title: New stimuli-responsive substrates for the dynamic control of spatiotemporal patterns and fate of cells by physical cues
creator: Linke, Philipp
subject: ddc-530
subject: 530 Physics
subject: ddc-540
subject: 540 Chemistry and allied sciences
subject: ddc-570
subject: 570 Life sciences
description: Biological cells sense not only biochemical cues but also physical cues from the surrounding microenvironment, and adapt their function and fate. Ample evidence suggests that changes in physical microenvironments of cells play critical roles in development, aging and diseases. However, the understanding of the dynamic response of cells to abrupt changes in physical microenvironments is still incomplete due to a lack of substrates that can provide well defined physical commands. The main thrust of this thesis is the design of two new types of substrates, which dynamically change elasticity or topography in order to unravel dynamic cellular response far out of equilibrium.   Chapter 4 presents the design of substrates with periodic wrinkles of adjustable wavelength for the switching of morphology and orientational order of mouse myoblasts. The substrates used in this study were fabricated by the deposition of hard polyimide on soft polydimethylsiloxane under axial strain. In stark contrast to commonly used approaches in topographic control of cells under static conditions (static contact guidance), the wrinkled substrates designed in this study are able to reversibly switch the wrinkle direction by 90° within 60 s simply by axial compression and relaxation. Dynamic contact guidance introduced in this study unraveled the kinetics of shape adaptation and orientational orders of cells as well as the existence of a critical wavelength for rearrangement of the focal adhesions and remodeling of cytoskeletons in response to the abrupt change in wrinkle direction.   Chapter 5 deals with the establishment of hydrogel substrates that can reversibly change the bulk elastic modulus for regulation of the morphology, active force generation and the fate decision of human mesenchymal stem cells derived from the bone marrow. The uniqueness of this study is to use hydrogels with reversible host-guest interactions, whose elasticity can be adjusted by the concentration of free host or guest molecules. In contrast to commonly used, chemically crosslinked hydrogel substrates with fixed elastic moduli, this enables to fine-adjust the substrate elasticity as well as to abruptly switch the substrate elasticity at any given time point. The mechanical strength of cell adhesion determined from a self-developed, high-throughput assay utilizing shock waves as well as the total energy dissipation by cellular traction forces indicated the presence of a critical substrate elasticity which triggers the mechanosensory system. Remarkably, an abrupt softening of substrate stiffness across this threshold instantaneously led to a decreasing total strain energy. Furthermore, frequent exchange of the substrate elasticity resulted in decreased proliferation without interfering with the multipotency of stem cells.   The dynamic cellular microenvironments established in this study open the new possibility to gain insight into the physical mechanism underpinning the plasticity of life, such as development, aging, and diseases.
date: 2020
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/29155/1/dissertation_philipp_linke_2020.pdf
identifier: DOI:10.11588/heidok.00029155
identifier: urn:nbn:de:bsz:16-heidok-291550
identifier:   Linke, Philipp  (2020) New stimuli-responsive substrates for the dynamic control of spatiotemporal patterns and fate of cells by physical cues.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/29155/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng