Fluidic force microscopy

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Fluidic force microscopy (FluidFM) is a type of scanning probe microscopy, and is typically used on a standard inverted light microscope.

Contents

The unique characteristic of FluidFM is that it introduces microscopic channels into AFM probes. Those channels can have an aperture of less than 300 nm, or 500 times thinner than a human hair. This nanometric features enables the handling of liquid volumes at the femtoliter (fL) scale as well as force controlled manipulations of sub-micron objects. Via the nanofluidic channels, substances can for example be inserted into single cells or cells can be isolated from a confluent layer.

Technology

Special micropipettes and nanopipettes are used as FluidFM probes with openings between 300 nm and 8 μm. A larger diameter is helpful for single cell adhesion experiments, whereas a smaller diameter provides good opportunities for nanolithography and handling of sub-micron objects. Compared to the traditional glass micropipettes FluidFM probes are much more gentle to soft samples such as cells. They can be controlled with pN and nm precision, and handle volumes more precise and consistent due to their wafer-based fabrication process. FluidFM has unique advantages for single cell applications and beyond.

To control volumes in the fL range FluidFM relies on pressure control. Either overpressure or vacuum is used, depending on the application. Typical operating pressures are in the range of a few hPa.

The FluidFM technology is typically used on top of an inverted microscope. In addition to standard AFM experiments, FluidFM provides the possibility to perform countless other applications, such as single cell injection and adhesion as well as nanolithography and spotting.

Applications

Single cell injection is an important tool for life sciences, biology and medicine. To perform single cell injection experiments, the probe pierces the cell and a substance can be injected. With FluidFM the success rate is almost 100%, in contrast to other methods, because the probes are small, sharp and force sensitive. [1] [2]

A single cell can be isolated either from an adherent, even confluent cell culture or a cell suspension. The isolated cell can then be analysed by established single cell methods or be used to grow a new colony. FluidFM has been used to isolate mammalian cells, yeast and bacteria. [3] [4] [5]

By measuring the adhesion of single cells, important information for different topics in biology and materialscience can be obtained. With FluidFM it is possible to increase the rate in which these experiments can be performed, and even to assess the adhesion of spread cells. The cell of interest is reversibly attached to the probe by applying an underpressure. By raising the probe, the force of the adhesion can be measured with pN resolution. [6] [7] [8]

The method to perform a single bacteria adhesion experiment is the same as for single cells. It provides information about how bacterial cells interact with their surface and with each other. [9]

Colloidal experiments give the opportunity to measure interaction forces between colloidal particles and surfaces as well as the local elasticity of complex substrates. The rate in which these experiments can be performed is rather low because normally colloids have to be pre-glued on an AFM probe. In contrast, the colloid probes can be reversibly attached to the FluidFM probe by underpressure. Therefore, one probe can be used for many experiments and many colloids. [8] [10]

Nanolithography is the process of etching, writing or printing structures in the range of nanometer. Small amounts of fluids can be dispensed via the tip of a probe. With FluidFM the dispensed volumes of sub fL to many pL. FluidFM operates both in air and liquid. [11] [12]

Spotting is the process of printing spots and high density arrays in the range of nanometer to single micrometer. It is possible to print almost any liquid. Printed particles can for example be oligonucleotides, proteins, DNA, virions or bacterial clones. The spots are created when the nanopipette makes contact with the surface and the substance is released of the probe with a short pressure pulse. [12] [13]

Related Research Articles

Colloid Mixture of an insoluble substance microscopically dispersed throughout another substance

A colloid is a mixture in which one substance consisting of microscopically dispersed insoluble particles is suspended throughout another substance. However, some definitions specify that the particles must be dispersed in a liquid, and others extend the definition to include substances like aerosols and gels. The term colloidal suspension refers unambiguously to the overall mixture. A colloid has a dispersed phase and a continuous phase. The dispersed phase particles have a diameter of approximately 1 nanometre to 1 micrometre.

Surface science Study of physical and chemical phenomena that occur at the interface of two phases

Surface science is the study of physical and chemical phenomena that occur at the interface of two phases, including solid–liquid interfaces, solid–gas interfaces, solid–vacuum interfaces, and liquid–gas interfaces. It includes the fields of surface chemistry and surface physics. Some related practical applications are classed as surface engineering. The science encompasses concepts such as heterogeneous catalysis, semiconductor device fabrication, fuel cells, self-assembled monolayers, and adhesives. Surface science is closely related to interface and colloid science. Interfacial chemistry and physics are common subjects for both. The methods are different. In addition, interface and colloid science studies macroscopic phenomena that occur in heterogeneous systems due to peculiarities of interfaces.

