We present experimentally determined photodisruption enhancement of 50 nm gold spheres irradiated with 780 nm 180 fs pulses using a pump-probe scattering system. Our results indicate a 300 nm cavitation bubble threshold reduction of 31 times when compared to an ultra-pure water base control solution. We utilize a method of matching time between bubble initiation in a continually circulated nanoparticle solution with theoretical focal volume size dependent time between particle-focal volume collision events based on simple particle kinetics. We propose the observed photodisruption is due to electrostatic particle ablation kinetics due to electron photoemission. We apply the Fowler-Dubridge theory for photoemission to nanospheres experiencing strong near-field enhancement to describe particle electric fields induced by non-zero particle charge densities resulting from emitted electrons. An apparent ultra-energy efficient photodisruption mechanism results from multiphoton emission processes in the sub 100 femtosecond pulse regime exceeding typical methods utilizing explosive boiling. In the process of explaining experimental results, we develop a near complete picture of nanoparticle mediated photodisruption as a function of identified relevant system non-dimensional groups and particle enhancement. These results may be used to guide the selection of laser and particle parameters for imaging and different photodisruption regimes. / text

This thesis deals with the numerical solution of cavitation bubble dynamics and with cyanobacteria gas vesicle behaviour. A program for the numerical calculation of bubble dynamics is created using the Rayleigh-Plesset equation and its modifications. Subsequently, bubbles of different sizes are investigated during acoustic cavitation with various driving frequencies. Furthermore, a model for hydrodynamic cavitation is created. The model combines CFD computation of flow in the Venturi nozzle with the cavitation bubble dynamics calculation. The last part of the work is dedicated to cyanobacteria gas vesicle behaviour in a variable pressure field and during passage through the Venturi nozzle.

Cette étude sur la stabilité d’une bulle unique de cavitation acoustique s’inscrit dans le cadre d’un projet ANR démarré en septembre 2009 (SONONUCLICE ANR-09-BLAN-0040-02). Elle se situe dans la continuité des travaux sur l’optimisation du procédé de lyophilisation de produits pharmaceutiques menés par l’équipe « Transferts couplés de matière et de chaleur » du laboratoire LAGEP (ESCPE/UCB, Lyon), équipe porteuse du projet, et des travaux sur la cristallisation assistée par ultrasons du laboratoire RAPSODEE. L’application des ultrasons de puissance dans un liquide produit des milliards de bulles. Ce phénomène est appelé cavitation acoustique. Les bulles formées ne font pas toutes la même taille, leurs oscillations ne sont pas en phase, et leur densité dans le fluide est très inhomogène : ce phénomène très complexe implique donc de nombreuses variables difficiles à isoler. Même si le phénomène est chaotique, la cavitation permet d’observer des effets macroscopiques notables sur la nucléation et la croissance des cristaux de glace dans une solution sous-refroidie. Ces effets sont d’une importance capitale pour des applications de congélation ou de lyophilisation. Bien que les effets des ultrasons présentent des intérêts certains sur la cristallisation, leur origine reste mal connue. L’observation directe des milliards de bulles ne fournit aucune piste sur les mécanismes microscopiques mis en jeu. Afin d’isoler l’acteur essentiel de ces effets, l’étude menée vise à isoler une bulle de cavitation acoustique. Pour cela, une cellule de lévitation carrée en verre a été conçue. Le verre a été retenu comme matériau pour sa rigidité et sa transparence. Dans cette cellule, une onde de pression acoustique est imposée par un piézoélectrique collé à la base de la cellule. Il a été possible de reconstruire la dynamique de la bulle. Les étapes d’expansion, d’implosion et de rebonds sont clairement visibles. En vue de l’étude de la cristallisation, un principe de détection des cristaux a été