Publication

Being able to activate and control microloads that would move within the bloodstream is a Grail of biomedical research. The current proposals are unfortunately characterized either by high technical complexity or by slow mobility, limited maneuverability and poor biocompatibility. Now, in this range of characteristic size around ten microns, an interesting candidate exists in the form of microbubbles covered with lipids, namely, already used for years as ultrasound contrast agents. Subjected to an ultrasonic’ pulse, they act as echogenic agents and allow a better visualization of vascularization, with resolutions improving from’year to year. For pulses of greater intensity,they can be destroyed and locally create stresses that open pathways between cells lining blood vessels, thereby promoting drug penetration towards their target.

In partnership with the University of Freiberg and the University of Twente, researchers and researchers from the Interdisciplinary Laboratory of Physics in Grenoble (LIPhy, CNRS /University Grenoble Alpes) studied the possibility of’activating these same microbubbles according to other acoustic modalities and demonstrated, via numerical simulations conducted in parallel with an experimental study, that, that these microbubbles can achieve a significant net displacement thanks to reproducible and non-destructive deflation and reinflation cycles. The direction of the swim can be controlled independently of the axis of propagation of the ultrasound, making these microbubbles good candidates for controlled piloting in ultrasound molecular imaging and drug delivery applications. Numerical modeling showed that well-designed microbubbles could swim at speeds of the order of m/s’ (an extraordinary order of magnitude given the size of these bubbles),thus allowing effective movements within the blood circulation. These results are published in the journal Engineering Communications.

References

Coated microbubbles swim via shell buckling, Georges Chabouh, Marcel Mokbel, Benjamin van Elburg, Michel Versluis, Tim Segers, Sebastian Aland, Catherine Quilliet, Gwennou Coupier, Communications Engineering, publié le 7 septembre 2023. Doi : 10.1038/s44172-023-00113-z

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For such big and fast objects, inertia combines with symmetry breaking (wing shape profile or ball rotation) to give rise to lift. However, lift forces are also at play at low Reynolds numbers, i.e. for small objects or slow flows where fluid viscosity dominates over inertia. Such forces stem from the key role played by the flow boundaries and the deformability of the objects involved: velocity gradients, elastic deformations or transport in boundary layers can lead to the emergence of lift forces. These are crucial in many soft matter and biophysics problems such as flows of suspensions, particle sorting, joint lubrication or blood circulation. In this article, we review three important mechanisms that give rise to lift and have initially been studied by separate research communities: (i) soft lubrication occurring when an object flows in the close vicinity of a deformable wall, (ii) elastohydrodynamic effects taking place when a deformable object is placed in a flow gradient, and (iii) electrokinetic lift arising from the transport of ions at the surface of an electrically charged object. We describe the main ingredients at the origin of such lift forces, discuss their respective magnitude and relevance, and point to other possible yet unexplored means of generating lift forces at zero Reynolds.

This review has been published in E. P. J. E. (https://link.springer.com/article/10.1140/epje/s10189-023-00369-5)

• Read more about Review : lift at low Reynolds number

Indeed, its geometry resembles that of the Tokamak used to magnetically confine hot plasmas for nuclear fusion experiments. 
When this bubble tokamak is excited by sound, the bubbles oscillate strongly. A first collective resonance of the 24 ring bubbles occurs, at around 500 Hz, twice as low as the resonance frequency of a single bubble, as the bubbles interact collectively in phase. At higher frequencies, other modes appear where the bubbles are not in phase.
An original feature of the acoustic field within the resonant Tokamak is its homogeneity, whereas acoustic fields usually vary greatly when moving close to a source, making it a unique acoustic object.

