U.S. patent application number 16/079236 was filed with the patent office on 2019-02-28 for substance labeling patch, method and apparatus for tissue diagnosis using the same.
The applicant listed for this patent is NOUL CO., LTD.. Invention is credited to Kyung Hwan Kim, Dong Young Lee, Chan Yang Lim.
Application Number | 20190064140 16/079236 |
Document ID | / |
Family ID | 59923756 |
Filed Date | 2019-02-28 |
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United States Patent
Application |
20190064140 |
Kind Code |
A1 |
Lee; Dong Young ; et
al. |
February 28, 2019 |
SUBSTANCE LABELING PATCH, METHOD AND APPARATUS FOR TISSUE DIAGNOSIS
USING THE SAME
Abstract
The present disclosure relates to a tissue diagnosis device
including a plate supporter configured to support a plate on which
a reaction region is placed and a sample is placed in the reaction
region, a patch controller configured to support the patch which
contains a labeling substance that specifically labels the target
substance, and control a position of the patch relative to the
reaction region so that the patch provides the labeling substance
to the reaction region, and a target substance detector configured
to detect the labeling substance and detect the target substance
included in the tissue sample.
Inventors: |
Lee; Dong Young; (Yongin,
Gyeonggi-do, KR) ; Lim; Chan Yang; (Seongnam,
Gyeonggi-do, KR) ; Kim; Kyung Hwan; (Yongin,
Gyeonggi-do, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOUL CO., LTD. |
Yongin, Gyeonggi-do |
|
KR |
|
|
Family ID: |
59923756 |
Appl. No.: |
16/079236 |
Filed: |
February 23, 2017 |
PCT Filed: |
February 23, 2017 |
PCT NO: |
PCT/KR2017/002029 |
371 Date: |
August 23, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62298959 |
Feb 23, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N 33/558 20130101;
G01N 2021/7723 20130101; G01N 1/31 20130101; C12Q 1/6844 20130101;
G06T 7/0014 20130101; G01N 2001/302 20130101; G01N 21/77 20130101;
B01L 7/52 20130101; G01N 2015/0693 20130101; C12Q 1/6848 20130101;
G01N 33/49 20130101; G01N 33/533 20130101; G01N 33/60 20130101;
B01L 3/505 20130101; G01N 1/312 20130101; G01N 33/4833 20130101;
C12Q 1/701 20130101; G01N 15/06 20130101; B01L 3/00 20130101; Y02P
20/582 20151101; C07K 16/3061 20130101; G01N 2021/7786 20130101;
G01N 15/14 20130101; G01N 33/5304 20130101; C12Q 1/686 20130101;
B01F 13/0093 20130101; G01N 33/52 20130101; G06T 7/0012 20130101;
G01N 1/30 20130101; G01N 33/5082 20130101; G01N 2015/0065 20130101;
C12Q 1/6848 20130101; C12Q 2563/159 20130101; C12Q 2565/625
20130101; C12Q 1/6844 20130101; C12Q 2563/159 20130101; C12Q
2565/518 20130101 |
International
Class: |
G01N 33/483 20060101
G01N033/483; G01N 1/31 20060101 G01N001/31; G01N 33/53 20060101
G01N033/53; G01N 33/533 20060101 G01N033/533; G01N 15/14 20060101
G01N015/14; G06T 7/00 20060101 G06T007/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 4, 2016 |
KR |
10-2016-0069936 |
Jun 4, 2016 |
KR |
10-2016-0069937 |
Jun 4, 2016 |
KR |
10-2016-0069938 |
Jul 27, 2016 |
KR |
10-2016-0095739 |
Sep 13, 2016 |
KR |
10-2016-0118462 |
Nov 1, 2016 |
KR |
10-2016-0144551 |
Feb 23, 2017 |
KR |
10-2017-0024390 |
Claims
1.-33. (canceled)
34. A tissue diagnosis method for detecting a target substance from
a tissue sample by using a patch which includes a mesh structural
body forming micro-cavities and is configured to contain a
substance in the micro-cavities, the tissue diagnosis method
comprising: placing the tissue sample in a reaction region;
providing a fluorescence labeling substance for specifically
labeling the target substance to the tissue sample by using a patch
that contains the fluorescence labeling substance; and detecting
the fluorescence-labeled target substance from the tissue
sample.
35. The tissue diagnosis method of claim 34, wherein the
fluorescence labeling substance is a fluorescence labeling complex
that includes a reaction derivative that reacts specifically with
the target substance and a fluorescence marker for detecting the
target substance.
36. The tissue diagnosis method of claim 34, wherein the detecting
of the fluorescence-labeled target substance is performed by
acquiring a fluorescence image of the tissue sample.
37. The tissue diagnosis method of claim 34, wherein: the target
substance is a target base sequence included in the tissue sample;
and the fluorescence labeling substance includes a
fluorescence-labeled nucleic acid probe, the nucleic acid probe
binding complementarily to the target base sequence.
38. The tissue diagnosis method of claim 34, wherein: the target
substance is a target protein included in the tissue sample; and
the fluorescence labeling substance include a fluorescence-labeled
antibody, the antibody binds specifically to the target
protein.
39. The tissue diagnosis method of claim 34, wherein the providing
of the fluorescence labeling substance to the tissue sample
includes: contacting the patch containing the fluorescence labeling
substance with the tissue sample; and when the patch is in contact
with the tissue sample, the fluorescence labeling substance is
allowed to move to the reaction region.
40. The tissue diagnosis method of claim 39, wherein: the providing
of the fluorescence labeling substances to the tissue sample
further includes separating the patch containing the fluorescence
labeling substances from the tissue sample; and when the patch is
separated from the tissue sample, a residual fluorescence labeling
substance that has not bound to the target substance of the
fluorescence labeling substance is removed from the reaction
region.
41. The tissue diagnosis method of claim 34, wherein the detecting
of the fluorescence-labeled target substance is performed by
measuring an amount of fluorescence emitted from the target
substance included in the tissue sample.
42. The tissue diagnosis method of claim 34, wherein the detecting
of the fluorescence-labeled target substance includes obtaining
information on distribution of the target substance in the tissue
sample.
43. A substance labeling patch comprising: a labeling substance
that binds to a target substance included in a tissue sample to
label the target substance; and a mesh structural body having a
mesh structure forming micro-cavities in which the labeling
substance is contained that is configured to come into contact with
the tissue sample and provide the labeling substance to a reaction
region in which the target substance is placed.
44. The substance labeling patch of claim 43, wherein the labeling
substance is a fluorescence labeling substance.
45. The substance labeling patch of claim 44, wherein: the
fluorescence labeling substance includes a fluorescence-labeled
antibody; and the target substance is a target protein included in
the tissue sample.
46. The substance labeling patch of claim 44, wherein: the
fluorescence labeling substance includes a fluorescence-labeled
nucleic acid probe; and the target substance is a target base
substance included in the tissue sample.
47. The substance labeling patch of claim 43, wherein the target
substance is a DNA included in the tissue sample.
48. The substance labeling patch of claim 43, wherein the labeling
substance is a color labeling substance.
49. The substance labeling patch of claim 48, wherein the color
labeling substance includes an enzyme-attached antibody; and the
target substance is a target protein included in the sample.
50. The substance labeling patch of claim 48, wherein: the color
labeling substance includes hematoxylin; and the target substance
is a nucleus included in the sample.
51. A tissue diagnosis device for detecting a target substance from
a tissue sample by using a patch which includes a mesh structural
body forming micro-cavities and is configured to contain a
substance in the micro-cavities, the tissue diagnosis device
comprising: a plate supporter configured to support a plate on
which a reaction region is placed and a sample is placed in the
reaction region; a patch controller configured to support the patch
which contains a labeling substance that specifically labels the
target substance, and control a position of the patch relative to
the reaction region so that the patch comes into contact with the
reaction region and provides the labeling substance to the reaction
region; and a target substance detector configured to detect the
labeling substance and detect the target substance included in the
tissue sample.
52. The tissue diagnosis device of claim 51, wherein the target
substance detector include an imaging module configured to acquire
an image of the reaction region in which the tissue sample is
placed.
53. The tissue diagnosis device of claim 51, wherein the target
substance detector includes a measurement module configured to
measure an amount of the target substance included in the tissue
sample.
Description
TECHNICAL FIELD
[0001] The present disclosure relates to a substance labeling
patch, a method of and apparatus for tissue diagnosis using the
same, and more particularly, to a patch that contains a labeling
substance and a method and apparatus capable of performing prompt
and accurate diagnosis on a tissue sample by using the patch and
labeling a portion of the tissue sample.
BACKGROUND ART
[0002] Due to a rapidly aging society and increasing need for
quality of life, the diagnostic market which aims at early
diagnosis and early treatment is growing every year in the world,
including South Korea, and quick and easy diagnosis is becoming an
important issue. In particular, forms of diagnosis are being
transitioned into forms in which diagnosis can be performed without
using large diagnostic equipment, such as in-vitro diagnosis (IVD)
or point-of-care testing (POCT) which is immediately performed next
to a patient. Immunochemical diagnosis, which is one specific
diagnostic field for performing IVD, is one diagnostic method that
accounts for a large portion in the IVD field and is widely
used.
[0003] Histological diagnosis is a concept that encompasses
pathological diagnoses performed with a tissue, which is a cellular
organizational level intermediate between cells and a complete
organ and is an ensemble of similar cells, as a sample.
Particularly, diagnoses performed with a tissue as a sample are
mostly used in cancer diagnosis. When development of cancer is
suspected through clinical or image diagnosis, a portion of a
tissue which is suspected as cancer is collected from a patient by
using a method such as fine needle aspiration. The collected tissue
is used in diagnosis after a tissue processing process. In this
case, diagnosis may be performed by observing the morphology of
cells that constitute the tissue or determining a presence of a
specific protein.
[0004] In a conventional tissue diagnosis method, in a process in
which a sample is stained or gone through the fluorescence process,
a washing process in which a large amount of washing solution is
poured on a plate or the like to rinse it in order to remove
staining reagent or fluorescent substances which are not bound to a
substance to be detected is necessarily required. In this case,
there is a disadvantage in that the large amount of washing
solution is required. Also, the conventional tissue diagnosis
method has a problem in that, when the above-described washing is
not performed properly, the remaining stains or remaining
fluorescent substances interfere with detection, and it becomes
difficult to perform accurate diagnosis.
[0005] Accordingly, a means for effectively removing factors that
interfere with detection while minimizing an amount of specimen
required for diagnosis is needed.
SUMMARY
[0006] An aspect of the present disclosure is to provide a patch
capable of storing a substance.
[0007] An aspect of the present disclosure is to provide a patch
capable of providing a reaction space for a substance.
[0008] An aspect of the present disclosure is to provide a patch
capable of providing a substance.
[0009] An aspect of the present disclosure is to provide a patch
capable of absorbing a substance.
[0010] An aspect of the present disclosure is to provide a patch
capable of providing an environment.
[0011] An aspect of the present disclosure is to provide a patch
that contains a labeling substance.
[0012] An aspect of the present disclosure is to provide a tissue
diagnosis method using a patch.
[0013] According to an aspect of the present disclosure, there is
provided a tissue diagnosis device for detecting a target substance
from a tissue sample by using a patch which includes a mesh
structural body forming micro-cavities and is configured to contain
a substance in the micro-cavities, the tissue diagnosis device
including a plate supporter configured to support a plate on which
a reaction region is placed and a sample is placed in the reaction
region, a patch controller configured to support the patch which
contains a labeling substance that specifically labels the target
substance, and control a position of the patch relative to the
reaction region so that the patch comes into contact with the
reaction region and provides the labeling substance to the reaction
region, and a target substance detector configured to detect the
labeling substance and detect the target substance included in the
tissue sample.
[0014] The target substance detector may include an imaging module
configured to acquire an image of the reaction region in which the
tissue sample is placed. The target substance detector may include
a measurement module configured to measure an amount of the target
substance included in the tissue sample.
[0015] According to another aspect of the present disclosure, there
is provided a tissue diagnosis method for detecting a target
substance from a tissue sample by using a patch which includes a
mesh structural body forming micro-cavities and is configured to
contain a substance in the micro-cavities, the tissue diagnosis
method including placing the tissue sample in a reaction region,
providing a fluorescence labeling substance for specifically
labeling the target substance to the tissue sample by using a patch
that contains the fluorescence labeling substance, and detecting
the fluorescence-labeled target substance from the tissue
sample.
[0016] The fluorescence labeling substance may be a fluorescence
labeling complex that includes a reaction derivative that reacts
specifically with the target substance and a fluorescence marker
for detecting the target substance.
[0017] The detecting of the fluorescence-labeled target substance
may be performed by obtaining a fluorescence image of the tissue
sample. The detecting of the fluorescence-labeled target substance
may be performed by measuring an amount of fluorescence emitted
from the target substance included in the tissue sample. The
detecting of the fluorescence-labeled target substance may include
obtaining information on distribution of the target substance in
the tissue sample.
[0018] The target substance may be a target base sequence included
in the tissue sample, the fluorescence labeling substance may
include a fluorescence-labeled nucleic acid probe, and the nucleic
acid probe may bind complementarily to the target base sequence.
Alternatively, the target substance may be a target protein
included in the tissue sample, the fluorescence labeling substance
may include a fluorescence-labeled antibody, and the antibody may
bind specifically to the target protein.
[0019] The providing of the fluorescence labeling substance to the
tissue sample may include contacting the patch containing the
fluorescence labeling substance with the tissue sample, and when
the patch is in contact with the tissue sample, the fluorescence
labeling substance may be allowed to move to the reaction
region.
[0020] The providing of the fluorescence labeling substance to the
tissue sample may include separating the patch containing the
fluorescence labeling substance from the tissue sample, and when
the patch is separated from the tissue sample, a residual
fluorescence labeling substance that has not bound to the target
substance of the fluorescence labeling substance may be removed
from the reaction region.
[0021] According to still another aspect of the present disclosure,
there is provided a tissue diagnosis method for detecting a target
substance from a tissue sample by using a patch which includes a
mesh structural body forming micro-cavities and is configured to
contain a substance in the micro-cavities, the tissue diagnosis
method including placing the tissue sample in a reaction region,
providing staining substance to the tissue sample by using a patch
that contains color labeling substance for assigning color to the
target substance, and detecting the color-assigned target
substance.
[0022] The color labeling substance may be a color labeling complex
that includes a reaction derivative that reacts specifically with
the target substance and a color marker for detecting the target
substance.
[0023] The detecting of the color-assigned target substance may be
performed by acquiring an image of the tissue sample. The detecting
of the color-labeled target substance may include obtaining an
amount of the color-labeled target substance in the tissue sample.
The detecting of the color-labeled target substance may include
obtaining a distribution of color-labeled regions in the tissue
sample.
[0024] The target substance may be a target base sequence included
in the tissue sample, the color labeling substance may include a
nucleic acid probe that binds complementarily to the target base
sequence. The target substance may be a target protein included in
the tissue sample, the color labeling substance may include an
antibody to which a marker for inducing color labeling is attached,
and the antibody may bind specifically to the target protein.
[0025] The providing of the color labeling substance to the tissue
sample may include contacting the patch containing the color
labeling substance with the tissue sample, and when the patch is in
contact with the tissue sample, the color labeling substance may be
allowed to move to the reaction region.
[0026] The providing of the color labeling substance to the tissue
sample may include separating the patch containing the color
labeling substance from the tissue sample, and when the patch is
separated from the tissue sample, a residual color labeling
substance that has not bound to the target substance of the color
labeling substance may be removed from the reaction region.
[0027] According to yet another aspect of the present disclosure,
there is provided a tissue diagnosis method for detecting a target
substance from a tissue sample by using a patch which includes a
mesh structural body forming micro-cavities and is configured to
contain a substance in the micro-cavities, the tissue diagnosis
method including placing the tissue sample in a reaction region,
providing a first fluorescence labeling substance for specifically
labeling a first target substance to the tissue sample by using a
patch that contains the first fluorescence labeling substance, and
providing a second fluorescence labeling substance for specifically
labeling a second target substance to the tissue sample by using a
patch that contains the second fluorescence labeling substance.
