Ultrasound and sonochemistry enhance education outcomes: From fundamentals and applied research to entrepreneurial potential.

With this manuscript we aim to initiate a discussion specific to educational actions around ultrasonics sonochemistry. The importance of these actions does not just derive from a mere pedagogical significance, but they can be an exceptional tool for illustrating various concepts in other disciplines, such as process intensification and microfluidics. Sonochemistry is currently a far-reaching discipline extending across different scales of applicability, from the fundamental physics of tiny bubbles and molecules, up to process plants. This review is part of a special issue in Ultrasonics Sonochemistry, where several scholars have shared their experiences and highlighted opportunities regarding ultrasound as an education tool. The main outcome of our work is that teaching and mentorship in sonochemistry are highly needed, with a balanced technical and scientific knowledge to foster skills and implement safe protocols. Applied research typically features the use of ultrasound as ancillary, to merely enhance a given process and often leading to poorly conceived experiments and misunderstanding of the actual effects. Thus, our scientific community must build a consistent culture and monitor reproducible practices to rigorously generate new knowledge on sonochemistry. These practices can be implemented in teaching sonochemistry in classrooms and research laboratories. We highlight ways to collectively provide a potentially better training for scientists, invigorating academic and industry-oriented careers. A salient benefit for education efforts is that sonochemistry-based projects can serve multidisciplinary training, potentially gathering students from different disciplines, such as physics, chemistry and bioengineering. Herein, we discuss challenges, opportunities, and future avenues to assist in designing courses and research programs based on sonochemistry. Additionally, we suggest simple experiments suitable for teaching basic physicochemical principles at the undergraduatelevel. We also provide arguments and recommendations oriented towards graduate and postdoctoral students, in academia or industry to be more entrepreneurial. We have identified that sonochemistry is consistently seen as a 'green' or sustainable tool, which particular appeal to process intensification approaches, including microfluidics and materials science. We conclude that a globally aligned pedagogical initiative and constantly updated educational tools will help to sustain a virtuous cycle in STEM and industrial applications of sonochemistry.

Microfluidic jet impact: Spreading, splashing, soft substrate deformation and injection.

HYPOTHESIS: Needle-free injections using microfluidic jets could be optimized by reducing splashing and controlling injection depth. However, this is impeded by an incomplete understanding on how jet characteristics influence impact outcome. We hypothesise that exploring the relation between microfluidic jet characteristics and substrate shear modulus on impact behavior will assist in predicting and giving insights on the impact outcome on skin and injection endpoints. EXPERIMENTS: To do so, a setup using microfluidic chips, at varying laser powers and stand-off distances, was used to create thermocavitation generated microfluidic jets with ranging characteristics (velocity: 7-77 m/s, diameter: 35-120 µm, Weber-number: 40-4000), which were impacted on substrates with different shear modulus. FINDINGS: Seven impact regimes were found, depending on jet Weber-number and substrate shear modulus, and we identified three thresholds: i) spreading/splashing threshold, ii) dimple formation threshold, and iii) plastic/elastic deformation threshold. The regimes show similarity to skin impact, although the opacity of skin complicated determining the threshold values. Additionally, we found that jet velocity has a higher predictive value for injection depth compared to the Weber-number, and consequently, the jet-diameter. Our findings provide fundamental knowledge on the interaction between microfluidic jets and substrates, and are relevant for optimizing needle-free injections.

Cavity dynamics after the injection of a microfluidic jet onto capillary bridges.

The ballistics of solid and liquid objects (projectiles) impacting on liquids and soft solids (targets) generally results in the creation and expansion of an air cavity inside the impacted object. The dynamics of cavity expansion and collapse depends on the projectile inertia as well as on the target properties. In this paper we study the impact of microfluidic jets generated by thermocavitation processes on a capillary bridge between two parallel planar walls. Different capillary bridge types were studied, Newtonian liquids, viscoelastic liquids and agarose gels. Thus, we compare the cavity formation and collapse between a wide range of material properties. Moreover, we model the critical impact velocity of a jet traversing a capillary bridge type. For agarose gels with a storage modulus of 176 Pa, the critical velocity is well predicted by the model used for liquids. However, the predicted critical velocity for liquids deviates for agarose gels with a storage modulus of 536 Pa and 3961 Pa. Additionally, we show different types of cavity collapse, depending on the Weber number and the capillary bridge properties. We conclude that the type of collapse determines the number and size of entrained bubbles. Furthermore, we study the effects of wettability on the adhesion forces and contact line dissipation. We also conclude that upon cavity collapse, for hydrophobic walls a Worthington jet is energetically favourable. In contrast, for hydrophilic walls, the contact line dissipation is in the same order of magnitude of the energy of the impacted jet, suppressing the Worthington jet formation. Our results provide strategies for preventing bubble entrapment and give an estimation of the cavity dynamics, of relevance for, among others, needle-free injection applications.

