Detection of Highly Dangerous Pathogens

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techniques (including soft lithography, photolithography, dip-pen lithography, cAFM ... 'Soft lithography' refers a group of methods, which include several ...
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Edited by Tanja Kostic, Patrick Butaye, and Jacques Schrenzel

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Detection of Highly Dangerous Pathogens Microarray Methods for BSL3 and BSL4 Agents

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Detection of Highly Dangerous Pathogens Microarray Methods for the Detection of BSL 3 and BSL4 Agents

Edited by Tanja Kostic, Patrick Butaye, and jacques Schrenzel

@9 WILEYBLACKWELL

WILEY-VCH Verlag GmbH & Co. KGaA

5 Patterning Techniques for Array Platforms Erhan

Pi~kin,

Bora Garipcan, Gokhan Demire/, and Oguzhan c;aglayan

5.1 Introduction

Thousands of genes and the products they encode (i.e. proteins) function in a complicated and orchestrated way that creates the mystery oflife of all organisms. In 'genomics', the genes of organisms, their functions and activities are investigated. Genomics is naturally linked to 'proteomics' -the study of the proteins encoded by the organism's genome. Genomics in combination with proteomics resulted in fascinating biomedical research; however, it requires large-scale and high-throughput methodologies [1-3]. High-throughput techniques using DNA and protein microarrays have accelerated _the process of understanding gene and protein functions in living organism. 'Macrochips' contain sample spot sizes of about 300 Jlm or larger, and can be easily imaged by existing gel and blot scanners. The sample spot sizes in a 'microchip' are typically less than 200 Jlm in diameter. The further improvement and developments in array technology led to the introduction of the term 'nanoarray technologies' in the literature. Nanometric biomolecular arrays may enable high-throughput screening of biomolecules at the single-molecule level. Also, with precise control on position and orientation of individual molecules, such arrays may become powerful tools for studying multivalent and multicomponent molecular interactions in biological systems (4]. To these ends, protein arrays andjor DNA arrays with feature sizes smaller than 100 nm have been fabricated by novel techniques, mostly using dip-pen nanolithography (DPN), conductive atomic force microscopy (cAFM) nanolithography and nanografting (4, 5]. One ofthe essential elements ofthe arrays at any size range is ofcourse patterning of the substrate surfaces. Surface patterning is a method tocreate two-dimensional predesigned heterogeneous surfaces with differentjdesired morphology, hydrophilic/ hydrophobic characteristics and/ or chemical functionality within well-defined regions in the micro- or nanoscale, as schematically exemplified in Figure 5.1. Different techniques (including soft lithography, photolithography, dip-pen lithography, cAFM

Detection of Highly Dangerous Pathogens: Microarray Methods for the Detection of BSL 3 and BSL 4 Agents Edited by Tanja Kostic, Patrick Butaye, and Jacques Schrenzel Copyright© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32275-6

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Patterning Techniques for Array Platforms

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lithography, nanoshaving, nanografting, etc.) have been developed to create novel patterned surfaces, which are briefly described in this chapter together with some recent interesting applications. We focus here mainly on preparation of array platforms for biorecognition of microorganisms.

5.2 Soft Lithography

'Soft lithography' refers a group of methods, which include several approaches such as 'rnicrocontact printing' (J.LCP), 'replica molding', 'rnicrotransfer molding' [6], 'rnicromolding in capillaries' [7], 'solvent-assisted rnicromolding' [8] and 'near-field phase shift lithography' [9, 10] In general, the common feature in soft lithography approaches is using an elastomeric stamp with pre-patterned structures on its solid surface. This creates patterns and structures with sizes in the range of 30 nm to 100 J.Lm on the target array platform surfaces. As schematically described in Figure 5.2, there are a series of common steps in soft lithography; for instance, J.LCP includes the following steps [10]. (1) A master pattern surface (usually silicon), which will be used as a mold, is prepared by different techniques (including 'photolithography' [11], 'e-beam patterning' [12], 'reactive ion etching' [13], etc.) in a selected design that will be the final pattern on the substrate surface. (2) A liquid pre· polymer (e.g. polydimethylsiloxane) is then cast on the structured master surface, and cured (for cross-linking) by applying heat andjor radiation [i.e. ultraviolet (UV) radiation] to reach a cross-linked elastomeric structure, which is subsequently used as the elastomeric stamp in the further steps. (3) The stamp is then treated ('inked') with the solution containing the molecules to be printed. (4) In the final step, the molecules are transferred by printing onto the substrate. Once the stamp has been inked and dried, the stamp is then briefly pressed onto a solid substrate via mechanical contact and the 'ink' molecules transfer from the polymeric stamp to