spécifiquement élaboré. Il repose sur le suivi de la modification de la périodicité de la bulle (mesurée par un microphone) provoquée par l’apparition d’un corps étranger à son voisinage. Une méthode utilisant la corrélation de signaux acoustiques du microphone filtré à la fréquence d’excitation du PZT et les harmoniques du signal du microphone directe a été développée. Elle permet de connaître le régime d’oscillation de la bulle et de détecter toutes les modifications de sa dynamique. Des expériences de perturbation de la bulle ont été menées à l’aide d’une micro fibre de 7 μm. Le principe de détection est alors mis en oeuvre pour déclencher l’enregistrement d’images par une caméra rapide lors des derniers instants d’existence de la bulle. Cette méthode devrait permettre de détecter l’apparition des premiers cristaux au voisinage de la bulle. Autour de la cellule de lévitation, différents systèmes ont été développés. Un système de dégazage et de remplissage de la cellule de cavitation ont permis de travailler avec de l’eau ayant des teneurs en gaz dissous de l’ordre de 20 % de la saturation. Un système d’éclairage avec une LED de puissance et un jeu de lentilles optiques a été conçu pour visualiser correctement la bulle. / This study of the stability of an acoustic cavitation bubble is part of an ANR project started in September 2009 (SONONUCLICE ANR-09-BLAN-0040-02). It takes place in the continuity of the works on the optimization process of lyophilisation of pharmaceutical products conducted by the “Transferts couplés de matière et de chaleur” team of LAGEP (ESCPE/UCB, Lyon) laboratory, which is the project’s team leader, and the studies of ultrasound-assisted crystallization in the RAPSODEE Centre. The application of power ultrasound into liquids produces thousands of bubbles. This phenomenon is called acoustic cavitation. The bubbles formed don’t have the same size, their oscillations are not in phase, and their spatial density in the fluid is not homogeneous: this phenomenon is very complex and involves multiple variables very difficult to isolate. Even if this phenomenon is chaotic, it allows to observe macroscopic effects on the nucleation and crystal growth of ice in undercooled solutions. These effects have a capital importance for industrial applications such as freezing and lyophilisation (also called freeze drying). Although ultrasound has a noticeable influence on crystallization, the origin of these effects remains unclear. The multi-bubble approach doesn’t give any hint on the microscopic mechanisms involved. In order to isolate the main actor of these effects, this study aims at isolating a single cavitation bubble. To do that, a cubic levitation cell made of optical glass was build. In this cell, an acoustic pressure is applied by a piezoelectric glued to the bottom’s external face of the cell. With this cell is possible to rebuild all the oscillations states of the bubble, and in combination with our optical system we can see the bubble’s dynamics and its stages like: expansion, collapse and rebounds. For the crystallization part of this study, a crystal’s detection system was developed. It is based on the variations of the bubble’s periodicity (measured by a microphone pill) introduced by the sudden appearance of a foreign body in its vicinity. This method requires the correlation of the signals from a filtered microphone and the harmonics signals from a microphone, in order to known the oscillation state of the bubble and detect variations on the bubble’s dynamics. Experiments of bubble perturbations by a thin wire were made. The detection system was used to trigger the image recording of a fast camera, in order to capture the final moments of the bubble. This method should be allowing the early detection of new crystals in the proximity of the bubble. Around the levitation cell, various systems have been developed. A degassing and filling system for the cavitation cell allow us to work with degased water around the 20 % of its saturated concentration of air. An illumination system based in a power LED and a set of optical lenses was used to view the bubble correctly.

