US20050003421A1 - Bioarray chip reaction apparatus and its manufacture - Google Patents
Bioarray chip reaction apparatus and its manufacture Download PDFInfo
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- US20050003421A1 US20050003421A1 US10/877,666 US87766604A US2005003421A1 US 20050003421 A1 US20050003421 A1 US 20050003421A1 US 87766604 A US87766604 A US 87766604A US 2005003421 A1 US2005003421 A1 US 2005003421A1
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Abstract
A body 300 having a cavity 310 for mounting a substrate 120 fabricated with probe sequences at known locations according to the methods disclosed in U.S. Pat. No. 5,143,854 and PCT WO 92/10092 or others, is provided. The cavity includes inlets 350 and 360 for introducing selected fluids into the cavity to contact the probes. Accordingly, a commercially feasible device for use in high throughput assay systems is provided.
Description
- This application is a continuation of U.S. application Ser. No. 10/229,759, filed on Aug. 28, 2002, which is a continuation of U.S. patent application Ser. No. 10/046,623, filed Jan. 14, 2002, now U.S. Pat. No. 6,551,817, which is a continuation of U.S. patent application Ser. No. 09/907,196, filed Jul. 17, 2001, now U.S. Pat. No. 6,399,365, which is a continuation of U.S. patent application Ser. No. 09/302,052, filed Apr. 29, 1999, now U.S. Pat. No. 6,287,850, which is a continuation of U.S. patent application Ser. No. 08/485,452, filed Jun. 7, 1995, now U.S. Pat. No. 5,945,334, which is continuation-in-part U.S. patent application Ser. No. 08/255,682, filed Jun. 8, 1994, now U.S. Pat. No. 6,140,044. Each of these applications is incorporated herein by reference in its entirety for all purposes.
- The present inventions relate to the fabrication and placement of materials at known locations on a substrate. In particular, one embodiment of the invention provides a method and associated apparatus for packaging a substrate having diverse sequences at known locations on its surface.
- Techniques for forming sequences on a substrate are known. For example, the sequences may be formed according to the pioneering techniques disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.), PCT WO 92/10092, or U.S. application Ser. No. 08/249,188, now U.S. Pat. No. 5,571,639, incorporated herein by reference for all purposes. The prepared substrates will have a wide range of applications, For example, the substrates may be used for understanding the structure-activity relationship between different materials or determining the sequence of an unknown material. The sequence of such unknown material may be determined by, for example, a process known as sequencing by hybridization. In one method of sequencing by hybridization, a sequences of diverse materials are formed at known locations on the surface of a substrate. A solution containing one or more targets to be sequenced is applied to the surface of the substrate. The targets will bind or hybridize with only complementary sequences on the substrate.
- The locations at which hybridization occurs can be detected with appropriate detection systems by labeling the targets with a fluorescent dye, radioactive isotope, enzyme, or other marker. Exemplary systems are described in U.S. Pat. No. 5,143,854 (Pirrung et al.) and U.S. patent application Ser. No. 08/143,312, also incorporated herein by reference for all purposes. Information regarding target sequences can be extracted from the data obtained by such detection systems.
- By combining various available technologies, such as photolithography and fabrication techniques, substantial progress has been made in the fabrication and placement of diverse materials on a substrate. For example, thousands of different sequences may be fabricated on a single substrate of about 1.28 cm2 in only a small fraction of the time required by conventional methods. Such improvements make these substrates practical for use in various applications, such as biomedical research, clinical diagnostics, and other industrial markets, as well as the emerging field of genomics, which focuses on determining the relationship between genetic sequences and human physiology.
- As commercialization of such substrates becomes widespread, an economically feasible and high-throughput device and method for packaging the substrates are desired.
- Methods and devices for packaging a substrate having an array of probes fabricated on its surface are disclosed. In some embodiments, a body containing a cavity is provided. A substrate having an array of probes is attached to the cavity using, for example, an adhesive. The body includes inlets that allow fluids into and through the cavity. A seal is provided for each inlet to retain the fluid within the cavity. An opening is formed below the cavity to receive a temperature controller for controlling the temperature in the cavity. By forming a sealed thermostatically controlled chamber in which fluids can easily be introduced, a practical medium for sequencing by hybridization is provided.
- In other embodiments, the body is formed by acoustically welding two pieces together. The concept of assembling the body from two pieces is advantageous. For example, the various features of the package (i.e., the channels, sealing means, and orientation means) are formed without requiring complex machining or designing. Thus, the packages are produced at a relatively low cost.
- In connection with one aspect of the invention, a method for making the chip package is disclosed. In particular, the method comprises the steps of first forming a plurality of probe arrays on a substrate and separating the substrate into a plurality of chips. Typically, each chip contains at least one probe array. A chip is then mated to a package having a reaction chamber with fluid inlets. When mated, the probe array is in fluid communication with the reaction chamber.
- In a specific embodiment, the present invention provides an apparatus for packaging a substrate. The present apparatus includes a substrate having a first surface and a second surface. The first surface includes a probe array and the second surface is an outer periphery of the first surface. The present apparatus also includes a body having a mounting surface, an upper surface, and a cavity bounded by the mounting surface and the upper surface. The second surface is attached to the cavity and the first surface is within the cavity. A cover attached to the mounting surface for defining an upper boundary to the cavity is also included. The cavity includes a diffuser and a concentrator. The diffuser and the concentrator permit laminar fluid flow through the cavity.
- A further understanding of the nature and advantages of the inventions herein may be realized by reference to the remaining portions of the specification and the attached drawings.
-
FIG. 1 a illustrates a wafer fabricated with a plurality of probe arrays. -
FIG. 1 b illustrates a chip. -
FIG. 2 a illustrates a scribe and break device. -
FIG. 2 b illustrates the wafer mounted on a pick and place frame. -
FIGS. 2 c-2 d illustrate the wafer, as displayed by the scribe and break device during alignment. -
FIG. 3 illustrates a chip packaging device. -
FIG. 4 illustrates the chip packaging device assembled from two components. -
FIGS. 5 a-5 b illustrate the top and bottom view of a top casing of the chip packaging device. -
FIG. 5 c illustrates a different cavity orientation. -
FIG. 6 illustrates a cross sectional view of the packaging device. -
FIG. 7 illustrates the bottom view of a bottom casing of the chip packaging device. -
FIGS. 8 a-8 b illustrate an acoustic welding system. -
FIGS. 9 a-9 c illustrate the acoustic welding process used in assembling the chip packaging device. -
FIG. 10 illustrates an adhesive dispensing system used in attaching the chip to the chip packaging device. -
FIGS. 11-13 illustrate in greater detail the adhesive dispensing system ofFIG. 10 . -
FIGS. 14 a-14 d illustrate the procedure for aligning the system ofFIG. 10 . -
FIGS. 15 a-15 e illustrate images obtained during the alignment process ofFIGS. 14 a-14 d. -
FIGS. 16 a-16 b illustrate an alternative embodiment of a packaging device. -
FIGS. 17 a-17 b illustrate another embodiment of a packaging device. -
FIG. 18 illustrates an alternative embodiment for attaching the chip to the packaging device. -
FIG. 19 illustrates another embodiment for attaching the chip to the packaging device. -
FIGS. 20 a-20 b illustrate yet another embodiment for attaching the chip to the packaging device. -
FIG. 21 illustrates an alternative embodiment for attaching the chip to the packaging device. -
FIG. 22 illustrates another embodiment for attaching the chip to the packaging device. -
FIG. 23 illustrates an alternative embodiment for sealing the cavity on the packaging device. -
FIG. 24 illustrates another alternative embodiment for sealing the cavity on the packaging device. -
FIG. 25 illustrates yet another embodiment for sealing the cavity on the packaging device. -
FIGS. 26 a-26 b illustrate an alternative embodiment for sealing the cavity on the packaging device. -
FIGS. 27 a-27 b illustrate an alternative embodiment for mounting the chip. -
FIG. 28 illustrates an agitation system. -
FIG. 29 illustrates an alternative embodiment of the agitation system. -
FIG. 30 illustrates another embodiment of the agitation system. -
FIG. 31 illustrates an alternative embodiment of a chip packaging device. -
FIG. 32 illustrates side-views of the chip packaging device ofFIG. 31 . -
FIGS. 33-35 illustrate in greater detail the chip packaging device ofFIG. 31 . -
FIG. 36 illustrates a further alternative embodiment of a chip packaging device. -
-
- I. Definitions
- II. General
- III. Details of One Embodiment of Invention
- a. Chip Package
- b. Assembly of Chip Package
- c. Chip Attachment
- IV. Details on Alternative Embodiments
- a. Chip Package
- b. Chip Attachment
- c. Fluid Retention
- d. Chip Orientation
- e. Parallel Diagnostics
- V. Details of an Agitation System
I. Definitions
- The following terms are intended to have the following general meanings as they are used herein:
-
- 1. Probe: A probe is a surface-immobilized molecule that is recognized by a particular target and is sometimes referred to as a ligand. Examples of probes that can be investigated by this invention include, but are not restricted to, agonists and antagonists for cell membrane receptors, toxins and venoms, viral epitopes, hormones (e.g., opioid peptides, steroids, etc.), hormone receptors, peptides, enzymes, enzyme substrates, cofactors, drugs, lectins, sugars, oligonucleotides or nucleic acids, oligosaccharides, proteins, and monoclonal antibodies.
