CA2175483C - Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics - Google Patents

Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics Download PDF

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Publication number
CA2175483C
CA2175483C CA002175483A CA2175483A CA2175483C CA 2175483 C CA2175483 C CA 2175483C CA 002175483 A CA002175483 A CA 002175483A CA 2175483 A CA2175483 A CA 2175483A CA 2175483 C CA2175483 C CA 2175483C
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Prior art keywords
electronic device
micro
locations
addressable
layer
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CA002175483A
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French (fr)
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CA2175483A1 (en
Inventor
Michael J. Heller
Eugene Tu
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Nanogen Inc
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Nanogen Inc
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    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
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    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
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    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
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    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
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Abstract

A self-addressable, self-assembling microelectronic device is designed and f abricated to actively carry out and control multi-step and multiplex molecular biological reactions in microscopic formats. These reactions include nucleic acid hybridization, antibody/a ntigen reaction, diagnostics, and biopolymer synthesis. The device can be fabricat ed using both microlithographic and micro-machining tech niques. The device can electronically control the transport and attachment of specif ic binding entities to specific micro-locations. The sp ecific binding entities include molecular biological molecules such as nucleic acids and po lypeptides. The device can subsequently control the tra nsport and reaction of analytes or reactants at the addressed specific micro-locations. The device is able to concentrate analytes and reactan ts, remove non-specifically bound molecules, provide stringency control for DNA hybridi zation reactions, and improve the detection of analytes. The device can be electronically replicated.

Description

DESCRIPTION
SELF-ADDRESSABLE SELF-ASSEMBLING
MICROELECTRONIC SYSTEMS AND DEVICES
FOR MOLECULAR BIOLOGICAL ANALYSIS AND DIAGNOSTICS
Field of the Invention This invention pertains to the design, fabrication, and uses of a self-addressable, self-assembling microelec ~tronic system which can actively carry out and control multi-step and multiplex reactions in microscopic formats.
In particular, these reactions include molecular biologi-cal reactions, such as nucleic acid hybridizations, anti-body/antigen reactions, clinical diagnostics, and biopoly-mer synthesi.$ .
The invention encompasses several aspects, including a device. Only the device is claimed in this application. However, it should be understood that the expression "the present invention" also covers those other aspects not claimed in this application.
Background of the Invention Molecular biology comprises a wide variety of tech-niques for the analysis of nucleic acid and protein, many of which form the basis of clinical diagnostic assays.
These techniques include nucleic acid hybridization analysis, restriction enzyme analysis, genetic sequence analysis, and separation and purification of nucleic acids and proteins (See, e.g., J. Sambrook, E. F. Fritsch, and T. Maniatis, Molecular ClonincZz A Laboratory Manual, 2 Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).

la Most molecular biology techniques involve carrying out numerous operations (e. g., pipetting) on a large number of samples. They are often complex and time consuming, and generally require a high degree of accuracy. Many a technique is limited in its application by a lack of sensitivity, specificity, or reproducibility.
For example, problems with sensitivity and specificity have so far limited the application of nucleic acid hybridization.

2~,~ ~Cr ~3 2 Nucleic acid hybridization analysis generally involves the detection of a very small numbers of specific target nucleic -acids (DNA or RNA) with probes among a large amount of non-target nucleic acids. In order to keep high specificity, hybridization is normally carried out under the most stringent condition, achieved through _ a combination of temperature, salts, detergents, solvents, chaotropic agents, and denaturants.
Multiple sample nucleic acid hybridization analysis has been conducted on a variety of filter and solid support formats (see G. A. Beltz et al., in Methods in Erlzymoloav, Vol. 100, Part B, R. Wu, L. Grossmam, K. Moldave, Eds., Academic Press, New York, Chapter 19, pp. 266-308, 1985). One format, the so-called "dot blot"
hybridization, involves the non-covalent attachment of target DNAs to a filter, which are subsequently hybridized with a radioisotope labeled probe(s). "Dot blot" hybridi-zation gained wide-spread use, and many versions were -developed (see M. L. M. Anderson and B. D. Young, in ~lucleic Acid Hybridization - A P-ractical Approach, B. D. Hames and S. J. Higgins, Eds., IRL Press, Washington DC, Chapter 4, pp. 73-111, 1985). It has been developed for multiple analysis of genomic mutations (D. Nanibhushan -and D. Rabin, in EPA 0228075, July S, 1987) and for the detection of overlapping clones and the construction of.
genomic maps (G. A_ Evahs, -in US Patent #5,219,726, June 15, 1993).
Another format, the so-called "sandwich" hybridiza tion, involves attaching oligonucleotide probes covalently to a solid support and using them to capture and detect, multiple nucleic acid targets. (M. Ranki et al., Gene, 21, pp. 77-85, 1983; A. M. Palva, T. M. Ranki, and H. E.
Soderlund, in UK Patent Application GB 2156074A, ' October 2, 1985; T. M. Ranki and H. E. Soderlund in US
Patent # 4,563,-419, January 7, 1986; A. D. B. Malcolm and J. A. Langdale, in PCT WO 86/03782, July 3, -1986;

wo ssnzsos rc'rrt~s9anaa~o Y. Stabinsky, in US Patent # 4,751,177, January 14, 1988;
T. H. Adams et al., in PCT WO 90/01564, February 22, 1990;
R. B. Wallace et al. 6 Nucleic Acid Res. 11, p. 3543, 1979; and B. J. Connor et al., 80 Proc. Natl. Acad. Sci.
USA pp. 278-282, 1983).
Using the current nucleic acid hybridization formats and stringency control methods, it remains difficult to detect low copy number (i_e., 1-100,000) nucleic acid targets even with the most sensitive reporter groups (enzyme, fluorophores, radioisotopes, etc.) and associated detection systems (fluorometers, luminometers, photon counters, scintillation counters, etc.).
This difficulty is caused by several underlying problems associated with direct probe hybridization. The first and the most serious problem relates to thestrin gency control of. hybridization reactions. Hybridization reactions are usually carried out under the most stringent conditions in order to achieve the highest degree of specificity. Methods of stringency control involve primarily the optimization of temperature, ionic strength, and denaturants in hybridization and subsequent washing procedures. Unfortunately, the application of these stringency conditions causes a significant decrease in the number of hybridized probe/target complexes for detection.
The second problem relates to the high complexity of DNA in most samples, particularly in human genomic DNA
samples. When a sample is composed o~ an enormous number of sequences which are closely related to the specific target sequence, even the most unique probe sequence has a large number of partial hybridizations with non-target sequences.
The third problem relates to the unfavorable hybridi-zation dynamics between a probe and its specific target.
Even under the best conditions, most hybridization reac-tions are conducted with relatively low concentrations of probes and target molecules. In addition, a probe often wo ssnzsos rca~s9amz~o has to compete with the complementary strand for. the target nucleic acid.
The fourth problem for most present hybridization formats is the high level of non-specific- background signal. This is caused by the affinity of DNA probes to almost any material. -Theae problems, either-individually or in combina-tion, lead to a loss of sensitivity and/or specificity for nucleic acid hybridization in the above described formats.
This is unfortunate because the detection of low copy number nucleic acid targets is necessary for most nucleic acid-based clinical diagnostic assays.
Because of the difficulty in detecting low copy number nucleic acid targets, the research community relies heavily on the -polymeraae chain reaction (PCR) for the amplification of target nucleic acid sequences (see M. A.
Innis et al., PCR Protocols: A Guide to Methods and "Applications, Academic Press, 1990). The enormous number of target nucleic acid sequences produced by the PCR
reaction improves the subsequent direct nucleic acid probe techniques, albeit at the cost of a lengthy and cumbersome procedure. -A distinctive exception to the general difficulty in detecting low copy number target nucleic acid with a direct probe is the in-situ hybridization technique. This technique allows low copy number unique nucleic acid sequences to be detected in individual cells. In the in-situ format, target nucleic acid is naturally confined to the area of a cell (-20-50 ~mz) or--a nucleus (-10 ~m~) at a relatively high local concentration. Furthermore, the -probe/target hybridization signal is confined to a morpho-logically distinct area; this- makes it easier to distin-guish a positive signal from-artificial or non-specific -aignals than hybridization on a solid support.

~ 17 5 4 8 3 PCT~S94112270 Mimicking the in-situ hybridization, new techniques are being developed for carrying out multiple sample nucleic acid hybridization analysis on micro-formatted multiplex or matrix devices (e.g., DNA chips) (see M.
5 Barinaga, 253 Science, pp. 1489, 1991; W. Bains, 10 Bio/Technology, pp. 757-758, 1992). These-methods usually attach specific DNA sequences to very small specific areas of a solid support, such as micro-wells of a DNA chip.
These hybridization formats are micro-scale versions of the conventional !'dot blot" and "sandwich" hybridization systems.
The micro-formatted hybridization can be used to carry out "sequencing by hybridization" (SBH) (see M.
Barinaga, 253 Science, pp.1489, 1991; W. Bains, 10 Bio/Technology, pp. '157-758, 1992). SBH makes use of all possible n-nucleotide oligomers (n-mers) to identify n-mers in an unknown DNA sample, which are subsequently aligned by algorithm analysis to produce the DNA sequence (R. Drmanac and R. Crkvenjakov, Yugoslav Patent Applica-tion #570/87, 1987; R. Drmanac et al., 4 Genomics, 114, 1989; Strezoska et al., 88 Proc. Natl. Acad. Sci. USA
10089, 1991; and R. Drmanac and R. B. Crkvenjakov, US
Patent #5,202,231, April 13, 1993).
There are -two formats for carrying out SBH. The first format involves creating an array of all possible n mers on a support, which is then hybridized with the target sequence. The second format involves attaching the target sequence to a support, which is sequentially probed with all possible n-mers. Both formats have the funda mental problems of direct probe hybridizations and addi tional difficulties related to multiplex hybridizations.
Southern, United Kingdom Patent Application GB
8810400, 1988; E. M. Southern et al., I3 Genomics 1008, 1992, proposed using the first format to analyze or sequence DNA. Southern identified a known single point mutation using PCR amplified genomic DNA. Southern also 21~ 5463 described a method for synthesizing an array of oligonu-cleotidea on a solid-support-forSBH. However, Southern did not address how to achieve optimal stringency condi-tion for each oligonucleotide-on an array.
Fodor et al., 364 Nature, pp. 555-556, 1993, used an array of 1,024 8-mer oligonucleotides on a solid support' to sequence DNA. In this case, the target DNA was a fluoreacently labeled single-stranded 12-mer oligonucleo-tide containing only nucleotides A and C. 1 pmol (-.6 x 1011 molecules) of the 12-mer target sequence was necessary for the hybridization with the 8-mer oligomers on the array. The results showed many mismatches. Like Southern, Fodor et al., did not address the-underlying problems of direct probe-hybridization, such as stringency control for multiplex- hybridizations. These problems, together with the requirement of a large quantity of the simple 12-mer target, indicate severe limitations to this SBH format.
Concurrently, Drmanac et al., 260 Science 1649-1652, 1993, used the second format to sequence several short (116 bp) DNA sequences. Target DNAs were attached to membrane supports ('dot blot" format). Eachfilter was sequentially hybridized with 272 labeled 10-mer and 11-mer oligonucleotides. A wide range of stringency condition was used to achieve specific hybridization for each n-mer probe; washing times varied from 5 minutes to overnight, and temperatures from 0°C to 16°C. Moat probes required 3 hours of washing at 16°C. The filters had to be exposed for 2 to 18 hours -in order to detect hybridization signals. The overall false positive hybridisation rate was 5% in spite of the simple- target sequences, -the reduced set of oligomer probes, and the use of the most stringent conditions available.
Fodor et al., 251 Science 767-773, 1991, used photolithographic techniques to synthesize oligonucleo tides on -a matrix. Pirrung et al., in US Patent wo 9snzsos 217 5 ~ 8 3 rc~rnTSSanzno # 5,143,854, September 1, 1992, teach large scale photo-lithographic solid phase synthesis of polypeptides in an array fashion on silicon substrates.
In another approach-of matrix hybridization, Beattie et al., in The 1992 San Dieao Conference Genetic RecocTni i n, November, 1992, used a microrobotic system to deposit micro-droplets containing specific DNA sequences into individual microfabricated sample wells on a glass substrate. The hybridization in each sample well is detected . by interrogating miniature electrode test fixtures, which surround each individual microwell with an alternating current (AC) electric field.
Regardless of the format, current micro-scale ANA
hybridization and SBH approaches do not overcome the underlying physical problems associated with direct probe hybridization reactions. They require very high levels of relatively short single-stranded target sequences or PCR
amplified DNA, and produce a high level of-false positive hybridization signals even under the most stringent condi-tions. In the case of multiplex formats using arrays of short oligonucleotide sequences, it is not possible to optimize the stringency condition for each individual sequence with any conventional approach because the arrays or devices used for these formats can not change or adjust the- temperature, ionic-strength, or denaturants at an individual location, relative to other locations. There-fore, a common stringency condition must be used for all the sequences on the device. This results in a large number of non-specific and partial hybridizations and severely limits the application of the device. The problem becomes more compounded as the number of different sequences on the array increases, and as the length of the sequences decreases. This is particularly troublesome for SBH, which requires a large number of short oligonucleotide probes.

