Apparatus and method for detecting and identifying infectious agents
First Claim
Patent Images
1. A microelectronic device, comprising:
- a substrate;
a plurality of micro-locations defined on the substrate, wherein each micro-location is for linking a macromolecule;
an independent photodetector integrated at each micro-location and optically coupled to each micro-location, each photodetector being configured to generate a sensed signal responsive to the photons of light emitted at the corresponding micro-location when a light-emitting chemical reaction occurs at that micro-location, each photodetector being independent from the photodetectors optically coupled to the other micro-locations; and
an electronic circuit coupled to each photodetector and configured to read the sensed signal generated by each photodetector and to generate output data signals therefrom that are indicative of the light emitted at each micro-location by the light-emitting chemical reactions, whereby the device detects photons of light emitted by light-emitting chemical reactions, wherein each micro-location is defined by a portion of the surface of the device.
1 Assignment
0 Petitions
Accused Products
Abstract
Solid phase methods for the identification of an analyte in a biological medium, such as a body fluid, using bioluminescence are provided. A chip designed for performing the method and detecting the bioluminescence is also provided. Methods employing biomineralization for depositing silicon on a matrix support are also provided. A synthetic synapse is also provided.
-
Citations
66 Claims
-
1. A microelectronic device, comprising:
-
a substrate;
a plurality of micro-locations defined on the substrate, wherein each micro-location is for linking a macromolecule;
an independent photodetector integrated at each micro-location and optically coupled to each micro-location, each photodetector being configured to generate a sensed signal responsive to the photons of light emitted at the corresponding micro-location when a light-emitting chemical reaction occurs at that micro-location, each photodetector being independent from the photodetectors optically coupled to the other micro-locations; and
an electronic circuit coupled to each photodetector and configured to read the sensed signal generated by each photodetector and to generate output data signals therefrom that are indicative of the light emitted at each micro-location by the light-emitting chemical reactions, whereby the device detects photons of light emitted by light-emitting chemical reactions, wherein each micro-location is defined by a portion of the surface of the device. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61)
the substrate is a semiconductor substrate, comprising a surface that is adapted for linking macromolecules;
each micro-location is defined by a portion of the surface that is adapted to allow a separate chemical reactant at that micro-location to be coupled thereto.
-
-
11. The device of claim 10, wherein the surface is coated with an inert material that is derivatized for linking macromolecules.
-
12. The microelectronic device of claim 1, wherein the electronic circuit includes a pixel unit cell circuit associated with each photodiode and a delta-sigma A/D conversion circuit, each pixel unit cell circuit being configured to integrate the sensed signal from the respective photodiode and the A/D conversion circuit being configured to quantize the integrated sensed signals.
-
13. The microelectronic device of claim 12, wherein each pixel unit cell circuit is addressable and the electronic circuit further includes an address control circuit for sequentially addressing each pixel unit cell circuit, and wherein the A/D conversion circuit quantizes the integrated sensed signal of the pixel unit cell circuit being addressed by the address control circuit.
-
14. The microelectronic device of claim 13, wherein each photodiode converts photons of light emitted by the chemical reaction into a photocurrent comprising a magnitude depending on the number of photons, and each pixel unit cell circuit includes a capacitance circuit comprising a charge that changes at a rate dependent on the magnitude of the photocurrent, whereby the sensed signal is integrated by the capacitance circuit.
-
15. The microelectronic device of claim 14, wherein each pixel unit cell circuit generates an output current that depends on the charge of the capacitance circuit when the pixel unit cell circuit is addressed, the electronic circuit also including a comparator circuit for comparing the output current of the addressed pixel unit cell circuit to a reference current to generate a feedback signal used to reset the capacitance circuit to an initial charge when the output current transitions with respect to the reference current.
-
16. The microelectronic device of claim 15, wherein the electronic circuit further includes an output control circuit that receives the feedback signal from each addressed pixel unit cell circuit, and generates the output data signals as a serial output data stream based upon the feedback signals, the rate of feedback signal transitions correlated with each micro-location being indicative of the emitted light at that micro-location.
-
17. The device of claim 1, further comprising a layer of reflective material on all or a portion of the surface of the device or above the surface of the device, whereby light generated in the reaction is reflected thereby enhancing the light signal detected by the photodetector.
