U.S. patent application number 09/928177 was filed with the patent office on 2003-02-13 for multifunctional opto-electronic biochip detection system.
Invention is credited to Lee, Chih-Kung, Lee, Shu-Sheng, Lin, Chii-Wann, Lin, Shiming, Shiue, Shuen-Chen, Wu, Jiun-Yan.
Application Number | 20030030817 09/928177 |
Document ID | / |
Family ID | 25455833 |
Filed Date | 2003-02-13 |
United States Patent
Application |
20030030817 |
Kind Code |
A1 |
Lee, Chih-Kung ; et
al. |
February 13, 2003 |
Multifunctional opto-electronic biochip detection system
Abstract
A multi-functional opto-electronic system is mainly applied to
the real-time metrologies of biomedical or biochemical reactions as
well as the in-situ manufacturing measurements of biochips. The
configuration of this system is built up by integration of at least
four different near-field optical metrological principles, which
share a part of common optical path design and allow to turn on
several functions such as ellipsometer, Laser Doppler vibrometer or
interferometer (LDV/I), surface plasmon resonance (SPR) for
amplitude and phase detection, phase shifting interference
microscope, photon tunneling microscope, optical coherence
tomography (OCT) and imaging microscope by switching few components
in the system. With the creation of a novel opto-mechanical design
and its associated signal processing methodologies, both the signal
detection of the biomedical reactions and biomedical imaging
concerned for the future trend in the modern biomedical sciences
are achieved with high resolutions.
Inventors: |
Lee, Chih-Kung; (Taipei,
TW) ; Shiue, Shuen-Chen; (Keelung, TW) ; Lee,
Shu-Sheng; (Taipei, TW) ; Wu, Jiun-Yan;
(Taipei, TW) ; Lin, Chii-Wann; (Taipei, TW)
; Lin, Shiming; (Taipei, TW) |
Correspondence
Address: |
J.C. Patents, Inc.
Suite 114
1340 Reynolds Ave.
Irvine
CA
92614
US
|
Family ID: |
25455833 |
Appl. No.: |
09/928177 |
Filed: |
August 10, 2001 |
Current U.S.
Class: |
356/491 |
Current CPC
Class: |
G01B 11/00 20130101 |
Class at
Publication: |
356/491 |
International
Class: |
G01B 009/02 |
Claims
What is claimed is:
1. A multifunctional opto-electronic detection system, suitable for
use in detection on a biochip, the system comprising: a linear
polarizing light source set, used to provide a needed polarizing
light source; a phase modulation unit, used to modulate a phase of
a passing light, so as to change a polarization state of the
passing light; a reference optical analyzing unit, comprising an
non-polarizing optical beam-splitter, an analysis plate and a first
photodetector and a second photodetector; a variable incident angle
optical set, comprising a quasi-paraboloidal reflective mirror, a
quasi-spherical reflective mirror, and a uniaxial displacement
stage that can be controlled by a feedback manner and carry a prism
set, wherein the variable incident angle optical set is used to
adjust an incident angle of a light onto the biochip; an optical
signal analysis unit, having an analyzer and a third photodetector;
and a microscope lens set having a camera function, comprising a
lens set with a sufficient high power and an array CCD (charges
coupled device), so that a reaction situation of bio-molecules can
be monitored.
2. The system of claim 1, wherein the linear polarizing light
source set comprises one selected from the group consisting of a
device to emit a signal wavelength light with a linear
polarization, a laser diode incorporating a linear polarization
film, and a light emitted diode incorporating a linear
polarizer.
3. The system of claim 1, wherein the phase modulation unit
comprises one selected from the group consisting of a compensator,
a liquid crystal phase modulator, and a photoelastic phase
modulator.
4. The system of claim 1, wherein in the variable incident angle
optical set, the prism comprises one selected from the group
consisting of a reflective mirror, a triangular prism, and a penta
prism.
5. The system of claim 1, wherein in the reference optical
analyzing unit, the first photodetector and the second
photodetector comprises one selected from the group consisting of a
photodiode and a charge coupled device (CCD).
6. The system of claim 1, wherein in the optical signal analysis
unit, the third photodetector comprises one selected from the group
consisting of a photodiode and a charge coupled device (CCD).
7. A multifunctional opto-electronic detection system, which has
abilities to observe bio-molecules and reconstruct an image under a
confocal scanning principle, the system comprising: a linear
polarizing light source set, used to adjust an intensity of a light
source, and determine an initial polarization state of the light
source, so as to form a sampling light beam; a phase modulation
unit, used to control a phase change of the sampling light beam, so
as to change a polarization state; a variable incident angle
optical set, comprising: a refraction member, used to lead the
sampling light beam to enter the variable incident angle optical
set with a different incident location; a motion platform, used to
carry and move the refraction member; and an optical element set,
including a focusing device and a normal reflection device, wherein
the focusing device is used to lead the sampling light beam to
transmit through a substrate by an incident angle, so that a first
total reflection occurs at a desired measuring point on the biochip
and a reflection light beam of the sampling light beam is formed,
and the normal reflection device can normally reflect the
reflection light beam of the sampling light beam to form a backward
light beam travelling back to the desire measuring point and being
reflected by a second total reflection, whereby a signal light beam
is formed and leaves the variable incident angle optical set; an
optical signal analysis unit, at least comprising: a focusing lens
set, used to focus the signal light beam; a pinhole device, used to
allow the focused signal light beam to pass; and a photosensor,
used to sense a light intensity of the signal light beam at the
pinhole; and a reference optical analyzing unit, used to detect a
light intensity and a polarization state of a referencing light
beam, so as to correct a nonlinear light intensity and a nonuniform
absorption on the phase modulator and thereby control the
polarization state of the sampling light beam.
8. The system of claim 7, wherein the linear polarizing light
source set comprises one selected from the group consisting of a
device to emit a signal wavelength light with a linear
polarization, a laser diode incorporating a linear polarization
film, and a light emitted diode incorporating a linear
polarizer.
9. The system of claim 7, wherein the phase modulation unit
comprises one selected from the group consisting of a compensator,
a liquid crystal phase modulator, a photoelastic phase modulator, a
1/2 wave plate, and a 1/4 wave plate.
10. The system of claim 7, wherein in the variable incident angle
optical set, the refraction member comprises one selected from the
group consisting of a reflective mirror, a triangular prism, and a
penta prism.
11. The system of claim 7, wherein in the variable incident angle
optical set, the motion platform comprises one selected from the
group consisting of a step-motor used to drive a uniaxial
displacement stage and a DC motor to drive a uniaxial displacement
stage.
12. The system of claim 7, wherein in the variable incident angle
optical set, the focusing device comprises a planar reflective
mirror.
13. The system of claim 7, wherein in the variable incident angle
optical set, the focusing device comprises a quasi-paraboloidal
mirror and the normal reflection device comprises a quasi-spherical
mirror.
14. The system of claim 7, wherein the optical signal analyzing
unit comprises one selected from the group consisting of an
analyzer with a photodiode, an analyzer with a charge coupled
device (CCD)
15. The system of claim 7, wherein the reference optical analyzing
unit comprises an analyzer with two photodetectors.
16. A multifunctional opto-electronic detection system, comprising:
a linear polarizing light source set, used to adjust an intensity
of a light source, and determine an initial polarization state of
the light source, so as to form a sampling light beam; a variable
incident angle optical set, comprising: a refraction member, used
to lead the sampling light beam to enter the variable incident
angle optical set with a different incident location; a motion
platform, used to carry and move the refraction member; and an
optical element set, including at least a focusing device, wherein
the focusing device is used to lead the sampling light beam to
transmit through a substrate by different incident angles at a
desired measuring point on the biochip, and a total reflection
occurs at the desired measuring point, so as to produce a signal
light beam after; and an optical signal analyzing unit, used to
detect variation of a light intensity of the signal light beam.
17. The system of claim 16, wherein the linear polarizing light
source set comprises one selected from the group consisting of a
device to emit a signal wavelength light with a linear
polarization, a laser diode incorporating a linear polarization
film, and a light emitted diode incorporating a linear
polarizer.
18. The system of claim 16, wherein in the variable incident angle
optical set, the refraction member comprises one selected from the
group consisting of a reflective mirror, a triangular prism, and a
penta prism.
19. The system of claim 16, wherein in the variable incident angle
optical set, the motion platform comprises one selected from the
group consisting of a step-motor used to drive a uniaxial
displacement stage and a DC motor to drive a uniaxial displacement
stage.
20. The system of claim 16, wherein in the variable incident angle
optical set, the focusing device comprises a focusing lens set or a
quasi-paraboloidal reflective mirror.
21. The system of claim 16, wherein the optical signal analyzing
unit comprises a lens set with a photodiode or a lens set with a
CCD.
22. A multifunctional opto-electronic detection system suitable for
use of measuring a surface reaction on a biochip, comprising: a
linear polarizing light source set, used to adjust an intensity of
a light source, and determine an initial polarization state of the
light source, so as to form a sampling light beam; a phase
modulator, used to control a phase change of the sampling light
beam, so as to change a polarization state; a variable incident
angle optical set, comprising: a refraction member, used to lead
the sampling light beam to enter the variable incident angle
optical set with a different incident location; a motion platform,
used to carry and move the refraction member; and an optical
element set, including a focusing device and a normal reflection
device, wherein the focusing device is used to lead the sampling
light beam to transmit through a substrate by an incident angle, so
that a first total reflection occurs at a desired measuring point
on the biochip and a reflection light beam of the sampling light
beam is formed, and the normal reflection device can normally
reflect the reflection light beam of the sampling light beam to
form a backward light beam travelling back to the desire measuring
point and being reflected by a second total reflection, whereby a
signal light beam is formed and leaves the variable incident angle
optical set; an optical signal analysis unit, used to detect a
phase change or a light intensity of the signal light beam; and a
reference optical analyzing unit, used to detect a light intensity
and a polarization state of a referencing light beam, so as to
correct a nonlinear light intensity and a nonuniform absorption on
the phase modulator and thereby control the polarization state of
the sampling light beam.
23. A multifunctional opto-electronic detection system suitable for
use of measuring a surface reaction on a biochip, comprising: a
linear polarizing light source set, used to adjust an intensity of
a measuring light source, split the measuring light source into a
reference light beam and a sampling light beam, and determine an
initial polarization state of the reference light beam and an
initial polarization state of the sampling light beam; a phase
modulator, used to control a phase change of the sampling light
beam, so as to change a polarization state; a beam expander, used
to expand an area of a sampling point; a variable incident angle
optical set, comprising: a refraction member, used to lead the
sampling light beam to enter the variable incident angle optical
set with a different incident location; a motion platform, used to
carry and move the refraction member; and an optical element set,
including a focusing device and a normal reflection device, wherein
the focusing device is used to lead the sampling light beam to
transmit through a substrate by an incident angle, so that a first
total reflection occurs at a desired measuring point on the biochip
and a reflection light beam of the sampling light beam is formed,
and the normal reflection device can normally reflect the
reflection light beam of the sampling light beam to form a backward
light beam travelling back to the desire measuring point and being
reflected by a second total reflection, whereby a signal light beam
is formed and leaves the variable incident angle optical set; an
optical signal analysis unit, used to detect a phase change or a
light intensity of the signal light beam; and a reference optical
analyzing unit, used to detect a light intensity and a polarization
state of the reference light beam, so as to correct a nonlinear
light intensity and a nonuniform absorption on the phase modulator
and thereby control the polarization state of the sampling light
beam.
