U.S. patent application number 15/814380 was filed with the patent office on 2018-03-29 for high sensitivity medical device and manufacturing thereof.
This patent application is currently assigned to Banpil Photonics, Inc.. The applicant listed for this patent is Banpil Photonics, Inc.. Invention is credited to Achyut K. Dutta.
Application Number | 20180088116 15/814380 |
Document ID | / |
Family ID | 50547593 |
Filed Date | 2018-03-29 |
United States Patent
Application |
20180088116 |
Kind Code |
A1 |
Dutta; Achyut K. |
March 29, 2018 |
HIGH SENSITIVITY MEDICAL DEVICE AND MANUFACTURING THEREOF
Abstract
A sensing device able to do concurrent real time detection of
different kinds of specimens of living beings, chemical,
biomolecule agents, or biological cells and their respective
concentrations using optical principles. The sensing system can be
produced at a low cost (below $1.00) and in a small size (.about.1
cm.sup.3). The novel sensing system may be of great value to many
industries, for example, medical, forensics, and military. The
fundamental principles of this novel invention may be implemented
in many variations and combinations of techniques.
Inventors: |
Dutta; Achyut K.;
(Sunnyvale, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Banpil Photonics, Inc. |
Santa Clara |
CA |
US |
|
|
Assignee: |
Banpil Photonics, Inc.
Santa Clara
CA
|
Family ID: |
50547593 |
Appl. No.: |
15/814380 |
Filed: |
November 15, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13843857 |
Mar 15, 2013 |
9851353 |
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15814380 |
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13041433 |
Mar 6, 2011 |
8641975 |
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13843857 |
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11552080 |
Oct 23, 2006 |
7922976 |
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13041433 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 21/774 20130101;
G01N 2021/058 20130101; G01N 33/56988 20130101; G01N 21/05
20130101; G01N 33/54373 20130101; G01N 2021/0346 20130101; G01N
33/56983 20130101 |
International
Class: |
G01N 33/569 20060101
G01N033/569 |
Claims
1. A sensing device comprising: a removable section, wherein said
removable section comprising: a nanochip having a first waveguide
with a core and a cladding, said cladding having a periodic
dielectric system that forms a photonic bandgap; an inlet for
specimens; a blood filtration system for separating plasma, wherein
said blood filtration system is configured to allow the separated
plasma to contact said nanochip; an outlet for specimens; and a
plurality of receptors for interacting with a specimen to be
sensed, said receptors disposed in the periodic dielectric system
of the cladding; a main body, wherein said main body comprising: a
substrate; a light source; a detector for converting optical
signals into electrical signals; at least one electrical processing
circuit for processing electrical signals received from the
detector, said electrical processing circuit configured to output a
first signal and a second signal, wherein the first signal
corresponds to the intensity of the optical signal passing through
the first waveguide without the specimen interaction with the
plurality of receptors, and the second signal corresponds to the
intensity of an optical signal passing through the first waveguide
with the specimen interaction with the plurality of receptors; at
least one monitoring system for determining the concentration of a
specimen based on signals received from the electrical processing
circuit, said monitoring system configured to calculate a ratio of
the first signal and the second signal, correlate said ratio to a
change in effective refractive index of the cladding resulting from
specimen interaction with the receptors, and correlate the change
in effective refractive index to the concentration of the specimen;
and a second waveguide for guiding optical signals from said light
source to said nanochip;
2. The sensing device of claim 1, further comprising at least one
display unit.
3. The sensing device of claim 1, further comprising a third
waveguide for guiding optical signals from said nanochip to said
detector.
4. A sensing device comprising: a removable section, wherein said
removable section comprising: a nanochip having a first waveguide
with a core and a cladding, said cladding having a periodic
dielectric system that forms a photonic bandgap; an inlet for
specimens; a blood filtration system for separating plasma, wherein
said blood filtration system is configured to allow the separated
plasma to contact said nanochip; an outlet for specimens; and a
plurality of receptors for interacting with a specimen to be
sensed, said receptors disposed in the periodic dielectric system
of the cladding; a main body, wherein said main body comprising: a
substrate; a light source; a detector for converting optical
signals into electrical signals; at least one electrical processing
circuit for processing electrical signals received from the
detector, said electrical processing circuit configured to output a
first signal and a second signal, wherein the first signal
corresponds to the intensity of the optical signal passing through
the first waveguide without the specimen interaction with the
plurality of receptors, and the second signal corresponds to the
intensity of an optical signal passing through the first waveguide
with the specimen interaction with the plurality of receptors; at
least one monitoring system for determining the concentration of a
specimen based on signals received from the electrical processing
circuit, said monitoring system configured to calculate a ratio of
the first signal and the second signal, correlate said ratio to a
change in effective refractive index of the cladding resulting from
specimen interaction with the receptors, and correlate the change
in effective refractive index to the concentration of the specimen;
at least one display unit; a second waveguide for guiding optical
signals from said light source to said nanochip, and; a third
waveguide for guiding optical signals from said nanochip to said
detector;
5. The sensing device of claim 4, wherein said plurality of
receptors are HIV-1 aptamers or antigens chosen for binding with
HIV-1 TAT protein.
6. The sensing device of claim 4, wherein said aptamer are selected
from the group consisting of aptamers-RNATat, aptamer-derived
second strand and combination thereof.
7. The sensing device of claim 4, comprising at least two nanochips
and/or at least two detectors, wherein each of said at least two
nanochips utilizes a different type of the plurality of
receptors.
8. The sensing device of claim 4, wherein the electrical processing
circuit comprises: an electrical signal integration circuit for
integrating electrical signals received from the detector over
time; a filter and sample-counter circuit for removing electrical
noise from the signals received from the electrical signal
integration circuit and generating corresponding digital signals;
and a read out circuit for storing digital signals received from
the filter and sample-counter circuit.
9. The sensing device of claim 4, wherein the electrical signal
integration circuit comprises: a transimpedance amplifier (TIA); a
first switch and a second switch; an analog memory; a first
integrator circuit and a second integrator circuit; a first
comparator and a second comparator; and a differentiator, wherein:
the TIA feeds through the first switch, through the analog memory,
to the first integrator circuit; the first integrator circuit feeds
to the first comparator, which is reset back to the first
integrator circuit; the first comparator feeds into the monitoring
system; the TIA feeds through the second switch to the
differentiator; the analog memory feeds to the differentiator; the
differentiator feeds to the second integrator circuit; the second
integrator circuit feeds to the second comparator, which is reset
back to the second integrator circuit; and the second comparator
feeds to said monitoring system.
10. The sensing device of claim 4, wherein the filter and
sample-counter circuit comprises: a common clock for generating a
clock signal; a first filter for filtering signals received from
the first comparator; a second filter for filtering signals
received from the second comparator; a first sample counter for
comparing signals received from the first comparator to signals
received from the first filter; and a second sample counter for
comparing signals received from the second comparator to signals
received from the second filter.
11. The sensing device of claim 4, wherein said blood filtration
system comprises: an inlet channel for inserting a blood sample,
wherein said inlet channel reduces gradually to a small narrower
channel; an output channel, wherein said output channel is wider
than said small narrower channel; and a microfluidic channel
connected laterally to said output channel for collecting separated
plasma.
12. A sensing device comprising: a removable section, wherein said
removable section comprising: a nanochip having a first series of
one or more waveguides, each with a core and a cladding, said
cladding having a periodic dielectric system that forms a photonic
bandgap; an inlet for specimens; a blood filtration system for
separating plasma, wherein said blood filtration system is
configured to allow the separated plasma to contact said nanochip;
an outlet for specimens; and a plurality of receptors for
interacting with the specimen to be sensed, said receptors disposed
in the periodic dielectric system of the cladding; a main body,
wherein said main body comprising: a substrate; a light source; a
splitter wherein the splitter splits a optical signal from the
light source to at least one optical signal, wherein the at least
one optical signal is passed to the first series of one or more
waveguides; at least one detector for converting the at least one
optical signal to at least one electrical signal; at least one
electrical processing circuit for processing the at least one
electrical signal received from the at least one detector, wherein
the electrical processing circuit outputs a first signal and a
second signal, wherein the first signal corresponds to the
intensity of the optical signal passing through the first series of
one or more waveguides without the specimen interaction with the
plurality of receptors, and the second signal corresponds to the
intensity of an optical signal passing through the first series of
one or more waveguides with the specimen interaction with the
plurality of receptors; at least one monitoring system for
determining the concentration of a specimen based on signals
received from the electrical processing circuit, wherein said
monitoring system calculates a ratio of the first signal and the
second signal, correlate said ratio to a change in effective
refractive index of the cladding resulting from the specimens
interaction with the receptors, and correlate the change in
effective refractive index to the concentration of the specimen; at
least one display unit; a second series of one or more waveguides
for guiding the at least one optical signal from the splitter to
said nanochip; and a third series of one or more waveguides for
guiding the at least one optical signal from said nanochip to the
at least one detector.
13. The sensing device of claim 12, wherein said plurality of
receptors are chosen for binding with HBsAg, anti-HBs, HBeAg,
anti-HBe, HBcAg, anti-HBc, or a combination thereof.
14. The sensing device of claim 12, comprising a plurality of
nanochips, and a plurality of detectors, wherein each of said
plurality of nanochips utilizes a different type of receptors.
15. The sensing device of claim 12, wherein the electrical
processing circuit comprises: an electrical signal integration
circuit for integrating electrical signals received from the
detector over time; a filter and a sample-counter circuit for
removing electrical noise from the signals received from the
electrical signal integration circuit and generating corresponding
digital signals; and a read out circuit for storing digital signals
received from the filter and sample-counter circuit.