-
18. The device of claim 17, therein the material is oriented polyethylene terephthalate.
-
19. The microelectronic device of claim 1, wherein:
-
the micro-locations defined on the substrate are for receiving a fluid sample for analysis, each micro-location comprising an attachment layer to which macromolecules are linked;
a macromolecule is linked to each of a plurality of the micro-locations via the attachment layer;
a linked macromolecule selectively binds to analyte present in the sample received by the device; and
each photodetector is configured to generate a sensed signal responsive to photons of light emitted at the corresponding micro-location when the selected analyte bound at that micro-location is exposed to a second macromolecule that binds to the first macromolecule or analyte linked to one or more components of a light-emitting reaction in the presence of the remaining components of the light-emitting reaction.
-
-
20. The device of claim 19, wherein each macromolecule is an antibody and the analyte is an antigen.
-
21. The device of claim 19, wherein the micro-locations defined on the substrate for receiving the fluid sample to be analyzed form wells in the surface of the device.
-
22. The device of claim 21, wherein one or a plurality of the wells comprise a reflective material disposed along the sides thereof or suspended across the well, whereby light is reflected to the photodetector.
-
23. The device of claim 19, comprising a layer of reflective material on all or a portion of micro-locations defined on the substrate that are for receiving a fluid sample.
-
24. The device of claim 23, wherein the reflective material is oriented polyethylene terephthalate.
-
25. The device of claim 19, wherein the light-emitting reaction is luminescence.
-
26. The device of claim 25, wherein the luminescence is bioluminescence.
-
27. The device of claim 19, further comprising at least one component of a bioluminescence generating system in each micro-location that comprises a macromolecule.
-
28. The device of claim 1, wherein the photodetector optically coupled to each micro-location is configured to generate a sensed signal responsive to bioluminescence emitted at the corresponding micro-location.
-
29. The device of claim 19, wherein the photodetector optically coupled to each micro-location is configured to generate a sensed signal responsive to bioluminescence emitted at the corresponding micro-location.
-
30. The device of claim 26, wherein the bioluminescence is produced by a bioluminescence generating system that comprises a luciferase or luciferin.
-
31. The device of claim 30, wherein the luciferase is a photoprotein.
-
32. The device of claim 26, wherein the bioluminescence is produced by a bioluminescence generating system that is selected from the group consisting of the Aequorea, Vargula, Renilla, Obelin, Porichthys, Odontosyllis, Aristostomias, Pachystomias, firefly, and bacterial bioluminescence generating systems.
-
33. The microelectronic device of claim 19, wherein the device comprises a plurality of different macromolecules each specific for a different analyte, each different macromolecule present at a different micro-location.
-
34. The microelectronic device of claim 19, wherein:
-
the micro-locations are in the form of an array;
the array of micro-locations includes a first and a second array of pixel elements comprising a first and a second size, respectively, the first and second sizes being different.
-
-
35. The microelectronic device of claim 34, wherein the macromolecule attached to the attachment layer of the first pixel element array is a receptor antibody that specifically binds a first selected analyte and the macromolecule attached to the attachment layer of the second pixel element array is a receptor antibody that specifically binds a second selected analyte different from the first selected analyte.
-
36. The microelectronic device of claim 19, wherein the substrate is semiconductor and each micro-location is located on a surface of the semiconductor substrate, with the surface at each micro-location defining the attachment layer for that micro-location.
-
37. The microelectronic device of claim 36, wherein:
-
the surface of the semiconductor substrate is derivatized to enhance the attachment of the macromolecule to the attachment layer at each micro-location; and
said macromolecule is a receptor antibody.
-
-
38. The microelectronic device of claim 37, wherein each photodetector includes a photodiode located at the surface of the respective micro-location, and the reaction produces photons of light converted by the photodiode into a photocurrent when the selected analyte is present in the sample, the photocurrent being the sensed signal generated by the photodiode.
-
39. The microelectronic device of claim 38, wherein the electronic circuit includes a pixel unit cell circuit associated with each photodiode and a delta-sigma A/D conversion circuit, each pixel unit cell circuit being configured to integrate the sensed signal from the respective photodiode and the A/D conversion circuit being configured to quantize the integrated sensed signals.
