U.S. patent application number 12/724117 was filed with the patent office on 2010-07-29 for sensors using high electron mobility transistors.
Invention is credited to Byoung-Sam Kang, Tanmay Lele, Stephen John Pearton, FAN REN, Hung-Ta Wang.
Application Number | 20100188069 12/724117 |
Document ID | / |
Family ID | 40468767 |
Filed Date | 2010-07-29 |
United States Patent
Application |
20100188069 |
Kind Code |
A1 |
REN; FAN ; et al. |
July 29, 2010 |
SENSORS USING HIGH ELECTRON MOBILITY TRANSISTORS
Abstract
Embodiments of the invention include sensors comprising high
electron mobility transistors (HEMTs) with capture reagents on a
gate region of the HEMTs. Example sensors include HEMTs with a thin
gold layer on the gate region and bound antibodies; a thin gold
layer on the gate region and chelating agents; a non-native gate
dielectric on the gate region; and nanorods of a non-native
dielectric with an immobilized enzyme on the gate region.
Embodiments including antibodies or enzymes can have the antibodies
or enzymes bound to the Au-gate via a binding group. Other
embodiments of the invention are methods of using the sensors for
detecting breast cancer, prostate cancer, kidney injury, glucose,
metals or pH where a signal is generated by the HEMT when a
solution is contacted with the sensor. The solution can be blood,
saliva, urine, breath condensate, or any solution suspected of
containing any specific analyte for the sensor.
Inventors: |
REN; FAN; (Gainesville,
FL) ; Pearton; Stephen John; (Gainesville, FL)
; Lele; Tanmay; (Gainesville, FL) ; Wang;
Hung-Ta; (Berkeley, CA) ; Kang; Byoung-Sam;
(Gainesville, FL) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK;A PROFESSIONAL ASSOCIATION
PO Box 142950
GAINESVILLE
FL
32614
US
|
Family ID: |
40468767 |
Appl. No.: |
12/724117 |
Filed: |
March 15, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2008/076885 |
Sep 18, 2008 |
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12724117 |
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60973302 |
Sep 18, 2007 |
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60975907 |
Sep 28, 2007 |
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60982310 |
Oct 24, 2007 |
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Current U.S.
Class: |
324/71.5 ;
257/194; 257/E29.246 |
Current CPC
Class: |
G01N 27/4145 20130101;
H01L 29/2003 20130101; H01L 29/7787 20130101; G01N 33/54306
20130101; G01N 33/0045 20130101 |
Class at
Publication: |
324/71.5 ;
257/194; 257/E29.246 |
International
Class: |
G01N 27/26 20060101
G01N027/26; H01L 29/778 20060101 H01L029/778 |
Claims
1. An AlGaN/GaN high electron mobility transistor (HEMT) based
sensor for one or more target molecules in a sample, the sensor
comprising: an AlGaN/GaN high electron mobility transistor (HEMT);
and at least one capture reagent on a gate region of the AlGaN/GaN
HEMT.
2. The sensor of claim 1, further comprising at least one wireless
communication circuit on a chip, wherein the AlGaN/GaN HEMT
comprises an array of HEMTs on the chip, and wherein a signal from
the sensor is wirelessly transmittable.
3. The sensor of claim 1, wherein the AlGaN/GaN HEMT comprises an
Au-comprising gate, and wherein the capture reagent binds or
otherwise associates with a breast cancer antigen.
4. The sensor of claim 3, wherein the capture reagent is an
antibody to a breast cancer antigen selected from EGF, c-erbB-2,
CA15-3, and any combination thereof.
5. The sensor of claim 3, further comprising a binding group layer
to couple the capture reagent to the Au-comprising gate.
6. The sensor of claim 3, wherein the binding group layer comprises
thioglycolic acid.
7. The sensor of claim 3, further comprising a control HEMT
connected to a source region of the AlGaN/GaN HEMT, wherein the
control HEMT includes the Au-comprising gate and a protective layer
covering the Au-comprising gate.
8. The sensor of claim 1, wherein the AlGaN/GaN HEMT comprises an
Au-comprising gate, the sensor comprising at least one chelating
agent as a capture reagent.
9. The sensor of claim 8, comprising at least one chelating agent
selected from the group consisting of thioglycolic acid
(HSCH.sub.2COOH), cysteamine (NH.sub.2CH.sub.2CH.sub.2SH),
1,2-ethanedithiol (HSCH.sub.2CH.sub.2SH), dimercaprol (BAL),
diaminoethanetetraacetic acid (EDTA), 2,3-bis-sulfanylbutanedioic
acid (DMSA), and 2,3-dimercapto-1-propanesulfonic acid (DMPS).
10. The sensor of claim 8, further comprising a control HEMT
connected to a source region of the AlGaN/GaN HEMT, wherein the
control HEMT includes the Au-comprising gate and a protective layer
covering the Au-comprising gate.
11. The sensor of claim 1, comprising a gate dielectric as a
capture reagent for detecting hydronium ion.
12. The sensor of claim 11, wherein the gate dielectric comprises a
non-native metal oxide.
13. The sensor of claim 12, wherein the metal oxide comprises at
least one of Sc.sub.2O.sub.3, Al.sub.2O.sub.3, TiO.sub.2, MgO,
In.sub.2O.sub.3, SnO.sub.2, ZnO, and ZnMgO.
14. The sensor of claim 11, further comprising a control HEMT
connected to a source region of the AlGaN/GaN HEMT, wherein the
control HEMT includes the gate dielectric and a protective layer
covering the gate dielectric.
15. The sensor of claim 1, wherein the AlGaN/GaN HEMT comprises an
Au-comprising gate, and wherein the capture reagent comprises an
antibody to kidney injury molecule-1 (KIM-1).
16. The sensor of claim 15, further comprising a binding group
layer to couple the antibody to the Au-comprising gate.
17. The sensor of claim 16, wherein the binding group layer
comprises thioglycolic acid.
18. The sensor of claim 15, further comprising a control HEMT
connected to a source region of the AlGaN/GaN HEMT, wherein the
control HEMT includes the Au-comprising gate and a protective layer
covering the Au-comprising gate.
19. The sensor of claim 1, wherein the AlGaN/GaN HEMT comprises an
Au-comprising gate, and wherein the capture reagent comprises a PSA
antibody.
20. The sensor of claim 19, further comprising a binding group
layer to couple the PSA antibody to the Au-comprising gate.
21. The sensor of claim 20, wherein the binding group layer
comprises thioglycolic acid.
22. The sensor of claim 19, further comprising a control HEMT
connected to a source region of the AlGaN/GaN HEMT, wherein the
control HEMT includes the Au-comprising gate and a protective layer
covering the Au-comprising gate.
23. The sensor of claim 1, comprising a gate dielectric layer
comprising nanorods on the gate region, and glucose oxidase
immobilized on the nanorods as the capture reagent.
24. The sensor of claim 23, wherein the nanorods comprise a metal
oxide.
25. The sensor of claim 24, wherein the metal oxide comprises at
least one of Sc.sub.2O.sub.3, Al.sub.2O.sub.3, TiO.sub.2, MgO,
In.sub.2O.sub.3, SnO.sub.2, ZnO, and ZnMgO.
26. The sensor of claim 23, further comprising a control HEMT
connected to a source region of the at least one AlGaN/GaN HEMT,
wherein the control HEMT includes the gate dielectric layer
comprising the nanorods and a protective layer covering the
Au-comprising gate.
27. A method of detecting a target molecule in a sample comprising
the steps of: providing a sample suspected of containing a target
molecule; and contacting the sample with a sensor comprising an
AlGaN/GaN high electron mobility transistor (HEMT) and at least one
capture reagent on a gate region of the AlGaN/GaN HEMT, wherein a
signal is generated by the sensor when the target molecule is
present in the sample and interacts with the capture reagent.
28. The method of claim 27, wherein the sensor further comprises at
least one wireless communication circuit on a chip, wherein the
HEMT comprises an array of HEMTs on a chip, and wherein the signal
is wirelessly transmittable.
29. The method of claim 28, further comprising the step of
transmitting wirelessly the signal to a receiver for the
signal.
30. The method of claim 27, wherein the sample is saliva, the
target molecule is a breast cancer antigen, the HEMT comprises an
Au-comprising gate, and the capture reagent is an antibody to the
breast cancer antigen.
31. The method of claim 30, wherein the sensor further comprises a
binding agent layer to couple the antibody to the Au-comprising
gate.
32. The method of claim 31, wherein the binding group layer
comprises thioglycolic acid.
33. The method of claim 27, wherein the sample is aqueous, the
target molecule is a metal, the HEMT comprises an Au-comprising
gate, and the capture reagent comprises a chelating agent.
34. The method of claim 33, wherein the metal is selected from the
group consisting of Hg.sup.2+, Cu.sup.+2, and Pb.sup.2+ ion.
35. The method of claim 27, wherein the sample is exhaled breath
condensate, the target molecule is hydronium ion, and the HEMT
comprises a gate dielectric that functions as a capture
reagent.
36. The sensor of claim 35, wherein the gate dielectric comprises a
non-native metal oxide.
37. The sensor of claim 36, wherein the non-native metal oxide
comprises at least one of Sc.sub.2O.sub.3, Al.sub.2O.sub.3,
TiO.sub.2, MgO, In.sub.2O.sub.3, SnO.sub.2, ZnO, and ZnMgO.
38. The method of claim 27, wherein the sample is aqueous, the
target molecule is kidney injury molecule-1(KIM-1), the HEMT
comprises an Au-comprising gate, and the capture reagent comprises
a KIM-1 antibody.
39. The method of claim 38, wherein the sensor further comprises a
binding group acid layer to couple the KIM-1 antibody to the
Au-comprising gate.
40. The method of claim 39, wherein the binding group layer
comprises thioglycolic acid.
41. The method of claim 27, wherein the sample is aqueous, the
target molecule is prostate specific antigen (PSA), the HEMT
comprises an Au-comprising gate, and the capture reagent comprises
a PSA antibody.
42. The method of claim 41, wherein the sensor further comprises a
binding group layer to couple the PSA antibody to the Au-comprising
gate.
43. The method of claim 42, wherein the binding group layer
comprises thioglycolic acid.
