Bubbles enable volumetric negative compressibility in metastable elastocapillary systems.

Although coveted in applications, few materials expand when subject to compression or contract under decompression, i.e., exhibit negative compressibility. A key step to achieve such counterintuitive behaviour is the destabilisations of (meta)stable equilibria of the constituents. Here, we propose a simple strategy to obtain negative compressibility exploiting capillary forces both to precompress the elastic material and to release such precompression by a threshold phenomenon - the reversible formation of a bubble in a hydrophobic flexible cavity. We demonstrate that the solid part of such metastable elastocapillary systems displays negative compressibility across different scales: hydrophobic microporous materials, proteins, and millimetre-sized laminae. This concept is applicable to fields such as porous materials, biomolecules, sensors and may be easily extended to create unexpected material susceptibilities.

Mesoscopic elasticity controls dynamin-driven fission of lipid tubules.

Mesoscale physics bridges the gap between the microscopic degrees of freedom of a system and its large-scale continuous behavior and highlights the role of a few key quantities in complex and multiscale phenomena, like dynamin-driven fission of lipid membranes. The dynamin protein wraps the neck formed during clathrin-mediated endocytosis, for instance, and constricts it until severing occurs. Although ubiquitous and fundamental for life, the cooperation between the GTP-consuming conformational changes within the protein and the full-scale response of the underlying lipid substrate is yet to be unraveled. In this work, we build an effective mesoscopic model from constriction to fission of lipid tubules based on continuum membrane elasticity and implicitly accounting for ratchet-like power strokes of dynamins. Localization of the fission event, the overall geometry, and the energy expenditure we predict comply with the major experimental findings. This bolsters the idea that a continuous picture emerges soon enough to relate dynamin polymerization length and membrane rigidity and tension with the optimal pathway to fission. We therefore suggest that dynamins found in in vivo processes may optimize their structure accordingly. Ultimately, we shed light on real-time conductance measurements available in literature and predict the fission time dependency on elastic parameters.

The local variation of the Gaussian modulus enables different pathways for fluid lipid vesicle fusion.

Viral infections, fertilization, neurotransmission, and many other fundamental biological processes rely on membrane fusion. Straightforward calculations based on the celebrated Canham-Helfrich elastic model predict a large topological energy barrier that prevents the fusion process from being thermally activated. While such high energy is in accordance with the physical barrier function of lipid membranes, it is difficult to reconcile with the biological mechanisms involved in fusion processes. In this work, we use a Ginzburg-Landau type of free energy that recovers the Canham-Helfrich model in the limit of small width-to-vesicle-extension ratio, with the additional ability to handle topological transitions. We show that a local modification of the Gaussian modulus in the merging region both dramatically lowers the elastic energy barrier and substantially changes the minimal energy pathway for fusion, in accordance with experimental evidence. Therefore, we discuss biological examples in which such a modification might play a crucial role.

A nanoscale view of the origin of boiling and its dynamics.

In this work, we present a dynamical theory of boiling based on fluctuating hydrodynamics and the diffuse interface approach. The model is able to describe boiling from the stochastic nucleation up to the macroscopic bubble dynamics. It covers, with a modest computational cost, the mesoscale area from nano to micrometers, where most of the controversial observations related to the phenomenon originate. In particular, the role of wettability in the macroscopic observables of boiling is elucidated. In addition, by comparing the ideal case of boiling on ultra-smooth surfaces with a chemically heterogeneous wall, our results will definitively shed light on the puzzling low onset temperatures measured in experiments. Sporadic nanometric spots of hydrophobic wettability will be shown to be enough to trigger the nucleation at low superheat, significantly reducing the temperature of boiling onset, in line with experimental results. The proposed mesoscale approach constitutes the missing link between macroscopic approaches and molecular dynamics simulations and will open a breakthrough pathway toward accurate understanding and prediction.

Classical nucleation of vapor between hydrophobic plates.

In this work, an extended classical nucleation theory (CNT), including line tension, is used to disentangle classical and non-classical effects in the nucleation of vapor from a liquid confined between two hydrophobic plates at a nanometer distance. The proposed approach allowed us to gauge, from the available simulation work, the importance of elusive nanoscale effects, such as line tension and non-classical modifications of the nucleation mechanism. Surprisingly, the purely macroscopic theory is found to be in quantitative accord with the microscopic data, even for plate distances as small as 2 nm, whereas in extreme confinement (<1.5 nm), the CNT approximations proved to be unsatisfactory. These results suggest how classical nucleation theory still offers a computationally inexpensive and predictive tool useful in all domains where nanoconfined evaporation occurs-including nanotechnology, surface science, and biology.