5. 2 Soft Lithography

(1)

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INK SOLUTION

(2)

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ARRAY PLATFORM Figure 5.2 Schematic description of the !J.CP protocol: (1) preparation of the master surface, (2) preparation of the elastomeric stamp, (3) 'inking' the patterned surface of the stamp and (4) printing (transfer of the 'ink') on the substrate surface.

the solid substrate where they self-assemble into pre-determined patterns by the relief patterns of the stamp. Soft lithography has attracted a lot ofresearch interest and is regarded as one of the most widely used patterning techniques due to the following advantages: low cost, easy to prepare, straightforward to apply and accessible, operates with a wide range of controllable surface chemistry options, many features can be printed simultaneously with one stamp application, a relatively high spatial resolution of features produced (line widths of less than lOOnm), large printing capability to form patterned microstructures on non-planar surfaces and, finally, it does not need a photoreactive surface to create a nanostructure. Nevertheless, it has also limitations, which will eventually be solved by future technological developments. The disadvantages are the restrictions in the resolution ofthe resulting patterns (which depends on the material and dimensions of the elastomeric stamp), the deformation and distortion of the elastomeric stamp, and the limitations concerning the reproducibility, which is dependent on the stamp's resistance to degradation. There are many reports on the preparation of patterned surfaces for a wide variety of application using soft lithography [14--16], Some examples are given below. Howell et al. designed and constructed patterned microarrays carrying antibody probes for detection of several bacteria (i.e. Escherichia coli and Renibacterium salmoninarum) [17]. They were able to demonstrate the selective binding of the bacteria on the regions containing specific antibodies. Weibel et al. developed a series ofbacterial stamps [18]. They started from an agarose stamp, attached the bacteria on the patterns from bacterial suspensions and then printed (transferred) the bacteria

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onto agar media in culture plates. They were able to deposit Vibrio fischeri colonies onto agar surface with different pattern designs.

5.3 Photolithography

Photolithography is one of the most widely studied lithography techniques and is a non-contact printing approach that has the following two advantages over mechanical contact printing methods: (i) reduced contamination and (ii) higher throughput [19-23]. It uses photoresistive masks and photoactive materialsjmolecules. In one of the most common approaches, the substrate surface carrying functional groups is first coated (usually spin-coated) with an inert but photoactive polymer layer. Then, it is exposed to UV light through a photomask (having patterned openings). As such, the UV-exposed areas are cross-linked, and the non-cross-linked parts are dissolved and removed from the surface. The created openings (patterns) can be used for further probe immobilization steps. Alternatively, substrate surfaces can also be coated first with photoactive molecules that carry functional groups for probe immobilization. The photomask is then placed onto the surface and the light activates or inactivates the surface photosensitive molecules through the openings in the mask. Thus, probe molecules are immobilized onto the activated molecules in a patterned way. A similar approach has been applied for manufacturing DNA arrays. Here, oligodeoxynucleotide (0 D N) probes are synthesized 'in situ' using photolithographic techniques and modified ODN synthesis chemistry [24, 25]. As schematically presented in Figure 5.3, the array substrate surface is coated with photosensitive modified

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5.4 Robotic Printing

nucleotides and then the selected parts are activated by turning the light on using a photomask (Mask 1). Subsequently, the second layer is attached via these activated molecules. The procedure is continued in a similar way until ODNs have reached the desired length. This state-of-the-art methodology provides the possibility to interrogating hundreds of thousands of sequences per assay, and allows wide flexibility in design ofcustom arrays without preliminary efforts in synthesis and maintenance ofa vast library of modified ODNs [26]. On the other hand, in situ synthesis does not allow quality control and purification of generated features, and the less-efficient phosphorarnidite monomer coupling gives poor yields for longer ODN probes.

5.4 Robotic Printing

There are several robotic printing techniques able to create patterned surfaces and immobilize probes (bioligands) on patterns. Usually a computer-controlled robotic holder ('ann') or motion-control print,head, with different types of pins carrying the probes molecules, moves on the substrate surface and delivers the probes to the designated areas. As the material is deposited in liquid form, water-based chemistry, which is common in biology, can be used. Here, we briefly discuss two common robotic printing technologies - micro-spotting and ink-jet printing. 5.4.1 Micro-Spotting

Micro-spotting technology is widely used for manufacturing nucleic acid and protein arrays [27, 28]. A typical system consists of a motion-control system fitted with a holder or print-head and one or more micro-spotting pins. As depicted schematically in Figure 5.4, the pin is first brought to the target point (1); it is moved in the Spotting pin

La1 Substrate

Figure 5.4 Delivery mechanism of micro-spotting.

