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Mathematical Models for Improved Design of Tissue Engineered Vascular Grafts /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Mathematical Models for Improved Design of Tissue Engineered Vascular Grafts // Jason Michael Szafron.
Author:	Szafron, Jason Michael,
Description:	1 electronic resource (188 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 83-03, Section: B.
Contained By:	Dissertations Abstracts International83-03B.
Subject:	Biomechanics. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28148188
ISBN:	9798538107315

Mathematical Models for Improved Design of Tissue Engineered Vascular Grafts /
Szafron, Jason Michael,

Mathematical Models for Improved Design of Tissue Engineered Vascular Grafts /Jason Michael Szafron. - 1 electronic resource (188 pages)

Source: Dissertations Abstracts International, Volume: 83-03, Section: B.

Many vascular pathologies require the use of implanted grafts to improve patient health. Implanted grafts have traditionally been autologous blood vessels or permanent synthetic conduits, but recent advances in tissue engineering have allowed for implantation of biodegradable polymeric scaffolds that promote neovessel development. Tissue engineered vascular grafts (TEVGs) offer hope for improved long-term functionality due to their ability to grow and remodel in conjunction with the native vessels. Indeed, the ability of infiltrating cells to alter their gene expression and matrix production or degradation kinetics in accordance with variations in mechanical stimuli allows for adaptation in maturation or changing hemodynamic loading. However, early TEVG remodeling is also dictated by the foreign body response to the polymeric scaffold. Variations in the material properties or microstructure of the scaffold can mediate changes in the phenotypes of the immune cells responsible for removing the scaffold and replacing it with new extracellular matrix. There is a complex interplay between the mechanobiological and immunobiological aspects of remodeling that determines the success or failure of implants. In the absence of sufficient production or mechanical conditioning of matrix, grafts can dilate and rupture, particularly in the high-pressure arterial circulation. With excessive matrix deposition, the graft can narrow and limit blood flow. As such, balancing these processes is critical in ensuring safe and effective treatments with TEVGs.Herein, we sought to develop computer models that describe and predict the behavior of TEVGs in venous and arterial applications. We adapted constrained mixture models of vascular growth and remodeling to capture the evolving geometric and mechanical properties of TEVGs implanted in both immuno-compromised and immuno-competent mice. This showed that the chosen functional forms for inflammatory constitutive relations could describe multiple biological conditions. It further revealed that early immuno-driven matrix production could inhibit the mechanobiological stimuli experienced by cells. We then adapted this model to predict the evolution of a scaffold used in an FDA-approved trial for the Fontan procedure. The clinical use of these grafts was met with stenotic complications, where early narrowing was treated with angioplasty. However, our model predicted that the early narrowing of the graft could be transient even in the absence of intervention. Exuberant matrix production via the foreign body response thickened the graft and caused narrowing, but the subsequent mechano-mediated neotissue degradation led to reopening with resolution of the inflammatory response. These predictions were confirmed in an ovine model, where 22/24 subjects exhibited reversible narrowing with an asymptomatic stenosis.We next compared outcomes of a single scaffold design implanted as a murine infrarenal aortic and inferior vena cava interposition graft and found that rapid loss of mechanical integrity in the arterial grafts led to dilatation and rupture, while the venous grafts performed well with little change in diameter through complete polymer mass loss. Additional parametric simulations suggested that even with changes in onset of scaffold degradation or the use of a stiffer material, loss of mechanical integrity would likely lead to eventual dilatation of the graft for arterial applications. With promising preliminary experiments for bi-layered grafts with differing degradation profiles in each layer, we developed a model that determined the stress profiles within the wall of these types of scaffolds. Because the fabrication methods led to swelling of the inner layer and residual stress in the outer layer, we also included these features to examine their effects on the mechanical behavior. Our analysis suggested that removing the swelling and residual stresses would improve the mechanical environment of the graft and that variations in scaffold geometry could improve mechanical conditioning of infiltrating cells.To move beyond parametric studies examining the effects of perturbations in scaffold parameters on graft outcomes, we coupled a venous TEVG growth and remodeling framework with formal optimization methods. We then formulated objective functions that were used to minimize deviations in the simulated behavior of the TEVG from that of the native vessel. Candidate scaffold designs were identified that allowed for long-term matching of caliber and compliance, though differences remained early in the time course, suggesting the need for more complex scaffold designs or pharmacologic interventions to enable complete matching throughout the entire implant duration. Overall, these studies showed the efficacy of an in silico approach to tissue engineering with a foundation in growth and remodeling methods.