Activation energy and force fields during topological transitions of fluid lipid vesicles.

Topological transitions of fluid lipid membranes are fundamental processes for cell life. For example, they are required for endo- and exocytosis or to enable neurotransmitters to cross the neural synapses. Here, inspired by the idea that fusion and fission proteins could have evolved in Nature in order to carry out a minimal work expenditure, we evaluate the minimal free energy pathway for the transition between two spherical large unilamellar vesicles and a dumbbell-shaped one. To address the problem, we propose and successfully use a Ginzburg-Landau type of free energy, which allows us to uniquely describe without interruption the whole, full-scale topological change. We also compute the force fields needed to overcome the involved energy barriers. The obtained forces are in excellent agreement, in terms of intensity, scale, and spatial localization with experimental data on typical fission protein systems, whereas they suggest the presence of additional features in fusion proteins.

Turning Molecular Springs into Nano-Shock Absorbers: The Effect of Macroscopic Morphology and Crystal Size on the Dynamic Hysteresis of Water Intrusion-Extrusion into-from Hydrophobic Nanopores.

Controlling the pressure at which liquids intrude (wet) and extrude (dry) a nanopore is of paramount importance for a broad range of applications, such as energy conversion, catalysis, chromatography, separation, ionic channels, and many more. To tune these characteristics, one typically acts on the chemical nature of the system or pore size. In this work, we propose an alternative route for controlling both intrusion and extrusion pressures via proper arrangement of the grains of the nanoporous material. To prove the concept, dynamic intrusion-extrusion cycles for powdered and monolithic ZIF-8 metal-organic framework were conducted by means of water porosimetry and in operando neutron scattering. We report a drastic increase in intrusion-extrusion dynamic hysteresis when going from a fine powder to a dense monolith configuration, transforming an intermediate performance of the ZIF-8 + water system (poor molecular spring) into a desirable shock-absorber with more than 1 order of magnitude enhancement of dissipated energy per cycle. The obtained results are supported by MD simulations and pave the way for an alternative methodology of tuning intrusion-extrusion pressure using a macroscopic arrangement of nanoporous material.

Detection of Pathological Markers of Neurodegenerative Diseases following Microfluidic Direct Conversion of Patient Fibroblasts into Neurons.

Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are clinically diagnosed using neuropsychological and cognitive tests, expensive neuroimaging-based approaches (MRI and PET) and invasive and time-consuming lumbar puncture for cerebrospinal fluid (CSF) sample collection to detect biomarkers. Thus, a rapid, simple and cost-effective approach to more easily access fluids and tissues is in great need. Here, we exploit the chemical direct reprogramming of patient skin fibroblasts into neurons (chemically induced neurons, ciNs) as a novel strategy for the rapid detection of different pathological markers of neurodegenerative diseases. We found that FAD fibroblasts have a reduced efficiency of reprogramming, and converted ciNs show a less complex neuronal network. In addition, ciNs from patients show misfolded protein accumulation and mitochondria ultrastructural abnormalities, biomarkers commonly associated with neurodegeneration. Moreover, for the first time, we show that microfluidic technology, in combination with chemical reprogramming, enables on-chip examination of disease pathological processes and may have important applications in diagnosis. In conclusion, ciNs on microfluidic devices represent a small-scale, non-invasive and cost-effective high-throughput tool for protein misfolding disease diagnosis and may be useful for new biomarker discovery, disease mechanism studies and design of personalised therapies.

Water cavitation from ambient to high temperatures.