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z-direction, usually close to or even on the surface, and leaves a droplet of liquid behind (2) . Then, the pin is moved to another point (3). A variety of different pins are available. The volume of the liquid that can be loaded on a pin ('loading volume') and the volume of the droplet delivered ('print volume') are in the range of 0.2-1.0 ).ll and 0.5-2.5 nl, respectively. Spot size can vary from 50 to 350 )liD and spot density from 500 to 10 000 spotsfcm2 • All these properties are dependent on the pin design and droplet properties (e.g. surface tension, viscosity, density, etc.). The volume of the droplet delivered cannot be programmed, which is one of the main disadvantages of micro-spotting; ·however, it is very simple compared to injection units and significantly cheaper. The number of pins that can be combined on a printing-head can be up to 64. The pins are usually made from brass and stainless steel, which provide superior gliding properties and durability. Micro-spotting pins can be made by using 'electrical discharge machining' (EDM) to hold tolerances to within a few tenths of a millimeter [29]. Here, the spot diameter is largely dependent on the dimensions of the pin tip, which can be controlled by EDM. There is little or no contact between the pin and the surface in order to deliver the sample, which minimizes or even eliminates the impact forces and increases the lifespan of the pins to several millions of cycles. The high quality of the substrates allows producing precise spot diameters. The diameters are by large independent of the quality of the motion control system. The pins are also capable of printing in any orientation, including horizontal and upside down, enabling custom manufacturing applications. Downward pin movement is controlled by gravity instead of springloading, which minimizes surface forces and allows printing on delicate surfaces (e.g. acrylamide gel layers and silicon wafers). There are many reports in the literature about applications of micro-spotting [27, 28, 30]. One interesting application of micro-spotting allowing the formation of bacteria colonies onto an agar slate was reported by Al-K.haldi et al. [31]. Their microarrays consisted of 40 micro-spots in five replicates of eight bacteria by using a micro-spotting robotic system. Ukewise, they could accurately identify the spotted microorganism by infrared spectroscopy in a timespan of 3 h . 5.4.2 Ink-Jet Printing

Ink-jet printing is a technology best known by its use in low-cost desktop printers [32, 33]. As schematically described in Figure 5.5, it is a 'drop-on-demand' delivery approach, in which a computer-controlled ejection of single microscopic droplet is delivered into computer-defined arrangements (patterns). Typically, piezoelectric dispensers (Figure 5.6A) or syringe-solenoid inject-type dispensers (Figure 5.6B) are used. Both dispensers allow programmable volume delivery, which is an important advantage over micro-spotting technology. Loading volumes of both types of dispenser are much higher than micro-spotting pins and are in the range of 5-10 ).ll. Print volumes with piezoelectric dispensers can go as low as 0.05 nl which is much better than micro-spotting pins, while in the case of syringe-solenoids it is significantly higher (4-100nl). Droplets ejected by the most sophisticated print

5.4 Robotic Printing

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heads will leave approximately 20--30 !!1- Spot densities of piezoelectric dispensers are comparable with the micro-spotting pins, in contrast to the syringe-solenoid dispensers that can offer only a low density. Ink-jet printing can deposit multiple layers of materials, which is an advantage. However, dispensers are much more complex and expensive (especially piezoelectric ones) than micro-spotting pins. There are many reports in the literature on the application of ink-jet printing [34-36] Recently, Allain et al. [37] developed an assay for Bacillus anthracis detection, based on DNA hybridization, using several dyes (eosin Y, fluorescein and 4-methylumbelliferone).

5.5

Lithography with AFM

AFM is one of the most widely used nanoscale imaging techniques [38-43]. As shown in Figure 5.7, AFM utilizes a molecular or atomically fine tip attached to the bottom of a flexible/reflective cantilever. As the tip scans the surface of the sample, the laser beam is deflected off the cantilever; therefore its position and the extent of deflection of the cantilever can be monitored. Both the lateral position of the cantilever and the distance of the tip to the sample are controlled by piezoelectric crystal tubes. It is possible to change the direction and scanning rate of the tip on the surface. One may also apply a specific voltage to the substrate surface using cAFM tips. We now discuss two options to use AFM as a lithographic system for surface patterning.

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5.5 Lithography with AFM

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Figure 5.8 Schematic description of DPN.

