Atomic Force Microscopy as a Tool to Study Transport Phenomena in Biological Systems

Biological interactions often involve the transport of molecules, ions, or other species across biological membranes or between interacting proteins. The understanding of these transport phenomena is crucial for the development of therapies for various diseases. Atomic force microscopy is a powerful tool that has been increasingly used to study biological systems at the nano scale. The high resolution, quantitative measurements, and the ability to probe biological interactions under near-physiological conditions make AFM an attractive tool for investigating transport phenomena in biological systems. In this article, we focus on the use of AFM in the study of the transport phenomena in biological systems. We discuss the principles of AFM, its instrumentation, and its application in the study of biomolecules and biological systems. We also provide a comprehensive overview of recent articles that have utilized AFM in the study of biomarkers in biological systems.

[1]  J. H. Viles.  Imaging Amyloid‐β Membrane Interactions: Ion‐Channel Pores and Lipid‐Bilayer Permeability in Alzheimer's Disease , 2023, Angewandte Chemie.

[2]  Mi Li,et al.  Nanomechanical Signatures of Extracellular Vesicles from Hematologic Cancer Patients Unraveled by Atomic Force Microscopy for Liquid Biopsy. , 2023, Nano letters.

[3]  P. D. de Pablo,et al.  Exploring nucleic acid condensation and release from individual parvovirus particles with different physicochemical cues. , 2023, Virology.

[4]  D. Alsteens,et al.  Stepwise Enzymatic-Dependent Mechanism of Ebola Virus Binding to Cell Surface Receptors Monitored by AFM. , 2022, Nano letters.

[5]  Joon Won Park,et al.  Nanoscale Force-Mapping-Based Quantification of Low-Abundance Methylated DNA. , 2022, Nano letters.

[6]  M. van Galen,et al.  Single-Molecule Force Spectroscopy of a Tetraaryl Succinonitrile Mechanophore , 2022, The journal of physical chemistry. C, Nanomaterials and interfaces.

[7]  S. Taneva,et al.  Morphometry and Stiffness of Red Blood Cells—Signatures of Neurodegenerative Diseases and Aging , 2021, International journal of molecular sciences.

[8]  N. Kodera,et al.  Macrocyclic Peptide-Conjugated Tip for Fast and Selective Molecular Recognition Imaging by High-Speed Atomic Force Microscopy. , 2021, ACS applied materials & interfaces.

[9]  M. Mulato,et al.  Electrochemical aptasensor for NS1 detection: Towards a fast dengue biosensor. , 2021, Talanta.

[10]  P. Nirmalraj,et al.  Spatial organization of protein aggregates on red blood cells as physical biomarkers of Alzheimer’s disease pathology , 2021, Science advances.

[11]  Chulhong Kim,et al.  Dual-pulse photoactivated atomic force microscopy , 2021, Scientific Reports.

[12]  Ping Ma,et al.  Details of Single-Molecule Force Spectroscopy Data Decoded by a Network-Based Automatic Clustering Algorithm. , 2021, The journal of physical chemistry. B.

[13]  S. Mallik,et al.  Dynamic cellular biomechanics in responses to chemotherapeutic drug in hypoxia probed by atomic force spectroscopy , 2021, Oncotarget.

[14]  Peng Zheng,et al.  Pioglitazone Inhibits Metal Cluster Transfer of mitoNEET by Stabilizing the Labile Fe-N Bond Revealed at Single-Bond Level. , 2021, The journal of physical chemistry letters.

[15]  A. Teixeira,et al.  Spatial Regulation of T-Cell Signaling by Programmed Death-Ligand 1 on Wireframe DNA Origami Flat Sheets , 2021, ACS nano.

[16]  J. Révilloud,et al.  Mechanical properties of 3D tumor spheroids measured by AFM , 2020, Computer Methods in Biomechanics and Biomedical Engineering.

[17]  Christian Fuentes,et al.  Activation of P2X4 receptors induces an increase in the area of the extracellular region and a decrease in receptor mobility , 2020, FEBS letters.