<div><br></div><div> Today, autoinjectors are developed for more viscous drug solutions, which require larger forces for actuating the syringe and impose larger stresses on the drug solution during the administration of autoinjectors. We developed experimentally validated high-fidelity simulations to investigate the liquid jet formation, liquid slosh and cavitation during the insertion process of an autoinjector. </div><div> </div><div> The jet formed due to an acceleration-deceleration motion of syringe is found to be governed by the interplay between inertial, viscous, surface tension and gravitational forces. A scaling for the jet velocity and a criterion for the jet breakup in a simplified geometry are proposed.</div><div> </div><div> When the syringe accelerates and decelerates during the insertion, liquid slosh occurs and there is a vehement motion of the air-liquid interface. Here, we quantified the area of air-liquid interface and hydrodynamic strain rate, which increase with the air gap size, syringe velocity, tilt angle and inner wall hydrophobicity, and decrease with the solution viscosity and hardly change with the liquid column height and surface tension. The strain rate is not sufficient to unfold the protein and the air-liquid interface is more likely to cause protein aggregation.</div><div> </div><div> In a spring-driven autoinjector, the plunger is actuated by the impact of a driving rod, which generates a strong pressure wave and can cause cavitation inception. The cavtiation bubbles can be impeded by the syringe walls and form a re-entrant jet shooting toward the syringe wall. During the process, the protein molecules are focused in the jet, pushed toward the syringe wall and spread across the wall, which can be the reason for the protein aggregation and adsorption on the syringe walls. The impedance effects of the wall decreases with the wall distance and increases with the maximum bubble size. The maximum bubble radius also increases with the liquid column size and nucleus size and decreases with the air gap pressure. Since inertia effects dominate in the cavitation process, the liquid viscosity and surface tension hardly changes the cavitation bubble dynamics. Small bubbles can also form in the bulk, which may generate aggregates in the bulk solution. Bubbles in the cavitation bubble cloud may coalesce with nearby bubbles and induce a higher pressure at the collapse (up to 1000 bar). This high pressure can potentially generate hydroxyl radicals that oxidize the protein molecules.</div><div> </div><div> The current study presents a detailed picture of fluid flows in autoinjectors and provide recommendations for mitigating the liquid slosh and cavitation generated in syringes. The results can be combined with future experiments to understand the implications of fluid flows on protein drugs and the performance of autoinjectors.</div>

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18998号 / 工博第4040号 / 新制||工||1622(附属図書館) / 31949 / 京都大学大学院工学研究科物質エネルギー化学専攻 / (主査)教授 作花 哲夫, 教授 安部 武志, 教授 田中 勝久 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Les technologies laser sont largement utilisées dans le contexte de l'impression 3D de matériaux de toute taille ainsique pour la bioimpression des constituants de tissue biologiques. Dans ce contexte, la bioimpression par laser (LAB), basée sur le procédé LIFT, a émergé comme une technique permettant de s'affranchir des inconvénients des technologies d'impression à jet d'encre(par exemple le colmatage). La bioimpression par Laser est une technique d'écriture directe de matériaux sous forme solide ou liquide dotée d'une haute résolution spatiale. La technique permet ainsi le transfert précis de microgouttelettes (volume de l'ordre du pL) de biomatériaux et de cellules sur un substrat de réception. Dans nos travaux de recherche, afin de mieux comprendre la dynamique du processus de transfert et d'utiliser la technique en ingénierie tissulaire, nous avons avons développé une approche expérimentale basée sur une méthode d'imagerie résolue en temps. Nous avons tout d'abord caractérisé les différents régimes d'éjection afin de définir des conditions appropriées à l'impressiond'éléments biologiques. Nous avons également exploré la fenêtre d'éjection, afin d'étudier l'influence de l'énergie laser sur la dynamique de jet. Ensuite, nous avons étudié une nouvelle de configuration bioimpression par laser pour laquelle des études paramétriques impliquant l'effet de la viscosité et de la distance d'impression sur la morphologie des gouttes imprimées ont été réalisées. Cette configuration permet d'imprimer des encres biologiques en obtenant des contours très lisses et uniformes jusqu’à une grande distance de séparation (≤10 mm). Les paramètres d'impression de cellules