Patent Application
20090074966
Measuring the binding affinity between materials, molecules, and cells is key to a broad spectrum of industries, including material development, semiconductor production, bioanalytical assays, biomedical diagnostics, and drug discovery. With the emergence of solid state array-based bioanalytical and genetic diagnostic instruments and related equipment, new methods for cost effective screening of a large number of reactions in a miniaturized solid state form have become increasingly desirable. A favored approach to date is to monitor changes in optical properties, usually fluorescence, when a known, fluorescently labeled molecule interacts with a known molecular species at a specific address in a molecular array. Such methods, however, often impose stereochemical constraints by the addition of reporter systems to the molecules used to interrogate the molecular array. Thus, label free, direct interrogation of molecular binding events using a micromechanical reporter is of obvious utility. More sophisticated and robust instrumentation for the creation of these molecular arrays is therefore desirable.
One method for the direct detection of molecular interaction events is the scanning probe microscope. One type of scanning probe microscope is the atomic force microscope (“AFM”). In the AFM, a sharp tip is situated at the end of a flexible cantilever and scanned over a sample surface. While scanning, the cantilever is deflected by the net sum of the attractive and repulsive forces between the tip and sample. If the spring constant of the cantilever is known, the net interaction force can be accurately determined from the deflection of the cantilever. The deflection of the cantilever is usually measured by the reflection of a focused laser beam from the back of the cantilever onto a split photodiode, constituting an “optical lever” or “beam deflection” mechanism. Other methods for the detection of cantilever deflection include interferometry and piezoelectric strain gauges.
The first AFMs recorded only the vertical displacements of the cantilever. More recent methods involve resonating the tip and allowing only transient contact, or in some cases no contact at all, between it and the sample. Plots of tip displacement or resonance changes as the tip traverses a sample surface are used to generate topographic images. Such images have revealed the three dimensional structure of a wide variety of sample types including material, chemical, and biological specimens. Some examples of the latter include DNA, proteins, chromatin, chromosomes, ion channels, and even living cells.
In addition to its imaging capabilities, the AFM can make extremely fine force measurements. The AFM can directly sense and measure forces in the micronewton (10-6) to picoNewton (10-12) range. Thus, the AFM can measure forces between molecular pairs, and even within single molecules. Moreover, the AFM can measure a wide variety of other forces and phenomena, such as magnetic fields, thermal gradients and viscoelasticity. This ability can be exploited to map force fields on a sample surface, and reveal with high resolution the location and magnitude of these fields, as in, for example, localizing complexes of interest located on a specific surface. To make molecular force measurements, the AFM probe may be functionalized with a molecule of interest.
Construction of molecular arrays on a solid support for use in an AFM is typically carried out by processes that can be divided into two general classes: in situ and ex situ, the latter including a mechanical deposition step to actually place the sample on the deposition surface. In situ synthesis methods and apparatuses may involve photochemical synthesis of nucleic acid or short peptides to define the spatial addresses on a silicon or a glass surface. These methods may be limited by the wavelength of light used for masking and the synthetic procedure. Furthermore, this procedure may also be limited by cost. A need therefore exists for a dedicated apparatus for the creation of molecular arrays that may create arrays in a quick and efficient manner.
An example of an ex situ method followed by the mechanical deposition on the surface may be illustrated by the “dip pen” method. The sample material is prepared in advance and then the dip pen is used to place the sample on the deposition surface. It has been shown that a dip-pen method may be used to draw a submicron molecular line or spot using an alkanethiolate monolayer utilizing a standard AFM to control the dip pen. Other prior art instruments may utilize a pin tool which is dipped in a solution containing the sample material. The pin tool then has a drop of solution on it, which is then placed on the deposition surface. This method, however, does not allow the creation of extremely small deposition domains. Up until this time, AFMs have been utilized for drawing sub-micron molecular lines or creating the molecular spots. AFMs, however, are not optimal for creating arrays because they lack features, such as a sub-micron precision sample stage under computer control, precise optical access for sample registration, and unencumbered access to the software code used to control tip motion. Furthermore, commercial AFM configurations are not amenable to the rapid deposition of large numbers of different molecular species. Finally, AFMs are designed for multiple tasks, not as a dedicated sample deposition instrument, and are therefore more expensive than is required for a dedicated arrayer. Still other features may also be desirable in a dedicated deposition instrument and not included with an AFM.
A need exists for a commercially practical deposition instrument that can be utilized to create a molecular deposition array or surface pattern that includes sub-micron deposition domains. This instrument may incorporate precise optical features for sample registration and may be controlled utilizing a computer control so that user defined array patterns and sizes may be created. It may be particularly advantageous if this instrument can operate autonomously in a high throughput format.
Some embodiments of the present invention provide an apparatus for creating molecular arrays comprising a base, a Z controller operably connected to the base wherein the Z controller is selectively positionable along a Z axis, a deposition probe removably and operably connected to the Z controller so that the deposition probe is selectively positionable along the Z axis by the Z controller, an X, Y controller operably connected to the base wherein the X, Y controller is selectively positionable along an X axis and a Y axis, the X, Y controller further comprising a deposition substrate operably attached thereto and wherein movement of the X, Y controller moves the deposition substrate between a first position and a second position, the second position being operably positioned relative to the deposition probe, and an X, Y translation stage operably connected to the base wherein the X, Y translation stage is selectively positionable along an X axis and a Y axis, the X, Y translation stage further comprising a loading substrate operably attached thereto and wherein movement of the X, Y translation stage moves the loading substrate between a first position and a second position, the second position being operably located relative to the deposition probe and the first position being in a position accessible by the user.
In some embodiments of the present invention, a method for creating a deposition domain is provided, and comprises: (a) obtaining a loading substrate, the loading substrate further including a deposition material, (b) loading the deposition material onto a deposition probe, and (c) creating a deposition domain on a deposition substrate by transferring a desired amount of the deposition material from the deposition probe to the deposition substrate.