Force spectroscopy is a set of techniques for the study of the interactions and the binding forces between individual molecules. These methods can be used to measure the mechanical properties of single polymer molecules or proteins, or individual chemical bonds. The name "force spectroscopy", although widely used in the scientific community, is somewhat misleading, because there is no true matter-radiation interaction.

Atomic force microscopy

Atomic force microscopy (AFM) or scanning force microscopy (SFM) is a very-high-resolution type of scanning probe microscopy (SPM), with demonstrated resolution on the order of fractions of a nanometer, more than 1000 times better than the optical diffraction-limit.

Scanning probe microscopy (SPM) is a branch of microscopy that forms images of surfaces using a physical probe that scans the specimen. SPM was founded in 1981, with the invention of the scanning tunneling microscope, an instrument for imaging surfaces at the atomic level. The first successful scanning tunneling microscope experiment was done by Gerd Binnig and Heinrich Rohrer. The key to their success was using a feedback loop to regulate gap distance between the sample and the probe.

Colloidal gold Suspension of gold nanoparticles in a liquid

Colloidal gold is a sol or colloidal suspension of nanoparticles of gold in a fluid, usually water. The colloid is usually either an intense red colour or blue/purple . Due to their optical, electronic, and molecular-recognition properties, gold nanoparticles are the subject of substantial research, with many potential or promised applications in a wide variety of areas, including electron microscopy, electronics, nanotechnology, materials science, and biomedicine.

Flocculation Process by which colloidal particles come out of suspension to precipitate as floc or flake

Flocculation, in the field of chemistry, is a process by which colloidal particles come out of suspension to sediment under the form of floc or flake, either spontaneously or due to the addition of a clarifying agent. The action differs from precipitation in that, prior to flocculation, colloids are merely suspended, under the form of a stable dispersion, in a liquid and are not truly dissolved in solution.

Self-assembled monolayer

Self-assembled monolayers (SAM) of organic molecules are molecular assemblies formed spontaneously on surfaces by adsorption and are organized into more or less large ordered domains. In some cases molecules that form the monolayer do not interact strongly with the substrate. This is the case for instance of the two-dimensional supramolecular networks of e.g. perylenetetracarboxylic dianhydride (PTCDA) on gold or of e.g. porphyrins on highly oriented pyrolitic graphite (HOPG). In other cases the molecules possess a head group that has a strong affinity to the substrate and anchors the molecule to it. Such a SAM consisting of a head group, tail and functional end group is depicted in Figure 1. Common head groups include thiols, silanes, phosphonates, etc.

Dip-pen nanolithography Scanning probe lithographic technique

Dip pen nanolithography (DPN) is a scanning probe lithography technique where an atomic force microscope (AFM) tip is used to create patterns directly on a range of substances with a variety of inks. A common example of this technique is exemplified by the use of alkane thiolates to imprint onto a gold surface. This technique allows surface patterning on scales of under 100 nanometers. DPN is the nanotechnology analog of the dip pen, where the tip of an atomic force microscope cantilever acts as a "pen," which is coated with a chemical compound or mixture acting as an "ink," and put in contact with a substrate, the "paper."

Single-molecule experiment

A single-molecule experiment is an experiment that investigates the properties of individual molecules. Single-molecule studies may be contrasted with measurements on an ensemble or bulk collection of molecules, where the individual behavior of molecules cannot be distinguished, and only average characteristics can be measured. Since many measurement techniques in biology, chemistry and physics are not sensitive enough to observe single molecules, single-molecule fluorescence techniques caused a lot of excitement, since these supplied many new details on the measured processes that were not accessible in the past. Indeed, since the 1990s, many techniques for probing individual molecules have been developed.

Lipid bilayer characterization is the use of various optical, chemical and physical probing methods to study the properties of lipid bilayers. Many of these techniques are elaborate and require expensive equipment because the fundamental nature of the lipid bilayer makes it a very difficult structure to study. An individual bilayer, since it is only a few nanometers thick, is invisible in traditional light microscopy. The bilayer is also a relatively fragile structure since it is held together entirely by non-covalent bonds and is irreversibly destroyed if removed from water. In spite of these limitations dozens of techniques have been developed over the last seventy years to allow investigations of the structure and function of bilayers. The first general approach was to utilize non-destructive in situ measurements such as x-ray diffraction and electrical resistance which measured bilayer properties but did not actually image the bilayer. Later, protocols were developed to modify the bilayer and allow its direct visualization at first in the electron microscope and, more recently, with fluorescence microscopy. Over the past two decades, a new generation of characterization tools including AFM has allowed the direct probing and imaging of membranes in situ with little to no chemical or physical modification. More recently, dual polarisation interferometry has been used to measure the optical birefringence of lipid bilayers to characterise order and disruption associated with interactions or environmental effects.