- 2. Target: A target is a molecule that has an affinity for a given probe and is sometimes referred to as a receptor. Targets may be naturally-occurring or manmade molecules. Also, they can be employed in their unaltered state or as aggregates with other species. Targets may be attached, covalently or noncovalently, to a binding member, either directly or via a specific binding substance. Examples of targets which can be employed by this invention include, but are not restricted to, antibodies, cell membrane receptors, monoclonal antibodies and antisera reactive with specific antigenic determinants (such as on viruses, cells or other materials), drugs, oligonucleotides or nucleic acids, peptides, cofactors, lectins, sugars, polysaccharides, cells, cellular membranes, and organelles. Targets are sometimes referred to in the art as anti-probes or anti-ligands. As the term “targets” is used herein, no difference in meaning is intended. A “Probe Target Pair” is formed when two macromolecules have combined through molecular recognition to form a complex.
- II. General
- The present invention provides economical and efficient packaging devices for a substrate having an array of probes fabricated thereon. The probe arrays may be fabricated according to the pioneering techniques disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.), PCT WO 92/10092, or U.S. application Ser. No. 08/249,188 filed May 24, 1994, already incorporated herein by reference for all purposes. According to one aspect of the techniques described therein, a plurality of probe arrays are immobilized at known locations on a large substrate or wafer.
-
FIG. 1 a illustrates awafer 100 on whichnumerous probe arrays 110 are fabricated. Thewafer 100 may be composed of a wide range of material, either biological, nonbiological, organic, inorganic, or a combination of any of these, existing as particles, strands, precipitates, gels, sheets, tubing, spheres, containers, capillaries, pads, slices, films, plates, slides, etc. The wafer may have any convenient shape, such as a disc, square, sphere, circle, etc. The wafer is preferably flat but may take on a variety of alternative surface configurations. For example, the wafer may contain raised or depressed regions on which a sample is located. The wafer and its surface preferably form a rigid support on which the sample can be formed. The wafer and its surface are also chosen to provide appropriate light-absorbing characteristics. For instance, the wafer may be a polymerized Langmuir Blodgett film, functionalized glass, Si, Ge, GaAs, GaP, SiO2, SiN4, modified silicon, or any one of a wide variety of gels or polymers such as (poly)tetrafluoroethylene, (poly)vinylidenedifluoride, polystyrene, polycarbonate, or combinations thereof. Other materials with which the wafer can be composed of will be readily apparent to those skilled in the art upon review of this disclosure. In a preferred embodiment, the wafer is flat glass or single-crystal silicon. - Surfaces on the solid wafer will usually, though not always, be composed of the same material as the wafer. Thus, the surface may be composed of any of a wide variety of materials, for example, polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, membranes, or any of the above-listed wafer materials.
-
Wafer 100 includes a plurality ofmarks 145 that are located in streets 150 (area adjacent to the probe arrays). Such marks may be used for aligning the masks during the probe fabrication process. In effect, the marks identify the location at which eacharray 110 is to be fabricated. The probe arrays may be formed in any geometric shape. In some embodiments, the shape of the array may be squared to minimize wasted wafer area. After the probe arrays haye been fabricated, the wafer is separated into smaller units known as chips. The wafer, for example, may be about 5×5 inches on which 16 probe arrays, each occupying an area of about 12.8 cm2, are fabricated. -
FIG. 1 b illustrates a chip that has been separated from the wafer. As illustrated,chip 120 contains aprobe array 110 and a plurality of alignment marks 145. The marks serve multiple functions, such as: 1) aligning the masks for fabricating the probe arrays, 2) aligning the scriber for separating the wafer into chips, and 3) aligning the chip to the package during the attachment process. In some embodiments, such chips may be of the type known as Very Large Scale Immobilized Polymer Synthesis (VLSIPS™) chips. - According to a specific embodiment, the chip contains an array of genetic probes, such as an array of diverse RNA or DNA probes. In some embodiments, the probe array will be designed to detect or study a genetic tendency, characteristic, or disease. For example, the probe array may be designed to detect or identify genetic diseases such as cystic fibrosis or certain cancers (such as P53 gene relevant to some cancers), as disclosed in U.S. patent application Ser. No. 08/143,312, already incorporated by reference.
- According to one embodiment, the wafer is separated into a plurality of chips using a technique known as scribe and break.
FIG. 2 a illustrates a fully programmable computer controlled scribe and break device, which in some embodiments is a DX-III Scriber breaker manufactured by Dynatex International™. As shown, thedevice 200 includes a base 205 with arotation stage 220 on which a wafer is mounted. The rotation stage includes a vacuum chuck for fixing the wafer thereon. A stepper motor, which is controlled by the system, rotatesstage 220. Located above the stage is ahead unit 230 that includes acamera 232 andcutter 231.Head unit 230 is mounted on a dual-axis frame. The camera generates an image of the wafer onvideo display 210. Thevideo display 210 includes a crosshair alignment mark 215. The camera, which includes a zoom lens and a fiber optic light, allows a user to inspect the wafer on thevideo display 210. A control panel 240 is located on the base for operatingdevice 200. - In operation, a user places a
wafer 100 on aframe 210 as illustrated inFIG. 2 b. The surface offrame 210 is composed of a flexible and sticky material. The tackiness of the frame prevents the chips from being dispersed and damaged during the breaking process. -
Frame 210 may be a pick and place frame or a hoop that is commonly associated with fabrication of semiconductors. Referring back toFIG. 2 a, a user places the frame with the wafer on therotation stage 220. In some embodiments, the frame is held on the rotation stage by vacuum pressure. The user then aligns the wafer by examining the image displayed on thevideo display 210. - According to one embodiment, wafer alignment is achieved in two steps. First, using the control panel 240, the user rotates
stage 220. The stage is rotated untilstreets 150 are aligned with thecross hair 215 on the display, as illustrated inFIG. 2 c. Next, the user moves the cutter until it is aligned at the center of one of the streets. This step is performed by aligninghorizontal line 216 of the cross hair between alignment marks 145, as shown inFIG. 2 d. - Once the cutter is aligned, the user instructs the device to scribe the wafer. In some embodiments, various options are available to the user, such as scribe angle, scribe pressure, and scribe depth. These parameters will vary depending on the composition and/or thickness of the wafer. Preferably, the parameters are set to scribe and break the wafer without causing any damage thereto or penetrating through the frame. The device repeatedly scribes the wafer until all the streets in one axis have been scribed, which in one embodiment is repeated 5 times (a 4×4 matrix of probe arrays). The user then rotates the stage 90° to scribe the perpendicular streets.