References:

Acoustic Tokamak with strongly coupled toroidal bubbles, A. Caumont, O. Stephan, E. Bossy, B. Dollet, C. Quilliet, and P. Marmottant, Physical Review E 108,  045105

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Easy to collect and store, blood is the subject of numerous in vitro studies. Being made up of a large quantity of deformable cells, mainly red blood cells, it is characterized by a complex mechanical behavior, which impacts its various functions such as the supply of nutrients and oxygen to the organs, the elimination of waste, the regulation of body temperature and active immune surveillance. In France, several research teams have focused on the behavior of blood in the microcirculation, where red blood cells pass through vessels that are barely larger than themselves. But before being used in in vitro experiments, red blood cells are stored and manipulated under conditions that can impact their mechanical properties. However, there is no universal protocol and each research team follows its own empirical methods. Seven laboratories of the Mechanics of Materials and Biological Fluids Research Group  (GDR MÉCABIO¹) gathered their researchers around a table to share, compare and test their protocols.

The scientists were thus able to issue new recommendations to minimize the impact of blood storage and preparation conditions on the individual or collective movement of red blood cells under a wide range of flow conditions. Their response must be as close as possible to that expected in a physiological situation. This first step towards a standardization of practices should facilitate the comparison of the mechanical properties of red blood cells between different research teams. This will be of particular benefit to studies on diseases where the mechanical properties of blood are at stake, such as sickle cell disease. These results were published in the Biophysical Journal.

References:

Influence of storage and buffer composition on the mechanical behavior of flowing red blood cells. Adlan Merlo, Sylvain Losserand, François Yaya, Philippe Connes, Magalie Faivre, Sylvie Lorthois, Christophe Minetti, Elie Nader, Thomas Podgorski, Celine Renoux, Gwennou Coupier, and Emilie Franceschini.
Biophysical Journal, Volume 122, Issue 2, 17 January 2023.
https://doi.org/10.1016/j.bpj.2022.12.005

• Read more about Influence of storage and buffer composition on the mechanical behavior of flowing red blood cells

The development of fiber optic endoscopes is motivated by certain biomedical applications such as brain imaging. Multimode fibers, whose size is typically comparable to that of a human hair, are excellent candidates for minimizing the invasiveness of these procedures. However, the propagation of light in multimode fibers is very complex. Indeed, in this type of fiber, the light propagates in an unpredictable way, producing patterns that are difficult to interpret at the fiber outlet. Techniques currently exist to reconstruct images from such patterns, but these techniques are very sensitive to the deformations applied to the fiber, which strongly limits the possibilities of applications in biology.

In this study, LIPhy scientists demonstrate that it is possible to produce intelligible images with multimode fibers even when these are deformed. For this, they were inspired by the kaleidoscope of Sir David Brewster, and swapped the usual fibers, which have a circular heart, for fibers with a square heart. Indeed, the symmetry properties of these fibers generate a remarkable kaleidoscopic effect, which transports information in a robust way to deformations. They tested this method by reconstructing images of fluorescent micro-sources through the fiber, even as it was randomly distorted, thus reproducing the dynamic aspect of the disturbances that typically occur when studying living organisms. They thus demonstrated that, despite these disturbances, it is possible to reconstruct faithful images of these micro-sources through the fiber. This new technique thus promises to be promising for the development of miniature endoscopes for biomedical imaging.

References :

Speckle-correlation imaging through a kaleidoscopic multimode fiber
Dorian Bouchet, Antonio Miguel Caravaca-Aguirre, Guillaume Godefroy, Philippe Moreau, Irène Wang, Emmanuel Bossy. PNAS - Juin 2023. DOI

• Read more about Speckle correlation imaging through kaleidoscopic multimode fiber

It generates thanks to the sudden activation of voltage-gated sodium channels that mediate a sub-millisecond sodium current responsible for the rising phase of the spike. Using a combination of ultrafast imaging techniques and a novel peptide selective for the sodium channel subtype Nav1.2, a LIPhy group analysed the action potential generation in the axon of cortical pyramidal neurons of the mouse [*]. They found that the sodium channel Nav1.2 also carries a calcium current that activates the BK potassium channel determining the shape of the action potential. This finding advances our knowledge of the action potential generation and it can be also important for the understanding of several neuronal disorders associated with membrane excitability.

Reference :

[*] Filipis L, Blömer LA, Montnach J, Loussouarn G, De Waard M, Canepari M. Nav1.2 and BK channel interaction shapes the action potential in the axon initial segment. J Physiol. 2023 Mar 22. doi: 10.1113/JP283801.

