WO1996042012A1 - Nanofabricated separation matrix for analysis of biopolymers and methods of making and using same - Google Patents
Nanofabricated separation matrix for analysis of biopolymers and methods of making and using same Download PDFInfo
- Publication number
- WO1996042012A1 WO1996042012A1 PCT/US1996/009999 US9609999W WO9642012A1 WO 1996042012 A1 WO1996042012 A1 WO 1996042012A1 US 9609999 W US9609999 W US 9609999W WO 9642012 A1 WO9642012 A1 WO 9642012A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- posts
- biopolymers
- electrodes
- chip
- electric field
- Prior art date
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44756—Apparatus specially adapted therefor
- G01N27/44773—Multi-stage electrophoresis, e.g. two-dimensional electrophoresis
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44704—Details; Accessories
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44756—Apparatus specially adapted therefor
- G01N27/44791—Microapparatus
Definitions
- This application relates to a novel form of separation matrix for the analysis of biopolymcrs, particularly nucleic acid polymers.
- separation matrices for the analysis of biopolymcrs is well established.
- agarose gels, polyacrylamide gel and other types of gel matrices are used routinely to separate proteins, polypcptides and polynuclcotidcs into subclasses based upon properties such as size, weight and molecular charge.
- Analysis of the separated subclasses is used to identify and characterize proteins, to detect and characterize mutant forms of proteins, and to detect and characterize polynucleotides.
- analysis of separated polynuclcotide fragments is a basic part of the process for most determinations of nucleic acid sequence.
- the obstacle course is made up of a regular array of posts having separations of 1 ⁇ m between the posts. DNA loaded onto the array was separated by size by the application of an electric field, and detected using epi fluorescence microscopy.
- the obstacle course described by Volkmuth et al. is not well-suited for use in diagnostic applications, however, because the total length of the DNA fragments in most diagnostic DNA sequencing applications, diagnostic RFLP (restriction fragment length polymorphism) procedures, and the like is between about 20 and 300 to 400 nuclcotidcs. As such, the looping of long strands of DNA observed by Volkmuth cannot be relied upon as a basis for separation. Furthermore, the fabrication process of Volkmuth et al. uses electron beam lithography to make each individual device, which would be prohibitively expensive for diagnostic applications.
- the present invention provides a separation matrix useful in the formation of solid-state mm- to cm-scale devices for the rapid, high-resolution separation of single- stranded DNA ladder bands generated by the Sanger dideoxy- or Maxam/Gilbcrt chemical DNA sequencing procedures. Such device are referred to herein as "DNA Sequencing Chips.”
- the separation matrix comprises a solid support having a plurality of posts disposed on a first major surface thereof to form an obstacle course of posts and pores.
- the posts arc arranged in a regular X,Y array and are separated one from another by a distance of 100 nm or less, preferably 10 to 30 nm.
- the separation matrix of the invention can be manufactured by first forming a mold, preferably a reusable mold using lithography techniques.
- the mold is the reverse of the desired pattern of posts and pores of the obstacle course, and is used for casting the obstacle course.
- the cast obstacle course is then fused to a solid support and separated from the mold.
- the separation matrix can be formed from a polymer which undergoes specific and quantifiable swelling in the presence of a selected chemical compound.
- the matrix is cast on a mold in a conventional manner with a spacing between posts greater than the desired final spacing of 100 um or less.
- a buffer solution saturated with the specific chemical agent that controls swelling is added, causing the posts to swell to a defined amount to achieve the desired separation.
- Figs. 1 A, IB and 1C shows a nanofabricatcd separation matrix according to the present invention
- Fig. 3 shows a layered composite useful for forming a mold to make the separation matrix of the invention
- Fig.4 shows an apparatus for manufacturing separation matrices
- Fig. 5 shows a layout of electrodes useful in the invention
- Fig. 6 shows a layout of electrodes useful in the invention
- Fig. 7 shows an apparatus in accordance with the invention
- Fig. 8 shows a loading device for loading separation matrices in accordance with the invention
- Fig. 9 shows a layout of an integrated DNA diagnostic chip in accordance with the invention.
- Fig. 1 A shows a separation matrix according to the present invention.
- the separation matrix has a solid support 1 on which arc disposed a plurality of lanes 2.
- each lane 2 is approximately 10 ⁇ m wide and 1 ⁇ m or less deep, and is separated from neighboring lanes by a separator 3 of approximately 10 ⁇ m in width.
- Fig. IB The width of each lane, and indeed the use of separated lanes at ail is a matter of design choice and is not critical to the invention, although it should be noted that lane separation allows each lane to act as a separate capillary. It will be appreciated, however, that the sizes noted above provide for the possibility of 50 lanes in a 1mm wide chip, which allows for very high throughput in a small area.
- Each lane 2 contains a plurality of posts 4 which form an obstacle course for the separation of the biopolymers as shown in the partial top view of one lane 2 and separator 3 in Fig. lC.
- the posts 4 are disposed in a regular pattern leavings pores 5 open for the passage of materials through the separation matrix.
- the spacing between the posts 4 must be large enough to permit passage of the biopolymer to be separated, yet small enough to provide an obstacle to passage which will result in separation.
- the determination of the appropriate size requires a consideration of many factors, including the overall size of the device, the degree of separation to be achieved by the device, and the size of the polymers to be separated.
- Each line of posts 4 may be in alignment with or offset with respect to adjacent lines of posts.
- the separation matrix may be advantageous to form the separation matrix such that the spacing between lines of posts is sufficient to allow migrating molecules to reassume a random distribution of orientations. If spacing is finer, and DNA does not achieve random reorientation, reptation behavior result. This would be a different mode of clectrophoresis, which may have useful properties as well.
- the appropriate size for the pores 5 between the posts 4 can be determined empirically, i.e., by testing a series of spacings to determine the effectiveness of each for separation of biopolymcric materials of a given size range, or it can be determined theoretically based upon the properties of the polymer in question.
- single-stranded DNA in a denaturing solvent is linear polymer with a random-coil configuration.
- the displacement length R is defined as the root-mean-square distance between the two terminal groups of the chain.
- This parameter is directly related to the radius of gyration S, which is defined as the root-mean-square distance of element i within the polymer from the center of gravity of the polymer. According to the derivation given by Flory in 1953, for a linear polymer in a random-coil configuration,
- N is the number of elements in the chain, (i.e., the number of nucleotide residues in a single-stranded oligonucleotide fragment) and L is the distance between centers of adjacent elements in the chain.
- the spacing between the posts is advantageously less than 100 nm, preferably 1 to 30 nm. Larger spacing between the posts may be particularly useful in a hybrid obstacle course as discussed more fully below.
