Craig Lanning

Changes in the structure-function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves

Extracellular matrix remodeling has been proposed as one mechanism by which proximal pulmonary arteries stiffen during pulmonary arterial hypertension (PAH). Although some attention has been paid to the role of collagen and metallomatrix proteins in affecting vascular stiffness, much less work has been performed on changes in elastin structure-function relationships in PAH. Such work is warranted, given the importance of elastin as the structural protein primarily responsible for the passive elastic behavior of these conduit arteries. Here, we study structure-function relationships of fresh arterial tissue and purified arterial elastin from the main, left, and right pulmonary artery branches of normotensive and hypoxia-induced pulmonary hypertensive neonatal calves. PAH resulted in an average 81 and 72% increase in stiffness of fresh and digested tissue, respectively. Increase in stiffness appears most attributable to elevated elastic modulus, which increased 46 and 65%, respectively, for fresh and digested tissue. Comparison between fresh and digested tissues shows that, at 35% strain, a minimum of 48% of the arterial load is carried by elastin, and a minimum of 43% of the change in stiffness of arterial tissue is due to the change in elastin stiffness. Analysis of the stress-strain behavior revealed that PAH causes an increase in the strains associated with the physiological pressure range but had no effect on the strain of transition from elastin-dominant to collagen-dominant behavior. These results indicate that mechanobiological adaptations of the continuum and geometric properties of elastin, in response to PAH, significantly elevate the circumferential stiffness of proximal pulmonary arterial tissue.

Real time multicomponent echo particle image velocimetry technique for opaque flow imaging

This letter reports on a contrast-based ultrasonic particle imaging technique (echo PIV) for measuring multicomponent velocity vectors in opaque flows with excellent temporal (up to 0.5ms) and spatial (up to 0.4mm) resolution. Ultrasound contrast microbubbles are used as flow tracers, and digitally acquired rf data are converted into B-mode images for PIV analysis. Here, velocity fields from various flow patterns (including rotating and transient vortex flows) that are difficult to measure using other opaque flow methods such as ultrasound Doppler or magnetic resonance imaging are measured using echo PIV. This nonintrusive technique should be a promising addition to opaque flow diagnostics.

IN VITRO AND PRELIMINARY IN VIVO VALIDATION OF ECHO PARTICLE IMAGE VELOCIMETRY IN CAROTID VASCULAR IMAGING

Noninvasive, easy-to-use and accurate measurements of wall shear stress (WSS) in human blood vessels have always been challenging in clinical applications. Echo particle image velocimetry (Echo PIV) has shown promise for clinical measurements of local hemodynamics and wall shear rate. Thus far, however, the method has only been validated under simple flow conditions. In this study, we validated Echo PIV under in vitro and in vivo conditions. For in vitro validation, we used an anatomically correct, compliant carotid bifurcation flow phantom with pulsatile flow conditions, using optical particle image velocimetry (optical PIV) as the reference standard. For in vivo validation, we compared Echo PIV-derived 2-D velocity fields obtained at the carotid bifurcation in five normal subjects against phase-contrast magnetic resonance imaging (PC-MRI)-derived velocity measurements obtained at the same locations. For both studies, time-dependent, 2-D, two-component velocity vectors; peak/centerline velocity, flow rate and wall shear rate (WSR) waveforms at the common carotid artery (CCA), carotid bifurcation and distal internal carotid artery (ICA) were examined. Linear regression, correlation analysis and Bland-Altman analysis were used to quantify the agreement of different waveforms measured by the two techniques. In vitro results showed that Echo PIV produced good images of time-dependent velocity vector maps over the cardiac cycle with excellent temporal (up to 0.7 ms) and spatial (∼0.5 mm) resolutions and quality, comparable with optical PIV results. Further, good agreement was found between Echo PIV and optical PIV results for velocity and WSR measurements. In vivo results also showed good agreement between Echo PIV velocities and phase contrast MRI velocities. We conclude that Echo PIV provides accurate velocity vector and WSR measurements in the carotid bifurcation and has significant potential as a clinical tool for cardiovascular hemodynamics evaluation.

