U.S. patent application number 15/119448 was filed with the patent office on 2017-01-26 for atomic force microscope measuring device.
This patent application is currently assigned to UNIVERSITAT BASEL. The applicant listed for this patent is ETH ZURICH, UNIVERSITAT BASEL. Invention is credited to Christoph GERBER, Sascha MARTIN, David MARTINEZ-MARTIN, Daniel J. MUELLER.
Application Number | 20170023611 15/119448 |
Document ID | / |
Family ID | 52875093 |
Filed Date | 2017-01-26 |
United States Patent
Application |
20170023611 |
Kind Code |
A1 |
MARTINEZ-MARTIN; David ; et
al. |
January 26, 2017 |
ATOMIC FORCE MICROSCOPE MEASURING DEVICE
Abstract
Atomic force microscope measuring device comprising a
micro-cantilever and an intensity modulated laser exciting the
cantilever, wherein the measuring device comprises an optical
microscope, in particular a fluorescence microscope, a confocal
microscope, a fluorescence energy transfer (FRET) microscope, a DIC
and/or phase contrast microscope, all of those in particular
construed as an inverted microscope.
Inventors: |
MARTINEZ-MARTIN; David;
(Basel, CH) ; MUELLER; Daniel J.; (Basel, CH)
; MARTIN; Sascha; (Basel, CH) ; GERBER;
Christoph; (Richterswil, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNIVERSITAT BASEL
ETH ZURICH |
Basel
Zurich |
|
CH
CH |
|
|
Assignee: |
UNIVERSITAT BASEL
Basel
CH
ETH Zurich
Zurich
CH
|
Family ID: |
52875093 |
Appl. No.: |
15/119448 |
Filed: |
February 17, 2015 |
PCT Filed: |
February 17, 2015 |
PCT NO: |
PCT/EP2015/000349 |
371 Date: |
August 17, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G02B 21/0088 20130101;
B81B 3/0029 20130101; G02B 21/16 20130101; B81B 2201/047 20130101;
G01N 21/6458 20130101; G02B 21/32 20130101; B81B 2201/0214
20130101; G01N 2021/6441 20130101; G01Q 30/025 20130101; G01N
2201/06113 20130101; G02B 21/26 20130101; G02B 21/24 20130101; G01N
21/65 20130101; B81B 2203/0118 20130101; G01Q 10/045 20130101; G01G
9/00 20130101 |
International
Class: |
G01Q 30/02 20060101
G01Q030/02; G02B 21/26 20060101 G02B021/26; G02B 21/16 20060101
G02B021/16; G02B 21/00 20060101 G02B021/00; G01N 21/64 20060101
G01N021/64; G01N 21/65 20060101 G01N021/65 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 17, 2014 |
EP |
14000560.4 |
Dec 16, 2014 |
EP |
14004244.1 |
Claims
1. Art atomic force microscope measuring device comprising a
micro-cantilever and an intensity modulated light source exciting
the cantilever, wherein the measuring device comprises an optical
microscope.
2. The measuring device according to claim 1, wherein the
cantilever is transparent for a wavelength of the visual
spectrum.
3. The measuring device according to claim 1, wherein the
cantilever has a length in the range of 10 .mu.m to 1000 .mu.m,
and/or a fundamental resonance frequency in a range of 1 Hz to 10
MHz when immersed in water and/or an oscillation amplitude when
excited at resonance in the range of 0.01 nm to 500 nm and/or the
exciting light has a wavelength in the range of 350 nm to 750
nm.
4. The measuring device according to claim 1, wherein the exciting
light spot is focused on the base of the cantilever.
5. The measuring device according to claim 1, wherein the exciting
light spot is smaller than 100 .mu.m in diameter.
6. The measuring device according to claim 1, wherein said optical
microscope is at least one selected from the group consisting of a
fluorescence microscope, a confocal microscope, a fluorescence
energy transfer (FRET) microscope, a DIC and/or phase contrast
microscope or a Raman spectrometer all of those in particular
construed as an inverted microscope.
7. The measuring device according to claim 3, wherein the
cantilever has a length in the size of 10 .mu.m to 500 .mu.m and/or
a fundamental resonance frequency in the range of 1 kHz to 2000
kHz, when immersed in water and/or an oscillation amplitude when
excited at resonance smaller than 100 nm and/or the exciting light
has a wavelength in a range of 350 nm to 450 nm.