- Separation matrices according to the invention can be manufactured using electron beam lithography to form a mold which is the reverse of the desired pattern of posts and pores making up the obstacle course, casting the obstacle course in the mask, and then fusing the cast obstacle course to a solid support for stripping from the mold.
- the mold is reusable.
- a substrate is coated with a pattern receiving layer or layers.
- a tungsten substrate 31 which will ultimately form the mold, may be coated with a thin layer of a dielectric such as silicon dioxide 32, a thin layer of a low cross-section, highly conductive metal, such as aluminum 33, and a layer of an electron sensitive resist 34.
- Preferred resists are positive resists such as polymethylmethacrylate derivatives, since these will in general provide the highest resolution.
- the resist layer is preferably deposited by spray deposition, although formation of a Langmuir/Blodgett film on water, followed by transfer to a solid surface can also be used for the formation of molds with resolution on the order of 50 to 80 nm.
- a Langmuir/Blodgett film on water followed by transfer to a solid surface can also be used for the formation of molds with resolution on the order of 50 to 80 nm.
- the coated substrate is positioned on the stage of an electron beam lithography tool having appropriate resolution to draw lines of the dimensions desired.
- Suitable tools for this purpose include the JEOL JBX-5DII(U) electron beam tool (resolution of 20 nm) and the Leica/Cambridge EBMF 10/5 CS electron beam lithographic instrument (resolution 150 nm).
- the electron beam is used to write a pattern in the resist which is either a positive image (in the case of a positive resist which hardens to resist removal when exposed to the electron beam) or a negative image (in the case of a negative resist which becomes removable when exposed to the electron beam) of the posts and pores of the desired obstacle course.
- the exposed resist is then developed, to leave the patterned mask on the substrate.
- the next step is the transfer of the pattern down through the layers of the substrate using successive treatments with specific chemical etchants, culminating in the etching of the substrate itself to produce a reusable mold for use in forming the separation matrix of the invention.
- the separation matrix of the invention can be made of any of a number of materials, and the manner of forming the matrix within the mold will depend to a large extent on the nature of the material selected.
- separation matrices made from silicon dioxide or similar materials can be formed using a chemical vapor deposition process to deposit material within the mold. Thereafter a glass base can be fused to the deposited materials, for example using the technique of field assisted silicon glass fusion (Wallis et al., J. Appl. Phys. 40: 3946-3949 ( 1969)) to increase the dimensional stability of the molded matrix and to facilitate its separation from the mold.
- the matrix may also be formed from a variety of polymeric materials, including polymethylmethacrylate, ultraviolet-curable polyurethanes, ultraviolet-curable epoxies and other polymers with suitable physical and chemical properties, i.e., optical transparency and low fluorescence at relevant wavelengths, thermal conductivity and lack of electric charge. These materials can be formed into the obstacle course relying on capillarity as in the techniques of polymer casting (Kim et al. Nature 376: 581-584 (1995), and then cured either chemically or photochemically.
- a mold as described above can also be used to form the separation matrix of the invention using the technique of imprint lithography as described by Chou et al.. Science 272: 85-87 (1996).
- a thin layer of a polymer resist such as polymethylmethacrylate is applied to a substrate.
- the polymer resist is then softened to a gel by heating it to a temperature above its glass transition temperature, and the mold is pressed against the softened resist to form a thickness contrast pattern.
- the mold is then removed and an anisotropic etching process such as reactive ion etching or wet etching is used to remove the resist from the compressed areas.
- swellable polymers In the case of swellable polymers, larger starting molds can be used because the unswelled spacing between the posts is greater, and thus presents less of a challenge in terms of molding and separation technology. Molds for this purpose can be made by ultraviolet light-based lithographic techniques because less resolution is needed. In this case, the key is to determine the maximum amount which a given polymer will swell when in the presence of a saturating amount of the swelling control agent, and then making the posts in a size such that when this amount of swelling occurs, the desired final dimensions are achieved.
- Suitable swellable polymers useful in the present invention are insoluble cross- linked polymers which are modified to have a specific affinity for a non-DNA material.
- Such polymers include polyvinylalcohol, polyethyleneimine. polyacryla ide, polystyrene, cross-linked dextran, and polyacrylic acid. Modifiers are selected to provide appropriate specificity to the polymer such that the amount of swelling can be controlled by addition of a selected agent. By including a saturating amount of the selected agent in the electrophoresis buffer, the degree of swelling of the polymer matrix can be consistently maintained, even after cycles of dehydration and rehydration. Synthesis of polymers of this type are described in the literature, including in International Patent Publication No. PCT/US91/12626 which is incorporated herein by reference.
- the obstacle course After the obstacle course is formed, it is placed on a solid support which will form a part of the final separation matrix, providing dimensional stability to the final product and to the obstacle course during separation from the mold.
- Suitable materials for the solid support include fine quartz or pyrex cover slips which can be fused to posts of silicon dioxide and similar materials by field-assisted silicon glass fusion. Wallis et al. J Appl. Phys. 40: 3946-3949 (1969).
- the separation matrix (support and posts) is separated from the mold.
- the separation matrix of the invention can be used for separation of biopolymcrs by filling the matrix with a buffer solution, placing opposing ends of the matrix in contact with solution electrodes, loading a sample at one end of the separation matrix, applying an electric field between the solution electrodes and detecting separated oligonucleotide fragments at the other end of the separation matrix.
- Fig. 4 shows an apparatus suitable for forming multiple replicate copies of a DNA sequencing chip, using a mold and a photopolymcrizablc material using the procedures discussed above.
- a moveable base 41 having a lamp 42 for delivering light suitable for inducing photopolymerization positioned therein is disposed within a housing 43.
- the base 41 supports a chemically treated glass cover slip or other substrate 44 in alignment with an injection port 45 in the housing.
- Monomer or prepolymcr solution is injected through the injection port 45 onto the top of the substrate 44.
- a piston 46 having the mold 47 for the pattern of plugs and pores is then pressed down into the solution on top of the substrate 44.
- the lamp 42 is then turned on to polymerize the solution in the mold, after which the molded polymer is separated from the mold 47 and the housing 43 by raising the piston 46 and lowering the base 41.
- a modified version of the device of Fig. 4 could instead be used to repetitively make multiple copies of a DNA sequencing chip by imprint lithography.
- a polymeric sheet would be used as the starting materials. This would be heated above the glass transition temperature and then piston 46 having mold 47 would be pressed down into the softened polymeric sheet to make the replica. The temperature would be lowered again below the glass transition point and then piston 46 and mold 47 would be removed.
