U.S. patent application number 13/491337 was filed with the patent office on 2012-11-08 for light collection system.
This patent application is currently assigned to LIFE TECHNOLOGIES CORPORATION. Invention is credited to Dar BAHATT, Konrad Faulstich.
Application Number | 20120282639 13/491337 |
Document ID | / |
Family ID | 46209520 |
Filed Date | 2012-11-08 |
United States Patent
Application |
20120282639 |
Kind Code |
A1 |
BAHATT; Dar ; et
al. |
November 8, 2012 |
LIGHT COLLECTION SYSTEM
Abstract
The present teachings provide a detection cell for a biological
material and methods for detecting biological material including a
photosensitive material optically coupled to an interior volume
containing the biological material so to avoid optical components
or an external light source.
Inventors: |
BAHATT; Dar; (Forster City,
CA) ; Faulstich; Konrad; (Salem-Neufrach,
DE) |
Assignee: |
LIFE TECHNOLOGIES
CORPORATION
Carlsbad
CA
|
Family ID: |
46209520 |
Appl. No.: |
13/491337 |
Filed: |
June 7, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11270263 |
Nov 9, 2005 |
8202479 |
|
|
13491337 |
|
|
|
|
60626784 |
Nov 9, 2004 |
|
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Current U.S.
Class: |
435/8 ; 422/52;
435/287.2; 435/288.7; 436/165 |
Current CPC
Class: |
G01N 21/66 20130101;
G01N 21/6428 20130101; G01N 21/645 20130101; G01N 33/581 20130101;
G01N 2021/6439 20130101; G01N 2021/6469 20130101; G01N 21/763
20130101; C12Q 1/66 20130101 |
Class at
Publication: |
435/8 ;
435/287.2; 435/288.7; 436/165; 422/52 |
International
Class: |
C12M 1/34 20060101
C12M001/34; G01N 21/76 20060101 G01N021/76 |
Claims
1. A detection cell for a biological material, the detection cell
comprising: an interior volume adapted to contain the biological
material; and a photosensitive material optically coupled to the
interior volume, the photosensitive material being adapted to
detect light emitted from the biological material in the interior
volume.
2. The detection cell for biological material of claim 1, wherein
the photosensitive material forms the interior volume.
3. The detection cell for biological material of claim 2, further
comprising a sandwich structure comprising at least two charge
coupled devices, wherein the at least two charge coupled devices
comprise the interior volume.
4. The detection cell for biological material of claim 2, the
interior volume is adapted to contain a liquid or solid.
5. The detection cell for biological material of claim 2, wherein
the photosensitive material forms an exterior layer of the interior
volume.
6. The detection cell for biological material of claim 2, wherein
the photosensitive material forms an interior layer of the interior
volume.
7. The detection cell for biological material of claim 1, wherein
the photosensitive material is part of at least one of a charge
coupled device, a photodiode, and a photomultiplier tube.
8. The detection cell 0 for biological material of claim 7, wherein
the photosensitive material is part of a channel formed around the
interior volume.
9. The detection cell for biological material of claim 18, further
comprising an avalanche breakdown system.
10. The detection cell for biological material of claim 2, wherein
the biological material comprises at least one of chemiluminescent
labeled nucleic acids and chemiluminescent labeled cells.
11. A method for detection of a biological material, the method
comprising: transporting the biological material to an interior
volume; providing a photo sensitive material optically coupled to
the interior volume; emitting light from a luminescent reaction of
the biological material; and detecting the light emitted from the
biological material in an interior volume of the detection cell,
wherein the light is emitted without an external light source.
12. The method for detection of biological materials of claim 11,
further comprising channeling the emitted light within a
waveguide.
13. The method for detection of biological materials of claim 12,
wherein channeling the emitted light further comprises reflecting
the emitted light into the interior volume.
14. The method for detection of biological materials of claim 12,
wherein channeling the emitted light comprises refracting the
emitted light in a wall of the detection cell.
15-20. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims a priority benefit under 35 USC
.sctn.119(e) from U.S. Patent Application No. 60/626,784 filed Nov.
9, 2004, which is incorporated herein by reference.
FIELD
[0002] The present teaching relate to methods and systems for
detection of biological samples.
INTRODUCTION
[0003] Detection of results from assays on biological samples is
usually done by detection of emission light from the biological
samples. Typically, excitation light is provided by an external
light source to excite a moiety of the biological sample to provide
emission light. The direction of excitation light to the biological
sample from the external light source and the direction of emission
light to a detector from the biological sample require optical
components to direct the light, such as lenses, mirrors, gratings,
prisms, etc. External light source and associated optical
components add complexity and size to detection systems. It is
desirable to select assays for the biological samples that do not
use external light sources and associated optical components.
[0004] Assays that do not use external light sources and associated
optical components provide results in the form of luminescent
light. Luminescent light originates from inside the biological
sample. Since excitation light does not have to reach the
biological sample detection can occur in the vicinity of the
biological sample. It is desirable to provide detection of the
luminescent light in the vicinity of the sample. Collection of the
luminescent light can be provided by the container of the
biological material. It is desirable to provide a container that
collects the luminescent light for detection in the vicinity of the
sample.
SUMMARY
[0005] In various embodiments, the present teachings provide a
detection cell for a biological material including an interior
volume adapted to contain the biological material, and a
photosensitive material optically coupled to the interior volume,
the photosensitive material being adapted to detect light emitted
from the biological material in the interior volume.
