Effects of Age, Sex, and Extracellular Matrix Integrity on Aortic Dilatation and Rupture in a Mouse Model of Marfan Syndrome.

BACKGROUND: Transmural failure of the aorta is responsible for substantial morbidity and mortality; it occurs when mechanical stress exceeds strength. The aortic root and ascending aorta are susceptible to dissection and rupture in Marfan syndrome, a connective tissue disorder characterized by a progressive reduction in elastic fiber integrity. Whereas competent elastic fibers endow the aorta with compliance and resilience, cross-linked collagen fibers confer stiffness and strength. We hypothesized that postnatal reductions in matrix cross-linking increase aortopathy when turnover rates are high. METHODS: We combined ex vivo biaxial mechanical testing with multimodality histological examinations to quantify expected age- and sex-dependent structural vulnerability of the ascending aorta in Fbn1C1041G/+ Marfan versus wild-type mice without and with 4-week exposures to ß-aminopropionitrile, an inhibitor of lysyl oxidase-mediated cross-linking of newly synthesized elastic and collagen fibers. RESULTS: We found a strong ß-aminopropionitrile-associated sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, with dilatation correlating with compromised elastic fiber integrity and rupture correlating with compromised collagen fibril organization. A lower incidence of rupture of ß-aminopropionitrile-exposed Marfan aortas associated with increased lysyl oxidase, suggesting a compensatory remodeling of collagen that slows disease progression in the otherwise compromised Fbn1C1041G/+ aorta. CONCLUSIONS: Collagen fiber structure and function in the Marfan aorta are augmented, in part, by increased lysyl oxidase in female and especially male mice, which improves structural integrity, particularly via fibrils in the adventitia. Preserving or promoting collagen cross-linking may represent a therapeutic target for an otherwise vulnerable aorta.

FN (Fibronectin)-Integrin α5 Signaling Promotes Thoracic Aortic Aneurysm in a Mouse Model of Marfan Syndrome.

BACKGROUND: Marfan syndrome, caused by mutations in the gene for fibrillin-1, leads to thoracic aortic aneurysms (TAAs). Phenotypic modulation of vascular smooth muscle cells (SMCs) and ECM (extracellular matrix) remodeling are characteristic of both nonsyndromic and Marfan aneurysms. The ECM protein FN (fibronectin) is elevated in the tunica media of TAAs and amplifies inflammatory signaling in endothelial and SMCs through its main receptor, integrin α5ß1. We investigated the role of integrin α5-specific signals in Marfan mice in which the cytoplasmic domain of integrin α5 was replaced with that of integrin α2 (denoted α5/2 chimera). METHODS: We crossed α5/2 chimeric mice with Fbn1mgR/mgR mice (mgR model of Marfan syndrome) to evaluate the survival rate and pathogenesis of TAAs among wild-type, α5/2, mgR, and α5/2 mgR mice. Further biochemical and microscopic analysis of porcine and mouse aortic SMCs investigated molecular mechanisms by which FN affects SMCs and subsequent development of TAAs. RESULTS: FN was elevated in the thoracic aortas from Marfan patients, in nonsyndromic aneurysms, and in mgR mice. The α5/2 mutation greatly prolonged survival of Marfan mice, with improved elastic fiber integrity, mechanical properties, SMC density, and SMC contractile gene expression. Furthermore, plating of wild-type SMCs on FN decreased contractile gene expression and activated inflammatory pathways whereas α5/2 SMCs were resistant. These effects correlated with increased NF-kB activation in cultured SMCs and mgR aortas, which was alleviated by the α5/2 mutation or NF-kB inhibition. CONCLUSIONS: FN-integrin α5 signaling is a significant driver of TAA in the mgR mouse model. This pathway thus warrants further investigation as a therapeutic target.

Perfluorocarbon nanodroplet size, acoustic vaporization, and inertial cavitation affected by lipid shell composition in vitro.

