CA2337155A1 - Sensor arrays for the measurement and identification of multiple analytes in solutions - Google Patents

Sensor arrays for the measurement and identification of multiple analytes in solutions Download PDF

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Publication number
CA2337155A1
CA2337155A1 CA002337155A CA2337155A CA2337155A1 CA 2337155 A1 CA2337155 A1 CA 2337155A1 CA 002337155 A CA002337155 A CA 002337155A CA 2337155 A CA2337155 A CA 2337155A CA 2337155 A1 CA2337155 A1 CA 2337155A1
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Prior art keywords
particle
cavity
supporting member
sensor array
fluid
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CA002337155A
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French (fr)
Inventor
John T. Mcdevitt
Eric V. Anslyn
Jason B. Shear
Dean P. Neikirk
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University of Texas System
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00279Features relating to reactor vessels
    • B01J2219/00306Reactor vessels in a multiple arrangement
    • B01J2219/00313Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315Microtiter plates
    • B01J2219/00317Microwell devices, i.e. having large numbers of wells
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00646Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports
    • B01J2219/00648Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports by the use of solid beads
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00659Two-dimensional arrays
    • CCHEMISTRY; METALLURGY
    • C40COMBINATORIAL TECHNOLOGY
    • C40BCOMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B60/00Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00Chemistry: molecular biology and microbiology
    • Y10S435/808Optical sensing apparatus
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00Chemistry: molecular biology and microbiology
    • Y10S435/973Simultaneous determination of more than one analyte
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00Chemistry: analytical and immunological testing
    • Y10S436/80Fluorescent dyes, e.g. rhodamine
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00Chemistry: analytical and immunological testing
    • Y10S436/805Optical property
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00Chemistry: analytical and immunological testing
    • Y10S436/807Apparatus included in process claim, e.g. physical support structures
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00Chemistry: analytical and immunological testing
    • Y10S436/807Apparatus included in process claim, e.g. physical support structures
    • Y10S436/809Multifield plates or multicontainer arrays
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/25Chemistry: analytical and immunological testing including sample preparation

Abstract

A system for the rapid characterization of multi-analyte fluids, in one embodiment, includes a light source, a sensor array, and a detector. The sensor array is formed from a supporting member into which a plurality of cavitites may be formed. A series of chemically sensitive particles microspheres are, in one embodiment positioned within the cavities. The particles may be configured to produce a signal when a receptor coupled to the particle interacts with the analyte. Using pattern recognition techniques, the analytes within a multi-analyte fluid may be characterized.

Description

CA 02337155 2002-Ol-16 T1:TLE: SENSOR ARRAYS FOR THE ~tSUREMF~1T AND IDENTIFICATION OF MIILTIpLE
ANALYTES IN SOLIJTiONS
STATE1~NT REGARDING FEDERALLY SPONSORED

Research leading to this invention was federally, supporoed, in part, by giant No. I R01 GM57306-01 entitled "The Development of an Electronic Tongae" fmm the National Institute of Health arid the U.S.
Government has certain rights to this invention.
BACKGROUND OF THE I~NTION
1. Fkld of the Invention The present invention relates to a method sad device for the de~axioa of aaalytes in s fluid. Morn psrticolarly, the invention celatea to the devebptment of a sensor array system capabk of discriminating mixdaes of analyses, toxins, and/or bacteria in medical, food/bevorage. ~1 environmental aoIutioos.
2. Brief Description of the Related Art The development of smart sensors cspoble of discriminating different analyoes, toxins, sad bacteria has become increasingly important for clinical, envitnnmaatal, health and safety, remote ceasing, military, foodlbeverage and chemical processing applisxtions. Although many sensors capabk of high senaidv'rty sad high xlectivity detection have been fashioned f~ siagk aaalyte dete~ioa, only in a few aekcted cases have srlay sensors barn prepared which display solution phase mahi-analyse detection capabilities. The advantages of arch away systems are their utility for the analysis of mnttiple analyses and their ability to be "trained" to rapoad to new at~li. Such on site adaptive aaalysia capsbititia afforded by the array stmcd~res make their utilization promising for a variety of future applications. Artay based sensors displaying the capacity to sense and identify complex vapor have been demonstrated recently using a aumb~ of distinct t:a~Ction ache. For example, functional sensors based on Surface Acoustic Wave (SAW), tic oxide (snow sensors, conductive organic polymers, and carbon blackfpolymer composites have been fashioned. T1u use of tin oxide sensors, for example, is described in U.S. Patent No. 5,654,497 to Hoflheins et al. These sensors display the capacity to identify and discriminate between s variety of organic vapors by virtue of small site-to-site diffetaaca is response characterlstica. Pattern recognition of the overall fiagecprint response for the spray setvea as the basis for as olfaction-like detection of the vapor phase analyse species. Indeed, several com~cial "electronic noses" have been developed recently, Most of the well established sensing elements are based on SaO~ arrays which have been derivatized so as to yield chemically distinct response properties. Arrays based on SAW crystals yield exueauly sensitive responses to vapor, however, engiueeriag challenges have prevented the ctention of large SAW.arrsys having multiple sensor sites. To our lrnowledge, the largest SA W device reported to date possesses only s 2 sensor elements. Additionally, limited chemical diversity sad the lack of understanding of the molecular fesaues of such systems makes their expansion into more complex analysis difficult.

CA 02337155 2002-Ol-16 3'f2 PCT/US99116162 Other structures have been developed that are capable of identifying and discriminating volatile organic molecules. One saucture involves a aeries of conductive polyttxr layers deposited onto metal contacting layers.
When these sensors ue exposed to volatile reagents, some of the volatile reagents adsorb into the polymer layers, lesding to small changes in the electrical resistance of these layers. It is the small differences in the behavior of the various sites that allows for a discrimiastio4 identification, and quantification of the vapors. The dettretion process takes only a few seconds, and sensitivities of part-per-billion can be achieved with this relatively simple approach.
This "electronic none" system is described in U.S. Patent No. 5,698,089 to Lewis et al. which is incorporated by reference as if set forth herein.
Although the above described el~tronic nox provides an impressive capability for monitoring volatile reagents, the system possesses a mmnber of undesirable characteristics that warrant the development of alternative sensor array systems. For example, the electronic nose can be used only for the identification of volatile reagents.
For many environmental, military, akdical, and commercial applications, the identification and quantification of analyzes gre~nt in liquid or solid-phase samples is necessary. Moreover, the electronic nose systerrrs are expansive (e.g., the Aromascan system costs about 550,000/unit) and bulky (> lft3).
Furthen~ore, the functional elements for the currently available electronic nose are composed of conductive polymer systems which possess little chemical selectivity for many of the analyzes which are of interest to the military and civilian communities.
One of the most commonly employed sensing techniques has exploited colloidal polymer microspheres for latex agglutination tests (1:.ATs) in clinical analysis. Com~cially available LATs for more than 60 analyzes are used routinely for the detection of infectious diseases, illegal drags, and early pregnancy teat. The vast mtljotity of these types of sensors operate on the principle of agglutination of latex particles (polymer microspherea) which occtas when the antibody-derivatized micmspheres become effectively "cross-linked" by s foreign antigen resulting in the attachment to, or the inability to pass through a filter. The dye-doped microspheres are then detxted colorimetrically upon removal of the antigen carrying solution.
However, the LATs lack the ability to be utilized for multiple, real time analyte detection schemes as the nature of the response intrinsically depends on a cooperative effect of the entire collection of microspheres. .
Similar to the electronic nose, array sensors that have shown great analytical promise are those based on the "DNA on a chip" technology. These devices possess a high density of DNA
hybridization sites that are affixed in a two-dimensional pattern on a planar substrate. To generate nucleotide sequence infornnation, a pattern is created from unknown DNA fragments binding to various hybridization sites.
Both radiochemical and optical methods have provided excellent det~tion limits for analysis of limited quantities of DNA. (Stimpson, D. L;
Hoijer, J. V.; Hsieh, W.; Jou, C.; Garden, J.; Theciault, T.; Gamble, R;
Baldcachwieler, J.D. Proe. Natl. Acad. Sci.
USA 1995, 92, 63T9). Although quite promising for the detection of DNA
fragments, these arrays arc generally not designed for non-DNA molecules, and accordingly show very little sensitivity to smaller organic molecules.
Many of the target molecules of interest to civilian sad military communities, however, do not possess DNA
components. Thus, the need for a flexible, non-DNA based se~or is still desired. Moreover, while a number of prototype DNA chips containing up to a few thousand different nucleic acid probes have been described, the existing technologies tend to be difficult to expand to a practical size. As a result, DNA chips may be prohibitively expensive for practical uses.
A system of analyzing fluid samples using an array formed of heterogeneous, semi-selective thin films CA 02337155 2002-Ol-16 wo ooro43n pcrros~nm6z _ which function as sensing receptor units is described in U.S. Pattat No.
5,512,490 to Walt et al., which is incorporated by reference as if set forth herein. Walt appears to describe the use of covalently attached polymeric "cones" which are grown via photopolymerization onto the distal face of fiber optic bundles. These sensor probes appear to be designed with the goal of obtaining unique, continuous, and reproducible responses from small localized regions of dye-doped polymer. The polymer appears to serve as a solid support for indicator molecules that provide information about test solutions through changes in optical properties. These polyrtxr snpporoed sensors have been used for the detection of amilytas such as pH, metaht, and specific biological entities. Methods for mannfscturiag large numbers of rtproducible season, however, ha: yet to be developed. Moreover, no methods for acquisitions of data streams in a simti>vaeous meaner are commercially avsihible with this system.
Optical alignment issues may also be problematic for throe systems.
A method of rapid sample analysis for use is the diagnostic microbiology field is also desirable. The techniques now used for rapid microbiology diagnostics detect either antigens or nucleic acids. Rapid antigen testing is based an the use of antibodies to recognize either the single cell organism or the presence of infected cell material. Inherent to this approach is the need to obtain and characterize the binding of the antibody to unique atructur~s on the organism being tested. Since the identification sad isolation of the appropriate antibodies is time conaaning, these oechniques are limited to a single agent per testing module and there is no opportunity W evsbuue the amount of agent present.
Most antibody methods are relatively insensitive sad require the presence of 10' to 10~ organisms. The response time of antibody-antigen reactions in diagnostic fasts of this type ranges from 10 to 120 minutes, depending on the method of detection. The fastest methods are generally agglutination ructions, but these methods are leas sensitive due to ditliculties in visual interpretation of the reactiom. Approaches with slower reaction times include a~igen recognition by antibody conjugated to either an enzyme or chromophore. These test types tend to be more sensitive, especially whoa Spectroptioto~ic methods are used to determine if an antigen-antibody reaction has occurred. These detection schemes do not, however, appear to allow the simnltaneoua detection of multiple analytes on a single detector platform.
The alternative to antigen detection is the detection of twcleic acids. An approach for diagnostic testing with nucleic acids uses hybridization to target unique regions of the target organism. These techniques require fewer organisms ( l0' to 10~, but require about five hours to complete. As with and'body-antigen reactions this approach has not boert devclopod for the simultaneous detection of multiple aaalytes.
The moat recent improvement in the detection of microorganisms has been the use of nucleic acid amplification. Nucleic acid amplification tests have been developed that generate both qualitative and quantitative data. However, the current limitations of these testing methods are related to delays caused by specimen ptrparat9oa, amplification, sad detection. CStrready, the standard assays require about five hours to complete. The ability to complete much faster detection for a variety of microorganisms would be of tremendous importance to military intelligence, national safety, medical, environmental, and food areas.
It is therefore desirable flat new sensors capable of discriminating different saalytes, toxins, and bacteria be developed for medical/clinical diagnostic, environmental, health and safety, remote sensing, military, foodlbeverage, and chemical processing applications. It is fiatlter desired that the sensing system be adaptable to CA 02337155 2002-Ol-16 the simultaneous detection of a variety of aualyDes to improve throughput during various chemical and biological analytical procedures.
SZJNflVIARY OF THE INVENTION
Herein we describe a system and method for the analysis of a fluid containing one or more analyzes. Tlu syaroem rosy be used for either liquid or gaseous fluids. The system, in some embodunents, may gentrate patterns that are diagrmstic for both the individual analyzes and mixtures of the analyzes. The system in some embodiments, is made of a phu~aGty of chemically sensitive particles, formed in an ordered array, capable of simultaneously detecting many different kinds of analytea rapidly. An aspect of the system is that the array may be formed using a microfabricatioa process, thus allowing the system to be manufactured in an inexpensive manner.
la an embodiment of a system for detecting analyoea, the system, in some embodimtnts, includes a light source, a sensor array, and a detector. The sensor array, in s~ embodiments, is formed of a supporting member which is configured to hold a variety of chemialty sensitive particles (herein referred to as "particles") in an ordered array. The particles are, in some embodiments, elements which will create a detectable signal in the presence of as analyze. The particles may produce optical (e.g., absorbence or reflectance) or fluottsceaceJphosphoresceat signals upon exposure to an analyze. Examples of particles include, but are not limited to Ctmctionalized polymeric beads, agamua beads, dextrose beads, polyacrylamide beads, control pore glass beads, metal oxides particles (e.g., silicon dioxide (SiO~ or aluminura oxides (Al=O~), polymer thin Ethos, metal quantum particles (e.g., silver, gold, platinum, ac.), and semiconductor quantum particles (e.g., Si, Ge, G8As, ere.). A detector (e.g., a charge-coupkd device "CCD'~ is one embodiareat is positioned below the sensor array to allow for the data acquisition. In aaotber embodiment, the detector may be positioned above the sensor array to allow for data acquisition frown reflec4ace of dte light otf of the particles.
Light originating from the light source may pass through the aenaar array sad out through the bottom aide of the sensor array. Light modulated by the particles may pass through the sensor array and onto the proximally spaced detector. Evaluation of the optical changes may be completed by visual inspection or by use of a CCD
detector by itself or in combination with an optical microscope. A
microprocessor may be coupled to the CCD
detector or the microscope. A fluid delivery system may be coupled to the supporting member of the sensor array.
The fluid delivery system, in some embodiaoents, is configured to introduce samples into and out of the sensor amy.
In an embodirneat, the sensor array system includes an array of particles. The particks may include a receptor molecule coupled to a polymeric bead. The receptors, in some embodiments, are chosen for interacting with analyzes. This interaction may take the form of a binding/association of the receptors with the analyzes. The supporting member may be made of any material capable of supporting the particles, while allowing the passage of the appropriate wavelengths of light. The supporting member may include a phu~ality of cavities. The cavities may be formed such that at least one particle is substantially contained within the cavity.
la an embodiment, the optical detector may be integrated within the bottom of the supporting member, rather than using a separate detecting device. The optical detectors may be coupled to a microprocessor to allow evaluation of fluids without the use of separate detecting components.
Additionally, a fluid delivery system may CA 02337155 2002-Ol-16 also be incorporated into the supporting number. Integration of detectors and a fluid delivery system into the supporting member may allow the formation of a compact and portable saslyte sensing system.
A high sensitivity CCD array may be used to ateasure changes in optical chsncteriatics which occur upon binding of the biologicaLchetaical sgeats. The CCD array: msy be interfaced with filters, light sources, fluid delivery sad aticromachined particle receptacles, so as to crests a functional sensor stray. Data acquisition and handling may be performed with existing CCD technology. CCD detectors may be configured to measure white light, ultraviolet light or fluorescence. Other detectors such as photoraultiplier tubes, charge induction devices, photo diodes, ph~odiode atssys, and microchannel plates may also be used.
A particle, in some embodiments, possess both the ability to bind the analyze of ituerest and to cnarte a modulated signal. The particle may include receptor molecules which posses the ability to bind the analyte of interest and to create a modulated aigttal. Altermtively, the particle may inchtde receptor molecules and indicators.
The receptor molecule may posses the ability to bind to an atutlyte o f interest. Upon binding the analyte of interest, the receptor tnokcule tray cause the indicator molecule to produce the modulated signal. The receptor molecules may be naturally occurring or synthetic t~ptone formed by rational design or combinatorial methods.
13 Sotne examples of aaAusl receptors include, but sre not limited to, DNA, RNA, pmtcins, enzymes, oligopeptides, antigens, sad antibodies. Either natural or synthetic recepwra may be chosen for their ability to bind to the aaalyte molecules in a specific manner.
In one embodiment, a naturally occurring or synthetic receptor is bound to a polynuric bead is order to create the particle. The particle, in sortx embodiments, is capable of both binding the analybe(a) of interest and . creating s detectable signal. In some embodiments, the particle will ctsate an optical signal when bourut to an anslytc of interest.
A variety of natural and synthetic receptors may be used. Tile synthetic receptors may costte fmm a variety of classes itxluding, but not limited to, polynuckotidea (e.g., aptamers), peptides (e.g., enzytnea and amibodies~ synthetic receptors, polymeric ututstursi biopolymers (e.g., polythioureas, polyguanidiniums), and ia>printed polymers. Polynucleoddes are relatively small fngttuab of DNA which may be derived by sequentially building the DNA sequence. Peptides include natural peptides such as antibodies or enzymes or may be synthesized fmm amino acids. Uunatunl biopolytacra are chetpical structure which are based on natural biopolymers, but which are built from unnatural licking units. For example, polythioureas and polyguanidiniums have a structure aitnilar to peptides, but may be synthesized froth diamines (i.e., compounds which include at least two amine functional groups) ether than amino acids. Synthetic receptors are designed organic or inorganic strucwres capable of binding various analytcs.
Is an embodiment, a large number of chenucaVbiological agents of interest to the military sad civilian commumtiea may be sensed readily by the described stray sensors. Bacteria may also be detected using a similar system. To detect, setae, and identify intact bacteria, the cell surface of one bacteria may be differentiated from other bacteria, or genomic material easy be detected using oligonucleic receptors. One method of aornmplishing this differentiation is to target cell surface oligossecharidea (i.e., sugar residues). The use of synthetic receptors which arc specific for oligosaccharides may be used to determiex the presence of specific bacteria by analyzing for cell surface oligosaccharides.

CA 02337155 2002-Ol-16 The above brief description as well as fiuther objects, features and advantages of the methods and apparatus of the present invention will be more fully appreciated by refueace to the following detailed description of presently preferred but nonetheless illustrative embodiments in accordance with the present invention when taken in conjunction with the accompanying drawings in which:
FIG. 1 depicts a xhetntttic of an aaslyte dctation system;
FIG. Z depicts s particle disposed in s cavity;
FIG. 3 depicts s sensor array;
FIG. 4A-F depicts the formation of a Fabty-Perot cavity on the back of a sensor array;
FIG. 5 depicts the chemical constituents of a particle;
FIG. 6 depicts the c6emicx! formulas of some receptor compotmds;
FIG. 7 depicts a plot of the absorbaace of green light vs. concentration of calcium (Ca'~) for a particle which includes an o-cresolphthaleia complexone receptor;
FIG. 8 depicts a schematic view of the a~ansfer of energy from a first indicator to a second indictor in the presence of as analyze;
FIG. 9 depicts a schematic of the interaction of a sugar molecule with s botonic acid based receptor.
FIG. 10 depicts various ayatltetic receptors;
FIG. I 1 depicts a synthttic pathway for the synthesis of polythiotueaa;
FIG. 12 depicts t synthetic pathway for the synthesis of polyguanidiniutns;
FIG. 13 depicts a synthetic pathway for the synthesis of diannina from amino acids;
FIG. 14 depicts fluorescent diammo monomers;
FIG. 15 depicts a plot of counta/sec. (i.e., intensity) vs. lime as the pH of a solution surroaading a particle coupled to o-cresolphthalein is cycled fmm acidic to basic conditions;
FIG. lti depicts the color responses of a variety of atnaing particles to solutions of Ca" and variaua pH
levels;
FIG. 17 depicts an analyte detection system which includes a sensor array disposed within a chamber;
FIG. 18 depicts an integrated analyze detection system;
FIG. 19 depicts a cross-sectional view of a cavity covered by a mesh cover;
FIG. 20 depicts a top view of a cavity coveted by a ateah cover;
FIG. 21 A-G depicts a crosraectioaal view of a aeries of processing steps for the formation of s aemor array which inchuiea a removable top and bottom cover;
FIG. 22A-G depicts a cross-sectional view of a aeries of processing sups for the formation of a sensor array which includes s removable top and a stationary bottom cover;
FIG. 23A-G depicts a cross-sectional view of s series of processing steps for the fottaatioa of a sensor stray which includes a removable top;
FIG. 24A-D depicts a crosrsectioaal view of a series of processing steps for the formation of s silicon based sensor array which includes a top and bottom cover with openings aligned with the cavity;
FIO. 25A-D depicts a cross-sectional view of a aeries of proceaavtg steps for the foranstion of a pho~iat based sensor stray which includes a top and bottom cover with openings aligned with the cavity;

CA 02337155 2002-Ol-16 WO 00/04372 PCTlUS99/16162 FIG. 26A-E depicts a cross-sectional view of a aeries of processing steps for the formation of a plastic based sensor array which includes a top and bottom cover with openings aligned with the cavity;
FIG. 27A-D depicts a cross-sectional view of a series of processing steps for the formation of a silicon based sensor array which includes a top cover with openings aligned with the cavity and a capered cavity;
S FIG. 28A-E depicts a cross-sectional view of a aeries of pressing steps for the fomostioa of a photoreeist based sensor array which includes a top cover with openings aligned with the cavity and a tapered cavity;
FIG. 29A-E depicts a cross-xctional view of a series of pr~essiag steps for the formation of a photoressist based xasor array which includes a top cover with openings aligned with the cavity and a bottom cover, FIG. 30A-D depicts a cross-sectional view of a series of processing steps for the formation of a plastic basod sensor array which includes s top cover with openings aligned with the cavity and s bottom cover, FIG. 31 depicts a cross-sectional view of s achematlc of a microptanp;
FIG. 32 depicts a top view of an elec>zohydrodynamic pump;
FIG. 33 depicts a cross-sectional view of a sensor array which inchrdea a micropump;
FIG. 34 depicts a cross-sectional view of a sensor amy which inchtdes a micropump and channels which IS are coupled to the cavities;
F1G. 3S depicts a cross-aectiooal view of a sensor array which includes multiple micropumps tech microptrmp being coupled to a cavity;
FIG. 36 depicts a top view of a sensor array which includes multiple electrohydtodynamic pumps;
FIG. 37 depicts a cross-sectimral view of a sensor array which includes a system for delivering a reagent from a reagent particle to a sensing cavity.
DETAILED DESCRIPTION OF PREFERRED EMBODIIYiENTS
Herein we describe a system and method for the simultaneous analysis of a fluid containing multiple anstytes. The system may be uxd for either liquid or gaa~us fluids. The rystem may generate patterns that are diagnostic for both individual analytes and mixtures of the anaiytes. The rystem, in some embodiments, is made of a combitwtion of chemically sensitive particles, formed in as ordered array, capablt of simultaneously detecting many different kinds of analytea rapidly. An aspect of the system is that the array may be formed using a microfabrication process, thus allowing the rystem to be manufactured in an inexpensive manner.
SYSTEM FOR ANALYSIS OF ANALYTES
Shown is FIG. 1 is an embodiment of s system for detecting analytes is a fluid The system, in some embodiments, includes s light source 110, a sensor array 120 and a detector 130. The light sourer 110 may be a white light source or light emitting diodes (LED). In one embodiment, light source 110 may be a blue light emitting diode (LED) for use in systems relying on changes in fluorescence signals. For colorimeuic (e.g., absorbance) based 3S systems, s white light source may be used. The sensor array 120, in some embodi~nts, is fornted of s supporting member which is configured to hold a variety of particles 124. A detecting device 130 (e.g., a charge-coupled device "CCD") may be positiaared below the sensor array to allow for data acquisition. In another embodiment, the detecting device 130 rnay be positioned about the xasor array.

