Off-campus WSU users: To download campus access dissertations, please use the following link to log into our proxy server with your WSU access ID and password, then click the "Off-campus Download" button below.
Non-WSU users: Please talk to your librarian about requesting this dissertation through interlibrary loan.
Access Type
WSU Access
Date of Award
January 2022
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Chemical Engineering and Materials Science
First Advisor
Carolyn Harris
Abstract
It has been hypothesized that physiological shear forces acting on medical devices implanted in the brain significantly accelerate the rate to device failure in patients with chronically indwelling neuroprosthetics. In hydrocephalus shunt devices, shear forces arise from cerebrospinal fluid (CSF) flow. The shunt’s unacceptably high failure rate is mostly due to obstruction with adherent inflammatory cells. Astrocytes are the dominant cell type bound directly to obstructing shunts, rapidly manipulating their activation via shear stress-dependent cytokine secretion. Here we developed a total internal reflection fluorescence microscopy (TIR-FM) combined with a microfluidic shear device chip (MSDC) for quantitative analysis and direct spatial-temporal mapping of secreted cytokines at the single-cell level under physiological shear stress to identify the root cause for shunt failure. Real-time secretion imaging enabled successful detection of a significant increase of astrocyte IL-6 cytokine secretion under shear stress greater than 0.5 dyne/cm2, validating our hypothesis and highlighting the importance of reducing shear stress activation of cells.The tissue obstructing neuroprosthetic devices is largely composed of inflammatory cells with a significant astrocyte component. In a first of its kind study, we profile the astrocyte phenotypes present on hydrocephalus shunts. qPCR and RNA in-situ hybridization were used to quantify pro-inflammatory (A1) and anti-inflammatory (A2) reactive astrocytes by analyzing C3 and EMP1 genes, respectively. Additionally, CSF cytokine levels were quantified using ELISA. The results showed a heterogeneous population of A1 and A2 reactive astrocytes on the shunts with obstructed shunts having a significantly higher fraction of A2 astrocytes. The pro-A2 cytokine IL-6 was also found at higher concentrations among CSF from obstructed samples. Furthermore, cytokine neutralizing antibodies produced a significant reduction in both A1 and A2 astrocyte activation and attachment in an in vitro model of astrocyte growth on shunts. Therefore, targeting cytokines involved with astrocyte activation is a promising intervention aimed to prevent shunt obstruction.
Recommended Citation
Khodadadei, Fatemeh, "Neuroprosthetic Device Failure Analysis: Impact Of Shear Stress And Blood-Brain Barrier Disruption" (2022). Wayne State University Dissertations. 3573.
https://digitalcommons.wayne.edu/oa_dissertations/3573