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Journal Club Theme of March 2011: Mechanics at Nano-Bio Interfaces

Sulin Zhang's picture

Continuum mechanics have been widely exploited to the interpretation and understanding of mechanical responses  of materials of various kinds, manifested by the commercialization of finite element codes on the basis of continuum  theories.  Nanomechanics emerged in parallel with the carbon nanotube technology, though many of us simply adopted  continuum theories, especially in the early years of nanotechnology, to solve carbon nanotube mechanics problems without carefully asking for their applicability, and still claimed such research as nanomechanics.  When animate biological materials are in contact inanimate materials, the underlying mechanics becomes richer and more complex, calling for solutions from mechanicians.  To name a few examples, endocytosis of nanoparticles by living cells, cell-substrate interactions, tissue-implant interactions, etc.  However, biologists often criticize that models developed by mechanicians are often physiologically irrelevant, indicating the need of a paradigm shift in the research methodologies in addressing mechanics in biology.

By no means an expert in the field, I would like to initiate possible discussions among mechanicians by providing some general observations and asking several questions below. One may ask millions of such questions and often without a conclusive answer. As such, no comments should be considered to be shallow; the major purpose is to learn via discussions and inject interests into mechanicians. I shall use biological cells as examples; the observations/questions are also applicable to tissues and organs.

•Thermodynamic equilibrium of an inanimate material can be described by the stress states. For a human being, the body temperature may be considered as one of the characteristic state variables. We take off our clothes in a warm condition, and put on our clothes in cold weather.  Cells would make similar actions/decisions to comfort themselves:cells undergo constant internal remodeling when adhering to the excellular matrix. If there exists a thermodynamic equilibrium for the cell, what are the characteristics of the thermodynamic equilibrium state?

• Differentiated biological tissues consist of a variety of cells of distinctive morphology, wherein the cells shapes are often reproduced with astonishing accuracy between individuals and across species. How cells communicate to produce multi-cellular structures and tissues? How could newly differentiated cells find their way to the right spots in would healing processes?


•The famous paper by Dennis Discher “Matrix elasticity directs stem cell lineage specification” makes it clear that cellular responses are not only related to the genetic structures, but also regulated by the mechanical environments. What are the underlying regulatory mechanisms?

•Adherent cells actively probe mechanical cues of their environments as they anchor and pull on the extra-cellular matrix. Micro/nano-fabricated substrates have been used to determine the cell forces, ranging from flexible membranes to micro-pillar arrays.  For the former, the displacement field can be easily determined by imaging, but the deformation (membrane folding) may be permanent, complicating the subsequent measurements. To obtain the cell forces, an inverse problem needs to be solved, which could be very involved. For the latter, measuring pillar deflections are not trivial,  often involving the use of fluorescent dyes.  These techniques are contributed by biologists, not mechanicians. Can our mechanicains design a better device to measure cell forces?

•A living cell is essentially a multiscale material in which substances of different kinds (ions, molecules, proteins, etc.), of different materials forms (monomers, filaments, membranes, etc.), and of different states (gel, fluid, and solid) work in concert to complete complex tasks. How does a cell organize itself from such a seemingly unorganizable chaos?

•What is the minimal yet physiologically relevant model for a living cell?

References:

Lo, C.M., H.B. Wang, M. Dembo, and Y.L. Wang, Cell movement is guided by the rigidity of the substrate. Biophysical Journal, 2000. 79: p. 144-152.

Engler, A.J., S. Sen, H.L. Sweeney, and D.E. Discher, Matrix elasticity directs stem cell lineage specification. Cell, 2006. 126(4): p. 677-689.

Tan, J.L., J. Tien, D.M. Pirone, D.S. Gray, K. Bhadriraju, and C.S. Chen, Cells lying on a bed of microneedles: An approach to isolate mechanical force. Proceedings of the National Academy of Sciences of the United States of America, 2003. 100(4): p. 1484-1489.

Deshpande, V.S., R.M. McMeeking, and A.G. Evans, A bio-chemo-mechanical model for cell contractility. Proceedings of the National Academy of Sciences of the United States of America, 2006. 103(38): p. 14015-14020.

S. Zhang, J. Li, G. Lykotrafitis, G. Bao, and S. Suresh. Size-dependent endocytosis of nanoparticles. Advanced Materials, 21, 419-424(2009); H. Y. Yuan, J. Li, G. Bao, and S. Zhang. Variable nanoparticle-cell adhesion strength regulates cellular uptake. Physical Review Letters, 105, 138101 (2010)

Gao, H., W. Shi, and L.B. Freund, Mechanics of receptor-mediated endocytosis. Proceedings Of The National Academy Of Sciences Of The United States Of America, 2005. 102(27): p. 9469-9474; Bao, G. and X.R. Bao, Shedding light on the dynamics of endocytosis and viral budding. Proceedings of the National Academy of Sciences of the United States of America, 2005. 102(29): p. 9997-9998.

Suresh, S., Biomechanics and biophysics of cancer cells. Acta Biomaterialia, 2007. 3(4): p. 413-438.