Some embodiments of the present invention provide an apparatus for creating an array comprising: a Z controller, a deposition probe operably attached to the Z controller, the deposition probe further comprising a tip, an X, Y controller operably attached to the Z controller, the X, Y controller selectively movable between a first position and a second position, and a deposition substrate operably affixed to the X, Y controller, wherein when the X, Y controller moves the deposition substrate to the second position the deposition substrate is operably positioned relative to the deposition probe.
In some embodiments, the present invention is a dedicated instrument for the creation of molecular arrays comprising deposition domains as small or smaller than 1 micron. Utilizing the present invention, an arrayer may limit the use of expensive reagents and test materials and may further help to conserve space in large scale combinatorial chemistry labs. Finally, some embodiments of the present invention may permit the testing of a large number of samples in a high throughput format because of the ease of making custom designed arrays with a variety of deposition materials placed thereon.
In some embodiments, the present invention utilizes a deposition technique in which a sample is transiently hydrated to form a capillary bridge. The capillary bridge may transport the deposition material from a loading substrate, to a deposition probe, and from the deposition probe to a deposition substrate to create a deposition domain. One or more deposition domains make up the array. The capillary bridge deposition technique utilized by the present invention apparatus is further described herein, and is also described in detail in co-pending U.S. application Ser. No. 09/574,519, which is herein incorporated by reference for all that it teaches.
Some embodiments of the present invention provide a system for depositing a material onto a substrate to create a desired surface pattern, wherein the system comprises a support; a surface patterning tool coupled to the support, the surface patterning tool adapted to deposit the material onto the substrate; a controller; and first, second, and third actuators electrically coupled to and controlled by the controller, wherein the first, second, and third actuators are operable to move the substrate in X, Y, and Z directions, respectively, with respect to the surface patterning tool, wherein the substrate is movable by the first, second, and third actuators to different positions with respect to the surface patterning tool, and wherein material is transferable from the surface patterning tool to the substrate in each of the different positions to define the desired surface pattern.
In some embodiments, a system for depositing a material onto a substrate to create a desired surface pattern is provided, and comprises a support; a surface patterning tool coupled to the support, the surface patterning tool adapted to deposit the material onto the substrate; a controller; and first and second piezoelectric drives electrically coupled to and controlled by the controller, wherein the first and second piezoelectric actuators are operable to move the substrate in X and Y directions, respectively, with respect to the surface patterning tool, wherein the substrate is movable by the first and second piezoelectric actuators to different positions with respect to the surface patterning tool, and wherein material is transferable from the surface patterning tool to the substrate in each of the different positions to define the desired surface pattern.
In some embodiments, a method of depositing a material onto a substrate to create a desired surface pattern is provided, and comprises loading the material onto a surface patterning tool; actuating a first actuator to move the substrate in an X direction with respect to the surface patterning tool; actuating a second actuator to move the substrate in a Y direction with respect to the surface patterning tool; actuating a third actuator to move the substrate in a Z direction with respect to the surface patterning tool and to a position with respect to the surface patterning tool; and transferring the material from the surface patterning tool to the substrate.
Other features and aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings.
a is a perspective view of an X, Y controller of one embodiment of the present invention.
b is a perspective view of an X, Y translation stage of one embodiment of the present invention.
Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Unless specified or limited otherwise, the terms “mounted,” “connected,” “supported,” and “coupled” and variations thereof are used broadly and encompass both direct and indirect mountings, connections, supports, and couplings. Further, “connected” and “coupled” are not restricted to physical or mechanical connections or couplings. Furthermore, terms such as “front,” “rear,” “top,” “bottom,” and the like are only used to describe elements as they relate to one another, but are in no way meant to recite specific orientations of the apparatus, to indicate or imply necessary or required orientations of the apparatus, or to specify how the invention described herein will be used, mounted, displayed, or positioned in use.
An arrayer and method of arrayer operation according to an embodiment of the present invention is illustrated in
As illustrated in
As illustrated in
The deposition substrate 25 utilized in the present invention apparatus may be formed of a variety of materials depending on the nature of the deposited material. A further description of such deposition substrates 25 can be found in U.S. application Ser. No. 09/574,519, but may be altered or changed without changing the nature or scope of the present invention.
As is further illustrated in
In one embodiment, as illustrated in
Each of these separate components of the arrayer 10 illustrated in
With reference to
One commercially available optical plate 24 that is suited for use in the arrayer 10 is available from Newport Corp., P.O. Box 19607, Irvine Calif. 92623-9607 as product number SA12. The plate may have ¼ inch holes drilled on one inch centers. Steel posts 26 well suited for the arrayer 10 are also be commercially available from the same manufacturer as product number SP12.
In alternative embodiments, the optical plate may be placed on top of an optical table. The optical table can be floated on nitrogen pistons to optimize elimination of vibrations, if desired.
With reference to
One X, Y controller 14 may be a piezo driven inchworm precision mechanical stage. The inchworm mechanism may have a significant range of motion while maintaining microfine precision desirable for some embodiments of the present invention. Such a stage may have approximately 20 nm spatial resolution in the X and Y planes and may further utilize encoders to ensure repeatability. The stage may be fitted with a plate designed by those skilled in the art to hold the sample deposition substrate 25. One inch worm stage that may be useful is commercially available from Burleigh Instruments, Burleigh Park, P.O. Box E, Fishers, N.Y. 14453-0755.
In some alternative embodiments, a piezo driven flexure stage may also be utilized as the X, Y controller 14. A piezo driven flexure may have essentially the same precision as the inchworm stage. In still further embodiments, a linear piezo ratchet mechanism, such as is available from NanoMotion, Israel, may be utilized.