5.5.1 Dip-Pen Lithography with AFM

Similar to classical lithographic methods describe above, AFM can be used to deliver molecules loaded on the tip in the desired patterns. Mirkin et al. in 1999 was the first to use AFM in lithography. They named it 'DPN' [44]. The concept of DPN is the printing of molecules with nanoscale writing. As shown in Figure 5.8, the AFM tip carrying the probe is moved in pre-programmed defined patterns. The tip will be in contact with the surface, either allowing the tip to dwell at a certain location or simply by rastering the tip close to the surface at a particular speed. As such, different shapes and sizes (i.e. dots, lines) can be created ('patterned') allowing molecules to diffuse onto the solid surface by means of capillary forces. Resolution of dip-pen patterning with AFM is down to line widths of about 15 nm, depending on the type of substrate, contact time (between the tip and substrate), scan speed, relative humidity and relative solubility of the molecules in the water meniscus [45]. Mirkin et al. described the effects of several factors on DPN lithography. Two different types of ODNs (thiol-functionalized and acrylamide-functionalized), were patterned onto gold and Si0 2 substrates, respectively. The size of the spots patterned increased significantly with both contact time and relative humidity. Much larger spots were observed in the case of acrylamide-functionalized ODNs on Si0 2 surfaces [46]. DPN is a suitable method for printing molecules with a variety of functional groups. Many materials can now be patterned using DPN -printed substrates [47-51]. Modification of gold-coated substrates [e.g. surface plasmon resonance (SPR) slides] by DPN technology are a good example. N-Alkane thiol molecules (or their derivatives) have been widely used for surface patterning of gold-coated surfaces, in which a gold-sulfur (Au-S) bond is formed. The alkene molecules are then directed to the

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surface ofthe patterned areas and make them hydrophobic. As a further modification step, one may backfill the bare regions with different thiol-functionalized molecules (e.g. ODNs carrying thiol end-groups as probes in SPR biosensors) simply by exposing the patterned substrate to a solution of other thiol molecules. Additionally, different probes can be deposited at different spots and therefore arrays can be produced. Weinberger et al. were able to deposit 1-octadecanethiol onto a gold surface of a multilayer substrate using DPN. Then they performed a selective etching to form nanostructures as possible protein and DNA nanoarray platforms [52]. Lee et al. developed a protein array by initially patterning 16-mercaptohexadecanoic acid (MHA) on a gold thin-film substrate in the form of dots or grids [53]. Proteins were absorbed on the preformed MHA patterns by immersing the substrate in a solution containing the desired protein. 5.5.2 cAFM Lithography

Scanning probe techniques, including 'cAFM', to form nanometer-scale patterns of organic molecules on silicon substrates have attracted much interest for their potential applications in chemical and biological sensors and molecular electronic device structures including DNA and protein arrays [54-56]. In cAFM, a voltage is applied to the AFM tip; while AFM is performing its normal scan. The tip acts as cathode, and the water meniscus formed between the tip and surface serves as electrolyte. As demonstrated by Hou et al. [57], the strong electric field near the tip causes electrochemical reactions in the water column as water decomposes into hydroxyl ions (OH-) and radicals (H").lbis results in breakdown, including field-induced ionization, of the water molecules yielding electrons, protons and free radicals (OH") as follows: H20+e-+OH- +H"

The OH" molecules can be consumed in three ways: they may (i) formed hydrogen peroxide (H 2 0 2) molecules, (ii) couple with H"radicals to produce water or (iii) could be electrochemically reduced to hydroxyl ions at the tip surface area [58, 59]: OH" + OH"-+ H202

The chemical environment that may be created during cAFM is schematically drawn in Figure 5.9.

5.5 Lithography with AFM

TIP MOTION

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Figure 5.9 Schematic description of cAFM nanolithography.

The organic monolayer composition and topography can be altered by using cAFM. There are several factors affecting the physical (topology) and chemical changes on the nanopatterned areas with the use of cAFM nanolithography, such as applied voltage, tip velocity, humidity, tip conductivity and tip diameter (58, 59]. cAFM nanolithography is widely used for immobilization of nanostructures including biomolecules to template-guided patterned areas (4, 60]. The technique allows the control of the .position and orientation of the patterns that may become powerfultools for biological applications such as protein and DNA arrays. A typical example of the use of cAFM is given by Gu et al., who prepared nanometric protein arrays on robust monolayers of a-hepta(ethylene glycol)methyl co-undecenyl ether associated with conductive silicon (111) [4]. After functionalizing the surface by cAFM lithography, avidin molecules were immobilized to these patterns. Note that avidin on these arrays serves as a template for the attaching proteins labeled with biotin. Recently, nanopatterns were created on alkene silane-functionalized silicon substrates by cAFM lithography (Figure 5.1 OA). Titanium wafers were first hydroxylated through a treatment with 20% HN0 3 at 80 oc for 30 min. They were then incubated in a trichlorohexeneylsilane (TCHS)jtoluene solution (2% vjv) to create double bonds on the substrate. Nanopattems as lines were created on these surfaces by cAFM lithography. Thus, alkene groups of the TCHS molecules were converted into carboxyl andjor hydroxyl groups on the patterned lines. As seen in Figure 5.10(B), the height of patterns decreased when the tip velocity decreased (61]. 5.5.3 Nanoshaving and Nanografting

