To better understand the mechanical response of these composites, we used a hyperelastic, constrained mixture model to assess and predict the response of these composite nanofibrous meshes for a range of compositions.

There are several biomechanical factors involved in the formation, growth, remodeling, and eventual rupture of intracranial aneurysms. In particular, hemodynamic forces have a decisive role in the biomechanical environment of the aneurysmal cerebral vasculature. Most of the previous studies on vascular mechanics assessment of intracranial aneurysms are based on idealized geometries, where it has been suggested [1] that it is highly unlikely that saccular aneurysms expand due to a limit point instability. In addition, it has been reported [2] that some saccular aneurysms with non-spherical initial shape tend to become spherical when subjected to uniform pressure, because a spherical geometry is optimal to resist the pressure load, yielding a homogenous wall stress. In the present work, we present a comparison between anisotropic and isotropic constitutive models, which allows us to analyze the biomechanics of patient-specific cerebral aneurysmal arteries subjected to flow-induced pulsatile pressure. The results describe the effects of material anisotropy in the resulting wall mechanics of the intracranial vasculature geometries.

This paper presents the development of a finite element model for the cornea as a first step towards a physiologically based model to study the role of cornea and sclera biomechanics in glaucoma. We developed a finite-deformation anisotropic constitutive model of the cornea that considers the effects of the fibrilar microstructure on the viscoelastic stress response. The model was base on the hypothesis that the dominant mechanism for the tensile viscoelastic behavior of the cornea is the viscoelastic stretching of the collagen lamellae. This approach yielded two main results. First, the viscoelastic properties of the cornea are derivable directly from the viscoelastic properties of the collagen fibrils and proteoglycan matrix. Second, the anisotropy in the stress response and creep response are determined solely by the arrangement collagen lamellae, which depends on orientation and material position. This allows the model parameters that determines anisotropy to be obtained from microstructural characterizations, such as the X-ray diffraction experiments of Meek and coworkers [1], while the model parameters that determines viscoelasticity to be determined from mechanical experiments. For this initial work, the viscoelastic parameters were fitted to the uniaxial tensile strip tests [2] and inflation tests with digital image correlation (DIC) [3] of bovine cornea performed by our group. Since microstructural characterizations are not available for bovine cornea, we used the data of Aghamohammadzadeh et. al. [1] for the human cornea.

Polymer trileaflet valves have been under investigation for the past 40–50 years in an attempt to produce a valve alternative that is both durable and non-thrombogenic. Most have met with limited success due to oxidative reactions and high dynamic stresses borne by the material [1]. With this knowledge, an oxidatively stable polyolefin, poly(styrene-b-isobutylene-b-styrene) (SIBS), was selected for the design of a fiber-reinforced polymer trileaflet heart valve. The hydrodynamic properties of prototype SIBS valves have been encouraging, but some valves failed prematurely as a result of insufficient durability during in vivo implantation in a sheep model or during accelerated in vitro fatigue.

In this study we performed two separate fluid structure interaction (FSI) simulations. A patient-specific Abdominal Aortic Aneurysm (AAA) geometry, and coronary vulnerable plaque (VP) geometry in idealized and in patient based geometries reconstructed from intravascular (IVUS) measurements. The patient specific AAA FSI simulations were carried out with both isotropic and anisotropic wall properties. An orthotropic material model was used to describe wall properties, closely approximating experimental results of AAA specimens [1]. The results predict larger deformations and stress values for the anisotropic material model as compared to the isotropic one. This difference indicates that the isotropic formulation may underestimate the risk of rupture. The ability to quantify stresses developing within the aneurysm wall based on FSI simulations will help clinicians to reach informed decisions in determining rupture risk of AAA and the need for surgical intervention. The risk of rupture of vulnerable plaques was studied in both idealized and patient specific geometries using FSI simulations. The idealized model included vessel wall, fibrous cap, and a lipid core. Regions susceptible to failure and the contribution of the various components were studied. The upstream side of the vulnerable plaque fibrous cap had the highest stresses. The presence of a calcified spot embedded within the fibrous cap proper was studied, and was demonstrated to enhance stresses within the fibrous cap, significantly contributing to its risk of rupture.