[0028] A wavelength band from which fluorescence emitted from the
first fluorescence labeling substance is detected and a wavelength
band from which fluorescence emitted from the second fluorescence
labeling substance is detected may be different from each other,
and the tissue diagnosis method may further include, after the
providing of the second florescence labeling substance to the
tissue sample, detecting the first target substance and the second
target substance included in the tissue sample.
[0029] The tissue diagnosis method may further include, after the
providing of the first fluorescence labeling substance to the
tissue sample, detecting the first target substance included in the
tissue sample by detecting fluorescence emitted from the first
fluorescence labeling substance, and may further include, after the
providing of the second fluorescence labeling substance to the
tissue sample, detecting the second target substance included in
the tissue sample by detecting fluorescence emitted from the second
fluorescence labeling substance.
[0030] The wavelength band from which the fluorescence emitted from
the first fluorescence labeling substance is detected and the
wavelength band from which the fluorescence is emitted from the
second fluorescence labeling substance is detected may at least
partially overlap each other, and the detecting of the fluorescence
emitted from the second fluorescence labeling substance may be
performed by comparing fluorescence detected from the tissue sample
after the second fluorescence labeling substance is provided to the
tissue sample and fluorescence detected from the tissue sample
before the second fluorescence labeling substance is provided to
the tissue sample.
[0031] According to yet another aspect of the present disclosure,
there is provided a substance labeling patch including a labeling
substance that binds to a target substance included in a tissue
sample to label the target substance, and a mesh structural body
having a mesh structure forming micro-cavities in which the
labeling substance is contained that is configured to come into
contact with the tissue sample and provide the labeling substance
to a reaction region in which the target substance is placed. The
target substance may be DNA included in the tissue sample.
[0032] The labeling substance may be a fluorescence labeling
substance.
[0033] The fluorescence labeling substance may include a
fluorescence-labeled antibody, and the target substance may be a
target protein included in the tissue sample. The fluorescence
labeling substance may include a fluorescence-labeled nucleic acid
probe, and the target substance may be a target base substance
included in the tissue sample.
[0034] The labeling substance may be a color labeling
substance.
[0035] The color labeling substance may include an enzyme-attached
antibody, and the target substance may be a target protein included
in the sample. The color labeling substance may include
hematoxylin, and the target substance may be a nucleus included in
the sample.
[0036] Solutions for solving the technical problems of the present
disclosure are not limited to the above-described solutions, and
other unmentioned solution should be clearly understood by those of
ordinary skill in the art to which the present disclosure pertains
from the present specification and the accompanying drawings.
[0037] According to the present disclosure, containing, providing,
and absorption of a substance can be easily performed.
[0038] According to the present disclosure, a reaction region for a
substance can be provided or a predetermined environment can be
provided to a target region.
[0039] According to the present disclosure, diagnosis performed
with a tissue as a sample can be more conveniently performed, and a
diagnosis result can be promptly obtained.
[0040] According to the present disclosure, providing and
absorption of a substance can be properly adjusted using a path,
and an amount of a solution consumed for diagnosis can be
significantly reduced.
[0041] According to the present disclosure, tissue diagnosis can be
performed by simultaneously detecting a plurality of targets.
[0042] Advantageous effects of the present disclosure are not
limited to those mentioned above, and unmentioned advantageous
effects should be clearly understood by those of ordinary skill in
the art to which the present disclosure pertains from the present
specification and the accompanying drawings.
BRIEF DESCRIPTION OF DRAWINGS
[0043] FIG. 1 illustrates an example of a patch in detail according
to the present application.
[0044] FIG. 2 illustrates an example of a patch in detail according
to the present application.
[0045] FIG. 3 illustrates providing of a reaction space as an
example of a function of a patch according to the present
application.
[0046] FIG. 4 illustrates providing of a reaction space as an
example of a function of a patch according to the present
application.
[0047] FIG. 5 illustrates providing of a substance as an example of
a function of a patch according to the present application.
[0048] FIG. 6 illustrates providing of a substance as an example of
a function of a patch according to the present application.
[0049] FIG. 7 illustrates providing of a substance as an example of
a function of a patch according to the present application.
[0050] FIG. 8 illustrates providing of a substance as an example of
a function of a patch according to the present application.
[0051] FIG. 9 illustrates providing of a substance as an example of
a function of a patch according to the present application.
[0052] FIG. 10 illustrates providing of a substance as an example
of a function of a patch according to the present application.
[0053] FIG. 11 illustrates providing of a substance as an example
of a function of a patch according to the present application.
[0054] FIG. 12 illustrates providing of a substance as an example
of a function of a patch according to the present application.
[0055] FIG. 13 illustrates providing of a substance as an example
of a function of a patch according to the present application.
[0056] FIG. 14 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0057] FIG. 15 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0058] FIG. 16 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0059] FIG. 17 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0060] FIG. 18 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0061] FIG. 19 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0062] FIG. 20 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0063] FIG. 21 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0064] FIG. 22 illustrates absorbing of a substance as an example
of a function of a patch according to the present application.
[0065] FIG. 23 illustrates providing of an environment as an
example of a function of a patch according to the present
application.
[0066] FIG. 24 illustrates providing of an environment as an
example of a function of a patch according to the present
application.
[0067] FIG. 25 illustrates providing of an environment as an
example of a function of a patch according to the present
application.
[0068] FIG. 26 illustrates performance of absorbing and providing
of a substance as an embodiment of a patch according to the present
application.
[0069] FIG. 27 illustrates performance of absorbing and providing
of a substance as an embodiment of a patch according to the present
application.
[0070] FIG. 28 illustrates performance of absorbing and providing
of a substance as an embodiment of a patch according to the present
application.
[0071] FIG. 29 illustrates performance of absorbing and providing
of a substance as an embodiment of a patch according to the present
application.
[0072] FIG. 30 illustrates performance of absorbing and providing
of a substance as an embodiment of a patch according to the present
application.
[0073] FIG. 31 illustrates performance of absorbing and providing
of a substance and providing of an environment as an embodiment of
a patch according to the present application.
[0074] FIG. 32 illustrates performance of absorbing and providing
of a substance and providing of an environment as an embodiment of
a patch according to the present application.
[0075] FIG. 33 illustrates an implementation of a plurality of
patches as an embodiment of a patch according to the present
application.
[0076] FIG. 34 illustrates an implementation of a plurality of
patches and a plate having a plurality of target regions as an
embodiment of a patch according to the present application.
[0077] FIG. 35 illustrates a flowchart for describing an example of
a tissue diagnosis method according to the present application.
[0078] FIG. 36 illustrates a flowchart for describing an example of
delivering a fluorescence labeling substance to a tissue sample in
a tissue diagnosis method according to an embodiment of the present
application.
[0079] FIG. 37 illustrates a flowchart for describing an example of
a tissue diagnosis method according to the present application.
[0080] FIG. 38 illustrates a flowchart for describing an example of
delivering a color labeling substance to a tissue sample in a
tissue diagnosis method according to an embodiment of the present
application.
[0081] FIG. 39 illustrates a flowchart for describing a case in
which a plurality of target substances are detected, as an example
of a tissue diagnosis method according to the present
application.
[0082] FIG. 40 illustrates a flowchart for describing a case in
which a plurality of target substances are detected, as an example
of a tissue diagnosis method according to the present
application.
[0083] FIG. 41 illustrates a flowchart for describing a case in
which a plurality of target substances are sequentially detected,
as an example of a tissue diagnosis method according to the present
application.
[0084] FIG. 42 illustrates an example of morphological diagnosis in
an embodiment of a tissue diagnosis method according to the present
application.
[0085] FIG. 43 schematically illustrates a part of a case in which
it is desired to detect a plurality of target substances, as an
example of a tissue diagnosis method according to the present
application.
[0086] FIG. 44 schematically illustrates a part of a case in which
it is desired to detect a plurality of target substances, as an
example of a tissue diagnosis method according to the present
application.
[0087] FIG. 45 schematically illustrates a part of a case in which
it is desired to detect a plurality of target substances, as an
example of a tissue diagnosis method according to the present
application.
[0088] FIG. 46 schematically illustrates a part of a case in which
it is desired to detect a plurality of target substances, as an
example of a tissue diagnosis method according to the present
application.
[0089] FIG. 47 schematically illustrates a part of a case in which
it is desired to detect a plurality of target substances, as an
example of a tissue diagnosis method according to the present
application.
[0090] FIG. 48 illustrates an embodiment of a tissue diagnosis
method according to the present application.
[0091] FIG. 49 illustrates an embodiment of a tissue diagnosis
method according to the present application.
[0092] FIG. 50 illustrates an embodiment of a tissue diagnosis
method according to the present application.
[0093] FIG. 51 illustrates a case in which a probe is used, as an
embodiment of a tissue diagnosis method according to the present
application.
[0094] FIG. 52 illustrates a case in which a probe is used, as an
embodiment of a tissue diagnosis method according to the present
application.
[0095] FIG. 53 illustrates a case in which a probe is used, as an
embodiment of a tissue diagnosis method according to the present
application.
[0096] FIG. 54 illustrates a case in which an antibody is used, as
an embodiment of a tissue diagnosis method according to the present
application.
[0097] FIG. 55 illustrates a case in which an antibody is used, as
an embodiment of a tissue diagnosis method according to the present
application.
[0098] FIG. 56 illustrates a case in which an antibody is used, as
an embodiment of a tissue diagnosis method according to the present
application.
[0099] FIG. 57 illustrates a case in which an antibody is used, as
an embodiment of a tissue diagnosis method according to the present
application.
[0100] FIG. 58 illustrates a case in which an antibody is used, as
an embodiment of a tissue diagnosis method according to the present
application.
[0101] FIG. 59 illustrates a case in which a washing patch is used,
as an embodiment of a tissue diagnosis method according to the
present application.
[0102] FIG. 60 illustrates a case in which a washing patch is used,
as an embodiment of a tissue diagnosis method according to the
present application.
[0103] FIG. 61 illustrates a case in which a washing patch is used,
as an embodiment of a tissue diagnosis method according to the
present application
[0104] FIG. 62 illustrates an embodiment of a tissue diagnosis
device according to the present application.
[0105] FIG. 63 illustrates a target substance detector in an
embodiment of a tissue diagnosis device according to the present
application in detail.
DETAILED DESCRIPTION
[0106] Since embodiments described herein are for clearly
describing the spirit of the present disclosure to those of
ordinary skill in the art to which the present disclosure pertains,
the present disclosure is not limited to the embodiments described
herein, and the scope of the present disclosure should be construed
as including revised examples or modified examples not departing
from the spirit of the present disclosure.
[0107] General terms currently being used as widely as possible
have been selected as terms used herein in consideration of
functions in the present disclosure, but the terms may be changed
according to intentions and practices of those of ordinary skill in
the art to which the present disclosure pertains or the advent of
new technologies, etc. However, instead, when a particular term is
defined as a certain meaning and used, the meaning of the term will
be separately described. Consequently, the terms used herein should
be construed on the basis of substantial meanings of the terms and
content throughout the present specification instead of simply on
the basis of names of the terms.
[0108] The accompanying drawings herein are for easily describing
the present disclosure. Since shapes illustrated in the drawings
may have been exaggeratedly depicted as much as necessary to assist
in understating the present disclosure, the present disclosure is
not limited by the drawings.
[0109] When detailed description of a known configuration or
function related to the present disclosure is deemed to obscure the
gist of the present disclosure in the present specification, the
detailed description related thereto will be omitted as
necessary.
1. Patch
1.1 Meaning of Patch
[0110] In the present application, a patch for managing a liquid
substance is disclosed.
[0111] The liquid substance may mean a substance which is in a
liquid state and can flow.
[0112] The liquid substance may be a substance formed of a single
component having fluidity. Alternatively, the liquid substance may
be a mixture that includes a substance formed of a plurality of
components.
[0113] When the liquid substance is a substance formed of a single
component, the liquid substance may be a substance formed of a
single chemical element or a compound including a plurality of
chemical elements.
[0114] When the liquid substance is a mixture, a portion of the
substance formed of a plurality of components may serve as a
solvent, and the other portion may serve as a solute. That is, the
mixture may be a solution.
[0115] A plurality of components constituting the mixture which
forms the substance may be uniformly distributed. Alternatively,
the mixture including the substance formed of a plurality of
components may be a uniformly mixed mixture.
[0116] The substance formed of a plurality of components may
include a solvent and a substance that is not dissolved in the
solvent and is uniformly distributed.
[0117] A portion of the substance formed of a plurality of
components may be non-uniformly distributed. The non-uniformly
distributed substance may include non-uniformly distributed
particle components in the solvent. In this case, the non-uniformly
distributed particle components may be in a solid phase.
[0118] For example, a substance that may be managed using the patch
may be in a state of 1) a liquid formed of a single component, 2) a
solution, or 3) a colloid, or according to circumstances, may be in
a state in which 4) solid particles are non-uniformly distributed
within another liquid substance.
[0119] Hereinafter, the patch according to the present application
will be described in more detail.
1.2 General Nature of Patch
1.2.1 Configuration
[0120] FIGS. 1 and 2 are views illustrating an example of a patch
according to the present application. The patch according to the
present application will be described below with reference to FIGS.
1 and 2.
[0121] Referring to FIG. 1, a patch PA according to the present
application may include a mesh structural body NS and a liquid
substance.
[0122] As the liquid substance, a base substance BS and an additive
substance AS may be taken into consideration separately.
[0123] The patch PA may be in a gel state (gel type). The patch PA
may be implemented as a gel-type structural body in which colloidal
molecules are bound and mesh tissues are formed.
[0124] The patch PA according to the present application is a
structure for managing a liquid substance SB, and may include a
three-dimensional mesh (net-like) structural body NS. The mesh
structural body NS may be a continuously distributed solid
structure. The mesh structural body NS may have a mesh structure in
which a plurality of micro-threads are intertwined. However, the
mesh structural body NS is not limited to the mesh form in which
the plurality of micro-threads are intertwined, and may also be
implemented in the form of an arbitrary three-dimensional matrix
that is formed by connection of a plurality of micro-structures.
For example, the mesh structural body NS may be a frame structural
body that includes a plurality of micro-cavities. In other words,
the mesh structural body NS may form a plurality of micro-cavities
MC.
[0125] FIG. 2 illustrates a structure of a patch according to an
embodiment of the present application. Referring to FIG. 2, the
mesh structural body of the patch PA may have a sponge structure
SS. The mesh structural body of the sponge structure SS may include
a plurality of micro-holes MH. Hereinafter, the terms micro-holes
MH and the micro-cavities MC may be used interchangeably, and
unless particularly mentioned otherwise, the term micro-cavities MC
is defined as encompassing the concept of the micro-holes MH.
[0126] The mesh structural body NS may have a regular or irregular
pattern. Furthermore, the mesh structural body NS may include both
a region having a regular pattern and a region having an irregular
pattern.
[0127] A density of the mesh structural body NS may have a value
within a predetermined range. Preferably, the predetermined range
may be set within a limit in which the form of the liquid substance
SB captured in the patch PA is maintained in a form that
corresponds to the patch PA. The density may be defined as a degree
to which the mesh structural body NS is dense or a mass ratio, a
volume ratio, or the like that the mesh structural body NS occupies
in the patch.
[0128] The patch according to the present application may manage
the liquid substance SB by having a three-dimensional mesh
structure.
[0129] The patch PA according to the present application may
include the liquid substance SB, and the fluidity of the liquid
substance SB included in the patch PA may be limited by the form of
the mesh structural body NS of the patch PA.
[0130] The liquid substance SB may freely flow within the mesh
structural body NS. In other words, the liquid substance SB is
placed in the plurality of micro-cavities formed by the mesh
structural body NS. An exchange of liquid substance SB may occur
between neighboring micro-cavities. In this case, the liquid
substance SB may be present in a state in which the liquid
substance SB permeating into a frame structural body that forms the
mesh tissues. In such a case, nano-sized pores into which the
liquid substances SB may permeate may be formed in the frame
structural body.
[0131] Further, whether to the liquid substance SB is filled in the
frame structural body of the mesh structure may be determined
depending on a molecular weight or a particle size of the liquid
substance SB to be captured in the patch PA. A substance having a
relatively large molecular weight may be captured in the
micro-cavities, and a substance having a relatively small molecular
weight may be captured by the frame structural body and filled in
the micro-cavities and/or the frame structural body of the mesh
structural body NS.
