Cell biomechanics

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Cell biomechanics a branch of biomechanics that involves single molecules, molecular interactions, or cells as the system of interest. Cells generate and maintain mechanical forces within their environment as a part of their physiology. Cell biomechanics deals with how mRNA, protein production, and gene expression is affected by said environment and with mechanical properties of isolated molecules or interaction of proteins that make up molecular motors. [1]

Contents

It is known that minor alterations in mechanical properties of cells can be an indicator of an infected cell. By studying these mechanical properties, greater insight will be gained in regards to disease. Thus, the goal of understanding cell biomechanics is to combine theoretical, experimental, and computational approaches to construct a realistic description of cell mechanical behaviors to provide new insights on the role of mechanics in disease. [2]

History

On Growth and Form by D'Arcy Wentworth Thompson On Growth and Form 1st Edition 1917 title page.jpg
On Growth and Form by D'Arcy Wentworth Thompson

In the late seventeenth century, English polymath Robert Hooke and Dutch scientist Antonie van Leeuwenhoek looked into ciliate Vorticella with extreme fluid and cellular motion using a simple optical microscope. In 1702 on Christmas day, van Leeuwenhoek described his observations, “In structure these little animals were fashioned like a bell, and at the round opening they made such a stir, that the particles in the water thereabout were set in motion thereby…which sight I found mightily diverting” in a letter. [3] Prior to this, Brownian motion of particles and organelles within living cells had been discovered as well as theories to measure viscosity. However, there were not enough accessible technical tools to perform these accurate experiments at the time. Thus, mechanical properties within cells were only supported qualitatively by observation.

With these new discoveries, the role of mechanical forces within biology was not always naturally accepted. In 1850, English physician William Benjamin Carpenter wrote “many of the actions taking place in the living body are conformable to the laws of mechanics, has been hastily assumed as justifying the conclusion that all its actions are mechanical." [4] Similarly, in 1917, Scottish mathematical biologist D'Arcy Wentworth Thompson noted “…though they resemble known physical phenomena, their nature is still the subject of much dubiety and discussion, and neither the forms produced nor the forces at work can yet be satisfactorily and simply explained” in his book On Growth and Form. [5]

In the nineteenth century industrialization era, the overall understanding of the cell and tissue mechanics finally developed as it related to the mechanical, structural testing and theory (indentation, beam bending, the Hertz model) of engines, boats, and bridges. [3] At the end of the nineteenth century, the mechanical properties of living cells were able to be experimentally analyzed and examined using techniques provided by large scale engineering mechanics. Since 2008, the nanoscale testing and modeling remains to be fundamentally based on these nineteenth century practices. [3]

Research methods

Various studies have been conducted to establish relationships between the structure, mechanical responses, and function of biological tissues (blood vessels, heart, cardiac muscle, lung). [6] To conduct this research, there have been several developed tools and techniques which are sensitive to detect such small forces. At this time, these techniques are only applicable in a controlled environment (test tube, petri dish). All of these methods ultimately give insight on mechanical properties of cells. [7]

These techniques can generally be split up into two sections: active methods and passive methods. Active methods are methods that apply forces onto cells in some manner to deform the cell. Passive methods are methods that sense mechanical forces and do not apply any external forces to the cell. [7]

Active methods

Atomic force microscopy diagram Atomic Force Microscopy diagram.jpg
Atomic force microscopy diagram

Atomic force microscopy

Atomic force microscopy is an interaction between a tip attached to a flexible cantilever and the molecule on a cell surface. The sharp tip can be used to probe single molecular events and image live cells. [8] The relative deformation of the cell and the tip can be used to estimate how much force was applied and how stiff the cell is. Since it is a high force measurement technique, large scale deformations and reorganizations can be observed and mapped. [9]

Some drawbacks of this technique include but are not limited to an overestimation of force-versus-indentation curve given no applied force, potential cell damage, variety of tip shapes that determine nature of force-deformation curve. [7]