Perfluorocarbon nanodroplets (PFCnDs) are ultrasound contrast agents that phase-transition from liquid nanodroplets to gas microbubbles when activated by laser irradiation or insonated with an ultrasound pulse. The dynamics of PFCnDs can vary drastically depending on the nanodroplet composition, including the lipid shell properties. In this paper, we investigate the effect of varying the ratio of PEGylated to non-PEGylated phospholipids in the outer shell of PFCnDs on the acoustic nanodroplet vaporization (liquid to gas phase transition) and inertial cavitation (rapid collapse of the vaporized nanodroplets) dynamics in vitro when insonated with focused ultrasound. Nanodroplets with a high concentration of PEGylated lipids had larger diameters and exhibited greater variance in size distribution compared to nanodroplets with lower proportions of PEGylated lipids in the lipid shell. PFCnDs with a lipid shell composed of 50:50 PEGylated to non-PEGylated lipids yielded the highest B-mode image intensity and duration, as well as the greatest pressure difference between acoustic droplet vaporization onset and inertial cavitation onset. We demonstrate that slight changes in lipid shell composition of PFCnDs can significantly impact droplet phase transitioning and inertial cavitation dynamics. These findings can help guide researchers to fabricate PFCnDs with optimized compositions for their specific applications.

Simulation of the 3D Hyperelastic Behavior of Ventricular Myocardium using a Finite-Element Based Neural-Network Approach.

High-fidelity cardiac models using attribute-rich finite element based models have been developed to a very mature stage. However, such finite-element based approaches remain time consuming, which have limited their clinical use. There remains a need for alternative methods for novel cardiac simulation methods of capable of high fidelity simulations in clinically relevant time frames. Surrogate models are one approach, which traditionally use a data-driven approach for training, requiring the generation of a sufficiently large number of simulation results as the training dataset. Alternatively, a physics-informed neural network can be trained by minimizing the PDE residuals or energy potentials. However, this approach does not provide for a general method to easily using existing finite element models. To address these challenges, we developed a hybrid approach that seamlessly bridged a neural network surrogate model with a differentiable finite element domain representation (NNFE). Given its importance in cardiac simulations, we applied this approach to simulations of the hyperelastic mechanical behavior of ventricular myocardium from recent 3D kinematic constitutive model (J Mech Behav Biomed Mater, 2020 doi: 10.1016/j.jmbbm.2019.103508). We utilized cuboidal domain and conducted numerical studies of individual myocardium specimens discretized by a finite element mesh and assigned with experimentally obtained myofiber architectures. Both parameterized Dirichlet and Neumann boundary conditions were studied. We developed a second-order Newton optimization method, instead of using stochastic gradient descent method, to train the neural network efficiently. The resulting trained neural network surrogate model demonstrated excellent agreement with the corresponding 'ground truth' finite element solutions over the entire physiological deformation range. More importantly, the NNFE approach provided a significantly decreased computational time for a range of finite element mesh sizes for online predictions. For example, as the finite element mesh sized increased from 2744 to 175615 elements the NNFE computational time increased from 0.1108 s to 0.1393 s, while the 'ground truth' FE model increased from 4.541 s to 719.9 s. These results suggests that NNFE run times can be significantly reduced compared with the traditional large-deformation based finite element solution methods. The trade off is to train the NNFE off-line within a range of anticipated physiological responses. However, training time would only have to be performed once before any number of application uses. Moreover, since the NNFE is an analytical function its computational performance will be amplified when the corresponding problem becomes more complex.

A Contemporary Look at Biomechanical Models of Myocardium.

Understanding and predicting the mechanical behavior of myocardium under healthy and pathophysiological conditions are vital to developing novel cardiac therapies and promoting personalized interventions. Within the past 30 years, various constitutive models have been proposed for the passive mechanical behavior of myocardium. These models cover a broad range of mathematical forms, microstructural observations, and specific test conditions to which they are fitted. We present a critical review of these models, covering both phenomenological and structural approaches, and their relations to the underlying structure and function of myocardium. We further explore the experimental and numerical techniques used to identify the model parameters. Next, we provide a brief overview of continuum-level electromechanical models of myocardium, with a focus on the methods used to integrate the active and passive components of myocardial behavior. We conclude by pointing to future directions in the areas of optimal form as well as new approaches for constitutive modeling of myocardium.

Spontaneous Nucleation of Stable Perfluorocarbon Emulsions for Ultrasound Contrast Agents.