- lamp 42 this apparatus would have a heating element.
- DNA Sequencing Chips in accordance with the invention include electrodes deposited on a bottom or top substrate to generate an electric field to induce migration of materials in the matrix.
- This can be a simple pair of electrode disposed at opposing ends of the separation matrix to impose an electric field in one direction on materials within the separation matrix.
- an extended series of micro-electrodes is disposed on the substrate, multiple electrodes within each lane of the device.
- Fig. 5 illustrates one arrangement of micro-electrodes and conducting wires on the substrate with posts and pores omitted for clarity.
- the micro-cathodes, 102, and micro-anodes, 103. are deposited in the lanes 2.
- Conducting leads 105 can be formed directly across the substrate 101 or if micro-holes are cut through the substrate, it is possible to construct the wire connections, 116, on the underside of the substrate 1, as illustrated in Fig. 6.
- the micro-electrodes and leads may be compositions of any relatively high conductance materials.
- the electrodes will be made of a coated or corrosion resistant material such as the noble metals platinum or gold. Corrosion resistance sufficient to withstand exposure to the buffer system employed in the separation is required, although noble metals are not necerney if the device is disposable.
- the pattern of the micro-electrodes on the substrate may be chosen according to the demands of the application for which the invention is employed. Two type of layouts are generally available. The first, illustrated in Fig. 5 is a spatially dispersed array in which each micro-electrode can be activated separately. Thus, electrodes which are required for a certain application may be turned on, while unnecessary ones may simply be turned off. The second option is a dedicated pattern which is employed for applications where known separation distances and voltages are available. In this case, the electrodes can be laid out in a fixed pattern which is known to be satisfactory for the desired application.
- the pores of the separation matrix are first filled with a separation fluid.
- a separation fluid This may be a buffer, a buffer containing a swelling agent, or it may be a suspension of a secondary obstacle which acts in concert with the posts of the separation matrix to form a hybrid separation matrix.
- the secondary obstacles will be a homogeously sized and distributed suspension of structures having a size on the same order as the radius of gyration of the polymers to be separated, i.e., about 0.5 to 5 times the radius of gyration.
- the secondary obstacles should also be compatible with the detection system used. Thus, for fluorescence detection the secondary obstacles should be transparent or translucent, with little or no fluorescence at the wavelengths of interest.
- Materials which can be used as secondary obstacles include monodisperse microspheres as described by Hosaka et al, Polym. Int. 30: 505-51 1 (1993) and Sanghvi et al, J. Microencaps. 10: 181-194 (1993), water-soluble fullerenes (C60) as described in Diederich et al.. Science 271 : 317-323 (1996), and self-assembling dendrimer as described in Newkome et al, J. Org. Chem. 58: 3123 (1993) and Zimmerman et al., Science llV. 1095-1098 (1996).
- the sample to be evaluated particularly a sample of a nucleic acid sequencing mixture prepared by the Sanger or Maxam/Gilbert methods is then loaded at one end of the separation matrix, for example in an integrated apparatus as shown schematically in Fig. 7.
- a plurality of samples are loaded, one to each lane of the separation matrix.
- a stacked electrophoresis zone 10 ⁇ m wide x 1 ⁇ m deep x 10 ⁇ m high (as in the entrance-way to a capillary channel of Figure 1) will occupy a volume of 0.1 pL. Therefore a very substantial reduction in volume (up to 16 6 -fold) may be required during the initial stacking process.
- Such high- efficiency stacking during the initial phase of electrophoresis can be achieved with the loading device 301 shown in more detail in Fig. 8.
- the device of Fig. 8 is shown in an orientation appropriate for loading sample into a channel of a DNA sequencing chip 203 that is in the vertical orientation.
- the loader consists of a large rectangular channel 201 attached at right angles to a second smaller rectangular channel 202.
- the upper face of the large rectangular channel 201 is open, and receives a volume (for example 100 nL of unconcentrated sample containing a DNA mixture to be separated.
- the lower face of the smaller rectangular channel 202 is also open and releases the concentrated sample (approx 1 pL) into one of the functional channels of the DNA sequencing chip 203.
- sample loaded into the top of the large channel 202 is electrophoresed using a filed generated between electrodes 205a and 205b.
- the DNA is collected on a semipermeable membrane 204a which has a molecular weight cutoff low enough to prevent passage of the DNA but which permits passage of the solvent from the sample, thereby effecting a first concentration of the sample on the semi-permeable membrane 204a.
- a second set of electrodes 206a and 206b are turned on to generate cause the concentrated sample to migrate in a direction perpendicular to the original migration from the semi permeable membrane 204a into the small channel 202.
- a second semipermeable membrane 204b retains sample within the small channel 202 while permitting passage of solvent.
- a third electrode set 207a and 207b is used to electrophorese the doubly-concentrated sample from the small channel 202 into one of the functional channels of the DNA sequencing chip 203.
- thermocouple strips 208 disposed about the periphery of the large channel 201 can achieve localized cooling of buffer in the large channel, via the Peltier effect.
- This strategy can be used to lower the temperature of a glycerol- containing buffer below the glass-transition temperature, thus creating a viscosity trap close to the semipermeable membrane 204a which prevents back-diffusion of concentrated DNA in the vertical direction within the large channel after the first concentration step.
- Electrode set 206a and 206b causes the concentrated sample to be electrophoresed directly into a DNA sequencing chip rather than into a second concentration channel.
- an electric field is applied to the sequencing chip 302 placed within holder 303 using power supply 305 to induce migration of the sample within the separation matrix.
- the field may be constant, or periodic field inversions can be used in increase the resolution of the single-stranded DNA ladder bands.
- Current can also be applied to successive electrodes along the length of the lane, or can be applied to parallel lines of electrodes within a lane to induce two-dimensional separation within the lane.
- the detector 304 may be of any type, and will vary depending on the nature of the material being detected.
- the sequencing reactions utilize a 5'-fluorescently labeled sequencing primer
- the separated bands can be detected by fluorescence.
- Three alternative illumination and detection schemes are exemplary of systems which can be used.
- fluorescence detection is the most common technique currently employed in analysis of DNA sequencing fragments, and thus is a preferred approach in the present invention
- other detector types can be used.
- a subject molecule labeled with a radioactive moiety may be detected with a radiation detector, such as X-Ray film or a scintillation counter.
- Unmodified nucleic acids may also be detected by shifting polarization of input radiation as disclosed in US Patent Application Serial No. 08/387,272, which application is incorporated herein by reference.