CA 02337155 2002-Ol-16 Light originating from the light source 110, in some entbodimeats, passes thtortgh the sensor array 120 and out through the bottom aide of the sensor array. The supporting member anti the particles together, in see embodiments, provide an assembly whose optical properties are well mate6ed for spectral analyses. Thus, light modtz>ated by the particles may peas through the sensor amy and onto tho proximally spaced detector 130.
Evahrarioa of the optical changes may be completed by visual inspection (e.g., with a microscope) or by use of a microprocessor 140 coupled to the detector. For ftuoteacence measurements, a filter 135 may be placed between supporting member 120 and detector 130 to remove the excitation wavelength. A
fluid delivery system 160 may be coupled to the supporting member. The fluid delivery system 160 may be configured to introduce samples into and out of the ataaor array.
Ice an embodiment, the sensor array system includes an smy of particles.
t;paai the surface and within tlx interior region of the particles are, in some embodiments, located a variety of receptors for interacting with analyzes. The supporting member, in some embodimonts, is used to localize these particles as well as to serve as a microenvironnxnt in which the chemical sways can be performed. For tho chemicafbiological agent sensor arrays, the particles used for analysis are about 0.05 - 500 microns in diameter, and may actually change size (e.g., swell or shrink) when the chemical environment changes. Typically, these changesoccur when the array system is exposed to t!x fluid stream which includes the analyzes. For example, a fluid stream which comprises a non-polar solvent, rosy cause non-polar particles to change in volume when the particles are exposed to the solvent. To accommodate thoao changes, it is pcefernd that the supporting member consist of as stray of cavities which serve as micro tsat_ tubes.
The supporting member zany be made of any malarial capable of supporting the particles, while allowing the passage of the appropriate wavelength of light. The supporting nxmber is also made of a material substantially inerpervioua to the fluid in which the analyze is pu~esent. A variety of materials may be used including plastics, glass, silicon based materials (e.g., silicon, silicon dioxide, silicon nitride, etc.) and metals. In one embodirnent, the supporting member includes a plurality of cavities. The cavities may be formed such that at least one particle is substsatially contained within the cavity. Alternatively, a plurality of particles may be contained within a single cavity.
In en embodiment, the supporting member may consist of a strip of plastic which is substantially transparent to the wavelength of light necessary for detection. A series of cavities may be formed within the strip.
The cavities may be configured to hold at least one particle. The particles may be contained within the strip by s transparent cover which is configured to allow passage of the analyze containing fluid into the cavities.
In another embodiment, the supporting member may be formed using a silicon wafer as depicted in FIG. 2.
The silicon wafer 210 may include a substantially >tanspareat layer 220 formed on the bottom surface of the wafer.
The cavities 230, in one embodiment, are formed by as anisotropic oteh process of the silicon wafer. In one embodiment, anisotropic etching of the silicon wafer is accomplished using a wet hydroxide etch.
Photolithographic techniques may be used to define the locations of the cavities. The cavities may be formed such that the aidewalls of the cavities are substantially tapered at as eagle of between about 50 to 60 degrees. Formation of ouch angled cavities racy be accomplished by wet anisotropic etching of <100> silicon. The term "<100>
silicon" refers to the crystal orientation of tire silicon wafer. Other typos of silicon, (e.g., <110> sad <1 l 1> silicon) may lead to atecper angled sidewalk. For example, <1 l 1> silicon may lead to sidewalk foraxd at about 90 CA 02337155 2002-Ol-16 degrees. The angled sides of the cavities in some embodiane~, servo as 'error layers" which may improve the light collection efficiency of the cavities. The etch process may be contralled so that the formed cavities extend through the silicon wafer to the upper surface of transparent layer 220. While depicted as pyramidal, the cavities may be formed in a number of shapes inchtding but not limited to, spherical, oval, cubic, or rectangulu. An advantage to using a silicon wafer for the support member, is that the silicon material is substantially opaque to the light produced from the light source. Thus, the light may be inhabited from passing from one cavity to adjacent cavities. In this raauner, light from one cavity may be inhibited from influencing the spectroscopic c6aages produced in an adjacent cavity.
The silicon wafer, in sortie embodiments, has an area of approxitastely 1 cm=
to about 100 cm= and includes about 10' to about 10~ cavities. In an embodiment, about 100 cavities are formed in a ten by ten matrix.
The crater to center distance between the cavities, in some embadiraents, is about 500 microns. Each of the cavities may inchtde at least one particle.
The oransparent layer 220 may xtve as a window, allowing light of a variety of wavelengths to peas through the cavities 230 and to the detector. Additionally, the transparent layer may serve as a platform onto which 1 S the individual particles 235 may be positioned. The transparent layer tray be formed of silicon dioxide (SiO~, silicon nitride (Si,N,) or silicon dioxide/silicon nitride multi~lsytr stacks.
The rraaspatent layer, in some embodiments, is deposited onto the silicon wafer prior to the formation of the cavities.
The cavities 230 may be sized to substantially contain a particle 235. The cavities are, in some embodiments, larger than a particle. The cavities are, in some embodiment:, sized to allow facile placement anti removal of the particle within the cavities. The cavity troy be substantially larger than the particle, thus allowing the particle to swell during use. For example, a particle racy have a size as depicted in FIG. 2 by particle 235.
During use, comact with a fluid (e.g., a solvent) may cause tl~ particle to swell, for example, to a size depicted as circle 236. In some embodiments, the cavity is sized to allow such swelling of the particle during use. A particle may be positioned at the bottom of a cavity using, e.g., a micromanipulator.
After a particle has been placed within the cavity, a transparent cover plate 240 may be placed on top of the supporting member to keep the particle is place.
When forming as array which includes s plurality of particles, the particles may be placed iwthe array in an ordered fashion using the rtticromanipulator. in this tnanaer, a ordered stray having a predefined configuration of particles uoay be formed. Alternatively, the particles may be randomly placed within the cavities. The array may subsequently undergo a calibration test to determine the identity of the particle at any specified location in the supporting trtember.
The transparent cover plate 240, in some emboditrxnd, is coupled to the upper surface of the silicon wafer 220 sash that the particles are inhibited from bccorning dislodged from the cavity. The transparent cover plate, is some embodiments, is positioned a fixed distance above the silicon wafer, as depicted in FIG. 2, to keep the particle in place, while allowing the entrance of fluids iMo the cavities. The transparent cover plate, in some embodiments, is positioned at a distance above the substrate which is substantially less than a width of the particle. The transparent cover plate may be made of any taateriai which is substantially iraaspanent to the wavelength of light being utilized by the detector. The transparent cover plate may be trade of plastic, glass, quartz, or silicon dioxide/ailxon nitride.

Ia one embodiment, the transparent cover plate 240, is a thin shoot of glass (e.g., a microscope slide cover slip). The slide may be positioned a fixed distance shove the silicon wafer.
Support structures 241 (See FIG. 2) may be plaid upon the silicon wafer 210 to position the haoaparent cover plate 240. The support strucauGR may be foraxd from a polynur or a silicon based natetial. In another embodiment, a polymeric substrate is coupled to the silicon wafer to form the support structures 241 for the hanspanent cover plate 240. In an embodiment, a plastic material with an adhesive backing (e.g., cetlophsne tape) is positioned on the silicon wafer 210. After the support structures 241 are placed on the wafer the Granaparent cover plate 240 is plied, upon the support structures. The support sauctures inhibit the transparent cover sheet from contacting the silicon wafer 200. In this mamier, a channel is formed between the silicon wafer and the transparent cover plate which allow the fluid to pass into the cavity, while inhibiting displacement of the particle by the fluid.
In another embodiment, the transparent cover plate 240 rosy be fad to the upper surface of the silicon wafer, as depicted is FIG. 3. In this embodiment, the fluid may be inhibited from entering the cavities 230 by the a~ansparent cover plate 240. To allow passage of the fluid into the cavities, a number of channels 250 may be formed is the silicon wafer. The charmels, in one embodiment, are oriented to allow passage of the fluid into 1 S substantially all of the cavities. Whoa contacted with the fluid, the particles may swell to a size which may plug the chumels. To prevent this plugging, the channel: may be formed near the upper portion of the cavities, as depicted in FIG 3. The channels, in one emboditr~nt, are formed using standard photolithogcsphic masking to define the regions whore the trenches arc to be formed, followed by the use of standard etching oechniqucs. A depth of the cavity may be such that the particle resides substantially below the position of the channel. In this way, the pluming of the channels due to swelling of the particle may be prevented.
The itmer surfaces of the cavities may be coated with a material to aid the positioning of the particles within the cavities. In one embodiment, a thin layer of gold m silver may be used to line the inner surface of the cavities. The gold or silver layer may act as an anchoring surface to anchor particles (e.g., via alkylthiol bonding).
la addition, the gold or silver layer may also increase the reflectivity of the inner surface of the cavities. The increased reflectance of the surface may enhance the snalyte detection sensitivity of the system. Alteraativety, polymer layers and self assembled monolayers formed upon the inner surface of the ctvities tray be used to contml the particle adhesion interactions. Additional chemical anchoring methods may be used for silicon surfaces such as those based on ailoxaae type reagents, which tray be attached to Si-OIi functionslities. Similarly, mononuric and polymeric reagents attached to an interior region of the cavities can be used to alter the local wetting characteristics of the cavities. This type of methodology can be used to anchor the particles as well as to alter the fluid delivery characteristics of the cavity. Furthermore, amplification of the signals for the aaalytes may be accomplished with this type of strategy by causing preconcentration of appropriate analytes in the appropriate typo of chemical emdronment.
In another embodiment, the optical detector may be integrated within the bottom transparent layer 220 of the supporting member, rather than using a separate de~ctiag device. The optical detectors may be formed using a semiconductor-based photodetector 255. The optical detectors may be coupled to a microprocessor to allow evaluation of fluids without the use of separate detecting components.
Additionally, the fluid delivery system may also be incorporated into the supporting member. Micro-pumps end micro-valves may also be incorporated into the silicon wafer to aid passage of the fluid through the cavities. Integration of detectors and a fluid delivery system into the supporting member may allow the formation of s compact and portable atulyce sensing system, Optical filters may also be integrated into the b~tom membrane of the cavities. These filters may prevent short wavelength excitation from producing "falx" signals in the optical detocti~ system (e.g., a CCD detector array) during fluorescence measurements.
S A sensing cavity may be formed oa the bottom aurfsce of the support subsaste. Aa example of a sealing cavity that may be used is a Fabry-Perot type cavity. Fabry-Perot cavity-based seasons may be used to detect changes in optical path length induced by either a change in the refractive index or a change in physical length of the cavity. Using micromachining techniques, Fabry-Pcrot sensors may be formed on the bottom surface of the cavity.
Figures 4A-F depict a sequence of pmcessiag steps for the formation of a cavity and a planar top diaphragm Fabry-Perot sensor on the bottom surface of a silicon based supporting member. A sacrificial barrier layer 262a/b is deposited upon both aides of a silicon supporting member 260.
The silicon supporting member 260 may be a double-side polished silicon wafer having a thicmeaa ranging from about 100 pat to about 500 Wn, preferably from about 200 ltm to about 400 ltm, and more preferably of about 300 ltm. The barrier layer 262e/b 1 S may be composed of silicon dioxide, silicon nitride, or silicon oxynitride. la one embodiment, the barrier layer 262a1b is composed of a stack of dielectric rnataials. As depicted in FIG 4A, the barrier layer 262 alb is composed of a stack of dielectric materials which includes a silicast nitride layer 271 alb and a silicon dioxide layer 272a/b.
Both layers may be deposited using a low pressure chemical vapor deposition ("LPCVD'~ process. Silicon nitride may be deposited using an LPCVD reactor by reaction of ammonia (NHS and dichloroailane (SiCIzH~ at a gas.
flow rate of about 3.5:1, a temperature of about 800 OC, and a presstrce of about 220 mTorr. The silicon nitride layer 271a/b is deposited to a thickness in the range from about 100 A to about 504 A, preferably from 200 A to shout 400 A, and more preferably of about 300 A. Silicon dioxide is may be deposited using an LPCVD reactor by tssction of ailane (SiH,) and oxygen (O~ at a gas flow rate of about 3:4, a temperattue of shout 450 OC, and a pzrssttre of about l 10 mToa. The silicon dioxide layer 272a1b is deposited to a thickness in the range from about 3000 A to about 7000 A, preferably from 4000 A to about 6000 A, and more preferably of about 5000 A. The front face silicon dioxide layer 272x, in one embodiment, acts as the train barrier layer. The underlying silicon nitride layer 27 t a acts as an intermediate barrier layer to inhibit overarching of the main barrier Iaycr during subsequent KOH wet anisotropic etching steps.
A bottom diaphragm layer 264a/b is deposited upon the barrier layer 262a1b on both sides of the supporting member 260. The bottom diaphragm layer 264a/b may be cotttposed of silicon nitride, silicon dioxide, or silicon oxyait<ide. In one embodiment, the bottom diaphragm layer 264 alb is composed of a stack of dielecoric materials. As depicted in FIG 4A, the bottom diaphragm Iayer 264a/b is composed of a stack of dielectric materials which includes a pair of silicon nitride layers 273a1b and 275e1b atvroundiag a silicon dioxide layer 274a/b. AU of the layers may be deposited using an LPCVD process. The silicon nitride layers 273a/b and 275a1b have a thickness in the range from about 500 A to about 1000 A, preferably from 700 A
to about 800 A, and more preferably of about 750 A. The silicon dioxide layer 274a/b has a thickness in the range from about 3000 A to about 7000 A, preferably from 4000 A to about 6000 A, and snore preferably of about 4500 A.
A cavity which will hold the particle may now be formed in the:<tpportiag member 260. The bottom diaphragm layer 264b and the barrier layer 262b formed on the back side 261 of the silicon supporting member 260 wo ooio4372 rcriUS99n6i6Z
arc patterned and etched using standard photolithogtaphic techniques. In one embodiment, the layers are subjected to a plasma etch process. The piastas etching of silicmt dioxide sad silicon nitride may be perfoctned using a mixture of carbontetrafluoride (CF,) and oxygen (0i). The patterned back side layers 262b sad 264b may be used as a atask for anisotropic etching of the silicon supporting member 260. The silicon suppordag member 260, in one embodiment, is anisottopically etched wide a 40~,6 potassium hydroxide ("KOH") solution at 80 l7C to form the cavity. The etch is stopped when the front sib silicon nitiride layer 271 a is reached, as depicted in FIG 4B. The sitic~ nitride layer 271a inhibiut etching of the main barrier layer 272a doting this each process. The cavity 26?
may be foaaed extending through the supporting tramber 260. After formation of the cavity, the remaining portions of the back side barrier lays 262b and the diaphragm layer 264b may be removed.
Etch windows 2b6 are formed through tb~e bottom diaphragm layer 264a on the front side of the wafer. A
ma:bag layer (not s6owa) is formed over the bottom diaphragm layer 264s and patterned using standard photolithograpbic techniques. Using the masking layer, etch windows 266 may be formod using a plasma etch.
The plasma etching of silicon dioxide and silicon nitride may be performed using a mocnue of carbontetrsfltwride (CF,) and oxygen (O=). The aching is continued through the bottom diaphragra lnyer 2b4a and partially into the barrier Iayer 262x. In one embodiment, the etching is stopped at appraximstely half the thickness of the bonier layer 262a. Thus, when the barrio layer 262a is subsequently removed the ach windows 266 will extend through the bouom diaphragm laytr 2b4a, communicating with the cavity Zb7. By stopping the etching at a midpoint of the barrier layer, voids or discontinuities may be reduced since the bottom diaphragm is still continuous due to the remaining barrier layer.
ARer the etch windows 266 are formed, a sacrificial spacer layer 268a1b is deposited upon the bottom diaphragm layer 264a and within cavity 267, as depicted is FIG. 4C. The neater layer may be formed from LPCVD polysilican. In one embodinicnt, the front side deposited spacer layer 268a will also at least partially fill the tech windows 266. Polysilicon may be deposited using an LPCVD reactor using silane (SiH,) at a temperature of about 65017C. The spacer layer 268a1b is deposited to a thiclwess in the range from about 4000 A to about 10,000 A, preferably from 6000 A to shout 8000 A, and more preferably of about 7000 A. The preferred thickness of the spacer layer 268a is dependent an the desired thiclmess of the internal sir cavity of tlx Fabry-Perot detector.
For example, if a Fabry-Perot detector which is to include a 7000 A sir cavity between the top end bottom diaphragm layer is desired, a spacer layer having a thicloteaa of about 7000 A
would be formed. After the spacer layer has been deposited, a masking layer for Itching the spacer layer 268a (not shown) is usod to define the etch regions of the spacer layer 2b8a. The etching may be performed using a composition of nitric acid (HNO,), water, and hydrogen fluoride (I~ in a ratio of 25:13:1, respectively, by volume. The lateral size of the subsequemly formed cavity is determined by the masking pattern used to define the etch regions of the spacer layer 268x.
Altar the spacer layer 2b8a has been etched, the top diaphragm layer 270a/b is formed. The top diaphagm 270a/b, in one embodiment, is dcpositod upon the spacer layer 268s/b on both sides of the supporting meaobcr. The top diaphragm 270s1b rnay be compoacd of silicon nitride, ailicoa dioxide, or aiiicon oxynitcidc. In one embodiment, the top diaphragm 270a/b is composed of a stack of dielectric materials. As depicted in FIG. 4C, the top diaphragm 270a/b is composed of a stack of dielectric materials which includes a pair of silicon nitride layers 283a/b and 285a/b sturounding a silicon dioxide layer 284a1b. All of the layers may be deposited using as LPCVD
process. The silicon nitride layers 283a1b sad 285a/b have a thickness in the range from about 1000 A to about 2000 A, preferably from 1200 A to abort 1700 A, sad more preferably of shout 1500 A. The silicon dioxide layer 284a/b has a thickness in the range frora about 5000 A to about 15,500 A, preferably from 7500 A to about 12,000 A, and ire preferably of about 10,500 A.
After depositing the top diaphragm 270a/b, all of the layers stacked on the bottom face of the supporting member (e.g., layers 268b, 283b, 284b, and 285b) are removed by multiple wet and plasma etching steps, as depicted in FIG. 4D. After these layers are removed, the now exposed ponders of the barrier layer 262a are also rrmoved. This exposes the spacer layer 268a which is present in the etch windows 266. The spacer layer 268 tray be removed from between the top diaphragm 270a sad the bottom diaphragm 264a by a wet etch using a KOH
solution, as depicted in FIG. 4D. Removal of the spacer material 2b8a, forms a cavity 286 between the top diaphragm layer 270a and the bottom diaphragm layer 264a. After removal of the spacer material, the cavity 286 may be washed using deionized water, followed by isopropyl alcohol to clean out any remaining etching solution.
The cavity 286 of the Fabry-Perot sensor may be filled with a sensing substrate 290, as depicted is FIG.
4E. To coat the cavity 286 with a sensing substrate 290, the sensing substrate may be dissolved is a solvent. A
solution 'of the sensing substrate is applied to the supporting member 260.
The solution is believed to rapidly eater the cavity 28b through the etched win~ws 266 in the bottom diaphragm 264a, aided is part by capillary action. As the solvent evaporates, a thin film of the aeming substrate 290 coats the inner walls of the cavity 286, as well as the outer surface of the bottom diaphragm 264a. By repeated treatment of the supporting member with the solution of the sensing substrate, the thickness of the sensing wbstrate may be varied.
In one embodiment, the sensing substrate 290 is poly(3-dodocylthiophena) whose optical propat~s change in response to changes in oxidation states. The sensing substrate poly(3-dodccylthiophene) tray be dissolved in a solvent such as chloroform or xylene. In one embodiment, a concentration of about 0.1 g of poly(3-dodecylthiopheneymL is used Application of the solution of poly(3-dodecylthiophene) to the supporting member causes a thin film of poly(3-dodecylthiopheae) to be formed on the inner surface of the cavity.
In some instances, the sensing substrate, when deposited within a cavity of a Fabry-Perot type detecxor, may cause stress in the top diaphragm of the detector. It is believed that when a seaaiug polymer coats a planar top diaphragm, extra residual stress on the top diaphragm causes the diaphragm to becoax deflected toward the bottom diaphragm. If the deflection becomes to severe, sticking between the top and bottom diaphragms tray occur. In one embodiment, this stress may be relieved by the use of supporting members 292 fomud within the cavity 286, as depicted in FIG. 4F. The supporting manbers 292 may be formed without soy cxrra processing steps to the above described pries: flow. The formation of supporting members may be accomplished by deh'berately leaving a portion of the spacer layer within the cavity. This may be accomplished by underetchiag the spacer layer (e.g., termioatiag the etch process before the entire etch process is finished). The remaining spacer will behave as a support member to reduce the deflection of the top diaphragm member. The size and shape of the support members may be adjusted by altering the etch time of ttu spacer layer, or adjusting the shape of the etch windows 266.
In another embodiment, a high sensitivity CCD array tray be used to measure chsages in optical characteristics which occur upon binding of the biologicaUchemical agents. The CCD arrays may be interfaced with filters, light sources, fluid delivery and micromachined particle receptacles, so as to create a functional season array. Data acquisition and handling may be performed with existing CCD
technology. Data streams (e.g., red, green, blue for colorimenic assays; gray intensity for fluorescence assays) may be transferred from the CCD to a computer via a data acquisition board. Current CCDs may allow for read-out rates of lOs pixels per second. Thus, the entire array of particles may be evaluated hundreds of times per second allowing for studies of the dynamics of the various bostguest intcractioa rates as well as the aoalyte/polymer diffusio~naI chatacicristics. Evahtatioa of this data may offer a method of idcatifying sad quantifying the c>temica)/biological comgtositioa of the tea satttples.
CCD detectors tray be configured to measure whirs light, ultraviolet light or fluorescence. Other detectors aach as photomultipiier tubes, charge induction devices, photodiode, photodiode amys, and tnicrochanael plates may also be used. It should be understood that while the detector is depicted as being positioned under the supporting tnemba, the detector may also be positioned above the sttpporartg member. It should slso be understood that the detector typically includes a sensing element for detecting the spectroscopic events and a component for displaying the detected events. The display component may be physically separated from the smaing element. The sensing element may be positioned above or below the sensor array while the display component is positioned close to a In one embodiment, a CCD detector tnay be used to record color changes of the chemical sensitive particles during analysis. As depicted in FIG. I, a CCD detector 130 stay be placed beneath the supporting rnetttber 120. The light transmitted through the cavities is captured sad analyzed by the CCD detector. In one embodimatt, the light is broken down into three wlor components, rod, green and bhte. To sitaplify the data, each color is recorded using 8 bits of data. Thus, the data for each of the colors will appear as a value between 0 and 255. The color of each chemical sensitive element may be represented as a red, blue and green value. 'For example, a blink particle (i.e., s particle which does not iatlude a receptor) will typically appear white. For example, when broken down into the red, green sad blue components, it is found that s typical blank particle exhibits s red vahu of about 253, a green value of about 250, and a blue value of sbont 222. This signifies thst s blank particle does not significantly absorb red, grew or blue light. When a particle with a receptor is scanned, the particle tray exhibit a color change, due to absorbance by the receptor. For example, it was found that when a particle which inchtdes a 5-carboxyfluorescein receptor is subjected to white Iight, the particle shows a strong abaorbance of blue light. The CCD detector valves for the 5-carboxyflnoresceia particle exlubita a red value of about 254, a green value of about 218, and a blue value of about 57. The decrease in transmittance of blue light is believed to be due to dte absorbance of bhre light by the 5-carboxyfluoresceia. In this manner, the color changes of a particle may be quantitatively characterized. An advantage of using a CCD
detector to monitor the color changes is that color changes which may not be noticeable to the human eye tray now he detected.
Tlte support array may be configured to allow a variety of detection modes to be practiced. In one embodimtnt, a light source is used to generate light which is directed toward the particles. The particles taay absorb s portion of the light as the light illutaiostes the particles. The light then reaches the detector, reduced in intensity by the absorbance of the particles. The detector tray be configure to measure the reduction in light intensity (i.e., the sbsorbance) due to the particles. In another embodiment, the detector tnay be placed above the supporting axmber. The detector may be camfigured to tnessure the amount of light reflected off of the particles.
The absorbsnce of light by the particles is taanifestcd by a reduction in dte amount of light being reflected from the cavity. The light source in either embodiment tnay be a white light source or a fluorescent light source.

