WO2017045107A1 - Biosensor - Google Patents

Biosensor Download PDF

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Publication number
WO2017045107A1
WO2017045107A1 PCT/CN2015/089549 CN2015089549W WO2017045107A1 WO 2017045107 A1 WO2017045107 A1 WO 2017045107A1 CN 2015089549 W CN2015089549 W CN 2015089549W WO 2017045107 A1 WO2017045107 A1 WO 2017045107A1
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WO
WIPO (PCT)
Prior art keywords
collimators
pixels
transparent window
signal
substrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/089549
Other languages
French (fr)
Inventor
Peiyan CAO
Yurun LIU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Genorivision Technology Co Ltd
Original Assignee
Shenzhen Genorivision Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Genorivision Technology Co Ltd filed Critical Shenzhen Genorivision Technology Co Ltd
Priority to EP15903798.5A priority Critical patent/EP3371575A4/en
Priority to PCT/CN2015/089549 priority patent/WO2017045107A1/en
Priority to US15/309,303 priority patent/US10670527B2/en
Priority to CN201580083141.7A priority patent/CN108449970A/en
Priority to TW105128985A priority patent/TWI704902B/en
Publication of WO2017045107A1 publication Critical patent/WO2017045107A1/en
Anticipated expiration legal-status Critical
Priority to US16/843,999 priority patent/US11366062B2/en
Ceased legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
    • G01N21/6454—Individual samples arranged in a regular 2D-array, e.g. multiwell plates using an integrated detector array
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6816—Hybridisation assays characterised by the detection means
    • C12Q1/6825—Nucleic acid detection involving sensors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068—Means for controlling the apparatus of the process
    • B01J2219/00702—Processes involving means for analysing and characterising the products
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N2021/6463—Optics
    • G01N2021/6471—Special filters, filter wheel

Definitions

  • the disclosure herein relates to biosensors, particularly biosensors based on optical detection.
  • a biosensor is an analytical device for detection of an analyte involved in a biological process.
  • the analyte may be a DNA, a protein, a metabolite, or even a living organism (e.g., bacteria, virus) .
  • a biosensor usually has a probe that interacts with the analyte.
  • the probe may be designed to bind or recognize the analyte.
  • Examples of the probe may include antibodies, aptamers, DNAs, RNAs, antigens, etc. Interaction between the probe and the analyte may lead to one or more detectable event.
  • the detectable event may be release of a chemical species or a particle (e.g., a quantum dot) , a chemical reaction, luminescence (e.g., chemiluminescence, bioluminescence, electrochemiluminescence, electroluminescence, photoluminescence, fluorescence, phosphorescence) , change in a physical property (e.g., Raman scattering, color) or chemical property (e.g., reactivity, reaction rate) .
  • a chemical species or a particle e.g., a quantum dot
  • luminescence e.g., chemiluminescence, bioluminescence, electrochemiluminescence, electroluminescence, photoluminescence, fluorescence, phosphorescence
  • change in a physical property e.g., Raman scattering, color
  • chemical property e.g., reactivity, reaction rate
  • a biosensor may have a detector that can detect the detectable event as a result of the interaction.
  • the detector may transform the detectable event into another signal (e.g., image, electrical signal) that can be more easily measured and quantified.
  • the detector may include circuitry that obtains data from the detectable event and processes the data.
  • a microarray can be a two-dimensional array on a solid substrate (e.g., a glass slide, a silicon wafer) .
  • the array may have different assays at different locations.
  • the assays at different locations may be independent controlled or measured, thereby allowing multiplexed and parallel sensing of one or many analytes.
  • a microarray may be useful in miniaturizing diagnosis assays. For example, a microarray may be used for detecting biological samples in the fields without sophisticated equipment, or be used by a patient who is not in a clinic or hospital to monitor his or her physiological symptoms.
  • an apparatus comprising: a probe carrier comprising: a substrate comprising a plurality of holes through a thickness of the substrate and a transparent window across an opening of each of the holes, wherein the transparent window closes the opening, wherein one or more locations on the transparent window are configured to have probes attached thereto, wherein interaction between the probes and an analyte generates a signal; an optical system comprising a plurality of collimators; a sensor comprising a plurality of pixels configured to detect the signal; wherein the collimators are configured to essentially prevent light from passing if a deviation of a propagation direction of the light from an optical axis of the collimators is greater than a threshold.
  • the substrate comprises silicon.
  • the probes and the substrate are on a same side of the probe carrier.
  • the probes and the substrate are on opposite sides of the probe carrier.
  • the transparent window is aligned with one of the collimators.
  • the transparent window encompasses more than one of the collimators.
  • the transparent window is a portion of a continuous transparent layer across the substrate.
  • the transparent window has a thickness from 10 to 50 micrometers.
  • the sidewall of the hole is not perpendicular to the transparent window.
  • the senor comprises a control circuit configured to control, acquire data from, or process data from the pixels.
  • the pixels are arranged such that each of the pixels is optically coupled to one or more of the locations.
  • the pixels are optically coupled to the locations by the collimators.
  • the signal is luminescence.
  • the signal is generated under excitation of an excitation radiation.
  • the optical system further comprises a filter, wherein the filter is configured to block at least a portion of the excitation radiation.
  • the filter is a dichroic filter.
  • the optical system further comprises or a transmissive layer.
  • the optical system further comprises a plurality of microlens.
  • the threshold is 20Ā°.
  • the collimators comprises a meta-material, quantum dots or a photonic crystal.
  • the collimators are configured to eliminate optical cross-talk between neighboring pixels among the plurality of pixels.
  • At least one of the collimators comprises a core and a sidewall surrounding the core.
  • the signal is generated under excitation of an excitation radiation; wherein the core is a material that essentially prevents the excitation radiation from passing through irrespective of propagation direction of the excitation radiation.
  • the signal is generated under excitation of an excitation radiation; wherein the core comprises a dichroic filter.
  • the core allows the signal to pass through essentially unabsorbed.
  • the core is a void space.
  • the sidewall attenuates a portion of the signal reaching the sidewall.
  • the sidewall is textured.
  • the apparatus further comprises a redistribution layer configured to route data from the pixels.
  • the filter comprises a meta-material, quantum dots or a photonic crystal.
  • Fig. 1A schematically shows an apparatus including a microarray.
  • Fig. 1B schematically shows an apparatus where detector capability is integrated into a microarray.
  • Fig. 2A schematically shows an apparatus, according to an embodiment.
  • Fig. 2B schematically shows an apparatus, according to an embodiment.
  • Fig. 3A schematically shows a probe carrier 300 wherein the probes and the substrate are on opposite sides of the probe carrier, according to an embodiment.
  • Fig. 3B schematically shows a probe carrier 310 wherein the sidewall of the hole is not perpendicular to the transparent window, according to an embodiment.
  • Fig. 4A schematically shows a probe carrier 400 wherein the probes and the substrate are on a same side of the probe carrier, according to an embodiment.
  • Fig. 4B schematically shows a probe carrier 410 wherein the sidewall of the hole is not perpendicular to the transparent window, according to an embodiment.
  • Fig. 4C schematically shows a probe carrier 420, according to an embodiment.
  • Fig. 5A schematically shows an apparatus 500 with a probe carrier 410, according to an embodiment.
  • Fig. 5B schematically shows an apparatus 510 comprising microlens and a probe carrier 410, wherein the microlens may be fabricated in the passivation layer, according to an embodiment.
  • Fig. 5C schematically shows an apparatus 520 comprising microlens and a probe carrier 410, wherein the microlens may be fabricated in the collimators, according to an embodiment.
  • Fig. 6A schematically shows an apparatus 600 with a probe carrier 420, according to an embodiment.
  • Fig. 6B schematically shows an apparatus 610 with a probe carrier 300, according to an embodiment.
  • Fig. 7A schematically shows a collimator, according to an embodiment.
  • Fig. 7B schematically shows a collimator, according to an embodiment.
  • Fig. 7C schematically shows a collimator, according to an embodiment.
  • Fig. 7D schematically shows a collimator, according to an embodiment.
  • Fig. 7E schematically shows an apparatus 700 wherein the filter and the transmissive layer are both omitted, according to an embodiment.
  • Fig. 7F and Fig. 7G each schematically show that the optical system may have a plurality of collimators arranged in an array, according to an embodiment.
  • Fig. 8 schematically shows an apparatus 800 in which the optical system may have a microfluidic system, according to an embodiment.
  • Fig. 9A schematically shows an apparatus 900 wherein a sensor in a microarray may have a signal transfer layer and that the optical system in the microarray may have a redistribution layer, according to an embodiment.
  • Fig. 9B schematically shows a top view of the sensor in Fig. 9A.
  • Fig. 9C schematically shows a bottom view of the optical system in Fig. 9A.
  • Fig. 10A schematically shows an apparatus 1000 wherein a sensor in a microarray may have a redistribution layer and that the optical system in the microarray may have a signal transfer layer, according to an embodiment.
  • Fig. 10B schematically shows a top view of the sensor in Fig. 10A, according to an embodiment.
  • Fig. 10C schematically shows a bottom view of the optical system in Fig. 10A, according to an embodiment.
  • Fig. 10D schematically shows a top view of the sensor in Fig. 10A, according to an embodiment.
  • Fig. 10E schematically shows a bottom view of the optical system in Fig. 10A to illustrate the positions of the bonding pads, which are positioned to connect to the vias shown in Fig. 10D.
  • Fig. 10F schematically shows a top view of the sensor in Fig. 10A, according to an embodiment.
  • Fig. 10G schematically shows a bottom view of the optical system in Fig. 10A to illustrate the positions of the bonding pad, which are positioned to connect to the via shown in Fig. 10F.
  • Fig. 11 schematically shows that system 1100 wherein a sensor in a microarray may have a redistribution layer with vias such as through-silicon vias (TSV) configured to electrically connect the transmission lines in the redistribution layer to bonding pads on the side opposite from the redistribution layer, according to an embodiment.
  • TSV through-silicon vias
  • Fig. 1A schematically shows an apparatus 100 including a microarray 105.
  • the system 100 may have an image sensor 101, an optical system 102, and/or an excitation source 109.
  • the image sensor 101 may be configured to measure an optical property (e.g., color, intensity) at different locations 106 of the microarray 105.
  • the locations 106 may have various probes 107 attached thereto.
  • the probes 107 may interact with analyte and the interaction may generate signals 108 detectable by the image sensor 101.
  • the generation of the signals 108 may need excitation by the excitation source 109 (e.g., laser, UV light, etc. ) .
  • the image sensor 101 and the optical system 102 of the system 100 tend to be bulky, fragile, or expensive and may not have high enough spatial resolution to distinguish one location from its neighboring locations.
  • Fig. 1B schematically shows a system 150 where detector capability is integrated into a microarray 155.
  • the microarray 155 may have multiple locations 156 with various probes 157 attached thereto.
  • the probes 157 may interact with various analytes and the interaction may generate signals 158 detectable by a sensor 151 integrated to the microarray 155.
  • the analytes are fluorophore-labeled nucleic acid or protein fragments; the probes are oligonucleotides or antibodies.
  • Locations with fluorophore-labeled analytes captured by the probes can be identified by detecting fluorescence from the fluorophores on the captured analytes.
  • the sensor 151 may have multiple pixels 170 configured to detect the signals 158 (e.g., color, intensity) .
  • the pixels 170 may have a control circuit 171 configured to control, acquire data from, and/or process data from the pixels 170.
  • the pixels 170 may be arranged such that each pixel 170 is optically coupled to one of the locations 156. However, the signals 158 generated at one location 156 may not entirely reach the pixel 170 optically coupled to that location 156. A portion 172 of the signals 158 may reach the pixel 170 optically coupled to that location 156 but another portion 173 may be scattered into neighboring pixels ( ā€œoptical cross- talkā€ ) and/or away from all pixels 170.
  • Generating the signals 158 may need an excitation radiation 161 (e.g., laser, UV light, etc. ) .
  • a portion 162 of the excitation radiation 161 may pass through the locations 156 unscattered.
  • a portion 163 of the excitation radiation 161 may be scattered into some of the pixels 170 or away from all pixels 170.
  • the portion 162 may be blocked by a filter 190 from reaching the pixels 170.
  • the filter 190 may be position below or above a transmissive layer 191. However, the filter 190 may be sensitive to incident directions and may not block the portion 163, despite portions 162 and 163 have the same wavelength. If the portion 163 reaches the pixels 170, it can overshadow signals 158.
  • Fig. 2A schematically shows an apparatus 200, according to an embodiment.
  • the system 200 includes a microarray 255 including an integrated sensor 251 and an optical system 285.
  • the microarray 255 may have multiple locations 256 with various probes 257 attached thereto.
  • the probes 257 may interact with various analytes and the interaction may generate signals 258 detectable by the sensor 251.
  • the sensor 251 may have multiple pixels 270 configured to detect the signals 258 (e.g., color, intensity) .
  • the pixels 270 may have a control circuit 271 configured to control, acquire data from, and/or process data from the pixels 270.
  • the pixels 270 may be arranged such that each pixel 270 is optically coupled to one or more of the locations 256.
  • the optical system 285 may include a filter 290 positioned below or above a transmissive layer 291 (Fig. 2B shows an example where the filter 290 is below the transmissive layer 291) .
  • the optical system 285 may include a plurality of collimators 295 configured to optically couple the pixels 270 to the locations 256.
  • the filter 290 and the transmissive layer 291 may not have to be fabricated on the same substrate as the collimators 295. Instead, the filter 290 and the transmissive layer 291 may be fabricated and bonded to the collimators 295.
  • the sensor 251 comprises quantum dots.
  • the transmissive layer 291 may include oxide or nitride.
  • the transmissive layer 291 may include glass.
  • the filter 290 may be a dichroic filter (also known as interference filter) .
  • the filter 290 may be a low-pass (passing frequency below a threshold) or band-pass filter.
  • the filter 290 may include a meta-material, quantum dots or a photonic crystal.
  • a meta-material has component materials arranged in repeating patterns, often at microscopic or smaller scales that are smaller than the wavelengths of the light the meta-material is designed to influence. The structure of the repeated patterns and the properties of the component materials may be selected to tailor the properties of the meta-material.
