Improving Tissue Engineered Vascular Graft Performance via Computational Modeling

PROJECT SUMMARY
Tissue engineered vascular grafts (TEVGs) have demonstrated potential to revolutionize cardiovascular care,
with multiple grafts now in clinical trials in children and adults. Yet, there remains a pressing need to optimize
these grafts to improve outcomes and enable wide-spread usage. In this proposal, we build upon a strong
foundation of prior findings but introduce an innovative multi-fidelity computational-experimental approach that
promises to accelerate greatly the development of improved TEVGs. Although the proposed approach is general
with broad applicability, we will focus on one particular application – TEVGs for congenital heart surgery – to
refine the approach and illustrate its utility. Specifically, we will use a pre-clinical juvenile ovine model to collect
the longitudinal data needed to develop and inform novel multiscale computational models that will be melded
to describe the in vivo development of a neovessel from an implanted biodegradable polymeric scaffold. Our
approach will be informed by data from three initial, non-optimal designs, then used to identify via formal methods
of optimization preferred microstructural scaffold parameters and an overall geometry that optimizes in vivo
function. Particularly novel will be our ability to account for normal developmental changes in the lamb
vasculature and coupling of cell signaling, growth and remodeling, and 3D hemodynamics in a novel multi-fidelity,
multiscale workflow that allows optimization of desired biological and physiological outcomes. To achieve these
goals, we propose three Specific Aims: 1) To quantify normal vascular development and performance of three
baseline TEVG designs in a lamb model; 2) To develop and employ a novel multiscale fluid-solid-growth (FSG)
simulation framework to optimize TEVG design; 3) To validate the model-identified optimal TEVG design in a
longitudinal large animal study. Our team is uniquely positioned for success, combining expertise in animal
models of congenital heart disease, development of TEVGs and their clinical translation, finite element
simulations of cardiovascular hemodynamics and biomechanics, modeling vascular growth and remodeling, and
identifying and modeling mechanisms of mechanobiology. Our approach is innovative in that we will 1) meld
macro (organ) level simulations of cardiovascular biomechanics with micro level simulations of vascular cell
signaling, 2) develop a novel, generally applicable paradigm for model-driven optimization of tissue engineered
structures that provides control over outcomes, and 3) facilitate clinical translation of TEVGs with improved
performance. Successful completion of this study will be significant in multiple ways – not only will it result in a
new (optimal) design of a TEVG for use in the Fontan surgical procedure, performed in children born with single
ventricle congenital heart defects, it will also establish a novel computational-experimental paradigm in
cardiovascular tissue engineering that promises to accelerate the development of diverse implants.

Grant Number: 5R01HL139796-08
NIH Institute/Center: NIH
Principal Investigator: christopher breuer