With reference to
In one embodiment, the X, Y translation stage 18 may utilize the same type of X, Y positionable inchworm or piezo device as the X, Y controller 14. In alternative embodiments, the X, Y translation stage 18 may not require such microfine control, since the deposition material may be placed in a much larger, and therefore easily accessible, domain on the loading substrate than the domain created on the deposition substrate 25. As illustrated in
In further embodiments, the X, Y translation stage 18 may have such a range of motion that the loading substrate 27 can be loaded in a first position and then transported into a second position underneath the deposition probe 12. In this manner, the loading substrate 27 may be cleaned and reloaded with a second deposition material after the first deposition material is loaded onto the deposition probe 12, all in an automatic fashion.
With reference to
In some embodiments, the Z controller 16 can be a commercially available controller from Newport Corporation, P.O. Box 19607, Irvine, Calif. 929623-9607, product number TSV 150. In the embodiment illustrated in
The deposition probe 12 can be fixed to the end of the Z controller 16, and is not visible in
A commercially available deposition probe 12 may be utilized as the deposition probe 12 of the arrayer 10. Such a deposition probe 12 may be a standard silicon nitride AFM probe available from Digital Instruments/Veeco, 112 Robin Hill Road, Santa Barbara, Calif.
A humidity controller 20 according to an embodiment of the present invention is illustrated in
In some embodiments, the humidity source 30 utilizes a wetted piece of filter paper or a sponge in a plastic cartridge. A dry inert gas, such as argon, is placed into the cartridge from the gas source 38 and kept under a positive pressure though the use of the solenoid valve 40 controlled by the control system. As illustrated in
As illustrated in
In alternative embodiments, a more sophisticated humidity generator may be utilized so that the precision and repeatability of the relative humidity surrounding the sample can be increased. In some embodiments, dry air may be continuously blown over the deposition probe 12, briefly stopped during the wet gas blast, and then immediately turned on again to minimize sample diffusion on a surface.
In some embodiments, a constant, humid environment may be adequate for sample loading and deposition. In such embodiments, the arrayer may include a plastic chamber or room that envelopes the deposition probe 12, the operative ends of the X, Y controller 14, and the X, Y translation stage 18, or the entire instrument. The chamber or room may be filled with a gas of the desired humidity for the duration of the loading and deposition program.
With reference to
In addition to the computer controller 22, a stepper motor controller card (A-100 from Mill-Shaf Technologies, Inc.) may be utilized to control the fine action of the X, Y controller 14, the Z controller 16, and the X, Y translation stage 18. In some embodiments, the stepper motor controller card may also be controlled by the LabView (National Instruments) software or other software written by those skilled in the art.
The force feedback monitor 50 according to an embodiment of the present invention will now be described. As previously noted, the force feedback monitor 50 may be operably attached to the Z controller 16 and the control computer 22. The force feedback monitor 50 may be able, along with the control computer 22, to accurately recognize when the deposition probe 12 and the loading substrate 27, or the deposition probe 12 and the deposition substrate 25, touch. Knowing the exact moment of contact between the deposition probe 12 and the substrates 25, 27 may more accurately allow transferal of deposition material from the loading substrate 27 to the deposition probe 12 and from the deposition probe 12 to the deposition substrate 25. Force feedback monitors 50 coupled with the control computer 22 are known to those in the art for achieving such a result.
In alternative embodiments, the force feedback monitor 50 can also or instead be used to determine the initial relationship of the substrates 25, 27 and the deposition probe 12.
Utilizing the arrayer 10 according to some embodiments of the present invention, the probe 12 may be brought into contact with the substrate 25, 27 and then drawn back up by 1 mm or more before being exposed to humid gas from the humidity controller 20, which can cause a capillary bridge to form, thus loading or depositing the deposition material. Once the position of the substrate 25, 27 is determined relative to the deposition probe 12, the control computer 22 may simply bring the probe 12 to the desired level above the substrate 25, 27 for subsequent depositions without having to touch the surface of the substrate 25, 27.
Various types of force feedback monitors 50 useful for the above process are known to those skilled in the art.
One commercially available force feedback monitor 50 that can be used in some embodiments is an AFM head from a Dimension 3100 series scanning probe microscope available from Digital Instruments. Other force feedback monitors may be utilized by those of reasonable skill in the art without changing the nature and scope of the present invention. In the embodiment illustrated in
With reference to
Although the deposition domains may be smaller than the wavelength of the light being used, they can be separated by distances on the order of 2 microns, allowing them to be separately observed by virtue of their optical characteristics. This is analogous to far field optical observation of sub-wavelength objects, such as individual DNA molecules and manometer scale colloidal metals by virtue of light collected from intercalated fluorophores or reflected photons, respectively. Thus, optical monitoring may be a useful method for preliminary evaluation of the deposition event as performed by an arrayer 10 according to embodiments of the present invention.
The method of use of the arrayer 10 illustrated in
As may be appreciated, the above-described process of depositing deposition material may be carried out many times before the deposition probe 12 is significantly depleted of deposition material. Thus, in some embodiments one to several deposition domains for each array can be constructed after loading the probe 12 just one time. Each time a new deposition material is deposited, the deposition probe 12 can be cleaned. In some embodiments, the deposition probe 12 can be cleaned with a UV or ozone burst before loading a second deposition material.
In some embodiments by way of example, a sample of protein at a concentration of about 0.1 mg/ml in PBS (a buffered saline solution) may be deposited as a microdrop on a clean glass surface and dried to serve as the deposition materials/loading substrate. The deposition tool may be allowed to contact the dried microdrop and the humidity controlled to allow adsorption of protein to the deposition probe tip 13. This process can result in loading of the deposition tool with sufficient material for 10 to 100 deposition events. The loaded deposition probe 12 can then be utilized to deposit the PBS onto a freshly prepared gold or gold/alkanethiolate surface.
