OPTICAL ASSAY SYSTEM WITH A MULTI-PROBE IMAGING ARRAY

• US 20110059016A1
• Filed: 09/29/2008
• Published: 03/10/2011
• Est. Priority Date: 09/27/2007
• Status: Abandoned Application

• Current Assignee: Duke University
• Original Assignee: Duke University
• Inventors: Yu, Bing, Brown, Jonathon Quincy, Ramanujam, Nirmala
• Application Number:
  US12/680,302
• Publication Number:
  US 20110059016A1
• Time in Patent Office: Days
• US Class Current: 424/9.1
• CPC Class Codes: A61B 5/0059 using light, e.g. diagnosis by transillumination, diascopy, fluorescence A61B5/0093, A61B5/1455, A61B5/02416 and A61B5/0261 take precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: G01N 2021/4747 Concentric bundles
• CPC Class Codes: G01N 2021/6484 Optical fibres
• CPC Class Codes: G01N 21/4795 spatially resolved investigating of object in scattering medium in vivo A61B
• CPC Class Codes: G01N 21/6456 Spatial resolved fluorescence measurements; Imaging
• CPC Class Codes: G01N 21/6486 Measuring fluorescence of biological material, e.g. DNA, RNA, cells G01N21/6428 takes precedence

Abstract

The subject matter described herein relates to an optical assay system having a multi-probe imaging array that orients a plurality of probes with respect to one another and to a sample. According to one aspect, the subject matter described herein includes a multi-probe imaging array for contacting biological samples and simultaneously illuminating a plurality of locations on the biological sample and collecting the reflected radiation from the locations. The multi-probe imaging array can be used for the rapid imaging of biological samples, for example, during surgery.

Claims

1. A multi-probe imaging array for imaging a sample, the multi-probe imaging array comprising a plurality of electromagnetic radiation probes and a probe holder for orienting the plurality of probes with respect to one another and to the sample, wherein at least some of the probes simultaneously illuminate the sample and detect resulting electromagnetic radiation from the sample.

2. The multi-probe imaging array of claim 1, wherein the probe holder orients the plurality of probes with respect to one another to avoid cross-talk between probes.

3. The multi-probe imaging array of claim 2, wherein each of the plurality of electromagnetic radiation probes comprises a fiber optic probe, wherein the fiber optic probe comprises a fiber bundle comprising at least one illumination fiber and at least one collection fiber.

4. The multi-probe imaging array of claim 3, wherein the fiber bundle comprises one or more of:

a symmetric ring of illumination fibers surrounding a core of collection fibers or a symmetric ring of collection fibers surrounding a core of illumination fibers;

at least one dead fiber or an absorptive material;

a central illumination core comprising 19 illumination fibers symmetrically surrounded by four collection fibers and a plurality of dead fibers; and

a central collection fiber surrounded by a symmetric ring of between 2 and 8 illumination fibers.

12. The multi-probe imaging array of claim 3, wherein the probe holder comprises a series of channels and a sample-imaging array interface surface comprising a series of holes, wherein each of the series of holes corresponds to one end of each of the channels, and wherein a portion of each of the fiber bundles is enclosed within one of the channels such that a first end of the fiber bundle extends up to or beyond a hole on the surface of the probe holder such that the first end of the fiber bundle is free of the probe holder.

17. The multi-probe imaging array of claim 12, wherein the probe holder further comprises one or more set screws to hold a probe in place, wherein each of the one or more set screws is oriented in the probe holder perpendicular to one of the channels.

18. The multi-probe imaging array of claim 12, further comprising a fiber junction to which a second end of each of the fiber bundles is coupled, wherein the fiber junction is further coupled to a detector and to an illumination source, wherein the detector receives electromagnetic radiation signals from the probes and converts the electromagnetic radiation signals to electrical signals, and wherein the illumination source provides electromagnetic radiation to the probes.

19. The multi-probe imaging array of claim 18, wherein illumination fibers from each of the fiber bundles are bundled at the fiber junction to form an illumination fiber bundle, and wherein the illumination fiber bundle is coupled from the fiber junction to an illumination source.

