U.S. patent application number 10/775781 was filed with the patent office on 2005-01-13 for semiconductor electrochemical bio-sensor array.
Invention is credited to Hassibi, Arjang.
Application Number | 20050006234 10/775781 |
Document ID | / |
Family ID | 33567278 |
Filed Date | 2005-01-13 |
United States Patent
Application |
20050006234 |
Kind Code |
A1 |
Hassibi, Arjang |
January 13, 2005 |
Semiconductor electrochemical bio-sensor array
Abstract
According to one embodiment, a semiconductor electrochemical
biosensor array (SEBA) is described. The SEBA includes an array of
electrodes to receive sample material from an external source and
sensor circuitry coupled to the array of electrodes. The sensor
circuitry includes a plurality of sensor cells to analyze the
sample material received at the array of electrodes.
Inventors: |
Hassibi, Arjang; (Palo Alto,
CA) |
Correspondence
Address: |
BLAKELY SOKOLOFF TAYLOR & ZAFMAN
12400 WILSHIRE BOULEVARD
SEVENTH FLOOR
LOS ANGELES
CA
90025-1030
US
|
Family ID: |
33567278 |
Appl. No.: |
10/775781 |
Filed: |
February 10, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60447087 |
Feb 13, 2003 |
|
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Current U.S.
Class: |
204/403.01 ;
204/406 |
Current CPC
Class: |
G01N 27/403
20130101 |
Class at
Publication: |
204/403.01 ;
204/406 |
International
Class: |
C25B 009/00; C25B
011/00 |
Claims
What is claimed is:
1. A semiconductor electrochemical biosensor array (SEBA),
comprising: an array of electrodes to receive sample material from
an external source; and sensor circuitry, coupled to the array of
electrodes, having a plurality of sensor cells to analyze the
sample material received at the array of electrodes.
2. The SEBA of claim 1 further comprising: a decoder, coupled to
the sensor circuitry, to select which of the plurality of sensor
cells are to be used to analyze the sample material; and control
circuitry, coupled to the sensor circuitry to enable a SEBA user to
activate a combination of electrodes and sensor cells.
3. The SEBA of claim 2 further comprising: a function generator,
coupled to the control circuitry, to generate signals for
measurements; and reference elements coupled to the sensor
circuitry.
4. The SEBA of claim 1 wherein the array of electrodes comprises a
plurality of triple electrode configurations each coupled to a
sensor cell.
5. The SEBA of claim 4 wherein the triple electrode arrangement
comprises: a common electrode; an active electrode; and a passive
electrode.
6. The SEBA of claim 5 wherein each of the sensor cells comprise:
an amplifier, having inputs coupled to an active electrode an a
passive electrode, to provide a variable gain based upon a type of
analysis being performed; a plurality of switches coupled to the
amplifier and a control register to control the plurality of
switches.
7. The SEBA of claim 6 wherein the amplifier receives one or more
select bits to in order to set a gain level.
8. The SEBA of claim 6 wherein the sensor cells are configured to
implement Charge Perturbation Signature (CPS) analysis.
9. The SEBA of claim 6 wherein the sensor cells are configured to
implement Impedance Spectroscopy (IS) analysis.
10. The SEBA of claim 6 wherein the sensor cells are configured to
implement Cyclic Voltammetry (CV) analysis.
11. The SEBA of claim 6 wherein the sensor cells are configured to
implement potentiometric measurements.
12. The SEBA of claim 1 wherein the sample material is chemical
samples.
13. The SEBA of claim 1 wherein the sample material is biological
samples.
Description
[0001] This is a non provisional application based on the
provisional application Ser. No. 60/447,087 filed on Feb. 13, 2003
and claims priority thereof.
COPYRIGHT NOTICE
[0002] Contained herein is material that is subject to copyright
protection. The copyright owner has no objection to the facsimile
reproduction of the patent disclosure by any person as it appears
in the Patent and Trademark Office patent files or records, but
otherwise reserves all rights to the copyright whatsoever.