Magnetic tweezers and magnetic twisting cytometry

Magnetic twisting cytometry is mainly used to determine physical properties of biological tissues. They can also be used for micromanipulating cells. [10]

Beads are exposed to magnetizing coils leading to a magnetic dipole moment. A weaker directional magnetic field is then applied to twist the beads through a specific angle or to move the beads lineary. Some disadvantages to this system include the difficulty to control the region of the cell that the beads, no guarantee of complete binding to the cell surface, and loss of magnetization with time. [7]

A variation of this technique is named optical tweezers where linear forces are applied to cells rather than magnetic ones. A laser beam is used alongside dielectric beads of high refractive indices to generate optical forces. Drawbacks of this method include potential photo-induced damage and a limited amount of force that can be generated. [7]

Micropipette aspiration

Dual Micropipette Aspiration Technique

Micropipette aspiration is primarily used for measuring absolute values of mechanical properties. On a cellular scale, it can map in space and time surface tension of interfaces within a tissue. On a tissue scale, it can measure mechanical properties such as viscoelasticity and tissue surface tension. [11] Like AFM, it is also a high force measurement technique, where large scale deformations and reorganizations can be observed and mapped. [9]

A micropipette gets placed on the surface of the cell and gently suctions the cell to deform it. The geometry of the deformation along with the applied pressure allows researchers to calculate the force applied along with mechanical properties of the cell. A dual micropipette assay can is also able to quantify the strength of cadherin-dependent cell-cell adhesion. [7]

Stretching devices

Stretching devices were developed to study effects of tensile stress on cells and tissues. [12] Cells are incubated on flexible silicone sheet elastic membranes with modifiable surfaces. They are then stretched either in an uniaxial, biaxial, or pressure-controlled manner. The stretching can also occur at different frequencies. The main downside to stretching devices is that they leave behind wrinkling patterns, distorting the actual forces that were applied on the sheets. [7] They are also large in size and generate both heat and shock, hindering the real-time imaging of cells. [12]

Carbon fiber-based systems

Carbon fibers are mounted in glass capillaries and attached to a position-control device with feedback control mechanism. The fibers then attach to cells and apply and record the active forces generated from the cell. This, however, may result in damage to the cells due to the attachment they have to the fibers, focus issues, and potential bias. [7]

Passive methods

Elastic substratum method

This method stems from the classical theory of small-strain, plane-stress elasticity. The elastic substratum method allows for analysis of the displacement field of the elastic substrate over the traction field. [13]

Cells are incubated onto a flexible silicone sheet substrate. The cells then apply force onto the sheets causing a wrinkling pattern and is analyzed through the number of wrinkles and patterns. The downside to this method is the difficulty in transforming the patterns into a traction force map leading to potential inaccuracy in identifying forces. [7]

Flexible sheets with embedded beads

Latex or fluorescently tagged beads are embedded into elastic substratum where the position of the beads are recorded over time. Cellular forces can be assumed by these displacements. The uncertainty with this method is the interdependence of bead displacement. [7]

A more improved technique named flexible sheets with micropatterned dots or grids considers this drawback and instead has the dots imprinted onto the flexible sheet. The deformation of the grid from the original grid is then analyzed. The same assumptions, however, are required to be made where the forces originate from the measured location and do not spread from another area. [7]

Micromachined cantilever beam

Cantilever beam (left supported) Cantilever beam (left supported) (real).svg
Cantilever beam (left supported)

A horizontal cantilever beam with an attachment pad and a well is used to measure cell traction forces as cells are seeded onto substrates and crawl over the cantilevers. These cantilevers are set to measure force through cantilever deflection, stiffness, and stress gradient. [14] Unlike the prior method, the uncertainty of no propagation is not an issue. Rather the cantilever beam can only move in only one direction leading to only one axis being measured. [7]

The array of vertical microcantilevers is a technique that overcomes the limitations of the typical micromachined cantilever beam where there are two axes of directions available rather than a single horizontal beam. Although there is an improvement in scale and resolution, it is not suited for rapid- mass production and is quite costly. With delicate properties, minor damage would require reproduction of the device. [7]

Applications and usage

In the last half-century, several studies have been conducted using cell biomechanics leading to greater biological control. Majority of these newly created devices are built to either provide greater insight into the human body’s reaction to disease or attempt to eradicate the disease as a whole.