[18]  Zuobin Wang,et al.  Direct imaging of antigen–antibody binding by atomic force microscopy , 2020, Applied Nanoscience.

[19]  Z. Kis,et al.  Topography, Spike Dynamics, and Nanomechanics of Individual Native SARS-CoV-2 Virions , 2020, bioRxiv.

[20]  T. Rakshit,et al.  Identification of Biomarker Hyaluronan on Colon Cancer Extracellular Vesicles Using Correlative AFM and Spectroscopy. , 2020, The journal of physical chemistry letters.

[21]  F. Braet,et al.  Biophysical nanocharacterization of liver sinusoidal endothelial cells through atomic force microscopy , 2020, Biophysical Reviews.

[22]  Yuen Kuan Yong,et al.  AFM Cantilever Design for Multimode Q Control: Arbitrary Placement of Higher Order Modes , 2020, IEEE/ASME Transactions on Mechatronics.

[23]  R. Daza,et al.  Functionalization of atomic force microscopy cantilevers and tips by activated vapour silanization , 2019, Applied Surface Science.

[24]  Jaydev P. Desai,et al.  Viscoelastic Properties of Human Autopsy Brain Tissues as Biomarkers for Alzheimer's Diseases , 2019, IEEE Transactions on Biomedical Engineering.

[25]  Lianqing Liu,et al.  Nanoscale Multiparametric Imaging of Peptide-Assembled Nanofibrillar Hydrogels by Atomic Force Microscopy , 2019, IEEE Transactions on Nanotechnology.

[26]  Tony M. Yen,et al.  Array atomic force microscopy for real-time multiparametric analysis , 2019, Proceedings of the National Academy of Sciences.

[27]  T. Hianik,et al.  DNA Aptamers in the Detection of Leukemia Cells by the Thickness Shear Mode Acoustics Method. , 2019, Chemphyschem : a European journal of chemical physics and physical chemistry.

[28]  B. Walkowiak,et al.  Sensing of silver nanoparticles on/in endothelial cells using atomic force spectroscopy , 2018, Journal of molecular recognition : JMR.

[29]  B. Shapiro,et al.  Dynamic Behavior of RNA Nanoparticles Analyzed by AFM on a Mica/Air Interface. , 2018, Langmuir : the ACS journal of surfaces and colloids.

[30]  Takayuki Uchihashi,et al.  Applications of high-speed atomic force microscopy to real-time visualization of dynamic biomolecular processes. , 2018, Biochimica et biophysica acta. General subjects.

[31]  Roger M. Leblanc,et al.  Crossing the blood‐brain barrier with nanoparticles , 2018, Journal of controlled release : official journal of the Controlled Release Society.

[32]  D. Müller,et al.  Combining confocal and atomic force microscopy to quantify single-virus binding to mammalian cell surfaces , 2017, Nature Protocols.

[33]  K. Sridharan,et al.  Tribochemical Wear of Diamond-Like Carbon-Coated Atomic Force Microscope Tips. , 2017, ACS applied materials & interfaces.

[34]  Mingjie Tang,et al.  Interrogation of drug effects on HeLa cells by exploiting new AFM mechanical biomarkers , 2017 .

[35]  A. J. Weymouth.  Non-contact lateral force microscopy , 2017, Journal of physics. Condensed matter : an Institute of Physics journal.

[36]  Jean-Luc Pellequer,et al.  Standardized Nanomechanical Atomic Force Microscopy Procedure (SNAP) for Measuring Soft and Biological Samples , 2017, Scientific Reports.

[37]  Lianqing Liu,et al.  A novel approach for extracting viscoelastic parameters of living cells through combination of inverse finite element simulation and Atomic Force Microscopy , 2017, Computer methods in biomechanics and biomedical engineering.

[38]  M. Šnejdárková,et al.  Characterization of the specific interaction between the DNA aptamer sgc8c and protein tyrosine kinase-7 receptors at the surface of T-cells by biosensing AFM , 2017, Analytical and Bioanalytical Chemistry.

