Robin Shandas - US grants

CTS-0114109
Jean Hertzberg, University of Colorado

In this proposal, funding is requested to purchase a Particle Image Velocimetry (PIV) system to enhance the research capabilities of the PI and four Co-PI's. They are actively engaged in a number of interesting research problems in fluid mechanics. These include real time simulation and control of a two-dimensional jet, evaluation of micro-electro-mechanical systems (MEMS) fluidic devices, cardiovascular fluid dynamics, and infectious aerosol generation.

DESCRIPTION (Applicant's Abstract): This proposal addresses the problem of evaluating the efficacy of newly developed agents for the treatment of primary pulmonary hypertension. The use of catheter techniques to measure pulmonary vascular resistance severely limits routine evaluation of such treatments. We propose to develop, refine and test a non-invasive ultrasound based means of accurately evaluating pulmonary vascular resistance in children with primary pulmonary hypertension. The hypothesis for this project is based on the relationship between changes in downstream impedance within a fluid system and the characteristics of the pressure pulse propagation wave that develops within the arterial walls. We propose to show that downstream impedance affects the pulse propagation wave traveling within the main pulmonary artery and that changes in downstream impedance, as would occur with treatments such as inhaled nitric oxide or infused prostaclyin, can be followed by measuring pulse propagation characteristics. Furthermore, we propose that the pressure pulse propagation in the main PA affects local velocities, and that such changes in local velocities can be quantified as a velocity propagation using non-invasive ultrasound color M-mode imaging. This should significantly aid in evaluating new treatments for primary pulmonary hypertension and thereby expand treatment options and improve quality of life for patients. The aims of this project, therefore, are: 1. Demonstrate analytically that a fundamentally rooted mathematical and physical foundation exists for using velocity data to extract pressure pulse propagation characteristics for pediatric primary pulmonary hypertension. 2. Develop and test a method for using color M-mode velocity data to predict downstream impedance using highly reproducible in vitro models. 3. Determine clinical utility of the color M-mode approach using existing clinical protocols studying the efficacy of nitric oxide and/or 100 percent 02 treatment in the catheterization laboratory to reduce pulmonary vascular resistance in children with primary pulmonary hypertension. 4. Determine whether color M-mode measured velocity propagation (Vel-prop) predicts pulmonary vascular resistance in the clinical situation.

The non-invasive imaging and quantitation of micro-scale flow within the body is still a challenge for current clinical imaging systems. The development of an ultrasound-based imaging system for detection and quantitation of micro-scale flows is proposed here.
Two sets of commercially available phased-array broadband transducers will be used. These will be coupled to custom electronics and analysis systems to image gas-filled micro-bubbles (diameters: 3 - 8 microns) within the flow field. The first part of this problem is precise particle detection and tracking. The second part is the development of an imaging system that reveals local flow characteristics. The non linear components of backscatter from the highly reflective micro-bubbles will be analyzed in the RF domain to detect particles. Once the particle is detected, a particle tracking algorithm will be employed to track the particles over a specified distance. This will allow calculation of local particle velocity. The project aims are:
1) Characterize the design specifications for an ultrasound-based micro-flow imaging system.
2) Build a prototype version of this system using a combination of existing broadband ultrasound transducers, coupled with custom electronics and algorithm development.
3) Validate the performance of this prototype system using a mock circulatory flow loop with velocity and flow quantified using independent reference techniques.
At the end of this project, significant work toward the development of an ultrasound-based micro-flow imaging system will be complete. The work can then move toward implementation of the system in hardware for testing under in vivo conditions.

DESCRIPTION (provided by applicant): The purpose of this application is to establish a new training program focused on cardiovascular bioengineering, specifically bio/fluid mechanics, instrumentation, devices, and imaging, on the campus of the University of Colorado Boulder (UCB), with participation from the University of Colorado Health Sciences Center (UCHSC), and The Children's Hospital (TCH). The objectives of this training grant are: 1) support pre-doctoral research on cardiovascular bioengineering at UCB; 2) support such research at the post-doctoral level at UCB; 3) further integrate existing research and educational efforts in modeling, cardiovascular hemodynamics, molecular and cellular biology, imaging, and device and instrumentation design. The program will be housed within the bioengineering program at the Mechanical Engineering Department, UCB, with participation from: 1) the Department of Pediatrics, TCH/UCHSC; 3) the Division of Cardiology, UCHSC; 4) the Department of Kinesiology and Applied Physiology (KAPH). Each of these program units has been successful in producing research relevant to cardiovascular bioengineering, and in training graduate students and post-doctoral fellows. This training grant will take advantage of recent expansions of existing individual research programs with the resultant goal of increasing the number of research opportunities for students and fellows. Until recently, research efforts in the area of cardiovascular bioengineering have been limited on the Boulder campus. However, recent faculty recruitments and a significant thrust in bioengineering from the Dean at the College of Engineering, including the creation of an inter-campus research center (MicroElectromechanical Devices in Cardiovascular Applications - MEDICA) and the beginning of the Institute for Micro and Nano Systems, have created strong core research interests in the relevant areas of this proposal. The timing is now right to leverage these existing research successes into an established program for training future scientists in cardiovascular bioengineering. The inter-disciplinary nature of the research and the personnel involved lend itself very well to the training of bioengineers with breadth of experience and depth of training.

