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Principal Investigator: Jay D. Humphrey
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $679,261
Funding agency: National Heart Lung and Blood Institute
Coronary artery bypass graft (CABG) surgery is the gold standard treatment for patients with diffuse, multi-vessel
coronary artery disease, with >350,000 surgeries performed each year in the USA. Due to the limited availability
of arterial grafts, saphenous vein grafts (SVG) are used in >95% of patients. Despite advances in surgical
technique and post-surgical management, SVG stenoses and occlusions occur at alarmingly high rates: 5-10%
of SVGs fail within one month after surgery, 25% within 12-18 months, and 40-50% within 10 years, resulting in
significant morbidity and mortality. Currently, there are no clinically available means to prevent SVG failure
following CABG beyond optimal medical therapy. Mechanical stimuli, including hemodynamic loads and
associated vessel wall deformations and stresses, are known to contribute to the cell-mediated structural
changes leading to SVG failure, yet, the precise mechanobiological mechanisms remain poorly understood. In
preliminary studies, we quantified mechanical stimuli in CABG simulations, identifying hemodynamic markers
associated with SVG stenosis. Importantly, we introduced the first computational growth and remodeling (G&R)
framework that can delineate adaptive vs. maladaptive responses of vein grafts, incorporating optimization to
accelerate parameter estimation. With this model, we then predicted that an external bioabsorbable sheath,
present over a short post-operative period, could mitigate intermediate-term graft failure. Our scientific premise
is supported by a preliminary in vivo ovine study. Our collaborative multi-disciplinary team will address this
critical unmet need through tightly integrated computational model-driven design, experimental, and
clinical approaches to uncover arterialization mechanisms and evaluate a novel bioabsorbable sheath
device for SVG failure prevention. In Aim 1, we will develop the first G&R model of SVG arterialization
incorporating inflammation. We will inform and validate the model with data from a longitudinal rabbit surgical
study, in which we will perform surgery to interpose a jugular graft in the carotid artery. In Aim 2, we will
synthesize these data and models into a first-of-its-kind 3D fluid-solid-growth (FSG) simulator to predict SVG
disease progression, validated against an independent subset of animal data. To further inform our models, we
will characterize human SVG tissue with biaxial tissue testing. We will increase rigor by incorporating uncertainty
quantification. In Aim 3, we will design, optimize and evaluate a novel external sheath device for the prevention
of SVG failure, integrating in silico and large animal in vivo studies. We will rapidly 3D print sheath designs from
a unique class of bioabsorbable elastomeric materials with tunable degradation rates. This proposal brings
together a multidisciplinary team with expertise in cardiovascular simulation, vascular mechanobiology,
optimization, imaging, biomaterials, additive manufacturing, and clinical cardiovascular care as well as a track
record of joint publications, funding, and open-source software. Our ultimate goal is to improve outcomes of
CABG patients via prediction and prevention of SVG failure, for whom there are limited treatment options.
Terms: <3-D><3-D print><3-D printer><3-Dimensional><3D><3D Print><3D printer><3D printing><Acceleration><Animals><Aortocoronary Bypass><Biocompatible Materials><Biological><Biology><Biomaterials><Blood Vessels><Body Tissues><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Caring><Carotid Arteries><Cell Body><Cells><Clinical><Computer Models><Computer software><Computerized Models><Computing Methodologies><Coronary Arteriosclerosis><Coronary Artery Bypass><Coronary Artery Bypass Grafting><Coronary Artery Bypass Surgery><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Coronary Vessels><Coronary arterial bypass><Data><Data Set><Device Designs><Devices><Diffuse><Disease Progression><Domestic Rabbit><Elastomers><Estimation Techniques><Failure><Funding Agency><Funding Source><Generalized Growth><Geometry><Goals><Growth><Heart Vascular><Histology><Human><Image><In Vitro><Inflammation><Joints><Jugular Veins><Liquid substance><Mechanics><Mediating><Medical><Medical Imaging><Methodology><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Operative Procedures><Operative Surgical Procedures><Oryctolagus cuniculus><Ovine><Ovis><Parameter Estimation><Pathologic Constriction><Pathological Constriction><Patients><Performance><Post-Operative><Postoperative><Postoperative Period><Preclinical Testing><Prevention><Process><Property><Publications><RNA Seq><RNA sequencing><RNAseq><Rabbits><Rabbits Mammals><Saphenous Vein><Scientific Publication><Sheep><Software><Solid><Stenosis><Stress><Structure><Structure of jugular vein><Surgical><Surgical Interventions><Surgical Procedure><Techniques><Testing><Tissue Grafts><Tissue Growth><Tissues><Uncertainty><Vein graft><Veins><Venous><animal data><atherosclerotic coronary disease><biologic><biological material><circulatory system><computational methodology><computational methods><computational modeling><computational models><computer based method><computer based models><computer based prediction><computer methods><computerized modeling><computing method><coronary arterial disease><coronary bypass><design><designing><doubt><elastomeric><experiment><experimental research><experimental study><experiments><fluid><graft failure><hemodynamics><high risk group><high risk individual><high risk people><high risk population><human data><human study><imaging><improved outcome><in silico><in vivo><innovate><innovation><innovative><liquid><manufacture><mechanic><mechanical><mechanical stimulus><mortality><multidisciplinary><novel><ontogeny><open source><pre-clinical testing><predictive modeling><prevent><preventing><response><simulation><standard care><standard treatment><surgery><three dimensional><three dimensional printing><tissue grafting><transcriptome sequencing><transcriptomic sequencing><translation strategy><translational approach><translational strategy><vascular>