Predicting cavitation has proved a formidable task, particularly for water. Despite the experimental difficulty of controlling the sample purity, there is nowadays substantial consensus on the remarkable tensile strength of water, on the order of -120 MPa at ambient conditions. Recent progress significantly advanced our predictive capability which, however, still considerably depends on elaborate fitting procedures based on the input of external data. Here a self-contained model is discussed which is shown able to accurately reproduce cavitation data for water over the most extended range of temperatures for which accurate experiments are available. The computations are based on a diffuse interface model which, as only inputs, requires a reliable equation of state for the bulk free energy and the interfacial tension. A rare event technique, namely the string method, is used to evaluate the free-energy barrier as the base for determining the nucleation rate and the cavitation pressure. The data allow discussing the role of the Tolman length in determining the nucleation barrier, confirming that, when the size of the cavitation nuclei exceed the thickness of the interfacial layer, the Tolman correction effectively improves the predictions of the plain Classical Nucleation Theory.

A Microfluidic Platform for Cavitation-Enhanced Drug Delivery.

An endothelial-lined blood vessel model is obtained in a PDMS (Polydimethylsiloxane) microfluidic system, where vascular endothelial cells are grown under physiological shear stress, allowing -like maturation. This experimental model is employed for enhanced drug delivery studies, aimed at characterising the increase in endothelial permeability upon microbubble-enhanced ultrasound-induced (USMB) cavitation. We developed a multi-step protocol to couple the optical and the acoustic set-ups, thanks to a 3D-printed insonation chamber, provided with direct optical access and a support for the US transducer. Cavitation-induced interendothelial gap opening is then analysed using a customised code that quantifies gap area and the relative statistics. We show that exposure to US in presence of microbubbles significantly increases endothelial permeability and that tissue integrity completely recovers within 45 min upon insonation. This protocol, along with the versatility of the microfluidic platform, allows to quantitatively characterise cavitation-induced events for its potential employment in clinics.

Giant Negative Compressibility by Liquid Intrusion into Superhydrophobic Flexible Nanoporous Frameworks.

Materials or systems demonstrating negative linear compressibility (NLC), whose size increases (decreases) in at least one of their dimensions upon compression (decompression) are very rare. Materials demonstrating this effect in all their dimensions, negative volumetric compressibility (NVC), are exceptional. Here, by liquid porosimetry and in situ neutron diffraction, we show that one can achieve exceptional NLC and NVC values by nonwetting liquid intrusion in flexible porous media, namely in the ZIF-8 metal-organic framework (MOF). Atomistic simulations show that the volumetric expansion is due to the presence of liquid in the windows connecting the cavities of ZIF-8. This discovery paves the way for designing novel materials with exceptional NLC and NVC at reasonable pressures suitable for a wide range of applications.

Tumor-on-a-chip platforms to study cancer-immune system crosstalk in the era of immunotherapy.

Immunotherapy is a powerful therapeutic approach able to re-educate the immune system to fight cancer. A key player in this process is the tumor microenvironment (TME), which is a dynamic entity characterized by a complex array of tumor and stromal cells as well as immune cell populations trafficking to the tumor site through the endothelial barrier. Recapitulating these multifaceted dynamics is critical for studying the intimate interactions between cancer and the immune system and to assess the efficacy of emerging immunotherapies, such as immune checkpoint inhibitors (ICIs) and adoptive cell-based products. Microfluidic devices offer a unique technological approach to build tumor-on-a-chip reproducing the multiple layers of complexity of cancer-immune system crosstalk. Here, we seek to review the most important biological and engineering developments of microfluidic platforms for studying cancer-immune system interactions, in both solid and hematological tumors, highlighting the role of the vascular component in immune trafficking. Emphasis is given to image processing and related algorithms for real-time monitoring and quantitative evaluation of the cellular response to microenvironmental dynamic changes. The described approaches represent a valuable tool for preclinical evaluation of immunotherapeutic strategies.

The interplay among gas, liquid and solid interactions determines the stability of surface nanobubbles.

Surface nanobubbles are gaseous domains found at immersed substrates, whose remarkable persistence is still not fully understood. Recently, it has been observed that the formation of nanobubbles is often associated with a local high gas oversaturation at the liquid-solid interface. Tan, An and Ohl have postulated the existence of an effective potential attracting the dissolved gas to the substrate and producing a local oversaturation within 1 nm from it that can stabilize nanobubbles by preventing outgassing in the region where gas flow would be maximum. It is this effective solid-gas potential - which is not the intrinsic, mechanical interaction between solid and gas atoms - its dependence on chemical and physical characteristics of the substrate, gas and liquid, that controls the stability and the other characteristics of surface nanobubbles. Here, we perform free energy atomistic calculations to determine, for the first time, the effective solid-gas interaction that allows us to identify the molecular origin of the stability and other properties of surface nanobubbles. By combining the Tan-An-Ohl model and the present results, we provide a comprehensive theoretical framework allowing, among others, the interpretation of recent unexplained experimental results, such as the stability of surface nanobubbles in degassed liquids, the very high gas concentration in the liquid surrounding nanobubbles, and nanobubble instability in organic solvents with high gas solubility.

