A computational bio-chemo-mechanical model of in vivo tissue-engineered vascular graft development.

Abstract

Stenosis is the primary complication of current tissue-engineered vascular grafts used in pediatric congenital cardiac surgery. Murine models provide considerable insight into the possible mechanisms underlying this situation, but they are not efficient for identifying optimal changes in scaffold design or therapeutic strategies to prevent narrowing. In contrast, computational modeling promises to enable time- and cost-efficient examinations of factors leading to narrowing. Whereas past models have been limited by their phenomenological basis, we present a new mechanistic model that integrates molecular- and cellular-driven immuno- and mechano-mediated contributions to in vivo neotissue development within implanted polymeric scaffolds. Model parameters are inferred directly from in vivo measurements for an inferior vena cava interposition graft model in the mouse that are augmented by data from the literature. By complementing Bayesian estimation with identifiability analysis and simplex optimization, we found optimal parameter values that match model outputs with experimental targets and quantify variability due to measurement uncertainty. Utility is illustrated by parametrically exploring possible graft narrowing as a function of scaffold pore size, macrophage activity, and the immunomodulatory cytokine transforming growth factor beta 1 (TGF-β1). The model captures salient temporal profiles of infiltrating immune and synthetic cells and associated secretion of cytokines, proteases, and matrix constituents throughout neovessel evolution, and parametric studies suggest that modulating scaffold immunogenicity with early immunomodulatory therapies may reduce graft narrowing without compromising compliance.

• Authors: Ramak Khosravi, Abhay B Ramachandra, Jason M Szafron, Daniele E Schiavazzi, Christopher K Breuer, Jay D Humphrey
• Journal: Integrative biology : quantitative biosciences from nano to macro (Integr Biol (Camb)) Vol. 12 Issue 3 Pg. 47-63 (04 14 2020) ISSN: 1757-9708 [Electronic] England
• PMID: 32222759 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Polymers
• Transforming Growth Factor beta1

Topics

• Algorithms
• Animals
• Bayes Theorem
• Blood Vessel Prosthesis
• Computer Simulation
• Fibroblasts (metabolism)
• Inflammation
• Macrophages (metabolism)
• Mice
• Monocytes (metabolism)
• Polymers (chemistry)
• Prosthesis Design
• Sensitivity and Specificity
• Signal Transduction
• Tissue Engineering (methods)
• Tissue Scaffolds
• Transforming Growth Factor beta1 (metabolism)
• Vena Cava, Inferior (surgery)