• Read more about Ionic currents underlying the generation of the action potential

In vivo, cells apply forces on their environment in order to move, divide or modify this environment, but also to communicate and coordinate with their neighbors at long distance. In standard approaches, the exploration of these mechanisms is done through external mechanical actuations that aim to mimic these mechanical signals. However, it remains difficult to assess how these external stimuli compare to the contractions that cells exert spontaneously. Biochemical treatments can modulate the cellular processes responsible for these signals, but their inability to target spatially defined areas of tissue and their low temporal resolution severely limit their potential. In this paper, a new approach is proposed to elucidate how cellular forces are generated, propagated and detected in physiological and pathological tissues.

Biophysicists from the Laboratoire Interdisciplinaire de Physique de Grenoble (CNRS - Univ. Grenoble Alpes) have sought to probe the mechanical properties of biological tissues "from the inside", as cells naturally do. To do this, they combined tissue engineering and optogenetics. Tissue engineering allowed them to generate three-dimensional microtissues, composed of fibroblasts encapsulated in collagen, suspended between two micropillars whose deflection allows to follow the tissue tension in real time. The optogenetic approach consists in genetically modifying fibroblasts in order to control the activity of a major regulator of their contractility by light. Thanks to the spatial and temporal resolution of the light stimulations, they induced local contractions in these microtissues, while measuring the resulting deformations. They thus quantified the viscoelastic properties of these microtissues, from the "point of view" of the cells, and demonstrated the potential of this approach to quantify the impact of collagen or fibrosis initiation on tissue elasticity. The ability to illuminate only a portion of the tissue allowed them to map local anisotropies in heterogeneous microtissues and influence the formation of these tissues. These results pave the way for spatio-temporal control of tissue formation while non-destructively mapping their rheology in real time, using their own constituent cells as internal actuators.

References:

Méry A, Ruppel A, Revilloud J, Balland M, Cappello G & Boudou T. Light-driven biological actuators to probe the rheology of 3D microtissues. Nat. Commun.14, 717 (2023). doi:10.1038/s41467-023-36371-w

• Read more about Probe the mechanics of biological tissues using their own cells as actuators

The proper circulation of red blood cells (RBCs in the following) in the body is an essential issue for the proper functioning of the human body, because in addition to their well-known function as vehicles for respiratory oxygen, they also transport numerous metabolites such as ATP, which are ultimately delivered to the organs via the terminal network of very small blood vessels (capillaries), whose diameter is barely larger than the size of the blood cells themselves.

The law of RBC transport in these microvessels remained poorly understood for decades. The classical picture that prevailed until today assumed that in each branch of the vascular network the blood flow did not depend on its previous path in the upstream blood vessels: thermal fluctuations, local flow disorders were assumed to make the trajectories random and the blood cells to choose at the intersections their direction at random.

In a study carried out at the Laboratoire Interdisciplinaire de Physique (LiPhy, CNRS / Université Grenoble Alpes), in collaboration with the Institut de Mécanique des Fluides de Toulouse (IMFT, CNRS / Toulouse INP / Université Toulouse - Paul Sabatier), and the Laboratoire ondes et Matière d'Aquitaine (LOMA, CNRS / Université de Bordeaux), researchers have proposed a model that clarifies, and even partially questions, this dogma. Indeed, when the flow concerns blood capillaries, they show that turbulence is no longer effective in making the transport of individual rigid particles chaotic, which are then advected by the flow in a very predictive manner, along the flow lines. When a particle comes to a crossroads, carried by the part of the flow that is destined to "turn left" for example, it will unsurprisingly do the same if its shape is sufficiently circular or spherical. The researchers note, however, that a sufficiently elongated and asymmetrical rigid shape is likely to give the particles a spirit of contradiction at each crossroads and make them take a different direction from that of the flow in which they are mostly immersed! This said, this opposition is systematic and in fact induces a much more predictable and therefore potentially dangerous trajectory if it is a question of carrying nutrients in a homogeneous manner in a network of capillaries. The lesser selectivity in the distribution of RBCs in the flow may in fact result downstream in inhomogeneities of distribution and induce biological stress in organs insufficiently supplied with RBCs.