Comments

Sulin,

 

Thanks for the note and the great thoughts on all of this. These are a wide diversity of subjects and I will not try to comment on all of them. One of them that we have been investigating more recently is using our tools in the mechanics areas and applying these to all kinds of "systems". While we do mammalian cells like many other groups, we have actually started looking at the beauty of nature and how these systems have evolved over millions of years to specific functions. We look at this with multicellular systems such as in Xenopus, but we have become very interested in microorganisms, which have specific functional behaviors. For example, we work with magnetic bacteria, geobacter (energy generating micro-organisms), microorganisms toward carbon sequestration, etc. One great recent example was the oil eating microbes that helped the Gulf Spill in a huge way...nature already had a solution! Each one of these microorganisms has fantastic abilities and we can learn about them using skills as mechanical engineers. This for us includes areas such as solid mechanics, control theory, thermodynamics, fluid mechanics, design, etc. In any case, hope this is helpful to people as I think that these are great future directions!

 

 

Sulin Zhang's picture

Phil,

Great comments. You are one of a few researchers who really have strong backgrounds in both mechanics and biology. So your comments are reprentative and very valuable, and I fully agree with your comments. There has never been more opportunities than now to mechanicians: while we are still revolutionizing mechanics as an important discipline by building new tools, interfacing mechanics with other disciplines particularly biology will lead to new momentum in the development of Mechanics as a discipline, while at the same time provide new perspectives in interpreting the fundamental physics in biology. 

I assume that mechanicians who start to work in biology related problems would have a general question to ask: how should we find interesting problems to solve? For instance, for your case, you are working on magnetic bacteria. What made you believe this topic has special potential?  What did lead you to this topic? If you could share with us the way you choose your topic, that would be terrific. 

By googling the term "geobacter", I found the following literature. It may help others follow up.

  1. ^ Lovley DR, Stolz JF, Nord GL, Phillips, EJP (1987). "Anaerobic Production of Magnetite by a Dissimilatory Iron-Reducing Microorganism". Nature 350: 252. 
  2. ^ Reguera G, McCarthy KD, Mehta T, Nicoll JS, Tuominen MT, Lovley DR (2005). "Extracellular electron transfer via microbial nanowires". Nature 435 (7045): 1098–101. 
  3. ^ Heider J and Rabus R (2008). "Genomic Insights in the Anaerobic Biodegradation of Organic Pollutants". Microbial Biodegradation: Genomics and Molecular Biology. Caister Academic Press. ISBN 978-1-904455-17-2. http://www.horizonpress.com/biod. 
  4. ^ Diaz E (editor). (2008). Microbial Biodegradation: Genomics and Molecular Biology (1st ed.). Caister Academic Press. ISBN 978-1-904455-17-2. http://www.horizonpress.com/biod.

Sulin

You raised a few very fundamental questions. They are mostly of biological
nature, and mechanics may or may not have a significant role to play. Thus as
mechanicians we need to approach such questions accordingly, i.e., not begin
the exploration with the notion that mechanics can alone explain the
observations. I learnt this lesson in a hard way.  Regarding your questions, I have some
comments (or opinions): 

Sulin: •Thermodynamic equilibrium: If there exists a thermodynamic
equilibrium for the cell, what are the characteristics of the thermodynamic
equilibrium state?

Taher: Cells are constantly at a state of evolution (dividing, migrating,
committing suicide, differentiating, influencing neighbors, …) both in vivo or
in-vitro. So, there might not be a thermodynamic equilibrium state for cells. In
between cell transitions (e.g., between divisions) there might be a
quasi-equilibrium state, but it might be a risky assumption without a deeper
understanding of the irreversible ongoing changes within the cell between the
transitions.     

Sulin: • Differentiated biological tissues: How cells communicate to produce
multi-cellular structures and tissues? How could newly differentiated cells
find their way to the right spots in would healing processes?

Taher: This is a central question in developmental biology. One of the
greatest developmental biologists, Santiago Ramon y Cajal, while studying the
process by which growth cones of developing nervous systems find their paths to
meet the distant muscles and other neurons, considered “what mysterious forces
precede the appearance of these processes … promote their growth and
ramification … and finally establish those protoplasmic kisses … which seem to
constitute the final ecstasy of an epic love story”. In modern biology, this
path finding is attributed to primarily chemical cues. The question is, are
there mechanical cues as well.  If so,
then mechanics must have a role to play in it.

 
Sulin: •The famous paper by Dennis Discher “Matrix elasticity directs stem cell
lineage specification”: What are the underlying regulatory mechanisms?

Sulin: •Adherent cells: Can our mechanicains design a better device to
measure cell forces?

Taher: I guess, this is happening through micro and nanotechnology.

Sulin: •A living cell is essentially a multiscale material: How does a cell
organize itself from such a seemingly unorganizable chaos?

Sulin: •What is the minimal yet physiologically relevant model for a living
cell?

Taher: We should probably ask, why do we need such a model of a single cell.
After all, it is the interaction between cells and between organs that give the
intricate complexity and diversity of the living.