24. The system of claim 23, further comprising a interference light
path control unit, having function to adjust a light path and a
phase, wherein an interference reference light beam with a phase
shift interferes with the backward light beam, so as to provide an
information to the optical signal analyzing unit for analyzing a
phase change.
25. A multifunctional opto-electronic detection system, suitable
for use of measuring a surface reaction on a biochip, the system
comprising: a linear polarizing light source set, used to provide a
measuring light beam and a referencing light beam; a phase
modulator, used to modulate an initial phase and polarization state
of the measuring light beam and the referencing light beam; a
reference analyzing unit, used to analyze the referencing light
beam, so as to correct a light intensity of the measuring light
beam; a variable incident angle optical set comprising: a
refraction member, used to lead the sampling light beam to enter
the variable incident angle optical set with a different incident
location; a motion platform, used to carry and move the refraction
member; and an optical element set, including a focusing device and
a normal reflection device, wherein the focusing device is used to
lead the sampling light beam to transmit through a substrate by an
incident angle, so that a first total reflection occurs at a
desired measuring point on the biochip and a reflection light beam
of the sampling light beam is formed, and the normal reflection
device can normally reflect the reflection light beam of the
sampling light beam to form a backward light beam travelling back
to the desire measuring point and being reflected by a second total
reflection, whereby a signal light beam is formed and leaves the
variable incident angle optical set; an interference referencing
light path control unit, capable of control a light path length of
a reference luminous light beam split from the measuring light
beam; an optical signal analysis unit, used to detect a
polarization state and a light intensity of the measuring light
beam.
26. The system of claim 25, wherein the reference analyzing unit
comprises an non-polarizing beam-splitter and a photodetector.
27. The system of claim 25, wherein the reference analyzing unit
comprises a polarized beam-splitter and a photodetector.
28. The system of claim 25, wherein the interference referencing
light path control unit comprises: a cavity, used to control the
light path length of the reference luminous light beam; a
reflective mirror to produce a reference wave front; and a voltage
driver.
29. The system of claim 25, wherein the variable incident angle
optical set comprises: a prism, used to deflect an incident beam by
90 degrees; a concave paraboloidal mirror, used to reflect the
measuring light beam to a measuring area on the biochip and form a
measuring point, wherein the paraboloidal mirror has a parabolic
surface crossing the measuring point and is associated with the
prism so as to produce different measuring angles; a concave
spherical mirror, which has a center point located on the measuring
point, after the measuring light beam reflects from the measuring
point from the biochip, the measuring light beam normally enters
the concave spherical mirror, and the concave spherical mirror
reflects the measuring light beam to the measuring point again; and
a feedback control displacement stage, used to determine the
measuring point.
30. The system of claim 25, wherein the variable incident angle
optical set comprises: a prism, used to deflect an incident beam by
90 degrees; a concave parabolic rod mirror, used to reflect the
measuring light beam to a measuring area on the biochip and form a
measuring point, wherein the parabolic rod mirror is moved and
associated with the prism so as to achieve a measuring area; a
concave cylindrical mirror, which is movable and is located at a
proper location to receive a measuring light beam reflected from
biochip and reflect the measuring light beam back to the biochip
with the measuring area; and a feedback control displacement stage,
used to determine the measuring point within the measuring
area.
31. A multifunctional opto-electronic detection system, suitable
for use of measuring a surface reaction on a biochip, the system
comprising: a linear polarizing light source set, used to provide a
measuring light beam and a referencing light beam; a phase
modulation unit, used to modulate an initial phase and polarization
state of the measuring light beam and the referencing light beam; a
reference analyzing unit, used to analyze the referencing light
beam, so as to correct a light intensity of the measuring light
beam; a variable incident angle optical set comprising: a
refraction member, used to lead the sampling light beam to enter
the variable incident angle optical set with a different incident
location; a motion platform, used to carry and move the refraction
member; and an optical element set, including a focusing device and
a normal reflection device, wherein the focusing device is used to
lead the sampling light beam to transmit through a substrate by an
incident angle, so that a first total reflection occurs at a
desired measuring point on the biochip and a reflection light beam
of the sampling light beam is formed, and the normal reflection
device can normally reflect the reflection light beam of the
sampling light beam to form a backward light beam travelling back
to the desire measuring point and being reflected by a second total
reflection, whereby a signal light beam is formed and leaves the
variable incident angle optical set; a light path adjusting unit,
capable of control a light path length of an interference reference
luminous light beam split from the measuring light beam; an optical
signal analysis unit, used to detect a polarization state and a
light intensity of the interference reference luminous light beam
interacting with a tested sample on the biochip, so as to produce
two signals normal to each other.
32. The system of claim 31, wherein the reference analyzing unit
comprises an non-polarizing beam-splitter and a photodetector.
33. The system of claim 31, wherein the reference analyzing unit
comprises a polarized beam-splitter and a photodetector.
34. The system of claim 31, wherein the interference referencing
light path control unit comprises: a cavity, used to control the
light path length of the reference luminous light beam; a
reflective mirror to produce a reference wave front; and a voltage
driver.
35. The system of claim 31, wherein the variable incident angle
optical set comprises: a prism, used to deflect an incident beam by
90 degrees; a concave paraboloidal mirror, used to reflect the
measuring light beam to a measuring area on the biochip and form a
measuring point, wherein the paraboloidal mirror has a parabolic
surface crossing the measuring point and is associated with the
prism so as to produce different measuring angles; a concave
spherical mirror, which has a center point located on the measuring
point, after the measuring light beam reflects from the measuring
point from the biochip, the measuring light beam normally enters
the concave spherical mirror, and the concave spherical mirror
reflects the measuring light beam to the measuring point again; and
a feedback control displacement stage, used to determine the
measuring point.
36. The system of claim 31, wherein the variable incident angle
optical set comprises: a prism, used to deflect an incident beam by
90 degrees; a concave parabolic rod mirror, used to reflect the
measuring light beam to a measuring area on the biochip and form a
measuring point, wherein the parabolic rod mirror is moved and
associated with the prism so as to achieve a measuring area; a
concave cylindrical mirror, which is movable and is located at a
proper location to receive a measuring light beam reflected from
biochip and reflect the measuring light beam back to the biochip
with the measuring area; and a feedback control displacement stage,
used to determine the measuring point within the measuring
area.
37. A multifunctional opto-electronic detection system, suitable
for use of measuring a surface reaction on a biochip, the system
comprising: a linear polarizing light source set, used to provide a
measuring light beam and a referencing light beam and determine an
initial polarization state of the measuring light beam and the
referencing light beam; a phase modulation unit, used to modulate
an initial phase and polarization state of the measuring light beam
and the referencing light beam; a variable incident angle optical
set comprising: a refraction member, used to lead the sampling
light beam to enter the variable incident angle optical set with a
different incident location; a motion platform, used to carry and
move the refraction member; and an optical element set, including a
focusing device and a normal reflection device, wherein the
focusing device is used to lead the sampling light beam to transmit
through a substrate by an incident angle, so that a first total
reflection occurs at a desired measuring point on the biochip and a
reflection light beam of the sampling light beam is formed, and the
normal reflection device can normally reflect the reflection light
beam of the sampling light beam to form a backward light beam
travelling back to the desire measuring point and being reflected
by a second total reflection, whereby a signal light beam is formed
and leaves the variable incident angle optical set; an optical
signal analysis unit, used to detect a polarization state and a
light intensity of the signal light beam; a reference optical
analyzing unit, used to analyze the referencing light beam, so as
to control a polarization state of the sampling light beam by
correcting a nonlinear light intensity and nonuniform absorption in
the phase modulation unit; and an interference referencing light
path control unit, capable of control a light path length of a
reference luminous light beam split from the measuring light beam,
so as to provide information to the optical signal analysis unit
for analyzing phase change.
38. The system of claim 37, wherein the linear polarizing light
source set comprises one selected from the group consisting of a
device to emit a signal wavelength light with a linear
polarization, a laser diode incorporating a linear polarization
film, and a light emitted diode incorporating a linear
polarizer.
39. The system of claim 37, wherein the phase modulation unit
comprises one selected from the group consisting of a compensator,
a liquid crystal phase modulator, a photoelastic phase modulator, a
1/2 wave plate, and a 1/4 wave plate.
40. The system of claim 37, wherein in the variable incident angle
optical set, the refraction member comprises one selected from the
group consisting of a reflective mirror, a triangular prism, and a
penta prism.
41. The system of claim 37, wherein in the variable incident angle
optical set, the motion platform comprises one selected from the
group consisting of a step-motor used to drive a uniaxial
displacement stage and a DC motor to drive a uniaxial displacement
stage.
42. The system of claim 37, wherein in the variable incident angle
optical set, the focusing device comprises a planar reflective
mirror.
43. The system of claim 37, wherein in the variable incident angle
optical set, the focusing device comprises a quasi-paraboloidal
mirror and the normal reflection device comprises a quasi-spherical
mirror.
43. The system of claim 37, wherein the optical signal analyzing
unit comprises one selected from the group consisting of an
analyzer with a photodiode, an analyzer with a charge coupled
device (CCD)
44. The system of claim 37, wherein the signal analyzing unit
comprises an analyzer with two photodetectors.
45. The system of claim 37, wherein the signal analyzing unit
comprises an analyzer with a CCD.
46. The system of claim 37, wherein the reference optical analyzing
unit comprises an analyzer with two photodetectors.
47. The system of claim 37, wherein the interference referencing
light path control unit comprises a voltage driver, a reflective
mirror, and a light path adjusting device.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of Invention
[0002] The present invention relates to a multifunctional
opto-electronic detecting technology. More particularly, the
present invention relates to a multifunctional opto-electronic
biochip detection system, suitable for use in production quality
test of biochip and detection of biochemical reaction signal.
[0003] 2. Description of Related Art
[0004] Conventional biomedical or chemical sensor are usually
comprised of two parts. One is molecular recognition element and
another one is signal generator or converter. Under this mechanism,
a bio-sensor mainly includes a piezoelectric crystals and a fiber
optical immunosensor.
[0005] the conventional technologies of for testing a biochip
include resonance mirror (RM), surface plasmon resonance (SPR)
detection, X-ray photoelectron spectroscopy, scanning probe
microscopy, and scanning tunneling microscopy. These technologies
have their advantages. However, the X-ray photoelectron
spectroscopy employs radiation for test. Even though the scanning
probe microscopy technology has good atom resolution, it may cause
a damage on the surface bio-molecules and change its activity when
the technology is applied to detect bio-molecules, resulting in
limited use. Moreover, it still has other technologies, such as
ultrasonic excitation, wave guide method and so on. In general,
each of the above technologies has its different detection
mechanism, and the associated chip design is also different. For
example, resonance mirror technology needs an agitator to satisfy
the requirement of testing condition, and a design concept of the
detection container is completely different from a design concept
of the chip used in the surface plasmon resonance detection.
Therefore, the conventional detector is usually restricted into
specific machine associating with specific detecting technique.
Currently, it is still absent for a detection system, which can
effectively integrate multiple detecting functions to satisfy the
great amount of need on the detecting platform in the current
biomedical technology.
