具壓深感測之奈米壓痕技術已廣泛應用於薄膜或多層鍍膜之奈米力學性質量測，由於具備簡諧震盪的壓痕探針及精密的荷重與位移感測器，此量測技術專長於獲得待測物之剛性與壓痕深度之連續變化關係圖。在本論文中，具壓深感測之奈米壓痕技術首度被應用於細胞力學之研究，同時也包含其可行性及應用性評估。本論文的實驗設計可以下列三方面進行闡述：驗證在奈米壓痕試驗的過程中，是否有能力正確決定探針與試片接觸表面的基礎研究；對不同形式細胞進行奈米壓痕試驗，對量測結果的詮釋及獲得有效資料之基礎研究；最後，透過建立的量測方法及參數，將此技術應用於研究在生醫領域具有重要性之議題。
首先，製作超薄磷脂質薄膜模擬細胞膜結構，用以分析奈米壓痕探針與分子接觸表面，結果顯示在2～4奈米厚之超薄膜的量測上，壓深感測奈米壓痕試驗不僅能夠偵測到接觸表面，同時亦能分析薄膜的品質。其次，活體、固定及脫水的NIH-3T3纖維母細胞被選用為不同細胞典型，以進行奈米力學性質的分析。針對貼附於玻璃基材上之固定及脫水細胞，從細胞邊緣板狀偽足到細胞核區進行序列奈米壓痕測試，連續式的簡諧接觸剛性量測結果清楚顯示，從細胞表面到玻璃基材的奈米力學性質變化，研究進一步發現，特別是在細胞板狀偽足的薄層區域，簡諧接觸剛性呈現三個階段的變化，判斷其依序分別代表細胞本質、基材效應影響及基材性質。依據此一發現，在第一階段的簡諧接觸剛性與深度關係曲線斜率，代表著細胞膜對簡諧震盪探針在最初約20奈米的接觸時之力學反應，並將此定義為奈米壓痕試驗中，不受基材效應影響的細胞力學性質之表示參數。最後，進一步將此參數應用於評估細胞膜膽固醇含量的變化對細胞力學性質造成的影響，研究結果顯示，隨著細胞膜膽固醇移除的時間增加，在第一階段的簡諧接觸剛性曲線斜率呈現指數下降的趨勢，此與典型的藥物動力學行為相符，而在細胞膜膽固醇回補的研究中亦發現，斜率會隨著回補的時間增加而逐漸升高。
基於上述基礎研究及應用，具壓深感測之奈米壓痕技術不僅在細胞層級，甚至在胞器或分子層級之奈米力學研究的應用性已獲得驗證。這些新穎的研究結果對與此技術相關的，以原子力顯微鏡進行的研究，也可能提供有助益的資訊。

Depth-sensing nano-indentation technique has been widely utilized in the measurement of nano-mechanical property of thin films or multi-layered coatings. With the harmonically oscillating indenter tip and sophisticated load and displacement sensors, this technique is specialized in demonstrating stiffness profile of the tested sample along the indentation path. In this thesis, pioneer applications of depth-sensing nano-indentation technique in the study of cell mechanics were performed with the evaluation of its practicability and applicability. The experimental design of this thesis can be elucidated and divided into the following three aspects: fundamental study to prove the capability of contact surface determination during nano-indentation, fundamental study to interpret and extract data from nano-indentation on cells in various forms, and ultimately, with the established methods and parameters, application of the technique to study issues of biomedical significance.
In the first part of this thesis, ultra-thin and soft phospholipid layers were fabricated as a model of cell membrane for the examination of nano-indenter tip-on-molecule contact point determination. The capabilities of depth-sensing nano-indentation in determining contact surface as well as examining the quality of the ultra thin soft layers within 2~4 nm in thickness were proven. Next, living, fixed, and dehydrated NIH-3T3 fibroblast cells were prepared as model cells for the examination of nano-mechanical property analysis. For the fixed and dehydrated cells adhered upon the glass substrate, serial indentations from the leading edge, i.e., the lamellipodium, to nucleus regions were evaluated. The results showed that cellular nano-mechanical properties from the initial tip-on-cell contact to deep into glass substrate were clearly characterized by continuous harmonic contact stiffness (HCS) measurements. An interesting three-stage HCS transition particularly on the thin lamellipodium regions was observed and further characterized into the following three stages, respectively contributed by cellular intrinsic (stage I), substrate effect dominant (stage II), and substrate (stage III) properties. According to the observation, the slope of HCS at stage I, which meant the averaged elastic response of cell membrane to the harmonically oscillating indenter tip within the initial displacement of around 20 nm, was defined as a parameter representing cellular mechanical properties. Eventually, further application of the established parameter was performed on the qualitative evaluation of nano-mechanical properties of membrane cholesterol-manipulated fibroblast cells. The results showed that, with the increased duration of cholesterol depletion, the slope of HCS at stage I of was observed in the tendency of exponential decay, which was in accordance with typical pharmacokinetic behavior. Moreover, the slope was found gradually elevated with the increase of incubation time for cholesterol replenishment.
Based on these fundamental studies and applications, the utility of depth-sensing nano-indentation technique in the study of nano-mechanics is verified not only on cellular but on organelle or molecular levels. These novel findings are presumably valuable as a reference complementary to the related work, e.g., accomplished by atomic force microscope.

