A Preclinical Study Evaluating and Comparing the Efficacy of Tissue Engineered Vascular Grafts to Polytetrafluoroethylene Grafts

PROJECT SUMMARY
Tissue engineering provides a strategy for developing improved prosthetic biomaterials for use in congenital
heart surgery. The overriding premise of our work is that tissue engineering can be used to regenerate
autologous neotissue to repair or replace cardiovascular tissues that are congenitally malformed and that the
tissue engineered constructs will perform better than prosthetic biomaterials. We developed a tissue engineered
vascular graft (TEVG) specifically for use in congenital heart surgery and are currently performing a clinical trial
evaluating its safety as an extracardiac conduit in the Fontan operation in which a vascular graft is used to
connect the inferior vena cava (IVC) to the pulmonary artery. The broad, long term objective of this study is to
translate this technology to the clinic for use in children with congenital heart disease. In order to obtain FDA
approval, we must demonstrate the efficacy of the TEVG in a relevant preclinical animal model. The goal of this
proposal is to evaluate the late term efficacy of TEVGs compared to PTFE grafts (the current clinical standard
of care) using the ovine IVC vascular interposition graft model which we previously developed and validated for
this purpose. To this end we propose three specific aims: In the first aim we will evaluate the physiological
properties of the TEVG implanted in the ovine model between 9-10 years including compliance and
vasoreactivity in addition to growth capacity. We will use intravascular ultrasound (IVUS) and invasive pressure
monitoring to measure and compare the compliance of the TEVG and native IVC in age- and sex-matched sheep
at various loading conditions. Next we will also use the IVUS and invasive pressure monitoring coupled with
pharmacological testing to evaluate and compare the response of the TEVG and the native IVC to various
pharmacological reagents at physiologically relevant doses. Finally, we will measure the change in size and
geometry of the TEVG using serial 3D angiography to rule out aneurismal dilation and determine the functional
growth capacity of the TEVG over the natural life span of the animals in our study. In our second aim we will use
computed tomography to evaluate and compare the degree of ectopic calcification between TEVGs and PTFE
grafts implanted in the ovine model. In the third aim we will evaluate and compare the hemodynamic performance
of TEVGs to PTFE grafts implanted in the ovine model using 4D MRI and invasive hemodynamic monitoring.
We will evaluate graft performance both at rest and during simulated stress using dobutamine stress testing then
use the 4D flow and invasive hemodynamic pressure data to analyze the degree of disordered flow and
associated energy loss within the grafts over cardiac and respiratory cycles at different hemodynamic states
using computational fluid dynamics. The development of an improved TEVG with growth capacity has the
potential to improve outcomes for children born with congenital heart disease.

Grant Number: 5R01HL163065-04
NIH Institute/Center: NIH
Principal Investigator: christopher breuer