- Once the wafer has been scribed, the user instructs the device to break or separate the wafer into chips. Referring back to
FIG. 2 a, thedevice 200 breaks the wafer by striking it beneath the scribe with an impulse bar located under the rotation table 220. The shock from the impulse bar fractures the wafer along the scribe. Since most of the force is dissipated along the scribe,device 200 is able to produce high breaking forces without exerting significant forces on the wafer. Thus, the chips are separated without causing any damage to the wafer. Once separated, the chips are then packaged. Of course, other more conventional techniques, such as the sawing technique disclosed in U.S. Pat. No. 4,016,855, incorporated herein by reference for all purposes, may be employed. - III. Details of One Embodiment of the Invention
- a. Chip Package
-
FIG. 3 illustrates a device for packaging the chips. Package 300 contains acavity 310 on which a chip is mounted. The package includesinlets cavity 310. Fluids are circulated through the cavity viainlets non-flush edge 320. In some detection systems, the packages may be inserted into a holder similar to an audio cassette tape. The asymmetrical design of the package will assure correct package orientation when inserted into the holder. -
FIG. 4 illustrates one embodiment of the package. As shown inFIG. 4 , the chip package is manufactured by mating two substantiallycomplementary casings finished assembly 300. Preferably,casings -
FIGS. 5 a-5 b show thetop casing 410 in greater detail.FIG. 5 a shows a top view andFIG. 5 b shows a bottom view. Referring toFIG. 5 a,top casing 410 includes an externalplanar surface 501 having acavity 310 therein. In some embodiments, the surface area ofcasing 410 sufficiently accommodates the cavity. Preferably, the top casing is of sufficient size to accommodate identification labels or bar codes in addition to the cavity. In a specific embodiment, the top casing is about 1.5″ wide, 2″ long, and 0.2″ high. -
Cavity 310 is usually, though not always, located substantially at the center ofsurface 501. The cavity may have any conceivable size, shape, or orientation. Preferably, the cavity is slightly smaller than the surface area of the chip to be placed thereon and has a volume sufficient to perform hybridization. In one embodiment, the cavity may be about 0.58″ wide, 0.58″ long, and 0.2″ deep. -
Cavity 310 may includeinlets -
FIG. 5 c illustrates an alternative embodiment in whichcavity 310 is oriented such that the edges of thecavity 310 and thecasing 410 are non-parallel. This configuration allowsinlets - Referring back to
FIG. 5 a, adepression 550 surrounds the cavity. In some embodiments, aridge 560 may be provided at the edge of the depression so as to form a trough. The ridge serves to support the chip above the cavity. To attach the chip to the package, an adhesive may be deposited in the trough. This configuration promotes efficient use of chip surface area, thus increasing the number of chips yielded from a wafer. -
Top casing 410 includes alignment holes 330 and 335. In some embodiments, holes 330 and 335 are different in size to ensure correct orientation of the package when mounted on an alignment table. Alternatively, the holes may have different shapes to achieve this objective. Optionally, the holes taper radially inward fromsurface 501 toward 502 to reduce the friction against alignment pins while still maintaining adequate contact to prevent slippage. - Referring to
FIG. 5 b,channels internal surface 502.Channels inlets depression 590 is formed below cavity. According to some embodiments, the shape ofdepression 590 is symmetrical to the cavity with exception tocorners depression 590 may be, for example, about 0.7″. As a result, the bottom wall of the cavity is about 0.05″ thick.Depression 590 may receive a temperature controller to monitor and maintain the cavity at the desired temperature. By separating the temperature controller and cavity with a minimum amount of material, the temperature within the cavity may be controlled more efficiently and accurately. Alternatively, channels may be formed onsurface 502 for circulating air or water to control the temperature within the cavity. - In some embodiments,
certain portions 595 ofinternal surface 502 may be eliminated or cored without interfering with the structural integrity of the package when assembled. Coring the casing reduces the wall thickness, causing less heat to be retained during the injection molding process; potential shrinkage or warpage of the casing is significantly reduced. Also, coring decreases the time required to cool the casing during the manufacturing process. Thus, manufacturing efficiency is improved. - In one embodiment, the top casing and bottom casing are mated together using a technique known as acoustic or ultrasonic welding. Accordingly, “energy directors” 510 are provided. Energy directors are raised ridges or points, preferably v-shaped, that are used in an acoustic welding process. The energy directors are strategically located, for example, to seal the channels without interfering with other features of the package and to provide an adequate bond between the two casings. Alternatively, the casings may be mated together by screws, glue, clips, or other mating techniques.
- FIGS. 6 shows a cross sectional view of the
cavity 310 withchip 120 mounted thereon in detail. As shown, adepression 550 is formed aroundcavity 310. The depression includes aridge 560 which supportschip 120. The ridge and the depression create a trough aroundcavity 310. In some embodiments, the trough is sufficiently large to receive an adhesive 630 for attaching the chip to the package. In one embodiment, the trough is about 0.08″ wide and 0.06″ deep. When mounted, the edge of the chip protrudes slightly beyondridge 550, but without contactingside 625 of the depression. This configuration permits the adhesive to be dispensed onto the trough and provides adequate surface area for the adhesive to attachchip 120 to the package. - According to some embodiments, the
back surface 130 ofchip 120 is at least flush or below the plane formed bysurface 501 ofcasing 410. As a result,chip 120 is shielded bysurface 501 from potential damage. This configuration also allows the packages to be easily stored with minimal storage area since the surfaces are substantially flat. - Optionally, the bottom of the cavity includes a light absorptive material, such as a glass filter or carbon dye, to prevent impinging light from being scattered or reflected during imaging by detection systems. This feature improves the signal-to-noise ratio of such systems by significantly reducing the potential imaging of undesired reflected light.
-
FIG. 7 shows the internal surface ofbottom casing 420 in greater detail. As shown, thebottom casing 420 is substantially planar and contains anopening 760 therein, Preferably, thecasing 420 is slightly wider or slightly longer than the top casing. In one embodiment, casing 420 is about 1.6″ wide, 2.0″ long, and 0.1″ deep, which creates a non-flush edge on the finish assembly. As previously mentioned, this design ensures that the package is correctly oriented when mounted onto the detection systems. - In some embodiments, opening 760 is spatially located at about the depression below the cavity. The opening also has substantially the same geometric configuration as the depression to allow the temperature controller to contact as much of the bottom of the cavity as possible.
-
Internal surface 701 ofcasing 420 includesdepressions port 731 is located indepression 730 and aport 741 is located indepression 740.Ports FIG. 5 b) when the package is assembled. Aseal 790, which may be a septum composed of rubber, teflon/rubber laminate, or other sealing material is provided for each depression. The septum may be of the type commonly used to seal and reseal vessels when a needle is inserted into the septum for addition/removal of fluids. The septums, when seated in the depressions, extend slightly above surface, which in some embodiments is about 0.01″. - This design causes
casings - Also, casing 420 includes the complementary
half alignment holes certain areas 765 oninternal surface 701 may be cored, as similar to the internal surface of the top casing. -
FIG. 31 is a simplified illustration of an alternative embodiment of achip packaging device 3100 according to the present invention. The chip packaging device includes a plurality ofcasings top casing 3200, amiddle casing 3300, and abottom casing 3400. The casings are made of known plastic materials such as ABS plastic, polyvinylchloride, polyethylene, products sold under the trademarks TEFLON™ and KALREZ™ and the like, among others. Preferably, the casings can be made by way of injection molding and the like. Assembling the chip packaging device from three casings simplifies construction for the fabrication of internal channels and the like, and can also be made at a relatively low cost. - Support structures (or alignment holes) exist at selected locations of the chip packing device. The support structures can be used to mount or position the chip packaging device to an apparatus, e.g., scanner or the like. In an embodiment, the
top casing 3200 includessupport structures center opening 3209. Themiddle casing 3300 includessimilar support structures support structures similar support structures - The present chip packaging device assembles with use of complementary alignment pins and bores on the casings. By way of alignment pins (not shown), the top casing aligns with and inserts into alignment bores 3301, 3303 in the
middle casing 3300. Alternatively, the middle casing can have alignment pins or the like and the top casing has the alignment bores or the like. The bottom casing includesalignment pins - A
center opening 3209 in the top casing overlies acenter portion 3317 of themiddle casing 3300. Thecenter portion 3317 of the middle casing includes an inner annular region (or cavity edges) with a bottom portion which is preferably a flat bottom portion. The flat bottom portion of the middle casing and portions of the bottom casing including edges define acavity 3405. A chip is placed overlying an underlying portion of thecavity 3407. - Optionally, a temperature control mechanism such as a heater, a cooler, or a combination thereof is disposed into the center opening against the bottom portion of the middle casing. The temperature control mechanism can be any suitable thermally controlled element such as a resistive element, a temperature controlled block or mass, thermoelectric modules, or the like. The temperature control mechanism transfers heat via conduction to the bottom center portion, which transfers heat to, for example, fluid in the cavity or the chip. Alternatively, the temperature control mechanism sinks heat away from, for example, fluid in the cavity or the chip through the bottom center portion. The temperature control mechanism maintains a selected temperature in the cavity. The temperature control mechanism also includes a temperature detection device such as a thermocouple which provides signals corresponding to temperature readings. A controller receives the signals corresponding to the temperature readings, and adjusts power output to the temperature control mechanism to maintain the selected temperature.