Phase-change contrast agents are rapidly developing as an alternative to microbubbles for ultrasound imaging and therapy. These agents are synthesized and delivered as liquid droplets and vaporized locally to produce image contrast. They can be used like conventional microbubbles but with the added benefit of reduced size and improved stability. Droplet-based agents can be synthesized with diameters on the order of 100 nm, making them an ideal candidate for extravascular imaging or therapy. However, their synthesis requires low boiling point perfluorocarbons (PFCs) to achieve activation (i.e., vaporization) thresholds within FDA approved limits. Minimizing spontaneous vaporization while producing liquid droplets using conventional methods with low boiling point PFCs can be challenging. In this study, a new method to produce PFC nanodroplets using spontaneous nucleation is demonstrated using PFCs with boiling points ranging from -37 to 56 °C. Sometimes referred to as the ouzo method, the process relies on saturating a cosolvent with the PFC before adding a poor solvent to reduce solvent quality, forcing droplets to spontaneously nucleate. This approach can produce droplets ranging from under 100 nm to over 1 µm in diameter. Ternary plots showing solvent and PFC concentrations leading to droplet nucleation are presented. Additionally, acoustic activation thresholds and size distributions with varying PFC and solvent conditions are measured and discussed. Finally, ultrasound contrast imaging is demonstrated using ouzo droplets in an animal model.

Kinetic Analysis of Ultrasound-Induced Oil Exchange in Oil-in-Water Emulsions through Contrast Variation Time-Resolved Small-Angle Neutron Scattering.

Ultrasound is one of the most commonly used methods for synthesizing and processing emulsion systems. In this study, the kinetics of acoustically induced emulsion oil exchange was examined using contrast variation time-resolved small-angle neutron scattering (CV-SANS). A custom-built sample environment was used to deliver acoustic forces while simultaneously performing CV-SANS experiments. It was observed that the oil exchange rate was significantly accelerated when sonicating at high acoustic pressures, where violent cavitation events can induce droplet coalescence and breakup. No significant oil exchange occurred at acoustic pressures below the cavitation threshold within the short time scales of the experiments. It was also observed that the oil exchange kinetics was deterred when emulsions were stabilized by surfactants. In addition, oil exchange rates varied nonlinearly with the concentration of surfactant, and exchange was slowest when the emulsions were stabilized by an intermediate concentration. It is hypothesized that emulsion size, electrostatic repulsion, and Gibbs elasticity of the oil-water interface play significant roles in the observed trends. The observed trends in oil exchange rates versus surfactant concentration coincide well with theoretical models for the fluctuation of the elasticity of the interface. Acoustically induced oil exchange was most inefficient when the interfacial elasticity was at its maximum value.

Interactions Between Structural Remodeling and Hypertrophy in the Right Ventricle in Response to Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) exerts substantial pressure overload on the right ventricle (RV), inducing RV remodeling and myocardial tissue adaptation often leading to right heart failure. The associated RV free wall (RVFW) adaptation involves myocardial hypertrophy, augmented intrinsic contractility, collagen fibrosis, and structural remodeling in an attempt to cope with pressure overload. If RVFW adaptation cannot maintain the RV stroke volume (SV), RV dilation will prevail as an exit mechanism, which usually decompensates RV function, leading to RV failure. Our knowledge of the factors determining the transition from the upper limit of RVFW adaptation to RV decompensation and the role of fiber remodeling events such as extracellular fibrosis and fiber reorientation in this transition remains very limited. Computational heart models that connect the growth and remodeling (G&R) events at the fiber and tissue levels with alterations in the organ-level function are essential to predict the temporal order and the compensatory level of the underlying mechanisms. In this work, building upon our recently developed rodent heart models (RHM) of PAH, we integrated mathematical models that describe volumetric growth of the RV and structural remodeling of the RVFW. The time-evolution of RV remodeling from control and post-PAH time points was simulated. The results suggest that the augmentation of the intrinsic contractility of myofibers, accompanied by an increase in passive stiffness of RVFW, is among the first remodeling events through which the RV strives to maintain the cardiac output. Interestingly, we found that the observed reorientation of the myofibers toward the longitudinal (apex-to-base) direction was a maladaptive mechanism that impaired the RVFW contractile pattern and advanced along with RV dilation at later stages of PAH. In fact, although individual fibers were more contractile post-PAH, the disruption in the optimal transmural fiber architecture compromised the effective contractile function of the RVFW, contributing to the depressed ejection fraction (EF) of the RV. Our findings clearly demonstrate the critical need for developing multiscale approaches that can model and delineate relationships between pathological alterations in cardiac function and underlying remodeling events across fiber, cellular, and molecular levels.

Sonocrystallization of conjugated polymers with ultrasound fields.