[0132] In the present specification, the term "capture" may be
defined as a state in which the liquid substance SB is placed in
the plurality of micro-cavities and/or nano-sized holes formed by
the mesh structural body NS. As described above, the state in which
the liquid substance SB is captured in the patch PA is defined as
including a state in which the liquid substance SB may flow between
the micro-cavities and/or the nano-sized holes.
[0133] As in the following, the base substance BS and the additive
substance AS may be taken into consideration separately as the
liquid substance SB.
[0134] The base substance BS may be a liquid substance SB having
fluidity.
[0135] The additive substance AS may be a substance that is mixed
with the base substance BS and has fluidity. In other words, the
base substance BS may be a solvent. The additive substance AS may
be a solute that is dissolved in the solvent or may be particles
that are not melted in the solvent.
[0136] The base substance BS may be a substance capable of flowing
inside a matrix formed by the mesh structural body NS. The base
substance BS may be uniformly distributed in the mesh structural
body NS or may be distributed only in a partial region of the mesh
structural body NS. The base substance BS may be a liquid having a
single component.
[0137] The additive substance AS may be a substance that is mixed
with the base substance BS or dissolved in the base substance BS.
For example, the additive substance AS may serve as a solute while
the base substance BS is a solvent. The additive substance AS may
be uniformly distributed in the base substance BS.
[0138] The additive substance AS may be fine particles that are not
dissolved in the base substance BS. For example, the additive
substance AS may include colloidal molecules and fine particles
such as microorganisms.
[0139] The additive substance AS may include particles larger than
the micro-cavities formed by the mesh structural body NS. When the
size of the micro-cavities is smaller than the size of the
particles included in the additive substance AS, fluidity of the
additive substance AS may be limited.
[0140] According to an embodiment, the additive substance AS may
include a component that is selectively included in the patch
PA.
[0141] The additive substance AS does not necessarily refer to a
substance that is lower in quantity or inferior in function in
comparison to the above-described base substance BS.
[0142] Hereinafter, characteristics of the liquid substance SB
captured in the patch PA may be presumed as characteristics of the
patch PA. That is, the characteristics of the patch PA may depend
on characteristics of a substance captured in the patch PA.
1.2.2 Characteristics
[0143] As described above, the patch PA according to the present
application may include the mesh structural body NS. The patch PA
may manage the liquid substance SB through the mesh structural body
NS. The patch PA may allow the liquid substance SB captured in the
patch PA to maintain at least some of its unique
characteristics.
[0144] For example, diffusion of a substance may occur in a region
of the patch PA in which the liquid substance SB is distributed,
and a force such as surface tension may come into action.
[0145] The patch PA may provide a liquid environment in which
diffusion of a target substance is caused due to thermal motion of
a substance or a difference in density or concentration thereof.
Generally, "diffusion" refers to a phenomenon in which particles
that constitute a substance are spread from a side at which
concentration is high to a side at which a concentration is low due
to a difference in concentration. Such a diffusion phenomenon may
be basically understood as a phenomenon that occurs due to motion
of molecules (translational motion in a gas or liquid, vibrational
motion in a solid, and the like). In the present application, in
addition to referring to the phenomenon in which particles are
spread from a side at which a concentration is high toward a side
at which a concentration is low due to a difference in
concentration or density, "diffusion" also refers to a phenomenon
in which particles move due to irregular motion of molecules that
occurs even when a concentration is uniform. The expression
"irregular motion" may also have the same meaning as "diffusion"
unless particularly mentioned otherwise. The diffused substance may
be a solute that is dissolved in the liquid substance SB, and the
diffused substance may be provided in a solid, liquid, or gas
state.
[0146] More specifically, a non-uniformly-distributed substance in
the liquid substance SB captured by the patch PA may be diffused in
a space provided by the patch PA. In other words, the additive
substance AS may be diffused in a space defined by the patch
PA.
[0147] The non-uniformly-distributed substance or the additive
substance AS in the liquid substance SB managed by the patch PA may
be diffused within the micro-cavities provided by the mesh
structural body NS of the patch PA. A region in which the
non-uniformly-distributed substance or the additive substance AS
may be diffused may be changed by the patch PA being connected or
coming into contact with another substance.
[0148] Even when, after the concentration of the substance or the
additive substance AS has become uniform, as a result of diffusion
of the non-uniformly-distributed substance or the additive
substance AS within the patch PA or within an external region
connected to the patch PA, the substance or the additive substance
AS may continuously move due to irregular motion of molecules
inside the patch PA and/or within the external region connected to
the patch PA.
[0149] The patch PA may be implemented to exhibit a hydrophilic or
hydrophobic property. In other words, the mesh structural body NS
of the patch PA may have a hydrophilic or hydrophobic property.
[0150] When properties of the mesh structural body NS and the
liquid substance SB are similar, the mesh structural body NS may be
able to manage the liquid substance SB more effectively.
[0151] The base substance BS may be a polar hydrophilic substance
or a nonpolar hydrophobic substance. The additive substance AS may
exhibit a hydrophilic or hydrophobic property.
[0152] The properties of the liquid substance SB may be related to
the base substance BS and/or the additive substance AS. For
example, when both the base substance BS and the additive substance
AS are hydrophilic, the liquid substance SB may be hydrophilic, and
when both the base substance BS and the additive substance AS are
hydrophobic, the liquid substance SB may be hydrophobic. When
polarities of the base substance BS and the additive substance AS
are different, the liquid substance SB may be hydrophilic or
hydrophobic.
[0153] When polarities of both the mesh structural body NS and the
liquid substance SB are hydrophilic or hydrophobic, an attractive
force may come into action between the mesh structural body NS and
the liquid substance SB. When polarities of the mesh structural
body NS and the liquid substance SB are opposite, e.g., when the
polarity of the mesh structural body NS is hydrophobic and the
polarity of the liquid substance SB is hydrophilic, a repulsive
force may act between the mesh structural body NS and the liquid
substance SB.
[0154] On the basis of the above-described properties, the patch PA
may be solely used, a plurality of patches PA may be used, or the
patch PA may be used with another medium to induce a desired
reaction. Hereinafter, functional aspects of the patch PA will be
described.
[0155] However, hereinafter, for convenience of description, the
patch PA is assumed as being a gel type that may include a
hydrophilic solution. In other words, unless particularly mentioned
otherwise, the mesh structural body NS of the patch PA is assumed
to have a hydrophilic property.
[0156] However, the scope of the present application should not be
interpreted as being limited to the gel-type patch PA having a
hydrophilic property. In addition to a gel-type patch PA that
includes a solution exhibiting a hydrophobic property, a gel-type
patch PA from which a solvent is removed and even a sol-type patch
PA, as long as it is capable of implementing functions according to
the present application, may belong to the scope of the present
application.
2. Functions of Patch
[0157] Due to the above-described characteristics, the patch
according to the present application may have some useful
functions. In other words, by capturing the liquid substance SB,
the patch may become involved in behavior of the liquid substance
SB.
[0158] Accordingly, hereinafter, in accordance with forms of
behavior of the substance with respect to the patch PA, a reservoir
function in which a state of the substance is defined in a
predetermined region formed by the patch PA and a channeling
function in which a state of the substance is defined in a region
including an external region of the patch PA will be separately
described.
2.1 Reservoir
2.1.1 Meaning
[0159] As described above, the patch PA according to the present
application may capture the liquid substance SB. In other words,
the patch PA may perform a function as a reservoir.
[0160] The patch PA may capture the liquid substance SB in the
plurality of micro-cavities formed in the mesh structural body NS
using the mesh structural body NS. The liquid substance SB may
occupy at least a portion of the fine micro-cavities formed by the
three-dimensional mesh structural body NS of the patch PA or be
penetrated in the nano-sized pores formed in the mesh structural
body NS.
[0161] The liquid substance SB placed in the patch PA does not lose
properties of a liquid even when the liquid substance SB is
distributed in the plurality of micro-cavities. That is, the liquid
substance SB has fluidity even in the patch PA, and diffusion of a
substance may occur in the liquid substance SB distributed in the
patch PA, and an appropriate solute may be dissolved in the
substance.
[0162] The reservoir function of the patch PA will be described
below in more detail.
2.1.2 Containing
[0163] In the present application, the patch PA may capture a
target substance due to the above-described characteristics. The
patch PA may have resistance to a change in an external environment
within a predetermined range. In this way, the patch PA may
maintain a state in which the substance is captured therein. The
liquid substance SB, which is a target to be captured, may occupy
the three-dimensional mesh structural body NS.
[0164] Hereinafter, for convenience, the above-described function
of the patch PA will be referred to as "containing."
[0165] However, "the patch PA containing the liquid substance" is
defined to encompass a case in which the liquid substance is
contained in a space formed by the mesh structure and/or a case in
which the liquid substance is contained in the frame structural
body constituting the mesh structural body NS.
[0166] The patch PA may contain the liquid substance SB. For
example, the patch PA may contain the liquid substance SB, due to
an attractive force that acts between the mesh structural body NS
of the patch PA and the liquid substance SB. The liquid substance
SB may be bound to the mesh structural body NS with an attractive
force of a predetermined strength or higher and contained in the
patch PA.
[0167] Properties of the liquid substance SB contained in the patch
PA may be classified in accordance with properties of the patch PA.
More specifically, when the patch PA exhibits a hydrophilic
property, the patch PA may be bound to a hydrophilic liquid
substance SB which is polar in general and contain the hydrophilic
liquid substance SB in the three-dimensional micro-cavities.
Alternatively, when the patch PA exhibits a hydrophobic property,
the hydrophobic liquid substance SB may be contained in the
micro-cavities of the three-dimensional mesh structural body
NS.
[0168] The amount of substance that may be contained in the patch
PA may be proportional to a volume of the patch PA. In other words,
the amount of substance contained in the patch PA may be
proportional to an amount of three-dimensional mesh structural body
NS that serves as a support body that contributes to the form of
the patch PA. However, there is no constant proportional factor
between the amount of substance that may be contained in the patch
PA and the volume of the patch PA, and thus the relationship
between the amount of substance that may be contained in the patch
PA and the volume of the patch PA may be changed in accordance with
the design or manufacturing method of the mesh structure.
[0169] The amount of substance contained in the patch PA may be
reduced due to evaporation, loss, etc. with time. The substance may
be additionally injected into the patch PA to increase or maintain
the content of the substance contained in the patch PA. For
example, a moisture keeping agent for suppressing evaporation of
moisture may be added to the patch PA.
[0170] The patch PA may be implemented in a form in which it is
easy to store the liquid substance SB. This signifies that, when
the substance is affected by environmental factors such as humidity
level, amount of light, and temperature, the patch PA may be
implemented to minimize denaturalization of the substance. For
example, to prevent the patch PA from being denaturalized due to
external factors such as bacteria, the patch PA may be treated with
a bacteria inhibitor.
[0171] A liquid substance SB having a plurality of components may
be contained in the patch PA. In this case, the substance formed of
a plurality of components may be placed together in the patch PA
before a reference time point, or a primarily-injected substance
may be first contained in the patch PA and then a secondary
substance may be contained in the patch PA after a predetermined
amount of time. For example, when a liquid substance SB formed of
two components is contained in the patch PA, the two components may
be contained in the patch PA upon manufacturing the patch PA, only
one component may be contained in the patch PA upon manufacturing
the patch PA and the other component may be contained therein
later, or the two components may be sequentially contained in the
patch PA after the patch PA is manufactured.
[0172] As described above, the substance contained in the patch may
exhibit fluidity, and the substance may move irregularly or be
diffused due to molecular motion in the patch PA.
2.1.3 Providing of Reaction Space
[0173] FIGS. 3 and 4 are views illustrating providing a reaction
space as an example of a function of the patch according to the
present application.
[0174] As illustrated in FIGS. 3 and 4, the patch PA according to
the present application may perform a function of providing a
space. In other words, the patch PA may provide a space in which
the liquid substance SB may move through a space formed by the mesh
structural body NS and/or a space constituting the mesh structural
body NS.
[0175] The patch PA may provide a space for activity other than
diffusion of particles and/or irregular motion of particles
(hereinafter referred to as activity other than diffusion). The
activity other than diffusion may refer to a chemical reaction, but
is not limited thereto, and may also refer to a physical state
change. More specifically, the activity other than diffusion may
include a chemical reaction in which a chemical composition of the
substance changes after the activity, a specific binding reaction
between components included in the substance, homogenization of
solutes or particles included in the substance and non-uniformly
distributed therein, condensation of some components included in
the substance, or a biological activity of a portion of the
substance.
[0176] When a plurality of substances become involved in the
activity, the plurality of substances may be placed together in the
patch PA before a reference time point. The plurality of substances
may be sequentially inserted into the patch PA.
[0177] By changing environmental conditions of the patch PA,
efficiency of the function of providing a space for activities
other than diffusion in the patch PA may be enhanced. For example,
the activity may be promoted or a start of the activity may be
induced by changing a temperature condition of the patch PA or
adding an electrical condition thereto.
[0178] According to FIGS. 3 and 4, a first substance SB1 and a
second substance SB2 placed in the patch PA may react inside the
patch PA and be deformed into a third substance SB3 or generate the
third substance SB3.
2.2 Channel
2.2.1 Meaning
[0179] Movement of a substance may occur between the patch PA and
an external region. The substance may be moved from the patch PA to
the external region of the patch PA or may be moved from the
external region to the patch PA.
[0180] The patch PA may form a substance movement path or get
involved in movement of the substance. More specifically, the patch
PA may become involved in movement of the liquid substance SB
captured in the patch PA or become involved in movement of an
external substance through the liquid substance SB captured in the
patch PA. The base substance BS or the additive substance AS may
move out from the patch PA, or an external substance may be
introduced from an external region to the patch PA.
[0181] The patch PA may provide a substance movement path. That is,
the patch PA may become involved in movement of the substance and
provide a substance movement channel. The patch PA may provide a
substance movement channel based on unique properties of the liquid
substance SB.
[0182] In accordance with whether the patch PA is connected to the
external region, the patch PA may be in a state in which the liquid
substance SB is movable between the patch PA and the external
region or a state in which the liquid substance SB is immovable
between the patch PA and the external region. When channeling
between the patch PA and the external region begins, the patch PA
may have unique functions.
[0183] Hereinafter, the state in which the substance is movable and
the state in which the substance is immovable will be described
first, and the unique functions of the patch PA will be described
in detail in connection with whether the patch PA and the external
region are connected.
[0184] Basically, irregular motion and/or diffusion of the
substance are fundamental causes of movement of the liquid
substance SB between the patch PA and the external region. However,
controlling an external environmental factor (e.g., controlling a
temperature condition, controlling an electrical condition, or the
like) in order to control movement of a substance between the patch
PA and the external region has already been described.
2.2.2 Movable State
[0185] In the state in which the substance is movable, a flow may
occur between the liquid substance SB captured in the patch PA
and/or the substance placed in the external region. In the state in
which the substance is movable, substance movement may occur
between the liquid substance SB captured in the patch PA and the
external region.
[0186] For example, in the state in which the substance is movable,
the liquid substance SB or some components of the liquid substance
SB may be diffused to the external region or moved due to irregular
motion. Alternatively, in the state in which the substance is
movable, an external substance placed in the external region or
some components of the external substance may be diffused to the
liquid substance SB in the patch PA or moved due to irregular
motion.
[0187] The state in which the substance is movable may be caused by
contact. The contact may refer to connection between the liquid
substance SB captured in the patch PA and the external region.
Contact may refer to at least a partial overlap between a flow
region of the liquid substance SB and the external region. The
contact may refer to the external substance being connected to at
least a portion of the patch PA. It may be understood that the
range in which the captured liquid substance SB may flow is
expanded in the state in which the substance is movable. In other
words, in the state in which the substance is movable, the range in
which the liquid substance SB may flow may be expanded to include
at least a portion of the external region of the captured liquid
substance SB. For example, when the liquid substance SB is in
contact with the external region, the range in which the captured
liquid substance SB may flow may be expanded to include at least a
portion of the external region in contact. More specifically, when
the external region is an external plate, the region in which the
liquid substance SB may flow may be expanded to include a region of
the external plate in contact with the liquid substance SB.