Cardiovascular cell mechanics and microcirculation

Tumor cells Tumor Cells.png
Tumor cells

Quantitative passive biomechanical models have been developed to predict cell motion and deformation in the mammalian red blood cell, a cell with a membrane with bending and shearing properties that are dependent upon strain, strain rate, and strain history, and a cytoplasm that in the normal red cell is predominantly a Newtonian viscous fluid, within a living organism. [15] Newly developed (2007) models constitutive to this one show that biomechanical analysis not only is a starting point for prediction of the whole cell and cell suspension behavior, but also provides a reference point for molecular models of cell membranes that originate from the crystal structure of its parts. [15]

Several generations of biomechanical models have also been developed for white blood cells, the basis of immune surveillance and inflammation. [15] These models have been proven to effectively predict cell-cell interactions in microcirculation. Similar additional models have been created for endothelium, platelets and metastatic tumor cells. [15]

Biomechanical analyses of different cell types in the circulation has brought greater understanding of cell interactions in the circulation, making it possible to predict cell behavior in narrow vessels. [15] As a result, several blood diseases like inflammation and cardiovascular disease now have biomechanical footing. Models have also been developing in organs like the lung, heart, skeletal muscle, and connective tissue that are able to predict basic aspects of organ perfusion. [15]

Cell enrichment and separation

Breast cancer cells Breast cancer cells (2).jpg
Breast cancer cells

From cell biomechanics, technology has been created to separate targeted cells. For the case of disease diagnosis and detection, said technology is able to separate healthy cells from cancerous ones through the difference in stiffness of the cell. [16]

Deformability-based enrichment devices are an example of this technology. These devices mostly deal with cancer cells from blood. Their main feature is their ability to identify if cancer cells have separated themselves from the tumor and have entered into the bloodstream as CTCs (Circulating Tumor Cells). If they have, these devices have recently also become able to count the number of CTCs in a millimeter of blood. Using this value, medical professionals are able to determine the effectiveness of a chemotherapy treatment. [17]

More specific examples include Clare Boothe Luce Assistant Professor of Mechanical Engineering at the Whiting School of Engineering Soojung Claire Hur’s microfluidic device and Woodruff School of Mechanical Engineering Professor Gonghao Wang’s microfluidic device that both deal with breast cancer cells. Hur’s device improves metastatic breast cancer cells by balancing deformability-induced and inertial lift forces that pushes larger metastatic cancer cells to move towards the centerline of a microchannel compared to blood cells. [18] Wang’s device separates stiffer less invasive breast cancer cells by having diagonal ridges where only more deformable and highly invasive breast cancer cells can squeeze through. [19]

Deformability-based enrichment devices, however, are not only exclusive to cancer cells. An example of this is Nanyang Technological University Researcher Han Wei Hou’s microfluidic device that separates and improves red blood cells from normal cells based on their stiffness through margination. [20] Infected red blood cells are generally stiffer, so through his device, stiffer red blood cells would be closer to the vessel wall when normal red blood cells would stay in the center. This allows the deformed red blood cells to be collected via a separate outlet on the sides.

Ongoing research concerns

In the 1800’s, cells were initially thought to be of homogeneous gels, sols, viscoelastic and plastic fluids. [3] Models currently have been developed into including a viscoelastic continuum, a combination of discrete mechanical elements, or a combination of viscoelastic fluid within a dense meshwork and have been proven to be highly accurate after experimentation. [3] Despite these improved and more refined models, there still remain to be flaws as several experimental proofs (soft glass rheology rheology phenomenon) that refute current existing models. [3] Thus, the time-dependent and predictive theoretical description of cell mechanics remains to be incomplete.

