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Journal Club Theme of January 2009: Impetus for Cell Mechanics

Rohit Khanna's picture

Welcome to the January 2009 issue. This issue addresses the important discussion on cell mechanics. Acute need to study cell mechanics is driven by the fundamental goal of tissue engineering i.e. to make tissue engineered constructs that can mimic the environment for tissue regeneration with a potential to replace the biological functions of damaged organs. There is now worldwide activity in the in vitro regeneration of tissues including nerve, liver, bone, heart valves, blood vessels, and kidney.

As we know that cells are highly dynamic: they walk, change shape and divide. A critical understanding of cell structure and mechanics is essential to elucidate many of the cellular functions, from adhesion to proliferation and differentiation. Studies into cell mechanics have rapidly emerged during the past decade and this progress has given rise to improvement in capabilities to probe the living cell with high force and displacement resolution and also to observe and manipulate the structure of cell. Such developments have led to opportunities to do better experiments and modeling & simulation in the field of cellular mechanics. Cellular responses to mechanical forces are closely related to tissue physiology and pathology. However, it is unclear that ‘how the cells respond to mechanical forces and convert them into biological responses and vice versa. This issue is further complicated by the highly dynamic and complex structure of cells (especially, eukaryotic cells) and their structure changes dramatically in response to mechanical forces. In the last few decades, various research efforts have been undertaken to understand the cellular mechanics by using various experimental tools and theoretical methods.

Cell and molecular mechanics of biological materials has been recently reviewed by Bao and Suresh (2003). Mechanical loading of the cells is essential for their normal functioning in physiological environment, which otherwise leads to a diseased state. Various experimental techniques have been developed over the years to study the mechanical behavior of living cells like AFM, magnetic twisting cytometry (MTC), optical trap, micropipette aspiration etc. Cellular deformation using a point probe, in tension or compression, pure shear, twisting or a combination of these modes have been studied during the last decade. Most of the techniques used for probing cells assume that cell behaves like a elastic solid due to strong cytoskeleton structure which provides the structural integrity to cell.

To be noted that interior of the cell consists of liquid phase (cytosol), a nucleus, the cytoskeleton consisting of networks of microtubules, actin and intermediate filaments, organelles of different sizes and shapes and other proteins.  That means cell can behave like elastic/plastic/viscoelastic, or combination of these. The cell's dynamic and complex structure makes it difficult to separate the contribution of each of the deformation modes i.e. elastic/plastic/viscoelastic. Another issue is: How to quantify the force distribution between the subcellular components inside the cell and to get the mechanical properties of each cellular component?. Any mechanical perturbation to the cell produces a biochemical signal e.g. cell could undergo remodeling or reorganization. This raises a fundamental question: Is it possible to study cell mechanics of living cell by mechanical forces?. There is also an acute need to determine the constitutive behavior of single cells e.g. to include stress-strain relations and time dependent variables to evaluate the viscoelastic behavior of cells. This can possibly help to understand the mechanics of cell in a better way.

G. Bao and S. Suresh: "Cell and molecular mechanics of biological materials", Nature materials 2, 715-725, 2003.

Cell responds to the stiffness of the substrate:

Cellular response to the stiffness of the substrate was first reported in the case of epithelial and fibroblasts cells, using ligand-coated gels of varied stiffness (Pelham and Yang, 1997). Epithelial cell attachment was found to be better on stiffer substrate as revealed by their spreading and cytoskeletal organization. Soft, lightly cross-linked gels (E~ 1kPa) showed dynamic focal adhesion complexes. In contrast, cells on stiff gels (E ~ 30-100 kPa) showed stable and static focal adhesion. In many of these investigations, the cellular responses on glass or standard cell culture plastic (relatively rigid), are compared with the more compliant materials like gels. This kind of fundamental study can be been used in investigation of cancer cells, tissue-repair strategy and disease detection. For understanding the fundamental science behind the effect of substrate stiffness on cell adhesion, this study can be quite meaningful.

D. E. Discher, P. Janmey, and Y-L Wang: "Tissue cells feel and respond to the stiffness of their substrate", Science 310, 1139, 2005.

To follow up from above discussion, one also needs to ponder that most of these kinds of studies are done on single cells using subconfluent cell culture substrates. In physiological environment, cells are not well separated from each other, so tissue level response is more common. Here, cell-ECM interactions play a significant role in influencing various cellular processes. The role of ECM microenvironment should be taken into an account.

Mimicking the mechanical properties of cells:

Another challenging question which comes to our mind is that the mostly 2D substrates are used e.g. glass, tissue culture polystyrene or soft gels, the question is how closely they resemble the mechanical properties of different types of living tissues in 3D physiological environment in the body and why only stiffness, what about physical properties/surface chemistry or topography of the substrates?  