Local oxidation nanolithography

Local oxidation nanolithography (LON) is a tip-based nanofabrication method. It is based on the spatial confinement on an oxidation reaction under the sharp tip of an atomic force microscope.

Bromocyclohexane (also called Cyclohexyl bromide, abbreviated CXB) is an organic compound with the chemical formula C6H11Br.

Nanofountain probe

A nanofountain probe (NFP) is a device for 'drawing' micropatterns of liquid chemicals at extremely small resolution. An NFP contains a cantilevered micro-fluidic device terminated in a nanofountain. The embedded microfluidics facilitates rapid and continuous delivery of molecules from the on-chip reservoirs to the fountain tip. When the tip is brought into contact with the substrate, a liquid meniscus forms, providing a path for molecular transport to the substrate. By controlling the geometry of the meniscus through hold time and deposition speed, various inks and biomolecules could be patterned on a surface, with sub 100 nm resolution.

The technique of vibrational analysis with scanning probe microscopy allows probing vibrational properties of materials at the submicrometer scale, and even of individual molecules. This is accomplished by integrating scanning probe microscopy (SPM) and vibrational spectroscopy. This combination allows for much higher spatial resolution than can be achieved with conventional Raman/FTIR instrumentation. The technique is also nondestructive, requires non-extensive sample preparation, and provides more contrast such as intensity contrast, polarization contrast and wavelength contrast, as well as providing specific chemical information and topography images simultaneously.

Scanning electrochemical microscopy (SECM) is a technique within the broader class of scanning probe microscopy (SPM) that is used to measure the local electrochemical behavior of liquid/solid, liquid/gas and liquid/liquid interfaces. Initial characterization of the technique was credited to University of Texas electrochemist, Allen J. Bard, in 1989. Since then, the theoretical underpinnings have matured to allow widespread use of the technique in chemistry, biology and materials science. Spatially resolved electrochemical signals can be acquired by measuring the current at an ultramicroelectrode (UME) tip as a function of precise tip position over a substrate region of interest. Interpretation of the SECM signal is based on the concept of diffusion-limited current. Two-dimensional raster scan information can be compiled to generate images of surface reactivity and chemical kinetics.

Colloidal probe technique

The colloidal probe technique is commonly used to measure interaction forces acting between colloidal particles and/or planar surfaces in air or in solution. This technique relies on the use of an atomic force microscope (AFM). However, instead of a cantilever with a sharp AFM tip, one uses the colloidal probe. The colloidal probe consists of a colloidal particle of few micrometers in diameter that is attached to an AFM cantilever. The colloidal probe technique can be used in the sphere-plane or sphere-sphere geometries. One typically achieves a force resolution between 1 and 100 pN and a distance resolution between 0.5 and 2 nm.

A depletion force is an effective attractive force that arises between large colloidal particles that are suspended in a dilute solution of depletants, which are smaller solutes that are preferentially excluded from the vicinity of the large particles. One of the earliest reports of depletion forces that lead to particle coagulation is that of Bondy, who observed the separation or 'creaming' of rubber latex upon addition of polymer depletant molecules to solution. More generally, depletants can include polymers, micelles, osmolytes, ink, mud, or paint dispersed in a continuous phase.

Electrochemical AFM (EC-AFM) is a particular type of Scanning probe microscopy (SPM), which combines the classical Atomic force microscopy (AFM) together with electrochemical measurements. EC-AFM allows to perform in-situ AFM measurements in an electrochemical cell, in order to investigate the actual changes in the electrode surface morphology during electrochemical reactions. The solid-liquid interface is thus investigated. This technique was developed for the first time in 1996 by Kouzeki et al., who studied amorphous and polycrystalline thin films of Naphthalocyanine on Indium tin oxide in a solution of 0.1 M Potassium chloride (KCl). Unlike the Electrochemical scanning tunneling microscope, previously developed by Itaya and Tomita in 1988, the tip is non-conductive and it is easily steered in a liquid environment.