-
40. The microelectronic device of claim 39, wherein each pixel unit cell is addressable and the electronic circuit further includes an address control circuit for sequentially addressing each pixel unit cell, and wherein the A/D conversion circuit quantizes the integrated sensed signal of the pixel unit cell circuit being addressed by the address control circuit.
-
41. The microelectronic device of claim 38, wherein:
-
photons of light are generated by a bioluminescence generating system that comprises a luciferase and a luciferin;
each photodiode converts photons of light emitted by the bioluminescence generating system into a photocurrent comprising a magnitude that depends on the concentration of the selected analyte in the sample, and each pixel unit cell circuit includes a capacitance circuit comprising a charge that changes at a rate dependent on the magnitude of the photocurrent, whereby the sensed signal is integrated.
-
-
42. The microelectronic device of claim 41, wherein each pixel unit cell circuit generates an output current that depends on the charge of the capacitance circuit when the pixel unit cell circuit is addressed, the electronic circuit also including a comparator circuit for comparing the output current of the addressed pixel unit cell circuit to a reference current to generate a feedback signal used to reset the capacitance circuit to an initial charge when the output current transitions with respect to the reference current.
-
43. The microelectronic circuit of claim 42, wherein the electronic circuit further includes an output control circuit that receives the feedback signal from each addressed pixel unit cell circuit, and generates the output data signals as a serial output data stream based upon the feedback signals, the rate of feedback signal transitions correlated with each micro-location being indicative of the bioluminescence emitted at that micro-location.
-
44. A system for detecting and identifying an analytes in a biological sample using luciferase-luciferin bioluminescence, comprising:
-
the microelectronic device of claim 1 wherein light emitted at the corresponding micro-location is bioluminescence;
a processing instrument including;
an input interface circuit coupled to the microelectronic device for receiving the output data signals indicative of the bioluminescence emitted at each micro-location;
a memory circuit for storing a data acquisition array comprising a location associated with each micro-location;
an output device for generating visible indicia in response to an output device signal; and
a processing circuit coupled to the input interface circuit, the memory circuit, and the output device, the processing circuit being configured to read the output data signals received by the input interface circuit, to correlate the output data signals with the corresponding micro-locations, to integrate the output data signals correlated with each micro-location for a desired time period by accumulating the output data signals in the data acquisition array, and to generate the output device signal which, when applied to the output device, causes the output device to generate visible indicia related to the presence of the selected analytes in the sample.
-
-
45. The system of claim 44, wherein the microelectronic device comprises:
-
an array of micro-locations for receiving the biological sample to be analyzed, each micro-location comprising an attachment layer;
a separate antibody attached to the attachment layer of each micro-location, each antibody specific for binding a selected analyte present in the sample received by the array;
a photodetector optically coupled to each micro-location, each photodetector being configured to generate a sensed signal responsive to bio-luminescence emitted at the corresponding micro-location; and
an electronic circuit coupled to each photodetector and configured to read the sensed signal generated by each photodetector and generate output data signals therefrom that are indicative of the bioluminescence emitted at each micro-location by the luciferase-luciferin reaction.
-
-
46. The system of claim 45, wherein;
-
each micro-location is located on a surface of a semiconductor substrate and each photodetector includes a photodiode located on the surface at the respective micro-location;
the bioluminescence generating reaction producing photons of light that are converted by the photodiode into a photocurrent when the selected analyte is present; and
the photocurrent is a sensed signal generated by the photodiode.
-
-
47. The system of claim 45, wherein the electronic circuit of the microelectronic device includes an output control circuit that generates a serial data stream comprising the output data signals, and the input interface circuit of the processing instrument includes a serial interface circuit configured to receive the serial data stream from the microelectronic device.
-
48. The system of claim 47, wherein the serial data stream includes multiplexed data representative of the bioluminescence emitted at each micro-location by the luciferase-luciferin reaction.
-
49. The system of claim 45, wherein the output device includes an electronic display, and the visible indicia includes light emitted by the display.
-
50. The system of claim 45, wherein the memory circuit also stores an analyte map identifying the selected analyte at each micro-location, and the processing circuit correlates the integrated output data signals in the data acquisition array with the analyte map to identify the selected analytes present in the sample, the output device signal being generated such that the visible indicia identifies the selected analytes present in the sample.
-
51. The system of claim 45, wherein the processing instrument further comprises an input device coupled to the processing circuit for generating desired integration time period signals used by the processing circuit to determine the desired integration time period for the output data signals.