Confinement effects on the dynamics of a rigid particle in a nanochannel.

The transport of nanoparticles in confined geometries plays a crucial role in several technological applications ranging from nanopore sensors to filtration membranes. Here we describe a Brownian approach to simulate the motion of a rigid-body nanoparticle of an arbitrary shape under confinement. A quaternion formulation is used for the nanoparticle orientation, and the corresponding overdamped Langevin equation, completed by the proper fluctuation-dissipation relation, is derived. The hydrodynamic mobility matrix is obtained via dissipative particle dynamics simulation equipped with a new method for enforcing the no-slip boundary condition for curved moving solid-liquid interfaces. As an application, we analyzed the motion of a nanoparticle in a cylindrical channel under the action of external fields. We show that both axial effective diffusion and rotational diffusion decrease with confinement.

Wetting and recovery of nano-patterned surfaces beyond the classical picture.

Hydrophobic (nano)textured surfaces, also known as superhydrophobic surfaces, have a wide range of technological applications, including in the self-cleaning, anti-moisture, anti-icing, anti-fogging and friction/drag reduction fields, and many more. The accidental complete wetting of surface textures, which destroys superhydrophobicity, and the opposite process of recovery are two crucial processes that can prevent or enable the technological applications mentioned before. Understanding these processes is key to designing surfaces with tailored wetting and recovery properties. However, recent experiments have suggested that the currently available theories are insufficient for describing the observed phenomena. In this work we offer a dynamic picture of these processes beyond the state of the art showing that the key ingredient determining the experimental behavior is the inertia of the liquid in the wetting and dewetting processes, which is neglected in microscopic and macroscopic quasi-static theories inspired by the classical nucleation theory. The present findings are also important for other related phenomena, such as heterogeneous cavitation, where vapor/gas bubbles form at surface asperities, condensation, dynamics of the triple line, micelle formation, etc.

Pore Morphology Determines Spontaneous Liquid Extrusion from Nanopores.

In this contribution we explore by means of experiments, theory, and molecular dynamics the effect of pore morphology on the spontaneous extrusion of nonwetting liquids from nanopores. Understanding and controlling this phenomenon is central for manipulating nanoconfined liquids, e. g., in nanofluidic applications, drug delivery, and oil extraction. Qualitatively different extrusion behaviors were observed in high-pressure water intrusion-extrusion experiments on porous materials with similar nominal diameter and hydrophobicity: macroscopic capillary models and molecular dynamics simulations revealed that the very presence or absence of extrusion is connected to the internal morphology of the pores and, in particular, to the presence of small-scale roughness or pore interconnections. Additional experiments with mercury confirmed that this mechanism is generic for nonwetting liquids and is rooted in the pore topology. The present results suggest a rational way to engineer heterogeneous systems for energy and nanofluidic applications in which the extrusion behavior can be controlled via the pore morphology.

The detailed acoustic signature of a micro-confined cavitation bubble.

Numerous scenarios exist for a cavitation bubble growing in a liquid. We focus here on cavitation phenomena within water under static tension in a confined environment. Drawing inspiration from the natural materials in plants, we design a novel experimental setup where a micrometric volume of water is confined by a hydrogel-based material. We show that, submerging the sample in a hypertonic solution, the water within the cavity is placed under tension and the acoustic emission produced by the resulting bubble nucleation is precisely detected. This new experimental procedure is able to strongly reduce the acoustic reflections occurring at the hydrogel/air interface with more classical techniques. We also propose a mathematical model to characterise the pressure wave emitted in order to correctly take into account the dissipation effect induced by the visco-elastic behaviour of the confining hydrogel. Both bubble resonant frequency and damping are captured by the model and quantitatively match the values found in the experiments.

Vapor nucleation paths in lyophobic nanopores.

