• SPM Applications in Biology


    It is hard to imagine a more fundamental as well as more complicated biological object than a living cell. In a short period of time the applications of AFM have been extended to such a complex field of biology as science of the cell [, , , ].

    In this field Atomic Force Microscopy features not only high-resolution imaging of cellular structures below the optical limit, which is quite "natural" for this method, but also evaluation of the micromechanical properties of the cell and the ability to monitor cell dynamics and processes running in it even in real time. At present, no other microscopic techniques are able to provide directly both structural information of a biological sample and related functional information at such high spatial resolution [357]. Using AFM cells can be imaged directly requiring little or no sample pre-treatment and, what is quite importnat, in their most native physiological media such as aqueous solutions. Offering several advantages over conventional microscopic techniques AFM is successfully employed in combination with other methods such as electron microscopy, SNOM, PCT and others [, , , , ].

    Direct imaging of fixed or living cells and subcellular structures provides important information on the architecture of the membrane, organelles and cytoskeleton of cells. AFM offers a unique opportunity to image, localize and identify integral membrane proteins at the surface of living cells [, , , , , ]. Although staining or fluorescent labeling to mark the proteins of interest can not be avoided due to the indiscriminative nature of AFM probing relative to chemical composition and nature of the objects, further improvements and extensions promise this problem to be solved. For instance, using a method proposed in [], the functionality of membrane proteins such as ion channels can be identified using the Patch Clamp Technique (PCT) [] and the density of the protein distribution over the membrane patch can also be estimated. This combination of AFM and PCT allows for lateral resolution of cytoskeletal elements from the patches as low as 10 nm [981]. To observe membrane structural features such as ruffles, lamellipodia, microspikes and microvilli, cell fixation is used [, ]. Because the plasma membrane prevents from observing the intracellular structure the means of its careful removal were developed [].

    Contact mode, commonly used in AFM, is not a very suitable mode for cell imaging since it affects the membrane in a destructive way. Therefore, tapping mode or intermittent contact AFM is preferable in such studies for high-resolution imaging of subcellular structures. The main problem that arises in this case is how to remove tje damping involved by the liquid environment and develop an appropriate contrast mechanism to improve quality [, , , ].

    Another major AFM application in cell studies is real-time monitoring of living cells dynamics, intercellular interactions and response to internal and external perturbing factors [357, ]. Examples include the exploration of exocytosis of a virus from an infected cell in real time [], platelets shape transformation upon activation [], cultured pancreas cells secreting the starch-digesting enzyme amylase [].

    The main problem in monitoring the dynamic behavior of the cell is minimizing the perturbation caused by the AFM probe during the scanning process as well as maintaining stable environmental conditions for both temperature and pH value [357, ]. Another technical challenge is achieving high temporal resolution since the time to acquire a full scan of a living cell often exceeds the characteristic alterations happening in it. Diminishing of undesirable cellular stimulation can be achieved by the implementation of the modified tapping mode technique in liquid or the development of a new technique in which much lower AFM cantilever loading forces are required, and/or the design of novel AFM  cantilever probes which are biochemically and mechanically compatible with biological samples [357]. The simplest remedy to increase temporal resolution is, obviously, to speed up the scan rate, often though at the expense of spatial resolution [, , , ]. Therefore, existing AFM apparatus and techniques allow to monitor certain dynamic cellular processes, such as cell growth, exocytotic and endocytotic events, which are not very fast in time and requires less power in spatial resolution, and to study the cell morphology in real time in the presence of growth factors, hormones, and other biological reagents. With the development of high scan rate AFM it may be possible to use AFM to monitor the processes that occur at the cell membrane during an antibody binding, vesicle transfer, channel blocking or gating, etc., and to obtain information on the delivery of a specific drug with molecular resolution [357].