[1] B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter, Molecular Biology of the Cell, 4th ed. New York: Garland Science, 2002.
[2] G. Bao and S. Suresh, "Cell and Molecular Mechanics of Biological Materials," Nature Materials, vol. 2, pp. 715-725, 2003.
[3] G. Y. H. Lee and C. T. Lim, "Biomechanics Approaches to Studying Human Diseases," Trends in Biotechnology, vol. 25, pp. 111-118, 2007.
[4] S. E. Cross, Y.-S. Jin, J. Rao, and J. K. Gimzewski, "Nanomechanical Analysis of Cells from Cancer Patients," Nature Nanotechnology, vol. 2, pp. 780-783, 2007.
[5] M. N. Starodubtseva, "Mechanical Properties of Cells and Ageing," Ageing Research Reviews, vol. In Press.
[6] R. Matzke, K. Jacobson, and M. Radmacher, "Direct, High-Resolution Measurement of Furrow Stiffening during Division of Adherent Cells," Nature Cell Biology, vol. 3, pp. 607-610, 2001.
[7] V. M. Laurent, S. Kasas, A. Yersin, T. E. Schäfer, S. Catsicas, G. Dietler, A. B. Verkhovsky, and J.-J. Meister, "Gradient of Rigidity in the Lamellipodia of Migrating Cells Revealed by Atomic Force Microscopy," Biophysical Journal, vol. 89, pp. 667-675, 2005.
[8] S. Park, D. Koch, R. Cardenas, J. Käs, and C. K. Shih, "Cell Motility and Local Viscoelasticity of Fibroblasts," Biophysical Journal, vol. 89, pp. 4330-4342, 2005.
[9] I. Titushkin and M. Cho, "Modulation of Cellular Mechanics during Osteogenic Differentiation of Human Mesenchymal Stem Cells," Biophysical Journal, vol. 93, pp. 3693-3702, 2007.
[10] K. A. Addae-Mensah and J. P. Wikswo, "Measurement Techniques for Cellular Biomechanics In Vitro," Experimental Biology and Medicine, vol. 233, pp. 792-809, July 1, 2008 2008.
[11] M. Radmacher, "Studying the Mechanics of Cellular Processes by Atomic Force Microscopy," in Methods in Cell Biology. vol. 83: Academic Press, 2007, pp. 347-372.
[12] E. K. Dimitriadis, F. Horkay, J. Maresca, B. Kachar, and R. S. Chadwick, "Determination of Elastic Moduli of Thin Layers of Soft Material Using the Atomic Force Microscope," Biophysical Journal, vol. 82, pp. 2798-2810, 2002.
[13] L. Sirghi and F. Rossi, "Adhesion and Elasticity in Nanoscale Indentation," Applied Physics Letters, vol. 89, pp. 243118-3, 2006.
[14] A.-Y. Jee and M. Lee, "Comparative Analysis on the Nanoindentation of Polymers Using Atomic Force Microscopy," Polymer Testing, vol. 29, pp. 95-99, 2010.
[15] T. G. Kuznetsova, M. N. Starodubtseva, N. I. Yegorenkov, S. A. Chizhik, and R. I. Zhdanov, "Atomic Force Microscopy Probing of Cell Elasticity," Micron, vol. 38, pp. 824-833, 2007.
[16] A. L. Weisenhorn, M. Khorsandi, S. Kasas, V. Gotzos, and H.-J. Butt, "Deformation and Height Anomaly of Soft Surfaces Studied with an AFM," Nanotechnology, vol. 4, p. 106, 1993.
[17] J. Domke and M. Radmacher, "Measuring the Elastic Properties of Thin Polymer Films with the Atomic Force Microscope," Langmuir, vol. 14, pp. 3320-3325, 05/15 1998.
[18] R. E. Mahaffy, S. Park, E. Gerde, J. Käs, and C. K. Shih, "Quantitative Analysis of the Viscoelastic Properties of Thin Regions of Fibroblasts Using Atomic Force Microscopy," Biophysical Journal, vol. 86, pp. 1777-1793, 2004.
[19] J. R. Withers and D. E. Aston, "Nanomechanical Measurements with AFM in the Elastic Limit," Advances in Colloid and Interface Science, vol. 120, pp. 57-67, 2006.
[20] C. Roduit, S. Sekatski, G. Dietler, S. Catsicas, F. Lafont, and S. Kasas, "Stiffness Tomography by Atomic Force Microscopy " Biophysical Journal, vol. 97, pp. 674-677, 2009.
[21] X. Li and B. Bhushan, "A Review of Nanoindentation Continuous Stiffness Measurement Technique and Its Applications," Materials Characterization, vol. 48, pp. 11-36, 2002.
[22] W. C. Oliver and G. M. Pharr, "An Improved Technique for Determining Hardness and Elastic Modulus Using Load and Displacement Sensing Indentation Experiments," Journal of Materials Research, vol. 7, pp. 1564-1583, 1992.
[23] W. C. Oliver and G. M. Pharr, "Measurement of Hardness and Elastic Modulus by Instrumented Indentation: Advances in Understanding and Refinements to Methodology," Journal of Materials Research, vol. 19, pp. 3-20, 2004.