[0006] The opto-electronic detecting technology in the various
related detecting technologies have been approved to be most useful
technology in the field of biochip technology. This conclusion is
made according to the observations from the biomedical field on the
opto-electronic detection technology at a few concerning points:
(1) non-contact and non-invasive, which would not affect the tested
sample, and (2) high sensitivity, wide bandwidth, and small probe
volume, which allow the great need still to be satisfied when the
biochips or test samples are in great shortage for the current
situation in the whole word. However, the function of the
opto-electronic detector has strong relation with the system of
chip mechanism. In developments for past years, most of detector
are still using the chip system which is based on the enzyme-linked
immunosorbent assays (ELISA) mechanism, in which the assays are
distributed on the biochip in an array manner. Through the signals
from the assays are detected or read by an analysis system, a
reaction chain including several different reactions can be
simultaneously detected, and then a sieving procedure can be
performed. This detecting mechanism associating with the biochip
has been widely used in the DNA research. Particularly in the past
few years, a technology of biomolecular interaction analysis (BIA)
based on the bio-reaction mechanism has been developed. The BIA
technology includes affixing assays on a surface of the sensing
chip by a specific arrangement. A biochemical reaction is triggered
by using interaction of continuous micro fluid with the sensing
chip. Then, an signal detecting system, usually in optical manner,
is used to read out signals for forming the sensorgram.
[0007] The detecting foundation theory is continuously updated in
the recent years. For example, B. Liedberg et al. in 1983 had
introduced the detecting system based on surface plasmon resonance
effect. The resolution can achieve to the level of ng/ml. H. Yang
et al. in 1994 had reported a technology based on electrochemistry
fluorescent detecting system, which technology has resolution
ranging from 10 pg/ml to 5 ng/ml. Brain Trotter et al. had
published in Optical Engineering at May, 1999 about a technology of
optical immunosensor assay detection based on the mechanism of
fixed-polarizer ellipsometry, which technology shows an
experimental result better than 4 pg/ml. This is a practical
application of fixed-polarizer ellipsometry in biochemical field,
and the fixed-polarizer ellipsometry technology is foreseen to be a
very useful detection tool in the biochemical field. From the
foregoing research reports, it is expected to have more
applications for the fixed-polarizer ellipsometry technology on the
biochip.
[0008] On the other hand, the biomedical detection function should
includes both the quantitative detection and the qualitative
observation. The signal detection and the three-dimensional image
displaying are very essential. The further conventional technology
of the current technology usually use optical microscopy, which has
insufficient resolution. Scanning electron microscope (SEM) and
atomic force microscope (AFM) may cause a damage on the assay
sample, in which the samples need to be pre-processed or be
operated in a vacuum environment, causing very inconvenient
operation. Therefore, optical technology for the test sample could
also be a trend in the next generation of biomedical detecting
technology.
[0009] Moreover, the conventional optical system is designed with a
single angle measurement and a signal incident angle. This can not
allow the image to be precisely displayed
SUMMARY OF THE INVENTION
[0010] The invention provides an opto-electronic biochip system
which is designed with a novel optical mechanism associating with
advanced optical detecting principles, so as to achieve high
resolution and be high repeatable.
[0011] The invention provides an opto-electronic biochip system
which uses an optical interferometer with sufficiently high
resolution to capture dynamic and static information of the
bio-molecules, and uses the optical tunneling effect, confocal
scanning, and optical coherence tomography (OCT) scanning
technology, so that a micro-change on the surface of the tested
sample can be well observed. Moreover, an advanced optical
representation with image reconstruction technology is employed in
design to achieve 3-D image display.
[0012] The invention provides a multifunctional opto-electronic
biochip system, satisfying needs for the overstriding platform
detection as shown in FIG. 1. The functional system is shown in
FIG. 2, so that all the sub-functional units are effectively
integrated, wherein some optical paths are commonly used. With
respect to different detecting platforms and the corresponding
detection mechanism, functions for signal detection and
opto-electronic transformation have been introduced. All the
optical detection function can also be effectively integrated into
a micro-electric system. The invention is suitable for use in
biochip developing stage or biochip production stage, and is a
complete multifunctional biochip platform.
[0013] In the invention, a multifunctional opto-electronic biochip
detection system is an optical system which includes four advanced
optical detecting theories ellipsometry (a first subsystem),
confocal scanning theory (a second subsystem), evanacent wave
theory (a third subsystem), and interferometry (a fourth
subsystem). Each subsystem has a commonly used optical path and in
combination with an optical member that has ability to receive
light with variable incident angle. The opto-mechanical unit can be
switched according to different detection theory, so that eight
function, including the ellipsometer, can be achieved.
[0014] the subsystem, such as the ellipsometer can be used in
development and production of biochip. The function includes
measuring refractive indices and thickness of coating layer, such
as gold film or protein film, on a substrate during production. The
ellipsometer is also a necessary tool in fabrication process of
lithography and etching during developing the biochip carrier. The
ellipsometry can also associate with an optical member with
variable incident angle, so that the parameters for the multi-layer
coating film can be analyzed, and it therefore is useful for
detection of more complicate biochemical reaction. A laser Doppler
interferometer can be used to measure the dynamic interaction
between protein chip, antibody, or antigen. The laser Doppler
interferometer has a dynamic bandwidth of a level of 100 MHz for
detecting a vibration, which is equivalent to a vibration of
10.sup.-10 meter, and can be used for insitu detection through
associating with ultrasonic technology that triggers the
combination of antibody-antigen. As a result, the dynamic
properties between bio-molecules can be analyzed.
[0015] The SPR configuration unit includes not only the function of
using SPR amplitude to measure critical angle, like what the
conventional commercial system technology has done, but also the
function of determining the critical angle by using double exciting
on SPR and measuring the phase. As a result, the sensitivity can be
improved several times. The system of the invention further
includes a combination of precise paraboloidal mirror with a
stepping motor or at least a DC motor, so as to achieve a precise
control of the incident angle, whereby the precision of measurement
on the critical angle can be improved by at least 10 times more
than conventional SPR. The object of function for measuring
amplitude in built-in multifunctional opto-electronic biomedical
detector and the surface plasmon resonance is to provide the
opto-electronic detection function with novel, instant, precise,
and high resolution. Particularly, when the invention is applied to
measurement in biology, medicine, and chemical reaction,
suitability of BIA and ELISA can be both considered. The biochip
for any type of above system configurations can be put on a
platform with double precision control. A laser light is incident
on metal and dielectric interface, so as to generate a surface
plasmon wave. A variable incident angle optical set is used to
control for obtain a total interval reflection. As the incident
angle of the total reflection is changed, the amplitude and
intensity of the generated surface plasmon wave is changed also.
When the resonant state is achieved, it is called the SPR.
[0016] In order to achieve the foregoing functions, the optical
system of the multifunctional opto-electronic biochip system of the
invention needs to associate with a biochip having a three-layer
structure that includes bio-molecules such as protein molecules or
DNA, a metal film such as gold or silver with a thickness of about
40-60 nm, and a substrate such as PMMA, glass or silicon material.
The incident light is led to the biochip, so as to generate the
surface plasmon wave for measuring the optical parameters produced
by the surface plasmon wave, so that the variation of the
refractive index of reaction assay can be real-time measured, and
the corresponding concentration variation of reaction and a
thickness of bio-molecules can also be computed out.
[0017] The interference microscopy configuration has function to
directly measure the surface topology of the biochip. If the
material is uniform, it stands for a surface configuration of the
tested sample or the bio-molecules. This function is equivalent to
the interference microscopy used in semiconductor fabrication. The
needed parameters used to design a biochip can be totally
controlled under the system of the invention. The invention further
combined the measurement of ellipsometer and the function of
backward calculation into the interference microscopy, so that the
practical surface configuration for the non-uniform surface can be
measured. This application function is essential while the chip is
under developing, quality control, and production.
[0018] The configuration of photon scanning tunneling microscopy
uses energy dissipation of the evanescent wave due to total
interval reflection to detect the surface configuration of the
tested body, wherein the energy dissipation is proportional to the
power index of the distance between the tested body and the total
reflection plane. In this manner, the height can be measured with a
precision up a level of 10.sup.-10.
[0019] The multifunctional opto-electronic biochip system of the
invention also includes functions of optical coherence tomography
scanner and confocal microscopy. The two functions are the
important tools in the biomedical technology for researching and
detecting. By means of the variable incident angle optical set and
the optical CT scanning technology, the biobody can be observed by
section, where a technology of random transformation to reconstruct
image is used, so that the spatial resolution is improved. This is
very helpful for three-dimensional image reconstruction between
bio-molecules, or the combination of the bio-molecules and the
biochip surface.
[0020] In addition to the foregoing function of built-in
multifunctional opto-electronic detection system, the invention
also disclose how the system to be set up two sample platforms. One
platform is designed to have a path of about 10 cm with precision
of micrometer. This platform can be used for scanning on the whole
biochip area. Another platform is designed to have a path of about
10 microns with precision of nm. This platform can be used for
scanning on ultra precision surface configuration and property of
biochemical reaction. In farther combination with local spatial
scanning, the probe volume of the optical detecting technology can
be further reduced, so as to improve spatial resolution. Moreover,
functions of the multifunctional opto-electronic medical detection
of the invention can be performed under BIA and ELISA system for
detection, whereby multiple testing sites can be tested in parallel
and the volume of tested sample is greatly reduced, time and cost
for testing and fabrication of biochip can be greatly reduced.
[0021] It is to be understood that both the foregoing general
description and the following detailed description are exemplary,
and are intended to provide further explanation of the invention as
claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The accompanying drawings are included to provide a further
understanding of the invention, and are incorporated in and
constitute a part of this specification. The drawings illustrate
embodiments of the invention and, together with the description,
serve to explain the principles of the invention. In the
drawings,
[0023] FIG. 1 is a drawing, schematically illustrating a layout and
light path of the multifunctional opto-electronic biomedical
detection system, according an embodiment of the invention;
[0024] FIG. 2 is a drawing, schematically illustrating a system
configuration of the multifunctional opto-electronic biomedical
detection system, according an embodiment of the invention;
[0025] FIG. 3 is a drawing, schematically illustrating a
conventional ellipsometer;
[0026] FIG. 4 is a layout drawing, schematically illustrating a
first subsystem configuration with phase modulation ellipsometry
polarizing function in the multifunctional opto-electronic
biomedical detection system, according an embodiment of the
invention;
[0027] FIGS. 5A-5B are drawings, schematically illustrating a
conventional confocal scanning theory;
[0028] FIG. 6 is a layout drawing, schematically illustrating a
second subsystem configuration with confocal image scanning
function in the multifunctional opto-electronic biomedical
detection system, according an embodiment of the invention;
[0029] FIGS. 7A-7B are drawings, schematically illustrating a
conventional optical configuration for theory of total reflection
evanacent wave excitation;
[0030] FIG. 8 is a layout drawing, schematically illustrating a
third subsystem configuration with confocal image scanning function
in the multifunctional opto-electronic biomedical detection system,
according a first embodiment of the invention;
[0031] FIG. 9 is a layout drawing, schematically illustrating a
third subsystem configuration with confocal image scanning function
in the multifunctional opto-electronic biomedical detection system,
according a second embodiment of the invention;
[0032] FIG. 10 is a layout drawing, schematically illustrating a
third subsystem configuration with photon tunneling scanning
microscope in the multifunctional opto-electronic biomedical
detection system, according a third embodiment of the
invention;
[0033] FIG. 11 is a drawing, schematically illustrating a
conventional Michaelson interferometer;
[0034] FIG. 12 is a layout drawing, schematically illustrating a
fourth subsystem configuration with phase interference technology
in the multifunctional opto-electronic biomedical detection system,
according the embodiment of the invention;
[0035] FIG. 13 is a layout drawing, schematically illustrating a
fourth subsystem configuration with optical coherence tomography
technology in the multifunctional opto-electronic biomedical
detection system, according the embodiment of the invention;
[0036] FIG. 14 is a layout drawing, schematically illustrating a
fourth subsystem configuration with Doppler laser interference
technology in the multifunctional opto-electronic biomedical
detection system, according the embodiment of the invention;
and
[0037] FIG. 15 is a layout drawing, schematically illustrating an
integration of the third and the fourth subsystem configurations,
wherein the phase detection of the surface plasmon wave under the
interferometer can be performed, according another embodiment of
the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0038] First Embodiment
[0039] A first subsystem about the theory of ellipsometry is
depicted in the following. The conventional structure for a
ellipsometry is shown in FIG. 3. In the invention, a
multifunctional opto-electronic biochip detection system first
includes a first subsystem which follows a conventional PMSA
ellipsometry and further includes a novel design of optical
configuration, so that the ellipsometry can be used with variable
incident angles. The multifunctional opto-electronic biochip
detection system, four subsystems commonly use the light path of
the first subsystem, so that the other units can be easily
switched, thereby to achieve the function of the subsystem designed
with its associated principle. The subsystem includes following
units.