- the invention is used to move and/or separate species of charged molecules, and in particular charged bio-molecules such as proteins and nucleic acids. Further, the instant invention may be used to purify one molecular species from a sample of mixed molecular species.
- the object of combining the post and pore separation matrix with closely positioned electrodes is the creation of localized very-high density electric fields in the separation matrix. These localized fields can be supported with very low energy power supplies, and are therefore energy efficient.
- US Patent Application Serial No. 08/332,577 which is incoiporated herein by reference demonstrates the usefulness of high density electric fields for separating charged molecules such as nucleic acids and proteins.
- Nucleic acids separated under extremely high electric fields (100-400 V/cm) over localized areas (1-5 mm 2 ) can be detected and/or used by conventional detectors, biosensors and micro-reactor components. These miniature components may be located at one site, or more than one site on the apparatus.
- the chips of the invention can also be used to perform more complicated and complete analysis.
- the chips of the invention can be fabricated so as to move samples from one well to another for different treatments, such as in an integrated DNA diagnostic chip.
- Fig. 9 shows an integrated DNA diagnostic chip which uses the diagnostic method of the above noted patent application.
- a highly simplified discussion of the steps involved in the hierarchical method is provided below.
- a group of exons of a gene to be diagnosed is examined for insertion and deletion mutations.
- the suspect exons of the patient are amplified by multiplexed PCR using oligonucleotide primers labeled with a fluorophore (not shown).
- the resulting fragments of DNA are loaded into the separation matrix, 801, with a loader, 802, at loading site. 803.
- the sample Upon activating a group of microelectrodes, 804, the sample will migrate through the separation matrix, 801, and resolve into discrete bands of distinct species, 805, 806 and 807.
- a laser source, 808, of a wavelength suitable to excite the fluorophore is directed to an excitation site, 809.
- the fluorescence emissions may be recorded or displayed, 811. If the band has an insertion or deletion relative to the normal gene, it will pass through the excitation zone at a time different from the expected time. Such a difference indicates the presence of a mutation in that fragment. The difference can be directly reported to the patient file.
- a separated DNA fragment is moved, according to the method of the instant invention, by a series of micro-electrodes, 812 to a reaction center, 813.
- Immobilized enzymes such as DNA sequencing enzymes may be located at reaction pools, as described in US Patents Nos. 4,975,175 and 5.286,364, which are incorporated herein by reference.
- the sequencing reaction may be carried out in situ on the diagnostic chip. After a suitable length of time, the reaction is completed.
- the sequenced DNA sample is then separated in a third direction by the activation of a third group of micro-electrodes, 815.
- the DNA sequence is obtained according to conventional fluorescence DNA sequencing:
- the laser source, 808, is directed to the excitation site, 816. Fluorescence emissions of the sample are recorded by a detector, 817 and recorded or displayed, 818. The presence or absence of point mutations is then recorded and reported to the patient file.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Electrochemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Dispersion Chemistry (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Apparatus Associated With Microorganisms And Enzymes (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU62718/96A AU698921B2 (en) | 1995-06-08 | 1996-06-07 | Nanofabricated separation matrix for analysis of biopolymers and methods of making and using same |
EP96921506A EP0830594A1 (en) | 1995-06-08 | 1996-06-07 | Nanofabricated separation matrix for analysis of biopolymers and methods of making and using same |
US08/973,932 US6110339A (en) | 1995-06-08 | 1996-06-07 | Nanofabricated separation matrix for analysis of biopolymers and methods of making and using same |
JP9503252A JPH11508042A (en) | 1995-06-08 | 1996-06-07 | Nanoscale fabricated separation matrices for the analysis of biopolymers, methods of making and using them |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3695P | 1995-06-08 | 1995-06-08 | |
US60/000,036 | 1995-06-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996042012A1 true WO1996042012A1 (en) | 1996-12-27 |
Family
ID=21689607
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/009999 WO1996042012A1 (en) | 1995-06-08 | 1996-06-07 | Nanofabricated separation matrix for analysis of biopolymers and methods of making and using same |
PCT/US1996/010110 WO1996042013A1 (en) | 1995-06-08 | 1996-06-07 | Microelectrophoresis chip for moving and separating nucleic acids and other charged molecules |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/010110 WO1996042013A1 (en) | 1995-06-08 | 1996-06-07 | Microelectrophoresis chip for moving and separating nucleic acids and other charged molecules |
Country Status (6)
Country | Link |
---|---|
US (3) | US6176990B1 (en) |
EP (2) | EP0830594A1 (en) |
JP (2) | JPH11508042A (en) |
AU (2) | AU698921B2 (en) |
CA (2) | CA2226405A1 (en) |
WO (2) | WO1996042012A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998054568A1 (en) * | 1997-05-27 | 1998-12-03 | Perseptive Biosystems, Inc. | Improved separation columns and methods for manufacturing the improved separation columns |
WO2001007150A2 (en) * | 1999-07-26 | 2001-02-01 | Kahl Johan Valentin | Method and device for the electrophoretic separation of particles, especially of macromolecules |
EP1162454A1 (en) * | 1999-03-02 | 2001-12-12 | Isao Karube | Two-dimensional separating method |
US6716584B2 (en) * | 1998-06-11 | 2004-04-06 | Hitachi, Ltd. | Polynucleotide separation method and apparatus therefor |