44. The method of claim 27, wherein the sample is exhaled breath
condensate, the target molecule is glucose, the HEMT comprises a
gate dielectric layer comprising nanorods, and the capture reagent
comprises glucose oxidase immobilized on the nanorods.
45. The method of claim 44, wherein the nanorods comprise a metal
oxide.
46. The method of claim 44, wherein the metal oxide comprises at
least one of ZnO, SnO, TiO.sub.2, MgO, ZnMgO, and
In.sub.2O.sub.3.
47. The method of claim 27, wherein the sample is exhaled breath
condensate, saliva, urine, blood, other biological fluids, or other
aqueous solutions.
48. A high electron mobility transistor (HEMT) based sensor for one
or more target molecules in a sample, comprising: an HEMT having a
two layer structure of group semiconductor materials, the first
layer of the two layer structure being a layer having a first ionic
strength and the second layer of the two layer structure being a
strained layer on the first layer and having a second ionic
strength different than the first ionic strength, where a high
density electron sheet carrier concentration channel of a
2-dimensional gas channel is induced by piezoelectric polarization
of the strained layer and spontaneous polarization of the different
ionic strengths between the second layer and the strained layer;
and at least one capture reagent on a gate region of the HEMT.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of International
Patent Application No. PCT/US2008/076885, filed Sep. 18, 2008,
which claims the benefit of U.S. Provisional Application Ser. No.
60/973,302, filed Sep. 18, 2007, U.S. Provisional Application Ser.
No. 60/975,907, filed Sep. 28, 2007, and U.S. Provisional
Application Ser. No. 60/982,310, filed Oct. 24, 2007, all of which
are hereby incorporated by reference herein in their entirety,
including any figures, tables, or drawings.
BACKGROUND OF THE INVENTION
[0002] Chemical sensors can be used to analyze a wide variety of
environmental and bodily gases, aerosols, and fluids for properties
of interest. For example, exhaled breath condensate (EBC) is widely
known to be a diagnostically important bodily fluid that can be
safely collected. In particular, the breath from deep within the
lungs (alveolar gas) is in equilibrium with the blood, and
therefore the concentrations of molecules present in the breath is
highly correlated with those found in the blood at any given time.
Analysis of molecules in exhaled breath condensate is a promising
method that can provide information on the metabolic state of the
human body, including certain signs of cancer, respiratory disease,
and liver and kidney function. Several different analysis methods
including gas chromatography (GC), chemiluminescence, selected ion
flow tube (SIFT), and mass spectroscopy (MS) have been used to
measure different exhaled biomarkers, including hydrogen peroxide,
nitrogen oxide, aldehydes, and ammonia. However, these methods vary
significantly in sensitivity.
[0003] Another example of sensing application using body fluid is
detecting breast cancer with saliva. The mortality rate in breast
cancer patients can be reduced by increasing the frequency of
screening. The overwhelming majority of patients are screened for
breast cancer by mammography. This procedure involves a high cost
to the patient. Moreover, the use of invasive radiation limits the
frequency of screening. Recent evidence suggests that salivary
testing for markers of breast cancer may be used in conjunction
with mammography. Saliva based diagnostics for the protein
c-erbB-2, a prognostic breast marker assayed in tissue biopsies of
women diagnosed with malignant tumors, has shown tremendous
potential. Soluble fragments of the c-erbB-2 oncogene and the
cancer antigen 15-3 were found to be significantly higher in the
saliva of women who had breast cancer than in those patients with
benign tumors. Another recent study concluded that epidermal growth
factor (EGF) is a promising marker in saliva for breast cancer
detection.
[0004] Pilot studies indicate that the saliva test is both
sensitive and reliable, and is potentially useful in initial
detection and follow-up screening for breast cancer. However,
currently saliva samples are typically obtained from a patient in a
dentist's office then sent to a testing lab; it typically takes a
few days to get the test results.
[0005] To fully realize the potentials of sensors for
environmental, health related, chemical and biomedical
applications, technologies are needed that will enable easy,
sensitive, and specific detection of chemical or biomolecules at
home or elsewhere. It is also desirable that a testing device
allows concomitant wireless data transmission into preprogrammed
destinations, such as transmitting breast cancer testing results to
a doctor or clinic. If inexpensive technologies that can detect and
wirelessly transmit testing results for environmental, health
related, chemical and biomedical applications can be developed,
early diagnosis of cancers or disease can significantly lower
mortality and the cost of health care. In addition, real-time
wireless remote sensing for chemicals in the environment may reduce
the incidence of disasters by alerting to a chemical hazard.
BRIEF SUMMARY
[0006] High electron mobility transistors (HEMTs), and the
particularly exemplified AlGaN/GaN HEMTs, are a key component of
the sensors according to embodiments of the invention. AlGaN/GaN
HEMTs with specified surface functionality perform as sensors to
detect various molecules, including biomarkers, of interest in
bodily fluid samples.
[0007] For example, embodiments of the invention are directed to
surface functionalized AlGaN/GaN HEMT based sensors that can detect
prostate cancer, breast cancer, pH, mercury, copper, glucose,
and/or evidence of acute kidney injury or renal failure in samples
of exhaled breath condensate, saliva, urine, blood, or other
fluids. In certain embodiments, the devices according to the
invention can wirelessly transmit results in order to facilitate
rapid analysis of the results.
[0008] One embodiment of the invention is a device for detecting
breast cancer that includes a gold-gated AlGaN/GaN HEMT
functionalized with an antibody to an antigen associated with
breast cancer as the capture reagent. A method for detection of
breast cancer in a saliva sample is also exemplified.
[0009] A second embodiment of the invention is a device for
detection of heavy metals. The device includes a gold-gated
AlGaN/GaN HEMT functionalized with a chelating agent as the capture
reagent. A method for detection of heavy metals in solution
comprises analyzing a sample with a gold-gated AlGaN/GaN HEMT
functionalized with a chelating agent such as thioglycolic acid
(HSCH.sub.2COOH), cysteamine (NH.sub.2CH.sub.2CH.sub.2SH),
1,2-ethanedithiol (HSCH.sub.2CH.sub.2SH), dimercaprol (BAL),
diaminoethanetetraacetic acid (EDTA), 2,3-bis-sulfanylbutanedioic
acid (DMSA), or 2,3-dimercapto-1-propanesulfonic acid (DMPS).
[0010] A third embodiment of the invention is a device for
detecting changes in pH. The device includes an AlGaN/GaN HEMT
having a gate dielectric coating, for example a thin
Sc.sub.2O.sub.3 layer, used as the capture reagent. The device can
further include a cooling element to obtain exhaled breath
condensates for testing. A method for detecting the pH of exhaled
breath condensate is also disclosed.
[0011] A fourth embodiment is a device for detecting prostate
cancer using a capture reagent formed via carboxylate succinimdyl
ester bound prostate specific antigen (PSA) antibodies linked to
thioglycolic acid immobilized on a gold-coated gate of an AlGaN/GaN
HEMT. A method of detecting prostate cancer by analysis of PSA in a
sample is also disclosed.
[0012] A fifth embodiment is a device for detecting acute kidney
injury or renal failure where a gold-gated AlGaN/GaN HEMT
functionalized with highly specific KIM-1 antibodies through a
self-assembled monolayer of thioglycolic acid acts as the detector.
A method to detect KIM-1 in a sample is also disclosed.
[0013] A sixth embodiment is a device for detecting glucose in
exhaled breath condensate. The device includes an AlGaN/GaN HEMT
having a nanorod array selectively grown on the gate area of the
HEMT that immobilizes glucose oxidase (GOx). The nanorods may be,
for example, metal oxide and nitride based nanorods. A method to
detect glucose in exhaled breath condensate is also disclosed.
[0014] In accordance with embodiments of the present invention,
normalized detection is provided.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIGS. 1A-1D show the chemical structures for BAL, EDTA,
DMSA, and DMPS, respectively.
[0016] FIG. 2 shows a schematic representation of an exemplary
embodiment of an AlGaN/GaN HEMT sensor of the present
disclosure.
[0017] FIG. 3A shows a scanning electron microscope (SEM) image of
an exemplary gateless HEMT.
[0018] FIG. 3B shows a schematic representation of an exemplary
HEMT with a non-native oxide as a gate dielectric layer.
[0019] FIG. 4A is a plot showing the effects of EBC exposure, in
the form of multiple exhaled breaths (each breath<1 sec), on the
current change.
[0020] FIG. 4B is a plot showing the effects of ventilation
strength on the HEMT current.
[0021] FIGS. 5A and 5B are photographs of the contact angle of a
water drop on the surface of bare Au (FIG. 5A) and thioglycolic
acid functionalized Au (FIG. 5B).
[0022] FIG. 6 illustrates a plot of changes in HEMT drain-source
current for bare Au-gate and Au-gate with thioglycolic acid
functionalization exposed to 10.sup.-5 M Hg.sup.2+ ion solutions
when using an AlGaN/GaN HEMT sensor of the invention.
[0023] FIG. 7A shows time dependent response of the drain current
as a function of Hg.sup.2, Cu.sup.2+, and Pb.sup.2+ ion
concentrations for a bare Au-gate AlGaN/GaN HEMT sensor.
[0024] FIG. 7B shows time dependent response of the drain current
as a function of Hg.sup.2+, Cu.sup.2+, and Pb.sup.2+ ion
concentrations for a thioglycolic acid functionalized Au-gate
AlGaN/GaN HEMT sensor.
[0025] FIG. 8A shows drain current changes in response to Hg.sup.2+
and Cu.sup.2+ ions as a function of the ion concentration for the
bare Au-gate AlGaN/GaN HEMT sensor.
[0026] FIG. 8B shows drain current changes in response to Hg.sup.2+
and Cu.sup.2+ ions as a function of the ion concentration for the
thioglycolic acid functionalized Au-gate AlGaN/GaN HEMT sensor.
[0027] FIG. 9 shows a plan view photograph of a multiple cell
AlGaN/GaN HEMT sensor.
[0028] FIG. 10 shows time dependent change in the drain current in
response to Na.sup.+ and Mg.sup.2+ with a bare Au-gated HEMT and a
thioglycolic acid functionalized Au-gated HEMT sensor of the
invention.