2115~a3 Nucleic acids of different size, charge, or conformation are routinely separated by electrophoresis -techniques which can distinguish hybridization species by their differential mobility in an electric field. Pulse field electrophoresis uses an arrangement of multiple electrodes around a medium (e. g., a gel) to separate very large DNA fragments which cannot be resolved by conventional gel electrophoresis systems (see R. Anand and -E. M. Southern in Gel Electrophoresis of Nucleic Acids A Practical Approach, 2 ed., D. Rickwood and B. D. Hames Eda., IRL Press, New York, pp. 101-122, 1990).
Pace, US Patent #4,908,112, March 13, 1990, teaches using micro-fabrication techniques to produce a capillary gel electrophoresis system on a silicon substrate. Mul-tiple electrodes are incorporated into the system to move -molecules through the separation medium within the device.
Soane and Soane, US Patent 5,126,022, June 30, 1992, teach that a number of-electrodes can be used-to control the linear movement of charged molecules in a mixture through a gel separation medium contained in a tube.
Electrodes have to be installed within the tube to control the movement and position of-molecules in the separation medium.
Washizu, M, and Kurosawa, O., 26 IEEE Transactions on -Industry Applications 6, pp.-1165-1172, 1990, used high-frequency alternating current (AC) fields to-orient DNA -molecules in electric field lines produced between .
microfabricated electrodes. However, the use of direct current (DC) fields is prohibitive for their work.
Washizu 25 Journal of Electrostatics -109-123, 1990, describes the manipulation of- cells and biological mole-cules using dielectrophoreais. Cells can be fused and biological molecules can be oriented along the electric = . ' fields lines produced by AC voltages between the micro=
electrode structures. However, the dielectrophoresis process requires a very high frequency AC (1 MHz) voltage and a low conductivity medium. While these techniques can orient DNA molecules of different sizes along the AC field lines, they cannot distinguish between hybridization complexes of the same size.
As is apparent from the preceding discussion, numerous attempts have been made to provide effective techniques to conduct multi-step, multiplex molecular biological reactions. However; for the reasons stated above, these techniques have been proved deficient.
Despite the long-recognized need for effective technique, no satisfactory solution has been proposed previously.
Summarv of the Invention The present invention relates to the design, fabrica tion, and uses of a self-addressable self-assembling microelectronic system and device which can actively carry out controlled multi-step and multiplex reactions in microscopic formats. These reactions include, but are not limited to, most molecular biological procedures, such as nucleic acid hybridization, antibody/antigen reaction, and related clinical, diagnostics. In addition, the claimed device is able to carry out multi-step combinational biopolymer synthesis, including, but not limited to, the synthesis of different oligonucleotides or peptides at specific micro-locations.
The claimed device is fabricated using both micro-lithographic and micro-machining techniques. The device.
has a matrix of addressable microscopic locations on its surface; each individual micro-location is able to elec-tronically control and direct the transport and attachment of-specific binding entities (e. g., nucleic acids, anti-bodies) to-itself. All micro-locations can be addressed with their specific binding entities. Using this device, the system can be self-assembled with minimal outside intervention.

2~~ X483 to The device is able to control and actively carry out a variety of assays and reactions. Analytes or reactants can be transported by free field electrophoresis to any specific micro-location where the analytes or reactants are effectively concentrated and reacted with the specific binding entity at said micro-location. The sensitivity for detecting a specific analyte or reactant is improved because of the concentrating effect. Any un-bound analytes or reactants can be removed by reversing the polarity of a micro-location. Thus, the device also improves the specificity ofassays and reactions.
The device provides independent stringency control for hybridization reactions at specific micro-locations.
Thus all the micro-locations on the matrix can have dif-ferent stringency conditions at the same time, allowing multiple hybridizations to- be conducted at optimal conditions.
The device also facilitates the detection of hybrid ized complexes at each micro=location by using an associ ated optical (fluorescent or spectrophotometric) imaging detector system or an integrated sensing component.
In addition, the active nature of the device allows complex multi-step reactions to be carried out with mini-mal outside physical manipulations. If desired, a master device addressed with specific. binding entities can be electronically replicated or copied to another base device.
Thus, the claimed device-can carry out multi-step and multiplex reactions with complete and precise-electronic.
control, preferably with a micro-processor. The rate, specificity, and sensitivity of multi-step and multiplex '-reactions are greatly improved at specific micro-locations of the claimed device. .
The present inventionovercomes the limitations of the arrays and devices for ittulti-sample hybridizations described in the background of the invention. Previous methods and devices are functionally passive regarding the actual hybridization process. While sophisticated photo-lithographic techniques were used to make an array, or microelectronic sensing elements were incorporated for detection, previous devices did nat control or influence the actual hybridization process. They are not designed to actively overcome any of the underlying physical problems associated with hybridization reactions.
This invention may utilize micro-locations of any size or shape consistent with the objective of the .invention. In the preferred embodiment of the invention, micro-locations in the sub-millimeter range are used.
By ~~specific binding entity" is generally meant a biological or synthetic molecule that has specific affinity to another molecule, through covalent bonding or non-covalent bonding. Preferably, a specific binding entity contains (either by nature or by modification) a functional chemical group (primary amine, sulfhydryl, aldehyde, etc.), a common sequence (nucleic acids), an epitope (antibodies), a hapten, or a ligand, that allows it to covalently react or non-covalently bind to a common functional group on the surface of a micro-location.
Specific binding entities include, but are not limited to:
deoxyribonucleic acids (DNA), ribonucleic acids (RNA), synthetic oligonucleotides, antibodies, proteins, pep-tides, lectins, modified polysaccharides, synthetic composite macromolecules, functionalized nanostructures, synthetic polymers, modified/blocked nucleotides/nucleo-sides, modified/blocked amino acids, fTuorophores, chromo-phones, ligands, chelates and haptens.
By "stringency control" is meant the ability to discriminate specific and non-specific binding interactions.

lla Thus, in a first aspect, the present invention features a device.
A first major embodiment of this aspect provides an electronic device adapted to receive a solution including electrolytes and one or more charged specific binding entities, the device comprising: a substrate, a selectively addressable electrode, the electrode being supported by the substrate, the electrode being adapted to receive current, a permeation layer which provides preferential passage from the solution to the electrode of the electrolytes relative to the charged specific binding entities and permits free transport of ions through the permeation layer to permit an electrophoretic transport of the specific binding entities, the permeation layer being disposed adjacent a first selectively addressable electrode, and an attachment layer adjacent the permeation layer.
A second major embodiment of this aspect provides an electronic device adapted to receive charged analytes comprising: a substrate, a plurality of selectively addressable electrodes, the electrodes being disposed upon the substrate, a current source, electrical connections to the electrodes, the electrical connections providing a selective current path from the current source, and a permeation layer adjacent to each electrode which permits electrophoretic transport of charged analytes disposed upon the device, forming addressable binding locations.
A third major embodiment of this aspect provides an electronic device comprising: a substrate, a plurality of selectively addressable electrodes, the electrodes being disposed upon the substrate, a current source for providing a selective current for the electrodes, individual buffer reservoirs associated with the electrodes, and individual llb permeation layers disposed adjacent the individual buffer reservoirs, forming addressable binding locations.
The device may have an array of electronically self-addressable microscopic locations. Each microscopic 2~'7 ~~8~ 12 location contains an underlying working direct current (DC) micro-electrode supported by a substrate. The surface of each micro-location has a permeation layer for the free transport of small counter-ions, and an attachment layer for the covalent coupling of specific binding entities.
By "array" or "matrix" is meant an arrangement of locations on the device. The locations can be arranged in two dimensional arrays, three-dimensional arrays, or other matrix formats. The number of locations can range-from several to at least hundreds of thousands.
In a second aspect, this invention features a method for transporting the binding entity to any specific micro-location on the device. When activated, a micro-location can affect the free field electrophoretic transport of any charged functionalized specific binding entity directly to itself. Upon contacting the specific micro-location, the functionalized specific binding entity immediately becomes covalently attached to the attachment layer surface of that specific micro-location. Other micro-locations can be simultaneously protected -by maintaining them at the opposite potential to thp charged molecules. The process can be rapidly repeated until all the micro-locations are addressed with their specific binding entities. , By "charged functionalized specific binding entity"
is meant a specific binding entity that is chemically reactive (i.e., capable- of covalent attachment to a location) and carrying a net change (either positive or negative).
In a third aspect, this inventions features a method for concentrating and reacting analytes or reactants at any specific micro-location=on the device. After the -attachment of the specific binding entities, the underly- ' ing microelectrode at each micro-location continues to function in a direct current (DC) mode. This unique feature allows relatively dilute charged analytes or R'O 95112808 PCTlUS94112270 2i~54~~

reactant molecules free in solution to be rapidly trans-ported, concentrated, and reacted in a serial or parallel manner at any specific .micro-locations which are main-tained at the opposite charge to the analyte or reactant molecules. Specific micro-locations can be protected or shielded by maintaining them at the -same charge as the analytes or reactants , molecules. This ability to concentrate dilute analyte or reactant molecules at selected micro-locations greatly accelerates the reaction rates at these micro-locations.
When the desired reaction is complete, the micro-electrode potential can be reversed to remove non-specific analytes or unreacted molecules from the micro-locations.
Specific analytes or reaction products may be released from any micro-location and transported to other locations for further analysis; or stored at other addressable locations; or removed completely from the system.
The- subsequent analysis of the analytes at the specific micro-locations is also greatly improved by the ability to repulse non-specific entities from these locations.
In a fourth aspect, this invention features a method for improving stringency control of nucleic acid hybridi nation reactions, comprising the steps of:
-rapidly concentrating dilute target DNA and/or probe DNA sequences at specific micro-locations) where hybridi-sation is to occur;
-rapidly removing non-specifically bound target DNA
sequences from specific micro-locations) where hybridi zation has occurred;
-rapidly removing competing complementary target DNA
sequences from specific micro-locations) where hybridi-zation has occurred;
-raising electric potential to remove partially hybridized DNA sequences (more than one base mis-match);

R'O 95/12808 PCTlUS94112270 2,,1583 -adjusting electric. potential to improve the resolution of single mis-match hybridizations (e.g., tc identify point mutations);
-applying independent electric potential control to individual hybridization events occurring in the same bulk solution; and -using electric potential control to improve hybridi-zation of un-amplified target DNA sequences to arrays of capture oligonucleotide probes.
In a fifth aspect, this invention features a method for synthesizing biopolymers-at micro-locations.
In a sixth aspect, this invention features a method for replicating a master device.
In a seventh aspect, this invention features methods for detecting and analyzing reactions that have occurred at the addressed micro-locations using self-addressed microelectronic devices with associated optical, optoelectronic or electronic-detection systems or self addresaed microelectronic devices with integrated optical, optoelectronic or electronic detection systems.
Brief Description of the Drawings FIGURE 1 is the cross-section of three self-address-able micro-locations fabricated using microlithographic techniques.
FIGURE 2 is the cross-section of a microlithograph-ically fabricated micro-location.
FIGURE 3 is a schematic representation of a self-addressable- 64 micro-location chip which was actually fabricated, addressed with oligonucleotides, and tested.
FIGURE 4 shows particular attachment chemistry proce-.
dure which allows rapid covalent coupling of specific.
oligonucleotides to the attachment surface of a mtcro-location.
FIGURE 5 is a blown-up schematic diagram of a micro-machined 96 micro-locations device.