[24] C.-W. Chang and J.-D. Liao, "Nano-Indentation at the Surface Contact Level: Applying A Harmonic Frequency for Measuring Contact Stiffness of Self-Assembled Monolayers Adsorbed on Au," Nanotechnology, vol. 19, p. 315703, 2008.
[25] S. Habelitz, S. J. Marshall, G. W. Marshall, and M. Balooch, "Mechanical Properties of Human Dental Enamel on the Nanometre Scale," Archives of Oral Biology, vol. 46, pp. 173-183, 2001.
[26] S. Hengsberger, A. Kulik, and P. Zysset, "Nanoindentation Discriminates the Elastic Properties of Individual Human Bone Lamellae under Dry and Physiological Conditions," Bone, vol. 30, pp. 178-184, 2002.
[27] M. L. Oyen, "Poroelastic Nanoindentation Responses of Hydrated Bone," Journal of Materials Research, vol. 23, pp. 1307-1314, 2008.
[28] L. Zou, H. Jin, W.-Y. Lu, and X. Li, "Nanoscale Structural and Mechanical Characterization of the Cell Wall of BambooFibers," Materials Science and Engineering: C, vol. 29, pp. 1375-1379, 2009.
[29] Y.-L. Wang and D. S. Discher, Cell Mechanics. Boston: Elsevier Academic Press, 2007.
[30] J. Wolff, The Law of Bone Remodeling. Berlin Heidelberg New York: Springer, 1986.
[31] D. E. Ingber, "Cellular Mechanotransduction: Putting All the Pieces Together Again," The FASEB Journal, vol. 20, pp. 811-827, 2006.
[32] T. A. McMahon, Muscles, Reflexes, and Locomotion. New Jersey: Princeton University Press, 1984.
[33] P. A. Huijing and R. T. Jaspers, "Adaptation of Muscle Size and Myofascial Force Transmission: a Review and Some New Experimental Results," Scandinavian Journal of Medicine & Science in Sports, vol. 15, pp. 349-380, 2005.
[34] J. R. Ralphs, A. D. Waggett, and M. Benjamin, "Actin Stress Fibres and Cell-Cell Adhesion Molecules in Tendons: Organisation in vivo and Response to Mechanical Loading of Tendon Cells in vitro," Matrix Biology, vol. 21, pp. 67-74, 2002.
[35] J. Komulainen, T. E. S. Takala, H. Kuipers, and M. K. C. Hesselink, "The Disruption of Myofibre Structures in Rat Skeletal Muscle after Forced Lengthening Contractions," Pflügers Archiv European Journal of Physiology, vol. 436, pp. 735-741, 1998.
[36] C. S. Chen, J. Tan, and J. Tien, "Mechanotransduction at Cell-Matrix and Cell-Cell Contacts," Annual Review of Biomedical Engineering, vol. 6, pp. 275-302, 2004.
[37] A. Buxboim, I. L. Ivanovska, and D. E. Discher, "Matrix Elasticity, Cytoskeletal Forces and Physics of the Nucleus: How Deeply Do Cells 'Feel' Outside and In?," Journal of Cell Science, vol. 123, pp. 297-308, 2010.
[38] C. Zhu, G. Bao, and N. Wang, "Cell Mechanics: Mechanical Response, Cell Adhesion, and Molecular Deformation," Annual Review of Biomedical Engineering, vol. 2, pp. 189-226, 2000.
[39] P. A. Janmey and C. A. McCulloch, "Cell Mechanics: Integrating Cell Responses to Mechanical Stimuli," Annual Review of Biomedical Engineering, vol. 9, pp. 1-34, 2007.
[40] G. Liu, C. D. Guibao, and J. Zheng, "Structural Insight into the Mechanisms of Targeting and Signaling of Focal Adhesion Kinase," Molecular and Cellular Biology, vol. 22, pp. 2751-2760, 2002.
[41] J. C. Friedland, M. H. Lee, and D. Boettiger, "Mechanically Activated Integrin Switch Controls alpha-5 beta-1 Function," Science, vol. 323, pp. 642-644, 2009.
[42] H. Huang, R. D. Kamm, and R. T. Lee, "Cell Mechanics and Mechanotransduction: Pathways, Probes, and Physiology," American Journal of Physiology: Cell Physiology, vol. 287, pp. C1-11, 2004.
[43] O. P. Hamill and B. Martinac, "Molecular Basis of Mechanotransduction in Living Cells," Physiological Reviews, vol. 81, pp. 685-740, 2001.
[44] C. S. Chen, "Mechanotransduction - A Field Pulling Together?," Journal of Cell Science, vol. 121, pp. 3285-3292, 2008.
[45] W. E. Brownell, A. A. Spector, R. M. Raphael, and A. S. Popel, "Micro- and Nnanomechanics of the Cochlear Outer Hair Cell," Annual Review of Biomedical Engineering, vol. 3, pp. 169-194, 2001.
[46] Y. C. Fang, Biomechanics: Mechanical Properties of Living Tissues, 2nd ed. New York: Springer, 1993.
[47] B. Morrison, K. E. Saatman, D. F. Meaney, and T. K. McIntosh, "In Vitro Central Nervous System Models of Mechanically Induced Trauma: A Review," Journal of Neurotrauma, vol. 15, pp. 911-928, 1998.
[48] D. H. Smith, J. A. Wolf, and D. F. Meaney, "A New Strategy to Produce Sustained Growth of Central Nervous System Axons: Continuous Mechanical Tension," Tissue Engineering, vol. 7, pp. 131-139, 2001.