 

 

Sulin Zhang's picture

Taher,

Your reply clarified a lot of my thoughts. Thanks.  I would like to further our discussions along the line.

Regarding the cell states, when a cell is placed on a substrate, it starts to pull its surroundings. In a way, cell communicates with the world via mechanical force, much like the way that a blind makes a decision in walkind direction by a stick. Note that cell pulling force (contractile force) leads to the growth of and stablilizes focal adhesions.  In turn, the growth of focal adhesions will increase the contractile forces due to the biochemical singnaling functions of focal adhesions. This seems to be a positive feedback loop. So when the loop stops? At the time that the loop stops, the cell reaches an state  that it is mostly is happy with? Why the cell wants to achieve that state (even this might be a trasient state)? Why the cell then dissociates the established states (by dissociating the established focal adhesions)?

I agree that there may not be an equilibrium state for a living cell. But thermodynamics always applies, for alive or dead systems.  From an energetics point of view, why the cell wants to migrate in certain direction in rigidity-guided metastasis? Is that because cell consumes least ATPs to gain a certain state? On the tissue level, can we consider that the constituent cells are in an average state that defines the mechanical properties of the tissue?

I would assume that the mechanical properties of the tissue is well defined even though the constituent cells undergo constant remodeling.  The mechanical properties of the tissue, to a large extent, is contributed to that of the constituent cells.  Is the average stress state of the cells in tissue is the state that an isolated cell wants to achieve? In another words, the cell state is genetically embedded into the cell? 

 

 

shangtee's picture

**Regarding the cell states, when a cell is placed on a substrate, it
starts to pull its surroundings. In a way, cell communicates with the
world via mechanical force, much like the way that a blind makes a
decision in walkind direction by a stick. Note that cell pulling force
(contractile force) leads to the growth of and stablilizes focal
adhesions.  In turn, the growth of focal adhesions will increase the
contractile forces due to the biochemical singnaling functions of focal
adhesions. This seems to be a positive feedback loop. So when the loop
stops? At the time that the loop stops, the cell reaches an state  that
it is mostly is happy with? Why the cell wants to achieve that state
(even this might be a trasient state)? Why the cell then dissociates the
established states (by dissociating the established focal adhesions)?

Sulin, one possible explanation is that cell traction forces or contractility is used to measure substrate stiffness. Let's assume that the cell durosensor is like a constant strain rheometer; ie the cell is trying to exert a constant strain on the ECM. Like you mention, the actomyosin contractility is probably autocatalytic (positive feedback). The ECM deformation can be thought of as the stop signal; when the cell exerts enough stress to deform the ECM to a certain amount, a signal is sent to stop the growth of focal adhesion, stress fibers, phosphorylation of myosin motors, etc.

This can explain why cells in vivo or cells grown on soft hydrogels do not have stress fibers or large focal adhesions whereas cells grown on glass substrates exhibit stress fibers and abnormally large focal adhesions. Grown on unphysiologically stiff substrates, the cellular durosensing mechanism goes haywire as it continuously activates its stress generating pathways to unsuccessfully try to deform its ECM.

Presumably, cells are always “measuring” the stiffness of their ECM and changing their states to achieve their in vivo functions. The dissociation of FA “resets” that particular durosensor to start another set of measurement.

Majid Minary's picture

So much of emphasize has been placed on cell mechanics. I have not come across many studies taking into account the extracellular matrix (EM) and its role on cell interaction with the substrate. Most cell deposited EM on the substrate and all the subsequent interaction involves the deposited and often assembled basal lamina. I would guess a complete understating of cell mechanics and its interaction with substrate would require an accurate model of the EM, which has been elusive.

Sulin Zhang's picture

Thanks for your comments, Majid. I have enjoyed several postoc years at Northwestern and really know the groups very well. 

There are some groups developed mechanistic models for cell-substrate interactions.  The joint work done by Vikram Deshpande, Tony Evans, and Bob McMeecking is a representative model of such kind.

From modeling point of view, the challenge is not on developing models for ECM; the challenge lies on the fact that living cells are active. How would one encapsulate the active responses to the model? Many models embed the active responses into the constitutive descriptions in a very empirical manner that may not be valid to biologists. As a result, biologists are strongly against such models by saying: you can alwasy arrive at some responses by manipulating the numbers, imposing constaints, etc. How do you know such manipulations are biologically relevant? It is very common for mechanicians receiving a comment of their manuscripts that are submitted to journals in biologist community: the work is biophysically irrelevant.

Prof. Taher Saif indicated "why we need models of this kind" if biologists do not accept it? So it is a key to promote bidirectional talks between biologists and mechanicians. 

I am maybe too pressmistic about the modeling of living cells. But if reading the literature, you will find the mechanistic understanding has been there for years. Biophysicists have put forward very simple but illustrative models to explain the cell-substrate interactions.  Keep in mind that mechanics models developed by our mechanicians generally aim at mechanistic understanding of the system under investigation. Since the mechanistic understanding is already mapped out by biophysicists, what new insights can we add? 

 

 

 

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