-
52. The system of claims 45, wherein the boluminescence generating system is selected from the group consisting of those isolated from the ctenophores, coelenterases, molluscan fish, ostracods, insects, bacteria, crustacea, annelids and earthworms.
-
53. The system of claim 45, wherein the component of the bioluminescence generating system linked to the macromolecule is selected from the group consisting of Aequorea, Vargula, Renilla, Obelin, Porichthys, Odontosyllis, Aristostomias, Pachystomias, firefly, and bacterial bioluminescence generating systems.
-
54. The system of claim 45, herein the antibody attached to the attachment layer at a first micro-location is specific for binding a first selected analyte and the antibody attached to the attachment layer at a second micro-location is specific for binding a second selected analyte different from the first selected analyte.
-
55. The device of claim 6, wherein a component of the bioluminescence generating system is selected from the group consisting of bacterial, mushroom, dinoflagellate, coelenterate, ctenophore, annelid, crustacea, ostracod, copepods, insect, oleopterid, diptera, echinoderm, chordate ticate and fish bioluminescence generating systems.
-
56. The device of claim 6, wherein a component of the bioluminescence generating system is selected from the group consisting of brittle star, sea cucumber, cartilaginous, bony fish, ponyfish, flashlight fish, angler fish, midshipman fish, midwater fish, marine polychaetes, syllid fireworm, jellyfish, hydroid, sea pansy, earthworm, mollusc, limpet, deep-sea fish, clam, firefly, click beetle, railroad worms and squid bioluminescence generating systems.
-
57. The device of claim 6, wherein a component of the bioluminescence generating system is selected from the group consisting of Aequorea, Vargula, Renilla, Obelin, Porichthys, Odontosyllis, Aristostomias, Pachystomias, Gonadostomias, Gaussia, Halisturia, Vampire squid, Glyphus, Mycotophids, Vinciguerria, Howella, Florenciella, Chaudiodus, Melanocostus, Paracanthus, Atolla, Pelagia, Pitilocarpus, Acanthophyra, Siphonophore, Periphylla, Cavarnularia, Ptilosarcus, Stylatula, Acanthoptilum, Parazoanthus and Sea Pens, Chiroteuthis, Eucleoteuthis, Onychoteuthis, Watasenia, cuttlefish, and Sepiolina.
-
58. The device of claim 6, wherein the bioluminescence generating system is selected from the group consisting of the Gonadostomias, Gaussia, Halisturia, Vampire squid, Glyphus, Mycotophids (fish), Vinciguerria, Howella, Florenciella, Chaudiodus, Melanocostus, Paracanthus, Atolla, Pelagia, Pitilosarcus, Acanthophyra, Siphonophore, Periphylla and Sea Pens (Stylata) bioluminescence generating systems.
-
59. The device of claim 6, wherein the bioluminescence generating system is selected from the group consisting of a marine, terrestrial or bacterial bioluminescence generating systems.
-
60. The device of claim 6, wherein the bioluminescence generating system is selected from the group consisting of fungal, algal, dinoflagellate, arthropod, mollusk, echinoderm, chordate and annelid bioluminescence generating systems.
-
61. The device of claim 1, further comprising a layer of reflective material on all or a portion of micro-locations defined on the substrate.
-
62. A microelectronic device, comprising:
-
a substrate;
a plurality of micro-locations defined on the substrate, wherein each micro-location is for linking a macromolecule and is defined by a portion of the surface of the device;
an independent photodetector integrated at each micro-location and optically coupled to each micro-location, each photodetector being configured to generate a sensed signal responsive to the photons of light emitted at the corresponding micro-location when a light-emnitting chemical reaction occurs at that micro-location, each photodetector being independent from the photodetectors optically coupled to the other micro-locations; and
an electronic circuit coupled to each photodetector and configured to read the sensed signal generated by each photodetector and to generate output data signals therefrom that are indicative of the light emitted at each micro-location by the light-emitting chemical reactions, whereby the device detects photons of light emitted by light-emnitting chemical reactions, wherein the electronic circuit includes a pixel unit cell circuit associated with each photodiode and a delta-sigma A/D conversion circuit, each pixel unit cell circuit being configured to integrate the sensed signal from the respective photodiode and the A/D conversion circuit being configured to quantize the integrated sensed signals.