Jet injectors: Perspectives for small volume delivery with lasers.

Needle-free jet injectors have been proposed as an alternative to injections with hypodermic needles. Currently, a handful of commercial needle-free jet injectors already exist. However, these injectors are designed for specific injections, typically limited to large injection volumes into the deeper layers beneath the skin. There is growing evidence of advantages when delivering small volumes into the superficial skin layers, namely the epidermis and dermis. Injections such as vaccines and insulin would benefit from delivery into these superficial layers. Furthermore, the same technology for small volume needle-free injections can serve (medical) tattooing as well as other personalized medicine treatments. The research dedicated to needle-free jet injectors actuated by laser energy has increased in the last decade. In this case, the absorption of the optical energy by the liquid results in an explosively growing bubble. This bubble displaces the rest of the liquid, resulting in a fast microfluidic jet which can penetrate the skin. This technique allows for precise control over volumes (pL to µL) and penetration depths (µm to mm). Furthermore, these injections can be tuned without changing the device, by varying parameters such as laser power, beam diameter and filling level of the liquid container. Despite the published research on the working principles and capabilities of individual laser-actuated jet injectors, a thorough overview encompassing all of them is lacking. In this perspective, we will discuss the current status of laser-based jet injectors and contrast their advantages and limitations, as well as their potential and challenges.

Mitigating losses: how scientific organisations can help address the impact of the COVID-19 pandemic on early-career researchers.

Scientific collaborations among nations to address common problems and to build international partnerships as part of science diplomacy is a well-established notion. The international flow of people and ideas has played an important role in the advancement of the 'Sciences' and the current pandemic scenario has drawn attention towards the genuine need for a stronger role of science diplomacy, science advice and science communication. In dealing with the COVID-19 pandemic, visible interactions across science, policy, science communication to the public and diplomacy worldwide have promptly emerged. These interactions have benefited primarily the disciplines of knowledge that are directly informing the pandemic response, while other scientific fields have been relegated. The effects of the COVID-19 pandemic on scientists of all disciplines and from all world regions are discussed here, with a focus on early-career researchers (ECRs), as a vulnerable population in the research system. Young academies and ECR-driven organisations could suggest ECR-powered solutions and actions that could have the potential to mitigate these effects on ECRs working on disciplines not related to the pandemic response. In relation with governments and other scientific organisations, they can have an impact on strengthening and creating fairer scientific systems for ECRs at the national, regional, and global level.

Correction: Mitigating losses: how scientific organisations can help address the impact of the COVID-19 pandemic on early-career researchers.

[This corrects the article DOI: 10.1057/s41599-021-00944-1.].

Impact of a microfluidic jet on a pendant droplet.

High speed microfluidic jets can be generated by a thermocavitation process: from the evaporation of the liquid inside a microfluidic channel, a rapidly expanding bubble is formed and generates a jet through a flow focusing effect. Here, we study the impact and traversing of such jets on a pendant liquid droplet. Upon impact, an expanding cavity is created, and, above a critical impact velocity, the jet traverses the entire droplet. We predict the critical traversing velocity (i) from a simple energy balance and (ii) by comparing the Young-Laplace and dynamic pressures in the cavity that is created during the impact. We contrast the model predictions against experiments, in which we vary the liquid properties of the pendant droplet and find good agreement. In addition, we assess how surfactants and viscoelastic effects influence the critical impact velocity. Our results increase the knowledge of the jet interaction with materials of well-known physical properties.

Assessment of cytotoxicity and sensitization potential of intradermally injected tattoo inks in reconstructed human skin.