217 5 4 8 3 pCT~S94J12270 WO 95l128m8 FIGURE 6 is the cross-section of a micro-machined device.
FIGURE 7 shows the mechanism the device uses to electronically concentrate analyte or reactant molecules at a specific micro-location.
FIGURE 8 shows the self-directed assembly of a device with three specific oligonucleotide binding entities (SSO-A, SSO-B, and SSO-C).
FIGURE 9 shows an electronically controlled hybridization process with sample/target DNA being concentrated at micro-locations containing specific DNA
capture sequences.
FIGURE 10 shows an electronically directed serial hybridization process.
FIGURE~ 11 shows the electronic stringency control (ESC) of a hybridization process for determining single point mutations.
FIGURE 12 shows a scheme for the detection of hybridized DNA without using labeled DNA probe, i.e., electronically controlled fluorescent dye detection process.
FIGURE 13 shows a scheme of electronically controlled replication of-devices.
FIGURE 14 shows a scheme of electronically directed combinatorial synthesis of oligonucleotides.
Detailed Description of the Invention __ The devices and the related methodologies of this invention allow important molecular biology and diagnostic reactions to be carried out under complete electronic control. The basic concept of this invention is a micro-electronic device with specially designed addressable microscopic locations. Each micro-location has a deriva-tized surface for the covalent attachment of specific binding entities (i.e., an attachment layer), a permeation layer, and an underlying direct current (DC) micro-WO 95!12808 PCTlUS94112270 21 ~ ~ 483 1 electrode. After the initial fabrication of the basic microelectronic structure, the device is able to self-direct the addressing of each specific micro-location with specific binding entities. The self-addressed device is ' subsequently able to actively carry out multi-step, combinatorial, and multiplex reactions at any of its micro-locations. The device -is able to electronically direct and control the rapid movement and concentration of analytes and reactants to or from any of its micro locations. The _ability of the device to electronically control the dynamic aspects of-various reactions provides a number of new and important advantages and improvements.
The concepts and embodiments of this invention are described in three sections. The first section, ~~Design and Fabrication of the Basic Devices,~~ describes the design of the basic underlying microelectronic device and the fabrication of the device using microlithographic and micromachining techniques. The second section, ~~Self Directed Addressing of the Devices,~~ describes the self addressing and self-assembly of the device, specifically the rapid transport and attachment of specific binding entities to each micro-location. Thethird section, ~~Applications of the Devices, ~~ describes how the device provides electronic control. of various multi-step, combinatorial, and multiplex reactions. This section also describes the various uses and applications of the device.
(1) DESIGN AND FABRICATION OF THE BASIC DEVICES
In order for a device to. carry out multi-step and multiplex reactions, its crucial electronic components must be able to maintain active operation in aqueous ' solutions. To satisfy this requirement, each micro-location must have an underlying functioning DC mode ' micro-electrode. Other considerations for the design and fabrication of a device include, but are not limited to, materials compatibilities, nature of the specific binding WO 95!12808 entities and the subsequent reactants and analytes, and the number of micro-locations.
By "a functioning DC mode micro-electrode" is meant a micro-electrode biased either positively or negatively, operating in a direct-current mode (either continuous or pulse), which can affect or cause- the free field-electrophoretic transport of charged specific binding entities, reactants, or analytes to or from any location on the device, or in the sample solution.
Within the scope of thin invention, the free field electrophoretic transport of molecules is not dependent on the electric field produced being bounded or confined by dielectrical material.
A device can be designed to have as few as two addressable micro-locations or as many as hundreds of thousands of micro-locations. In general, a complex device with a large number of micro-locations is fabri cated using microlithography techniques. Fabrication is carried out on silicon or other suitable substrate materials, such as glass, silicon dioxide, plastic, or ceramic materials. These microelectronic "chip" designs would be considered large scale array or multiplex analysis devices. A device with a small number of micro locations would be fabricated using micro-machining techniques.
Addressable micro-locations can be of any shape, preferably round, square, or rectangular. The size of an addressable micro-location can be of any size, preferably range from sub-micron (-0.5 Vim) to several centimeters (cm), with 5 ~Cm to 100 um being the most preferred size range for devices fabricated -using, microlithographic techniques, and I00 wm to -5 millimeters being the most preferred size range for devices fabricated using the micro-machining techniques. To make micro-locations smaller than the resolution of microlithographic methods would require techniques --such as electron beam lithography, ion beam lithography, or molecular beam epitaxy. While microscopic locations are desirable for analytical and diagnostic type applications, larger addressable locations (e.g., larger than 2 mm) are '5 desirable for preparative scale biopolymer synthesis.
After micro-locations have been created by using microlithographic and/or micro-machining techniques, chemical techniques are used to create the specialized attachment and permeation layers which would allow the DC
mode micro-electrodes under the micro-locations to: (1) affect or cause the free field electrophoretic transport of specific (charged) binding entities from any location;
(2) concentrate and covalently attach the specific binding entities to the specially modified surface of the specific micro-location; and (3) continue to actively function in the DC mode after the attachment of specific binding entities so that other reactants and analytes can be transported to or from the micro-locations.
DESIGN PARAMETERS (MICROLITHOGRAPHY) Figure 1 shows a basic design of self-addressable micro-locations fabricated using microlithographic techniques. The three micro-locations (10) (ML-1, ML-2, ML-3) are formed on the surface of metal sites (12) which have been deposited on 'an insulator layer/base material(14).
The metal sites (12) serve as the underlying micro electrode structures (10). An insulator material separates the metal sites (12) from each other. Insulator materials include, but are not limited to, silicon dioxide, glass, resist, rubber, plastic, or ceramic materials.
Figure 2 shows the basic features of an individual micro-location (10) formed on a microlithographically produced metal site (12). The addressable~micro-location is formed~on the metal site (12), and incorporates an cxidatior. layer (20), a permeation layer (22), ar_ W095112808 2 i 7 5 4 8 3 PCTlU594112270 attachment layer (24), and a binding entity layer f26).
The metal oxide layer provides a base for the covalent coupling of the permeation layer. The permeation layer provides spacing between the metal surface and the attach-ment/binding entity layers and allows solvent molecules, small counter-ions, and gases to freely pass to and from the metal surface. The thickness of the permeation layer for microlithographically produced devices can range from approximately 1 nanometers (nm) to 10 microns (~Cm), with 2 nm to 1 ~m being the most preferred. The attachment layer provides a base for the covalent binding of the binding entities. The thickness of the attachment layer for microlithographically produced devices can range from 0.5 nm to 1 Vim, with 1 nm to 200 nm being the most preferred. In some cases, the permeation and attachment layers can be formed from the same material. The specific binding entities are covalently coupled to the attachment layer, and form the specific binding entity layer. The specific binding entity layer is usually a mono-layer of the specific binding molecules. However, in some cases the binding entity layer can have several- or - even many layers of binding molecules.
Certain design and functional aspects of the permea tion and attachment layer are dictated by the physical (e.g., size-and shape) and the chemical properties of the specific binding entity molecules. They are also dictated to some extent by the physical and chemical properties of the reactant and analyte molecules, which will be subsequently transported. and bound to the micro-location.
For example, oligonucleotide binding entities can be attached to one type of micro-location surface without causing a loss of the DC mode function, i.e., the underlying micro-electrode can still cause the rapid free field electrophoretic transport of other analyte molecules to or from the surface to which the oligonucleotide binding entities are attached. However, if. large globular protein binding entities (e. g., antibodies) are attached to the same type of surface, they may effectively insulate the surface and cause a decrease or a complete loss of the .
DC mode function. Appropriate modification of the 5 attachment layer-would have to be carried out so as to either reduce the number of large binding entities (e. g., large globular proteins) or provide spacing between the binding entities on the surface.
The spacing between micro-locations is determined by 10 the ease of fabrication, the requirement for detector resolutionbetween micro-locations, and the number- of micro-locations desired on a device. However, particular spacings between micro-locations, or special arrangement or geometry of the micro-locations is not necessary for 15 device function, in that any combination of micro-locations (i.e., underlying micro-electrodes) can operate over the complete device area. Nor- is it necessary to enclose the device or confine the micro-locations with dielectric boundaries. This is because complex electronic 20 field patterns or dielectric boundaries are not required to selectively move, separate, hold, or orient specific molecules in the space or medium between any of the elec-trodes. The device accomplishes this by attaching the specific binding molecules and subsequent analytes and reactants to the surface of an addressable micro-location.
Free field= electrophoretic propulsion provides for the rapid and direct transport of any charged molecule between any and all locations on the device.
As the number of micro-locations increases beyond several hundred, the complexity of the underlying cir cuitry of the micro-locations increases. In this case the micro-location grouping patterns have to be changed and spacing distances increased proportionally, or multi-layer circuitry can be fabricated into the basic device.
In addition to micro-locations which have been addressed with specific binding entities, a device will WO 95112808 217 5 4 B 3 PCTlUS94112270 contain some un-addressed, or plain micro-locations which serve other functions. These micro-locations can be used to store reagents, to temporarily hold reactants or analytes, and as disposal units for excess reactants, analytes, or other interfering components in samples.
Other un-addressed micro-locations can be used in combina-tion with the addressed micro-locations to affect or influence the reactipns, that are occurring at these specific micro-locations. These micro-locations add to intra-device activity and control. It is also possible for --the micro-locations to interact and transport molecules between two separate devices. This provides a mechanism for loading a- working device with binding entities or reactants from a storage device, and for copying or replicating a device.
Figure 3 shows a matrix type device containing 64 addressable micro-locations (30). A 64 micro-location device is a convenient design, whichfits with standard microelectronic chip packaging components. Such a device is fabricated on a silicon chip substrate approximately 1.5 cm x 1.5 cm, with a central area approximately 750 um x 750 ~m containing the 64 micro-locations. Each micro-location (32) is approximately 50 ~m square with 50 ~m spacing between neighboring micro-locations. Connective circuitry for each individual underlying micro-electrode runs to an outside perimeter (10 mm x 10 mm) of metal contact pads (300 ~m square) (34). A raised inner peri-meter can be formed between -the area with the micro-locations and the contact pads, producing a cavity which can hold approximately 2 to 10 microliters (~l) of a sample solution. -The "chip" can be mounted in a standard quad package, and the chip-contact pads (34) wired to the quad package pins. The packaged chip can then be plugged into a microprocessor controlled DC power supply and multimeter apparatus which can control and operate the device.

wo 9snisos rc~rrUSSa~aaZ7o 2~~5~a~ 1 FABRICATION PROCEDURES (MICROLITFiOGRAPHY1 Microlithoaraphv Fabrication Stgps General microlithographic or photolithographic techniques can be used for the fabrication of the complex "chip" type device which has a large number of small micro-locations. While the fabrication of devices does not require complex photolithography, the selection of materials and the requirement that an electronic device function actively in aqueous solutions does require special considerations.
The 64 micro-location device (30) shown in Figure 3 can be fabricated using relatively simple mask design and standard microlithographic techniques. Generally, the base substrate material would be a 1 to 2 centimeter square silicon wafer or a chip approximately 0.5 mini-meter in thickness. The silicon chip is first overcoated with a 1 to 2 ~m thick silicon dioxide (SiO,) insulation coat, which is applied by plasma enhanced chemicalvapor deposition (PECVD).
In the next step, a 0.2 to 0.5 ~Cm metal layer (e. g., aluminum) is deposited by vacuum evaporation. In addition to aluminum, suitable metals for circuitry include gold, silver, tin, copper, platinum, palladium, carbon, and various metal combinations. Special techniques for ensuring proper adhesion -to the insulating substrate materials (SiO,) are used with different metals.
The chip is next overcoated with a positive photo-resist (Shipley, Microposit AZ 1350 J), masked (light field) with the cizcuitzy pattern, exposed and developed.
The photosolubilized-resist is removed, and the exposed aluminum is etched away. The- resist island is now removed, leaving the aluminum circuitry pattern on the chip. This includes an outside perimeter of metal contact pads, the connective circuitry (wires), and the center array of micro-electrodes which serve as the underlying base for the addressable micro=locations.