16. The sensing device of claim 15, wherein the electrical signal
integration circuit comprises: a transimpedance amplifier (TIA); a
first switch and a second switch; an analog memory; a first
integrator circuit and a second integrator circuit; a first
comparator and a second comparator; and a differentiator, wherein:
the TIA feeds through the first switch, through the analog memory,
to the first integrator circuit; the first integrator circuit feeds
to the first comparator, which is reset back to the first
integrator circuit; the first comparator feeds into the monitoring
system; the TIA feeds through the second switch to the
differentiator; the analog memory feeds to the differentiator; the
differentiator feeds to the second integrator circuit; the second
integrator circuit feeds to the second comparator, which is reset
back to the second integrator circuit; and the second comparator
feeds to said monitoring system.
17. The sensing device of claim 15, wherein the filter and/or
sample-counter circuit comprises: a common clock for generating a
clock signal; a first filter for filtering signals received from
the first comparator; a second filter for filtering signals
received from the second comparator; a first sample counter for
comparing signals received from the first comparator to signals
received from the first filter; and a second sample counter for
comparing signals received from the second comparator to signals
received from the second filter.
18. The sensing device of claim 12, wherein the monitoring system
comprises: a digital divider circuit for calculating said ratio;
and an n-bit digital signal processing (DSP) unit for determining
concentration of the specimen based on said ratio.
19. The sensing device according to claim 12, further comprising a
microfluidic system for allowing specimen to move from said inlet
to said nanochip.
20. The sensing device of claim 12, wherein the splitter is coupled
to the light source and wherein the at least one optical signal is
passed to the second series of one or more waveguides.
Description
[0001] This application is a continuation of pending U.S. patent
application Ser. No. 13/843,857, filed on Mar. 15, 2013, which is a
continuation-in-part of U.S. patent application Ser. No.
13/041,433, filed on Mar. 6, 2011 (now U.S. Pat. No. 8,641,975),
which is a divisional application of U.S. patent application Ser.
No. 11/552,080, filed on Oct. 23, 2006 (now U.S. Pat. No.
7,922,976). This present application is also related to U.S. patent
application Ser. No. 14/145,806, filed on Dec. 31, 2013 (now U.S.
Pat. No. 9,680,046) which is a divisional of U.S. patent
application Ser. No. 13/041,433, filed on Mar. 6, 2011 (now U.S.
Pat. No. 8,641,975). This present application hereby claims the
benefit of these earlier filing dates under 35 U.S.C. .sctn.
120.
FIELD OF THE INVENTION
[0002] The present invention relates to high sensitivity sensor
devices and its related signal processing circuits to detect the
gas, biomolecules, or biochemical agents. More specifically, this
invention is related to sensor device comprising with at least one
nano-chip for application in biomedical and industrial
applications.
BACKGROUND OF THE INVENTION
[0003] A large benefit of this sensor according to this invention,
is that there can be several on a single wafer. It is a device able
to measure chemical agent concentrations at the part-per-billion
(ppb) level and accurately determine the biomolecule agent and
volume of biological cells present in human body. There is no
device in the state-of-art, which allows concurrent detection of a
chemical agent, biomolecule agent, and biological cell, all in a
single system.
[0004] There are various kinds of sensor system. FIG. 1 shows a
schematic representing the prior art of a sensor system 1 to detect
biological cells, biomolecule agents or chemical agents (hereafter
mentioned as specimen). The system 1 usually comprising with the
sensor cell 2, power supply 4, detector 6, and analyzer 8. The
system 1 usually detects or senses by detecting the electrical
signal 10 induced due to absorption of the specimen. Detector 6
will detect the output signal 10 and send to the analyzer 8 to
analyze the concentration of the specimen.
[0005] Several techniques can be found as the prior art for
detecting concentration of specimen (common term used hereafter
separately for chemical, biomolecule agents, or biological cells).
However, most of them are based on the standard electrical
technique wherein only single specimen is considered to detect. In
addition, most technique requires long time in detection and/or not
highly sensitive. The following, as a point of reference, are some
methods, which are already patented and described as biosensors,
used for detection of biological cells.
[0006] Peeters, in U.S. Pat. No. 6,325,904, (issued on Dec. 4,
2001), discloses a nanosensor, using an array of electrodes at the
atomic or nano scale (nanoelectrodes) level, formed by using
specific receptors. Utilizing the level of current flow while
specific biological cells attached determine the concentration. The
drawbacks of such technique are: (i) requiring STM to position the
receptor which time consuming fabricating such sensor, (ii)
requiring specific nano-scale level gap in between electrodes
containing receptor to conduct current, (iii) difficulties in
measuring low current level (corresponding to low concentration)
due to use of computer controlled technique, and (iv) requiring
high power due to using of computer controlled signal
processing.
[0007] Bornhop, et al., in U.S. Pat. No. 6,809,828, (issued Oct.
26, 2004), discloses an sensor system for detecting proteins or
DNA. Concentration is estimated based on the fringe pattern,
detected by the CCD camera in addition with laser beam analyzer.
Fringe pattern is usually depending on the laser intensity and
position of the CCD camera. The drawback of this technique are, (i)
in accuracy in concentration measurement as fringe pattern is
dependent on the laser intensity and position, (ii) difficulties in
low level concentration measurement due to difficulties in finding
small changes in fringe pattern, and (iii) complete system becoming
bulky as CCD camera, position sensor, and laser beam analyzer are
to be used.
[0008] Britton, Jr., et al., in U.S. Pat. No. 6,167,748, (issued
Jan. 2, 2001), discloses a technique for detecting the glucose
concentration in blood. Measurement of concentration is performed
based on standard technique of measuring the changes in
capacitance. Technique uses cantilever coated with the receptor for
absorbing the glucose. Main drawbacks are: (i) inability to detect
low level concentration as very low changes in the capacitive is
difficult to measure, and (ii) difficulties of detection of
different kind of biological cell at the same time as each
cantilever require different coating. Similar detection techniques
can also be found in other patents such as U.S. Pat. No. 6,856,125,
of Kermani (issued Feb. 15, 2005), U.S. Pat. No. 5,798,031 Charlton
et al., (issued Aug. 25, 1998), U.S. Pat. No. 5,264,103 of Yoshioka
et. al., (issued Nov. 23, 1993), and U.S. Pat. No. 5,120,420 of
Nankai et. al., (issued Jun. 9, 1992), in all of which capacitive
techniques are used to detect the concentration.
[0009] Chemical and biological sensors can be miniaturized using
nanowires or carbon nanotubes. Continued advances in nanoscience
and nanotechnology require tiny sensors and devices to analyze
small sample sizes. The following is a discussion of the prior art
in sensor fabrication.
[0010] After discussing the above issues pertaining to the
state-of-art biosensors, chemical sensors, and biomolecule sensors,
and methods of making them, we would now like to introduce a novel
technique where multiple chemical agents can concurrently be
detected in real time and the information can quickly be
transmitted to a main station and displayed. It is small in size,
so the end user may carry it anywhere to measure the biological
cell volume, protein, and biomolecule cells in a medical science
application and is also able to do concurrent real time detection
of different kinds of chemical agents.
[0011] Despite the advances in therapeutics and improved public
health measures, infectious diseases still remain the major cause
of morbidity and mortality in most parts of the world. Clinical
syndromes are rarely specific for single pathogens, so multiplexed
diagnostics provide good detection sensitivity, but are often slow,
bulky, expensive, and reliant on trained medical personnel. The
development of handheld diagnostic systems that can provide rapid
diagnosis for multiplexed detection of pathogens could
significantly contribute to the prevention and treatment of
infectious diseases.
[0012] Similarly, that same multiplexed detection technology can be
utilized to diagnose a single condition, such as HIV. Studies have
shown that people newly infected with HIV are most contagious
because of the initial high viral loads. However, early stage
detection is currently expensive and inaccurate. Many potentially
infected people cannot afford the laboratory testing necessary, or
cannot justify the cost due to the chances of a misdiagnosis. The
multiplexed sensor described herein, however, will be relatively
inexpensive, can be used by the average consumer, and will give
results quickly and accurately.
SUMMARY OF THE INVENTION
[0013] According to this current invention, it is an object to
provide a sensor system comprising with a sensor more specifically
relates to a novel nano-sensor. It is also object to provide the
embodiments including novel methods, systems, devices, and
apparatus for sensing one or more characteristics. One aspect of
the present invention is a sensor, which is capable of
distinguishing between different molecular structures in chemical
agents at the same time. It is also capable of distinguishing
between different types of biomolecule agents or biological cell
concentrations. It is capable of detecting the concentration of
different types of chemical agents, biomolecule agents, and
biological cells.
[0014] This present sensor system is based on any type waveguide,
including but not limited to: the slab waveguide, the ridge
waveguide, or a dielectric materials structure based waveguide. Its
bottom clad (hereafter mentioned as substrate) can be formed using
an array of various dielectric materials, structured periodically,
which can form the photonic-band-gap (PBG). In waveguide, the
guided light usually suffers radiation loss due to weak optical
confinement; this happens when the structure is not well optimized
or the structural parameters are interrupted. The sensor structure
is optimized for a fixed wavelength and is designed in such a way
that the propagation loss is minimal. Alternatively, according to
this invention, the sensor can also be designed to operate in
broadband light operation. In that case, the waveguide for
nano-chip can be designed to operate multi-mode of operation.