[0006] In various embodiments, the present teachings provide a
method for detection of a biological material including
transporting the biological material to an interior volume,
emitting light from a luminescent reaction of the biological
material, and detecting the light emitted from the biological
material in an interior volume of the detection cell, wherein the
light is emitted without an external light source.
[0007] Some advantages of the present teaching will be set forth in
part in the description which follows, and in part will be obvious
from the description, or may be learned by practice of the various
embodiments. The advantages of the embodiments will be realized and
attained by means of the elements and combinations particularly
pointed out in the appended claims.
[0008] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not to be restrictive of the
embodiments, as claimed.
[0009] The accompanying drawings, which are incorporated in and
constitute a part of this specification, illustrate several
embodiments and together with the description, serve to explain the
principles of the present teaching.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 is a perspective view of a representative biological
detection cell according to various embodiments of the present
teachings;
[0011] FIG. 2 is a perspective view of a representative biological
detection cell according to various embodiments of the present
teachings;
[0012] FIG. 3 is a perspective view of a representative biological
detection cell according to various embodiments of the present
teachings;
[0013] FIG. 4 is a perspective view of a representative biological
detection cell according to various embodiments of the present
teachings;
[0014] FIG. 5A is a cross-sectional view of a representative
biological detection cell according to various embodiments of the
present teachings;
[0015] FIG. 5B is a cross-sectional view of a representative
biological detection cell according to various embodiments of the
present teachings; and
[0016] FIG. 6 illustrates a representative biological detection
system according to various embodiments of the present
teachings;
[0017] FIG. 7 illustrates an example of an assay that can generate
luminescent light;
[0018] FIG. 8 illustrates a graph showing the intensity of
luminescent light detected from different directions relative an
internal volume; and
[0019] FIG. 9 illustrates a graph showing the relative intensity of
luminescent light detection from different directions relative to
an internal volume.
[0020] It is to be understood that the figures are not drawn to
scale. Further, the relation between objects in a figure may not be
to scale, and may in fact have a reverse relationship as to size.
The figures are intended to bring understanding and clarity to the
structure of each object shown, and thus, some features may be
exaggerated in order to illustrate a specific feature of a
structure.
[0021] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only, and are intended to provide an explanation of
various embodiments of the present teachings.
DESCRIPTION OF THE EMBODIMENTS
[0022] In this application, the use of the singular includes the
plural unless specifically stated otherwise. In this application,
the use of "or" means "and/or" unless stated otherwise.
Furthermore, the use of the term "including", as well as other
forms, such as "includes" and "included", is not limiting. Also,
terms such as "element" or "component" encompass both elements and
components comprising one unit and elements and components that
comprise more than one subunit unless specifically stated
otherwise. Wherever possible, the same reference numbers will be
used throughout the drawings to refer to the same or like
parts.
[0023] The section headings used herein are for organizational
purposes only, and are not to be construed as limiting the subject
matter described. All documents cited in this application,
including, but not limited to patents, patent applications,
articles, books, and treatises, are expressly incorporated by
reference in their entirety for any purpose. In the event that one
or more of the incorporated literature and similar materials
differs from or contradicts this application, including but not
limited to defined terms, term usage, described techniques, or the
like, this application controls.
[0024] The term "optically coupled" as used herein refers to the
ability to propagate light without the used of optical components
to direct the light, such as lenses, mirrors, gratings, prisms,
etc. According to the present teachings, the interior volume
containing the biological material or the container walls are not
optical components, but can be used to channel the emission light
from the biological material to the photosensitive material.
[0025] The term "external light source" as used herein refers to a
source of irradiance that can provide excitation that results in
fluorescent emission. External light sources can include, but are
not limited to, white light, halogen lamp, laser, solid state
laser, laser diode, diode solid state lasers (DSSL),
vertical-cavity surface-emitting lasers (VCSEL), LEDs, phosphor
coated LEDs, organic LEDs (OLED), thin-film electroluminescent
devices (TFELD), phosphorescent OLEDs (PHOLED), inorganic-organic
LEDs, LEDs using quantum dot technology, LED arrays, an ensemble of
LEDs, a floodlight system using LEDs, and/or white LEDs, filament
lamps, arc lamps, gas lamps, and fluorescent tubes. External light
sources can have high irradiance, such as lasers, or low
irradiance, such as LEDs. The different types of LEDs mentioned
above can have a medium to high irradiance.
[0026] The term "photosensitive material" as used herein refers to
any component, portion thereof, or system of components that can
interact with, alter the path of, and/or detect light including a
reflective material, mirror, charged coupled device (CCD),
back-side thin-cooled CCD, front-side illuminated CCD, a CCD array,
a photodiode, a photodiode array, a photo-multiplier tube (PMT), a
PMT array, complimentary metal-oxide semiconductor (CMOS) sensors,
CMOS arrays, an avalanche diode structure, a charge-injection
device (CID), CID arrays, etc. The detector can be adapted to relay
information to a data collection device for storage, correlation,
and/or manipulation of data, for example, a computer, or other
signal processing system.
[0027] Photosensitive material can provide multi-color detection by
multi-layered material with each layer sensitive to a different
color. For example, the color photodetectors organized in three
layers within a sensor to form full-color pixels (Foveon, Inc.,
Santa Clara, Calif.). By dedicating three color photodetectors for
each pixel, images are sharper, have better color detail, and are
more immune to color artifacts. Alternatively, photosensitive
material in multi-color photodiodes can provide multi-color
detection. Examples of such photodiodes include those based on
silicon and gallium arsenic.