To avoid this selectivity, which is essentially induced by the very small diameter of the capillaries (and probably also to avoid vascular occlusions linked to the dangerously comparable diameters of the capillaries and RBCs), the researchers show that evolutionary processes have produced an extremely clever response, by endowing the RBCs with a flexibility that forces them to deform when they arrive at intersections where the shear changes significantly. This deformation locally retroacts on the flow and induces a temporary chaoticity which finally makes the GR's choice of direction at the exit of the bifurcation random. From a more global point of view, the lateral exploration of the arteriolar network then becomes diffusive and ensures a statistically homogeneous visit of the network by an assembly of GRs distributed upstream in an identical way. In a complementary way, the researchers also show that when the concentration of RBCs is sufficiently high, interactions between RBCs induce enough dynamic perturbations at bifurcations to also generate normal diffusion, even in the presence of stiffer globules.

The scope of this work is not limited to RBCs, but is valid for any deformable particle, such as drops, capsules, and cells with nuclei (such as those of the immune system or cancer cells). This study could therefore help to better understand the transport properties of a wide range of systems, and guide, for example, the design of microfluidic circuits for lab-on-a-chip biotechnologies for cell diagnostics and sorting. These results are published in the journal Physical Review Letters.

(Reprinted from INP CNRS news of 6 February 2023)

• Read more about Red blood cells bend for our health!

To expand and simplify the story let’s use a metaphor. A cell looks like a factory where the proteins represent the laborious working-class. They transform energy and compounds, they provide mechanical force for motility, and stability; they decode the genetic information. When we increase slightly the temperature the efficiency of their activity increases. It is like a boost of energy. They have more “strength” and “energy” to accomplish the task. From the physical point of view, this is explained by what is known as Boltzmann factor. Temperature also influences another and subtle aspect, it increases the transport of matters inside the cell. However, when a critical temperature is reached, proteins get destabilised. The efficiency of the work is compromised. Back to the original question: at the critical temperature (known as cell death temperature) all the working class stops producing or just a bunch of workers, that control key positions in the productive chain, stop their activity?
We have recently looked at the issue (read the manuscript open access here: https://pubs.acs.org/doi/10.1021/acscentsci.2c01078), and found support to the idea that just a little amount of proteins actually unfolds and stops to be operative at the cell death temperature. In parallel, by melting the proteins alter the dynamical properties of the surrounding environment. The local viscosity dramatically increases. In some sense, according to our initial metaphor, it is like that by unfolding they slow down all the assembly-lines inside the factory. The molecular reason of this effect is not surprising at all. When a protein unfolds it becomes a floppy and long spaghetti that tends to glue the surrounding macromolecules and the environment starts looking like a gel. In short, not necessarily the few proteins that unfold must act as pivotal enzymes in critical metabolic patterns. Their unfolding might be enough for suppressing some metabolic reactions that are controlled by the local diffusivity. The question is open…..

More Info

Temperature and death cell : a story of viscosity (CNRS)

• Read more about Cell death and proteome dynamics

We evidenced the origin of this intermittent dynamics, by creating a biomimetic leaf containing the basic elements of real leaves. Crucially, vein networks contain pits, which are nanometric constrictions between sap-conducting cells; we mimicked such pits by inserting constrictions between larger microfluidic channels, embedded within a flexible and permeable material, like the leaves.

We have recovered an intermittent drying dynamics, characterised by an arrest of the embolism inside the constriction, followed by a fast jump at the constriction exit. We have shown that two phenomena drive this dynamics: the pinning of an air/liquid interface on the corners of the constriction, and the channel compliance under the decrease of water pressure during the pinning phase. Therefore, in plants, pits act as capillary traps for embolisms... but only for a limited amount of time.

Reference
Keiser, L., Marmottant, P., & Dollet, B. (2022). Intermittent air invasion in pervaporating compliant microchannels. Journal of Fluid Mechanics, 948, A52.

• Read more about The physical origin of the intermittent drying of leaves