TherecentlydevelopedAFM-basednanolithography'nanoshaving' and 'nanografting', allowed the fabrication of nanoscale surface structures of alkane thiols, proteins

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and DNA [54, 62, 63]. In nanoshaving, in a first step, self-assembled monolayers (SAMs) are formed. Usually, long-chain alkane thiols having ro-terminal functionality (or not) are used on substrate surfaces (usually coated with a gold layer) (Figure 5.11). Then, the desired nanopattems are formed by nanoshaving by

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making trenches on the SAM using the AFM tip. Different probes ('bioligands') are immobilized on to different trenches and, likewise, nanoarrays are formed. Nanostructures (nanoparticles, nanowires, nanotubes, etc.) may be first functionalized for immobilization of probes on their surfaces. These functionalized nanostructures may then be grafted onto pre-patterned surfaces (e.g. nanoshaved). This is referred as nanografting (Figure 5.12). Note that by using this approach the substrate surface area can be extended and therefore resolution (sensitivity) can be increased significantly. Zhao et al. recently used nanoshaving for making trenches on the alkylthiol SAM by using an AFM tip [54]. In the first step, they deposited mouse IgG on the shaved trenches. In the second step, they shaved another array of trenches and deposited human IgG on these. Finally, Alexa Fluor 546-labeled anti-mouse IgG nanotubes were allowed to interact on the mouse IgG trenches and fluorescein isothiocyanatelabeled anti-human IgG nanotubes onto the human IgG. Recently, we initiated a study in which nanopatteming of alkene-silane-modified silicon wafers by cAFM nanolithography were used as nanoarray platform. Silicon nanowires were synthesized via a gold-catalyzed chemical vapor deposition method (64) and functionalized using 3-aminopropylmethoxysilane molecules. Immobilization of these functionalized nanowires onto the patterned areas of the nanoarrays created novel nanobioarrays. These can have diverse applications, including detection of pathogenic microorganisms.

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5.6 Conclusions

Array technologies offer a number of advantages for the screening oflarge number of . analytes including speed, convenience and high-throughput analysis. Array platforms consist of patterned surfaces and probe molecules immobilized onto these patterns. There are two main approaches for patterning: (1) surfaces are first patterned and then different probe molecules are selectively immobilized onto different locations on the surface (a two step process) or (2) different probe molecules are delivered to different locations on the surface to form a patterned surface (two steps together). Several techniques (e.g. soft lithography, photolithography, robotic printing, etc.) have been developed to prepare array platforms, even at the commercial scale, which usually contain micron-size spots (locations) for different probes on the same platform. In this chapter, some approaches have been described and some interesting uses further exemplified. Each method has advantages and limitations when compared to the others. The most suitable one should be selected mainly based on the target use and available facilities. Even very simple techniques may be suitable for the efficient detection of target molecules. Nanopatterns can be created using some novel techniques including dip-pen lithography with AFM, nanoshaving and nanografting, and will certainly trigger the development of novel array platforms. Nanotechnology is a rather new field attracting a lot of scientific and technological interest in the recent years. By nanopatterning one can potentially load millions of different probe molecules on a small surface area and perform millions of parallel

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References 181

measurements. However, one should carefully select the correct size level for the use of an array platform (e.g. in cell arrays, an array platform with nanopatterns would be simply unrealistic or even a wrong approach). In addition, it should be noted that in order to detect any kind ofinteraction on the surface (with the immobilized probe and target molecules), which is usually realized by using labels (fluorescence dyes, etc.), a minimum amount of emission is needed. Therefore, resolution in the measurements may limit the application of nanopatterned array platforms.

Acknowledgments

E.P. is supported by the Turkish Academy of Sciences as a Full Member. G.D. is also supported as a Post-doctoral Fellow by TOBiTAK.

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