[0040] A linear polarizing light source member used to provide the
needed polarizing light source for the invention.
[0041] A phase modulation unit has function of phase modulation to
change the polarizing state of the light.
[0042] A reference optical analyzing unit includes a non-polarizing
optical beam-splitter, an analysis plate and two
photodetectors.
[0043] A variable incident angle optical set has a
quasi-paraboloidal reflective mirror, a quasi-spherical reflective
mirror, and a uniaxial displacement stages that can be controlled
by a feedback manner and carry a prism set. The function of
variable incident angle optical set is used to adjust the angle of
incident light beam onto the biochip.
[0044] An optical signal analysis unit has an analyzer and a
photodetector.
[0045] A microscope lens set includes a camera apparatus having a
high power lens set and a CCD array, so as to monitor the reaction
situation of bio-molecules on the surface.
[0046] The variable incident angle optical set of the subsystem of
ellipsometer in the multifunctional opto-electronic biochip
detection system can cause the measuring light to transverse back
along the same light path to the test sample, and enter the optical
signal analysis unit. The optical signal analysis unit can let the
measuring light pass the tested sample twice, resulting in
improvement of precision and sensitivity for the ellipsometry.
Moreover, with respect to different needs, the optical signal
analysis unit can switch the measuring light, which is incident to
the tested sample, into a line measurement of a point measurement.
Furthermore, the incident angle of the measuring light can be
precisely controlled and adjusted the incident direction. This a
breakthrough comparing with the conventional issues being unable to
easily and precisely change the incident angle. Further still, the
size of the ellipsometer is greatly reduced, so that it can be
applied to various biomedical real-time detection.
[0047] In the foregoing descriptions, the polarization lens set can
include a single band visible light, an attenuator to modulate
light intensity, and a linear polarization element. The light
source can be a light emitted diode or a laser diode. The linear
polarization element can include a linear polarizer, a polarizer,
or any element to polarize the light.
[0048] In the foregoing, the phase modulation unit having the
function to change phase includes a compensator, a liquid crystal
phase modulator or an optical pick phase modulator, so that various
polarizing state is provided.
[0049] In the foregoing, the variable incident angle optical set
can include a penta prism or a triangular prism. It can even
include a reflective mirror to adjust the incident angle of
incident light onto the biochip. The foregoing paraboloidal mirror,
and spherical reflective mirror can be alternatively replaced with
a parabolic-profile cylindrical mirror and circular-profile
cylindrical mirror, so that the measuring light is to be linear.
The quasi-paraboloidal reflective mirror and the quasi-spherical
reflective mirror can be properly arranged, so as to have focusing
power and transmitting the dielectric material. The paraboloidal
mirror also includes, for example, a parabolic rod mirror and the
spherical mirror also includes, for example, cylindrical
mirror.
[0050] In the foregoing, the photodetector of the reference optical
analyzing unit can include a photodiode or a linear array CCD.
[0051] FIG. 4 is a layout drawing, schematically illustrating a
first subsystem configuration with phase modulation ellipsometric
function in the multifunctional opto-electronic biomedical
detection system, according an embodiment of the invention.
[0052] In FIG. 4, a laser light 101 emits a measuring light beam
100, which transverses through an attenuator 102, a reflective
mirror 103, and a non-polarizing beam-splitter 104, and then is
split into two light beams 110, 120. The light beams on the light
path 120 is reflected by a reflective mirror 105 and transverses
through a linear polarizer 106, a phase modulator 2, and a
reference optical analyzing unit 3, to complete the reference light
path. The light beam on the light path 110 is reflected by the
non-polarizing beam-splitter 104 and transverse through a polarizer
106, the phase modulator 2, to form the sampling light beam and
enter a variable incident angle optical set 6. The light beam
enters tested sample on the biochip 12 at the specific detection
site. The light beam is back and forth incident on biochip for
twice, and then a back light path transverse back along the light
path of forwarding sampling light beam 110, and then reaches to
non-polarizing beam-splitter 4, 7. The back light beam is split by
the non-polarizing beam-splitter 7 into two light beams 113, 114.
The light beam 113 transverses through the analyzer 1101 and is
propagated the photodetector 1104. In addition, an observing light
beam 114 is propagated to the microscope lens set 8.
[0053] In the first embodiment, the system is under programmable
control to separately process capturing signals, control the
incident angle, and compute the index of reflection for the tested
sample, wherein the main control program is executed by a graphic
manner. The laser light 101 can be activated by issuing a TTL
modulation signal from the main program to the laser driver, so as
to modulate the detecting signals. Moreover, in order to use the
feedback control system to control the liquid crystal phase
modulator 2, the light beam 100 is split into a referencing light
beam and sampling light beam by the beam-splitter 104. After the
referencing light beam and sampling light beam are led to the
linear polarizer 106 and the phase modulator 2, then the light
intensity and polarization state of the referencing light beam 120
are used as a reference for comparing with the light intensity and
polarization state of the sampling light beam 110. The detail about
signal processing is using a beam-splitter 301 to split the
referencing light beam 120 into two light beams 121, 122. The light
beam 121 is directly propagated to the photodetector 304, and the
other light beam 122 is propagated to the photodetector 303 through
an analyzing pate 302. At this time, the system main program read
the light intensity from the photodetector 303, 304 through the
signal fetching card 305, 306, that include optical beam expanders
305, 306. The measured light intensities can be either used for
control the liquid crystal in feedback manner, or providing for the
measuring analysis.
[0054] the sampling light beam 110 enters the variable incident
angle optical set 6, where the refracted light beam 111 and the
light beam 110 normal incident to the penta prism 601 are
perpendicular to each other. The perpendicular condition is assured
by the property of the penta prism 601. The refracted light beam
111 can also serve as a horizontal incident beam for the concave
paraboloidal reflective mirror 602. In this embodiment, the main
program can control the uniaxial displacement stage 605, which is
used to hold the penta prism 601, through a motion control card
(MCC) 604 and limit switches 607, 608. When the motion is moving
back-and-forth along the Z-axis, the incident angle onto the sample
of the light beam 1111 can therefore be controlled. The function of
the variable incident angle optical set 6 is to allow the light
beam 1111 to propagate through the substrate of the biochip 12 and
reach to a measuring point on the coated metal film on the
substrate, whereby a reflective light beam 1112 of the sampling
light beam. The light intensity of the reflection light beam varies
as changes of the thickness of tested sampled on the biochip and
the refractive indices, that is the size of the bio-molecules and
the sample concentration. The reflected light beam transverses
through the quasi-spherical reflective mirror 603 along the
original incident light path, and transverses through the
photodetector 1104. A measured signals are then obtained.
[0055] In this embodiment, the concave quasi-paraboloidal
reflective mirror 602 and the concave quasi-spherical reflective
mirror 603 are incorporated, whereby the reflection light beam 1112
of the sampling light beam can be normal incident onto the concave
quasi-spherical reflective mirror 603. After reflection from the
concave quasi-spherical reflective mirror 603, the incident light
beam 1121 on the backward light path is formed. The light beam 1121
transverse along the light path of the light beam 1112 and enter
the substrate 12 of the biochip. At the same measuring point, a
reflection occur again. Thus, light intensity of the light beam
1122 on the backward light path has been changed for twice,
resulting in improvement of the resolution.
[0056] In the embodiment, the microscope lens set 8 includes a lens
set 801, a CCD array 802, and a frame-grabbing card 803 to have the
function of camera. The microscope lens set 8 is used to observe
and adjust the measuring point on the sliding plate. The observing
light beam and the sampling light beam 110 are provided by the
laser source 11, so that the system does not need extra light
source. The microscope lens set 8 read the image at the measuring
point through the frame-grabbing card 803. The image can be
instantly observed when it is connected to computer or monitor, and
simultaneously serves as an autocollimator for the sampling light
beam 110.
[0057] Second Embodiment
[0058] A second subsystem uses the confocal scanning theory is
depicted as follows. FIGS. 5A and 5B are drawings, schematically
illustrating a conventional confocal scanning theory. In the
multifunctional opto-electronic biochip detection system of the
invention, the first subsystem can be switched to include a beam
expander, so as to expand the sampling area, and a focusing lens
set is inserted before the photodetector with respect to signal
analyzing unit. The focused light beam is led through a pinhole,
whereby a confocal microscope is formed. The detailed light path
and the layout of elements are shown in FIG. 6. The subsystem
includes several unit as follows.
[0059] A linear polarized light source set includes a visible light
source, an attenuator for modulating light intensity, and a linear
polarization member. The light source is formed by, for example,
light emitted diode (LED) or laser diode. The linear polarization
member includes, for example, a dichroic linear polarizer, a linear
polarizer, or a polarizing means for polarizing light.
[0060] A phase modulating unit having capability for modulating the
phase includes a compensator, a liquid crystal phase modulator, or
a photoelastic phase modulator. The phase modulating unit is used
to produce a light with various polarization state.
[0061] An optical beam expander with a lens set is used to expand
the area of the sampling point.
[0062] A referencing beam optical analysis unit includes an
non-polarizing beam-splitter, an analyzer, and at least two
photodetectors.
[0063] A variable incident angle optical set includes a
quasi-paraboloidal mirror, a quasi-spherical reflective mirror, and
a uniaxial displacement stage with feedback control for loading a
prism set. The prism set includes, for example, a penta prism or a
triangular prism, or even includes a reflector. Function of the
variable incident angle optical set is to adjust an incident angle
of the incident light beam onto an interface between the substrate
of the biochip 12 and the coating metal film.
[0064] An optical signal detecting unit has at least a
photodetector, a focusing lens set, and a pinhole set. The
photodetector includes, for example, a photodioide or a linear
array of CCD.
[0065] A microscope lens set has a lens set with high power, and an
array of CCD, so as to serve as a camera that is used to monitor
the reacting phenomenon of bio-molecular interaction.