WO ~~~ PCT/US99116162 CSEMICALLY SENSItTIVE PARTICLES
A particle, in some embodiments, possess both the ability to bind the anslyte of interest and to create s modulated signal. The particle may include receptor molecules which posses the ability to bind the analyte of interest sad to create a modulated signal. Alternatively, the particle may include receptor molecules and indicators.
The receptor molecule may posses the ability to bind to as attslyte o f interest. Upon binding the edalytc of inbereat, the receptor molecule may cause the indicator rmleculc to produce the modulated signal. The receptor molecules tray be naturally occurring or synthetic tecepton formed by ntiaoal design or combinatorial metbOds.
Some examples of ttahual recepbora include, but are not limited to, DNA, RNA, proteins, enzymes, o)igopep~~
antigens, and antibodies. Either naatnl or synthetic receptors may be chosen for their ability to bind to the analyte molecules is a specific manner. The foroes which drive associatiot><rocognition between molecules inchrde the hydrophobic effect, anion-canon attraction, and hydmgea bonding. The restive strtngths of thex forces depend upon factors such as the solvent dielectric properties, the shape of the host tnolecule, and how it complements the guest. Upon host-guest association, attractive interactions occur and the molecules stick together. The most widely used analogy for this chemical interaction is that of a "loci and key". The fit of the key molecule (the guest) into the lock (the host) is a molecular recognition event.
A naturally occurring or synthetic receptor may be bound to a polymeric resin in order to create the particle. The polymeric resin may be made from a variety of polymers including, but not limited to, agarous, dextrose, aaylamid4, control pore ghiaa beads, polystyrene-polyethylene glycol resin, polystyrene-divinyl betrune resin, foratylpolystyrene resin, trityl-polystyrene resin, acetyl polystyrene resin, chloroacetyl polystyrene resin., amiaomethyl polystyrene-divinylbeazene resin, carboxypolystyrene resin, chlommethylated polystyrene-divinylbenzeae resin, hydroxymethyl poly:tyreae-divinyresin, 2-chlorotrityl chloride polystyrene re:;n, 4-benzyloxy-2'4'- dimethoxybenzhydcol resin (Rink Acid rerun), triphenyl methanol polystyrene main, dipheaylmethanol resin, be~ltydml resin, succinimidyl carbonate resin, p-aitrophenyl carbonate resin, imidezole carbonate resin, polyacrylamide resin, 4-aulfamylbenzoylrf-methylbenzhydrylaminc-resin (Safety-catch resin), 2-amino-2-(2'-nitrophenyt) propionic acid-aminomethyl resin (ANP Resin), p-beazyloxybenryl alcohol-divinylbenzene resin (Wang resin), p-methYlbeazhYdtyiamine-divinylbenzene rrsin (MHHA resin), Ftnoc-2,4-dimetboxy-4'-(carboxymethyloxyrbenzhydryhunine linked to resin (Know resin), 4-(2',4'.Dimeihoxyphenyl-Fmoc-aminotaethyl~phenoxy resin (Rink resin), 4.hydroxytaethyl-benzoyl-4'-methylbenzhydrylamine resin (HMBA-MBIiA Resin), p~nitrobeawpheaone oxime resin (Kaiser oxime resin), sad amino-2,4-dimethoxy-4'-(carboxymethyloxyrbenzhydrylamine handle linked to 2-chlorotrityl rosin (Knorr-2-chlomtrityl resin). In one embodiment, the material uxd to form the polymeric resin is con>pahble with the solvent in which the analyte is dissolved. For example, polystyrene-divinyl benzene resin will awoU within non-polar solvents, but does sot significantly swell within polar solvents. Thos, polystyrene-diviayl benzene resin may be used for the analysis of analytea within nonpolar solvents. Alternatively, polystyrene-polyethylene glycol resin will swell with polar solvents such as water. Polystyrene-polyethylene glycol resin may be useful for the analysis of aqueous fluids.
Is one embodiaxat, a polystyrene-polyethylene glycol-divinyl benzene material is used to form the polymeric resin. The polystyrene-polyethylene glycol-diviayl beaxene resin is formed from a mixture of polystyrene 375, divinyl lxnzeae 380 sad polystyrene-polyethylene glycol 385, sec FIG. 5. The polyethylene glycol portion of the polystyrene-polyethylene glycol 385, in one embodiaxat, may be terminated with an amine.

The amine nerves as a chemical handle to anchor both receptors and indicator dyes. Odter chenticel ftmctianal grontps may be positioned at the terminal end of the polyethylene glycol to allow appropriate coupling of the polytt~eric resin to the receptor rrmlecules or indicators.
The chemically sensitive particle, in one embodhnent, is capable of both binding the analyte(:) of interest and creating a detectable signal. In one embodiment, the particle will create an optical signal when bound to an anslyte of interest. The use of such a polytrxrle bound receptors offers advantages both in terms of cost and configurability. Instead of having to synthesize or attach a receptor directly to a supposing member, the polymeric bound receptors may be synthesized en masse and distributed to multiple different supporting members. This allows the cost of the sensor array, a major hurdle to the development of mass-produced environmental probes and medical diagnostics, to be reduced. Additionally, serwor arrays which incorporate polymeric bound receptors ~y be reconfigured much more quickly than array systems in which the receptor is attached directly tot he supporting member. For example, if a new variant of a pathogen or a ~tthogea that contains a genetically engineered protein is a threat, then a new sensor array system may be readily created to detect thex modified analytea by simply adding new sensor elements (e.g., polymeric bound receptors) to a previously formed supporting member.
In one embodiment, a receptor, which is xatitive to changes in the pH of a fluid sample is bound to a polymeric resin to create a particle. That is, the receptor is sensitive to the concentration of hydrogen catiom (H~.
The receptor in this case is typically sensitive to the concentration of H" is a fluid solution. The analyte of interest may therefore be H'. There are many types of molecules which undergo a color change when the pH of the fluid is changed. For example, many types of dyes undergo significant color changes as the pH of the fluid medium is altered. Examples of receptors which may be used to monitor the pH of a fluid sample include 5-cuboxyfluorescein and alizarin compkxone, depicted in FIG. 6. Each of these recepwrs undergoes significant color changes as the pH of the fluid is altered. 5-catboxyfluoresaeia undergoes a change from yellow to orange as the pH of the fluid is increased. Alizarin compkxone undergoes two color changes, first from yellow to red, then from red to blue ss the pH of the fluid increases. By monitoring the change is color caused by dyes attached to a polymeric particle, the pH of a solution away be qualitatively end, with the ux of a detector (e.g., a CCD detector), quantitatively monitored.
In another embodiment, a receptor which is sensitive to presence of metal canons is bound to a polyr~ric particle to create a particle. The receptor in this case is typically sensitive to the conxatratioa of one or more metal canons present in s fluid solution. 1n general, colored molecules which will bind carious may be used to determine the presence of a metal ration in a fluid solution. Examples of receptors which may be used to monitor the presence of rations in a fluid sample include alizarin emrtplexoae and o-cresotphthalein complexone, sea FIG. 6.
Each of these receptors undergoes significant color chaagss as the concentrrnon of a specific metal ion in the fluid is altered. Alizarin complexone is particularly sensitive to Lathanum ions. 1n the absence of lanthanum, alizarin complexoae will exhibit a yellow color. As the concentration of lanthanum is increaxd, alizarin complexone will change to a red color. o-Cresolphthalein complexone is particularly sensitive to calcium ions. In the absence of calcium, o-ecesolphthalein complexone is colorless. An the concentration of calcium is increased, o-creaolphthalein coaepkxone will change to a blue color. By monitoring the change is color of metal radon sensitive receptors attached to s polymeric particle, the presence of a specific metal ion may be qualitatively and, with the use of a detector (e.g.. a CCD detector), qusatitatively monitored.

Referring to FIG. 7, a graph of the absorbance of green light vs. coacemration of calcium (Ca'~ is depicted for a particle which inchtdea an o-cresolphthalein complexone receptor. As the concentration of calcium is increased, the absorbance of green light increases in a linear manner up to a concentration of about 0.0006 M. A
concentration of 0.0006 M is the solubility hit of calcium in the fluid, thus no significant change in absorbance is noted after this point. The linear relationship between concentration and absorbance allows the concentration of calcium to be detumiaed by measuring the absorbance of the fluid sample.
In one embodiment, a detectable signal may be caused by the altering of the physical properties of an indicator ligand bound to the receptor or the polymeric resin. In one etnbodiment, two di~'ereat indicators are attached to a receptor or the polymeric resin. Whca an analyze is captured by the recxptor, the physical distance between the two indicators may be sltercd such that a change in the spectroscopic properties of the indicawrs is produced. A variety of fluorescent and phosphorescent indicators may be used for this sensing scheme. This process, known as Forster energy transfer, is extremely sensitive to small changes in the distance between the indicator molecules.
For example, a first fluorescent indicator 320 (e.g.. a fluorescein derivative) and a second fluorescent indictor 330 (e.g., a rbodamine derivative) may be attached to a receptor 300, as depicted in FIG. 8. Whar no aaalyte is present short wavelength excitation 310 may excite the first fluorescent indicator 320, which fluoresces as indicated by 3I2. The short wavelength excitation, however, may cause little or no fluorescence of the second fluorescent indicator 330. After binding of analyze 350 to the receptor, a structural change in the receptor taolecule may bring the fu~st sad second fluorescent indicators closer to each other.
This change is intermolecular diauacs may allow the excited first indicatar 320 to transfer a portion of its fluorescent energy 325 to the second fluorescent indicator 330. This transfer in energy may be measured by either a drop in energy of the fluorescence of the fast indicator molecule 320, or the detection of increased fluorescence 314 by the second indicator tnolecule 330.
Alternatively, the first sad second fluorescent indicator may initially be positioned such that short wavekagth excitation, may cause fluorescence of both the fn~st and second fluorescent indicators, as described above. After binding of analyze 350 to the receptor, a structural change in the receptor molecule may cause the first sad second fluorescent indicators to move further apart. This change in intermolecular distance may inhibit the transfer of fluorescent energy from the first indicator 320 to the second fluorescent indicator 330. This change in the transfer of energy may be measured by either a drop in energy of the fluorescence of the second indicator molecule 330, or the detection of increased fluorescence by the first indicator molecule 320.
1n another embodiment, as indicator ligtad may be preloaded onto tire receptor. An analyze may then displace the indicator ligand to produce a change in the spectroscopic properties of the particles. In this case, the initial background absorbance is relatively large sad decreases when the analyte is prt;sent. The indicator ligaad, in one embodiment, has a variety of spectroscopic properties which may be treasured. These spectroscopic properties include, but are not limited to, ultraviolet absorption, visible absorption, infrared absorption, fluorescence, and msgxtic resonance. In one ernbodimeat, the indicator is a dye having either a strong fluorescence, a strong ultraviolet absorption, a strong visible absorption, or a combination of these physical properties. Examples of indicators inchuie, but are not limited to, carboxyfluorssceia, ethidium bromide, 7-dimethylamino.4-methylcournarin, 7-diethylamino-4-methylcoumarin, eosin, erythrosia, fluorescein, Oregon Green 488, pyrene, Rhodamine Red, tetramethylrhodamine, Texas Red, Methyl Violet, Crystal Violet, Ethyl Violet, Malachite green, Methyl Green, Alizarin Red S, Medtyl Red, Neutral Red, o-cresohtulfonephthskin, o-craolphthalein, phenolphthalein, Acridiae Orange, B-aaphthol, cotnnuin, and a-naphthionic acid. When the indicator is muted with the receptor, the receptor and indicator iatenet with each other such that the shove mentioned apatroscopie properdies of the indicator, as well as other spectroscopic properties tray be altered. The nature of this interaction tray be a binding interaction, wherein the indicator and receptor are attracted to each other with a sufficient force to allow the newly formed receptor-indicator complex to function as a single unit. The binding of the indicator and receptor to each other may take the form of a covalent bond, an ionic bond, a hydrogen bond, a van tier Waals interaction, or s combination of these bond:.
The indicator may be chosen such that the binding strength of the indicator to the receptor is loss than the binding strr~ of the analyze to the receptor. Thus, in the presetxe of an snalyte, the binding of the indicator with the receptor may be disrupted, releasing the iadicat~or from the receptor.
When rehxxd, the physical properties of the indicator may be altered from those it exhrbited whoa bound to the receptor. The indicator may revert bxk to its original structure, thus regaining its original physical properties. For example, if s fluorescent indicator is attached to a particle that includes a receptor, the fluorescence of the particle may be strong before trestaxat with an analyze containing fluid. When the analyte interacts with the particle, the fluorescent indicator may be released.
Release of the indicator may cattle a decrease in the fluorescence of the particle, sins the particle now has leas indicator molecules associated with it.
An example of this type of system is illustrated by the use of a boronic acid substituted train 505 as a particle. Prior to testing, the bomnic arid substituted resin 505 is treated with s sugar 510 which is tagged with en indicator (e.g., resontfm) as dtpicted in FIG. 9. The auger 510 binds to the boranic acid receptor 500 imparting s color change to the boronic substituted resin 505 (yelbw for the resocufin tagged sugar). When the boroaic acid reaiu 505 is treated with a fluid sample which includes s :agar 520, the tagged sugar 510 stay be displaced, causing a decrease in the amount of color pmducad by the boronic acid substituted resin 505. This decrease may be qualitatively or, with the use of a deuctor (e.g., a CCD detector), quantitatively mot>itored.
Ice another embodiment, a designed synthetic receptor may be used. in one embodiment, a polycarboxylic acid receptor may be attached to a polymeric resin. The polycarboxylic receptors are discussed in U. S. patent application serial no. 081950,712 which is incorporated herein by reference.
In an embodiment, the analyte molecules in the fluid may be pretreated with an indicator ligand.
Pretreatment may involve covalent attachment of an indicator ligand to the analyze molecule. After the indicator has bean attached to the analyx, the fluid may be passtd over the aensittg particles. lntencaon of the receptors on the sensing particles with the saalytes may t~emove the analyzes from the solution. Since the aaelytes include as indicator, the apcctroscopic properties of the indicator may be passed onto the particle. By analyzing the physical properties of the sensing particles afbcr passage of as analyte stream, the presence and concentration of as analyze may be determined.
For example, the analytes within a fluid may be derivatized with a fluorescent tag before introducing the stream to the particles. As analyze molecules are adsorbed by the particles, the fluorescence of the particles may increase. The presence of a fluorescent ugaat may be rued to deterrnine the presence of a spec analyte.
Additionally, the strength of the fluorescence may be used to determine the amount of analyte within the streua WO 00/4~t372 PCTlUS99l16162 RECEPTORS
A variety of natural and synthetic receptors tray be used. The symhetic receptors may come from s variety of classes including, but not limited to, polynucleotidea (e.g., aptamas), peptides (e.g., enzymes and antibodies), synthetic recxptore, polymeric utmatural biopolytaera (e.g..
polythioureas, potyguanidiniuma), and imptusted polymers., some of which are gcaecally depicted in FIG. 10. Natural based synthetic rocepoors include receptors which arc structurally similar to naturally occurring molecular.
Poiynucleotides are relatively unall fragments of DNA which may be derived by sequentially building die DNA
seqttcnce. Peptides may be rynthesized from amino acids. Unnatural biopolymers are chemical structure which axe based on natural biopolymecs, but which are built from unoatuni linking units. Unnaaual biapolya~rs such as polythiottreas and l0 polyguanidiniucns may be synthesized from diamines (l.c., compounds which include at least two amino functional groups). Thcac molecules are structurally simile to naturally occurring receptors, (e.g., peptides). Some diaari»
may, in taro, be synthesized from amino acids. The use of amino acids as the building blocks for there compounds allow a wide variety of molecular recogattion units to be devised. For example, the twenty natural amino acids have side chains that possess hydrophobia residues, cationx and anionic residues, as well as hydrogen bonding groups. These side char may provide a good chemical match to bind s large number of targets, from small txuolecules to large oligosaccharidcs. Amino acid based peptides, polythiatmas, and polyguanidiniums are depicted in FIG. 10.
Techniques for the building of DNA fragments and polypeptide ~agments on a polymer particle are weH
known. Techniques for the immobilization of naturally occurring attd'bodxa and enzyme: on a polymeric rain are also well known. The synthesis of polythiotmas upon s resin particle may be accomplished by the synthetic pathway depicted in FIG. 11. The procedure may begin by depaotatiom of the terminal tBoc protecting group on an amino acid coupled to a polymeric particle. Removal of the protecting group is followed by coupling of the rigid spacer 410 to the resulting amine 405 using diiaopropylcarbodiimidc (DIC) and 1-hydroxybenzotriazole hydrate (HOBT). The spacer group may inhibit formation of a thiazolone by reaction of the fast amino acids with subsequently formed thioureas. After the apaar group is coupled to the an>ino acid, another tHoe deprotection is performed to remove the spacer protecting group, giving the amine 415. At this point, monomer may be added incrementally to the growing chain, each time followed by a tHoc deprottction.
The addmon of a derivative of the diamine 420 (e.g., an isothiocyartate) to amino 415 gives the mono-thiourea 425. The addition of a second thiourea aubsttnent is also depicted. After the addition of the desired number of manomera, a sohttion of bcazylisoihiocyanste or acetic anhydride may be added to cap any remaining amines on the growing oligomers.
Between 1 to 20 threatens groups may be formed to produce a synthetic polythiourea receptor.
The synthesis of polyguanidiniutns rnay be accomplished as depicted in FIG.12.
la order to incorporate these guaaidinium groups into the receptor, the coupling of a thiottrea wilt a term'roal amine in the presence of Mukaiyama's reagent may be utilized. The coupling of the fast threaten diamine 430 with as amino gmap of a polymeric particle gives the mono-guanidinium 434. Coupling of the resulting mono-guanidinium with a aecoud thiousea diansute 436 gives a di-guanidiaium 438. Further coupling may create a tri-guanidinium 440. Between 1 to 20 guaaidinium groups may be formed to produce a synthetic polyguanidiniutn receptor.
The above descn'b~d methods for making polythioureas and polyguanidiniutns are based on the incorporation of diamines (i.e., molecules which include at least two amine functional groups) into the oligomeric WO 00104372 PCT/US99/16I62 _ receptor. The method may be general for any coarpmind having a least two amino grotipa. In one embodiment, the dismine tnsy be derived from amino acids. A method for fornsing diamiaes from amino acids is shown in FIG.
l3. Treataxnt of a protected amino acid 450 with borane-T11F educes the auboxylic acid portion of the amino acid to the primary alcohol 452. The primary alcohol is trated with phthalimide under Mitsunobu conditions (PPhtIDEAD). The resulting compound 454 is treated with aqueous tttethy>a>irine to form the desired rnoaoprotected diamine 456. The process may be accotapliahed such that the enantioomeric purity of the starting amino acid is maintained. Any natural or synthetic amino acid may be used in the above descnbed method.
The three coupling atrategiea used to form the reapectiva functional groups any be completely compatible with each other. The capability to mix linldrig groin (rmidea, thioureaa, and guanidituums) as well as the side chains (hydrophobic, cati~ic, ani~ic, sad hydrogen bonding) may allow the creation of s diversity in the oligotriers that is beyond the diversity of raeptors typically found with natural biological receptors. Thus, we ~y produce ultra-sensitive and ultra-selective receptors which exhibit interactions for specific toxins, bacteria, and environmental chemicals. Additionally, these synthetic schemes may be uud to build combinatorial 1'braries of particles for use in the sensor array.
In an embodiment, the indicator ligand may be incorporated into synthetic receptors during the ayatheaia of the receptors. The ligand may be incorporated into a monometic unit, such as a diamine, that is used during the synthesis of tlx receptor. In this manner, the indicator may be covalently attached to the receptor in a controlled position. By placing the indicator within the receptor during the synthesis of the receptor, the positioning of the indicator ligand within the receptor tnay be controlled. This control tray be difFtcult to achieve aRer syathesia of the receptor is completed.
In one embodiment, a fluorescent group may be incotporsted into a diamine monomer for use is the synthetic sequences. Examples of monomeric utsita which may be used for the ayathesis of a receptor are depicted in FIG. 14. The depicted monomers include fhioreacent indicator groups. After synthesis, the interaction of the receptor with the analyte may induce changes in the spectroscopic properties of the molecule. Typically, hydrogen bonding or ionic substituents on the fluorescent monomer involved in snalyte binding have the capacity to change the electron density andlor rigidity of the fluorescent ring system, thereby causing observable changes in the spectroscopic properties of the indicator. For fluorescent indicators such changes may be exhibited as changes in the fluorescence quantum yield, maximum excitation wavelength, and/or maximum emission wavelength. This approach does not require the dissociation of s preloaded fluorescent ligand, which may be limited in naponse time by lc~~. While fluorescent ligands are shown here, it is to be understood that a variety of other ligand may be used including colorimctric ligaads.
In another embodiment, two fluorescent rtionomers for signaling may be used for the synthesis of the receptor. For example, compound 470 (a derivative of fluorescein) and compound 475 (a derivative of rhodamine), depicted in FIG. 14, may both be incorporated into s synthetic receptor.
Compound 470 contains a common colorimettic/fluoreacent probe that will, in some embodiments, send out s modulated signal upon analyze binding.
The modulation may be due to resonance energy trsnafer to compound 475. Whoa as analyte binds to the receptor, stmctia~al changes in the receptor may alter the distance between mono»ic nnib 470 and 475. It is well known that excitation of fluorescein can result in emission from rhodamiae when these molecules are oriented correctly.
The eff ciency of resonance energy transfer from monomers 470 to 475 will depend strongly upon the presence of WO 00/04372 PC'f/US99/161G2 atulyte binding; thus, mesauremeat of rhodamine fluorexeace intensity (at a aubstaatially longer wavelength than throreacein fluorescence) may serve as an indicator of tnalybe binding. To greedy improve the likelihood of a modufatory fluarescein-rhodamine interaction, multiple rhodamine tags may be attat:)xd at different sites along a receptor molecule without substantially iocmasiag background rhodemine fluorescence (only rhodamine very clox to tluorescein will yield appreciable signal). This methodology may be applied to a number of alternate fluareacent pairs.
In an embodiment, a large number of cheaticaUbiological agents of interest to the military and civilian comrrwnities may be sensed readily by the described array xasors including both small and medium size molecules. For example, it is known that serve gases typically produce phosphate strnctnres upon hydrolysis in water. The presence of molecules which contain phosphate functional groups may be detected using polyguanidiniums. Nerve gnats which have contaminated water:ources rosy be detected by the use of the polyguanidinium receptors described above.
In order to identify, sense, sad quantitate the presence of various bacteria using the proposed micro-machined sensor, two strategies may be used. First, small molecule ra:ognitioa and detection may be exploited.
I S Since each bacteria possesses a unique and distinctive concentration of the various cellular molecules, such as DNA, proteins, metabolites, and sugars, the fingerprint (i.e., the concentration and types of DNA, proteins, metabolites, and sugars) of each organism is expected to be unique. Hence, the analytea obtained from whole bacteria or broken down bacteria may be uxd to determine the of apecifie bacteria. A xries of reaptora specific for DNA molecules, proteins, metabolites, and augsra may be incorporated into an array. A solution containing bacteria, or more preferably broken down bacteria, may be peaxd over the array of particles. Tire individual eeDular components of the bacteria rosy interact in a different manner with each of the particles. This interaction will provide a pattern within the easy which stay be unique for the individual bacteria. In this manner, the presence of bacteria within a fluid may be determined.
In another embodiment, bacteria may be detected as whole entities, as found in ground water, aerosols, or blood. To detect, senx, and identify intact bscoeris, the cell surface of one bacteria may be differentiated from other bacteria. One method of accomplishing this diflorentiation is to target cell surface oligoaaccharides (i.e. auger residtrcs). Each bacterial class (gram negative, gram positive, ere.) displays a ditlarenr oligosaocharide on their cell surfaces. The oligosaceharide, which is the code that is read by other cells giving an identification of the cell, is part of the cell-cell recognition and co~uaication process. The ux of synthetic receptors which are specific for oligoaaccharides may be uxd to deterrniae the presenx of apxific bacteria by analyzing for the cell surface oligosaccharides.
In another embodiment, the sensor array may be used to optimize which receptor molecules should be used for a specific analyze. An stray of receptors may be placed within the cavities of the supporting member and a stream containing an analyze may be passed over the array. The reaction of each portion of the sensing array to the known analyze rosy be analyzed and the optimal receptor determined by determining which particle, and therefore which receptor, exhibits the strongest reaction toward the analyze. In this manner, a large number of potential receptors may be rapidly scanned. The optimal receptor may then be incorporated into s system used for the detection of the specific analyze in a mixture of analyzes.