It is also not fully understood whether mechanical phenomena are side products of biological processes or they are controlled at the genetic and physiological level through feedback loops, actuation and response pathways given our existing knowledge of cell physiology or neurophysiology. [3]

Related Research Articles

Rheology is the study of the flow of matter, primarily in a fluid state, but also as "soft solids" or solids under conditions in which they respond with plastic flow rather than deforming elastically in response to an applied force. Rheology is a branch of physics, and it is the science that deals with the deformation and flow of materials, both solids and liquids.

<span class="mw-page-title-main">Biomechanics</span> Study of the mechanics of biological systems

Biomechanics is the study of the structure, function and motion of the mechanical aspects of biological systems, at any level from whole organisms to organs, cells and cell organelles, using the methods of mechanics. Biomechanics is a branch of biophysics.

<span class="mw-page-title-main">Tendon</span> Type of tissue that connects muscle to bone

A tendon or sinew is a tough band of dense fibrous connective tissue that connects muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tension.

Force spectroscopy is a set of techniques for the study of the interactions and the binding forces between individual molecules. These methods can be used to measure the mechanical properties of single polymer molecules or proteins, or individual chemical bonds. The name "force spectroscopy", although widely used in the scientific community, is somewhat misleading, because there is no true matter-radiation interaction.

<span class="mw-page-title-main">Atomic force microscopy</span> Type of microscopy

Atomic force microscopy (AFM) or scanning force microscopy (SFM) is a very-high-resolution type of scanning probe microscopy (SPM), with demonstrated resolution on the order of fractions of a nanometer, more than 1000 times better than the optical diffraction limit.

<span class="mw-page-title-main">Soft tissue</span> Tissue in the body that is not hardened by ossification

Soft tissue is all the tissue in the body that is not hardened by the processes of ossification or calcification such as bones and teeth. Soft tissue connects, surrounds or supports internal organs and bones, and includes muscle, tendons, ligaments, fat, fibrous tissue, lymph and blood vessels, fasciae, and synovial membranes. 

<span class="mw-page-title-main">Stiffness</span> Resistance to deformation in response to force

Stiffness is the extent to which an object resists deformation in response to an applied force.

Hemorheology, also spelled haemorheology, or blood rheology, is the study of flow properties of blood and its elements of plasma and cells. Proper tissue perfusion can occur only when blood's rheological properties are within certain levels. Alterations of these properties play significant roles in disease processes. Blood viscosity is determined by plasma viscosity, hematocrit and mechanical properties of red blood cells. Red blood cells have unique mechanical behavior, which can be discussed under the terms erythrocyte deformability and erythrocyte aggregation. Because of that, blood behaves as a non-Newtonian fluid. As such, the viscosity of blood varies with shear rate. Blood becomes less viscous at high shear rates like those experienced with increased flow such as during exercise or in peak-systole. Therefore, blood is a shear-thinning fluid. Contrarily, blood viscosity increases when shear rate goes down with increased vessel diameters or with low flow, such as downstream from an obstruction or in diastole. Blood viscosity also increases with increases in red cell aggregability.

Durotaxis is a form of cell migration in which cells are guided by rigidity gradients, which arise from differential structural properties of the extracellular matrix (ECM). Most normal cells migrate up rigidity gradients.

Electromanipulation is a micro-material analyzing method mostly used for manipulations of biological cells that uses properties of diverse electric fields. In nanotechnology, nanomaterials are so small that they can hardly be directly mechanically manipulated. Hence, electric fields are applied to them to make field-induced movements or deformations. It is a recently developed technology and is still in progress of widening applications. Types of Electronmanipulation includes dielectrophoresis, electro-rotation, electro-deformation, electro-disruption, electro-destruction, electroporation, and electro-fusion. Diverse electromanipulations are achieved using various electric fields including AC(alternating current), DC(direct current), and pulsed(deliver high-energy discharges at very short periods) electrical fields. Electromanipulation of cells permits diverse cell manipulations with minimal mechanical contact between cells and device structures. Although predominantly used in cells, elctromanipulation also contributes to other scientific fields such as Hybridoma technology and nanoelectronic devices development.

