Abstract
This thesis is about controlling the properties of microbubbles for high-precision medical applications.
First a method to control the monodisperse microbubble production is introduced. Here, a transmission-based laser system is used to detect passing microbubbles in a flow-focusing device. This allows for the real-time measurement of the on-chip microbubble size and production rate, which is then used to control the flow-focusing device with a feedback loop. The system is capable of producing bubbles with a radius between 2.7 and 20 μm.
Next the variation in viscoelastic properties of individual bubbles formed by flow-focusing is investigated. Differences in the phase separation of the shell components between microbubbles are observed using fluorescent microscopy. Resonance curves of individual microbubbles show that there is a wide spread in viscoelastic properties and acoustically driven dissolution behaviour.
Subsequently a method to control the viscoelastic properties is devised. The surface elasticity of monodisperse microbubbles formed by microfluidic flow-focusing can be controlled by the addition of palmitic acid to a DSPC and DPPE-PEG5000 shell. The surface elasticity can be tuned between 0.5 and 4.5 N/m by varying the palmitic acid concentration in the formulation. The full surface elasticity vs surface dilatation curves show that the increase in surface elasticity due to the palmitic acid is localized at a small surface dilatation range of a few percent around the equilibrium microbubble surface.
Then the problem of ambient pressure driven dissolution of bubbles formed by flow-focusing is solved by reducing the amount of PEGylated lipid in the shell. The concentration of PEGylated lipid, necessary for microfluidic operation, can be used to tune the buckling pressure and thereby increase bubble stability. The PEGylated lipid concentration can be changed either directly during bubble production or, more conveniently, by heating the microbubbles after production.
Finally, sonoporation, the intracellular drug delivery facilitated by ultrasound-driven microbubble oscillations, is optimized using the size control over the microbubbles. The sonoporation efficiency is strongly dependent on the equilibrium bubble size and is most efficiently induced by bubbles with a radius of 4.7 μm. Furthermore, the sonoporation efficiency correlated well with an estimate of the bubble-induced normal stress.
First a method to control the monodisperse microbubble production is introduced. Here, a transmission-based laser system is used to detect passing microbubbles in a flow-focusing device. This allows for the real-time measurement of the on-chip microbubble size and production rate, which is then used to control the flow-focusing device with a feedback loop. The system is capable of producing bubbles with a radius between 2.7 and 20 μm.
Next the variation in viscoelastic properties of individual bubbles formed by flow-focusing is investigated. Differences in the phase separation of the shell components between microbubbles are observed using fluorescent microscopy. Resonance curves of individual microbubbles show that there is a wide spread in viscoelastic properties and acoustically driven dissolution behaviour.
Subsequently a method to control the viscoelastic properties is devised. The surface elasticity of monodisperse microbubbles formed by microfluidic flow-focusing can be controlled by the addition of palmitic acid to a DSPC and DPPE-PEG5000 shell. The surface elasticity can be tuned between 0.5 and 4.5 N/m by varying the palmitic acid concentration in the formulation. The full surface elasticity vs surface dilatation curves show that the increase in surface elasticity due to the palmitic acid is localized at a small surface dilatation range of a few percent around the equilibrium microbubble surface.
Then the problem of ambient pressure driven dissolution of bubbles formed by flow-focusing is solved by reducing the amount of PEGylated lipid in the shell. The concentration of PEGylated lipid, necessary for microfluidic operation, can be used to tune the buckling pressure and thereby increase bubble stability. The PEGylated lipid concentration can be changed either directly during bubble production or, more conveniently, by heating the microbubbles after production.
Finally, sonoporation, the intracellular drug delivery facilitated by ultrasound-driven microbubble oscillations, is optimized using the size control over the microbubbles. The sonoporation efficiency is strongly dependent on the equilibrium bubble size and is most efficiently induced by bubbles with a radius of 4.7 μm. Furthermore, the sonoporation efficiency correlated well with an estimate of the bubble-induced normal stress.
| Original language | English |
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| Qualification | Doctor of Philosophy |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 12 Jan 2024 |
| Place of Publication | Enschede |
| Publisher | |
| Print ISBNs | 978-90-365-5967-6 |
| Electronic ISBNs | 978-90-365-5968-3 |
| DOIs | |
| Publication status | Published - 12 Jan 2024 |