[0003] 1. Field of the Invention
[0004] The present invention relates to the field of chemical and
biological analysis and synthesis.
[0005] 2. Background
[0006] There are many applications where one desires to detect
and/or characterize a molecular motion and/or interaction (e.g.,
the occurrence of a binding event (either covalent or non-covalent)
between two or more molecules, in a sample). Such applications find
use in a variety of different fields, including research and
medical (e.g., diagnostic fields). Because of the importance of
such applications to such a wide variety of different disciplines,
an enormous variety of different protocols and methodologies have
been developed to perform such applications.
[0007] Many protocols and methodologies use detectable labels,
where labels can adversely modify the characteristics of a
molecule(s) of interest. Some other protocols use indirect chemical
or physical measurements to analyze the sample, yet in most of
these protocols, either expensive and complicated detection devices
must be employed, or sensitivity is quite limited.
[0008] As such, there is continued interest in the development of
new methodologies for use in the characterization of molecular
motion and/or interactions in a sample.
SUMMARY
[0009] According to one embodiment, a semiconductor electrochemical
biosensor array (SEBA) is described. The SEBA includes an array of
electrodes to receive sample material from an external source and
sensor circuitry coupled to the array of electrodes. The sensor
circuitry includes a plurality of sensor cells to analyze the
sample material received at the array of electrodes.
[0010] In a further embodiment, the SEBA includes a decoder and
control circuitry coupled to the sensor circuitry. The decoder
selects which of the plurality of sensor cells are to be used to
analyze the sample material. The control circuitry enables a user
to activate a combination of electrodes and sensor cells. Further,
the SEBA includes a function generator coupled to the control
circuitry to generate signals for measurements, and reference
elements coupled to the sensor circuitry.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The present invention will be understood more fully from the
detailed description given below and from the accompanying drawings
of various embodiments of the invention, which, however, should not
be taken to limit the invention to the specific embodiments, but
are for explanation and understanding only.
[0012] FIG. 1 illustrates one embodiment of a semiconductor
electrochemical biosensor array;
[0013] FIG. 2 illustrates another embodiment of a semiconductor
electrochemical biosensor array;
[0014] FIG. 3 illustrates a block diagram of one embodiment of a
semiconductor electrochemical biosensor array;
[0015] FIG. 4 illustrates one embodiment of a triple electrode
design;
[0016] FIG. 5 illustrates one embodiment of a semiconductor
electrochemical biosensor cell design;
[0017] FIG. 6 illustrates one embodiment of a Charge Perturbation
Signature (CPS) sensor circuit;
[0018] FIG. 7 illustrates one embodiment of a differential
Impedance Spectroscopy sensor circuit;
[0019] FIG. 8 illustrates one embodiment of a single ended
Impedance Spectroscopy sensor circuit with external load
impedance;
[0020] FIG. 9 illustrates one embodiment of a single ended
Impedance Spectroscopy sensor circuit with no external load
impedance;
[0021] FIG. 10 illustrates one embodiment of an active electrode
array circuit with three controllable voltage sources;
[0022] FIG. 11 illustrate one embodiment of a binding experiment
for an unknown species carried out with Impedance Spectroscopy (IS)
analysis; and
[0023] FIG. 12 illustrates one embodiment of an interactive test
for CV analysis.
DETAILED DESCRIPTION
[0024] According to one embodiment, a semiconductor electrochemical
biosensor array is described. The electrochemical biosensor array
is a multiplexed, semiconductor based, electrochemical sensor array
for chemical and biological analysis and synthesis. In one
embodiment, a matrix of electrodes, configured to receive
biological or chemical samples of interest, is connected to an
integrated set of analysis and synthesis circuitry embedded in a
semiconductor chip.