English

ISBN: 9798538107315Subjects--Topical Terms:

548685
Biomechanics.
Subjects--Index Terms:

Polymeric scaffold

Mathematical Models for Improved Design of Tissue Engineered Vascular Grafts /
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520 $a Many vascular pathologies require the use of implanted grafts to improve patient health. Implanted grafts have traditionally been autologous blood vessels or permanent synthetic conduits, but recent advances in tissue engineering have allowed for implantation of biodegradable polymeric scaffolds that promote neovessel development. Tissue engineered vascular grafts (TEVGs) offer hope for improved long-term functionality due to their ability to grow and remodel in conjunction with the native vessels. Indeed, the ability of infiltrating cells to alter their gene expression and matrix production or degradation kinetics in accordance with variations in mechanical stimuli allows for adaptation in maturation or changing hemodynamic loading. However, early TEVG remodeling is also dictated by the foreign body response to the polymeric scaffold. Variations in the material properties or microstructure of the scaffold can mediate changes in the phenotypes of the immune cells responsible for removing the scaffold and replacing it with new extracellular matrix. There is a complex interplay between the mechanobiological and immunobiological aspects of remodeling that determines the success or failure of implants. In the absence of sufficient production or mechanical conditioning of matrix, grafts can dilate and rupture, particularly in the high-pressure arterial circulation. With excessive matrix deposition, the graft can narrow and limit blood flow. As such, balancing these processes is critical in ensuring safe and effective treatments with TEVGs.Herein, we sought to develop computer models that describe and predict the behavior of TEVGs in venous and arterial applications. We adapted constrained mixture models of vascular growth and remodeling to capture the evolving geometric and mechanical properties of TEVGs implanted in both immuno-compromised and immuno-competent mice. This showed that the chosen functional forms for inflammatory constitutive relations could describe multiple biological conditions. It further revealed that early immuno-driven matrix production could inhibit the mechanobiological stimuli experienced by cells. We then adapted this model to predict the evolution of a scaffold used in an FDA-approved trial for the Fontan procedure. The clinical use of these grafts was met with stenotic complications, where early narrowing was treated with angioplasty. However, our model predicted that the early narrowing of the graft could be transient even in the absence of intervention. Exuberant matrix production via the foreign body response thickened the graft and caused narrowing, but the subsequent mechano-mediated neotissue degradation led to reopening with resolution of the inflammatory response. These predictions were confirmed in an ovine model, where 22/24 subjects exhibited reversible narrowing with an asymptomatic stenosis.We next compared outcomes of a single scaffold design implanted as a murine infrarenal aortic and inferior vena cava interposition graft and found that rapid loss of mechanical integrity in the arterial grafts led to dilatation and rupture, while the venous grafts performed well with little change in diameter through complete polymer mass loss. Additional parametric simulations suggested that even with changes in onset of scaffold degradation or the use of a stiffer material, loss of mechanical integrity would likely lead to eventual dilatation of the graft for arterial applications. With promising preliminary experiments for bi-layered grafts with differing degradation profiles in each layer, we developed a model that determined the stress profiles within the wall of these types of scaffolds. Because the fabrication methods led to swelling of the inner layer and residual stress in the outer layer, we also included these features to examine their effects on the mechanical behavior. Our analysis suggested that removing the swelling and residual stresses would improve the mechanical environment of the graft and that variations in scaffold geometry could improve mechanical conditioning of infiltrating cells.To move beyond parametric studies examining the effects of perturbations in scaffold parameters on graft outcomes, we coupled a venous TEVG growth and remodeling framework with formal optimization methods. We then formulated objective functions that were used to minimize deviations in the simulated behavior of the TEVG from that of the native vessel. Candidate scaffold designs were identified that allowed for long-term matching of caliber and compliance, though differences remained early in the time course, suggesting the need for more complex scaffold designs or pharmacologic interventions to enable complete matching throughout the entire implant duration. Overall, these studies showed the efficacy of an in silico approach to tissue engineering with a foundation in growth and remodeling methods.
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650 4 $a Tissue engineering. $3 823582
650 4 $a Mechanical properties. $3 3549505
650 4 $a Synthetic products. $3 770075
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650 4 $a Blood vessels. $3 3561732
650 4 $a Mathematical models. $3 522882
650 4 $a Trends. $3 3560051
650 4 $a Optimization. $3 891104
650 4 $a Immunology. $3 611031
650 4 $a Medical imaging. $3 3172799
650 4 $a Stress analysis. $3 3681390
650 4 $a Genotype & phenotype. $3 3561790
650 4 $a Cell cycle. $3 766119
650 4 $a Polymers. $3 535398
650 4 $a Simulation. $3 644748
650 4 $a Gene expression. $3 643979
650 4 $a Thrombosis. $3 793052
650 4 $a Collagen. $3 892448
650 4 $a Heart surgery. $3 3681537
650 4 $a Experiments. $3 525909
650 4 $a Coronary vessels. $3 3680599
650 4 $a Veins & arteries. $3 3681939
650 4 $a Bone marrow. $3 1621080
650 4 $a Pulmonary arteries. $3 3685017
653 $a Polymeric scaffold
653 $a Tissue engineering
653 $a Vascular grafts
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690 $a 0982
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710 2 $a Yale University. $b Biomedical Engineering. $e degree granting institution. $3 3818985
720 1 $a Humphrey, Jay D. $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 83-03B.
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