It should be emphasized that although some particles may be purposefully designed to bind to importint apaies (biological agents, toxins, nerve gasses, ate.), moat structures will possess nonspecific receptor groups. One of the advantages associated with the proposed sensor array is the capacity to standardize each array of particle via exposure to various aaalytes, followed by storage of the patterns which arise from interaction of the analyzes with the particles. Therefore, there may not be a need to lrnow the identity of the actaal receptor on each particle. Only the characteristic pattern for each array of particles is impo<dmt. In fact, for many applications it may be less time consuming to place the various particles into their respective holdtrs without taking precautions to characterize the location associated with the specific particka. When used in this manner, each individual xnaor array may require standardization for the type of analyze to be studied.
On-site calibration for new or unlmown toxins stay also be possible with this type of amy. Upon complexation of an aaalyte, the local microenvironment of each indicator may change, resulting in a modulation of the light absorption and/or ensiasion properties. The use of aunda;d pattern recognition algorithms completed on a computer glatform may serves as the intelligence factor for the analysis. The "fingerprint" flee response evoked from the simultaneous interactions occurring at multiple sites within the substrate may be used to idemify the species present is unknown samples.
The above described sensor array system offers a number of distinct advantages over exiting technologies.
One advantage is that "real time" detection of aaalytes may be performed.
Another advantage is that the simultaneous detection of multiple analyzes may be realized. Yet another advantage is that the sensor array system allows the use of synthetic reagents as well as biologically produced reagents. Synthetic magenta typically have superior sensitivity and specificity toward analyzes when compared to the biological ragents. Yet another advantage is that the sensor array system may be readily modified by simply changing the particles which are placed within the sensor array. This interchangability may also reduce production costs.
EXAMPLES
1. The determination of pH using a chemically sensitive particle.
Shown in F1G. 15 is the magnitude of the optical signal transmitted through a single polymer particle derivatized with o-cresolphthalein. Here, a filter is uud to focus the analysis on those wavelengths which the dye absorbs most strongly (i.e., about 550 am). Data is provided for the particle as the pH is cycled between acid and basic environments. In acidic media (i.e., at times of 100-150 seconds and 180-210 seconds), the particle is clear and the system yields large signals (up to grzatcr than 300,000 counts) at the optical detector. Between times of 0~
100 and 150-180 seconds, the sohxtion was made basic. Upon raising the pH
(i.e., making the solution rr~re basic), the particle taros purple in color and the transmitted green light is greatly diminished. Large signal reductions are recorded under such circumstances. The evolution of the signal changes show that the response time is quite rapid, on the order of 10 seconds. Furthermore, the behavior is highly reproduct'ble.
2. T'he simultaneous detection of Ca", Cc ', and pH by a sensor array system.
The synthesis of four different particles was accomplished by coupling a variety of indictor ligands to a polyethylene glycol-polystyrene ("PEG-PS") resin particle. T'he PEG-PS resin particles were obtained from Novtbiochem Corp., La lolls, Ca. The particle: have as average diameter of about 130 pin when dry and about WO OOI0437z PCT/US99/16162 _ 250 we when wet. The indicator ligatrds of fluorcacein, o-ctesolphthaleia complexono, and alizuin conrplexone were each attached to PEG-PS resin particles using a dicyclohexykarbodiimide (DCC) coupling between a ttrrmiml resin bound amine and s carboxylic acid on the indicator ligaad.
These synthetic raxptors, localized on the PEG-PS resin to create sensing particles, were positioned within micromachiacd wells formed in silicod~licon nitride wafers, thus confining the particles to individually addressable positions on a multicompotxat chip. These wells were sized to hold the particles in both swollen and unswollen states. Rapid introduction of the test fluids can be accomplished using these structures while albwing sp~rophotometric assays to probe for the presence of analyzes. For the idenHfteatioa sad quantification of sttalyce species, changes in the light absorption sad light emission properties of the immobilized resin particles can be expbihed; although only identification based upon absorption properties are discussed here. Upon exposure to analytea, color changes for the particles were found to be 90% complete within one minute of exposure, although typically only seconds were required. To make the analysis of the colorimeftic changes efficient, rapid, and sensitive, a charge-coupled-device (CCD) was directly interfaced with the sensor array. Thus, data streams rna>posed of red, green, and blue (RGB) light intensities were acquired and processed for each of the individual l 5 particle elements. The red, blue, and green responses of the particles to various sohetions are graphically depicted in FIG. 16.
The true power of the described bead sauor array ocaas when simultaneous evaluation of multiple chemically distinct bead structures is completed A demonsoration of the capacity of five different beads is provided in FIG. 16. In this case, blank, alizarin, o.creaol phthalein, tluotescein, and alizarin-Ce3+ complex derivatized beads serve as a matrix for subtle difl'uentiation of chemical enviro~enis. The blank bead is simply a polystyrene sphere with no chemical derivatization. The bead de 'rrvatized with o-c~aolphthalein responds to G+2 st pHs values around 10Ø The binding of calcium is noted from the large green color attenuation noted for this dye while exposed to the canon. Similarly, the tluorescein derivatized bead acts as a pH sensor. At pHs below 7.4 it is Gght yellow, but st higher pHa it tunes duk orange. labeceatiag, the alizuin complexone plays three distinct roles. First, it acts as a pintos sensor yielding a yeltow color at pHs below 4.5, orange is noted at plis between 4.5 and 11.5, and at pHs above 11.5 a blue hue is observed. Second, it functions as a sensor for lanthanum ions at lower pHs by turning yellow to orange. Third, the combination of both fluoride sad lanthanum ions results in yellowlorange coloration.
The analysis of aolutioos containing various smottat of Ca" or 1: at various pH levels was performed using alizarin c~plcxone, o-cresolphthaleia complexone, 5-carboxy fluoraceio, and alizarin-Ce'* complex. A
blank particle in which the tern>iaal amines of a PEG-PS resin particle have been acylated was also used. In this example, the presence of Ca" (0.1 M Ca(NO~=) was analyzed under conditions of varying pH. The pH was varied to values of 2, 7, and 12, all buffered by a mixture of 0.04 M phosphate, 0.04 M acetate, and 0.04 M borate. The RGB patterns for each sensor element is all environments were measured. The bead derivatized with o-cresolphthalein responds to Ca+' at pH values around 12. Similarly, the 5-eatboxy fluoreseein derivatized bead acts as a pH sensor. At pHs below 7.4 it is light yelbw, but at higher pHs it turns dark orange. Interesting, the alizarin complexone playa three distinct roles. First, it acts as a proton sensor yielding a yellow color at pHs below 4.5, orange is noted at pHa between 4.5 and 11.5, and at pHs above 11.5 a blue hue is o~erved. Second, it titactiams as a sensor for lanthanum ions at lower pHs by turning yellow to orange. Third, the combination of both fluoride and Isathaatun ions results in yellow/orange coloration.
This example demonstrates a number of important factors related to the design, testing, and fimctionaliiy of micmmacluned stray sensors for aolutimr analyses. First, derivstizatioa of polymer particles with both cobrimetric sad fluorescent dyes was completed. These stntcriues were shown to respond to pH and Ca", Second, response tunes well under 1 minute wen found Third, micromachined arrays suitable both for confinement of particles, es well as optical characterization of the particles, have been prepared Fourth, integration of the test bad arrays with cotrunercially available CCD detectors has bees accomplished. Finally, simultaneous detection of several analyzes in a mixture was made possible by analysis of tire ROB color patterns created by the sensor atzay.
3. The debxtion of suttar molecules using a boronic acid based receptor.
A xries of receptors were prepared with functionalitics that associate strongly with sugar molecules, as depicted in FIG. 9. Is this case, a boronic acid sugar receptor 500 was utilized to demonstrate the functionality of a I S new type of sensing sche~ in which competitive displacement of a resorufm derivatized galactose sugar molecule was used to assess the presence (or lack thereof] of other sugar molecules.
The boronic acid receptor 500 was formed via s substitution reaction of a benrylic bromide. The boronic acid receptor was attached to a polyethylene glycol-polystyrene ("PEG-PS's resin particle at the "R" position. Initially, the botonic acid derivatized particle wa loaded with resorufm de 'rnatized gahtctose 510. Upon exposure of the particle to a solution containing glucose 520, the resorufin derivatized galactox molecules 510 sre displaced from the particle receptor sites. Visual inspection of the optical photographs taken before and after exposure to the sugar solution show that the boron substituted resin is capable of sequestering sugar molecules from an aqueous solution. Moreover, the subsequent exposure of the colored particles to a solution of a non-tagged sugar (e.g., glucose) leads to a displacement of the bound colored sugar reporter molecule. DispLcement of this molecule leads to a change in the color of the particle.
ZS The augur sensor toms from dark orange to yellow in solutions containing glucose. The particles were also in conditions of varying pH. It was noted that the color of the particles changes from dark orange to yellow as the pH is varied from low pH to high pH.
FURTHER IMPROVEMENTS
Shown in FIG. 17 is an embodiment of a system for detecting anslytes in a flnid In one embodiment, the system inchrdes a light source 512, a sensor array 522, a chamber 550 for supporting the sensor array and a detector 530. The sensor array S22 may include a supporting member which is configured to hold a variety of particles. In one embodiment, light originating from t6c light source 512 passes through the sensor array 522 and out through the bottom side of the sensor array. Light modulated by the particles may be detected by a proximally spaced detector 530. While depicted as being positioned below tire sensor array, it should be understood that the detector may be positioned above the sensor array for reflectance measurements.
Evaluation of the optical changes may be completed by visual inspection (e.g., by eye, or with the aid of a microscope) or by use of a microprocessor 540 coupled to tire detector.

WO 00/04372 PCTNS9911b1b2 In this embodiraeat, the sensor atny S22 is positioned within a chamber SSO.
The chamber 550, may be coofigurod to allow a fluid stream to peas through the chaanber such that the fluid stream interacts with the sensor atxay 522. The chamber may be conatructcd of glass (e.g, borosilicate glass or quartz) or a plastic material which is banaparent to a portion of the light from the light source. If a plastic material is used, the plastic material s slro be aulxttaatially unreactive toward the fluid. Examples of plastic materials which may be used to form the chamber include, but are not limited to, acrylic resins, polycarbonates, polyester rosins, polyethyknes, polyimidea, polyvinyl polymers (e.g., polyvinyl chloride, polyvinyl acetate, polyvinyl dichloride, polyvinyl fluoride, etc.), polystyrenes, polypropylenes, polytetrafluomethyknea, and polyurethanes. An example of such a chamber is a Sykes-Moon chamber, which is commercially available from Bellco Glass, Inc., is New Jersey. Chamber 550, in (0 ~e embodiment, includes a fluid inlet port 552 and a fluid outlet port 554.
The fluid inlet SS2 and outlet S54 p~
are configured to allow s fluid stream to puss into the interior 556 of the chamber during use. The inlet and outlet ports may be configured to allow facile placement of a conduit for transferring the fluid to the chamber. In one embodiment, the ports may be hollow conduits. The hollow conduits may be configured to have an outer diam~a which is substantially equal to the inner diameter of a tube fm trtutsferring the fluid to or away from the chamber.
For example, if a plastic or rubber tube is used for the transfer of the fluid, the internal diameter of the plastic tube is substantially equal to the outer diameter of the inlet and outlet ports.
In another embodiment, the inlet sad outlet ports may be Luer lock style connectors. Preferably, the inlet ud outlet ports are female Luer lock connectors. The use of female Luer lock connectors will allow the fluid to be ini:oduced via a syringe. Typically, syringes iachtde a male Luer lock connector at the dispensing end of the syringe. For the introduction of liqu~ samples, the use of Leer lock connectors may allow samples to be transferred directly from a syringe to the chamber 550. Leer lock conaecbors may also allow plastic or rubber tubing to be connected to the chamber using Luer lock tubing ooonectots.
The chamber may be configured to allow the passage of a fluid sample to be substantially confined to the interior S56 of the chamber. By confining the fluid to a small interior volume, the amount of fluid required for an 2S analysis may be minimized. The interior vohtme may be specifically modified for the desired application. For example, for the analysis of small volumes of fluid samples, the chamber may be designed to have a small interior chamber, thus reducing the amount of fluid needed to fill the chamber. For larger sangrlea, a larger interior chamber may be used. Larger chambers tray allow a faster thmughpat of the fluid during ux.
In another embodiment, depicted in FIG. 18, a system for detecting analyzes in a fluid includes a light source 512, a sensor army 522, a chamber SSO for supporting the sensor array and a detector 530, all enclosed within a detection system enclosure 560. As deacn'bed above, the sensor array 522 is preferably formed of s supporting member which is configured to hold a variety of particles. Thus, in a single enclosure, all of the components of an aoalyte detection system rue included.
The formation of an analyte detection system is a single enclosure tray allow the formation of s portable detection system. For example, a small controller 570 may be coupled to the saalyte detection system. The controller 570 may be configured to interact with the detector and display the results from the analysis. In one embodiment, the controller includes a display device 572 for displaying information to a user. The controller may also include input devices 574 (e.g., buttons) to allow the user to contml the operation of the analyze detection system. For example, the controller may control the operation of the light solace 512 sad the operation of the detector 530.
The detection system encioatm 560, tnsy be interchangeable with the conh~oller. Coupling members 576 sad 578 may be used to reeve the detection system enclosure 560 from the controller 570. A second detection system enclosure may be readily coupled to the controller using coupling members 576 and 578. 1n this manner, a variety of different types of anslyCcs may be detx;c>;ng using s variety of different detection system encloataea.
Each of the detection system cacloatues may iochtde different aet>sar arrays mounted within their chambers.
Instead of having to exchange the sa>sor array for different types of analyraia, the ere detecti~ system enclosure may be exchanged. This may prove advantageous, when a variety of detection schemes arc used. For example a fast detection system enclosure may be configured for white light applications. The fast detection system enclosure may include a white light sotme, a sensor that includes particles that produce a viatbk light response in the presence of an analyze, and a detector sensitive to white light. A second detection system enclosure may be configured for fluorescent applications, including a ttttoresceat light source, a sensor array which includes particles which produce a fluorescent response on the prtaence of an analytc, and a fluoreacaat detector. The second I S detection system eneloswe may also include other components necessary for pmdtrctag a proper detection aysoeno.
For example, the second detection system tray also include a filter for preventing short wavelength excitation from producing "false" signals is the optical detection aymm during fluorescence ttieasurements. A user need only select the proper detection system enclosure for the detection of the desired analyte. Since each detection system enclosure includes many of the required components, a user does not have to make light source selections, sensor atvay selections or detector arrangement selections to produce a viable detection ayskm In another embodiment, the individual components of tht system may be i~erchangeable. The system may inchtde coupling members 573 and 575 that allow the light source and the detector, respectively, to be removed from the chamber 550. This may allow a more modular design of the system. For example, as analysis may be fast performed with a white light source to give data correspond'rag to an abaorbancvrefkchmce analysis. After this analysis is perforated the light source trtay be chaagsd to a ultraviolet light:ource to allow ultraviolet ttnaly:;s of the particles. Since the particles have already been treated with the fluid, the analysis may be preformed without further treatment of the particles with a fluid. In this tttattner a variety of tests tray be performed using a single sensor array.
In one embodiment, the supporting member is made of any material capable of supporting the particles, wht3e allowing the passage of the appropriate wavelength of light. The supporting member may also be made of a material substantially itttpetvious to the fluid in which the analyte is present. A varlety of materials may be used inchtding plastics (e.g., photoresist tuaterials, acrylic polymers. carbonate polymer, ere.), glass, silicon based tnsterials (e.g., silicon, silicon dioxide, silicon nitride, ere.) and metals.
In one embodioneat, the supporting member inchtdea a plurality of cavities. The cavities arc preferably formed such that at leant arse particle is substantially comained within the cavity. Alternatively, a phuality of particles may be contained within s single cavity.
In some embodiments, it will be accessory to pass liquids over the sensor sorry. The dynamic motion of iiquida across the settaor stray may lead to displacement of the particles from the cavities. In another embodiment, the particles are preferably held within cavities formed in a supporting member by the use of a aansmission electron microscope ("TEM") grid. As depicted in FIG. 19, a cavity 580 is formed in a supporting member 582.

After placement of a particle 584 within the cavity, a TEM grid 586 may be placed atop the supporting member 582 and secured into position. T'EM grids and adhesives for securing TEM grids to a support are commercially available firrom Ted Pelts, Inc., Redding, CA. The TEM grid 586 may be made frorir a number of materials inchrding, bnt not limited to, copper, nickel, gold, silver, dumintmt, molybden>tm, titanium, nylon, beryllium, carbon, sad beryllium-copper. The mesh structure of the TEM grid may allow solution access as well as optical access to the particles that are placed in the cavities. FIG. 20 Rather depicts a top view of a sensor array with a TEM grid 586 formed upon the upper surface of the supporting member 582. The TEM gild 586 may be placed on the upper surface of the supporting member, trapping particles 584 within the cavities 580. As depicted, the openings 588 is the TF.M grid 586 may be sized to hold the particles 584 within the cavities 580, while allowing fluid and optical access to cavities 580, In another embodiment, a season array iachtdea a supporting member coafigttred to support the particles, while allowing the passage of the appropriate wavelength of light to the particle. The supporting member, in one embodiment, includes a plurality of cavities. The cavities may be formed such that at least one particle is substantially contained within the cavity. The supporting member may be configured to substantially iniubit the displacement of the particles from the cavities doting use. Tha supporting member may also be configured to allow the passage of the fluid through cavities, e.g., the fluid may flow from the top surface of the supporting member, peat the particle, and out the bottom surface of the supporting atember. This may increase the contact flux between the particle and the fluid.
Figures 21 A-G depict a aeqtterace of processing steps for the formation of a silicon based supporting member which includes a removable top cover and bottom cover. The removable top cover may be configured to allow fluids to pass through the top cover and into the cavity. The removable bottom cover may also be coafrgtaed to allow the fluid to pass through the bottom cover and out of the cavity. As depicted in FIG. 21A, a series of layers may be deposited upon both sides of a silicon substrate 610. First removable layers 612 may be deposited upon the silicon substrata. The removable layers 612 may be silicon dioxide, silicon nitride, or photareaist tnateciaL
In one embodiment, a layer of silicon dioxide 612 is deposited upon both surfaces of the silicon substrate 610.
Upon these removable layers, covers 614 may be forrtted. In one embodiment, covets 6l4 are formed from a material that differs from the material used to form the removable layers 612 and which is substantially transparent to the light source of a detection system. For example, if the removable layers 612 ate formed from silicon dioxide, the cover may be formed from silicon nitride. Second removable layers 616 may be formed upon the covers 614.
Socond removable layers 616 may be formed from a material that differs from the material used to form the covers 614. Second removable layers ti 1 ti stay be formed from a material similar to the material used to form the foal removable layers 612. in one embodiment, first and second removable layers 612 and 616 are formed from silicon dioxide sad covers 614 are formed from silicon nitride. The layers are patterned and etched using standard photolithographic techniques. la one ecnbodiroenf, the remaining portions of the layers are substantially aligned is the position where the cavities are to be farmed in ~e silicon substrate 610.
After the layers have been etched, spacer struchues may be formed oa the sidewalk of the fast reawvabk layer 612, the covers ti 14, and the second removable layers 616, as depicted in FIG. 21B. The spacer atructttres may be formed from the same material used to form the second removable layers 6lti. In one embodiment, depositing a spacer layer of the appropriate material and subjecting the raatcrial to an aniaottopic etch may form the spacer structures. As anisotropic etch, such as s plasma etch, employs both physical sad chemical removal rncchaniams. Ions are typically bombarded at an angle substantially perpendicular to the aemicondactor substrate upper surface. This causes subatantislly horizot~l surfaces to be removed faster than substantially vertical surfaces. During this etching procedure the spacer layers are preferably removed such that the only regions of the spacer layers that remain may be those regiom roar substsatially vertical surfaces, e.g., spacer structures 618.
After foamatioa of the spacer a>zucaues 618, cover support structures 620, depicted in FIG. 21C, may be formod. The cover support stnrctures may be initially formed by depositing a support structure layer upon the second removable layer 616 and spacer structures 618. The support structure layer is then patterned sad etched, using standard photolithography, to form the support structures 620. In one embodi~nt, the support structures are formed from a material that differs from the removable layers material. In one embodiment, the removable layers may be formed from silicon dioxide while the support structures and covers may be formed from silicon nitride.
Turning to FIG. 21 D, the second removable layers 616 and an upper portion of the spacer atrucdues 618 are preferably removed using s wet etch process. Removal of the second removable layers leaves the top aaufice of the covers 514 exposed. This allows the covers to be patberaed and etched arch that openings 622 are formed extending through the covers. These openings 622 may be formed in the covers 614 to allow the passage of fluid thmngh the cover layers. In one ernbodinxut, the openings 622 ate formed to allow fluid to pass through, while inhibiting di~lacxmeat of the particles from the subsequently formed cavities.
ARer the openings 622 have been forward, the ren~sinder of the fast removable layers 612 and the remainder of the spacer structures 618 may be removed trslag a wet etch. The removal of the removable layers sad the spacer structures creates "floating" coven 614, as depicted in FIG. 21E.
The covesa 614 rosy be held in proximity to the silicon aubstrade 610 by the support structures 620. The covers 614 may now be removed by sliding the covers away from the support stmeua~es 620. In this manner removable covers 614 may be formed.
After the coven 614 are removed, cavities 640 may be formed in the silicon substrate 610, as depicted in FIG. 21F. The cavities 640 may be formed by, initially patterning and etching a photoresist material 641 to farm a raaakiag layer. After the photoresist material 641 is patterned, the cavities 640 rosy be etched into the ailuon substrate 610 using a hydroxide etch, as described previously.
ARer the cavities 640 are formed, the photorrsiat material may be removed sad particles 642 rosy be placed within the cavities, as depicted in FIG. 21 G. The particles 642, may be ialubioed fiom being displaced from tine cavity 640 by placing covets 614 back onto dre upper and lower faces of the silicon substrate 610.
In another embodiment, a senior array may be formed using a supporting member, a removable cover, sad a secured bottom layer. FIGS. 22 A-G depict a series of processing steps for the formation of a silicon based supporting member which includes a removable top cover and a accrued bottom layer. The removable top cover is preferably configured to allow fluids to pass through the top cover and into the cavity. As depicted is FIG. 22A, a series of layers may be deposited upon both sides of a silicon substrate 610.
A feat removable layer 612 may be deposited upon the upper face 611 of the silicon substrate 610. The removable layer b12 may be silicon dioxide, silicon nitride, or photoresist material. In one embodiment, a layer of silicon dioxide 612 is deposited upon the silicon substrate 610. A cover 614 may be formed upon the removable layer 612 of the silicon substrate 610. In one embodiment, the cover 614 is formed from a material that differs from the material used to form the raaovable layer 612 sad is substantially transparent to the light source of a detection system. For example, if the ~vabk WO 00/04372 PCT/US99/1b162 _ layer b 12 is formed 6 om silicon dioxidt~ the cover l aye 614 may be formed from silicon nitride. In one embodiment, a bottom layer 615 is formed on the bottom surface 613 of the silicon sub:trau 610. In one embodinxat, the bottom layer 615 is formed from a material that is aubstantisliy asasparent to the light source of a detection systeta A second removable layer 616 trtay be formed upon the cover 614. Second removable layer 616 may be formed from a maurial that differs from the material used to form the cover layer 614. Sexond remmvabk layer 61 b may be formed from a material similar to the material usead to form the first texaovable layer 612. In one embodiment, first and second ttmovable layers 612 and 616 are: formed from silicon dioxide and cover 614 is formed from silicon nitride. The layests formed on the upper surface b 11 of the silicon aubstrau may be and etched using standard photolithogtsphic tea:haiques. In one embodimcat, the remaining portions of the layer formed on the upper surface are substantially aGgncd in the position where the cavities are to be formed in the silicon substrau 610.
ARer the layers have; been etched, spacxr strucaures may be formed oa the side wsl): of the; fast removable layer 612, the cover 614, and the second removable layer 616, as ekpicud in FIG. 22B. The spacer atrucdues rosy be formed from the same material used to form the second removable layer 616.
In one embodiment, the spacer structure may be formed by depositing a spaces layer of the appmpriau aostexiul and subjecting the spacer layer to an snisotropic etch. During this cubing procedure the spacer Isyer is preferably removed such that the only resgions of the spacer layer which remain may be those regions near substantially vertical surfaces, e.g., spacer structures 618.
After formation of the spacer structures 618, cover support structures 620, depicted is FIG. 22C, troy be formed upon the removable layer b 1 b and the spactr structures 618. The cover support strucdues b20 may be:
formed by depositing a support structure flyer upon the aetcond ramovabk layer 616 and spacer atruchue;a 618. The setpport atmcture layer is then patterned lard ebc>>ad, using standard photolithography, to form the support stsucaaes 620. In otie embodiment, the: support structures are formed from a mate;riai that differs from the removable layes~
materials. In one embodiment, the removable layers may be formed from silicon dioxide while the support structures and cover may be: formed from silicon aittide.
Taming to FIG. 22 D, the: second re~vable layer 616 and an upper portion of the spacer structnrers 618 may be removed using a wet etch process. Removal of die second removable layer leaven the top surface of the cover 614 exposed. This allows the cover 6i4 to be pattemexi and etched such that openings 622 rue formed extending dtrough the cover 614. These openings 622 may be fomned in the cover 614 to allow the passage of fLeid through the cover. In one embodiment, the opeaiaga 622 arc fortned to allow fluid to pass through, while inhibiting disphicement of the particle from a cavity. The bottom layer 615 may also be similarly patterned sad etched such that openings 623 may be formed exuading thorough the bottom layer b 15.
After the openings 622 and b23 are formed, the first removable layer 612 and the remainder of the spacer atructure~ 6I8 may be removexi using a wet etch. The removal of the removable layers sad then spacer atntcdu~ea creates a "floating" cover 614, as depicted in FIG. 22E. The cover 614 may be held in proximity to the silicon substrate 610 by the support strictures 620. The covtc 614 may now be removed by Biding the cover 614 away from the support structures 620. In this manaex a retaovsbk cover 614 tray be foratexl After the covtr 614 is removed, cavities 640 may be formed in the silicon substrau 610, as depictexl is FIG. 22F. 'Ihe cavities 640 may be formed by, initially patterning and etching a photoraist material 641 to form a masking liyer. After the phototesiat material 614 is patterned, the csvidea 640 may be etched into the salicon anbahate 610 using a hydroxide etcb, as deacrtbed previously.
After the cavities 640 are formed, the p>z#aresist material may be removed and particles 642 may be placed within the cavities, as depicted in FIG. 22G. The particles 642, may be inhibited from being displaced fram the cavity 640 by placing cover 614 back onto the upper face 611 of the silicon substrate 610. The bottom layer 61 S may also aid in inhibiting the particle 642 6rom being displaced from the cavity 640. Openings 622 in cover 614 sad openings 623 in bottom layer 615 may allow fluid to pans through the cavity during six.
Ice another embodiment, a sensor array may be formed using a supporting member a~ a ranovabk cover.
FIGS. 23A-G depict a xries of processing steps for the formation of a silicon based a>pportiag masher which includes a removable cover. The removable cover is preferably configured to allow ttlnids to pass through the cover and into the cavity. As depicted in FIG. 23A, a seciea of layers rosy be deposited upon the upper surface 611 of a silicon aubatnte 610. A foal removable layer 612 rosy be deposited upon the upper face 611 of the s0icon substrate 610. The removable layer 612 may be ailic~ dioxide, silicon nitride, or photoresist material. In one embodiment, a layer of silicon dioxide 612 is deposited upon the silicon:ubsaate 610. A cover 614 may be formed upon the removable layer 612. In one embodiment, the cover is formed from a material which differs frays the material used to form the ~vable layer 612 and which is subah~atially t<anaperent to the light source of s deoestion system. For example, if the removable layer 612 is formed from silicon dioxide, the cover 614 may be fomted from silicon nitride. A second removable layer 616 may be formed upon the cover 614. Second removable layer 616 may be formed from a material that diifua from the material used to from the cover 614. Second removable layer 616 rosy be foczned from a material similar to the material uxd to farm the fu~st removable layer 612. In one embodiment, first and second removable Lyera 612 sad 616 are formed from silicon dioxide and cover 614 is formed from silicon nitride. The layers farmed on the upper:urface 611 of the ~licoa substrata may be patterned and etched using standard pbotoli>bogcaphic techniques. In one embodiment, the remaining portioa~ of the layers formed on the upper surface ate substantially aligned in the position where the cavities are to be forayed is the silicon substrate 610.
ARtr the layers have been etched, spacer attucNcea 618 rosy be formed on the side walls of the fait removable layer 612, the cover layer 614, and the second remanrabk layer 616, as depicoed in FIG. 23B. The spacer sues 618 may be formed from the same material used to form the second removable layer 616. In one embodiment, the spacerx may be formed by depositing a spacer layer of the a~rmptiste material upon the second removable layer and subjecting the material to an snisotropic etch. During this etching procedure the spacer layer is preferably removed such that the only regions of the spacer layer which remain tnsy be those regions near substantially vertical autfacea, e.g., spacer atracutrea 618.
After formation of the spacer atntctutes 618, cover support stnteWrea 620, depicted in FIG. 23C, may be formed upon the removable layer 616 and the spacer structures 618. The cover support structure may be formed by initially depositing a support structure layer upon the xcond removable layer 6 t 6 sad spacer strucanes 618. The support structure layer is then psttemed and etched, using standard photolithography, to form the support strucdues 620. Ice one embodiment, the support structures 620 an formed fi~om a material that differs from the removable layer materials. In one embodiment, the removable layers tray be formed from silicon dioxin while the support structure sad cover layer may be formed from silicon nitride.