[0029] FIG. 11A shows recyclability for the bare Au-gate.
[0030] FIG. 11A shows recyclability for the thioglycolic acid
functionalized Au-gate surface.
[0031] FIG. 12A shows a plan view photomicrograph of a completed
HEMT device of the invention with a 5-nm Au film in the gate
region.
[0032] FIG. 12B shows a schematic of an AlGaN/GaN HEMT of the
invention, where the Au-coated gate area was functionalized with
PSA antibody on thioglycolic acid.
[0033] FIG. 13A shows I-V characteristics of an AlGaN/GaN HEMT
sensor of the invention before and after PSA incubation.
[0034] FIG. 13B shows drain current over time for PSA when
sequentially exposed to PBS, BSA, and PSA when using an AlGaN/GaN
HEMT sensor of the invention.
[0035] FIG. 14A shows drain current over time for PSA from 10 pg/ml
to 1 ng/ml when using an AlGaN/GaN HEMT sensor of the
invention.
[0036] FIG. 14B illustrate change of source and drain current
versus different concentrations from 10 pg/ml to 1 .mu.g/ml of PSA
using an AlGaN/GaN HEMT sensor of the invention.
[0037] FIG. 15 shows the drain current over time using a HEMT with
a gate dielectric of a non-native oxide and a fixed source-drain
bias of 0.25 V for pH from 3-10.
[0038] FIG. 16 shows the drain current over time using a HEMT with
a gate dielectric of a non-native oxide at fixed source-drain bias
of 0.25 V for pH from 7-8.
[0039] FIG. 17A shows a plan view photomicrograph of a completed
device with a 5-nm Au film on the gate region.
[0040] FIG. 17B shows a schematic device cross section where the
Au-coated gate area was functionalized with KIM-1 antibody on
thioglycolic acid.
[0041] FIG. 18 shows I.sub.DS-V.sub.DS characteristics of an HEMT
in both PBS buffer and 100 ng/ml KIM-1.
[0042] FIG. 19 shows time dependent current signal when exposing
the HEMT to 1 ng/ml and 10 ng/ml KIM-1 in PBS buffer.
[0043] FIG. 20 shows the current change for a HEMT as a function of
KIM-1 concentration.
[0044] FIG. 21 shows field emission SEM images of ZnO nanorod
arrays grown on the Si substrate spin-coated with different size
precursors (Preparation time of ZnO nanoparticle precursors from
(a) to (d): 0.5, 1, 1.5, and 2 h).
[0045] FIG. 22 shows (a) Schematic of ZnO nanorod gated AlGaN/GaN
HEMT; (b) SEM image of ZnO nanorod gated AlGaN/GaN HEMT. Upper
right inset shows HRTEM image of a ZnO nanorod array grown on the
gate area with different scales.
[0046] FIG. 23 shows plot of drain current versus time with
successive exposure of glucose from 500 pM to 125 .mu.M in 10 mM
phosphate buffer saline with a pH value of 7.4.
[0047] FIG. 24 shows plot of change of drain current as a function
of glucose concentrations from 500 pM to 125 .mu.M in 10 mM
phosphate buffer saline with a pH value of 7.4.
[0048] FIG. 25A shows a schematic diagram of a differential
amplifier circuit that can be used to output the signal from the
response of a normalized temperature sensor in accordance with an
embodiment of the present invention.
[0049] FIG. 25B shows a plan view schematic representation of
contact pads for a normalized sensing device in accordance with an
embodiment of the present invention.
[0050] FIG. 26A shows a cross-sectional view of an active and
control sensor configuration for a normalized sensing device for
heavy metal detection in accordance with one embodiment of the
present invention.
[0051] FIG. 26B shows a cross-sectional view of an active and
control sensor configuration for a normalized sensing device for
prostate cancer antigen detection in accordance with one embodiment
of the present invention.
[0052] FIG. 26C shows a cross-sectional view of an active and
control sensor configuration for a normalized sensing device for pH
detection in accordance with one embodiment of the present
invention.
[0053] FIG. 26D shows a cross-sectional view of an active and
control sensor configuration for a normalized sensing device for
kidney injury molecule-1 detection in accordance with one
embodiment of the present invention.
[0054] FIG. 26E shows a cross-sectional view of an active and
control sensor configuration for a normalized sensing device for
glucose detection in accordance with one embodiment of the present
invention.
[0055] FIG. 26F shows a cross-sectional view of an active and
control sensor configuration for a normalized sensing device for
breast cancer antigen detection in accordance with one embodiment
of the present invention.
[0056] FIG. 27 shows a plot of diode current vs. bias voltage
comparing a related art differential sensor to a normalized sensor
in accordance with an embodiment of the present invention.
DETAILED DISCLOSURE
[0057] One shortcoming of HEMT sensors has been a lack of
selectivity to different analytes due to the chemical inertness of
the HEMT surface. Sensor devices according to embodiments of the
invention solve this sensitivity problem by functionalization of
the gate surface with capture reagents.
[0058] The sensor devices of the subject invention can be used with
a variety of samples having environmental and/or bodily origins,
including saliva, urine, blood, breath (including exhaled breath
condensates) and other samples. For example, in certain embodiments
of the invention, mercury or cancer detection is improved.
Additionally, sensors according to embodiments of the invention can
be re-used, without substantial diminishment of efficacy.
[0059] Group III-N based wide bandgap semiconductors are used as
sensitive chemical sensors, especially when made with piezoelectric
materials. GaN/AlGaN high electron mobility transistors (HEMTs)
form a high density electron sheet carrier concentration channel
induced by piezoelectric polarization of the strained AlGaN layer
and spontaneous polarization of the different ionic strength
between the GaN and AlGaN layer. The conducting 2-dimensional
electron gas (2DEG) channel of GaN/AlGaN based HEMTs is very close
to the surface and extremely sensitive to the ambient environment,
allowing enhanced detection sensitivity.
[0060] GaN-based wide energy bandgap semiconductor material systems
are extremely chemically stable; this stability is minimally
degraded by adsorbed cells. The bond between Ga and N is ionic and
proteins easily attach to the GaN surface. This is an important
factor for preparation of a sensitive biosensor having a useful
lifetime.
[0061] The HEMT sensors of the subject invention can be used to
detect, for example, gases, ions, pH values, proteins, and/or DNA
with good selectivity by modification of the surface in the gate
region of the HEMT. HEMT structures can be used in microwave power
amplifiers as well as gas and liquid sensors because of their high
2DEG mobility and saturation velocity.
[0062] In certain embodiments of the invention, a 2-dimensional
electron gas (2DEG) at the interface of AlGaN/GaN heterostructures
is formed through the hetero junction of AlGaN and GaN, which have
different bandgaps. The 2DEG channel is connected to an Ohmic-type
source and drain contacts. The source-drain current is modulated by
a third contact, a Schottky-type gate, on the top of the 2DEG
channel. For sensing applications, the third contact is affected by
the sensing environment, i.e. the sensing targets change the
charges on the gate region and the behavior of the gate. When
analytes accumulate on the gate area, the net charge on the HEMT
surface is changed. The net surface charge alters the 2DEG
concentration. This electrical detection technique is simple, fast,
and convenient.
[0063] The detecting signal from the gate can be amplified through
the drain-source current, making the sensor very sensitive. The
electric signal can be easily quantified, recorded and transmitted,
unlike fluorescence detection methods that need human inspection
and are difficult to be precisely quantified and transmitted.
[0064] Gateless HEMT structures can distinguish liquids with
different polarities and can quantitatively measure pH over a broad
range. The sensing mechanism for chemical adsorbates in
piezoelectric materials originates from compensation of the
polarization induced bound surface charge by interaction with the
polar molecules in liquids. In gateless AlGaN/GaN heterostructure
transistors, the native oxide on the nitride surface is responsible
for the pH sensitivity of the response to electrolyte solutions. By
coating a thin non-native metal oxide, for example Sc.sub.2O.sub.3,
on the gate sensing area, more sensitive and reproducible hydronium
ion, H.sub.3O.sup.+ (pH) sensing is achieved. In embodiments of the
invention, the non-native metal oxide on the gate sensing area of
the HEMT is referred to as a gate dielectric layer.
[0065] Usually, it is difficult to control the compositions and
thickness of native oxides. For embodiments of the invention, a
metal oxide such as Sc.sub.2O.sub.3 is grown by a molecule beam
epitaxy system with excellent composition and thickness control. In
certain embodiments of the invention, other gate dielectric layers,
such as metal nitrides, can be used rather than metal oxide
dielectric layers. The pH response of an oxide/nitride interface
can be modeled in terms of formation of hydroxyl groups that lead
to a hydronium ion concentration (pH) dependent net surface change
with a resulting change in voltage drop at the semiconductor/liquid
interface.
[0066] According to one embodiment of the subject invention,
real-time detection of the pH of exhaled breath uses a breathing
tube and ice bath with an AlGaN/GaN HEMT. The breathing tube
samples exhaled breath and the ice bath condenses the sample that
is applied to the AlGaN/GaN HEMT.
[0067] In one embodiment, the device may include an AlGaN/GaN HEMT
that is operably coupled to a thermal electric cooling device,
which condenses exhaled breath samples. The thermal water vapor and
volatile organic compounds from the exhaled breath condensate
change the surface charge on the HEMT, thus changing the current
flowing in the HEMT device for a fixed applied bias voltage. In one
embodiment, an exhaled breath condensate (EBC) biosensor of the
present disclosure can be handheld, low in cost, and capable of
real-time detection without consumable carrier gases.
[0068] Biologically modified field effect transistors (bioFETs),
either at conventional or nano-dimensions, can directly detect
biochemical interactions in aqueous solutions for a wide variety of
biosensing applications. To enhance the practicality of bioFETs, a
device according to embodiments of the invention is sensitive to
biochemical interactions on its surface that is functionalized to
probe specific biochemical interactions. In one embodiment, the
device is stable in aqueous solutions across a range of pH and salt
concentrations. In other embodiments, the gate region of the device
is covered with capture reagents for molecules of interest. The
conductance of the device changes as interaction occurs between
these capture reagents and appropriate species (the molecules of
interest) in a sample.