[0015] This sensor detects the concentration of gases (that exist
in air) based on the change in the effective refractive index of
the substrate caused when biomolecule gas/chemical agents fill the
air (or receptor) spaces. The changes in the effective refractive
index reduce the output optical power (measurable parameter). By
comparing the output optical power with the reference input optical
power, the proposed nanosensor can detect the biomolecule
gas/chemical agent concentration in ppb levels.
[0016] It is noted here that the type of chemical agent/gas can be
specified by using a fixed receptor specifically made for absorbing
said agent/gas. Also, the type of biomolecule agent or biological
cell can be specified by using a fixed receptor to absorb the said
biomolecule agent or biological cell. The concentration of the
agent/gas and the biomolecule agent, and the volume of biological
cells can be ascertained by measuring the output optical power,
which is a function of the change in effective refractive index and
density. In this case, the detector will detect the presence of a
chemical agent/gas or a biomolecule agent or a biological cell.
Then it will generate an electrical signal, which will be processed
through a processing circuit. After the processing circuit, a
digital monitoring system will display the actual concentration
present via LED.
[0017] The materials used for the nanosensor and surrounding
surfaces are selected based on their electrical and chemical
properties. The PBG arrays may be included in a chamber, which can
retain fluid for biological applications; another set of arrays can
be used for chemical agents/gas detection. Several arrays may be
used in a single chamber and several different chambers may be used
in a single chip. Thus, one system may detect chemical agents/gas,
biomolecule agents, and biological cells.
[0018] This proposed PBG based nanosensor array and chamber as
attached should be separated from each other on a chip, so that
each system works properly for each individual application. A
Digital Signal Processing (DSP) function, Analog to Digital
Converter (ADC), and microprocessor are provided to analyze signals
from the nanosensors and/or do real time calculations of the
accurate values obtained from the nanosensor.
[0019] In some other embodiments a communication setup is used in
order to relay the output values long distances. This communication
setup is included to analyze the real time sensing values
remotely.
[0020] Further embodiments, forms, features, objects and advantages
of the present invention will be apparent from the following
description.
[0021] Further, two specific embodiments for medical application
are included. First, described is an embodiment for detecting
pathogens, such as Hepatitis B (HBV), through testing of blood,
saliva, or other body tissue. Second, described is an embodiment
for detecting HIV in the blood.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The features and advantages of the present invention will
become apparent from the following detailed description of the
system, taken in conjunction with the accompanying drawings,
wherein
[0023] FIG. 1 is a schematic of sensor system in prior art.
[0024] FIG. 2 are the block diagrams representing the schematic of
the sensor system for detecting the gas, bio-molecule, or
biological cell concentration.
[0025] FIG. 3A is a enlarged view of a nano-chip comprising with a
waveguide based on photonic bandgap (or photonic crystal)
structures having rectangular lattice, according to this invention,
and
[0026] FIG. 3B is a cross-section view across AA' as shown in FIG.
3A.
[0027] FIG. 4 is a schematic diagram of a nano-chip comprising with
a waveguide based on photonic bandgap (or photonic crystal)
structures having triangular lattice according to this invention,
and FIG. 4B is a cross-section view across BB' as shown in FIG.
4A.
[0028] FIG. 5 is a schematic diagram of a nano-chip comprising with
a waveguide based on photonic bandgap (or photonic crystal)
structures having rectangular lattice, according to this invention,
and FIG. 5B is a cross-section view across CC' as shown in FIG. 5A.
where the PBG is rectangular in shape with holes and a slab
waveguide is used.
[0029] FIG. 6 is a schematic diagram of a nano-chip comprising with
a waveguide based on photonic bandgap (or photonic crystal)
structures having defects and rectangular lattice, according to
this invention, and FIG. 6B is a cross-section view across DD' as
shown in FIG. 6A.
[0030] FIG. 7 is a schematic diagram of a nano-chip comprising with
a waveguide based on photonic bandgap (or photonic crystal)
structures having defects, according to this invention.
[0031] FIG. 8 is schematic of interconnection between the nano-chip
and its detector.
[0032] FIG. 9 is the block diagram representing an example of an
electrical signal processing circuit to detect the specimen,
according to this invention.
[0033] FIG. 10A is a schematic representing a integration circuit
unit for signal pre-processing, a part of processing circuit, as
shown in FIG. 9, according to this invention, and FIGS. 10B and 10C
are output signals at points A and B, shown in FIG. 10A.
[0034] FIG. 11A is a schematic representing a filter circuit unit,
a part of signal post processing, according to this invention, and
FIGS. 11B and 11C are output signals showing with capture points,
with and without specimen absorption.
[0035] FIG. 12 is a schematic representing a read-out circuit used
to store the reference signal.
[0036] FIG. 13 is a block diagrams representing monitoring unit
according to this invention.
[0037] FIG. 14 is a schematic representing an alternative read-out
circuit to store the reference signal.
[0038] FIG. 15 is a schematic showing an example of a complete
sensor device for multiple specimens' detection, according to this
invention.
[0039] FIG. 16 is a schematic showing an example of a complete
sensor device, packaged in small form-factor, according to this
invention.
[0040] FIG. 17 is a schematic showing the manufacturing process for
the photonic crystal.
[0041] FIG. 18 is a schematic showing an embodiment including a
blood filtration system on a disposable test strip.
[0042] FIG. 19 is a detailed illustration of a potential
embodiment, based on the schematic shown in FIG. 18.
[0043] FIG. 20A is a diagram of the functionality of HIV-1
RNA.sup.TAT aptamers as bioreceptors for HIV-1 TAT protein
binding.
[0044] FIG. 20B is a diagram of the functionality of HIV-1 antigens
as bioreceptors for binding with antibodies.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0045] In the following detailed description of the preferred
embodiments, reference is made to the accompanying drawings, which
form a part hereof, and in which is shown by way of illustration
specific preferred embodiments in which the inventions may be
practiced. These embodiments are described in sufficient detail to
enable those skilled in the art to practice the invention and it is
to be understood that other embodiments may be utilized. The
following detailed description is, therefore, not to be taken in a
limiting sense, and the scope of the present invention is defined
only by the appended claims.
[0046] According to this current invention, it is our objective to
provide a sensing device comprising with nano-sensor and its signal
processing circuit which can have the significantly high
sensitivity. The sensor device detects the specimen concentration
based on the principle of optics. Using of the nano-sensor and
signal processing circuit, according to this invention, high
sensitivity can be achieved. Detection is mainly based on detecting
the difference in intensity of optical signal obtained after
specimen absorb in the receptor and converting to electrical signal
and their arithmetic processing to achieve significant high
sensitivity.
[0047] FIG. 2 shows a block diagram of the system according to this
invention. In block diagram 22, input optical signal 14 is
generated from a laser 12 having a wavelength ranging from
ultra-violet to infrared. The signal 14 will pass through the
nano-chip 16(a, b, c, d, e). For a unique and optimized design
(with no presence of specimen or sample) intensity of output
optical power 18 from the nano-chip 16(a, b, c, d, e) can be same
as that of input optical power 14. This means that the coupling
loss though the nano-chip is be zero. The presence of the specimen
or sample inside of the nano-chip 16(a, b, c, d, e) will cause a
reduction in the output optical power 18, detected by the detector
20. The reduction in output optical power 18, if any, is due to the
change in the refractive index of the receptors with and without
absorption of the specimen. The receptor is usually contained in
the nano-chip 16(a, b, c, d, e), explained later in FIG. 3. The
detector 20 is used to convert the optical signal 18 into an
electrical signal 26 and the said electrical signal 26 is processed
through the processing circuit 28, explained later in detail in
FIGS. 9-13. The resultant signals 29(a) and 29(b) from said
processing circuit 28 is passed through digital signal processing
circuit (DSP) 30 where related arithmetic function can be performed
to monitor actual concentration of the specimen in real time.
Details of the DSP circuits are provided in FIG. 13.
[0048] According to this invention, the processing circuit can be
made in hybrid using different functional chips or using single
chip having all functions, and those can be fabricated from 350 nm
or less geometry. The detector can be chosen based on the
wavelength of the light to be used in the system 22. For example,
if the wavelength is selected in visible region, the
silicon-detector can be used in system 22. On the other hands, if
the wavelength of near infrared is chosen, then the detector made
from III-V compound semiconductor is required for having higher
sensitivity.
[0049] According to this invention, the system 22 can be
miniaturized into a very small package (e.g. less than 1 to 0.5
inches in dimension). The main advantage of the system 22,
according to this invention, is that only the power of output
optical signal 18 needs to be known in order to ascertain the
concentration. In system 22, very little power will be absorbed by
the nano-chip and this is based on the percentage of the refractive
index change. The system 22 has two parts: the first is a
`detection part` comprising of laser 12, nano-chip 16(a, b, c, d,
e), and the detector 20; the second is an `analyzing part`,
comprising of signal processing circuits 28 and 30.
[0050] According to this invention, different nano-chips 16(a, b,
c, d, e) are explained in FIGS. 3 to 7. FIG. 3A shows a schematic,
representing the enlarge view of a nano-chip 16a and FIG. 3B is the
cross-sectional view of section AA', as shown in FIG. 3A. According
to this invention, the nano-chip 16a can be made from photonic
crystal comprising of dielectric rods 32 arranged periodically in
hollow clad 33 (hereafter we define clad as a substrate with a
refractive index `n.sub.sub`) to form a photonic-band-gap (PBG)
structure, having rectangular lattice 34. The nano-chip 16a has
waveguide structure having core 35 having refractive index of
`n.sub.core`. Each rod 32 has a radius of `r` (from 0.1 .mu.m to
0.3 .mu.m or may be in different size depending on the design) and
they are separated by a distance `a` (known as pitch or lattice
constant) 36, which is equal to or greater than `2r`. Receptors 40
can be placed in-between the spaces of the rods 32 in hollow clad
33.