The intervertebral disc is comprised of complex components that provide the disc with nonlinear, viscoelastic and anisotropic mechanical properties. The annulus fibrosus (AF) is a highly organized structure composed of concentric layers of collagen fibers embedded in a proteoglycan matrix. The AF has a high tensile stiffness and supports the large loads encountered by the disc. Mathematical models are needed to interpret and elucidate the meaning of experimental measurements made in mechanical tests. Based upon the classic work of Spencer [1], the AF has been modeled as a fiber-induced anisotropic hyperelastic material [e.g.,2–6], using the principle invariants of the Green deformation tensor and structural tensors representing the collagen fiber populations. Contributions of other AF components to mechanical behaviors are less understood than the fibers or matrix and may include connections between collagens and proteoglycans that can be incorporated into models through fiber-matrix interactions [2–4]. The previous models, however, have not been applied to experimental data from both nondegenerate and degenerate tissue. Constitutive modeling applied to nondegenerate and degenerate AF may elucidate microstructural changes with degeneration, will be useful for finite element models [5], and provide targets for disc treatments, such as tissue engineered constructs [7].

Cardiac function is influenced by the three-dimensional organization of the myocardial fibers. Cardiac fibers are arranged in a circumferential, longitudinal, and a sheet-like fashion, forming counter-wound helices from the base to the apex of the heart. This fiber organization is responsible for the delicate balance between mechanical and electrical functioning of the heart. When electrical disruption of this coordinated function occurs, this is associated with cardiac arrhythmias which may lead to more serious conditions like ventricular fibrillation.

Collagen is a principal constituent of the extracellular matrix (ECM) and as such, defines the microenvironmental milieu in which cells reside. In fiber-reinforced musculoskeletal tissues, collagen fibers are highly organized and generate the direction-dependent mechanical properties critical to the function of these structures. Given its primary role, collagen is particularly attractive for tissue engineering (TE) applications where scaffolds are coupled with cells to repair or regenerate damaged tissues. One method for producing collagen-based scaffolds is through electrospinning. This technique yields nano- to micron-scale fibers similar in diameter to those of the native ECM. Towards engineering orthopaedic tissues, methods have been devised to electrospin fibers into aligned arrays that can recapitulate the anisotropy of fiber-reinforced tissues [1]. While a number of polymers have been electrospun, collagen-based scaffolds are especially promising as they provide a biomimetic interface for cell attachment [2]. Numerous investigators have electrospun collagen [3], one major drawback is their inherent instability in aqueous environments. To address this, various crosslinking agents including glutaraldehyde (GA), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, and N-hydroxysuccinimide chemistries have been used, but these chemicals often prove cytotoxic or excessively laborious in application [4]. Even with crosslinking, dry as-formed nanofibrous collagen scaffolds with moduli greater than 50MPa diminish by 100-fold with rehydration [5].

Cross-linking of fibrous collagenous tissues occurs during late-stage wound healing and during aging. The attendant changes in micro-scale kinematics and macro-scale mechanics are not well understood. In this study we used glutaraldehyde as a model cross-linking agent, and in vitro reconstituted collagen gel as a model collagenous tissue. Collagen gels are in vitro assembled hydrated networks of collagen fibrils. Glutaraldehyde is a commonly used cross-linking agent for bioprosthetic tissues and is chemically well-characterized. Glutaraldehyde cross-linking is known to decrease the deformability of arterial valves, but the micro-scale mechanism of its action is not known. In this study, collagen gels with anisotropic fibril orientation were subjected to increasing cross-link density, and the concurrent change in biaxial mechanical properties was monitored. The extent of cross-linking is determined by biochemical analysis. Structural modeling of the biaxial mechanics of a fibrous microstructure was performed for three potential cross-link mechanisms. The trends in the simulated mechanics for increasing cross-link density were compared against that of the experimental data.

In spite of the high therapeutic potential of macromolecular drugs, it has proven difficult to apply them to recovery after injury and treatment of cancer, Parkinson’s disease, and other neurodegenerative diseases. One barrier to systemic administration is low capillary permeability, i.e., the blood-brain and blood-spinal cord barrier. To overcome this barrier, convection-enhanced delivery (CED) infuses agents directly into tissue to supplement diffusion and increase the distribution of large molecules in the brain [1,2]. Predictive models of distribution during CED would be useful in treatment optimization and planning. To account for large infusion volumes, such models should incorporate tissue boundaries and anisotropic tissue properties.