[0028] The term "interior volume" as used herein refers to any
structure, such as a sample region, channel, micro-fluidic channel,
or chamber that provides containment for a sample, such as a
biological material in a liquid or solid sample. The interior
volume can be bounded by walls that can be opaque or transparent
and can include a semiconductor material, such as silicon,
germanium, silicon germanium, gallium arsenide, etc.; or an
insulator, such as glass, SiO.sub.2, fused silica, etc.; polymers,
or an organic-inorganic hybrid material.
[0029] In various embodiments, an organic-inorganic hybrid material
for containing a solid sample can be one obtained by a sol-gel
method. In such embodiments, the interior volume can be bound by a
sol-gel or the interior volume itself can be a sol-gel. Examples of
sol-gels include those using precursors such as
3-trimethoxysilylpropyl methacrylate (MPTS,
H.sub.2C.dbd.C(CH.sub.3)CO.sub.2(CH.sub.2).sub.3Si(OCH.sub.3).sub.-
3, made by Aldrich Chemical) and heptadecafluorodecyl
trimethoxysilane (PFAS,
CF.sub.3(CF.sub.2).sub.7(CH.sub.2).sub.2Si(OCH.sub.3).sub.3, made
by Toshiba). The two precursors, MPTS and PFAS, can be mixed with
water in presence of 0.05N hydrochloric acid (HCl) as a catalyst
for sol-gel reaction. After stirring the solution of MPTS(3),
PFAS(1) and water(2) in the presence of 0.05N HCl (where the
bracketed numbers indicate molar equivalents) for 9 hours at
60.degree. C., a totally transparent solution can be obtained.
Subsequently, the transparent solution can be filtered through a
0.22 .lamda.m-size filter to remove impurities and gas bubbles. The
filtered solution can be kept still for 30 minutes to remove gas
bubbles resulting from the stirring and filtering. The filtered
solution can be used as the internal volume where biological
samples filter in via diffusion. Alternatively, the filtered
solution can be used to coat the boundary of the internal volume.
For example, the sol-gel can be coated onto a p-doped Si(100) wafer
by spin-coating at 2000 rpm for 30 seconds. Finally, the coated
film can then be cured thermally for 12 hours at 150.degree. C. UV
(200-260 nm) by light irradiation, using for example, a Oriel 82511
Hg/Xg lamp, which gives a power density of 45 mJ/cm.sup.2.
[0030] Further, the interior volume can take any shape including a
well, a tube, a channel, a micro-fluidic channel, a vial, a
cuvette, a capillary, a cube, an etched channel plate, a molded
channel plate, an embossed channel plate, etc. The interior volume
can be part of a combination of multiple interior volumes grouped
into a row, an array, an assembly, etc. Multi-chamber arrays can
include 12, 24, 36, 48, 96, 192, 384, or more, interior volume
chambers.
[0031] The term "biological material" as used herein refers to any
biological or chemical substance, alone or in solution, with
components that can emit light in a liquid sample or solid sample.
Examples of luminescent moieties that can be included in biological
material are listed in Table 1 with emission wavelengths and
fluorescent concentrations (Albrecht, Steffen, et al.
Chemiluminescence: Reaction systems and their application under
special consideration of biochemistry and medicine, Huthig GhbH,
Heidelberg, Germany, pp. 9-10, 1996):
TABLE-US-00001 TABLE 1 Emission Wavelength .phi..sub.CL Luminescent
Moiety (max. in nm) (Einstein/mol) Luminol 424 0.01 Isoluminiol 425
0.001 Lucigenin 530 0.02 Aryloxalate + Fluorescer -- 0.05-0.50
p-Chlorophenyl 475 10.sup.-6-10.sup.-8 Magnesium Bromide Bacterial
Luciferine/ 460-480 0.05-0.30 Luciferasen Aequorin 469 0.15-0.20
Pholasin 495 0.10 Firefly Luciferine/ 565 0.90 Luciferase
Adamantandioxetane 477 10.sup.-4 (in DMSO bis 0.20)
The biological material can include luminescent labels that can
combine with luminescent moieties in a detection reaction or can be
luminescent themselves to provide detection of certain analytes in
the biological material; examples of which are listed in Table 2
showing examples of luminescence including chemiluminescence (CL)
and bioluminescence (BL) (Albrecht, Steffen, et al.
Chemiluminescence: Reaction systems and their application under
special consideration of biochemistry and medicine, Huthig GmbH,
Heidelberg, Germany, pp. 35-36, 1996):
TABLE-US-00002 TABLE 2 Luminescent Label Detection Reaction Analyte
Acridiniumester +H.sub.2O.sub.2/OH .fwdarw. CL T.sub.3, T.sub.4,
TSH, FT.sub.3, FT.sub.4, CKMB, Ferritin, .beta.HCG, PSA, Vit.