For myocardial tissue engineering, the key is to engineer 3D cardiac tissue that could eventually be used to repair damaged heart tissue inside the body, test new drugs, and study cardiac cells development and functions. In principle, it could theoretically lead to the creation of an entire heart. Before its realization, there are potential challenges that must be solved thorough rigorous research investigations. The major challenges in developing tissue-engineered grafts for myocardial repair are to find the structural and mechanical compatibility of three dimensional (3D) scaffolds with the formation of new biomimetic tissue.

Recently, Dr. Langer and Dr. Freed's group at MIT published a very interesting article in nature materials (December 2008) entitled, "Accordion-like honeycombs for tissue engineering of cardiac anisotropy". In their research work, they designed a novel biomimetic 3D scaffolds made of a biodegradable polymer (poly glycerol sebacate) with accordion-like honeycomb structure, and reasoned that these scaffold materials can mimic anisotropic mechanical properties of native myocardium cells, provide low resistance to contraction, and can also provide structural capacity to guide cardiomyocytes under the physiological environment.

Engelmayr  et al. (2008) focused their studies to adult rat right ventricular myocardium as the right ventricular myocardium was more anisotropic and compliant than its left ventricular counterpart. They envisioned that right ventricular myocardial grafts have a potential to grow, regenerate and remodel, which could repair congenital hear defects. It is appreciated that such kind of research has provided the answers to some of the potential issues in the tissue engineering i.e. as per the major conclusion of this work: accordion-like honeycomb scaffolds have the potential to overcome the major challenges with structural and mechanical integrity of scaffolds for myocardial tissue engineering by closely mimicking the anisotropic mechanical properties of adult rat right ventricular myocardium, while simultaneously promoting the preferential orientation of cultured neonatal heart cells in absence of external stimuli.

G. C. Engelmayr Jr, M. Cheng, C. J. Bettinger,  J. T. Borenstein, R. Langer and L. E. Freed, "Accordion-like honeycombs for tissue engineering of cardiac anisotropy", Nature Materials, 7, 1003, 2008.

Investigations made so far on cell mechanics may set the initial stage for better understanding of mechanosenstivity in cell-cell interations during embryonic and tissue regeneration processes. Nonetheless, the role of various cellular processes including cellular mechanics in tissue regeneration needs to be better understood before we can actually realize the goals of tissue engineering.

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Zhigang Suo's picture

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ruogang zhao's picture

Hi Rohit and Zhigang,

Thanks for your help on solving the posting problem. In response to Rohit's comments in my blog, I'd like to discuss some of the challenges regarding the material constants of a single cell.

One of the problems in this area is that there are significant limitations on the material constants derived based on popular modeling techniques. Simple analytical models incorporating simple constitutive models had been used to derive material parameters of single cell. For example, linear elastic Hertz model has been used for AFM experiments and linear elastic half-space model had been used for micropipette aspiration (Sato et al.,1990).  However, as the finite element technique developed, more complicated FE models that incorporate large strain, viscoelastic constitutive material model have been used to interpret the mechanical testing results of the single cell (Vaziri and Mofrad, 2007; Vaziri et al, 2007) .
Material constants derived based on FE model take into account complicated material behaviors such as large strain and viscoelasticity, thus can more truly represent the mechanical properties of the cell than those derived based on analytical models (Baaijens et al, 2005). However, even with these complicated material properties, FE model still has not been able to simulate the active component of the cell and the discrete cytoskeleton components. The latter limitation is caused by the inherent continuum approach of the FE model. It is believed that as the modeling techniques develop, more “true” mechanical properties of single cell will be revealed. However, at this stage, the limitation on the mechanical properties derived based on popular modeling techniques is still apparent.
Aside from the “long-term” goal of single cell mechanics, in really, the biomedical research community is still in the transition from the analytical model to the FE model and the material properties derived based on FE model has not even been widely recognized. In one of our studies, it has been found that the material constants derived using analytical model are significantly different from those derived using FE model (Zhao et al, 2008). However, this concept has not been widely recognized and many latest publications in biomedical engineering still used analytical models (Dahl et al, 2005; Merryman et al, 2006). One of the reasons causing this response lag in the biomedical research community is that not all the researchers in this field have the expertise on FE analysis so it is hard to apply FE analysis in every single study. Another reason is in the study comparing mechanical properties between cells in different pathological states, the material constants derived based on analytical model can do the job (Trickey et al, 2000). It is not necessary to use those derived based on FE model for comparison. There is still long way to go for the FE model to become a standard tool in biomedical research.
Another problem regarding the material constants of a single cell is that the absolute values of material constant have not become a critical parameter to the research fields except for cell mechanics. The absolute stiffness or viscoelasticity of single cells play important role in the cell-ECM interaction. However, not many researches in tissue engineering or microdevice have considered these absolute values when designing their tissue scaffold or designing the microdevice. Part of the reason in tissue engineering is that the contribution to the tissue mechanical properties from single cells is not very significant due to the porous nature of the ECM in many tissue types (Merryman et al, 2006). Topics taking into account the cell-tissue mechanical interaction and cell-device mechanical interaction need to be further explored.