2.2.3 Immovable State
[0188] In the state in which the substance is immovable, substance
movement may not occur between the liquid substance SB captured in
the patch PA and the external region. However, substance movement
may respectively occur in the liquid substance SB captured in the
patch PA and in external substance placed in the external
region.
[0189] The state in which the substance is immovable may be a state
in which the contact is released. In other words, in the state in
which contact between the patch PA and the external region is
released, substance movement is not possible between the liquid
substance SB remaining in the patch PA and the external region or
the external substance.
[0190] More specifically, the state in which the contact is
released may refer to a state in which the liquid substance SB
captured in the patch PA is not connected to the external region.
The state in which the contact is released may refer to a state in
which the liquid substance SB is not connected to an external
substance placed in the external region. For example, the state in
which movement of the substance is impossible may be caused by
separation between the patch PA and the external region.
[0191] In the present specification, although "movable state" has a
meaning differentiated from that of "immovable state," a transition
may occur between the states due to an elapse of time, an
environmental change, and the like. In other words, the patch PA
may be in the immovable state after being in the movable state, in
the movable state after being in the immovable state, or may be in
the movable state again, after being in the immovable state after
being in the movable state.
2.2.4 Differentiation of Functions
2.2.4.1 Delivery
[0192] In the present application, due to the above-described
characteristics, the patch PA may deliver at least a portion of the
liquid substance SB captured in the patch PA to a desired external
region. The delivery of the substance may refer to separation of a
portion of the liquid substance SB captured in the patch PA from
the patch PA due to a predetermined condition being satisfied. The
separation of the portion of the liquid substance SB may refer to
the portion of the substance being extracted, emitted, or released
from a region that is affected by the patch PA. This is a concept
subordinate to the above-described channeling function of the patch
PA, and may be understood as defining transfer (delivery) of the
substance placed in the patch PA to the outside of the patch
PA.
[0193] The desired external region may be another patch PA, a dried
region, or a liquid region.
[0194] The predetermined condition for the delivery to occur may be
set as an environmental condition such as a temperature change, a
pressure change, a change in an electrical characteristic, and a
change in a physical state. For example, when the patch PA is in
contact with an object whose force of binding to the liquid
substance SB is larger than a force of binding to the mesh
structural body NS of the patch PA, the liquid substance SB may be
chemically bound with the object in contact, and as a result, at
least a portion of the liquid substance SB may be provided to the
object.
[0195] Hereinafter, for convenience, the above-described function
of the patch PA will be referred to as "delivery."
[0196] The delivery may occur between the patch PA and the external
region, via the state in which the liquid substance SB is movable
and the state in which the liquid substance SB is immovable between
the patch PA and the external region.
[0197] More specifically, when the liquid substance SB is in the
movable state, the liquid substance SB may be diffused between the
patch PA and the external region or may be moved to the external
region due to irregular motion. In other words, the base solution
and/or the additive substance AS included in the liquid substance
SB may be moved from the patch PA to the external region. In the
state in which the liquid substance SB is immovable, the liquid
substance SB is unable to move between the patch PA and the
external region. In other words, due to a transition from the
movable state to the immovable state, a portion of the substance
that has moved from the patch PA to the external region due to
diffusion and/or irregular motion of the liquid substance SB become
unable to move back to the patch PA. Thus, a portion of the liquid
substance SB may be provided to the external region.
[0198] The delivery may be performed due to a difference between an
attractive force between the liquid substance SB and the mesh
structural body NS and an attractive force between the liquid
substance SB and the external region or the external substance. The
attractive force may be caused by similarity between polarities or
a specific binding relationship.
[0199] More specifically, when the liquid substance SB is
hydrophilic and the external region or the external substance is
more hydrophilic than the mesh structural body NS, at least a
portion of the liquid substance SB captured in the patch PA may be
provided to the external region via the movable state and the
immovable state.
[0200] The delivery of the liquid substance SB may also be
performed selectively. For example, when a specific binding
relationship exists between some components included in the liquid
substance SB and the external substance, some of the ingredients
may be selectively delivered via the state in which the substance
is movable and the state in which the substance is immovable.
[0201] More specifically, when it is assumed that the patch PA
provides a substance to an external plate PL, which is in a form of
a flat plate, a substance that binds specifically to a portion of
the liquid substance SB captured in the patch PA (e.g., a portion
of a solute) may be applied on the external plate PL. In this case,
the patch PA may selectively deliver a portion of the solute that
binds specifically to the substance applied on the external plate
PL from the patch PA to the plate PL via the movable state and the
immovable state.
[0202] The delivery as a function of the patch PA will be described
below according to a few examples of different regions to which the
substance is moved. However, in giving the detailed description,
the concepts of "release" of the liquid substance SB and "delivery"
of the liquid substance SB may be interchangeably used.
[0203] Here, a case in which the liquid substance SB is provided
from the patch PA to a separate external plate PL will be
described. For example, a case in which the substance is moved from
the patch PA to a plate PL, such as a slide glass, may be taken
into consideration.
[0204] As the patch PA and the plate PL come into contact, at least
a portion of the liquid substance SB captured in the patch PA is
diffused to the plate PL or moved due to irregular motion. When the
contact between the patch PA and the plate PL is released, the
portion of the substance that has been moved from the patch PA to
the plate PL (that is, the portion of the liquid substance SB)
become unable to move back to the patch PA. As a result, the
portion of the substance may be provided from the patch PA to the
plate PL. In this case, the portion of the substance being provided
may be the additive substance AS. For a substance in the patch PA
to be "provided" by the contact and separation, an attractive force
and/or binding force that acts between the substance and the plate
PL should be present, and the attractive force and/or the binding
force should be larger than the attractive force acting between the
substance and the patch PA. Therefore, if the above-described
"delivery condition" is not satisfied, delivery of a substance may
not occur between the patch PA and the plate PL.
[0205] The delivery of a substance may be controlled by providing a
temperature condition or an electrical condition to the patch
PA.
[0206] The movement of a substance from the patch PA to the plate
PL may depend on an extent of a contact area between the patch PA
and the plate PL. For example, the substance movement efficiency
between the patch PA and the plate PL may be increased or decreased
in accordance with an extent of an area in which the patch PA and
the plate PL come into contact.
[0207] When the patch PA includes a plurality of components, only
some of the components may be selectively moved to the external
plate PL. More specifically, a substance that binds specifically to
some of the plurality of components may be fixed to the external
plate PL. In this case, the substance fixed to the external plate
PL may be in a liquid or solid state, or may be fixed to a
different region. In this case, a portion of the substance of the
plurality of components moves to the plate PL and binds
specifically to the plate PL due to contact between the patch PA
and the different region, and when the patch PA is separated from
the plate PL, only some of the components may be selectively
released to the plate PL.
[0208] FIGS. 5 to 7 illustrate delivery of a substance from the
patch PA to the external plate PL as an example of delivery of a
substance from among the functions of the patch PA according to the
present application. According to FIGS. 5 to 7, by the patch PA
coming into contact with the external plate PL, a portion of a
substance contained in the patch PA may be provided to the plate
PL. In this case, providing of the substance may become possible by
the patch PA coming into contact with the plate so that the
substance is movable. In this case, a water film WF may be formed
in the vicinity of a contact surface at which the plate and the
patch PA come into contact, and the substance may be movable
through the formed water film WF.
[0209] Here, a case in which the liquid substance SB is provided
from the patch PA to a substance having fluidity SL will be
described. The substance having fluidity SL may be a liquid
substance that is held in other containing space or that is
flowing.
[0210] As the patch PA and the substance having fluidity come into
contact (for example, the patch PA is put into a solution), at
least a portion of the liquid substance SB captured in the patch PA
may be diffused or moved due to irregular motion to the substance
having fluidity SL. When the patch PA and the substance having
fluidity SL are separated, a portion of the liquid substance SB
that has been moved from the patch PA to the substance having
fluidity become unable to move back to the patch PA so that a
portion of the substance in the patch PA may be provided to the
substance having fluidity.
[0211] The substance movement between the patch PA and the
substance having fluidity SL may depend on an extent of a contact
area between the patch PA and the substance having fluidity SL. For
example, the substance movement efficiency between the patch PA and
the substance having fluidity SL may be increased or decreased in
accordance with an extent of an area at which the patch PA and the
substance having fluidity SL come into contact (for example, a
depth at which the patch PA is immersed into a solution or the
like).
[0212] The substance movement between the patch PA and the
substance having fluidity SL may be controlled through physical
separation between the patch PA and the substance having
fluidity.
[0213] A partial concentration of the additive substance AS in the
liquid substance SB and a partial concentration of the additive
substance AS in the substance having fluidity may be different, and
the additive substance AS may be provided from the patch PA to the
substance having fluidity.
[0214] However, in the patch PA providing the liquid substance SB
to the substance having fluidity SL, the physical separation
between the patch PA and the substance having fluidity SL is not
essential. For example, when a force (driving force/casual force)
that causes a substance to move from the patch PA to a liquid
having fluidity disappears or is decreased to a reference value or
lower, the movement of the substance may be stopped.
[0215] In "delivery" between the patch PA and the substance having
fluidity SL, the above-described "delivery condition" between the
patch PA and the substance having fluidity SL may not be required.
It may be understood that substances that have already moved to the
substance having fluidity SL are diffused and/or moved due to
irregular motion in the substance having fluidity SL, and the
substance has been provided to the substance having fluidity SL
when a distance between the moved substance and the patch PA become
larger a predetermined distance. Since, while in the case of the
plate PL, a movable range expanded due to the contact is extremely
limited, and thus the attractive force between the patch PA and the
substances that have moved to the plate PL may be significant, in
the relationship between the patch PA and the substance having
fluidity, a movable range expanded due to contact between the patch
PA and the plate PL is relatively much wider, and thus the
attractive force between the patch PA and the substances that have
moved to the substance having fluidity SL is insignificant.
[0216] FIGS. 8 to 10 illustrate delivery of a substance from the
patch PA to the substance having fluidity as an example of delivery
of a substance from among the functions of the patch PA according
to the present application. According to FIGS. 8 to 10, the patch
PA may deliver a portion of a substance contained in the patch PA
to an external substance having fluidity. The delivery of the
portion of the contained substance may be performed by the patch PA
being inserted into or coming into contact with the substance
having fluidity so that substance movement is possible between the
liquid substance SB captured in the patch PA and the substance
having fluidity.
[0217] Here, it is assumed that a substance is moved from the patch
PA to another patch PA. In a contact region in which the patch PA
and the other patch PA are in contact, at least a portion of the
liquid substance B provided in the patch PA may be moved to the
other patch PA.
[0218] In the contact region, the liquid substance SB provided in
each patch PA may be diffused and moved to the other patch PA. In
this case, due to the movement of the substance, a concentration of
the liquid substance SB provided in each patch PA may be changed.
Also in the present embodiment, as described above, the patch PA
and the other patch PA may be separated, and a portion of the
liquid substance SB in the patch PA may be provided to the other
patch PA.
[0219] The substance movement between the patch PA and the other
patch PA may be performed through a change in an environmental
condition including a change in a physical state.
[0220] The substance movement between the patch PA and another
patch PA may depend on an extent of a contact area between the
patch PA and the other patch PA. For example, the substance
movement efficiency between the patch PA and the other patch PA may
be increased or decreased in accordance with an extent of an area
where the patch PA comes into contact with the other patch PA.
[0221] FIGS. 11 to 13 illustrate delivery of a substance from a
patch PA1 to another patch PA2 as an example of delivery of a
substance among the functions of the patch PA according to the
present application. According to FIGS. 11 to 13, the patch PA1 may
deliver a portion of a substance contained in the patch PA1 to the
other patch PA2. The delivery of the portion of the substance may
be performed by the patch PA1 coming into contact with the other
patch PA2 and becoming a state in which a liquid substance SB
captured in the patch PA1 and a substance captured in the other
patch PA2 are exchangeable.
2.2.4.2 Absorption
[0222] Prior to description, it should be noted that, among the
functions of the patch PA according to the present application,
"absorption" may be managed similarly as the above-described
"delivery" in some embodiments. For example, in a case in which a
substance moves due to a concentration differences between
substances, the "absorption" may be similar to the "delivery" in
that a concentration of the liquid substance SB, particularly, a
concentration of the additive substance AS, may be changed to
control a direction in which the substance is moved. The
"absorption" may also be similar to "delivery" in terms of
controlling movement and selective absorption of a substance
through a release of physical contact with the patch PA, and this
may be clearly understood by those of ordinary skill in the art to
which the present application pertains.
[0223] Due to the above-described characteristics, the patch PA
according to the present application may capture an external
substance. The patch PA may pull in an external substance present
outside a region defined by the patch PA toward a region affected
by the patch PA. The pulled external substance may be captured
along with the liquid substance SB of the patch PA. The pulling of
the external substance may be caused by an attractive force between
the external substance and the liquid substance SB already captured
in the patch PA. Alternatively, the pulling of the external
substance may be caused by an attractive force between the external
substance and a region of the mesh structural body NS not occupied
by the liquid substance SB. The pulling of the external substance
may be caused by a force of surface tension.
[0224] Hereinafter, for convenience, the above-described function
of the patch PA will be referred to as "absorption." Absorption may
be understood as a concept subordinate to the above-described
channeling function of the patch PA, the concept defining movement
of an external substance to the patch PA.
[0225] The absorption may occur by the patch PA via a state in
which the substance is movable and a state in which the substance
is immovable.
[0226] A substance that is absorbable by the patch PA may be in a
liquid or solid state. For example, when the patch PA comes into
contact with an external substance including a solid state
substance, absorption of the substance may be performed due to an
attractive force between the solid state substance included in the
external substance and the liquid substance SB placed in the patch
PA. As another example, when the patch PA comes into contact with a
liquid external substance, the absorption may be performed due to
binding between the liquid external substance and the liquid
substance SB placed in the patch PA.
[0227] The external substance absorbed into the patch PA may be
moved to the inside of the patch PA through the micro-cavities of
the mesh structural body NS forming the patch PA or may be
distributed on a surface of the patch PA. Positions at which the
external substance is distributed may be set on the basis of a
molecular weight or a particle size of the external substance.
[0228] While the absorption is performed, the form of the patch PA
may be changed. For example, the volume, color, and the like of the
patch PA may be changed. While the absorption into the patch PA is
being performed, the absorption into the patch PA may be activated
or delayed by adding external conditions such as a temperature
change and a physical state change to an absorption environment of
the patch PA.
[0229] The absorption will be described below as a function of the
patch PA according to some examples of an external region that
provides a substance to be absorbed into the patch PA when the
absorption occurs.
[0230] Hereinafter, it will be assumed that the patch PA absorbs an
external substance from a external plate PL. An example of the
external plate may include a plate PL in which the external
substance may be placed while the external substance is not
absorbed thereinto.
[0231] A substance may be applied on the external plate PL.
Particularly, a substance may be applied in a form of powder on the
plate PL. The substance applied on the plate PL may be a single
component or a mixture of a plurality of components.
[0232] The plate PL may have the shape of a flat plate. The shape
of the plate PL may be deformed for improvement in ability to
contain the substance or the like. For example, a well may be
formed to improve the ability to contain the substance, a surface
of the plate PL may be deformed by engraving or embossing, or a
patterned plate PL may be used to improve contact with the patch
PA.
[0233] The absorption of a substance from the plate PL by the patch
PA according to the present application may be performed through
contact between the plate PL and the patch PA. In this case, in a
contact region in the vicinity of a contact surface between the
plate PL and the patch PA, a water film WF may be formed due to the
liquid substance SB captured in the patch PA and/or the substance
applied on the plate PL. When the water film (aquaplane,
hydroplane) WF is formed in the contact region, the substance
applied on the plate PL may be captured by the water film WF. The
substance captured in the water film WF may freely flow within the
patch PA.
[0234] When the patch PA is spaced a predetermined distance or more
apart and separated from the plate PL, the water film WF may be
moved along with the patch PA, and the substance applied on the
plate PL may be absorbed into the patch PA. The substance applied
on the plate PL may be absorbed into the patch PA as the patch PA
is separated a predetermined distance or more apart from the plate
PL. When the patch PA and the plate PL are spaced apart and
separated, the liquid substance SB provided to the patch PA may not
be moved to the plate PL, or only an insignificant amount thereof
may be absorbed into the patch PA.
