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dc.contributor.author
Stefopoulos, Georgios
dc.contributor.supervisor
Poulikakos, Dimos
dc.contributor.supervisor
Dejana, Elisabetta
dc.contributor.supervisor
Ferrari, Aldo
dc.date.accessioned
2019-04-10T09:24:47Z
dc.date.available
2018-03-26T09:50:32Z
dc.date.available
2018-03-26T10:33:10Z
dc.date.available
2018-03-27T07:41:21Z
dc.date.available
2019-03-25T12:02:55Z
dc.date.available
2019-04-10T09:24:47Z
dc.date.issued
2018
dc.identifier.uri
http://hdl.handle.net/20.500.11850/252870
dc.identifier.doi
10.3929/ethz-b-000252870
dc.description.abstract
Heart failure is a condition in which the heart is unable to provide adequate blood flow to the vital organs of the human body. Up to date, the most effective treatment is heart transplantation. Availability of donor hearts, however, is limited. Consequently, the number of patients in the heart transplant waiting list rises every year. Recently, an artificial solution has been developed, involving the implantation of ventricular assist devices, in order to provide temporary support to the patient’s heart and bridge the time to transplantation. A ventricular assist device (VAD) is an implantable electromechanical apparatus, responsible for assisting the function of a failing heart. Device implantation, however, is tied to poor survival rates of patients. Causal role have the severe thromboembolic events which, in turn, lead to device malfunction and patient death. These adverse phenomena, triggered by the direct contact between blood and synthetic material, necessitate the administration of intense and lifelong anticoagulation therapies. Coating the luminal surface of the device with a fully hemocompatible blood-foreign interface would halt coagulation and simultaneously improve patient survivability and life quality. Additionally, a hemocompatible surface would provide opening for VADs to be used as a destination therapy. To this extent, optimal protection could be represented by an autologous endothelial cell layer, the natural interfacial layer between blood and tissue, through the process of surface endothelialization. The Zurich Heart project, aims at improving contemporary VAD designs (System modification) as well as developing new concepts for VADs (Alternative systems). The work presented in this thesis is part of the System modification track. The long term goal is to develop a fully hemocompatible ventricular assist device. Hence, we envision to generate and maintain a functional endothelium on the luminal surface of the device. Realization of the abovementioned objective requires, however, to successfully tackle bottlenecks associated with endothelialization of devices. In the first part of this thesis, such challenges are identified and discussed. In the next two chapters, we introduce strategies, utilizing rationally designed surface topographies, to enhance endothelial cell retention under realistic hemodynamic conditions. In the last chapter, we focus on understanding the responses of human endothelia under supraphysiological magnitudes of wall shear stress. Regarding the clinical integration of cardiovascular devices, the paucity of source cells is a potentially calamitous scenario. Therefore, the development of surface engineering strategies to achieve full endothelialization, while minimizing the amount of endothelial cells required to seed the surface, is necessary. Stable endothelialization is the outcome of the interaction between endothelial cells, flow-generated wall shear stress and the substrate topography. In the 2nd part of the thesis, a novel strategy is presented and validated, based on the use of optimized surface topographies, combined with confined islands of seeded endothelial cells. With this approach, when approximately half of the substrate is covered with endothelial cells, the time to full endothelialization, compared to an unstructured surface, is almost halved. These results demonstrate a novel approach on the endothelialization of cardiovascular devices featuring partial endothelial cell seeding prior to implantation and exploiting the wound healing potential of endothelia to yield prompt endothelialization in situ. The second step towards full endothelialization of devices is the investigation of endothelia responses under pro-inflammatory signaling, expected in cardiovascular patients. Pro-inflammatory milieu, in conjunction with high magnitudes of wall shear stress, could potentially compromise endothelial integrity and survival. In the 3rd part of this thesis, we deal with this underlying danger by challenging human endothelial monolayers with the pro-inflammatory factor TNF-α under realistic hemodynamic conditions. Moreover, we demonstrate that the simple contact between endothelial cells and an optimized surface geometry can inhibit NF-kB activation downstream of TNF-α, yielding eventually increased stability of cell-to-cell junctions and focal adhesions. Importantly, the suggested topographic modifications can be implemented on a range of artificial substrates, enabling their endothelialization under the expected device operational conditions. Endothelial cell function under physiological flow conditions has been the scope of extensive research the past years. Information is incomplete, however, regarding the responses of confluent endothelia under supraphysiological wall shear stresses. The last part of this thesis investigates a differential response of the endothelium under these conditions. Supraphysiological magnitudes of wall shear stress, drive human endothelia monolayers to a stable perpendicular to the flow orientation. Importantly, this observation finds a common physiological reference to the valvular endothelial cells, which also exhibit a vertical to the flow phenotype. Pre-aligning endothelia with physiological levels of wall shear stress, and then exposing them to supraphysiological WSS magnitude, leads the endothelium to an unstable state, obtaining a random phenotype. This isotropic orientation decreases the resistance of endothelial cells to supraphysiological wall shear stress and results in loss of endothelium connectivity. Last, we report on the temporal evolution of the traction force fingerprint during endothelial phenotypic alteration. In particular, we utilize a traction force microscopy platform, previously developed from researchers in our laboratory.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
ETH Zurich
en_US
dc.rights.uri
http://rightsstatements.org/page/InC-NC/1.0/
dc.subject
Cardiovascular devices
en_US
dc.subject
Endothelialization
en_US
dc.subject
Topography
en_US
dc.subject
Vascular-Endothelial Cadherin
en_US
dc.subject
NF-kB
en_US
dc.subject
Biomaterials
en_US
dc.subject
Mechanobiology
en_US
dc.subject
Heart failure
en_US
dc.subject
Thrombosis
en_US
dc.subject
Microfabrication
en_US
dc.subject
Wall shear stress
en_US
dc.subject
Inflammation
en_US
dc.subject
Endothelial cells
en_US
dc.subject
TNF-alpha
en_US
dc.subject
Ventricular assist device (VAD)
en_US
dc.subject
Traction force microscopy
en_US
dc.title
Towards Long Term Endothelialization of Cardiovascular Devices
en_US
dc.type
Doctoral Thesis
dc.rights.license
In Copyright - Non-Commercial Use Permitted
ethz.size
161 p.
en_US
ethz.identifier.diss
24798
en_US
ethz.publication.place
Zurich
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02130 - Dep. Maschinenbau und Verfahrenstechnik / Dep. of Mechanical and Process Eng.::02627 - Institut für Energietechnik / Institute of Energy Technology::03462 - Poulikakos, Dimos / Poulikakos, Dimos
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02130 - Dep. Maschinenbau und Verfahrenstechnik / Dep. of Mechanical and Process Eng.::02627 - Institut für Energietechnik / Institute of Energy Technology::03462 - Poulikakos, Dimos / Poulikakos, Dimos
en_US
ethz.date.deposited
2018-03-26T09:50:33Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.date.embargoend
2019-03-26
ethz.rosetta.installDate
2018-03-26T10:33:25Z
ethz.rosetta.lastUpdated
2019-04-10T09:25:15Z
ethz.rosetta.versionExported
true
ethz.COinS
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