[0066] The multifunctional opto-electronic biochip detection system
of the invention has the function of novel confocal microscope that
is different from the conventional confocal microscope. The
confocal microscope of the invention uses OBMorph structure to have
design of variable incident angle. It is therefore that the section
of sample is not limited to only the perpendicular direction. The
novel confocal microscope can make a section on the tested sample
from different angles, so that a 3-dimensional structure of image
can be more precisely displayed.
[0067] The light path is described as follows. A measuring light
beam 100 transverses through an attenuator 102, a reflector 103 and
non-polarizing beam-splitter 104, so as to divide the measuring
light beam 100 into two beams. One beam transverses along the light
path 120 through a reflective mirror 105, a polarizer 106, a phase
modulator 2, a referencing beam optical analysis unit 3, and then
the light path is accomplished. Another sampling light beam
transverses along the light path 110. After being split by the
non-polarizing beam-splitter 104, the light beam transverses
through the polarizer 106, the phase modulator 2, and the optical
beam expander 804. The sampling light beam 110 enters the variable
incident angle optical set 6, and then the light on the specific
measuring points on the test sample on the substrate 12 of the
biochip is secondly reflected. A backward light path 112 is along
the original light path 110 but the traveling direction is
backward. The backward light path 112 continuously transverses
through the non-polarizing beam-splitters 4, 7 that splits the
light beam into two beams 113, 114 again. The light beam 113
transverses through the analyzer 1101, the lens set 1102, and the
pinhole 1103, and then reaches to the photodetector 1104. The light
beam 114, serving as an observation beam, is propagated to the
microscopy lens set 8.
[0068] In this embodiment, the detecting system is of programmable
control, so as to separately process the captured signal, control
the incident angle, and compute the refractive indices, wherein the
main program can be constructed in a graphic manner. The laser
light source 101 can be activated by sending a TTL adjusting signal
from the main program to the laser driver. Moreover, the phase
delay under measuring the amplitude can be adjusted to zero by
using the phase modulator 2 of the feedback control system. The
light beam 100 is split by the beam-splitter 104 into the
referencing beam and sampling beam. The referencing beam and the
sampling beam are led to linear polarizer 106, liquid crystal
modulator 2, and the optical beam expander 804. The light intensity
and polarization state of the measuring light beam 120 also provide
a reference of the light intensity and polarization state of the
sampling beam 110 for control. The detection method is splitting
the light beam 120 into two light beams by using beam-splitter 31.
One light beam 121 is directly propagated to the photodetector 304,
and another light beam 122 transverses through the polarizer 302
and is propagated to the photodetector 303. At this time, the main
program reads the light intensity values on the photodetector 303,
304 through the signal acquisition card 305, 306.
[0069] The sampling light beam 110 can enter the variable incident
angle optical set 6. Due to the optical properties of the penta
prism 601, it is assured that the refractive light beam 111 is
perpendicular to the light beam 110 normally incident onto the
penta prism. The light beam 111 can also serve as the horizontal
incident beam for the concave quasi-paraboloidal reflective mirror
602. In this embodiment, the main program controls the uniaxial
displacement stage 605 of the penta prism 601 through the motion
control card 604, the limited switches 607, 608, so as to move
back-and-forth along the Z-axis and then control the incident angle
of the light beam 111 on the tested sample. The variable incident
angle optical set 6 is used to allow the light beam 111 to
transverse through the substrate 12 of biochip to the coated metal
film at the specific location. A total reflection occurs at the
interface between the substrate for the biochip and the coated
metal film, so that a sampling light beam 1112 is formed. Under the
adjustment of the incident angle with the range of total
reflection, the surface plasmon wave on the interface has changed.
These changes are related to the thickness and refractive indices
of the tested sample, that is, the size of the bio-molecules and
the concentration of the tested sample.
[0070] Due to the combination of the concave quasi-paraboloidal
mirror 602 and the concave quasi-spherical mirror 603, the sampling
light beam 1112 is normally incident on to the concave
quasi-spherical mirror 603 and is reflected as the incident light
beam 1121 on the backward light path. The center point of the
quasi-spherical mirror 603 is, for example, located on the
measuring point. It transverses along the same light path of the
light beam 1112 and enters the substrate 12 of the biochip. At the
same measuring point to cause a reflection, the backward light beam
1122 is amplified for twice, so that the resolution of the plasma
resonant angle is improved, when comparing with convention
structure.
[0071] In the embodiment, the microscopy lens set 8 serves as a
camera device by including the lens set 801, the CCD array 802, and
the frame-grabbing card 803. The microscopy lens set 8 can be used
to observe and adjust the measuring point on the sliding block. The
microscopy lens set 8 uses the same laser light source 101 for
observing light source and the sampling light beam 110. In this
manner, there is no need of an extra light source. Moreover, the
microscopy lens set 8 read the image at the measuring point through
the frame-grabbing card 803. When it is connected to computer or
monitor, image can be instantly observed and it can also be used as
an autocollimator for the sampling light beam 110.
[0072] By using the location of the penta prism associating with
the quasi-paraboloidal mirror, the angle of the section can be
determined. As the incident light transverses through the penta
prism, the quasi-paraboloidal mirror would reflect the light beam
to the biochip. The reflected light beam then transverses back to
the penta prism and is led to a pinhole through a splitting mirror.
The purpose of the arrangement is to filter out the image losing
its focus, so as to achieve the section performance. Then a
photodetector is used to measure the light intensity. This is the
process for point measurement. By using the micro-shift platform of
the biochip associating with the spatial mapping technology of the
invention, it is possible to scan on the XY plane, wherein the
micro-displacement stage is moving along the Z axis for performing
section. When the image for the section incorporate to the
technology of three-dimensional image reconstruction, the
configuration of the bio-molecules on the biochip can be displayed.
This allows to measure static property at the whole area on the
protein chip and antibody or antigen.
[0073] Third Embodiment
[0074] A third subsystem according to the evanacent wave theory is
depicted below. FIGS. 7A-7B are drawings, schematically
illustrating a conventional optical configuration for theory of
total reflection evanacent wave excitation. According to the
conventional principle, the invention designs a novel system. In
the multifunctional opto-electronic biochip detection system of the
invention, under the first subsystem, a polarizer is used to adjust
the sampling light beam into a p wave. The variable incident angle
optical set is used to adjust, so as to cause the sampling light
path and the signal light path to be either separating or in
common, so as to achieve an angle modulation. This results in two
different designs for the amplitude surface plasmon resonance
detection. If a lens set of beam expander for expanding the
sampling area, then a photo tunneling microscope (PTM) is formed.
The above three types of design are based on the evanacent wave
theory. The plasma signal detector and the PTM can be activated by
switching some elements of the multifunctional opto-electronic
biochip detection system. The subsystem includes several units as
follows.
[0075] A linear polarized light source set includes a visible light
source, an attenuator for modulating light intensity, and a linear
polarization member. The light source includes, for example, light
emitted diode (LED) or laser diode. The linear polarization member
includes, for example, a dichroic linear polarizer, a linear
polarizer, or a polarizing means for polarizing light.
[0076] A phase modulating unit having capability for modulating the
phase includes a compensator, a liquid crystal phase modulator, or
a photoelastic phase modulator. The phase modulating unit is used
to produce a light with various polarization state.
[0077] An optical beam expander with a lens set is used to expand
the area of the sampling point.
[0078] A referencing beam optical analysis unit includes an
non-polarizing beam-splitter, an analyzer, and at least two
photodetectors.
[0079] A variable incident angle optical set includes a
quasi-paraboloidal mirror, a quasi-spherical reflective mirror, and
a uniaxial displacement stage with feedback control for loading a
prism set. The sample light beam on the measuring point has at
least one back-and-forth reflection. The prism set includes, for
example, a penta prism or a triangular prism, or even includes a
reflector. Function of the variable incident angle optical set is
to adjust an incident angle of the incident light beam onto an
interface between the substrate of the biochip 12 and the coated
metal film.
[0080] An optical signal detecting unit has at least a
photodetector. The photodetector includes, for example, a
photodioide or a linear array of CCD. The optical signal detecting
unit can separately associate with a lens set or analyzer to
accomplish the detecting function.
[0081] A microscope lens set has a lens set with high power, and an
array of CCD, so as to serve as a camera that is used to monitor
the reacting phenomenon of bio-molecules.
[0082] First Embodiment for the Third Subsystem
[0083] This embodiment is an amplitude surface plasmon resonance
detection system. FIG. 8 is a layout drawing, schematically
illustrating a third subsystem configuration with confocal image
scanning function in the multifunctional opto-electronic biomedical
detection system, according a first embodiment of the invention. In
FIG. 8, the light beam 100 transverses through the attenuator 102,
the reflector 103, and the non-polarizing beam-splitter 104, and
then is split into two light beams. One beam transverse along the
light path 120 and then transverses through the reflective mirror
105, the polarizer 106, the phase modulator 2, the referencing
optical analysis unit 3, so that the light propagation is
accomplished. Another light transverses along the light path 110
through the non-polarizing beam-splitter 104. After splitting, the
light beam continuously transverses through the polarizer 106, the
phase modulator 2, so that the p-state polarizing wave of the
sampling light beam 110 on the biochip is adjusted and then enters
the variable incident angle optical set 6. The light beam at the
specific detection point of the substrate 12 is reflected to a
photodetector 609.
[0084] In the embodiment, the laser light source 101 can be
activated by sending a TTL modulating signal to the laser driver.
Moreover, the liquid crystal phase modulator 2 used in feedback
control can adjust the phase delay to zero under the amplitude
measuring manner. The light beam 100 is split into the reference
light beam and the sampling light beam by the beam-splitter 104.
Then the reference light beam and the sampling light beam are led
through the polarizer 106 and the liquid crystal phase modulator 2.
The results of the light intensity and polarization state of the
reference light beam 120 are used as references for controlling the
light intensity and polarization state of the sampling light beam
110. The detection method includes using the beam-splitter 31 to
split the reference light beam 120 into two light beams 121, 122.
The light beam 121 is directly propagated to the photodetector 304,
and the light beam 122 transverses through the analyzer 302 and
then propagated to the photodetector 303. In the mean time, the
system main program read the light intensity stored on the
photodetector 303, 304 through the signal acquisition card 305,
306.
[0085] The sampling light beam 110 can enter the variable incident
angle optical set 6. Due to the optical properties of the penta
prism 601, it is assured that the refractive light beam 111 is
perpendicular to the light beam 110 normally incident onto the
penta prism. The light beam 111 can also serve as the horizontal
incident beam for the concave quasi-paraboloidal reflective mirror
602. In this embodiment, the main program controls the uniaxial
displacement stage 605 of the penta prism 601 through the motion
control card 604, the limited switches 607, 608, so as to move
back-and-forth along the Z-axis and then control the incident angle
of the light beam 1111 on the tested sample. The variable incident
angle optical set 6 is used to allow the light beam 111 to
transverse through the substrate 12 of biochip to the coated metal
film at the specific location. A total reflection occurs at the
interface between the substrate for the biochip and the coated
metal film, so that a sampling light beam 1112 is formed. Under the
adjustment of the incident angle with the range of total
reflection, the surface plasmon wave on the interface has changed.
These changes are related to the thickness and refractive indices
of the tested sample, that is, the size of the bio-molecules and
the concentration of the tested sample.
[0086] In this embodiment, the concave quasi-paraboloidal mirror
602 on the XZ plane has focusing capability, and on the Y direction
has uniform cross-section shape. When the light beam 110 is
reflected by the concave quasi-paraboloidal mirror 602 to the
substrate 12 of the biochip, it would be focused on the coated
metal film. The reflected light 1112 is incident to a planar light
intensity photodetector 609, so that several measuring points can
be parallel measured to observe the variation of the surface
plasmon resonant angle.