In recent years, technologies revolving around the use of lyophobic nanopores gained considerable attention in both fundamental and applied research. Owing to the enormous internal surface area, heterogeneous lyophobic systems (HLS), constituted by a nanoporous lyophobic material and a non-wetting liquid, are promising candidates for the efficient storage or dissipation of mechanical energy. These diverse applications both rely on the forced intrusion and extrusion of the non-wetting liquid inside the pores; the behavior of HLS for storage or dissipation depends on the hysteresis between these two processes, which, in turn, are determined by the microscopic details of the system. It is easy to understand that molecular simulations provide an unmatched tool for understanding phenomena at these scales. In this contribution we use advanced atomistic simulation techniques in order to study the nucleation of vapor bubbles inside lyophobic mesopores. The use of the string method in collective variables allows us to overcome the computational challenges associated with the activated nature of the phenomenon, rendering a detailed picture of nucleation in confinement. In particular, this rare event method efficiently searches for the most probable nucleation path(s) in otherwise intractable, high-dimensional free-energy landscapes. Results reveal the existence of several independent nucleation paths associated with different free-energy barriers. In particular, there is a family of asymmetric transition paths, in which a bubble forms at one of the walls; the other family involves the formation of axisymmetric bubbles with an annulus shape. The computed free-energy profiles reveal that the asymmetric path is significantly more probable than the symmetric one, while the exact position where the asymmetric bubble forms is less relevant for the free energetics of the process. A comparison of the atomistic results with continuum models is also presented, showing how, for simple liquids in mesoporous materials of characteristic size of ca. 4nm, the nanoscale effects reported for smaller pores have a minor role. The atomistic estimates for the nucleation free-energy barrier are in qualitative accord with those that can be obtained using a macroscopic, capillary-based nucleation theory.

Perspectives on cavitation enhanced endothelial layer permeability.

Traditional drug delivery systems, where pharmaceutical agents are conveyed to the target tissue through the blood circulation, suffer of poor therapeutic efficiency and limited selectivity largely due to the low permeability of the highly specialised biological interface represented by the endothelial layer. Examples concern cancer therapeutics or degenerative disorders where drug delivery is inhibited by the blood-brain barrier (BBB). Microbubbles injected into the bloodstream undergo volume oscillations under localised ultrasound irradiation and possibly collapse near the site of interest, with no effect on the rest of the endothelium. The resulting mechanical action induces a transient increase of the inter-cellular spaces and facilitates drug extravasation. This approach, already pursed in in vivo animal models, is extremely expensive and time-consuming. On the other hand in vitro studies using different kinds of microfluidic networks are firmly established in the pharmaceutical industry for drug delivery testing. The combination of the in vitro approach with ultrasound used to control microbubbles oscillations is expected to provide crucial information for developing cavitation enhanced drug delivery protocols and for screening the properties of the biological interface in presence of healthy or diseased tissues. Purpose of the present review is providing the state of the art in this rapidly growing field where cavitation is exploited as a viable technology to transiently modify the permeability of the biological interface. After describing current in vivo studies, particular emphasis will be placed on illustrating characteristics of micro-devices, biological functionalisation, properties of the artificial endothelium and ultrasound irradiation techniques.

A T-junction device allowing for two simultaneous orthogonal views: application to bubble formation and break-up.

A novel design for the classical microfluidic device known as T-junction is proposed with the purpose of obtaining a simultaneous measurement of the in-plane velocity components in two orthogonal planes. A crucial feature of the proposed configuration is that all three velocity components are available along the intersection of the two planes. A dedicated optical set-up is developed to convey the two simultaneous views from the orthogonal planes into the sensor of a single camera, where a compound image is formed showing on either half one of the two views. A commercial micro-particle image velocimetry system is used to measure the velocity in the two planes. Feeding the T-junction with a liquid continuous phase and a dispersed gas phase, the velocity is measured by phase averaging along the bubble formation and break-up process showing the potentialities of the new design. The accuracy analysis shows that the error is dominated by a systematic component due to the thickness of the measurement slice. The error can be reduced by applying confocal microscopy to the present system with no further modifications so as to reduce the thickness of the measurement slab thereby reducing the error. Moreover, by sweeping the planes across the region of interest, a full three-dimensional reconstruction of the velocity field can be readily obtained. Finally, the simultaneous views offer the possibility to extract the principal curvatures of the bubble meniscus thereby providing access to the Laplace pressure.