Apr 222018

The two papers I am reviewing are “Biomechanics: Cell Research and Application for the Next Decade” by Dennis Discher et al. at University of Pennsylvania and “Experimental techniques for single cell and single molecule biomechanics” by C.T. Lim et al at National University of Singapore. Both the papers have their own approach of looking at the field of biomechanics in the context of cell structure and its function but both of them highlight the various possibilities in cell biomechanics and what the future holds for the researchers to currently focus on. The first paper explores the various accomplishments that have already been made in the field and what are some other developments and challenges that we can look forward to in the coming decades. The second paper highlights the importance of research in the field of cell mechanics and how to test various mechanical properties. Lim, in detail, explains three experimental techniques, and how he has used those techniques in the lab, and also how other researches are planning to use the particular experimental technique.

Cells make each and every component of our body, and therefore, are immensely complicated. Understanding the processes that take place in the cells can considerably expand our understanding about the human body. This can further help us create diagnosis techniques, drugs or preventative methods of handling the various diseases. As pointed out in the papers, these conditions are greatly in relation to the mechanics that takes place inside the cell. This is due to the constant stresses and strains acting on these cells and it turns out that these parameters greatly affect the mechanisms taking place inside the cells. An understanding not just at the cellular level, but also molecular level is required to fully comprehend the various functionalities of the cells. To provide an example, in cells that have malaria, as the disease progresses into worse conditions, various differences in mechanical and viscoelastic properties are observed.

Just how a body has different organs, each defined to vary out various tasks, the cell also has numerous components that are responsible for the very basic tasks. The following figure shows a typical animal cell with various of it components labelled. The main components and their uses have been mentioned below.[1] The outer layers of the animal cell is called the cell membrane and it is a semi-permeable membrane that helps in holding the cell together and monitors what enters and exits the cell. At the center of the cell is the nucleus, which is the largest organelle in the cell containing the entire genetic code with hereditary information shaped in a double helix. This is the brain of the cell as it controls all the cellular activities and is even responsible for cell division. In terms of biomechanics, the nucleus is the hardest to study, since it contains heavily entangled chromosomes with very high ductility. The mechanism of cell division and the cell decisions are still not still not completely understood from biomechanics point of view. Vacuole is the fluid sac, which is relatively small in animal cell, helps in storing the food and other waste materials. Cytoplasm is the fluid contained inside the cell. It helps in keeping the cell stable and protects the cell organelles by separating them from each other. Finally, ribosome are the site for protein synthesis composed of ribosomal RNA and proteins. These are just some of the organelles contained in the cell. It can be seen from all the above listed organelles that the cell has a very complicated structure.

The beauty of the cells is that there are different types of cells that the human body is composed of, all of them specified to perform a certain assigned task. These include nervous, epithelial, cardiovascular cells and many more kinds. In some cases, we can generalise many of the properties found through the biomechanics analysis for all the cells, however, in some cases, that is not viable and the hypothesis and conclusions have to made for every particular cell differently.

Cells have molecular mechanisms for mechanotransduction, which is the process by which cells sense mechanical signals and convert them into chemical responses so that they can be comprehended by the human body. For experimental techniques we develop, a similar approach is required where we can convert the mechanical responses from the cells to electrical analogue data so that it can be read. This will be explored later in the review.

Numerous advances have already been made in the field of cell mechanics in the last 40 years. One of the essential findings confirmed that the cells are not just exposed to various forces, stresses and tensions, but that they can also actively generate their own. The very first cell that Discher discusses is the red blood cell that consists of two components – a membrane with bending and shearing properties and cytoplasm which is predominantly a Newtonian viscous fluid. In the study related to red blood cells, the models recognized that under the influence of membrane tension the lipid bilayer preserves membrane area with narrow limits. The new constitutive methods being developed in biomechanics show the power of the biomechanics analysis show the prediction of the whole cell and cell suspension behaviour and can also act like a reference for other cells. On the other hand, the white blood cells are responsible for immune surveillance and inflammation and several models have been developed for that too. The paper also discusses the importance of endothelial cells that are anywhere between 150-500m thick and are found on the inner surface of all blood vessels. Various responses are developed in these cells that respond to different properties of blood. Therefore, various vital functions have through this transition layer of cells that are necessary for life. It also allows white blood cells to travel freely through the vessels without being blocked, since it is essential for immune system of the body.

Various cardiovascular cells also show response to the fluid shear stresses and a direct and a disturbed or turbulent flow is widely recognised as being a leading cause atherosclerosis. However, these responses are different for various specialisation, for example, the endothelial cells elongate in the direction of flow but vascular smooth muscle cells elongate in the direction of fluid shear. One interesting finding was that in order to show response  to this shear flow, the cells do not have a chemical whose concentration is affected by the shear flow but they respond to shear flow themselves. They may be utilizing receptors, a feature encountered in mechanotransduction. This also suggests that various chemical pathways may also be responsive to fluid shear stress.