[0069] In one embodiment of the invention, a saliva based breast
cancer detector is functionalized in the gate region with chemicals
that can bind (or otherwise interact with) breast cancer markers.
The gate region of the HEMT can be a few nanometers to a few
millimeters in size. An array of the HEMT sensors can be fabricated
on a single chip. Each HEMT can be functionalized with a capture
reagent for a breast cancer marker. A set of testing results can be
obtained from a series of different capture reagents. Simultaneous
breast cancer detections with different capture reagents can
increase the accuracy of the cancer detection.
[0070] Because the surface of AlGaN is extremely inert and
difficult to oxidize, a thin layer of gold of, for example, about 5
nm can be used as an intermediate layer between AlGaN and certain
capture reagents used in embodiments of the invention. A molecule
containing a thiol group can be immobilized on the Au surface by an
Au--S bond. Other functional groups can then bind with a capture
reagent. These other functional groups c an be, for example,
alcohol, aldehyde, carboxylic acid, phosphate or amine groups. The
immobilized capture reagents can bind with breast cancer biomarkers
(or other target molecules). In one embodiment an Au-gated
GaN/AlGaN HEMT is used as a sensor for the detection of breast
cancer markers in a saliva sample.
[0071] In some embodiments, sensors comprise chemical adsorbates on
AlGaN/GaN HEMTs where detection originates from compensating or
inducing charges at the AlGaN/GaN interface due to polar molecules
in the liquids bonded to the AlGaN/GaN surface. In certain
embodiments, the device is functionalized at the AlGaN/GaN/HEMT
surface having an Au-coated gate region by chemicals selected for
their interaction with a target being detected.
[0072] According to one embodiment of the invention, thioglycolic
acid can be used to assist in functionalizing an AlGaN/GaN HEMT
sensor. For example, a self-assembled monolayer of thioglycolic
acid can be adsorbed onto an Au-gate due to interaction between
gold and the thiol-group. Following placement of the thioglycolic
acid on the sensor surface, a specific functionality of interest
may be conjugated to the surface, where the functionality is a
capture reagent for a specific target being sensed.
[0073] According to certain embodiments of the invention, a sensor
can include a synthetic or natural compound as a capture reagent
with the ability to associate with a desired target molecule, such
as a biomarker. The capture reagent associates with the desired
target molecule by interacting with the target molecule in a way
that is detectable by the HEMT. The capture reagent may associate
with the target molecule by binding with the target molecule, but
embodiments are not limited thereto.
[0074] The capture reagents of certain embodiments of the invention
include naturally occurring and/or synthetic compounds that
preferably display high specificity and sensitivity to a target
molecule of interest. Suitable compounds include, but are not
limited to, antibodies, proteins, and aptamers that can associate
with a biomarker. The term "biomarker" refers to a biochemical in
the body with a particular molecular trait that makes it useful for
diagnosing a condition, disorder, or disease, and for measuring or
indicating the effects or progress of a condition, disorder, or
disease. Antibodies are protein molecules that are typically
composed of heavy and light polypeptide amino acid chains held
together with disulfide bonds. These highly specialized proteins
are able to recognize and selectively bind certain types of antigen
molecules. In embodiments of the invention, a sensor employs
antibodies to detect specific antigens.
[0075] In an embodiment of the invention, the chemistry of the
system occurs along a conductive layer, for example, a gold layer.
The conductive layer supports the propagation of a high frequency
test signal and is capable of binding to (or otherwise associating
with) a target molecule, which is typically an antigen or other
analyte. In one embodiment, thioglycolic acid bonds the Au layer to
antibodies for breast cancer antigens including (but not limited
to) EGF, c-erbB-2 and CA15-3 in saliva, where the thiogylcolic acid
forms a self-assembled monolayer on the gold surfaces. Upon binding
of the immobilized antibody to an antigen, the gate potential of
the HEMT changes, resulting in a change in current of the HEMT at
fixed bias voltage. This change in current allows identification
and, preferably, quantification of the amount of the target
molecule, for example a cancer biomarker, in the sample.
[0076] One embodiment of the invention is a portable or hand-held
saliva based breast cancer sensor. Other embodiments of the
invention are sensors to analyze other bodily fluids or excretions
such as breath, urine or blood. Advantages of the sensors include
fast response time for results, portability and low cost. In one
embodiment, a chemical sensor array can be integrated with wireless
communication circuits for remote sensor applications. For example,
a digital signal cancer detector can wirelessly send the testing
results directly to a user's doctor.
[0077] In another embodiment of the invention, evidence of kidney
injury is detected by an HEMT functionalized with thioglycolic acid
coupling kidney injury molecule-1 (KIM-1) antibodies to a gold
surface of the gate of the HEMT. When in the presence of KIM-1, the
gate potential of the HEMT changes, resulting in a current change
in the HEMT at fixed bias voltage. This change in current can be
used to detect and, preferably, quantify KIM-1 biomarker present in
a sample.
[0078] In yet another embodiment of the invention, the sensor is
used to detect heavy metals. Heavy metal detection can involve an
HEMT functionalized with a densely coated capture reagent.
Hg.sup.2+, Cu.sup.+2 and Pb.sup.2+ detection can be achieved ac
cording to the invention. One embodiment is a method in which
chelating agents remove heavy metal ions from a sample, where
chelating ligands and metal ions bind to form metal complexes,
normally called "chelation." A strong chelating agent is
dimercaprol (BAL), which contains two thiol groups capable of
reacting with arsenic, lead and mercury. Other widely used
chelating agents include diaminoethanetetraacetic acid (EDTA),
2,3-bis-sulfanylbutanedioic acid (DMSA), and
2,3-dimercapto-1-propanesulfonic acid (DMPS). FIGS. 1A-1D show the
chemical structures for BAL, EDTA, DMSA, and DMPS,
respectively.
[0079] In one embodiment of the invention, Hg.sup.2+, Cu.sup.+2 or
Pb.sup.2+ is detected when chelating agents used as the capture
reagent immobilize the metal on the HEMT surface. The surface of
AlGaN can have a thin layer (.about.5 nm) of gold between the AlGaN
surface and the chelating agent. Gold permits deposition of any
chelating agent comprising a thiol group on the surface through
Au--S bonding. The thiol, amine, and carboxyl groups of the bound
chelating agents bind heavy metal ions to the surface of the
HEMT.
[0080] FIG. 2 shows a schematic of an exemplary embodiment of an
AlGaN/GaN HEMT sensor according to an embodiment of the invention.
The functionalization is an Au-coated gate area with thioglycolic
acid, HSCH.sub.2COOH, for Hg(II) detection. A self assembled
monolayer of thioglycolic acid molecules is adsorbed onto the gold
gate by a S--Au bond between the gold surface and thiol-group. The
immobilized carboxyl groups function as capture reagents to capture
Hg.sup.2+, Cu.sup.+2, and/or Pb.sup.2+ ions. Alternative binding
groups that can function as capture reagents are derived, for
example, from cysteamine (NH.sub.2CH.sub.2CH.sub.2SH) or
1,2-ethanedithiol (HSCH.sub.2CH.sub.2SH).
[0081] In one embodiment, the gold-gated region is functionalized
with chelating agents immobilized on the HEMT surface, such as BAL,
EDTA, DMSA, and DMPS. One portion of the chelating agent binds to
the Au surface and the other portion functions as a capture reagent
of heavy metals by chelating with heavy metals, such as Hg.sup.2+,
Cu.sup.+2, or Pb.sup.2+. The charge of the metal ions affects the
gate potential of HEMTs. The change in current in the HEMT at fixed
bias voltage allows detection and, preferably, quantification of
the amount of the heavy metal ions in a sample.
[0082] In one embodiment, the device is a portable or hand-held
trace heavy-metal sensor for environmental and health related
applications. The sensor can detect heavy metals in aqueous
solution including breath condensate, urine or blood. Advantages of
the sensing device include fast response time, portability and low
cost. In one embodiment, a heavy metal detector can be used as a
wireless based sensor to transmit a digital signal of the test
results directly to a recipient.
[0083] Another embodiment of the invention is a pH meter for fluids
such as breath, saliva, urine or blood. Gates of HEMTs can be
functionalized with noble metal oxides for detecting proton and
hydroxide ions. In one embodiment, a Sc.sub.2O.sub.3 gate
dielectric is formed on AlGaN/GaN HEMTs to provide high sensitivity
for detecting changes in pH of electrolyte solutions. HEMTs with
Sc.sub.2O.sub.3 exhibit a linear change in current of 37 .mu.A/pH
between a pH range of 3 to 10. The HEMT pH sensors are stable with
a resolution of <0.1 pH over the entire pH range. The HEMTs can
be used to monitor solution pH changes between 7 and 8, a range of
interest for testing human blood.
[0084] FIG. 3A shows a scanning electron microscope (SEM) image of
a HEMT with a gate dielectric layer. FIG. 3B shows a schematic
diagram of a HEMT with a gate dielectric layer (labeled as oxide).
FIG. 4A shows the effects of EBC exposure, in the form of multiple
exhaled breaths (where each breath<1 second), on the current.
FIG. 4B shows the effects of ventilation strength on the HEMT
current, where the duration of the breath is 5 seconds.
[0085] In other embodiments of the invention, a nanorod gated
AlGaN/GaN HEMT is a detector for glucose. The nanorod arrays can be
selectively grown on the gate area to immobilize glucose oxidase
(GOx). The nanorods can be, for example, metal oxide and/or nitride
based nanorods. Nanorod metal oxides include, but are not limited
to, SnO, TiO.sub.2, GaN, MgO, ZnMgO, and In.sub.2O.sub.3 nanorods.
For example, one-dimensional ZnO nanorods on the gate area result
in a very high specific surface area with high surface to volume
ratio and provide favorable micro-environments for the
immobilization of GOx.
[0086] The AlGaN/GaN HEMT drain-source current has a rapid
response, of less than 5 seconds, when glucose in a buffer with a
pH value of 7.4 is added to the GOx immobilized ZnO nanorods
surface. A wide range of glucose concentrations from to 0.5 nM to
125 .mu.M can be detected. For example one sensor according to an
embodiment of the invention exhibited a linear range from 0.5 nM to
14.5 .mu.M with a limit of detection of 0.5 nM.