BACKGROUND: The number of people within the European population having at least one tattoo has increased notably, and with it the number of tattoo-associated clinical complications. Despite this, safety information and testing regarding tattoo inks remain limited. OBJECTIVE: To assess cytotoxicity and sensitization potential of 16 tattoo inks after intradermal injection into reconstructed human skin (RHS). METHODS: Commercially available tattoo inks were injected intradermally into RHS (reconstructed epidermis on a fibroblast-populated collagen hydrogel) using a permanent makeup device. RHS biopsies, tissue sections, and culture medium were assessed for cytotoxicity (thiazolyl blue tetrazolium bromide assay [MTT assay]), detrimental histological changes (haematoxylin and eosin staining), and the presence of inflammatory and sensitization cytokines (interleukin [IL]-1α, IL-8, IL-18; enzyme-linked immunosorbent assay). RESULTS: Varying degrees of reduced metabolic activity and histopathological cytotoxic effects were observed in RHS after ink injection. Five inks showed significantly reduced metabolic activity and enhanced sensitization potential compared with negative controls. DISCUSSION: Using the RHS model system, four tattoo inks were identified as highly cytotoxic and classified as potential sensitizers, suggesting that allergic contact dermatitis could emerge in individuals carrying these inks. These results indicate that an RHS-based assessment of cytotoxicity and sensitization potential by intradermal tattoo ink injection is a useful analytical tool to determine ink-induced deleterious effects.

Challenges and opportunities for small volumes delivery into the skin.

Each individual's skin has its own features, such as strength, elasticity, or permeability to drugs, which limits the effectiveness of one-size-fits-all approaches typically found in medical treatments. Therefore, understanding the transport mechanisms of substances across the skin is instrumental for the development of novel minimal invasive transdermal therapies. However, the large difference between transport timescales and length scales of disparate molecules needed for medical therapies makes it difficult to address fundamental questions. Thus, this lack of fundamental knowledge has limited the efficacy of bioengineering equipment and medical treatments. In this article, we provide an overview of the most important microfluidics-related transport phenomena through the skin and versatile tools to study them. Moreover, we provide a summary of challenges and opportunities faced by advanced transdermal delivery methods, such as needle-free jet injectors, microneedles, and tattooing, which could pave the way to the implementation of better therapies and new methods.

Cavitation intensifying bags improve ultrasonic advanced oxidation with Pd/Al2O3 catalyst.

Advanced oxidation processes can potentially eliminate organic contaminants from industrial waste streams as well as persistent pharmaceutical components in drinking water. We explore for the first time the utilization of Cavitation Intensifying Bags (CIB) in combination with Pd/Al2O3 catalyst as possible advanced oxidation technology for wastewater streams, oxidizing terephthalic acid (TA) to 2-hydroxyterephthalic acid (HTA). The detailed characterization of this novel reaction system reveals that, during sonication, the presence of surface pits of the CIB improves the reproducibility and thus the control of the sonication process, when compared to oxidation in non-pitted bags. Detailed reaction kinetics shows that in the CIB reactor the reaction order to TA is zero, which is attributed to the large excess of TA in the system. The rate of HTA formation increased ten-fold from ~0.01 µM*min-1 during sonication in the CIB, to ~0.10 µM*min-1 for CIB in the presence of the Pd/Al2O3 catalyst. This enhancement was ascribed to a combination of improved mass transport, the creation of thermal gradients, and Pd/Al2O3 catalyst near the cavitating bubbles. Further analysis of the kinetics of HTA formation on Pd/Al2O3 indicated that initially the reaction underwent through an induction period of 20 min, where the HTA concentration was ~0.3 µM. After this, the reaction rate increased reaching HTA concentrations ~6 µM after 40 min. This behavior resembled that observed during oxidation of hydrocarbons on metal catalysts, where the slow rate formation of hydroperoxides on the metal surface is followed by rapid product formation upon reaching a critical concentration. Finally, a global analysis using the Intensification Factor (IF) reveals that CIB in combination with the Pd/Al2O3 catalyst is a desirable option for the oxidation of TA when considering increased oxidation rates and costs.

Delivery Strategies for Skin: Comparison of Nanoliter Jets, Needles and Topical Solutions.