[39]  N. Xi,et al.  The dynamic interactions between chemotherapy drugs and plasmid DNA investigated by atomic force microscopy , 2017, Science China Materials.

[40]  Q. Zou,et al.  Design, fabrication, and characterization of polymer-based cantilever probes for atomic force microscopes , 2016 .

[41]  Yuechao Wang,et al.  Nanoscale Quantifying the Effects of Targeted Drug on Chemotherapy in Lymphoma Treatment Using Atomic Force Microscopy , 2016, IEEE Transactions on Biomedical Engineering.

[42]  Qing Luo,et al.  Cell stiffness determined by atomic force microscopy and its correlation with cell motility. , 2016, Biochimica et biophysica acta.

[43]  Lianqing Liu,et al.  Rapid recognition and functional analysis of membrane proteins on human cancer cells using atomic force microscopy. , 2016, Journal of immunological methods.

[44]  N. Xi,et al.  Effects of methotrexate on the viscoelastic properties of single cells probed by atomic force microscopy , 2016, Journal of biological physics.

[45]  Peter Schön,et al.  Imaging and force probing RNA by atomic force microscopy. , 2016, Methods.

[46]  X. Fang,et al.  Metformin is a novel suppressor for transforming growth factor (TGF)-β1 , 2016, Scientific Reports.

[47]  Bingqian Xu,et al.  Real-time single molecular study of a pretreated cellulose hydrolysis mode and individual enzyme movement , 2016, Biotechnology for Biofuels.

[48]  Blake W Erickson,et al.  Harnessing the damping properties of materials for high-speed atomic force microscopy. , 2016, Nature nanotechnology.

[49]  Y. Dufrêne,et al.  Atomic force microscopy reveals a dual collagen‐binding activity for the staphylococcal surface protein SdrF , 2016, Molecular microbiology.

[50]  M. Lekka.  Discrimination Between Normal and Cancerous Cells Using AFM , 2016, BioNanoScience.

[51]  Yves F Dufrêne,et al.  Sticky microbes: forces in microbial cell adhesion. , 2015, Trends in microbiology.

[52]  Shu Han Chen,et al.  Gold-coated AFM tips for tip-enhanced Raman spectroscopy: theoretical calculation and experimental demonstration. , 2015, Optics express.

[53]  H. Sugiyama,et al.  Small molecule binding to a G-hairpin and a G-triplex: a new insight into anticancer drug design targeting G-rich regions. , 2015, Chemical communications.

[54]  Bingqian Xu,et al.  High-resolution probing heparan sulfate-antithrombin interaction on a single endothelial cell surface: single-molecule AFM studies. , 2015, Physical chemistry chemical physics : PCCP.

[55]  Qingze Zou,et al.  An Atomic Force Microscope Study Revealed Two Mechanisms in the Effect of Anticancer Drugs on Rate-Dependent Young’s Modulus of Human Prostate Cancer Cells , 2015, PloS one.

[56]  Kristina Haase,et al.  Investigating cell mechanics with atomic force microscopy , 2015, Journal of The Royal Society Interface.

[57]  O. Sahin,et al.  Imaging and three-dimensional reconstruction of chemical groups inside a protein complex using atomic force microscopy. , 2015, Nature nanotechnology.

[58]  Miguel A R B Castanho,et al.  Apoptotic human neutrophil peptide-1 anti-tumor activity revealed by cellular biomechanics. , 2015, Biochimica et biophysica acta.

[59]  V. Yadavalli,et al.  Spatial recognition and mapping of proteins using DNA aptamers , 2014, Nanotechnology.

[60]  A. Alessandrini,et al.  Phase transitions in supported lipid bilayers studied by AFM. , 2014, Soft matter.

[61]  Bingqian Xu,et al.  Mapping single molecular binding kinetics of carbohydrate-binding module with crystalline cellulose by atomic force microscopy recognition imaging. , 2014, The journal of physical chemistry. B.

[62]  Bingqian Xu,et al.  Determining the elastic properties of aptamer-ricin single molecule multiple pathway interactions , 2014 .