[0025] In the platform, integrated control circuitry activates
independent cells within the array, and further analyzes or
synthesizes are performed on bio-molecular samples on different
sites. The sensor cells can perform various analyses methods, such
as Charge Perturbation Signature (CPS) analysis, single-ended and
differential Impedance Spectroscopy (IS), single-ended and
differential Cyclic Voltammetry (CV), and also potentiometric
measurements.
[0026] In a further embodiment, the array can also be used to work
as an active electrode matrix, by putting particular potential on
different electrode sets to activate electrophoretic experiments
and amperometric processes.
[0027] In the following description, numerous details are set
forth. It will be apparent, however, to one skilled in the art,
that the present invention may be practiced without these specific
details. In other instances, well-known structures and devices are
shown in block diagram form, rather than in detail, in order to
avoid obscuring the present invention.
[0028] Reference in the specification to "one embodiment" or "an
embodiment" means that a particular feature, structure, or
characteristic described in connection with the embodiment is
included in at least one embodiment of the invention. The
appearances of the phrase "in one embodiment" in various places in
the specification are not necessarily all referring to the same
embodiment.
[0029] FIG. 1 illustrates one embodiment of a semiconductor
electrochemical biosensor array (SEBA) 100. SEBA 100 includes an
electrode array 110 mounted on a substrate 120, and connectors 130
that connect the array 120 to a pad matrix 140 mounted on a
semiconductor 150. Electrode array 110 serves as an input to pad
matrix 140. According to one embodiment, electrode array 110
comprises an array of identical triple pad configurations that
receive biological or chemical samples of interest from an external
source.
[0030] Substrate 120 is a substance (organic or inorganic) that
functions as a base layer. In one embodiment, substrate 120 is
comprised of silicon oxide (SiO.sub.2), while the electrode is
comprised of gold (AU). In other embodiments, substrate 120 may be
comprised of silicon nitride (N.sub.4Si.sub.3), and the electrode
is comprised of aluminum (Al).
[0031] In a further embodiment, each electrode in array 110 is
covered with a coating containing an enzyme, which causes the
reaction of substrate 120 to produce a species to which the
electrode responds. In particular, substrate 120 operates as an
electron shuttle to transport electrons adsorbed from electrodes
110 to pad matrix 140 via connectors 130.
[0032] Pad matrix 140 is electrically coupled to connectors 130, as
described above. Pad matrix 140 includes a matrix of sensor cells
mounted on a semiconductor 150 substrate. The sensors of matrix 140
analyze biological and/or chemical samples received at electrode
array 110. According to one embodiment, semiconductor 150 is a CMOS
chip. However, one of ordinary skill in the art will appreciate
that other semiconductor fabrication technologies may be
implemented without departing from the scope of the invention.
[0033] FIG. 2 illustrates another embodiment of SEBA 100. In this
embodiment, electrode array 110 is mounted directly on pad matrix
140. Moreover, pad matrix 140 is mounted semiconductor 150. Thus,
in this embodiment, additional connectors are not implemented and
the electrodes are directly connected to the internal sensors
through the metal layers of the semiconductor processes. SEBA 100
also includes leads 170. Leads are used to transmit the analog or
digital electrical signal, detected and/or amplified by the sensor
circuitry, to the external devices. The transmitted signal
subsequently can be analyzed and correlated to the intrinsic
characteristics of the samples within the electrode matrix.
[0034] FIG. 3 illustrates a block diagram of one embodiment of SEBA
100. Included in SEBA 100 is sensor circuitry 310 coupled to
electrode array 110, decoder 320, reference elements 330, analysis
control 340 and function generator 350. Sensor circuitry 310 is
logic circuitry associated with sensor cells of pad matrix 140.
Sensor circuitry 310 analyzes signals received from electrode array
110. In one embodiment, the output of sensor circuitry 310 is an
analog signal that is transmitted to a central processing unit
(CPU) 370 via an analog to digital (A/D) converter 360.
[0035] Decoder 320 is used to select various sensor cells to use
for analysis. Reference elements 330 is a reference element bank
that is implemented for the accurate loading of circuit elements.
