From patient-specific

Institut Mines-Télé[email protected]

From patient-specific finite-element

modeling towards prediction of

aneurysm progression

Prof Stéphane AVRIL

PARIS

AUVERGNE RHONE-ALPES

MINES SAINT-

ETIENNE

Institut Mines-Télé[email protected]@emse.fr

OUTLINE

 PART I: Risk factors for aortic rupture

 PART II: Computational prediction of aortic weakening

 PART III: Role of SMCs in aortic weakening

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr

OUTLINE

 PART I: Risk factors for aortic rupture

 PART II: Computational prediction of aortic weakening

 PART III: Role of SMCs in aortic weakening

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Goal: find factors of aortic rupture

Aneurysms and Dissections of the ascending thoracic aorta

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Collection of human samples

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Bulge inflation test

III) Inflation test device. Speckle pattern is made before starting the

inflation test Circumferential

A x ia l

Romo et al. Journal of Biomechanics -2014.

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Institut Mines-Télé[email protected]@emse.fr

Undeformed Deformed

x y

Full-field measurements using sDIC

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Davis et al. BMMB – 2015.

Davis et al. JMBBM – 2016

Zhao et al. Acta Biomaterialia - 2016

Identification of local material properties

s

strain

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Institut Mines-Télé[email protected]@emse.fr

Correlation between the stretch-based rupture risk and the tangent elastic modulus

Duprey A, et al. Biaxial rupture properties of ascending thoracic aortic aneurysms. Acta Biomaterialia 2016.

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

E _in-vitro (MPa)

Ru pture ris k

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago Sample 1

Sample 2

Sample 3

Sample 4

Sample 5

Sample 6

Prediction of tissue rupture with the local tangent stiffness

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Institut Mines-Télé[email protected]@emse.fr

SUMMARY

 Local tangent stiffness is heterogeneous and a risk factor for aortic rupture

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr

OUTLINE

 PART I: Risk factors for aortic rupture

 PART II: Computational prediction of aortic weakening

 PART III: Role of SMCs in aortic weakening

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr

Aneurysms and Dissections of the ascending thoracic aorta

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Goal: Predict weakening in the aortic wall

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Institut Mines-Télé[email protected]

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Introduction - Assumption

ATAAs are triggered by local proteolytic injury, which induce adaptation in the ascending thoracic aorta

Guzzardi et al, JACC (2014), Condemi et al, IEEE TBME (2019)

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Institut Mines-Télé[email protected]@emse.fr

Proteolytic injury and tissue adaptation

PROTEOLYTIC INJURY

Strain HEALING

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Stress

Stress

Institut Mines-Télé[email protected]@emse.fr

Layer-specific constitutive model

Strain-energy function based on the constrained mixture theory

Humphrey & Rajagopal, Math Models Methods Appl Sci. (2002) ; Bellini et al, ABME (2014), Mousavi & Avril, BMMB (2017)

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Deposition stretch of each constituent:

Collagen Elastin

SMC

Load

Institut Mines-Télé[email protected]

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𝐅 _tot ^𝑗 = 𝐅 _elc ^𝑗 𝐅 _gr ^𝑗 𝐅 _gr ^𝑗 = 𝐅 _r ^𝑗 𝐅 _g ^𝑗

𝐅 _r ^𝑗 and 𝐅 _g ^𝑗 should be updated if the artery is not in the homeostatic state

Elastic and inelastic decomposition of deformation gradient

Layer-specific constitutive model

Mousavi & Avril, BMMB (2017), Mousavi et al, BMMB (2019) Ghavamian et al, Front Bioeng Biotech (2020)

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Institut Mines-Télé[email protected]@emse.fr

Abaqus finite-element

implementation and verification

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

 FE software ABAQUS coupled with UMAT

 Hexahedral and tetrahedral elements

 Structural mesh (𝑟, 𝜃, 𝑧)

 Two different layers (media and adventitia)

Mousavi et al, IJNMBE, 2018

Institut Mines-Télé[email protected]@emse.fr

Growth and Remodeling in

homogenized constrained mixture

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Collagen mass production

ሶϱ ^𝑗 (t) = ϱ ^𝑗 (t)𝑘 _σ ^𝑗 𝜎 ^𝑗 𝑡 − 𝜎 _h ^𝑗

𝜎 _h ^𝑗 + ሶ𝜉 ^𝑗 (𝑡)

Inelastic deformation due to remodeling

Cyron et al, BMBB (2016), Braeu et al, BMMB (2017), Laubrie et al, IJNMBE (2019)

Collagen Elastin

SMC

Load

Institut Mines-Télé[email protected]

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Patient-specific predictions

Growth and remodeling of a two–layer patient–specific human ATAAs due to elastin loss

Mousavi et al, BMMB (2019)

.