[0235] A portion of or the entire substance applied on the plate PL
may react specifically with a portion of or the entire substance
captured in the patch PA. In this respect, absorption of a
substance from the plate PL by the patch PA may be selectively
performed. Particularly, the absorption may be performed
selectively when the patch PA has a stronger attractive force than
the plate PL with respect to a portion of the substance captured in
the patch PA.
[0236] As an example, a portion of the substance may be fixed to
the plate PL. In other words, a portion of the substance may be
fixed to the plate PL while another portion of the substance is
applied to have fluidity or not be fixed. In this case, when the
patch PA and the plate PL are brought into contact and separated,
the substance, excluding the portion of the substance fixed to the
plate PL of the substance applied on the plate PL, may be
selectively absorbed into the patch PA. Instead, the selective
absorption may also occur due to polarities of a substance placed
on the plate PL and a substance captured in the patch PA regardless
of whether the substance is fixed.
[0237] As another example, when the liquid substance SB captured in
the patch PA is bound specifically to at least a portion of a
substance applied on the plate PL, only the portion of the
substance applied on the plate PL bound specifically to the liquid
substance SB may be absorbed into the patch PA when the patch PA is
brought into contact with and then separated from the substance
applied on the plate PL.
[0238] As yet another example, a portion of the substance applied
on the plate PL may react specifically with a substance fixed to
the plate PL in advance. In this case, only a remaining substance,
excluding the substance that reacts specifically with the substance
fixed to the plate PL in advance of the substance being applied to
the plate PL, may be absorbed into the patch PA.
[0239] FIGS. 14 to 16 illustrate absorption of a substance from an
external plate PL by the patch PA as an example of absorption of a
substance from among the functions of the patch PA according to the
present application. According to FIGS. 14 to 16, the patch PA may
absorb a portion of a substance placed on the external plate PL
from the external plate PL. The absorption of the substance may be
performed by the patch PA coming into contact with the external
plate PL, the water film WF being formed in the vicinity of a
contact region between the external plate PL and the patch PA, and
the substance being movable to the patch PA through the water film
WF.
[0240] Here, it will be assumed that a substance is absorbed into
the patch PA from the substance having fluidity SL. The substance
having fluidity SL may refer to a liquid external substance that is
held in other containing space or that is flowing. More
specifically, by having an environment in which the substance
having fluidity SL and the liquid substance SB captured in the
patch PA may flow to and from each other, a portion of or the
entire substance having fluidity SL may be absorbed into the patch
PA. In this case, the environment in which the substance having
fluidity SL and the liquid substance SB may flow to and from each
other may be formed by the patch PA coming into contact with at
least a portion of the substance having fluidity SL.
[0241] When the patch PA comes into contact with the substance
having fluidity SL, the patch PA may be in a state in which a
substance is movable from the substance having fluidity SL. When
the patch PA is separated from the substance having fluidity SL, at
least a portion of the substance having fluidity SL may be absorbed
into the patch PA.
[0242] The absorption of a substance into the patch PA from the
substance having fluidity SL may depend on a concentration
difference between the substance captured in the patch PA and the
substance having fluidity SL. In other words, when the
concentration of the liquid substance SB captured in the patch PA
with respect to a predetermined additive substance AS is lower than
the concentration of the substance having fluidity SL with respect
to the predetermined additive substance AS, the predetermined
additive substance AS may be absorbed into the patch PA.
[0243] When a substance is absorbed into the patch PA from the
substance having fluidity SL, in addition to the absorption
depending on the concentration difference while the patch PA and
the substance having fluidity SL are in contact as described above,
the absorption into the patch PA may also be controlled by adding
an electrical factor or changing a physical condition. Further,
without direct contact between the substance captured in the patch
PA and a substance to be absorbed, the absorption of a substance
may also be performed through indirect contact therebetween via a
medium.
[0244] FIGS. 17 to 19 illustrate absorption of a substance from the
substance having fluidity SL by the patch PA as an example of
absorption of a substance from among the functions of the patch PA
according to the present application. According to FIGS. 17 to 19,
the patch PA may absorb a portion of the substance having fluidity
SL. The absorption of a substance may be performed by the patch PA
being immersed into the substance having fluidity SL or coming into
contact with the substance having fluidity SL so that the liquid
substance SB captured in the patch PA and the substance having
fluidity SL are movable to and from each other.
[0245] Here, it will be assumed that the patch PA absorbs an
external substance from another patch PA.
[0246] The absorption of an external substance from another patch
PA by the patch PA may be performed due to a difference in binding
force between the absorbed external substance and the substance
already captured in the patch PA and between the absorbed external
substance and the external substance not absorbed into the patch
PA. For example, when the absorbed substance exhibits hydrophilic
property, the patch PA exhibits hydrophilic property, and an
attractive force between the absorbed substance and the patch PA is
stronger than an attractive force between the other patch PA and
the absorbed substance (that is, when the patch PA is more
hydrophilic than the other patch PA), at least a portion of the
external substance may be absorbed into the patch PA when the patch
PA and the other patch PA are separated after being brought into
contact.
[0247] FIGS. 20 to 22 illustrate absorption of a substance from
another patch PA4 by a patch PA3 as an example of absorption of a
substance among the functions of the patch PA according to the
present application. According to FIGS. 20 to 22, the patch PA3 may
absorb a portion of a substance placed in the other patch PA4. The
absorption of the substance may be performed by the patch PA3
coming into contact with the other patch PA4 so that a liquid
substance SB captured in the patch PA3 and a liquid substance SB
captured in the other patch PA4 are exchangeable.
[0248] A binding force of the patch PA to the external substance
absorbed thereinto may be changed in accordance with a proportion
of a frame structural body of the three-dimensional mesh structural
body NS constituting the patch PA with respect to the total volume
of the patch PA. For example, as the proportion of a volume
occupied by the frame structural body in the entire patch PA
increases, the amount of substance captured in the structural body
may be reduced. In this case, a binding force between the patch PA
and a target substance may be reduced due to a reason such as
reduction in a contact area between the target substance and the
substance captured in the patch PA.
[0249] In relation to this, ratios of materials that constitutes
the mesh structural body NS may be adjusted during manufacturing
process of the patch PA so that polarity of the patch PA is
controlled. For example, in the case of a patch PA manufactured
using agarose, a concentration of the agarose may be controlled to
adjust a degree of the absorption.
[0250] When the certain region has a weaker binding force than the
patch PA with respect to a substance provided from the patch PA,
and the patch PA and another patch PA are brought into contact and
then separated, the absorbed external substance may be separated
from the other patch PA along with the patch PA.
2.2.4.3 Providing of Environment
[0251] Due to the above-described characteristics, the patch PA
according to the present application may perform a function of
adjusting an environmental condition of a desired region. The patch
PA may provide an environment due to the patch PA to the desired
region.
[0252] The environmental condition due to the patch PA may depend
on the liquid substance SB captured in the patch PA. The patch PA
may create a desired environment in a substance placed in an
external region on the basis of characteristics of a substance
accommodated in the patch PA or for a purpose of making the
environment correspond to characteristics of the substance
accommodated in the patch PA.
[0253] The adjustment of the environment may be understood as
changing an environmental condition of the desired region. The
changing of the environmental condition of the desired region may
be implemented in a form in which a region affected by the patch PA
is expanded to include at least a portion of the desired region or
a form in which an environment of the patch PA is shared with the
desired region.
[0254] Hereinafter, for convenience, the above-described function
of the patch PA will be referred to as "providing of an
environment."
[0255] The providing of an environment by the patch PA may be
performed in a state in which a substance is movable between the
patch PA and an external region subject to provide the environment.
The providing of an environment by the patch PA may be performed
through contact. For example, when the patch PA comes into contact
with a desired region (for example, an external substance, a plate
PL, or the like), a specific environment may be provided to the
desired region by the patch PA.
[0256] The patch PA may adjust an environment of a target region TA
by providing an environment with an appropriate pH, osmotic
pressure, humidity level, concentration, temperature, and the like.
For example, the patch PA may provide fluidity (liquidity) to the
target region TA or a target substance. Such providing of fluidity
may occur due to movement of a portion of a substance captured in
the patch PA. A moist environment may be provided to the target
region TA through the liquid substance SB or the base substance BS
captured in the patch PA.
[0257] The environmental factors provided by the patch PA may be
constantly maintained in accordance with a purpose. For example,
the patch PA may provide homeostasis to the desired region. As
another example, as a result of providing an environment, the
substance captured in the patch PA may be adapted to an
environmental condition of the desired region
[0258] The providing of an environment by the patch PA may result
from diffusion of the liquid substance SB included in the patch PA.
That is, when the patch PA and the desired region come into
contact, a substance may be movable through a contact region that
is formed due to contact between the patch PA and the desired
region. In relation to this, an environmental change due to an
osmotic pressure, an environmental change due to a change in ionic
concentration, providing of a moist environment, and a change in a
pH level may be implemented in accordance with a direction in which
the substance is diffused.
[0259] FIGS. 23 to 25 illustrate providing of a predetermined
environment to an external plate PL by the patch PA as an example
of providing of an environment among the functions of the patch PA
according to the present application. According to FIGS. 23 to 25,
the patch PA may provide a predetermined environment to an external
plate PL on which a fourth substance SB4 and a fifth substance SB5
are placed. For example, the patch PA may provide a predetermined
environment to the plate PL for the fourth substance SB4 and the
fifth substance SB5 to react and form a sixth substance SB6. The
providing of the environment may be performed by the patch PA
coming into contact with the plate PL so that a water film WF is
formed in the vicinity of a contact region and the fourth substance
SB4 and the fifth substance SB5 are captured in the water film
WF.
3. Application of Patch
[0260] The patch PA according to the present application may be
implemented to perform various functions by suitably applying the
above-described functions of the patch PA.
[0261] The technical spirit of the present application will be
described below by disclosing some embodiments. However, the
technical scope to which functions of the patch PA disclosed by the
present application are applied may be interpreted in a broad sense
within the scope that may be easily derived by those of ordinary
skill in the art, and the scope of the present application should
not be interpreted as being limited by the embodiments disclosed
herein.
3.1. In-Patch
[0262] The patch PA may provide a reaction region for a substance.
In other words, a reaction of a substance may occur in at least a
portion of a spatial region affected by the patch PA. In this case,
the reaction of a substance may be a reaction between liquid
substances SB captured in the patch PA and/or a reaction between
the captured liquid substance SB and a substance provided from the
outside of the patch PA. The providing of a reaction region for a
substance may activate or promote a reaction of a substance.
[0263] In this case, the liquid substance SB captured in the patch
PA may include at least one of a substance added upon manufacturing
the patch PA, a substance additive into the patch PA after the
manufacturing of the patch PA and contained in the patch PA, and a
substance temporarily captured in the patch PA. In other words,
regardless of a form in which a substance is captured in the patch
PA, any substance captured in the patch PA at a time point at which
a reaction in the patch PA is activated may react in the patch PA.
Further, a substance injected after the manufacturing of the patch
PA may also act as a reaction initiator.
[0264] The providing of a reaction region for a reaction related to
the liquid substance SB captured in the patch PA may be a concept
subordinate, in terms of embodiment, to the above-described Section
2.1.3 (that is, providing of reaction space). Alternatively, the
providing of a reaction region for a reaction related to the liquid
substance SB captured in the patch PA may consist of multiple
concepts that perform combined functions of the above-described
Section 2.1.3 and Section 2.2.4.2 (that is, absorption). The
providing of a reaction region for a reaction related to the liquid
substance SB captured in the patch PA is not limited thereto and
may be implemented in the form in which two or more functions are
combined.
3.1.1 First Embodiment
[0265] Hereinafter, description will be given by assuming that the
function of absorption into the patch PA and the function of
providing of a reaction space (hereinafter referred to as
"providing function") are performed by a single patch PA. In this
case, the absorption function and the providing function may be
simultaneously-performed functions, functions performed at
different time points, or functions sequentially performed to
perform another function. The patch PA further including other
functions in addition to the absorption and providing functions may
also be considered as belonging to the present embodiment.
[0266] As described above, the patch PA may perform a function of
capturing a substance, and the substance may have fluidity even
when the substance is captured. When some components of the liquid
substance SB are non-uniformly distributed, the non-uniform
components may be diffused. Even when components of the liquid
substance SB are uniformly distributed, the liquid substance SB may
have a predetermined level of mobility due to irregular motion of
particles. In this case, a reaction between substances, for
example, specific binding between substances, may occur inside the
patch PA.
[0267] For example, in the patch PA, in addition to a reaction
between captured substances, a reaction in a form in which a
substance having fluidity that is newly captured in the patch PA
and the substance that has been captured in the patch PA bind
specifically to each other may also be possible.
[0268] The reaction between the substance having fluidity and the
substance that has been captured in the patch PA may also occur
after the substance patch being separated from an space that has
been provided. For example, after the patch PA absorbs the
substance having fluidity from an arbitrary space, the patch PA may
be separated from the arbitrary space, and a reaction between the
absorbed substance and the substance that has been captured in the
patch PA may occur in the patch PA.
[0269] In addition, the patch PA may allow a reaction of a
substance captured therein to occur by performing the absorption
function with respect to a substance having fluidity. In other
words, the absorption of the substance having fluidity by the patch
PA may act as a trigger for a reaction between the absorbed
substance and the substance that has been captured in the patch PA.
The reaction may occur inside a space defined by the patch PA.
[0270] A composition of the liquid substance SB captured in the
patch PA may be changed due to the reaction occurring inside the
patch PA. When, particularly, a substance captured inside the patch
PA is a compound, a chemical composition thereof may be changed
before and after a reaction. Alternatively, a composition
distribution of a substance may be changed in accordance with a
position of the substance in the patch PA. For example, this may be
due to diffusion or particles having an attractive force specific
to another substance.
[0271] When the composition of the liquid substance SB is changed
due to a reaction inside the patch PA, a portion of the substance
may be absorbed into the patch PA due to a concentration difference
between the patch PA and a substance outside the patch PA (when a
substance in contact with the patch PA is present, the
corresponding substance), or the substance may be released from the
patch PA to the substance outside the patch PA.
3.1.2 Second Embodiment
[0272] Hereinafter, an embodiment in which the containing function
of the patch PA and the function of providing of a reaction space
for a substance are performed together for at least a predetermined
amount of time will be described. More specifically, the patch PA
may perform a function of providing a space for at least a portion
of the liquid substance SB contained in the patch PA to react.
[0273] The patch PA may contain a substance and provide a reaction
space for the contained substance. In this case, the reaction space
provided by the patch PA may be the micro-cavities formed by the
mesh structural body NS of the patch PA or a surface region of the
patch PA. Particularly, when a substance contained in the patch PA
and a substance applied on a surface of the patch PA react, the
reaction space may be the surface region of the patch PA.
[0274] The reaction space provided by the patch PA may serve to
provide a specific environmental condition. While a reaction occurs
in the liquid substance SB placed in the patch PA, an environmental
condition of the reaction may be adjusted by the patch PA. For
example, the patch PA may serve as a buffer solution.
[0275] By containing a substance through a mesh structure, the
patch PA does not require a container, separately. When the
reaction space of the patch PA is a surface of the patch PA, a
reaction may be easily observed through the surface of the patch
PA. For this, the shape of the patch PA may be deformed into a
shape that facilitates the observation.
[0276] The liquid substance SB contained in the patch PA may be
denaturalized or react with a different type of substance. The
composition of the liquid substance SB contained in the patch PA
may be changed with time.
[0277] The reaction may refer to a chemical reaction in which a
chemical formula is changed, a physical state change, or a
biological reaction. In this case, the liquid substance SB
contained in the patch PA may be a substance formed of a single
component or a mixture including a plurality of components.
3.2 Providing of Movement Path (Channeling)
[0278] Hereinafter, the patch PA that performs a function of
providing a substance movement path will be described. More
specifically, as described above, the patch PA may capture, absorb,
release, and/or contain a substance having fluidity. Various
embodiments of the patch PA that performs the function of providing
a substance movement path may be implemented by each of the
above-described functions of the patch PA or a combination thereof.
However, a few embodiments will be disclosed for a better
understanding.