    Information about the micromechanical properties is quite important for cellular systems because it helps understanding cell architecture and its functions [975, , , , , , , ]. Local elastic properties of a cell can be quantitatively derived from the force versus distance (F-S) curves obtained at fixed surface points using AFM. Cytosceleton is the main characteristic feature observed in AFM images and it is responsible for the mechanical properties of the cell. Cytosceleton generally defines the shape, activity and mobility of the cell. Data acquired from AFM measurements contains information about both topography and elasticity and these two types must be distinguished from each other. This can be done using the elasticity mapping technique. The accuracy of elasticity measurements depends upon a number of factors considered in [357]. Attention should be paid in the quantitative study of cell micromechanical properties [, 988, ].

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    Kinetic analysis of the mitotic cycle of living vertebrate cells by atomic force microscopy
    J. A. Dvorak, E. Nagao
    Exp. Cell. Res., 242 (1998) 1, 69-74
    Elastic properties of living fibroblasts as imaged using force modulation mode in atomic force microscopy
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    Arch. Histol. Cytol., 61 (1998) 1, 57-63
    Atomic force microscopy: application to investigation of Escherichia coli morphology before and after exposure to cefodizime
    P. C. Braga, D. Ricci
    Antimicrob. Agents Chemother., 42 (1998) 1, 18-22
    Imaging of the surface of living cells by low-force contact-mode atomic force microscopy
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    Biophys. J., 75 (1998) 2, 695-703
    Structure of the erythrocyte membrane skeleton as observed by atomic force microscopy
    M. Takeuchi, H. Miyamoto, Y. Sako, H. Komizu, A. Kusumi
    Biophys. J., 74 (1998) 5, 2171-2183
    Atomic force microscopy in effusion cytology
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    Anal. Quant. Cytol. Histol., 20 (1998) 2, 97-104
    Elasticity of normal and cancerous human bladder cells studied by scanning force microscopy
    M. Lekka, P. Laidler, D. Gil, J. Lekki, Z. Stachura, A. Z. Hrynkiewicz
    European Biophysics Journal, 28 (1999) 4, 312-316
    Atomic force microscopy to study the degranulation in rat peritoneal mast cells after activation
    R. Nakamura, M. Nakanishi
    Immunology Letters, 69 (1999) 3, 307-310
    Cell adhesion force microscopy
    G. Sagvolden, I. Giaever, E. O. Pettersen, J. Feder
    Proc. Natl. Acad. Sci. USA, 96 (1999) 2, 471-476
    Phase imaging by atomic force microscopy: analysis of living homoiothermic vertebrate cells
    E. Nagao, J. A. Dvorak
    Biophys. J., 76 (1999) 6, 3289-3297
    Continuous detection of extracellular ATP on living cells by using atomic force microscopy
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    Proc. Natl. Acad. Sci. USA, 96 (1999) 21, 12180-12185
    Imaging of living cultured cells of an epithelial nature by atomic force microscopy
    T. Ushiki, J. Hitomi, T. Umemoto, S. Yamamoto, H. Kanazawa, M. Shigeno
    Arch. Histol. Cytol., 62 (1999) 1, 47-55
    Selective cleaning of the cell debris in human chromosome preparations studied by scanning force microscopy
    J. Tamayo, M. Miles, A. Thein, P. Soothill
    J. Struct. Biol., 128 (1999) 2, 200-210
    Topography of cell traces studied by atomic force microscopy