- The
top casing 3200 also includeschannels channels annular regions middle casing 3300 for fluid transfer. A septum, a plug, an o-ring, a gasket, or the like viaannular regions top casing channels channels channels bottom casing channels middle casing channels - The chip packaging device provides an even distribution of fluid (or fluid flow) through the cavity over a top surface (or inner or active surface) of the chip. For example, a selected fluid enters
channel 3207, flows throughchannel 3307, changes direction and flows throughchannel 3411, and evenly distributes into thecavity 3405 over the top surface of the chip. As previously noted, the cavity is defined by the flat bottom portion and cavity edges. A selected fluid exits the cavity by way ofchannel 3413,channel 3305, andchannel 3205. The fluid flow over the top surface of the chip is preferably laminar, but may also be turbulent, a combination thereof or the like. By way of the present chip packaging device, a substantial portion of turbulent flow remains at an upper portion of thechannel 3411, and does not enter the cavity. - Preferably, a selected fluid enters the cavity by way of
channel 3205,channel 3305, and channel 413. The selected fluid exits the cavity throughchannel 3411,channel 3307, andchannel 3207. In a preferred embodiment, the fluid flows against the direction of gravity through the cavity. Of course, other fluid flow routes may also be employed depending upon the particular application. -
FIG. 32 illustrates an assembledchip packaging device 3100 according to the present invention. As shown are a top-view 3200, a side-view 3500, a bottom-view 3400, and a front-view 3600 of the assembledchip packaging device 3100. The assembledchip packaging device 3100 includes thebottom casing 3400, themiddle casing 3300, and thetop casing 3200. - The top-
view 3200 of the top casing includesalignment structures opening 3209. Theopening 3209 includes a bevelledannular region 3211 surrounding the periphery of thechannel 3209. The alignment bores 3203 and 3201 also include bevelledannular regions annular region fluid channel - The bottom-
view 3400 of the bottom casing includesalignment structures cavity 3405. The cavity includes a flat bottomperipheral portion 3415, abevelled portion 3417 extending from the flat bottom peripheral portion, and a flatupper portion 3419 surrounding the bevelled portion. The chip includes an outer periphery which rests against the flat bottomperipheral portion 3415. The bevelled portion aligns the chip onto the flat bottomperipheral portion 3415. Similar to the previous embodiments, the top casing extends outside 3421 the middle and bottom casings. - The
cavity 3405 is preferably located at a center of the bottom casing, but may also be at other locations. The cavity may be round, square, rectangular, or any other shape, and orientation. The cavity is preferably smaller than the surface area of the chip to be placed thereon, and has a volume sufficient to perform hybridization and the like. - In one embodiment, the cavity includes dimensions such as a length of about 0.6 inch, a width of about 0.6 inch and a depth of about 0.07 inch. In a preferred embodiment, the bottom casing with selected cavity dimensions may be removed from the middle and top casings, and replaced with another bottom casing with different cavity dimensions. This allows a user to attach a chip having a different size or shape by changing the bottom casing, thereby providing ease in using different chip sizes, shapes, and the like. Of course, the size, shape, and orientation of the cavity will depend upon the particular application.
-
FIGS. 33-35 illustrate in greater detail the chip packaging device ofFIG. 31 .FIG. 33 illustrates simplified top-view 3260 and bottom-view 3250 diagrams of thetop casing 3200. As shown, the reference numerals refer to the same elements as the top casing ofFIG. 31 .FIG. 34 illustrates a simplified top-view 3350 and bottom-view 3360 diagrams of themiddle casing 3300. As shown, the reference numerals refer to the same elements as the middle casing ofFIG. 31 . In addition, the bottom-view of the casing includes a substantially smooth andplanar bottom surface 3361. A portion of the bottom surface defines an upper portion of the cavity. But the bottom surface can also be textured, ridged, or the like to create turbulence or a selected fluid flow through the cavity. The bottom surface is preferably a hydrophobic surface which enhances laminar flow through the cavity. Of course, the type of bottom surface depends upon the particular application. -
FIG. 35 illustrates simplified top-view 3460 and bottom-view 3450 diagrams of thebottom casing 3400. As shown, the reference numerals refer to the same elements as the bottom casing ofFIG. 31 . In an embodiment, fluid fromchannel 3305 changes direction at anupper portion 3431 of the channel and flows to alower portion 3433 of the channel. Fluid evenly distributes from thelower portion 3433 via afluid distribution point 3435. The distributed fluid evenly passes over a slanted edge (or bevelled edge) 3437 which drops fluid evenly to a top surface of the chip in the cavity. By way of slantededge 3427 which slopes up to afluid concentration point 3425, fluid leaves the cavity and enters thechannel 3411. In particular, fluid leaves the cavity and enters alower portion 3423 of the channel, flows through the channel, and changes directions at anupper portion 3421 of the channel. Each channel includes a length L and a width W. The distribution point and the concentration point are positioned at a distance away from the cavity to substantially prevent turbulence from forming in the cavity, and in particular over the top surface of the chip. The channels are each angled at an angle Θ ranging from about 2 degrees to about 90 degrees, but is preferably about 5 degrees to about 45 degrees. The angle enhances an even distribution of laminar flow into the cavity. Of course, the exact angle, channel shape, and dimensions depend upon the particular application. -
FIG. 36 illustrates a simplified cross-sectional view of an alternative-embodiment 3600 of the chip packaging device. The chip packaging device includes the threecasings cavity 3405. Preferably, eachpin 3601 includes anexternal opening 3609, atubular region 3611, aninner opening 3607, apointed tip 3605, and other elements. The pin is made from a suitable material such as a glass, a stainless steel or any other high quality material to transfer fluids to and from thecavity 3405. - In a preferred embodiment, each pin is inserted into its
channel region annular region channel 3205 and at least a portion of 3305), enters the upper region ofchannel 3413, and into thecavity 3405. The selected fluid travels from the cavity, throughpin 3601, and to the external apparatus. Alternatively, the selected fluid enters the cavity viapin 3601 and exits the cavity viapin 3603. The selected fluid may also enter the cavity via pin and exit the cavity through the channels without use of a pin. The selected fluid may further enter the cavity through the channels without use of a pin and exit through a pin. Of course, the particular pin used and fluid flow will depend upon the application. - It should be noted that the even distribution of fluid flow through the cavity prevents “hot spots” from occurring in the cavity. For example, the even distribution of fluid through the cavity by way of the previous embodiment substantially prevents fluid from becoming substantially turbulent at certain locations. This prevents “hot spots” caused by such turbulent fluid. The hot spots are often caused by higher chemical activity or exothermic reactions and the like by way of turbulence in such certain locations.
