The problem of intracellular delivery is not only about permeating the outer membrane but also about mixing with the inner ones; when the state matters and when it doesn't.

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A cartoon of the cell highlighting the crowded membranous intracellular environment from the textbook by Prof. Sackmann

Following is an excerpt from an email exchange on the topic of why measuring the thermodynamic state is important in violent hydrodynamic forcing (through processes like micro jets ) of drugs into cells and bacteria.

When we use the word “state” we mean knowing the location of the system on a scalar function S(x), which is at least known locally on (x), where x is a vector with a basis that depends on what quantities you want to follow or observe e.g. energy, volume, charge, ion concentrations. This is the equation of state. The equation of state is essential for solving both the hydrodynamic problem (streaming, jets, cavitation, collapse, shocks, etc.) and physical chemistry problem (reaction, kinetics, permeability, etc.).Every problem in mechanics that concerns us is essentially an optimization problem on entropy with conservation laws as constraints. The equation of state embodies the second law in our calculations. This is the very idea behind Hugoniots in shock theory (an example of a violent hydrodynamic process). I know some don’t prefer such generalist viewpoints, but let me give an example of how the microjet-based concern are implicit and taken care of in the state-based approach. …


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Fig.1 Figure shows previous work on the electromechanical spike propagation in monomolecular nanofilms of lipids at three different pressures in the film such that (i)>(ii)>(iii). The spike only appears at the intermediate pressure (ii) when the molecules in the films are near the phase transition. For details, please see ref (1–5)

The patent application for the design sponsored by Oxford University Innovation was published this week. The salient features of the platform that set it apart from the competition are (a) mimics axonal computation including collisions, (b) computes in-material using analog non-linear spikes that propagate in a substantially reversible manner, (c) operates at room temperature, and (d) uses biodegradable material.

Cutting edge fundamental research into the thermodynamics of signaling in neurons has led to the design of a platform that can potentially provide a fundamentally new benchmark for the energy efficiency of neuromorphic systems. The platform uses the remarkable properties of sound waves in waveguides made of lipid (fat molecules) films. …


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The main significance of this paper

This paper shows that it is much easier to rupture (cavitate) water if it contains lipids that are about to “melt”; water with lipids in a frozen or liquid state is harder to cavitate. Second; the paper shows that when a cavitation bubble expands the lipids at the surface of the bubble can condense and “freeze”.

Medical Applications of Acoustic Cavitation

Acoustic cavitation has a number of medical application. In diagnostic ultrasound imaging, when visualisation of blood flow is important then small microbubbles of gas are injected into the bloodstream (and yes it is safe to inject small microbubbles of gas) and the response of these bubbles makes the vessels light up. This is widely accepted in the imaging community. …


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A cartoon describing the study

Summary for our article published in American Chemical Society Materials & Interfaces https://pubs.acs.org/doi/pdf/10.1021/acsami.8b21398

Just like the rays of sunlight focussed through a lens can easily cause a burn, sound waves can also be concentrated deep inside the human body to produce a physical effect. The “destructive” power of acoustic waves has had remarkable success in treating many ailments that require micro-ablation or incisions, as I covered in a previous post. State of the art now allows precise control and delivery of acoustic energy into various internal organs of the human body where the energy can be focussed to form controlled lesions on incisions. However, in comparison, the biophysics of how acoustic fields interact with biological matter at a microscopic level lags far behind. …


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In our latest publication, we show that the width of the emission spectrum of fluorescent dyes embedded in lipid membranes is related to (1) the heat capacity of the dye-membrane system and (2) the acoustic response of a lipid membrane. Thus it is shown that fluorescence emission wavelengths should be treated as a thermodynamic state variable of the system and not just the dye. The work is based on a top-down approach to thermodynamics, in particular, we drew inspiration from its application to the phenomenon of blackbody radiation, critical opalescence and specific heat of solids.

