Graduate Thesis Or Dissertation


Covalent Adaptable Hydrogels to Probe Cellular Mechanotransduction Public Deposited
  • In tissues, cells reside within a complex meshwork of proteins called the extracellular matrix (ECM) with which they are intrinsically linked. Cells chemically remodel the ECM by secreting proteins that degrade and rebuild the ECM; additionally, cells physically remodel the ECM by applying stress that permanently deforms the matrix. However, the relationship is reciprocal given that the ECM provides biochemical and biophysical cues that directly influence cellular processes such as migration, transcription, differentiation, proliferation, and morphology. Hydrogels are synthetic water swollen polymer networks that can recapitulate many of the properties of the ECM. The focus of this thesis was to design hydrogels with dynamic cross-links to study the effect of time-dependent biophysical signals on cellular mechanotransduction. Covalent adaptable reactions were harnessed to provide the experimenter with spatial and temporal control of the time-dependent viscoelastic properties. First, the reversible-exchange of allyl sulfide cross-links with thiyls was leveraged to develop a photo-degradable hydrogel with degradation kinetics that increased as a function of light intensity and thiol concentration. This hydrogel system was used to rapidly erode thick cell-laden hydrogels in specific areas to create well defined three-dimensional structures and to capture released cells for further expansion. We then expanded upon the utility of the reversible-exchange reaction and designed a network tethered photoinitiator for use in conjunction with the allyl sulfide cross-linker to achieve photo-induced viscoelasticity without concurrent photo-degradation. We characterized the viscoelasticity of these hydrogels as a function of the photo-initiation rate and the chain-transfer agent concentration and demonstrated that bone marrow derived mesenchymal stem cells quickly move away from regions of localized viscoelasticity. Lastly, the reversible-addition of boronic acid and vicinal diol was exploited as another adaptable chemistry to create hydrogels with tunable viscoelastic spectra. By tuning the viscoelastic processes of these hydrogels to occur on distinct timescales, we find that NIH-3T3 fibroblasts sense and respond to the mechanical properties of their substrate on timescales of less than a second. Collectively, these systems exemplify how reversible covalent cross-links can be utilized to impart viscoelastic characteristics into cytocompatible hydrogels and how these strategies can be employed to study the regulation of biochemical machinery by mechanical forces at the cell-matrix interface.
Date Issued
  • 2019
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Last Modified
  • 2019-11-14
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