- b. Assembly of Chip Package
- According to one embodiment, the top and bottom casing are attached by a technique known as ultrasonic or acoustic welding.
FIG. 8 a is a schematic diagram of acoustic welding system used for assembling the package. In some embodiments, thewelding system 800 is a HS Dialog ultrasonic welder manufactured by Herrmann Ultrasonics Inc.System 800 includes aplatform 850 mounted onbase 810.Platform 850 accommodates the top and bottom casings during the assembling process. - An
acoustic horn 860 is mounted on a frame aboveplatform 850. The horn translates vertically (toward and away from platform 850) on the frame by air pressure. The horn is connected to afrequency generator 870, which in some embodiments is a 20 KHz generator manufactured by Herrmann Ultrasonics Inc.System 800 is controlled by acontroller 880, which, for example, may be a Dialog 2012 manufactured by Herrmann Ultrasonics Inc.Controller 880 may be configured to accept commands from adigital computer system 890.Computer 890 may be any appropriately programmed digital computer of the type that is well known to those skilled in the art such as a Gateway 486DX operating at 33 MHz. -
FIG. 8 b illustratesplatform 850 in greater detail. Theplatform 850 is substantially planar and includes alignment pins 851 and 852. Alignment pins 851 and 852 are used to align both the top and bottom casings during the welding process. In some embodiments, apad 890, which may be composed of silicone rubber or other energy absorbing material, is located onplatform 850 to prevent damage to the package during assembly. -
FIG. 9 a illustrates the acoustic welding system in operation. As shown,bottom casing 420, having aseptum 790 seated in each depression, is mounted onto platform table 850 and held in place by alignment pins.Top casing 410 is then aligned above the bottom casing with alignment pins. The system then commences the welding process by loweringhorn 860 until it contacts the top surface ofcasing 410. -
FIG. 9 b illustrates the casing and horn in detail. As shown, thehorn 860 presses againsttop casing 410, thereby forcingenergy directors 510 to interface withbottom casing 420. The system then activates the frequency generator, causing the welding horn to vibrate. -
FIG. 9 c illustrates in detail the energy directors during the welding process. As shown instep 9001, weldinghorn 860forces energy directors 510 againstbottom casing 420. Atstep 9002, the system vibrates the welding horn, which in some embodiments is at 20 KHz. The energy generated by the horn melts the energy directors. Simultaneously, the horn translates downward against the package. Atstep 9003, the pressure exerted by the horn causes the energy directors to fuse with the bottom casing. Atstep 9004, the welding process is completed when the horn reaches its weld depth, for example, of about 0.01″. Of course, the various welding parameters may be varied, according to the composition of the materials used, to achieve optimum results. - c. Chip Attachment
- According to some embodiments, an ultraviolet cured adhesive attaches the chip to the package.
FIG. 10 schematically illustrates an adhesive dispensing system used in attaching the chip. Thedispensing system 1000 includes an attachment table 1040 to accommodate the package during the attachment process. A chip alignment table 1050 for aligning the chip is located adjacent to attachment table 1040. Ahead unit 1030 for dispensing the adhesive is located above tables 1040 and 1050. Thehead unit 1030 also includes a camera that generates an output tovideo display 1070.Video display 1070, in some embodiments, includes a crosshair alignment mark 1071. The head unit is mounted on a dual-axis (x-y) frame for positioning during alignment and attachment of the chip. The operation of the dispensing system is controlled by acomputer 1060, which in some embodiments may be Gateway 486DX operating at 33 MHz. -
FIG. 11 illustrates the attachment table in greater detail. The attachment table 1040 has a substantiallyflat platform 1110 supported by a plurality oflegs 1105. Alignment pins 1115 and 1116, which secure the package during the attachment process, are located on the surface ofplatform 1110. - Optionally, a
needle 1120 is provided.Needle 1120 includes achannel 1121 and is connected to a vacuum pump. In operation, the needle is inserted into one of the ports of the package in order to generate a vacuum in the cavity. The vacuum pressure secures the chip to the package during the attachment process. -
FIG. 12 a shows table 1050 in greater detail. Table 1050 includes a substantiallyflat platform 1210 having adepression 1240 for holding a chip. In some embodiments, aport 1241 is provided indepression 1240.Port 1241 is connected to a vacuum pump which creates a vacuum in the depression for immobilizing the chip therein.Platform 1210 is mounted on a combination linearrotary stage 1246, which in some embodiments may be a model 26LR manufactured by DARDAL, and a singleaxis translation stage 1245, which may be a model CR2226HSE2 manufactured by DARDAL. -
FIG. 12 b illustratesdepression 1240 in greater detail. As shown, aledge 1241 surrounds thedepression 1240.Ledge 1241 supports the chip when it is placed abovedepression 1240. Since the chips are placed over the depression with the probes facing the table, this design protects the probes from being potentially damaged during alignment. -
FIG. 13 illustrates thehead unit 1030 in greater detail. As shown, thehead unit 1030 includes acamera assembly 1320 that generates an output to a video display. A light 1360 is provided to enable the camera to focus and image an object of interest. The head unit also includes anultraviolet light 1350 for curing the adhesive, avacuum pickup 1330 for moving chip during the attachment process, and anadhesive dispenser 1340. - In operation, a chip package is placed onto table 1040. As previously described, the alignment pins on the table immobilize the package. The user begins the chip attachment process by calibrating the head unit. This may be done by moving the camera above the package and aligning it with a mark on the package, as shown in
FIG. 14 a. For convenience, one of the alignment pins may be used as an alignment mark.FIG. 14 b illustrates atypical image 1440 generated by the camera during this step. As shown, the head unit is not aligned withpin 1480. To align the head unit, the user translates it in both the x and y direction untilpin 1480 is located at theintersection 1477 of the cross hair on the video display, as illustrated inFIG. 14 c. - Next, the chip is inserted into the depression on the chip alignment table.
FIG. 14 c is a flow chart indicating the steps for aligning the chip. Atstep 1410, the system positions the camera (head unit) above one of the chip's alignment marks. The camera images the alignment mark on the video display. At this point, the mark is normally misaligned (i.e., the mark is not located at the intersection of the cross hair alignment mark). Atstep 1420, the user adjusts the chip alignment table in both the x and y direction until the mark is substantially located at the intersection of the cross hair. Since no rotational adjustments were made, the mark may be misaligned angularly. - At
step 1430, the user instructs the system to move the camera above a second alignment mark, which usually is at an opposite corner of the chip. Again, an image of the alignment mark is displayed. At this stage, the alignment mark is probably misaligned in the x, y, and angular directions. Atstep 1440, the user adjusts the rotational stage, x-stage, and y-stage, if necessary, to align the mark with the cross hair on the video display. In instances where the rotational stage has been rotated, the first alignment mark will become slightly misaligned. To compensate for this shift, the user repeats the alignment process beginning atstep 1450 until both marks are aligned. Of course, image processing techniques may be applied for automated head unit and chip alignment. -
FIG. 15 a is an example of an image displayed by the video screen duringstep 1410. As shown, the first alignment mark (lower left corner of the chip) is not aligned with the cross hair marking.FIG. 15 b exemplifies an image of the first alignment mark after adjustments were made by the user.FIG. 15 c illustrates a typical image displayed by video screen duringstep 1430. As illustrated, the second alignment mark (upper right corner of the chip) is misaligned in the x, y, and angular directions.FIG. 15 d illustrates an image of the second mark following initial adjustments by the user atstep 1440.FIG. 15 e illustrates the orientation of the second alignment mark after the chip has been aligned. - Once the chip is aligned, the vacuum holding the chip on the attachment table is released. Thereafter, the pickup on the head unit removes the chip from the table and aligns it on the cavity of the package. In some embodiments, the chip is mated to the pickup by a vacuum.