US6787314B2 (en) * | 1998-06-11 | 2004-09-07 | Hitachi, Ltd. | Polynucleotide separation method and apparatus therefor |
Families Citing this family (95)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2255599C (en) * | 1996-04-25 | 2006-09-05 | Bioarray Solutions, Llc | Light-controlled electrokinetic assembly of particles near surfaces |
US6143152A (en) * | 1997-11-07 | 2000-11-07 | The Regents Of The University Of California | Microfabricated capillary array electrophoresis device and method |
DE19815882A1 (en) * | 1998-04-08 | 1999-10-14 | Fuhr Guenther | Method and device for manipulating microparticles in fluid flows |
FR2781885B1 (en) * | 1998-07-28 | 2000-09-08 | Jacques Toledano | ELECTROSTATIC DEVICE AND METHOD FOR FINE IMMUNOLOGICAL DETECTION |
WO2000046595A1 (en) * | 1999-02-03 | 2000-08-10 | Aclara Biosciences, Inc. | Multichannel control in microfluidics |
DE19927535B4 (en) * | 1999-06-16 | 2004-06-17 | Merck Patent Gmbh | Miniaturized analysis system with device for discharging substances |
JP2001108619A (en) * | 1999-10-12 | 2001-04-20 | Minolta Co Ltd | Analyzer, sample operation needle, and sample take-out method |
US6451191B1 (en) | 1999-11-18 | 2002-09-17 | 3M Innovative Properties Company | Film based addressable programmable electronic matrix articles and methods of manufacturing and using the same |
US6267884B1 (en) * | 2000-01-04 | 2001-07-31 | Waters Investments Limited | Capillary columns employing monodispersed particles |
US6930818B1 (en) | 2000-03-03 | 2005-08-16 | Sipix Imaging, Inc. | Electrophoretic display and novel process for its manufacture |
US6933098B2 (en) * | 2000-01-11 | 2005-08-23 | Sipix Imaging Inc. | Process for roll-to-roll manufacture of a display by synchronized photolithographic exposure on a substrate web |
US7715088B2 (en) * | 2000-03-03 | 2010-05-11 | Sipix Imaging, Inc. | Electrophoretic display |
US7052571B2 (en) * | 2000-03-03 | 2006-05-30 | Sipix Imaging, Inc. | Electrophoretic display and process for its manufacture |
US6947202B2 (en) * | 2000-03-03 | 2005-09-20 | Sipix Imaging, Inc. | Electrophoretic display with sub relief structure for high contrast ratio and improved shear and/or compression resistance |
US20070237962A1 (en) * | 2000-03-03 | 2007-10-11 | Rong-Chang Liang | Semi-finished display panels |
US7557981B2 (en) * | 2000-03-03 | 2009-07-07 | Sipix Imaging, Inc. | Electrophoretic display and process for its manufacture |
US7233429B2 (en) * | 2000-03-03 | 2007-06-19 | Sipix Imaging, Inc. | Electrophoretic display |
US7158282B2 (en) * | 2000-03-03 | 2007-01-02 | Sipix Imaging, Inc. | Electrophoretic display and novel process for its manufacture |
US6865012B2 (en) | 2000-03-03 | 2005-03-08 | Sipix Imaging, Inc. | Electrophoretic display and novel process for its manufacture |
US6831770B2 (en) | 2000-03-03 | 2004-12-14 | Sipix Imaging, Inc. | Electrophoretic display and novel process for its manufacture |
US6833943B2 (en) | 2000-03-03 | 2004-12-21 | Sipix Imaging, Inc. | Electrophoretic display and novel process for its manufacture |
US7408696B2 (en) | 2000-03-03 | 2008-08-05 | Sipix Imaging, Inc. | Three-dimensional electrophoretic displays |
US6885495B2 (en) * | 2000-03-03 | 2005-04-26 | Sipix Imaging Inc. | Electrophoretic display with in-plane switching |
US6788449B2 (en) * | 2000-03-03 | 2004-09-07 | Sipix Imaging, Inc. | Electrophoretic display and novel process for its manufacture |
US6537433B1 (en) | 2000-03-10 | 2003-03-25 | Applera Corporation | Methods and apparatus for the location and concentration of polar analytes using an alternating electric field |
US6558523B1 (en) * | 2000-04-10 | 2003-05-06 | The Regents Of The University Of California | Injector-concentrator electrodes for microchannel electrophoresis |
US6413792B1 (en) * | 2000-04-24 | 2002-07-02 | Eagle Research Development, Llc | Ultra-fast nucleic acid sequencing device and a method for making and using the same |
US8232582B2 (en) | 2000-04-24 | 2012-07-31 | Life Technologies Corporation | Ultra-fast nucleic acid sequencing device and a method for making and using the same |
US7001792B2 (en) * | 2000-04-24 | 2006-02-21 | Eagle Research & Development, Llc | Ultra-fast nucleic acid sequencing device and a method for making and using the same |
US9709559B2 (en) | 2000-06-21 | 2017-07-18 | Bioarray Solutions, Ltd. | Multianalyte molecular analysis using application-specific random particle arrays |
AU2001272993B2 (en) | 2000-06-21 | 2005-03-10 | Bioarray Solutions, Ltd. | Multianalyte molecular analysis |
US20030045005A1 (en) * | 2000-10-17 | 2003-03-06 | Michael Seul | Light-controlled electrokinetic assembly of particles near surfaces |
US6881317B2 (en) * | 2000-12-18 | 2005-04-19 | The Trustees Of Princeton University | Fractionation of macro-molecules using asymmetric pulsed field electrophoresis |
US6795138B2 (en) * | 2001-01-11 | 2004-09-21 | Sipix Imaging, Inc. | Transmissive or reflective liquid crystal display and novel process for its manufacture |
US8282762B2 (en) * | 2001-01-11 | 2012-10-09 | Sipix Imaging, Inc. | Transmissive or reflective liquid crystal display and process for its manufacture |
TW556044B (en) * | 2001-02-15 | 2003-10-01 | Sipix Imaging Inc | Process for roll-to-roll manufacture of a display by synchronized photolithographic exposure on a substrate web |
WO2002091028A2 (en) * | 2001-05-03 | 2002-11-14 | Colorado School Of Mines | Devices employing colloidal-sized particles |
DE10122659A1 (en) * | 2001-05-10 | 2002-12-05 | Infineon Technologies Ag | Biochip arrangement |
US20020195343A1 (en) * | 2001-06-20 | 2002-12-26 | Coventor, Inc. | Microfabricated separation device employing a virtual wall for interfacing fluids |
US7262063B2 (en) | 2001-06-21 | 2007-08-28 | Bio Array Solutions, Ltd. | Directed assembly of functional heterostructures |
DE10136275C1 (en) * | 2001-07-25 | 2002-12-12 | Fraunhofer Ges Forschung | Device for storing fluids has double-walled second shut-off cock with an inner monitoring space connected to first shut-off cock by double-walled connecting element with monitoring space |