8. The measuring device according to claim 5, wherein the exciting
light spot is smaller than 50 .mu.m in diameter in diameter.
9. The measuring device according to claim 1, wherein the exciting
light spot is smaller than 10 .mu.m in diameter.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a 371 National Stage application of
International Application No. PCT/EP2015/000349 tiled on Feb. 17,
2015, which claims priority of European Patent (EP) application
Serial Number 14000560.4 filed on Feb. 17, 2014 and European Patent
(EP) application Serial Number 14004244.1 filed on Dec. 16, 2014,
all of which are incorporated herein by reference in their
entireties.
BACKGROUND OF THE INVENTION
[0002] Field of the Invention
[0003] The invention relates to an atomic force microscope
measuring device comprising a micro-cantilever and an intensity
modulated light source exciting the cantilever.
[0004] Description of the Prior Art
[0005] The invention proposed herein is based on Atomic Force
Microscopy technology. It allows to determine topography, physical,
chemical and biological properties of biological systems such as
single cells, tissues, single molecules, protein crystal
structures, over time and in physiological relevant environment. In
addition this device can be applied to characterize any other type
of material and it is able to work in other environments such as
air ambient conditions or vacuum. Furthermore our device is useful
to study cell-cell or cell-tissue interactions. This invention has
been developed to be fully compatible with optical techniques as
fluorescence, Differential Interference Contrast (DIC), phase
contrast, Raman spectroscopy and related techniques.
[0006] The atomic force microscopy (AFM) has not stopped developing
since its invention. In U.S. Pat. No. 6,330,824 B1 new imaging
method for AFM is described. As a novelty this method excites the
cantilever probe of the AFM using an intensity modulated laser.
[0007] There are different architectures to build an AFM based on
photothermal excitation. In many cases, an optical microscope is
used to focus the intensity modulated laser on the cantilever. This
microscope can be simultaneously used to focus a second laser on
the cantilever in order to read out its movement as. Of course, the
optical microscope used in this configuration enables to see the
cantilever and therefore to position and focus the laser or lasers
on the cantilever. However, this configuration does not allow to
use the optical microscope to obtain any other type of information
from the sample such as Differential Interference Contrast (DIC),
epifluorescence or similar techniques.
[0008] Other architectures use an additional set of optical
elements to focus the laser for the photothermal excitation
allowing to use a top-view optical microscope [5] with many
restrictions. The optical microscope in this configuration is
mainly used to locate properly the laser on the cantilever.
However, as in the previous eases, this type of architecture is not
compatible with important optical techniques for cell biology as
for instance DIC, fluorescence.
[0009] Atomic Force Microscopy (AFM) has reached an exciting stage
that allows studying topography, physical, chemical and biological
properties and interactions of samples with piconewton sensitivity
and subnanometer resolution. These capabilities together with its
ability to work in liquids make AFM a powerful multifunctional
toolbox to study a big variety of biological systems, ranging from
single molecules to single cells or tissues, in or close to their
physiological environment.
[0010] Despite of AFM is able to extract important information when
working in liquids, its performance is severely hampered due to
undesired hydrodynamic effects that can perturb the cantilever,
limiting importantly the conditions that can be applied in order to
extract quantitative information from samples. The origin of this
limitation is related with the fact that many operation AFM modes
require to excite the cantilever, which in the vast majority of the
instruments is done by using a dither piezo. This excitation method
is very easy to implement and requires a very small cost. In
addition it works very efficiently in vacuum or air ambient
conditions. However its performance in liquids drops dramatically
since it does not shake only the cantilever but the liquid where
the sample and cantilever are submerged in, which disturbs
significantly the movement of the cantilever making very difficult
its interpretation and hence extracting quantitative information
from the sample.
[0011] The previous limitations can be overcome by exciting the
cantilever using an intensity modulated laser (photothermal
excitation). This laser is generally focused at the base of the
cantilever and produces a very localized heating that stresses the
cantilever surface resulting in a cantilever bending. Since just
the cantilever is excited, its movement follows an expected
behavior which is very close to an ideal driven and damped harmonic
oscillator. Nevertheless, AFM's based on this excitation method has
not been developed so far to be compatible with optical techniques
such as DIC, fluorescence and other related techniques, lacking the
possibility of addressing important questions that required both
types of information to be acquired.
[0012] It is an object of the invention to improve these known
devices.