  • the meta-material may provide optical transparency at all frequencies except at the selected frequency or frequencies which it is configured to block (for example particular laser frequencies that could cause harm to a user) .
  • a photonic crystal is a periodic dielectric structure that has a band gap that forbids propagation of a certain frequency range of light.
  • the filter 290 may have multiple thin layers of materials with different refractive indices and may be made by alternately depositing thin layers of these materials.
  • a quantum dot (QD) is a nanocrystal made of semiconductor materials that is small enough to exhibit quantum mechanical properties. Specifically, its excitons are confined in all three spatial dimensions. Quantum dots of the same material, but with different sizes, can absorb light of different wavelengths due to the quantum confinement effect. The larger the quantum dot, the redder (lower energy) its absorption. Conversely, smaller quantum dots absorb bluer (higher energy) light.
  • the filter 290 may be an absorptive filter but it would have sufficient thickness to be effective.
  • Fig. 3A schematically shows a probe carrier 300 wherein the probes and the substrate are on opposite sides of the probe carrier, according to an embodiment.
  • the probe carrier 300 comprises a substrate 301 comprising a plurality of holes 302 through a thickness of the substrate 301 and a transparent window 303 across an opening of each of the holes 302.
  • the transparent window 303 closes the opening, and one or more locations on the transparent window are configured to have probes 357 attached thereto. Interactions between the probes 357 and an analyte generate a signal 358.
  • the probe carrier 300 is separate and independent from the microarray 255 that includes the optical system 285 and integrated sensor 251. Therefore, the probe carrier 300 may be assembled with a microarray prior before its use, and the probe carrier 300 may be detached from the microarray and disposed after its use. Because fabrication of microarray is costly, the probe carrier 300 allows reuse of the microarray 255 including its optical systems and sensors. In addition, the probe carrier 300 allows a user to choose from various microarrays to use with the probe carrier 300, which provides more flexibility and reduces cost in fabrication.
  • the substrate 301 comprises silicon or other suitable materials.
  • the transparent window 303 comprises silicon oxide, silicon nitride or other suitable material.
  • the transparent window 303 is a portion of a continuous transparent layer 304 across the substrate.
  • the transparent window 303 or transparent layer 304 has a thickness from 10 to 50 micrometers.
  • the substrate 301 can mechanically support the transparent window 303 or the transparent layer 304.
  • the probe carrier is made by the following method: 1) providing a silicon wafer as a substrate; 2) disposing a transparent layer such as a layer of silicon oxide on the substrate; 3) etching the substrate to form holes in the substrate.
  • a dry etching process include, but are not limited to, inductively coupled plasma reactive ion etch (ICP RIE) process, and the Bosch process.
  • ICP RIE inductively coupled plasma reactive ion etch
  • wet etching process include, but are not limited to, a metal assisted chemical etch (MACE) process.
  • probes are deposited after forming the holes in the substrate. In another embodiment, probes are deposited before forming the holes in the substrate.
  • the probes and the substrate are on opposite sides of the probe carrier. In embodiments as shown in Figs. 4A and 4B, the probes and the substrate are deposited on the same side of the probe carrier.
  • the sidewall 305 of the hole 302 or sidewall 405 of the hole 402 may be perpendicular to the transparent window.
  • the sidewall 306 of the hole 307 or the sidewall 406 of the hole 407 may be not perpendicular to the transparent window.
  • the size and shape of sidewall of the holes may be controlled by a suitable wet or dry etching technique.
  • multiple locations on a single transparent window 303 are configured to have probes attached thereto.
  • the configuration of more than one location provides options of attaching different probes and enhancing the flexibility of the microarray.
  • an apparatus 500 comprises a probe carrier 410 and a microarray 255 that comprises an optical system 285 with collimators 295 and an integrated sensor 251.
  • the probe carrier 410 may be mounted to the microarray 255 with a suitable technique.
  • the biosensor function of the apparatus 500 may be carried out with appropriate probes on the probe carrier 410.
  • the transmissive layer 291 may be an insulating material such as silicon oxide or silicon nitride. In an embodiment, the transmissive layer 291 may even be omitted.
  • an apparatus 510 comprises a probe carrier 410 and a microarray 255 that comprises an optical system 285 with collimators 295 and an integrated sensor 251, wherein the optical system 285 may have a plurality of microlens 292.
  • the microlens 292 may be fabricated in the passivation layer 291 as shown in Fig. 5B. Alternatively, the microlens 292 may be fabricated in the collimators 295 as shown in Fig. 5C.
  • the microlens 292 may be configured to focus light generated by the probes into the collimators 295.
  • the microlens 292 may be configured to direct a greater portion of luminescence signal from probes into the pixels coupled thereto. For example, a microlen 292 may capture the portion 273 that otherwise would not reach the pixel coupled to the location 256 where the portion 273 is from.
  • a transparent window of the probe carrier encompasses more than one of the collimators. This is achieved by controlled fabrication process such that the holes in the probe carrier have a greater width than the width of the collimators in the microarray.
  • the width of the hole or the width of the collimators refers to a size in the dimension that is parallel to the plane of the probe carrier. In such embodiments, no alignment of the probe carrier with the microarray is required during assembly of the probe carrier with the microarray to form the biosensor apparatus.
  • each location is aligned with one of the collimators. This is achieved by controlled fabrication process such that the holes in the probe carrier has a same width than the width of the collimators in the microarray, and appropriate alignment of the probe carrier with the microarray is required during assembly of the probe carrier with the microarray to form the biosensor apparatus.
  • an apparatus 600 comprises a probe carrier 420 and a microarray 255 that comprises an optical system with collimators 295 and an integrated sensor 251.
  • other types of probe carrier including but not limited to, 300, 310, 400 or 410 may be used alternatively to form the biosensor apparatus.
  • an apparatus 610 comprises a probe carrier 300 and a microarray 255 that comprises an optical system with collimators 295 and an integrated sensor 251.
  • microarrays may be used with any of the aforementioned probe carriers to form a biosensor apparatus. Some examples of such microarrays are illustrated as below.
  • the filter 290, the transmissive layer 291 if present, the microlens 292 if present and the collimator 295 may be integrated on the same substrate.
  • the collimator 295 may be configured to essentially prevent (e.g., prevent more than 90%, 99%, or 99.9%of) light from passing if the deviation of the propagation direction of the light from an optical axis of the collimator 295 is greater than a threshold (e.g., 20Ā°, 10Ā°, 5Ā°, or 1Ā°) .
  • a portion 272 of the signals 258 may propagate towards the pixel 270 optically coupled to that location 156 but another portion 273 may be scattered towards neighboring pixels ( ā€œoptical cross-talkā€ ) and/or away from all pixels 270.
  • the collimator 295 may be configured to essentially eliminate optical cross-talk by essentially preventing the portion 273 from passing through the collimator 295.
  • Generating the signals 258 may need an excitation radiation 261 (e.g., laser, UV light, etc. ) .
  • a portion 262 of the excitation radiation 261 may pass through the locations 256 unscattered.
  • a portion 263 of the excitation radiation 261 may be scattered into other directions towards some of the pixels 270 or away from all pixels 270.
  • the portion 262 may be blocked by the filter 290 from reaching the pixels 270.
  • the filter 290 may be sensitive to incident directions and may not block the portion 263, despite portions 262 and 263 have the same wavelength.
  • the collimators 295 may be configured to essentially prevent the excitation radiation from passing through irrespective of the propagation direction, or to essentially prevent the portion 263 scattered away from the propagation direction of the portion 261 from passing through.
  • each of the collimators 295 extends from one of the locations 256 to the pixel 270 optically coupled to that one location.
  • the collimator 295 may have a core 296 surrounded by a sidewall 297.
  • the core 296 may be a material that essentially prevents (e.g., prevents more than 90%, 99%, or 99.9%of) the excitation radiation 261 from passing through irrespective of the propagation direction of the excitation radiation 261.
  • the core 296 may be a material that attenuates (absorbs) the excitation radiation 261.
  • the core 296 may allow the signals 258 to pass through essentially unabsorbed.
  • the filter 290 may be omitted.
  • the core 296 may have a structure 299 that essentially prevents (e.g., prevents more than 90%, 99%, or 99.9%of) a portion of the excitation radiation 261 from passing through if the deviation of the propagation direction of the portion (e.g., portion 272) from the optical axis of the collimator 295 is smaller than a threshold (e.g., 20Ā°, 10Ā°, 5Ā°, or 1Ā°) .
  • the structure 299 may have a dichroic filter, a meta-material, quantum dots or a photonic crystal.
  • the core 296 may allow the signals 258 to pass through essentially unabsorbed (i.e., less than 10%absorbed) .
  • the filter 290 may be omitted.
  • the sidewall 297 of the collimator 295 may attenuate (absorb) the excitation radiation.
  • the portion 263 of the excitation radiation 261 may pass through the filter 290 and enter the collimator 295 but is likely to reach the sidewall 297 before it can reach the pixels 270.
  • the sidewall 297 that can attenuate (absorb) the excitation radiation will essentially prevent stray excitation radiation from reaching the pixels 270.
  • the core 296 may be a void space. Namely, the sidewall 297 surrounds a void space.
  • the sidewall 297 may attenuate (absorb) any portion of the signal 258 reaching the sidewall, which will essentially prevent optical cross-talk.
  • the sidewall 297 is textured.
  • the interface 298 between the sidewall 297 and the core 296 (which can be a void space) may be textured. Textured sidewall 297 can help further attenuate light incident thereon.
  • the filter 290 and the transmissive layer 291 may be both omitted.
  • the collimator 295 may have a top surface 294 exposed.
  • the top surface 294 may be of a different material from its neighboring surface, thereby facilitating functionalization of the top surface 294.
  • the probes 457 may be selectively attached directly to the top surface 294.
  • the optical system 285 may have a plurality of collimators 295 arranged in an array.
  • the optical system 285 may have a dedicated collimator 295 for each pixel 270.
  • the optical system 285 may have a collimator 295 shared by a group of pixels 270.
  • the collimator 295 may have any suitable cross-sectional shape, such as circular, rectangular, and polygonal.
  • the collimators 295 may be made by etching (by e.g., deep reactive ion etching (deep RIE) , laser drilling) holes into a substrate.
  • the sidewall 297 may be made by depositing a material on the sidewall of the holes.
  • the core 296 may be made by filling the holes. Planarization may also be used in the fabrication of the collimators 295.
  • the filter 290 may be omitted or its function may be integrated into the collimators 295.
  • the optical system 285 may have a microfluidic system 850 to deliver reactants such as the analyte and reaction product to and from the locations 256.
  • the microfluidic system 850 may have wells, reservoirs, channels, valves or other components.
  • the microfluidic system 850 may also have heaters, coolers (e.g., Peltier devices) , or temperature sensors.
  • the heaters, coolers or temperature sensors may be located in the optical system 285, above or in the collimators 295.
  • the heaters, coolers or temperature sensors may be located above or in the sensor 251.
  • the biosensor apparatus 800 may be used for a variety of assays.
  • the biosensor apparatus 800 can be used to conduct real-time polymerase chain reaction (e.g., quantitative real-time PCR (qPCR) ) .
  • Real-time polymerase chain reaction e.g., quantitative real-time PCR (qPCR)
  • qPCR quantitative real-time PCR
  • Real-time PCR detects amplified DNA as the reaction progresses. This is in contrast to traditional PCR where the product of the reaction is detected at the end.
  • One real-time PCR technique uses sequence-specific probes labelled with a fluorophore which fluoresces only after hybridization of the probe with its complementary sequence, which can be used to quantify messenger RNA (mRNA) and non-coding RNA in cells or tissues.
  • mRNA messenger RNA
  • the optical system 285 and the sensor 251 may be fabricated in separate substrates and bonded together using a suitable technique, such as, flip-chip bonding, wafer-to-wafer direct bonding, or gluing.
  • the sensor 251 has a signal transfer layer 252.
  • the signal transfer layer 252 may have a plurality of vias 510.
  • the signal transfer layer 252 may have electrically insulation materials (e.g., silicon oxide) around the vias 510.
  • the optical system 285 may have a redistribution layer 289 with transmission lines 520 and vias 530.
  • the transmission lines 520 connect the vias 530 to bonding pads 540.
  • the vias 510 and the vias 530 are electrically connected. This configuration shown in Fig. 9A allows the bonding pads 540 to be positioned away from the probes 257.
  • Fig. 9B shows a top view of the sensor 251 in Fig. 9A to illustrate the positions of the vias 510 relative to the pixels 270 and the control circuit 271.
  • the pixels 270 and the control circuit 271 are shown in dotted lines because they are not directly visible in this view.
  • Fig. 9C shows a bottom view of the optical system 285 in Fig. 9A to illustrate the positions of the vias 530 relative to the transmission lines 520 (shown as dotted lines because they are not directly visible in this view) .
  • the sensor 251 has a redistribution layer 629.
  • the redistribution layer 629 may have a plurality of vias 610 and a plurality of transmission lines 620.
  • the redistribution layer 629 may have electrically insulation materials (e.g., silicon oxide) around the vias 610 and the transmission lines 620.
  • the vias 610 electrically connect the control circuit 271 to the transmission lines 620.
  • the optical system 285 may have a layer 619 with bonding pads 640.
  • the redistribution layer 629 may also have vias 630 electrically connecting the transmission lines 620 to the bonding pads 640, when the sensor 251 and the optical system 285 are bonded.
  • the bonding pads 640 may have two parts connected by a wire buried in the layer 619. This configuration shown in Fig. 10A allows the bonding pads 640 to be positioned on an opposite side from the probe carrier.
  • Fig. 10B shows a top view of the sensor 251 in Fig. 10A to illustrate the positions of the vias 610, the vias 630 and the transmission lines 620, relative to the pixels 270 and the control circuit 271, according to an embodiment.
  • the pixels 270, the control circuit 271 and the transmission lines 620 are shown in dotted lines because they are not directly visible in this view.
  • Fig. 10C shows a bottom view of the optical system 285 in Fig. 10A to illustrate the positions of the bonding pads 640, which are positioned to connect to the vias 630 shown in Fig. 10B.
  • the bonding pads 640 may have two parts connected by a wire buried in the layer 619.
