Towards controlled needle-free delivery!
Diana van der Ven is a PhD student in the Department Mesoscale Chemical Systems. Promotors are prof.dr.ir. D. Fernandez Rivas and prof.dr. J.G.E. Gardeniers from the Faculty of Science & Technology.
This thesis revolved around characterizing and optimizing the BuBble-Gun system, to improve needle-free delivery by gaining control over injection depth. It relies on a continuous-wave laser and glass microfluidic chips. A thermocavitation bubble is generated upon laser exposure, which expands and extrudes the liquid from the chip as a liquid jet. Jet characteristics are controlled by altering the chip filling level and absorbed laser energy, or by changing the chip architecture. Since the jet characteristics in turn control the injection outcome, we can ultimately control the injection behavior by controlling the jetting behavior.
Chapter 1 focused on the interplay of measurement settings, chip design and jetting behavior. We explored the bubble dynamics in four chip designs, using the channel specific hydraulic resistance to describe the found behavior. The tapered chips showed jet acceleration compared to the rectangular chip, the extend of which depends on how channel design and the flow-focusing effect relate to the filling level. The ejected volume is impeded by increasing hydraulic pressure within the channel.
Chapter 2 focused on gaining insight into the jet impact behavior, for which we designed two novel systems. First, using laser Doppler vibrometery to measure the deflection speed of cantilevers impacted by jets. Jet impact was captured at 0.1 mN sensitivity, however, it triggered cantilever resonance, thereby complicating data analysis. Second, the Fast-Force sensor had a range of 13 mN (1.46 N−1 sensitivity) and a bandwidth of 75 kHz. Jet impact was captured but resulted in a resonating signal close to the noise-floor. For both systems, improved designs could prevent resonance, while the quality of data of the current system could be improved with more refined image processing techniques.
Chapter 3 provided the theoretical background on the skin related topics, and detailed on: skin anatomy and physiology, dermal drug delivery and the complex mechanical properties of skin. The mechanical output of skin depends on the mechanical input and varies orders of magnitude, depending on the scale (e.g. probing size) or the severity of deformation (e.g. probing depth/force/speed). 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. Seven distinct regimes were identified, based on the jet Weber-number and substrate shear modulus. This allows to calculate the thresholds between jet spreading and splashing, the threshold for elastic material deformation, and between elastic and plastic material deformation. Based on this improved understanding, it is recommended to explore jets with higher Weber-number for ex vivo injections as these are associated with reduced splash-back and squeeze-out, thereby enhancing delivery efficiency and decreasing infection risks. However, the used substrates lack the structural complexity of skin and therefore further studies are needed to validate any comparison.
Chapter 5 provided this initial validation. We delivered insulin and liposomes to the epidermis and dermis in human ex vivo, without observing skin damage. Both compounds showed deeper uptake and enhanced diffusion rates compared to the topical controls. Increasing the injection number from 25 to 50 led to a 3-fold deeper uptake insulin, while increasing to 100 led to a 2.6-fold increase in depth, indicating that the injection depth can be controlled be controlling the number of jets. However, the exact relationship between number of jets and penetration depth needs to be further studied, and the validity should be tested across the inter-patient variability of skin stiffness. We conclude that the main process of weakening the skin barrier integrity is based on microscopic ruptures in the intercellular pathway, caused by the mechanical forces resulting from the jet impact. How these microscopic changes in turn affect the injectate uptake, depends on the physiochemical properties of the delivered compound.
Chapter 6 explored techniques to enhance the validity of our ex vivo results. Near-field infrared imaging detects injectate in skin cross-sections label-free at high sensitivity, and avoids skin auto-fluorescence. However, it does require an injectate with a distinct absorption spectrum. Confocal and 2-photon microscopy can be used to image within the skin surface, until ~50 µm below the stratum cornuem. The effective imaging depth could be increased by optimizing sample preparation. Using 2-photon microscopy is advised over confocal due to the lower rates of photobleaching and higher imaging depths. 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. An essential step in this would be 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.
