Molecular response to variations in vascular morphology in

endothelialized 3D-printed intracranial aneurysm models

Jason Lim1 Naeel Uddin1 Ashley Abel2 Christian Mandrycky3 Venkat Chivukula4 Ying Zheng1,3Alberto Aliseda1,2,4
Samuel Levy1,2 Cory Kelly1,2 Louis Kim1,2,5 Michael Levitt1,2,4,5 sanscenter.org

1Stroke Stroke & Applied NeuroScience Center

& Applied NeuroScience Center 2Neurological Surgery 3Bioengineering 4Mechanical Engineering 5Radiology, University of Washington, Seattle, WA

Summary Purpose Current Work

•Vascular morphology plays a crucial role in the molecular To study how differential hemodynamic stresses impact the morphology and molecular Idealized Bifurcation Models
expression of endothelial cells in 3D-printed models of intracranial aneurysms.
pathophysiology of intracranial aneurysms.
(A)
•This study explores the interactions between vascular Materials and Methods (A) Maximum,
morphology, hemodynamics, and molecular expression of 1. A 3D rotational angiogram (3DRA) was obtained during the patient’s standard clinical care. minimum, and mean Models:
2. A ‘positive’ aneurysm model was 3D-printed and embedded in polydimethylsiloxane (PDMS). angle of bifurcation dParent vessel = 3.2 mm
endothelial cells seeded in 3D-printed intracranial
3. EC morphology was visualized in five parts of the model using confocal microscopy. were obtained from dDaughter PCA = 2.0 mm
aneurysm models.
4. ECs were harvested from distinct regions of the model for mRNA collection and qPCR. 172 bifurcation Φ= φ1 + φ2
5. Morphology and mRNA quantification were analyzed and CFD simulations were conducted. aneurysm cases from Φ Max = 219˚
Background four peer-reviewed Φ Mean = 163˚
(A) journal articles.7,8,9,10 Φ Min = 82.3˚
(A) A 3DRA of an
3% of the general population aneurysm.6 (B) A 3D-
has an unruptured brain (B) (C) (D)
aneurysm1 printed ‘positive’
aneurysm model. 6 (C)
35% of patients do not A PDMS aneurysm
survive a ruptured aneurysm1 model ready for cell
seeding and flow
60 years is the mean age of
patients affected by unruptured
experiments.6
brain aneurysms1 Results (B) Maximum, (C) minimum, and (D) mean angles of bifurcation.
(A) Anatomical depiction of a human brain.2
(A) (B)
Every year about 300,000 Americans are affected by an
intracranial aneurysm (IA) rupture, leading to hemorrhagic (E) (F)
stroke, a devastating and deadly affliction.3 Vascular
morphology plays a crucial role in the onset and progression
of IA. Notably, regions of vessel bifurcation tend to be more
susceptible to aneurysm formation. Computational fluid
dynamics (CFD) can be used to simulate the physical
Cite levitt paper
properties of blood flow, otherwise known as hemodynamics. for all these
figures
Numerous studies utilizing CFD focus solely on the (E) Preprocessed 3D-printed ‘positive’ model. (F) Processed
interactions between hemodynamics and vascular aneurysm models encased in PDMS waiting to be cured and
morphology, or between hemodynamics and molecular rescued.
expression. Few studies have investigated the relationship
between vascular morphology and molecular expression, Conclusion
particularly genes known to be related to EC pathological Endothelialized 3D-printed aneurysm models with idealized
response. (C) geometry can recapitulate the microenvironment of
(B) (C) intracranial aneurysms. Such models can be effective in
studying molecular pathophysiology of intracranial
aneurysms. Furthermore, it is possible to quantify the
endothelial cell response to varying hemodynamic stress by
subjecting these models to pulsatile flow.
References
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3. Cerebral AneColacinourysms Fact Sheet. (n.d.). Available from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Cerebral-Aneurysms-Fact-Sheet

(A) CFD analysis indicated that flow in the saccular region of the aneurysm is significantly lower 4. Varble N, Rajabzadeh-Oghaz H, Wang J, Siddiqui A, Meng H, Mowla A. Differences in Morphologic and Hemodynamic Characteristics for "PHASES-Based" Intracranial Aneurysm
Locations. American Journal of Neuroradiology. 2017. doi: 10.3174/ajnr.A5341.
5. Mach, Georg. (2017). A Highly Versatile Tool Chain for Robust Computational Fluid Dynamics Simulations. 10.13140/RG.2.2.23490.79048.

(B) CFD derived velocity streamlines shown in various compared to other regions near the aneurysm.6 (B) ECs seeded in the patient-specific aneurysm 6. Levitt MR, Mandrycky C, Abel A, Kelly CM, Levy S, Chivukula V, et al. (2019). Genetic correlates of wall shear stress in a patient-specific 3D-printed cerebral aneurysm model.
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locations of aneurysm formation.4 (C) Angiogram of a model after being subjected to pulsatile flow at the rate of 150µL/min for 24 hours.6 (C) qPCR 101(1), 108-113. doi:10.3171/jns.2004.101.1.0108
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basilar bifurcation aneurysm.5 analysis of mRNA collected from ECs in three regions of the model (proximal, aneurysmal, and 9. Tütüncü F, Schimansky S, Baharoglu MI, Gao B, Calnan D, Hippelheuser J,et al.(2014). Widening of the basilar bifurcation angle: Association with presence of intracranial
aneurysm, age, and female sex. Journal of Neurosurgery, 121(6), 1401-1410. doi:10.3171/2014.8.jns1447
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distal).6
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