SUMMARY OF THE PRESENT INVENTION
[0013] According to a first aspect of the invention, a solution to
this technical problem is solved by providing an atomic force
microscope measuring device comprising a micro-cantilever and an
intensity modulated light source exciting the cantilever, wherein
the measuring device comprises an optical microscope, in particular
a fluorescence microscope, a confocal microscope, a fluorescence
energy transfer (FRET) microscope, a DIC and/or phase contrast
microscope, all of those in particular construed as an inverted
microscope. The light source can be any source of electromagnetic
radiation with a wavelength preferably within the range of 350 nm
to 750 nm. The electromagnetic radiation can be coherent or
non-coherent, monochromatic or non-monocromatic. In particular the
intensity modulated light source can be a laser.
[0014] Due to the importance of being able to simultaneously track
the topography and physical, chemical and biological properties of
biological systems together with its functional state, the AFM is
able to work based on photo thermal excitation but in addition is
fully compatible with modem optical microscopy and spectroscopy
techniques such as fluorescence, fluorescence energy transfer
(FRET), confocal microscopy, DIC and/or phase contrast or Raman
spectroscopy, and in general all those based on an inverted
microscope. Therefore the device enables to extract and correlate
the most accurate information obtained by this combination of
tools.
[0015] Although there are Atomic Force Microscopes (AFM) that
oscillate the cantilever by photothermal excitation, those systems
are not compatible with modem optical techniques such as DIC,
fluorescence microscopy, etc. A typical reason is that, in general,
those AFM systems use an optical microscope to focus an intensity
modulated laser on the cantilever in order to excite (oscillate)
the cantilever, which eliminates the possibility of using that
microscope for fluorescence imaging. On the contrary, the device
described herein is designed in such a way that the intensity
modulated laser can be positioned and focused on the cantilever
with a special set of optical elements and nanopositioners. The
optical pathway allows optical access from the top and bottom of
the device without compromising the cantilever excitation
mechanism. Additionally the reverse is also true, meaning that the
cantilever excitation do not compromise the acquisition of
information by modem optical techniques, being both types of
systems able to work simultaneously. This fact together with the
transparency of the cantilever, cantilever holder and sample holder
is designed to be fully compatible with modem optical techniques.
It is important to note that the device described herein shares
some features with systems used for near field optics, however
there are major differences. For instance, some systems used for
near field optics, have a cantilever and attached to it a
waveguide. A laser is focused on the waveguide which has to be very
close to a sample (typically several nanometers or tens of
nanometers) containing metals in order to excite plasmons. The
device described herein does not have a waveguide attached to the
cantilever. In addition, the device described herein does not use a
laser to induce effects of near field optics such as the excitation
of plasmons but to deflect the cantilever over time. Furthermore,
the device described herein is able to extract the information from
the sample without the need of containing metals. Moreover, the
device utilizes a second laser which is located near the free end
of the cantilever in order to read out the deflection of the
cantilever. However, this second laser is not compulsory and other
systems can be applied such as piezoelectric cantilevers,
piezoresistive cantilevers, Doppler interferometers, etc.
[0016] Another inventive aspect relates to an atomic force
microscopy measuring device, wherein the cantilever is transparent
for a wave length of the visual spectrum. The cantilever can be
partially or totally transparent for the wave length of the visual
spectrum. This allows for a combination with important optical
techniques in cell biology.
[0017] Preferably, the part of the cantilever that is close to its
free end is partially transparent for at least some wave length of
the visual spectrum and it is not smaller than 10 .mu.m.times.10
.mu.m. This window of transparency or partial transparency for at
least some wavelength of the visual spectrum is a requirement for
the device to be compatible with techniques such as DIC
(Differential Interference Contrast) or equivalents techniques,
which allow obtaining crucial. information about the morphology of
the biological sample even when the sample is being probed by the
cantilever or when there is a biological system sitting on or close
to the free end of the cantilever. These types of techniques,
require a special type of illumination, which has to go through the
sample and be collected using a special optical microscope located
opposite to the illumination source. In addition to the DIC
information, the objective allows our device to get fluorescence
information from the sample. However the transparency or partial
transparency of the cantilever is not a requirement for the
fluorescence information, since the illumination to excite the
fluorescence of the sample can be driven through the objective,
which collects simultaneously the fluorescence light emitted from
the sample.
