Vascular adaptation in the presence of external support - A modeling study

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Abstract

Vascular grafts have long been used to replace damaged or diseased vessels with considerable success, but a new approach is emerging where native vessels are merely supported, not replaced. Although external supports have been evaluated in diverse situations – ranging from aneurysmal disease to vein grafts or the Ross operation – optimal supports and procedures remain wanting. In this paper, we present a novel application of a growth and remodeling model well suited for parametrically exploring multiple designs of external supports while accounting for mechanobiological and immunobiological responses of the supported native vessel. These results suggest that a load bearing external support can reduce vessel thickening in response to pressure elevation. Results also suggest that the final adaptive state of the vessel depends on the structural stiffness of the support via a mechano-driven adaptation, although luminal encroachment may be a complication in the presence of chronic inflammation. Finally, the supported vessel can stiffen (structurally and materially) along circumferential and axial directions, which could have implications on overall hemodynamics and thus subsequent vascular remodeling. The proposed framework can provide valuable insights into vascular adaptation in the presence of external support, accelerate rational design, and aid translation of this emerging approach.

Introduction

Many medical devices have been designed to augment vascular function in disease and injury. External support is a promising medical technology that has found applications in multiple clinical scenarios, including aortic dilatation (Cohen et al., 2007), Marfan syndrome (Treasure et al., 2014, Verbrugghe et al., 2013), the Ross procedure (Vastmans et al., 2018, Nappi et al., 2015), vein graft disease (Mehta et al., 1998, Yasuda et al., 2018, Sato et al., 2016), and tissue engineering (Zhao et al., 2016). The objective of external support in each of these applications is different — for example, it can maintain valve function and prevent over distension and rupture in Marfan syndrome, provide structural reinforcement against elevated pressure and flow in a vein graft, and reduce the potential of collapse in a tissue engineered trachea. A common underlying theme across these applications is the complex interaction between a foreign body and a soft tissue in the presence of a potentially altered mechanical environment. Multiple animal studies and human trials have reported results superior to standard care/sham controls (Treasure et al., 2014, Vastmans et al., 2018, Nappi et al., 2015, Sato et al., 2016, Jeremy et al., 2004) while other human studies have been disappointing (Murphy et al., 2007). We still lack a fundamental understanding of the effect of both the foreign body response and the altered mechanical loading on acute and chronic remodeling of the vessel. There is, therefore, a pressing need for a systematic approach to the design of these supports. To that end we propose a computational bilayered model that can simulate mechano-adaptation of a vessel in the presence of an external support that promotes inflammation. Motivated by our prior work (Latorre and Humphrey, 2018a) and availability of experimental data (Bersi et al., 2016), we use a C57BL6/J murine descending thoracic aorta as our model system.

Section snippets

Bilayered growth and remodeling theory

Mechano-adaptation in the presence of an external support is modeled using a bilayered constrained mixture theory of soft tissue growth (change in mass) and remodeling (change in structure), denoted herein as G&R (Latorre and Humphrey, 2018a, Latorre and Humphrey, 2018b). Global equilibrium equations for the bilayered construct, at each G&R time s, expressed in terms of layer-specific mean stresses, are given by (Latorre and Humphrey, 2018a, Latorre and Humphrey, 2018b), σVθθhV+σSθθhS=Pa,σVzzπhV

Effect of support stiffness — nondegradable support, no inflammation

Prior applications have used materials ranging from natural tissue to synthetic polymers (Treasure et al., 2014, Vastmans et al., 2018, Sato et al., 2016, Jeremy et al., 2004, Liu et al., 1999) as external supports. We simulate mechano-adaptation of a native vessel to simulated pressure elevation in the presence of an external support with modulus cp equal to 1, 10, 100 and 1000 times the modulus of elastin (ce), to reflect the wide range of potential materials (Fig. 3). The acute

Discussion

Despite significant advances in both the development of new synthetic biomaterials and tissue engineering, transplant of autologous vessels remains the mainstay of vascular grafting procedures. The short- and long-term performance of these grafts is far from ideal (David et al., 2014, Oury et al., 1998, Fitzgibbon et al., 1996), however, and the community continues to explore new avenues for augmenting graft adaptation. Of these, though still under evaluation, external support has emerged as a

CRediT authorship contribution statement

Abhay B. Ramachandra: Conceptualization, Methodology, Software, Formal analysis, Investigation, Resources, Data curation, Writing - original draft, Writing- review & editing, Visualization, Project administration. Marcos Latorre: Conceptualization, Methodology, Software, Resources, Writing - original draft, Writing- review & editing, Visualization. Jason M. Szafron: Conceptualization, Resources, Writing - original draft, Writing- review & editing, Visualization. Alison L. Marsden: Writing -

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by NIH grants R01 HL128602 and HL139796 to J. D. H.

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