Localization function around the point of TAWSS max

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]

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Growth and remodeling of a two–layer patient–

specific human ATAAs due to elastin loss

Normalized Thickness Small growth parameter

Patient-specific predictions

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Mousavi et al, BMMB (2019)

Institut Mines-Télé[email protected]@emse.fr

Background: Aneurysms and Dissections of the ascending thoracic aorta

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

dissection

vSMC

Humphrey et al, Science, 2014

Institut Mines-Télé[email protected]@emse.fr

Effects of active SMC contraction

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Collagen Elastin

SMC passive

Load

SMC active

σ

Basal tone

Institut Mines-Télé[email protected]

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Length-tension relationship of SMCS

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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σ ^act =

Murtada et al, J Theor Biol 2012, Ghavamian et al, Front Bioeng Biotech (2020)

σ ^act

λ ^act λ _max

λ ₀ λ ^act =1

λ ^act =λ _max

1

Basal tone ~50kPa

Institut Mines-Télé[email protected]@emse.fr

Future work: test other assumptions

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Combination of local decrease of SMC active stress and proteolytic injury

Large WSS

resulting in reduced SMC contractility

Large RRT

resulting in possibly increased

proteolytic effects

Mousavi et al, ABME (2020, submitted)

Institut Mines-Télé[email protected]

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Sensitivity analysis

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Ghavamian et al, Front Bioeng Biotech (2020)

λ ^act λ ^act λ ^act

σ act (Pa) σ act (Pa) σ act (Pa)

Case I Case II Case III

Institut Mines-Télé[email protected]

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Evolution of the active stress of SMCs

Stéphane Avril - 2019 July 9 – ESB Vienna

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σ act (Pa)

Years Years Years

Relative displacement and thickness

Case I Case II Case III

Institut Mines-Télé[email protected]@emse.fr

SUMMARY

 Patient-specific numerical model based on the constrained mixture theory including damage and G&R – coupling with CFD analyses, + active role of SMCs

 Marginal contribution of the active stress of SMCs but a critical state can be reached when the active stress reaches zero due to large stretching

 One of the major role of SMCs is mechanoregulation.

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr

OUTLINE

 PART I: Risk factors for aortic rupture

 PART II: Computational prediction of aortic weakening

 PART III: Role of SMCs in aortic weakening

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr

The major role of SMCs in Aneurysms and Dissections of

the ascending thoracic aorta

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

vSMC

Humphrey et al, Science, 2014

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Institut Mines-Télé[email protected]@emse.fr

Future work: mechanosensitivity impairment

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

ሶϱ ^𝑗 (t) = ϱ ^𝑗 (t)𝑘 _σ ^𝑗 χ ∗ 𝜎 ^𝑗 𝑡 − 𝜎 _h ^𝑗

𝜎 _h ^𝑗 + ሶ𝜉 ^𝑗 (𝑡) 0 ≤ χ ≤ 1: impairment coefficient

χ = 1 χ = 0.8 χ = 0.9

T an ge nt stif fne ss after 10 y ea rs

Mousavi et al, ABME (2020, submitted)

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Traction force microscopy on aortic smooth muscle cells

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Several stiffness values

Aortic SMCs from human primary culture (AoSMC, Lonza), passages 5-7, cultured in a differenciating medium (SmBM, Lonza)

• Fluorescent microscopy + DIC : track the displacement of fluorescent microbeads

• Cell unbinding method (with trypsin) : assess the homeostatic state of single SMCs

𝐾 = 2

Traction force microscopy on aortic smooth muscle cells

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Institut Mines-Télé[email protected]@emse.fr

Traction force of aortic smooth muscle cells depend on the surrounding stiffness

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Modelling of SMCs cytoskeletal mechanics

Chan & Odde, Science 2008.

Kharkaneh et al, Acta Biomaterialia 2020.

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Institut Mines-Télé[email protected]@emse.fr

Modelling of SMCs cytoskeletal mechanics

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Stiffness characterization of aortic smooth muscle cells using AFM indentation

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Institut Mines-Télé[email protected]@emse.fr Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]@emse.fr

SUMMARY AND FUTURE WORK

 Decipher the link between cytoskeletal SMC mechanics and mechanosensitivity in aortic aneurysms

 Include SMC models into the G&R models of aortic aneurysms

 Clinical translation

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

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Institut Mines-Télé[email protected]

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Computational mechanics in the OR for vascular surgery?

www.predisurge.com

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Institut Mines-Télé[email protected]@emse.fr

Acknowledgements

Stéphane Avril - 2020 Oct 30 - CBIO Santiago

Funding:

ERC-2014-CoG BIOLOCHANICS

 Olfa Trabelsi

 Aaron Romo

 Jin Kim

 Pierre Badel

 Frances Davis

 Victor Acosta

 Jamal Mousavi

 Solmaz Farzeneh

 Francesca Condemi

 Cristina Cavinato

 Jérôme Molimard

 Baptiste Pierrat

 Joan Laubrie

 Claudie Petit

 Ali Kharkaneh

 Ataollah Ghavamian

 Ambroise Duprey

 Jean-Pierre Favre

 Jean-Noël Albertini

 Salvatore Campisi

 Magalie Viallon

 Pierre Croisille

 Chiara Bellini

 Matthew Bersi

 Jay Humphrey

 Katia Genovese

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