    H. Zimmermann, R. Hagedorn, E. Richter, G. Fuhr
    European Biophysics Journal, 28 (1999) 6, 516-525
    Effect of streptolysin O on the microelasticity of human platelets analyzed by atomic force microscopy
    M. Walch, U. Ziegler, P. Groscurth
    Ultramicroscopy, 82 (2000) 1-4, 259-267
    Bacterial turgor pressure can be measured by atomic force microscopy
    M. Arnoldi, M. Fritz, E. Bauerlein, M. Radmacher, E. Sackmann, A. Boulbitch
    Phys. Rev. E: Stat. Phys. Plasmas Fluids Relat. Interdiscip. Topics, 62 (2000) 1/B, 1034-1044
    Celery (Apium graveolens L.) parenchyma cell walls examined by atomic force microscopy: effect of dehydration on cellulose microfibrils
    J. C. Thimm, D. J. Burritt, W. A. Ducker, L. D. Melton
    Planta, 212 (2000) 1, 25-32
    Atomic force microscopy of the cell nucleus
    L. F. Jimenez-Garcia, R. Fragoso-Soriano
    J. Struct. Biol., 129 (2000) 2-3, 218-222
    Plasmodium falciparum-infected erythrocytes: qualitative and quantitative analyses of parasite-induced knobs by atomic force microscopy
    E. Nagao, O. Kaneko, J. A. Dvorak
    J. Struct. Biol., 130 (2000) 1, 34-44
    Atomic force microscopy imaging of living cells: a preliminary study of the disruptive effect of the cantilever tip on cell morphology
    H. X. You, J. M. Lau, S. Zhang, L. Yu
    Ultramicroscopy, 82 (2000) 1-4, 297-305
    Elasticity mapping of living fibroblasts by AFM and immunofluorescence observation of the cytoskeleton
    H. Haga, S. Sasaki, K. Kawabata, E. Ito, T. Ushiki, T. Sambongi
    Ultramicroscopy, 82 (2000) 1-4, 253-258
    Mechanical stimulation of individual stereocilia of living cochlear hair cells by atomic force microscopy
    M. G. Langer, A. Koitschev, H. Haase, U. Rexhausen, J. K. Horber, J. P. Ruppersberg
    Ultramicroscopy, 82 (2000) 1-4, 269-278
    Plasma membrane plasticity of Xenopus laevis oocyte imaged with atomic force microscopy
    H. Schillers, T. Danker, H. J. Schnittler, F. Lang, H. Oberleithner
    Cell. Physiol. Biochem., 10 (2000) 1-2, 99-107
    Tapping-mode atomic force microscopy on intact cells: optimal adjustment of tapping conditions by using the deflection signal
    V. Vie, M. C. Giocondi, E. Lesniewska, E. Finot, J. P. Goudonnet, C. Le Grimellec
    Ultramicroscopy, 82 (2000) 1-4, 279-288
    Volume dynamics in migrating epithelial cells measured with atomic force microscopy
    S. W. Schneider, P. Pagel, C. Rotsch, T. Danker, H. Oberleithner, M. Radmacher, A. Schwab
    Pflugers. Arch., 439 (2000) 3, 297-303
    Local mechanical properties measured by atomic force microscopy for cultured bovine endothelial cells exposed to shear stress
    M. Sato, K. Nagayama, N. Kataoka, M. Sasaki, K. Hane
    J. Biomech., 33 (2000) 1, 127-135
    Molecular basis of cell adhesion to polymers characterized AFM
    T. Boland, Y. Dufrene, B. Barger, G. Lee
    Crit. Rev. Biomed. Eng., 28 (2000) 1-2, 195-196
    Adapting atomic force microscopy for cell biology
    P. P. Lehenkari, G. T. Charras, A. Nykanen, M. A. Horton
    Ultramicroscopy, 82 (2000) 1-4, 289-295
    Volume dynamics in migrating epithelial cells measured with atomic force microscopy
    S. W. Schneider, P. Pagel, C. Rotsch, T. Danker, H. Oberleithner, M. Radmacher, A. Schwab
    Pflugers. Arch., 439 (2000) 3, 297-303
    Atomic force microscopy can be used to mechanically stimulate osteoblasts and evaluate cellular strain distributions
    G. T. Charras, P. P. Lehenkari, M. A. Horton
    Ultramicroscopy, 86 (2001) 1-2, 85-95