WO 00/043?2 Pt'.:'T/US99/16162 Tut>vag to FIG. 23D, the salad removable layer 6I6 and as upper portion of the spacer sirucdrres 618 may be removed using a wet etch process. Removal of the secot~ removable layer leaven the top surface of the cover 614 exposed. This allows the cover 614 to be pattemad and etched such that openings 622 are farmed exoeading through the cover 614. These opeai~ 622 may be formed in the cover 614 to allow the passage of fhtid through the cover 614.
After the openings 622 are formed, the remainder of the first removable layer 612 and the remainder of the apacec atrucdrres 618 nuy be removed using a wet etch. The removal of the removable layers and the spacer sttncdaes creates a "floating" cover 614, as depicted in Flfi. 23E. The cover 614 is preferably held is proxianitY bo the silicon substrate 610 by the support sttvctuces 620. The cover 614 may now be rea>oved by sliding the cover 614 sway from the support structures 620. In this manner a carrovsble cover 614 may be fomud.
After the cover 614 is removed, cavities 640 away be formed is the silicon substrate ti 10, as depicted in FIG. 23F. The cavities 640 may be formed by initially depositing and patterning s photoresist ataterial 641 upon the silicon support ti 10. After the photorcaiat material 614 is patterned, the cavities 640 may be etched into the silicon aubat<ate 610 using s hydroxide etch, as deaaibed previously. The etching of the cavities may be accomplished sucb that a bottom width of the txvity 643 is less than a width of a particle 642. In one erabodimeat, the width of the bottom of the cavity may be controlled by varying the etch time. Typically, longer etching times result in a larger opening at the bottom of the cavity. By fotmiag a cavity is thin marmcr, a particle placed in the cavity may be too large to pass through the bottom of the cavity. Thus, a supporting member that does not inchule a bottom layer may be formed. An advantage of this process is that the pmcea:irtg steps may be reduced malting production eiarpla.
After the cavities 640 are formed, the pl>otosesist material may be removed sad particles 642 rosy be placed within the cavities, as depicted is FIG. 23G. The particles b42, away be inhrbited from being displaced fiomo the cavity 644 by placing cover 614 back onto the upper face 611 of the silicon substrate 6t0. The narrow bottom portion of the cavity may also aid in inhibiting the particle 642 from being displaced firom the cavity 640.
Figures 24A-d depict a sequence of processing steps for the formation of a atlicoa based supporting member which includes a top partial cover and a bottom partial cover. The top partial cover and bottom partial covers are. in one embodiment, configured to allow fluids to pass into the cavity and out through the bott~t of the cavity. As depicted in FIG. 24A, a bottom liyer 712 may be deposited onto the bottom surface of a silicon substrate 710. The bottom layer 712 may be silicon dioxide, silicon nitride, or photorrsiat material. In one embodiment, a layer of silicon nitride 712 is deposited upon the silicon substrate 710. In one embodir~nt, openings 714 are formed through the bottom lays as depicted in FIG. 24A. 714, in one embodiment, are sabatamially aligned with the position of the cavities to be subsequently formed. The opaniags 714 may have a width that is substantially less than a width of a particle. Thus s particle will be inhabited from passing through the openinga714.
Gvities 716 awy be formed in the silicon substrate 710, as depicted in FIG.
24B. The cavities 716 may be fomsed by initially depositing and patterning s p6otoresist layer upon the s~1'coa substrate 710. Aftcr.thc photoreaist material is patterned, cavities 716 may be etched into the silicon substrate 710 using a number of etching techniques, including wet sad plasma etches. The width of the cavities 716 is preferably greater than the width of a particle, thus allowing a particle to be placed within each of the cavities. The cavities 716, in one embodiment, are preferably formal such that the cavities arc aubataadally aligned over the openiaga 714 formed in the bottom layer.
Aftsr tire cavities have been famed, particles 718 may be ioaa~ted into the caritits 716, as depicted in FIG. 24C. The etched bottom layer 712 may save as a support for the particles 718. Thus the particles 718 may be inhibited from being displaced from the cavities by the both layer 712. The opeainga 714 in the bottom layer 712 may allow fluid to peas thmugh the bottaat layer during use.
After the particles are phuxd in the cavities, a top layer 720 may be pLced upon the upper surface 717 of the silicon :abetrslc. In orre embodiment, the top layer 720 is foraxd fiom a material is snbabntially transparent to the light source of a detection system. The top lays may be formed flvnm silicon nitride, silicon dioxide or plloboct:ist amterisl. In one embodiment, a aht~et of pbotareaiat tnataial is naed. After the top layer 620 is formed, openings 719 may be farmed in the Dop layer to allow the passage of the fluid into the cavities. if the top layer 720 is composed of photoresist material, after depositing the p6otoreaiat material across the upper surface of the silicon aubatrate, the openings may be initially formed by exposing the photoreaist material to the appropriate wavelength and pattern of light. If the top layer is compose of silicon dioxide or silicon nitride the top layer 720 may be developed by forming a photoresist layer upon the top layer, developing the p6otoresiat, and using the photoresist to etch the underlying top layer.
Similar sensor arrays may be produced using materials other than silicon for the supporting member. For example, as depicted in FIG 25 A-D, the supporting member may be composed of photoreaist material Ia one embodiment, sheets of photoreaist film tray be used to form the supporting member. Photoresist film sheets are commercially available from E. I. du Pont de Nanours and Company, Wilmington, DE under the commnercial name RISTbN. The sheets come in a variety of sizes, the moat cxusnnon having a thiclmesa ranging from about 1 mr~.
(2S pm) to about 2 mil. (50 pan).
In an embodiment, a fa~at photoresist layer 722 is developed and etched such that openiaga 724 ere formed. The openings may be formed proximate the loation of the ~rbseqaeatly formal cavities. Preferably, the opmiaga have a width that is aubatsatially smaller thaw a width of the particle. The openings may inhibit displacement of the particle from a cavity. After the fast photoreaiat layer 720 is pattemtd sad etched, a main lays 726 is formed upon the bottom layer. The main layer 720 is preferably formed from a photorcsist film that has a thiclaiess substantially grtater than a typical width of a particle. Thus, if the particles have s width of about 30 pm, a main layer may be composed of s 50 ltm photoresist tnaterisl. Alternatively, the photoreaist layer may be comq~oaed of a multitude of p6otoresist layers placed upon each other until the desired t6icimess is achieved, as will be depicted in later embodiments.
The main photoreaist layer may be patterned and etched to form the cavities 728, as depicted in FIG. 25B.
The cavities, in one embodiment, are subataatialIy aligned above the previously formed openings 724. Cavities 728, in one embodiment, have a width which is greater than a width of s particle.
For many types of analysis, the photoresist material is substantially transparent to the light source used.
Thna, as opposed to a silicon supporting member, the photoreaitt material used for the main supporting layer may be aubstaatWiy transparent to the light used by the light source. In some circumstance, the transparent natsae of the supporting member may allow light fiom the cavity to migrate, through the supporting member, into a second cavity. This leakage of light from one cavity to the next may lead to detection problems. For example, if a first WO OOI04372 PCT/US99/1tL162 pertick is a flm cavity produces a fluoresecnc signal in raponae to an analyze, this signal may be aansmitoed through the supporting member and detected in a proximate cavity. Thin may lead to inacetuate readings for the proximately spaced cavities, especially if a particularly strong signal is produced by the interaction of the particle with an aaalytc.
To reduce the occusreace of this "emas~~Ilc", a substantially reflective layer 730 may be formed along the inner surface of the cavity. In one embodiment, the reflective layer 730 is compoaod of a metal layer which is fad on the user surface of the main layer and the inner surface of the cavity.
The metal layer rosy be deposited using chemical vapor deposition or other known techniques for depositing thin metal layers. The presence of a reflective layer may inhibit "cross-talk" between the cavities.
ARer the cavities 728 have been formed, particles 718 essay be inserted into the cavities 728, sa fepictod in FIG. 25C. The first photoresist layer 722 may serve as a support for the particles 718. The particles may be inhibited from being displaced from the cavities by the fast photoresist layer 722. The openings 724 in the fast plbtoresist layer 722 may allow fluid to pass through the bottom layer dntmg use.
ARer tho particles 728 are placed in the cavities 728, a top phatoresist layer 732 may be placed upon the upper atuface of the silicon substrax. After the cover layer is formed, openings 734 may be formed in the cover Lyer to allow the passage of the fluid into the cavities.
In another cmboditnent, the attpportiog member may be formed from a plastic aubauate, as depictod in FIG. 26A-D. In one embodiment, the plastic substrate is composed of a material which is substamially resistant to the fluid which includes the aaalyte. Pacamplea of plastic materials which may be usod to form the plastic sub~aoe include, but are not limited to, acrylic resins, polycxrbonates, polyester resins, polyethylenea, polyimides, polyvinyl poi (a~B~, PoIY~YI chloride, polyvinyl acetate. polyvinyl dichloride, polyvinyl fluoride, etc.), polystyrmea, polYPmPYI~. PolY~~uoroethylenes, sad polyurethanea. The plastic sttbst<ate may be substantially asosprent or nrbatsatially opaque to the light produced by the light source. Attar obtaining a suitable plastic material 740, a series of cavities 742 may be formed in the plastic material. The cavities 740 may be formed by drilling (either tnechsaically or with a laser), transfer molding (e.g., forming the cavities when the plastic material is fozmed using approptisoely shaped molds), or using a punching apparatus to punch cavities into the plastic material. 1n one embodiment, the cavities 740 arc formed ouch that a lower portion 743 of the cavities is substantially narrower than an upper portion 744 of the cavities. The lower portion 743 of the cavities may have a width substantially less than a width of a particle. The lows portion 743 of the cavities 740 may inhibit the disp~at of a particle from the cavity 740. While depicted as rectangular, with a narrower rectangular opening at the bottom, it should be understood that the cavity may be formed in a member of shapes including but not limited to pyramidal, triangular, trapezoidal, and oval shapes. An example of a pyramidal cavity which is tapered such that dte particle is inhibited from being displaced from the cavity is depicted in FIG. 25D.
After the cavities 742 are forn>ed, particles 718 rosy be inserted into the cavities 742, as depicted in FIG.
26B. The lower portion 743 of the cavities may serve as a support for the particles 718. The particles 718 may be inhibited from being displaced from the cavities 742 by the lowor portion 743 of the cavity. Atter the particles are placed is the cavities 740, a cover 744 may be placed upon the upper surface 745 of the plastic substrate 740, as depicted in FIG. 26C. In one embodiment, the cover is formed from a film of photoraist material. ARer the cover WO OO/a4372 PGTNS99/16162 744 is placed on the plastic substrata 740, openings 739 may be formed in the cover layer to allow the passage of the fluid into the cavitita.
In some circurastattces a substantially ttanspareat plastic material may be used. As described above, the use of a transparent supporting member may lead to "cross-talk" between the cavities. To ieduee the occurrence of this "cross-talk", a substantially reflective layer 748 may be formed on the i~ar surface 746 of the cavity, as depicted in FIG. 26E. In one embodiment, the reflective layer 748 is composed of a metal layer which is formed on the inner surface of the cavities 742, The metal layer may be deposited using chemical vapor deposition or other techniques for depositing thin metal iayens. The presence of a reflective layer may inhrbit emss-talk between the cavities.
In another embodiment, a silicon based supporting member for a sensing particle maybe formed without a bottom layer. In this embodiment, the cavity may be tapered to inhibit the passage of the particle from the cavity, through the bottom of the supporting member. FIG. 27A-D, depicts the formation of a supporting member from a silicon substrate. In this embodiment, a photoresist layer 750 is formed upon an upper surface of a silicon substrate 752, as depicted in FIG. 27A. The photoresist layer ?50 may be patterned and developed such that the rogioaa of IS the silicon substrate in which the cavities will be formed are exposed.
Cavities 754 may now be formed, as depicted in FIG. 27B, by subjecting the silicon substrate to se amsotropic etch. In one embodiment, a potassium hydroxide etch is used to produced tapered cavities. The etching may be controlled such that the width of the bottom of the cavities 750 is less than a width of the particle. After the cavities have been etchod, a particle 756 may be inserted into the cavities 754 ss depicted in FIG. 27C. The particle 756 may be inhibited from passing out of the cavities ?54 by the narrower bottom pordoa of the cavities. After the particle is positioned within the cavities 734, a cover 738 may be f~ upon the silicon substrate 752, as depicted in FIG. 27D. The cover tray be formed of any material substantially Gtamparent to the light produced by the light source used for analysis. Openings 759 may be formed is the cover 758 to allow the fluid to pass into the cavity from the tcrp face of the supporting member 752. The openings 759 is the cover and the opening at the bottom of the cavities 754 together may allow fluid to pass through the cavity during use.
In another embodiment, a supporting member for n sensing particle may be formed from a plurality of layers of a photoreaist material. in thin embodiment, the cavity may be tapered to inhibit the passage of the particle from the cavity, through the bottom of the supporting member. FIGS. 28A-E
depict the formation of a supporting member from a plurality of pbotoresist layers. In an embodiment, a first photoresist layer 760 is developed sad etched to form a stries of openings 762 which are positioned at dre bottom of subsequently formed cavities, as depicted in FIG. 28A. As depicted in FIG. 288, a second layer of photoresist material 764 may be formed upon the first pbotoresist layer 760. The second photoresist layer may be developed sad etched to form openings substantially aligned with the openings of the first phobreaist layer 760. The openings formed in the second photoreaist layer 764, in one embodiment, are substantially larger than the layers formed in the t3rst photoresist lays 760. In this manner, a tapered cavity tnay be formed while using multiple photoresist layers.
An depicted is FIG. 28C, additional layers of photoresist material 766 and 768 may be formed ups the second photoresist layer 764. The openings of the additional photoresist layers 766 and 768 may be progressively largo as each layer is added to the stack. In this manner, a tapered cavity tasy be formed. Additional layers of photoresist material tray be added until the desired thickness of the supporting member is obtained. The thickness of the supporting member, in one embodiment, is greater than a width of a particle. For exanapk, if a layer of pbotoraist material has s thickness of about 2S ltett and a particle has a width of about 100 Ntn, a supporting member may be fomud from four or more layers of photoreaist material. While depicted as pyramidal, the cavity may be fomxd in a number of different shapes, including but not limited to, rectangular, circular, oval, triangular, and trapezoidal Any of these shapes may be obtained by appmpriate patterning and etching of the pbotoresist layers as they are formed.
In some instances, the photoresist material may be substantially transparent to the light produced by the light source. As described above, the use of a t<ataparent supporting member may lead to "cross-talk" between the cavities. To reduce the occurrence of this "cross-talk", a substantially refixtive layer 770 may be formed along the inner surface of the cavities 762, as depicted is FIG. 28D. In one embodiment, the reflective layer is can>posed of a metal Layer which is formed on the inner surfax of the cavities 762. The metal lays may be deposited using chemical vapor deposition or other teelsaiques for depositing thin metal layers. The presence of a reflective laytr may inhibit "cmss-talk" between the cavities.
After the cavities 762 arc formed, particles 772 may bt inserted into the cavities 762, as depicted in FIG.
28D. The narrow portions of the cavities 762 may serve as a support for the particles 772. The particles 772 away be ialtibited from being displaced from the cavities 762 by the lower portion of the cavities. After the particle: 772 are placed in the cavities 762, a cover T74 may be placed upon the upper surface of the cop layer 776 of the supporting member, as dtpicted in fIG. 28E. In one embodiment, the cover 774 is also formed from a film of pltotoresist material. After the cover layer is formed, openings 778 may be formed in the cover 774 to allow the passage of the fluid into the cavities.
In another embodiment, a supporting member for a sensing particle may be feed from photoreaiat tnattrisl which includes s particle support layer. FIGS. 29A-B depict the formation of a supporting mamba frost a series of photoresist layers. In an erabodimcat, a first photoresist layer 780 is developed and etched to form a :cries of openings 782 which may become part of subsequently formed cavities. In another embodiment, a cavity having the appropriate depth may be formed by forming nruitiple layers of a photoreaist material, as described previously.
A: depicted in FIG. 29B, a second photoresist layer 784 may be formed upon the first photoresist layer 780. The second photoresist layer 784 may be patterned to form openings substantially aligned with the openings of the fast photoresist layer 782. The openings formed in the second photoreaist lays 784 may be substantially equal in size to the previously formed openings. Alternatively, the openings may be variable is size to form different shaped cavities.
For reasons described above, a substantially reflective layer 786 a>ay be formed along the inner surface of the cavities 782 and the upper surface of the second photoresist layer 784, as depicted in FIG. 29C. In one cmbodimatt, the reflective layer is composed of a metal layer. The metal layer may be deposited using chemical vapor deposition or other teclitiques for depositing thin metal layers. The presence of a reflective layer may inhibit "cmss-talk" between the cavities.
After the metal layer is deposited a particle support layer 788 may be formed on the bottom surface of the first photoreaiat layer 780, as depicted in FIG. 29D. The particle support layer 788 may be formed from photoresist material, silicon dioxide, silicon nitride, glass or a substantially transparent plastic material. The particle support WO 00/04372 Pf.:T/US99/1b1b2 _ layer 788 may serve as a support for the particles placed in the cavities 782.
The patark support layer, in one embodiment, is formed from a maoerial that is sttbstaatially >raasp;rent to the light produced by the light source.
After the particle supporting lays: 788 is formed, particles 785 may be inserted onto the cavities 782, as depicted in FIG. 29E. The particle support layer 788 may serve as a support for the particles. Thus the particles 785 tasy be inhibited from being displaced from the cavities by the particle support layer 788. After tha particles 785 are placed in the cavities 782, a cover 787 may be placed upon the upper surface of the second photoresist layer 784, as depicted is FIG. 29E. Ia one embodiment, the cover is also formed from a film of photoresiat material. After the cover is formed, openings 789 stay be formed is tire cover 787 to allow the passage of the fluid into the cavities. In this embodiment, the fluid is iahbitod from flowing thmugh the supporting member. Instead, the fluid may flow into sad out of the cavities via the openings 789 fortmed in the cover 787.
A similar supporting tnember may be formed from a plastic material, as depicted in FIGS. 30A-D. The plastic material may be substantially resistant to the fluid which includes the anslyte. The plastic material may be snbstaatially transparent or substantially opaque to the light produced by the light source. After obtaining s suitable plastic substrate 790, a series of cavities 792 may be formed in the plastic substrate 790. The cavities may be formed by drilling (either mcchamcally or with a laser), transfer molding (e.g., forming the cavities when the plastic substrate is formed using appropriately shaped molds). or using a pvmchiag machine to form the cavities. In one embodiment, the cavities extend through s portion of the plastic substrate, termiaatiag proximaoe the bottom of the plastic substrate, without passing through the plastic substrate. After the cavities 792 are formed, particles 795 may be ibserted into the cavities 792, as depicted is FIG. 30H. The bottom of the cavity may serve as a support for the particles 795. Ather the particles are placed in the cavities, a cover 794 may be placed upon the upper surface of the plastic substrate 790, as depicted in FIG. 30C. In one embodiment, the cover stay be formed fiom a film of p>mtoresist material. Aftor the cover 794 is formed, opetiiaga 796 may be formed in the cover to allow the passage of the fluid into the cavities. While depicted as rectangular, is should be understood that the cavities may be formed is a variety of differeut shapes, including triangular, pyramidal, pentagonal, polygonal, oval, or circu)a. It should also be understood that cavities having a variety of different shapes may be formed into the same plastic substrate, as depicted lm FIG. 30D.
In one embodiment, a series of eirannela mray be fomud in the supporting member interconnecting some of the cavities, as depicted is FIG. 3, Pumps and valves may also be incotparatcd into the supporting mtmber to aid passage of tha fluid through the cavities. A schematic figtue of a diaphragm pump 800 is depicted in FIO. 31.
Diaphragm pumps, in general, include a cavity 810, a flexible diaphragm 812, an inlet valve 814, and an outlet valve 816. The flexible diaphragm 8I2, during use, is deflected as shown by arrows 818 to create a pumping force.
As the diaphragm is deflocted toward the cavity B10 it may cause the islet valve 814 to close, the outlet valve 816 to op~ and any liquid which is in the cavity 810 will be forced toward the outlet 81 b. As the diaphragm moves away from the cavity 810, the outlet valve 816 may be pulled to a closed position, and the inlet valve 8l4 tray be opened, allowing additioasl fitud to enter the cavity 810. In this manner a pump may be used to pump fluid through the cavities. It should be understood that the imp depicted in FIG. 31 is a generalized version of a diaphragm based pndtp. Actual diaphragm pumps may have different shapes or mey have inlet and outlet valves which are separate from the pumping device.