B.sub.12, auto-Thyroid AK, Folsr., LH, FSH, Prolactin, HGH, PTH,
Cortisol Aequorin +Ca.sup.2+.fwdarw. BL Progesteron, Transferrin
Alkaline Phosphatase +AMPPD.fwdarw. CL AFP, CA 125, CA 19-9, CA
15-3, TSH, LH, HGH, Thyroid diagnostics, Fertility, Anemia ATP
Firefly Luciferin- T.sub.4, Myoglobin Luciferase.sup.+.fwdarw. BL
.beta.-Galactosidase, sensing Peroxyoxalate-CL T.sub.4
.gamma.-Cyclodextrin Glucoseoxidase H.sub.2O.sub.2 by
Peroxyoxalate-CL Glucose in aqueous solution Firefly Luciferase BL
Methotrexat Fluorescin Peroxyoxalate-CL IgG Rhodamin
Peroxyoxalate-CL LDL Glucoseoxidase H.sub.2O.sub.2 by
Peroxyoxalate-CL 17-Hydroxyprogesteron Glucose-6-phosphate
NAD(P)H-dependent BL Progesteron, LH, Prolactin, hydrogenase AFP
Haemin Catalysis of Luminol-CL .beta.2-Microglobulin
Horseradish-Peroxidase Catalysis of Luminol-CL AFP, CEA, Ferritin,
LH, FSH, Progesteron, T.sub.3, T.sub.4, FT.sub.3, FT.sub.4, TSH,
TBG, Cortisol, Estriol, Estradiol Horseradish-Peroxidase Catalysis
of Thyroid diagnostics, Blot Acridanoxidation techniques Luminol-
or Isoluminol H.sub.2O.sub.2/Catalyst .fwdarw. CL Thyroid
diagnostics, derivative Fertility, Tumor marker, Reproduction,
Cortisol, Progesteron Bacterielle Luciferase BL Immuoglobuline
NAD.sup.+ BL Estriol Pyruvatkinase ATP-dependent Firefly-BL
Transferrin, Insulin Xanthinoxidase H.sub.2O.sub.2-generation +
Luminol IgE, Prolactin, T.sub.4, TSH .fwdarw. CL
Examples of these luminescent labels and luminescent moieties in
biological material are manufactured by companies like Byk Sangtec,
Ciba Corning, Nichols Diagnostics, Brahms GmbH, Boeringer Mannheim,
Millipore, Celcius Limited, and Biotrace Limited. In various
embodiments, the luminescent moiety can be dioxetane. Dioxitane can
provide a detection reaction with alkaline phosphatase luminescent
label. Example of such reactions can detect antibodies in lysed
cells (U.S. Pat. No. 6,686,171).
[0032] The biological material can include one or more nucleic acid
sequences to be monitored. The biological material can be monitored
by polymerase chain reaction (PCR) and other reactions such as
ligase chain reaction, antibody binding reaction (immunoassay),
oligonucleotide ligations assay, and hybridization assay. In
various embodiments, the biological material can also be subjected
to thermal cycling or iso-thermal cycling. In various embodiments,
the biological material can be subjected to an electric current. An
example of an immunoassay is illustrated by FIG. 7 providing a
biological material that can react with an electrode to provide
electrochemiluminescence. In various embodiments, the electrode
used to generate the electrochemiluminesce can also provide current
for manipulating the biological material in a liquid. For example,
electrowetting on a diaelectric (U.S. Pat. No. 6,565,727).
[0033] The biological material can include a combination of
luminescent moieties that generate different and spectrally
distinguishable luminescence. For example, the biological sample
can include different analytes, labels, and/or luminescent moieties
that emit light at different wavelengths to provide multi-color
detection. In various embodiments, luminescent moieties can be
paired with fluorescent dyes such that emission wavelengths of the
luminescent moieties can activate the fluorescent dyes. Such
pairing can provide better spectral separation and facilitate
multi-color detection for end-point quantitation and/or real-time
detection. Examples of fluorescent dyes with desirable excitation
and emission wavelengths can include 5-FAM.TM., SYBR Green,
TET.TM., VIC.TM., JOE, TAMRA, NED, ROX, CY3, Texas Red, CY5, etc.
The present teaching applies at least to red dyes, green dyes, and
blue dyes.
[0034] The term "refractive material" as used herein refers to any
material that can reflect a predetermined wavelength of light.
Refractive materials can be metals that reflect all wavelengths.
Refractive materials can be a coating, a distinct layer, or a
various components described herein can themselves act as a
reflective materials. Some exemplary reflective materials include,
for example, insulators, such as SiO.sub.2, TiN, SiON;
semiconductor materials, such as silicon, germanium, silicon
germanium, and compound semiconductors; polymers, such as
Teflon.RTM., Teflon.RTM. AF; an organic-inorganic hybrid material
as disclosed above, or any other reflective material that will be
known to one of ordinary skill in the art. In various embodiments,
the refractive material can permit external light to penetrate the
internal volume to manipulate the biological material, but not
provide excitation. For example, biological material in liquid can
be manipulated by optically activated electrowetting on dielectrics
(U.S. Pat. App. 2003/0224528 A1) and optically activated
dielectrophoresis (Chiou, P. Y., et al., A Novel Optoelectri
Tweezer Using Light Induced Dielectrophoresis, Proceeding of
IEEE/LEOS Intl Conf. Optical MEMS, pp 8-9, 2003).
[0035] The term "on" as used herein can be any of on an exterior
surface, on an interior surface, or inside of a material.
[0036] An embodiment of the present teaching shown in FIG. 1
includes a detection cell 10 including an interior volume 20, a
wall 30, and a photosensitive material 40. Photosensitive material
40 can be optically coupled to interior volume 20. As used herein,
the term optically coupled is understood to mean that light emitted
in the interior volume 20 is capable of reaching photosensitive
material 40. Moreover, interior volume 20 can be adapted to contain
a sample, such as a liquid 50 that can be in contact with a
biological material 60. Further, in various embodiments, interior
volume 20 can include at least one closed end 70. In various
embodiments, interior volume 20 can be filed with a solid, such as
a sol-gel permitting biological material 60 to diffuse into the
sol-gel. The sol-gel can include conditions for the detection
reaction, for example, suspension of the luminescent label.
[0037] In various embodiments, the biological material 60 can be
transported to the interior volume 20 along with the liquid 50 or
the liquid 50 can be received by the interior volume 20 separately.