[0051] Receptors 40, shown in FIG. 3 (For example:
ACh--Acetylcholine covers for nerve agents, AH--Aromatic
Hydrocarbon, etc.) can be used inside the nano-chip 16(a, b, c, d,
e). Here, receptor 40 is used to detect the type of specimen and
they absorb/interact with the respective specimen (e.g. biomolecule
or chemical agents or biological cell) present in between the
spaces of the dielectric rods.
[0052] Each rod 32 has a refractive index `n` which can be either
equal to `n.sub.core` or refractive index `n` can be greater or
less than the core refractive index n.sub.core'. Optical signal
input 14 to nano-chip 16a is transmitted through the core 35. Based
on the absorption of the specimen (not shown here) by the receptor
40 located in the space between the rods 32, the refractive index
of the substrate `n.sub.sub` in combination with hollow clad 33 and
receptor 40 is changed to `n.sub.eff`, the effective refractive
index, and as a result, the power output optical signal 18 is
reduced. The concentration of the specimen can be determined by
calculating the change of the refractive index of the receptors 40
after and before of absorption of the specimen and the changes in
power of the optical signal 18 with respect to input optical signal
14. Changes in power of optical signals between 14 and 18 can be
determined by the power-factor, which is defined as the ratio of
the output optical power over the input optical power. According to
this invention, the main advantage is that by knowing the power
factor, the changes in refractive index and also the concentration
of the specimen can be determined. By calculating the power-factor,
this proposed sensor would give the real-time concentration of the
specimen.
[0053] Nano-chip 16a used for system 22 is based on
photonic-crystal and they are having different structures.
Two-dimensional (2-D) or three-dimensional (3-D) photonic crystal
can be used to fabricate the nano-chip 16a. In FIG. 3A, the
photonic crystal is formed based on the dielectric rods 32.
Alternatively, the photonic crystal can be also made from holes,
periodically arranged inside the dielectric materials.
[0054] FIG. 4A shows a schematic, representing the enlarge view of
an alternative nano-chip 16b and FIG. 4B is the cross-sectional
view of section BB', as shown in FIG. 4A, according to this
invention wherein the same numerals in FIGS. 4A and 4B represent
the same parts in FIGS. 3A and 3B, so that repeated explanation is
omitted here. Only difference in FIGS. 4A and 4B as compared with
FIGS. 3A and 3B is that the photonic crystal is made from the
dielectric rods 32 placed in hollow clad 33, wherein the rods 32 is
having the triangular lattice 44.
[0055] FIG. 5A shows a schematic, representing the enlarge view of
an alternative nano-chip 16c and FIG. 5B is the cross-sectional
view of section CC', as shown in FIG. 5A, according to this
invention, wherein the same numerals in FIGS. 5A and 5B represent
the same parts in FIGS. 3A, 3B 4A, and 4B, so that repeated
explanation is omitted here. The main difference in FIGS. 5A and 5B
as compared with FIGS. 3A, 3B, 4A, and 4B is that the photonic
crystal is based on the holes 51 periodically arranged inside the
slab acting as the clad 53, wherein the holes 51 are filled up with
the receptors 40 and also the holes 51 is having the rectangular
shaped lattice 50. According to this invention, optical signal 14
is guided through the slab-type waveguide 48 located inside slab
(or clad) 53. Each hole 51 in nano-chip 16c has a radius of `r` and
they are separated by a distance `a` (also known as lattice
constant) 52. Inside each hole, receptors 40 are present to
absorb/interact with the specimen/sample. 54 shows the cross
sectional view of this nano-chip 16c. The nano-chip can also be
designed by making holes in a triangular shape. Specification of
the radii of the holes `r` and lattice constant `a` 52 will be
optimized depending on the size of the nano-chip 16c.
[0056] FIG. 6A shows a schematic, representing the enlarge view of
an alternative nano-chip 16d and FIG. 6B is the cross-sectional
view of section DD', as shown in FIG. 6A, according to this
invention, wherein the same numerals in FIGS. 6A and 6B represent
the same parts in FIGS. 3A, 3B 4A, 4B, 5A, and 5B, so that repeated
explanation is omitted here. The main difference in FIGS. 6A and 6B
as compared with FIGS. 5A and 5B is that the nano-chip 16d is also
based on photonic crystal, but comprising with defects 56 in the
holes periodically structure in the core 57. "Defects in the
holes," means that the diameter of some holes is bigger than the
diameter of the `regular` holes, all structured periodically.
According to this invention, the defects 56 can also be filled with
the receptor 40 and they can be created either using of holes 56,
as shown in FIGS. 6A and 6B, or using of the solid rods having
specific radius (not shown here).
[0057] FIG. 7 shows a schematic, representing the enlarge view of
an alternative nano-chip 16e, according to this invention, wherein
the same numerals in FIG. 7 represent the same parts in FIGS. 6A
and 6B, so that repeated explanation is omitted here. The main
difference in FIG. 7 as compared with FIGS. 6A and 6B is that the
nano-chip 16e is based on the solid slab 58 acting as the clad and
the core 59 to guide the optical signal 14, comprises with holes as
defects 60 arranged periodically inside core 59 forming photonic
band gap structure. As mentioned earlier, any type of specimen can
be detected and their concentration can be known after processing
the output optical signal 18 from nanochip. Type and concentration
of any specimen such as gases, biomolecules, or any biological
cells can be detected by making them to absorb on corresponding
receptor 40 to be used in the holes 60.
[0058] The nano-chip 16(a, b, c, d, and e), can be fabricated using
dielectrics, semiconductor, or polymer materials. The dielectric
material can cover all kind of materials having dielectric or
optical properties (e.g. refractive index), such as glass, quartz,
polymer etc. According to this invention, alternatively, the
nano-chip can also be fabricated from semiconductor materials, such
as Si, GaAs, InP, GaN, SiC, diamond, graphite etc. which can be
fabricated using standard's IC fabrication technology. This
nano-chip itself can be from rigid or flexible substrate.
[0059] The nano-chip can be fabricated by standard dry or wet
etching to form the holes or rods embedded inside the solid or
hollow substrate. Alternatively, this can also be fabricated using
spin-coated polymer or preformed polymer. The low shrinkage in
polymerization and the transparency of the synthesized polyurethane
can also be used in fabrication of infiltrated inverse opal
elastomeric photonic-crystal structures for the nano-chip according
to this invention. The nano-chip 16 (a, b, c, d, and e) can have
high-symmetry cross-sections and can allow integrated optical
networks to be formed by only placing either the rods in air or air
cylinders in the dielectric. The nano-chip 16 can also be
fabricated in multiple layers by stacking the slabs on top of one
another, separating them with a separator. According to this
invention, the nano-chip 16(a, b, c, d, and e) and surrounding
circuitry can be made into the single chips using today's IC
process technology.
[0060] The specific specimen can be detected using the nanochip
with specific receptor. For example, Avidin Biotin which is the
most common uses as a receptor for glycoconjugate analysis and DNA
detection systems, can be used also as the receptor 40 in the
nanochip 16(a,b,c,d, and e). Single receptor agent or solution
linked with other molecule acting as the receptor (for the specific
specimen) can also be used as receptor 40. For example,
Dimethylsulfoxide (DMSO) solution containing 4 mg/ml of the
heterobifunctional linker molecule succinimidyl-6-hexanoate
(biotinamido) for a 1 hour at room temperature and the resultant
receptor can be used as receptor 40 for DNA detection. According to
this invention, the receptor 40 can be gel-type, solid, or solution
based.
[0061] A derivation is given here for the generalized analytical
equation for the nanochip described earlier in FIGS. 3 to 7. This
derivation helps to understand the insight of this current
invention for high sensitivity sensor device. For simplicity in
derivation, nano-chip, as shown in FIG. 7, consisting of a ridge
waveguide in the core formed by periodically structured PBG, is
considered as the example and this nanochip can be considered as a
linear system. The waveguide structure is considered to be
optimized for providing almost same output optical power 18 for the
specific wavelength of the optical input 14. By knowing the output
optical power the concentration of the specimen (e.g. biological
cells, industrial gas, or biological cell agents) can be detected.
According to this current invention, nano-chip is considered to be
formed based on the 2-D photonic crystals. Related generalized
equations, required for determining specimen concentration is
described herewith. Noted here that type of specimen can be known
from the specific receptor 40, as explained earlier. The specific
receptor is used for specific link or bond.
[0062] According to this invention, the waveguide structure is to
be designed in such a way that maximum optical power for optical
signal 18 is achieved (or very to optical power of input optical
signal 14), and that condition (or optical power) can be considered
as the reference (i.e. with specimen present) in the holes. The
symbol used in derivation is summarized in Table I.