[63]  Juan Li,et al.  Detection of erythrocytes in patients with Waldenstrom macroglobulinemia using atomic force microscopy. , 2014, Acta biochimica et biophysica Sinica.

[64]  Kecheng Li,et al.  Interactive forces between lignin and cellulase as determined by atomic force microscopy , 2014, Biotechnology for Biofuels.

[65]  Marco M. Domingues,et al.  Antimicrobial protein rBPI21-induced surface changes on Gram-negative and Gram-positive bacteria. , 2014, Nanomedicine : nanotechnology, biology, and medicine.

[66]  Bingqian Xu,et al.  Transition model for ricin-aptamer interactions with multiple pathways and energy barriers. , 2014, Physical review. E, Statistical, nonlinear, and soft matter physics.

[67]  S. Lindsay,et al.  Application of catalyst-free click reactions in attaching affinity molecules to tips of atomic force microscopy for detection of protein biomarkers. , 2013, Langmuir : the ACS journal of surfaces and colloids.

[68]  R. Kumar,et al.  Mapping out the structural changes of natural and pretreated plant cell wall surfaces by atomic force microscopy single molecular recognition imaging , 2013, Biotechnology for Biofuels.

[69]  Bingqian Xu,et al.  Measurements of single molecular affinity interactions between carbohydrate-binding modules and crystalline cellulose fibrils. , 2013, Physical chemistry chemical physics : PCCP.

[70]  G. Meyer,et al.  Different tips for high-resolution atomic force microscopy and scanning tunneling microscopy of single molecules , 2013 .

[71]  Catharine G. Clark,et al.  Atomic force microscopy to characterize binding properties of α7‐containing nicotinic acetylcholine receptors on neurokinin‐1 receptor‐expressing medullary respiratory neurons , 2013, Experimental physiology.

[72]  N. Xi,et al.  Atomic force microscopy imaging and mechanical properties measurement of red blood cells and aggressive cancer cells , 2012, Science China Life Sciences.

[73]  Xiaohong Fang,et al.  Living cell study at the single-molecule and single-cell levels by atomic force microscopy. , 2012, Nanomedicine.

[74]  Jilin Tang,et al.  Single molecular recognition force spectroscopy study of a luteinizing hormone-releasing hormone analogue as a carcinoma target drug. , 2012, The journal of physical chemistry. B.

[75]  Byungkyu Kim,et al.  Cell Stiffness Is a Biomarker of the Metastatic Potential of Ovarian Cancer Cells , 2012, PloS one.

[76]  Bingqian Xu,et al.  Imaging and measuring single-molecule interaction between a carbohydrate-binding module and natural plant cell wall cellulose. , 2012, The journal of physical chemistry. B.

[77]  D. Fotiadis.  Atomic force microscopy for the study of membrane proteins. , 2012, Current opinion in biotechnology.

[78]  Clarice Steffens,et al.  Atomic Force Microscopy as a Tool Applied to Nano/Biosensors , 2012, Sensors.

[79]  Guowen Zhang,et al.  Probing the binding of the flavonoid diosmetin to human serum albumin by multispectroscopic techniques. , 2012, Journal of agricultural and food chemistry.

[80]  Zbigniew Stachura,et al.  Cancer cell detection in tissue sections using AFM. , 2012, Archives of biochemistry and biophysics.

[81]  Bingqian Xu,et al.  Following aptamer-ricin specific binding by single molecule recognition and force spectroscopy measurements. , 2012, Chemical communications.

[82]  Richard E. Carson,et al.  Reduced Amygdala Serotonin Transporter Binding in Posttraumatic Stress Disorder , 2011, Biological Psychiatry.

[83]  R. Lal,et al.  Potential role of atomic force microscopy in systems biology , 2011, Wiley interdisciplinary reviews. Systems biology and medicine.

[84]  C. Wyman,et al.  Protein-DNA interactions in high speed AFM: single molecule diffusion analysis of human RAD54. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[85]  N. Voelcker,et al.  Atomic force microscopy-based antibody recognition imaging of proteins in the pathological deposits in pseudoexfoliation syndrome. , 2011, Ultramicroscopy.

