Patent Grant
9517469
The temperature dependence of biochemical and chemical reaction rates poses a particular challenge to efforts to improve reaction efficiency and speed by miniaturization. A time-domain approach, whereby not only the reaction volume but also the entire housing is kept at a desired temperature, is only suitable for isothermal conditions. If temperature needs to be changed or cycled in a rapid and controlled manner, the added thermal mass of the housing limits the rate and/or precision that can be achieved.
In the space-domain approach (see, e.g., Kopp, M. U., de Mello, A. J., Manz, A., Science 1998, 280, 1046-1048; Burns, M. A., Johnson, B. N., Bralunansandra, S. N., Handique, K., Webster, J. R., Krishman, M., Sammarco, T. S., Man, P. M., Jones, D., Heldsinger, D., Mastrangelo, C. H., Burke, D. T., Science 1998, 282, 484-487; Chiou, J., Matsudaira, P., Sonn, A., Ehrlich, D., Anal. Chem. 2001, 73, 2018-2021; and Nakano, H., Matsuda, K., Yohda, M., Nagamune, T., Endo, I., Yamane, T., Biosci. Biotechnol. Biochem. 1994, 58, 349-352), different parts of the reaction housing are kept at different temperatures, and reaction volume is brought in thermal contact with a desired part of the housing to keep it at the temperature of that part. If necessary, the reaction volume can then be moved to a different part of the housing to change the temperature; and, depending on the trajectory of the reaction volume, the temperature profile of it can be adjusted or cycled as desired. To date, most of the implementations of the space-domain dynamic thermal control have been directed to miniaturized PCR thermocycling. Continuous meandering or spiral channels laid across temperature zones have been demonstrated for continuous flowthrough amplification (see, e.g., Fukuba T, Yamamoto T, Naganuma T, Fujii T Microfabricated flow-through device for DNA amplification—towards in situ gene analysis CHEMICAL ENGINEERING JOURNAL 101 (1-3): 151-156 Aug. 1, 2004); direct-path arrangements with a reaction slug moving back and forth have been described (see, e.g., Chiou, J., Matsudaira, P., Sonn, A., Ehrlich, D., Anal. Chem. 2001, 73, 2018-2021); and finally, cycling of an individual reaction through a loop has been demonstrated (see, e.g., Jian Liu Markus Enzelberger Stephen Quake A nanoliter rotary device for polymerase chain reaction Electrophoresis 2002, 23, 1531-1536).
The existing devices do not provide for passage of the reaction volume through a detection site during each thermal cycle, which would provide a real-time PCR capability. Nor do they employ a multitude of parallel channels, each containing multiple reaction volumes, to improve throughput.
In one aspect, a method for conducting a nucleic acid amplification reaction requiring different temperatures is disclosed. The method comprises the steps of: (a) providing at least one reaction droplet to an electrowetting array comprising at least two reaction zones, each reaction zone having a different temperature needed for the nucleic acid amplification reaction, the reaction droplet comprising a nucleic acid of interest and reagents needed to effect amplification of the nucleic acid; (b) conducting the nucleic acid amplification reaction by moving, using electrowetting, the at least one reaction droplet through the at least two reaction zones such that a first cycle of the nucleic acid amplification reaction is completed; and (c) optionally, repeating step (b) to conduct further cycles of the nucleic acid amplification reaction.
In another aspect, a method for amplifying a nucleic acid of interest is disclosed. The method comprises the steps of: (a) providing at least one reaction droplet to an electrowetting array, the reaction droplet comprising a nucleic acid of interest and reagents needed to effect amplification of the nucleic acid, the reagents including nucleic acid primers; (b) moving the droplet(s), using electrowetting, through a first reaction zone of the electrowetting array having a first temperature such that the nucleic acid of interest is denatured; (c) moving the droplet(s), using electrowetting, through a second reaction zone of the electrowetting array having a second temperature such that the primers are annealed to the nucleic acid of interest; (d) moving the droplet(s), using electrowetting, through a third reaction zone of the electrowetting array having a third temperature such that extension of the nucleic acid primers occurs, thus amplifying the nucleic acid of interest; and optionally repeating steps (b), (c), and (d).