3.2.1 Third Embodiment
[0279] The patch PA may be implemented to perform functions
described in Section 2.2.4.1 (that is, the section related to
delivery) and Section 2.2.4.2 (that is, the section related to
absorption) among the above-described functions of the patch PA. In
this case, the absorption function and the delivery function may be
provided together or sequentially provided.
[0280] The patch PA may perform the absorption and delivery
functions together to provide a substance movement path.
Particularly, the patch PA may absorb an external substance and
provide the absorbed external substance to an external region,
thereby providing a movement path to the external substance.
[0281] The providing of the movement path of the external substance
by the patch PA may be performed by absorbing the external
substance and releasing the external substance. More specifically,
the patch PA may come into contact with the external substance,
absorb the external substance, come into contact with the external
region, and deliver the external substance to the external region.
In this case, the capturing of the external substance and the
delivery of the captured external substance to the external region
by the patch PA may be performed through a process similar to those
of the above-described absorption and delivery.
[0282] The external substance absorbed into the patch PA and
provided may be in a liquid phase or a solid phase.
[0283] In this way, the patch PA may allow a portion of the
external substance to be provided to another external substance.
The external substance and the other external substance may
simultaneously come into contact with the patch PA. The external
substance and the other external substance may come into contact
with the patch PA at different time points.
[0284] The external substance and the other external substance may
come into contact with the patch PA at different time points. When
the external substances come into contact with the patch PA at
different time points, the external substance may come into contact
with the patch PA first, and after the external substance and the
patch PA are separated, the patch PA and the other external
substance may come into contact. In this case, the patch PA may
temporarily contain a substance captured from the external
substance.
[0285] The patch PA may simultaneously provide a substance movement
path and additionally provide a time delay. The patch PA may
perform a function of suitably adjusting an amount of substance
provided to another external substance and a speed of such
providing.
[0286] Such a series of processes may be carried out in one
direction with respect to the patch PA. As a specific example,
absorption of a substance may be performed through a surface of the
patch PA, an environment may be provided in an inner space of the
patch PA, and the substance may be released through another surface
facing the surface.
3.2.2 Fourth Embodiment
[0287] The patch PA may perform the absorbing and releasing of a
substance among the above-described functions of the patch PA and
the providing of a reaction space for the substance simultaneously.
In this case, the absorption and release of the substance and the
providing of the reaction space may be performed simultaneously or
sequentially.
[0288] According to an embodiment, in performing the processes of
absorbing and releasing an external substance, the patch PA may
provide a reaction space to the absorbed external substance for at
least a predetermined amount of time. The patch PA may provide a
specific environment for at least some time to the liquid substance
SB captured in the patch PA, including the absorbed external
substance.
[0289] The liquid substance SB that has been captured in the patch
PA and the external substance captured in the patch PA may react
inside the patch PA. The external substance absorbed into the patch
PA may be affected by an environment provided by the patch PA. The
substance released from the patch PA may include at least a portion
of a substance generated through the reaction. The external
substance may be released from the patch PA after the composition,
characteristics, and the like of the external substance are
changed.
[0290] The absorbed substance may be released from the patch PA.
The external substance being absorbed into the patch PA and being
released from the patch PA may be understood as the external
substance passing through the patch PA. The external substance that
has passed through the patch PA may lose integrity due to a
reaction inside the patch PA or an influence of an environment
provided by the patch PA.
[0291] The above-described processes of absorption of an external
substance, reaction of a substance, and providing of the substance
may be carried out in one direction. In other words, the absorption
of a substance may be performed at one position of the patch PA,
the providing of an environment may be performed at another
position of the patch PA, and the release of the substance may be
performed at yet another position of the patch PA.
[0292] FIGS. 26 to 28 illustrate providing of a substance movement
path between two plates PL as an embodiment of the patch PA
according to the present application. According to FIGS. 26 to 28,
the patch PA may provide a substance movement path between a plate
PL1 on which a seventh substance SB7 is applied and a plate PL2 on
which an eighth substance SB8 is applied. As a specific example,
when the seventh substance SB7 is capable of binding to the eighth
substance, and the eighth substance is fixed to the plate PL2, the
patch PA may come into contact with the plates PL1 and PL2 so that
the seventh substance SB7 is moved through the patch PA and bound
to the eighth substance SB8. The seventh substance SB7 and the
eighth substance SB8 may be connected to the patch PA through a
water film WF formed by the patch PA coming into contact with the
plates PL1 and PL2.
[0293] FIGS. 29 and 30 illustrate providing of a substance movement
path between two patches as an embodiment of the patch PA according
to the present application. According to FIGS. 29 and 30, a patch
PA6 configured to provide the movement path may be in contact with
a patch PA5 configured to contain a substance to be moved, and a
patch PA7 configured to receive the substance to be moved. The
patch PA6 configured to provide the movement path may come into
contact with the patch PA5 configured to contain the substance to
be moved and the patch PA7 configured to receive the substance to
be moved, and the substance to be moved may be moved to the patch
PA7 configured to receive the substance to be moved. The movement
of the substance between the patches may be performed by a water
film WF formed in the vicinity of a contact region between the
patches.
[0294] FIGS. 31 and 32 illustrate providing of a substance movement
path between two patches as an embodiment of the patch according to
the present application. According to FIGS. 29 and 30, a patch PA9
configured to provide the movement path may be in contact with a
patch PA8 configured to contain a ninth substance SB9 and a patch
PA10 configured to receive a substance. The patch PA9 providing the
movement path may come into contact with the patch PA8 configured
to contain the ninth substance SB9 to absorb the ninth substance
SB9. The absorbed ninth substance SB9 may react with a tenth
substance SB10 contained in the patch PA9, which is configured to
provide the movement path, and generate an eleventh substance. An
eleventh substance SB11 may be provided from the patch PA9
configured to provide the movement path to the patch PA10
configured to receive the substance. The movement of a substance
between the patches PA may be performed through a water film WF
formed in the vicinity of a contact region between the patches
PA.
3.3 Multi-Patch
[0295] A patch PA may be solely used, or a plurality of patches PA
may be used together. In this case, the plurality of patches PA
being able to be used together includes a case in which the
plurality of patches PA are sequentially used as well as a case in
which the plurality of patches PA are used simultaneously.
[0296] When the plurality of patches PA are used simultaneously,
the patches PA may perform different functions. Although each patch
PA of the plurality of patches PA may contain the same substance,
the plurality of patches PA may also contain different
substances.
[0297] When the plurality of patches PA are used simultaneously,
the patches PA may not come into contact with each other such that
substance movement does not occur between the patches PA, or a
desired function may be performed in a state in which substances
contained in the patches PA are exchangeable.
[0298] Although the plurality of patches PA used together may be
manufactured in shapes similar to each other or in the same size,
the plurality of patches PA may be used together even when the
plurality of patches PA have different shapes. Each patch PA
constituting the plurality of patches PA may be manufactured such
that densities of the mesh structural bodies NS are different or
components constituting the mesh structural bodies NS are
different.
3.3.1 Contact with Plurality of Patches
[0299] When a plurality of patches PA are used, the plurality of
patches PA may come into contact with a single target region TA.
The plurality of patches PA may come into contact with the single
target region TA and perform a desired function.
[0300] When a plurality of target regions TA are present, the
plurality of patches PA may come into contact with different target
regions TA. When the plurality of target regions TA are present,
the plurality of patches PA may respectively come into contact with
corresponding target regions TA and perform a desired function.
[0301] The plurality of patches PA may come into contact with a
substance applied on the target region TA. In this case, the
substance applied on the target region TA may be fixed or have
fluidity.
[0302] The desired function may be a function of providing or
absorbing the substance. However, each patch PA does not
necessarily provide the same substance or absorb the same
substance, and the patches PA may provide different substances to
the target region TA or absorb different components from a
substance placed in the target region TA.
[0303] The desired function may be different for each patch PA
constituting the plurality of patches PA. For example, one patch PA
may perform the function of providing a substance to the target
region TA, and another patch PA may perform the function of
absorbing the substance from the target region TA.
[0304] The plurality of patches PA may include different
substances, and the different substances may be provided to a
single target region TA and used to induce a desired reaction. When
a plurality of components of a substance is required for the
desired reaction to occur, the plurality of components may be
contained in a plurality of patches PA respectively and provided to
the target region TA. Such use of the plurality of patches PA may
be particularly useful when properties of substances required for a
desired reaction are lost or altered when the substances required
for the reaction being mixed for reasons such as being contained in
a single patch PA.
[0305] According to an embodiment, when the plurality of patches PA
include substances formed of different components, and the
substances formed of different components have different specific
binding relationships, the substances formed of different
components may be provided to the target region TA. The plurality
of patches PA may be used to detect a plurality of specific
bindings from the substances applied on the target region TA, by
providing the substances including different components.
[0306] According to another embodiment, the plurality of patches PA
may include substances formed of the same component, but each patch
PA may have a different concentration with respect to the substance
formed of the same component. The plurality of patches PA including
the substances formed of the same component may come into contact
with the target region TA and be used to determine an influence in
accordance with a concentration of the substance included in the
plurality of patches PA.
[0307] When the plurality of patches PA are used as described
above, the patches PA may be grouped into more efficient forms and
used. In other words, the configuration of the plurality of patches
PA being used may be changed every time the plurality of patches PA
are used. The plurality of patches PA may be manufactured in the
form of a cartridge and used. In this case, the form of each patch
PA being used may be suitably standardized and manufactured.
[0308] The plurality of patches PA in the form of a cartridge may
be suitable when patches PA configured to contain a plurality of
types of substances are manufactured to be used by being chosen as
necessary.
[0309] Particularly, when attempting to detect a specific reaction
of each substance from the target region TA using a plurality of
types of substances, a combination of specific reactions to be
detected may be changed every time the detection is performed.
[0310] FIG. 33 illustrates a case in which the plurality of patches
PA are used together as an embodiment of the patch PA according to
the present application. According to FIG. 33, the plurality of
patches PA according to an embodiment of the present application
may simultaneously come into contact with a target region TA placed
on a plate PL. The patches PA constituting the plurality of patches
PA may have a standardized form. The plurality of patches PA may
include a first patch and a second patch, and a substance contained
in the first patch may be different from a substance contained in
the second patch.
[0311] FIG. 34 illustrates a case in which the plurality of patches
PA are used and the plate PL includes a plurality of target regions
TA. According to FIG. 34, the plurality of patches PA according to
an embodiment of the present application may simultaneously come
into contact with the plurality of target regions TA placed on the
plate PL. The plurality of patches PA may include a first patch PA
and a second patch PA, the plurality of target regions TA may
include a first target region and a second target region, and the
first patch may come into contact with the first target region and
the second patch may come into contact with the second target
region.
3.3.2 Fifth Embodiment
[0312] The plurality of patches PA may perform a plurality of
functions. As described above, the patches PA may simultaneously
perform a plurality of functions, and the patches PA may also
simultaneously perform different functions. However, embodiments
are not limited to the above, and the functions may also be
combined and performed in the plurality of patches PA.
[0313] First, in the case in which the patches PA simultaneously
perform the plurality of functions, the patches PA may perform both
containing and release of a substance. For example, the patches PA
may contain different substances and release substances contained
in the target regions TA. In this case, the contained substances
may be simultaneously or sequentially released.
[0314] Next, in the case in which the patches PA simultaneously
perform different functions, the patches PA may separately perform
containing and release of a substance. In this case, only some of
the patches PA may come into contact with a target region TA and
release a substance to the target region TA.
3.3.3 Sixth Embodiment
[0315] When a plurality of patches PA are used, as described above,
the plurality of patches PA may perform a plurality of functions.
First, the patches PA may simultaneously perform containing,
releasing, and absorbing of substances. Alternatively, the patches
PA may also separately perform the containing, releasing, and
absorbing of the substances. However, embodiments are not limited
thereto, and the functions may also be combined and performed in
the plurality of patches PA.
[0316] For example, at least some of the plurality of patches PA
may contain a substance and release the contained substance to the
target region TA. In this case, at least a remainder of the
plurality of patches PA may absorb a substance from the target
region TA. Some of the plurality of patches PA may release a
substance that binds specifically to a substance placed in the
target region TA. In this case, specific binding may be detected by
absorption of a substance that has not formed specific binding from
the substance placed in the target region TA using another patch
PA.
3.3.4 Seventh Embodiment
[0317] When a plurality of patches PA are used, the patches PA may
simultaneously perform containing and release of a substance and
providing of an environment. Alternatively, the patches PA may
separately perform the containing and release of a substance and
providing of an environment. However, embodiments are not limited
thereto, and the functions may also be performed in combination in
the plurality of patches PA.
[0318] For example, a patch PA among the plurality of patches PA
may release a substance contained therein to the target region TA.
In this case, another patch PA may provide an environment to the
target region TA. Here, the providing of an environment may be
implemented in the form in which an environmental condition of a
substance contained in the other patch PA is provided to the target
region TA. More specifically, a reacting substance may be provided
to the target region TA by the patch PA, and the other patch PA may
come into contact with the target region TA and provide a buffering
environment.
[0319] As another example, the plurality of patches PA may be in
contact with each other. In this case, at least one patch PA may
contain a substance and release the substance contained therein to
another patch PA configured to provide an environment. In the
present embodiment, the patch PA configured to provide an
environment may release a substance, come into contact with at
least one other patch PA that is not in contact with the patch PA
configured to provide an environment, and absorb a substance from
the patch PA.
4. Tissue Diagnosis
[0320] The above-described patch according to the present
application may also be applied in performing diagnosis of a
tissue. Hereinafter, tissue diagnosis to which the patch of the
present application is applied will be described.
4.1 Introduction
4.1.1 Meaning
[0321] In the present application, tissue diagnosis may be defined
as a concept in which diagnosis, prediction, or management of an
illness or a disease is performed with a tissue as a sample to be
diagnosed that is differentiated from performing diagnosis with a
bodily fluid or cells as a sample.
[0322] In the narrow sense, "tissue" may refer to a tissue
collected from the human body. For example, "tissue" may refer to a
partial tissue, an epithelial tissue, or the like. In the broad
sense, "tissue" may refer to tissues collected from animals and
plants as well as the human body and may further include artificial
tissues. Hereinafter, it will be assumed that "tissue" refers to
the tissue in the narrow sense.
[0323] In applying the patch of the present application to
immunoassay, the above-described base substance and additive
substance may be properly changed in accordance with a site to
which the patch is applied.
4.1.2 Classification of Tissue Diagnosis
[0324] In the present application, tissue diagnosis may be
classified in accordance with a few standards.
[0325] Tissue diagnosis may be classified in accordance with
methods of manufacturing a sample or states of the sample. A sample
used in tissue diagnosis may be a microtome cut tissue filled with
paraffin or a frozen section of tissue.
[0326] Tissue diagnosis may be classified in accordance with a
target which is a standard of diagnosis (that is, a target
substance). In other words, tissue diagnosis may be differently
performed in accordance with a case in which it is desired to
detect a target base sequence (or, a target nucleic acid sequence)
and perform diagnosis, a case in which it is desired to detect a
target protein (in particular, an antigen) and perform diagnosis,
and a case in which it is desired to observe the morphology of
cells that constitute a tissue. The target substance may include a
target protein, a target base sequence, a DNA, and the like
included in a tissue sample.
[0327] Tissue diagnosis may be classified in accordance with a
method of obtaining a diagnosis result. The tissue diagnosis may be
performed including a method of acquiring an image or a method of
obtaining a quantitative measurement value of a target substance
included in a sample. The acquiring an image may refer to acquiring
an image acquired in a bright field or a method of acquiring a
fluorescence image.
4.1.3 Methods of Tissue Diagnosis
4.1.3.1 Immunological Diagnosis
[0328] Tissue diagnosis according to the present application may
refer to performing diagnosis by obtaining a distribution of target
proteins in a tissue sample SA. In this case, an immunological
method may be used. In other words, target proteins may be detected
by an antigen-antibody reaction, and a distribution of the target
proteins may be obtained.