ABSTRACT

Proposal No. CTS-0421461
Principal Investigator: R. Shandas, University of Colorado

Determination of the velocity field of opaque fluid flows is a challenge in many areas of fluids research, ranging from the imaging of flows in complex shapes that are difficult to render in transparent media, to the demanding constraints of flow in the aerated surf zone. In the context f cardiovascular research, the added requirements of measurements made in living creatures limit the choices and capabilities of flow field instrumentation even further. This grant is to develop a system to meet these needs, based on the synthesis of two existing technologies, Particle Image Velocimetry (PIV) and Brightness-Mode (B-mode) contrast ultrasound echo imaging: Echo PIV. Medical B-mode contrast echo imaging is achieved by the backscatter of ultrasound from "contrast agent", thin-shelled microbubbles of gas that have been injected into the bloodstream. Two sequential images are then subjected to PIV analysis, in which a cross correlation between the two images gives the displacement of the particles, allowing a velocity vector field to be determined based on the time between images. A prototype system is currently in use, but the off-the-shelf components result in spatial resolution and dynamic range inadequate for the current research program in cardiovascular fluid dynamics at the University of Colorado (CU). Advances in ultrasound technology will be required, but are feasible. This system will be used in support of a range of studies of cardiovascular flow at UCHSC. In particular, this system will enable the measurement of fluid shear near the walls of small arteries, answering many questions about the role of shear in vascular diseases. It will enable the measurement of the complex, time dependent flows in the large vasculature, such as the main pulmonary artery and aortic arch in vivo, allowing the validation of modeling efforts that seek to combine realistic solid mechanics models of the walls with pulsatile 3-d flows. It will also be used to increase understanding of ventricular flows, where fluid-physics-based analysis may lead to the differentiation of changes due to age from those due to illness. This work will be disseminated into both the biomedical and experimental fluid dynamics communities via presentations and publications. The PIs are recipients of an NIH training grant, and University of Colorado is the recipient of a grant promoting underrepresented groups in biomedical research: the combination ensures the participation of a wide range of graduate and undergraduate students in the development of this system. Also, this system will be used as examples in both freshman and graduate design courses.