An aspect of the method for amplifying a nucleic acid of interest disclosed above is also provided. The method comprises the steps of: (a) providing at least one reaction droplet to an electrowetting array, the reaction droplet comprising a nucleic acid of interest and reagents needed to effect amplification of the nucleic acid, the reagents including nucleic acid primers; (b) moving the droplet(s), using electrowetting, through a first reaction zone of the electrowetting array having a first temperature such that the nucleic acid of interest is denatured; (c) moving the droplet(s), using electrowetting, through a second reaction zone of the electrowetting array having a second temperature such that the primers are annealed to the nucleic acid of interest and such that extension of the nucleic acid primers occurs, thus amplifying the nucleic acid of interest; and optionally repeating steps (b) and (c).
In another aspect, a device for conducting chemical or biochemical reactions at various temperatures is disclosed. The device comprises a microfluidics apparatus comprising at least one reaction path, at least one detection site, and at least one return path and means for actuating a reaction droplet or a reaction volume through the reaction path(s), detection zone(s), and return path(s). The device also comprises at least two reaction zones, each reaction zone capable of maintaining a temperature different from the other reaction zones, where the reaction path travels through at least two reaction zones.
An aspect of the device disclosed above is also provided. The device comprises a microfluidics apparatus comprising a plurality of reaction paths, at least one detection site, and at least one return path and means for actuating a reaction droplet or a reaction volume through the reaction paths, detection zone(s), and return path(s). The device also comprises at least two reaction zones, each reaction zone capable of maintaining a temperature different from the other reaction zones, where each of the reaction paths travels through at least two reaction zones, and where at least one of the reaction paths is fluidly connected to at least one detection zone.
In another aspect, a device for conducting chemical or biochemical reactions at various temperatures is disclosed. The device comprises an electrowetting array comprising a plurality of electrowetting electrodes forming at least one reaction path, at least one detection site, and at least one return path. The device further comprises at least two reaction zones, each reaction zone capable of maintaining a temperature different from the other reaction zones, where the reaction path travels through at least two reaction zones and the electrowetting array is capable of manipulating a reaction droplet through the reaction path(s), detection zone(s), and return path(s).
In another aspect, a method for conducting a reaction requiring different temperatures is disclosed. The method comprises: (a) providing at least one reaction droplet to an electrowetting array comprising at least two reaction zones, each reaction zone having a different temperature needed for the reaction, the reaction droplet comprising reagents needed to effect the reaction; (b) conducting the reaction by moving, using electrowetting, the at least one reaction droplet through the at least two reaction zones such that a first cycle of the reaction is completed; and (c) optionally repeating step (b) to conduct further cycles of the reaction.
An aspect of the method for conducting a reaction requiring different temperatures disclosed above is also provided. The method comprises: (a) providing at least one reaction droplet or volume to a microfluidics apparatus comprising at least two reaction zones and at least one detection site, each reaction zone having a different temperature needed for the reaction, the reaction droplet comprising reagents needed to effect the reaction; (b) conducting the reaction by moving, using actuation means, the at least one reaction droplet or volume through the at least two reaction zones such that a first cycle of the reaction is completed; and (c) optionally repeating step (b) to conduct further cycles of the reaction.
The present invention relates to methods and devices for conducting chemical or biochemical reactions that require multiple reaction temperatures. The methods involve moving one or more reaction droplets or reaction volumes through various reaction zones having different temperatures on a microfluidics apparatus. The devices comprise a microfluidics apparatus comprising appropriate actuators capable of moving reaction droplets or reaction volumes through the various reaction zones.
Methods and Devices Using electrowetting
In one embodiment, the devices comprise an electrowetting array comprising a plurality of electrowetting electrodes, and the method involves using electrowetting to move one or more reaction droplets through various reaction zones on the electrowetting array having different temperatures in order to conduct the reaction.
The electrowetting array of the device may comprise one or more reaction paths that travel through at least two reaction zones of the device. Each reaction zone may be maintained at a separate temperature in order to expose the reaction droplets to the desired temperatures to conduct reactions requiring multiple reaction temperatures. Each reaction path may comprise, for example, a plurality of electrodes on the electrowetting array that together are capable of moving individual droplets from one electrode to the next electrode such that the reaction droplets may be moved through the entire reaction path using electrowetting actuation. Electrowetting arrays, electrowetting electrodes, and devices incorporating the same that may be used include those described in U.S. Pat. Nos. 6,565,727 and 6,773,566 and U.S. Patent Application Publication Nos. 2004/0058450 and 2004/0055891, the contents of which are hereby incorporated by reference herein.