[0087] Second Embodiment for the Third Subsystem
[0088] This embodiment is an amplitude surface plasmon resonance
detection system. FIG. 9 is a layout drawing, schematically
illustrating a third subsystem configuration with confocal image
scanning function in the multifunctional opto-electronic biomedical
detection system, according a second embodiment of the invention In
FIG. 9, the light beam 100 transverses through the attenuator 102,
the reflector 103, and the non-polarizing beam-splitter 104, and
then is split into two light beams. One beam transverses along the
light path 120 and then transverses through the reflective mirror
105, the polarizer 106, the phase modulator 2, the referencing
optical analysis unit 3, so that the light propagation is
accomplished. Another light transverses along the light path 110
through the non-polarizing beam-splitter 104. After splitting, the
light beam continuously transverses through the polarizer 106, the
phase modulator 2, so that the p-state polarizing wave of the
sampling light beam 110 on the biochip is adjusted and then enters
the variable incident angle optical set 6. The light beam at the
specific detection point of the substrate 12 is reflected
back-and-forth for twice and then forms the backward light beam
112, which transverses back along the sampling light path 110 and
propagates to non-polarizing beam-splitter 4, 7. After that the
light beam 112 is further split into two light beams 113, 114. The
light beam 113 transverses through the analyzer 1101 and propagates
to the photodetector 1104. The other beam 114 directly propagates
to the microscope lens set 8.
[0089] In this embodiment, the detecting system is of programmable
control, so as to separately process the captured signal, control
the incident angle, and compute the refractive indices, wherein the
main program can be constructed in a graphic manner. The laser
light source 101 can be activated by sending a TTL adjusting signal
from the main program to the laser driver. Moreover, the phase
delay under measuring the amplitude can be adjusted to zero by
using the phase modulator 2 of the feedback control system. The
light beam 100 is split by the beam-splitter 104 into the
referencing beam and sampling beam. The referencing beam and the
sampling beam are led to linear polarizer 106, liquid crystal
modulator 2, and the optical beam expander 804. The light intensity
and polarization state of the measuring light beam 120 also provide
a reference of the light intensity and polarization state of the
sampling beam 110 for control. The detection method is splitting
the light beam 120 into two light beams by using beam-splitter 31.
One light beam 121 is directly propagated to the photodetector 304,
and another light beam 122 transverses through the polarizer 302
and is propagated to the photodetector 303. At this time, the main
program reads the light intensity values on the photodetector 303,
304 through the signal acquisition card 305, 306.
[0090] The sampling light beam 110 can enter the variable incident
angle optical set 6. Due to the optical properties of the penta
prism 601, it is assured that the refractive light beam 111 is
perpendicular to the light beam 110 normally incident onto the
penta prism. The light beam 111 can also serve as the horizontal
incident beam for the concave quasi-paraboloidal reflective mirror
602. In this embodiment, the main program controls the uniaxial
displacement stage 605 of the penta prism 601 through the motion
control card 604, the limit switches 607, 608, so as to move back
and forth along the Z-axis and then control the incident angle of
the light beam 1111 on the tested sample. The variable incident
angle optical set 6 is used to allow the light beam 1111 to
transverse through the substrate 12 of biochip to the coated metal
film at the specific location. A total reflection occurs at the
interface between the substrate for the biochip and the coated
metal film, so that a sampling light beam 1112 is formed. Under the
adjustment of the incident angle with the range of total
reflection, the surface plasmon wave on the interface has changed.
These changes are related to the thickness and refractive indices
of the tested sample, that is, the size of the bio-molecules and
the concentration of the tested sample.
[0091] Due to the combination of the concave quasi-paraboloidal
mirror 602 and the concave quasi-spherical mirror 603, the sampling
light beam 1112 is norm incident on to the concave quasi-spherical
mirror 603 and is reflected as the incident light beam 1121 on the
backward light path. It transverses along the same light path of
the light beam 1112 and enters the substrate 12 of the biochip. At
the same measuring point to cause a reflection, the intensity of
backward light beam 1122 is modulated for twice, so that the
resolution of the surface plasmon resonant angle is improved, when
comparing with convention structure.
[0092] In the embodiment, the microscopy lens set 8 serves as a
camera device by including the lens set 801, the CCD array 802, and
the frame-grabbing card 803. The microscopy lens set 8 can be used
to observe and adjust the measuring point on the sliding block. The
microscopy lens set 8 uses a same laser light source 101 for
observing light source and the sampling light beam 110. In this
manner, there is no need of an extra light source. Moreover, the
microscopy lens set 8 read the image at the measuring point through
the frame-grabbing card 803. When it is connected to computer or
monitor, image can be instantly observed and it can also be used as
an autocollimator for the sampling light beam 110.
[0093] Third Embodiment for the Third Subsystem
[0094] This embodiment is photon tunneling microscope detection
system. FIG. 10 is a layout drawing, schematically illustrating a
third subsystem configuration with photon tunneling scanning
microscope in the multifunctional opto-electronic bio-medical
detection system, according to a third embodiment of the invention.
In FIG. 10, the light beam 100 transverses through the attenuator
102, the reflector 103, and the non-polarizing beam-splitter 104,
and then is split into two light beams. One beam transverses along
the light path 120 and then transverses through the reflective
mirror 105, the polarizer 106, the phase modulator 2, the
referencing optical analysis unit 3, so that the light propagation
is accomplished. Another light transverses along the light path 110
through the non-polarizing beam-splitter 104. After splitting, the
light beam continuously transverses through the polarizer 106, the
phase modulator 2 and an optical beam expander 804, so that the
sampling light beam 110 enters the variable incident angle optical
set 6. The light beam at the specific detection point of the
substrate 12 is led to transverse back-and-forth for twice, and
then form the backward light beam 112, which transverses in
opposite direction along the same light path of the sample light
beam and propagates to the non-polarizing beam-splitters 4, 7. The
light beam 112 is further split into two light beams 112, 113. The
light beam 113 transverses through the analyzer 1101 and reaches
the photodetector 1104. The other light beam 114 directly
transverses to the microscope lens set 8.
[0095] In the embodiment, the laser light source 101 can be
activated by sending a TTL modulating signal to the laser driver.
Moreover, the liquid crystal phase modulator 2 used in feedback
control can adjust the phase delay to zero under the amplitude
measuring manner. The light beam 100 is split into the reference
light beam and the sampling light beam by the beam-splitter 104.
Then the reference light beam and the sampling light beam are led
through the polarizer 106 and the liquid crystal phase modulator 2.
The results of the light intensity and polarization state of the
reference light beam 120 are used as references for controlling the
light intensity and polarization state of the sampling light beam
110. The detection method includes using the beam-splitter 31 to
split the reference light beam 120 into two light beam 121, 122.
The light beam 121 is directly propagated to the photodetector 304,
and the light beam 122 transverses through the analyzer 302 and
then propagated to the photodetector 303. In the mean time, the
system main program read the light intensity stored on the
photodetector 303, 304 through the signal acquisition card 305,
306.
[0096] The sampling light beam 110 can enter the variable incident
angle optical set 6. Due to the optical properties of the penta
prism 601, it is assured that the refractive light beam 111 is
perpendicular to the light beam 110 normally incident onto the
penta prism. The light beam 111 can also serve as the horizontal
incident beam for the concave quasi-paraboloidal reflective mirror
602. The main program controls the uniaxial displacement stage 605
of the penta prism 601 through the motion control card 604, the
limit switches 607, 608, so as to move back-and-forth along the
Z-axis and then control the incident angle of the light beam 1111
on the tested sample. The variable incident angle optical set 6 is
used to allow the light beam 1111 to transverse through the
substrate 12 of biochip to the coated metal film at the specific
location. A total reflection occurs at the interface between the
substrate for the biochip and the coated metal film, so that a
sampling light beam 1112 is formed. Under the adjustment of the
incident angle with the range of total reflection, the surface
plasmon wave on the interface has changed. These changes are
related to the thickness and refractive indices of the tested
sample, that is, the size of the bio-molecules and the
concentration of the tested sample.
[0097] In this embodiment, the concave quasi-paraboloidal mirror
602 on the XZ plane has focusing capability, and on the Y direction
has uniform cross-section shape. When the light beam 110 is
reflected by the concave quasi-paraboloidal mirror 602 to the
substrate 12 of the biochip, it would be focused on the coated
metal film. The reflected light 1112 is incident to a planar light
microscope 609, which includes a lens set, a CCD array and an
frame-grabbing card to serve as an camera. It has function to
observe and adjust the measuring points on the biochip. The
microscope 609 and the sampling light beam 110 use the same laser
source 11, so that there is no need an extra light source.
Moreover, the microscope 609 uses the frame-grabbing card to read
the image on each measuring point. When the microscope 609 is
connected to a computer or a monitor, the image can be instantly
observed. According to the image shade, the configuration of
bio-molecules on the biochip can be reconstructed. The measurements
of the whole area static property on the relation between protein
chip, antibody, and antigen can also be used as an autocollimator
for the sampling light beam 110. As a result, the multiple sampling
points can be parallel measured about the thickness and refractive
indices of the sample.
[0098] Fourth Embodiment
[0099] A fourth subsystem of the invention is a design integrated
with Michaelson interferometer configuration. FIG. 11 is a drawing,
schematically illustrating a conventional Michaelson
interferometer. The multifunctional opto-electronic biochip
detection system of the invention includes a built-in optical
interferometer, which is a novel design to integrate various
advantages into one. It includes an optical interferometer shown in
FIG. 12, an optical coherence tomography shown in FIG. 13. And a
laser Doppler vibrometer/interferometer shown in FIG. 14. Since the
invention has achieved the high resolution, cross-sectional
perspective view, and dynamic measurement, the invention is
suitable for use in biology, medicine, and chemical reaction, which
includes both the suitability of two frames of BIA an ELISA. The
above functions with respect to the subsystem can be performed by
switching a few elements. The fourth subsystem includes several
units as follows.
[0100] A linear polarized light source set includes a visible light
source, an attenuator for modulating light intensity, and a linear
polarization member. The light source includes, for example, light
emitted diode (LED) or laser diode. The linear polarization member
includes, for example, a dichroic linear polarizer, a linear
polarizer, or a polarizing means for polarizing light.
[0101] A phase modulating unit having capability for modulating the
phase includes a compensator, a liquid crystal phase modulator, or
a photoelastic phase modulator. The phase modulating unit is used
to produce a light with various polarization states.
[0102] An optical beam expander with a lens set is used to expand
the area of the sampling point.
[0103] A referencing beam optical analysis unit includes an
non-polarizing beam-splitter, an analyzer, and at least two
photodetectors.
[0104] An interferometer light path control unit has a phase
adjusting driver and a light path adjusting element.
[0105] A variable incident angle optical set includes a
quasi-paraboloidal mirror, a quasi-spherical reflective mirror, and
a uniaxial displacement stage with feedback control for loading a
prism set. The prism set includes, for example, a penta prism or a
triangular prism, or even includes a reflector. The function of the
variable incident angle optical set is to adjust an incident angle
of the incident light beam onto the biochip.