in one embodiutent, the diaphragm 810 may be made from a piezoelectric material. This material will contract or expand when an appropriate voltage is applied to the diaphragm.
Pumps using a pirioelectric diaphragms are described in U.S. Patent Nos. 4,344,743, 4,938,742, 5,611,676, 5,705,018, and 5,759,015, all of which are incorporated by reference. In other embodiments, the diaphragm may be activated using a pneumatic system. In these systems, as air system may be coupled to the diaphragm such that changes in sir density about t>u diaphragm, induced by the pneumatic system, may cause the diaphragm to move toward and away from the cavity.
A pneumatically controlled pump is described is United States Patent No.
5,499,909 which is incorporated by reference. The diaphragm may also be controlled using a heat activated material. The diaphragm may be fom~ed from a temperature sensitive material. In one embodiment, the diaphragm may be formed from a material which is conftgutod to expand and contract in response to temperature changes. A pump system which relies on teayxrature activated diaphragm is described in United States Patent No. 5,288,214 which is incorporated by reference.
In another embodiment, an electrode pump system may be used. FIG. 32 depicts a typical electrode based system. A series of electrodes 820 stay be arranged along a channel 822 which may lead to a cavity 824 which includes a particle 826. By varying the voltage in the electrodes 820 a corneal flow may be induced in the fluid I S within the channel 822. Examples of electrode based systems include, but are not limited to, electroosmosis systems, electrohydrodynamic systems, and combinations of electroosmosis and electrohydrodynamic systems.
Electrohydrodynamic pumping of fluids is lmown and may be applied to small capillary channels, In an electrohydrodynamic system electrodes are typically placed in contact with the fluid when a voltage is applied. The applied voltage may cause a transfer in charge either by transfer or removal of as electron to or from the fluid. This electron transfer typically induces liquid flow in the direction from the charging elearodc to the oppositely charged electrode. Electrohydrodynamic pumps may be used for pumping fluids snch as organic solvents.
Electroosmosis, is a process which involves applying a voltage to a fluid in a small space, such as a capillary channel, to cause tlx fluid to flow. The surfaces of many solids, inchiding quartz, glass and the like, become variously charged, negatively or positively, in the presence of ionic materials, such as for example salts, ZS acids or bases. The charged surfaces will attract oppoaitely charged (positive or negative) counterions in aqueous solutions. The application of a voltage to such a solution resole in a migration of the counterioas to the oppositely charged electrode, and moves the bulk of the fluid as well. The volume flow rate is proportional to the current, and the volume flow generated in the fluid is also proportional to the applied voltage. An electroosmosis pump system is described in United States Patent No. 4,908,112 which is incorporated by reference.
In another embodiment, a combination of electroosmosis pumps and electrohydrodynamic pumps may be used. Wire electrodes may be inserted into the walls of a channel at preselected intervals to form alternating electroosmosis sad electrohydrodynamic devices. Because electrooamosis and electrohydrodynamic pumps are both present, s plurality of different solutions, both polar and non-polar, may be pomp along a single channel.
Alternatively, a plurality of different solutions may be passed along a plurality of different channels connected to a cavity. A system which includes a combination of electroosmosis pumps and electrohydrodynamic pumps is dexribed in United States Patent No. 5,632,876 which is incorporated by reftxeace.
In an embodiment, a pump may be incasporated into a sensor array system, as depicted in FIG. 32. A
sensor array 830 includes at least one cavity 832 in which a particle 834 may be placed The cavity 832 may be configured to allow fluid to pass through the cavity during use. A puatp 836 may be incorporated onto a portion of the supporting member 838. A channel 831 may be formed in the supporting member 838 coupling the pump $3b to the cavity 832. The channel 831 may be coaflgured to allow the fluid to pass from the pump 836 to the cavity 832. The pump 836 may be positioned away from the cavity 832 to allow light to be directed through the cavity during use. The supporting member 838 and the pump 835 may be formed from a silicon substrate, a plastic material, or photoresist material. The pump 836 may be configured to pump fluid to the cavity via the channel, as depicted by the arrows in FIG. 32. When the fluid reaches the cavity 832, the fluid may flow past the particle 834 and out through the bottom of the cavity. An advantage of using pumps is that better flow thmugh the channels may be achieved. Typically, the channels and cavities may have a small volume.
The small volume of the cavity and channel tends to inhibit flow of the fluid through the cavity. By incorporating a pump, the flow of fhtid to the cavity and through the cavity may be incxeaaed, allowing more rapid testing of the fluid sample. While a diaphragm based pump system is depicted is FIG. 33, it should be understood that electrode bawd pumping systems may also be incorporated into the sensor array to produce fluid flows.
Ia another embodiment, a pump may be coupled to a supporting member for analyzing analyzes in a fhtid stream, as depicted in FIG. 34. A channel 842 may couple a pump $4b to multiple cavities 844 formed in a supporting member 840. 'The cavities B42 may include sensing particles 848.
The pump may Ix configured to create a flow of the fluid through the channel 842 to the cavities 848. In one embodianeat, the cavities may inhibit the flow of the fluid through the cavities 844. The fluid may flow into the cavities 844 and pant the particle 848 to create a flow of fluid through the sensor array system. In this manner a single pump tray be used to pass the fluid to multiple cavities. While a diaphragm pump system is depicted in FIG. 33, it should be understood that elec><ode pumping systems may also be incorporated into the supporting member to create simiLv fluid flows..
In another embodiment, tmtltiple pumps tray be coupled to a supporting member of a sensor array ayatem.
In otte etnbodimcnt, the pumps may be coupled in series with each other to pump fluid to each of the cavities. As depicoed in FIG. 35, a first pump 852 and a second pump 854 may be coupled to a supporting member 850. The first pump 852 may be coupled to a first cavity 85b. The first pump tray lx configured to transfer fluid to the fast cavity 856 during use. The cavity 856 may be configured to allow the fluid to pass through the cavity to a first cavity outlet channel 858. A second pump 854 may also be coupled to the supporting member 850. The axond pump 854 tray be coupled to a second cavity 860 and the first cavity outlet channel 858. The second pump 854 may be configured to transfer fluid from the first cavity outlet channel 858 to the second cavity 860. The pumps may be ayncbronized such that a steady flow of fluid through the cavities is obtained Additional pumps may be coupled to the second cavity outlet channel 862 such that the fluid may be pumped to additional cavities. In one embodiment, each of the cavities in the supporting member is coupled to a pump configured to pump the fluid stream to the cavity.
In another embodiment, multiple electrode based pumps may be incorporated into the sensor stray system. The pumps may be formed along the channels which couple the cavities.
. As depicted in FIG. 3b, a phuality of cavities 870 may be formed in a supporting member 872 of a sensor array. Channels 874 may also be fortxted in the supporting member 872 interconnecting the cavities 870 with each other. An inlet channel 876 and an outlet channel 877, which allow the fluid to pass into and out of the acnsor array, respectively, may also be formed. A series of electrodes 878 may be positioned over the channels 874, 876, and 877. The electrodes may be used to form an electroosmosis pumping system or an elecirohydrodynamic pumping system. The electrodes may be coupled to a controller g80 which may apply the appropriate voltage to the appropriate electrodes to produce a flow of the fluid thmtrgh the chatutels. The putups may be synchronized such that a steady Bow of fluid through the cavities is obtained. The electrodes may be positioned between the cavities such that the electrodes do not significantly interfere with the application of light to the cavities.
In some instances it may be necessary to add a reagent to a particle before, during or after an analysis process. Reagents may include receptor molecules or indicator molecules.
Typically, such reagtnts may be added by passing a fluid stream which includes the reagent over the sensor array. In an embodiment, the reagent may be incorporated into the sensor array system which inchtdes two particles. In this embodiment, a sensor array system 900 may include two particles 910 and 920 for each sensing position of the sensor array, as depicted in FIG. 3T.
The first particle 910 may be positioned in a fast cavity 912. The second particle 920 tray be positioned in a second cavity 922. In one embodiment, the second cavity is coupled to the first cavity via a channel 930. The stcond particle includes a reagent which is at least partially removable from the second particle 920. The'reagent may also be configured to modify the fu~st particle 910, when the reagent is contacted with the first particle, such that the first particle will produce a signal when the fu~st particle interacts with an aaalyte during use. The reagent may be added to the first cavity before, during or after a fluid analysis. The reagent is preferably coupled to the second particle 920. The a portion of the reagent coupled to the second particle may be decoupled from the particle by passing a decoupling solution past the second particle. The decoupling solution may include a decoupling agent which will cause at least a portion of the reagent to be at released by the particle. A reservoir 940 may be formed on the sensor array to hold the decoupling solution.
A first pump 950 and a second pump 960 may also be coupled to the supporting member 915. The fast pump 950 may be co~gured to pump fluid from a fluid inlet 952 to the first cavity 912 via channel 930. Tlte fluid inlet 952 is the location where the fluid, which includes the analyte, is introduced into the sensor array system. A
second pump 950 may be coupled to the reservoir 940 and the second cavity 92Z.
The s~ond pump 960 may be used to transfer the decoupling solution from the reservoir to the second cavity 922. The decoupling solution may pass through the second cavity 922 and into first cavity 912. Thus, as the reagent is removed the second particle it may be transferred to the first cavity912, where the reagent may interact with the fast particle 910. The reservoir may be refilled by removing the reservoir outlet 942, and adding additional fluid to the reservoir 940. While diaphragm based pump systems are depicted in FiG. 37, it should be understood that electrode based pumping systems may also be incorporated into the sensor array to product fluid flows.
The use of such a system is described by way of example. In some instances it may be desirable to add a rtagent to the first particle prior to paasiag the fluid which includes the analyze to the first particle. The reagent may be coupled to the second particle and placed is the sensor array prior to use, typically during construction of the array. A decoupliag solution may be added to the reservoir before use. A
controller 970 may also be coupled to the system to allow automatic operation of the pumps. The controller 970 tray be configured to initiate the analysis sequence by activating the second pump 960, causing the decoupling soiution to flow from the reservoir 940 to the second cavity 922. As the fluid passes through the second cavity 922, the decoupling solution may cause at least some of the reagtat molecules to be released from the second particle 920. The decoupling solution may be passed out of the second cavity 922 and into the fu~st cavity 912. As the solution passes through the fast cavity, some of the reagent molecules may be captured by the first particle 910. After a sufficient number of molecules have been captured by the first particle 910, flow of fluid thorough the second cavity 922 may be stopped. Daring this initialization of the system, the flow of fluid through the fast pump may be inhibited.
After the system is initialized, the second pump may be stopped and the fluid may be introduced to the fast cavity. The first pump may be used to transfer the fluid to the first cavity. The second pump may remain off, thus inhibiting flow of fluid from the reservoir to the first cavity. It should be understood that the reagent solution may be added to the first cavity while the fluid is added to the first cavity.
In this embodiment, both the fast and socond pumps may be operated substantially simultaneously.
Alternatively, the reagent tray be added after an analysis. In some instances, a particle may interact with an anelyte such that a change in the receptors attached to the fast particle occurs. This change may not, however produce a detectable signal. The reagent attached to the second bead may be used to produce a detectable signal when it interacts with the first particle, if a specific aaalyte is present.
In this embodiment, the fluid is introduced into the cavity first. After the analyte has been given time to react with the particle, the reagent may be added to the first Cavity. The interaction of the reagent with the particle may produce a detectable signal. For example, an indicator reagent may react with a particle which has been exposed to an analyze to produce a color change on the particle. Particle which have not been exposed to the analyze tray remain unchanged or show a different color c6snge.
As shown in FIG. 1, a system for detecting analyzes in a fluid may include a light source 110, a sensor array 120 and a detector 130. The sensor array 120 is preferably formed of a supporting member which is configured to hold a variety of particles 124 in an ordered array. A high sensitivity CCD stray may be used to measure changes in optical characteristics which occur upon binding of the biologicallchemical agents. Data scquisition and handling is preferably petfowned with existing CCD technology.
As described above, colorimeaic analysis may be performed using a white light source and a color CCD detector.
However, color CCD detectors are typically more expensive than gray scale CCD detectors.
Is one etnbodinxat, a gray scale CCD detector may be used to detect colotimeoric changes. In one embodiment, a gray scale detector may be disposed below a sensor array to measure the intensity of light being transmitted through the sensor array. A series of lights (e.g., light emitting diodes) may be arranged above the sensor array. In one embodiment, groups of three LED lights tray be arranged above each of the cavities of the array. Each of these groups of LED lights may include a rod, blue and a green light. Each of the lights may be operated individually such that one of the lights may be on while the other two lights are off. In order to provide color information while using a gray scale detector, each of the lights is sequentially turned on and the gray scale detector is used to nteasure the intensity of the light passing through the sensor stray. After information from each of the lights is collected, the information may be processed to derive the absocptioa changes of the particle.
In one embodiment, the data collected by the gray scale detector may be recorded using 8 bits of data.
Thus, the data will appear as a value between 0 and 255. The color of each chemical sensitive element may be represented as a red, blue and green value. For example, a blank particle (l.c., a particle which does not include a receptor) will typically appear white. When each of the LED lights (red, blue and greta) are operated the CCD
detector will record a value corresponding to the amount of light transmitted through the cavity. The intensity of the light tnay be compared to a blanit particle, to determine the absorbance of a particle with respect to the LED
light which is used. Thus, the red, green and blue components may be recorded individnally without the use of a WO 00/04372 PCT/US99/itii62 color CCD detector. In one embodiment, it is found that a blank particle exhibits an absorbance of about 253 when illuminated with a red LED, a value of about 250 whoa ilhttninated by a green LED, and a value of about 222 when illuminated with a blue LED. 'Ibis signifies that a blank particle does not significantly absorb red, green or blue light. When a particle with a receptor is scanned, the particle may exlabit a color change, due to absorbance by the receptor. For example, it was found that when a pariicie which includes a 5-carboxyfluorescein receptor is subjected to white light, the particle shows a strong absorbattce of blue light. When a red LED is used to illuminate the particle, the gray scale CCD detector tray detect a value of about 254.
When the green LED is used, the gray scale detector may detect a value of about 218. When a blue LED light is used, a gray scale detector tray detect a value of about 57. The decrease in iranstnittaace of blue light is believed to be due to the absorbance of blue light by the S-carboxyfluoresccin. In this manner the color changes of s particle may be quantitatively characterized using a gray scale detector.
As descn'bed above, after the cavities are formed in the supporting member, s particle may be positioned at the bottom of a cavity using a microtaanipulator. This allows the location of a particular particle to be precisely controlled during the production of the array. The use of a tnicromanipulator may, however, be impractical for production of sensor stray systems. An alternate method of placing the particles into the cavities may involve dte use of a silk screen like process. A series of masking materials may be placed on the upper surface of the ser~or array prior to filling the cavities. The masking materials tray be composed of glass, metal or plastic materials. A
collection of particles may be placed upon the upper surface of the masking materials and the particles tray be moved across the surface. When a cavity is eaconntered, a particle may drop into the cavity if the cavity is uttcaaaked. Thus particles of known composition are placed in only the unnoaslced regions. After the utuassked cavities are filled, the masking pattern may be altered and a second type of panicles may be spread across the surface. Preferably, the rnaslring rnatetisl will mask the cavities that have already bees filled with particle. The masking material may also mask other non-filled cavities. This technique tray be rtpeated until all of the cavities are filled. After filling the cavities, a cover may be placed on the support member, as described above, to inhibit the displacement and rruxing of the particles. An advantage of such a process is that it tray be snore amenable to industrial production of supporting rt>anbers.
Futthtr modifications and alternative embodiments of various aspects of the iaveatioa will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the propose of teachi»g those skilled in the art the general manner of carrying out the invention It is to be understood that the forms of the invention shown and described herein are to be taken as the presently preferred embodiments. Elements and materials raay be substituted for those illustrated and descn'bed het~ein, parts and processes may be reversed, sad certain features of the invention may be utilized independently, au as would be ap~tent to one skilled in the art after having the benefit of this description of the invention. Changes tray be trade in the elements described herein without departing from the spirit and scope of the invention as desen'bed in the following claims.

Claims

What is claimed is:
1. A sensor array for detecting an analyte in a fluid comprising:
a supporting member; wherein at least one cavity is formed within the supporting member;
a particle positioned within the cavity, wherein the particle is configured to produce a signal when the particle interacts with the analyze;
a barrier layer positioned over the cavity, the barrier layer being configured to inhibit dislodgment of the particle during use.
2. The sensor array of claim 1, further comprising a plurality of particles positioned within the cavity.
3. The sensor array of claims 1 and 2, wherein the particle comprises a receptor molecule coupled to a polymeric resin.
4. The sensor array of claims 1-3, wherein the particle has a size ranging from about 0.05 micron to about 500 microns in diameter.
5. The sensor array of claims 1-4, wherein the cavity is configured to substantially contain the particle.
6. The sensor array of claims 1-5, wherein the supporting member comprises a plastic material.
7. The sensor array of claims 1-5, wherein the supporting member comprises a silicon wafer.
8. The sensor array of claim 7, wherein the cavity extends through the silicon wafer.
9. The sensor array of claims 7-8, wherein the cavity is substantially pyramidal in shape and wherein the sidewalls of the cavity are substantially tapered at an angle of between about 50 to about 60 degrees.
10. The sensor array of claims 7-9, further comprising a substantially transparent layer positioned on a bottom surface of the silicon wafer.
11. The sensor array of claims 7-10, further comprising a substantially transparent layer positioned on a bottom surface of the silicon wafer, wherein the substantially transparent layer comprises silicon dioxide, silicon nitride, or silicon oxide/silicon nitride multilayer stacks.
12. The sensor array of claims 7-11, further comprising a substantially transparent layer positioned on a bottom surface of the silicon wafer, wherein the substantially transparent layer comprises silicon nitride.
13. The sensor array of claims 7-12, wherein the silicon wafer has an area of about 1 cm2 to about 100 cm2.
14. The sensor array of claims 7-13, further comprising a plurality of cavities formed in the silicon wafer, and wherein from about 10 to about 10 6 cavities are formed in the silicon wafer.
15. The sensor array of claims 1-14, further comprising channels in the supporting member, wherein the channels are configured to allow the fluid to flow through the channels into and away from the cavity.
16. The sensor array of claims 1-15, further comprising an inner surface coating, wherein the inner surface coating is configured to inhibit dislodgment of the particle.
17. The sensor array of claims 1-16, further comprising a detector coupled to the bottom surface of the supporting member, wherein the detector is positioned below the cavity.
18. The sensor array of claim 17, wherein the detector is a semiconductor based photodstector.
19. The sensor away of claim 17, wherein the detector is a Fabry-Perot type detector.
20. The sensor array of claim 17, further comprising an optical fiber coupled to the detector, wherein the optical fiber is configured to transmit optical data to a microprocessor.
21. The sensor array of claims 1-20, further comprising an optical filter coupled to a bottom surface of the sensor array.
22. The sensor array of claims 1-21, wherein the barrier layer comprises a substantially transparent cover plate positioned over the cavity, and wherein the cover plate is positioned a fixed distance over the cavity such that the fluid can enter the cavity.
23. The sensor array of claim 22, wherein the barrier layer comprises plastic, glass, quartz, silicon oxide, or silicon nitride.
24. The sensor array of claims 1-23, further comprising a plurality of particles positioned within a plurality of cavities formed in the supporting member.
25. The sensor array of claims 1-24, wherein the plurality of particles produce a detectable pattern in the presence of the analyte.
26. The sensor array of claims 1-25, wherein the sensor array further comprises a bottom layer and a top cover layer, wherein the bottom layer is positioned below a bottom surface of the supporting member, and wherein the bottom layer and the barrier layer are positioned such that the particle is substantially contained within the cavity by the bottom layer and the barrier layer.
27. The sensor array of claims 1-26, wherein the bottom layer and the barrier layer are substantially transparent to light produced by a light source.
28. The sensor array of claims 1-27, wherein the sensor array further comprises a bottom layer, wherein the bottom layer is coupled to a bottom surface of the supporting member, and wherein both the bottom layer and the barrier layer are coupled to the supporting member such that the particle is substantially contained within the cavity by the bottom layer and the barrier layer.
29. The sensor array of claims 1-28, wherein a volume of the particle changes when contacted with the fluid.
30. The sensor array of claims 1-29, wherein the particle comprises a metal oxide particle.
31. The sensor array of claims 1-30, wherein the particle comprises a metal quantum particle.
32. The sensor array of claims 1-31, wherein the particle composes a semiconductor quantum particle.
33. The sensor array of claims 1-32, wherein the particle comprises a receptor molecule coupled to a polymeric resin.
34. The sensor array of claim 33, wherein the polymeric resin composes polystyrene-polyethylene glycol-divinyl benzene.