20. The multi-probe imaging array of claim 19, wherein the illumination source comprises an electromagnetic radiation source and an illumination adapter.

21. The multi-probe imaging array of claim 20, wherein the illumination fiber bundle is separated at the illumination adapter into a plurality of sets, wherein each of the sets comprises illumination fibers that emit a common wavelength range from the plurality of probes.

23. The multi-probe imaging array of claim 20, wherein the electromagnetic radiation source comprises an incandescent lamp which is filtered through a series of bandpass optical filters, a spectral dispersion element, or a diffraction grating.

25. The multi-probe imaging array of claim 18, wherein collection fibers from each of the fiber bundles are bundled at the fiber junction to form a collection fiber bundle, and wherein the collection fiber bundle is coupled from the fiber junction to the detector.

26. The multi-probe imaging array of claim 25, wherein the detector further comprises a collection adapter for arranging collection fibers such that detector ends of collection fibers detecting the same wavelength range are not adjacent to each other to minimize cross-talk, wherein the collection adapter is coupled to an imaging device.

27. The multi-probe imaging array of claim 26, wherein the imaging device comprises a charge-coupled device (CCD).

28. The multi-probe imaging array of claim 27, wherein the imaging device comprises a spectral dispersion element, wherein the spectral dispersion element is coupled between the CCD and the collection adapter.

32. The multi-probe imaging array of claim 1, further comprising an adapter for attaching the multi-probe imaging array to a biological sample containment and illumination apparatus such that ends of at least some of the probes contact the sample through apertures in the biological sample containment and illumination apparatus.

33. The multi-probe imaging array of claim 1, wherein at least some of the probes simultaneously illuminate the sample with electromagnetic radiation at one or more wavelengths ranging between 250 nm and 900 nm.

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22. (canceled)

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29-31. -31. (canceled)

34. A method for testing a biological sample, the method comprising:

contacting the biological sample with a multi-probe imaging array, wherein the multi-probe imaging array comprises a plurality of electromagnetic radiation probes and a probe holder for orienting the plurality of probes with respect to one another and to the sample;

illuminating the biological sample using the probes, wherein illuminating the sample comprises illuminating plural locations on the biological sample surface in parallel; and

detecting electromagnetic radiation reflected from or emitted by plural locations on the biological sample in response to the illumination.

35. The method of claim 34, wherein the probe holder orients the plurality of probes with respect to one another to avoid cross-talk between probes.

36. The method of claim 35, wherein each of the plurality of electromagnetic radiation probes comprises a fiber optic probe, wherein the fiber optic probe comprises a fiber bundle comprising at least one illumination fiber and at least one collection fiber.

37. The method of claim 36, wherein the fiber bundle comprises one or more of:

a symmetric ring of illumination fibers surrounding a core of collection fibers or a symmetric ring of collection fibers surrounding a core of illumination fibers;

at least one dead fiber or an absorptive material;

a central illumination core comprising 19 illumination fibers symmetrically surrounded by four collection fibers and a plurality of dead fibers; and

a central collection fiber surrounded by a symmetric ring of between 2 and 8 illumination fibers.

45. The method of claim 36, wherein the probe holder comprises a series of channels and a sample-imaging array interface surface comprising a series of holes, wherein each of the series of holes corresponds to one end of each of the channels, and wherein a portion of each of the fiber optic probes is enclosed within one of the channels such that a first end of the fiber bundle extends up to or beyond a hole on the surface of the probe holder such that the first end of the fiber bundle is free of the probe holder.

50. The method of claim 45, wherein contacting the biological sample with the multi-probe imaging array comprises placing the sample-imaging array interface surface against an outer surface of the biological specimen.

51. The method of claim 50, wherein the biological sample is located in a subject and is selected from the group consisting of a body cavity surface, a superficial tumor, and an undersurface of a skin flap created during a surgery.