[49] D. E. Ingber, "Mechanobiology and Diseases of Mechanotransduction," Annals of Medicine, vol. 35, pp. 564 - 577, 2003.
[50] C. T. Lim, E. H. Zhou, and S. T. Quek, "Mechanical Models for Living Cells--a Review," Journal of Biomechanics, vol. 39, pp. 195-216, 2006.
[51] W. R. Trickey, G. M. Lee, and F. Guilak, "Viscoelastic Properties of Chondrocytes from Normal and Osteoarthritic Human Cartilage," Journal of Orthopaedic Research, vol. 18, pp. 891-898, 2000.
[52] M. J. King, J. Behrens, C. Rogers, C. Flynn, D. Greenwood, and K. Chambers, "Rapid Flow Cytometric Test for the Diagnosis of Membrane Cytoskeleton-Aassociated Haemolytic Anaemia," British Journal of Haematology, vol. 111, pp. 924-933, 2000.
[53] S. S. An, B. Fabry, X. Trepat, N. Wang, and J. J. Fredberg, "Do Biophysical Properties of the Airway Smooth Muscle in Culture Predict Airway Hyperresponsiveness?," American Journal of Respiratory Cell and Molecular Biology, vol. 35, pp. 55-64, 2006.
[54] J. Guck, S. Schinkinger, B. Lincoln, F. Wottawah, S. Ebert, M. Romeyke, D. Lenz, H. M. Erickson, R. Ananthakrishnan, D. Mitchell, J. Käs, S. Ulvick, and C. Bilby, "Optical Deformability as an Inherent Cell Marker for Testing Malignant Transformation and Metastatic Competence," Biophysical Journal, vol. 88, pp. 3689-3698, 2005.
[55] M. Lekka, P. Laidler, D. Gil, J. Lekki, Z. Stachura, and A. Z. Hrynkiewicz, "Elasticity of Normal and Cancerous Human Bladder Cells Studied by Scanning Force Microscopy," European Biophysics Journal, vol. 28, pp. 312-316, 1999.
[56] B. Lincoln, H. M. Erickson, S. Schinkinger, F. Wottawah, D. Mitchell, S. Ulvick, C. Bilby, and J. Guck, "Deformability-Based Flow Cytometry," Cytometry Part A, vol. 59A, pp. 203-209, 2004.
[57] R. A. Lemons and C. F. Quate, "Acoustic Microscopy: Biomedical Applications," Science, vol. 188, pp. 905-911, 1975.
[58] N. J. Wandersee, S. C. Olson, S. L. Holzhauer, R. G. Hoffmann, J. E. Barker, and C. A. Hillery, "Increased Erythrocyte Adhesion in Mice and Humans with Hereditary Spherocytosis and Hereditary Elliptocytosis," Blood, vol. 103, pp. 710-716, 2004.
[59] R. Suwanarusk, B. M. Cooke, A. M. Dondorp, K. Silamut, S. Jetsumon, N. J. White, and R. Udomsangpetch, "The Deformability of Red Blood Cells Parasitized by Plasmodium falciparum and P. vivax," The Journal of Infectious Diseases, vol. 189, pp. 190-194, 2004.
[60] G. B. Nash, E. O'Brien, E. C. Gordon-Smith, and J. A. Dormandy, "Abnormalities in the Mechanical Properties of Red Blood Cells Caused by Plasmodium Falciparum," Blood, vol. 74, pp. 855-861, 1989.
[61] M. Paulitschke and G. B. Nash, "Membrane Rigidity of Red Blood Cells Parasitized by Different Strains of Plasmodium Falciparum," The Journal of laboratory and clinical medicine, vol. 122, pp. 581-589, 1993.
[62] S. Suresh, J. Spatz, J. P. Mills, A. Micoulet, M. Dao, C. T. Lim, M. Beil, and T. Seufferlein, "Connections between Single-Cell Biomechanics and Human Disease States: Gastrointestinal Cancer and Malaria," Acta Biomaterialia, vol. 1, pp. 15-30, 2005.
[63] J. P. Shelby, J. White, K. Ganesan, P. K. Rathod, and D. T. Chiu, "A Microfluidic Model for Single-Cell Capillary Obstruction by Plasmodium Falciparum-Infected Erythrocytes," Proceedings of the National Academy of Sciences of the United States of America, vol. 100, pp. 14618-14622, 2003.
[64] M. M. Brandão, A. Fontes, M. L. Barjas-Castro, L. C. Barbosa, F. F. Costa, C. L. Cesar, and S. T. O. Saad, "Optical Tweezers for Measuring Red Blood Cell Elasticity: Application to the Study of Drug Response in Sickle Cell Disease," European Journal of Haematology, vol. 70, pp. 207-211, 2003.
[65] E. A. Evans and P. L. La Celle, "Intrinsic Material Properties of the Erythrocyte Membrane Indicated by Mechanical Analysis of Deformation," Blood, vol. 45, pp. 29-43, 1975.
[66] R. M. Hochmuth, P. R. Worthy, and E. A. Evans, "Red Cell Extensional Recovery and the Determination of Membrane Viscosity," Biophysical Journal, vol. 26, pp. 101-114, 1979.