Using PECVD, the chip is overcoated first with a 0.2 to 0.4 micron layer of Si0l, and then with a 0.1 to 0.2 micron layer of silicon nitride LSi3N4).- The chip is then covered with positive photoreaist, masked for--the contact pads and micro-electrode locations, exposed, and developed_ Photosolubilized resist is removed, and the Si02 and Si3N4 layers are etched avray to-expose the aluminum contact pads and micro-electrodes. The surrounding island resist is then removed, the connective wiring between the contact pads and the micro-electrodes remains insulated by the SiOa and Si3N4 layers.
The SiOa and Si3Nq layers provide important properties for the functioning of-the device. First, the second si0, layer has better contact and improved sealing with the aluminum circuitry. It is also possible to use resist materials to insulate and seal. This prevents undermining of the circuitry due to electrolysiseffects when the micro-electrodes are operating. The final surface layer coating of Si3N4 is used because it has much less reactivity with the subsequent reagents used to modify the micro-electrode surfaces, for ,the. attachment of specific binding entities.
Permeation and Attachment Laver Formation Stens At this point the micro-electrode locations on the device are ready to be modified with a specialized permea tion and attachment-layer. This represents the most important aspect of the invention, and is crucial for the active functioning of the device. The objective is to create on the micro-electrode an intermediate permeation layer with selective diffusion properties and an attach-ment surface layer with optimal binding properties. The attachment layer should have from 105 to 10' functionalized locations per square micron-(gym') for the optimal attach-ment of specific -binding entities.-- However, the attachment of specific binding entities must not overcoat wo vsnasos rc~rms9anzz~o or insulate the surface. ~o as to prevent the underlying micro-electrode from functioning. A functional device requires some fraction (-. 5% to 25%) of the actual metal micro-electrode surface to remain accessible to solvent (H=O) molecules, and to allow the diffusion of counter-ions (e.g., Na' and C1-) and electrolysis gases (e.g., OZ and H2) to occur.
The intermediate permeation- layer must also allow diffusion to occur. Additionally, the permeation layer should have a pore limit property which inhibits or impedes the larger binding entities, reactants, and analytes from physical contact with the micro-electrode -surface.- The permeation layer keeps the active micro-electrode surface physically distinct from the binding entity layer of the micro-location.
In terms of the primary device function, this design allows the electrolysis reactions required for electro-phoretic transport to occur on micro=electrode surface, but avoids adverse electrochemical effects to the binding entities, reactants, and analytes.
One preferred procedure for the derivatization of the metal micro-electrode surface uses aminopropyltriethoxy silane (APS). APS reacts readily with the oxide and/or hydroxyl groups on metal and silicon surfaces. APS
provides a-combined-permeation layer and attachment layer, with primary amine groups for. the subsequent covalent coupling of binding entities: -In terms of surface binding sites, APS produces a relatively high level.. of functionalization (i.e., a large number-of primary amine groups) on slightly oxidized aluminum surfaces, an inter-mediate level of functionalization on SiOz surfaces, and very limited functionalization of Si,N, surfaces.
The APS reaction is carried out by treating the whole device (e.g., a chip) surface-for 30 minutes with a 10%
solution of APS in toluene at 50°C. The chip is then washed in toluene, ethanol, and then dried for one hour at 2 7 7 5 4 8 3 PCT~S9411227D
2s 50°C. The micro--electrode metal surface is functionalized with a large number of primary amine groups (lO5 to 106 per square micron). Binding, entities can now be covalently bound to the derivatized micro-electrode surface.
The APS procedure works well-for the attachment of oligonucleotide binding entities. Figure 4 shows the mechanism for the attachment of 3'-terminal aldehyde derivatized oligonucleotides (40) to an APS functionalized surface (42). While this represents one of the preferred approaches, a variety of other attachment reactions are possible for both the covalent and non-covalent attachment of many types of binding entities.
DESIGN-AND FABRICATION (MICRO-MACHINING) This section describes how to use micro-machining techniques (e. g., drilling, milling, etc.) or non lithographic techniques to fabricate devices. In general, these devices have relatively larger micro-locations (> 100-microns) than those produced by microlithography.
These devices could be used for analytical applications, as well as-for preparative type applications, such as biopolymer synthesis. Large addressable locations could be fabricated in three dimensional formats (e.g., tubes or cylinders) in order to carry a large amount of ,binding entities. Such devices could be fabricated using a variety of materials, including, but not limited to, plastic, -rubber, silicon, glass (e. g., microchannelled, microcapillary, etc.), or cexamics. In the case of micro-machined devices, connective circuitry and larger electrode structures can, be printed onto materials using standard circuit board printing techniques known to those skilled in the art.
Addressable micro-location devices can be fabricated relatively easily using micro-machining techniques.
Figure 5 is a schematic of a representative 96 micro-location device. This micro-location device is fabricated WO 951128 ~ ~ ~ ~ . PCTIU894112270 from a suitable material.stock (2 cm x 4 cm x 1 cm), by drilling 96 proportionately spaced holes (1 mm in diame-ter) through the material- An electrode circuit board (52) is formed on a thin sheet of plastic material stock, which fit precisely over the_top of the micro-location component (54). The underside of the circuit board contains the individual wires (printed- circuit) to each micro-location (55). Short platinum electrode structures (- 3-4 mm) (62) are designed-to extended down into the individual micro-location chambers (57). The printed circuit wiring is coated with a suitable water-proof insulating material.- The printed circuit wiring converges to a socket, which allows connection to a multiplex switch controller (56) arid DC power supply (58). The device is partially immersed and operates in a common buffer reservoir (59).
While the primary function of the micro-locations in devices fabricated by micro-machining and microlithography techniques is the same, their designs are different. In devices fabricated by microlithography, the permeation and attachment layers are formed directly on the underlying metal micro-electrode. In devices fabricated-by micro-machining techniques, the permeation and attachment layers are physically separated from their individual metal electrode structure (62) by a buffer solution inthe individual chamber or reservoir (57) (see Figure 6). In micro-machined devices the permeation and attachment layers can be formed using functionalized hydrophilic gels, membranes, or other suitable porous materials.
In general, the thickness of the combined permeation and attachment layers ranges from 10 ICm to 10 mm. For example, a modified hydrophilic gel of 26% to 35 % polya-crylamide (with 0.1% polylysine), can be used to partially fill (- 0.5 mm) each of -the individual -micro-location chambers in the device. This concentration of gel forms an ideal permeation layer with a pore limit of from 2 nm WO 95!12808 to 3 nm. The polylysine incorporated into the -gel pro-vides primary amine functional groupsfor the subsequent attachment of specific binding entities. This type of gel permeation layer allows the electrodes to function actively in the DC mode. When the. electrode is activated, the gel permeation layer allows small counter-ions to pass through it, but -the larger specific binding entity molecules are concentrated on the outer surface. Here they become covalently bonded to the outer layer of primary amines, which effectively becomes the attachment layer.
An alternative technique for the formation of the permeation and attachment layers is to incorporate into the base of.each micro-location chamber a porous membrane material. The outer- surface of. the membrane is then derivatized with chemical functional groups to form the attachment layer. appropriate techniques and materials for carrying out this approach are known to those skilled in the art.
The above description for the design and fabrication of a device should not- be considered as a limit to other variations or forms of the basic device. Many variations of the device with larger or smaller--numbers of address-able micro-locations are Qnvisioned for different analy-tical and preparative applications. variations of the device with larger addressable locations are envisioned for preparative biopolymer synthesis applications. Varia-tions are also contemplated as electronically addressable and controllable reagent dispensers for use with other devices, including those produced by microlithographic techniques.
(2) SELF-DIRECTED ADDRESSING OF THE DEVICES
The claimed devices are able to electronically self address -each micro-location with a specific binding entity. The device itself directly affects or causes the transport and attachment of'specific binding entities to specific micro-locations. The device self-assembles itself in the sense that no outside process, mechanism, or equipment is needed to physically direct, position, or place a -specific binding entity at a specific micro-location. This self-addressing process is both rapid and specific, and can be carried out in either a serial or parallel manner.
A device can be serially addressed with specific binding entities by maintaining the selected micro location in a DC mode and at the opposite charge (poten tial) to that of a specific binding entity. All other micro-locations are maintained at the same charge as the specific binding entity. In cases where the binding entity is not in excess of the attachment sites on the micro-location, it is necessary to activate only one other micro-electrode to affect the electrophoretic transport to the specific micro-location. The specific binding entity is rapidly transported (in a few seconds, or preferably less than a second) through the-solution, and concentrated directly at the specific micro-location where- it immediately becomes covalently bonded to the special surface. The ability to electronically concentrate reactants or analytes (70) on-a specific micro-location (72) is shown in Figure 7. All other micro-locations remain unaffected by that specific binding entity. Any unreacted binding entity is removed by reversing the polarity of that specific micro-location,-and electro-phoreaing it to a -disposal location. The cycle is repeated until all desired micro-locations are addressed with their specific binding entities. Figure 8 shows the serial process for addressing- specific micro-locations (81, 83, 85) with specific --oligonucleotide binding entities (82, 84, 86).
The parallel process for addressing micro-locations simply involves simultaneously activating a large number 217 ~ ~ 8 3 pCT~S94112270 WO 95!12808 (particular group or line) of micro-electrodes so that the same specific binding entity is transported, concentrated, and reacted with more than one specific micro-locations.
(3) APPLICATIONS OF THE DEVICES
Once a devicehas been self-addressed with specific binding entities, a variety of molecular biology type multi-step and multiplex reactions and analyses can be carried out on the device. The devices of this invention are -able to electronically provide -active or dynamic control over a number of important reaction parameters.
This electronic control leads to significant improvements in reaction rates, specificities, and sensitivities. The improvements in these reaction parameters come from the ability of the -device to- electronically control- and affect: (1) the rapid transport of reactants or analytes to a specific micro-location containing attached specific binding entities; (2) improvement in reaction rates due to the concentrated reactants or analytes reacting with the specific binding entities at that specific micro-location;
and (3) the rapid and selective removal of un-reacted and non-specifically bound components from that micro-loca-tion. These advantages are utilized in a novel process called "electronic stringency control".
The self-addressed devices of this invention are able to rapidly carry out a variety of micro-formatted multi step and/or multiplex reactions and procedures; which include, but are not limited to:
- DNA and RNA hybridizations procedures and analysis in conventional formats, and new improved matrix formats;
- molecular biology reaction procedures, e.g., restriction enzyme reactions and analysis, ligase reactions, kinasing reactions, and amplification procedures;

