Abstract
This thesis revolved around characterizing and optimizing the BuBble-Gun system, to improve needle-free delivery by gaining control over injection depth.
Chapter 1 focused on the interplay of measurement settings, chip design and jetting behavior. We explored bubble and jet dynamics in four chip designs, and found that tapered chips show jet acceleration compared to rectangular chips. Ejected volume is impeded by increasing hydraulic pressure within the channel.
Chapter 2 focused on the jet impact behavior. We designed two novel systems to capture the brief impact. First, using laser Doppler vibrometery to measure the deflection speed of cantilevers impacted by jets, capturing jet impact at 0.1 mN sensitivity. Second, the Fast-Force sensor (range of 13 mN, 1.46 N−1 sensitivity, 75 kHz bandwidth). However, jet impact triggered resonance in both systems. Improved designs could prevent resonance, while the quality of the current data could be improved with more refined image processing techniques.
Chapter 3 provided background on the skin related topics: skin anatomy and physiology, dermal drug delivery and the complex mechanical properties of skin, and detailing on how to take the latter into account in research. Additionally, skin models were discussed and the models used in this thesis (agarose gels and ex vivo skin) were introduced.
Chapter 4 investigated the influence of jet characteristics on impact outcome in relation to substrate shear modulus, and we identified seven distinct impact regimes. This allows to calculate the thresholds between jet spreading and splashing, the threshold for elastic material deformation, and between elastic and plastic material deformation. However, the used substrates lack the structural complexity of skin and therefore further studies are needed to validate comparison.
Chapter 5 provided this initial validation. We delivered insulin and liposomes to the epidermis and dermis in human ex vivo skin, without observing any damage. Increasing the injection number from 25 to 50, to 100 led to a 3-fold and 2.6-fold deeper uptake, indicating a relation between number of jets and injection depth. The exact relationship needs to be further studied, and tested across the interpatient variability of skin stiffness. We conclude that the main process of weakening the skin barrier integrity is based on microscopic ruptures within the intercellular pathway, caused by the mechanical forces resulting from jet impact. How these microscopic changes in turn affect the injectate uptake depends on the physiochemical properties of the delivered compound.
Chapter 6 explored additional imaging techniques. Near-field infrared imaging detects injectate in skin cross-sections label-free at high sensitivity, and avoids skin auto-fluorescence. Confocal and 2-photon microscopy can be used to image within the skin surface, until ~50 µm below the stratum cornuem. Using vis-sOCT we non-invasively identified a ~20 nL injection site. When applying additional spectral analysis on the obtained data we clearly distinguished the injectate from the surrounding tissue.
With promising perspectives on the horizon for the BuBble-Gun system, much work needs to be done for clinical applications. First, increasing the jetting rate to enable more experimental conditions. Additionally, the delivery efficiency needs to be increased and splash-back needs to be reduced. Furthermore, it should be verified how the observed phenomena acts across the interpatient variability of skin mechanical properties.
Chapter 1 focused on the interplay of measurement settings, chip design and jetting behavior. We explored bubble and jet dynamics in four chip designs, and found that tapered chips show jet acceleration compared to rectangular chips. Ejected volume is impeded by increasing hydraulic pressure within the channel.
Chapter 2 focused on the jet impact behavior. We designed two novel systems to capture the brief impact. First, using laser Doppler vibrometery to measure the deflection speed of cantilevers impacted by jets, capturing jet impact at 0.1 mN sensitivity. Second, the Fast-Force sensor (range of 13 mN, 1.46 N−1 sensitivity, 75 kHz bandwidth). However, jet impact triggered resonance in both systems. Improved designs could prevent resonance, while the quality of the current data could be improved with more refined image processing techniques.
Chapter 3 provided background on the skin related topics: skin anatomy and physiology, dermal drug delivery and the complex mechanical properties of skin, and detailing on how to take the latter into account in research. Additionally, skin models were discussed and the models used in this thesis (agarose gels and ex vivo skin) were introduced.
Chapter 4 investigated the influence of jet characteristics on impact outcome in relation to substrate shear modulus, and we identified seven distinct impact regimes. This allows to calculate the thresholds between jet spreading and splashing, the threshold for elastic material deformation, and between elastic and plastic material deformation. However, the used substrates lack the structural complexity of skin and therefore further studies are needed to validate comparison.
Chapter 5 provided this initial validation. We delivered insulin and liposomes to the epidermis and dermis in human ex vivo skin, without observing any damage. Increasing the injection number from 25 to 50, to 100 led to a 3-fold and 2.6-fold deeper uptake, indicating a relation between number of jets and injection depth. The exact relationship needs to be further studied, and tested across the interpatient variability of skin stiffness. We conclude that the main process of weakening the skin barrier integrity is based on microscopic ruptures within the intercellular pathway, caused by the mechanical forces resulting from jet impact. How these microscopic changes in turn affect the injectate uptake depends on the physiochemical properties of the delivered compound.
Chapter 6 explored additional imaging techniques. Near-field infrared imaging detects injectate in skin cross-sections label-free at high sensitivity, and avoids skin auto-fluorescence. Confocal and 2-photon microscopy can be used to image within the skin surface, until ~50 µm below the stratum cornuem. Using vis-sOCT we non-invasively identified a ~20 nL injection site. When applying additional spectral analysis on the obtained data we clearly distinguished the injectate from the surrounding tissue.
With promising perspectives on the horizon for the BuBble-Gun system, much work needs to be done for clinical applications. First, increasing the jetting rate to enable more experimental conditions. Additionally, the delivery efficiency needs to be increased and splash-back needs to be reduced. Furthermore, it should be verified how the observed phenomena acts across the interpatient variability of skin mechanical properties.
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 Jul 2024 |
Place of Publication | Enschede |
Publisher | |
Print ISBNs | 978-90-365-6168-6 |
Electronic ISBNs | 978-90-365-6169-3 |
DOIs | |
Publication status | Published - Jul 2024 |