Keefe B. Manning - US grants

Anastomosis; Anastomosis - action; Aorta; Aortic Valve; Aortic arch structure; Aortic valve structure; Arch of the Aorta; Arch, Aortic; CRISP; Cannulas; Computer Programs; Computer Retrieval of Information on Scientific Projects Database; Computer software; Condition; Distal; Flow, Pulsating; Funding; Goals; Grant; Heart; Hemolysis; Institution; Investigators; Left; Left Ventricles; Left ventricular structure; Modeling; NIH; National Institutes of Health; National Institutes of Health (U.S.); Operation; Operative Procedures; Operative Surgical Procedures; Pattern; Perfusion, Pulsatile; Plant Leaves; Plant Roots; Platelet Activation; Position; Positioning Attribute; Pulsatile Flow; Research; Research Personnel; Research Resources; Researchers; Resistance; Resources; Software; Source; Surgical; Surgical Interventions; Surgical Procedure; Thrombosis; United States National Institutes of Health; Work; aortic arch; aortic valve; base; computer program/software; leaf; resistant; root; surgery; ventricular assist device

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this work is to study pulsatile flow in a sudden expansion which represents a modeled stenosis which is an abnormal narrowing in a blood vessel . The sudden expansion is used to obtain adverse flow patterns, such as separation, reattachment and eddy formation, that are likely to be seen in stenoses. Computational fluid dynamic (CFD) simulations will be used to obtain velocity and turbulent characteristics of the flow through the sudden expansion at a mean throat Reynolds number of 2000, a peak throat Reynolds number of 4600 and a mean flow rate of 1.25 l/min, which is representative of the flow seen in the iliac artery. The iliac artery is elliptical in cross section with a major axis of 1.53 cm and minor axis of 1.3 cm at the aortic bifurcation, and hence the inlet diameter of our model, which is 12 mm, is representative of the mean diameter of the iliac artery. The variation of the throat Reynolds number from a low of 400 to a high of 4600 will produce flow than transitions from laminar to turbulent. The CFD results of the flow will be compared against the velocity and turbulence characteristics obtained using a three-component laser Doppler velocimetry experimental technique. While previous studies of pulsatile flow in stenoses have only been conducted using one-component LDV, this study uses three-component LDV which enables us to simultaneously capture all three components of flow, and hence allows us to compute turbulence data that is more accurate. Also, previous studies of pulsatile flow in stenoses using computational techniques have relied on direct numerical simulation (DNS) techniques to produce accurate representations of the flow. We will use a less computationally expensive implicit large eddy (ILES) technique to predict the flow in the sudden expansion and intend to show that the ILES simulation results match the experimental results just as accurately as DNS. The threshold level of turbulent shear stress responsible for blood damage in a submerged jet was found to be 4000 by other researchers. We will correlate the levels of blood damage that may occur in pulsatile stenotic flows by comparing the turbulent stress measured in the sudden expansion to this threshold level. We hypothesize that the mean turbulent shear stress in the flow will be low compared to steady flow at similar Reynolds numbers. However, the instantaneous values of turbulent shear stress may be much larger, resulting in higher levels of blood damage. This work may provide valuable insights to researchers to better predict the stresses seen in pulsatile stenotic flows and their implications to blood damage and thrombus formation.

Summary: The most popular replacement heart valve designs (so called ?bioprosthetic heart valves? or BHV) continue to be fabricated from xenograft biomaterials for both current and novel valve designs (e.g. standard stented valve, percutaneous delivery). Failure continues to be the result of leaflet structural deterioration mediated by fatigue and/or tissue mineralization, with durability limited to 10-15 years. Such limitations results from a combination of valve design and the intrinsic fatigue response of the constituent xenograft biomaterials. Thus, improved durability remains an important clinical goal and represents a unique cardiovascular engineering challenge resulting from the extreme valvular mechanical demands that occur with blood contact. Yet, current BHV assessment relies exclusively on device-level evaluations, which are confounded by simultaneous and highly coupled biomaterial mechanical behaviors and fatigue, valve design, hemodynamics, and calcification. Thus, despite decades of clinical BHV usage and growing popularity, there exists no acceptable method for simulating replacement valve function and durability at both the device and component biomaterial levels. This situation has contributed to the current stagnation in BHV development, limiting rationally developed improvements in prosthetic heart valve durability. We thus hypothesize that with the use of advanced biosolid mechanics simulations of the fatigue response of xenograft biomaterials coupled to state-of-the-art fluid-structure interaction (FSI) methods, a biomechanically rigorous and physiologically realistic approach to predict BHV performance can be developed. We will develop these coupled computational goals first in parallel, then combine and validate them in a final project stage.   