- antibody/antigen reaction procedures involving large=or small antigens and haptens;
- diagnostic assays, e:g., hybridization analysis, gene analysis; fingerprinting, and immuno 5 diagnostics;
- biomolecular conjugation procedures (i.e. the covalent and non-covalent labeling of nucleic acids, enzymes, proteins, or antibodies with reporter groups);
10 - biopolymer synthesis procedures, e.g., combinatorial synthesis of oligonucleotides or peptides;
- water soluble s~mthetic polymer synthesis, e.g., carbohydrates or linear polyacrylates; and 15 - macromolecular and nanostructure (manometer size particles and structures) synthesis and fabrication.
NUCLEIC ACID HYBRIDIZATION -Nucleic acid hybridizations are used as examples of 20 this invention because they characterize the most diffi cult multi-step and multiplex reactions.
The claimed device and methods allow nucleic acid hybridization to be carried out in a variety of conven-tional and new formats. The ability of the device to 25 electronically control reaction --parameters greatly improves nucleic acid hybridization analysis, particularly the ability of the device to provide electronic stringency control (ESC).
By "nucleic acid hybridization" is meant hybridiza 30 tion between all-natural and synthetic forms and deriva tives of nucleic acids, including: deoxyribonucleic acid (DNA), ribonucleic ..acid (RNA), polynucleoEides and ' oligonucleotides-.
Conventional hybridization formats, such as "dot blot" hybridization and "sandwich" hybridization, can be R'O 95112808 PCT/US94I12270 carried out with the claimed device as well as large scale array or matrix formats.
As an example, a device for DNA hybridization analy sis is designed, fabricated, and used in the following manner. Arrays of micro-locations are first fabricated using microlithographic techniques. The number of addressable micro-locations on an array depends on the final use. The device:is rapidly self-addressed in a serial manner with a group .of specific-oligonucleotides.
In this case, the specific oligonucleotides are 3'-terminal aldehyde fuhctionalized oligonucleotides (in the range of 6-mer to 100-mer). The aldehyde functional group allows for covalent attachment to the specific micro-location attachment surface (see Figure 4). This group of-specific oligonucleotides can be readily synthesized on a conventional DNA synthesizer using conventional tech-niques.
The synthesis of each specific oligonucleotide is initiated from a ribonucleotide controlled pore glass (CPG) support. Thus, the 3'-terminal position contains a ribonucleotide, which is then easily converted after synthesis and purification to a terminal dialdehyde derivative by periodate oxidation. The aldehyde containing oligonucleotides (40) will react readily with the primary amine functional groups on the surface of micro-locations-by a Schiff's base reaction process.
The electronic addressing of the device with specific.
oligonucleotides is shown in Figure 8. The addressing of the firstspecific micro-location (ML-1) (81) with its specific sequence oligonucleotide (SSO-1) (82) is accom-plished by maintaining the specific microelectrode (ML-1) at a positive DC potential, while all other microelec-trodes are maintained at a negative potential (Fig. 8(A)).
The aldehyde functionalized specific sequence (SSO-1) in aqueous buffered solution is free field electrophoresed to the ML-1 address, where it concentrates (> 106 fold) and immediately becomes covalently bound to the surface of ML-1 (81). All other microelectrodes are maintained nega-tive, and-remain protected orshielded from reacting with SSO-1aequence (82).The ML-1 potential is then reversed to negative (-) to electrophores any unreacted SSO-1 to a disposal system. The cycle is repeated, SSO-2 (84) --->
ML-2 (83), SSO-3 (86) ---> ML-3 (85), SSO-n ----> ML-n until- all the desired micro-locations are addressed with their-specific DNA sequences CFig. 8(D)).
Another method for addressing the device is to trans-port specific binding entities such as specific oligonu-cleotides from an electronic reagent supply device. This supply device would hold a large quantity of binding ' entities or reagents and would be used to load analytical devices. Binding entities would he electronically trans-ported between the two devices. Such a process eliminates the need for physical manipulations, such as pipetting, in addressing a device with binding entities.
Yet another method for addressing the device is to carry out the combinatorial synthesis of the specific oligonucleotides at the. specific micro-locations.
Combinatorial synthesis is described in a later section.
After the device is addressed with specific DNA
sequences, the micro-locations on the array device remain as independent working direct- current (DC) electrodes.
This is possible because the attachment to the electrode surface is carried out in such a manner that the underly-ing micro-electrode does not hecomechemically or physi-cally insulated. Each micro-electrode can still produce the strong direct currents necessary for the free field electrophoretic transport of other charged DNA molecules to and from the micro-location surface. The DNA array device provides -complete electronic control over all aspects of -the DNA hybridization and any other subsequent reactions.

WO 95112808 ~ ~ ~ ~ ~r ~ ~ PCT/US94I12270 An example ofan electronically controlled hybridiza-tion process is shown in Figure 9. - In this case, each addressable micro-location has a specific capture sequence (90). A sample solution containing target DNA (92) is applied to the device- All the micro-locations are acti-vated and the sample DNA is concentrated at the micro-locations (Fig. 9(B)). Target DNA molecules from the dilute solution become highly concentrated at the micro-locations, allowing very rapid hybridization to the specific complementary DNA sequences on the surface.
Reversal of the micro-electrode potential repels all un-hybridized DNA from the micro-locations, while the target DNA remains hybridized (Fig. 9(C)). In similar fashion, reporter probes are hybridized in subsequent steps to detect hybridized complexes.
The electronic control.of the hybridization pirocess significantly improves the subsequent detection of the target DNA molecules by enhancing the overall hybridiza-tion efficiency and by removing non-specific DNA from the 2D micro-location areas. It is expected that 10,ODD to 100,000 copies of target sequences in un-amplified genomic DNA will be detectable. Hybridization reactions of this type can be carried out in a matter of minutes, with minimal outside manipulations. Extensive washing is not necessary. -Another common format for DNA hybridization assays involves having target DNAs immobilized on a surface, and then hybridizing specific probes to these target DNAS.
This format can involve either the same target DNAs at multiple locations, or different target DNAs at specific locations. Figure 10 shows an improved version of this serial hybridization format. In this case micro-locations (101-107) are addressed with different capture DNAs.
These are hybridized in a aerial fashion with different sequence specific oligonucleotides (108,109). The micro-locations are sequentially biased positive to transport 2~~~~a3 molecules to itself and then biased negative to transport molecules to the next micro-location. Specifically hybridized DNA will remain at the micro-location regardless of electrode potential. The sequence specific oligonucleotides can be labeled with a suitable reporter group such as a fluorophore.
The claimed device= is -able to provide electronic stringency control. Stringency control is necessary for hybridization specificity, and is particularly important for resolving one base mismatches in pointmutations.
Figure 11 shows how electronic stringency control can be used for improving-hybridization specificity for onebase.
mismatch analysis. The electronic stringency controlcan also be applied to multiple-base mismatch analysis.
Perfectly matched DNA hybrids (110) are more stable -than mismatched DNA (112) hybrids. By biasing the micro-locations negative (Fig. 11(B)) and delivering a defined amount of power in a given time, it is possible to denature or remove the mismatched DNA hybrids while retaining the perfectly matched DNA hybrids (Fig. 11(C)).
In a further refinement, the claimed device provides code-pendent stringency control to-each specific hybridization reaction occurring on the device. With a conventional or passive array format, it is impossible to achieve optimal stringency for all the hybridization events which are occurring in the same hybridization solution. However, the active array devices of ,this invention are able to provide different electronic stringency to hybridizationa at different micro-locations, even though they are occurring in the same bulk hybridization solution. This attribute overcomes a major-limitation to conventional matrix hybridization formats, sequencing by hybridization=
(SBH) formats, and other multiplex analyses.
The ability to provide electronic stringency control to hybridizations also provides mechanisms for detecting DNA hybridization without reporter group labeled DNA

2 ~ 7 5 ~ 8 3 ~cTfussa~ixx~o wo 9snxsos probe. It provides a way tocarry out- a more direct detection of the hybridization process itself. A fluore-scent dye detection process is shown in Figure 12 and described in Examples 4 and 6. Direct detection of DNA
5 hybrids can be achieved by using DNA binding dyes such as ethidium bromide. The dye binds to both double-stranded and single-stranded DNA but with a greater affinity for the former. In Figure 12(B) positively charged dye (122) is transported to negatively biased micro-locations. The 10 dye binds to both hybridized (I20) and unhybridized (121) DNA sequences (Fig. 12c). By biasing the micro-locations positive and delivering a defined amount of power in a given amount of time, the dye molecules bound to unhybridized micro-locationsis selectively removed. The 15 amount of power applied does not adversely affect the DNA
hybrids.
The hybridized DNAs with associated dye molecules are then fluorescently detected using associated or integrated optical systems.
20 The following reiterates the important advantages the devices of this invention provide for nucleic acid hybridi-zation reactions and analysis:
(1) The rapid transport of dilute target DNA and/or probe DNA sequences to specific micro 25 location(s)- where hybridization is to occur.
This process takes place in no more than a few seconds.
(2) Concentrating dilute target DNA and/or probe DNA
sequences at specificmicro-locations) where 30 hybridization is to occur: The concentrating effect can be, well over a million fold (> 106).
(3) The rapid removal of non-specifically bound target DNA sequences from specific micro location(s) where hybridization has occurred.
35 This process takes 10 to 20 seconds.