When the biological material 60 is in contact with the liquid 50,
the biological material 60 can emit light, shown in FIG. 1 with
arrows 80. For example, the liquid can contain a luminescent label
that causes the detection reaction with an analyte. In this
instance, the biological material is both the analyte before the
detection reaction, the reaction complex of analyte with
luminescent label and after reacting to produce emission light.
[0038] In various embodiments, the biological material can emit
either a single or a narrow band of light, or the biological
material can emit multiple wavelengths or multiple narrow bands of
light. Moreover, in various embodiments, multiple biological
materials including multiple analytes, multiple luminescent labels,
etc. can be received by the interior volume 20. Multiple
wavelengths or multiple narrow bands can be optically coupled to
the photosensitive material 40 and can be spectrally resolved by a
detector connected to the photosensitive material 40. For example,
a first biological material can produce a first wavelength.
Similarly, a second biological material can produce a second
wavelength. Each of the first and second wavelengths can be
optically coupled to the photosensitive material 40 and they can be
detected and resolved by a detector (not shown).
[0039] In various embodiments, some examples of which will be
described below, the photosensitive material 40 can be positioned
on interior volume 20. For example, an exterior surface 91, an
interior surface 92, and/or the inside 93 of wall 30, can include
photosensitive material 40. The photosensitive material 40 can also
be positioned on an end 70 of interior volume 20 and/or wall 30.
Similarly, "on an end" is understood to be any of on an exterior
surface (not shown), an interior surface (not shown), or inside of
end 70 (not shown). Further, "on an end" is understood to mean
substantially at the end of the interior volume and/or wall 30. For
example, the photosensitive material can be positioned such as to
provide a gap for liquid to pass from the interior volume to the
exterior of the wall, where the gap is sufficiently narrow to
permit the interior volume and/or the wall to be optically coupled
to the photosensitive material. In certain embodiments, the
photosensitive material 40 can be positioned on all or a portion of
interior volume 20 and/or wall 30. Further, in various embodiments,
photosensitive material 40 can be manufactured to form interior
volume 20, end 70, and/or wall 30.
[0040] The light from the biological material is emitted within the
interior volume 20 without the use of an external light source. In
various embodiments, because the biological material is surrounded
by the interior volume 20, the photosensitive material will detect
a substantial amount of the emitted light. As such, there are
smaller losses from embodiments described herein than in other
systems.
[0041] In various embodiments there is a detection cell 200, such
as a micro-fluidic biological material detector, as shown in FIG.
2, including a first surface 210a and a second surface 210b that
when touched together form a sandwich structure. Detection cell 200
also includes an interior volume 220 that can be defined by first
surface 210a and second surface 210b. In various embodiments, first
surface 210a and second surface 210b can be formed on a wall 230,
which serves as a substrate to support the surfaces. Further, in
certain embodiments, detection cell 200 can further include an end
(not shown) positioned at the end of interior volume 220. Detection
cell 200 can also include a photosensitive material 240 optically
coupled to interior volume 220 and/or the end of interior volume
220.
[0042] In various embodiments at least one of first surface 210a,
second surface 210b, and wall 230 can include a semiconductor
material, such as silicon, germanium, gallium arsenide, etc.; an
insulator, such as SiO.sub.2; fused silica; plastic; or any other
suitable material that can support interior volume 220. In various
embodiments, Teflon.RTM. AF can be on the interior volume 220
and/or on wall 230.
[0043] In various embodiments, the interior volume can be bound by
a flexible sheet film. This film could be thick enough to create
the interior volume over a flat substrate. Most existing CCD system
are sold with a protective clear material to protect the
photosensitive material underneath. Rather than forming the
interior volume in the photosensitive material, the interior volume
can be shaped by the flexible sheet film to provide optical
coupling with the off-the-shelf CCD.
[0044] In various embodiments, the luminescent labels can be
deposited on the flexible sheet film forming the interior volume
such that the biological material emits light from the surface of
the flexible sheet. In various embodiments, the photosensitive
material can be positioned to be proximate to the location on the
flexible sheet film where the luminescent labels are located to
provide increased collection of emission light.
[0045] In various embodiments, the interior volume 220 can be
formed in at least one of the first surface 210a and second surface
210b. The interior volume 220 can be formed by standard etching,
casting, or molding techniques, or by other techniques as will be
known to one of ordinary skill in the art.
[0046] In various embodiments, interior volume 220 can serve as a
waveguide. For example, the index of refraction of the interior of
interior volume 220, and/or its contents, can be greater than the
index of refraction of the first surface 210a, second surface 210b,
and walls 230. As such, light can be channeled through the
waveguide by total internal reflection as will be known to one of
ordinary skill in the art.
[0047] In various embodiments, at least one of first surface 210a,
second surface 210b, wall 230, and the end of interior volume 220
can include various photosensitive materials 240. For example, in
an embodiment, first surface 210a and second surface 210b can
include a reflective material and the end of interior volume 220
can include the photosensitive material, such as, for example, a
CCD structure, a photodiode, or a portion of a photomultiplier
tube. In another embodiment, at least one of first surface 210a and
second surface 210b can include the photosensitive material 240. It
will be understood that various combinations of photosensitive
materials 240 can be used on interior volume 220. A substantial
portion of the light emitted inside of interior volume 220 can be
optically coupled to the photosensitive material 240.