  • Fig. 10D shows a top view of the sensor 251 in Fig. 10A to illustrate the positions of the vias 610, the vias 630 and the transmission lines 620, relative to the pixels 270 and the control circuit 271, according to an embodiment.
  • the pixels 270, the control circuit 271 and the transmission lines 620 are shown in dotted lines because they are not directly visible in this view.
  • the pixels 270 may be read out column by column. For example, signal from one 270 may be stored in register in the control circuit 271 associated with that pixel 270; the signal may be successively shifted from one column to the next, and eventually to other processing circuitry through vias 630.
  • Fig. 10E shows a bottom view of the optical system 285 in Fig. 10A to illustrate the positions of the bonding pads 640, which are positioned to connect to the vias 630 shown in Fig. 10D.
  • the bonding pads 640 may have two parts connected by a wire buried in the layer 619.
  • Fig. 10F shows a top view of the sensor 251 in Fig. 10A to illustrate the positions of the vias 610, the via 630 and the transmission lines 620, relative to the pixels 270 and the control circuit 271, according to an embodiment.
  • the pixels 270, the control circuit 271 and the transmission lines 620 are shown in dotted lines because they are not directly visible in this view.
  • the pixels 270 may be read out pixel by pixel.
  • signal from one 270 may be stored in register in the control circuit 271 associated with that pixel 270; the signal may be successively shifted from one pixel to the next, and eventually to other processing circuitry through via 630.
  • Fig. 10G shows a bottom view of the optical system 285 in Fig. 10A to illustrate the positions of the bonding pad 640, which are positioned to connect to the via 630 shown in Fig. 10F.
  • the bonding pads 640 may have two parts connected by a wire buried in the layer 619.
  • the sensor 251 has a redistribution layer 729.
  • the redistribution layer 729 may have a plurality of vias 710 and a plurality of transmission lines 720.
  • the redistribution layer 729 may have electrically insulation materials (e.g., silicon oxide) around the vias 710 and the transmission lines 720.
  • the vias 710 electrically connect the control circuit 271 to the transmission lines 720.
  • the redistribution layer 729 may also have vias 730 (e.g., through-silicon vias (TSV) ) electrically connecting the transmission lines 720 to bonding pads 740 on the side opposite from the redistribution layer 729.
  • TSV through-silicon vias

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Abstract

Disclosed herein is an apparatus (200, 500, 510, 520, 600, 700, 800, 900, 1000, 1100) comprising: a probe carrier (300, 310, 400, 410) comprising: a substrate (301, 401) comprising with holes (302, 402) through a thickness of the substrate (301, 401) and a transparent window (303) across an opening of each of the holes (302, 402), wherein the transparent window (303) closes the opening, wherein one or more locations on the transparent window (303) are configured to have probes (357, 457) attached thereto, wherein interaction between the probes (357, 457) and an analyte generates a signal; an optical system (285) comprising a plurality of collimators (295); a sensor (251) configured to detect the signal; wherein the collimators (295) can essentially prevent light from passing if a deviation of a propagation direction of the light from an optical axis of the collimators (295) is greater than a threshold. Because the probe carrier (300, 310, 400, 410) is separate and independent from the microarray (255), the probe carrier (300, 310, 400, 410) may be assembled with a pre-existing microarray (255) prior to its use, and be detached from the microarray (255) and disposed after its use.

Description

[Title established by the ISA under Rule 37.2] BIOSENSOR TechnicalĀ Field
TheĀ disclosureĀ hereinĀ relatesĀ toĀ biosensors,Ā particularlyĀ biosensorsĀ basedĀ onĀ opticalĀ detection.
Background
AĀ biosensorĀ isĀ anĀ analyticalĀ deviceĀ forĀ detectionĀ ofĀ anĀ analyteĀ involvedĀ inĀ aĀ biologicalĀ process.Ā ForĀ example,Ā theĀ analyteĀ mayĀ beĀ aĀ DNA,Ā aĀ protein,Ā aĀ metabolite,Ā orĀ evenĀ aĀ livingĀ organismĀ (e.g.,Ā bacteria,Ā virus)Ā .
AĀ biosensorĀ usuallyĀ hasĀ aĀ probeĀ thatĀ interactsĀ withĀ theĀ analyte.Ā TheĀ probeĀ mayĀ beĀ designedĀ toĀ bindĀ orĀ recognizeĀ theĀ analyte.Ā ExamplesĀ ofĀ theĀ probeĀ mayĀ includeĀ antibodies,Ā aptamers,Ā DNAs,Ā RNAs,Ā antigens,Ā etc.Ā InteractionĀ betweenĀ theĀ probeĀ andĀ theĀ analyteĀ mayĀ leadĀ toĀ oneĀ orĀ moreĀ detectableĀ event.Ā ForĀ example,Ā theĀ detectableĀ eventĀ mayĀ beĀ releaseĀ ofĀ aĀ chemicalĀ speciesĀ orĀ aĀ particleĀ (e.g.,Ā aĀ quantumĀ dot)Ā ,Ā aĀ chemicalĀ reaction,Ā luminescenceĀ (e.g.,Ā chemiluminescence,Ā bioluminescence,Ā electrochemiluminescence,Ā electroluminescence,Ā photoluminescence,Ā fluorescence,Ā phosphorescence)Ā ,Ā changeĀ inĀ aĀ physicalĀ propertyĀ (e.g.,Ā RamanĀ scattering,Ā color)Ā orĀ chemicalĀ propertyĀ (e.g.,Ā reactivity,Ā reactionĀ rate)Ā .
AĀ biosensorĀ mayĀ haveĀ aĀ detectorĀ thatĀ canĀ detectĀ theĀ detectableĀ eventĀ asĀ aĀ resultĀ ofĀ theĀ interaction.Ā TheĀ detectorĀ mayĀ transformĀ theĀ detectableĀ eventĀ intoĀ anotherĀ signalĀ (e.g.,Ā image,Ā electricalĀ signal)Ā thatĀ canĀ beĀ moreĀ easilyĀ measuredĀ andĀ quantified.Ā TheĀ detectorĀ mayĀ includeĀ circuitryĀ thatĀ obtainsĀ dataĀ fromĀ theĀ detectableĀ eventĀ andĀ processesĀ theĀ data.
OneĀ typeĀ ofĀ biosensorĀ isĀ microarrays.Ā AĀ microarrayĀ canĀ beĀ aĀ two-dimensionalĀ arrayĀ onĀ aĀ solidĀ substrateĀ (e.g.,Ā aĀ glassĀ slide,Ā aĀ siliconĀ wafer)Ā .Ā TheĀ arrayĀ mayĀ haveĀ differentĀ assaysĀ atĀ  differentĀ locations.Ā TheĀ assaysĀ atĀ differentĀ locationsĀ mayĀ beĀ independentĀ controlledĀ orĀ measured,Ā therebyĀ allowingĀ multiplexedĀ andĀ parallelĀ sensingĀ ofĀ oneĀ orĀ manyĀ analytes.Ā AĀ microarrayĀ mayĀ beĀ usefulĀ inĀ miniaturizingĀ diagnosisĀ assays.Ā ForĀ example,Ā aĀ microarrayĀ mayĀ beĀ usedĀ forĀ detectingĀ biologicalĀ samplesĀ inĀ theĀ fieldsĀ withoutĀ sophisticatedĀ equipment,Ā orĀ beĀ usedĀ byĀ aĀ patientĀ whoĀ isĀ notĀ inĀ aĀ clinicĀ orĀ hospitalĀ toĀ monitorĀ hisĀ orĀ herĀ physiologicalĀ symptoms.
Summary
DisclosedĀ hereinĀ isĀ anĀ apparatusĀ comprising:Ā aĀ probeĀ carrierĀ comprising:Ā aĀ substrateĀ comprisingĀ aĀ pluralityĀ ofĀ holesĀ throughĀ aĀ thicknessĀ ofĀ theĀ substrateĀ andĀ aĀ transparentĀ windowĀ acrossĀ anĀ openingĀ ofĀ eachĀ ofĀ theĀ holes,Ā whereinĀ theĀ transparentĀ windowĀ closesĀ theĀ opening,Ā whereinĀ oneĀ orĀ moreĀ locationsĀ onĀ theĀ transparentĀ windowĀ areĀ configuredĀ toĀ haveĀ probesĀ attachedĀ thereto,Ā whereinĀ interactionĀ betweenĀ theĀ probesĀ andĀ anĀ analyteĀ generatesĀ aĀ signalļ¼›Ā anĀ opticalĀ systemĀ comprisingĀ aĀ pluralityĀ ofĀ collimatorsļ¼›Ā aĀ sensorĀ comprisingĀ aĀ pluralityĀ ofĀ pixelsĀ configuredĀ toĀ detectĀ theĀ signalļ¼›Ā whereinĀ theĀ collimatorsĀ areĀ configuredĀ toĀ essentiallyĀ preventĀ lightĀ fromĀ passingĀ ifĀ aĀ deviationĀ ofĀ aĀ propagationĀ directionĀ ofĀ theĀ lightĀ fromĀ anĀ opticalĀ axisĀ ofĀ theĀ collimatorsĀ isĀ greaterĀ thanĀ aĀ threshold.
AccordingĀ toĀ anĀ embodiment,Ā theĀ substrateĀ comprisesĀ silicon.
AccordingĀ toĀ anĀ embodiment,Ā theĀ probesĀ andĀ theĀ substrateĀ areĀ onĀ aĀ sameĀ sideĀ ofĀ theĀ probeĀ carrier.
AccordingĀ toĀ anĀ embodiment,Ā theĀ probesĀ andĀ theĀ substrateĀ areĀ onĀ oppositeĀ sidesĀ ofĀ theĀ probeĀ carrier.
AccordingĀ toĀ anĀ embodiment,Ā theĀ transparentĀ windowĀ isĀ alignedĀ withĀ oneĀ ofĀ theĀ collimators.
AccordingĀ toĀ anĀ embodiment,Ā theĀ transparentĀ windowĀ encompassesĀ moreĀ thanĀ oneĀ ofĀ theĀ collimators.
AccordingĀ toĀ anĀ embodiment,Ā theĀ transparentĀ windowĀ isĀ aĀ portionĀ ofĀ aĀ continuousĀ transparentĀ layerĀ acrossĀ theĀ substrate.
AccordingĀ toĀ anĀ embodiment,Ā theĀ transparentĀ windowĀ hasĀ aĀ thicknessĀ fromĀ 10Ā toĀ 50Ā micrometers.
AccordingĀ toĀ anĀ embodiment,Ā theĀ sidewallĀ ofĀ theĀ holeĀ isĀ notĀ perpendicularĀ toĀ theĀ transparentĀ window.
AccordingĀ toĀ anĀ embodiment,Ā theĀ sensorĀ comprisesĀ aĀ controlĀ circuitĀ configuredĀ toĀ control,Ā acquireĀ dataĀ from,Ā orĀ processĀ dataĀ fromĀ theĀ pixels.
AccordingĀ toĀ anĀ embodiment,Ā theĀ pixelsĀ areĀ arrangedĀ suchĀ thatĀ eachĀ ofĀ theĀ pixelsĀ isĀ opticallyĀ coupledĀ toĀ oneĀ orĀ moreĀ ofĀ theĀ locations.
AccordingĀ toĀ anĀ embodiment,Ā theĀ pixelsĀ areĀ opticallyĀ coupledĀ toĀ theĀ locationsĀ byĀ theĀ collimators.
AccordingĀ toĀ anĀ embodiment,Ā theĀ signalĀ isĀ luminescence.
AccordingĀ toĀ anĀ embodiment,Ā theĀ signalĀ isĀ generatedĀ underĀ excitationĀ ofĀ anĀ excitationĀ radiation.
AccordingĀ toĀ anĀ embodiment,Ā theĀ opticalĀ systemĀ furtherĀ comprisesĀ aĀ filter,Ā whereinĀ theĀ filterĀ isĀ configuredĀ toĀ blockĀ atĀ leastĀ aĀ portionĀ ofĀ theĀ excitationĀ radiation.
AccordingĀ toĀ anĀ embodiment,Ā theĀ filterĀ isĀ aĀ dichroicĀ filter.
AccordingĀ toĀ anĀ embodiment,Ā theĀ opticalĀ systemĀ furtherĀ comprisesĀ orĀ aĀ transmissiveĀ layer.
AccordingĀ toĀ anĀ embodiment,Ā theĀ opticalĀ systemĀ furtherĀ comprisesĀ aĀ pluralityĀ ofĀ microlens.
AccordingĀ toĀ anĀ embodiment,Ā theĀ thresholdĀ isĀ 20Ā°.
AccordingĀ toĀ anĀ embodiment,Ā theĀ collimatorsĀ comprisesĀ aĀ meta-material,Ā quantumĀ dotsĀ orĀ aĀ photonicĀ crystal.
AccordingĀ toĀ anĀ embodiment,Ā theĀ collimatorsĀ areĀ configuredĀ toĀ eliminateĀ opticalĀ cross-talkĀ betweenĀ neighboringĀ pixelsĀ amongĀ theĀ pluralityĀ ofĀ pixels.
AccordingĀ toĀ anĀ embodiment,Ā atĀ leastĀ oneĀ ofĀ theĀ collimatorsĀ comprisesĀ aĀ coreĀ andĀ aĀ sidewallĀ surroundingĀ theĀ core.
AccordingĀ toĀ anĀ embodiment,Ā theĀ signalĀ isĀ generatedĀ underĀ excitationĀ ofĀ anĀ excitationĀ radiationļ¼›Ā whereinĀ theĀ coreĀ isĀ aĀ materialĀ thatĀ essentiallyĀ preventsĀ theĀ excitationĀ radiationĀ fromĀ passingĀ throughĀ irrespectiveĀ ofĀ propagationĀ directionĀ ofĀ theĀ excitationĀ radiation.
AccordingĀ toĀ anĀ embodiment,Ā theĀ signalĀ isĀ generatedĀ underĀ excitationĀ ofĀ anĀ excitationĀ radiationļ¼›Ā whereinĀ theĀ coreĀ comprisesĀ aĀ dichroicĀ filter.
AccordingĀ toĀ anĀ embodiment,Ā theĀ coreĀ allowsĀ theĀ signalĀ toĀ passĀ throughĀ essentiallyĀ unabsorbed.