wo 9snasog rcTms9anaa~o 2~~ ~4~3 (4) Rapid removal of, competing complementary target DNA sequences ~rom- specific micro-locations) where hybridi-zationhas occurred. This process takes 10 to 20 seconds. ' (6) The ability to carry out a complete hybridization process in several minutes.
(7) The ability to carry out a hybridization process with minimal outside manipulations or washing steps.
(8) The use of electronic stringency control (ESC) to .
remove partially hybridized DNA sequences.
(9) The ability to carry out hybridization analysis of un-amplified genomic target DNA sequences in the 1000 to 100,000 copy range.
(10) The use of ESC to improve the resolution of single base mis-match hybridizations (point mutations).
(11) The use of ESC to provide individual stringency control in matrix hybridizations.
(12) Improving the detection of hybridization event by removing non-specific background components.
(13) The development of new procedures which elimi nate the need fog using covalently labeled reporter probes or target DNA to detect the hybridization events.
REPRODUCTION OF DEVICES
In addition to separately addressing individual devices with specific binding entities, it is also pos-sible to produce a master device, which can copy specific -binding entities to other devices. This represents another method for the production of devices. The process for the replication of devices is shown in Figure 13. A
master device containing micro-locations which have been addressed with specific binding sequences is hybridized with respective complementary DNA sequences (130). These 217 5 4 8 3 P~~S94112270 R'O 95/128~8 complementary sequences are activated and thus capable of covalent binding to the micro-location attachment layer.
An unaddressed sister device (132) containing an attachment layer is aligned with the hybridized master device (Fig. 13(B)). , The master device micro-locations are biased negative and the sister device micro-locations are biased positive. The DNA hybrids are denatured and are transported to the sister device, where the activated DNA sequence binds covalently to the micro-location (Fig. 13(C)). The process can be performed in parallel or in series, depending on -the device geometry so that crosstalk between the micro-locations is minimized. The hybrids can be denatured by applying a sufficient negative potential or by using a positively charged chaotropic agent or. denaturant.
nFTF~TION SYSTEM
In the case of fluorescent binding reactions, it is possible to use an epifluorescent type microscopic detec-tion system forthe analysis of the binding reactions.
The sensitivity of the. system depends on the associated imaging detector element (CCD, ICCD, Microchannel Plate) or photon counting PMT system. One alternative is to associate a sensitive CCD detector or avalanche photodiode (APD) detector directly with the device in a sandwich arrangement. Another alternative is to integrate opto-electronic or microelectronics detection in the device.
COMBINATORIAL BIOPO YMER SYNTHESIS
The devices of this invention are also capable of carrying out combinatorial synthesis of biopolymers such as oligonucleotides and peptides. Such a process allows self-directed synthesis to occur without the need for any outside direction or influence. This combinatorial syn-thesis allows very large numbers of sequences to be synthesized on a device. The basic concept for combina-211:~~~33 torial synthesis involves the use of the device to trans-port, concentrate, and react monomers, coupling reagents, or deblocking reagents at the-addressable micro-locations.
The concept capitalizes on-the ability of the device to protect certain locations from the effects of nearby reagents. Also important to the concept-is-the identifi-cation of selective steps in these chemical synthesis processes where one or more of the reactants has either a net positive or negative charge, or to create .such suitable reagents for these processes.
One method for combinatorial oligonucleotide synthe-sis is shown in Figure 14. This method begins with a set of selectively addressable micro-locations (140) whose surfaces have been derivatized with blocked primary amine (X-NH-) groups (142). The initial step in the process involves selective deblocking of electrodes using a charged deblocking reagent (144). In this case, the reagent would carry a positive (+) charge. The process is carried out by applying a negative potential to those electrodes being de-blocked, and a positive potential to those which are to remain protected (Fig. 14(B)).
Application of positive and negative potentials to selective electrodes causes the charged reagents to be concentrated at those micro-locations being de-blocked, and excludes the reagents from the other electrode surfaces.
In the second step, chemical coupling of the first base, in this case cytosine, to the deblocked micro locations is carried out by simply exposing the system to the phosphoramidite-- reagent- (x-C) (146). The (C) nucleotide couples to de-blocked micro-location surfaces, but not to any of - the blocked electrode surfaces (Fig. 14(C) and (D)). At this point normal phosphoramide chemistry IS carried out until the next de-blocking step.
At the second de-blocking step (Fig. 14(D)), those electrode positions which are to be coupled withthe next PCTlUS94112270 i base are -made negative,, and those which are to remain protected are made positive. The system is now exposed to the next base to be coupled, in this case (x-A) (148), and selective coupling to the de-blocked micro-location is achieved (Fig. 14(E) and -(F)). The coupling and de-blocking procedures are repeated, until all the different DNA sequences have been synthesized on each of the addressable micro-location surfaces.
The above example represents one possible approach for the synthesis of nucleic acids.- Another approach involves a complete water soluble DNA synthesis. In this case, charged water soluble coupling agents, such as 1 ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCA), is used to carry out oligonucleotide synthesis with water soluble nucleotide-derivatives. This approach would have significant advantages over present organic solvent based methods which require extensive blocking of the base moieties. Water soluble synthesis would be less expensive and eliminate the use of many toxic substances used in the present organic solvent based processes. A third approach involves the use of charged monomers.
In addition to DNA synthesis, asimilar process can be developed for peptide synthesis, and other- complex polymers. Examples contemplated in this disclosure represent the initial potential-for this technique, and are based on organic solvent based synthetic procedures forDNA or peptide synthesis.
The recipes for buffers, solutions, and media in the following examples are described in J. Sambrook, E. F.
Fritsch, and T. Maniatis, Molecular Cloning: A Laboratory Manual, 2 Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989.
Example 1~. . Ql~~TOmer Reagents Synthetic DNA probes were made using conventional phosphoramidite chemistry on Applied Biosystems automated ~'~T~4'33 DNA synthesizers. Oligomers were designed to contain either a 5' amino or a 3' ribonucleoside terminus. The 5' functionality was incorporated by using the ABI Aminolink 2 reagent and the 3' functionality was introduced by initi-5 sting synthesis from an RNA CPG support. The 3' -ribonucleotide terminus can be converted to a terminal dialdehyde by the periodate oxidation method which-can react with primary amines to dorm a Schiff's base. Reac-tion conditions were as follows: Dissolve 20-30 O.D.
10 oligomer in water to a final concentration of 1 OD/~1.
Add 1 vol of O.1M sodium acetate, pH 5.2 and 1 vol 0.45M
sodium periodate (made fresh in water). Stir and incubate reaction for at least 2 hours at ambient temperature, in the dark. Load reaction mix onto a Sephadex G-1D column 15 (pasteur pipette, 0.6 .X 5.5 cm) equilibrated in O.1M
sodium phosphate, pH 7.4. Collect 200 ~l fractions, spot 2 wl aliquots on thin layer chromatography (TLC) and pool ultra violet (UV) absorbing fractions.
The following oligomers contain 3' ribonucleoside 20 termini (U):
ET12R 5'- GCT AGC CCC TGC TCA.TGA GTC TCU
CP-1 5'- AAA AAA AAA AAA'AAA AAA AAU
AT-A1 5'- CTA CGT GGA CCT FGA GAG GAA GGA GAC TGC CTG U
AT-A2 5'- GAG TTC AGC AAA TTT GGA GU
25 AT-A3 5'- CGT AGA ACT CCT .CAT CTC CU
AT-A4 5'- GTC TCC TTC CTC TCC AGU
AT-A5 5'- GAT GAG CAG TTC TAC GTG GU
AT-A6 5'- CTG GAG AAG AAG GAG ACU
AT-A7 5'- TTC CAC AGA CTT AGA TTT GAC U
30 AT-A8 5'- TTC-CGC AGA TTT AGA AGA TU
AT-A9 5'- TGT TTG CCT GTT CTC AGA CU
AT-A10 5'- CAT CGC TGT GAC AAA ACA TU
Oligomers containing 5' amine groups were generally ' reacted with fluorophores, such as Texas Red (TR, ex.
35 590nm, em. 610nm). Sulfonyl chlorides are-very reactive towards primary amines forming a stable sulfonamide wo 9snzsos rcTrt~svanzz~o ~17~4$3 linkage. Texas Red-DNA conjugates were made as follows:
Texas Red Probes) was sulfonyl chloride (Molecular dissolved in dimethyl formamide -(DMF) to a final concentration was dissolved of 50 mg/ml,(80 mM). Oligomer in 0.4M sodium bicarbonate, pH 9.0-9.1,to a final concentra tion of 1 O.D./~1 (5.4 for a 1-mer). In a mM 2 micro tes t tube, 10 ~.1 oligomer ul Texas Red was and 20 combined. Let reaction proceed in the dark for hour.

Quench action with ammonia or re hydroxylamine, lyophilize sample et al.,1989, supra).
and purify by PAGE
(Sambrook The following oligomers contain ami no termini:
5' ET21A 5'- Aminolink2 - TGC GAG CTG CAG TCA GAC AT -ET10AL 5'--Aminolink2 - GAG AGA CTC ATG AGC AGG

ET11AL 5'- Aminolink2 - CCT GCT CAT GAG TCT CTC

T2 5'- Aminolink2 - TTT TTT TTT TTT TTT TTT TT

RC-A1 5'- Aminolink2 - CAG GCA GTC TCC TTC CTC TCC AGG

TCC ACG
TAG

RC-A2 5'- Aminolink2 - CTC CAA ATT TGC TGA ACT C

RC-A3 5'- Aminolink2 - GGA GAT GAG GAG TTC TAC G

5'- Aminolink2 - CTG GAG AGG AAG GAG AC

RC-A5 5'- Aminolink2 - CCA CGT AGA ACT -GCT CAT C-RC-A6 5'- Aminolink2 - GTC-TCC TTC TTC TCC AG

RC-A7 5'- Aminolink2 - GTC AAA TCT AAG-TCT GTG GAA

RC-A8 5'- Aminolink2 - ATC TTC TAA ATC TGC GGA A

RC-A9 5-'- Aminolink2 - GTC TGA GAA CAG GCA AAC A

RC-A10 5'- Aminolink2 - ATG TTZ TGT CAC AGC GAT G

Example 2: 'wtronicallv Addressable Micro-locations on a Microfabricated Device - Polvlvsine Microelectrodes were fabricated from microcapillary tubes (0.2 mm x 5 mm). The microcapillaries were filled with 18-26~ polyacrylamide containing 0.1 - 1.0% poly-lysine and allowed to polymerize. The excess capillary was scored and removed to prevent air bubbles from being trapped within the tubes and to standardize the tube R'O 95!12808 PCf/US94112270 length. Capillaries were mounted in a manner such that they shared a common upper- buffer reservoir and had individual lower buffer reservoirs. Each lower buffer reservoir contained a platinum wire electrode.
The top surface of the microcapillary in the upper reservoir was considered to-be the addressable micro-location. Upper and lower--reservoirs were filled with 0.1 M sodium phosphate, pH 7.4 and prerun for 10' at 0.05 mA constant using a BioRad 500/1000 power supply. Pipette 2 /tl (0.1 O.D.) periodate oxidized ET12R into the upper reservoir while the power is-on and electrophorese for 2-5 minutes at constant current. Reverse polarity so that the test capillary is now biased negative and electrophorese an additional 2-5 minutes. Unbound DNA is repulsed while-the covalently attached DNA remains.
Aspirate upper reservoir buffer- and rinse with buffer. Disassemble apparatus and mount a fresh reference capillary. Refill reservoir and add fluorescently labeled complement DNA, i.e., ET10AL-TR. Electrophoretically concentrate the oligomer at the positively biased test micro-location for 2-5 minutes at 0.05 mA constant.
Reverse the polarity and remove unbound complement. Remove test capillary and examine by fluorescence. Negative control for nonspecific binding was performed as described above substituting a noncomplementary DNA sequence ET21A-TR for ET10AL-TR.
A cross-section of the capillary micro-locations were examined under a Jena epifluorescent microscope fitted with a Hamamatsu ICCD camera imaging system. Fluorescent results indicate that complement ET10AL-TR hybridized to the binding entity/capture sequence and remained ' hybridized even when the potential was changed to negative. ET21A-TR noncomplement was not retained at the.
test capillary when the potential was reversed.

PCTlUS94112270 w~9~'~~g 2175483 Example 3: ,~','t ctronicallv Addressable Micro-locations on a Microfabricated Device - Succinimidvl A~rvlate Method This example describes an alternative attachment chemistry which covalently binds the 5' terminus of the oligomer. Capillaries were fabricated as described above except that 1% auccinimidyl acrylate-(Molecular Probes) was substitute for the polylysine. The capillaries were made fresh because the auccinimidyl ester reacts with primary amines and is labile, especially above pH 8Ø
The capillaries were mounted as described above and the reservoirs were ~illed with 0.1 M sodium phosphate, pH
7.4. Prerun the capillaries for 10 minutes at 0.05 mA.
Pipette 2 ~1 ET10AL (D.1 O.D.), which contains a 5' amino terminus, into the upper reservoir while the power is on and electrophorese for 2-5 minutes. Reverse polarity so that the test capillary is now biased negative and elec-trophorese an additional 2-5 minutes. Unbound DNA is repulsed while the covalently attached DNA remains.
Aspirate upper reservoir buffer and rinse with buffer. Unmount the reference capillary and mount a fresh reference capillary. Refill reservoir and add fluorescent labeled complement oligomer, ET11AL-TR and electrophorese as described above. Negative control for nonspecific binding was performed as described above substituting a noncomplement DNA sequence ET21A-TR for ET11AL-TR.
Fluorescent results indicate that complement ET11AL-TR hybridized to the capture sequence and remained hybridized even when the potential was changed to negative. ET21A-TR noncomplement was not retained at the working capillary when the potential was reversed.
Example 4: ~-~''ronicallv Controlled Fluorescent Dve D_erA~~~on Process-PAGE
DNA dyes such as ethidium bromide (EB) become fluore-scent when intercalated into DNA. The fluorescence and WO 95/12808 PCTlUS94/12270 ,.1~ :~~33 L

binding affinity is greater when the DNA is double stranded than single stranded.- Prepare capillaries as in Example 1 and hybridize as described above. EB was added to the solution (- 0.05 mM EB final concentration) and the test capillary was biased negative because EB is posi-tively charged. Thecapillaries were observed by epifluor-escence at 550 nm excitation and 600+ nm emission. Both the hybridized and unhybridized micro-locations showed red fluorescence (from EB).
1D The capillaries were ~re-mounted -biased positive to repulse EB. Maintain constant current at O.D5 mA for 0.03 Volt-Hours.
Capture Target Normalized Signal ET10AL ET11AL (Pos.) >200 ET10AL ET21A (Neg.) 1 Fluorescence at the unhybridized micro-locations diminished while the hybridized capillary retained fluore-scence. Fluorescent signal was measured using an ICCD
camera imaging system and represent peak fluorescent intensities. The signal to noise ratio would -be » 1000 fold if the entire fluorescent signal area was integrated.
This demonstrates a method for-increasing signal to noise ratios and thus the dynamic range of the assay.
Example 5: F-lectronicallv Addressab~P Locations on Metal Substrates Aluminum (A1) and gold (Au) wire (0.25 mm, Aldrich) was reacted with 10% 3-aminopropyltriethoxysilane (APS) in toluene. The APS reagent reacts readily with the oxide and/or hydroxyl groups on the metal surface to form cova-lent bonds between the oxide and/or hydroxyl groups and the primary amine groups. No pretreatment of the aluminum was necessary. The gold wire was subjected to electrolysis in 5 x SSC solution to form an oxide layer. Alternatively the metal wire can be oxidized by a perchloric.acid bath.