[0087] Following are examples that illustrate embodiments of the
invention. These examples should not be construed as limiting. All
percentages are by weight and all solvent mixture proportions are
by volume unless otherwise noted.
Example 1
Selective Detection of Hg(II) Ions from Cu(II) and Pb(II)
[0088] Hg.sup.2+ and Cu.sup.2+ ions are easily detected with
sensors fabricated with Au-gated and thioglycolic acid
functionalized Au-gated GaN/AlGaN HEMTs.
[0089] The HEMT structures consisted of a 2 .mu.m thick undoped GaN
buffer and 250 .ANG. thick undoped Al.sub.0.25Ga.sub.0.75N cap
layer. The epi-layers were grown by molecular beam epitaxy system
on 2'' sapphire substrates at SVT Associates. Mesa isolation was
performed with an Inductively Coupled Plasma (ICP) etching with
Cl.sub.2/Ar based discharges at -90 V dc self-bias, ICP power of
300 W at 2 MHz, and a process pressure of 5 mTorr. Ohmic contacts
of 50.times.50 .mu.m.sup.2 separated with gaps of 10, 20, and 50
.mu.m were formed by e-beam deposition of Ti/Al/Pt/Au patterns by
lift-off and annealed at 850.degree. C. for 45 sec under flowing
N.sub.2 for source and drain metal contacts. A 5-nm thin gold film
was deposited as the gate metal for two sets of sample sensors. One
sensor had a bare Au-gate and the other sensor had an Au-gate that
was functionalized with a self-assembled monolayer of thioglycolic
acid. An increase in the hydrophilicity of the surface treated with
thioglycolic acid functionalization was confirmed by contact angle
measurements of a water drop of the surface of bare Au (see FIG.
5A) and thioglycolic acid functionalized Au (see FIG. 5B), which
showed a change in contact angle from 58.4.degree. to 16.2.degree.
after the surface treatment. A 500-nm-thick poly(methyl
methacrylate) (PMMA) film was used to encapsulate the source/drain
regions, with only the gate region exposed to allow the liquid
solutions to access the bare Au-gate or functionalized Au-gate
surface. The source-drain current-voltage characteristics were
measured at 25.degree. C. using an Agilent 4156C parameter analyzer
with the Au-gated region exposed to different concentrations of
Hg.sup.2+, Cu.sup.2+, Pb.sup.2+, Mg.sup.+ or Na.sup.+ solutions. AC
measurements were performed to prevent side electrochemical
reactions with modulated 500-mV bias at 11 Hz.
[0090] A schematic cross-section of the device with Hg.sup.2+ ions
bound to thioglycolic acid functionalized on the gold gate region
is shown in FIG. 2. A self assembled monolayer of thioglycolic acid
molecule was adsorbed onto the Au-gate due to strong interaction
between gold and the thiol-group for the functionalized sensors.
Excess thioglycolic acid molecules were rinsed from the monolayer
using DI water. XPS and electrical measurements confirmed a high
surface coverage of thioglycolic acid molecules with Au--S bonding
formation on the AlGaN surface.
[0091] FIG. 6 shows the change in drain current of a bare Au-gated
AlGaN/GaN HEMT sensor and a thioglycolic acid functionalized
AlGaN/GaN HEMT sensor exposed to 10.sup.-5 M Hg.sup.2+ ion
solutions as compared to being exposed to DI water
(I.sub.H.sub.2.sub.O-I.sub.10.sup.-5.sub.M of HgCl.sub.2). The
drain current of both sensors decreased after exposure to Hg.sup.2+
ion solutions. The drain current reduction of the thioglycolic acid
functionalized AlGaN/GaN HEMT sensors exceeded that of the bare
Au-gate sensor by almost 80%. Though not to be bound by theory, the
mechanisms of the drain current reduction for bare Au-gate and
thioglycolic acid functionalized AlGaN/GaN HEMT sensors are
probably quite different. For the thioglycolic acid functionalized
AlGaN/GaN HEMT, the thioglycolic acid molecules on the Au surface
align with carboxylic acid functional groups extending toward the
solution. The carboxylic acid functional group of the adjacent
thioglycolic acid molecules can form chelates
(R--COO.sup.-(Hg.sup.2+).sup.-OOC--R) with the Hg.sup.2+ ions. Upon
chelation, one would expect the charges of trapped Hg.sup.2+ ion in
the R--COO.sup.-(Hg.sup.2+).sup.-OOC--R to change the polarity of
the thioglycolic acid molecules. Because Hg.sup.2+ ions were used
in the experiments, no Au-mercury amalgam is expected to form on
the bare Au-surface.
[0092] FIGS. 7A and 7B show time dependence of the drain current
for the two types of sensors for detecting Hg.sup.2+, Cu.sup.2+,
and Pb.sup.2+ ions. Both type of sensors showed very short response
time (less than 5 seconds), when exposed to Hg.sup.2+ ion solution.
The limits of detection for Hg.sup.2+ ion detection for the bare
Au-gate and thioglycolic acid functionalized sensor were 10.sup.-6
and 10.sup.-7 M, respectively. Neither sensor could detect
Pb.sup.2+ ions. For the Cu.sup.2+ ions, the detection limit of the
thioglycolic acid functionalized sensor was around 10.sup.-7 M,
while the bare Au-gate could not detect the Cu.sup.2+ ions as shown
in FIG. 7.
[0093] FIGS. 8A and 8B show the drain current changes in response
to Hg.sup.2+ and Cu.sup.2+ ions as a function of the ion
concentration for the two different surfaces. The difference in the
response between the bare Au-gate and the thioglycolic acid
functionalized sensor offers the possibility for selective
detection for Hg.sup.2+ and Cu.sup.2+ ions presented in a single
solution with a sensor chip containing both types of sensors, as
shown in FIG. 9. The dimension of the active area of the AlGaN/GaN
HEMT sensor is less than 50 .mu.m.times.50 .mu.m, and the sensors
can be fabricated as an array of individual sensors. The
fabrication of both sensors is identical except for the
thioglycolic acid functionalized sensor, which has an additional
functionalization step. This step can be accomplished with a
micro-inkjet system to locally functionalize surfaces. The bare
Au-gate and thioglycolic acid functionalized sensors also showed
excellent sensing selectivity (over 100 times higher selectivity)
over Na.sup.+ and Mg.sup.2+ ions. As illustrated in FIG. 10, there
was almost no detection of Na.sup.+ and Mg.sup.2+ ions for both
types of sensors with 0.1 M concentrations.
[0094] Most semiconductor based chemical sensors are not reusable.
The bare Au-gate and thioglycolic acid functionalized sensors
showed very good reusability, as shown in FIGS. 11A and 11B,
respectively. After a simple rinse with DI water, the sensors can
be reused for Hg.sup.2+ ion detection repeatedly and the responses
to different ionic solutions remain unchanged. The stability of
thioglycolic acid functionalized Au surface is affected by several
factors, such as oxygen level, light, and initial packing quality.
The subject devices were stored in nitrogen ambient and repeatedly
used over a couple of weeks without substantial diminishment of
efficacy.
[0095] The Hg.sup.2+/Ca.sup.2+ sensor can operate at 0.5 V of drain
voltage and 2 mA of drain current. However, the operation voltage
and device size can be further reduced to minimize the power
consumption to .mu.W range. The sensor can be integrated with a
commercially available hand-held wireless transmitter to realize a
portable, fast response and high sensitivity Hg.sup.2+ and
Cu.sup.2+ ion detector.
[0096] In summary, bared Au-gate and thioglycolic acid
functionalized AlGaN/GaN HEMT sensors have demonstrable ability to
detect heavy ions. The bare Au-gate sensor was sensitive to
Hg.sup.2+, and thioglycolic acid functionalized sensors could
detect both Hg.sup.2+ and Cu.sup.2+ ions. By fabricating an array
of the sensors on a single chip and selectively functionalizing
some sensors with thioglycolic acid, a multi-functional specific
detector can be fabricated. Such a sensor array can be used to
quantitatively detect Hg.sup.2+ ions in Cu.sup.2+ ion solution or
Cu.sup.2+ ions in Hg.sup.2+ ion solution. Both bare Au-gate and
thioglycolic acid functionalized sensors can be repeatedly used
after a simple DI water rinse.
Example 2
Detection of Prostate Specific Antigen
[0097] Functionalized of Au-gated AlGaN/GaN HEMTs of the invention
were used to detect prostate specific antigen (PSA). The PSA was
specifically recognized through PSA antibody, anchored to the gate
area in the form of carboxylate succinimidyl ester. A wide range of
concentrations from to 1 .mu.g/ml to 10 pg/ml of PSA was
investigated, which is lower than the cut-off value of 2.5 ng/ml
that is used as an indication for the need of biopsy.
[0098] The HEMT structures consisted of a 3 .mu.m thick undoped GaN
buffer, a 30 .ANG. thick Al.sub.0.3Ga.sub.0.7N spacer, and a 220
.ANG. thick Si-doped Al.sub.0.3Ga.sub.0.7N cap layer. Epi-layers
were grown by rf plasma-assisted Molecular Beam Epitaxy on the
thick GaN buffers produced on sapphire substrates by metal organic
chemical vapor deposition (MOCVD). Mesa isolation was performed
with an Inductively Coupled Plasma (ICP) etching with Cl.sub.2/Ar
based discharges at -90 V dc self-bias, ICP power of 300 W at 2
MHz, and a process pressure of 5 mTorr. 10.times.50 .mu.m.sup.2
Ohmic contacts separated with gaps of 5 .mu.m were formed by e-beam
deposited Ti/Al/Pt/Au patterned by lift-off and annealed at
850.degree. C. for 45 sec under flowing N.sub.2. Poly(methyl
methacrylate) (PMMA) was used to form 400-nm-thick layer
encapsulating the source/drain regions, with only the gate region
exposed to allow the liquid solutions to contact the gate surface.
The source-drain current-voltage characteristics were measured at
25.degree. C. using an Agilent 4156C parameter analyzer with the
gate region exposed to solution. AC measurements were performed
with modulated 500-mV bias at 11 Hz to prevent side electrochemical
reactions.