Ultrasound acoustic waves are demonstrated to assemble poly-3-hexylthiophene (P3HT) chains into nanofibers after they are fully dissolved in what are commonly considered to be 'good' solvents. In the absence of ultrasound, the polymer remains fully dissolved and does not self-assemble for weeks. UV-vis spectroscopy, ultra-small angle X-ray scattering (USAXS) and small angle neutron scattering (SANS) are used to characterize the induced assembly process and to quantify the fraction of polymer that forms nanofibers. It is determined that the solvent type, insonation time, and aging periods are all important factors affecting the structure and final concentration of fibers. The effect of changing polymer regio-regularity, alkyl chain length, and side chain to thiophene ratio are also explored. High intensity focused ultrasound (HIFU) fields of variable intensity are utilized to reveal the physical mechanisms leading to nanofiber formation, which is strongly correlated to cavitation events in the solvent. This in situ HIFU cell, which is designed for simultaneous scattering analysis, is also used to probe for structural changes occurring over multiple length scales using USAXS and SANS. The proposed acoustic assembly mechanism suggests that, even when dispersed in 'good' solvents such as bromobenzene, dichlorobenzene and chloroform, P3HT chains are still not in a thermodynamically stable state. Instead, they are stabilized by local energy barriers that slow down and effectively prevent crystallization. Ultrasound fields are found to provide enough mechanical energy to overcome these barriers, triggering the formation of small crystalline nuclei that subsequently seed the growth of larger nanofibers.

A small-angle scattering environment for in situ ultrasound studies.

Ultrasonic devices are common tools in laboratory and industrial settings to produce cavitation events for cleaning, emulsification, cell lysis and other materials applications. Effects of sonication at the macroscopic scale can be visible while effects at the molecular and nano-scales are not easily probed and, therefore, not fully understood. We present a new small angle scattering sample environment designed specifically to study structural changes occurring in various types of dispersions at the nano-scale due to ultrasonic acoustic waves. The sample environment features two face-to-face high-intensity focused ultrasound transducers coaxially aligned and normal to the neutron/X-ray beam propagation direction. A third broadband transducer is fixed beneath the scattering volume to acoustically monitor for cavitation events. By correlating acoustic data to scattering data, measured structural changes can be correlated to changes in parameters such as frequency, acoustic pressure, or cavitation pressure threshold. Several example applications of colloidal systems effectively influenced by ultrasound fields are also presented to demonstrate the capabilities of the device and to motivate future work on in situ scattering analysis of ultrasound materials processing methods.

Polypyrrole-Coated Perfluorocarbon Nanoemulsions as a Sono-Photoacoustic Contrast Agent.

A new contrast agent for combined photoacoustic and ultrasound imaging is presented. It has a liquid perfluorocarbon (PFC) core of about 250 nm diameter coated by a 30 nm thin polypyrrole (PPy) doped polymer shell emulsion that represents a broadband absorber covering the visible and near-infrared ranges (peak optical extinction at 1050 nm). When exposed to a sufficiently high intensity optical or acoustic pulse, the droplets vaporize to form microbubbles providing a strong increase in imaging sensitivity and specificity. The threshold for contrast agent activation can further drastically be reduced by up to 2 orders of magnitude if simultaneously exposing them with optical and acoustic pulses. The selection of PFC core liquids with low boiling points (i.e., perfluorohexane (56 °C), perfluoropentane (29 °C), and perfluorobutane (-2 °C)) facilitates activation and reduces the activation threshold of PPy-coated emulsion contrast agents to levels well within clinical safety limits (as low as 0.2 MPa at 1 mJ/cm2). Finally, the potential use of these nanoemulsions as a contrast agent is demonstrated in a series of phantom imaging studies.

Modeling closure of circular wounds through coordinated collective motion.

Wound healing enables tissues to restore their original states, and is achieved through collective cell migration into the wound space, contraction of the wound edge via an actomyosin filament 'purse-string,' as well as cell division. Recently, experimental techniques have been developed to create wounds with various regular morphologies in epithelial monolayers, and these experiments of circular closed-contour wounds support coordinated lamellipodial cell crawling as the predominant driver of gap closure. Through utilizing a particle-based mechanical tissue simulation, exhibiting long-range coordination of cell motility, we computationally model these closed-contour experiments with a high level of agreement between experimentally observed and simulated wound closure dynamics and tissue velocity profiles. We also determine the sensitivity of wound closure time in the model to changes in cell motility force and division rate. Our simulation results confirm that circular wounds can close due to collective cell migration without the necessity for a purse-string mechanism or for cell division, and show that the alignment mechanism of cellular motility force with velocity, leading to collective motion in the model, may speed up wound closure.

A multi-scale computational model for the passive mechanical behavior of right ventricular myocardium.