AccordingĀ toĀ anĀ embodiment,Ā theĀ coreĀ isĀ aĀ voidĀ space.
AccordingĀ toĀ anĀ embodiment,Ā theĀ sidewallĀ attenuatesĀ aĀ portionĀ ofĀ theĀ signalĀ reachingĀ theĀ sidewall.
AccordingĀ toĀ anĀ embodiment,Ā theĀ sidewallĀ isĀ textured.
AccordingĀ toĀ anĀ embodiment,Ā theĀ apparatusĀ furtherĀ comprisesĀ aĀ redistributionĀ layerĀ configuredĀ toĀ routeĀ dataĀ fromĀ theĀ pixels.
AccordingĀ toĀ anĀ embodiment,Ā theĀ filterĀ comprisesĀ aĀ meta-material,Ā quantumĀ dotsĀ orĀ aĀ photonicĀ crystal.
BriefĀ DescriptionĀ ofĀ Figures
Fig.Ā 1AĀ schematicallyĀ showsĀ anĀ apparatusĀ includingĀ aĀ microarray.
Fig.Ā 1BĀ schematicallyĀ showsĀ anĀ apparatusĀ whereĀ detectorĀ capabilityĀ isĀ integratedĀ intoĀ aĀ microarray.
Fig.Ā 2AĀ schematicallyĀ showsĀ anĀ apparatus,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 2BĀ schematicallyĀ showsĀ anĀ apparatus,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 3AĀ schematicallyĀ showsĀ aĀ probeĀ carrierĀ 300Ā whereinĀ theĀ probesĀ andĀ theĀ substrateĀ areĀ onĀ oppositeĀ sidesĀ ofĀ theĀ probeĀ carrier,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 3BĀ schematicallyĀ showsĀ aĀ probeĀ carrierĀ 310Ā whereinĀ theĀ sidewallĀ ofĀ theĀ holeĀ isĀ notĀ perpendicularĀ toĀ theĀ transparentĀ window,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 4AĀ schematicallyĀ showsĀ aĀ probeĀ carrierĀ 400Ā whereinĀ theĀ probesĀ andĀ theĀ substrateĀ areĀ onĀ aĀ sameĀ sideĀ ofĀ theĀ probeĀ carrier,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 4BĀ schematicallyĀ showsĀ aĀ probeĀ carrierĀ 410Ā whereinĀ theĀ sidewallĀ ofĀ theĀ holeĀ isĀ notĀ perpendicularĀ toĀ theĀ transparentĀ window,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 4CĀ schematicallyĀ showsĀ aĀ probeĀ carrierĀ 420,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 5AĀ schematicallyĀ showsĀ anĀ apparatusĀ 500Ā withĀ aĀ probeĀ carrierĀ 410,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 5BĀ schematicallyĀ showsĀ anĀ apparatusĀ 510Ā comprisingĀ microlensĀ andĀ aĀ probeĀ carrierĀ 410,Ā whereinĀ theĀ microlensĀ mayĀ beĀ fabricatedĀ inĀ theĀ passivationĀ layer,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 5CĀ schematicallyĀ showsĀ anĀ apparatusĀ 520Ā comprisingĀ microlensĀ andĀ aĀ probeĀ carrierĀ 410,Ā whereinĀ theĀ microlensĀ mayĀ beĀ fabricatedĀ inĀ theĀ collimators,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 6AĀ schematicallyĀ showsĀ anĀ apparatusĀ 600Ā withĀ aĀ probeĀ carrierĀ 420,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 6BĀ schematicallyĀ showsĀ anĀ apparatusĀ 610Ā withĀ aĀ probeĀ carrierĀ 300,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 7AĀ schematicallyĀ showsĀ aĀ collimator,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 7BĀ schematicallyĀ showsĀ aĀ collimator,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 7CĀ schematicallyĀ showsĀ aĀ collimator,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 7DĀ schematicallyĀ showsĀ aĀ collimator,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 7EĀ schematicallyĀ showsĀ anĀ apparatusĀ 700Ā whereinĀ theĀ filterĀ andĀ theĀ transmissiveĀ layerĀ areĀ bothĀ omitted,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 7FĀ andĀ Fig.Ā 7GĀ eachĀ schematicallyĀ showĀ thatĀ theĀ opticalĀ systemĀ mayĀ haveĀ aĀ pluralityĀ ofĀ collimatorsĀ arrangedĀ inĀ anĀ array,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 8Ā schematicallyĀ showsĀ anĀ apparatusĀ 800Ā inĀ whichĀ theĀ opticalĀ systemĀ mayĀ haveĀ aĀ microfluidicĀ system,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 9AĀ schematicallyĀ showsĀ anĀ apparatusĀ 900Ā whereinĀ aĀ sensorĀ inĀ aĀ microarrayĀ mayĀ haveĀ aĀ signalĀ transferĀ layerĀ andĀ thatĀ theĀ opticalĀ systemĀ inĀ theĀ microarrayĀ mayĀ haveĀ aĀ redistributionĀ layer,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 9BĀ schematicallyĀ showsĀ aĀ topĀ viewĀ ofĀ theĀ sensorĀ inĀ Fig.Ā 9A.
Fig.Ā 9CĀ schematicallyĀ showsĀ aĀ bottomĀ viewĀ ofĀ theĀ opticalĀ systemĀ inĀ Fig.Ā 9A.
Fig.Ā 10AĀ schematicallyĀ showsĀ anĀ apparatusĀ 1000Ā whereinĀ aĀ sensorĀ inĀ aĀ microarrayĀ mayĀ haveĀ aĀ redistributionĀ layerĀ andĀ thatĀ theĀ opticalĀ systemĀ inĀ theĀ microarrayĀ mayĀ haveĀ aĀ signalĀ transferĀ layer,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 10BĀ schematicallyĀ showsĀ aĀ topĀ viewĀ ofĀ theĀ sensorĀ inĀ Fig.Ā 10A,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 10CĀ schematicallyĀ showsĀ aĀ bottomĀ viewĀ ofĀ theĀ opticalĀ systemĀ inĀ Fig.Ā 10A,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 10DĀ schematicallyĀ showsĀ aĀ topĀ viewĀ ofĀ theĀ sensorĀ inĀ Fig.Ā 10A,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 10EĀ schematicallyĀ showsĀ aĀ bottomĀ viewĀ ofĀ theĀ opticalĀ systemĀ inĀ Fig.Ā 10AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ bondingĀ pads,Ā whichĀ areĀ positionedĀ toĀ connectĀ toĀ theĀ viasĀ shownĀ inĀ Fig.Ā 10D.
Fig.Ā 10FĀ schematicallyĀ showsĀ aĀ topĀ viewĀ ofĀ theĀ sensorĀ inĀ Fig.Ā 10A,Ā accordingĀ toĀ anĀ embodiment.
Fig.Ā 10GĀ schematicallyĀ showsĀ aĀ bottomĀ viewĀ ofĀ theĀ opticalĀ systemĀ inĀ Fig.Ā 10AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ bondingĀ pad,Ā whichĀ areĀ positionedĀ toĀ connectĀ toĀ theĀ viaĀ shownĀ inĀ Fig.Ā 10F.
Fig.Ā 11Ā schematicallyĀ showsĀ thatĀ systemĀ 1100Ā whereinĀ aĀ sensorĀ inĀ aĀ microarrayĀ mayĀ haveĀ aĀ redistributionĀ layerĀ withĀ viasĀ suchĀ asĀ through-siliconĀ viasĀ (TSV)Ā configuredĀ toĀ electricallyĀ connectĀ theĀ transmissionĀ linesĀ inĀ theĀ redistributionĀ layerĀ toĀ bondingĀ padsĀ onĀ theĀ sideĀ oppositeĀ fromĀ theĀ redistributionĀ layer,Ā accordingĀ toĀ anĀ embodiment.
DetailedĀ Description
Fig.Ā 1AĀ schematicallyĀ showsĀ anĀ apparatusĀ 100Ā includingĀ aĀ microarrayĀ 105.Ā TheĀ systemĀ 100Ā mayĀ haveĀ anĀ imageĀ sensorĀ 101,Ā anĀ opticalĀ systemĀ 102,Ā and/orĀ anĀ excitationĀ sourceĀ 109.Ā  TheĀ imageĀ sensorĀ 101Ā mayĀ beĀ configuredĀ toĀ measureĀ anĀ opticalĀ propertyĀ (e.g.,Ā color,Ā intensity)Ā atĀ differentĀ locationsĀ 106Ā ofĀ theĀ microarrayĀ 105.Ā TheĀ locationsĀ 106Ā mayĀ haveĀ variousĀ probesĀ 107Ā attachedĀ thereto.Ā TheĀ probesĀ 107Ā mayĀ interactĀ withĀ analyteĀ andĀ theĀ interactionĀ mayĀ generateĀ signalsĀ 108Ā detectableĀ byĀ theĀ imageĀ sensorĀ 101.Ā TheĀ generationĀ ofĀ theĀ signalsĀ 108Ā mayĀ needĀ excitationĀ byĀ theĀ excitationĀ sourceĀ 109Ā (e.g.,Ā laser,Ā UVĀ light,Ā etc.Ā )Ā .Ā TheĀ imageĀ sensorĀ 101Ā andĀ theĀ opticalĀ systemĀ 102Ā ofĀ theĀ systemĀ 100Ā tendĀ toĀ beĀ bulky,Ā fragile,Ā orĀ expensiveĀ andĀ mayĀ notĀ haveĀ highĀ enoughĀ spatialĀ resolutionĀ toĀ distinguishĀ oneĀ locationĀ fromĀ itsĀ neighboringĀ locations.
Fig.Ā 1BĀ schematicallyĀ showsĀ aĀ systemĀ 150Ā whereĀ detectorĀ capabilityĀ isĀ integratedĀ intoĀ aĀ microarrayĀ 155.Ā TheĀ microarrayĀ 155Ā mayĀ haveĀ multipleĀ locationsĀ 156Ā withĀ variousĀ probesĀ 157Ā attachedĀ thereto.Ā TheĀ probesĀ 157Ā mayĀ interactĀ withĀ variousĀ analytesĀ andĀ theĀ interactionĀ mayĀ generateĀ signalsĀ 158Ā detectableĀ byĀ aĀ sensorĀ 151Ā integratedĀ toĀ theĀ microarrayĀ 155.Ā ForĀ example,Ā theĀ analytesĀ areĀ fluorophore-labeledĀ nucleicĀ acidĀ orĀ proteinĀ fragmentsļ¼›Ā theĀ probesĀ areĀ oligonucleotidesĀ orĀ antibodies.Ā LocationsĀ withĀ fluorophore-labeledĀ analytesĀ capturedĀ byĀ theĀ probesĀ canĀ beĀ identifiedĀ byĀ detectingĀ fluorescenceĀ fromĀ theĀ fluorophoresĀ onĀ theĀ capturedĀ analytes.Ā TheĀ sensorĀ 151Ā mayĀ haveĀ multipleĀ pixelsĀ 170Ā configuredĀ toĀ detectĀ theĀ signalsĀ 158Ā (e.g.,Ā color,Ā intensity)Ā .Ā TheĀ pixelsĀ 170Ā mayĀ haveĀ aĀ controlĀ circuitĀ 171Ā configuredĀ toĀ control,Ā acquireĀ dataĀ from,Ā and/orĀ processĀ dataĀ fromĀ theĀ pixelsĀ 170.Ā TheĀ pixelsĀ 170Ā mayĀ beĀ arrangedĀ suchĀ thatĀ eachĀ pixelĀ 170Ā isĀ opticallyĀ coupledĀ toĀ oneĀ ofĀ theĀ locationsĀ 156.Ā However,Ā theĀ signalsĀ 158Ā generatedĀ atĀ oneĀ locationĀ 156Ā mayĀ notĀ entirelyĀ reachĀ theĀ pixelĀ 170Ā opticallyĀ coupledĀ toĀ thatĀ locationĀ 156.Ā AĀ portionĀ 172Ā ofĀ theĀ signalsĀ 158Ā mayĀ reachĀ theĀ pixelĀ 170Ā opticallyĀ coupledĀ toĀ thatĀ locationĀ 156Ā butĀ anotherĀ portionĀ 173Ā mayĀ beĀ scatteredĀ intoĀ neighboringĀ pixelsĀ (Ā ā€œopticalĀ cross- talkā€Ā )Ā and/orĀ awayĀ fromĀ allĀ pixelsĀ 170.Ā GeneratingĀ theĀ signalsĀ 158Ā mayĀ needĀ anĀ excitationĀ radiationĀ 161Ā (e.g.,Ā laser,Ā UVĀ light,Ā etc.Ā )Ā .Ā AĀ portionĀ 162Ā ofĀ theĀ excitationĀ radiationĀ 161Ā mayĀ passĀ throughĀ theĀ locationsĀ 156Ā unscattered.Ā AĀ portionĀ 163Ā ofĀ theĀ excitationĀ radiationĀ 161Ā mayĀ beĀ scatteredĀ intoĀ someĀ ofĀ theĀ pixelsĀ 170Ā orĀ awayĀ fromĀ allĀ pixelsĀ 170.Ā TheĀ portionĀ 162Ā mayĀ beĀ blockedĀ byĀ aĀ filterĀ 190Ā fromĀ reachingĀ theĀ pixelsĀ 170.Ā TheĀ filterĀ 190Ā mayĀ beĀ positionĀ belowĀ orĀ aboveĀ aĀ transmissiveĀ layerĀ 191.Ā However,Ā theĀ filterĀ 190Ā mayĀ beĀ sensitiveĀ toĀ incidentĀ directionsĀ andĀ mayĀ notĀ blockĀ theĀ portionĀ 163,Ā despiteĀ portionsĀ 162Ā andĀ 163Ā haveĀ theĀ sameĀ wavelength.Ā IfĀ theĀ portionĀ 163Ā reachesĀ theĀ pixelsĀ 170,Ā itĀ canĀ overshadowĀ signalsĀ 158.