[0018] Preferably the cantilever has a length in the range of 10
.mu.m to 1000 .mu.m and/or a resonance frequency for the
fundamental mode in the range of 1 Hz to 10 MHz in air ambient
conditions. Finally the cantilever preferably has an oscillation
amplitude when excited at the fundamental resonance in the range of
0.01 nm to 500 nm, preferably smaller than 100 nm. To optimize the
measuring device it is possible to choose or adapt a cantilever by
adapting the cantilever dimensions for different applications.
[0019] Preferably the wave length of the exciting light is in a
range from 350 nm to 750 nm, it may be between 350 nm and 550 nm.
Specifically a wave length of 405 nm may be used which has the
additional advantage that it is far enough from many of the wave
lengths used in fluorescence microscopy. However, depending on the
cantilever material other wave lengths may be used as well. In
particular, the wave length of the exciting light is chosen such
that it is strongly absorbed by the cantilever.
[0020] Advantageously the position, diameter and focus of the
exiting light spot on the cantilever may be adjusted and may be
located at the base of the cantilever or close to the base of the
cantilever. This maximizes the excitation efficiency. The exiting
light spot may be smaller than 100 .mu.m, preferably smaller than
50 .mu.m in diameter, preferably smaller than 10 .mu.m in diameter.
This size allows exciting the cantilever with high efficiency and
at the same time allows having the laser far from the biological
system to avoid interactions with the sample.
[0021] There are two ways to include the scanner or scanners into
the system: [0022] 1.--The scanner holds and moves the cantilever
or cantilever holder with respect the sample. In addition, if
necessary, the scanner holds and moves other elements of the device
to ensure that the excitation of the cantilever and the read out of
its movement are properly done. Equivalently and for simplicity,
the scanner can hold and move the whole device with respect the
sample. We refer to this system as head scanner. [0023] 2.--The
scanner holds and moves the sample with respect to the cantilever.
We refer to this system as sample scanner.
[0024] Supplementary, any combination of the two previous
strategies can be used in order to achieve a specific performance
of the instrument.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The invention will be described in more detail hereinafter
with reference to an exemplary embodiment. In the drawing,:
[0026] FIG. 1 shows a schematic sketch of a head scanner,
[0027] FIG. 2 shows schematic three-dimensional cross sectional
drawing o a head scanner,
[0028] FIG. 3 shows schematic three-dimensional top view drawing of
a head scanner,
[0029] FIG. 4 shows a sketch of a sample scanner,
[0030] FIG. 5 shows schematic three-dimensional cross sectional
drawing of a sample scanner,
[0031] FIG. 6 shows schematic three-dimensional top view drawing of
a sample scanner and
[0032] FIG. 7 shows schematic two-dimensional top view drawing of a
head and sample scanner (since they are identical in this
perspective) with arrows that indicate the directions of
movement.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0033] As can be seen the FIGS. 1 and 4, a 405 nm laser (7) is
focused on the base of a microcantilever using a set of optical
elements represented as (5) and the dichroic mirror (4) in order to
photothermally excite the cantilever. The movement of the
cantilever is detected using a beam deflection scheme but other
methods can be also applied. The laser beam (8) is focused at the
end of the cantilever using a set of optical elements represented
as (9) and the dichroic mirror (3). The laser beam (8) reflects
partially on the cantilever (20) and hits a gold mirror (12) that
addresses the beam into a four quadrants photodetector (13) to be
analyzed. Thanks to the optical properties of the dichroic mirrors
(3) and (4) together with the cantilever holder (19), the
cantilever itself which is totally or partially transparent and the
sample holder (18), special light generated in (2) can go through
the sample and be collected with an inverted microscope (21) for
DIC imaging or similar techniques. In addition, the microscope (21)
allows to illuminate the sample with suitable light to excite
fluorescent and collect back the fluorescent emitted light from the
sample according to an inverted microscope set-up. An XYZ scanner
enables to locate the cantilever in different positions of the
sample by either moving the sample holder (18) or the box (11) with
subnanometer resolution. The actuators (15) carry out a coarse
vertical movement to approach or withdraw the cantilever to the
sample. In addition these actuators can tilt the box (11) with
respect to the sample holder (18).