TW527529B (en) * | 2001-07-27 | 2003-04-11 | Sipix Imaging Inc | An improved electrophoretic display with color filters |
TW539928B (en) | 2001-08-20 | 2003-07-01 | Sipix Imaging Inc | An improved transflective electrophoretic display |
TWI308231B (en) * | 2001-08-28 | 2009-04-01 | Sipix Imaging Inc | Electrophoretic display |
CA2741049C (en) | 2001-10-15 | 2019-02-05 | Bioarray Solutions, Ltd. | Multiplexed analysis of polymorphic loci by probe elongation-mediated detection |
WO2003035228A1 (en) * | 2001-10-19 | 2003-05-01 | Trustees Of Princeton University | Method and apparatus for generating electric fields and flow distributions for rapidly separating molecules |
CA2470274A1 (en) * | 2001-12-19 | 2003-07-03 | Biogen, Inc. | Methods for detecting half-antibodies using chip-based gel electrophoresis |
JP2005164242A (en) * | 2001-12-28 | 2005-06-23 | Cluster Technology Co Ltd | Microchip for electrophoresis |
US7261812B1 (en) | 2002-02-13 | 2007-08-28 | Nanostream, Inc. | Multi-column separation devices and methods |
JP2002357607A (en) * | 2002-03-20 | 2002-12-13 | Olympus Optical Co Ltd | Integrated reactor |
TWI221523B (en) * | 2002-05-21 | 2004-10-01 | Sony Corp | Bioassay method, bioassay device, and bioassay substrate |
DE10224567B4 (en) * | 2002-06-03 | 2014-10-23 | Boehringer Ingelheim Vetmedica Gmbh | Sensor arrangement and method for operating a sensor arrangement |
EP2177902B1 (en) * | 2002-06-07 | 2011-09-21 | Picosep A/S | Method and system for multi-stage isoelectric focussing |
US20050238506A1 (en) * | 2002-06-21 | 2005-10-27 | The Charles Stark Draper Laboratory, Inc. | Electromagnetically-actuated microfluidic flow regulators and related applications |
JPWO2004008132A1 (en) * | 2002-07-11 | 2005-11-10 | 三菱電機株式会社 | Biomolecule separation cell, method for producing the same, and DNA sorting apparatus |
US6911132B2 (en) | 2002-09-24 | 2005-06-28 | Duke University | Apparatus for manipulating droplets by electrowetting-based techniques |
US7329545B2 (en) * | 2002-09-24 | 2008-02-12 | Duke University | Methods for sampling a liquid flow |
JP4075765B2 (en) * | 2002-10-30 | 2008-04-16 | 日本電気株式会社 | Separation apparatus, manufacturing method thereof, and analysis system |
US7010964B2 (en) * | 2002-10-31 | 2006-03-14 | Nanostream, Inc. | Pressurized microfluidic devices with optical detection regions |
US7526114B2 (en) | 2002-11-15 | 2009-04-28 | Bioarray Solutions Ltd. | Analysis, secure access to, and transmission of array images |
TWI297089B (en) | 2002-11-25 | 2008-05-21 | Sipix Imaging Inc | A composition for the preparation of microcups used in a liquid crystal display, a liquid crystal display comprising two or more layers of microcup array and process for its manufacture |
US8023071B2 (en) * | 2002-11-25 | 2011-09-20 | Sipix Imaging, Inc. | Transmissive or reflective liquid crystal display |
KR100538469B1 (en) * | 2003-07-18 | 2005-12-23 | 한국과학기술원 | Biochemical analysis apparatus using micropillar arrays and periodically crossed electric fields and method thereof |
US20050032238A1 (en) * | 2003-08-07 | 2005-02-10 | Nanostream, Inc. | Vented microfluidic separation devices and methods |
TW594007B (en) * | 2003-08-15 | 2004-06-21 | Prec Instr Dev Ct Nat | Biochemical detection device and method of magnetic fluid bead control combining digital fluid and electromagnetic field |
US7927796B2 (en) | 2003-09-18 | 2011-04-19 | Bioarray Solutions, Ltd. | Number coding for identification of subtypes of coded types of solid phase carriers |
AU2004276761B2 (en) | 2003-09-22 | 2009-12-24 | Bioarray Solutions, Ltd. | Surface immobilized polyelectrolyte with multiple functional groups capable of covalently bonding to biomolecules |
US20050079598A1 (en) * | 2003-10-08 | 2005-04-14 | Davis Randall W. | Apparatus and method for identification of biomolecules, in particular nucleic acid sequences, proteins, and antigens and antibodies |
JP2007521017A (en) | 2003-10-28 | 2007-08-02 | バイオアレイ ソリューションズ リミテッド | Optimization of gene expression analysis using immobilized capture probes |
WO2005045060A2 (en) | 2003-10-29 | 2005-05-19 | Bioarray Solutions, Ltd. | Multiplexed nucleic acid analysis by fragmentation of double-stranded dna |
WO2005052567A1 (en) * | 2003-11-24 | 2005-06-09 | Biogen Idec Ma Inc. | Methods for detecting half-antibodies using chip-based gel electrophoresis |
JP4544570B2 (en) * | 2004-01-16 | 2010-09-15 | 正之 藤本 | Electrophoresis device |
WO2005072793A1 (en) * | 2004-01-29 | 2005-08-11 | The Charles Stark Draper Laboratory, Inc. | Implantable drug delivery apparatus |
US7867194B2 (en) | 2004-01-29 | 2011-01-11 | The Charles Stark Draper Laboratory, Inc. | Drug delivery apparatus |
US7848889B2 (en) | 2004-08-02 | 2010-12-07 | Bioarray Solutions, Ltd. | Automated analysis of multiplexed probe-target interaction patterns: pattern matching and allele identification |
JP4645110B2 (en) | 2004-09-15 | 2011-03-09 | ソニー株式会社 | Hybridization detection unit using dielectrophoresis, sensor chip including the detection unit, and hybridization detection method |
TWI259913B (en) * | 2004-12-30 | 2006-08-11 | Ind Tech Res Inst | Color filter and methods of making the same |
CN101146595B (en) | 2005-01-28 | 2012-07-04 | 杜克大学 | Apparatuses and methods for manipulating droplets on a printed circuit board |
US7344583B2 (en) * | 2005-03-31 | 2008-03-18 | 3M Innovative Properties Company | Methods of making metal particles within cored dendrimers |
US8486629B2 (en) | 2005-06-01 | 2013-07-16 | Bioarray Solutions, Ltd. | Creation of functionalized microparticle libraries by oligonucleotide ligation or elongation |
WO2007149111A2 (en) * | 2005-10-06 | 2007-12-27 | Massachusetts Institute Of Technology | Continuous biomolecule separation in a nanofilter |
JP5144666B2 (en) * | 2006-09-19 | 2013-02-13 | スリーエム イノベイティブ プロパティズ カンパニー | Templated metal oxide particles and manufacturing method |
US9046192B2 (en) | 2007-01-31 | 2015-06-02 | The Charles Stark Draper Laboratory, Inc. | Membrane-based fluid control in microfluidic devices |