-
-
63. A microelectronic device, comprising:
-
a substrate;
a plurality of micro-locations defined on the substrate, wherein each micro-location is for linking a macromolecule and is defined by a portion of the surface of the device;
an independent photodetector integrated at each micro-location and optically coupled to each micro-location, each photodetector being configured to generate a sensed signal responsive to the photons of light emitted at the corresponding micro-location when a light-emitting chemical reaction occurs at that micro-location, each photodetector being independent from the photodetectors optically coupled to the other micro-locations;
a layer of polyethylene terephthalate reflective material on all or a portion on the surface of the device or above the surface of the device, whereby light generated in the reaction is reflected thereby enhancing the light signal detected by the photodetector; and
an electronic circuit coupled to each photodetector and configured to read the sensed signal generated by each photodetector and to generate output data signals therefrom that are indicative of the light emitted at each micro-location by the light-emitting chemical reactions, whereby the device detects photons of light emitted by light-emitting chemical reactions.
-
-
64. A microelectronic device, comprising:
-
a substrate;
a plurality of micro-locations defined on the substrate, wherein each micro-location is for linking a macromolecule and is defined by a portion of the surface of the device;
an independent photodetector integrated at each micro-location and optically coupled to each micro-location, each photodetector being configured to generate a sensed signal responsive to the photons of light emitted at the corresponding micro-location when a light-emitting chemical reaction occurs at that micro-location, each photodetector being independent from the photodetectors optically coupled to the other micro-locations, wherein the photodetector optically coupled to each micro-location is configured to generate a sensed signal responsive to bioluminescence emitted at the corresponding micro-location; and
an electronic circuit coupled to each photodetector and configured to read the sensed signal generated by each photodetector and to generate output data signals therefrom that are indicative of the light emitted at each micro-location by the light-emitting chemical reactions, whereby the device detects photons of light emitted by light-emitting chemical reactions.
-
-
65. A microelectronic device, comprising:
-
a substrate;
a plurality of micro-locations defined on the substrate, wherein each micro-location is for linking a macromolecule and the micro-locations are in the form of an array, the array of micro-locations including a first and a second array of pixel elements comprising a first size and a second size, respectively, the first and second sizes being different;
an independent photodetector integrated at each micro-location and optically coupled to each micro-location, each photodetector being configured to generate a sensed signal responsive to the photons of light emitted at the corresponding micro-location when a light-emitting chemical reaction occurs at that micro-location, each photodetector being independent from the photodetectors optically coupled to the other micro-locations; and
an electronic circuit coupled to each photodetector and configured to read the sensed signal generated by each photodetector and to generate output data signals therefrom that are indicative of the light emitted at each micro-location by the light-emitting chemical reactions, whereby the device detects photons of light emitted by light-emitting chemical reactions, wherein;
the micro-locations defined on the substrate are for receiving a fluid sample for analysis, each micro-location comprising an attachment layer to which macromolecules are linked;
a macromolecule is linked to each of a plurality of the micro-locations via the attachment layer;
a linked macromolecule selectively binds to analyte present in the sample received by the device; and
each photodetector is configured to generate a sensed signal responsive to photons of light emitted at the corresponding mnicro-location when the selected analyte bound at that micro-location is exposed to a second macromolecule that binds to the first macromolecule or analyte linked to one or more components of a light-emitting reaction in the presence of the remaining components of the light-emitting reaction.
-
-
66. A microelectronic device, comprising:
-
a substrate;
a plurality of micro-locations defined on the substrate, wherein each micro-location is for linking a macromolecule and is defined by a portion of the surface of the device;
a layer of reflective material on all or a portion of the micro-portions defined on the substrate;
an independent photodetector integrated at each micro-location and optically coupled to each micro-location, each photodetector being configured to generate a sensed signal responsive to the photons of light emitted at the corresponding micro-location when a light-emitting chemical reaction occurs at that micro-location, each photodetector being independent from the photodetectors optically coupled to the other micro-locations; and
an electronic circuit coupled to each photodetector and configured to read the sensed signal generated by each photodetector and to generate output data signals therefrom that are indicative of the light emitted at each micro-location by the light-emitting chemical reactions, whereby the device detects photons of light emitted by light-emitting chemical reactions.
-
Specification