Fig.Ā 2AĀ schematicallyĀ showsĀ anĀ apparatusĀ 200,Ā accordingĀ toĀ anĀ embodiment.Ā TheĀ systemĀ 200Ā includesĀ aĀ microarrayĀ 255Ā includingĀ anĀ integratedĀ sensorĀ 251Ā andĀ anĀ opticalĀ systemĀ 285.Ā TheĀ microarrayĀ 255Ā mayĀ haveĀ multipleĀ locationsĀ 256Ā withĀ variousĀ probesĀ 257Ā attachedĀ thereto.Ā TheĀ probesĀ 257Ā mayĀ interactĀ withĀ variousĀ analytesĀ andĀ theĀ interactionĀ mayĀ generateĀ signalsĀ 258Ā detectableĀ byĀ theĀ sensorĀ 251.Ā TheĀ sensorĀ 251Ā mayĀ haveĀ multipleĀ pixelsĀ 270Ā configuredĀ toĀ detectĀ theĀ signalsĀ 258Ā (e.g.,Ā color,Ā intensity)Ā .Ā TheĀ pixelsĀ 270Ā mayĀ haveĀ aĀ controlĀ circuitĀ 271Ā configuredĀ toĀ control,Ā acquireĀ dataĀ from,Ā and/orĀ processĀ dataĀ fromĀ theĀ pixelsĀ 270.Ā TheĀ pixelsĀ 270Ā mayĀ beĀ arrangedĀ suchĀ thatĀ eachĀ pixelĀ 270Ā isĀ opticallyĀ coupledĀ toĀ oneĀ orĀ moreĀ ofĀ theĀ locationsĀ 256.Ā TheĀ opticalĀ systemĀ 285Ā mayĀ includeĀ aĀ filterĀ 290Ā positionedĀ belowĀ orĀ aboveĀ aĀ transmissiveĀ layerĀ 291Ā (Fig.Ā 2BĀ showsĀ anĀ exampleĀ whereĀ theĀ filterĀ 290Ā isĀ belowĀ theĀ transmissiveĀ layerĀ 291)Ā .Ā TheĀ opticalĀ systemĀ 285Ā mayĀ includeĀ aĀ pluralityĀ ofĀ collimatorsĀ 295Ā configuredĀ toĀ opticallyĀ coupleĀ theĀ pixelsĀ 270Ā toĀ theĀ locationsĀ 256.Ā TheĀ filterĀ 290Ā andĀ theĀ transmissiveĀ layerĀ 291Ā mayĀ notĀ haveĀ toĀ beĀ fabricatedĀ onĀ theĀ sameĀ substrateĀ asĀ theĀ collimatorsĀ 295.Ā Instead,Ā theĀ  filterĀ 290Ā andĀ theĀ transmissiveĀ layerĀ 291Ā mayĀ beĀ fabricatedĀ andĀ bondedĀ toĀ theĀ collimatorsĀ 295.Ā InĀ anĀ embodiment,Ā theĀ sensorĀ 251Ā comprisesĀ quantumĀ dots.
InĀ anĀ embodiment,Ā theĀ transmissiveĀ layerĀ 291Ā mayĀ includeĀ oxideĀ orĀ nitride.Ā ForĀ example,Ā theĀ transmissiveĀ layerĀ 291Ā mayĀ includeĀ glass.
InĀ anĀ embodiment,Ā theĀ filterĀ 290Ā mayĀ beĀ aĀ dichroicĀ filterĀ (alsoĀ knownĀ asĀ interferenceĀ filter)Ā .Ā TheĀ filterĀ 290Ā mayĀ beĀ aĀ low-passĀ (passingĀ frequencyĀ belowĀ aĀ threshold)Ā orĀ band-passĀ filter.Ā TheĀ filterĀ 290Ā mayĀ includeĀ aĀ meta-material,Ā quantumĀ dotsĀ orĀ aĀ photonicĀ crystal.Ā AĀ meta-materialĀ hasĀ componentĀ materialsĀ arrangedĀ inĀ repeatingĀ patterns,Ā oftenĀ atĀ microscopicĀ orĀ smallerĀ scalesĀ thatĀ areĀ smallerĀ thanĀ theĀ wavelengthsĀ ofĀ theĀ lightĀ theĀ meta-materialĀ isĀ designedĀ toĀ influence.Ā TheĀ structureĀ ofĀ theĀ repeatedĀ patternsĀ andĀ theĀ propertiesĀ ofĀ theĀ componentĀ materialsĀ mayĀ beĀ selectedĀ toĀ tailorĀ theĀ propertiesĀ ofĀ theĀ meta-material.Ā ForĀ example,Ā theĀ meta-materialĀ mayĀ provideĀ opticalĀ transparencyĀ atĀ allĀ frequenciesĀ exceptĀ atĀ theĀ selectedĀ frequencyĀ orĀ frequenciesĀ whichĀ itĀ isĀ configuredĀ toĀ blockĀ (forĀ exampleĀ particularĀ laserĀ frequenciesĀ thatĀ couldĀ causeĀ harmĀ toĀ aĀ user)Ā .Ā AĀ photonicĀ crystalĀ isĀ aĀ periodicĀ dielectricĀ structureĀ thatĀ hasĀ aĀ bandĀ gapĀ thatĀ forbidsĀ propagationĀ ofĀ aĀ certainĀ frequencyĀ rangeĀ ofĀ light.Ā TheĀ filterĀ 290Ā mayĀ haveĀ multipleĀ thinĀ layersĀ ofĀ materialsĀ withĀ differentĀ refractiveĀ indicesĀ andĀ mayĀ beĀ madeĀ byĀ alternatelyĀ depositingĀ thinĀ layersĀ ofĀ theseĀ materials.Ā AĀ quantumĀ dotĀ (QD)Ā isĀ aĀ nanocrystalĀ madeĀ ofĀ semiconductorĀ materialsĀ thatĀ isĀ smallĀ enoughĀ toĀ exhibitĀ quantumĀ mechanicalĀ properties.Ā Specifically,Ā itsĀ excitonsĀ areĀ confinedĀ inĀ allĀ threeĀ spatialĀ dimensions.Ā QuantumĀ dotsĀ ofĀ theĀ sameĀ material,Ā butĀ withĀ differentĀ sizes,Ā canĀ absorbĀ lightĀ ofĀ differentĀ wavelengthsĀ dueĀ toĀ theĀ quantumĀ confinementĀ effect.Ā TheĀ largerĀ theĀ quantumĀ dot,Ā theĀ redderĀ (lowerĀ energy)Ā itsĀ absorption.Ā  Conversely,Ā smallerĀ quantumĀ dotsĀ absorbĀ bluerĀ (higherĀ energy)Ā light.Ā TheĀ filterĀ 290Ā mayĀ beĀ anĀ absorptiveĀ filterĀ butĀ itĀ wouldĀ haveĀ sufficientĀ thicknessĀ toĀ beĀ effective.
Fig.Ā 3AĀ schematicallyĀ showsĀ aĀ probeĀ carrierĀ 300Ā whereinĀ theĀ probesĀ andĀ theĀ substrateĀ areĀ onĀ oppositeĀ sidesĀ ofĀ theĀ probeĀ carrier,Ā accordingĀ toĀ anĀ embodiment.Ā TheĀ probeĀ carrierĀ 300Ā comprisesĀ aĀ substrateĀ 301Ā comprisingĀ aĀ pluralityĀ ofĀ holesĀ 302Ā throughĀ aĀ thicknessĀ ofĀ theĀ substrateĀ 301Ā andĀ aĀ transparentĀ windowĀ 303Ā acrossĀ anĀ openingĀ ofĀ eachĀ ofĀ theĀ holesĀ 302.Ā TheĀ transparentĀ windowĀ 303Ā closesĀ theĀ opening,Ā andĀ oneĀ orĀ moreĀ locationsĀ onĀ theĀ transparentĀ windowĀ areĀ configuredĀ toĀ haveĀ probesĀ 357Ā attachedĀ thereto.Ā InteractionsĀ betweenĀ theĀ probesĀ 357Ā andĀ anĀ analyteĀ generateĀ aĀ signalĀ 358.
AccordingĀ toĀ theĀ embodiment,Ā theĀ probeĀ carrierĀ 300Ā isĀ separateĀ andĀ independentĀ fromĀ theĀ microarrayĀ 255Ā thatĀ includesĀ theĀ opticalĀ systemĀ 285Ā andĀ integratedĀ sensorĀ 251.Ā Therefore,Ā theĀ probeĀ carrierĀ 300Ā mayĀ beĀ assembledĀ withĀ aĀ microarrayĀ priorĀ beforeĀ itsĀ use,Ā andĀ theĀ probeĀ carrierĀ 300Ā mayĀ beĀ detachedĀ fromĀ theĀ microarrayĀ andĀ disposedĀ afterĀ itsĀ use.Ā BecauseĀ fabricationĀ ofĀ microarrayĀ isĀ costly,Ā theĀ probeĀ carrierĀ 300Ā allowsĀ reuseĀ ofĀ theĀ microarrayĀ 255Ā includingĀ itsĀ opticalĀ systemsĀ andĀ sensors.Ā InĀ addition,Ā theĀ probeĀ carrierĀ 300Ā allowsĀ aĀ userĀ toĀ chooseĀ fromĀ variousĀ microarraysĀ toĀ useĀ withĀ theĀ probeĀ carrierĀ 300,Ā whichĀ providesĀ moreĀ flexibilityĀ andĀ reducesĀ costĀ inĀ fabrication.
InĀ anĀ embodiment,Ā theĀ substrateĀ 301Ā comprisesĀ siliconĀ orĀ otherĀ suitableĀ materials.Ā InĀ anĀ embodiment,Ā theĀ transparentĀ windowĀ 303Ā comprisesĀ siliconĀ oxide,Ā siliconĀ nitrideĀ orĀ otherĀ suitableĀ material.Ā InĀ anĀ embodiment,Ā theĀ transparentĀ windowĀ 303Ā isĀ aĀ portionĀ ofĀ aĀ continuousĀ transparentĀ layerĀ 304Ā acrossĀ theĀ substrate.Ā InĀ anĀ embodiment,Ā theĀ transparentĀ windowĀ 303Ā orĀ  transparentĀ layerĀ 304Ā hasĀ aĀ thicknessĀ fromĀ 10Ā toĀ 50Ā micrometers.Ā TheĀ substrateĀ 301Ā canĀ mechanicallyĀ supportĀ theĀ transparentĀ windowĀ 303Ā orĀ theĀ transparentĀ layerĀ 304.
InĀ anĀ embodiment,Ā theĀ probeĀ carrierĀ isĀ madeĀ byĀ theĀ followingĀ method:Ā 1)Ā providingĀ aĀ siliconĀ waferĀ asĀ aĀ substrateļ¼›Ā 2)Ā disposingĀ aĀ transparentĀ layerĀ suchĀ asĀ aĀ layerĀ ofĀ siliconĀ oxideĀ onĀ theĀ substrateļ¼›Ā 3)Ā etchingĀ theĀ substrateĀ toĀ formĀ holesĀ inĀ theĀ substrate.Ā OneĀ ofĀ ordinaryĀ skillĀ inĀ theĀ artĀ willĀ recognizeĀ thatĀ wetĀ orĀ dryĀ etchingĀ orĀ otherĀ suitableĀ techniquesĀ mayĀ beĀ usedĀ toĀ removeĀ portionsĀ ofĀ theĀ substrateĀ toĀ formĀ theĀ holesĀ ofĀ aĀ desiredĀ depth.Ā ExamplesĀ ofĀ aĀ dryĀ etchingĀ processĀ include,Ā butĀ areĀ notĀ limitedĀ to,Ā inductivelyĀ coupledĀ plasmaĀ reactiveĀ ionĀ etchĀ (ICPĀ RIE)Ā process,Ā andĀ theĀ BoschĀ process.Ā ExamplesĀ ofĀ wetĀ etchingĀ processĀ include,Ā butĀ areĀ notĀ limitedĀ to,Ā aĀ metalĀ assistedĀ chemicalĀ etchĀ (MACE)Ā process.
InĀ anĀ embodiment,Ā probesĀ areĀ depositedĀ afterĀ formingĀ theĀ holesĀ inĀ theĀ substrate.Ā InĀ anotherĀ embodiment,Ā probesĀ areĀ depositedĀ beforeĀ formingĀ theĀ holesĀ inĀ theĀ substrate.
InĀ theĀ embodimentsĀ asĀ shownĀ inĀ Figs.Ā 3AĀ andĀ 3B,Ā theĀ probesĀ andĀ theĀ substrateĀ areĀ onĀ oppositeĀ sidesĀ ofĀ theĀ probeĀ carrier.Ā InĀ embodimentsĀ asĀ shownĀ inĀ Figs.Ā 4AĀ andĀ 4B,Ā theĀ probesĀ andĀ theĀ substrateĀ areĀ depositedĀ onĀ theĀ sameĀ sideĀ ofĀ theĀ probeĀ carrier.
InĀ theĀ embodimentsĀ asĀ shownĀ inĀ inĀ Figs.Ā 3AĀ andĀ 4A,Ā theĀ sidewallĀ 305Ā ofĀ theĀ holeĀ 302Ā orĀ sidewallĀ 405Ā ofĀ theĀ holeĀ 402Ā mayĀ beĀ perpendicularĀ toĀ theĀ transparentĀ window.Ā InĀ theĀ embodimentsĀ asĀ shownĀ inĀ Figs.Ā 3BĀ andĀ 4B,Ā theĀ sidewallĀ 306Ā ofĀ theĀ holeĀ 307Ā orĀ theĀ sidewallĀ 406Ā ofĀ theĀ holeĀ 407Ā mayĀ beĀ notĀ perpendicularĀ toĀ theĀ transparentĀ window.Ā TheĀ sizeĀ andĀ shapeĀ ofĀ sidewallĀ ofĀ theĀ holesĀ mayĀ beĀ controlledĀ byĀ aĀ suitableĀ wetĀ orĀ dryĀ etchingĀ technique.
InĀ anĀ embodimentĀ asĀ shownĀ inĀ inĀ Fig.Ā 4C,Ā multipleĀ locationsĀ onĀ aĀ singleĀ transparentĀ windowĀ 303Ā areĀ configuredĀ toĀ haveĀ probesĀ attachedĀ thereto.Ā TheĀ configurationĀ ofĀ moreĀ thanĀ  oneĀ locationĀ providesĀ optionsĀ ofĀ attachingĀ differentĀ probesĀ andĀ enhancingĀ theĀ flexibilityĀ ofĀ theĀ microarray.