TABLE-US-00001 TABLE I Description of the symbols used in
derivation Parameter Description n.sub.cref Reference refractive
index of the core n.sub.ceff Effective (new) refractive index of
the core N Gladstone-Dale constant P.sub.in Input optical Power
P.sub.out Output Optical Power Power Factor = P.sub.out/P.sub.in
Ratio of output optical power and input optical power .rho..sub.ref
Reference density (air or filled with receptor) .rho..sub.new New
density after specimen absorbed .DELTA..rho. Change in density
[0063] For linear system with ridge waveguide, Power Factor, ratio
of output optical power (P.sub.out) to input optical power can be
derived as follows:
Power Factor = P out P i n = 1 - n cref 2 - n ceff 2 n cref 2 - n
clad 2 ( 1 a ) ##EQU00001##
[0064] Where, n.sub.cref is the reference refractive index of the
core with optimized waveguide. n.sub.ceff is the effective
refractive index of the core and n.sub.clad is the refractive index
of the clad. From Eq. (1a), coupling loss can be written as
Coupling Loss=1-Power Factor (1b)
[0065] Where, Coupling Loss is,
Coupling Loss = n cref 2 - n ceff 2 n cref 2 - n clad 2 ( 1 c )
##EQU00002##
[0066] From Eq. (1a), relationship between Power Factor and density
of the gas can be derived. The relationship between n.sub.cref,
reference core refractive index (with no gas condition) and
.rho..sub.ref, reference density of receptor can be expressed by
using of Gladstone-Dale relationship,
n.sub.cref-1=.rho..sub.ref.times.N (2)
where, N is the Gladstone-Dale constant
[0067] As mentioned earlier, after sensing the gas, the density of
the receptor .rho..sub.new, after absorbing the gas which changes
the effective refractive index of the substrate, nceff (mentioned
as new core effective refractive index). Similarly, nceff relates
with .rho..sub.new as,
n.sub.ceff-1=.rho..sub.new.times.N (3)
[0068] From Eqs. (2) and (3), this following expression can be
derived:
n cref - 1 n ceff - 1 = .rho. ref XN .rho. eff XN ( 4 )
##EQU00003##
[0069] From Eq. (4) n.sub.ceff expression can be derived as:
n ceff = 1 + ( n cref - 1 ) .rho. ref .rho. new ( 5 a )
##EQU00004##
[0070] After substituting Eq. (5a) into Eq. (1a), we get the new
density as follows:
.rho. new = [ n cref 2 - ( 1 - Power Factor ) ( n cref 2 - n clad 2
) - 1 ] .rho. ref ( n cref - 1 ) ( 5 b ) ##EQU00005##
[0071] Changes in density .rho. can be expressed as,
.DELTA..rho.=.rho..sub.new-.rho..sub.ref (6)
[0072] Concentration of the specific gas (considered here only for
the biomolecule or industrial gas) in ppm, which is a function of
the molecular weight and .DELTA..rho., and ppm can be written
as
ppm = .DELTA..rho. .times. 24.45 Molecular Weight ( 7 )
##EQU00006##
[0073] After substituting Eq. (6) into Eq. (7), the concentration
of gas in ppm can be expressed as:
ppm = ( .rho. new - .rho. ref ) ( 24.45 ) MolecularWeight ( 8 )
##EQU00007##
[0074] Now substitute value of .rho..sub.new in Eq. (8) and we can
derive ppm, which is
ppm = [ [ n cref 2 - ( 1 - PowerFactor ) ( n cref 2 - n clad 2 ) -
1 ] .rho. ref ( n cref - 1 ) - .rho. ref ] .times. ( 24.45 )
MolecularWeight ( 9 ) ##EQU00008##
[0075] Alternatively, particularly for medical diagnosis purposes,
the above calculations can instead be done to allow for sensing
target biomolecules in a non-gaseous form, and at even lower
concentrations, such as parts per billion (ppb).
ppb = [ [ n cref 2 - ( 1 - PowerFactor ) ( n cref 2 - n clad 2 ) -
1 ] .rho. ref ( n cref - 1 ) - .rho. ref ] .times. ( 0.024 )
MolecularWeight ( 10 ) ##EQU00009##
[0076] Potentially, biomolecules might be detectable in ppb or even
smaller concentrations, such as parts per trillion or even
quadrillion.
[0077] According to this invention, by knowing the power factor
(which is ratio of power of optical out 18 to power of optical in
12 to and from the nanochip 16, respectively to the optical input),
and appropriate arithmetic signal processing, the concentration of
the specimen can be known. According to this invention, the gas is
considered, it can be also be used for biomolecule gas, or
biomolecule cells, if corresponding receptor is used. From FIGS. 8
to 14, the signal processing for detecting small change in power
factor are given. FIGS. 15 and 16 explain the sensor device
according to this invention.
[0078] FIG. 8 shows a schematic representing the nano-chip and its
detection block diagram according to this invention wherein same
numerals represents the similar parts shown in FIGS. 2, 3, 4, 5, 6,
and 7, so that similar explanation is omitted here. In FIG. 8, the
optical signal 18 from nano-chip 16 (a, b, c, d, or e) is detected
by the (optical) detector 61 to convert into corresponding
electrical signal 26. The detector 61 should be selected based on
the wavelength of the light used in the nano-chip. For example, for
visible wavelength, Si-based photodetector can be used which can
provide quantum efficiency close to 100% over visible wavelength.
For Near infrared wavelength, III-V compound semiconductor based
detector can be used.
[0079] Photodiodes can be used in either zero bias or reverse bias.
In zero bias, light falling on the diode causes a voltage to
develop across the device, which leads to current flowing in the
forward bias direction. Diodes usually have extremely high
resistance when reverse biased. This resistance is reduced when
light of an appropriate wavelength incident onto the junction.
Hence, a reverse biased diode can be used to generate the photo
current. Circuit with reverse-biased detector is more sensitive to
light than one with zero-biased detector.
[0080] The detector can be p-n junction based detector or avalanche
photodiode (APD) detector, According to this invention; both type
photodetector (p-n or APD) can be used. Only difference is there
operational voltage. For example, APD requires high voltage and on
the other hands, p-n junction requires low voltage. By using of
APD, according to this invention, single photon level difference in
optical power between input to nano-chip and output from nano-chip
can be detected.
[0081] FIG. 9 shows the signal processing block diagrams according
to this invention wherein same numerals represents the similar
parts shown in FIG. 8, so that similar explanation is omitted here.
According to this invention, Electrical-processing circuit 28,
shown in FIG. 9, comprises with electrical signal integration
circuit 66, filtering and sample-counter circuit 68 to remove
electrical noise, and a read-out circuit 70 to store the data. Each
of these blocks 66, 68, and 70 are explained in details in FIGS.
10, 11, and 12. The electrical signal outputs from this
signal-processing unit 28 are reference signal 29(a) and signal
29(b) after specimen absorbed by the nano-chip. In absence of
specimen absorption, the electrical signals 29(a) and 29(b) are the
same.
[0082] FIG. 10A shows the integrated circuit block in details, of
the block diagrams, as shown in FIG. 9, and FIGS. 10B and 10C are
the waveforms of point A and B, as shown in FIG. 10A, according to
this invention wherein same numerals represent the similar parts
shown in FIGS. 8 and 9, so that similar explanation is omitted
here. The electrical integration circuit 66 means as shown in FIG.
10 is a part of the electrical processing circuits 28. According to
this invention, electrical integration circuit 66 means comprises
with transimpedance amplifier (TIA) 72, two sets of switches 77 and
78, a an analog memory 74 to store the reference value as reference
voltage 76, and two sets of integrator circuits 73(a) and 79(a),
two sets of comparators 73(b) and 79(b), and one differentiator
82.
[0083] According to this invention, the signal 26 input to TIA 72
of the integrated circuit 66 to have the proportional voltage
output V.sub.in. Initially, the switch S1 77 is on and switch S2 78
is off. While the Switch S1 77 is on, the proportional voltage
output V.sub.in, is directly feed through the analog memory 74 to
store the initial voltage as the reference voltage 76 (output of
analog memory 74). Noted here that the reference voltage V.sub.ref
can be either same or greater than that the proportional voltage
output V.sub.in. The reference voltage V.sub.ref is integrated by
the integrator 73(a) and its output is directly feed to the
comparator 73(b) whose other input is set to V.sub.ref. While the
integrator 73(a) output is reached to V.sub.ref, the comparator
73(b) output will reset the integrator 73(a). The resultant
waveform 63 from comparator 73(b) is saw-tooth type waveforms as
shown in FIG. 10B for the point A of FIG. 10A. The resultant
waveform 63 is acted as the output of V.sub.ref and mentioned here
as V.sub.out1, while there is no absorption of the specimen in the
nano-chip explained earlier. As soon as integration for the
pre-desired cycle (explained later in FIG. 10B) is completed, the
switch S1 77 is turned to OFF and at the same time S2 78 is turned
on and the output from the TIA 72 is directly feed to the
differentiator 82 whose other input is output 76 from Analog memory
74. The differences 80, output from the differentiator 82 is
similarly feed to the integrator 79(a), whose output is again feed
to the comparator 79(b). Noted here that other input to the
comparator 79(b) is V.sub.ref. The resultant waveform 65 is also
saw-tooth like waveform (mentioned as V.sub.out2), as shown in FIG.
10C (at point B) and it can be generated by the reset 81, as
mentioned earlier. The differences between two sets of circuits as
shown in FIG. 10A after and before switch S1 77 ON and OFF is that
they process the signals without and specimen absorption,
respectively. According to this invention, the output waveforms 63
and 65 comprises with stream of saw-tooth like waveforms 83(a) and
83(b) which can be processed for captured explained later in FIG.
12.