ont aussi été analysées par TRI en fonction de la concentration cellulaire des encres. Nos résultats fournissent des renseignements clés sur l'optimisation et devraient permettre un meilleur contrôle du mécanisme de transfert du processus de LAB. Enfin à la lumière de ces études, nous proposons un mécanisme complet pour la bioimpression par laser. / Laser-based approaches are among the pioneering works in cell printing. These techniques are being extensively focussed for two or three-dimensional structures of any size in transferring pattern materials including deposition of 3D biological constructs. In this context, Laser-Assisted Bioprinting (LAB), based on Laser-Induced Forward Transfer (LIFT) has emerged as a nozzleless method to surmount the drawbacks (e.g. clogging) of inkjet printing technologies. LAB is a laser direct-write technique that offers printing micropatterns with high spatial resolution from a wide range of solid or liquid materials, such as dielectrics, biomaterials and living cells. The technique enables controlled transfer of droplets onto a receiving substrate. A typical LAB setup comprises three key components: (i) a pulsed laser source, (ii) a ribbon coated with the material to be transferred and (iii) a receiving substrate. The ribbon integrates three layers: (i) a quartz disk support transparent to laser wavelength, (ii) a thin (1–100 nm) absorbing layer (like Ti or Au), and (iii) a bioink layer (few tens of microns) incorporating the material to print. The receiving substrate is faced to the bioink and placed at 100 μm to 1 mm distance from the ribbon. Rapid thermal expansion of metallic layer (on absorbing laser pulse) propels a small volume (~pL) of the ink towards a receiving substrate. Such a metallic interlayer eliminates direct interaction between the laser beam and the bioink. Volume of deposited material depends linearly on the laser pulse energy, and that a minimum threshold energy is required for microdroplet ejection. The thickness of the absorbing layer, viscosity and thickness of the bioink, different optical parameters such as the focus spot and the laser fluence are the controlling parameters to obtain a microscopic resolution and to limit the shock inflicted on the ejected cells. In our research works, we considered experimental approach to study the physical mechanism involved in the LAB using a time-resolved imaging method in order to gain a better insight into the dynamics of the transfer process and to use the technique for printing biomaterials. First we designed and implemented a novel configuration of LAB for upward printing. Then we characterized different ejection regimes to define suitable conditions for bioprinting. We further explored jetting window to study the influence of laser energy on jet dynamics. Ejection dynamics has been investigated by temporal evolution of the liquid jet for their potential use in cell printing. In addition parametric studies like effect of viscosity and printing distance on the morphology of the printed drops were conducted to explore jetting “window”. This configuration allows debris-free printing of fragile bioinks with extremely smooth and uniform edges at larger separation distance (ranging from 3 to 10mm). Material criteria required for realization of the cell printing are discussed and supported by experimental observations obtained by TRI investigation of cell printing from donors with different cell concentrations. These results provide key insights into optimization and better control of transfer mechanism of LAB. Finally, in the light of these studies, a comprehensive mechanism is proposed for printing micro-drops by LAB.

Ce travail de thèse concerne l’utilisation des décharges électriques de haute tension (DEHT) en milieu aqueux comme méthode d’extraction des polyphénols à partir de pépins de raisin.Les arcs électriques produits en milieu aqueux provoquent une succession de phénomènes (ondes de choc, bulles de cavitation) qui ont pour effet de fragmenter toute matière première située à proximité de l’arc électrique. L’objectif de cette thèse est d’étudier ces phénomènes afin d’améliorer la compréhension et l’efficacité des DEHT en tant que méthode d’extraction.Dans un premier temps, une étude des conditions d’apparition de l’arc électrique dans l’eau a permis de montrer que l’arc apparaît initialement dans des bulles de vapeur générées à la surface de l’électrode à cause de l’échauffement du liquide par effet Joule. Des mesures électriques, des prises de vues à haute vitesse, ainsi qu’une simulation numérique du problème ont permis de vérifier cette hypothèse. Une étude paramétrique des phénomènes générés par l’arc électrique (onde de choc et bulle de cavitation) a été menée. Grâce à des mesures de la pression