Devices that may be used for conducting reactions requiring multiple reaction temperatures typically comprise a first, flat substrate and a second, flat substrate substantially parallel to the first substrate. A plurality of electrodes that are substantially planer are typically provided on the first substrate. Either a plurality of substantially planar electrodes or one large substantially planer electrode are typically provided on the second substrate. Preferably, at least one of the electrode or electrodes on either the first or second substrate are coated with an insulator. An area between the electrodes (or the insulator coating the electrodes) on the first substrate and the electrodes or electrode (or the insulator coating the electrode(s)) on the second substrate forms a gap that is filled with filler fluid that is substantially immiscible with the liquids that are to be manipulated by the device. Such filler fluids include air, benzenes, or a silicone oil. In some embodiments, the gap is from approximately 0.01 mm to approximately 1 mm, although larger and smaller gaps may also be used. The formation and movement of droplets of the liquid to be manipulated are controlled by electric fields across the gap formed by the electrodes on opposite sides of the gap.
Other devices comprising electrodes on only one substrate (or devices containing only one substrate) may also be used for conducting reactions requiring multiple reaction temperatures. U.S. Patent Application Publication Nos. 2004/0058450 and 2004/0055891, the contents of which are hereby incorporated by reference herein, describe a device with an electrowetting electrode array on only one substrate. Such a device comprises a first substrate and an array of control electrodes embedded thereon or attached thereto. A dielectric layer covers the control electrodes. A two-dimensional grid of conducting lines at a reference potential is superimposed on the electrode array with each conducting line (e.g., wire or bar) running between adjacent drive electrodes.
Each reaction path of the devices for conducting chemical or biochemical reactions includes at least two reaction zones. The reaction zones are maintained at specified temperatures such that reactions requiring multiple reaction temperatures may be conducted. The reaction droplet or droplets are moved through (or allowed to remain in) each reaction zone for an appropriate time according to the specific reaction being performed. The temperatures in the reaction zones are maintained at a substantially constant temperature using any type of heating or cooling, including, for example, resistive, inductive, or infrared heating. The devices for conducting the reactions may further comprise the mechanisms for generating and maintaining the heat or cold needed to keep the reaction zones at a substantially constant temperature.
The devices for conducting chemical or biochemical reactions may optionally have a detection site positioned in or after the reaction paths. In one embodiment, the device comprises a detection site after the last reaction zone in each reaction path. The detection site, which is also part of the electrowetting array of the device, may be designed such that detection of indicia of the reaction (e.g., a label indicating that the reaction occurred or did not occur) or detection of an analyte in the reaction droplet (for quantitation, etc.) may be detected at the detection site. For example, the detection site may comprise a transparent or translucent area in the device such that optical indicia of a feature of the reaction may be optically or visually detected. In addition, a detector may be positioned at the detection site such that the reaction indicia may be detected with or without a transparent or translucent area. Translucent or transparent detection sites may be constructed using a substrate made from, for example, glass or plastic and an electrode made from, for example, indium tin oxide or a thin, transparent metal film. Reaction indicia may comprise, for example, fluorescence, radioactivity, etc., and labels that may be used include fluorescent and radioactive labels. In addition, the detection site may contain bound enzymes or other agents to allow detection of an analyte in the reaction droplets.
As stated above, the reaction path or paths of the device may comprise an array of electrowetting electrodes. In addition, the reaction paths may further comprise a conduit or channel for aiding in defining the fluid path. Such channels or conduits may be part of the electrowetting electrodes themselves, may be part of an insulating coating on the electrodes, or may be separate from the electrodes.
The reaction paths may have various geometrical configurations. For example, the reaction paths may be a circular path comprising at least two reaction zones, a linear path that crosses at least two reaction zones, or other shaped paths. In addition, the devices may comprise an array of electrowetting electrodes that includes multiple possible reaction paths and multiple reaction zones such that the device may be reconfigured for various reactions.