InĀ anĀ embodimentĀ asĀ shownĀ inĀ Fig.Ā 5A,Ā anĀ apparatusĀ 500Ā comprisesĀ aĀ probeĀ carrierĀ 410Ā andĀ aĀ microarrayĀ 255Ā thatĀ comprisesĀ anĀ opticalĀ systemĀ 285Ā withĀ collimatorsĀ 295Ā andĀ anĀ integratedĀ sensorĀ 251.Ā TheĀ probeĀ carrierĀ 410Ā mayĀ beĀ mountedĀ toĀ theĀ microarrayĀ 255Ā withĀ aĀ suitableĀ technique.Ā TheĀ biosensorĀ functionĀ ofĀ theĀ apparatusĀ 500Ā mayĀ beĀ carriedĀ outĀ withĀ appropriateĀ probesĀ onĀ theĀ probeĀ carrierĀ 410.
InĀ anĀ embodiment,Ā theĀ transmissiveĀ layerĀ 291Ā mayĀ beĀ anĀ insulatingĀ materialĀ suchĀ asĀ siliconĀ oxideĀ orĀ siliconĀ nitride.Ā InĀ anĀ embodiment,Ā theĀ transmissiveĀ layerĀ 291Ā mayĀ evenĀ beĀ omitted.
InĀ anĀ embodimentĀ asĀ shownĀ inĀ Fig.Ā 5B,Ā anĀ apparatusĀ 510Ā comprisesĀ aĀ probeĀ carrierĀ 410Ā andĀ aĀ microarrayĀ 255Ā thatĀ comprisesĀ anĀ opticalĀ systemĀ 285Ā withĀ collimatorsĀ 295Ā andĀ anĀ integratedĀ sensorĀ 251,Ā whereinĀ theĀ opticalĀ systemĀ 285Ā mayĀ haveĀ aĀ pluralityĀ ofĀ microlensĀ 292.Ā TheĀ microlensĀ 292Ā mayĀ beĀ fabricatedĀ inĀ theĀ passivationĀ layerĀ 291Ā asĀ shownĀ inĀ Fig.Ā 5B.Ā Alternatively,Ā theĀ microlensĀ 292Ā mayĀ beĀ fabricatedĀ inĀ theĀ collimatorsĀ 295Ā asĀ shownĀ inĀ Fig.Ā 5C.Ā TheĀ microlensĀ 292Ā mayĀ beĀ configuredĀ toĀ focusĀ lightĀ generatedĀ byĀ theĀ probesĀ intoĀ theĀ collimatorsĀ 295.Ā TheĀ microlensĀ 292Ā mayĀ beĀ configuredĀ toĀ directĀ aĀ greaterĀ portionĀ ofĀ luminescenceĀ signalĀ fromĀ probesĀ intoĀ theĀ pixelsĀ coupledĀ thereto.Ā ForĀ example,Ā aĀ microlenĀ 292Ā mayĀ captureĀ theĀ portionĀ 273Ā thatĀ otherwiseĀ wouldĀ notĀ reachĀ theĀ pixelĀ coupledĀ toĀ theĀ locationĀ 256Ā whereĀ theĀ portionĀ 273Ā isĀ from.
InĀ embodimentsĀ asĀ shownĀ inĀ Fig.Ā 5A-5C,Ā aĀ transparentĀ windowĀ ofĀ theĀ probeĀ carrierĀ encompassesĀ moreĀ thanĀ oneĀ ofĀ theĀ collimators.Ā ThisĀ isĀ achievedĀ byĀ controlledĀ fabricationĀ  processĀ suchĀ thatĀ theĀ holesĀ inĀ theĀ probeĀ carrierĀ haveĀ aĀ greaterĀ widthĀ thanĀ theĀ widthĀ ofĀ theĀ collimatorsĀ inĀ theĀ microarray.Ā AsĀ usedĀ herein,Ā theĀ widthĀ ofĀ theĀ holeĀ orĀ theĀ widthĀ ofĀ theĀ collimatorsĀ refersĀ toĀ aĀ sizeĀ inĀ theĀ dimensionĀ thatĀ isĀ parallelĀ toĀ theĀ planeĀ ofĀ theĀ probeĀ carrier.Ā InĀ suchĀ embodiments,Ā noĀ alignmentĀ ofĀ theĀ probeĀ carrierĀ withĀ theĀ microarrayĀ isĀ requiredĀ duringĀ assemblyĀ ofĀ theĀ probeĀ carrierĀ withĀ theĀ microarrayĀ toĀ formĀ theĀ biosensorĀ apparatus.
InĀ embodimentsĀ asĀ shownĀ inĀ Fig.Ā 6AĀ andĀ 6B,Ā eachĀ locationĀ isĀ alignedĀ withĀ oneĀ ofĀ theĀ collimators.Ā ThisĀ isĀ achievedĀ byĀ controlledĀ fabricationĀ processĀ suchĀ thatĀ theĀ holesĀ inĀ theĀ probeĀ carrierĀ hasĀ aĀ sameĀ widthĀ thanĀ theĀ widthĀ ofĀ theĀ collimatorsĀ inĀ theĀ microarray,Ā andĀ appropriateĀ alignmentĀ ofĀ theĀ probeĀ carrierĀ withĀ theĀ microarrayĀ isĀ requiredĀ duringĀ assemblyĀ ofĀ theĀ probeĀ carrierĀ withĀ theĀ microarrayĀ toĀ formĀ theĀ biosensorĀ apparatus.
InĀ anĀ embodimentĀ asĀ shownĀ inĀ Fig.Ā 6A,Ā anĀ apparatusĀ 600Ā comprisesĀ aĀ probeĀ carrierĀ 420Ā andĀ aĀ microarrayĀ 255Ā thatĀ comprisesĀ anĀ opticalĀ systemĀ withĀ collimatorsĀ 295Ā andĀ anĀ integratedĀ sensorĀ 251.Ā InĀ otherĀ embodiments,Ā otherĀ typesĀ ofĀ probeĀ carrier,Ā includingĀ butĀ notĀ limitedĀ to,Ā 300,Ā 310,Ā 400Ā orĀ 410Ā mayĀ beĀ usedĀ alternativelyĀ toĀ formĀ theĀ biosensorĀ apparatus.Ā ForĀ example,Ā inĀ anĀ embodimentĀ asĀ shownĀ inĀ Fig.Ā 6B,Ā anĀ apparatusĀ 610Ā comprisesĀ aĀ probeĀ carrierĀ 300Ā andĀ aĀ microarrayĀ 255Ā thatĀ comprisesĀ anĀ opticalĀ systemĀ withĀ collimatorsĀ 295Ā andĀ anĀ integratedĀ sensorĀ 251.
InĀ otherĀ embodiments,Ā otherĀ typesĀ ofĀ microarraysĀ mayĀ beĀ usedĀ withĀ anyĀ ofĀ theĀ aforementionedĀ probeĀ carriersĀ toĀ formĀ aĀ biosensorĀ apparatus.Ā SomeĀ examplesĀ ofĀ suchĀ microarraysĀ areĀ illustratedĀ asĀ below.
InĀ anĀ embodiment,Ā theĀ filterĀ 290,Ā theĀ transmissiveĀ layerĀ 291Ā ifĀ present,Ā theĀ microlensĀ 292Ā ifĀ presentĀ andĀ theĀ collimatorĀ 295Ā mayĀ beĀ integratedĀ onĀ theĀ sameĀ substrate.
InĀ anĀ embodiment,Ā theĀ collimatorĀ 295Ā mayĀ beĀ configuredĀ toĀ essentiallyĀ preventĀ (e.g.,Ā preventĀ moreĀ thanĀ 90ļ¼…,Ā 99ļ¼…,Ā orĀ 99.9ļ¼…of)Ā lightĀ fromĀ passingĀ ifĀ theĀ deviationĀ ofĀ theĀ propagationĀ directionĀ ofĀ theĀ lightĀ fromĀ anĀ opticalĀ axisĀ ofĀ theĀ collimatorĀ 295Ā isĀ greaterĀ thanĀ aĀ thresholdĀ (e.g.,Ā 20Ā°,Ā 10Ā°,Ā 5Ā°,Ā orĀ 1Ā°)Ā .Ā AĀ portionĀ 272Ā ofĀ theĀ signalsĀ 258Ā mayĀ propagateĀ towardsĀ theĀ pixelĀ 270Ā opticallyĀ coupledĀ toĀ thatĀ locationĀ 156Ā butĀ anotherĀ portionĀ 273Ā mayĀ beĀ scatteredĀ towardsĀ neighboringĀ pixelsĀ (Ā ā€œopticalĀ cross-talkā€Ā )Ā and/orĀ awayĀ fromĀ allĀ pixelsĀ 270.Ā TheĀ collimatorĀ 295Ā mayĀ beĀ configuredĀ toĀ essentiallyĀ eliminateĀ opticalĀ cross-talkĀ byĀ essentiallyĀ preventingĀ theĀ portionĀ 273Ā fromĀ passingĀ throughĀ theĀ collimatorĀ 295.Ā GeneratingĀ theĀ signalsĀ 258Ā mayĀ needĀ anĀ excitationĀ radiationĀ 261Ā (e.g.,Ā laser,Ā UVĀ light,Ā etc.Ā )Ā .Ā AĀ portionĀ 262Ā ofĀ theĀ excitationĀ radiationĀ 261Ā mayĀ passĀ throughĀ theĀ locationsĀ 256Ā unscattered.Ā AĀ portionĀ 263Ā ofĀ theĀ excitationĀ radiationĀ 261Ā mayĀ beĀ scatteredĀ intoĀ otherĀ directionsĀ towardsĀ someĀ ofĀ theĀ pixelsĀ 270Ā orĀ awayĀ fromĀ allĀ pixelsĀ 270.Ā TheĀ portionĀ 262Ā mayĀ beĀ blockedĀ byĀ theĀ filterĀ 290Ā fromĀ reachingĀ theĀ pixelsĀ 270.Ā TheĀ filterĀ 290Ā mayĀ beĀ sensitiveĀ toĀ incidentĀ directionsĀ andĀ mayĀ notĀ blockĀ theĀ portionĀ 263,Ā despiteĀ  portions Ā 262Ā andĀ 263Ā haveĀ theĀ sameĀ wavelength.Ā TheĀ collimatorsĀ 295Ā mayĀ beĀ configuredĀ toĀ essentiallyĀ preventĀ theĀ excitationĀ radiationĀ fromĀ passingĀ throughĀ irrespectiveĀ ofĀ theĀ propagationĀ direction,Ā orĀ toĀ essentiallyĀ preventĀ theĀ portionĀ 263Ā scatteredĀ awayĀ fromĀ theĀ propagationĀ directionĀ ofĀ theĀ portionĀ 261Ā fromĀ passingĀ through.
InĀ anĀ embodiment,Ā eachĀ ofĀ theĀ collimatorsĀ 295Ā extendsĀ fromĀ oneĀ ofĀ theĀ locationsĀ 256Ā toĀ theĀ pixelĀ 270Ā opticallyĀ coupledĀ toĀ thatĀ oneĀ location.
InĀ anĀ embodiment,Ā theĀ collimatorĀ 295Ā mayĀ haveĀ aĀ coreĀ 296Ā surroundedĀ byĀ aĀ sidewallĀ 297.
InĀ anĀ embodimentĀ schematicallyĀ shownĀ inĀ Fig.Ā 7A,Ā theĀ coreĀ 296Ā mayĀ beĀ aĀ materialĀ thatĀ essentiallyĀ preventsĀ (e.g.,Ā preventsĀ moreĀ thanĀ 90ļ¼…,Ā 99ļ¼…,Ā orĀ 99.9ļ¼…of)Ā theĀ excitationĀ radiationĀ 261Ā fromĀ passingĀ throughĀ irrespectiveĀ ofĀ theĀ propagationĀ directionĀ ofĀ theĀ excitationĀ radiationĀ 261.Ā ForĀ example,Ā theĀ coreĀ 296Ā mayĀ beĀ aĀ materialĀ thatĀ attenuatesĀ (absorbs)Ā theĀ excitationĀ radiationĀ 261.Ā TheĀ coreĀ 296Ā mayĀ allowĀ theĀ signalsĀ 258Ā toĀ passĀ throughĀ essentiallyĀ unabsorbed.Ā InĀ thisĀ embodiment,Ā theĀ filterĀ 290Ā mayĀ beĀ omitted.
InĀ anĀ embodimentĀ schematicallyĀ shownĀ inĀ Fig.Ā 7B,Ā theĀ coreĀ 296Ā mayĀ haveĀ aĀ structureĀ 299Ā thatĀ essentiallyĀ preventsĀ (e.g.,Ā preventsĀ moreĀ thanĀ 90ļ¼…,Ā 99ļ¼…,Ā orĀ 99.9ļ¼…of)Ā aĀ portionĀ ofĀ theĀ excitationĀ radiationĀ 261Ā fromĀ passingĀ throughĀ ifĀ theĀ deviationĀ ofĀ theĀ propagationĀ directionĀ ofĀ theĀ portionĀ (e.g.,Ā portionĀ 272)Ā fromĀ theĀ opticalĀ axisĀ ofĀ theĀ collimatorĀ 295Ā isĀ smallerĀ thanĀ aĀ thresholdĀ (e.g.,Ā 20Ā°,Ā 10Ā°,Ā 5Ā°,Ā orĀ 1Ā°)Ā .Ā ForĀ example,Ā theĀ structureĀ 299Ā mayĀ haveĀ aĀ dichroicĀ filter,Ā aĀ meta-material,Ā quantumĀ dotsĀ orĀ aĀ photonicĀ crystal.Ā TheĀ coreĀ 296Ā mayĀ allowĀ theĀ signalsĀ 258Ā toĀ passĀ throughĀ essentiallyĀ unabsorbedĀ (i.e.,Ā lessĀ thanĀ 10ļ¼…absorbed)Ā .Ā InĀ thisĀ embodiment,Ā theĀ filterĀ 290Ā mayĀ beĀ omitted.