[0099] A plan view photomicrograph of a completed device is shown
in FIG. 12A and a schematic cross-section of the device is shown in
FIG. 12B. The Au surface was functionalized with a specific
bifunctional molecule. Here, thioglycolic acid, HSCH.sub.2COOH, was
attached to the Au surface in the gate area as a self assembled
monolayer adsorbed on the gold gate.
[0100] The devices were first placed in the ozone/UV chamber for 3
minutes and then submerged in a 1 mM aqueous solution of
thioglycolic acid for 24 hours at room temperature, resulting in
binding of the thioglycolic acid to the Au surface in the gate area
with the COOH groups available for further chemical
functionalization. XPS and electrical measurements were taken to
confirm a high surface coverage and Au--S bonding formation on the
surface. The device was freshly cleaned with deionized water to
remove unlinked thioglycolic acids. The carboxylic acid functional
groups were activated by submerging the device in a 0.1 mM solution
of N,N'-dicyclohexylcarbodiimide (DCC) in dry acetonitrile for 30
minutes and then in a 0.1 mM solution of N-hydroxysuccinimide in
dry acetonitrile for 1 hour. These functionalization steps resulted
in the formation of succinimidyl ester groups on the gate area of
AlGaN/GaN HEMT, as shown in FIG. 12B. The device was incubated in a
phosphate buffered saline (PBS) solution of anti-PSA monoclonal
antibody for 18 hours before real time measurement of PSA.
[0101] After incubation in a PBS buffered solution containing PSA
at a concentration of 1 .mu.g/ml, the device surface was thoroughly
rinsed with deionized water and dried with a nitrogen stream. The
electrical properties of the devices, source and drain current,
were measured before and after PSA incubation as shown in FIG. 13A.
As previously described, the electrons in 2DEG channel of the
AlGaN/GaN HEMT are induced by piezoelectric and spontaneous
polarization effects. Positive counter-charges at the AlGaN surface
layer are induced by the 2DEG. Any slight changes in the ambient
environment of the AlGaN/GaN HEMT affect the surface charges of the
AlGaN/GaN HEMT. These changes in the surface charge are transduced
into a change in the concentration of the 2DEG in the AlGaN/GaN
HEMTs, leading to the slight decrease in the conductance for the
device after PSA incubation.
[0102] FIG. 13B shows the real time PSA detection in PBS buffer
solution using change in the source-to-drain current with a
constant bias of 500 mV. No current change can be seen with the
addition of buffer solution around 100 sec and the addition of
nonspecific bovine serum albumin (BSA) around 200 sec, showing
relatively high stability of the device and chemical surface
modification. In clear contrast, the current change showed a rapid
response of less than 5 seconds when 10 ng/ml PSA was introduced to
the antibody on the surface. The abrupt current change, mainly due
to the exposure of PSA in a buffer solution, stabilized after the
PSA thoroughly diffused into the buffer solution.
[0103] Further real-time testing for the detection limit of PSA of
less dilute concentrations was carried out as shown in FIG. 14A.
Three different concentrations of the exposed target PSA in a
buffer solution were observed from 10 pg/ml to 1 ng/ml. The
amplitude of current change for the device exposed to PSA in a
buffer solution was about 3%, as illustrated in FIG. 14B. The clear
current decrease of 64 nA as 10 pg/ml of PSA also indicated that
the detection limit could be lowered up to several pg/ml, showing
the promise of a portable electronic biological sensor for PSA
screening.
[0104] As demonstrated herein, through a chemical modification
sequence, the Au-gated region of an AlGaN/GaN HEMT structure can be
functionalized for the detection of PSA with a sensitivity of 10
pg/ml in a buffer at clinical concentration. This electronic
detection of biomolecules can occur with a compact sensor chip,
which can be integrated with a commercially available hand-held
wireless transmitter to realize a portable, fast and
high-sensitivity prostate cancer detector.
Example 3
Detection of Changes in pH in Electrolyte Solutions
[0105] A Sc.sub.2O.sub.3 gate dielectric on AlGaN/GaN HEMTs is
shown to provide high sensitivity for detecting changes in pH of
electrolyte solutions, and is superior to the use of native oxide
in the gate region.
[0106] The HEMT structures consisted of a 2 .mu.m thick undoped GaN
buffer and 250 .ANG. thick undoped Al.sub.0.25Ga.sub.0.75N cap
layer. The epi-layers were grown by Metal-Organic Chemical Vapor
Deposition on 100 mm (111) Si substrates at Nitronex Corporation.
The sheet carrier concentration was .about.1.times.10.sup.13
cm.sup.-2 with a mobility of 980 cm.sup.2/V-s at room temperature.
Mesa isolation was achieved by using an ICP system with Ar/Cl.sub.2
based discharges. Ohmic contacts of 50.times.50 .mu.m.sup.2
separated with gaps of 10, 20, and 50 .mu.m were formed by lift-off
of e-beam deposited Ti(200 .ANG.)/Al(800 .ANG.)/Pt(400
.ANG.)/Au(800 .ANG.). The contacts were annealed at 850.degree. C.
for 45 sec under a flowing N.sub.2 ambient in a Heatpulse 610T
system. A 100 .ANG. Sc.sub.2O.sub.3 layer was deposited as a gate
dielectric through a contact window of SiN.sub.x layer. Before
oxide deposition, the wafer was exposed to ozone for 25 minutes,
and heated in-situ at 300.degree. C. for 1.0 minutes inside the
growth chamber. The Sc.sub.2O.sub.3 was deposited by rf
plasma-activated MBE at 100.degree. C. using elemental Sc
evaporated from a standard effusion cell at 1130.degree. C. and
O.sub.2 derived from an Oxford RF plasma source.
[0107] For comparison, devices with only the native oxide present
in the gate region and devices with the UV ozone-induced oxide were
fabricated. FIG. 3A shows a scanning electron microscopy (SEM)
image and FIG. 3B shows a cross-sectional schematic of the
completed device. The gate dimension of the device is 2.times.150
.mu.m.sup.2. The pH solution was applied using a syringe
autopipette (2-20 .mu.l).
[0108] Prior to the pH measurements, pH 4, 7, and 10 buffer
solutions from Fisher Scientific were used to calibrate the
electrode and the measurements at 25.degree. C. were carried out in
the dark using an Agilent 4156C parameter analyzer to avoid
parasitic effects. The pH solution was made by the titration method
using HNO.sub.3, NaOH, and distilled water. The electrode was a
conventional Acumet standard Ag/AgCl electrode.
[0109] The adsorption of aqueous solution of different pH on the
surface of the HEMT affected the surface potential and device
characteristics. FIG. 15 shows the current at a bias of 0.25V as a
function of time from the HEMTs with Sc.sub.2O.sub.3 in the gate
region exposed for 150 sec to a series of solutions whose pH was
varied from 3-10. The current significantly increased as the pH was
decreased upon exposure to these aqueous solutions. The change in
current was 37 .mu.A/pH. The HEMTs show stable operation with a
resolution of .about.0.1 pH over the entire pH range, illustrating
the remarkable sensitivity of the HEMT to relatively small changes
in concentration of the hydronium ion in solution. By comparison,
devices with the native oxide in the gate region showed a higher
sensitivity of .about.70 .mu.A/pA but a poor resolution of
.about.0.4 pH and showed delays in response of 10-15 seconds. The
delays may result from deep traps at the interface between the
semiconductor and native oxide, whose density is much higher than
at the Sc.sub.2O.sub.3-nitride interface. The devices with UV-ozone
oxide in the gate region did not show these incubation times for
detection of pH changes and showed similar sensitivities of gate
source current as the Sc.sub.2O.sub.3 gate devices (.about.40
.mu.A/pH), but displayed poorer resolution (.about.0.25 pH). FIG.
15 shows that the HEMT sensor with Sc.sub.2O.sub.3 gate dielectric
is sensitive to the concentration of the polar liquid and therefore
could be used to differentiate between liquids into which a small
amount of leakage of another substance has occurred.
[0110] The pH range of interest for human blood is 7-8. FIG. 16
shows the change in current of the HEMTs with Sc.sub.2O.sub.3 at a
bias of 0.25V for different pH values in this range. The resolution
of the measurement is <0.1 pH. As previously described, the
electrons in the 2DEG channel of the AlGaN/GaN HEMT are induced by
piezoelectric and spontaneous polarization effects. Positive
counter charges at the AlGaN surface layer are induced by the 2DEG.
Any change in the ambient environment of the AlGaN/GaN HEMT affects
the surface charges of the device. These changes in the surface
charge are transduced into a change in the concentration of the
2DEG. Different pHs exhibit different degrees of interaction with
the Sc.sub.2O.sub.3 surface. These results show that using a higher
quality oxide is useful in improving pH resolution.
Example 4
Detection of Kidney Injury Molecule-1
[0111] The HEMT structure consisted of a 2 .mu.m thick undoped GaN
buffer and 250 .ANG. thick undoped Al.sub.0.25Ga.sub.0.75N cap
layer. The epi-layers were grown by metal-organic chemical vapor
deposition on 100 mm (111) Si substrates. Mesa isolation was
performed with ICP etching with Cl.sub.2/Ar based discharges at
.+-.90 V dc self-bias, ICP power of 300 W at 2 MHz, and a process
pressure of 5 mTorr. Ohmic contacts of 50.times.50 .mu.m.sup.2
separated with gaps of 20 .mu.m were formed by e-beam deposited
Ti/Al/Pt/Au patterned by lift-off and annealed at 850.degree. C.
for 45 sec under a N.sub.2 stream. A 5-nm thin gold film was
deposited as a gate metal and functionalized as a self-assembled
monolayer of thioglycolic acid. Poly(methyl methacrylate) (PMMA)
was used to form a 500-nm-thick encapsulate of the source/drain
regions, with the gate region exposed using e-beam lithography. A
plan view photomicrograph of a completed device is shown in FIG.
17A.
[0112] Before depositing the thioglycolic acid coating, the sample
was exposed to UV ozone for 5 minutes to remove surface
contamination. A self-assembled monolayer of thioglycolic acid
molecule was adsorbed onto the Au-gate. Excess thioglycolic acid
was rinsed off with PBS buffer. An increase in the hydrophilicity
of the treated thioglycolic acid functionalization surface was
confirmed by contact angle measurements, which showed a change in
contact angle from 58.4.degree. to 16.2.degree. after the surface
treatment (see e.g., FIGS. 5A and 5B).