des ondes de choc, des mesures de la taille des bulles de cavitation, et grâce des mesures électriques précises (notamment de la résistance électrique de l’arc), il apparaît que l’amplitude des phénomènes dépendent essentiellement de l’énergie dépensée dans l’arc. Cette énergie doit être distinguée de l’énergie totale d’une impulsion électrique, dont une partie est dépensée avant le claquage, mais également de l’énergie disponible au moment du claquage, dont une partie importante est dépensée dans le circuit électrique. La partition de cette énergie entre l’arc et le circuit électrique dépend du rapport entre la résistance du circuit et la résistance de l’arc. Ainsi une méthode pour augmenter significativement l’amplitude des phénomènes étudiés, et donc l’efficacité du procédé est d’améliorer le rapport entre ces résistances. Il a par exemple été observé qu’en augmentant la longueur de l’arc électrique de 2.5 mm à 2 cm, la résistance de l’arc augmente de 40 m à 0.55, et l’amplitude de l’onde de choc augmente de 135%. Pour finir, une étude paramétrique sur l’efficacité des DEHT comme procédé d’extraction des polyphénols des pépins de raisin a été menée. Entre autres, les effets sur l’extraction de la conductivité du liquide, du rapport liquide-solide, du nombre d’impulsion, de l’énergie par impulsion, de la distance inter-électrode ont été étudiés. Ces études ont mis en évidence l’importance de la répartition de l’énergie totale d’une impulsion en énergie dépensée avant le claquage, énergie dépensée au claquage dans le circuit électrique et énergie dépensée dans l’arc électrique. Ces études ont montré comment cette répartition est influencée par ces différents paramètres, et comment cela influence l’efficacité d’extraction. L’influence de la distance inter-électrode, et donc de la longueur de l’arc, a été particulièrement été mise en évidence par les résultats d’extraction. / This thesis work focuses on the use of high voltage electrical discharges (HVED) in aqueous media as a method for extracting polyphenols from grape seeds. Electric arcs generated in an aqueous environment cause a succession of phenomena (shock waves, cavitation bubbles) that have the effect of fragmenting any raw material located near the electric arc. The objective of this thesis is to study these phenomena in order to improve the understanding and effectiveness ofHVED as an extraction method. First, a study of the conditions under which the electric arc appears in water showed that the arc initially appears in vapour bubbles generated on the electrode surface due to the heating of the liquid due to Joule effect. Electrical measurements, high-speed photography and a numerical simulation of the problem have allowed this hypothesis to be verified. A parametric study of the phenomena generated by the electric arc (shock wave and cavitation bubble) was carried out. Through measurements of shock wave pressure, of cavitation bubble size, and precise electrical measurements (including the electrical resistance of the arc), it appears that the amplitude of the phenomena depends essentially on the energy consumed in the arc. This energy mustbe distinguished from the total energy of an electrical pulse, part of which is spent before the breakdown. The energy spent in the electric arc must also be distinguishedfrom the energy available at electrical breakdown, as a significant part of breakdown energy is spent in the electrical circuit. The partition of breakdown energy between the arc and the electrical circuit depends on the ratio between the resistance of the circuit and that of the arc. Thus a method to significantly increase the amplitude of the studied phenomena (and therefore the efficiency of the process), is to improve the ratio between these resistances. For example, it has been observed that by increasing the length of the electric arc from 2.5 mm to 2 cm, the resistance of the arc increases from 40 m to 0.55, and the amplitude of the shock wave increases by 135%. Finally, a parametric study on the efficiency of DEHT as a process for extracting polyphenols from grape seedswas carried out. Among other things, the effects on the extraction of liquid conductivity, liquid-solid ratio, number of pulses, energy per pulse, and distance between electrodes were studied. These studies highlighted the importance of the distribution of the total pulse energy into energy spent before the breakdown, energy spent after breakdown in the electrical circuit and energy spent in the arc. These studies have shown howthis distribution is influenced by these different parameters, and how it influences extraction efficiency. The influence of the inter-electrode distance, and therefore the length of the arc, was particularly highlighted by the extraction results.