Drug diffusion within the skin with a needle-free micro-jet injection (NFI) device was compared with two well-established delivery methods: topical application and solid needle injection. A permanent make-up (PMU) machine, normally used for dermal pigmentation, was utilized as a solid needle injection method. For NFIs a continuous wave (CW) laser diode was used to create a bubble inside a microfluidic device containing a light absorbing solution. Each method delivered two different solutions into ex vivo porcine skin. The first solution consisted of a red dye (direct red 81) and rhodamine B in water. The second solution was direct red 81 and rhodamine B in water and glycerol. We measured the diffusion depth, width and surface area of the solutions in all the injected skin samples. The NFI has a higher vertical dispersion velocity of 3 × 105µm/s compared to topical (0.1 µm/s) and needle injection (53 µm/s). The limitations and advantages of each method are discussed, and we conclude that the micro-jet injector represents a fast and minimally invasive injection method, while the solid needle injector causes notable tissue damage. In contrast, the topical method had the slowest diffusion rate but causes no visible damage to the skin.

Acoustophoretic focusing effects on particle synthesis and clogging in microreactors.

The handling of solids in microreactors represents a challenging task. In this paper, we present an acoustophoretic microreactor developed to manage particles in flow and to control the material synthesis process. The reactor was designed as a layered resonator with an actuation frequency of 1.21 MHz, in which a standing acoustic wave is generated in both the depth and width direction of the microchannel. The acoustophoretic force exerted by the standing wave on the particles focuses them to the channel center. A parametric study of the effect of flow rate, particle size and ultrasound conditions on the focusing efficiency was performed. Furthermore, the reactive precipitation of calcium carbonate and barium sulfate was chosen as a model system for material synthesis. The acoustophoretic focusing effect avoids solid deposition on the channel walls and thereby minimizes reactor fouling and thus prevents clogging. Both the average particle size and the span of the particle size distribution of the synthesized particles are reduced by applying high-frequency ultrasound. The developed reactor has the potential to control a wide range of material synthesis processes.

Is reproducibility inside the bag? Special issue fundamentals and applications of sonochemistry ESS-15.

In this paper we report our most recent attempts to tackle a notorious problem across several scientific activities from the ultrasonics sonochemical perspective: reproducibility of results. We provide experimental results carried out in three different laboratories, using the same ingredients: ultrasound and a novel cavitation reactor bag. The main difference between the experiments is that they are aimed at different applications, KI liberation and MB degradation; and exfoliation of two nanomaterials: graphene and molybdenum disulfide. Iodine liberation rates and methylene blue degradation were higher for the cases where a cavitation intensification bag was used. Similarly, improved dispersion and more polydisperse exfoliated layers of nanomaterials were observed in the intensified bags compared to plain ones. The reproducibility of these new experiments is compared to previous experimental results under similar conditions. Our main conclusion is that despite knowing and understanding most physicochemical phenomena related to the origins and effects of cavitation, there is still a long path towards reproducibility, both in one laboratory, and compared across different laboratories. As emphasized in the sonochemical literature, the latter clearly illustrates the complexity of cavitation as nonlinear phenomenon, whose quantitative estimation represents a challenging aspect. We also provide a list of procedural steps that can help improving reproducibility and scale-up efforts.

Electrolysis-Driven and Pressure-Controlled Diffusive Growth of Successive Bubbles on Microstructured Surfaces.

Control over the bubble growth rates forming on the electrodes of water-splitting cells or chemical reactors is critical with respect to the attainment of higher energy efficiencies within these devices. This study focuses on the diffusion-driven growth dynamics of a succession of H2 bubbles generated at a flat silicon electrode substrate. Controlled nucleation is achieved by means of a single nucleation site consisting of a hydrophobic micropit etched within a micrometer-sized pillar. In our experimental configuration of constant-current electrolysis, we identify gas depletion from (i) previous bubbles in the succession, (ii) unwanted bubbles forming on the sidewalls, and (iii) the mere presence of the circular cavity where the electrode is being held. The impact of these effects on bubble growth is discussed with support from numerical simulations. The time evolution of the dimensionless bubble growth coefficient, which is a measure of the overall growth rate of a particular bubble, of electrolysis-generated bubbles is compared to that of CO2 bubbles growing on a similar surface in the presence of a supersaturated solution of carbonated water. For electrolytic bubbles and under the range of current densities considered here (5-15 A/m2), it is observed that H2 bubble successions at large gas-evolving substrates first experience a stagnation regime, followed by a fast increase in the growth coefficient before a steady state is reached. This clearly contradicts the common assumption that constant current densities must yield time-invariant growth rates. Conversely, for the case of CO2 bubbles, the growth coefficient successively decreases for every subsequent bubble as a result of the persistent depletion of dissolved CO2.