CN101118235B (en) * | 2007-05-22 | 2011-07-27 | 华中科技大学 | Measurement mechanism for trace quantity electric charge and method thereof |
WO2009021233A2 (en) | 2007-08-09 | 2009-02-12 | Advanced Liquid Logic, Inc. | Pcb droplet actuator fabrication |
DE102008020428B3 (en) * | 2008-04-24 | 2009-07-16 | Johannes-Gutenberg-Universität Mainz | Apparatus and method and gel system for analytical and preparative electrophoresis |
KR100948703B1 (en) * | 2008-05-20 | 2010-03-22 | 연세대학교 산학협력단 | Method of measuring reaction temperature of bio fluids, microcalorimeter using the same and method of manufacturing the microcalorimeter |
GB0818609D0 (en) | 2008-10-10 | 2008-11-19 | Univ Hull | apparatus and method |
US8876795B2 (en) | 2011-02-02 | 2014-11-04 | The Charles Stark Draper Laboratory, Inc. | Drug delivery apparatus |
EP2571190B1 (en) | 2011-09-19 | 2016-07-20 | Alcatel Lucent | System and method for selective protection switching |
KR20130034326A (en) * | 2011-09-28 | 2013-04-05 | 류준환 | Electric-field assisted deposition of dna on polymer surfaces |
JP2014171432A (en) * | 2013-03-08 | 2014-09-22 | Sony Corp | Apparatus and method for preparing nucleic acids |
US10020178B2 (en) | 2014-06-27 | 2018-07-10 | Uvic Industry Partnerships Inc. | System and method for matrix-coating samples for mass spectrometry |
SE540776C2 (en) | 2016-09-05 | 2018-11-06 | Oboe Ipr Ab | Ion pump with hyperbranched polymers |
US10726909B1 (en) | 2019-03-20 | 2020-07-28 | Marvell International Ltd. | Multi-port memory arrays with integrated worldwide coupling mitigation structures and method |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0471949A1 (en) * | 1990-08-21 | 1992-02-26 | Hewlett-Packard Company | Situ sample pretreatment in electrophoresis capillary |
EP0500211A2 (en) * | 1991-02-01 | 1992-08-26 | Beckman Instruments, Inc. | On-column pre-concentration of samples in capillary electrophoresis |
WO1993000986A1 (en) * | 1991-07-12 | 1993-01-21 | Astromed Limited | A method and an apparatus for electrophoretic separation |
WO1994029707A1 (en) * | 1993-06-08 | 1994-12-22 | British Technology Group Usa Inc. | Microlithographic array for macromolecule and cell fractionation |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4390403A (en) * | 1981-07-24 | 1983-06-28 | Batchelder J Samuel | Method and apparatus for dielectrophoretic manipulation of chemical species |
JPS6126848A (en) * | 1984-07-17 | 1986-02-06 | Shimadzu Corp | Two-dimensional electrophoresis device |
GB2191110B (en) * | 1986-06-06 | 1989-12-06 | Plessey Co Plc | Chromatographic separation device |
US4988568A (en) * | 1988-03-30 | 1991-01-29 | Nippon Zeon Co., Ltd. | Hydrophilic fine gel particles and process for production thereof |
US4908112A (en) * | 1988-06-16 | 1990-03-13 | E. I. Du Pont De Nemours & Co. | Silicon semiconductor wafer for analyzing micronic biological samples |
US5011586A (en) * | 1988-08-12 | 1991-04-30 | Mj Research, Inc. | Constrained uniform field gel electrophoresis |
FR2639253B2 (en) * | 1988-09-06 | 1991-07-26 | Bertin & Cie | MULTIPLE ELECTROPHORESIS DEVICE FOR PROVIDING CONTROLLED MIGRATION OF MACROMOLECULES IN RECTANGULAR GEL PLATES |
JPH02176457A (en) * | 1988-09-15 | 1990-07-09 | Carnegie Inst Of Washington | Pulse oriented electrophoresis |
US4911817A (en) * | 1988-10-20 | 1990-03-27 | Eastman Kodak Company | Electrophoresis apparatus |
EP0391674B1 (en) | 1989-04-05 | 1996-03-20 | New York University | A method for characterising particles |
US5071531A (en) * | 1989-05-01 | 1991-12-10 | Soane Technologies, Inc. | Casting of gradient gels |
JPH03167468A (en) * | 1989-11-27 | 1991-07-19 | Aloka Co Ltd | Multielectrode electrophoretic apparatus |
US5126022A (en) * | 1990-02-28 | 1992-06-30 | Soane Tecnologies, Inc. | Method and device for moving molecules by the application of a plurality of electrical fields |
GB2244135B (en) * | 1990-05-04 | 1994-07-13 | Gen Electric Co Plc | Sensor devices |
SE470347B (en) * | 1990-05-10 | 1994-01-31 | Pharmacia Lkb Biotech | Microstructure for fluid flow systems and process for manufacturing such a system |
US5135627A (en) | 1990-10-15 | 1992-08-04 | Soane Technologies, Inc. | Mosaic microcolumns, slabs, and separation media for electrophoresis and chromatography |
FR2683771B1 (en) | 1991-11-18 | 1994-01-07 | Michelin & Cie | TREAD HAVING GROOVES WITH WALLS WITH INCISIONS. |
US5846708A (en) * | 1991-11-19 | 1998-12-08 | Massachusetts Institiute Of Technology | Optical and electrical methods and apparatus for molecule detection |
GB2264783A (en) * | 1992-02-24 | 1993-09-08 | Gen Electric Co Plc | Electrophoretic analysis method utilising wave effect |
JPH05322849A (en) * | 1992-05-19 | 1993-12-07 | Jasco Corp | Kinetic chromatography method |
DE59410283D1 (en) * | 1993-11-11 | 2003-06-18 | Aclara Biosciences Inc | Device and method for the electrophoretic separation of fluid substance mixtures |
AU2550695A (en) * | 1994-05-13 | 1995-12-05 | Novel Experimental Technology | Coated plastic mold for electrophoresis gel |
US5500071A (en) * | 1994-10-19 | 1996-03-19 | Hewlett-Packard Company | Miniaturized planar columns in novel support media for liquid phase analysis |
US5627022A (en) * | 1994-11-01 | 1997-05-06 | Visible Genetics Inc. | Microgels for use in medical diagnosis and holders useful in fabricating same |
US6017434A (en) | 1995-05-09 | 2000-01-25 | Curagen Corporation | Apparatus and method for the generation, separation, detection, and recognition of biopolymer fragments |
-
1996
- 1996-06-07 JP JP9503252A patent/JPH11508042A/en not_active Ceased
- 1996-06-07 WO PCT/US1996/009999 patent/WO1996042012A1/en not_active Application Discontinuation
- 1996-06-07 WO PCT/US1996/010110 patent/WO1996042013A1/en not_active Application Discontinuation
- 1996-06-07 EP EP96921506A patent/EP0830594A1/en not_active Withdrawn
- 1996-06-07 AU AU62718/96A patent/AU698921B2/en not_active Ceased
- 1996-06-07 CA CA002226405A patent/CA2226405A1/en not_active Abandoned