The device may also comprise a return path from the end of the reaction path or from the detection site (if the device includes a detection site after the end of the reaction path) to the beginning of the same reaction path (or to a new, identical reaction path) such that multiple cycles of the reaction may be conducted using the same reagents. That is, the device may contain a return path such that multiple reaction cycles may be conducted using a loop path or a meandering path for the total path of the reaction droplets. As with the reaction path and the detection site, the return path comprises one or more electrowetting electrodes and is part of the electrowetting array of the device. The return path may include a channel or conduit for aiding in defining the fluid path. The return path may go through one or more of the reaction zones or may entirely bypass the reaction zones. In addition, the return path may have a substantially constant temperature (different from or identical to one of the temperatures maintained in the reaction zones) that is maintained by appropriate heating or cooling mechanisms. In addition, the return path may be operated such that reaction droplets are returned to the beginning of the same or a new reaction path faster than the time the reaction droplets spend in the reaction path.
When multiple reaction paths are contained in a device, there may be multiple return paths (e.g., one return path for each reaction path) or there may be less return paths than reaction paths (e.g., only one return path). When there are less return paths than reaction paths, the droplets may be manipulated on the electrowetting array such that the reaction droplets that traveled through a particular path on the first reaction cycle are returned to the identical reaction path for the second reaction cycle, therefore allowing results of each progressive cycle for a particular reaction droplet to be compared to the results of the previous cycles for the same reaction droplet.
In other embodiments, the reaction droplets may be moved to the beginning of the same reaction path without a return path in order to perform cycles of the same reaction. Such a return path may not be needed where the reaction path and any detection site form a loop, or where the reaction path and any detection site do not form a loop (e.g., a linear path) and the reaction droplets are moved in the opposite direction along the same path to return them to the beginning of the same reaction path. The devices comprising an electrowetting array are capable of moving the reaction droplets both unidirectionally in the array for some reactions as well as bidirectionally in a path, as needed. In addition, such devices may be capable of moving reaction droplets in any combination of directions in the array needed to perform a particular reaction and such devices are not limited to linear movement in the electrowetting arrays.
The device may also comprise appropriate structures and mechanisms needed for dispensing liquids (e.g., reaction droplets, filling liquids, or other liquids) into the device as well as withdrawing liquids (e.g., reaction droplets, waste, filling liquid) from the device. Such structures could comprise a hole or holes in a housing or substrate of the device to place or withdraw liquids from the gap in the electrowetting array. Appropriate mechanisms for dispensing or withdrawing liquids from the device include those using suction, pressure, etc., and also include pipettes, capillaries, etc. In addition, reservoirs formed from electrowetting arrays as well as drop meters formed from electrowetting arrays, for example, as described in U.S. Pat. No. 6,565,727, may also be used in the devices described herein.
The methods of conducting chemical or biochemical reactions that require multiple reaction temperatures comprise providing at least one reaction droplet to an electrowetting array of a device described herein and then conducting the reaction by moving, using electrowetting, the at least one reaction droplet through the at least two reaction zones. The at least two reaction zones are maintained at the different temperatures needed for the reaction. If desired, the reaction may be repeated with the same reaction droplet by again moving, using electrowetting, the at least one reaction droplet through the at least two reaction zones. Such repetition may be desired where multiple reaction cycles are needed or preferred for a particular reaction.
The reaction droplet or droplets comprise the reagents needed to conduct the desired reaction, and the reaction droplets (including any sample to be tested) may be prepared outside of the device or may be prepared by mixing one or more droplets in the device using the electrowetting array. In addition, further reagents may be added to the reaction droplet (e.g., by mixing a new reaction droplet containing appropriate reagents) during the reaction or after a reaction cycle and before conducting a new reaction cycle.
The devices described herein are suitable for, but not limited to, conducting nucleic acid amplification reactions requiring temperature cycling. That is, the device is useful for conducting reactions for amplifying nucleic acids that require more than one temperature to conduct portions of the overall reaction such as, for example, denaturing of the nucleic acid(s), annealing of nucleic acid primers to the nucleic acid(s), and polymerization of the nucleic acids (i.e., extension of the nucleic acid primers).
Various nucleic acid amplification methods require cycling of the reaction temperature from a higher denaturing temperature to a lower polymerization temperature, and other methods require cycling of the reaction temperature from a higher denaturing temperature to a lower annealing temperature to a polymerization temperature in between the denaturing and annealing temperatures. Some such nucleic acid amplification reactions include, but are not limited to, polymerase chain reaction (PCR), ligase chain reaction, and transcription-based amplification.