Each cycle of loading the deposition probe 12 and making one domain on the deposition substrate 25 may take as little as 1 minute. In addition, the actual deposition event can be relatively short, so the difference between making one and several spots with a single source material in some embodiments can be only a few seconds at most. Thus, to build one or many 10×10 molecular arrays of 100 different molecular species may take approximately 1 hour and 40 minutes in some embodiments. In alternative embodiments, this process may be further streamlined and scaled up to allow construction of much more complex arrays (hundreds to thousands of molecular species), and larger numbers of arrays in a similar time frame, without changing the nature and scope of the present invention. All of these steps may be coordinated through LabView utilizing the control computer 22.
In still further embodiments, there may be several X, Y translation stages 18 to bring loading substrates 27 into an operable position underneath the deposition probe 12. In this manner, multiple deposition materials can be accessed on the multiple loading substrates 27, allowing for the creation of a diverse array.
In some alternative embodiments, the optical microscope 52 may be utilized to locate registration marks for sample deposition in defined physical locations.
Also, in some embodiments, the deposition probe 12 may be washed using a microfabricated well with a simple fluidic feed. The washing solution (e.g., water) may be fed into the device, forming a protruding bubble held in place by surface tension. The deposition tool may then be washed in the bubble by piezo driven oscillation of the bubble in the deposition probe 12.
As will be appreciated by those skilled in the art, spot size can be a function of the radius of curvature of the deposition tool, tool and surface hydrophobicity/hydrophilicity, and control of humidity during the deposition event. Some embodiments of the present invention may allow spot sizes in the 200 nm diameter range (the tool radius can be 40 nm, in some embodiments) reproducibly when the appropriate parameters are carefully monitored. It is noteworthy that spots quite a bit smaller than this may be possible depending on the sample material and the purposes envisioned for the deposition domain.
A controller 122 (also sometimes referred to herein as “control computer”) can be connected to the arrayer 100 to control at least one of the printhead 108, the X-Y-Z stage positioning assembly 110, the environment control system 113, the Z printhead-positioning assembly 116, and the imaging system 118. Any number of devices can be used to control one or more of these elements, assemblies, and systems of the arrayer 100. In this regard, it should be noted that such devices can include microprocessor-based systems and other systems operable to execute software or other instructions. However, it should also be noted that such devices can include, without limitation, solid state and other electronic systems adapted to receive one or more signals and to generate control outputs accordingly, and need not necessarily execute software or other instructions. As used herein, the terms “controller” or “control computer” encompass all such devices. In other words, the controller 122 can include software-based and/or hardware-based components, and control of the arrayer 100 can be accomplished with software-based commands, hardware-based commands, or combinations thereof.
As used herein and in the appended claims, the term “arrayer” is used to refer to a device that is capable of depositing material onto a substrate in any patterned or patternless manner, including without limitation in a random or non-random manner, in any number of arrays, letters, words, symbols, and other graphics, in straight and/or curved lines, and the like. Also as used herein and in the appended claims, the terms “pattern” and “surface pattern” in their various forms do not alone indicate or imply the deposition of material in any particular manner (e.g., arrangement, format, and the like), and encompass deposition of material in any manner, including without limitation in a random or non-random manner, in any number of arrays, letters, words, symbols, and other graphics, in straight and/or curved lines, and the like.
As used herein and in the appended claims, the term “deposition material” (sometimes referred to herein and in the appended claims as simply “material”) is used to refer to the material or substance that is deposited onto a surface or substrate with an arrayer 10 or 100 of the present invention. The deposition material can include organic materials, inorganic materials, and combinations thereof. Organic materials can include, but are not limited to, cells, subcellular organelles, subcellular extracts, cell extracts, tissues, nucleic acids, PCR primers, DNA, RNA, proteins, antibodies, lipids, aptamers, carbon nanotubes, carbon nanoparticles, biochemicals, metabolites, extracellular matrix materials, or combinations thereof. Inorganic materials can include, but are not limited to, salts, adhesives, nanoparticles, dendrimers, catalysts, solvents, etchants, colloidal metals, colloidal ceramics, silica particles, metals, ceramics, polymers (e.g., monomers and/or copolymers, such as, block copolymers), or combinations thereof.
The support 102 illustrated in
The support 102 can be formed of a variety of materials, including, without limitation at least one of granite, other stones, metals (e.g., aluminum, steel, invar, titanium, etc.), polymers (e.g., nylon, polypropylene, polycarbonate, polystyrene, etc.), and combinations thereof. In some embodiments, such as those employing polymers, the polymer can include internal and/or external supports and buttresses to provide desired structural rigidity and performance. The support 102 can be coupled to or can include structures necessary to isolate the arrayer 100 from external or environmental vibrations. For example, the support 102 can include an optical table, as described above, which can in turn be floated on pistons to minimize the transmission of vibrations to the arrayer 100.
The type of substrate 114 used can vary depending at least in part upon the type of print tool 146 used, the type of deposition material used, and the desired surface pattern. The substrate 114, or portion thereof, onto which the deposition material is deposited can be two-dimensional (e.g., a surface of a glass slide) or three-dimensional (e.g., a polymer matrix). Also, the substrate 114 can include a variety of base materials, including transparent materials, translucent materials, opaque materials, or combinations thereof. For example, the substrate 114 can include, but is not limited to glass, quartz, ruby, diamond, plastics, elastomeric materials, ceramics, silicon, silicon dioxide, silicon nitride, metal, silicon, semiconductor materials, mica, muscovite mica, or combinations thereof. Silicon base materials can include an etched pattern that at least partially defines the resulting surface pattern.