35. The sensor array of claims 33-34, wherein the receptor molecule produces the signal in response to the pH of the fluid.
36. The sensor array of claims 33-34, wherein the analyte comprises a metal ion, and wherein the receptor produces the signal in response to the presence of the metal ion.
37. The sensor array of claims 33-34, wherein the analyte comprises a carbohydrate, and wherein the receptor produces a signal in response to the presence of a carbohydrate.
38. The sensor array of claims 33-37, wherein the particles further comprises a first indicator and a second indicator, the first and second indicators being coupled to the receptor, wherein the interaction of the receptor with the analyte causes the first and second indicators to interact such that the signal is produced.
39. The sensor array of claims 33-37, wherein the particles further comprises an indicator, wherein the indicator is associated with the receptor such that in the presence of the analyte the indicator is displaced from the receptor to produce the signal.
40. The sensor array of claims 33-39, wherein the receptor comprises a polynucleotide.
41. The sensor array of claims 33-39, wherein the receptor comprises a peptide.
42. The sensor array of claims 33-39, wherein the receptor comprises an enzyme.
43. The sensor array of claims 33-39, wherein the receptor comprises a synthetic receptor.

44. The sensor array of claims 33-39, wherein the receptor comprises an unnatural biopolymer.
45. The sensor array of claims 33-39, wherein the receptor comprises an antibody.
46. The sensor array of claims 33-39, wherein the receptor comprises an antigen.
47. The sensor array of claims 1-39, wherein the analyte comprises phosphate functional groups, and wherein the particle is configured to produce the signal in the presence of the phosphate functional groups.
48. The sensor array of claims 1-39, wherein the analyte comprises bacteria, and wherein the particle is configured to produce the signal in the presence of the bacteria.
49. The sensor array of claims 1-48, further comprising channels in the supporting member, wherein the channels are configured to allow the fluid to flow through the channels into and away from the cavities, and wherein the barrier layer comprises a cover plate positioned upon an upper surface of the supporting member, and wherein the cover plate inhibits passage of the fluid into the cavities such that the fluid enters the cavities via the channels.
50. A system for detecting an analyte in a fluid comprising:
a light source;
a sensor array as described in any of claims 1-49; and a detector, the detector being configured to detect the signal produced by the interaction of the analyze with the particle during use;
wherein the light source and detector are positioned such that light passes from the light source, to the particle, and onto the detector during use.
51. The system of claim 50, wherein the system comprises a plurality of particles positioned within a plurality of cavities, and wherein the system is configured to substantially simultaneously detect a plurality of analytes in the fluid.
52. The system of claims 50-51, wherein the light source comprises a light emitting diode.
53. The system of claims 50-52, wherein the light source comprises a white light source.
54. The system of claims 50-53, further comprising a fluid delivery system coupled to the supporting member.
55. The system of claims 50-54, wherein the detector comprises a charge-coupled device.
56. The system of claims 50-55, wherein the detector comprises an ultraviolet detector.
57. The system of claims 50-55, wherein the detector comprises a fluorescence detector.
58. The system of claims 50-54, wherein the detector comprises a semiconductor based photodetector, and wherein the detector is coupled to the sensor array.
59. A method of sensing the analyte in a fluid comprising:
passing a fluid to an analyze detection system as described in any of claims 50-58;
monitoring a spectroscopic change of the particle as the fluid is passed over the sensor array, wherein the spectroscopic change is caused by the interaction of the analyte with the particle.
60. The method of claim 59, wherein the spectroscopic change comprises a change in absorbance of the particle.

61. The method of claim 59, wherein the spectroscopic change comprises a change in fluorescence of the particle.

62. The method of claim 59, wherein the spectroscopic change comprises a change in phosphorescence of the particle.

63. The method of claims 59-62, wherein the analyte is a proton atom, and wherein the spectroscopic change is produced when the pH of the fluid is varied, and wherein monitoring the spectroscopic change of the particle allows the pH of the fluid to be determined.

64. The method of claims 59-62, wherein the analyze is a metal cation, and wherein the spectroscopic change is produced in response to the presence of the metal cation in the fluid.

65. The method of claims 59-62, wherein the analyte is an anion, and wherein the spectroscopic change is produced in response to the presence of the anion in the fluid.

66. The method of claims 59-62, wherein the analyze is a DNA molecule, and wherein the spectroscopic change is produced in response to the presence of the DNA molecule in the fluid.

67. The method of claims 59-62, wherein the analyte is a protein, and wherein the spectroscopic change is produced in response to the presence of the protein in the fluid.

68. The method of claims 59-62, wherein the analyte is a metabolite, and wherein the spectroscopic change is produced in response to the presence of the metabolite in the fluid.

69. The method of claims 59-62, wherein the analyte is a sugar, and wherein the spectroscopic change is produced in response to the presence of the sugar in the fluid.

70. The method of claims 59-62, wherein the analyte is a bacteria, and wherein the spectroscopic change is produced in response to the presence of the bacteria in the fluid.

71. The method of claims 59-70, wherein the particle comprises a receptor coupled to a polymeric resin, and further comprising exposing the panicle to an indicator prior to passing the fluid over the sensor array.

72. The method of claim 71, wherein a binding strength of the indicator to the receptor is less than a binding strength of the analyte to the receptor.

73. The method of claims 71-72, wherein the indicator is a fluorescent indicator.

74. The method of claims 72-73, further comprising treating the fluid with an indicator prior to passing the fluid over the sensor array, wherein the indicator is configured to couple with the analyze.

75. The method of claim 70, wherein the analyte is bacteria and further comprising breaking down the bacteria prior to passing the fluid over the sensor array.

76. The method of claims 59-75, further comprising measuring the intensity of the spectroscopic change, and further comprising calculating the concentration of the analyte based on the intensity of the spectroscopic change.

115. A method for forming a sensor array configured to detect an analyte in a fluid, comprising:
forming a cavity in a supporting member, wherein the supporting member comprises a silicon wafer;
placing a particle is the cavity, wherein the particle is configured to produce a signal when the particle interacts with the analyte; and forming a cover upon a portion of the supporting member, wherein the cover is configured to inhibit dislodgment of the particle from the cavity.

116. The method of claim 115, wherein forming the cavity comprises anisotropically etching the silicon wafer.

117. The method of claim 115, wherein forming the cavity comprises anisotropically etching the silicon wafer with a wet hydroxide etch.

118. The method of claim 115, wherein forming the cavity comprises anisotropically etching the silicon wafer such that sidewalls of the cavity are tapered at an angle from about 50 degrees to about 60 degrees.

119. The method of claim 115, wherein the silicon wafer has an area of about 1 cm2 to about 100 cm2.

120. The method of claim 115, further comprising forming a substantially transparent layer upon a bottom surface of the silicon wafer below the cavity.

121. The method of claim 115, further comprising forming a substantially transparent layer upon a bottom surface of the silicon wafer, wherein the cavity extends through the silicon wafer and wherein the substantially transparent layer is positioned to support the particle.

122. The method of claim 115, wherein the substantially transparent layer comprises silicon nitride.

123. The method of claim 115, wherein the cover comprises plastic, glass, quartz, silicon nitride, or silicon oxide.

124. The method of claim 115, wherein forming the cover comprises coupling the cover to the silicon wafer at a distance above the silicon wafer substantially less than a width of the particle.

125. The method of claim 115, further comprising etching channels in the silicon wafer prior to forming the cover on the silicon wafer, wherein forming the cover comprises placing the cover against the upper surface of the silicon wafer, and wherein the channels are configured to allow the fluid to pass through the silicon wafer to and from the cavities.

126. The method of claim 115, further comprising coating an inner surface of the cavity with a material to increase adhesion of the particle to the inner surface of the cavity.

127. The method of claim 115, further comprising coating an inner surface of the cavity with a material to increase reflectivity of the inner surface of the cavity.

128. The method of claim 115, further comprising forming an optical detector upon a bottom surface of the supporting member below the cavity.

129. The method of claim 115, further comprising forming a sensing cavity upon a bottom surface of the supporting member below the cavity.

130. The method of claim 129, wherein forming the sensing cavity comprises:
forming a barrier layer upon a bottom surface of the silicon wafer;
forming a bottom diaphragm layer upon the barrier layer;
forming etch windows extending through the bottom diaphragm layer;
forming a sacrificial spacer layer upon the bottom diaphragm layer;
removing a portion of the spacer layer;
forming a top diaphragm layer; and removing a remaining portion of the spacer layer.

131. The method of claim 130, further comprising filling a portion of the sensing cavity with a sensing substrate.

132. The method of claim 115, further comprising forming an optical filter upon the bottom surface of the supporting member.

133. The method of claim 115, further comprising forming a plurality of cavities in the silicon wafer.

134. The method of claim 115, wherein from about 10 to about 10 6 cavities are formed in the silicon wafer.

135. A sensor array produced by the method of claim 115.

136. A method of sensing an analyze in a fluid comprising:
passing a fluid over a sensor stray, the sensor array comprising at least one particle positioned within a cavity of a supporting member;

monitoring a spectroscopic change of the particle as the fluid is passed over the sensor array, wherein the spectroscopic change is caused by the interaction of the analyte with the particle.

137. The method of claim 136, wherein the spectroscopic change comprises a change in absorbance of the particle.

138. The method of claim 136, wherein the spectroscopic change comprises a change is fluorescence of the particle.

139. The method of claim 136, wherein the spectroscopic change comprises a change in phosphorescence of the particle.

140. The method of claim 136, wherein the analyte is a proton atom, and wherein the spectroscopic change is produced when the pH of the fluid is varied, and wherein monitoring the spectroscopic change of the particle allows the pH of the fluid to be determined.

141. The method of claim 136, wherein the analyte is a metal cation, and wherein the spectroscopic change is produced in response to the presence of the metal cation in the fluid.

142. The method of claim 136, wherein the analyte is an anion, and wherein the spectroscopic change is produced in response to the presence of the anion in the fluid.

143. The method of claim 136, wherein the analyte is a DNA molecule, and wherein the spectroscopic change is produced in response to the presence of the DNA molecule is the fluid.

144. The method of claim 136, wherein the analyte is a protein, and wherein the spectroscopic change is produced in response to the presence of the protein in the fluid.

145. The method of claim 136, wherein the analyte is a metabolite, and wherein the spectroscopic change is produced in response to the presence of the metabolite in the fluid.

146. The method of claim 136, wherein the analyte is a sugar, and wherein the spectroscopic change is produced in response to the presence of the sugar in the fluid.

147. The method of claim 136, wherein the analyte is a bacteria, and wherein the spectroscopic change is produced in response to the presence of the bacteria in the fluid.

148. The method of claim 136, wherein the particle comprises a receptor coupled to a polymeric resin, and further comprising exposing the particle to an indicator prior to passing the fluid over the sensor array.

149. The method of claim 148, wherein a binding strength of the indicator to the receptor is less than a binding strength of the analyte to the receptor.

150. The method of claim 148, wherein the indicator is a fluorescent indicator.

151. The method of claim 136, further comprising treating the fluid with an indicator prior to passing the fluid over the sensor stray, wherein the indicator is configured to couple with the analyte.

152. The method of claim 136, wherein the analyte is bacteria and further comprising breaking down the bacteria prior to passing the fluid over the sensor array.

153. The method of claim 136, wherein monitoring the spectroscopic change is performed with a CCD
device.

154. The method of claim 136, further comprising measuring the intensity of the spectroscopic change, and further comprising calculating the concentration of the analyte based on the intensity of the spectroscopic change.

155. A sensor array for detecting an analyte in a fluid comprising:
a supporting member, wherein the supporting member comprises a silicon wafer, and wherein a plurality of cavities are formed within the supporting member;
a plurality of particles, at least one particle being positioned in each of the cavities, wherein the particles are configured to produce a signal when the particles interact with the analyte.

156. A method of sensing an analyte in a fluid comprising:
passing a fluid over a sensor stray, the sensor array comprising:
a supporting member, wherein the supporting member comprises a silicon wafer, and wherein a plurality of cavities are formed within the supporting member, and a plurality of particles, at least one particle being positioned in each of the cavities, wherein the particles are configured to produce a signal when the particles interact with the analyte at least one particle positioned within a cavity of a supporting member;
monitoring a spectroscopic change of the particle as the fluid is passed over the sensor array, wherein the spectroscopic change is caused by the interaction of the analyte with the particle.

157. The method of claim 156, wherein the spectroscopic change comprises a change in absorbance of the particle.

158. The method of claim 156, wherein the spectroscopic change comprises a change in reflectance of the particle.

159. The method of claim 156, wherein the spectroscopic change comprises a change in fluorescence of the particle.

160. The method of claim 156, wherein the spectroscopic change comprises a change in phosphorescence of the particle.

161. The method of claim 156, wherein the analyte is a proton atom, and wherein the spectroscopic change is produced when the pH of the fluid is varied, and wherein monitoring the spectroscopic change of the particle allows the pH of the fluid to be determined.

162. The method of claim 156, wherein the analyte is a metal ration, and wherein the spectroscopic change is produced in response to the presence of the metal cation in the fluid.

163. The method of claim 156, wherein the particle comprises a receptor coupled to a polymeric resin, and further comprising exposing the particle to an indicator prior to passing the fluid over the sensor array.

164. The method of claim 156, wherein a binding strength of the indicator to the receptor is less than a binding strength of the analyte to the receptor.

165. The method of claim 156, wherein the indicator is a fluorescent indicator.

166. The method of claim 156, further comprising treating the fluid with an indicator prior to passing the fluid over the sensor array, wherein the indicator is configured to couple with the analyte.

167. The method of claim 156, wherein the analyte is bacteria and further comprising breaking down the bacteria prior to passing the fluid over the sensor array.

168. The method of claim 156, wherein monitoring the spectroscopic change is performed with a CCD
device.

169. The method of claim 156, further comprising measuring the intensity of the spectroscopic change, and further comprising calculating the concentration of the analyte based on the intensity of the spectroscopic change.

170. A system for detecting an analyze in a fluid comprising a light source;
a sensor array, the sensor array comprising at least one particle coupled to the sensor array, wherein the particle is configured to produce a signal when the particle interacts with the analyte; and a detector configured to detect the signal produced by the interaction of the analyte with the particle;

wherein the light source and detector are positioned such that tight passes from the light source, to the particle, and onto the detector during use.

171. A sensor array for detecting an analyte in a fluid comprising:
at least one particle coupled to the sensor array, wherein the particle is configured to produce a signal when the particle interacts with the analyte.

172. A method of sensing an analyte in a fluid comprising:
passing a fluid over a sensor array, the sensor array comprising at least one particle coupled to a supporting member;
monitoring a spectroscopic change of the particle as the fluid is passed over the sensor array, wherein the spectroscopic change is caused by the interaction of the analyte with the particle.

173. A sensor array for detecting an analyte in a fluid comprising:
a supporting member; wherein at least one cavity is formed within the supporting member, a particle positioned within the cavity, wherein the particle is configured to produce a signal when the particle interacts with the analyte;
wherein the cavities are configured to allow the fluid to pass through the supporting member during use.

174. The sensor array of claim 173, further comprising a plurality of particles positioned within the cavity.

175. The sensor stray of claim 173, wherein the particle comprises a receptor molecule coupled to a polymeric resin.

176. The sensor array of claim 173, wherein the particle has a size ranging from about 0.05 micron to about 500 microns in diameter.

177. The sensor array of claim 173, wherein the cavity is configured to substantially contain the particle.

178. The sensor array of claim 173, further comprising a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein the cover layer and the bottom layer are removable.

179. The sensor array of claim 173, further comprising a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein the cover layer and the bottom layer are removable, and wherein the cover layer and the bottom layer include openings that are substantially aligned with the cavities during use.

180. The sensor array of claim 173, further comprising a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein the bottom layer is coupled to a bottom surface of the supporting member and wherein the cover layer is removable, and wherein the cover layer and the bottom layer include openings that are substantially aligned with the cavities during use.

181. The sensor array of claim 173, further comprising a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein an opening is formed in the cover layer substantially aligned with the cavity, and wherein an opening is formed in the bottom layer substantially aligned with the cavity.

182. The sensor array of claim 173, wherein the cavity is substantially tapered such that the width of the cavity narrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the cavity is substantially less than a width of the particle.

183. The sensor array of claim 173, wherein a width of a bottom portion of the cavity is substantially less than a width of a top portion of the cavity, and wherein the width of the bottom portion of the cavity is substantially less than a width of the particle.

184. The sensor array of claim 173, further comprising a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein the bottom layer is configured to support the particle, and wherein an opening is formed in the cove layer substantially aligned with the cavity.

185. The sensor array of claim 173, further comprising a removable cover layer coupled to the supporting member.

186. The sensor array of claim 173, wherein the supporting member comprises a plastic material.

187. The sensor array of claim 173, wherein the supporting member comprises a silicon wafer.

188. The sensor array of claim 173, wherein the supporting member comprises a dry film photoresist material.

189. The sensor array of claim 173, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.

190. The sensor array of claim 173, wherein an inner surface of the cavity is coated with a reflective material.

191. The sensor array of claim 173, further comprising channels in the supporting member, wherein the channels are configured to allow the fluid to flow through the channels into and away from the cavity.

192. The sensor array of claim 173, further comprising a plurality of additional particles positioned within a plurality of additional cavities formed in the supporting member.

193. A system for detecting an analyte in a fluid comprising:
a light source;
a sensor array, the sensor array comprising a supporting member comprising at least one cavity formed within the supporting member, wherein the cavity is configured such that the fluid entering the cavity passes through the supporting member during use;
a particle, the particle positioned within the cavity, wherein the particle is configured to produce a signal when the particle interacts with the analyte during use; and a detector, the detector being configured to detect the signal produced by the interaction of the analyte with the particle during use;
wherein the light source and detector are positioned such that light passes from the light source, to the particle, and onto the detector during use.

194. The system of claim 193, wherein the system comprises a plurality of particles positioned within a plurality of cavities, and wherein the system is configured to substantially simultaneously detect a plurality of analytes in the fluid.

195. The system of claim 193, wherein the system comprises a plurality of particles positioned within the cavity.

196. The system of claim 193, wherein the light source comprises a light emitting diode.

197. The system of claim 193, wherein the light source comprises a red light emitting diode, a blue light emitting diode, and a green light emitting diode.

198. The system of claim 193, wherein the light source comprises a white light source.

199. The system of claim 193, wherein the sensor array further comprises a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein the cover layer and the bottom layer are removable.

200. The system of claim 193, wherein the sensor array further comprises a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein the cover layer and the bottom layer are removable, and wherein the cover layer and the bottom layer include openings that are substantially aligned with the cavities during use.

201. The system of claim 193, wherein the sensor array further comprises a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein the bottom layer is coupled to a bottom surface of the supporting member and wherein the cover layer is removable, and wherein the cover layer and the bottom layer include openings that are substantially aligned with the cavities during use.

202. The system of claim 193, wherein the sensor array further comprises a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein an opening is formed in the cover layer substantially aligned with the cavity, and wherein an opening is formed in the bottom layer substantially aligned with the cavity.

203. The system of claim 193, wherein the cavity is substantially tapered such that the width of the cavity narrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the cavity is substantially less than a width of the particle.

204. The system of claim 193, wherein a width of a bottom portion of the cavity is substantially less than a width of a top portion of the cavity, and wherein the width of the bottom portion of the cavity is substantially less than a width of the particle.

205. The system of claim 193, wherein the sensor array further comprises a cover layer coupled to the supporting member and a bottom layer coupled to the supporting member, wherein the bottom layer is configured to support the particle, and wherein an opening is formed in the cover layer substantially aligned with the cavity.

206. The system of claim 193, further comprising a removable cover layer.

207. The system of claim 193, wherein the supporting member comprises a plastic material.

208. The system of claim 193, wherein the supporting member comprises a silicon wafer.

209. The system of claim 193, wherein the supporting member comprises a dry film photoresist material.

210. The system of claim 193, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.

211. The system of claim 193, wherein an inner surface of the cavity is coated with a reflective material.

212. The system of claim 193, further comprising channels in the supporting member, wherein the channels are configured to allow the fluid to flow through the channels into and away from the cavity.

213. The system of claim 193, wherein the detector comprises a charge-coupled device.

214. The system of claim 193, wherein the detector comprises a semiconductor based photodetector, and wherein the detector is coupled to the sensor array.

215. The system of claim 193, wherein the particle comprises a receptor molecule coupled to a polymeric resin.

216. The system of claim 215, wherein the polymeric resin comprises polystyrene-polyethylene glycol-divinyl benzene.

217. The system of claim 215, wherein the receptor molecule produces the signal in response to the pH of the fluid.

218. The system of claim 215, wherein the analyze comprises a metal ion, and wherein the receptor produces the signal in response to the presence of the metal ion.

219. The system of claim 215, wherein the analyte comprises a carbohydrate, and wherein the receptor produces a signal in response to the presence of a carbohydrate.

220. The system of claim 215, wherein the particles further comprises a first indicator and a second indicator, the first and second indicators being coupled to the receptor, wherein the interaction of the receptor with the analyte causes the first and second indicators to interact such that the signal is produced.

221. The system of claim 215, wherein the particles further comprises an indicator, wherein the indicator is associated with the receptor such that in the presence of the analyte the indicator is displaced from the receptor to produce the signal.

222. The system of claim 215, wherein the receptor comprises a polynucleotide.

223. The system of claim 215, wherein the receptor comprises a peptide.

224. The system of claim 215, wherein the receptor comprises an enzyme.

225. The system o f claim 215, wherein the receptor comprises a synthetic receptor.

226. The system of claim 215, wherein the receptor comprises an unnatural biopolymer.

227. The system of claim 215, wherein the receptor comprises an antibody.

228. The system of claim 215, wherein the receptor comprises as antigen.

229. The system of claim 193, wherein the analyte comprises phosphate functional groups, and wherein the particle is configured to produce the signal in the presence of the phosphate functional groups.

230. The system of claim 193, wherein the analyze comprises bacteria, and wherein the particle is configured to produce the signal in the presence of the bacteria.

231. The system of claim 193, wherein the system comprises a plurality of particles positioned within a plurality of cavities, and wherein the plurality of particles produce a detectable pattern in the presence of the analyte.

232. A sensor array for detecting an analyte in a fluid comprising:
a supporting member, wherein at least one cavity is formed within the supporting member;
a particle positioned within the cavity, wherein the particle is configured to produce a signal when the particle interacts with the analyte; and a pump coupled to the supporting member, wherein the pump is configured to direct the fluid towards the cavity;
wherein a channel is formed in the supporting member, the channel coupling the pump to the cavity such that the fluid flows through the channel to the cavity during use.

233. The sensor array of claim 232, wherein the particle comprises a receptor molecule coupled to a polymeric resin.

234. The sensor array of claim 232, wherein the supporting member comprises a plastic material.

235. The sensor array of claim 232, wherein the supporting member comprises a silicon wafer.

236. The sensor array of claim 232, wherein the supporting member comprises a dry film photoresist material.

237. The sensor array of claim 232, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.

238. The sensor array of claim 232, wherein an inner surface of the cavity is coated with a reflective material.
239. The sensor stray of claim 232, further comprising a detector coupled to the bottom surface of the supporting member, wherein the detector is positioned below the cavity.
240. The sensor array of claim 232, further comprising a barrier layer positioned over the cavity, the barrier layer being configured to inhibit dislodgment of the particle during use.
241. The sensor array of claim 232, further comprising a barrier layer positioned over the cavity, the barrier layer being configured to inhibit dislodgment of the particle during use, wherein the barrier layer comprises a transmission electron microscope grid.
242. The sensor array of claim 232, further comprising a plurality of particles positioned within a plurality of cavities formed in the supporting member.
243. The sensor array of claim 232, wherein the system comprises a plurality of particles positioned within a plurality of cavities, and wherein the plurality of particles product a detectable pattern in the presence of the analyte.
244. The sensor array of claim 232, wherein the pump comprises a diaphragm pump.
245. The sensor array of claim 232, wherein the pump comprises an electrode pump.
246. The sensor array of claim 232 wherein the pump comprises a piezoelectric pump.
247. The sensor away of claim 232, wherein the pump comprises a pneumatic activated pump.
248. The sensor array of claim 232, wherein the pump comprises a heat activated pump.
249. The sensor array of claim 232, wherein the pump comprises a peristaltic pump.
250. The sensor array of claim 232, wherein the pump comprises an electroosmosis pump.
251. The sensor array of claim 232, wherein the pump comprises an electrohydrodynamic pump.
252. The sensor array of claim 232, wherein the pump comprises an electroosmosis pump and an electrohydrodynamic pump.