This Research Experiences for Undergraduates (REU) Site at Pennsylvania State University-University Park, entitled Penn State Cardiovascular Research: Engineering A Translational Experience (CREATE)," will expose students to research that will elucidate cellular/molecular processes governing biological responses to materials as applied to cardiovascular disease (CVD) and the development of therapeutic CVD interventions. This focus on education in cardiovascular disease (CVD) is extremely important and highly relevant for two reasons. First, CVD remains the number one killer in the United States. Thus, there is a great need to develop a pipeline of new engineers and scientists who can become leaders in the detection, prevention, and treatment of the disease. Second, the underlying etiology of CVD and its associated technologies combine to form a perfect platform for training in the creative and integrative thinking that is the hallmark of biomedical engineering. The objectives of this program are: 1) To conduct research on multi-scale problems to improve the understanding and treatment of CVD, 2) To apply the creative process to solve engineering problems applied to CVD treatment or intervention, 3) To be able to describe the process of translating research into marketable technology, and 4) To be able to identify requirements for success in graduate and professional schools.

Over a three year period, this REU program will engage undergraduate students in a 10-week intensive hands-on summer research and professional development/training experience, where they will develop proficiency in the underlying concepts and practice of cellular/molecular engineering, microscopy, or computational methods in biomedical engineering while integrating the creative process towards understanding CVD. The program will include individual research projects with faculty research mentors, seminars on safety training, research needs, and responsible conduct of research, workshops on the creative process applied to research, medical device development and intellectual property, outreach/dissemination of student research, and a research symposium. Through these activities Penn State CREATE will provide young researchers with new avenues of investigation, new technologies in quantitative and analytical methods, and new opportunities in novel diagnostic and interventional tools in medicine.

An optical method of flow visualization, Tomographic Particle Image Velocimetry (Tomo PIV), measures instantaneous three-dimensional (3D), three-component (3C) flow velocity. This Major Research Instrumentation project supports ongoing research and education in fluid dynamics at several Penn State campuses and other nearby institutions. The project will enable new cross disciplinary collaborations among 15 researchers across the Penn State campuses and with fluid dynamics researchers at other institutions. The instrumentation provides unprecedented access to the details of the physics of turbulent flows, enabling fundamental research with a significant impact on the engineering, biology, mathematics, physics, and medical communities. The instrumentation will be incorporated into undergraduate courses and undergraduate and graduate student researchers will gain an understanding of experimental design, setup, data acquisition, and analysis using the high-tech Tomo PIV system. The researchers will provide tools for K-12 education and outreach activities, thereby increasing the public awareness in science and engineering and inspiring students to pursue advanced degrees or careers in STEM majors. The investigators will also engage students from underrepresented groups in their research.

This Tomo PIV system enables fundamental research in a variety of application areas. One study will examine the highly 3D nature of coherent structures in transitioning and turbulent boundary layers over oscillating geometries, with direct applications to flapping flight. The 3D Tomo PIV system will enable researchers to measure the complex velocity fields so that they can completely characterize the 3D behavior of vortex structures on flapping wings. Another project will conduct fundamental research to enable the development of cardiovascular devices with reduced risk of blood cell damage and clot formation. The Tomo PIV will enable researchers to better understand 3D cardiovascular structures and the influence of turbulence on cellular components and the formation of clots on surfaces. By capturing instantaneous complex flow structures, the instrumentation will enable the researchers to develop enhanced computational models to validate cardiovascular device design through improved understanding of the 3D velocity fields and shear stresses.

Project Summary / Abstract The objective of this research is to develop improved analytical and experimental methods used in a structured approach for the design of blood pumps with reduced potential for adverse events. We propose to continue our efforts focusing on the development of a computational platform using an open source code that integrates and couples shear-induced blood damage, thrombosis susceptibility potential, platelet activation, and thrombosis models simultaneously during the design process. Currently, only hemolysis models are used in the design phase and platelet activation used in rare cases, but neither has been integrated into a single computational model simultaneously. Our use of large eddy simulation computational fluid dynamics (CFD) provides a flow field capturing much of the turbulent flow field. We will apply this structured approach on a prototype bladed rotary ventricular assist device (VAD) that we are developing. To accomplish these goals, we will focus on the following specific aims: 1. Integrate a newly developed shear-induced blood damage model based upon dissipation (7), a thrombosis susceptibility potential (TSP) (8-10), and a platelet activation model (11) into a single computational platform to design a rotary blood pump incorporating the interaction of the VAD and native heart pulsatility. This research is intended to culminate in inclusion of a continuum-based macroscopic thrombosis model to refine the pump design. 2. Develop a continuum-based macroscopic thrombosis model for both laminar and turbulent flow and shear induced platelet activation that will be used to refine the pump design. The thrombosis model will be validated through in vitro platelet adhesion studies using a rotating disk system (RDS), an in vitro backward facing step (BFS) model using whole blood, and clinical LVAD patients. 3. Perform in vivo animal studies of a prototype rotary VAD system in non-anticoagulated animals to a) assess location, severity, and time course of thrombosis and embolization, b) study the effect of pump speed and pulsatile flow, and c) measure platelet activation, global coagulation, and hemolysis. This research will yield improved design and analysis tools in a structured approach that will be applicable to a broad range of blood pumps and blood contacting cardiovascular devices.