In one particular embodiment, a method for conducting a reaction requiring different temperatures is provided. The method comprises (a) providing at least one reaction droplet to an electrowetting array comprising at least two reaction zones and (b) conducting the reaction by moving, using electrowetting, the at least one reaction droplet through the at least two reaction zones such that a first cycle of the reaction is completed. Each reaction zone has a different temperature needed for the reaction. The reaction droplet comprises reagents needed to effect the reaction. Step (b) may optionally be repeated in order to conduct further cycles of the reaction.
In another particular embodiment, a method for conducting a nucleic acid amplification reaction requiring different temperatures is provided. The method comprises (a) providing at least one reaction droplet to an electrowetting array comprising at least two reaction zones and (b) conducting the nucleic acid amplification reaction by moving, using electrowetting, the at least one reaction droplet through the at least two reaction zones such that a first cycle of the nucleic acid amplification reaction is completed. Each reaction zone has a different temperature needed for the nucleic acid amplification reaction. The reaction droplet comprises a nucleic acid of interest and reagents needed to effect amplification of the nucleic acid. Such reagents may include appropriate nucleic acid primers, nucleotides, enzymes (e.g., polymerase), and other agents. Step (b) may optionally be repeated in order to conduct further cycles of the nucleic acid amplification reaction.
In a further embodiment, another method for amplifying a nucleic acid of interest is provided. The method comprises the steps of (a) providing at least one reaction droplet to an electrowetting array, the reaction droplet comprising a nucleic acid of interest and reagents needed to effect amplification of the nucleic acid, the reagents including nucleic acid primers; (b) moving the droplet(s), using electrowetting, through a first reaction zone of the electrowetting array having a first temperature such that the nucleic acid of interest is denatured; (c) moving the droplet(s), using electrowetting, through a second reaction zone of the electrowetting array having a second temperature such that the primers are annealed to the nucleic acid of interest; and (d) moving the droplet(s), using electrowetting, through a third reaction zone of the electrowetting array having a third temperature such that extension of the nucleic acid primers occurs, thus amplifying the nucleic acid of interest. Steps (b), (c), and (d) may optionally be repeated in order to conduct further cycles of the nucleic acid amplification reaction
In yet another embodiment, another method for amplifying a nucleic acid of interest is provided comprising the steps of: (a) providing at least one reaction droplet to an electrowetting array, the reaction droplet comprising a nucleic acid of interest and reagents needed to effect amplification of the nucleic acid, the reagents including nucleic acid primers; (b) moving the droplet(s), using electrowetting, through a first reaction zone of the electrowetting array having a first temperature such that the nucleic acid of interest is denatured; (c) moving the droplet(s), using electrowetting, through a second reaction zone of the electrowetting array having a second temperature such that the primers are annealed to the nucleic acid of interest and such that extension of the nucleic acid primers occurs, thus amplifying the nucleic acid of interest. Steps (b) and (c) may optionally be repeated in order to conduct further cycles of the nucleic acid amplification reaction.
When the methods are used to conduct PCR, the reagents in the reaction droplets may include deoxynucleoside triphosphates, nucleic acid primers, and a polymerase such as, for example, a thermostable polymerase such as Taq DNA polymerase.
A method is disclosed for conducting chemical or biochemical reactions at various temperatures by moving multiple reaction droplets through parts of a housing kept at desired temperatures, with or without them moving through a detection site at desired time points. The device provided for this purpose comprises path(s) for moving the reactions through the zones having controlled temperature, optional detection sites, and optional return paths for repeating a temperature cycle a desired number of times.
A particular embodiment for realizing real-time PCR is shown in
Methods and Devices Using Other Fluidic or Microfluidic Actuators
In addition to using electrowetting arrays and electrodes in order to actuate the reaction droplets through the reaction zones on the apparatus, other actuation means may be used with the devices and methods described herein. That is, any mechanism for actuating reaction droplets or reaction volumes may be used in the device and methods described herein including, but not limited to, thermal actuators, bubble-based actuators, and microvalve-based actuators. The description of the devices and methods herein where electrowetting is used to manipulate the liquid to conduct the reaction is equally applicable to devices and methods using other actuation means.