253. The sensor stray of claim 232, wherein the cavity is substantially tapered such that the width of the cavity harrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the cavity is substantially less than a width of the particle.
254. The sensor array of claim 232, wherein a width of a bottom portion of the cavity is substantially less than a width of a top portion of the cavity, and wherein the width of the bottom portion of the cavity is substantially less than a width of the particle.
255. A system for detecting an analyze in a fluid comprising:
a light source;
a sensor array, the sensor array comprising a supporting member comprising at least one cavity formed within the supporting member, a pump coupled to the supporting member, wherein the pump is configured to direct the fluid towards the cavity, and wherein a channel is formed in the supporting member, the channel coupling the pump to the cavity such that the fluid flows through the channel to the cavity during use:
a particle, the particle positioned within the cavity, wherein the particle is configured to produce a signal when the particle interacts with the analyte during use; and a detector, the detector being configured to detect the signal produced by the interaction of the analyte with the particle during use;
wherein the tight source and detector are positioned such that light passes from the light source, to the particle, and onto the detector during use.
256. The system of claim 255, wherein the system comprises a plurality of particles positioned within a plurality of cavities, and wherein the system is configured to substantially simultaneously detect a plurality of analytes in the fluid.
257. The system of claim 255, wherein the light source comprises a light emitting diode.
258. The system of claim 255, wherein the light source comprises a red light emitting diode, a blue light emitting diode, and a green light emitting diode.
259. The system of claim 255, wherein the light source comprises a white light source.
260. The system of claim 255, wherein the supporting member comprises a plastic material.
261. The system of claim 255, wherein the supporting member comprises a silicon wafer.
262. The system of claim 255, wherein the supporting member comprises a dry film photoresist material.

263. The system of claim 255, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.
264. The system of claim 255, wherein an inner surface of the cavity is coated with a reflective material.
265. The system of claim 255, further comprising a barrier layer coupled to the supporting member, wherein the barrier layer is positioned over the cavity, the barrier layer being configured to inhibit dislodgment of the particle during use.
266. The system of claim 255, wherein the pump comprises a diaphragm pump.
267. The system of claim 255, wherein the pump comprise an electrode pump.
268. The system of claim 255 wherein the pump comprises a piezoelectric pump.
269. The system of claim 255, wherein the pump comprises a pneumatic activated pump.
270. The system of claim 255, wherein the pump comprises a heat activated pump.
271. The system of claim 255, wherein the pump comprises a peristaltic pump.
272. The system of claim 255, wherein the pump comprises as electroosmosis pump.
273. The system of claim 255, wherein the pump comprises an electrohydrodynamic pump.
274. The system of claim 255, wherein the pump comprises an electroosmosis pump and an electrohydrodynamic pump.
275. The system of claim 255, wherein the cavity is substantially tapered such that the width of the cavity narrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the cavity is substantially less than a width of the particle.
276. The system of claim 255, wherein a width of a bottom portion of the cavity is substantially less than a width of a top portion of the cavity, and wherein the width of the bottom portion of the cavity is substantially less than a width of the particle.
277. The system of claim 255, wherein the detector comprises a charge-coupled device.

278. The system of claim 255, wherein the particle comprises a receptor molecule coupled to a polymeric resin.

279. The system of claim 278, wherein the polymeric resin comprises polystyrene-polyethylene glycol-divinyl benzene.

280. The system of claim 278, wherein the particles further comprises a first indicator and a second indicator, the first and second indicators being coupled to the receptor, wherein the interaction of the receptor with the analyze causes the first and second indicators to interact such that the signal is produced.

281. The system of claim 278, wherein the particles further comprises an indicator, wherein the indicator is associated with the receptor such that in the presence of the analyze the indicator is displaced from the receptor to produce the signal.

282. The system of claim 278, wherein the receptor comprises a polynucleotide.

283. The system of claim 278, wherein the receptor comprises a peptide.

284. The system of claim 278, wherein the receptor comprises an enzyme.

285. The system of claim 278, wherein the receptor comprises a synthetic receptor.

286. The system of claim 278, wherein the receptor comprises an unnatural biopolymer.

287. The system of claim 278, wherein the receptor comprises an antibody.

288. The system of claim 278, wherein the receptor comprises as antigen.

289. The system of claim 255, wherein the analyte comprises bacteria, and wherein the particle is configured to produce the signal in the presence of the bacteria.

290. The system of claim 255, wherein the system comprises a plurality of particles positioned within a plurality of cavities, and wherein the plurality of particles produce a detectable pattern in the presence of the analyte.

291. A sensor array for detecting an analyze in a fluid comprising:
a supporting member; wherein a first cavity and a second cavity are formed within the supporting member;
a first particle positioned within the first cavity;
a second particle positioned within the second cavity, wherein the second particle comprises a reagent, wherein a portion of the reagent is removable from the second particle when contacted with a decoupling solution, and wherein the reagent is configured to modify the first particle, when the reagent is contacted with the first particle, such that the first particle will produce a signal when the first particle interacts with the analyze during use;
a first pump coupled to the supporting member, wherein the pump is configured to direct the fluid towards the first cavity;
a second pump coupled to the supporting member, wherein the second pump is configured to direct the decoupling solution towards the second cavity;
wherein a first channel is formed in the supporting member, the first channel coupling the first pump to the first cavity such that the fluid flows through the first channel to the first cavity during use, and wherein a second channel is formed in the supporting member, the second channel coupling the second cavity to the first cavity such that the decoupling solution flows from the second cavity through the second channel to the first cavity during use.
292. The sensor array of claim 291, wherein the first particle comprises a receptor molecule coupled to a first polymeric resin, and wherein the second particle comprises an indicator molecule coupled to a second polymeric resin.
293. The sensor array of claim 291, wherein the first particle comprises an indicator molecule coupled to a first polymeric resin, and the second particle comprises a receptor molecule coupled to a second polymeric resin.
294. The sensor array of claim 291, wherein the first particle comprises a first polymeric resin configured to bind to the receptor molecule, and wherein the second particle comprises the receptor molecule coupled to a second polymeric resin.
295. The sensor array of claim 291, wherein the supporting member comprises a plastic material.
296. The sensor array of claim 291, wherein the supporting member comprises a silicon wafer.
297. The sensor array of claim 291, wherein the supporting member comprises a dry film photoresist material.
298. The sensor array of claim 291, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.
299. The sensor array of claim 291, wherein an inner surface of the first cavity is coated with a reflective material.
300. The sensor array of claim 291, further comprising a detector coupled to the bottom surface of the supporting member, wherein the detector is positioned below the first cavity.
301. The sensor array of claim 291, further comprising a plurality of additional particles positioned within a plurality of additional cavities formed in the supporting member, and wherein the second cavity is coupled to the additional cavities such that the reagent may be transferred from the second particle to the additional cavities during use.
302. The sensor array of claim 291, wherein the first and second pumps comprise a diaphragm pomp.
303. The sensor array of claim 291, wherein the first and second pumps comprise an electrode pump.
304. The sensor array of claim 291, wherein the first pump comprises a diaphragm pump or an electrode pump and wherein the second pump comprises a diaphragm pump or an electrode pump.
305. The sensor array of claim 291, wherein the first cavity is substantially tapered such that the width of the first cavity narrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the first cavity is substantially less than a width of the first particle, and wherein the second cavity is substantially tapered such that the width of the second cavity narrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the second cavity is substantially less than a width of the second particle.
306. The sensor array of claim 291, wherein a width of a bottom portion of the fast cavity is substantially less than a width of a top portion of the first cavity, and wherein the width of the bottom portion of the first cavity is substantially less than a width of the first particle, and wherein a width of a bottom portion of the second cavity is substantially less than a width of a top portion of the second cavity, and wherein the width of the bottom portion of the second cavity is substantially less than a width of the second particle.
307. The sensor stray of claim 291, further comprising a reservoir coupled to the second pump, the reservoir configured to hold the decoupling solution.

308. A system for detecting an analyte in a fluid comprising:
a light source;
a sensor array, the sensor array comprising:
a supporting member; wherein a first cavity and a second cavity are formed within the supporting member;
a first particle positioned within the first cavity;
a second particle positioned within the second cavity, wherein the second particle comprises a reagent, wherein a portion of the reagent is removable from the second particle when contacted with a decoupling solution, and wherein the reagent is configured to modify the first particle, when the reagent is contacted with the first particle, such that the first particle will produce a signal when the first particle interacts with the analyte during use;
a first pump coupled to the supporting member, wherein the pump is configured to direct the fluid towards the first cavity;
a second pump coupled to the supporting member, wherein the second pump is configured to direct the decoupling solution towards the second cavity;
wherein a first channel is formed in the supporting member, the first channel coupling the first pump to the first cavity such that the fluid flows through the first channel to the first cavity during use, and wherein a second channel is formed in the supporting member, the second channel coupling the second cavity to the first cavity such that the decoupling solution flows from the second cavity through the second channel to the first cavity during use; and a detector, the detector being configured to detect the signal produced by the interaction of the analyte with the particle during use;
wherein the light sotuce and detector are positioned such that light passes from the light source, to the particle, and onto the detector during use.
309. The system of claim 308, wherein the sensor array further comprises a plurality of additional particles positioned within a plurality of additional cavities, and wherein the system is configured to substantially simultaneously detect a plurality of analytes is the fluid, and wherein the second cavity is coupled to the additional cavities such that the reagent may be transferred from the second particle to the additional cavities during use.
310. The system of claim 308, wherein the light source comprises a light emitting diode.
311. The system of claim 308, wherein the light source comprises a red light emitting diode, a blue light emitting diode, and a green light emitting diode.
312. The system of claim 308, wherein the light source comprises a white light source.
313. The system of claim 308, wherein the first particle comprises a receptor molecule coupled to a first polymeric resin, and wherein the second particle comprises an indicator molecule coupled to a second polymeric resin.
314. The system of claim 308, wherein the fast particle comprises an indicator molecule coupled to a first polymeric resin, and the second particle comprises a receptor molecule coupled to a second polymeric resin.
315. The system of claim 308, wherein the first particle comprises a first polymeric resin configured to bind to the receptor molecule, and wherein the second particle comprises the receptor molecule coupled to a second polymeric resin.
316. The system of claim 308, wherein the supporting member comprises a plastic material.
317. The system of claim 308, wherein the supporting number comprises a silicon wafer.
318. The system of claim 308, wherein the supporting member comprises a dry film photoresist material.
319. The system of claim 308, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.
320. The system of claim 308, wherein an inner surface of the first cavity is coated with a reflective material.
321. The system of claim 308, wherein the first and second pumps comprise a diaphragm pump.
322. The system of claim 308, wherein the first and second pumps comprise an electrode pump.
323. The system of claim 308, wherein the first pump comprises a diaphragm pump or an electrode pump and wherein the second pump comprises a diaphragm pump or an electrode pump.
324. The system of claim 308, wherein the first cavity is substantially tapered such that the width of the first cavity narrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the first cavity is substantially less than a width of the first particle, and wherein the second cavity is substantially tapered such that the width of the second cavity narrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the second cavity is substantially less than a width of the second particle.
325. The system of claim 308, wherein a width of a bottom portion of the first cavity is substantially less than a width of a top portion of the first cavity, and wherein the width of the bottom portion of the first cavity is substantially less than a width of the first particle, and wherein a width of a bottom portion of the second cavity is substantially less than a width of a top portion of the second cavity, and wherein the width of the bottom portion of the second cavity is substantially less than a width of the second particle.
326. The system of claim 308, wherein the sensor array further comprises a reservoir coupled to the second pump, the reservoir configured to hold the decoupling solution.
327. The system of claim 308, wherein the analyte comprises bacteria, and wherein the first particle is configured to produce the signal in the presence of the bacteria.
328. A method for forming a sensor array configured to detect an analyte in a fluid, comprising:
forming a cavity in a supporting member, wherein the cavity is configured to allow the fluid to pass through the supporting member;
placing a particle in the cavity, wherein the particle is configured to produce a signal when the particle interacts with the analyte; and placing a cover upon a portion of the supporting member, wherein the cover is configured to inhibit dislodgment of the particle from the cavity.
329. The method of claim 328, further comprising forming a substantially transparent layer upon a bottom surface of the supporting member below the cavity, wherein the bottom layer is configured to inhibit the displacement of the particle from the cavity while allowing the fluid to pass through the supporting member.
330. The method of claim 328, further comprising forming an optical detector upon a bottom surface of the supporting member below the cavity.
331. The system of claim 328, wherein a width of a bottom portion of the cavity is substantially less than a width of a top portion of the cavity, and wherein the width of the bottom portion of the cavity is substantially less than a width of the particle.
332. The method of claim 328, further comprising forming channels is the supporting member wherein the channels are configured to allow the fluid to pass through the supporting member to and from the cavity.
333. The method of claim 328, further comprising forming a pump on the supporting member, the pump being configured to pump the fluid to the cavity.

334. The method of claim 328, further comprising forming additional cavities is the supporting member and further comprising placing additional particles in the additional cavities.

335. The method of claim 328, further comprising forming a cover, wherein forming the cover comprises:
forming a removable layer upon the upper surface of the supporting member;
forming a cover upon the removable layer;
forming support structures upon the supporting member, the support structures covering a portion of the cover; and dissolving the removable layer.

336. The method of claim 335, wherein the cover layer is formed prior to forming the cavity.

337. The method of claim 335, wherein forming the cover further comprises forming openings in the cover, wherein the openings are substantially aligned with the cavity.

338. The method of claim 328, wherein the particles are placed in the cavities using a micromanipulator.

339. The method of claim 328, further comprising forming additional cavities within the supporting member, and further comprising placing additional particles in the additional cavities, wherein placing the additional particles in the additional cavities comprises:
placing a first masking layer on the supporting member. wherein the first masking layer covers a first portion of the additional cavities such that passage of a particle into the first portion of the additional cavities is inhibited, and wherein the first masking layer a second portion of the cavities substantially unmasked,;
placing the additional particles on the supporting member; and moving the additional particles across the supporting member such that the particles fall into the second portion of the cavities.

340. The method of claim 339, further comprising:
removing the first making layer, placing a second masking layer upon the supporting member, wherein the second masking layer covers the second portion of the cavities and a portion of the first portion of the cavities while leaving a third portion of the cavities unmasked;
placing additional particles on the supporting member; and moving the additional particles across the supporting member such that the particle fall into the third portion of the cavities.

341. The method of claim 328, wherein forming the cover comprises coupling the cover to the supporting member at a distance above the supporting member substantially less than a width of the particle.

342. The method of claim 328, wherein the supporting member comprises a silicon wafer.
343. The method of claim 342, wherein forming the cavity comprises anisotropically etching the silicon wafer.
344. The method of claim 342, wherein forming the cavity comprises anisotropically etching the silicon wafer such that the width of the cavity narrows in a direction from a top surface of the supporting member toward a bottom surface of the supporting member, and wherein a minimum width of the cavity is substantially less than a width of the particle.
345. The method of claim 328, wherein the supporting member comprises a dry film photoresist material.
346. The method of claim 328, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.
347. The method of claim 346, wherein forming the cavity comprises:
etching a first opening through a first dry film photoresist layer, the first opening having a width substantially less than a width of the particle;
placing a second dry film photoresist layer upon the first dry film photoresist layer, etching a second opening through the second dry film photoresist layer, the second opening being substantially aligned with the first opening, wherein a width of the second opening is substantially greater than the width of the first opening.
348. The method of claim 347, wherein the second dry film photoresist layer comprises a thickness substantially greater than a width of the particle.
349. The method of claim 345, further comprising forming a reflective layer upon the inner surface of the cavity.
350. The method of claim 328, wherein the supporting material comprises a plastic material.
351. The method of claim 350, wherein the cavity is formed by drilling the supporting material.
352. The method of claim 350, wherein the cavity is formed by transfer molding the supporting member.
353. The method of claim 350, wherein the cavity is formed by a punching device.
354. A sensor array produced by the method of claim 328.

355. A sensor array produced by the method of claim 342.
356. A sensor array produced by the method of claim 345.
357. A sensor array produced by the method of claim 345.
358. A sensor array produce by the method of claim 350.
359. A method of sensing an analyte in a fluid comprising:
passing a fluid over a sensor array, the sensor array comprising at least one particle positioned within a cavity of a supporting member, wherein the cavity is configured such that the fluid entering the cavity passes through the supporting member;
monitoring a spectroscopic change of the particle as the fluid is passed over the sensor array, wherein the spectroscopic change is caused by the interaction of the analyte with the particle.
360. The method of claim 359, wherein the spectroscopic change comprises a change in absorbance of the particle.
361. The method of claim 359, wherein the spectroscopic change comprises a change is fluorescence of the particle.
362. The method of claim 359, wherein the spectroscopic change comprises a change is phosphorescence of the particle.
363. The method of claim 359, wherein the analyte is a proton atom, and wherein the spectroscopic change is produced when the pH of the fluid is varied, and wherein monitoring the spectroscopic change of the particle allows the pH of the fluid to be determined 364. The method of claim 359, wherein the analyte is a metal ration, and wherein the spectroscopic change is produced in response to the presence of the metal cation in the fluid.
365. The method of claim 359, wherein the analyte is an anion, and wherein the spectroscopic change is produced in response to the presence of the action is the fluid.
366. The method of claim 359, wherein the analyte is a DNA molecule, and wherein the spectroscopic change is produced in response to the presence of the DNA molecule in the fluid.
367. The method of claim 359, wherein the analyte is a protein, and wherein the spectroscopic change is produced in response to the presence of the protein in the fluid.

368. The method of claim 359, wherein the analyte is a metabolite, and wherein the spectroscopic change is produced in response to the presence of the metabolite is the fluid.
369. The method of claim 359, wherein the analyte is a sugar, and wherein the spectroscopic change is produced in response to the presence of the sugar in the fluid.
370. The method of claim 359, wherein the analyte is a bacteria, and wherein the spectroscopic change is produced in response to the presence of the bacteria in the fluid.
371. The method of claim 359, wherein the particle comprises a receptor coupled to a polymeric resin, and further comprising exposing the particle to an indicator prior to passing the fluid over the sensor array.
372. The method of claim 371, wherein a binding strength of the indicator to the receptor is less than a binding strength of the analyte to the receptor.
373. The method of claim 371, wherein the indicator is a fluorescent indicator.
374. The method of claim 359, further comprising treating the fluid with an indicator prior to passing the fluid over the sensor array, wherein the indicator is configured to couple with the analyze.
375. The method of claim 359, wherein the analyte is bacteria and further comprising breaking down the bacteria prior to passing the fluid over the sensor stray.
376. The method of claim 359, wherein monitoring the spectroscopic change is performed with a CCD
device.
377. The method of claim 359, further comprising measuring the intensity of the spectroscopic change, and further comprising calculating the concentration of the analyze based on the intensity of the spectroscopic change.
378. The method of claim 359, wherein monitoring the spectroscopic change comprises:
directing a red light source at the particle;
detecting the absorbance of red light by the particle;
directing a green light source at the particle;
detecting the absorbance of green light by the particle;
directing a blue light source at the particle; and detecting the absorbance of blue tight by the particle.

379. A sensor array for detecting an analyte in a fluid comprising:
at least one particle coupled to a supporting member, wherein the particle is configured to produce a signal when the particle interacts with the analyte.

380. The sensor array of claim 379, wherein the particle is coupled to the supporting member with via an adhesive material.

381. The sensor array of claim 379, wherein the particle are coupled to the supporting member via a gel material.

382. The sensor array of claim 379, wherein the particle is suspended in a gel material, the gel material covering a portion of the supporting member, and wherein a portion of the particle extends from the upper surface of the gel.

383. The sensor array of claim 379, further comprising a cover positioned above the particle.

384. The sensor array of claim 379, further comprising a cover coupled to the supporting member, positioned above the particle, wherein a force exerted by the cover on the particle inhibits the displacement of the particle from the supporting member.

385. The sensor array of claim 379, wherein the particle comprises a receptor molecule coupled to a polymeric resin.

386. The sensor array of claim 379, wherein the supporting member comprises a plastic material.

387. The sensor array of claim 379, wherein the supporting member comprises a dry film photoresist material.

388. The sensor array of claim 379, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.

389. The sensor array of claim 379, wherein the supporting member comprises glass.

390. The sensor array of claim 379, further comprising a detector coupled to the bottom surface of the supporting member, wherein the detector is positioned below the particle.

391. The sensor away of claim 379, further comprising a plurality of particles coupled to the supporting member.

392, The sensor array of claim 379, wherein the supporting member is composed of a material substantially transparent to visible light.

393. The sensor array of claim 379, wherein the supporting member is composed of a material substantially transparent to ultraviolet light.

394. A system for detecting an analyte in a fluid comprising:
a light source;
a sensor array, the sensor array comprising at least one particle coupled to a supporting member, wherein the particle is configured to produce a signal when the particle interacts with the analyte, and wherein the supporting member is substantially transparent to a portion of light produced by the light source; and a detector configured to detect the signal produced by the interaction of the analyte with the particle;
wherein the light source and detector are positioned such that light passes from the light source, to the particle, and onto the detector during use.

395. The system of claim 394, wherein the system comprises a plurality of additional particles coupled to the supporting member, and wherein the system is configured to substantially simultaneously detect a plurality of analytes in the fluid.

396. The system of claim 394, wherein the light source comprises a light emitting diode.

397. The system of claim 394, wherein the light source comprises a red light emitting diode, a blue light emitting diode, and a green light emitting diode.

398. The system of claim 394, wherein the light source comprises a white light source.

399. The system of claim 394, wherein the particle is coupled to the supporting member with via an adhesive material.

400. The system of claim 394, wherein the particle are coupled to the supporting member via a gel material.

401. The system of claim 394, wherein the particle is suspended in a gel material, the gel material covering a portion of the supporting member, and wherein a portion of the particle extends from the upper surface of the gel.

402. The system of claim 394, wherein the sensor array further comprises a cover positioned above the particle.

403. The system of claim 394, wherein the sensor array further comprises a cover coupled to the supporting member, positioned above the particle, wherein a force exerted by the cover on the particle inhibits the displacement of the particle from the supporting member.

404. The system of claim 394, wherein the particle comprises a receptor molecule coupled to a polymeric resin.

405. The system of claim 394, wherein the supporting member comprises a plastic material.

406. The system of claim 394, wherein the supporting member comprises a dry film photoresist material.

407. The system of claim 394, wherein the supporting member comprises a plurality of layers of a dry film photoresist material.

408. The system of claim 394, wherein the supporting member comprises glass.

409. The system of claim 394, wherein the supporting member is composed of a material substantially transparent to ultraviolet light.

410. The system of claim 394, wherein the detector comprises a charge-coupled device.

411. The system of claim 394, wherein the particle comprises a receptor molecule coupled to a polymeric resin.

412. The system of claim 394, wherein the system comprises a plurality of particles coupled to the supporting member, and wherein the plurality of particles produce a detectable pattern in the presence of the analyte.
CA002337155A 1998-07-16 1999-07-16 Sensor arrays for the measurement and identification of multiple analytes in solutions Abandoned CA2337155A1 (en)

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US09/287,248 US6908770B1 (en) 1998-07-16 1999-04-07 Fluid based analysis of multiple analytes by a sensor array
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