This award provides support for the travel of two invited speakers from underrepresented groups and twelve students and young investigators to attend the 6th International Conference on Clinical and Engineering Frontiers in Pediatric and Congenital Heart Disease, to be held in Philadelphia, PA, from May 9-11, 2019. The meeting will bring together global leaders in both the clinical and engineering study of congenital heart disease along with the next generation of researchers needed to address this important challenge. The conference will focus on disseminating the current state of the art with respect to advances in fundamental engineering and science that impact the understanding of both the pathophysiology and treatment of congenital heart disease. In addition, significant time will be spent identifying the gaps in knowledge that require new advancements in engineering in order to develop solutions in the future. Engineering and medical students from the region will also be encouraged to attend in order to better understand how engineers and clinicians can work together to address these challenges through advances in both fundamental engineering and clinical science.

This conference will bring together clinical and fundamental researchers to exchange knowledge and identify areas that are key targets for future research. Award funds will be used to support young investigators and students who will be able to present their research to an audience of leaders in the field. This will support the professional development and career advancement of these individuals. In addition, the award will support two underrepresented assistant professors to present invited talks. These individuals, who are developing leaders in the field, will serve as mentors and role models to other individuals from underrepresented groups.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

The research supported by this award will develop a new tool to better understand potentially dangerous complications that can occur with biomedical implants. Blood-contacting devices such as a heart valves, stents, catheters, and blood pumps are successfully implanted into thousands of patients every year in the United States. While huge strides have been made in improving their safety and effectiveness, the formation of blood clots in these devices remains a leading problem. When a clot forms in a device, it can prevent it from working properly, or break away from the device and result in complications such as stroke. This work will develop a computational tool to simulate how blood flow and biochemistry in these devices interact to result in clotting. This tool will take advantage of state-of-the-art supercomputing resources made available by the National Science Foundation. Thanks to recent efforts to promote the use of such computer simulations in approval of new biomedical devices, there is potential for this work to impact human health. Specifically, the model developed here may be used to offer additional evidence of safety and effectiveness of new devices, reduce development costs, and shorten time to market. This research combines several disciplines, including biochemistry, physics, and high-performance computing, and will help broaden the participation of underrepresented groups.

Various blood-contacting cardiovascular devices have been shown to improve outcomes in patients with cardiovascular disease, but thromboembolism remains as a leading risk factor. The nature of these devices makes in-vitro investigation of thromboembolism complicated and costly, leaving gaps in the understanding of the complex interactions between the device and the body. The goal of this research is to develop an in-silico method to model thromboembolism, incorporating biochemical surface interactions between blood and synthetic materials, the kinetics of the coagulation cascade, and the viscoelastic properties of blood clots into a fluid-dynamics solver. Important model processes will be experimentally validated, including concentration curves of pro-coagulant plasma proteins, clot mechanical properties, and fluid-dynamic conditions where embolization occurs. To address the large uncertainties and phenomenology in many of the simulated processes, Monte-Carlo experiments will be used to evaluate the credibility of the models? predictions.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Summary For the estimated 700,000 acute ischemic strokes (AIS) that occur each year in the United States, new stent retriever devices have shown an increase in recanalization of occluded cerebral arteries. However, over 15% of thromboemboli are still unable to be cleared and another 17% of patients die within 90 days despite successful recanalization. To date, there is little understanding of the upstream thrombosis and embolization processes that lead to AIS and why some thromboemboli are successfully removed and others are not. To better understand the entire progression of AIS, we will develop computational models of the upstream thrombosis, thrombus embolization, lodging and adhesion in the cerebral vasculature, and removal via applied forces from a thrombectomy device. These models will be validated with ex vivo mock circulatory flow loops that enable real-time tracking of thrombus growth and embolization and for AIS occlusion to be simulated in physiologically accurate scenarios. Furthermore, patient-specific anatomy and blood chemistry will be used. The results of these studies will provide insight to AIS occlusion but provide an opportunity to improve overall patient outcomes.