The substrate 114 can include a base material alone or can include a surface treatment or coating applied to or coupled to a base material to enhance positioning and/or binding of deposition material to the substrate 114. A variety of chemistries can be used for the coating or surface treatment. The type of coating or surface treatment used can depend at least in part on the type of deposition material used, the desired surface pattern, and the type of print tool 146 used. Coatings or surface treatments can include, but are not limited to, at least one of oligonucleotides, poly-l-lysine, amino-silanes, epoxy-silanes, aldehyde-silanes, NHS-esters, peptides, antibodies (e.g., for antibody-based capture assays), hydrogels, polymer matrices, metals (e.g., gold, silver, platinum, titanium, nickel, or any other suitable metals), polydimethyl siloxane (PDMS), Advanced Protective Technology for Engineering Structures (APTES) treatments (e.g., on muscovite mica), nitrocellulose (e.g., FAST™ slides, available from Whatman Schleicher & Schuell BioScience, which include glass slides coated with a proprietary nitrocellulose polymer, and PATH™ slides, available from GenTel Biosurfaces, which include a proprietary ultra-thin nitrocellulose film), lipids, biomembranes, cellular surfaces, and any other coating or surface treatment suitable to the deposition material of interest.
The substrate(s) 114 can be coupled to the stage 112 in a number of different manners, including, without limitation, one or more fasteners (e.g., clips, pins, clamps, nails, screws, bolts, rivets, magnets and the like), adhesive or cohesive bonding material (e.g., tape, such as double-sided Scotch tape, available from 3M), or any combination thereof. For example, in some embodiments, one or more magnets can be embedded in the stage 112 (such as by forming one or more recesses in an underside of the stage 112 and housing magnets in the recesses). In such cases, the substrate(s) 114 positioned on the stage 112 can include a ferrous bottom coating to allow the substrate(s) 114 to be coupled to the stage 112 with magnetic force. Also in such embodiments, the magnet(s) can be positioned strategically with respect to the stage 112 to allow proper positioning of the substrate(s) 114. In some embodiments, the magnet(s) can include electromagnets so that the magnetism can be controlled to be effective only when needed. Still other manners of coupling one or more substrates 114 to the stage 112 are possible, and fall within the spirit and scope of the present invention.
As also shown in
In some embodiments, the imaging system 118 can include an optical microscope and/or a camera or other recording device (not shown). One example of a camera that can be used with the present invention is a DXC-LS1 ¼″ Hyper HAD CCD Color Lipstick Camera (available from Sony) with a 768×494 pixel resolution, digital zoom up to 3×, and National Television Systems Committee (NTSC) output via an S-video cable. If desired, a monitor or other display device can be coupled to the microscope, camera and/or other recording device to display images to a user. As shown in
In some embodiments, the printhead 108 includes a housing 140, which can have a cover 142 dimensioned to at least partially cover an open portion 144 (e.g., an open front portion 144 in the embodiment illustrated in
The print tool holder 148 can be coupled to the housing 140 in a variety of different manners, including, but not limited to one or more fasteners (e.g., one or more bolts, screws, nails, clamps, clips, rivets, brads, pins, and combinations thereof), magnetic force, gravity, frictional engagement, adhesive or cohesive bonding material (e.g., tape, such as double-sided Scotch tape, available from 3M), a threaded or press-fit connection, one or more inter-engaging elements (e.g., snap-fits), or any other suitable manner for coupling the print tool holder 148 to the housing 140. Similarly, the SPT 146 can be coupled to the print tool holder 148 in a variety of different manners, including, but not limited to, any of the manners mentioned above with regard to the connection between the print tool holder 148 and the housing 140.
In some embodiments, the printhead 108 further includes one or more sensing systems 159, including, without limitation, at least one of a force feedback system (e.g., an optical lever system that includes an electromagnetic radiation source and position-sensitive photodetecor), any other optical sensing system, a capacitance sensing system, a resistance sensing system, an inductance sensing system, a conductance sensing system, a pressure sensing system, and any combination thereof. Examples of an optical sensing system include, but are not limited to, observation of material deposition (e.g., spot and/or line formation), pattern recognition, machine vision, birefringence, interferometry, and combinations thereof.
By way of example only, the illustrated arrayer 100 has a force feedback sensing system 159 that employs an optical lever system 163 (see
The printhead 108 can also include components necessary to house or support various portions of one or more sensing systems 159. For example, the printhead 108 illustrated in
The housing 140 can also include a second aperture 157 positioned adjacent the collar 154 when the laser positioning device 150 is in an assembled state. The second aperture 157 allows the laser 152 to emit a laser beam into the interior of the housing 140. In some embodiments, the collar 154 or other structure retaining the laser 152 in position with respect to the housing 140 can be part of the housing 140, rather than a separate element or structure permanently or releasably attached to the housing 140.
The laser positioning device 150 can be a stationary, structural component used to couple the laser 152 to the printhead 108. Alternatively, the laser positioning device 150 can be a controllable and manipulatable unit. For example, in some embodiments, the laser positioning device 150 includes a goniometer that can be positioned locally and manually (e.g., by positioning knobs 151, shown in
The printhead 108 can further include a detector positioning device 155 to which a detector 158 can be coupled. The detector positioning device 155 and detector 158 can be positioned on a side of the housing 140 suitable for detecting various information from the laser 142 regarding the position of the SPT 146. The detector positioning device 155 and the detector 158 can be coupled together in any manner, including those described above with reference to the connection between the X-Y-Z stage-positioning assembly 110 and the base 124.
In the optical lever system 163 illustrated in
The laser/beam deflection path can be initially directed to the center of the split photodiode such that each of the two halves 165 of the split photodiode receive equal (i.e., half) of the total reflected light. Displacement (e.g., angular displacement) of the SPT 146 can cause one half 165 of the split photodiode to receive more electromagnetic radiation that the other half 165, resulting in an output signal (e.g., the difference value between the two halves normalized by their sum) that is proportional to the deflection of the SPT 146. Two types of information can result from the optical lever system 163: a sum and a difference. The sum value is the total amount of electromagnet radiation striking the detector 158, whereas the difference value is the difference between the two halves 165 of the split photodiode, normalized by their sum. Rapid changes to the sum and/or difference values can be indicative of displacement of the SPT 146, and can result from a contact or interaction between the SPT 146 and a substrate 114 from which the SPT 146 is loading a material, or onto which the SPT 146 is depositing a material.
