Characterizing Endothelial Damage During Ischemic Stroke Treatment with 3D Cerebrovascular Live Cellular and Finite Element Models
Date of Award
Master of Science (MS)
Biomedical and Chemical Engineering and Sciences
Venkat Keshav Chivukula
James R. Brenner
Stent retriever mechanical thrombectomy (SRMT) is part of the clinical standard-of-care for acute ischemic stroke (AIS) patients with large vessel occlusion (LVO). Endothelial injury (EI) is widely associated with SRMT. Studies report finding EI markers in over 50% of retrieved clots, suggesting the frequency of EI in MT patients is rather common. The mechanism of EI and its contribution to MT failure and clinical outcomes remain poorly understood because of a lack of techniques to observe EI and study it in vitro. This study aims to investigate the mechanisms of EI induced by SRMT, as well as the effect stent retriever diameter has on the extent of EI after SRMT, by developing and analyzing an in vitro live cellular 3D cerebrovascular model, and an in silico finite element model (FEM). Extent of EI and effect the size of a stent retriever has on resulting EI from SRMT is then analyzed qualitatively and quantitatively both in vitro and in silico. The in silico FEM consisted of a tubular artery model with a stent expanding and passing through it. The results show a high variability in the shear stresses experienced by the artery depending on the location, and its proximity to the stent and its movement: different points in one same circumferential region of the artery can experience different levels of shear stress. The results also suggest that the region where the stent expands experiences shear stresses that remain partially present even after the stent has passed, and that the passing of the stent edges results in higher shear stresses compared to the middle body. Lastly, while the stent movement still has an effect on the areas it has passed through, the areas close to stent movement but that do not experience actual contact with the stress remain relatively unaffected with low shear stress values. The 3D cerebrovascular live cell model consisted of tubular artery constructs produced using 3D printing and PDMS casting techniques, with endothelial cells seeded on the inner wall. After a functional and confluent testbed was established, an SRMT was simulated using two different stent sizes. Extent of EI as well and impact the stent size had was then assessed using qualitative and quantitative analysis. A system to seed a confluent layer of endothelial cells with general homogeneity throughout PDMS artery models was successfully developed. The combined results show clear signs of EI caused by both stent sizes, which was seen as areas with significant denudation of cells, and wrapping of cells over each other into 3D structures. Statistically significant difference was achieved between the control condition and the smaller stent size condition for number of nuclei (p = 0.04, 95% C.I. = [11.57, 450.88]), and between the control condition and both stent sizes for percent cell coverage (p = 0.002, 95% C.I. = [23.58, 72.93]). Additionally, the results show the smaller stent size resulted in a higher degree of EI compared to the larger size. Although more testing is needed to assert the accuracy of the results, this finding is supported by other studies that have found an increased risk of restenosis and other adverse cardiac events with smaller stent diameters.
Martinez Dehesa, Ana Regina, "Characterizing Endothelial Damage During Ischemic Stroke Treatment with 3D Cerebrovascular Live Cellular and Finite Element Models" (2023). Theses and Dissertations. 1264.