We have previously demonstrated the importance of myofiber-collagen mechanical interactions in modeling the passive mechanical behavior of right ventricle free wall (RVFW) myocardium. To gain deeper insights into these coupling mechanisms, we developed a high-fidelity, micro-anatomically realistic 3D finite element model of right ventricle free wall (RVFW) myocardium by combining high-resolution imaging and supercomputer-based simulations. We first developed a representative tissue element (RTE) model at the sub-tissue scale by specializing the hyperelastic anisotropic structurally-based constitutive relations for myofibers and ECM collagen, and equi-biaxial and non-equibiaxial loading conditions were simulated using the open-source software FEniCS to compute the effective stress-strain response of the RTE. To estimate the model parameters of the RTE model, we first fitted a 'top-down' biaxial stress-strain behavior with our previous structurally based (tissue-scale) model, informed by the measured myofiber and collagen fiber composition and orientation distributions. Next, we employed a multi-scale approach to determine the tissue-level (5 x 5 x 0.7 mm specimen size) RVFW biaxial behavior via 'bottom-up' homogenization of the fitted RTE model, recapitulating the histologically measured myofiber and collagen orientation to the biaxial mechanical data. Our homogenization approach successfully reproduced the tissue-level mechanical behavior of our previous studies in all biaxial deformation modes, suggesting that the 3D micro-anatomical arrangement of myofibers and ECM collagen is indeed a primary mechanism driving myofiber-collagen interactions.

Biomechanical and transcriptional evidence that smooth muscle cell death drives an osteochondrogenic phenotype and severe proximal vascular disease in progeria.

Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process in proximal elastic arteries that was less evident in distal muscular arteries. Changes in aortic structure and function were then associated with changes in transcriptomics assessed via both bulk and single cell RNA sequencing, which suggested a novel sequence of progressive aortic disease: adverse extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotype that results in an accumulation of proteoglycans that thickens the aortic wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased central artery pulse wave velocity is known to drive left ventricular diastolic dysfunction, the primary diagnosis in progeria children. It appears that mechanical stresses above ~ 80 kPa initiate this progressive aortic disease process, explaining why elastic lamellar structures that are organized early in development under low wall stresses appear to be nearly normal whereas other medial constituents worsen progressively in adulthood. Mitigating early mechanical stress-driven smooth muscle cell loss/phenotypic modulation promises to have important cardiovascular implications in progeria patients.

Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford progeria syndrome.

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends the lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe perimorbid cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, neither treatment with the mTOR inhibitor rapamycin alone nor dual treatment with lonafarnib plus rapamycin improved outcomes over that achieved with lonafarnib monotherapy.

Neural operator learning of heterogeneous mechanobiological insults contributing to aortic aneurysms.

Thoracic aortic aneurysm (TAA) is a localized dilatation of the aorta that can lead to life-threatening dissection or rupture. In vivo assessments of TAA progression are largely limited to measurements of aneurysm size and growth rate. There is promise, however, that computational modelling of the evolving biomechanics of the aorta could predict future geometry and properties from initiating mechanobiological insults. We present an integrated framework to train a deep operator network (DeepONet)-based surrogate model to identify TAA contributing factors using synthetic finite-element-based datasets. For training, we employ a constrained mixture model of aortic growth and remodelling to generate maps of local aortic dilatation and distensibility for multiple TAA risk factors. We evaluate the performance of the surrogate model for insult distributions varying from fusiform (analytically defined) to complex (randomly generated). We propose two frameworks, one trained on sparse information and one on full-field greyscale images, to gain insight into a preferred neural operator-based approach. We show that this continuous learning approach can predict the patient-specific insult profile associated with any given dilatation and distensibility map with high accuracy, particularly when based on full-field images. Our findings demonstrate the feasibility of applying DeepONet to support transfer learning of patient-specific inputs to predict TAA progression.

On the Three-Dimensional Mechanical Behavior of Human Breast Tissue.