- Optionally, the user may check to ensure that the chip is correctly aligned on the cavity by examining the chip's alignment marks with the camera. If the chip is out of position, the chip is removed and realigned on the alignment table. If the chip is correctly positioned, the system deposits an adhesive by moving the dispenser along the trough surrounding the cavity. In some embodiments, the vacuum is released before depositing the adhesive in the trough. This step is merely precautionary and implemented to ensure that the vacuum does not cause any adhesive to seep into the cavity. Once the adhesive is deposited, the system reexamines the chip to determine if the adhesive had moved the chip out of position. If the chip is still aligned, the head unit locates the ultraviolet light above the adhesive and cures it for a time sufficient to harden the adhesive, which in one embodiment is about 10 seconds. Otherwise, the chip is realigned.
- Upon completion, the chip package will have a variety of uses. For example, the chip package will be useful in sequencing genetic material by hybridization. In sequencing by hybridization, the chip package is mounted on a hybridization station where it is connected to a fluid delivery system. Such system is connected to the package by inserting needles into the ports and puncturing the septums therein. In this manner, various fluids are introduced into the cavity for contacting the probes during the hybridization process.
- Usually, hybridization is performed by first exposing the sample with a prehybridization solution. Next, the sample is incubated under binding conditions with a solution containing targets for a suitable binding period. Binding conditions will vary depending on the application and are selected in accordance with the general binding methods known including those referred to in: Maniatis et al., Molecular Cloning: A Laboratory Manual (1989), 2nd Ed., Cold Spring Harbor, N.Y. and Berger and Kimmel, Methods in Enzymology, Volume 152, Guide to Molecular Cloning Techniques (1987), Academic Press, Inc., San Diego, Calif.; Young and Davis (1983) Proc. Natl. Acad. Sci. (U.S.A.) 80: 1194, which are incorporated herein by reference. In some embodiments, the solution may contain about 1 molar of salt and about 1 to 50 nanomolar of targets. Optionally, the fluid delivery system includes an agitator to improve mixing in the cavity, which shortens the incubation period. Finally, the sample is washed with a buffer, which may be 6× SSPE buffer, to remove the unbound targets. In some embodiments, the cavity is filled with the buffer after washing the sample.
- Thereafter, the package may be aligned on a detection or imaging system, such as those disclosed in U.S. Pat. No. 5,143,854 (Pirrung et al.) or U.S. patent application Ser. No. 08/495,889 (Attorney Docket Number 11509-117), already incorporated herein by reference for all purposes. Such detection systems may take advantage of the package's asymmetry (i.e., non-flush edge) by employing a holder to match the shape of the package specifically. Thus, the package is assured of being properly oriented and aligned for scanning. The imaging systems are capable of qualitatively analyzing the reaction between the probes and targets. Based on this analysis, sequence information of the targets is extracted.
- IV. Details on Alternative Embodiments
- a. Chip Package Orientation
-
FIGS. 16 a-16 b illustrate an alternative embodiment of the package.FIG. 16 a shows a top view andFIG. 16 b shows a bottom view. As shown inFIG. 16 a, acavity 1620 is located on atop surface 1610 of thepackage body 1600. The body includes alignment holes 121 and 1622 that are used, for example, in mating the chip to the package. Optionally, a plurality ofridges 1690 is located atend 1660 of the body. The friction created byridges 1690 allows the package to be handled easily without slippage. - The body also includes two substantially
parallel edges edge 1640 is narrowed atend 1665 to create anuneven edge 1645. The asymmetrical design of the body facilitates correct orientation when mounted onto detection systems. For example, detection systems may contain a holder, similar to that of an audio cassette tape, in which end 1665 is inserted. - Referring to
FIG. 16 b,ports cavity 1620. A seal is provided for each port to retain fluids in the cavity. Similar to the top surface, the bottom surface may optionally include a plurality ofridges 1690 atend 1660. -
FIGS. 17 a-17 b illustrate an alternative embodiment of the package.FIG. 17 a shows a top view andFIG. 17 b shows a bottom view. Referring toFIG. 17 a, acavity 1720 is located on atop surface 1710 of thepackage body 1700. The body may be formed in the shape of a disk with two substantiallyparallel edges edges Edges - As shown in
FIG. 17 b,ports bottom surface 1715 of the package.Ports cavity 1720 and each include aseal 1780 for sealing fluids in the cavity. - b. Chip Attachment
-
FIG. 18 illustrates an alternative embodiment for attaching the chip to the package. As shown, twoconcentric ledges cavity 310.Ledge 1820 supports thechip 120 when mounted abovecavity 310.Ledge 1810, which extends beyondchip 120, receives an adhesive 1860 such as ultraviolet cured silicone, cement, or other adhesive for attaching the chip thereto. -
FIG. 19 illustrates another embodiment for attaching the chip to the package. According to this embodiment, aledge 1910 is formed aroundcavity 310. Preferably, the ledge is sufficiently large to accommodate an adhesive 1920 such as an adhesive film, adhesive layer, tape, or any other adhesive layer.Chip 120 attaches to the package when it contacts the adhesive film. -
FIG. 20 a illustrates yet another embodiment for attaching a chip to the package. As shown, aclamp 2010, such as a frame having a plurality offingers 2015, attaches the chip to the package.FIG. 20 b illustrates a cross sectional view. Aridge 2020 onsurface 501 surroundscavity 310. The ridge includes aledge 2025 upon whichchip 120 rests. Optionally, a gasket or aseal 2070 is located between the ledge and chip to ensure a tight seal aroundcavity 310.Clamp 2010 is attached toside 2040 ofridge 2020 andsurface 501. In some embodiments,clamp 2010 is acoustically welded to the body. Accordingly,clamp 2010 includesenergy directors 2050 located at its bottom. Alternatively, screws, clips, adhesives, or other attachment techniques may be used to mateclamp 2010 to the package. When mated,fingers 2015secure chip 120 to the package. -
FIG. 21 illustrates an alternative embodiment for attaching the chip to the package. Aridge 2110, having anotch 2115 at or near the top ofridge 2110, encompasses thecavity 310.Chip 120 is wedged and held into position bynotch 2115. Thereafter, a process known as heat staking is used to mount the chip. Heat staking includes applying heat and force atside 2111 of ridge, thus forcing ridge tightly against or aroundchip 120. -
FIG. 22 shows another embodiment of attaching a chip onto a package. As shown, achannel 2250 surroundscavity 310. Anotch 2240 for receiving thechip 120 is formed along or near the top of thecavity 310. In some embodiments, a gasket orseal 2270 is placed at the bottom of the notch to ensure a tight seal when the chip is attached. Once the chip is located at the notch, a V-shapedwedge 2260 is inserted intochannel 2250. The wedge forces the body to press against chip's edges andseal 2260, thus mating the chip to the package. This process is known as compression sealing. - Other techniques such as insert molding, wave soldering, surface diffusion, laser welding, shrink wrap, o-ring seal, surface etching, or heat staking from the top may also be employed.