In one embodiment, reference elements 330 include tuning circuits
(e.g. crystal), resistors and passive elements. Analysis control
340 enables a user of SEBA 100 to activate independent, or a
combination of, sensors and electrodes, through user-defined inputs
via sensor circuitry 310.
[0036] Function generator 350 is controlled by a SEBA 100 user to
generate signals for active measurements, such as IS and CV
analyses. In one embodiment, the function generator is capable of
producing electrical waveforms with controllable amplitude and
shape (e.g. sine-wave vs. square-wave) within a particular
frequency region. Function generator 350 may be internal or
external to SEBA 100.
[0037] According to one embodiment, the inputs of the SEBA 100
platform are the addresses of a specific sensor cell or cells to be
activated, and the analysis method type defined by the user. The
output of the system is an analog output signal of the requested
sensor cell or cells, based on the user-defined analysis method.
For instance, in CPS analysis, the output signal is a transient
signal generated by specific bindings of ions to the
electrode-electrolyte interface of the active electrode. In the
case of IS analysis, the output is a single tone with fixed
amplitude and phase, in the case of CV analysis, a periodic
waveform.
[0038] In one embodiment, signals obtained from electrode array 110
can be read sequentially. Further, the total analysis time and
sampling rate for the entire matrix may also be calculated
depending on the time assigned for analysis of each electrode of
interest. Further, the analog signal generated from experiments may
also be quantized by an analog to digital converter (A/D), which
may be either internal or external to SEBA 100.
[0039] As described above, electrode array 110 comprises an array
of identical triple pad configurations. FIG. 4 illustrates one
embodiment of a triple electrode design. The configuration includes
a Common electrode (C), an Active electrode (A), and a Reference
electrode (R). The circuit also includes series resistors R.sub.1,
R.sub.12, and R.sub.2, and capacitors C.sub.1, C.sub.12, and
C.sub.2. Each resistor, capacitor pair may be denoted as impedances
(e.g., Z.sub.1, Z.sub.12, and Z.sub.2,).
[0040] According to one embodiment, biological samples of interest
are either spotted or chemically synthesized onto the Active
electrode. The Reference electrode, positioned in close proximity
to the Active electrode, is free of any target sample. The Common
electrode is used in active measurements and the induced signal is
introduced into solution via this electrode. The Common electrode
can also be shared within the matrix.
[0041] In one embodiment, each triple electrode configuration is
electrically connected to a single sensor cell in pad matrix 140.
In a further embodiment, many possible topologies and sizes of the
electrodes/pads may be configured to suit the application,
depending on the application. For example, circular, rectangular
and rectangular with a shared common electrode configurations may
be implemented.
[0042] FIG. 5 illustrates one embodiment of a cell 500 of pad
matrix 140. Cell 500 includes amplifier 510 and control register
550. In addition, cell 500 includes addressing lines and switches
S.sub.0-S.sub.7. Amplifier 510 is a differential amplifier that has
inputs coupled to electrode A and electrode R, via switch S.sub.3.
The output of amplifier 510 is coupled to switch S.sub.7.
[0043] In one embodiment, amplifier 510 provides a variable gain
depending upon a specific application. Thus, amplifier 510 receives
select bits S.sub.8 and S.sub.9 that are used to select which
transistors within amplifier 510 are activated in order to choose a
particular gain level. In a further embodiment, cell 500 is
activated by two address lines (row-select and column-select)
received from decoder 220.
[0044] Control register 550 within each cell 500 controls the
internal functional switches S.sub.0-S.sub.7 of the cell. Further,
control register 550 can be programmed by the control-bus. Also,
analog input and output lines are shared between all cells 500 in
matrix 140. Depending on the application, the analog input and
output lines can be routed from or into one node within the cell
500.
[0045] As described above, multiple electrochemical tests can be
performed in the SEBA 100 platform. In one embodiment, the methods
observe a certain macroscopic characteristic of the
electrolyte-electrode interface region. Since a biochemical species
of interest or target is located in this region, the spatial
electrical characteristics obtained contain information about their
structure, quantity, and behavior.