<p>  </p> <p>Cavitation, liquid slosh, and splashes are ubiquitous in science and engineering. However, these phenomena are not fully understood. Yet to date, we do not understand when or why sometimes the splash seals, and other times does not. Regarding cavitation, a high temporal resolution method is needed to characterize this phenomenon. The low temporal resolution of experimental data suggests a model-based analysis of this problem. However, high-fidelity models are not always available, and even for these models, the sensitivity of the model outputs to the initial input parameters makes this method less reliable since some initial inputs are not experimentally measurable. As for sloshing, the air-liquid interface area and hydrodynamic stress for the liquid slosh inside a confined accelerating cylinder have not been experimentally measured due to the challenges for direct measurement.</p>

<p>Autoinjectors are pen-like devices that typically deliver drug products of 2 mL or less. They shield the needle before and after use, reducing patient anxiety from needle phobia and mitigating the risk of needlestick injuries and accidental contamination. Additionally, automatic delivery ensures more consistent needle penetration depth and injection force than manual injection methods. </p> <p><br></p> <p>To optimize autoinjector design, this thesis presents experimentally validated computational models that describe the processes of needle insertion, drug delivery, and transport of subcutaneously administered therapeutic proteins in the body. A multi-objective optimization framework is also proposed to guide the design of autoinjectors.</p> <p><br></p> <p>This thesis focuses on spring-driven autoinjectors, the most common type of autoinjector. It begins with an overview of the interactions between the spring-driven autoinjector, tissue, and therapeutic proteins. Moving on to Chapter 2, a computational model is presented to accurately predict the kinematics of the syringe barrel and plunger during the needle insertion process.</p> <p><br></p> <p>In Chapter 3, we present a quasi-steady model for the drug delivery process, which considers the rheology of therapeutic proteins. The Carreau model is adopted to describe protein viscosity, and explicit relationships between flow rate and pressure drop in the needle are derived. Furthermore, the applicable regime for the power-law model for protein viscosity is identified.</p> <p><br></p> <p>Chapter 4 quantifies the impact of sloshing and cavitation on therapeutic proteins in the syringe. Additionally, a workflow is presented to integrate available simulation tools to predict the performance of spring-driven autoinjectors. The influence of each design parameter of spring-driven autoinjectors on their performance is also discussed. </p> <p><br></p> <p>The spring-driven autoinjector delivers therapeutic proteins through subcutaneous administration. To gain insights into the transport process of therapeutic proteins, Chapter 5 presents a physiologically-based pharmacokinetic model that has been validated against experimental data for humans and rats. The lymph flow rate significantly affects the bioavailability of therapeutic proteins. This finding highlights the importance of studying the transport of therapeutic proteins in the lymphatic system in future research.</p> <p><br></p> <p>Chapter 6 provides a multi-objective design optimization framework for the spring-driven autoinjector. The computational model is replaced with an accurate deep neural network surrogate to improve the computational efficiency.  Using this surrogate model, we conduct a sensitivity analysis to identify essential design parameters. After that, we perform multi-objective optimization to find promising design candidates.</p> <p><br></p> <p>Chapter 7 presents a model for bubble dynamics in a protein solution. An explicit expression for the bubble dissolution rate is derived, enabling extraction of the interfacial properties of the protein-coated interface from the measured bubble radii. Moreover, analytical solutions for the response of a protein-coated bubble to an imposed acoustic pressure are derived. This work provides insight into protein-coated bubbles, which are used as vehicles to deliver drugs, as active miniature tracers to probe the rheology of soft and biological materials, or as contrast agents to enhance the ultrasound backscatter in ultrasonic imaging.</p> <p><br></p> <p>At last, in Chapter 8, we introduce a model for laser-induced cavitation that considers several key factors, such as liquid compressibility, heat transfer, and non-equilibrium evaporation and condensation. Our model's predictions for the time-course of bubble radii have been validated with experimental data. Moreover, our model reveals that the reduction of the bubble's oscillation amplitude is primarily due to a decrease in the number of vapor molecules inside the bubble, highlighting the crucial role of phase change in laser-induced cavitation bubbles.</p> <p><br></p> <p>The developed computational models and framework provide crucial insights into the development of spring-driven autoinjectors and cavitation bubbles. These studies can also enhance the efficacy and safety of the delivery of therapeutic proteins, ultimately improving patient outcomes.</p>