[0329] The obtaining of the distribution of the target proteins may
be performed using antibodies that bind specifically to the target
proteins. In other words, the obtaining of the distribution of the
target proteins may be performed by detecting a product PD due to a
chemical reaction of a substrate catalyzed by enzymes attached to
the antibodies that bind specifically to the target proteins. The
obtaining of the distribution of the target proteins may be
performed using first antibodies that bind specifically to the
target proteins and second antibodies that bind specifically to the
first antibodies. In this case, labels that facilitate checking of
the distribution of the target proteins may have been attached to
the second antibodies.
[0330] Alternatively, the obtaining of the distribution of the
target proteins may be performed by detecting fluorescence emitted
from fluorophores attached to the antibodies that bind specifically
to the target proteins.
[0331] As an example of the above-described immunological tissue
diagnosis, whether cancer has developed may be checked by detecting
a specific protein, expression of which is increased or decreased
due to the development of cancer.
4.1.3.2 Morphological Diagnosis
[0332] Tissue diagnosis according to the present application may be
performed by observing the morphology or distribution of cells and
other substance that constitute a tissue sample SA. In this case, a
staining process that makes parts constituting a tissue to exhibit
color to facilitate performance of the morphological diagnosis may
be accompanied.
[0333] As an example of the morphological tissue diagnosis, the
morphology of cells that constitute a tissue sample SA may be
observed and the characteristic morphology of malignant cells may
be detected to determine a presence or type of tumor.
4.1.3.3 DNA Diagnosis
[0334] Tissue diagnosis according to the present application may be
performed in accordance with a constitution of DNA included in a
tissue sample SA. The tissue diagnosis may be performed by
detecting a specific base sequence from a tissue sample SA.
[0335] As an example of the DNA tissue diagnosis, a tumorigenic
gene (an oncogene) may be detected to predict the likelihood of
developing cancer. Also, the DNA tissue diagnosis may be used in
early detection of a genetic disease with likelihood of
development, prenatal testing, and the like.
4.2 Preparation for Tissue Diagnosis
[0336] Tissue diagnosis according to the present application may be
performed using the above-described patch PA with a tissue sample
SA as a target.
4.2.1 Preparation of Sample to be Diagnosed
[0337] In tissue diagnosis according to the present application,
diagnosis of a lesion may be performed for a tissue collected from
a human body. The tissue collected from the human body may have
been pre-processed to facilitate performance of diagnosis.
[0338] The tissue sample SA may be a microtome cut tissue sample SA
that has been filled with paraffin or a frozen section of tissue.
Gelatin may have been embedded in the tissue sample SA which is a
frozen section of tissue. However, this is merely an example, and a
medium other than paraffin, such as celloidin and carbowax, may
also have been embedded in the tissue sample SA.
[0339] The tissue sample SA may be collected from the human body
and provided after going through fixation, washing, dehydration,
cleaning, infiltration, embedding, and microtome cutting. The
provided tissue sample SA may be dried.
[0340] The tissue sample SA may be fixated by formaldehyde, ethyl
alcohol, acetone, and the like.
[0341] The tissue sample SA may be formed as a thin section of
tissue of 3 to 5 .mu.m. The microtome-cut sample SA may be
manufactured using a microtome such as a rotary microtome and a
freezing microtome.
[0342] The tissue sample SA according to the present application
may be placed on a plate PL. The tissue sample SA may be fixated on
the plate PL.
[0343] The plate PL may refer to a general slide glass or a solid
plate PL such as a plate PL manufactured with polystyrene,
polypropylene or the like. A form of a bottom or transparency of
the plate PL may be different in accordance with a detection means.
The plate PL may include a reaction region which comes into contact
with the patch PA or in which a desired reaction may occur.
[0344] The above-described plate, reaction region that may be
placed on the plate, and tissue sample that may be placed in the
reaction region may be interchangeably used in accordance with the
context. Particularly, it is defined that, as a subject that comes
into contact with the patch, the plate, the reaction region, and
the tissue sample may be substituted with each other.
[0345] The tissue sample SA may be a living body. However, in the
present application, unless particularly mentioned otherwise, it is
assumed that diagnosis is performed on a tissue sample SA provided
for histological analysis.
[0346] A method of performing diagnosis using a tissue sample SA
placed on a plate PL will be described below.
4.1.1 Preparation of Patch
[0347] Tissue diagnosis according to the present application may be
performed using the above-described patch PA.
[0348] The patch PA may contain a staining reagent for staining the
tissue sample SA. The patch PA may contain the staining reagent and
provide the staining reagent to the tissue sample SA. The staining
reagent may include hematoxylin for staining a nucleus of the
tissue or eosin for staining a cytoplasm. The staining reagent may
be an immunostaining reagent for labeling a specific protein by an
antigen-antibody reaction. The immunostaining reagent may include
an antibody to which a specific protein binds specifically.
[0349] The patch PA may contain a fluorescence reagent for
observing the tissue sample SA. The patch PA may contain the
fluorescence reagent and provide the fluorescence reagent to the
tissue sample SA. The fluorescence reagent may contain some
substance that label a target substance, label a target protein, or
label a target DNA. The patch PA may contain a labeling substance
such as a color labeling substance (e.g., hematoxylin) and a
fluorescence labeling substance (e.g., an antibody with a
fluorophore attached thereto).
[0350] The patches PA may be used separately or in combination in
accordance with methods of performing tissue diagnosis.
4.2 Performance of Tissue Diagnosis
[0351] Tissue diagnosis according to the present application may be
differently performed in accordance with detection patterns of
diagnosis results.
[0352] When it is desired to acquire a bright-field image,
diagnosis may be performed by staining (that is, color-labeling) of
some components of the tissue sample SA. When it is desired to
acquire a fluorescence image, diagnosis may be performed by
fluorescence-labeling of some components of the tissue sample
SA.
[0353] The diagnosis performed by staining of some components of
the tissue sample SA and the diagnosis performed by
fluorescence-labeling of components of the tissue sample SA will be
described below with reference to FIGS. 35 to 38.
[0354] Referring to FIG. 35, a tissue diagnosis method according to
an embodiment of the present application may include placing a
tissue sample SA in a reaction region (S200), providing
fluorescence labeling substance to the tissue sample SA (S300), and
detecting a fluorescence-labeled target substance TS (S400). The
tissue diagnosis method may include detecting the target substance
TS from the tissue sample SA by using a patch PA, which includes a
mesh structural body forming micro-cavities and is configured to
contain a substance in the micro-cavities.
[0355] In this case, the target substance TS may be a target base
sequence included in the tissue sample SA, the fluorescence
labeling substance may include a fluorescence-labeled nucleic acid
probe, and the nucleic acid probe may bind complementarily to the
target base sequence. Alternatively, the target substance TS may be
a fluorescence-labeled target protein, the fluorescence labeling
substance may include a fluorescence-labeled antibody, and the
antibody may bind specifically to the target protein.
[0356] The fluorescence labeling substance may be a fluorescence
labeling complex that includes a reaction derivative that reacts
specifically with the target substance TS and a fluorescence marker
for detecting the target substance TS.
[0357] In this case, the reaction derivative may refer to a part
that binds specifically to the target substance. For example, the
reaction derivative may include a probe that binds complementarily
to a target base sequence, an antibody that binds specifically to a
target protein, or the like.
[0358] Also, the fluorescence marker may refer to a portion
attached to the reaction derivative to induce a fluorescence
detection. For example, the fluorescence marker may include a
fluorophore attached to an antibody, and an enzyme that induces
fluorescence emission by a chemical reaction with a fluorophore,
which is attached to a probe, or a substrate.
[0359] The fluorescence-labeled probe may be a probe to which a
fluorophore capable of emitting fluorescence is attached. The
fluorescence-labeled probe may be a probe to which an enzyme that
reacts with a substrate and induces fluorescence emission is
attached.
[0360] The placing of the tissue sample SA in the reaction region
(S200) may include fixating the tissue sample SA on the reaction
region or the plate PL. The tissue sample SA may be a tissue sample
SA which is cut with a microtome after going through at least some
of fixation, washing, dehydration, cleaning, infiltration, and
embedding.
[0361] The providing of the fluorescence labeling substance to the
tissue sample SA (S300) may include providing the fluorescence
labeling substance to the tissue sample SA by using the patch PA
that contains the fluorescence labeling substance for specifically
labeling the target substance TS.
[0362] The detecting of the fluorescence-labeled target substance
TS (S400) may include detecting the fluorescence-labeled target
substance TS from the tissue sample SA.
[0363] The detecting of the fluorescence label may be performed by
acquiring a fluorescence image of the tissue sample SA. The
fluorescence image may refer to an image in which the fluorescence
labeled to the target substance is identifiably displayed.
[0364] The detecting of the fluorescence-labeled target substance
TS may be performed by measuring an amount of fluorescence emitted
from the target substance TS included in the tissue sample SA. The
detecting of the fluorescence-labeled target substance TS may
include obtaining information on distribution of the target
substance TS in the tissue sample SA.
[0365] The obtaining of the distribution of the target substance in
the tissue sample may include obtaining positions at which the
target substance is distributed, regions at which the target
substance is distributed, forms of the distribution, or an amount
of the distributed target substance.
[0366] Referring to FIG. 36, in the tissue diagnosis method
according to the present application, the providing of the
fluorescence labeling substance to the tissue sample SA (S300) may
include contacting the patch PA which contains the fluorescence
labeling substance with the tissue sample SA (S310) and separating
the patch PA which contains the fluorescence labeling substance
from the tissue sample SA (S330).
[0367] In the contacting of the patch PA which contains the
fluorescence labeling substance with the tissue sample SA (S310),
when the patch PA is in contact with the tissue sample SA, the
fluorescence labeling substance may be allowed to move to the
reaction region.
[0368] In the separating of the patch PA which contains the
fluorescence labeling substance from the tissue sample SA (S330),
when the patch PA is separated from the tissue sample SA, a
residual fluorescence labeling substance that has not bound to the
target substance TS of the fluorescence labeling substance may be
removed from the reaction region.
[0369] Referring to FIG. 37, the tissue diagnosis method according
to an embodiment of the present disclosure may include placing a
tissue sample SA in a reaction region (S500), providing a color
labeling substance to the tissue sample (S600), and detecting a
color-labeled target substance TS (S700). The tissue diagnosis
method may include detecting the target substance TS from the
tissue sample SA by using a patch PA, which includes a mesh
structural body forming micro-cavities and is configured to contain
a substance in the micro-cavities.
[0370] The color labeling substance may be a color labeling complex
that includes a reaction derivative that reacts specifically with
the target substance TS and a color marker for detecting the target
substance TS.
[0371] In this case, the reaction derivative may refer to a part
that binds specifically to the target substance. For example, the
reaction derivative may include a probe that binds complementarily
to a target base sequence, an antibody that binds specifically to a
target protein, or the like.
[0372] Also, the color marker may refer to a portion attached to
the reaction derivative to induce a color detection. For example,
the color marker may include an enzyme which is attached to an
antibody and induces fluorescence emission by a chemical reaction
with a substrate or the enzyme attached to a probe.
[0373] The target substance TS may be a target base sequence
included in the tissue sample SA, and the color labeling substance
may include a nucleic acid probe that binds complementarily to the
target base sequence. Alternatively, the target substance TS may be
a target protein included in the tissue sample SA, the color
labeling substances may include an antibody to which a marker which
induces color labeling is attached, and the antibody may bind
specifically to the target protein. The target protein included in
the tissue sample may be an antigen.
[0374] The placing of the tissue sample SA in the reaction region
(S500) may be performed similarly as in the above-described
embodiment.
[0375] The providing of the color labeling substance to the tissue
sample SA (S600) may include providing a staining substance to the
tissue sample SA by using a patch PA which contains the color
labeling substance for assigning color to the target substance TS.
The assigning of the color may refer to binding particles which
exhibit color to the target substance, infiltrating a substance
which exhibits color to the target substance, or the like.
[0376] The detecting of the color-assigned target substance TS
(S700) may be performed by acquiring an image of the tissue sample
SA. In this case, the image of the tissue sample SA may be an image
in which the color labeling is displayed.
[0377] Referring to FIG. 38, in the tissue diagnosis method
according to the present embodiment, the providing of the color
labeling substances to the tissue sample SA (S600) may include
contacting the patch PA which contains the color labeling
substances with the tissue sample SA (S610) and separating the
color labeling substances from the tissue sample SA (S630).
[0378] In the contacting of the patch PA which contains the color
labeling substances with the tissue sample SA (S610), when the
patch PA is in contact with the tissue sample SA, the color
labeling substances may be movable to the reaction region.
[0379] In the separating of the color labeling substances from the
tissue sample SA (S630), when the patch PA is separated from the
tissue sample SA, a residual color labeling substance that has not
reacted with the target substance TS of the color labeling
substances may be removed from the reaction region.
[0380] FIGS. 48 to 50 schematically illustrate the detecting of the
target substance TS included in the tissue sample SA by using the
patch PA, as an embodiment of the tissue diagnosis method according
to the present application. According to FIGS. 48 to 50, the tissue
sample SA may be placed on the plate PL, labeling substances LA may
be provided to the tissue sample SA, and the target substance TS
labeled by the labeling substances LA may be detected. The labeling
substances LA in the present embodiment may be a fluorescence
labeling substance or color labeling substance.
[0381] In this case, the providing of the labeling substances LA
may be performed using a patch PA that contains the labeling
substances LA.
[0382] The providing of the labeling substances LA may be performed
by contacting the patch PA which contains the labeling substances
LA with the tissue sample SA (or the reaction region) and then
separating the patch PA therefrom (S310, S330, S610, S630). By
contacting the patch PA which contains the labeling substances LA
with the tissue sample SA (S310, S610), a water film WF may be
formed in the vicinity of a contact portion. The labeling
substances LA may be allowed to move to the reaction region (or the
tissue sample SA) through the formed water film WF. The labeling
substances LA which have been allowed to move to the reaction
region may react specifically with or bind specifically to the
target substance TS included in the tissue sample SA or be attached
to the target substance TS.
[0383] By separating the patch PA from the plate PL or the tissue
sample SA (S330, S630), a labeling substance LA that has not
reacted with the target substance TS (that is, the residual
labeling substance) may be removed from the plate PL. When the
patch PA is separated from the plate PL, the water film WF which
has been formed may move along with the patch PA, and the residual
labeling substance may be captured in the water film WF and
absorbed into the patch PA. The residual labeling substance may be
removed from the plate PL when the patch PA is separated from the
plate PL. The residual labeling substance may include a residual
color labeling substance or a residual fluorescence labeling
substance.
[0384] The target substance TS included in the tissue sample SA may
be detected by detecting the labeling substances LA which have
reacted specifically with or bound specifically to the target
substance TS and are placed on the plate PL.
[0385] FIGS. 51 to 53 illustrate a case in which a probe PR is used
to detect a target base sequence TB included in a tissue sample SA,
as an embodiment of the tissue diagnosis method according to the
present application. Referring to FIGS. 51 to 53, a tissue sample
SA may be placed on the plate PL, a labeling probe PR having a
complementary relationship with the target base sequence TB may be
provided to the tissue sample SA, and the target base sequence TB
labeled by the labeling probe PR may be detected. In this case, the
providing of the labeling probe PR may be performed using a patch
PA that contains the labeling probe PR.
[0386] The providing of the labeling probe PR may be performed by
contacting the patch PA which contains the labeling probe PR with
the tissue sample SA and separating the patch PA therefrom (S310,
S330, S610, S630). By contacting the patch PA which contains the
labeling probe PR with the tissue sample SA (S310, S610), a water
film WF may be formed in the vicinity of a contact portion. The
labeling probe PR may become movable to the reaction region through
the formed water film WF. The labeling probe PR which has become
movable to the reaction region may bind complementarily to the
target base sequence TB included in the tissue sample SA.
[0387] By separating the patch PA from the plate PL or the tissue
sample SA (S330, S630), a labeling probe PR which has not bound to
the target base sequence TB (that is, residual labeling probe) may
be removed from the plate PL. When the patch PA is separated from
the plate PL, the water film WF, which has been formed, may move
along with the patch PA, and the residual labeling probe may be
captured in the water film WF and absorbed into the patch PA. The
residual labeling probe may be removed from the plate PL when the
patch PA is separated from the plate PL.
[0388] FIGS. 51 to 53 merely schematically illustrate the detection
of the target base sequence by using a labeling probe, and the
labeling probe may substantially infiltrate into cells of the
tissue sample SA and bind specifically to the target base sequence
TB.