As the human breast undergoes complex, large-scale, fully three dimensional deformations in vivo, three-dimensional (3D) characterization of its mechanical behavior is fundamental to its diagnosis, treatment, and surgical modifications. Its anisotropic, heterogeneous fibrous structure results in complex behavior at both the tissue and organ levels. Mathematically modeling of this complex anisotropic behavior is thus critical to the proper simulation of the human breast. Yet, current breast tissue constitutive models do not account for these complexities, so that there is a pressing need for more detailed fully 3D analysis. To this end, we performed a full 3D kinematic mechanical evaluation of human fibroglandular and adipose breast tissues. We utilized our recently developed 3D kinematic numerical-experimental approach to acquire force-displacement data from both breast tissue subtypes. This was done by subjecting cuboidal test specimens, aligned to the anatomical axes,to both pure shear and simple compression loading paths. We then developed novel constitutive model that was able to simulate the unique anisotropic tension/compression behaviors observed. Constitutive model parameters were determined using a detailed finite element model of the experimental setup coupled to nonlinear optimization. We found that human breast tissues displayed complex anisotropic behavior, with strong, directionally dependent non-linearities. This was especially true for the fibroglandular tissue. The novel constitutive model was also able fully capture these behaviors, including states of combined tension and compression (i.e. in pure shear). The results of this study suggest that human breast tissue is complex in its mechanical response, exhibiting varying levels of anisotropy. Future studies will be required to link the observed anisotropy to the physical structure of the tissue, as well as mapping this heterogeneity and anisotropy across individuals.

Microfluidic particle sorting utilizing inertial lift force.

A simple passive microfluidic device that continuously separates microparticles is presented. Its development is motivated by the need for specific size micro perfluorocarbon (PFC) droplets to be used for a novel gas embolotherapy method. The device consists of a rectangular channel in which inertial lift forces are utilized to separate particles in lateral distance. At the entrance of the channel, particles are introduced at the center by focusing the flow from a center channel with flow from two side channels. Downstream, large particles will occupy a lateral equilibrium position in shorter axial distance than small particles. At the exit of the channel, flow containing large particles is separated from flow containing small particles. It is shown that 10.2-µm diameter microspheres can be separated from 3.0-µm diameter microspheres with a separation efficiency of 69-78% and a throughput in the order of 2 ·104 particles per minute. Computational Fluid Dynamics (CFD) calculations were done to calculate flow fields and verify theoretical particle trajectories. Theory underlying this research shows that higher separation efficiencies for very specific diameter cut-off are possible. This microfluidic channel design has a simple structure and can operate without external forces which makes it feasible for lab-on-a-chip (LOC) applications.

A High-Fidelity 3D Micromechanical Model of Ventricular Myocardium.

Pulmonary arterial hypertension (PAH) imposes a pressure overload on the right ventricle (RV), leading to myofiber hypertrophy and remodeling of the extracellular collagen fiber network. While the macroscopic behavior of healthy and post-PAH RV free wall (RVFW) tissue has been studied previously, the mechanical microenvironment that drives remodeling events in the myofibers and the extracellular matrix (ECM) remains largely unexplored. We hypothesize that multiscale computational modeling of the heart, linking cellular-scale events to tissue-scale behavior, can improve our understanding of cardiac remodeling and better identify therapeutic targets. We have developed a high-fidelity microanatomically realistic model of ventricular myocardium, combining confocal microscopy techniques, soft tissue mechanics, and finite element modeling. We match our microanatomical model to the tissue-scale mechanical response of previous studies on biaxial properties of RVFW and examine the local myofiber-ECM interactions to study fiber-specific mechanics at the scale of individual myofibers. Through this approach, we determine that the interactions occurring at the tissue scale can be accounted for by accurately representing the geometry of the myofiber-collagen arrangement at the micro scale. Ultimately, models such as these can be used to link cellular-level adaptations with organ-level adaptations to lead to the development of patient-specific treatments for PAH.

Real-time interleaved spectroscopic photoacoustic and ultrasound (PAUS) scanning with simultaneous fluence compensation and motion correction.

For over two decades photoacoustic imaging has been tested clinically, but successful human trials have been limited. To enable quantitative clinical spectroscopy, the fundamental issues of wavelength-dependent fluence variations and inter-wavelength motion must be overcome. Here we propose a real-time, spectroscopic photoacoustic/ultrasound (PAUS) imaging approach using a compact, 1-kHz rate wavelength-tunable laser. Instead of illuminating tissue over a large area, the fiber-optic delivery system surrounding an US array sequentially scans a narrow laser beam, with partial PA image reconstruction for each laser pulse. The final image is then formed by coherently summing partial images. This scheme enables (i) automatic compensation for wavelength-dependent fluence variations in spectroscopic PA imaging and (ii) motion correction of spectroscopic PA frames using US speckle tracking in real-time systems. The 50-Hz video rate PAUS system is demonstrated in vivo using a murine model of labelled drug delivery.