InĀ anĀ embodiment,Ā schematicallyĀ shownĀ inĀ Fig.Ā 7C,Ā theĀ sidewallĀ 297Ā ofĀ theĀ collimatorĀ 295Ā mayĀ attenuateĀ (absorb)Ā theĀ excitationĀ radiation.Ā TheĀ portionĀ 263Ā ofĀ theĀ excitationĀ radiationĀ 261Ā mayĀ passĀ throughĀ theĀ filterĀ 290Ā andĀ enterĀ theĀ collimatorĀ 295Ā butĀ isĀ likelyĀ toĀ reachĀ theĀ sidewallĀ 297Ā beforeĀ itĀ canĀ reachĀ theĀ pixelsĀ 270.Ā TheĀ sidewallĀ 297Ā thatĀ canĀ attenuateĀ (absorb)Ā theĀ excitationĀ radiationĀ willĀ essentiallyĀ preventĀ strayĀ excitationĀ radiationĀ fromĀ reachingĀ theĀ pixelsĀ 270.Ā InĀ anĀ embodiment,Ā theĀ coreĀ 296Ā mayĀ beĀ aĀ voidĀ space.Ā Namely,Ā theĀ sidewallĀ 297Ā surroundsĀ aĀ voidĀ space.
InĀ anĀ embodiment,Ā theĀ sidewallĀ 297Ā mayĀ attenuateĀ (absorb)Ā anyĀ portionĀ ofĀ theĀ signalĀ 258Ā reachingĀ theĀ sidewall,Ā whichĀ willĀ essentiallyĀ preventĀ opticalĀ cross-talk.
InĀ anĀ embodiment,Ā schematicallyĀ shownĀ inĀ Fig.Ā 7D,Ā theĀ sidewallĀ 297Ā isĀ textured.Ā ForĀ example,Ā theĀ interfaceĀ 298Ā betweenĀ theĀ sidewallĀ 297Ā andĀ theĀ coreĀ 296Ā (whichĀ canĀ beĀ aĀ voidĀ space)Ā mayĀ beĀ textured.Ā TexturedĀ sidewallĀ 297Ā canĀ helpĀ furtherĀ attenuateĀ lightĀ incidentĀ thereon.
InĀ anĀ embodiment,Ā schematicallyĀ shownĀ inĀ Fig.Ā 7E,Ā inĀ apparatusĀ 700,Ā theĀ filterĀ 290Ā andĀ theĀ transmissiveĀ layerĀ 291Ā mayĀ beĀ bothĀ omitted.Ā TheĀ collimatorĀ 295Ā mayĀ haveĀ aĀ topĀ surfaceĀ 294Ā exposed.Ā TheĀ topĀ surfaceĀ 294Ā mayĀ beĀ ofĀ aĀ differentĀ materialĀ fromĀ itsĀ neighboringĀ surface,Ā therebyĀ facilitatingĀ functionalizationĀ ofĀ theĀ topĀ surfaceĀ 294.Ā TheĀ probesĀ 457Ā mayĀ beĀ selectivelyĀ attachedĀ directlyĀ toĀ theĀ topĀ surfaceĀ 294.
InĀ anĀ embodiment,Ā schematicallyĀ shownĀ inĀ Fig.Ā 7FĀ andĀ Fig.Ā 7G,Ā theĀ opticalĀ systemĀ 285Ā mayĀ haveĀ aĀ pluralityĀ ofĀ collimatorsĀ 295Ā arrangedĀ inĀ anĀ array.Ā ForĀ example,Ā theĀ opticalĀ systemĀ 285Ā mayĀ haveĀ aĀ dedicatedĀ collimatorĀ 295Ā forĀ eachĀ pixelĀ 270.Ā ForĀ example,Ā theĀ opticalĀ systemĀ 285Ā mayĀ haveĀ aĀ collimatorĀ 295Ā sharedĀ byĀ aĀ groupĀ ofĀ pixelsĀ 270.Ā TheĀ collimatorĀ 295Ā mayĀ haveĀ anyĀ suitableĀ cross-sectionalĀ shape,Ā suchĀ asĀ circular,Ā rectangular,Ā andĀ polygonal.
InĀ anĀ embodiment,Ā theĀ collimatorsĀ 295Ā mayĀ beĀ madeĀ byĀ etchingĀ (byĀ e.g.,Ā deepĀ reactiveĀ ionĀ etchingĀ (deepĀ RIE)Ā ,Ā laserĀ drilling)Ā holesĀ intoĀ aĀ substrate.Ā TheĀ sidewallĀ 297Ā mayĀ beĀ madeĀ byĀ depositingĀ aĀ materialĀ onĀ theĀ sidewallĀ ofĀ theĀ holes.Ā TheĀ coreĀ 296Ā mayĀ beĀ madeĀ byĀ fillingĀ theĀ holes.Ā PlanarizationĀ mayĀ alsoĀ beĀ usedĀ inĀ theĀ fabricationĀ ofĀ theĀ collimatorsĀ 295.
InĀ anĀ embodiment,Ā theĀ filterĀ 290Ā mayĀ beĀ omittedĀ orĀ itsĀ functionĀ mayĀ beĀ integratedĀ intoĀ theĀ collimatorsĀ 295.
InĀ anĀ embodimentĀ asĀ schematicallyĀ shownĀ inĀ Fig.Ā 8,Ā inĀ apparatusĀ 800,Ā theĀ opticalĀ systemĀ 285Ā mayĀ haveĀ aĀ microfluidicĀ systemĀ 850Ā toĀ deliverĀ reactantsĀ suchĀ asĀ theĀ analyteĀ andĀ reactionĀ productĀ toĀ andĀ fromĀ theĀ locationsĀ 256.Ā TheĀ microfluidicĀ systemĀ 850Ā mayĀ haveĀ wells,Ā reservoirs,Ā channels,Ā valvesĀ orĀ otherĀ components.Ā TheĀ microfluidicĀ systemĀ 850Ā mayĀ alsoĀ haveĀ heaters,Ā coolersĀ (e.g.,Ā PeltierĀ devices)Ā ,Ā orĀ temperatureĀ sensors.Ā TheĀ heaters,Ā coolersĀ orĀ temperatureĀ sensorsĀ mayĀ beĀ locatedĀ inĀ theĀ opticalĀ systemĀ 285,Ā aboveĀ orĀ inĀ theĀ collimatorsĀ 295.Ā TheĀ heaters,Ā coolersĀ orĀ temperatureĀ sensorsĀ mayĀ beĀ locatedĀ aboveĀ orĀ inĀ theĀ sensorĀ 251.Ā TheĀ biosensorĀ apparatusĀ 800Ā mayĀ beĀ usedĀ forĀ aĀ varietyĀ ofĀ assays.Ā ForĀ example,Ā theĀ biosensorĀ apparatusĀ 800Ā canĀ beĀ usedĀ toĀ conductĀ real-timeĀ polymeraseĀ chainĀ reactionĀ (e.g.,Ā quantitativeĀ real-timeĀ PCRĀ (qPCR)Ā )Ā .Ā Real-timeĀ polymeraseĀ chainĀ reactionĀ (real-timeĀ PCR)Ā detectsĀ amplifiedĀ DNAĀ asĀ theĀ reactionĀ progresses.Ā ThisĀ isĀ inĀ contrastĀ toĀ traditionalĀ PCRĀ whereĀ theĀ productĀ ofĀ theĀ reactionĀ isĀ detectedĀ atĀ theĀ end.Ā OneĀ real-timeĀ PCRĀ techniqueĀ usesĀ sequence-specificĀ probesĀ labelledĀ withĀ aĀ fluorophoreĀ whichĀ fluorescesĀ onlyĀ afterĀ hybridizationĀ ofĀ theĀ probeĀ withĀ itsĀ complementaryĀ sequence,Ā whichĀ canĀ beĀ usedĀ toĀ quantifyĀ messengerĀ RNAĀ (mRNA)Ā andĀ non-codingĀ RNAĀ inĀ cellsĀ orĀ tissues.
TheĀ opticalĀ systemĀ 285Ā andĀ theĀ sensorĀ 251Ā mayĀ beĀ fabricatedĀ inĀ separateĀ substratesĀ andĀ bondedĀ togetherĀ usingĀ aĀ suitableĀ technique,Ā suchĀ as,Ā flip-chipĀ bonding,Ā wafer-to-waferĀ directĀ bonding,Ā orĀ gluing.
InĀ anĀ embodiment,Ā schematicallyĀ shownĀ inĀ Fig.Ā 9A,Ā inĀ apparatusĀ 900,Ā theĀ sensorĀ 251Ā hasĀ aĀ signalĀ transferĀ layerĀ 252.Ā TheĀ signalĀ transferĀ layerĀ 252Ā mayĀ haveĀ aĀ pluralityĀ ofĀ viasĀ 510.Ā TheĀ signalĀ transferĀ layerĀ 252Ā mayĀ haveĀ electricallyĀ insulationĀ materialsĀ (e.g.,Ā siliconĀ oxide)Ā aroundĀ theĀ viasĀ 510.Ā TheĀ opticalĀ systemĀ 285Ā mayĀ haveĀ aĀ redistributionĀ layerĀ 289Ā withĀ  transmissionĀ linesĀ 520Ā andĀ viasĀ 530.Ā TheĀ transmissionĀ linesĀ 520Ā connectĀ theĀ viasĀ 530Ā toĀ bondingĀ padsĀ 540.Ā WhenĀ theĀ sensorĀ 251Ā andĀ theĀ opticalĀ systemĀ 285Ā areĀ bonded,Ā theĀ viasĀ 510Ā andĀ theĀ viasĀ 530Ā areĀ electricallyĀ connected.Ā ThisĀ configurationĀ shownĀ inĀ Fig.Ā 9AĀ allowsĀ theĀ bondingĀ padsĀ 540Ā toĀ beĀ positionedĀ awayĀ fromĀ theĀ probesĀ 257.
Fig.Ā 9BĀ showsĀ aĀ topĀ viewĀ ofĀ theĀ sensorĀ 251Ā inĀ Fig.Ā 9AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ viasĀ 510Ā relativeĀ toĀ theĀ pixelsĀ 270Ā andĀ theĀ controlĀ circuitĀ 271.Ā TheĀ pixelsĀ 270Ā andĀ theĀ controlĀ circuitĀ 271Ā areĀ shownĀ inĀ dottedĀ linesĀ becauseĀ theyĀ areĀ notĀ directlyĀ visibleĀ inĀ thisĀ view.Ā Fig.Ā 9CĀ showsĀ aĀ bottomĀ viewĀ ofĀ theĀ opticalĀ systemĀ 285Ā inĀ Fig.Ā 9AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ viasĀ 530Ā relativeĀ toĀ theĀ transmissionĀ linesĀ 520Ā (shownĀ asĀ dottedĀ linesĀ becauseĀ theyĀ areĀ notĀ directlyĀ visibleĀ inĀ thisĀ view)Ā .
InĀ anĀ embodiment,Ā schematicallyĀ shownĀ inĀ Fig.Ā 10A,Ā inĀ apparatusĀ 1000,Ā theĀ sensorĀ 251Ā hasĀ aĀ redistributionĀ layerĀ 629.Ā TheĀ redistributionĀ layerĀ 629Ā mayĀ haveĀ aĀ pluralityĀ ofĀ viasĀ 610Ā andĀ aĀ pluralityĀ ofĀ transmissionĀ linesĀ 620.Ā TheĀ redistributionĀ layerĀ 629Ā mayĀ haveĀ electricallyĀ insulationĀ materialsĀ (e.g.,Ā siliconĀ oxide)Ā aroundĀ theĀ viasĀ 610Ā andĀ theĀ transmissionĀ linesĀ 620.Ā TheĀ viasĀ 610Ā electricallyĀ connectĀ theĀ controlĀ circuitĀ 271Ā toĀ theĀ transmissionĀ linesĀ 620.Ā TheĀ opticalĀ systemĀ 285Ā mayĀ haveĀ aĀ layerĀ 619Ā withĀ bondingĀ padsĀ 640.Ā TheĀ redistributionĀ layerĀ 629Ā mayĀ alsoĀ haveĀ viasĀ 630Ā electricallyĀ connectingĀ theĀ transmissionĀ linesĀ 620Ā toĀ theĀ bondingĀ padsĀ 640,Ā whenĀ theĀ sensorĀ 251Ā andĀ theĀ opticalĀ systemĀ 285Ā areĀ bonded.Ā TheĀ bondingĀ padsĀ 640Ā mayĀ haveĀ twoĀ partsĀ connectedĀ byĀ aĀ wireĀ buriedĀ inĀ theĀ layerĀ 619.Ā ThisĀ configurationĀ shownĀ inĀ Fig.Ā 10AĀ allowsĀ theĀ bondingĀ padsĀ 640Ā toĀ beĀ positionedĀ onĀ anĀ oppositeĀ sideĀ fromĀ theĀ probeĀ carrier.
Fig.Ā 10BĀ showsĀ aĀ topĀ viewĀ ofĀ theĀ sensorĀ 251Ā inĀ Fig.Ā 10AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ viasĀ 610,Ā theĀ viasĀ 630Ā andĀ theĀ transmissionĀ linesĀ 620,Ā relativeĀ toĀ theĀ pixelsĀ 270Ā andĀ theĀ controlĀ circuitĀ 271,Ā accordingĀ toĀ anĀ embodiment.Ā TheĀ pixelsĀ 270,Ā theĀ controlĀ circuitĀ 271Ā andĀ theĀ transmissionĀ linesĀ 620Ā areĀ shownĀ inĀ dottedĀ linesĀ becauseĀ theyĀ areĀ notĀ directlyĀ visibleĀ inĀ thisĀ view.Ā Fig.Ā 10CĀ showsĀ aĀ bottomĀ viewĀ ofĀ theĀ opticalĀ systemĀ 285Ā inĀ Fig.Ā 10AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ bondingĀ padsĀ 640,Ā whichĀ areĀ positionedĀ toĀ connectĀ toĀ theĀ viasĀ 630Ā shownĀ inĀ Fig.Ā 10B.Ā TheĀ bondingĀ padsĀ 640Ā mayĀ haveĀ twoĀ partsĀ connectedĀ byĀ aĀ wireĀ buriedĀ inĀ theĀ layerĀ 619.