[67] G. B. Nash, C. S. Johnson, and H. J. Meiselman, "Mechanical Properties of Oxygenated Red Blood Cells in Sickle Cell (HbSS) Disease," Blood, vol. 63, pp. 73-82, 1984.
[68] M. R. Clark, N. Mohandas, and S. B. Shohet, "Osmotic Gradient Ektacytometry: Comprehensive Characterization of Red Cell Volume and Surface Maintenance," Blood, vol. 61, pp. 899-910, 1983.
[69] N. Wang, J. P. Butler, and D. E. Ingber, "Mechanotransduction Across the Cell Surface and Through the Cytoskeleton," Science, vol. 260, pp. 1124-1127, 1993.
[70] E. Fuchs and D. W. Cleveland, "A Structural Scaffolding of Intermediate Filaments in Health and Disease," Science, vol. 279, pp. 514-519, 1998.
[71] G. T. Charras and M. A. Horton, "Single Cell Mechanotransduction and Its Modulation Analyzed by Atomic Force Microscope Indentation," Biophysical Journal, vol. 82, pp. 2970-2981, 2002.
[72] F. Gittes, B. Mickey, J. Nettleton, and J. Howard, "Flexural Rigidity of Microtubules and Actin Filaments Measured from Thermal Fluctuations in Shape," The Journal of Cell Biology, vol. 120, pp. 923-934, 1993.
[73] D. Stamenovic and N. Wang, "Cellular Responses to Mechanical Stress: Invited Review: Engineering approaches to cytoskeletal mechanics," Journal of Applied Physiology, vol. 89, pp. 2085-2090, 2000.
[74] D. E. Ingber, "Cellular Tensegrity: Defining New Rules of Biological Design That Govern the Cytoskeleton," Journal of Cell Science, vol. 104, pp. 613-627, 1993.
[75] D. E. Ingber, "Tensegrity I. Cell Structure and Hierarchical Systems Biology," Journal of Cell Science, vol. 116, pp. 1157-1173, 2003.
[76] D. E. Ingber, "Tensegrity II. How Structural Networks Influence Cellular Information-Processing Networks," Journal of Cell Science, vol. 116, pp. 1397-1408, 2003.
[77] R. B. Fuller, "Tensegrity," Portfolio Artnews Annual, vol. 4, pp. 112-127, 1961.
[78] K. Snelson, "Snelson on the Tensegrity Invention," International Journal of Space Structures, vol. 11, pp. 43-48, 1996.
[79] J. Chen, B. Fabry, E. L. Schiffrin, and N. Wang, "Twisting Integrin Receptors Increases Endothelin-1 Gene Expression in Endothelial Cells," American Journal of Physiology: Cell Physiology, vol. 280, pp. C1475-C1484, 2001.
[80] F. J. Alenghat, B. Fabry, K. Y. Tsai, W. H. Goldmann, and D. E. Ingber, "Analysis of Cell Mechanics in Single Vinculin-Deficient Cells Using a Magnetic Tweezer," Biochemical and Biophysical Research Communications, vol. 277, pp. 93-99, 2000.
[81] R. M. Hochmuth, "Micropipette Aspiration of Living Cells," Journal of Biomechanics, vol. 33, pp. 15-22, 2000.
[82] D. Mitrossilisa, J. Foucharda, A. Guiroya, N. Desprata, N. Rodrigueza, B. Fabryb, and A. Asnaciosa, "Single-Cell Response to Stiffness Exhibits Muscle-Like Behavior," Proceedings of the National Academy of Sciences of the United States of America, vol. 106, pp. 18243-18248, 2009.
[83] S. Usami, H.-H. Chen, Y. Zhao, S. Chien, and R. Skalak, "Design and Construction of a Linear Shear Stress Flow Chamber," Annals of Biomedical Engineering, vol. 21, pp. 77-83, 1993.
[84] B. J. Pfister, T. P. Weihs, M. Betenbaugh, and G. Bao, "An In Vitro Uniaxial Stretch Model for Axonal Injury," Annals of Biomedical Engineering, vol. 31, pp. 589-598, 2003.
[85] R. J. Pelham and Y.-l. Wang, "Cell Locomotion and Focal Adhesions Are Regulated by Substrate Flexibility," Proceedings of the National Academy of Sciences of the United States of America, vol. 94, pp. 13661-13665, 1997.
[86] C. T. Lim, E. H. Zhou, A. Li, S. R. K. Vedula, and H. X. Fu, "Experimental Techniques for Single Cell and Single Molecule Biomechanics," Materials Science and Engineering C, vol. 26, pp. 1278-1288, 2006.
[87] G. Binnig, C. F. Quate, and C. Gerber, "Atomic Force Microscope," Physical Review Letters, vol. 56, pp. 930-933, 1986.
[88] G. Binnig, H. Rohrer, C. Gerber, and E. Weibel, "Surface Studies by Scanning Tunneling Microscopy," Physical Review Letters, vol. 49, pp. 57-61, 1982.
[89] I. N. Sneddon, "The Relation Between Load and Penetration in the Axisymmetric Boussinesq Problem for a Punch of Arbitrary Profile," International Journal of Engineering Science, vol. 3, pp. 47-57, 1965.
[90] M. Radmacher, "Measuring the Elastic Properties of Biological Samples with the AFM " IEEE Engineering in Medicine and Biology Magazine, vol. 16, pp. 47-57, 1997.