[0113] The thioglycolic acid surface was treated with monoclonal
anti-rat kidney injury molecule-1 (KIM-1) antibody in a solution of
10 mM phosphate buffer containing 4 mM sodium cyano-borohydride
with pH 8.8 at room temperature for 2 hours. This antibody
immobilization is based on a strong reaction between the carboxyl
group on thioglycolic acid and the amine group on KIM-1 antibody.
Excess KIM-1 antibodies were washed from the surface using a PBS
buffer and the unreacted surface carboxyl groups were passivated by
a blocking solution of 100 mM ethanolamine in 10 mM phosphate
buffer with pH 8.8. FIG. 17B shows a schematic device cross-section
with thioglycolic acid followed by KIM-1 antibody coating. The
source-drain current-voltage characteristics were measured at
25.degree. C. using an Agilent 4156C parameter analyzer with the
KIM-1 antibody functionalized Au-gated region exposed to different
concentrations of KIM-1/PBS buffer. AC measurements were performed
to prevent side electrochemical reactions with modulated 500-mV
bias at 11 Hz.
[0114] The source-drain current(I.sub.DS) vs. voltage(V.sub.DS) for
the devices, were measured in PBS buffer and 100 ng/ml KIM-1 in PBS
buffer, as shown in FIG. 18. There is a clear conductance decrease
with KIM-1 exposure and this suggests that through the selective
binding of KIM-1 with antibody, there are charges accumulated at
the surface of the HEMT and these surface charges are transduced
into a change in the carrier concentration of AlGaN/GaN 2DEG,
leading to the obvious decrease in the conductance of the device
after KIM-1 exposure.
[0115] FIG. 19 shows the time dependent source-drain current signal
with a constant bias of 500 mV for KIM-1 detection in PBS buffer
solution. No current change can be seen with the addition of buffer
solution around 50 sec. This stability excludes the possibility of
noise due to the mechanical change of the buffer solution. By sharp
contrast, the current change showed a rapid response in less than
20 seconds when 1 ng/ml KIM-1 was switched to the surface at 150
sec. The abrupt current change due to the exposure of KIM-1 in a
buffer solution stabilized after the KIM-1 thoroughly mixed with
the buffer. A 10 ng/ml KIM-1 solution was then applied at 350 sec,
which was accompanied by a larger signal due to the higher KIM-1
concentration.
[0116] Additional real-time tests were carried out to explore the
limits of detection of KIM-1 antibody. Referring to FIG. 20, the
device was exposed to 10 pg/ml, 100 pg/ml, 1 ng/ml, 10 ng/ml, and
100 ng/ml individually with each concentration repeated five times
to determine the standard deviation of source-drain current
response for each concentration. The limit of detection of this
device was 1 ng/ml KIM-1 in PBS buffer solution and the
source-drain current change is nonlinearly proportional to the
KIM-1 concentration. Between each test, the device was rinsed with
a wash buffer of 10 .mu.M phosphate buffer solution containing 10
.mu.M KCl with pH 6 to strip the antibody from the antigen. These
results suggest that the HEMTs are compatible with AKI biomarker,
KIM-1; are very sensitive relative to other currently available
nano-devices; and are useful for preclinical and clinical
applications. Similar surface modifications can be applied for
detecting other important disease biomarkers and a compact disease
diagnosis array can be realized for multiplex disease analysis.
Example 5
Glucose Detection
[0117] The HEMT structure consisting of a 3 .mu.m thick undoped GaN
buffer, 30 .ANG. thick Al.sub.0.3Ga.sub.0.7N spacer, 220 .ANG.
thick Si-doped Al.sub.0.3Ga.sub.0.7N cap layer was provided.
Epi-layers were grown by both molecular beam epitaxy and metal
organic chemical vapor deposition (MOCVD) on thick GaN buffers on
sapphire substrates. Mesa isolation was performed with an ICP
etching with Cl.sub.2/Ar based discharges at -90 V dc self-bias,
ICP power of 300 W at 2 MHz, and a process pressure of 5 mTorr.
50.times.50 .mu.m.sup.2 Ohmic contacts separated with gaps of 10
.mu.m were formed by e-beam deposited Ti/Al/Pt/Au patterned by
lift-off and annealed at 850.degree. C. for 45 sec under flowing
N.sub.2.
[0118] ZnO nanorods were grown in a solution of 20 mM zinc acetate
hexahydrate (Zn(NO.sub.3).sub.2.6H.sub.2O) and 20 mM
hexamethylenetriamine (C.sub.6H.sub.12N.sub.4) in a flask with
polypropylene autoclavable cap at a controlled temperature and pH
on the HEMT substrate. Subsequently, the substrate was removed from
solution, thoroughly rinsed with acetone followed by deionized
water to remove any residual salts and dried in air at room
temperature. The ZnO nanoparticle size was highly dependent on the
nanocrystal seed preparation time. The diameters of ZnO nanorods
can be carefully controlled from tens of nanometers to several
hundred micrometers by the seed size used to grow the nanorods.
FIG. 21 shows the effect of nanocrystal seed size on the diameters
of ZnO nanorods grown on a Si (111) substrate.
[0119] By incorporating the nanorods on the HEMT gate sensing area,
the total sensing area increases significantly as shown in FIG.
22(a). The conventional AlGaN/GaN HEMT detects the ambient changes
through the "gate sensing area". This area is defined as gate
length.times.gate width in the regular HEMT. Although, the gate
width can be increased in order to gain higher drain current from
the transistor, the sensor detection sensitivity will be the same
for the HEMT having both short and longer gate width. This is due
to the signal and background current proportionally increasing at
the same time. The other dimension of the gate is the gate length.
However, increasing the gate length increases the parasitic
resistance of the HEMT and the drain current decreases. Thus, the
detection sensitivity goes down. Therefore, the only way to
increase the sensitivity with the same "gate dimension" is to grow
3D structures on the gate sensing area to increase the total
sensing area with the area expansion to the third dimension.
[0120] FIG. 22(b) shows SEM pictures of ZnO nanorods grown on the
AlGaN/GaN HEMT gate sensing area. The upper right inset in FIG.
22(b) shows a closer view of ZnO nanorod arrays grown on the gate
area with different scales. The ZnO nanorods matrix provides a
microenvironment for immobilizing negatively charged GOx while
retaining its bioactivity, and passes charges produce during the
GOx and glucose interaction to the AlGaN/GaN HEMT.
[0121] A GOx solution was prepared with a concentration of 10 mg/mL
in the 10 mM phosphate buffer saline (pH value of 7.4., Sigma
Aldrich). After fabricating the device, 5 .mu.l GOx (.about.100
units/mg, Sigma Aldrich) solution was dropped on the surface of
HEMT device. The HEMT device was kept at 4.degree. C. in the
solution for 48 hours for GOx immobilization on the ZnO nanorod
arrays followed by an extensive washing to remove the unimmobilized
GOx. The HEMT device was kept in the incubator for 30 minutes to
make the enzyme active around 37.degree. C.
[0122] The target glucose was applied on the device through a
syringe autopipette (2-20 .mu.l). The current-voltage
characteristics were measured using an Agilent 4156C parameter
analyzer with the gate region exposed.
[0123] FIG. 23 shows the real time glucose detection in PBS buffer
solution using the drain current change with constant bias of 250
mV. No current change can be seen with the addition of buffer
solution at around 200 sec, showing the specificity and stability
of the device. By sharp contrast, the current change showed a rapid
response in less than 5 seconds when target glucose was added to
the surface. The response is very linear from 0.5 nM to 14.5 .mu.M
and showed an experimental limit of detection of 0.5 nM.
[0124] Immobilization of the negatively charged GOx on the
positively charged ZnO nanorod arrays is maximized around the pH
value of 7.4 and reduces to about 80% for pH=5 to 6. Once the pH
value is larger than 8, the activity drops significantly. The human
pH value can vary depending on the health condition, e.g. the pH
value for patients with acute asthma was reported as low as
5.23.+-.0.21 (n=22) as compared to 7.65.+-.0.20 (n=19) for the
control subjects. In order to get accurate measurements of glucose
concentration in the EBC, one needs to know the correlation of the
pH value of the EBC and the sensitivity of GOx functionalized for
specific sensors. The low detection limit of the sensor permitted
dilution of <0.1.mu.-liter of exhaled breath condensate (EBC) in
100-200.mu.-liter PBS and the direct measurement of the glucose
concentration to eliminate the effect of pH variation of the EBC.
FIG. 24 shows the changes of drain current as a function of glucose
concentration. A very good linear relationship of glucose
concentration vs. drain current changes was obtained. Because of
the fast response time and low volume of the EBC required, a
handheld real-time glucose sensor can be made.
[0125] Embodiments are provided for improved temperature response
that utilize a normalized diode or field effect transistor (FET)
configuration. According to an embodiment, a control sensor and an
active sensor are arranged in a common ground configuration. A
differential amplifier can be connected to the normalized
HEMT-based sensor to provide an amplified output of the sensor's
response to the target molecule in solution (i.e., the element
being detected in the environment). The differential amplifier
amplifies the difference between the two sensors and rejects the
signal that is common to the inputs. For example, FIG. 25A shows a
schematic representation of a normalized sensor output circuit 5 in
accordance with one embodiment of the present invention. The
control sensor 2 is connected to one input of the output circuit 5
and the active sensor 3 is connected to another input of the output
circuit 5. The control sensor 2 and the active sensor 3 are also
connected to a common node providing a common voltage V.sub.common.
In other embodiments, the schematic shown in FIG. 25A can be
replaced with any suitable differential amplifier circuit. Though
not shown in the figures, an initialization circuit can be included
to reset the sensor and/or to bias the output circuit 5. Any
suitable biasing circuit can be used. FIG. 25B shows contact pads
for the sensor 10 according to one embodiment. A first contact pad
11 can connect the control sensor to the differential amplifier
circuit; a second contact pad 12 can connect the common node of the
control sensor and the active sensor to a ground signal; and a
third contact pad 13 can connect the active sensor to the
differential amplifier circuit.