[86]  S. Kazarian,et al.  Tip-enhanced Raman mapping with top-illumination AFM , 2011, Nanotechnology.

[87]  Yong Chen,et al.  AFM force measurements of the gp120-sCD4 and gp120 or CD4 antigen-antibody interactions. , 2011, Biochemical and biophysical research communications.

[88]  M. Dong,et al.  A nanomechanical interface to rapid single-molecule interactions. , 2011, Nature communications.

[89]  Bharath Bhikkaji,et al.  A New Scanning Method for Fast Atomic Force Microscopy , 2011, IEEE Transactions on Nanotechnology.

[90]  V. Ramgopal Rao,et al.  A novel technique for microfabrication of ultra-thin affinity cantilevers for characterization with an AFM , 2010 .

[91]  S. Howorka,et al.  Nanomechanical recognition measurements of individual DNA molecules reveal epigenetic methylation patterns. , 2010, Nature nanotechnology.

[92]  Mitchel J Doktycz,et al.  Atomic force microscopy of biological samples. , 2010, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[93]  Dora Brites,et al.  Looking at the blood–brain barrier: Molecular anatomy and possible investigation approaches , 2010, Brain Research Reviews.

[94]  N. Santos,et al.  Atomic force microscopy-based molecular recognition of a fibrinogen receptor on human erythrocytes. , 2010, ACS nano.

[95]  Georg E. Fantner,et al.  Kinetics of Antimicrobial Peptide Activity Measured on Individual Bacterial Cells Using High Speed AFM , 2010, Nature nanotechnology.

[96]  U. Mony,et al.  Atomic force microscopic study of folate receptors in live cells with functionalized tips , 2009 .

[97]  N. Wilson,et al.  Carbon nanotube tips for atomic force microscopy. , 2009, Nature nanotechnology.

[98]  Y. Lyubchenko,et al.  AFM for analysis of structure and dynamics of DNA and protein-DNA complexes. , 2009, Methods.

[99]  John H. White,et al.  Atomic force microscopy of the EcoKI Type I DNA restriction enzyme bound to DNA shows enzyme dimerization and DNA looping , 2009, Nucleic acids research.

[100]  M. Kawakami,et al.  A new atomic force microscope force ramp technique using digital force feedback control reveals mechanically weak protein unfolding events , 2008, Nanotechnology.

[101]  F. Kienberger,et al.  Multiple receptors involved in human rhinovirus attachment to live cells , 2008, Proceedings of the National Academy of Sciences.

[102]  Ehsan Gazi,et al.  Measurement of elastic properties of prostate cancer cells using AFM. , 2008, The Analyst.

[103]  C. Lim,et al.  AFM indentation study of breast cancer cells. , 2008, Biochemical and biophysical research communications.

[104]  David A. Rendon,et al.  Localized elasticity measured in epithelial cells migrating at a wound edge using atomic force microscopy. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[105]  Ludger Koenders,et al.  Aspects of scanning force microscope probes and their effects on dimensional measurement , 2008 .

[106]  Francesc Pérez-Murano,et al.  Crystalline silicon cantilevers for piezoresistive detection of biomolecular forces , 2008 .

[107]  Hongbin Li,et al.  Atomic force microscopy reveals parallel mechanical unfolding pathways of T4 lysozyme: Evidence for a kinetic partitioning mechanism , 2008, Proceedings of the National Academy of Sciences.

[108]  Chunhai Fan,et al.  Aptamer-based biosensors , 2008 .

[109]  M. Taranta,et al.  Probing the interaction between p53 and the bacterial protein azurin by single molecule force spectroscopy , 2008, Journal of molecular recognition : JMR.

[110]  Ricardo Garcia,et al.  Force microscopy imaging of individual protein molecules with sub‐pico Newton force sensitivity , 2007, Journal of molecular recognition : JMR.

[111]  W. Coetzee,et al.  The regulation of ion channels and transporters by glycolytically derived ATP , 2007, Cellular and Molecular Life Sciences.