[0084] FIG. 11A is an example of the schematic showing the
Filter-circuit of processing circuits 28 blocks shown in FIG. 9,
according to this invention wherein the similar numerals represent
the same parts as shown in FIGS. 10A, 10B, and 10C. The filter
& sample-counter means block 68 is a part of the electrical
processing circuit 28 and comprises with an common clock signal 84,
two sets of filters 85(a) and 85(b), and two sets of sample
counters 86(a) and 86(b). Two sets are used to process the outputs
63 and 65 separately. The filter & sample-counter block 68 is
used to convert the waveforms achieved from the reference value 63
(with no specimen present) and new value 65 (with specimen
present). In FIG. 11A, "Filter" blocks 85(a) and (85(b) are used to
avoid glitches of the signals generated from the integrated
circuit, explained in FIG. 10A. The "Sampler & Counter" blocks
86(a) and 86(b) can be used to compare the values of "Filter"
blocks 85(a) and 85(b) to the values from the integrated circuit
66, in FIG. 10A.
[0085] FIGS. 11B and 11C show the output signals 63 and 65 with
capture time at different points for example at 87(a) and 87(b).
These two signals 63 and 65 will provide us with two saw-tooth
based waveforms with different slopes; represent the output signal
amplitude (not shown here). They can have the different time
intervals for example. t.sub.1, t.sub.2, t.sub.3 - - - t.sub.n,
total of `tn` for output signal 63 (no specimen absorption) and
t.sub.1', t.sub.2', - - - t.sub.n, total of the same time `tn` for
output signal 65 (with specimen absorption) for analysis. Several
techniques can be used to analyze the waveforms to detect the
concentration of the specimen absorbed. According to this
invention, certain capture point 87(a) and 87(b) in waveforms 63
and 65, respectively, can be used at different intervals and
different amplitude to avoid the noise, if any, presence in the
signals. The output signals from sampler and counter circuits 86(a)
and 86(b) after capturing can be the stream of the digital signals
88 as shown FIG. 11B, and 88 and 29(b) as shown in FIG. 11A. The
corresponding analog signals output from filter circuits 85(a) and
85(b) is an integrated signals 90(a) and 90(b), respectively.
[0086] FIG. 12 is the schematic showing an example of read-out
circuit, a part of processing circuits 28 blocks shown in FIG. 9,
according to this invention wherein the similar numerals represent
the same parts as shown in FIGS. 10A and 11A. The read-out circuit
means 70 shown in FIG. 12 averages the waveforms and then stores in
the memory. Signals 88 received for reference value, will be stored
into a read-out circuit 70, shown in FIG. 12, which is a part of
the electrical processing circuit 28, as shown in FIG. 9. Read-out
circuit 70 could be one for each of the reference value or specimen
value to store (not shown here). Alternatively, one read-out
circuit for reference value store can also be used which is used in
FIG. 9 as for example. Any number of bits can be used for read-out
circuit. As for example, a 12-bit circuit is considered in FIG. 12.
This read-out circuit 70 can be fabricated utilizing standard CMOS
process technology. For example, this read-out circuit can be
fabricating with standard 350 nm, 3.3 volt, and thin-oxide digital
CMOS process geometry or less. The data will come to each bit
(1-12) 91 of pass-gate transistor for storage. After the data is
stored in the transistor, read-out port 92 will give us the stored
values as outputs 29(a) for the reference value 88. This circuit
will have a `reset` line 93, so that we can flush out the older
data, if necessary. This circuit can be single transistor CMOS, p
and n-channel transistor CMOS, or capacitive based circuit, which
can be fabricated using conventional CMOS technology.
[0087] FIG. 13 is the schematics showing the block diagrams of the
monitoring system, according to the invention, wherein the same
numerals represent the same parts, explained in FIGS. 9, 10A, 11A,
and 12, so that repeated explanation is omitted here. This
monitoring system 30 comprise of several blocks such as: "Divider
for (1-Power Factor)" block 94, Digital Signal Processing (DSP)
unit 96, Digital to Analog Conversion (DAC) block 100, Radio
Frequency (RF) Transceiver block 102, Concentration Display block
104 and remote Station block 106 to monitor the analyzed value. The
RF unit 102 is for remotely monitor the specimen.
[0088] The signals 29(a) and 29(b) from the processing circuit unit
28 feed to the divider circuit 94 to calculate (1-power factor), as
shown in EQ. 9, and its resultant output signal 95 feeds to the
n-bit digital signal-processing unit 96, where n is the number of
the bit. Other inputs to DSP unit are known parameters such as
reference concentration (mentioned as background concentration of
the specimen, if any), other required refractive indices related to
the nano-chips, explained earlier. The DSP unit 96 is commercially
available from various vendors or the unit can be fabricated with
standard CMOS technology, depending on the specification criterion.
This DSP unit 96 includes a system controller for coordination. The
system controller of the DSP unit 96 may be chosen to be an n-bit
RISC/CISC-type processor, which is commercially available by
various vendors such as Texas Instrument, INtel. The processor and
system controller may share a memory for program and data
storage.
[0089] Output signals of the DSP block 96, which are digital
signals, can be converted into analog by using the "DAC" block 100.
Output signals from the "DAC" block 100 can be transmitted through
the "RF Transceiver" block 102. Signals from block 102 may be
wirelessly monitored from the remote "Station" block 106 by using
standard wireless protocol such as BLUETOOTH, 802.11a/b/g protocol
or other proprietary protocols. The system can be embed with the
standard (display) based monitoring unit 104 by feeding a part of
DSP signal to the monitoring unit 104 to monitor in real time the
concentration of the specimen.
[0090] According to this invention, whole processing unit can be
made into a single chip and can be fabricated using standard IC
technology. Alternatively, whole processing unit can be also build
hybridly.
[0091] According to this invention, FIGS. 9 to 13 explain the
signal-processing unit to monitor the specimen concentration. This
is given for example only. Various signal processing ways
(utilizing similar idea as shown in FIGS. 9-13) can be used to
monitor the specimen concentration. For example, alternatively,
single switch (single pole double through) can be used instead of
using two switches (S1 and S2), explained in FIG. 10A. In addition,
alternatively analog divider (not shown here) can also be used
instead of using digital divider 94, (shown in FIG. 13). Additional
analog to digital converter may require converting the resultant
analog signal after dividing by divider (not shown here).
[0092] According to this current invention, any microprocessor,
FPGA, or ASIC circuit can be used instead of DSP to perform the DSP
functionality. These are available from the commercial vendors. For
example, microprocessor can be obtained from Intel, FPGA from Actel
and Xilinx, and ASIC circuit could be custom designed for required
functionality, and it can be off-shore design and
manufacturing.
[0093] According to this invention, alternatively the read-out
memory circuit can be made based on capacitive load. FIG. 14 shows
a schematic diagram of an alternative read-out circuit, wherein
same numerals represent the same parts as shown in FIG. 12, so that
repeated explanation is omitted here. The difference of read-out
circuit as shown in FIG. 12 is that read-out circuit 118 in FIG. 14
is based on capacitive load 110 and a 1 to 1 switch 112. The
advantages of using this circuit are: low area and low power. At
least one 1 to 1 switch 112 and at least one capacitive load 110
can be used for single bit of memory. Input signal 88 can be stored
by each capacitor 110 and the stored values can be as output signal
29(a) as a reference (initial) value.
[0094] According to this invention, the signal processing unit and
the monitoring units both as shown in FIGS. 9 to 14 can be
fabricated monolithically into a single chip. Standard Si-CMOS
technology can be used for fabricating the signal processing and
monitoring chip either in single chip form or multiple chips. The
geometry of the silicon-CMOS technology can be ranged from 0.35
.mu.m 20 nm or less. The divider 94 can be designed in different
ways for example carry-save, Boolean, binary type or synthesis
library specific type, depending on the desired performance and
area.
[0095] FIG. 15 shows a schematic of the nano-sensing detection
system unit according to this invention wherein the same numerals
represent the same parts as explained in FIGS. 2 to 14, so that
repeated explanation is omitted here. The sensing means 120
comprises with at least one laser 12 connecting with electrical
driver 122 through electrical connection 124, splitter 126,
nano-chip 16(a, b, c, d, e), at least one detector 20, signal
processing unit 130, connecting with the external power supplies
through connection 132, and a common carrier substrate 134.
According to this invention, light 14 having fixed wavelength is
made to couple to the 1.times.k splitter 126 (where k is the number
of splitters which is at least one) to split the intensity of light
14 into k numbers and made to pass through the nano-sensor 16(a,b,
c, d and e). Alternatively, according to this invention, the
splitter and nano-chip can also be designed to operate in broadband
light. In that case, the waveguide is to be multi-mode to operate
in broad spectrum of light.
[0096] The splitter can be designed based on the photonics crystals
having rod or holes, arranged periodically to made photonic band
gap structure. Both splitter and nano-chips can have the same
photonic band gap structure or different, and they can be
fabricated on the common substrate 136. Alternatively, the splitter
can be designed based on the homogeneous (solid) substrate (without
photonics crystal) and the nano-chip can be based on photonic
crystal base. Again, they can be fabricated onto the common
substrate 136, or both splitter 126 and nanochip 16(a, b, c, d and
e) can be fabricated in separate substrates, and afterwards
hybridly packaged onto the common substrate (not shown here). To
detect different types of specimens. For example different
bio-molecules, different types of receptors can be used in the
nanochips. The outputs from each nanochip are made to incident to
the detector 20 to convert optical signal into corresponding
electrical signals (not shown here). The electrical signal is
processed by the IC 130 to determine the concentration of each
specimen. The electrical IC 130 can be single chip or multiple chip
based on the circuit means, as explained previously from FIGS. 9 to
14. All electrical components can be made into the single chip.
Optical chip comprising with the splitter and the waveguide, and
single chip can be packaged on the common substrate 134 to make the
small package of dimension below 1''.times.1''.times.0.5''
(W.times.L.times.H). A key feature of this system 120 is that
multiple sensors can be fabricated on a single wafer 136. Utilizing
the multiple sensor help to detect multiple specimens at the same
time. For example, one sensor can detect chemical agent sensor, the
second can be a biomolecule sensor, and the third can be a
biological cell detector, and so on. Other example could be a
single sensor unit can detect different gases or different types of
bio-molecules simultaneously in real time, and any combination
thereof.