[0046] The electrochemical analysis techniques can be categorized
into two distinctive categories. The first category is to measure
the response of the electrolyte-electrode system. This is achieved
by applying a perturbing signal into the system, such as a
potential waveform. The methods which implement the above
methodologies are called active measurements (e.g., IS and CV
analyses methods). The second analysis technique is known as
passive measurement, wherein the electrical output of the system
without perturbing the system is observed (e.g., CPS and various
potentiometric measurement methodologies).
CPS and Potential Measurements
[0047] CPS is a Passive electrochemical technique to analyze DNA
and other nano-biological entities. CPS technology is based on
measuring the variation of the net charge of molecules (e.g., DNA)
in proximity of an electrode when exposed to different
reagents.
[0048] In the case of DNA analysis for example, primed single
strand DNA molecules are immobilized on an electrode and placed in
a solution containing polymerase. When nucleotides are added and
extension occurs, the electrostatic response of a group of
identical DNA molecules creates a unique waveform from which one
can potentially use to recognize the pattern (for SNP or DNA
sequencing), evaluate the mass (for gene expression).
[0049] FIG. 6 illustrates one embodiment of a cell 500 configured
for CPS analyses. In the CPS analysis method, switches are turned
on according to the adequate configuration for CPS analysis. In one
embodiment, the switch configuration is such that switches S.sub.0,
S.sub.1, S.sub.2 and S.sub.4 are off while switches S.sub.3,
S.sub.5, S.sub.6 and S.sub.7 are on. In addition, select bits
S.sub.8 and S.sub.9 are controlled by the user to control the gain
of amplifier 510.
[0050] For the CPS analysis method, a single low noise amplifier is
needed. In one embodiment, the signal generated by CPS, has less
than 10 kHz bandwidth and is in the region of about 1 kHz. As shown
in FIG. 6, the solution and samples on the electrodes are
capacitively coupled to the sensor by the natural double-layer
capacitance of the electrode-electrolyte interface
[0051] The binding phenomenon that occurs within the electrode cell
creates a potential which is modeled by V(t), and the whole signal
is amplified before being placed on the output line. In one
embodiment, load elements can be added to the amplifier input to
enhance the performance, depending on the application required.
IS (Differential and Single Ended)
[0052] Impedance spectroscopy (IS) is an active measurement where
the electrode system is perturbed by an alternating signal of small
magnitude. As a result, the way in which the system follows the
perturbation in steady state is observed. In one embodiment, the
induced signal is created by a voltage source with frequency
.omega. and a relatively small amplitude (small signal with no
nonlinear effects). The measured variable is the overall impedance,
which the system has in frequency .omega..
[0053] The impedance measured is a function of three factors:
mobility of ions in the solution and their diffusion rate; the
surface electrical characteristics of the interface; and the size
and shape of both a reservoir and the electrodes. Because the
observed impedance is a function of the system, any structural or
quantitative change which electrically affects the system in steady
state can be observed and measured.
[0054] FIG. 11 illustrates one embodiment of a binding experiment
for unknown species (species "X") carried out with Impedance
Spectroscopy (IS) analysis. The surface characteristic of the
electrode system (the surface double layer capacitance) is
different in the case of binding, (e.g., when "A" is truly present
at the surface) compared to the non-binding effect (e.g., when
species "A" does not find its complimentary). IS analysis can
potentially differentiate between the above two scenarios, and thus
detect the existence of species "A" on an electrode.
[0055] According to one embodiment, two methods of IS analysis may
be implemented at cell 500 of pad matrix 140 shown in FIG. 5. One
IS method is the Differential IS method, which measures the current
through the reference electrode and the active electrode when the
potential is induced through the common electrode. FIG. 7
illustrates one embodiment of a cell 500 configured for the
Differential IS analysis method. In one embodiment, the switch
configuration is such that switches S.sub.0, S.sub.2, and S.sub.4
are off while switches S.sub.1, S.sub.3, S.sub.5, S.sub.6 and
S.sub.7 are on. Also, select bits S.sub.8 and S.sub.9 are
controlled by the user to control the gain of amplifier 510.