- 1996-06-07 JP JP50327497A patent/JP2001507441A/en active Pending
- 1996-06-07 EP EP96921542A patent/EP0830595A1/en not_active Withdrawn
- 1996-06-07 CA CA002222628A patent/CA2222628A1/en not_active Abandoned
- 1996-06-07 AU AU62746/96A patent/AU702083B2/en not_active Ceased
- 1996-06-07 US US08/973,933 patent/US6176990B1/en not_active Expired - Fee Related
-
2000
- 2000-02-17 US US09/505,659 patent/US6261430B1/en not_active Expired - Fee Related
-
2001
- 2001-07-16 US US09/907,001 patent/US20020029969A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0471949A1 (en) * | 1990-08-21 | 1992-02-26 | Hewlett-Packard Company | Situ sample pretreatment in electrophoresis capillary |
EP0500211A2 (en) * | 1991-02-01 | 1992-08-26 | Beckman Instruments, Inc. | On-column pre-concentration of samples in capillary electrophoresis |
WO1993000986A1 (en) * | 1991-07-12 | 1993-01-21 | Astromed Limited | A method and an apparatus for electrophoretic separation |
WO1994029707A1 (en) * | 1993-06-08 | 1994-12-22 | British Technology Group Usa Inc. | Microlithographic array for macromolecule and cell fractionation |
Non-Patent Citations (2)
Title |
---|
G. WALLIS: "FIELD ASSISTED GLASS-METAL SEALING", JOURNAL OF APPLIED PHYSICS, vol. 40, no. 10, September 1969 (1969-09-01), pages 3946 - 3949, XP000601832 * |
S. Y. CHOU: "IMPRINT LITHOGRAPHY WITH 25-NANOMETER RESOLUTION", SCIENCE, vol. 272, April 1996 (1996-04-01), pages 85 - 87, XP000602257 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998054568A1 (en) * | 1997-05-27 | 1998-12-03 | Perseptive Biosystems, Inc. | Improved separation columns and methods for manufacturing the improved separation columns |
US6156273A (en) * | 1997-05-27 | 2000-12-05 | Purdue Research Corporation | Separation columns and methods for manufacturing the improved separation columns |
US6596144B1 (en) | 1997-05-27 | 2003-07-22 | Purdue Research Foundation | Separation columns and methods for manufacturing the improved separation columns |
US6716584B2 (en) * | 1998-06-11 | 2004-04-06 | Hitachi, Ltd. | Polynucleotide separation method and apparatus therefor |
US6787314B2 (en) * | 1998-06-11 | 2004-09-07 | Hitachi, Ltd. | Polynucleotide separation method and apparatus therefor |
US6893823B2 (en) * | 1998-06-11 | 2005-05-17 | Hitachi, Ltd. | Polynucleotide separation method and apparatus therefor |
EP1162454A1 (en) * | 1999-03-02 | 2001-12-12 | Isao Karube | Two-dimensional separating method |
EP1162454A4 (en) * | 1999-03-02 | 2006-01-18 | Institute Katayanagi | Two-dimensional separating method |
WO2001007150A2 (en) * | 1999-07-26 | 2001-02-01 | Kahl Johan Valentin | Method and device for the electrophoretic separation of particles, especially of macromolecules |
WO2001007150A3 (en) * | 1999-07-26 | 2001-07-26 | Kahl Johan Valentin | Method and device for the electrophoretic separation of particles, especially of macromolecules |
US7204922B1 (en) | 1999-07-26 | 2007-04-17 | Johan-Valentin Kahl | Method and device for the electrophoretic separation of particles, especially of macromolecules, by electrophoresis |
Also Published As
Publication number | Publication date |
---|---|
AU702083B2 (en) | 1999-02-11 |
EP0830595A1 (en) | 1998-03-25 |
US20020029969A1 (en) | 2002-03-14 |
JP2001507441A (en) | 2001-06-05 |
AU6274696A (en) | 1997-01-09 |
US6176990B1 (en) | 2001-01-23 |
CA2226405A1 (en) | 1996-12-27 |
AU698921B2 (en) | 1998-11-12 |
WO1996042013A1 (en) | 1996-12-27 |
CA2222628A1 (en) | 1996-12-27 |
US6261430B1 (en) | 2001-07-17 |
AU6271896A (en) | 1997-01-09 |
JPH11508042A (en) | 1999-07-13 |
EP0830594A1 (en) | 1998-03-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU698921B2 (en) | Nanofabricated separation matrix for analysis of biopolymers and methods of making and using same | |
US6110339A (en) | Nanofabricated separation matrix for analysis of biopolymers and methods of making and using same | |
US5661028A (en) | Large scale DNA microsequencing device | |
ES2325393T3 (en) | POROUS FLOW EQUIPMENT THROUGH MICROFABRICATED FOR THE DIFFERENTIATED DETECTION OF UNION REACTIONS. | |
US9719980B2 (en) | Devices and methods for determining the length of biopolymers and distances between probes bound thereto | |
US6749734B1 (en) | Microfabricated capillary array electrophoresis device and method | |
EP2173467B1 (en) | Method and apparatus using electric field for improved biological assays | |
JP4034351B2 (en) | Light-controlled electrokinetic assembly of particle-proximal surfaces | |
US20050191663A1 (en) | Microfabricated flowthrough porous apparatus for discrete detection binding reactions | |
US20070048745A1 (en) | Systems and methods for partitioned nanopore analysis of polymers | |
EP2435185B1 (en) | Devices and methods for determining the length of biopolymers and distances between probes bound thereto | |
US20050170342A1 (en) | Flowthrough device for multiple discrete binding reactions | |
JP2002532715A (en) | Separation of charged particles by spatially and temporally varying electric fields | |
US20050164211A1 (en) | Carbon nanotube molecular labels | |
JPWO2004008132A1 (en) | Biomolecule separation cell, method for producing the same, and DNA sorting apparatus | |
JP3979919B2 (en) | Biopolymer analysis method and apparatus | |
JP4189123B2 (en) | Bio-related substance detection method, chip device and device | |
Webster | Monolithic structures for integrated capillary electrophoresis systems | |
Cross et al. | FOR BIOLOGICAL SEPARATIONS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase |
Ref country code: US Ref document number: 1996 703710 Date of ref document: 19960827 Kind code of ref document: A Format of ref document f/p: F |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2226405 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1996921506 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1997 503252 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08973932 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1996921506 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1996921506 Country of ref document: EP |