[0126] In accordance with embodiments of the present invention,
both the control and the active sensor are exposed to the ambient
temperature. The control (or reference) sensor of an embodiment of
the present invention has the exact same gate functionalization to
semiconductor interface as the active sensor of the subject device.
Further, the gate functionalization of the control sensor is
covered with another layer, a layer with a similar binding
functional group but different terminated functional group, or
antibodies not sensitive to the designated detection. An example
where the gate functionalization of the control sensor is covered
with a layer with similar binding functional group but different
terminated function group is using methyl mercaptans (HS--CH.sub.3
or HS--(CH.sub.2).sub.n--CH.sub.3, where n=0, 1, 2, . . . ) for the
reference sensor for Hg ion detection where thioglycolic acid
(HS--CH.sub.2--CH.sub.2--COOH) is used for the active sensor.
[0127] The additional layer can be a protective layer of metal,
dielectric, antibody, Bovine serum albumin (BSA), protein, aptamer,
or polymer, which is inert to the element being detected in the
surrounding environment or inhibits the gate functionalization
material of the control sensor from being exposed to the element
being detected in the surrounding environment.
[0128] According to an embodiment of the present invention, the
sensing response signal is output from the potential difference
between the control sensor and the active sensor. The source
regions of the sensors are grounded together for diode mode sensing
and the drain regions of the sensor are floated. If the FET mode is
used for the sensing, the drain current or threshold voltage of the
HEMT is used to monitor the concentration of the element being
detected instead of diode current used in the diode mode
sensing.
[0129] The normalized configuration provides a built-in control
diode to reduce false alarms due to temperature swings or voltage
transients. Since both the control and the active sensor have the
same interface between the semiconductor material of the HEMT and
the gate functionalization, the diode or FET characteristics will
be substantially the same regardless of ambient temperature. Thus,
the differences in diode or FET characteristics for the two sensors
(control and active) occur only in their exposure to the
environment. Specifically, the active sensor will respond to
elements being detected in the environment and the control sensor
will not.
[0130] The HEMT amplifies the signal detected from the gate of the
active sensor, thereby enabling extremely sensitive sensing. The
amplified signal of the active sensor can then be compared to the
control sensor signal through, for example, the differential
amplifier circuit of FIG. 25A to provide a normalized signal. In
addition, embodiments of the present invention can accomplish these
reductions in false alarms at a wide range of temperatures. In
certain embodiments, the subject sensor can reduce false alarms for
temperatures between -40.degree. C. and 80.degree. C.
[0131] According to embodiments of the present invention, a
normalized diode configuration is provided where the control device
includes the same HEMT interface structure as the gate
functionalization of the active device, but further includes the
metal of a final metal layer, dielectrics, antibody, BSA, protein,
aptamer, or polymers.
[0132] In one embodiment example, referring to FIG. 26A, for heavy
metal detection, the active member 20 of the normalized pair has a
gold-based gate contact 21 with a chelating agent 22 bonded
thereto, and the control member 23 of the normalized pair has a
gold-based gate contact 21 and a protective layer 24. The
protective layer 24 can be a metal layer, a dielectric layer,
antibody, BSA, protein, aptamer, methyl mercaptans (HS--CH.sub.3 or
HS--(CH.sub.2).sub.n--CH.sub.3), or a polymer layer. When a metal
layer is used for the protective layer 24, it can be the metal
layer(s) used for final metal contacts 25 of the device. In certain
implementations of a heavy metal normalized sensor, the control
sensor can be functionalized similarly to the active sensor by
coating the reference sensor with the methyl mercaptans
(HS--CH.sub.3 or HS--(CH.sub.2).sub.n--CH.sub.3), metal,
dielectric, or polymer instead of thioglycolic acid
(HS--CH.sub.2--CH.sub.2--COOH).
[0133] In another embodiment example, referring to FIG. 26B, for
prostate specific antigen detection, the active member 26 of the
normalized pair has a gold-based gate contact 27 with PSA antibody
28 anchored to the gate area with a binding agent 29 to the
gold-based gate contact 27, and the control member 30 of the
normalized pair has a gold-based gate contact 27 and a protective
layer 31. The protective layer 31 can be a metal layer, a
dielectric layer, antibodies not sensitive to the prostate specific
antigen, BSA, protein, aptamer, methyl mercaptans (HS--CH.sub.3 or
HS--(CH.sub.2).sub.n--CH.sub.3), or a polymer layer. When a metal
layer is used for the protective layer 31, it can be the metal
layer(s) used for final metal contacts 32 of the device. In certain
implementations of a PSA normalized sensor, the control sensor can
be functionalized similarly to the active sensor by coating the
gate area of the reference sensor with the metal, dielectric,
antibodies not sensitive to the prostate specific antigen, BSA,
protein, aptamer, methyl mercaptans (HS--CH.sub.3 or
HS--(CH.sub.2).sub.n--CH.sub.3), or polymer.
[0134] In yet another embodiment example, referring to FIG. 26C,
for detection of changes in pH in electrolyte solutions, the active
member 33 of the normalized pair has a non-native oxide 34 on the
gate region, and the control member 35 of the normalized pair has
the non-native oxide 34 and a protective layer 36. The protective
layer 36 can be a metal layer, another dielectric layer, or a
polymer layer. When a metal layer is used for the protective layer
36, it can be the metal layer(s) used for final metal contacts 37
of the device.
[0135] In another embodiment example, referring to FIG. 26D, for
kidney injury molecule-1 detection, the active member 38 of the
normalized pair has a gold-based gate contact 39 with KIM-1
antibody 40 anchored to the gate area with a binding agent 41 to
the gold-based gate contact 39, and the control member 42 of the
normalized pair has the gold-based gate contact 39 and a protective
layer 43. The protective layer 43 can be a metal layer, a
dielectric layer, antibodies not sensitive to the kidney injury
molecule-1, BSA, protein, aptamer, methyl mercaptans (HS--CH.sub.3
or HS--(CH.sub.2).sub.n--CH.sub.3), or a polymer layer. When a
metal layer is used for the protective layer 43, it can be the
metal layer(s) used for final metal contacts 44 of the device. In
certain implementations of a KIM-1 normalized sensor, the control
sensor can be functionalized similarly to the active sensor by
coating the gate area of the reference sensor with the metal,
dielectric, antibodies not sensitive to the kidney injury
molecule-1, BSA, protein, aptamer, methyl mercaptans (HS--CH.sub.3
or HS--(CH.sub.2).sub.n--CH.sub.3), or polymer.
[0136] In one embodiment example, referring to FIG. 26E, for
glucose detection, the active member 45 of the normalized pair has
ZnO nanorods 46 on the gate region, and the control member 47 of
the normalized pair has the ZnO nanorods 46 and a protective layer
48. The protective layer 48 can be a metal layer, an enzyme layer
not sensitive to the glucose, a dielectric layer, or a polymer
layer. When a metal layer is used for the protective layer 48, it
can be the metal layer(s) used for final metal contacts 49 of the
device.
[0137] In yet another embodiment example, referring to FIG. 26F,
for breast cancer specific antigen detection, the active member 50
of the normalized pair has a gold-based gate contact 51 with breast
cancer specific antibody 52, such as EGF, c-erbB-2, and CA15-3,
anchored to the gate area with a binding agent 53 to the gold-based
gate contact 51, and the control member 54 of the normalized pair
has a gold-based gate contact 51 and a protective layer 55. The
protective layer 55 can be a metal layer, a dielectric layer,
antibodies not sensitive to the breast cancer specific antigen,
BSA, protein, aptamer, methyl mercaptans (HS--CH.sub.3 or
HS--(CH.sub.2).sub.n--CH.sub.3), or a polymer layer. When a metal
layer is used for the protective layer 55, it can be the metal
layer(s) used for final metal contacts 56 of the device. In certain
implementations of the normalized sensor, the control sensor can be
functionalized similarly to the active sensor by coating the gate
area of the reference sensor with the metal, dielectric, antibodies
not sensitive to the breast cancer specific antigen, BSA, protein,
aptamer, methyl mercaptans (HS--CH.sub.3 or
HS--(CH.sub.2).sub.n--CH.sub.3), or polymer.
[0138] Advantageously, by providing both the control device and the
active device with a same or similar gate functionalization,
Schottky characteristics exist for both devices. In addition, the
inclusion of the same gate functionalization to HEMT semiconductor
interface for both the active device and the control device brings
the work function of the control device in line with the active
device, thereby making the response to different temperature
ambients in line with each other and reducing the effects of having
different responses to the different temperature ambients. This
effect can be seen in FIG. 27. FIG. 27 shows a plot of the
difference of diode current vs. bias voltage between a reference
(control) and an active sensor for active and control sensors using
different Schottky metallization at three temperature ambients
compared to an example embodiment where the active and control
sensors use a same Schottky metallization. It should be noted that
these plots represent the current in an ambient environment having
no element being detected. Therefore, for the sensing device of
embodiments of the present invention, the temperature and bias
dependence of the response signal can be minimized and the signal
be normalized to indicate only the presence of the element being
detected (as opposed to temperature dependence).
[0139] Specifically, as shown in FIG. 27, by not providing both the
control device and the active device with a same or similar gate
functionalization, the device where the control and active sensors
use different Schottky metallization as the gate contact shows
sensitivity to temperature changes and applied bias. In contrast,
an embodiment of the present invention using same Schottky
metallization as the gate contact is capable of maintaining a
constant current over change in bias and temperature. As shown in
the plot, even where a control diode is used (but does not have the
same gate metal as the active diode), the difference of the diode
current from the control and active diode is not zero (normalized).
This is due to the gate metal/semiconductor interface of the
control sensor being different from the active diode. The work
function of the different metal/semiconductor interfaces is
different and the diode current of the two sensors (control and
active) would be different at different bias as well as different
temperature.
[0140] All patents, patent applications, provisional applications,
and publications referred to or cited herein are incorporated by
reference in their entirety, including all Figures and tables, to
the extent they are not inconsistent with the explicit teachings of
this specification.
[0141] It should be understood that the examples and embodiments
described herein are for illustrative purposes only and that
various modifications or changes in light thereof will be suggested
to persons skilled in the art and are to be included within the
spirit and purview of this application.
* * * * *