    Quantification of red blood cells using atomic force microscopy
    M. O'Reilly, L. McDonnell, J. O'Mullane
    Ultramicroscopy, 86 (2001) 1-2, 107-112
    Atomic force microscopy of the erythrocyte membrane skeleton
    A. H. Swihart, J. M. Mikrut, J. B. Ketterson, R. C. Macdonald
    J. Microsc., 204 (2001) 3, 212-225
    Application of atomic force microscopy to microbial surfaces: from reconstituted cell surface layers to living cells
    Y. F. Dufrene
    Micron, 32 (2001) 2, 153-165
    Probing molecular interactions and mechanical properties of microbial cell surfaces by atomic force microscopy
    Y. F. Dufrene, C. J. P. Boonaert, H. C. van der Mei, H. J. Busscher, P. G. Rouxhet
    Ultramicroscopy, 86 (2001) 1-2, 113-120
    Artificially induced unusual shape of erythrocytes: an atomic force microscopy study
    M. Girasole, A. Cricenti, R. Generosi, A. Congiu-Castellano, G. Boumis, G. Amiconi
    J. Microsc., 204 (2001) 1, 46-52
    Scanning force microscopy observation of tumor cells treated with hematoporphyrin IX derivatives
    R. Bischoff, G. Bischoff, S. Hoffmann
    Ann. Biomed. Eng., 29 (2001) 12, 1092-1099
    High-Q dynamic force microscopy in liquid and its application to living cells
    J. Tamayo, A. D. Humphris, R. J. Owen, M. J. Miles
    Biophys. J., 81 (2001) 1, 526-537
    Atomic Force Microscopy Study of the Adhesion of Saccharomyces cerevisiae
    W. R. Bowen, R. W. Lovitt, C. J. Wright
    J. Colloid. Interface. Sci., 237 (2001) 1, 54-61
    Blood cell adhesion on sensor materials studied by light, scanning electron, and atomic-force microscopy
    G. Hildebrand, S. Kunze, M. Driver
    Ann. Biomed. Eng., 29 (2001) 12, 1100-1105
    Local mechanical properties of guinea pig outer hair cells measured by atomic force microscopy
    M. Sugawara, Y. Ishida, H. Wada
    Hear Res., 174 (2002) 1-2, 222-229
    Atomic force microscopy of height fluctuations of fibroblast cells
    B. Szabo, D. Selmeczi, Z. Kornyei, E. Madarasz, N. Rozlosnik
    Phys. Rev. E: Stat. Nonlin. Soft. Matter. Phys., 65 (2002) 4/1, 41910
    Potassium-selective atomic force microscopy on ion-releasing substrates and living cells
    P. Schar-Zammaretti, U. Ziegler, I. Forster, P. Groscurth, U. E. Spichiger-Keller
    Anal. Chem., 74 (2002) 16, 4269-4274
    Lamellar subcomponents of the cuticular cell membrane complex of mammalian keratin fibres show friction and hardness contrast by AFM
    J. R. Smith, J. A. Swift
    J. Microsc., 206 (2002) 3, 182-193
    The biophysics of sensory cells of the inner ear examined by atomic force microscopy and patch clamp
    M. G. Langer, A. Koitschev
    Methods Cell Biol., 68 (2002) 141-169
    Investigating live and fixed epithelial and fibroblast cells by atomic force microscopy
    K. Sinniah, J. Paauw, J. Ubels
    Curr. Eye. Res., 24 (2002) 3, 188-195
    High-resolution three-dimensional imaging of the lateral plasma membrane of cochlear outer hair cells by atomic force microscopy
    C. Le Grimellec, M. C. Giocondi, M. Lenoir, M. Vater, G. Sposito, R. Pujol
    J. Comp. Neurol., 451 (2002) 1, 62-69
    Experimental and numerical analyses of local mechanical properties measured by atomic force microscopy for sheared endothelial cells
    T. Ohashi, Y. Ishii, Y. Ishikawa, T. Matsumoto, M. Sato
    Biomed. Mater. Eng., 12 (2002) 3, 319-327
    Characterization of the adhesive mucilages secreted by live diatom cells using atomic force microscopy
    M. J. Higgins, S. A. Crawford, P. Mulvaney, R. Wetherbee
    Protist, 153 (2002) 1, 25-38