[0048] In various embodiments, the biological material 60 can be
transported to the interior volume 220 along with the liquid 50 or
the liquid 50 can be received by the interior volume 220
separately. As described above, when the biological material 60 can
emit light under the proper conditions. In various embodiments, the
biological material can emit either a single or a narrow band of
light, or the biological material can emit multiple wavelengths or
multiple narrow bands of light. Moreover, in various embodiments
multiple biological materials can be received by the interior
volume 220. Multiple wavelengths or multiple narrow bands can be
optically coupled to the photosensitive material 240 and can be
spectrally resolved by a detector connected to the photosensitive
material 240. For example, a first biological material can produce
a first wavelength. Similarly, a second biological material can
produce a second wavelength. Each of the first and second
wavelengths can be optically coupled to the photosensitive material
240 and they can be detected and resolved by a detector (not
shown).
[0049] The biological material 60 and the liquid 50 are surrounded
by the interior volume 220. A substantial amount of the emitted
light is contained inside interior volume 220 is detected by the
photosensitive material 240. In situations where one of first
surface 210a and second surface 210b includes a reflective or
refractive material, the light emitted by the of biological
material 60 is reflected or refracted back inside of interior
volume 220 and is detected by photosensitive material 240.
[0050] In various embodiments, after the emitted light has been
monitored, the liquid sample 50 and the biological material 60 can
be purged from the detection cell 200.
[0051] In various embodiments, there is a detection cell 300, such
as a micro-fluidic biological material detector, as shown in FIG.
3, including a light channeling structure 330, such as the wall of
a tube surrounding an interior volume 320. The light channeling
structure 330 further includes a first surface 310a around a second
surface 310b. The detection cell 300 further includes a
photosensitive material 340, such as, for example, a CCD, a
photodiode, or a photomultiplier tube, positioned on at least an
end 370 of the interior volume 320.
[0052] It is to be understood that the light channeling structure
330 can assume any applicable shape. For example, the light
channeling structure can be a cylindrical, rectangular, square,
oval, etc. Further, the light channeling structure can have a
uniform diameter or it can be tapered. Moreover, the light
channeling structure can include any of silica, SiO.sub.2, plastic,
or any suitable waveguide material. In various embodiments, the
light channeling structure can be mounted onto a substrate.
[0053] In various embodiments, the interior volume 320 and/or its
contents, can include a first refractive index, and the light
channeling structure 330 can include a second refractive index. In
general, the first and second refractive indexes are adjusted such
that light inside the channel is internally reflected within the
interior volume 320.
[0054] In various embodiments, at least one of the first surface
310a and the second surface 310b can include a reflective material
such that light impinging the reflective material from inside the
interior volume 320 is reflected back inside the interior volume.
In an embodiment, a reflective material can be on the first surface
310a. In this case, light emitted from the interior volume 320 can
be transmitted through the second surface 310b. Upon reaching the
first surface 310a, the light is sent back into the interior volume
320. In another embodiment, a reflective material can be on the
second surface 310b. In this case, light emitted in the interior
volume 320 that reaches the second surface 310b is sent back into
the interior volume 320. In yet another embodiment, the material of
the light channeling structure 330 between the first surface 310a
and the second surface 310b can include a graded refractive index.
In this case, light having a particular wavelength can be sent back
into the interior volume 320. In any case, light sent back into the
interior volume 320 can be channeled through the interior volume
320. A substantial portion of the light emitted inside of interior
volume 320 can be optically coupled to the photosensitive material
340 and the light can be detected by a detector (not shown) coupled
to the photosensitive material 340.
[0055] In various embodiments, the biological material 60 can be
transported to the interior volume 320 along with the liquid 50, or
the liquid 50 can be received by the interior volume 320
separately. As described above, when the biological material 60 can
emit light. In various embodiments, the biological material can
emit either a single or a narrow band of light, or the biological
material can emit multiple wavelengths or multiple narrow bands of
light. Moreover, in various embodiments, multiple biological
materials can be received by the interior volume 320. In either
case, when multiple wavelengths or multiple narrow bands are
emitted, they can be spectrally resolved by a detector connected to
the photosensitive material 340. For example, a first biological
material can produce a first wavelength. Similarly, a second
biological material can produce a second wavelength. Each of the
first and second wavelengths can be optically coupled to the
photosensitive material 340 and they can be detected and resolved
by a detector (not shown).
[0056] Light emitted by the biological material can be channeled
through the waveguide formed by interior volume 320 and can be
detected by the photosensitive material 340. Because the biological
material 60 and the liquid 50 is surrounded by the interior volume
320, a substantial amount of the emitted light can be contained
inside interior volume 320 and sent to the photosensitive material
340 for detection. In situations where one of first surface 310a
and second surface 310b includes a reflective material, the light
emitted by the biological material 60 and liquid 50 is sent back to
interior volume 320 and is detected by photosensitive material
340.
[0057] In various embodiments after the emitted light has been
monitored, the liquid 50 and the biological material 60 can be
purged from the detection cell 300.
[0058] In various embodiments there is detection cell 400, such as
a micro-fluidic biological material detector, as shown in FIG. 4
including a light channeling material 430, such as the wall of a
tube surrounding an interior volume 420. The light channeling
material 430 further includes a first surface 410a around a second
surface 410b. The detection cell 400 further includes a
photosensitive material 440, such as a CCD, a photodiode, or a
photomultiplier tube positioned on and optically coupled to at
least an end 470 of the interior volume 420.
[0059] It is to be understood that the light channeling material
430 can assume any applicable shape. For example, the light
channeling material 430 can be a cylindrical, rectangular, square,
oval, etc. Further, the light channeling material can have a
uniform diameter or it can have tapering. Moreover, the light
channeling material can include any of silica, SiO.sub.2, plastic,
or any suitable waveguide material. In various embodiments, the
light channeling material 430 can be mounted onto a substrate (not
shown).