<span class="mw-page-title-main">Bio-MEMS</span>

Bio-MEMS is an abbreviation for biomedical microelectromechanical systems. Bio-MEMS have considerable overlap, and is sometimes considered synonymous, with lab-on-a-chip (LOC) and micro total analysis systems (μTAS). Bio-MEMS is typically more focused on mechanical parts and microfabrication technologies made suitable for biological applications. On the other hand, lab-on-a-chip is concerned with miniaturization and integration of laboratory processes and experiments into single chips. In this definition, lab-on-a-chip devices do not strictly have biological applications, although most do or are amenable to be adapted for biological purposes. Similarly, micro total analysis systems may not have biological applications in mind, and are usually dedicated to chemical analysis. A broad definition for bio-MEMS can be used to refer to the science and technology of operating at the microscale for biological and biomedical applications, which may or may not include any electronic or mechanical functions. The interdisciplinary nature of bio-MEMS combines material sciences, clinical sciences, medicine, surgery, electrical engineering, mechanical engineering, optical engineering, chemical engineering, and biomedical engineering. Some of its major applications include genomics, proteomics, molecular diagnostics, point-of-care diagnostics, tissue engineering, single cell analysis and implantable microdevices.

Erythrocyte deformability refers to the ability of erythrocytes to change shape under a given level of applied stress, without hemolysing (rupturing). This is an important property because erythrocytes must change their shape extensively under the influence of mechanical forces in fluid flow or while passing through microcirculation. The extent and geometry of this shape change can be affected by the mechanical properties of the erythrocytes, the magnitude of the applied forces, and the orientation of erythrocytes with the applied forces. Deformability is an intrinsic cellular property of erythrocytes determined by geometric and material properties of the cell membrane, although as with many measurable properties the ambient conditions may also be relevant factors in any given measurement. No other cells of mammalian organisms have deformability comparable with erythrocytes; furthermore, non-mammalian erythrocytes are not deformable to an extent comparable with mammalian erythrocytes. In human RBC there are structural support that aids resilience in RBC which include the cytoskeleton- actin and spectrin that are held together by ankyrin.

Mechanobiology is an emerging field of science at the interface of biology, engineering, chemistry and physics. It focuses on how physical forces and changes in the mechanical properties of cells and tissues contribute to development, cell differentiation, physiology, and disease. Mechanical forces are experienced and may be interpreted to give biological responses in cells. The movement of joints, compressive loads on the cartilage and bone during exercise, and shear pressure on the blood vessel during blood circulation are all examples of mechanical forces in human tissues. A major challenge in the field is understanding mechanotransduction—the molecular mechanisms by which cells sense and respond to mechanical signals. While medicine has typically looked for the genetic and biochemical basis of disease, advances in mechanobiology suggest that changes in cell mechanics, extracellular matrix structure, or mechanotransduction may contribute to the development of many diseases, including atherosclerosis, fibrosis, asthma, osteoporosis, heart failure, and cancer. There is also a strong mechanical basis for many generalized medical disabilities, such as lower back pain, foot and postural injury, deformity, and irritable bowel syndrome.

<span class="mw-page-title-main">Nanobiomechanics</span>

Nanobiomechanics is an emerging field in nanoscience and biomechanics that combines the powerful tools of nanomechanics to explore fundamental science of biomaterials and biomechanics.

An organ-on-a-chip (OOC) is a multi-channel 3-D microfluidic cell culture, integrated circuit (chip) that simulates the activities, mechanics and physiological response of an entire organ or an organ system. It constitutes the subject matter of significant biomedical engineering research, more precisely in bio-MEMS. The convergence of labs-on-chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context. By acting as a more sophisticated in vitro approximation of complex tissues than standard cell culture, they provide the potential as an alternative to animal models for drug development and toxin testing.