DESCRIPTION (provided by applicant): The development of a real-time non-invasive method to measure the multiple components of blood flow would be enormously useful for a number of cardiovascular, neurological, renal, and radiological applications. Currently, the only means of obtaining multiple blood velocity components is through MRI phase velocity mapping techniques, which are cumbersome, time-consuming, and limited in temporal resolution. Furthermore, MRI phase velocity mapping and its various counterparts are not real-time techniques. We have recently developed an ultrasound-based particle image velocimetry technique that has shown promise in the measurement of complex blood flow patterns. This method, termed echo-PIV, takes advantage of the non-linear backscatter characteristics of ultrasound contrast micro bubbles analyzed in the RF domain to distinguish individual micro bubbles, which are then tracked over time to obtain the local velocity vector. We have developed software algorithms to analyze this information and have obtained promising data from in vitro and in vivo studies. The method now requires optimization and implementation into hardware to form a real-time non-invasive velocimetry method. Our experience with ultrasound and Doppler imaging, experimental fluid dynamics including the development and use of a variety of optical PIV systems, and long-standing relationship with the ultrasound industry, make the satisfactory completion of this project highly probable. The specific aims of this project are: 1) Use numerical modeling of backscatter from micro bubbles to study which driving conditions (frequency, pulse shape, pulse length, power, etc.) will maximize the non-linear response of the bubbles and thereby increase the accuracy of the echo PIV algorithm. 2) Assemble the hardware components to implement the real-time echo PIV imaging system, based on maximizing the specifications for the two clinical applications described above. 3) Test the prototype imaging system using in vitro models with laser-based optical particle image velocimetry as the standard for comparison.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Minimally invasive surgical techniques to implant cardiovascular devices for treatment of a variety of valvular, vascular and extra-vascular complications are increasingly exploited to improve patient outcomes, and reduce morbidity and cost. Originally based on simple metals, these devices are now becoming more sophisticated through the use of precisely engineered materials such as metal bimorphs (shape memory alloys) and new polymer structures. Polymers, in particular, exhibit significant advantages in these applications over metals and metal alloys, including ease of surface modification that enhances biocompatibility, greater mechanical flexibility to more accurately simulate native mechanical behavior, and availability of a wide variety of base structural configurations. Manipulation of polymers to produce shape memory characteristics is the most recent evolution, which due to their high degree of shape recoverability (order of magnitude greater than metal alloys) promises significantly greater freedom in designing minimally invasive cardiovascular devices. However, several substantial challenges preclude reliable and direct applications of shape memory polymers (SMPs) as innovative biomaterials for surgical implants. The goal of this project is to remove this limitation in the SMP design process by explicitly quantifying the thermomechanical properties of one promising type of SMP, and infusing this information into a commercially available finite element model (ABAQUS). This will provide designers of cardiovascular devices who wish to use SMPs with two enhancements required to enable exploitation of SMP biomaterials in future surgical devices: (1) new SMP engineering benchmarking characteristics required for rational design and proof-of-concept for SMP-based devices, and (2) a powerful a priori evaluation tool to refine and test device designs prior to fabrication. The model will then be exercised to produce two increasingly complex prototype devices: a vascular stent with significantly greater shape recoverability than currently available using metal shape memory alloys, and a prosthetic heart valve. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a relatively poorly understood disease in children and requires constant monitoring and chronic treatment to mitigate excess right ventricular afterload effects. Such monitoring requires regular and frequently invasive clinical imaging sessions. However, even with invasive techniques, the extent of clinical information currently obtained is incomplete, involving primarily pulmonary vascular resistance (PVR) and its component parameters: mean pulmonary artery (PA) pressure and right sided cardiac output (Qp). Given this paucity of quantitative information currently available to evaluate PAH clinically, opportunities exist to develop and evaluate more comprehensive measures of PAH using a combination of advanced cardiovascular imaging and sophisticated computational modeling. Furthermore, information gained from such endeavors should also assist in the development of novel non-invasive diagnostics, which by allowing easier acquisition of pulmonary vascular characteristics, serial monitoring, and bedside evaluation of reactivity, should widen the clinician's ability to characterize this complex disease. The overall hypothesis for these studies is that pulmonary vascular input impedance provides a more comprehensive measure of pulmonary vascular function than PVR alone since impedance includes both dynamic (stiffness or compliance) and steady-state (resistance) components of the vascular circuit. The aims of this project are therefore divided into studies establishing the use of impedance clinically, studies exploring why impedance is a good reflector of pulmonary vascular hemodynamics and mechanics, and studies developing novel non-invasive diagnostics that extract the relevant parameters found in invasivelymeasured impedance, namely PVR and pulmonary vascular stiffness (PVS). This K24 project proposes a unique combination of research studies and training efforts to advance clinical evaluation of PAH while training clinical research fellows with both solid fundamental understanding of underlying physics and hemodynamics and accurate application of such principles to novel clinical diagnostics.

Pulmonary arterial hypertension (PAH) is a relatively poorly understood disease in children and requires constant monitoring and chronic treatment to mitigate excess right ventricular afterload effects. Such monitoring requires regular and frequently invasive clinical imaging sessions. However, even with invasive techniques, the extent of clinical information currently obtained is incomplete, involving primarily pulmonary vascular resistance (PVR) and its component parameters: mean pulmonary artery (PA) pressure and right sided cardiac output (Qp). Given this paucity of quantitative information currently available to evaluate PAH clinically, opportunities exist to develop and evaluate more comprehensive measures of PAH using a combination of advanced cardiovascular imaging and sophisticated computational modeling. Furthermore, information gained from such endeavors should also assist in the development of novel non-invasive diagnostics, which by allowing easier acquisition of pulmonary vascular characteristics, serial monitoring, and bedside evaluation of reactivity, should widen the clinician's ability to characterize this complex disease. The overall hypothesis for these studies is that pulmonary vascular input impedance provides a more comprehensive measure of pulmonary vascular function than PVR alone since impedance includes both dynamic (stiffness or compliance) and steady-state (resistance) components of the vascular circuit. The aims of this project are therefore divided into studies establishing the use of impedance clinically, studies exploring why impedance is a good reflector of pulmonary vascular hemodynamics and mechanics, and studies developing novel non-invasive diagnostics that extract the relevant parameters found in invasively- measured impedance, namely PVR and pulmonary vascular stiffness (PVS).