[0060] In various embodiments, the interior volume 420 and/or its
contents can include a first refractive index, and the light
channeling material can include at least a second refractive index.
In general, the first and second refractive indexes are adjusted
such that light inside the interior volume 420 is transmitted
through the second surface 410b and is internally reflected by the
first surface 410a such that the light is internally reflected and
stays within the light channeling material 430.
[0061] For example, in various embodiments, a reflective material
can be on the first surface 410a. In this case, light emitted from
the interior volume 420 can be transmitted through the second
surface 410b. Upon reaching the first surface 410a, the light is
internally reflected back into the wall of the light channeling
material 430. In another embodiment, a reflective material can be
on the second surface 410b. In this case, light emitted in the
interior volume 420 that reaches the second surface 410b initially
transmits through the second surface 410b and is confined within
the light channeling material 430 between the first surface 410a
and the second surface 410b. In yet another embodiment, the light
channeling material 430 between the first surface 410a and the
second surface 410b can include a graded refractive index. In this
case, as will be understood by one of ordinary skill in the art,
particular wavelengths of light can be confined to different
distances between the first surface 410a and the second surface
410b. In any case, light confined within the light channeling
material 430 can be channeled through the light channeling material
430 and the light can be detected by the photosensitive material
440.
[0062] In various embodiments, the biological material 60 can be
transported to the interior volume 420 along with the liquid 50, or
the liquid 50 can be received by the interior volume 420
separately. As described above, the biological material 60 can emit
light. In various embodiments, the combination can emit either a
single or a narrow band of light, or the combination can emit
multiple wavelengths or multiple narrow bands of light. Moreover,
in various embodiments, multiple biological materials can be
received by the interior volume 420. In either case, when multiple
wavelengths or multiple narrow bands are emitted, they can be
spectrally resolved by a detector connected to the photosensitive
material 440.
[0063] Light emitted by the biological material can be channeled
through the waveguide formed by light channeling material 430 and
can be detected by the photosensitive material 440. Because the
biological material 60 and the liquid 50 is surrounded by the light
channeling material 430, which serves as a waveguide, the emitted
light is contained inside light channeling material 430 by total
internal reflection. Further, the photosensitive material 440 will
detect substantial amounts of the emitted light. In situations
where one of first surface 410a and second surface 410b includes a
reflective material, the light emitted by the biological material
60 is confined within the light channeling material 430 and is
detected by photosensitive material 440.
[0064] For example, a first biological material can produce a first
wavelength. Similarly, a second biological material can produce a
second wavelength. Each of the first and second wavelengths can be
optically coupled to the photosensitive material 440 and they can
be detected and resolved by a detector (not shown).
[0065] In various embodiments, after the emitted light has been
monitored, the liquid sample 50 and the biological material 60 can
be purged from the detection cell 400.
[0066] In various embodiments, there is a detection cell 500, such
as a micro-fluidic biological material detector, as shown in FIGS.
5A and 5B. The detection cell 500 includes a first semiconductor
material 510a including a first dopant of a first conductivity type
positioned around an interior volume 52. The detection cell 500
further includes a second semiconductor material 510b around the
first semiconductor material 510a. The second semiconductor
material includes a second dopant of a second conductivity
type.
[0067] In various embodiments, the first and second semiconductor
materials can include silicon, germanium, silicon germanium,
compound semiconductor materials such as III-V, and II-VI
semiconductors, and any other compound semiconductor material.
Further, the first and second dopants can be boron, arsenic,
phosphorous, or any semiconductor dopant material that will be
known to one of ordinary skill in the art.
[0068] In various embodiments, the detection cell 500 further
includes an insulating material 512, such as SiO.sub.x, GeO, etc.,
contacting an inner surface 514 of the first semiconductor
material. Insulating material 512 can be transparent to certain
wavelengths of light emitted in the interior volume 520.
[0069] In various embodiments, the first and second semiconductor
material 510a and 510b of detection cell 500 can form an avalanche
breakdown system. Light emitted in the interior volume 520 can be
optically coupled to the interface of the first and second
semiconductor materials. For example, light emitted in the interior
volume 520 impinging the interface of the first and second
semiconductor materials can cause a stimulated emission of
electrons. Further, in various embodiments, the detection cell 500
can further include a detector (not shown) coupled to the first and
second semiconductor materials adapted to detect stimulated
electrons. The detector can generate a data signal that includes
information about the stimulated electrons.
[0070] In various embodiments, the detection cell 500 can further
include a voltage supply (not shown) electrically connected between
the first and second semiconductor materials 510a and 510b. The
voltage supply can establish a bias, such as a forward bias or
reverse bias, between the first and second semiconductor materials
that can assist in the generation of the stimulated emission. In
various embodiments, the voltage supply can include a piezoelectric
element.
[0071] It is to be understood that the first and second
semiconductor materials can 510a and 510b can assume any applicable
shape. For example, the first and second semiconductor materials
510a and 510b can form a cylinder, rectangle, square, oval, etc.
Further, the first and second semiconductor materials 510a and 510b
can have a uniform diameter or can be tapered. In various
embodiments, the first and second semiconductor materials 510a and
510b can be mounted onto a substrate (not shown).
[0072] In various embodiments, the biological material 60 can be
transported to the interior volume 520 along with the liquid 50, or
the liquid 50 can be received by the interior volume 520
separately. The biological material 60 can emit light. In various
embodiments, the biological material can emit either a single or a
narrow band of light, or the biological material can emit multiple
wavelengths or multiple narrow bands of light. Moreover, in various
embodiments, multiple biological materials s can be received by the
interior volume 520. In either case, when multiple wavelengths or
multiple narrow bands are emitted, they can separately stimulate
electrons at the interface of the first and second semiconductor
materials 510a and 510b.