[91] W. T. Chen, "Computation of Stresses and Displacements in A Layered Elastic Medium," International Journal of Engineering Science, vol. 9, pp. 775-800, 1971.
[92] Y.-O. Tu and D. C. Gazis., "The Contact Problem of A Plate Pressed between Two Spheres," Journal of Applied Mechanics, vol. 31, pp. 659-666, 1964.
[93] E. M. Darling, S. Zauscher, J. A. Block, and F. Guilak, "A Thin-Layer Model for Viscoelastic, Stress-Relaxation Testing of Cells Using Atomic Force Microscopy: Do Cell Properties Reflect Metastatic Potential?," Biophysical Journal, vol. 92, pp. 1784-1791, 2007.
[94] Y. Cao, D. Yang, and W. Soboyejoy, "Nanoindentation Method for Determining the Initial Contact and Adhesion Characteristics of Soft Polydimethylsiloxane," Journal of Materials Research, vol. 20, pp. 2004-2011, 2005.
[95] G. Cao and N. Chandra, "Evaluation of Biological Cell Properties Using Dynamic Indentation Measurement," Physical Review E, vol. 81, p. 021924, 2010.
[96] X. Li and B. Bhushan, "A Review of Nanoindentation Continuous Stiffness Measurement Technique and Its Applications," Materials Characterization, vol. 48, pp. 11-36, 2002.
[97] D. Tabor, The Hardness of Metals. Oxford: Oxford University Press, 1951.
[98] B. Bhushan, Handbook of Micro/nanotribology, 2nd ed. Boca Raton (FL): CRC Press, 1999.
[99] W. C. Oliver, "Alternative Technique for Analyzing Instrumented Indentation Data," Journal of Materials Research, vol. 16, pp. 3202-3206, 2001.
[100] A. C. Fischer-Cripps, Nanoindentation, 2nd ed. New York: Springer, 2004.
[101] X. Li, H. Gao, C. J. Murphy, and K. K. Caswell, "Nanoindentation of Silver Nanowires," Nano Letters, vol. 3, pp. 1495-1498, 2003.
[102] L. H. He, N. Fujisawa, and M. V. Swain, "Elastic Modulus and Stress–Strain Response of Human Enamel by Nano-Indentation," Biomaterials, vol. 27, pp. 4388-4398, 2006.
[103] A. J. Bushby, V. L. Ferguson, and A. Boyde, "Nanoindentation of Bone: Comparison of Specimens Tested in Liquid and Embedded in Polymethylmethacrylate," Journal of Materials Research, vol. 19, pp. 249-259, 2004.
[104] W. Gindl, H. S. Gupta, T. Schöberl, H. C. Lichtenegger, and P. Fratzl, "Mechanical Properties of Spruce Wood Cell Walls by Nanoindentation," Applied Physics A, vol. 79, pp. 2069-2073, 2004.
[105] D. M. Ebenstein and L. A. Pruitt, "Nanoindentation of Soft Hydrated Materials for Application to Vascular Tissues," Journal of Biomedical Materials Research A, vol. 69, pp. 222-232, 2004.
[106] R. Akhtar, N. Schwarzer, M. J. Sherratt, R. E. B. Watson, H. K. Graham, A. W. Trafford, P. M. Mummery, and B. Derby, "Nanoindentation of Histological Specimens: Mapping the Elastic Properties of Soft Tissues," Journal of Materials Research, vol. 24, pp. 638-646, 2009.
[107] D. M. Ebenstein and L. A. Pruitt, "Nanoindentation of Biological Materials," Nano Today, vol. 1, pp. 26-33, 2006.
[108] W.-T. Li, "Investigation of Molecular Interactions in Mixed Monolayers Composed of Catanionic Vesicle-Forming Materials," in Department of Chemical Engineering. vol. PhD Thesis: National Cheng Kung University, 2008.
[109] C. Evora, I. Soriano, R. A. Rogers, K. M. Shakesheff, J. Hanes, and R. Langer, "Relating the Phagocytosis of Microparticles by Alveolar Macrophages to Surface Chemistry: the Effect of 1,2-Dipalmitoylphosphatidylcholine," Journal of Controlled Release, vol. 51, pp. 143-152, 1998.
[110] C.-H. Hsieh, J.-D. Liao, C.-S. Kuo, C.-Y. Huang, B.-H. Wu, and F.-Y. Chang, "Lithographical Method by Oxidation through a Conductive Template in Contact with a Silicon Substrate Mediated by a Thin Water Layer," Japanese Journal of Applied Physics, vol. 47, pp. 2456-2459, 2008.
[111] G. Odegard, T. Gates, and H. Herring, "Characterization of Viscoelastic Properties of Polymeric Materials through Nanoindentation," Experimental Mechanics, vol. 45, pp. 130-136, 2005.
[112] D. A. Lucca, K. Herrmann, and M. J. Klopfstein, "Nanoindentation: Measuring Methods and Applications," CIRP Annals - Manufacturing Technology, vol. 59, pp. 803-819.
[113] G. G. Bilodeau, "Regular Pyramid Punch Problem," Journal of Applied Mechanics, vol. 59, pp. 519-523, 1992.