In some embodiments, a surface-induced deflection of the SPT 146 moves the reflected beam from front to back along the left side of the interior of the printhead 108 (when viewed as shown in
The laser 152, laser positioning device 150, detector positioning device 155, and detector 158 (if employed) make up part of the surface sensing system 159 used for detecting deflection of the SPT 146 when the SPT 146 contacts or interacts with a substrate 114 or material on the substrate 114. In some embodiments, the controller 122 can control the relative positions of the laser 152 and/or the detector 158. Also, in some embodiments, based at least in part upon the signals received by the controller 122 from the detector 158, the controller 122 can control the positioning of the print tool holder 148 to alter the position of the SPT 146 relative to the substrate 114. In addition, in some embodiments, based at least in part upon the signals received by the controller 122 from the detector 158, the controller 122 can control the Z printhead-positioning assembly 116 to alter the position of the SPT 146 relative to the substrate 114. Also, in some embodiments, based at least in part upon the signals received by the controller 122 from the detector 158, the controller 122 can control the X-Y-Z stage-positioning assembly 110 to alter the position of the stage 112, and accordingly, the position of the substrate 114 to alter the relative position between the SPT 146 and the substrate 114.
In some embodiments, the printhead 108 can further include one or more nozzles 160 that define air or gas inlets into an interior space 162 of the housing 140. The nozzles 160 can allow a humidity source or other environment controlling device to be fluidly connected to the interior space 162 of the housing 140 in order to create a desired local deposition environment surrounding or proximate the SPT 146. As shown in
The enclosure 300 surrounds a portion of the arrayer 100 and is coupled, directly or indirectly, to the support 102. In some embodiments, the enclosure 300 forms part of the support 102. In the embodiment illustrated in
The temperature sensor 302 and the humidity sensor 303 can be coupled to any portion of the arrayer 100, within the enclosure 300. For example, the temperature sensor 302 and the humidity sensor 303 can be coupled to the support 102, as shown in
In some embodiments, as shown in
Dry gas can be directed into the enclosure 300 via a dry gas inlet 326. In some embodiments, as mentioned above, the dry gas inlet 326 can be in fluid communication with a dry, inert gas. Based on feedback from the humidity sensor 303, the controller 122 (or a local controller) can monitor the humidity within the enclosure 300 and open or close a valve (e.g., a solenoid valve) in fluid communication with the dry, inert gas to start or stop, respectively, dispensing of the dry inert gas into the enclosure 300. Dispensing of humid or dry gas into the enclosure 300 can be done in a pulsing mode, a continuous mode, or a combination thereof. A user can set (e.g., via a graphical user interface) which mode should be used for a particular application. As shown in
As mentioned above, the environment control system 113 can further control the local environment surrounding the SPT 146 (or “sample point environment,” generally indicated by reference numeral 315) for precise control of deposition and surface patterning conditions. As described above with reference to
The first nozzle 106A can be fluidly coupled to a gas source 317, with a humidity source 316 (see also
As shown in
The controller 122 can include or be connected to the environment control system 113. By way of example only, one embodiment of a portion of the controller 122 is illustrated in
In the embodiment illustrated in
The humidity sources 306 and 316 shown in the illustrated embodiment each include a ddiH2O bubbler flask, as describe above. However, a variety of suitable humidity sources can be used without departing from the spirit and scope of the present invention
In some embodiments, as described above with respect to the arrayer 10, controlling the local humidity surrounding the SPT 146 can control one or more of loading and deposition processes. However, in some embodiments, the deposition material can include a buffered solution. In some embodiments, the buffered solution can include glycerol and a surfactant that does not dry out or require humid gas to rehydrate it. For example, in some embodiments, a protein to be deposited can be present in a solution containing glycerol at a concentration of about 0.1 mg/mL, and can be deposited as a drop (e.g., a microdrop). In this example, humid gas is not required at the sample point environment 315, because the glycerol-containing deposition material will not dry under the deposition conditions. Other surfactants can be used in other embodiments.
The printhead 108 can be formed of a variety of materials or combinations of materials. In some embodiments, various components of the printhead 108 are formed of a polymer (e.g., nylon, UHMW, and the like), including without limitation the housing 140, the cover 142, the print tool holder 148, the laser positioning device 150, the detector positioning device 155, and/or the nozzles 160. In some embodiments, some components of the printhead 108 that are formed of a polymer can be constructed using rapid prototyping. Rapid prototyping allows the creation of convoluted structures, undercuts, or internal structures that are difficult or impossible to achieve with conventional machining or molding techniques. Some types of rapid prototyping include a layer-by-layer polymerization of liquid or granular solid polymeric materials to form three-dimensional structures. In some embodiments, each layer of a part formed by rapid prototyping may be a few microns or less in thickness.
Some types of SPTs 146 yield enhanced results over other types of SPTs, depending upon the substrate 114 on which the deposition material is to be deposited, and/or upon the type of deposition material used. The best type of SPT 146 for a particular application can be determined empirically. The present invention can include a variety of types of SPTs 146, and any suitable SPT 146 can be used without departing from the spirit and scope of the present invention.