WO 95112808 PCTfUS94112270 The APS reaction was performed as follows: Wires were cut to-3 inches and placed in a glass dish. Toluene was added to completely cover the wires and the tempera-ture was brought to 50-60 °C on a heat plate. APS was 5 added to a final concentration of 100. Mix solution and continue the reaction for 30 minutes. Rinse 3 times with copious volumes of toluene, then rinse 3 times with copious volumes of alcohol and dry.in=50°C oven. The APS
treated wire can then be reacted with an aldehyde to form 10 a Schiff's base. Binding entity ET12R was periodate oxidized as described elsewhere. The electrodes were placed in a reservoir of-degassed water: Power was applied at .05 mA constant for about 30 seconds. Activated ET12R
was immediately added. .Power was applied, the liquid was 15 aspirated and fresh water was added and then aspirated again. The test (biased positive) and reference elec-trodes were -placed in Hybridization Buffer (HB, 5XSSC, 0.1o SDS) containing fluorescent labeled complement DNA, ET10-TR. After 2 minutes the electrodes were washed three 20 times for one minute each in Wash Buffer (1 x SSC, 0.1's SDS) and observed by fluorescence (ex. 590 nm, em.
610 nm).
Results demonstrate that ET12R was specifically coupled to the treated metal-surfaces. The test electrode 25 was fluorescent while the reference electrode was not.
Nonspecific adsorption of the DNA to the metal was prevented by the presence of SDS in the Hybridization Buffer. Attachment to gold substrates by electrolysis and subsequent APS treatment was effective. Signal obtained 30 was significantly stronger than observed with non-oxidized gold. More importantly, this example showed that the metal surfaces could be chemically functionalized and derivatized with a binding entity and not become insulated from the solution. The APS method represents one of many 35 available chemistries to form DNA-metal conjugates.

,.L17.~~~83 Example 6. Electron~ca~TV Controlled Fluore~~Pnr D~te_ Detection Process - Metal Wire DNA-aluminum electrode substrates were prepared and hybridized as described in Example-5. A hybridized and an ' unhybridized DNA-A1 electrode were processed with an underivatized A1 wire as the reference. EB was added to the solution and the test DNA electrodes were biased negative to attract the dye. The solution was aspirated and fresh buffer was added.- The metal surfaces were examined under the microscope.
Remount the device and apply a positive potential for a defined volt-hour. -The buffer was aspirated, the elec-trodes were observed by epifluorescence. This was repeated until -there was a significant difference in fluorescence between the hybridized and unhybridized metal surfaces.
Capture Target Normalized Signal ET12R ET10AL (Pos.) >140 ET12R None (Neg.) 1 Fluorescence _at the unhybridized metal surfaces diminished while the hybridized metal surfaces retained fluorescence. Fluorescent signal was measured using an ICCD camera imaging system and represent peak-fluorescent intensities. The signal to noise ratio would be »1000 fold if the entire fluorescent signal area was integrated.
This example-demonstrates a method for increasing signal to noise ratios and thus the dynamic range of the assay.
Similar results were obtained using capillary gel configu-ration, suggesting that electrochemical effects do not significantly affect the performance of the assay.
Example 7: Active Proarammable Electron~~ Matrix (APEX) - Micro-machine Fabri ation A radial array of 6 addressable 250 um capillary locations was micro-machined. The device has a common upper reservoir and separate lower reservoirs such that 217 ~ ~ $ 3 pCT~S94I12270 R'O 95112808 the potential at each micro-location is individually addressable. A uniqueoligomer binding entity is localized and coupled to a specific capillary micro-location by the methods described elsewhere. The test micro-location has a positive potential while the other micro-locations have negative potentials to prevent nonspecific interactions.
The array ie washed and then hybridized with a complementary fluorescently labeled DNA probe. The array is washed to remove excess probe and then observed under an epifluorescent microscope. Only the specifically addressed micro-location will be fluorescent. The process will be repeated with another binding entity at another location and verified by hybridization with a probe labeled with another fluorescent moiety.
DNA sequences are specifically located to predeter-mined positions with negligible crosstalk with the other locations. This enables the fabrication of micromatrices with several to hundreds of unique sequences at predeter-mined locales.
Example 8: Active Procrrammable Electronic Matrix _(APEX) Microlithoaraphic Fabrication An 8 X 8 matrix of 50um square aluminum electrode pads on a silicon wafer (see Figure 3) was designed, fabricated and packaged with a switch box (see Device Fabrication Section far details). Several materials and process improvements, as described below, were made to increase the selectivity and effectiveness of the chip.
ea) Selection of Topcoat The APS process involves the entire chip. Selecti vity of the functionalization process was dependent on the reactivity of the chip surfaces. In order to reduce func tionalization and subsequent DNA attachment of the areas surrounding the micro-locations, a material that is less reactive to APS than SiO, or metal oxide is needed. Photo wo 9snzsos rcart~s9anzi~o ~1~'~~~~
~m resists and silicon nitride were- tried. - The different topcoats were applied to silicon dioxide chips. The chips were examined by epifluorescence and the then treated with APS followed by covalent attachment of periodate oxidized ' polyA RNA sequences (Sigma, MW 100,000). The chips were hybridized with 200 nM solution of Texas Red labeled 20 mer (T2-TR) in Hybridization Buffer, for 5 minutes at 37°C.
The chips were washed 3 times in WB and once-in 1 x SSC.
The chips were examined by fluorescence at 59D nm excita tion and 610 nm emission.
Silicon nitride was chosen because it had much less reactivity to APS relative to silicon dioxide and was not inherently fluorescent like the photoresist tested. Other -methods such as W burnout of the background areas are also possible.
8b) APEX Phvsical Characterization A finished matrix chip was visually examined using a Probe Test Station (Micromanipulator Model 6D00) fitted with a B & L microscope and a CCD camera. The chip was tested for continuity between the test pads and the outer contact pads. This was done-by contacting the pads with the manipulator probe tips which were connected to a multimeter. Continuity ensures that the pads have been etched down to the metal surface. The pads were then checked for stability in electrolytic environments. The metal wires were rated to handle up to 1 mA under normal dry conditions. However, reaction to a wet environment was unknown. A drop (1-5 ~l) of buffered solution (1 x SSC) was pipetted onto the SXS matrix. Surface tension keeps the liquid in place Zeaving the outer contact pad area dry. A probe tip was contacted to a contact pad and another probe tip was contacted with the liquid. The current was incremented up to 50 nA at max voltage of 50 V using a HP 6625A power supply and HP3458A digital multimeter.

PCT/US94112f70 _ The initial fabrication consisted of the silicon substrate, a silica dioxide insulating layer, aluminum deposition and patterning, and a silicon nitride topcoat.
These chips were not very stable in wet environments because the metal/nitride interface was physical in nature and electrolysis would undermine the nitride layer. This would result in the pads being electrically shorted.
Furthermore, silicon nitride and A1 have different expan-sion coefficients such that the nitride layer would crack when current was applied. This would allow.solution to contact the metal directly, again resulting in electrol-ysis which would further undermine the layer.
The second fabrication process included a silicon dioxide insulating layer between the aluminum metal and silicon nitride layers. Silicon dioxide and A1 have more compatible physical properties and form a better chemical interface. to provide a more stabile and robust chip.
8c) DNA Attachment A matrix chip was functionalized with APS reagent as described in Example 5. The chip was then treated with periodate oxidized polyA RNA (Sigma, average MW 100,000).
The chip was washed in WB to remove excess and unbound RNA. This process coated the entire chip with the capture sequence with a higher.. density at the exposed metal surfaces than at the nitride covered areas. The chip was hybridized with a 200 nM solution of T2-TR in HB for 5 minutes at 37°C. Then washed 3 times in WB and once in 1XSSC for one minute each at ambient temperature. The chip was examined by fluorescence at 590 nm excitation and 610,nm emission.
The opened metal areas were brightly fluorescent and had the shape of the pads. how fluorescent intensities and/or irregular borders would suggest that the pads were not completely opened. Additional plasma etch times would be recommended.

211 ~ ~~~
8d) ~lectronicallv Controlled Hybridization Active hybridization was performed by using a chip from Example 8c and biasing one micro-location positive.
This was done by using the switch box which would also 5 automatically bias the remaining micro-locations negative or by using an external solution electrode. Three micro-liters of water was deposited on the matrix pads only. A
current, -1-5 nA, was applied for several seconds and 0.1 pmole of T2-TR was added to tYie solution. The liquid was 10 removed and the chip was dried and examined - by fluorescence at Texas Red wavelengths (ex.590 nm, em.610 nm) .
Only the positively biased micro-location was fluorescent. This can be repeated many times to hybridize 15 other micro-locations selectively. Additionally, the fluorescence DNA at one micro-location can be translocated to another micro-location by biasing the initial location negative and the destination positive.
Se) Electronically Controlled Addressincr and Device 20 Fabrication The matrix was functionalized with APS as described above. Binding entity CP-1 was activated by periodate oxidation method. Four micro-locations were biased post-tive in the matrix and the remainder were biased negative.
25 Two microliters of water was deposited on the matrix and a current was applied. Binding entity, CP-1, was added and allowed-to concentrate atthe designated locations.
The liquid was removed, the chip was rinsed briefly with water and two microliters of-water was deposited on the 30 chip. Again, current was- applied for several seconds and 0.1 pmole of T2-TR was added. The liquid was removed after a short time and the entire chip was washed in-WB, ' 3 times. The chip was -dried and examined for fluorescence.