[0097] FIG. 16 is a schematic representing the small form-factor
sensor system, according to this invention, wherein the same
numerals represent the same parts, as explained in FIGS. 2 to 7 and
15, so that repeated explanation is omitted here. The small form
factor sensor system 138 comprises with two parts wherein first
part is a passive section of the system and comprises with sample
handler 140, two waveguides 142(a) and 142(b) for incoming and
outgoing optical signals 14 and 18, respectively, and a common
substrate 144, and the second part is an active section of the
system and it comprises with carrier substrate 146, laser 12, laser
driver 122, detector 20, preamplifier 148, signal processing
integrator circuit 150, and electrical connection 152.
[0098] According to this invention, specimen 154(a) is made to pass
through the inlet 156(a) of the specimen handler 140 and pass out
the specimen 154(b) from the outlet 156(b). The passive section of
the sensor system 138 is designed in a way that a portion of its
internal section is made to expose to the nanochip 16 to make
enough contact of the specimen while passing through this specimen
handler 140. The optical signal 14 is made to propagate through the
nanochip 16 via waveguides 142(a) and 142(b) used for guiding the
signals on the passive section of nano-chip 16. For simplicity in
handling and also for the purpose of reusage of the sensor system
for long time, the passive section can be a separate section apart
from the active section, and can be replaceable and easily
stackable to the active section. Alternatively, both passive and
active sections could be single section attached permanently. In
FIG. 16, an example of a small form-factor sensor system containing
a single nano-chip 16 is shown for simplicity in drawing. This can
cover also for m-number of sensors containing in passive section of
the sensor system (not shown here) for m-number of specimens
detection. In that case, at least one specimen handler can be used
and each nano-chip can have with same or different receptors.
[0099] According to this invention, the active section of the
sensor system 138 has signal transmitting section, OE (optical to
electrical conversion), and signal processing units (not shown
separately). Transmitting section comprises with the laser 12 and
driver 122, OE unit comprises with detector 20 and preamplifier
148, and signal processing unit comprising with a chip 150 for
further signal processing and monitoring. The signal processing
chip 150 contains pre-processing unit, post processing, and
monitoring units, explained earlier in FIGS. 9 to 14. Transmitting,
OE, and signal processing units are placed on the carrier substrate
146 and they can be hybridly integrated on carrier substrate 146 or
fabricated monolithically as single chip. The carrier substrate 146
has the groove 158, housed appropriate to the passive section
holding. Under operation, both waveguides 142(a) and 142(b) are
coupled to the laser 12 and detector 20, respectively to transmit
and receive the signals 14 and 18 to and away from the nano-chip.
Source (e.g. laser diode or light emitting diode) 12 with specific
wavelength or ranges of wavelength, appropriate to the refractive
index of the nanochip 16 can be used and it can be electrically
drived by the driver circuit 122. The OE section has the detector
20, having high sensitivity to the source light, can be used to
convert the optical signal to electrical. The detector signal is
amplified by the pre-amplifier 148 and processed by the chip 150
for post processing and monitoring the concentration of the
specimen. The electrical connection 152 connects all electrical
components to the external power supplies (not shown here).
According to this invention, transmitter section, OE section, and
signal processing section can be fabricated into a single chip
utilizing the standard IC technology. Alternatively, each component
in active section could be a separate component, hybridly
integrated on the substrate (e.g. 146).
[0100] According to this invention, the nano-chip described from
FIGS. 3 to 7 and FIGS. 14 and 15, can be fabricated using any kind
of substrates which cover, semiconductor, polymer, ceramic,
exhibiting optical properties. Semiconductor cover Si, III-V or
II-VI based compound semiconductors. The rods or holes,
periodically arranged inside substrate and/or in waveguide to form
the photonic crystal structure, can be made by utilizing standard
wet or dry-etching process frequently using in IC manufacturing.
Alternatively, electrochemical or photo-electro-chemical etching
process can also be used to create the holes inside the substrate.
According to this, alternatively air-spheres inside can also be
used forming photonic crystal based nano-chip, and they can be made
by conventional electrochemical process. For example, large scale
of air-spheres in silicon, strong variation of the diameter with a
length of the lattice constant can be made using
photo-electro-chemical process for crating photonic crystal
structure for the nanochip. Alternatively, porous material
(semiconductor, insulator, polymer, or metal) having pores can also
be used for fabricating nanochip. The waveguide and the substrate
carrying the waveguide could be same kind of material or different
material. Alternatively, nanochip can also be made from the
combination of the nanoparticles deposited or synthesized on the
substrate arranged in periodically.
[0101] Alternatively, according to this invention, the nanometer
sized rods, wire or tubes can also be made from the carbon type
materials (semiconductor, insulators, or metal like performances)
such as carbon nano-tubes, which could be single, or multiple
layered. They can be made using standard growth process for
example, MOCVD, MBE, or standard epitaxial growth. According to
this invention, the self-assembled process can also be used to make
wires, rods, or tubes and their related pn-junction to increase the
junction area. These tubes can be grown on the semiconductors
(under same group or others), polymers, or insulator.
Alternatively, according to this invention, these rods, wire, or
tubes, can be transferred to the foreign substrate or to the layer
of foreign substrate acting as a common substrate for waveguide for
nano-chip. The foreign substrate or the layer of material can be
any semiconductor such as Si, Ge, InP, GaAs, GaN, ZnS, CdTe, CdS,
ZnCdTe, HgCdTe, etc. The substrate can cover also all kinds of
polymers or ceramics such as AlN, Silicon-oxide etc. The material
can be conductive or non-conductive.
[0102] According to this invention, different substrates can be
used for making sensing device as shown in FIGS. 14 and 15. For
example, carrier substrate 134 and common substrate 136 for the
splitter and nanochip can be same or both can be different
substrate, in hybrid integrated together. Alternatively, the
splitter used for the multiple nanochip can be fabricated from the
separate substrate and integrated on the carrier substrate 134. As
a carrier substrate, substrate made of any kind of material such as
semiconductor, ceramic, metal, or polymer can be used.
[0103] According to this invention, concentration measurement by
determining the power factor is explained here. This nanochip based
on photonics crystal can also detect the concentration by other
methods, such as measuring the fringe-pattern by using of CCD
camera and laser beam analyzer, or absorption spectrum of the
optical output by spectroscopy. The concentration and type of the
specimen can be known by comparing with the reference pattern for
the case fringe pattern technique, and by comparing intensity and
chemical absorption for the case of absorption spectrum
technique.
[0104] Turning now to FIG. 17a-g, the photonic crystal structure
can be fabricated in a number of ways. For example, this
description will use Silicon Nitride (SiNx) based photonic crystal
structures which have a refractive index of 1.5-2.0. FIG. 17
summarizes the procedure for preparing SiNx PC structure. A fused
silica substrate 200 may be used as the common substrate to
integrate multiple PC-W sensors. In FIG. 17a, the functional SiNx
material 201 is deposited either using PECVD or LPCVD. In FIG. 17b,
photoresist layer 202 is deposited on the SiNx. In FIG. 17c,
photoresist layer 202 is lithographically patterned followed by, in
FIG. 17d, the deposition of a thin layer of chrome 203 to serve as
a mask for subsequent pattern transfer of the PC holes. With the
residual photoresist removed via acetone liftoff, in FIG. 17e, Cr
mask on the remaining surface defines the areas that are to be
etched in SiNx layer using anisotropic NF.sub.3 dry etch, as shown
in FIG. 17f. The remaining chrome layer is then removed in FIG.
17g. The structure shown in FIGS. 17a-g are intended to show a
cross-sectional view of the photonic crystal.
[0105] The materials discussed above are, however, merely an
example. Other systems can be used, for example, when desiring
formation of a disposable test strip. In such a case, microfluidics
based blood plasma filtration unit coupled with PC-W sensing
platform may be provided as disposable plastic test strips. To keep
the material and fabrication cost down for fabricating plastic
based PC-W sensors and blood plasma filtration unit in a single
microfluidic channel, replica molding procedure provides a low-cost
alternative.
[0106] In addition to the PC-W structural design, surface treatment
to covalently conjugate bioreceptors is a part of the sensor design
and optimization. The key parameters of surface treatments that
influence the biosensor performance include the orientation and
surface coverage of the conjugated bioreceptors. Due to the
glass-like surfaces of the SiNx and fused silica all-dielectric
photonic crystal, typical surface treatment techniques from
biochemistry such as chemical etching techniques, vapor or plasma
deposition, and the formation of self-assembled monolayers (SAMs)
can be utilized for immobilizing bioreceptor layer.