- c. Fluid Retention
-
FIG. 3 shows an alternative embodiment of package that employs check valves to seal the inlets. As shown,depressions cavity 310 throughinlets valves depressions -
FIG. 24 illustrates another package that uses reusable tape for sealing thecavity 310. As shown, atape 2400 is located aboveinlets end 2430 of tape is permanently fixed tosurface 2480 whileend 2410 remains unattached. Themid section 2420 of the tape is comprised of non-permanent adhesive. This design allows inlets to be conveniently sealed or unsealed without completely separating the tape from the package. -
FIG. 25 illustrates yet another embodiment of the package that uses plugs to retain fluids within the cavity. As shown,depressions cavity 310 viainlets plug 2510, which in some embodiment may be composed of rubber or other sealing material, is mated to each of the depressions.Plugs 2510 are easily inserted or removed for sealing and unsealing the cavity during the hybridization process. -
FIG. 26 a illustrates a package utilizing sliding seals for retaining fluids within the cavity. The seals are positioned inslots 2610 that are located above the inlets. The slots act as runners for guiding the seals to and from the inlets.FIG. 26 b illustrates the seal in greater detail.Seal 2640, which may be composed of rubber, teflon rubber, or other sealing material, is mated to eachslot 2610. The seal includes ahandle 2650 which extends through the slot. Optionally, the bottom of the seal includes anannular protrusion 2645 to ensure mating withinlet 350. The inlet is sealed or unsealed by positioning the seal appropriately along the slot. Alternatively, spring loaded balls, rotary ball valves, plug valves, or other fluid retention techniques may be employed. - d. Chip Orientation
-
FIGS. 27 a-27 b illustrate an alternative embodiment of the package.FIG. 27 a illustrates a top view andFIG. 27 b shows a cross sectional view. As shown,package 2700 includes acavity 2710 on asurface 2705. Achip 2790 having an array ofprobes 2795 onsurface 2791 is mated to the bottom ofcavity 2710 with an adhesive 2741. The adhesive, for example, may be silicone, adhesive tape, or other adhesive. Alternatively, clips or other mounting techniques may be employed. Optionally, the bottom of the cavity may include a depression in which a chip is seated. - This configuration provides several advantages such as: 1) permitting the use of any type of substrate (i.e., non-transparent or non-translucent), 2) yielding more chips per wafer since the chip does not require an edge for mounting, and 3) allowing chips of various sizes or multiple chips to be mated to the package.
- A
cover 2770 is mated to the package for sealing the cavity. Preferably,cover 2770 is composed of a transparent or translucent material such as glass, acrylic, or other material that is penetrable by light.Cover 2270 may be mated to surface 2705 with an adhesive 2772, which in some embodiments may be silicone, adhesive film, or other adhesive. Optionally, a depression may be formed around the cavity such that surface 2271 of the cover is at least flush withsurface 2705. Alternatively, the cover may be mated to surface 2705 according to any of the chip attachment techniques described herein. -
Inlets cavity 2710. Selected fluids are circulated through the cavity viainlets - e. Parallel Hybridization and Diagnostics
- In an alternative embodiment, the body is configured with a plurality of cavities. The cavities, for example, may be in a 96-well micro-titre format. In some embodiments, a chip is mounted individually to each cavity according to the methods described above. Alternatively, the probe arrays may be formed on the wafer in a format matching that of the cavities. Accordingly, separating the wafer is not necessary before attaching the probe arrays to the package. This format provides significant increased throughput by enabling parallel testing of a plurality of samples.
- V. Details of an Agitation System
-
FIG. 28 illustrates an agitation system in detail. As shown, theagitation system 2800 includes twoliquid containers Container 2810 communicates withport 350 viatube 2850 andcontainer 2820 communicates withport 360 viatube 2860. Aninlet port 2812 and avent port 2811 are located at or near the top ofcontainer 2810.Container 2820 also includes aninlet port 2822 and avent 2821 at or near its top.Port 2812 ofcontainer 2810 andport 2822 ofcontainer 2820 are both connected to avalve assembly 2828 viavalves agitator 2801, which may be a nitrogen gas (N2) or other gas, is connected tovalve assembly 2828 by fitting 2851.Valves container 2810, for introducing a buffer and/or other fluid into the cavity. - In operation, a fluid is placed into
container 2810. The fluid, for example, may contain targets that are to be hybridized with probes on the chip.Container 2810 is sealed by closingport 2811 whilecontainer 2820 is vented by openingport 2821. Next, N2 is injected intocontainer 2810, forcing the fluid throughtube 2850,cavity 310, and finally intocontainer 2820. The bubbles formed by the N2 agitate the fluid as it circulates through the system. When the amount of fluid incontainer 2810 nears empty, the system reverses the flow of the fluid by closingvalve 2840 andport 2821 andopening valve 2841 andport 2811. This cycle is repeated until the reaction between the probes and targets is completed. - In some applications, foaming may occur when N2 interacts with the fluid. Foaming potentially inhibits the flow of the fluid through the system. To alleviate this problem, a detergent such as CTAB may be added to the fluid. In one embodiment, the amount of CTAB added is about 1 millimolar. Additionally, the CTAB affects the probes and targets positively by increasing the rate at which they bind, thus decreasing the reaction time required.
- The system described in
FIG. 28 may be operated in an alternative manner. According to this technique, back pressure formed in the second container is used to reverse the flow of the solution. In operation, the fluid is placed incontainer 2810 and bothports container 2810, the fluid is forced throughtube 2850,cavity 310, and finally intocontainer 2820. Because the vent port incontainer 2820 is closed, the pressure therein begins to build as the volume of fluid and N2 increases. When the amount of fluid incontainer 2810 nears empty, the flow of N2 intocontainer 2810 is terminated by closingvalve 2840. Next, the circulatory system is vented by openingport 2811 ofcontainer 2810. As a result, the pressure incontainer 2820 forces the solution back through the system towardcontainer 2810. In one embodiment, the system is injected with N2 for about 3 seconds and vented for about 3 seconds. This cycle is repeated until hybridization between the probes and targets is completed. -
FIG. 29 illustrates an alternative embodiment of the agitation system.System 2900 includes avortexer 2910 on which thechip package 300 is mounted. Acontainer 2930 for holding the fluid communicates withinlet 350 viatube 2950. Avalve 2935 may be provided to control the flow of solution into the cavity. In some embodiments,circulator 2901, which may be a N2 source or other gas source, is connected tocontainer 2930. Alternatively, a pump or other fluid transfer device may be employed. The flow of N2 intocontainer 2930 is regulated by avalve 2936.Circulator 2901 is also connected toinlet tube 2950 via avalve 2902. - A
waste container 2920 communicates withport 360 viaoutlet tube 2955. In one embodiment, aliquid sensor 2940 may be provided for sensing the presence of liquid inoutlet tube 2955. Access to the waste container may be controlled by avalve 2921. Optionally, additional containers (not shown), similar tocontainer 2930, may be employed for introducing a buffer or other fluid into the cavity. - The system is initialized by closing all valves and filling
container 2930 with, for example, a fluid containing targets. Next,valves container 2930 which forces the fluid to flow throughtube 2950 and into the cavity. When the cavity is filled,valves valve waste container 2920. Subsequently, the cavity may be filled with a buffer or other fluid. -
FIG. 30 illustrates an alternative embodiment in which the agitation system is partially integrated into the chip package. As shown,chip package 300 includes acavity 310 on which the clip is mounted.Cavity 310 is provided withinlets chambers port 3021 is provided inchamber 3010 and is connected toinlet 360 by achannel 3025. -
Chamber 3010 is equipped withports 3011 and 3012.Port 3012 communicates withinlet 350 through achannel 3015.Channel 3015 is provided with awaste port 3016 that communicates with afluid disposal system 3500 via atube 3501. Avalve 3502 regulates the flow of fluids into the disposal system. In some embodiments, the disposal system includes awaste container 3510 andfluid recovery container 3520 which are connected totube 3501. Avalve 3530 is provided to direct the flow of fluids into either the waste container or recovery container. - Port 3011 is coupled to a
fluid delivery system 3600 through atube 3601. Fluids flowing intochamber 3010 from the fluid delivery system are regulated by avalve 3602. The fluid delivery system includesfluid containers tube 3690.Container 3610, which may hold a fluid containing targets, includesports Port 3616 is connected totube 3690. Avalve 3612 controls the flow of the fluid out ofcontainer 3610. Acirculator 3605, which may be a N2 source, is connected toport 3615 ofcontainer 3610. Alternatively, any type of gas, pump or other fluid transfer device may be employed. The flow of N2 intocontainer 3610 is controlled by avalve 3618. Avalve 3619 may also be provided to ventcontainer 3610. -
Container 3620, which may hold a buffer, is provided withports Circulator 3605 is connected toport 3625. Avalve 3621 is provided to control the flow of N2 intocontainer 3620.Port 3626 is connected totube 3690 via avalve 3622.Valve 3622 regulates the flow of the buffer out ofcontainer 3620. Optionally, additional containers (not shown), similar tocontainer 3620, may be configured for introducing other fluids into the cavity. Avalve 3690 connects circulator 3605 totube 3690 for controlling the flow of N2 directly into the package. Avalve 3652 is provided for venting the fluid delivery system. - In the initial operating state, all valves are shut. To start the hybridization process, a fluid containing targets is introduced into chamber 301 by opening
valves container 3610 which forces the fluid to flow through 3601 and intochamber 3010. Whenchamber 3010 is filled,valves valve 3642 is opened, allowing N2 to flow directly intochamber 3010. The N2 agitates and circulates the fluid intocavity 310 and out tochamber 3020. As the volume of fluid and N2 inchamber 3020 increase, likewise does the pressure therein. Whenchamber 3020 approaches its capacity,valve 3642 is closed to stop the fluid flow. Thereafter, the system is vented by openingvalve 3652. Venting the system allows the back pressure inchamber 3020 to reverse the flow of fluids back intochamber 3010. Whenchamber 3010 is filled,valve 3652 is closed andvalve 3642 is opened to reverse the fluid flow. This cycle is repeated until hybridization is completed. - When hybridization is completed, the system may be drained. This procedure depends on which chamber the fluid is located in. If the fluid is located in
chamber 3020, thenvalve 3502 is opened, whilevalve 3530 is positioned to direct the fluid into the appropriate container (recovery or waste). The pressure inchamber 3020 forces the fluid throughport 3016,tube 3501, and into the disposal system. If the fluid is inchamber 3010, thenvalve chamber 3010 throughport 3501 and into the disposal system. - Once the system is emptied, all valves are closed. A buffer or other fluid may be introduced into the cavity. For example, the cavity may be filled with a buffer by opening
valves container 3620 which forces the buffer therein to flow through the system until it fillscavity 310. In the alternative, ultrasonic radiation, heat, magnetic beads, or other agitation techniques may be employed. - The present inventions provide commercially feasible devices for packaging a probe chip. It is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those skilled in the art upon reviewing the above description. Merely as an example, the package may be molded or machined from a single piece of material instead of two. Also, other asymmetrical designs may be employed to orient the package onto the detection systems.