PCTlUS94J12270 Results indicate that the positively biased micro-locations were fluorescent. This example demonstrates the selective addressing of micro-locations with a specific binding entity, the localization and covalent coupling of sequences to the micro-locations, and the specific hybridi-zation of complementary target sequences to the deriva-tized micro-locations.
8f) Genetic Tvnina APEX Chip DNA binding entities with 3' ribonucleoside termini are synthesized which are specific for the polymorphisms of HLA gene dQa. The binding entities are activated by periodate oxidation as described above. The reverse complements are also synthesized with 5' amino termini and are conjugated with fluorophores, such as Texas Red, Rhodamine or Bodipy dyes, as described elsewhere. The micro-locations are functionalized with primary amines by treatment with APS, as described elsewhere. A couple microliters of solution are placed over the matrix but leaving the contact pads dry. A specific micro-location is addressed by biasing that micro-location positive, the periodate oxidized DNA oligomer is added, -0.1 pmole, and is translocated and covalently coupled to that location.
The polarity is reversed and the unbound binding entity molecules are removed. - This is repeated for another binding entity at another addressed micro-location until all the unique binding entities are bound to the chip.
The chip is then hybridized to individual fluorescently labeled complement sequences to determine the specificity of the coupling reaction as well as en masse to visualize all addressed micro-locations at once. On the same chip which is denatured to remove complementary oligomers (10 minutes at 90°C in 0.05% SDS), the addressed micro-locations are hybridized with unlabeled reverse comple-menu or-genomic DNA. Detection is via the fluorescent dye detection assay as described elsewhere.

wo 9snasos rcTrus9anza~o Results will demonstrate that micro-locations are specifically addressed with -unique binding- entities.
Nonspecific binding to negatively biased micro-locations will be negligible. The device and associated binding entity chemistry is stable under denaturation conditions, thus making the addressed and fabricated device reusable.
Alternative methods for denaturing the hybrids would be to increase the current and/or increase the time it is applied.
Example 9: Electronic Btrinaencv Control The ability of the device to affect electronic stringency-control is demonstrated with the Ras oncogene model system. A single -base pair mismatch adversely affects the melting temperature (Tm), a measure of the stability of theduplex. -Traditianal methods to discrimi-nate between mismatch and perfect match (i.e., stringency control) rely on temperature and salt conditions. Strin-gency can also be affected by the electrophoretic poten-tial. Oligomers listed below can be paired such that resulting hybrids have 0-2- mismatches. Oligomer binding entities are-coupled to the micro-location and hybridized as described elsewhere. The polarity at the micro-location is then reversed and the hybrids are subjected to constant current for a given time, or defined power levels to denature -the mismatch without affecting the perfect match.
Ras-G 5'- GGT GGT GGG CSC CG~ CGG TGT GGG CAA GAU =3' Ras-1 3'- CC GAG GCS GCC-ACA C - Aminolink2 -5' Ras-2 3' - CC GAG GCS GCC ACA C - Aminolink2 -5' Ras-3 3' - CC GAG GCS GCC ACA C - Aminolink2 -5' Ras-T 5'- GGT GGT GGG CSC CGT CGG TGT GGG CAA GAU -3' Microelectrodes are fabricated fro m microcapillary tubes as described elsewhere.-Binding entities Ras-G is periodate to the addressed oxidized and covalently bound micro -location. Ras-G micro=location-is then hybridized with Ras-1-TR which is-the perfect match, Ras-2-TR which is a one base pair mismatch (G-A) or Ras-3-TR which is a two base pair mismatch (G-A and G-T). The micro-locations are examined fluorescently to verify whether complementary sequences are hybridized and to what extent. The micro-capillaries are re-mounted and subjected to controlled time at constant current until the mismatched hybrids are removed without significantly affecting the perfectly matched hybrids.
Results will indicate that stringency could be affected by the electrophoretic potential. This example demonstrates that each micro-location can have individual stringency control, thus overcomes a major obstacle to large scale parallel processing techniques which had been limited to a single common stringency level.

Claims (62)

CLAIMS:
1. An electronic device adapted to receive a solution including electrolytes and one or more charged specific binding entities, the device comprising:
a substrate, a selectively addressable electrode, the electrode being supported by the substrate, the electrode being adapted to receive current, a permeation layer which provides preferential passage from the solution to the electrode of the electrolytes relative to the charged specific binding entities and permits free transport of ions through the permeation layer to permit an electrophoretic transport of the specific binding entities, the permeation layer being disposed adjacent a first selectively addressable electrode, and an attachment layer adjacent the permeation layer.
2. The electronic device of claim 1, further including a second selectively addressable electrode, which is supported by the substrate, the selectively addressable electrodes being insulated from one another prior to the application of the solution.
3. The electronic device of claim 1, wherein the substrate includes a base and an overlying insulator.
4. The electronic device of claim 1, wherein the substrate is made of a material chosen from the group consisting of silicon, glass, silicon dioxide, plastic, resist, rubber and ceramic.
5. The electronic device of claim 3, wherein the base is made of a material chosen from the group consisting of silicon, glass, silicon dioxide, plastic, resist, rubber and ceramic.
6. The electronic device of claim 3, wherein the base is made of silicon.
7. The electronic device of claim 3 or 6, wherein the insulator is silicon dioxide.
8. The electronic device of any one of claims 1 to 7, wherein the substrate comprises a circuit board.
9. The electronic device of claim 2, wherein the first selectively addressable electrode and the second selectively addressable electrode are separated by an insulator supported by the substrate.
10. The electronic device of claim 9, wherein the insulator is made of a material chosen from the group consisting of silicon dioxide, plastic, glass, resist, rubber and ceramic.
11. The electronic device of claim 9, wherein silicon nitride is disposed upon the insulator.
12. The electronic device of any one of claims 1 to 11, further including a current source.
13. The electronic device of claim 12, wherein the current source is a direct current source.
14. The electronic device of claim 13, wherein the direct current source is operated in a pulse mode.
15. The electronic device of claim 13, wherein the direct current source is operated in a continuous mode.
16. The electronic device of any one of claims 1 to 15, wherein the permeation layer is aminopropyltriethoxy silane.
17. The electronic device of any one of claims 1 to 15, wherein the permeation layer is made of a material selected from the group consisting of functionalized hydrophilic gels, membranes and porous materials.
18. The electronic device of any one of claims 1 to 15, wherein the permeation layer reduces the electrochemical effects resulting from electrolysis at the electrode on the specific binding entities.
19. The electronic device of any one of claims 1 to 18, wherein the attachment layer is adapted for attachment of the specific binding entity.
20. The electronic device of claim 19, wherein the attachment of the specific binding entity to the attachment layer is covalent.
21. The electronic device of claim 19, wherein the attachment of the specific binding entity to the attachment layer is non-covalent.
22. The electronic device of any one of claims 1 to 15, wherein the permeation layer and the selectively addressable electrode are separated by a buffer reservoir.
23. The electronic device of any one of claims 1 to 22, wherein the electrode is chosen from the group consisting of aluminum, gold, silver, tin, copper, platinum, palladium, carbon, semiconductor materials, and combinations thereof.
24. The electronic device of any one of claims 1 to 23, wherein the electrode is round.
25. The electronic device of any one of claims 1 to 7, wherein the substrate comprises a printed circuit pattern.
26. The electronic device of any one of claims 1 to 25, further including one or more un-addressed microlocations or electrodes.
27. An electronic device adapted to receive charged analytes comprising:

a substrate, a plurality of selectively addressable electrodes, the electrodes being disposed upon the substrate, a current source, electrical connections to the electrodes, the electrical connections providing a selective current path from the current source, and a permeation layer adjacent to each electrode which permits electrophoretic transport of charged analytes disposed upon the device, forming addressable binding locations.
28. The electronic device of claim 27, further comprising a switch controller for selectively connecting the current source to said addressable electrodes.
29. The electronic device of claim 27 or 28, further comprising an attachment layer disposed on the permeation layer, forming addressable binding locations.
30. The electronic device of any one of claims 27 to 29, wherein the electrodes are made of a material chosen from the group consisting of aluminum, gold, silver, tin, copper, platinum, palladium, carbon, semiconductor material, and combinations thereof.
31. The electronic device of any one of claims 27 to 30, further including an electronic insulative material disposed between the plurality of selectively addressable electrodes.
32. The electronic device of any one of claims 27 to 31, wherein the addressable binding locations are arranged in an array.
33. The electronic device of any one of claims 27 to 32, further including a cavity for holding a solution including binding entities, reagents and analytes.
34. The electronic device of any one of claims 27 to 33, further including specific binding entities bound to the addressable binding locations.
35. The electronic device of any one of claims 27 to 34, wherein the binding locations have a width on the device of between 0.5 microns and 200 microns.
36. The electronic device of any one of claims 27 to 35, wherein the electrodes have a width on the device of between 5 microns and 100 microns.
37. The electronic device of any one of claims 27 to 36, wherein the permeation layer is made of a material selected from the group consisting of functionalized hydrophilic gels, membranes and porous materials.
38. The electronic device of any one of claims 27 to 37, wherein the current source is a direct current source.
39. The electronic device of claim 38, wherein the direct current source is operated in a pulse mode.
40. The electronic device of claim 38, wherein the direct current source is operated in a continuous mode.
41. An electronic device comprising:

a substrate, a plurality of selectively addressable electrodes, the electrodes being disposed upon the substrate, a current source for providing a selective current for the electrodes, individual buffer reservoirs associated with the electrodes, and individual permeation layers disposed adjacent the individual buffer reservoirs, forming addressable binding locations.
42. The electronic device of claim 41, further comprising a common reservoir for containing solutions including binding entities, reagents, and analytes.
43. The electronic device of claim 41 or 42, further comprising an attachment layer disposed on said permeation layer, forming addressable binding locations.
44. The electronic device of claim 41, 42 or 43, wherein the addressable binding locations are arranged in an array.
45. The electronic device of any one of claims 41 to 44, wherein the permeation layer is made of a material selected from the group consisting of functionalized hydrophilic gels, membranes, and porous materials.
46. The electronic device of any one of claims 41 to 45, further including specific binding entities bound to the addressable binding locations.
47. The electronic device of any one of claims 41 to 46, wherein the electrodes are separated from each other at a distance of between 50 microns and 2 centimeters.
48. The electronic device of any one of claims 41 to 47, wherein the addressable binding locations are separated from each other on the device at a distance of between 100 microns and 5 millimeters.
49. The device of any one of claims 1 to 26, further including a system for detecting fluorescent or colorimetric binding reactions and assays, comprising:
a detector system positioned adjacent the selectively addressable electrode.
50. The device of claim 49, wherein the detector is an optoelectronic detector chosen from the group consisting of a photodiode, an avalanche photodiode, and a photomultiplier tube.
51. The device of claim 49, wherein the detector is an optoelectronic imaging detector chosen from the group consisting of a charged coupled device, a cooled charged coupled device, an intensified charged coupled device, and a microchannel device.
52. The device of claim 49, wherein the detector is capable of detecting emission of fluorescent radiation.
53. The device of claim 49, wherein the detector is capable of detecting absorption of spectrophotometric radiation.
54. An electronic device for a controlled multi-step or multiplex reaction using an aqueous solution containing (1) a charged biological or synthetic binding entity having a specific affinity to another molecule and (2) a small counter ion for the charged binding entity, which comprises:
a substrate; and an array of electronically self-addressable microscopic locations, each comprising:

(a) an underlying working direct current (DC) microelectrode supported by the substrate;

(b) an intermediate permeation layer over a surface of the microelectrode, the permeation layer allowing passage of water, the small counter ion and electrolysis gases selected from Oz and Hz but having a pore limit property which inhibits the charged binding entity from a physical contact with the microelectrode; and (c) an outer attachment layer on the permeation layer to which the charged binding entity attaches when the aqueous solution comes in contact with the device and the microelectrode is in a DC mode.
55. The device according to claim 54, which further comprises:
boundaries separating the electronically self-addressable microscopic locations from each other, each boundary comprising a SiO2 layer on the substrate and an Si3N4 layer on the SiO2 layer.
56. The device according to claim 54 or 55, wherein each electronically self-addressable microscopic location also comprises:

(d) a metal oxide layer directly sandwiched by the microelectrode and the intermediate permeation layer.
57. The device according to claim 56, wherein the metal oxide layer has been treated with aminopropyltriethoxy silane (APS) to form both the permeation layer and the attachment layer, whereby the attachment layer has an amino group for attaching to the charged binding entity.
58. The device according to claim 54 or 55, which further comprises:

a chamber for receiving a buffer solution when in use, the chamber separating the microelectrode from the permeation layer.
59. The device according to claim 58, wherein the permeation and attachment layers are together formed of a functionalized porous material.
60. The device according to claim 59, wherein the porous material is hydrophilic gel or membrane.
61. The device according to claim 59, wherein the functionalized porous material is polyacrylamide gel containing polylysine.
62. The device according to any one of claims 54 to 61, wherein the microscopic locations each have a size of 5 µm to 5 mm;

the intermediate permeation layer has a thickness of 1 nm to 10 µm; and the attachment layer has a thickness of 0.5 nm to 1 µm.
CA002175483A 1993-11-01 1994-10-26 Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics Expired - Fee Related CA2175483C (en)

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US08/146,504 US5605662A (en) 1993-11-01 1993-11-01 Active programmable electronic devices for molecular biological analysis and diagnostics
US08/146,504 1993-11-01
PCT/US1994/012270 WO1995012808A1 (en) 1993-11-01 1994-10-26 Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics

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