The SPT 146 can be a cantilever type SPT, a non-cantilever type SPT, or a combination thereof. A cantilever type SPT can include a back-loaded deposition tool (e.g., a quill-type deposition tool 146A, such as that illustrated in
In embodiments employing a back-loaded deposition tool, the SPT 146 either includes or is in fluid communication with a reservoir or source containing material to be deposited. For example, with reference to
With continued reference to
The actuator 170 can take a number of different forms that allow motion control in increments of between about 200 nm and several microns, including without limitation a servo motor, a stepper motor, and the like. In other embodiments, actuators capable of greater precision are possible and can be used, including without limitation the types of actuators described below with reference to the X-Y-Z stage-positioning assembly 110. In the embodiment shown in
When the ball screw 172 is rotated, the ball screw 172 is rotated within the threaded aperture 171, causing the carriage 174 to move in a substantially linear manner. The movable plate 164 can be coupled to the carriage 174, and accordingly, can move relative to a base 180 of the Z printhead positioning assembly 116 when the carriage 174 is moved. The base 180 of the Z printhead positioning assembly 116 can be coupled to the substantially vertically-oriented face 128 of the support 102 shown in
The Z printhead positioning assembly 116 shown in
As mentioned above, the stage 112 can be coupled to and movable by the X-Y-Z stage-positioning assembly 110. One embodiment of the X-Y-Z stage-positioning assembly 110 is shown in
In the embodiment shown in
The X portion 200 and the Y portion 202 can make up an X-Y stage-positioning assembly 210. In some embodiments, the stage 112 is not movable in the Z direction, but is instead coupled to the X-Y stage-positioning assembly 210 for movement in an X-Y plane. The X-Y stage-positioning assembly 210 is shown in greater detail in
As shown in
In some embodiments, the first platform 212 of the X portion 200 is coupled to the base 124 of the support 102 (or other underlying structure), thereby forming a stationary base for the X-Y stage-positioning assembly 210 (and the X-Y-Z stage-positioning assembly 110). Also, in some embodiments the first platform 216 of the Y portion 202 is coupled to the second platform 214 of the X portion 200. Thus, the first platform 216 of the Y portion 202 (and any elements coupled to the first platform 216) can be movable with the second platform 214 of the X portion 200 in an X direction relative to the first platform 212 of the X portion 200 and the base 124 of the support 102 or other underlying structure. Furthermore, the second platform 218 of the Y portion 202 (and any elements coupled to the second platform 218) can be movable in a Y direction relative to the first platform 216 of the Y portion 202. The second platform 218 can include an upper surface 222 to which various elements can be coupled (e.g., the Z portion 204, the stage 112, and any elements coupled thereto).
Because motion in the X direction is controlled by the X portion 200 and motion in the Y direction is controlled by the Y portion 202, the X-Y stage-positioning assembly 210 allows for movement in the X direction independent of movement in the Y direction. That is, a substrate 114 positioned on the stage 112 can be independently moved in the X direction and the Y direction, and the substrate 114 can be moved in the X direction simultaneously to being moved in the Y direction.
Each of the second platforms 214, 218 can be moved by an actuator 220, 224, respectively. The actuators 220, 224 can be the same or different from one another, and can take a number of different forms capable of moving and positioning the second platforms 214, 218 in a precise and repeatable manner. In some embodiments, either or both actuators 220, 224 are capable of such motion to achieve a spatial resolution of less than approximately 20 nm, and less than approximately 1 nm in some embodiments. In some embodiments, either or both actuators 220, 224 are capable of a reproducible spatial resolution of less than about 1 micron, and in some embodiments less than about 500 nm. In some embodiments, either or both actuators 220, 224 are capable of speeds of up to about 5 mm/second, and in some embodiments, up to about 7 mm/second. For example, in the illustrated embodiment, the actuators 220, 224 each include a piezo inchworm actuator, the mechanism of which is shown in
In other embodiments, either or both of the platforms 214, 216 can be moved by other types of actuators capable of the above-described precision, including a number of different electromotive actuators currently available. For example, either or both platforms 214, 216 can be moved by any other type of piezoelectric actuator. As used herein and in the appended claims, the term “piezo actuator” or “piezoelectric actuator” is used to refer to any piezoelectric-driven mechanism or actuator, including, but not limited to, piezo inchworm actuators, piezo flexure stages or nanopositioners, piezo ratchet devices, piezo devices, piezo ceramic devices, piezo bimorph stacks, piezoelectric linear or rotary stick-slip actuators, piezoelectric stack actuators, piezoelectric shear actuators, piezoelectric tube actuators, and the like, and/or any other suitable piezoelectric-driven actuator or mechanism.
In some embodiments, either or both platforms 214, 216 are driven by actuators or mechanisms other than piezoelectric actuators. As an example, either or both platforms 214, 216 can be coupled to and driven by electrostrictive actuators, such as electrostrictive stack actuators, electrostrictive ring actuators, electrostrictive elastomers, and the like. As another example, either or both platforms 214, 216 can be coupled to and driven by magnetostrictive actuators, such as coil and rod magnetostrictive actuators. As yet another example, either or both platforms 214, 216 can be coupled to and driven by a micro-electro-mechanical system (MEMS) actuator, such as residual stress cantilevered (RSC) MEMS actuators, vertical thermal MEMS actuators (VTA), scratch drive MEMS actuators (SDA), horizontal thermal MEMS actuators (HTA), and the like.
With reference again to
The clamping elements 244 of the embodiment illustrated in
Movement of the X-Y stage-positioning assembly 210 can be controlled by the controller 122, or the X-Y stage-positioning assembly 210 can be controlled by one or more local controllers, as shown in
In some embodiments, the platform 262 can be movable in the Z direction in a precise and repeatable fashion to allow the stage 112, and any substrate 114 positioned or otherwise supported on the stage 112, to be moved in a spatial resolution of less than approximately 20 nm, in some embodiments, less than 10 nm in some embodiments, and about 1 nm, in some embodiments. In some embodiments, the platform 262 is movable with respect to the base 260 by a total distance of less than approximately 200 microns, in some embodiments less than approximately 100 microns, and in some embodiments, less than approximately 50 microns. In some embodiments, the platform 262 has a full range repeatability of about +/−100 nm or less, in some embodiment about +/−50 nm or less, and in some embodiments, about +/−20 nm or less. In some embodiments, a Z portion 204 that can achieve this total range of motion, spatial resolution and repeatability is a piezo flexure nanopositioner (e.g., a Vertical PZT Flexure Stage, available from PI, product no. P-762.TL). However, a number of other electromotive actuators can instead be employed to provide the same or comparable spatial resolution and range of motion, including those described above with reference to the actuators for the X and Y portions 200, 202.