[0107] Silicon Nitride (SiNx) structure surface can be modified by
using one of the two SAM organosilanes, i.e. 3-(2-aminoethylamino)
propyltrimethoxysilane (for NH.sub.2 grafting), or
10-(Carbomethoxy) decyl dimethylchlorosilane (for COOH grafting
after activation with HCl). To perform the NH.sub.2 silanization
the samples need to be placed in a solution containing methanol and
acetic acid glacial, eventually adding the
C.sub.8H.sub.22N.sub.2O.sub.3Si. For COOH grafting, the samples
need to be immersed in a solution of C.sub.14H.sub.29ClO.sub.2Si
dissolved in a mixture of CCl.sub.4 and n-C.sub.7H.sub.16 followed
by final immersion of the samples in HCl solution. After successful
silanization of the surface, the bioreceptors may be selectively
immobilized through diffusion onto the sensor surface by placing
several small drops of bioreceptors directly above the respective
PC-W sensor units. The samples then need to be incubated and
thoroughly cleaned to remove any unbounded bioreceptors onto the
surface. To passivate the sensor surface from non-specific
biomolecule binding, detergent blockers such as Tween-20, Triton
X-100 or protein blockers such as Bovine serum albumin (BSA) may be
used.
[0108] While it has previously already been mentioned that the
above embodiments can be used to identify any number of
biomolecules, a few specific applications are also beneficial.
Specifically, an embodiment for sensing pathogens (such as
Hepititis B) or HIV can be created. FIG. 18 shows one such
embodiment. As shown in the figure, when using the invention to
test for specific molecules within the human body, some additions
and modifications to the structure are favorable. FIG. 18 shows,
for example, where a portion of the device, 302, is removable from
the main body 300. Here, a blood sample enters the inlet 304 on the
test strip 302, passes through a blood filtration system 306, the
PC-W sensing platform 308, and then exits the strip through outlet
310. The laser and laser source 312 are placed on the main body 300
in such a way as to direct the laser into waveguide 314 located on
the test strip 302. The laser signal then travels through the PC-W
sensing platform 308, exits out of waveguide 316, and is sensed by
the detector 318 on the main body of the device. The integrated
circuit 320 converts the laser signal to an electrical signal,
analyzes it, and displays the result in the display screen 322.
Connections between the various components are not displayed in
FIG. 18.
[0109] FIG. 18 shows an additional component from those embodiments
discussed previously (such as that shown in FIG. 16), known as a
blood filtration system 306. During measurement, a small volume of
blood sample needs to be flow into the microfluidic channel (not
shown). The microfluidic channel will include a filtration chip for
extracting plasma from the whole blood sample. The filtration chip
comprises microfluidic channels that use hydrodynamic forces to
separate human plasma from blood cells. Individual filtration unit
comprises an inlet that is reduced by approximately 20 times to a
small constrictor channel. This channel opens out to a larger
output channel with a relatively small lateral channel for the
collection of plasma. Studies have shown that this type of
filtration unit was capable of removing 97.05.+-.0.5 percentage of
cells at 200 .mu.l min.sup.-1 flowrate. A detailed explanation of
the filtration chip design and working principle is illustrated in
[A. I. Rodriguez-Villarreal, M. Arundell, M. Carmona, J. Samitier.
High flow rate microfluidic device for blood plasma separation
using a range of temperatures (2010), 2, 211-219]. The plasma from
the filtration chip flows onto the PC-W sensing units through a
dedicated channel allowing the target biomolecules to bind to the
bioreceptors. Before the optical measurement, a stringent cleaning
procedure using a buffer solution may be used to eliminate
non-specific biomolecule interactions since they can negatively
influence the output optical signal. The two waveguides, 314 and
316, attached to the test strip facilitate the transport of the
optical signals from the laser source to the PC-W sensing arrays
and from there into the signal processing unit for data analysis. A
small display unit 322 will be included for displaying the test
results real-time. The integrated point-of-care diagnostic platform
can be powered by conventional Li-ion batteries.
[0110] FIG. 19 in included as an example of a more detailed diagram
from the generalized FIG. 18. It is included merely as an
additional aid to visualize possible embodiments, and is not
intended to be limiting.
Pathogen-Sensing
[0111] The embodiment may be designed to have arrays of independent
biosensing units coupled onto the photonic crystal platform,
providing parallel detection of multiple biomarkers. While this is
beneficial for all types of detection, this is especially
beneficial when detecting certain pathogens, such as HBV, which
have multiple detectable markers. Numerous HBV markers include
hepatitis B surface antigen (HBsAg), hepatitis B surface antibody
(anti-HBs), hepatitis B e antigen (HBeAg), hepatitis B e antibody
(anti-HBe), hepatitis B core antigen (HBcAg), and hepatitis B core
antibody (anti-HBc). For maximum accuracy, test strips may be
designed to detect approximately five different HBV markers.
[0112] Although this embodiment specifically utilizes a blood
filtration system, alternatively the embodiment might be designed
to detect biomarkers in saliva or other body tissue. If this is the
case, then the blood filtration system may be omitted or replaced
with a different type of filtration system. For example, due to the
viscosity of saliva, movement through a simple sample inlet may be
difficult. A microfluidic system may be used to aid the movement of
the sample into the PC-W sensor platform.
HIV-Sensing
[0113] Another alternate embodiment is one which is designed to
detect HIV. Currently, HIV diagnosis in general is costly, and
additionally inaccurate during the initial window after infection.
This embodiment is a diagnostic system that can diagnose HIV
infection within the window period based on parallel detection of
two characteristic HIV-1 biomarkers, i.e. HIV-1 Tat protein and
HIV-1 antibodies (here in referred as antibodies). Tat protein is a
primary HIV gene that regulates the early stage replication of HIV,
whereas antibodies are produced by the body in order to combat the
assortment of proteins produced by HIV infection.
[0114] The multi-analyte diagnostic platform is based on photonic
crystal-based biosensing platform measuring the miniscule
refractive index changes when the biomarkers in the sample bind to
the characteristic bioreceptors. The integration of blood plasma
separation, optical biosensing and data processing assembly on the
same platform makes possible the development of a sample-to-answer
system with automated data analysis providing a rapid diagnostic
readout (<30 min). In addition, the use of robust bioreceptors
that have high storage stability at ambient conditions offers the
potential to use the proposed diagnostic system in remote settings
without cold storage facilities.
[0115] Structurally, the embodiment for detecting HIV may be very
similar to that of the embodiment for detecting pathogens. It may
utilize the same disposable plastic test strips and blood
filtration system, and the only significant difference would be the
biomarkers used in the photonic crystal arrays.
[0116] Detection of HIV can be done through detection of two
indicators: HIV-1 Tat proteins or HIV-1 antibodies. For the
detection of HIV-1 Tat protein, shown in FIG. 20A, one may use an
aptamer that binds to the Tat protein with two orders of magnitude
greater (133-fold) affinity over the TAR RNA of HIV-1. Recently,
two aptamers: Probe aptamers-RNA.sup.Tat and aptamer-derived second
strand (5'-UCGGUCGAUCGCUUCAUAA-3''-NH.sub.2 (SEQ ID NO:1) and
5'-GAAGCUUGAUCCCGAA-3' (SEQ ID NO:2) were developed to function as
bioreceptors for the detection of real HIV-1 Tat protein extracted
from blood. At first, the probe RNA.sup.Tat aptamers are covalently
attached to the photonic crystal surface of the PC-W sensing
platform. Once exposed to a blood sample, any present HIV-1 TAT
proteins bind to the probe aptamers along with aptamer-derived
second strands, thereby forming duplex structures. The high storage
stability of aptamers even at ambient conditions can be used to
develop diagnostic systems that do not require refrigeration to
maintain their detection performance. Alternatively, a simple
annealing step at 70.degree. C. for 3 min may be used to recover
the functional activity of immobilized aptamers up to 90%.
[0117] On the other hand, for the detection of HIV-1 antibodies,
HIV proteins called antigens, shown in FIG. 20B, may be used as
bioreceptors. The antigens are covalently attached to the photonic
crystal of the PC-W sensing platform. Once exposed to a blood
sample, any present HIV-1 antibodies bind to the antigens.
[0118] For maximum accuracy in testing, the embodiment may be
designed, similarly to the HBV detector, with multiple independent
parallel biosensing units, wherein each unit detects a different
biomarker.
[0119] Whereas many alterations and modifications of the present
invention will no doubt become apparent to a person of ordinary
skill in the art after having read the foregoing description, it is
to be understood that the particular embodiments shown and
described by way of illustration are in no way intended to be
considered limiting. Therefore, reference to the details of the
preferred embodiments is not intended to limit their scope.
Although the invention has been described with respect to specific
embodiment for complete and clear disclosure, the appended claims
are not to be thus limited but are to be construed as embodying all
modification and alternative constructions that may be occurred to
one skilled in the art which fairly fall within the basic teaching
here is set forth.
[0120] Although the invention has been described with respect to
specific embodiment for complete and clear disclosure, the appended
claims are not to be thus limited but are to be construed as
embodying all modification and alternative constructions that may
be occurred to one skilled in the art which fairly fall within the
basic teaching here is set forth.
[0121] The present invention is expected to be found practically
use in the industrial, commercial, and bio-medical application.
Using of such sensor device will help to detect very low level
concentration (in ppb level) of gases, requiring in industrial
application. Example of various gases detection using proposed
invention can be found in (Sengupta, Rabi and Dutta, A., `Novel
nanosensor for biomedical and industrial applications`, SPIE
Proceed. 6008, Paper No. 60080T, November, 2005). This sensor
devices is not limited to use in chemical gas, bio-molecule gas
only, this can also be used in biological cell detection and their
low level concentration measurement. The main advantages of this
invention are that detection and concentration of multiple
specimens at a real time can be possible. Multiple specimens can be
multiple gases, multiple bio-molecules, or multiple bio-logical
cells, or their combinations.
Sequence CWU 1
1
2119RNAHuman immunodeficiency virus type 1 1ucggucgauc gcuucauaa
19216RNAHuman immunodeficiency virus type 1 2gaagcuugau cccgaa
16
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