DESCRIPTION (provided by applicant): Pulmonary hypertension in children is a critical determinant of morbidity and mortality in various pediatric diseases. Despite advances in therapies, long-term outcome in many settings remain poor. Although reasons for this are multi-factorial, one critical component is the relative lack of disease-defining knowledge regarding the functional impact of the disease on the right heart and coupled pulmonary vasculature. In fact, clinically, pulmonary arterial hypertension continues to be evaluated predominantly as a distal vascular phenomenon, and only limited recognition is given to the fact that the pulmonary arterial system (PA) is intimately coupled with right ventricular function in health and disease. Functionally speaking, RV-PA coupling is driven by the principles of hydrodynamic and mechanical energy transfer and is thus not markedly dependent on the biological heterogeneity of the pediatric PH population. Over the last 7 years, our group using a reverse bedside-to-bench approach have developed novel markers of RV afterload using vascular input impedance principles, and have shown on studies of over 250 pediatric subjects with pulmonary hypertension that PVR does not represent the sole metric of RV afterload, that PA stiffness increases dramatically in pediatric pulmonary hypertension patients and consequently loads the RV to a proportionally greater level, and that inclusion of impedance and PA stiffness measures improves prediction of 1-year outcomes. These clinical studies generated a series of mechanistic studies to understand how the upstream pulmonary vessels stiffen, which have led to novel and interesting hypotheses regarding the role of extracellular matrix proteins in upstream vascular remodeling, mechanisms of healthy versus maladaptive remodeling, and differences in the developing versus the fully developed RV-PA system. These are currently being tested by our group and others through parallel efforts. In this project, we intend to complete the RV-PA axis picture by extending our clinical studies on evaluating RV afterload to include pump function from global and local viewpoints and thereby develop and test clinically usable methods to functionally phenotype the pediatric PH patient. In parallel and since biological maladaptation of the RV may precede discernable functional maladaptation, we will biologically phenotype these patients using an established circulating marker of cardiac failure (BNP and NTproBNP) and emerging circulating biomarkers of cardiac failure (micro RNAs). Together these studies will test our hypotheses that RV decompensation in pediatric PH is significantly correlated to deteriorating RV-PA coupling, and that comprehensive functional and biological phenotyping of the RV-PA axis in pediatric PH provides significantly greater prediction of 1- and 2-year clinical outcomes. Through the coordinated, multidisciplinary approach proposed here, which involves experts in bioengineering, imaging, pediatric heart failure, pediatric pulmonary hypertension, and micro RNAs, we should: 1) gain greater understanding of precisely how the human, pediatric RV compensates or decompensates under hypertensive load; 2) generate novel yet clinically usable techniques for the routine evaluation of the RV-PA function; 3) identity the combination of functional and biological phenotypes that best predict outcomes in this complex disease population; and 4) advance our understanding of the functional relationship between RV-PA coupling and RV health. As in prior work, we believe methods, questions and results generated from this study should help guide mechanistic studies to elucidate specific pathways of RV and RV-PA decompensation.

PROJECT SUMMARY The training program in ?Cardiovascular Biomechanics and Imaging? has the primary goal of attracting highly qualified, multi-disciplinary scientists in the area of cardiovascular bioengineering at pre- and post- doctoral levels. This supplement will expand this training to two laboratories involved in cardiovascular biomechanics and imaging in heart defects and cardiovascular pathologies in models of Down syndrome. This additional focus will leverage collaborations with the Linda Crnic Institute for Down Syndrome on the Anschutz Medical Campus at the University of Colorado and will attract more researchers to Down syndrome research. The new portions of this supplement will use human trisomy 21 iPSC lines and Down syndrome mouse models provided by the Crnic Institute for targeted, high-risk, high-reward basic science studies on chromosome 21. These projects will specifically address the NHLBI INCLUDE funding priorities of characterization of differentiation of disease-related tissue types in induced pluripotent stem cells (iPSCs) derived from cells from individuals with Down syndrome and compared to euploid iPSCs, and characterization in animal models of the morphological events occurring in early heart development that give rise to the specific forms of congenital heart disease that are the primary cause of death during the first year of life for infants born with Down syndrome.