An Artificial Right Ventricle for Failing Fontan: In Vitro and Computational Study

BACKGROUND The aim of this study is to develop a destination low-pressure artificial right ventricle (ARV) to correct the impaired hemodynamics in the failing Fontan circulation. METHODS An in vitro model circuit of the Fontan circulation was created to reproduce the hemodynamics of the failing Fontan and test ARV performance under various central venous pressures (CVP) and flows. A novel geometry of the extracardiac conduit was designed to adapt to the need of the pump. The ARV was a low-pressure axial flow pump designed to produce a low suction inflow pressure and moderate outflow increase. With the power off, the passive forward gradient across the propeller is 2 mm Hg at 4.5 L/min. The ARV would require 4 watts at a rotation of 5000 rpm. To examine the shear loading on the red blood cells, virtual particles were injected upstream of the ARV inducer and tracked by computerized modeling. RESULTS The effect of the ARV on the failing Fontan was studied at various CVP pressures and flows, and under constant values of lung resistances and left atrial pressure set respectively to 2.5 Woods Units and 7 mm Hg. The CVP pressures decreased respectively from 25, 22.5, 20, 17.5, 15, and 10 mm Hg to a minimal value of 2 to 5 mm Hg with a pump speed varying from 1700 to 4500 rpm. The pulmonary artery pressures increased moderately between 12.5 and 25 mm Hg at 4500 rpm. Cardiac output at 4500 rpm was increased by an average gain of 2 L/min. The average blood damage index was 0.92%, far below the 5% value considered to cause hemolysis. The flow structure produced by the pump was suitable. CONCLUSIONS The performance of this novel low-pressure ARV was satisfactory, showing good decrease of CVP pressures, a moderate increase of pulmonary artery pressures, adequate increase of cardiac output, and minimal hemolysis. The use of a mock Fontan model circuit facilitates device prototyping and design to a far greater extent than can be achieved using animal studies, and is an essential first step for rapid design iteration of a novel ARV device. The next steps are the manufacturing of this device, including an electromagnetic engine, a regulatory system, and further testing the device in a survival animal experiment.

Building Biocompatible Hydrogels for Tissue Engineering of the Brain and Spinal Cord

Tissue engineering strategies employing biomaterials have made great progress in the last few decades. However, the tissues of the brain and spinal cord pose unique challenges due to a separate immune system and their nature as soft tissue. Because of this, neural tissue engineering for the brain and spinal cord may require re-establishing biocompatibility and functionality of biomaterials that have previously been successful for tissue engineering in the body. The goal of this review is to briefly describe the distinctive properties of the central nervous system, specifically the neuroimmune response, and to describe the factors which contribute to building polymer hydrogels compatible with this tissue. These factors include polymer chemistry, polymerization and degradation, and the physical and mechanical properties of the hydrogel. By understanding the necessities in making hydrogels biocompatible with tissue of the brain and spinal cord, tissue engineers can then functionalize these materials for repairing and replacing tissue in the central nervous system.

Simulations of Congenital Septal Defect Closure and Reactivity Testing in Patient-Specific Models of the Pediatric Pulmonary Vasculature: A 3D Numerical Study With Fluid-Structure Interaction

Clinical imaging methods are highly effective in the diagnosis of vascular pathologies, but they do not currently provide enough detail to shed light on the cause or progression of such diseases, and would be hard pressed to foresee the outcome of surgical interventions. Greater detail of and prediction capabilities for vascular hemodynamics and arterial mechanics are obtained here through the coupling of clinical imaging methods with computational techniques. Three-dimensional, patient-specific geometric reconstructions of the pediatric proximal pulmonary vasculature were obtained from x-ray angiogram images and meshed for use with commercial computational software. Two such models from hypertensive patients, one with multiple septal defects, the other who underwent vascular reactivity testing, were each completed with two sets of suitable fluid and structural initial and boundary conditions and used to obtain detailed transient simulations of artery wall motion and hemodynamics in both clinically measured and predicted configurations. The simulation of septal defect closure, in which input flow and proximal vascular stiffness were decreased, exhibited substantial decreases in proximal velocity, wall shear stress (WSS), and pressure in the post-op state. The simulation of vascular reactivity, in which distal vascular resistance and proximal vascular stiffness were decreased, displayed negligible changes in velocity and WSS but a significant drop in proximal pressure in the reactive state. This new patient-specific technique provides much greater detail regarding the function of the pulmonary circuit than can be obtained with current medical imaging methods alone, and holds promise for enabling surgical planning.

Initial experience with the development and numerical and in vitro studies of a novel low-pressure artificial right ventricle for pediatric fontan patients

The Fontan operation, an efficient palliative surgery, is performed for patients with single-ventricle pathologies. The total cavopulmonary connection is a preferred Fontan procedure in which the superior and inferior vena cava are connected to the left and right pulmonary artery. The overall goal of this work is to develop an artificial right ventricle that can be introduced into the inferior vena cava, which would act to reverse the deleterious hemodynamics in post-Fontan patients. We present the initial design and computational analysis of a micro-axial pump, designed with the particular hemodynamics of Fontan physiology in mind. Preliminary in vitro data on a prototype pump are also presented. Computational studies showed that the new design can deliver a variety of advantageous operating conditions, including decreased venous pressure through proximal suction, increased pressure rise across the pump, increased pulmonary flows, and minimal changes in superior vena cava pressures. In vitro studies on a scaled prototype showed trends similar to those seen computationally. We conclude that a micro-axial flow pump can be designed to operate efficiently within the low-pressure, low-flow environment of cavopulmonary flows. The results provide encouragement to pursue this design to for in vitro studies and animal studies.