- The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the appended claims along with their full scope of equivalents.
Claims (25)
1-92. (Canceled).
93. A method of interrogating an addressable array unit having a transparent substrate with a back surface, and an array with a plurality of different chemical features on a front surface, the method comprising: (a) illuminating the features while the array is dry, with an interrogating light which is directed trough the substrate from the back surface and onto the chemical features on the front surface; and (b) detecting light emitted from respective features in response to the interrogating light, which detected light has passed from the front surface, through the substrate and out the back surface; wherein the light is emitted from locations of the features which are spaced from the front surface a distance of less than one-eighth of the wavelength of the illuminating light in a gas or a vacuum which is in contact with the dry array.
94. A method according to claim 93 wherein the light emitting locations of the chemical features are spaced from the front surface a distance of less than one-tenth of the wavelength of the illuminating light.
95. A method according to claim 93 wherein the light emitting locations of the chemical features are spaced from the front surface a distance of less than one-twentieth of the wavelength of the illuminating light.
96. A method according to claim 93 wherein the light emitting locations of the chemical features are spaced from the front surface a distance of less than one-fiftieth of the wavelength of the illuminating light.
97. A method according to claim 93 wherein the interrogating light is directed toward the back surface at an angle of between 0 and 45 degrees to a normal to the back surface.
98. A method according to claim 97 wherein the angle is less than 25 degrees.
99. A method according to claim 97 wherein the angle is less than 10 degrees.
100. A method according to claim 93 wherein the chemical features are polynucleotides.
101. A method according to claim 93 wherein the chemical features are amino acid polymers.
102. A method of interrogating an addressable array unit having a transparent substrate with a back surface, and an array with a plurality of different chemical features on a front surface, the method comprising: (a) illuminating the features while the array is dry, with an interrogating light which is directed through the substrate from the back surface and onto the chemical features on the front surface; and (b) detecting light emitted from respective features in response to the interrogating light, which detected light has passed from the front surface, through the substrate and out the back surface; wherein the light is emitted from locations of the features which are spaced from the front surface a distance of less than one-eighth of the wavelength of the emitted light in a gas or a vacuum which is in contact with the dry array.
103. A method according to claim 102 wherein the light is emitted from locations of the features which are spaced from the front surface a distance of less than one-tenth of the emitted light wavelength.
104. A method according to claim 102 wherein the light is emitted from locations of the features which are spaced from the front surface a distance of less than one fiftieth of the emitted light wavelength.
105. A method of interrogating an addressable array unit having a substrate with a back surface, and an array with a plurality of different chemical features on a front surface, the method comprising: (a) illuminating the features while the array is dry, with an interrogating light which is directed through the substrate from the back surface and onto the chemical features on the front surface; and (b) detecting light emitted from respective features in response to the interrogating light, which detected light has passed from the front surface, through the substrate and out the back surface; wherein the light is emitted from locations of the features which are spaced from the front surface a distance such that the average detected signal from the dry array is at least 10% greater than would be detected under the same conditions except with the interrogating light and detected emitted light not passing through the substrate.
106. A method according to claim 105 wherein the average detected signal from the array is at least 40% greater.
107. A method according to claim 105 wherein the average detected signal from the array is at least 80% greater.
108. A package comprising: an addressable array unit having a transparent substrate with a back surface, and an array with a plurality of different chemical features on a front surface, the chemical features having a thickness of less than 100 nm; and instructions to: (i) interrogate the array with an interrogating light which is directed through the substrate from the back surface and onto the chemical features on the front surface; and (ii) detect light emitted from respective features in response to the interrogating light, which detected light has passed from the front surface, through the substrate and out the back surface.
109. A package according to claim 108 wherein the features have a thickness of less than 50 nm.
110. A package according to claim 108 wherein the features have a thickness of less than 10 nm.
111. A method according to claim 1 additionally comprising, prior to the illuminating and detecting: exposing the array to a sample in a liquid; and washing and drying the array.
112. A method for use with an interrogating an addressable array unit having a transparent substrate with a back surface, and an array with a plurality of different chemical features on a front surface, the method comprising: (a) machine reading an identifier associated with the array unit; (b) based on the read identifier, retrieving by a processor an instruction that the array should be interrogated and read through the substrate from the back surface.
113. A method according to claim 112 wherein the identifier is on the array substrate or a housing carrying the array substrate.
114. A method according to claim 112 wherein the instruction is retrieved from the read identifier.
115. A method according to claim 112 wherein the instruction is retrieved from a memory using data from the read identifier.
116. A method according to claim 20 additionally comprising checking that the array is oriented within an array reader such that the array can be interrogated and read by the reader through the substrate from the back surface.
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Also Published As
Publication number | Publication date |
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US20010041341A1 (en) | 2001-11-15 |
US20030003499A1 (en) | 2003-01-02 |
US20040171054A1 (en) | 2004-09-02 |
US20040166525A1 (en) | 2004-08-26 |
US20050191630A1 (en) | 2005-09-01 |
US20050106615A1 (en) | 2005-05-19 |
US20060040380A1 (en) | 2006-02-23 |
US20050106617A1 (en) | 2005-05-19 |
US20020058331A1 (en) | 2002-05-16 |
US6733977B2 (en) | 2004-05-11 |
US20060234267A1 (en) | 2006-10-19 |
US6551817B2 (en) | 2003-04-22 |
US20050106618A1 (en) | 2005-05-19 |
US20050084895A1 (en) | 2005-04-21 |
US20050158819A1 (en) | 2005-07-21 |
US20050208646A1 (en) | 2005-09-22 |
US20050089953A1 (en) | 2005-04-28 |
US20040106130A1 (en) | 2004-06-03 |
US6287850B1 (en) | 2001-09-11 |
US7364895B2 (en) | 2008-04-29 |
US6399365B2 (en) | 2002-06-04 |
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