[0056] In one embodiment, if both electrodes have the same
electrical behavior and surface characteristics, the current is
zero (e.g., no binding or activity occurs on electrode). However,
any small impedance change between the active and the reference
electrode (e.g., binding of specific molecules into the active
electrode surface) causes a differential current to be observed.
This technique enhances the performance by suppressing the effects
of common impedances between the common electrode and both active
and reference electrode.
[0057] The second analysis method is the Single-Ended IS method. In
the Single-Ended IS method, the impedance of the
electrode-electrolyte is obtained in frequency .omega. by measuring
the voltage amplitude and phase across a known load impedance in
series with the unknown system impedance. FIG. 8 illustrates one
embodiment of cell 500 configured for the Single-Ended IS analyses
method with an external load impedance.
[0058] In one embodiment, the load impedance is configured as a
tuned circuit (e.g., piezo-electric crystal) for higher
sensitivity. In another embodiment, the load impedance is
configured as the input impedance of the differential amplifier
itself. The switch configuration for the Single-Ended IS method
with external load impedance is such that switches S.sub.0 and
S.sub.2 are off while switches S.sub.1, S.sub.3, S.sub.4 and
S.sub.7 are on. Switches S.sub.5 and S.sub.6 are in a don't care
state.
[0059] FIG. 9 illustrates one embodiment of cell 500 configured for
the Single-Ended IS analyses method with no external load
impedance. The switch configuration for the Single-Ended IS method
with no external load impedance is such that switches S.sub.0,
S.sub.2, and S.sub.3 are off while switches S.sub.1, S.sub.4 and
S.sub.7 are on. Switches S.sub.5 and S.sub.6 are in a don't care
state.
CV (Differential and Single Ended)
[0060] Cyclic Voltammetry (CV) analysis and other potential sweep
methods are used to obtain the complete electrochemical behavior of
a system. This is achieved by introducing a series of different
potentials waveforms and steps, and recording the current-potential
curves obtained (FIG. 8). FIG. 12 illustrates one embodiment of an
interactive test for CV analysis. Like the IS analyses method, CV
analysis features Differential analysis and Single-Ended IS
analyses.
[0061] According to one embodiment, the sensor cell 500 circuitry
is unchanged from the IS analysis method discussed above (e.g.,
FIGS. 7-9). However in CV analysis, the electrode is driven to a
condition far from equilibrium and the response (usually a
transient signal from non-linear elements) is observed. The large
potentials in multiple CV can be measured by the circuit topology.
The Single-Ended and Differential CV methods have different
applications, but overall the differential method has much more
sensitivity when studying electrodes interfacial behavior.
CV (Differential and Single Ended)
[0062] The other feature of the SEBA 100 is its capability to be
used as an Electrophoretic system. An Electrophoretic system is
implemented to repel or attract specific ions. FIG. 10 illustrates
one embodiment of cell 500 configured as an Electrophoretic system.
In one embodiment, the switch configuration is such that switches
S.sub.3, S.sub.4, S.sub.5, S.sub.6 and S.sub.7 are off while
switches S.sub.0, S.sub.1, and S.sub.2 are on. In addition, select
bits S.sub.8 and S.sub.9 are also off. In a further embodiment, all
three electrodes are controlled by external voltage supplies. In
yet another embodiment, Electrochemical synthesis is also possible
with this topology.
[0063] 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 any particular embodiment shown and described
by way of illustration is in no way intended to be considered
limiting. Therefore, references to details of various embodiments
are not intended to limit the scope of the claims, which in
themselves recite only those features regarded as essential to the
invention.
[0064] Thus, a semiconductor electrochemical biosensor array has
been described.
* * * * *