52. The method of claim 51, wherein the subject is a human subject.

53. The method of claim 51, wherein the body cavity surface is in an oral cavity and wherein detecting electromagnetic radiation further comprises detecting a signal indicative of blood volume in the subject.

54. The method of claim 51, wherein the biological sample is a superficial tumor and wherein detecting electromagnetic radiation further comprises detecting a signal indicative of one or more of the group consisting of a response to a medical therapy, a lack of response to a medical therapy, the presence of cancer cells, and the absence of cancer cells.

55. The method of claim 51, wherein the body cavity surface is in open surgical cavity and wherein detecting electromagnetic radiation further comprises detecting a signal indicative of the presence or absence of cancer cells.

56. The method of claim 51, wherein the biological sample is a skin flap created during a skin-saving mastectomy surgery, and wherein detecting electromagnetic radiation further comprises detecting a signal indicative of the presence or absence of cancer cells.

57. The method of claim 50, wherein the multi-probe imaging array further comprises a protective cover mounted over the sample-imaging array interface surface to protect the probes from contamination by the biological sample.

60. The method of claim 45, wherein the method further comprises placing the biological sample in an interior space defined by a biological sample containment and illumination apparatus having a plurality of frame members, at least one of which includes a plurality of probe receiving locations for receiving a plurality of electromagnetic radiation probes and for positioning the probes with respect to the sample to allow illumination of plural locations of the sample by the probes.

61. The method of claim 60, wherein the biological sample comprises an excised tumor tissue.

62. The method of claim 60, wherein at least one of the plurality of frame members is translatable with respect to another frame member such that the volume of interior space can be altered in at least one direction.

65. The method of claim 60, wherein the probe receiving locations comprise a plurality of apertures adapted to receive fiber optic probes.

66. The method of claim 65, wherein contacting the biological sample with the sample-imaging array interface surface comprises contacting the sample-imaging array interface surface with an outer surface of a frame member of the biological sample containment and illumination apparatus and inserting a plurality of fiber optic probe tips into a plurality of apertures so that the probe tips are flush with an interior surface of the frame member.

72. The method of claim 34, wherein detecting electromagnetic radiation further comprises detecting a signal indicative of one or more of the group consisting of a biomarker concentration, a scattering coefficient, and a change in contrast in response to the presence of a contrast agent.

73. The method of claim 72, wherein detecting the signal indicative of one or more of the group consisting of a biomarker concentration, a scattering coefficient, and a change in contrast in response to the presence of a contrast agent comprises applying an inverse Monte Carlo reflectance and fluorescence algorithm to convert an electromagnetic radiation signals to one of the group consisting of a biomarker concentration, a scattering coefficient, and a change in contrast in response to the presence of a contrast agent.

74. The method of claim 72, wherein the contrast agent is selected from the group consisting of acetic acid, acriflavin, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (NBDG), and fluorescein.

75. The method of claim 72, wherein the biomarker concentration is selected from the group consisting of oxyhemoglobin concentration, deoxyhemoglobin concentration, beta carotene concentration, hemoglobin saturation, total hemoglobin concentration, NADH, FAD, collagen, porphyrin, elastin, keratin, tryptophan, or retinol.

76. The method of claim 72, further comprising preparing a parameter map image of the biological sample, wherein the image provides a value for a plurality of points on the biological specimen, wherein said value is a value related to one of the group consisting of mean reduced scattering coefficient, a biomarker concentration, hemoglobin saturation, and any combination thereof.

78. The method of claim 34, wherein the method is performed during a surgery to remove a tumor, and detecting electromagnetic radiation comprises providing tumor margin assessment.

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79. A system for imaging a biological sample, the system comprising:

a multi-probe imaging array for simultaneously illuminating a plurality of locations of the biological sample with electromagnetic radiation generated by an electromagnetic radiation source and for detecting electromagnetic radiation reflected from or emitted by the biological sample, the multi-probe imaging array comprising a plurality of electromagnetic radiation probes and a probe holder for orienting the plurality of probes with respect to one another and to the sample;

a detector coupled to the multi-probe imaging array for receiving electromagnetic radiation signals indicative of the electromagnetic radiation detected by the probes and for converting the electromagnetic radiation signals to electrical signals; and

a processor coupled to the detector for receiving the electrical signals and for determining, based on the electrical signals an indication of a physical property of the biological sample.