<span class="mw-page-title-main">Colloidal probe technique</span>

The colloidal probe technique is commonly used to measure interaction forces acting between colloidal particles and/or planar surfaces in air or in solution. This technique relies on the use of an atomic force microscope (AFM). However, instead of a cantilever with a sharp AFM tip, one uses the colloidal probe. The colloidal probe consists of a colloidal particle of few micrometers in diameter that is attached to an AFM cantilever. The colloidal probe technique can be used in the sphere-plane or sphere-sphere geometries. One typically achieves a force resolution between 1 and 100 pN and a distance resolution between 0.5 and 2 nm.

The Optical Stretcher is a dual-beam optical trap that is used for trapping and deforming ("stretching") micrometer-sized soft matter particles, such as biological cells in suspension. The forces used for trapping and deforming objects arise from photon momentum transfer on the surface of the objects, making the Optical Stretcher - unlike atomic force microscopy or micropipette aspiration - a tool for contact-free rheology measurements.

As humans move through their environment, they must change the stiffness of their joints in order to effectively interact with their surroundings. Stiffness is the degree to a which an object resists deformation when subjected to a known force. This idea is also referred to as impedance, however, sometimes the idea of deformation under a given load is discussed under the term "compliance" which is the opposite of stiffness . In order to effectively interact with their environment, humans must adjust the stiffness of their limbs. This is accomplished via the co-contraction of antagonistic muscle groups.

Traction force microscopy (TFM) is an experimental method for determining the tractions on the surface of a biological cell by obtaining measurements of the surrounding displacement field within an in vitro extracellular matrix (ECM).

Cell mechanics is a sub-field of biophysics that focuses on the mechanical properties and behavior of living cells and how it relates to cell function. It encompasses aspects of cell biophysics, biomechanics, soft matter physics and rheology, mechanobiology and cell biology.