[0106] A Doppler signal analyzing unit includes a 1/2 wave plate,
an non-polarizing beam-splitter, and two intensity photo-detecting
sets. Each of the intensity photo-detecting set includes a
polarizer and two intensity photodetectors.
[0107] An interferometric signal analyzing unit includes an
analyzer and a photodetector. The photodetector includes, for
example, a light emitted diode, a linear array of CCD.
[0108] A microscope lens set has a lens set with high power, and an
array of CCD, so as to serve as a camera that is used to monitor
the reacting phenomenon of bio-molecules.
[0109] FIG. 12 is a layout drawing, schematically illustrating a
fourth subsystem configuration with phase shift interference
microscope in the multifunctional opto-electronic biomedical
detection system, according the embodiment of the invention. In
FIG. 12, the light path is depicted. The light beam 100 transverses
through the attenuator 102, the reflector 103, and the
non-polarizing beam-splitter 104, and then is split into two light
beams. One beam transverses along the light path 120 and then
transverses through the reflective mirror 105, the polarizer 106,
the phase modulator 2, the referencing optical analysis unit 3, so
that the light propagation is accomplished. Another light
transverses along the light path 110 through the non-polarizing
beam-splitter 104. After traveling through the beam-splitter 104,
the light beam also transverses through the linear polarizer 106,
the phase modulator 2, the optical beam expander 804, and then is
split into two light beams 111 and 131 by the non-polarizing
beam-splitter 4. The light beam 111 serves as a sampling light beam
to measure the surface configuration used in the interferometer.
The light beam 131 serves as an interference light beam for
measurements of phase variation.
[0110] the sampling light beam 111 is incident onto the variable
incident angle optical set 6, and transverses back and forth for
twice at the specific measuring point on the substrate 12 of the
biochip, and then a backward light beam 112 is formed. The backward
light beam 112 transverses back along the light path of the
sampling beam 110, and reaches to the non-polarizing beam-splitter
4. The light beam 131 through, for example, a Febry-Perot device,
can be adjusted to have the same total light path as that of the
light path 112, so that after the light beam 132 and the light beam
112 transverse through the non-polarizing beam-splitter 4, an
interference occurs between the transmitting and reflection
components. This interfered light beam is further split into two
light beams 113, 114 by the non-polarizing beam-splitter 7. The
light beam 113 propagates to the to the photodetector 1104 through
the analyzer 1101, and the light beam 114, serving as an
observation light beam, propagates to the microscope lens set
8.
[0111] The invention is under programmable control to separately
process capturing signals, control the incident angle, and compute
the index of reflection for the tested sample, wherein the main
control program is executed by a graphic user interface. The laser
light source unit 1 can be activated by issuing a TTL modulation
signal from the main program to the laser driver, so as to modulate
the detecting signals. Moreover, in order to use the feedback
control system to control the liquid crystal phase modulator 2, the
main program properly sends a voltage square wave to the liquid
crystal, so as to control the phase delay. However, as the liquid
crystal plate is used as the phase modulator, a birefringence
phenomenon occurs under the driving of voltage. As a result, the
phase delay angle is nonlinear for the transmitting light
intensity. The absorption property is also nonuniform. The light
beam 100 is then necessary to be split by the beam-splitter 104 to
for the referencing light beam 104 and the sampling beam. The
referencing light beam and the sampling light beam are led to
transverse through the linear polarizer and liquid crystal phase
modulator 2, and then results of intensity and polarization state
of the referencing light beam 120 are used as the references for
the sampling light beam. The detection manner is using the
beam-splitter 301 to split the referencing light beam 120 into two
light beams 121, 122. The light beam 121 directly propagates to the
photodetector 304, and another light beam 122 transverses through
the analyzer 302 and reaches to the photodetector 303. At this
situation, the system main program reads the intensity stored in
the photodetectors 303, 304 through the signal acquisition
card.
[0112] The sampling light beam 110 can enter the variable incident
angle optical set 6. Due to the optical properties of the penta
prism 601, it is assured that the refractive light beam 111 is
perpendicular to the light beam 110 normally incident onto the
penta prism. The light beam 111 can also serve as the horizontal
incident beam for the concave quasi-paraboloidal reflective mirror
602. The main program controls the uniaxial displacement stage 605
of the penta prism 601 through the motion control card 604, the
limited switches 607, 608, so as to move back-and-forth along the
Z-axis and then control the incident angle of the light beam 1111
on the tested sample. The variable incident angle optical set 6 is
used to allow the light beam 1111 to transverse through the
substrate 12 of biochip to the coated metal film at the specific
location. A total reflection occurs at the interface between the
substrate for the biochip and the coated metal film, so that a
sampling light beam 1112 is formed. The concave quasi-paraboloidal
reflective mirror 602 and the concave quasi-spherical reflective
mirror 603 are associated with each other, so that the reflection
light of sampling light beam 1112 is normal incident onto the
concave quasi-spherical reflective mirror 603 and then a light beam
1121 is formed. The light beam 1121 transverses back along the
original light path of the sampling light beam 1112 and then enters
the substrate 12 of the biochip. A reflection occurs at the
detecting point, so that phase of the reflected light beam 1122 has
been changed twice. The phase variation is related to the surface
configuration of bio-molecules of tested sample on the biochip,
whereby the system configuration of the invention has higher in
resolution than the conventional interferometer.
[0113] As a five-step phase shifting manner is used to perform the
optical interference, the phase change of the reflection light beam
1122 is to be captured. In the foregoing description, under the
reflection condition, the voltage control driver 501 has changed
the light path of the light beam 132. The light beams 132 and the
light beam 112 interfere and can generate five different phases.
The DCT reconstruction method is used to backward calculate the
phase value of the backward light beam 112.
[0114] In the embodiment, the invention includes a lens set 801, an
array CCD 802, and an frame-grabbing card 803 to have the function
of camera. The microscope lens set 8 is used to observe and adjust
the measuring point on the sliding plate. The observing light
source and the sampling light beam 110 are from the laser source
11, so that the system does not need extra light source. The
microscope lens set 8 read the image at the measuring point through
the frame-grabbing card 803. The image can be instantly observed
when it is connected to computer or monitor, and simultaneously
serves as an autocollimator for the sampling light beam 110.
[0115] FIG. 13 is a layout drawing, schematically illustrating a
fourth subsystem configuration with optical coherence tomography
technology in the multifunctional opto-electronic biomedical
detection system, according the embodiment of the invention. In
FIG. 13, a polarized light source unit 1 includes alight source
101, intensity modulator 102, a reflective mirror 103, a
non-polarizing beam-splitter 104, a reflective mirror 105 and a
polarizer 106. The light source 101 produces a light beam 100,
which transverses through the intensity modulator 120 and the
reflective mirror 103 and reaches the beam-splitter 104. The
beam-splitter 104 splits the light beam 100 into a measuring light
beam 110 and a referencing light beam 120. The measuring light beam
110 and a referencing light beam 120 transverse through the
polarizer 106 and enter the phase modulating unit 2. The phase
modulating unit 2 includes a liquid crystal associating with
feedback control system. Then, a referencing light beam 120 enters
a reference analyzing unit 3, which includes two beam-splitters
301, 302 and two photodetectors 303, 304. The referencing light
beam 120 is split by the beam-splitter 301 into two light beams
121, 122 that are respectively detected by the photodetectors 304
and 303. The measuring results are used to adjust the light
intensity of the measuring light beam 110. After the measuring
light beam 110 transverses to the beam-splitter 4, a referencing
light beam 130 is split out. The referencing luminous light beam
130 enters the light path adjusting unit 5 and transverses through
a Febry-Perot reflection cavity 504, and then reaches the
reflective mirror 502. The reflective mirror can produce a
referencing wave front. After reflection, it transverses through
the Febry-Perot reflection cavity 504 again and leaves the light
path adjusting unit 5. The residual portion of the measuring light
beam 110 enters the variable incident angle optical set 6, and
reaches to the penta prism 601. The penta prism 601 refracts the
light beam into the paraboloidal mirror 602. The paraboloidal
reflective mirror 603 reflects the light to the substrate 12 of the
biochip. The light beam can enter the substrate 12 by a specific
measuring point, and then is reflected to the spherical mirror 603
through the substrate 12. The light is reflected to the tested
sample on substrate again by the spherical mirror 603 along the
same light path. After reflection by the substrate, the light beam
leaves the variable incident angle optical set 6. After traveling
twice on the tested sample, the measuring light beam 110 and the
referencing light beam 130 are superimposed at the beam-splitter 4.
It continuously transverses to the beam-splitter 7, which split a
portion of the light beam into the image capturing unit 8. The
image capturing unit 8 has a lens set 801 and CCD for recording the
interference pattern.
[0116] In the foregoing, Febry-Perot reflection cavity 504 can
control the light path and its total track of the referencing light
beam 130 to provide the same light path as the light beam 110, and
further control the points, which can cause the interference
pattern, to be located at the desired location with respect to the
sectional area of the tested sample. Moreover, the light path
adjusting unit includes a voltage driver 501 to control the
location of the reflective mirror 502. It is helpful for operation
of the 5-step phase shifting procedure. As a result, the phase of
the interference pattern is obtained. The penta prism 601 can be
moved up-and-down by a motor, whereby the incident angle of the
measuring light beam 110 is changed but the measuring point is
still the same.
[0117] The optical mechanical structure of the multifunctional
opto-electronic biochip detection system can perform function of
the optical coherence tomography. Moreover, the invention can also
includes other functional units to enhance the function of the
invention, so as to achieve the multifunctional detection system
for biology, medical, and chemical reaction.
[0118] FIG. 14 is a layout drawing, schematically illustrating a
fourth subsystem configuration with Doppler laser interference
technology in the multifunctional opto-electronic biomedical
detection system, according the embodiment of the invention. In
FIG. 14, another embodiment is designed with a Doppler
vibrometer/interferometer. a polarized light source unit 1 includes
a light source 101, attenuator 102, a reflective mirror 103, a
beam-splitter 104, a reflective mirror 105 and a polarizer 106. The
light source 101 produces a light beam 100, which transverses
through the intensity modulator 102 and the reflective mirror 103
and reaches the beam-splitter 104. The beam-splitter 104 splits the
light beam 100 into a measuring light beam 110 and a referencing
light beam 120. The measuring light beam 110 and a referencing
light beam 120 transverse through the polarizer 106 and enter the
phase modulating unit 2. The phase modulating unit 2 includes a
liquid crystal associating with feedback control system. Then, the
referencing light beam 120 enters a reference analyzing unit 3,
which includes two beam-splitters 301, 302 and two photodetectors
303, 304. The referencing light beam 120 is split by the
beam-splitter 301 into two light beams 121, 122 that are
respectively detected by the photodetectors 304 and 303. The
measuring results are used to adjust the light intensity of the
measuring light beam 110. After the measuring light beam 110
transverses to the beam-splitter 4, a referencing light beam 131 is
split out. The referencing light beam 131 enters the light path
adjusting unit 5 and transverses through a Febry-Perot reflection
cavity 504, and then reaches the reflective mirror 502. After
reflection, it transverses through the Febry-Perot reflection
cavity 504 again and leaves the light path adjusting unit 5.