Another mechanical property the cells are able to show a response to is mechanical loading. This is closely related to muscle atrophy or dystrophy. An overuse of the muscle leads to osteoporosis but too much bed rest or weightlessness of space leads to atrophy. It was found that a strain of atleast 1000 microstrain for a few times a day is absolutely necessary to create that mechanical loading and prevent atrophy or dystrophy. These parameters also seem to be lined to biomechanical factors, soluble mediators and genetic programming. These musculoskeletal cells shows a high stimulus to their biomechanical environment.

For future research, the author mentions the presence of MRI, ultrasound and other methods can be used not just to view what is happening but also to determine the rate dependent viscoelastic properties in the whole tissue without damaging it. Various methods have been developed that already do measure mechanical strain and strain rates for localized cytoplasmic regions. Cell mechanics has application to all human diseases and therefore, its inclusion into health related research efforts is expected to rapidly emerge in the near future. BY doing this, we will also be able to improve health by creative new effective drugs and inexpensive replacement tissues.

In the second paper by Lim et al. the author discusses the various present experimental techniques to learn about the cells at cellular and molecular levels. Lim suggests a chart where depending on the type, size and mechanical properties of the biological structure and the biomechanical and biophysical properties, the user can decide which experimental technique to use. He suggests three of those in the paper being reviewed.

The first is the optical trap method where laser light is made to shine on a dielectric particle whose refractive index is higher than the medium. This causes a small pressure difference which makes the particle move towards the focal point. This motion is caused by a net force which is measured and studied. Using this experiment, various mechanical properties can be extracted. In one of the study, they found that when the red blood cells are invaded by the malaria pathogens, there is significant reduction in the deformability of the red cells and this can lead to blockage of microvasculature and anemia. It is also found RBCs in this process become more rigid, however, an theoretical explanation of this is not discovered yet. The advantage of using this technique is that there is no physical contact with the sample. Also, using this technique, we can sense forces upto sub pN, which as the author notifies, is hard to achieve using other techniques.

The second experimental technique discussed is called the micropipette aspiration (MA), which also tried to find the mechanical properties of a single cell. Using a very small pipette with diameter ranging from 1µm to 10µm is made in contact with the cell. A suction is created and the distortion of the cell when it is going inside the pipette is recorded and analysed. Through the analysis, various mechanical properties can be found. This method is used to measure the membrane elasticity of many times of cells including red blood cells and leukocytes. It can also be used to determine the lipid or protein distribution under stress. An experiment was carried out using the malaria affected cells again to measure their deformability. Again it was found that the deformation ability of RBCs decreases as the parasite in RBC matures. This is explained due to the multiplication of the parasite inside the red blood cells. The apparent bulk modulus of these cells was found to be 50. One of the disadvantages of using this method is that there is a stress concentration at the pipette edge and friction between the pipette surface and cell membrane.

Finally, the last technique describes is atomic force microscopy (AFM). AFM is a powerful imaging tool and a force sensor with piconewton resolution. A very small sharp tip is mounted at the end of a flexible cantilever which directly senses a sample surface. These all can be controlled using computer-controlled piezoelectric stage or cantilever holder. A sensitive photodiode is then used to capture the change in the movement and direction of the reflected laser beam. AFM can even image samples in the fluid and this allows the imagine of biological materials in their native and physiological environment.

From the above analysis of the two papers, we have observed that the scope of biomechanics does not stop after looking at tissue level, it can definitely be expanded to the cellular level and has been done already. For me, the most exciting part was to learn about the micropipette aspiration technique and how simple its mechanism is. Yet, the analysis of the data from the machine requires a rigorous analysis.

Another learning moment while reading these papers for me was how complicated simple cell structures can be. I found it extremely interesting how cells can sense mechanical loading and fluid shears. This has helped me appreciate the complexity involved in tiny little cells of which we are composed of.

[1] “Cell Structure.” Cell Structure | Cell Structure and Function | Biology@TutorVista.com, biology.tutorvista.com/cell/cell-structure.html.

Pranav Mohan

Change and progress are two words that define my character and my ultimate goals. I have a vision to bring a global change by targeting the psychology, because that is the easiest to change. My aim is to incur a self-progressive routine for myself and then help the people around me to progress themselves. In my perspective, walking towards a defined target should be everyone’s goal while keeping in mind that things don’t go as planned but still the target should remain unchanged.

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