Emulsification in novel ultrasonic cavitation intensifying bag reactors.

Cavitation Intensifying Bags (CIBs), a novel reactor type for use with ultrasound, have been recently proposed as a scaled-up microreactor with increased energy efficiencies. We now report on the use of the CIBs for the preparation of emulsions out of hexadecane and an SDS aqueous solution. The CIBs have been designed in such a way that cavitation effects created by the ultrasound are increased. It was found that the CIBs were 60 times more effective in breaking up droplets than conventional bags, therewith showing a proof of principle for the CIBs for the preparation of emulsions. Droplets of 0.2µm could easily be obtained. To our knowledge, no other technology results in the same droplet size more easily in terms of energy usage. Without depending on the wettability changes of the membrane, the CIBs score similarly as membrane emulsification, which is the most energy friendly emulsification method known in literature. Out of the frequencies used, 37kHz was found to require the lowest treatment time. The treatment time decreased at higher temperatures. While the energy usage in the current non-optimised experiments was on the order of 107-109J/m3, which is comparable to that of a high-pressure homogenizer, we expect that the use of CIBs for the preparation of fine emulsions can still be improved considerably. The process presented can be applied for other uses such as water treatment, synthesis of nanomaterials and food processing.

Synergy of Microfluidics and Ultrasound : Process Intensification Challenges and Opportunities.

A compact snapshot of the current convergence of novel developments relevant to chemical engineering is given. Process intensification concepts are analysed through the lens of microfluidics and sonochemistry. Economical drivers and their influence on scientific activities are mentioned, including innovation opportunities towards deployment into society. We focus on the control of cavitation as a means to improve the energy efficiency of sonochemical reactors, as well as in the solids handling with ultrasound; both are considered the most difficult hurdles for its adoption in a practical and industrial sense. Particular examples for microfluidic clogging prevention, numbering-up and scaling-up strategies are given. To conclude, an outlook of possible new directions of this active and promising combination of technologies is hinted.

Continuous-wave laser generated jets for needle free applications.

We designed and built a microfluidic device for the generation of liquid jets produced by thermocavitation. A continuous wave (CW) laser was focused inside a micro-chamber filled with a light-absorbing solution to create a rapidly expanding vapor bubble. The chamber is connected to a micro-channel which focuses and ejects the liquid jet through the exit. The bubble growth and the jet velocity were measured as a function of the devices geometry (channel diameter D and chamber width A). The fastest jets were those for relatively large chamber size with respect to the channel diameter. Elongated and focused jets up to 29 m/s for a channel diameter of [Formula: see text] and chamber size of [Formula: see text] were obtained. The proposed CW laser-based device is potentially a compact option for a practical and commercially feasible needle-free injector.

Measuring cavitation and its cleaning effect.

The advantages and limitations of techniques for measuring the presence and amount of cavitation, and for quantifying the removal of contaminants, are provided. After reviewing chemical, physical, and biological studies, a universal cause for the cleaning effects of bubbles cannot yet be concluded. An "ideal sensor" with high spatial and temporal resolution is proposed. Such sensor could be used to investigate bubble jetting, shockwaves, streaming, and even chemical effects, by correlating cleaning processes with cavitation effects, generated by hydrodynamics, lasers or ultrasound.

Enhancing acoustic cavitation using artificial crevice bubbles.

We study the response of pre-defined cavitation nuclei driven continuously in the kHz regime (80, 100 and 200 kHz). The nuclei consist of stabilized gaspockets in cylindrical pits of 30 µm diameter etched in silicon or glass substrates. It is found that above an acoustic pressure threshold the dynamics of the liquid-gas meniscus switches from a stable drum-like vibration to expansion and deformation, frequently resulting in detachment of microbubbles. Just above this threshold small bubbles are continuously and intermittently ejected. At elevated input powers bubble detachment becomes more frequent and cavitation bubble clouds are formed and remain in the vicinity of the pit bubble. Surprisingly, the resulting loss of gas does not lead to deactivation of the pit which can be explained by a rectified gas diffusion process.