[0034] In order to ensure a very high stability of the excitation
of the cantilever, the exciting laser diode is kept at a fixed
temperature by using a peltier element. This thermoelectric system
ensures that wavelength and intensity of the laser will not shift
due to temperature changes. By modulating the current that feeds
the diode, the intensity of the laser can be modulated at a certain
frequency. However other ways to modulate the light intensity can
be applied as for instance by using acousto-optical or
electro-optical modulators. The light emitted by the laser diode is
then introduced into an optical fiber in order to reach an optical
collimator which is located in the head of the instrument. The
optical collimator is focusable and allows to get a laser beam with
parallel rays. However, in order to modify the laser waist (minimum
spot diameter) the collimator can be set to produce non parallel
rays as well. At the end of the collimator and attached to it there
is a micro focus optics which ensures that the laser light will be
focus at a certain distance, usually the distance or close to the
distance the cantilever is at.
[0035] The end of the optical fiber, together with the collimator
and the micro focus optics (46 in FIG. 2) are mounted on a
nanopositioner system (40 in FIG. 3) which is able to travel
several millimeters with nanometric resolution. This nanopositioner
system allows to modify the distance between the cantilever (51 in
FIG. 2) and the optical system (46). Doing so, the system has a
very precise and comfortable way to modify the laser spot size on
the cantilever, just by changing the position where the beam waist
is. This adjustment can be very important in order to optimize the
cantilever excitation for the following reasons: [0036] 1.--It
enables to find the optimum laser spot diameter to excite the
cantilever using the minimum power. This fact, for instance, can be
very important when a biological sample is sitting close the end of
the cantilever, since that part of the cantilever might be required
to be at a physiological temperature and hence to excite the
cantilever with very low power can be a need. [0037] 2. It brings
the possibility of modifying the length and/or material of the
cantilever holder (50 in FIG. 2) making the system very versatile
to work using for instance petri dishes of different heights or
dealing with a special sample holder in order to keep the sample
under incubation conditions by using for instance air with 5% CO2
and high humidity.
[0038] In addition the nanopositioner system (40 in FIG. 3) is held
by a set of nanopositioners (41 in FIG. 3) which enable to move in
XY directions the optical system (46) in order to ensure that the
laser hits the cantilever on the desired location. This set of
nanopositioners hold as well a dichroic mirror (39 in FIG. 2) which
deviates in 90 degrees the laser light coming from the optical
system (46) but not other wavelengths of the visual spectrum. This
way, the laser (44) can hit on the cantilever with almost normal
incidence and simultaneously other types of illumination such as
DIC, phase contrast or related techniques can be utilized from the
top.
[0039] A laser diode can be used in the device as a source of light
to excite the cantilever, however the use of laser light is not a
requirement and other types of light can be used.
[0040] The advantage of our invention over the state of the art is
that our device allows using a photothermal based AFM in filly
combination with modern optical techniques such as DIC,
fluorescence, FRET, confocal microscopy and in general all those
based on an inverted microscope.
[0041] Reference numbers for FIGS. 1 and 4: [0042] 1. Atomic force
microscope measuring device [0043] 2. DIC, phase contrast or other
type of illumination to characterize the morphology of biological
samples [0044] 3. Dichroic mirror that reflects the 850 nm
wavelength allowing other wavelengths in the visual spectrum to go
through [0045] 4. Dichroic minor that reflects the 405 nm
wavelength allowing other wavelengths in the visual spectrum and
the 850 nm wavelength to go through [0046] 5. Optical system to
correct and focus the 405 nm laser beam (6) [0047] 6. 405 nm laser
beam [0048] 7. 405 nm laser diode and optical fiber to drive the
laser into the optical system (5) [0049] 8. 850 nm laser beam
[0050] 9. Optical system to correct and focus the 850 nm laser (8)
[0051] 10. 850 nm laser diode and optical fiber to drive the laser
into the optical system (9) [0052] 11. Base of the box to hold the
apparatus [0053] 12. Mirror that reflects the 850 nm laser (8) to
hit the photodiode (13) [0054] 13. Four quadrant photodiode [0055]
14. Band-pass filter center at 850 nm. It allows the 850 nm laser
beam to reach the photodiode (13) but blocks other wavelengths
[0056] 15. Actuators to move the box and hence the cantilever along
the vertical direction. These actuators for instance allow
approaching and withdrawing the cantilever to the sample [0057] 16.
