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A. Yahyazadeh Shourabi
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The cell membrane is a crucial biological interface to consider in biomedical research, as a significant proportion of drugs interacts with this barrier. While understanding membrane–drug interactions is important, existing in vitro platforms for drug screening predominantly focus on interactions with whole cells or tissues. This preference is partly due to the instability of membrane-based systems and the technical challenges associated with buffer replacement around lipid membranes formed on microfluidic chips. Here, we introduce a novel microfluidic design capable of forming stable freestanding lipid bilayers with efficient replacement of the media in their local environment for molecular delivery to the membrane. With the use of bubble traps and resistance channels, we achieved sufficient hydrodynamic control to maintain membrane stability during the membrane formation and the molecular delivery phases. As a proof of concept, we successfully formed 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) bilayers on the chip and delivered the antibiotic azithromycin at low (5 μM) and high (250 μM) doses. Using optical tweezers, we characterized how azithromycin influenced the membrane elastic properties, including tension and bending rigidity. This microfluidic device is a versatile tool that can deliver various buffers, molecules or nano-/microparticles to freestanding membranes, and study the resulting impact on the membranes' properties.
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The cell membrane is a crucial biological interface to consider in biomedical research, as a significant proportion of drugs interacts with this barrier. While understanding membrane–drug interactions is important, existing in vitro platforms for drug screening predominantly focus on interactions with whole cells or tissues. This preference is partly due to the instability of membrane-based systems and the technical challenges associated with buffer replacement around lipid membranes formed on microfluidic chips. Here, we introduce a novel microfluidic design capable of forming stable freestanding lipid bilayers with efficient replacement of the media in their local environment for molecular delivery to the membrane. With the use of bubble traps and resistance channels, we achieved sufficient hydrodynamic control to maintain membrane stability during the membrane formation and the molecular delivery phases. As a proof of concept, we successfully formed 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) bilayers on the chip and delivered the antibiotic azithromycin at low (5 μM) and high (250 μM) doses. Using optical tweezers, we characterized how azithromycin influenced the membrane elastic properties, including tension and bending rigidity. This microfluidic device is a versatile tool that can deliver various buffers, molecules or nano-/microparticles to freestanding membranes, and study the resulting impact on the membranes' properties.
Lipid bilayers are fundamental to cell membranes. This thesis develops novel opto-microfluidic platforms for studying artificial cell membranes, addressing long-standing experimental challenges. Utilizing the developed tools, the work investigates thermomechanical properties of phase-separated membranes, the impact of lipid tail-asymmetry and cholesterol on mechanical properties, electrophysiological measurements on freestanding bilayers, and the effect of azithromycin on bilayers. This research provides new insights into membrane biophysics and advances drug-screening capabilities.
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Lipid bilayers are fundamental to cell membranes. This thesis develops novel opto-microfluidic platforms for studying artificial cell membranes, addressing long-standing experimental challenges. Utilizing the developed tools, the work investigates thermomechanical properties of phase-separated membranes, the impact of lipid tail-asymmetry and cholesterol on mechanical properties, electrophysiological measurements on freestanding bilayers, and the effect of azithromycin on bilayers. This research provides new insights into membrane biophysics and advances drug-screening capabilities.
Journal article
(2024)
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A. Yahyazadeh Shourabi, R.Y. Kieffer, W.J. de Jong, D.S.W. Tam, M.E. Aubin-Tam
Coexistence of lipid domains in cell membranes is associated with vital biological processes. Here, we investigate two such membranes: a multi-component membrane composed of DOPC and DPPC lipids with gel and fluid separated domains, and a single component membrane composed of PMPC lipids forming ripples. We characterize their mechanical properties below their melting point, where ordered and disordered regions coexist, and above their melting point, where they are in fluid phase. To conduct these inquiries, we create lipid bilayers in a microfluidic chip interfaced with a heating system and optical tweezers. The chip features a bubble trap and enables high-throughput formation of planar bilayers. Optical tweezers experiments reveal interfacial hydrodynamics (fluid-slip) and elastic properties (membrane tension and bending rigidity) at various temperatures. For PMPC bilayers, we demonstrate a higher fluid slip at the interface in the fluid-phase compared to the ripple phase, while for the DOPC:DPPC mixture, similar fluid slip is measured below and above the transition point. Membrane tension for both compositions increases after thermal fluidization. Bending rigidity is also measured using the forces required to extend a lipid nanotube pushed out of the freestanding membranes. This novel temperature-controlled microfluidic platform opens numerous possibilities for thermomechanical studies on freestanding planar membranes.
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Coexistence of lipid domains in cell membranes is associated with vital biological processes. Here, we investigate two such membranes: a multi-component membrane composed of DOPC and DPPC lipids with gel and fluid separated domains, and a single component membrane composed of PMPC lipids forming ripples. We characterize their mechanical properties below their melting point, where ordered and disordered regions coexist, and above their melting point, where they are in fluid phase. To conduct these inquiries, we create lipid bilayers in a microfluidic chip interfaced with a heating system and optical tweezers. The chip features a bubble trap and enables high-throughput formation of planar bilayers. Optical tweezers experiments reveal interfacial hydrodynamics (fluid-slip) and elastic properties (membrane tension and bending rigidity) at various temperatures. For PMPC bilayers, we demonstrate a higher fluid slip at the interface in the fluid-phase compared to the ripple phase, while for the DOPC:DPPC mixture, similar fluid slip is measured below and above the transition point. Membrane tension for both compositions increases after thermal fluidization. Bending rigidity is also measured using the forces required to extend a lipid nanotube pushed out of the freestanding membranes. This novel temperature-controlled microfluidic platform opens numerous possibilities for thermomechanical studies on freestanding planar membranes.