In some embodiments, movement of the platform 262 can be accomplished using a piezo ceramic device (e.g., a piezo bimorph stack) that applies a force at a particular position of the platform 262. The piezo ceramic device can be mounted within the Z portion 204 in a variety of locations to obtain the desired degree of motion as a function of piezo expansion. The hinge 266 can be formed of a material and dimensioned to allow repeated flexing with minimal material degradation. A plurality of hinges 266 and levers 268 can be used in the Z portion 204 and can be positioned throughout the Z portion 204 to move the platform 262 in the Z direction (see arrow 270 in
The Z portion 204, and specifically, the motion of the platform 262 can be controlled by the controller 122. In some embodiments, however, the Z portion 204 is controlled by a local controller 272 in addition to, or in lieu of, the controller 122. In some embodiments, the local controller 272 can include a linear variable differential transformer (LVDT) or other position monitoring devices, which can include a displacement feedback circuit to monitor and control movement of the platform 262. In this regard, LVDTs or other position monitoring devices can be coupled to the X portion 200, Y portion 202, and/or the Z printhead-positioning assembly 116 for monitoring and controlling movement of such arrayer devices.
In some embodiments, the Z printhead positioning assembly 116 is responsible for moving the printhead 108 (and, accordingly, the SPT 146) by moving the mounting plate 120 and the movable plate 164 of the Z printhead positioning assembly 116 into relatively close proximity to a substrate 114 on or otherwise supported by the stage 112. The Z printhead positioning assembly 116 in such embodiments can be generally responsible for coarse movement of the printhead 108, and can include a larger spatial resolution than that achieved by the X-Y-Z stage-positioning assembly 110. The controller 122 can be used to move and control the position of the Z printhead positioning assembly 116. After the printhead 108 has been positioned in close proximity with a substrate 114 onto which material is to be deposited (and/or loaded from, in some embodiments), the controller 122 can be used to control the X-Y-Z stage-positioning assembly 110 to move the stage 112, and accordingly, the substrate 114, in an X direction, a Y direction and a Z direction to load materials from the substrate 114 and/or to deposit materials from the SPT 146 onto the substrate 114.
In some embodiments, the X-Y-Z stage positioning assembly 110 is repeatedly moved to deposit one or more arrays of spots upon the substrate 114. The array(s) created by this process can include at least 2 spots and as many as several thousand (or more) spots in a variety of patterns or shapes deposited at a resolution as small as about 20 nm and each having a spot size of about 250 nm to about 25 microns in some embodiments (although smaller or larger spot sizes are possible).
Also, in some embodiments, the SPT 146 can deposit material in the form of lines. In such embodiments, the lines can have thicknesses of about 250 nm to about 50 microns in some embodiments, (although thinner or thicker lines are possible). Spots, lines, and combinations thereof can be used to create various designs or patterns on the substrate 114.
In the illustrated embodiment of
With reference to
However, in other embodiments, such coarse and fine adjustment is possible through the use of different actuator types used to move and position the stage 112 and the SPT 146. For example, the SPT 146 can also or instead be coupled to and driven in the Z direction by any of the electromotive actuators described above with reference to the X and Y portions 200, 202 in the illustrated embodiment of
Any of the actuators employed to move the X, Y, and Z portions 100, 102, 104 of the X-Y-Z stage positioning assembly 110 and the SPT 146 can be replaced or supplemented with an actuator having relatively less precision (e.g., a ball screw linear actuator, a servo motor, a stepper motor) or with an actuator having a relatively higher precision (e.g., those electromotive actuators described above with reference to the X and Y portions 200, 202 in the illustrated embodiment of
Although the SPT 146 illustrated in the embodiment of
Also, in some embodiments, the SPT 146 is movable in the X direction by an actuator of any type described herein. In some embodiments, such an actuator can have relatively high precision, such as those described above with reference to the X and Y portions 200, 202 in the illustrated embodiment of
Similarly, in some embodiments, the SPT 146 is also or instead movable in the Y direction by an actuator of any type described herein. In some embodiments, such an actuator can have relatively high precision, such as those described above with reference to the X and Y portions 200, 202 in the illustrated embodiment of
With reference to the various arrayer embodiments described and illustrated herein, any one or more of the actuators in such embodiments can be controlled independently of the others. In some embodiments, each of actuators is controllable independently of the other actuators, thereby providing a significant degree of control over relative motion of the SPT 146 and stage 112.
The information and examples described herein are for illustrative purposes and are not meant to exclude any derivations or alternative methods that are within the conceptual context of the invention. It is contemplated that various deviations can be made to this embodiment without deviating from the scope of the present invention. Accordingly, it is intended that the scope of the present invention be dictated by the appended claims rather than by the foregoing description of this embodiment. Various features and aspects of the invention are set forth in the following claims.
Priority is hereby claimed to U.S. Provisional Patent Application No. 60/643,084, filed Jan. 10, 2005, the entire contents of which are incorporated herein by reference. In addition, this is a continuation-in-part patent application of U.S. patent application Ser. No. 09/929,865, filed Aug. 14, 2001, the entire contents of which are incorporated herein by reference, and claims priority to U.S. Provisional Patent Application No. 60/225,434, filed Aug. 15, 2000.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US06/00708 | 1/10/2006 | WO | 00 | 9/15/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60643084 | Jan 2005 | US |