Platform that holds the box (11). The platform contains XY
positioner that allow to do a coarse movement of the box (11) with
respect to the sample holder (18) [0058] 17. Hollow scanner system
that holds the sample holder (18). It allows the move the sample
holder (18) in three orthogonal directions (X, Y and Z) with
respect to the box (11). The system contains in addition XY
positioners that allow to do a coarse movement of the sample holder
(18) with respect to the box (11) [0059] 18. Sample holder [0060]
19. Cantilever holder [0061] 20. Cantilever chip [0062] 21.
Inverted microscope. It is compatible with modern optical
techniques such as fluorescence, DIC, phase contrast, confocal
microscopy, FRET, raman spectroscopy [0063] 22. Hollow scanner
system that allows to move the box (11) with respect to the sample
holder (18) in three orthogonal directions (X, Y and Z). In
addition the scanner contains two positioners to do a coarse
movement of the box (11) with respect to the sample holder (18)
Reference numbers for FIGS. 2 to 3 and 5 to 7: [0064] 30. Atomic
force microscope measuring device [0065] 31. Base of the box to
hold the apparatus [0066] 32. Actuators to move the box and hence
the cantilever along the vertical direction. These actuators for
instance allow approaching and withdrawing the cantilever to the
sample [0067] 33. Actuator that moves the mirror (43) by spinning
the minor's holder. This actuator allows addressing (reflecting)
the 850 nm laser (45) on the photodiode (49) [0068] 34. Dichroic
mirror that reflects the 850 nm wavelength allowing other
wavelengths in the visual spectrum to go through [0069] 35.
Positioner system that holds the optical system to focus the 850 nm
laser (45). This system can move as shown by the arrows, which for
instance allows modifying the laser spot diameter on the cantilever
(51) [0070] 36. Positioner system that holds the positioner system
(35) and the dichroic mirror (34). The system can move as shown by
the arrows, which allows positioning the 850 nm laser beam (45) to
hit on a certain place as for instance the cantilever (51) [0071]
37. Window to allow DIC, phase contrast or other illumination types
[0072] 38. Positioner system that allows moving the photodiode as
shown by the arrows. This system for instance can be used in
combination with (33) to make the 850 nm laser hit on a certain
part of the photodiode [0073] 39. Dichroic mirror that reflects the
405 nm wavelength allowing other wavelengths in the visual spectrum
and the 850 nm wavelength to go through [0074] 40. Positioner
system that holds the optical system to focus the 405 nm laser
(44). This system can move as shown by the arrows, which for
instance allows modifying the laser spot diameter on the cantilever
(51) [0075] 41. Positioner system that holds the positioner system
(40) and the dichroic mirror (39). The system can move as shown by
the arrows, which allows positioning the 405 nm laser beam (44) to
hit on a certain place as for instance the cantilever (51) [0076]
42. Hollow scanner system that allows to move the box (31) with
respect to the sample holder (53) in three orthogonal directions
(X, Y and Z). In addition the scanner contains XV positioners to do
a coarse movement of the box (31) with respect to the sample holder
(53) [0077] 43. Mirror that reflects the 850 nm laser (45) to hit
the photodiode (49) [0078] 44. 405 nm laser beam [0079] 45. 850 nm
laser beam [0080] 46. Optical system to correct and focus the 405
nm laser (44) [0081] 47. Optical system to correct and focus the
850 nm laser (45) [0082] 48. Band-pass filter center at 850 nm. It
allows the 850 nm laser beam to reach the photodiode (49) but
blocks other wavelengths [0083] 49. Four quadrant photodiode [0084]
50. Cantilever holder [0085] 51. Cantilever chip [0086] 52.
Inverted microscope. It is compatible with modem optical techniques
such as fluorescence, DIC, phase contrast, confocal microscopy,
FRET, Raman spectroscopy [0087] 53. Sample holder. It contains XY
positioners to do a coarse movement of the sample holder (53) with
respect to the box (31) [0088] 54. Platform where the box (31) is
sitting. The platform contains XY positioner for a coarse movement
of the box (31) with respect to the sample holder (53) [0089] 55.
Hollow scanner system that holds the sample holder (53). It allows
to move and scan the sample holder (53) with respect to the box
(31) in three orthogonal directions (XYZ). In addition contains XY
positioners for a coarse movement of the sample holder (53) with
respect to the box (31)
[0090] Having described preferred embodiments of the invention, it
will be apparent to those skilled in the art to which this
invention relates, that modifications and amendments to various
features and items can be effected and yet still come within the
general concept of the invention. It is to be understood that all
such modifications and amendments are intended to be included
within the scope of the present invention.
* * * * *