[0119] The measuring light beam 110 is also split a portion by the
beam-splitter 4 to form a measuring light beam 111 which has the
same intensity as the light beam 131. The light beam 111 enters the
variable incident angle optical set 6, in which the penta prism 601
refracts the light beam into the paraboloidal mirror 602. The
paraboloidal mirror 602 reflects the light beam to the substrate 12
and reaches to a specific measuring point. After reflection from
the measuring point, the light beam transverses through the
substrate and is incident to the spherical mirror 603. After
reflection again, the light beam along the same light path enters
the substrate at the specific point. The tested sample reflects the
light beam. As a result, the light beam leaves the variable
incident angle optical set 6.
[0120] The reflection cavity 504 can control a length of the light
path of the referencing light beam 130, so as to have the same
light path as the measuring light beam 110, and further control the
points, which can cause the interference pattern, to be located at
the desired location with respect to the sectional area of the
tested sample. The light beam 131 transverses through the
reflection cavity 504, 1/4 wave plate, and the reflective mirror
controlled by the voltage driver, and then a reflection light beam
132 is formed. The reflection cavity 504 associating with
reflective mirrors 502, 505, 506 and the voltage driver 501 are
used to control the light beams 131 and the reflection light beam
132 to have the same light path. As a result, the referencing
luminous light beam 132 and the measuring light beam 112 before
interference can transverse back to the non-polarizing
beam-splitter 4 with the same total length of the light path. At
the same time, issue of the coherence length of laser light can be
solved. The light beams 131, 132 transverses twice through the 1/4
wave plate, causing a polarization state with 90.degree. difference
from the measuring light beam 110.
[0121] After reflection twice, the light beam 112 and the light
beam 131 meet at the beam-splitter 4 and cause interference.
Through the beam-splitter 7, the merged light beam is split into a
signal light beam 113 and an observing light beam 114. The signal
light beam 113 is led to the signal analyzing unit 9 by the
rotation reflective mirror 10. The observing light beam 114
propagates to the microscope lens set 8.
[0122] Returning to the beam-splitter 4 which splits the light beam
into two light beams 131 and 132, it can be computed according to
the Jones computation rule. 1 E 1 = [ 1 0 ] e j2 ft E 2 = [ 1 0 ] e
j ( 2 ( f + 2 f d ) t + ) , ( 1 )
[0123] where f represent the laser frequency and also indicates the
Doppler frequency of the tested sample in motion. .phi. is a light
path difference or a relative phase difference due to reflection.
The phase difference does not vary with time.
[0124] In the signal analyzing unit 9, due to the fast axis of the
1/4 wave plate 901 is placed along the direction having 45.degree.
polarization from the light beam 115. After the light beam 115
transverses through the 1/4 wave plate, a right-handed
circular-polarized light beam and a left-handed circular-polarized
light beam are produced. Since the two light beams has four times
of Doppler frequency 4 f.sub.d due to circular rotation. After
interference, a circular-polarized light beam with circular
frequency is produced, in which the low frequency carries the high
frequency. The low frequency is 2 f.sub.d and the high frequency is
2 (f-f.sub.d). The interference light beam is formed after
traveling through the 1/4 wave plate 901, the non-polarizing
beam-splitter 4 splits the light beam into two polarizing light
beams P and Q with equal light intensity. The light beam P
transverses through a polarizer with 45.degree. polarization. The
light beam Q transverses through a polarizer with the polarization
direction along the x-axis. These two light beam P and Q are
respectively detected by the photodetectors for light intensity.
Due to the limitation of the frequency, the light intensity
detected by the photodetector varies as the low frequency of 4
f.sub.d. After being converted to voltage and being amplified, a
signal with normal shift in phase between two light beams is
obtained. This is a sine/cosine signal. The detected signal then
forms a Lissajous circle, which can be used for bi-pase
identification. This can solve the directional ambiguity in the
interferometer, so that the moving direction of the tested sample
can be determined.
[0125] Moreover, the microscope lens set 8 uses the frame-grabbing
card 803 to read the image at the measuring point. After connection
to the computer or monitor, the image can be instantly observed. By
the measured gray step of the image, the surface configuration of
bio-molecules on the biochip can be reconstructed. The measurements
of the whole area static property on the relation between protein
chip, antibody, and antigen can also be used as an autocollimator
for the sampling light beam 110. As a result, the multiple sampling
points can be parallel measured about the thickness and refractive
indices of the sample.
[0126] In the invention, the detection unit for the PQ signal
associating with a ultrasonic device to excite the bio-molecules on
the biochip through a band width. From dynamic frequency response
of the bio-molecule transformation function for the signal
detection and the input signal source, the recombination capability
between molecules and the bio-molecules can be clearly observed.
Since the weight of the bio-molecules is small and the frequency is
high, the Doppler vibrometer or interferometer incorporate to
ultrasonic exciting mechanism is a very useful tool in biology,
medicine and chemical reaction.
[0127] Another embodiment with integration of the third subsystem
and the fourth subsystem, using interferometry and phase difference
in surface plasmon resonance is described as follows.
[0128] In this embodiment, the invention utilizes a Michaelson
interferometer in corporate to the technology of surface plasmon
resonance by switching a few elements, so that a novel function to
detect the phase difference with surface plasmon resonance is
disclosed. The subsystem includes several units as follows.
[0129] A linear polarization light source set includes a single
frequency visible light, an attenuator for modulating light
intensity and a linear polarization device. The light source
includes, for example, LED or laser diode. The linear polarization
device includes, for example, a linear polarization film, a linear
polarizer or any linear polarizer.
[0130] a phase modulator, having modulating function, includes a
compensator, a liquid crystal phase modulator or a photoelastic
phase modulator, so as to provide various polarization states.
[0131] A referencing optical analyzing unit includes an
non-polarizing beam-splitter, an analyzer, and two
photodetector.
[0132] An interference light path control unit includes a driver
for changing phase and a light path adjustable device.
[0133] A variable incident angle optical set has a
quasi-paraboloidal reflective mirror, a quasi-spherical reflective
mirror, and a uniaxial displacement stage that can be controlled by
a feedback manner and carry a prism set. The variable incident
angle optical set is used to adjust the incident angle of light
onto the biochip.
[0134] An optical signal analysis unit has an analyzer and a
photodetector. The photodetector includes, for example, an LED or a
linear array CCD.
[0135] A microscope lens set includes a camera apparatus having a
high power lens set and an array CCD, so as to monitor the reaction
situation of bio-molecules on the surface.
[0136] FIG. 15 is a layout drawing, schematically illustrating an
integration of the third and the fourth subsystem configurations,
wherein the phase detection of the surface plasmon wave under the
interferometer can be performed, according another embodiment of
the invention. In FIG. 15, the multifunctional opto-electronic
biochip detection system is designed as a phase measurement with
surface plasmon resonator. The light beam 100 transverses through
the attenuator 102, the reflector 103, and the non-polarizing
beam-splitter 104, and then is split into two light beams. One beam
transverses along the light path 120 and then transverses through
the reflective mirror 105, the polarizer 106, the phase modulator
2, the referencing optical analysis unit 3, so that the light
propagation is accomplished. Another light transverses along the
light path 110 through the non-polarizing beam-splitter 104. After
traveling through the beam-splitter 104, the light beam also
transverses through the linear polarizer 106 and the phase
modulator 2, and then is split into two light beams 111 and 131 by
the non-polarizing beam-splitter 4. The light beam 111 is used as a
sampling light beam to measure the surface plasma resonance. The
light beam 131 serves as an interference light beam used in
capturing phase variation.
[0137] The invention is of programmable control to separately
process captured signals, control the incident angle, and compute
the index of reflection for the tested sample, wherein the main
control program is executed by a graphic manner. The laser light
source unit 1 can be activated by issuing a TTL modulation signal
from the main program to the laser driver, so as to modulate the
detecting signals. Moreover, in order to use the feedback control
system to control the liquid crystal phase modulator 2, the main
program properly sends a voltage square wave to the liquid crystal,
so as to control the phase delay. However, as the liquid crystal
plate is used as the phase modulator, a birefringence phenomenon
occurs under the driving of voltage. As a result, the phase delay
angle is nonlinear for the transmitting light intensity. The light
beam 100 is then necessary to be split by the beam-splitter 104 to
for the referencing light beam 104 and the sampling beam. The
referencing light beam and the sampling light beam are led to
transverse through the linear polarizer 106 and the liquid crystal
phase modulator 2, and then results of intensity and polarization
state of the referencing light beam 120 are used as the references
for the sampling light beam 110. The detection manner is using the
beam-splitter 301 to split the referencing light beam 120 into two
light beams 121, 122. The light beam 121 directly propagates to the
photodetector 304, and another light beam 122 transverses through
the analyzer 302 and reaches to the photodetector 303. At this
situation, the system main program read the intensity stored in the
photodetectors 303, 304 through the signal acquisition card.
[0138] The sampling light beam 110 can enter the variable incident
angle optical set 6. Due to the optical properties of the penta
prism 601, it is assured that the refractive light beam 111 is
perpendicular to the light beam 110 normally incident onto the
penta prism. The light beam 111 can also serve as the horizontal
incident beam for the concave quasi-paraboloidal reflective mirror
602. The main program controls the uniaxial displacement stage 605
of the penta prism 601 through the motion control card 604, the
limit switches 607, 608, so as to move back and forth along the
Z-axis and then control the incident angle of the light beam 1111
on the tested sample. The variable incident angle optical set 6 is
used to allow the light beam 1111 to transverse through the
substrate 12 of biochip to the coated metal film at the specific
location. A total reflection occurs at the interface between the
substrate for the biochip and the coated metal film, so that a
sampling light beam 1112 is formed. Within the condition for
causing total reflection, the incident angle is changed, so as to
trigger a surface plasmon wave on the interface between the
substrate 12 and the coated metal film. The P-wave of the
reflection light beam 1112 has phase change. This phase change is
related to the thickness and refractive indices of the tested
sample on the chip, which is also related with the size of
bio-molecules and concentration.
[0139] The concave quasi-paraboloidal reflective mirror 602 and the
concave quasi-spherical reflective mirror 603 are associated with
each other, so that the reflection light beam 1112 of sampling
light beam is normal incident onto the concave quasi-spherical
reflective mirror 603 and then a light beam 1121 is formed. The
light beam 1121 transverses back along the original light path of
the reflection light beam 1112 of the sampling light beam and then
enters the substrate 12 of the biochip. A reflection occurs at the
detecting point, so that phase of the P-wave of the reflected light
beam 1122 has been changed twice. Therefore, the resolution of the
surface plasma resonance angle has been effectively improved while
comparing with the conventional technology.
[0140] In the embodiment, the microscope lens set 8 includes a lens
set 801, a CCD array 802, and an frame-grabbing card 803 to have
the function of camera. The microscope lens set 8 is used to
observe and adjust the measuring point on the sliding plate. The
observing light source and the sampling light beam 110 are from the
laser source 11, so that the system does not need extra light
source. The microscope lens set 8 read the image at the measuring
point through the frame-grabbing card 803. The image can be
instantly observed when it is connected to computer or monitor, and
simultaneously serves as an autocollimator for the sampling light
beam 110.
[0141] The invention discloses the multifunctional opto-electronic
biochip detection system. The invention not only can perform the
surface plasmon resonance techniques, but also can use
interferometer to obtain the phase information. The resolution is
greatly improved, resulting in a great tool on the biochemical
detection system.
[0142] It will be apparent to those skilled in the art that various
modifications and variations can be made to the structure of the
present invention without departing from the scope or spirit of the
invention. In view of the foregoing, it is intended that the
present invention covers modifications and variations of this
invention provided they fall within the scope of the following
claims and their equivalents.
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