[114] J. Spinke, J. Yang, H. Wolf, M. Liley, H. Ringsdorf, and W. Knoll, "Polymer-Supported Bilayer on A Solid Substrate," Biophysical Journal, vol. 63, pp. 1667-1671, 1992.
[115] F. Giess, M. G. Friedrich, J. Heberle, R. L. Naumann, and W. Knoll, "The Protein-Tethered Lipid Bilayer: A Novel Mimic of the Biological Membrane," Biophysical Journal, vol. 87, pp. 3213-3220, 2004.
[116] D. K. Martin, Nanobiotechnology of Biomimetic Membranes. New York: Springer, 2007.
[117] G. Roberts, Langmuir-Blodgett Films. New York: Plenum, 1990.
[118] J. Saccani, S. Castano, B. Desbat, and D. Blaudez, "A Phospholipid Bilayer Supported under a Polymerized Langmuir Film," Biophysical Journal, vol. 85, pp. 3781-3787, 2003.
[119] S. H. Chen, C. Y. Liao, H. W. Huang, T. M. Weiss, M. C. Bellisent-Funel, and F. Sette, "Collective Dynamics in Fully Hydrated Phospholipid Bilayers Studied by Inelastic X-Ray Scattering," Physical Review Letters, vol. 86, pp. 740-743, 2001.
[120] J. M. Solletti, M. Botreau, F. Sommer, W. L. Brunat, S. Kasas, T. M. Duc, and M. R. Celio, "Elaboration and Characterization of Phospholipid Langmuir-Blodgett Films," Langmuir, vol. 12, pp. 5379-5386, 1996.
[121] A. G. Lee, "Lipid-Protein Interactions in Biological Membranes: A Structural Perspective," Biochimica et Biophysica Acta (BBA) - Biomembranes, vol. 1612, pp. 1-40, 2003.
[122] K. Mitra, I. Ubarretxena-Belandia, T. Taguchi, G. Warren, and D. M. Engelman, "Modulation of the Bilayer Thickness of Exocytic Pathway Membranes by Membrane Proteins Rather Than Cholesterol," Proceedings of the National Academy of Sciences of the United States of America, vol. 101, pp. 4083-4088, 2004.
[123] B. A. Lewis and D. M. Engelman, "Lipid Bilayer Thickness Varies Linearly with Acyl Chain Length in Fluid Phosphatidylcholine Vesicles," Journal of Molecular Biology, vol. 166, pp. 211-217, 1983.
[124] S.-R. Kim, S.-A. Choi, and J.-D. Kim, "The Monolayer Behavior and Transfer Characteristics of Phospholipids at the Air/Water Interface," Korean Journal of Chemical Engineering, vol. 13, pp. 46-53, 1996.
[125] M. H. Greenhall, P. J. Lukes, M. C. Petty, J. Yarwood, and Y. Lvov, "The Formation and Characterization of Langmuir-Blodgett Films of Dipalmitoylphosphatidic Acid," Thin Solid Films, vol. 243, pp. 596-601, 1994.
[126] C. Yuan, D. Ding, Z. Lu, and J. Liu, "Molecular Positional Order in A Dipalmitoylphosphatidic Acid Langmuir-Blodgett Monolayer by Atomic Force Microscopy," Colloids and Surfaces A: Physicochemical and Engineering Aspects, vol. 150, pp. 1-6, 1999.
[127] D. E. Discher, P. Janmey, and Y.-l. Wang, "Tissue Cells Feel and Respond to the Stiffness of Their Substrate," Science, vol. 310, pp. 1139-1143, 2005.
[128] I. Levental, P. C. Georges, and P. A. Janmey, "Soft Biological Materials and Their Impact on Cell Function," Soft Matter, vol. 3, pp. 299-306, 2007.
[129] A. J. Engler, S. Sen, H. L. Sweeney, and D. E. Discher, "Matrix Elasticity Directs Stem Cell Lineage Specification," Cell, vol. 126, pp. 677-689, 2006.
[130] J. Solon, I. Levental, K. Sengupta, P. C. Georges, and P. A. Janmey, "Fibroblast Adaptation and Stiffness Matching to Soft Elastic Substrates," Biophysical Journal, vol. 93, pp. 4453-4461, 2007.
[131] F. Braet, C. Rotsch, E. Wisse, and M. Radmacher, "Comparison of Fixed and Living Liver Endothelial Cells by Atomic Force Microscopy," Applied Physics A: Materials Science & Processing, vol. 66, pp. S575-S578, 1998.
[132] B. Bhushan and X. Li, "Nanomechanical Characterisation of Solid Surfaces and Thin Films," International Materials Reviews, vol. 48, pp. 125-164, 2003.
[133] J. Wang, F. G. Shi, T. G. Nieh, B. Zhao, M. R. Brongo, S. Qu, and T. Rosenmayer, "Thickness Dependence of Elastic Modulus and Hardness of on-Wafer Low-k Ultrathin Polytetrafluoroethylene Films," Scripta Materialia, vol. 42, pp. 687-694, 2000.
[134] C. Rotsch and M. Radmacher, "Drug-Induced Changes of Cytoskeletal Structure and Mechanics in Fibroblasts: An Atomic Force Microscopy Study," Biophysical Journal, vol. 78, pp. 520-535, 2000.