[0073] For example, a first biological material can produce a first
wavelength. Similarly, a second biological material can produce a
second wavelength. Each of the first and second wavelengths can be
optically coupled to the interface to the two semiconductor
materials. The wavelengths can then be detected and resolved by a
detector (not shown).
[0074] Because the biological material 60 and the liquid 50 are
surrounded the first and second semiconductor materials 510a and
510b, a substantial amount of the emitted light impinges the
interface between the first and second semiconductor materials 510a
and 510b.
[0075] In various embodiments, after the emitted light has been
monitored, the liquid 50 and the biological material 60 can be
purged from the detection cell 500.
[0076] In various embodiments, there is a biological detection
system 600, as shown for example in FIG. 6, including an input port
611, a first channel 615 connected to the input port 611, a
detection cell 618 connected to the first channel, and an interior
volume 620. The detection cell 618 includes a photosensitive
material (not shown). The biological detection system 600 further
includes a display 650 that displays a data signal representative
of light emitted in the interior volume 620.
[0077] In various embodiments, the biological material detection
system 600 further includes a processor 660 that processes and
converts the signal representative of the emitted light into the
data signal that can be displayed on display 650.
[0078] In various embodiments, the biological material can be
deposited into input port 611 and transported to the detection cell
618 and into interior volume 620 along with a liquid, or the liquid
can be received by the interior volume 620 separately. As described
above, the biological material can emit light. In various
embodiments, the combination can emit either a single or a narrow
band of light, or the combination can emit multiple wavelengths or
multiple narrow bands of light. Moreover, in various embodiments,
multiple biological materials can be received by the interior
volume 620. In either case, when multiple wavelengths or multiple
narrow bands are emitted, they can be detected by photosensitive
material.
[0079] For example, a first biological material can produce a first
wavelength. Similarly, a second biological material can produce a
second wavelength. Each of the first and second wavelengths can be
optically coupled to the photosensitive material 440, and they can
be detected and resolved by the detection system.
[0080] The photosensitive material can generate a signal that is
representative of the emitted light. The signal can then be
processed by processor 660. Processor 660 then generates a data
signal that can be displayed on display 650 in a visual format
readable by a user.
Example
[0081] FIGS. 8 and 9 show the results of an example of a detection
cell for biological material. A 2.5 microliter luminescent reaction
was set up containing 2.times.10-13 moles of pyrophosphate, ATP
sulfurlase, adenosine-5'-O-phosphosulfate and luciferase. The
reaction was combined in a tube and then introduced into a glass
capillary (0.4 mm inside diameter, 0.86 outside diameter, 15 mm in
length). Light intensity produced by the reaction was quantified
using a Turner TD 20/20 luminometer. Luminescence was measured from
five different orientations of the capillary using the same
capillary and reaction. Each of the measurements were taking over
25 seconds. FIG. 8 shows the results of intensity over time. The
five data sets for the five orientations resulted in line 810
representing light from capillary wall and ends, line 830
representing light from one end of the capillary, line 840
representing light from the capillary wall only (ends taped with
black tape), line 820 representing light from one end of the
capillary (capillary wall covered by reflective tube holder), line
800 representing light from the capillary wall (ends taped with
black tape and covered by reflective tube holder). The data from
the chart of FIG. 8 is adjusted to determine the light emission
detected by the PMT as relative intensity versus capillary
orientation. FIG. 9 shows the average real-time data stream over
the 25 seconds. The relative intensity block 900 representing the
light from the capillary wall was significantly less than the
relative intensity block 910 representing the light from one
capillary end. Hence, the capillary was able to act as a light
guide and concentrate the emission light to ends of the
capillary.
[0082] For the purposes of this specification and appended claims,
unless otherwise indicated, all numbers expressing quantities of
ingredients, percentages or proportions of materials, reaction
conditions, and other numerical values used in the specification
and claims, are to be understood as being modified in all instances
by the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the following specification
and attached claims are approximations that may vary depending upon
the desired properties sought to be obtained by the present
invention. At the very least, and not as an attempt to limit the
application of the doctrine of equivalents to the scope of the
claims, each numerical parameter should at least be construed in
light of the number of reported significant digits and by applying
ordinary rounding techniques.
[0083] Notwithstanding that the numerical ranges and parameters
setting forth the broad scope of the invention are approximations,
the numerical values set forth in the specific examples are
reported as precisely as possible. Any numerical value, however,
inherently contains certain errors necessarily resulting from the
standard deviation found in their respective testing measurements.
Moreover, all ranges disclosed herein are to be understood to
encompass any and all subranges subsumed therein. For example, a
range of "1 to 10" includes any and all subranges between (and
including) the minimum value of 1 and the maximum value of 10, that
is, any and all subranges having a minimum value of equal to or
greater than 1 and a maximum value of equal to or less than 10,
e.g., 5.5 to 10.
[0084] It is noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the," include
plural referents unless expressly and unequivocally limited to one
referent. Thus, for example, reference to "a photosensitive
material" includes two or more photosensitive materials.
Furthermore, the use of the term "including", as well as other
forms, such as "includes" and "included", is not limiting.
[0085] It will be apparent to those skilled in the art that various
modifications and variations can be made to various embodiments
described herein without departing from the spirit or scope of the
present teachings. Thus, it is intended that the various
embodiments described herein cover other modifications and
variations within the scope of the appended claims and their
equivalents.
* * * * *