Sato M, Theret DP, Wheeler LT, Ohshima N, Nerem RM. Application of the micropipette technique to the measurement of cultured porcine aortic endothelial cell viscoelastic properties. J Biomech Eng. 1990 Aug;112(3):263–268.
Baaijens F.P.T., Trickey W.R., Laursen T.A., Guilak F. 2005, “Large Deformation Finite Element Analysis of Micropipette Aspiration to Determine the Mechanical Properties of the Chondrocyte,” Ann. Bio. Eng; vol. 33, pp. 494-501.
Vaziri, A., Mofrad, M. R. K. (2007). "Mechanics and deformation of the nucleus in micropipette aspiration experiment." Journal of Biomechanics 40: 2053–2062.
A.Vaziri, Z. Xue, R.D. Kamm, M.R. Kaazempur Mofrad, A computational study on power-law rheology of soft glassy materials with application to cell mechanics, Comput. Methods Appl. Mech. Engrg. 196 (2007) 2965–2971
Kris Noel Dahl, Adam J.Engler, J.David Pajerowski, and Dennis E. Discher, Power-Law Rheology of Isolated Nuclei with Deformation Mapping of Nuclear Substructures, Biophysical Journal, 2005, Volume 89 ,2855–2864
W. David Merryman, Inchan Youn, Howard D. Lukoff, Paula M. Krueger,Farshid Guilak, Richard A. Hopkins, and Michael S. Sacks, Correlation between heart valve interstitial cell stiffness and transvalvular pressure: implications for collagen biosynthesis, Am J Physiol Heart Circ Physiol 290: H224–H231, 2006.
Trickey W. R., Lee G. M., and Guilak F. 2000, “Viscoelastic Properties of Chondrocytes Isolated from Normal and Osteoarthritic Human Cartilage,” J Ortho Res, vol. 18, pp. 891–898.
Zhao, R.G., Wyss, K., Simmons. C.A. 2008. Comparison of three material models to predict the time-dependent deformation of a single cell under micropipette aspiration. Proceedings of the ASME 2008 Summer Bioengineering Conference, June 25-29, Marco Island, Florida, USA
W. David Merryman, Hsiao-Ying Shadow Huang, Frederick J. Schoen,Michael S. Sacks, The effects of cellular contraction on aortic valve leaflet flexural stiffness, Journal of Biomechanics 39 (2006) 88–96

Rohit Khanna's picture

Hi Zhao,

 Nice to hear from you. As far as readers understanding, it is not apparent that these are your views or contribution from important papers which you must have identified. please mention the references whererever required. 

For e.g. you mentioned about the porous nature of ECM in many tissue types, we need a reference here, which tissue type... ? and also cite important refs. on FE modeling. 

 While talking about ECM, it is important to mention which tissue type, in synthesizing 3 D porous scaffolds, many factors play a role like microstructure, biodegradability of materials, mechanical properties, porosity, etc. and that is even more complicated to include in FE models or any other modeling. As far as experimentation is concerned, hydration state of the tissue during the testing is also important. can you be more specific about what is known till now. Your write up looks too general without references. 





ruogang zhao's picture

Hi Rohit,

Thanks for the advice on the reference. I should have included references in the discussion. I've updated my post with added references.

My statement on the correlation between cell stiffness and the tissue stiffness is in terms of the heart valve leaflet tissue. The paper I cited discussed the contractility of valve cells caused by chemical stimulus on the bending stiffness of the valve leaflet tissue. However, the cell's stiffness value either in quiescent state or in stimulated state was not explicitly correlated with the tissue stiffness. In their conclusion, the authors speculated that the mechanical contribution of the valvular cells to the biomechanics of valvular function is negligible and the mechanical property change of valvular cells is more related to the local mechanical environment, which I agree.   

By the way, the perspectives in my discussion are just based on my knowledge in the field. I'd like to hear comments and exchange ideas on these topics. 

Rohit Khanna's picture

hi Ruogang:

It was very nice to hear from you. I am sorry i am not expert on your specific topics. Lets see if someone from imechanica community can answer your comments and share ideas with you.

The literature on cellular behavior/mechanics is so vast depending on
cell type. It is not possible to know everything and present
perspectives on everything you may like to discuss!.


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