80. The system of claim 79, wherein the probe holder orients the plurality of probes with respect to one another to avoid cross-talk between probes.

81. The system of claim 80, wherein each of the plurality of electromagnetic radiation probes comprises a fiber optic probe, wherein said fiber optic probe comprises a fiber bundle comprising at least one illumination fiber and at least one collection fiber.

82. The system of claim 81, wherein the fiber bundle comprises one or more of:

a symmetric ring of illumination fibers surrounding a core of collection fibers or comprises a symmetric ring of collection fibers surrounding a core of illumination fibers;

at least one dead fiber or an absorptive material;

a central illumination core comprising 19 illumination fibers symmetrically surrounded by four collection fibers and a plurality of dead fibers; and

a central collection fiber surrounded by a symmetric ring of between 2 and 8 illumination fibers.

90. The system of claim 81, wherein the probe holder comprises a series of channels and a sample-imaging array interface surface comprising a series of holes, wherein each of the series of holes corresponds to one end of each of the channels, and wherein a portion of each of the fiber bundles is enclosed within one of the channels such that a first end of the fiber bundle extends up to or beyond a hole on the surface of the probe holder such that the first end of the fiber bundle is free of the probe holder.

95. The system of claim 90, wherein the probe holder further comprises one or more set screws to hold a one or more probes in place, wherein each of the one or more set screws is oriented in the probe holder perpendicular to one of the channels.

96. The system of claim 90, further comprising a fiber junction to which a second end of each of the fiber bundles is coupled, wherein the fiber junction is further coupled to the detector and to an illumination source, wherein the illumination source provides electromagnetic radiation to the probes.

97. The system of claim 96, wherein illumination fibers from each of the fiber bundles are bundled at the fiber junction to form an illumination fiber bundle, and wherein the illumination fiber bundle is coupled from the fiber junction to an illumination source.

98. The system of claim 97, wherein the illumination source comprises an electromagnetic radiation source and an illumination adapter.

99. The system of claim 98, wherein the illumination fiber bundle is separated at the illumination adapter into a plurality of sets, wherein each of the sets comprises illumination fibers that emit a common wavelength range from the plurality of probes.

101. The system of claim 98, wherein the electromagnetic radiation source comprises an incandescent lamp which is filtered through a series of bandpass optical filters, a spectral dispersion element, or a diffraction grating.

103. The system of claim 96, wherein collection fibers from each of the fiber bundles are bundled at the fiber junction to form a collection fiber bundle, and wherein the collection fiber bundle is coupled from the fiber junction to the detector.

104. The system of claim 103, wherein the detector further comprises a collection adapter for arranging collection fibers such that detector ends of collection fibers detecting the same wavelength range are not adjacent to each other to minimize cross-talk, wherein the collection adapter is coupled to an imaging device.

105. The system of claim 104, wherein the imaging device comprises a charge-coupled device (CCD).

106. The system of claim 105, wherein the imaging device comprises a spectral dispersion element, wherein the spectral dispersion element is coupled between the CCD and the collection adapter.

108. The system of claim 79, further comprising a biological sample containment and illumination apparatus for holding a biological sample for illumination by the multi-probe imaging array, the biological containment and illumination apparatus comprising a plurality of frame members positioned with respect to each other to form an interior space for receiving a biological sample, wherein at least one of the plurality of frame members includes a plurality of probe receiving locations for receiving a plurality of electromagnetic radiation probes and for positioning the probes with respect to the biological sample to allow illumination of plural locations of the biological sample by the probes.

109. The system of claim 108, further comprising an adapter for attaching the multi-probe imaging array to the biological sample containment and illumination apparatus.

110. The system of claim 108, wherein at least one of the plurality of frame members is translatable with respect to another frame member such that the volume of interior space can be altered in at least one direction.

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