[112]  B. Ruozi,et al.  Application of atomic force microscopy to characterize liposomes as drug and gene carriers. , 2007, Talanta.

[113]  Olav Solgaard,et al.  An atomic force microscope tip designed to measure time-varying nanomechanical forces , 2007, Nature Nanotechnology.

[114]  Lei Jiang,et al.  MAC mode atomic force microscopy studies of living samples, ranging from cells to fresh tissue. , 2007, Ultramicroscopy.

[115]  Ling Wang,et al.  Single-molecule force spectroscopy and imaging of the vancomycin/D-Ala-D-Ala interaction. , 2007, Nano letters.

[116]  Yves F Dufrêne,et al.  Atomic force microscopy of microbial cells: application to nanomechanical properties, surface forces and molecular recognition forces. , 2007, Colloids and surfaces. B, Biointerfaces.

[117]  J. A. Plaza,et al.  Modified atomic force microscopy cantilever design to facilitate access of higher modes of oscillation , 2006 .

[118]  Daniel J. Muller,et al.  A new technical approach to quantify cell-cell adhesion forces by AFM. , 2006, Ultramicroscopy.

[119]  S. Connell,et al.  The atomic force microscope as a tool for studying phase separation in lipid membranes (Review) , 2006 .

[120]  S. Cannistraro,et al.  Single molecule recognition between cytochrome C 551 and gold-immobilized azurin by force spectroscopy. , 2005, Biophysical journal.

[121]  B. Clare,et al.  Antigen binding forces of single antilysozyme Fv fragments explored by atomic force microscopy. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[122]  Ferry Kienberger,et al.  Single molecule studies of antibody-antigen interaction strength versus intra-molecular antigen stability. , 2005, Journal of molecular biology.

[123]  T. Camesano,et al.  Polysaccharide properties probed with atomic force microscopy , 2003, Journal of microscopy.

[124]  A. Vasella,et al.  Probing specific lectin-carbohydrate interactions using atomic force microscopy imaging and force measurements , 2003 .

[125]  V. Daggett,et al.  Can non-mechanical proteins withstand force? Stretching barnase by atomic force microscopy and molecular dynamics simulation. , 2001, Biophysical journal.

[126]  Ami Chand,et al.  Probing protein–protein interactions in real time , 2000, Nature Structural Biology.

[127]  M. Esashi,et al.  Capacitive AFM Probe for High Speed Imaging , 1998 .

[128]  Gang-yu Liu,et al.  Atomic Force Microscopic Study of Specific Antigen/Antibody Binding , 1997 .

[129]  H Schindler,et al.  Detection and localization of individual antibody-antigen recognition events by atomic force microscopy. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[130]  C. Quate,et al.  Atomic resolution with an atomic force microscope using piezoresistive detection , 1993 .

[131]  H. Hansma,et al.  Atomic force microscopy of DNA in aqueous solutions. , 1993, Nucleic acids research.

[132]  N. Amer,et al.  Novel optical approach to atomic force microscopy , 1988 .

[133]  Małgorzata Lekka,et al.  Atomic force microscopy as a tool for assessing the cellular elasticity and adhesiveness to identify cancer cells and tissues. , 2018, Seminars in cell & developmental biology.

[134]  Ning Xi,et al.  Viscoelastic Properties Measurement of Human Lymphocytes by Atomic Force Microscopy Based on Magnetic Beads Cell Isolation. , 2016, IEEE transactions on nanobioscience.

[135]  I. Martins,et al.  Dengue virus capsid protein interacts specifically with very low-density lipoproteins. , 2014, Nanomedicine : nanotechnology, biology, and medicine.

[136]  Jiye Cai,et al.  Detection of erythrocytes in patient with elliptocytosis complicating ITP using atomic force microscopy. , 2011, Micron.

[137]  Tomasz Grodzicki,et al.  Erythrocyte stiffness probed using atomic force microscope. , 2005, Biorheology.

[138]  Gerber,et al.  Atomic Force Microscope , 2020, Definitions.