References

  1. ↑ Herzog, Walter (2009), "Molecular and Cellular Biomechanics", in Binder, Marc D.; Hirokawa, Nobutaka; Windhorst, Uwe (eds.), Encyclopedia of Neuroscience, Berlin, Heidelberg: Springer, pp. 2389–2393, doi:10.1007/978-3-540-29678-2_3541, ISBN   978-3-540-29678-2 , retrieved 2022-10-27
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  3. 1 2 3 4 5 6 7 Pelling, Andrew E.; Horton, Michael A. (2008-04-01). "An historical perspective on cell mechanics". Pflügers Archiv: European Journal of Physiology. 456 (1): 3–12. doi: 10.1007/s00424-007-0405-1 . ISSN   1432-2013. PMID   18064487. S2CID   1540759.
  4. ↑ Carpenter, William Benjamin (1850-01-01). "XXXVI. On the mutual relations of the vital and physical forces". Philosophical Transactions of the Royal Society of London. 140: 727–757. doi: 10.1098/rstl.1850.0037 . S2CID   186212683.
  5. ↑ Thompson, D'Arcy Wentworth (1945). On growth and form / by D'Arcy Wentworth Thompson. Cambridge: University Press. doi:10.5962/bhl.title.6462.
  6. ↑ Dumont, Sophie; Prakash, Manu (2014-11-05). "Emergent mechanics of biological structures". Molecular Biology of the Cell. 25 (22): 3461–3465. doi:10.1091/mbc.e14-03-0784. ISSN   1059-1524. PMC   4230603 . PMID   25368421.
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  8. ↑ Trache, Andreea; Meininger, Gerald A. (February 2008). "Atomic Force Microscopy (AFM)". Current Protocols in Microbiology. 8 (1): Unit 2C.2. doi:10.1002/9780471729259.mc02c02s8. ISSN   1934-8525. PMID   18770536. S2CID   16893014.
  9. 1 2 Dahl, Kris Noel; Kalinowski, Agnieszka; Pekkan, Kerem (April 2010). "Mechanobiology and the Microcirculation: Cellular, Nuclear and Fluid Mechanics". Microcirculation. 17 (3): 179–191. doi:10.1111/j.1549-8719.2009.00016.x. PMC   2881226 . PMID   20374482.
  10. ↑ Gosse, Charlie; Croquette, Vincent (2002-06-01). "Magnetic Tweezers: Micromanipulation and Force Measurement at the Molecular Level". Biophysical Journal. 82 (6): 3314–3329. Bibcode:2002BpJ....82.3314G. doi:10.1016/S0006-3495(02)75672-5. ISSN   0006-3495. PMC   1302119 . PMID   12023254.
  11. ↑ Guevorkian, K.; Maître, J. -L. (2017-01-01), Lecuit, Thomas (ed.), "Chapter 10 - Micropipette aspiration: A unique tool for exploring cell and tissue mechanics in vivo", Methods in Cell Biology, Cell Polarity and Morphogenesis, Academic Press, 139: 187–201, doi:10.1016/bs.mcb.2016.11.012, PMID   28215336 , retrieved 2022-11-01
  12. 1 2 Kim, Jaewon; Kim, Sein; Uddin, Shahab; Lee, Sung Sik; Park, Sungsu (2022-08-02). "Microfabricated Stretching Devices for Studying the Effects of Tensile Stress on Cells and Tissues". BioChip Journal. 16 (4): 366–375. doi:10.1007/s13206-022-00073-0. ISSN   2092-7843. S2CID   251230196.
  13. ↑ Dembo, M.; Oliver, T.; Ishihara, A.; Jacobson, K. (1996-04-01). "Imaging the traction stresses exerted by locomoting cells with the elastic substratum method". Biophysical Journal. 70 (4): 2008–2022. Bibcode:1996BpJ....70.2008D. doi:10.1016/S0006-3495(96)79767-9. ISSN   0006-3495. PMC   1225170 . PMID   8785360.
  14. ↑ Baek, Chang-Wook; Kim, Yong-Kweon; Ahn, Yoomin; Kim, Yong-Hyup (2005-01-03). "Measurement of the mechanical properties of electroplated gold thin films using micromachined beam structures". Sensors and Actuators A: Physical. 117 (1): 17–27. doi:10.1016/j.sna.2003.11.041. ISSN   0924-4247.
  15. 1 2 3 4 5 6 Discher, Dennis; Dong, Cheng; Fredberg, Jeffrey J.; Guilak, Farshid; Ingber, Donald; Janmey, Paul; Kamm, Roger D.; Schmid-Schönbein, Geert W.; Weinbaum, Sheldon (2009-03-04). "Biomechanics: Cell Research and Applications for the Next Decade". Annals of Biomedical Engineering. 37 (5): 847–859. doi:10.1007/s10439-009-9661-x. ISSN   0090-6964. PMC   2895972 . PMID   19259817.
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  18. ↑ Hur, Soojung Claire; Henderson-MacLennan, Nicole K.; McCabe, Edward R. B.; Carlo, Dino Di (2011-03-07). "Deformability-based cell classification and enrichment using inertial microfluidics". Lab on a Chip. 11 (5): 912–920. doi:10.1039/C0LC00595A. ISSN   1473-0189. PMID   21271000.
  19. ↑ Wang, Gonghao; Mao, Wenbin; Byler, Rebecca; Patel, Krishna; Henegar, Caitlin; Alexeev, Alexander; Sulchek, Todd (2013-10-16). "Stiffness Dependent Separation of Cells in a Microfluidic Device". PLOS ONE. 8 (10): e75901. Bibcode:2013PLoSO...875901W. doi: 10.1371/journal.pone.0075901 . ISSN   1932-6203. PMC   3797716 . PMID   24146787.
  20. ↑ Hou, Han Wei; Bhagat, Ali Asgar S.; Chong, Alvin Guo Lin; Mao, Pan; Tan, Kevin Shyong Wei; Han, Jongyoon; Lim, Chwee Teck (2010-09-06). "Deformability based cell margination—A simple microfluidic design for malaria-infected erythrocyte separation". Lab on a Chip. 10 (19): 2605–2613. doi:10.1039/C003873C. ISSN   1473-0189. PMID   20689864.
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