[135] J.-Y. Rho and G. M. Pharr, "Effects of Drying on the Mechanical Properties of Bovine Femur Measured by Nanoindentation," Journal of Materials Science: Materials in Medcine, vol. 10, pp. 485-488, 1999.
[136] T. Y. Tsui and G. M. Pharr, "Substrate Effects on Nanoindentation Mechanical Property Measurement of Soft Films on Hard Substrates," Journal of Materials Research, vol. 14, pp. 292-301, 1999.
[137] D. A. Brown and E. London, "Structure and Function of Sphingolipid- and Cholesterol-rich Membrane Rafts," Journal of Biological Chemistry, vol. 275, pp. 17221-17224, 2000.
[138] F. R. Maxfield, "Plasma Membrane Microdomains," Current Opinion in Cell Biology, vol. 14, pp. 483-487, 2002.
[139] K. Jacobson, O. G. Mouritsen, and R. G. W. Anderson, "Lipid Rafts: at A Crossroad between Cell Biology and Physics," Nature Cell Biology, vol. 9, pp. 7-14, 2007.
[140] K. Simons and E. Ikonen, "Functional Rafts in Cell Membranes," Nature, vol. 387, pp. 569-572, 1997.
[141] K. Simons and D. Toomre, "Lipid Rafts and Signal Transduction," Nature Reviews Molecular Cell Biology, vol. 1, pp. 31-39, 2000.
[142] R. G. Parton and J. F. Hancock, "Lipid Rafts and Plasma Membrane Microorganization: Insights from Ras," Trends in Cell Biology, vol. 14, pp. 141-147, 2004.
[143] M. Qi, Y. Liu, M. R. Freeman, and K. R. Solomon, "Cholesterol-Regulated Stress Fiber Formation," Journal of Cellular Biochemistry, vol. 106, pp. 1031-1040, 2009.
[144] I. Levitan, Y. Fang, A. Rosenhouse-Dantsker, and V. Romanenko, "Cholesterol and Ion Channels," in Cholesterol Binding and Cholesterol Transport Proteins. vol. 51, 2010, pp. 509-549.
[145] J. Kwik, S. Boyle, D. Fooksman, L. Margolis, M. P. Sheetz, and M. Edidin, "Membrane Cholesterol, Lateral Mobility, and the Phosphatidylinositol 4,5-Bisphosphate-Dependent Organization of Cell Actin," Proceedings of the National Academy of Sciences of the United States of America, vol. 100, pp. 13964-13969, 2003.
[146] T. J. Pucadyil and A. Chattopadhyay, "Cholesterol Depletion Induces Dynamic Confinement of the G-Protein Coupled Serotonin1A Receptor in the Plasma Membrane of Living Cells," Biochimica et Biophysica Acta (BBA) - Biomembranes, vol. 1768, pp. 655-668, 2007.
[147] O. G. Ramprasad, G. Srinivas, S. Rao, P. Joshi, J. P. Thiery, S. Dufour, and G. Pande, "Changes in Cholesterol Levels in the Plasma Membrane Modulate Cell Signaling and Regulate Cell Adhesion and Migration on Fibronectin," Cell Motility and the Cytoskeleton, vol. 64, pp. 199-216, 2007.
[148] L. M. Pierini, R. J. Eddy, M. Fuortes, S. Seveau, C. Casulo, and F. R. Maxfield, "Membrane Lipid Organization Is Critical for Human Neutrophil Polarization," Journal of Biological Chemistry, vol. 278, pp. 10831-10841, 2003.
[149] J. Gatfield and J. Pieters, "Essential Role for Cholesterol in Entry of Mycobacteria into Macrophages," Science, vol. 288, 2000.
[150] P. L. Yeagle, The Membrane of Cells, 2nd ed. San Diego: Academic Press, 1993.
[151] D. Needham and R. S. Nunn, "Elastic Deformation and Failure of Lipid Bilayer Membranes Containing Cholesterol," Biophysical Journal, vol. 58, pp. 997-1009, 1990.
[152] F. J. Byfield, H. Aranda-Espinoza, V. G. Romanenko, G. H. Rothblat, and I. Levitan, "Cholesterol Depletion Increases Membrane Stiffness of Aortic Endothelial Cells," Biophysical Journal, vol. 87, pp. 3336-3343, 2004.
[153] T. K. Klausen, C. Hougaard, E. K. Hoffmann, and S. F. Pedersen, "Cholesterol Modulates the Volume-Regulated Anion Current in Ehrlich-Lettre Ascites Cells via Effects on Rho and F-Actin," American Journal of Physiology: Cell Physiology, vol. 291, pp. C757-C771, 2006.
[154] E. Morachevskaya, A. Sudarikova, and Y. Negulyaev, "Mechanosensitive Channel Activity and F-Actin Organization in Cholesterol-Depleted Human Leukaemia Cells," Cell Biology International, vol. 31, pp. 374-381, 2007.
[155] H. Oh, E. R. Mohler, A. Tian, T. Baumgart, and S. L. Diamond, "Membrane Cholesterol Is A Biomechanical Regulator of Neutrophil Adhesion," Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, pp. 1290-1297, 2009.
[156] M. Westermann, F. Steiniger, and W. Richter, "Belt-Like Localisation of Caveolin in Deep Caveolae and Its Re-Distribution after Cholesterol Depletion," Histochemistry and Cell Biology, vol. 123, pp. 613-620, 2005.