References

  1. ↑ 2013. O. Guillaume - Gentil, E. Potthoff, D. Ossola, P. Dörig, T. Zambelli & J. A. Vorholt. Force-controlled fluidic injection into single cell nuclei. Small, 9 (11), 1904 – 1907. doi : 10.1002/ smll.201202276
  2. ↑ 2009. A. Meister, M. Gabi, P. Behr, P. Studer, J. Vörös, P. Niedermann, J. Bitterli, J. Polesel - Maris, M. Liley, H. Heinzelmann & T. Zambelli. FluidFM: Combining atomic force microscopy and nanofluidics in a universal liquid delivery system for single cell applications and beyond. Nano Letters, 9 (6), 2501 – 2507. doi : 10.1021/ nl901384x
  3. ↑ 2014 O. Guillaume-Gentil, T. Zambelli & J.A. Vorholt. Isolation of single mammalian cells from adherent cultures by fluidic force microscopy. Lab on a chip, 14(2), 402–14. doi : 10.1039/c3lc51174j
  4. ↑ 2010. P. Dörig, P. Stiefel, P. Behr, E. Sarajlic, D. Bijl, M. Gabi, J. Vörös, J.A. Vorholt & T. Zambelli. Force-controlled spatial manipulation of viable mammalian cells and micro-organisms by means of FluidFM technology. Applied Physics Letters, 97(2), 023701 1–3. doi : 10.1063/1.3462979
  5. ↑ 2013. P. Stiefel, T. Zambelli & J.A. Vorholt. Isolation of optically targeted single bacteria by application of fluidic force microscopy to aerobic anoxygenic phototrophs from the phyllosphere. Applied and Environmental Microbiology, 79(16), 4895–4905. doi : 10.1128/AEM.01087-13
  6. ↑ 2014. E. Potthoff, D. Franco, V. D’Alessandro, C. Starck, V. Falk, T. Zambelli, J. A. Vorholt, D. Poulikakos & A. Ferrari. Toward a rational design of surface textures promoting endothelialization. Nano Letters, 14 (2), 1069 – 1079. doi : 10.1021/nl4047398
  7. ↑ 2012. E. Potthoff, O. Guillaume - Gentil, D. Ossola, J. Polesel - Maris, S. LeibundGut - Landmann, T. Zambelli & J. A. Vorholt. Rapid and Serial Quantification of Adhesion Forces of Yeast and Mammalian Cells. PLoS ONE, 7 (12), e52712. doi : 10.1371/journal.pone.0052712
  8. 1 2 2013. P. Dörig, D. Ossola, A. M. Truong, M. Graf, F. Stauffer, J. Vörös & T. Zambelli. Exchangeable colloidal AFM probes for the quantification of irreversible and long-term interactions. Biophysical Journal, 105 (2), 463 – 472. doi : 10.1016/j.bpj.2013.06.002
  9. ↑ 2015. E. Potthoff, D. Ossola, T. Zambelli & J. A. Vorholt. Bacterial adhesion force quantification by fluidic force microscopy. (2015) Nanoscale, 7 (9), 4070 – 4079. doi : 10.1039/c4nr06495j
  10. ↑ 2015. B. R. Simona, L. Hirt, L. Demkó, T. Zambelli, J. Vörös, M. Ehrbar & V. Milleret. Density gradients at hydrogel interfaces for enhanced cell penetration. Biomater. Sci. doi : 10.1039/C4BM00416G
  11. ↑ 2013. R. R. Grüter, J. Vörös & T. Zambelli. FluidFM as a lithography tool in liquid: spatially controlled deposition of fluorescent nanoparticles. Nanoscale, 5 (3), 1097 – 104. doi : 10.1039/c2nr33214k
  12. 1 2 2014. H. Dermutz, R. R. Grüter, A.M. Truong, L. Demkó, J. Vörös & T. Zambelli. Local polymer replacement for neuron patterning and in situ neurite guidance. Langmuir: the ACS journal of surfaces and colloids, 30 (23), 7037 – 46. doi : 10.1021/la5012692
  13. ↑ 2009. A. Meister, J. Polesel - Maris, P. Niedermann, J. Przybylska, P. Studer, M. Gabi, P. Behr, T. Zambelli, M. Liley, J. Vörös & H. Heinzelmann. Nanoscale dispensing in liquid environment of streptavidin on a biotin-functionalized surface using hollow atomic force microscopy probes. Microelectronic Engineering, 86( 4-6), 1481 – 1484. doi : 10.1016/j.mee.2008.10.025
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