Fig.Ā 10DĀ showsĀ aĀ topĀ viewĀ ofĀ theĀ sensorĀ 251Ā inĀ Fig.Ā 10AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ viasĀ 610,Ā theĀ viasĀ 630Ā andĀ theĀ transmissionĀ linesĀ 620,Ā relativeĀ toĀ theĀ pixelsĀ 270Ā andĀ theĀ controlĀ circuitĀ 271,Ā accordingĀ toĀ anĀ embodiment.Ā TheĀ pixelsĀ 270,Ā theĀ controlĀ circuitĀ 271Ā andĀ theĀ transmissionĀ linesĀ 620Ā areĀ shownĀ inĀ dottedĀ linesĀ becauseĀ theyĀ areĀ notĀ directlyĀ visibleĀ inĀ thisĀ view.Ā TheĀ pixelsĀ 270Ā mayĀ beĀ readĀ outĀ columnĀ byĀ column.Ā ForĀ example,Ā signalĀ fromĀ oneĀ 270Ā mayĀ beĀ storedĀ inĀ registerĀ inĀ theĀ controlĀ circuitĀ 271Ā associatedĀ withĀ thatĀ pixelĀ 270ļ¼›Ā theĀ signalĀ mayĀ beĀ successivelyĀ shiftedĀ fromĀ oneĀ columnĀ toĀ theĀ next,Ā andĀ eventuallyĀ toĀ otherĀ processingĀ circuitryĀ throughĀ viasĀ 630.Ā Fig.Ā 10EĀ showsĀ aĀ bottomĀ viewĀ ofĀ theĀ opticalĀ systemĀ 285Ā inĀ Fig.Ā 10AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ bondingĀ padsĀ 640,Ā whichĀ areĀ positionedĀ toĀ connectĀ toĀ theĀ viasĀ 630Ā shownĀ inĀ Fig.Ā 10D.Ā TheĀ bondingĀ padsĀ 640Ā mayĀ haveĀ twoĀ partsĀ connectedĀ byĀ aĀ wireĀ buriedĀ inĀ theĀ layerĀ 619.
Fig.Ā 10FĀ showsĀ aĀ topĀ viewĀ ofĀ theĀ sensorĀ 251Ā inĀ Fig.Ā 10AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ viasĀ 610,Ā theĀ viaĀ 630Ā andĀ theĀ transmissionĀ linesĀ 620,Ā relativeĀ toĀ theĀ pixelsĀ 270Ā andĀ theĀ controlĀ circuitĀ 271,Ā accordingĀ toĀ anĀ embodiment.Ā TheĀ pixelsĀ 270,Ā theĀ controlĀ circuitĀ 271Ā andĀ theĀ transmissionĀ linesĀ 620Ā areĀ shownĀ inĀ dottedĀ linesĀ becauseĀ theyĀ areĀ notĀ directlyĀ visibleĀ inĀ thisĀ  view.Ā TheĀ pixelsĀ 270Ā mayĀ beĀ readĀ outĀ pixelĀ byĀ pixel.Ā ForĀ example,Ā signalĀ fromĀ oneĀ 270Ā mayĀ beĀ storedĀ inĀ registerĀ inĀ theĀ controlĀ circuitĀ 271Ā associatedĀ withĀ thatĀ pixelĀ 270ļ¼›Ā theĀ signalĀ mayĀ beĀ successivelyĀ shiftedĀ fromĀ oneĀ pixelĀ toĀ theĀ next,Ā andĀ eventuallyĀ toĀ otherĀ processingĀ circuitryĀ throughĀ viaĀ 630.Ā Fig.Ā 10GĀ showsĀ aĀ bottomĀ viewĀ ofĀ theĀ opticalĀ systemĀ 285Ā inĀ Fig.Ā 10AĀ toĀ illustrateĀ theĀ positionsĀ ofĀ theĀ bondingĀ padĀ 640,Ā whichĀ areĀ positionedĀ toĀ connectĀ toĀ theĀ viaĀ 630Ā shownĀ inĀ Fig.Ā 10F.Ā TheĀ bondingĀ padsĀ 640Ā mayĀ haveĀ twoĀ partsĀ connectedĀ byĀ aĀ wireĀ buriedĀ inĀ theĀ layerĀ 619.
InĀ anĀ embodiment,Ā schematicallyĀ shownĀ inĀ Fig.Ā 11,Ā inĀ apparatusĀ 1100,Ā theĀ sensorĀ 251Ā hasĀ aĀ redistributionĀ layerĀ 729.Ā TheĀ redistributionĀ layerĀ 729Ā mayĀ haveĀ aĀ pluralityĀ ofĀ viasĀ 710Ā andĀ aĀ pluralityĀ ofĀ transmissionĀ linesĀ 720.Ā TheĀ redistributionĀ layerĀ 729Ā mayĀ haveĀ electricallyĀ insulationĀ materialsĀ (e.g.,Ā siliconĀ oxide)Ā aroundĀ theĀ viasĀ 710Ā andĀ theĀ transmissionĀ linesĀ 720.Ā TheĀ viasĀ 710Ā electricallyĀ connectĀ theĀ controlĀ circuitĀ 271Ā toĀ theĀ transmissionĀ linesĀ 720.Ā TheĀ redistributionĀ layerĀ 729Ā mayĀ alsoĀ haveĀ viasĀ 730Ā (e.g.,Ā through-siliconĀ viasĀ (TSV)Ā )Ā electricallyĀ connectingĀ theĀ transmissionĀ linesĀ 720Ā toĀ bondingĀ padsĀ 740Ā onĀ theĀ sideĀ oppositeĀ fromĀ theĀ redistributionĀ layerĀ 729.Ā ThisĀ configurationĀ shownĀ inĀ Fig.Ā 11Ā allowsĀ theĀ bondingĀ padsĀ 740Ā toĀ beĀ positionedĀ onĀ anĀ oppositeĀ sideĀ fromĀ theĀ probeĀ carrier.
WhileĀ variousĀ aspectsĀ andĀ embodimentsĀ haveĀ beenĀ disclosedĀ herein,Ā otherĀ aspectsĀ andĀ embodimentsĀ willĀ beĀ apparentĀ toĀ thoseĀ skilledĀ inĀ theĀ art.Ā TheĀ variousĀ aspectsĀ andĀ embodimentsĀ disclosedĀ hereinĀ areĀ forĀ purposesĀ ofĀ illustrationĀ andĀ areĀ notĀ intendedĀ toĀ beĀ limiting,Ā withĀ theĀ trueĀ scopeĀ andĀ spiritĀ beingĀ indicatedĀ byĀ theĀ followingĀ claims.

Claims (30)

  1. AnĀ apparatusĀ comprising:
    aĀ probeĀ carrierĀ comprising:
    aĀ substrateĀ comprisingĀ aĀ pluralityĀ ofĀ holesĀ throughĀ aĀ thicknessĀ ofĀ theĀ substrate,
    aĀ transparentĀ windowĀ acrossĀ anĀ openingĀ ofĀ eachĀ ofĀ theĀ holes,Ā whereinĀ theĀ transparentĀ windowĀ closesĀ theĀ opening,
    whereinĀ oneĀ orĀ moreĀ locationsĀ onĀ theĀ transparentĀ windowĀ areĀ configuredĀ toĀ haveĀ probesĀ attachedĀ thereto,Ā whereinĀ interactionĀ betweenĀ theĀ probesĀ andĀ anĀ analyteĀ generatesĀ aĀ signalļ¼›
    anĀ opticalĀ systemĀ comprisingĀ aĀ pluralityĀ ofĀ collimatorsļ¼›
    aĀ sensorĀ comprisingĀ aĀ pluralityĀ ofĀ pixelsĀ configuredĀ toĀ detectĀ theĀ signalļ¼›
    whereinĀ theĀ collimatorsĀ areĀ configuredĀ toĀ essentiallyĀ preventĀ lightĀ fromĀ passingĀ ifĀ aĀ deviationĀ ofĀ aĀ propagationĀ directionĀ ofĀ theĀ lightĀ fromĀ anĀ opticalĀ axisĀ ofĀ theĀ collimatorsĀ isĀ greaterĀ thanĀ aĀ threshold.
  2. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ substrateĀ comprisesĀ silicon.
  3. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ probesĀ andĀ theĀ substrateĀ areĀ onĀ aĀ sameĀ sideĀ ofĀ theĀ probeĀ carrier.
  4. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ probesĀ andĀ theĀ substrateĀ areĀ onĀ oppositeĀ sidesĀ ofĀ theĀ probeĀ carrier.
  5. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ transparentĀ windowĀ isĀ alignedĀ withĀ oneĀ ofĀ theĀ collimators.
  6. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ transparentĀ windowĀ encompassesĀ moreĀ thanĀ oneĀ ofĀ theĀ collimators.
  7. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ transparentĀ windowĀ isĀ aĀ portionĀ ofĀ aĀ continuousĀ transparentĀ layerĀ acrossĀ theĀ substrate.
  8. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ transparentĀ windowĀ hasĀ aĀ thicknessĀ fromĀ 10Ā toĀ 50Ā micrometers.
  9. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ sidewallĀ ofĀ theĀ holeĀ isĀ notĀ perpendicularĀ toĀ theĀ transparentĀ window.
  10. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ sensorĀ comprisesĀ aĀ controlĀ circuitĀ configuredĀ toĀ control,Ā acquireĀ dataĀ from,Ā orĀ processĀ dataĀ fromĀ theĀ pixels.
  11. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ pixelsĀ areĀ arrangedĀ suchĀ thatĀ eachĀ ofĀ theĀ pixelsĀ isĀ opticallyĀ coupledĀ toĀ oneĀ orĀ moreĀ ofĀ theĀ locations.
  12. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ pixelsĀ areĀ opticallyĀ coupledĀ toĀ theĀ locationsĀ byĀ theĀ collimators.
  13. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ signalĀ isĀ luminescence.
  14. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ signalĀ isĀ generatedĀ underĀ excitationĀ ofĀ anĀ excitationĀ radiation.
  15. TheĀ apparatusĀ ofĀ claimĀ 14,Ā whereinĀ theĀ opticalĀ systemĀ furtherĀ comprisesĀ aĀ filter,Ā whereinĀ theĀ filterĀ isĀ configuredĀ toĀ blockĀ atĀ leastĀ aĀ portionĀ ofĀ theĀ excitationĀ radiation.
  16. TheĀ apparatusĀ ofĀ claimĀ 15,Ā whereinĀ theĀ filterĀ isĀ aĀ dichroicĀ filter.
  17. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ opticalĀ systemĀ furtherĀ comprisesĀ orĀ aĀ transmissiveĀ layer.
  18. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ opticalĀ systemĀ furtherĀ comprisesĀ aĀ pluralityĀ ofĀ microlens.
  19. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ collimatorsĀ compriseĀ aĀ meta-material,Ā quantumĀ dotsĀ orĀ aĀ photonicĀ crystal.
  20. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ collimatorsĀ areĀ configuredĀ toĀ eliminateĀ opticalĀ cross-talkĀ betweenĀ neighboringĀ pixelsĀ amongĀ theĀ pluralityĀ ofĀ pixels.
  21. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ atĀ leastĀ oneĀ ofĀ theĀ collimatorsĀ comprisesĀ aĀ coreĀ andĀ aĀ sidewallĀ surroundingĀ theĀ core.
  22. TheĀ apparatusĀ ofĀ claimĀ 21,Ā whereinĀ theĀ signalĀ isĀ generatedĀ underĀ excitationĀ ofĀ anĀ excitationĀ radiationļ¼›Ā whereinĀ theĀ coreĀ isĀ aĀ materialĀ thatĀ essentiallyĀ preventsĀ theĀ excitationĀ radiationĀ fromĀ passingĀ throughĀ irrespectiveĀ ofĀ propagationĀ directionĀ ofĀ theĀ excitationĀ radiation.
  23. TheĀ apparatusĀ ofĀ claimĀ 21,Ā whereinĀ theĀ signalĀ isĀ generatedĀ underĀ excitationĀ ofĀ anĀ excitationĀ radiationļ¼›Ā whereinĀ theĀ coreĀ comprisesĀ aĀ dichroicĀ filter.
  24. TheĀ apparatusĀ ofĀ claimĀ 21,Ā whereinĀ theĀ coreĀ allowsĀ theĀ signalĀ toĀ passĀ throughĀ essentiallyĀ unabsorbed.
  25. TheĀ apparatusĀ ofĀ claimĀ 21,Ā whereinĀ theĀ coreĀ isĀ aĀ voidĀ space.
  26. TheĀ apparatusĀ ofĀ claimĀ 21,Ā whereinĀ theĀ sidewallĀ attenuatesĀ aĀ portionĀ ofĀ theĀ signalĀ reachingĀ theĀ sidewall.
  27. TheĀ apparatusĀ ofĀ claimĀ 21,Ā whereinĀ theĀ sidewallĀ isĀ textured.
  28. TheĀ apparatusĀ ofĀ claim15,Ā whereinĀ theĀ filterĀ comprisesĀ aĀ meta-material,Ā quantumĀ dotsĀ orĀ aĀ photonicĀ crystal.
  29. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ pixelsĀ areĀ arrangedĀ inĀ anĀ arrayĀ andĀ areĀ configuredĀ toĀ beĀ readĀ outĀ columnĀ byĀ column.
  30. TheĀ apparatusĀ ofĀ claimĀ 1,Ā whereinĀ theĀ pixelsĀ areĀ arrangedĀ inĀ anĀ arrayĀ andĀ areĀ configuredĀ toĀ beĀ readĀ outĀ pixelĀ byĀ pixel.
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US15/309,303 US10670527B2 (en) 2015-09-14 2015-09-14 Biosensor
CN201580083141.7A CN108449970A (en) 2015-09-14 2015-09-14 Biosensor
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CN108449970A (en) 2018-08-24
US20180180547A1 (en) 2018-06-28
EP3371575A1 (en) 2018-09-12
TWI704902B (en) 2020-09-21
TW201729754A (en) 2017-09-01
US20200249167A1 (en) 2020-08-06
US10670527B2 (en) 2020-06-02

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