Vascular Mechanobiology: growth and remodeling in the aorta in health and disease

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1 Vascular Mechanobiology: growth and remodeling in the aorta in health and disease Dr.-Ing. Christian J. Cyron Technical University of Munich funded by the German Research Foundation (Emmy-Noether Grant CY 75/2-1) (no conflicts of interest to declare) 6th Munich Vascular Conference, Munich, December 1st 2016 Christian J. Cyron, Technical University of Munich 1

2 Motivation healthy abdominal aorta: nearly straight and cylindrical pathological deformations observed particularly in elderly individuals o tortuosity: highly curved centerline o aneurysm: focal dilatation pathological deformations slowly grow over years aortic aneurysm [Cuete, Radiopedia.org] healthy aorta [Llanas et al. (2011)] which principles govern growth and remodeling in the aorta? what can we learn from these principles? tortuous aorta [Llanas et al. (2011)] Christian J. Cyron, Technical University of Munich 2

3 Which principles govern growth and remodeling in the aorta? Christian J. Cyron, Technical University of Munich 3

4 Homeostatic stress state Technical University of Munich size of blood vessels and blood pressure differ significantly between different species (tension ~ blood pressure radius) however, Cauchy stress in the vessel wall is nearly the same in all species (~10 2 kpa) (Cauchy stress = tension / wall thickness) [Wolinsky et al. (1967) Circ Res 20] Wolinsky & Glagov (1967) There exists a preferred homeostatic stress state in living tissue Christian J. Cyron, Technical University of Munich 4

5 Tensional homeostasis: growth Technical University of Munich if blood pressure increases, arterial wall thickens by approximately the same factor so that the original mechanical stress in wall is restored [Matsumoto & Hayashi (1994) J Biomech Eng 216(3): ] normotensive vessel hypertensive vessel tensional homeostasis: living tissue seeks to maintain homeostatic stress state by mechano-regulated growth increased stress lead to deposition of more tissue mass Christian J. Cyron, Technical University of Munich 5

6 Tensional homeostasis: remodeling Technical University of Munich collagen gels are seeded with fibroblasts and subjected to different boundary conditions initially stress-free gel builds up homeostatic stress cruciform collagen gel in vitro [Hu, Humphrey & Yeh (2009)] experiment [Ezra et al. (2010)] when gel is compressed, homeostatic stress is restored when gel is stretched, homeostatic stress is restored generally: in case of perturbations, microstructure is remodeled by fibroblasts until homeostatic stress is reattained Christian J. Cyron, Technical University of Munich 6

7 Mathematical Modeling Technical University of Munich first model of mechano-regulated soft tissue growth by Rodriguez (1994) since then numerous important contributions, e.g., by Humphrey & Rajagopal (2002), Watton et al. (2004), Kroon & Holzapfel (2009), State of the art: o only constrained mixture models model wall as mixture of different constituents (collagen, elastin and smooth muscle) o only a handful of fully three-dimensional constrained mixture models proposed so far, all them limited to isotropic growth anisotropic growth o however, experimental observations rather suggest anisotropic growth in thickness direction [Matsumoto et al. (1994)] isotropic growth Christian J. Cyron, Technical University of Munich 7

8 Homogenized constrained mixture models in 2016 we developed the first constrained mixture (finite element) model for general anisotropic growth and remodeling in three dimensions [Braeu et al. (2016)] Strain energy of the consrained mixture of collagen, smooth muscle, and elastin (cf. Holzapfel et al., Humphrey et al.) Stress computation Balance of linear momentum Kinematic relations: multiplicative split of deformation gradient into elastic, remodeling and growth deformation Homogenized computation of growth and remodeling of each constituent Christian J. Cyron, Technical University of Munich 8

9 Adaptation of healthy vessel to hypertension Christian J. Cyron, Technical University of Munich 9

10 Adaptation of healthy vessel to hypertension anisotropic growth: experimental observations by Matsumoto et al. (1994) can be well reproduced isotropic growth: instable dilatation of blood vessel even after minor perturbation of pressure and for very high ECM production rates Christian J. Cyron, Technical University of Munich 10

11 What can be learn from computer simulations of vascular growth and remodeling? Christian J. Cyron, Technical University of Munich 11

12 Axisymmetric model aorta: symmetric damage damage stiffness, collagen production, half-life mechanotransduction/ matrix turnover mechanical removal of part of elastin normal low in case of low collagen production, ECM half-life, and stiffness blood vessels cannot compensate for local damages initiation of aneurysms Christian J. Cyron, Technical University of Munich 12

13 Morphology of aneurysms Technical University of Munich Fusiform Abdominal Aortic Aneurysm [Cuete, Radiopedia.org] Saccular Abdominal Aortic Aneurysm [Di Muzio, Radiopedia.org] What determines the evolution of an aneurysm into either a fusiform or a saccular shape? Christian J. Cyron, Technical University of Munich 13

14 Axisymmetric model aorta: asymmetric damage damage stiffness, collagen production, half-life mechanotransduction/ matrix turnover mechanical removal of part of elastin normal low asymmetric damage with low collagen production, ECM half-life and stiffness leads to saccular aneurysms (less pronounced neck for mechanical damage) Christian J. Cyron, Technical University of Munich 14

15 Conclusions & Outlook Technical University of Munich we developed the first anisotropic three-dimensional constrained mixture model for volumetric growth and remodeling in the vasculature computational studies reveal o mechanical damage alone (in otherwise healthy vessel) appears not able to initiate aneurysm o aneurysms form in vessels susceptible by low mechano-regulated collagen production, short half-life of ECM, and low stiffness o anisotropic ECM deposition in wall thickness direction important mechanism for stabilization of vessel geometry after perturbations possible future applications o enhanced rupture risk prediction by computer-aided prediction of future aneurysm growth (based on follow-up CT scans & simulations) o computer-aided design and analysis of experiments in vascular biology Christian J. Cyron, Technical University of Munich 15 15