Thus, a device for conducting chemical or biochemical reactions that requires multiple reaction temperatures may comprise a microfluidics apparatus comprising at least one reaction path that travels through at least two reactions zones on the device. The device may include one or more detection sites and one or more return paths. The device further comprises means for actuating a reaction droplet or a reaction volume through the reaction path(s), detection site(s), and/or return path(s), and such reaction path(s), detection site(s), and/or return path(s) of the device may be fluidly connected in various ways.
In one embodiment, the device includes multiple reaction paths that travel through at least two reaction zones, wherein each reaction path may include multiple reaction droplets/volumes. In another embodiment, the device includes at least one detection site in or after the one or more reaction paths. In such an embodiment, the detection site(s) and one or more of the reaction paths may be fluidly connected.
As described above, the reaction paths may have various geometrical configurations. For example, the reaction paths may be a circular path comprising at least two reaction zones, a linear path that crosses at least two reaction zones, or other shaped paths.
The devices may also comprise a return path from the end of the reaction path or from the detection site (if the device includes a detection site after the end of the reaction path) to the beginning of the same reaction path (or to a new, identical reaction path) such that multiple cycles of the reaction may be conducted using the same reagents. That is, the device may contain a return path such that multiple reaction cycles may be conducted using a loop path or a meandering path for the total path of the reaction droplets/volumes. The return path may go through one or more of the reaction zones or may entirely bypass the reaction zones. In addition, the return path may have a substantially constant temperature (different from or identical to one of the temperatures maintained in the reaction zones) that is maintained by appropriate heating or cooling mechanisms. In addition, the return path may be operated such that reaction droplets/volumes are returned to the beginning of the same or a new reaction path faster than the time the reaction droplets/volumes spend in the reaction path.
When multiple reaction paths are contained in a device, there may be multiple return paths (e.g., one return path for each reaction path) or there may be less return paths than reaction paths (e.g., only one return path). When there are less return paths than reaction paths, the droplets/volumes may be manipulated on the apparatus such that the reaction droplets/volumes that traveled through a particular path on the first reaction cycle are returned to the identical reaction path for the second reaction cycle, therefore allowing results of each progressive cycle for a particular reaction droplet/volume to be compared to the results of the previous cycles for the same reaction droplet/volume.
In other embodiments, the reaction droplets/volumes may be moved to the beginning of the same reaction path without a return path in order to perform cycles of the same reaction. Such a return path may not be needed where the reaction path and any detection site form a loop, or where the reaction path and any detection site do not form a loop (e.g., a linear path) and the reaction droplets/volumes are moved in the opposite direction along the same path to return them to the beginning of the same reaction path.
Multiple reaction volumes/droplets may be simultaneously moved through the microfluidics apparatus. In addition, multiple reaction paths may be used having multiple reaction volumes/droplets.
In one particular embodiment, the device comprises multiple reaction paths, at least one detection site either in or after one of the reaction paths, and at least one return path. In such embodiments, when one return path is used, the multiple reaction paths, the at least one detection site, and the return paths may be fluidly connected to form a loop. When multiple return paths are used, multiple loops may be formed.
As also described above, the methods of conducting chemical or biochemical reactions that require multiple reaction temperatures comprise providing at least one reaction droplet/volume to a microfluidics apparatus described herein and then conducting the reaction by moving, using any actuation means, the at least one reaction droplet/volume through the at least two reaction zones. The at least two reaction zones are maintained at the different temperatures needed for the reaction. If desired, the reaction may be repeated with the same reaction droplet by again moving, using the actuation means, the at least one reaction droplet through the at least two reaction zones. Such repetition may be desired where multiple reaction cycles are needed or preferred for a particular reaction.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.
This application claims the benefit of U.S. Provisional Application No. 60/679,714, filed May 11, 2005, the entirety of which is incorporated herein by reference.
This invention was made with Government support awarded by the United States Army Medical Research Acquisition Activity on behalf of the United States Department of Homeland Security Advanced Research Projects Agency pursuant to Other-Transaction-for-Prototype Agreement Number W81XWH-04-9-0019 (HSARPA Order No. TTA-1-103). The United States has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind | 371c Date |
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| PCT/US2006/018088 | 5/10/2006 | WO | 00 | 10/29/2007 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2006/124458 | 11/23/2006 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20080274513 A1 | Nov 2008 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60679714 | May 2005 | US |