The state dependence of fluorescence is showcased by using a mixture of lipids that undergo a synergistic phase transition where the heat capacity is maximum. While 14 carbon chain phosphocholine lipids undergo a conformational transition or melting at 24 degC and 16 carbon chain phosphocholine lipids undergo a conformational transition at 41 deg C, a 50:50 mixture of them undergoes a phase transition at 32 deg C. Furthermore, if we now also add the dye Laurdan into the mix, we show that the spectrum width of the dye relates to the synergistic heat capacity of the mixture. …


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A membrane pulse represented as a propagating perturbation in a thermodynamic manifold

The article summarises our approach to the physics of action potential and addresses some of the criticism and misconception related to its application to nerves, in particular, how it addresses the dissipation and temperature dependence of action potentials.

Recently, Scientific American and Spektrum magazines highlighted our alternative perspective on how signals in neurons propagate physically. Our approach has been presented as a mechanical one as opposed to an electrical one, which I believe creates a false dichotomy that needs to be addressed. For this blog entry, I didn’t want to list the limitations of the Hodgkin and Huxley based equations, vis a vis our thermodynamic or acoustic theory and address them one by one. There are many other research articles, blogs, and forums for that including the recent articles in Scientific American. Here I want to go beyond that and touch upon, in simple language, why the Hodgkin and Huxley model is unsatisfying at a deeper, more fundamental, and philosophical level. …


The following is a list of my key papers on electromechanical waves in pure lipid monolayers, essentially a negative control for Hodgkin and Huxley based description of Action Potentials (AP) (without channel, pumps and chemical gradient). (posted previously as tweets)1/18

The observed electromechanical waves propagate as sound and not via ions and behave exactly like action potentials near a nonlinearity in the state diagram of the monolayer, e.g. due to a phase transition. 2/18

Also, some key control experiments from my colleagues related to channel and synapse activity are included that show how all these phenomena are related by the state (compressibility, heat capacity, etc.) …


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Cartoon depicts the vision of a sound-wave propagating in a neuron as an action potential.

Sound waves in lipid films can annihilate each other upon collision, just like action potentials in neurons

Nerve impulses, also known as action potentials, are believed to propagate in a manner similar to the conduction of current in an electrical cable. However, for as long as the electrical theory has been around, scientists have also been measuring various other physical signals that are equally characteristic of a nerve impulse, such as changes in the mechanical and optical properties that propagate in sync with the electrical signal. Furthermore, several studies have reported reversible temperature changes that accompany a nerve impulse, which is inconsistent with the electrical model from a thermodynamic standpoint. To address these inconsistencies, researchers had previously proposed that nerve pulse propagation results from the same fundamental principles that cause the propagation of sound in a material and not the flow of ions or current. …


The black and white image of a developing fetus, also known as Sonogram, is a familiar sight for most of us and the imagery already has an iconic status in the story of humanity. From prenatal sonograms and real-time images of various other parts of human anatomy to advanced applications in monitoring blood flow and elastography, ultrasound (US) imaging or sonography is central to our medical diagnostic capabilities. But can the same technology be used for therapeutic purposes as well?

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Ultrasound image sequence from a study of valves in a patient’s heart. Generated by Kieran Maher using OsiriX and ImageJ (https://commons.wikimedia.org/wiki/File:Valves_Of_Heart_Ultrasound.gif)

The diagnostic US has been around for clinical use since the 1950s. It uses high-frequency sound waves, inaudible to human ears, which are emitted and received by a transducer device placed topically on the skin near the region of interest. Sound waves are focused deep into the human body and the reflected sound carries information about the physical properties of the focal region. The information is then analyzed either to form a real-time image or provide advanced properties of the probed anatomic structure, such as its elasticity, which for example, can indicate the presence of fibrosis or a tumor. The technology has been shown to be completely safe and without any significant side effects. However, this depends upon very particular US settings that are used for diagnostic purposes. For example, higher intensities can ablate tissue or even brake kidney stones, which were indeed among the first therapeutic applications of ultrasound. …


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with Prof. Mishra and Chaitanya after graduation May 2008

I have heard people say, “it hasn’t sunk in yet”. I think today for the first time I know what do they mean by that. I came to know about Prof. Mishra’s demise this morning. …

About

Shamit Shrivastava

Biophysics of sound in membranes and its applications. Post Doctoral Researcher, Engineering Sciences, University of Oxford, UK www.shamits.org

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