Development and validation of implantable sensors for monitoring function of prosthetic heart valves: in vitro studies.

The development of a ‘smart’ heart valve prosthesis, with the intrinsic ability to monitor thrombus formation, mechanical failure and local haemodynamics and to relay this information externally, would be of significant help to clinicians. The first step towards such a valve is development of the sensors and examination of whether sensor output provides predictive information on function. Custom-made piezo-electric sensors were mounted onto the housing of mechanical valves with various layers of simulated thrombus and bioprosthetic valves with normal and stiffened leaflets. Sensor output was examined using joint time-frequency analysis. Sensors were able to detect leaflet opening and closing with high fidelity for all types of valve. The frequency content of the closing sounds for the mechanical valves contained several peaks between 100 Hz and 10 kHz, whereas closing sounds for the bioprosthetic valve contained energy in a lower frequency range (<1 kHz). A frequency peak of 47±15 Hz was seen for the normal bioprosthetic valve; this peak increased to 115±12 Hz for the valve with visibly stiffened leaflets. Total low-frequency (80–3500 Hz) energy content diminished predictably with increasing levels of thrombus for the mechanical valves. Lastly, closing sound intensity correlated well with closing pressure dynamics (dp/dt) (y=190x−443; r=0.90), indicating that the sensors also provide information on haemodynamics. These studies provide initial evidence regarding the use of embedded sensors to detect prosthetic valve function. Efforts to encapsulate these sensors with telemetry into a custom valve are currently underway.

Application of A Microstructural Constitutive Model of the Pulmonary Artery to Patient-Specific Studies: Validation and Effect of Orthotropy

We applied a statistical mechanics based microstructural model of pulmonary artery mechanics, developed from our previous studies of rats with pulmonary arterial hypertension (PAH), to patient-specific clinical studies of children with PAH. Our previous animal studies provoked the hypothesis that increased cross-linking density of the molecular chains may be one biological remodeling mechanism by which the PA stiffens in PAH. This study appears to further confirm this hypothesis since varying molecular cross-linking density in the model allows us to simulate the changes in the P-D loops between normotensive and hypertensive conditions reasonably well. The model was combined with patient-specific three-dimensional vascular anatomy to obtain detailed information on the topography of stresses and strains within the proximal branches of the pulmonary vasculature. The effect of orthotropy on stressstrain within the main and branch PAs obtained from a patient was explored. This initial study also puts forward important questions that need to be considered before combining the microstructural model with complex patient-specific vascular geometries.

Evaluation of segmentation algorithms for vessel wall detection in echo particle image velocimetry

Recent in-vitro and in-vivo validation studies confirmed the accuracy of echo particle image velocimetry (echo PIV), a simple non-invasive means of measuring multi-component blood velocity vectors. Echo PIV should also be useful for direct measurement of wall shear stress (WSS) in clinical studies. However, calculation of WSS requires accurate delineation of vessel walls in ultrasound images, which may be problematic when conventional segmentation techniques are used. In this paper, we proposed two methods for segmenting contrast enhanced B-mode images. The first is based on the intensity profile of ultrasound images, termed intensity-based edge detection (IBED) and the second based on the movement of microbubbles, termed movement-based quadratic difference (MBQD). The parameters related with the two methods were optimized over large sets of microbubble images acquired from human carotid vessels using an echo PIV system (Illumasonix LLC, Boulder, CO). A validation study on the two algorithms was carried out against manual delineations on both common carotid artery (CCA) and carotid bifurcation images, with 20 frames for each group. The inter-observer variability of three manual delineations, in pixels (about 80 µm/pixel), was 0.9±0.4, 1.3±0.6, 1.3±0.6 on CCA images, and 2.5±1.0, 3.9±1.1, 2.3±1.1 on bifurcation images. The absolute difference (mean±SD) between each computer-generated contour and the ground truths, taken as the average of three manual delineations, were 1.3±0.8, 3.8±0.8, 5.3±0.5 on CCA images, and 2.3±0.9, 4.6±1.3, 6.3±0.6 on bifurcation images, for the MBQD, IBED and active contour methods, respectively. The MBQD method shows comparable performance with manual delineations on particle images even with poor intima-media layer quality.