[0389] FIGS. 54 to 58 schematically illustrate a case in which an
antibody AB is used to detect a target protein included in a tissue
sample SA, as an embodiment of the tissue diagnosis method
according to the present application. Referring to FIGS. 54 to 58,
a tissue sample SA may be placed on the plate PL, an antibody AB
may be provided to the tissue sample SA, and a target protein may
be detected from the tissue sample SA.
[0390] In this case, the providing of the antibody AB may be
performed using a patch PA that contains the antibody AB. Also, a
label for identification may be attached to the antibody AB.
[0391] The providing of the antibody AB may be performed by
contacting the patch PA which contains the antibody AB with the
tissue sample SA and separating the patch PA therefrom. By
contacting the patch PA which contains the antibody AB with the
tissue sample SA, a water film WF may be formed in the vicinity of
a contact portion. The antibody AB may become movable to the
reaction region through the formed water film WF. The antibody AB
which has become movable to the reaction region may bind
specifically to the target protein included in the tissue sample
SA.
[0392] By separating the patch PA from the plate PL or the tissue
sample SA, an antibody AB that has not bound to the target protein
(that is, residual antibody AB) may be removed from the plate PL.
When the patch PA is separated from the plate PL, the water film
WF, which has been formed, may move along with the patch PA, and
the residual antibody AB may be captured in the water film WF and
absorbed into the patch PA. The residual antibody AB may be removed
from the plate PL when the patch PA is separated from the plate
PL.
[0393] When, as described above, the antibody AB bind specifically
to the target protein and an identification label is attached to
the antibody AB itself, the identification label may be detected in
a state in which only the antibody AB is provided, and the target
protein may be detected. However, when an enzyme is attached to the
antibody AB, a patch PA that contains a substrate SU may be may be
separately provided and used. Providing the substrate SU to the
reaction region by using the patch PA which contains the substrate
SU may be similar to the above-described providing of the antibody
AB (see FIGS. 57 and 58).
[0394] Although a method of identifying a target protein using an
antibody by Direct Enzyme-Linked Immunosorbent Assay (ELISA) has
been described with respect to the present embodiment, a method
using Indirect ELISA may also be used. In this case, Indirect ELISA
refers to detecting a target substance using a first antibody that
binds specifically to the target substance and a second antibody
that has a property of binding specifically to the first antibody
and has an identification label attached thereto.
[0395] Hereinafter, a case in which diagnosis is performed by
staining a target substance to be detected TS included in a tissue
sample SA and a case in which diagnosis is performed by assigning
fluorescence to a target substance to be detected TS will be
separately reviewed. However, each diagnosis method is not
necessarily performed independently, and the two diagnosis methods
may also be performed together in a single diagnostic process. In
other words, the diagnostic methods disclosed herein are not
necessarily independent of each other or performed as separate
processes. For example, a bright-field image and a fluorescence
image of the same tissue sample SA may be obtained through a single
process. When a plurality of diagnostic methods are used in a
single diagnostic process, information acquired in accordance with
the diagnostic methods may be different.
4.2.1 Performance of Staining Diagnosis--Acquisition of
Bright-Field Image
[0396] Staining may be used to observe a tissue sample SA. Since
most elements that constitute a tissue do not exhibit color,
diagnosis may be performed by staining the tissue sample SA so that
components of a tissue are distinguishable and are easy to
observe.
[0397] The staining herein includes, in addition to using a
substance that exhibits color to stain a target substance TS so
that the target substance TS exhibits color, using a label capable
of generating a precipitation and locating a color label in the
target substance TS. Specifically, the staining of the tissue may
be performed using vital staining, staining using selective
dissolution, staining using a chemical color reaction, staining
using a metal infiltration technique, staining using a staining
reagent, or the like.
[0398] A few embodiments of a method of performing tissue diagnosis
by staining a portion of a tissue sample SA will be described
below.
[0399] Performing tissue diagnosis according to the present
application may include placing a tissue sample SA in a reaction
region, providing a staining substance to the tissue sample SA by
using a patch PA, and acquiring a bright-field image of the tissue
sample SA located in the reaction region.
[0400] The placing of the tissue sample SA in the reaction region
may include placing the tissue sample SA on the plate PL. The
placing of the tissue sample SA in the reaction region may include
fixating the tissue sample SA on the reaction region or the plate
PL. The fixating of the tissue sample SA may be performed by drying
the tissue sample SA.
[0401] The providing of the staining substance to the tissue sample
SA may include providing a staining substance for determining the
morphology of cells that constitute the tissue sample SA. The patch
PA may contain the staining substance for determining the
morphology of cells that constitute the tissue sample SA and
provide the staining substance to the sample SA or the reaction
region.
[0402] The staining substance for determining the morphology of
cells that constitute the tissue sample SA may be an ionic staining
substance. In other words, the staining substance may exhibit
acidity and assign color to a portion of the tissue sample SA that
exhibits basicity. Alternatively, the staining substance may
exhibit basicity and assign color to a portion of the tissue sample
SA that exhibits acidity.
[0403] The staining substance for determining the morphology of
cells that constitute the tissue sample SA may be an immunostaining
substance. The staining substance may include an antibody that
binds specifically to a target protein by an antigen-antibody
reaction. The antibody that binds specifically to the target
protein may indicate a region in which the target protein is
distributed. Therefore, morphological analysis on the tissue sample
SA may be performed by analyzing the region in which the target
protein is distributed.
[0404] The providing of the staining substance to the tissue sample
SA may include providing a staining substance for labeling the
target protein. The patch PA may contain the staining substance for
labeling the target protein and provid the staining substance to
the sample SA or the reaction region.
[0405] The staining substance for labeling the target protein may
be a staining substance that uses an antigen-antibody reaction. In
other words, the target protein may be an antigen related to a
specific disease, and the providing of the staining substance may
include providing an antibody, which binds specifically to the
antigen and has an enzyme attached thereto, and a substrate SU,
which is catalyzed by the enzyme and generates a precipitation
which exhibits color.
[0406] The staining substance for labeling the target protein may
induce a color reaction in a region in which the target protein is
located. In this case, the tissue diagnosis according to the
present embodiment may be performed by performing colorimetric
measurement according to the color reaction and obtaining
information on a presence of target proteins, distribution of
target proteins, and the like.
[0407] The providing of the staining substance to the tissue sample
SA may include providing a staining substance for labeling a target
base sequence. The patch PA may contain a staining substance for
labeling a DNA (or a specific base sequence) included in the tissue
sample SA and provide the staining substance to the tissue sample
SA or the reaction region.
[0408] In this case, the target base sequence to be detected may be
a target base sequence that causes a disease to be diagnosed.
[0409] The staining substance for labeling the target base sequence
may be for detecting the target base sequence by in situ
hybridization (IS H). The staining substance for labeling the
target sequence may use a nucleic acid probe to detect a target
base sequence. Specifically, the staining substance for labeling
the target base sequence may include a probe that binds
specifically (or complementarily) to the target base sequence and
generates a color precipitation substance. The detecting of the
target base sequence may be performed using chromogenic in situ
hybridization (CISH).
[0410] A diagnostic method for detecting a target base sequence may
be used to determine whether cancer (e.g., breast cancer) has
developed or whether a person is infected with human
papillomavirus.
[0411] The providing of the staining substance may be performed by
contacting a patch PA which contains the staining substance with
the reaction region (hereinafter, the reaction region is defined as
a concept that encompasses the sample SA and the reaction region)
and separating the patch PA from the reaction region. According to
a method of staining the tissue sample SA according to the present
application, in comparison to a conventional method in which
staining of a tissue is performed by applying a large amount of
staining reagent, a significantly smaller amount of staining
reagent is required in staining, and thus diagnosis may be more
economically performed.
[0412] In this case, the providing of the staining substance may be
performed by contacting the patch PA with the reaction region so
that the staining substance becomes movable to the reaction region,
and the staining substance binding to a staining target substance
TS included in the reaction region. In this case, when the patch PA
is separated from the reaction region, a staining substance that
has not bound to the staining target substance TS of the staining
substance that has moved to the reaction region may be absorbed
into the patch PA.
[0413] Specifically, the providing of the staining substance may be
performed by contacting the patch PA with the reaction region so
that, through a water film WF formed in the vicinity of a contact
region, the staining substance becomes movable to the reaction
region and binds to the staining target substance TS included in
the reaction region. In this case, when the patch PA is separated
from the reaction region, a staining substance that has not bound
to the staining target substance TS of the staining substance that
has moved to the reaction region may be captured in the water film
WF and absorbed into the patch PA.
[0414] When the staining substance is provided using the patch PA
as described above, just by separating the patch PA from the
reaction region, the staining substance that has not bound to the
staining target substance TS may be removed from the sample SA.
Therefore, when the tissue diagnosis method according to the
present application is used, an amount of consumed reagent may be
reduced and prompt diagnosis may be performed in comparison to a
conventional method in which a washing process has to be performed
using a separate washing solution to remove a substance that has
not bound specifically to a staining target substance TS (that is,
residual staining substance).
[0415] The acquiring of the bright-field image of the tissue sample
SA may include acquiring an image in which a target substance which
becomes a basis of the tissue diagnosis (that is, the staining
target substance TS) is stained, color-developed, or colored.
Alternatively, acquiring of the bright-field image may include
acquiring an image in which color particles are bound to the target
substance TS or a pigment is precipitated on the target substance
TS. The bright-field image may be an image in which some elements
which are a basis of the morphological analysis of cells that
constitute the tissue sample SA are stained or colored. The
bright-field image may be an image in which a target protein
included in the tissue sample SA is color-labeled. The bright-field
image may be an image in which a DNA or target base sequence
included in the tissue sample is color-labeled.
[0416] The acquiring of the bright-field image of the tissue sample
SA may be performed using bright field microscopy. The acquiring of
the bright-field image of the tissue sample SA may be performed
using a light microscope. The acquiring of the bright-field image
may include making light incident on one surface of a plate PL on
which the tissue sample SA is placed and recognizing the light
which has been incident and has passed through the tissue sample SA
to acquire the bright-field image. The acquiring of the
bright-field image of the tissue sample SA may be performed using
an imaging module such as a complementary metal-oxide semiconductor
(CMOS) image sensor and a charge coupled device (CCD) image sensor.
The acquiring of the bright-field image may include acquiring a
single image including an entire region of the tissue sample SA.
Alternatively, the acquiring of the bright-field image may include
acquiring a plurality of unit images by separately imaging a
plurality of unit regions of the tissue sample SA placed in the
reaction region and combining the plurality of acquired unit
images.
[0417] The tissue diagnosis according to the present embodiment may
further include analyzing the acquired bright-field image.
[0418] The analyzing of the acquired image may include performing
morphological analysis.
[0419] For example, the analyzing of the acquired image may be
performed to determine whether cancer has developed from the sample
SA. Specifically, a presence of an irregular morphology of a
nucleus may be determined from morphologies of nuclei included in
the tissue sample SA, an adhesiveness between cells may be
determined from a binding state between cells included in the
tissue sample SA, or whether the arrangement of cells included in
the tissue sample SA is uniform may be determined to determine
whether cancer has developed from the tissue sample SA. However,
the above subjects of determination are merely examples, and
various other morphological aspects may be applied to determine a
presence of tumor cells in the tissue sample SA.
[0420] For example, FIG. 42 schematically illustrates tumor cells
and normal cells in an embodiment of tissue diagnosis according to
the present application. Referring to FIG. 42, normal cells have
uniform morphology, have a large cytoplasm and a nucleus for each
cell, the nucleus has a nucleolus, and chromatins are densely
distributed in the nucleus. In contrast, tumor cells have irregular
morphology, have a small cytoplasm and multiple nuclei for each
cell, a plurality of nucleoli may be present in each nucleus, and
chromatins may be sparsely distributed in the nucleus. Using such
differences in morphological characteristics of tumor cells and
normal cells, the presence of tumor cells may be determined or a
distribution of tumor cells may be obtained from an image of a
tissue sample SA.
[0421] The analyzing of the acquired image may include obtaining a
distribution of a substance to be detected TS. For example, a
distribution of target proteins may be obtained. In other words, a
presence of a target antigen related to a disease to be diagnosed
or positions at which the antigen is distributed in the tissue
sample SA may be obtained. Alternatively, a distribution of a
target base sequence may be obtained. For example, whether a target
base sequence related to a disease to be diagnosed is included in
the tissue sample SA and a distribution of the target base sequence
in the tissue sample SA may be obtained from the tissue sample
SA.
[0422] The above-described image analysis may be performed by
artificial intelligence. In other words, the above-described
detection of a basis of diagnosis from an image or acquisition of a
diagnosis result by analyzing the image may be performed by
machine-learned artificial intelligence.
[0423] The acquired image is not only used in diagnosis of cancer
or tumor but may also be used in observing a cell organelle,
predicting a disease with likelihood of development, and managing a
disease that developed in the past.
[0424] The tissue diagnosis according to the present embodiment may
include measuring an amount of target substance TS included in the
tissue sample SA. The target substance TS may include a substance
such as a target protein and a target base sequence which is a
basis of diagnosis.
[0425] The measuring of the amount of target substance TS may be
performed by measuring an amount of stained target substance TS in
the tissue sample SA.
[0426] Alternatively, the measuring of the amount of the target
substance TS included in the tissue sample SA may be performed
using an electrochemical method. In other words, in the measuring
of the amount of target substance TS, the amount of substance
provided from the patch PA to the reaction region may vary in
accordance with the amount of target substance TS included in the
tissue sample SA, in providing of the staining substance to the
tissue sample SA or the reaction region by using the patch PA. In
this case, the measuring of the amount of target substance TS
included in the tissue sample SA may be performed by measuring a
change in an electrical characteristic of the patch PA or the plate
PL on which the reaction region is placed that occurs due to the
providing of substance from the patch PA to the reaction
region.
[0427] However, the obtaining of the amount of target substance TS
is not necessarily performed independently from the above-described
acquisition of the image of the tissue sample SA, and the acquiring
of the image to diagnose the sample SA and the measuring of the
amount of target substance TS included in the sample SA may also be
simultaneously performed.
4.2.2 Performance of Fluorescence Diagnosis--Acquisition of
Fluorescence Image
[0428] Performing tissue diagnosis according to the present
application may include placing a tissue sample SA in a reaction
region, providing a fluorescent substance to the tissue sample SA
by using a patch PA, and acquiring a fluorescence image of the
tissue sample SA placed in the reaction region.
[0429] The placing of the tissue sample SA in the reaction region
may include placing the tissue sample SA on a plate PL. The placing
of the tissue sample SA in the reaction region may include fixating
the tissue sample SA on the reaction region or the plate PL. The
fixating of the tissue sample SA may be performed by drying the
tissue sample SA.
[0430] The providing of the fluorescent substance to the tissue
sample SA by using the patch PA may include providing a fluorescent
substance for determining the morphology of cells that constitute
the tissue sample SA. The patch PA may contain a fluorescent
substance for determining the morphology of cells that constitute
the tissue sample SA and provide the fluorescent substance to the
sample SA or the reaction region.
[0431] The fluorescent substance for determining the morphology of
cells that constitute the tissue sample SA may be an immunological
fluorescent substance. The fluorescent substance may include an
antibody that binds specifically to a target protein by an
antigen-antibody reaction. The antibody which binds specifically to
the target protein may indicate a region in which the target
protein is distributed. The morphological analysis of the tissue
sample SA may be performed by analyzing the region in which the
target protein is distributed.
[0432] The providing of the fluorescent substance to the tissue
sample SA by using the patch PA may include providing the
fluorescent substance for detecting a target protein from the
tissue sample SA. The fluorescent substance may be a fluorescent
substance for labeling the target protein. The patch PA may contain
a fluorescent substance for labeling the target protein and provide
the fluorescent substance to the sample SA or the reaction
region.
[0433] The fluorescent substance for labeling the target protein
may be a fluorescent substance that uses an antigen-antibody
reaction. The target protein may be an antigen related to a
specific disease. The providing of the fluorescent substance may
include providing an antibody, which binds specifically to the
antigen and has an enzyme attached thereto, and a substrate SU,
which is catalyzed by the enzyme and generates a precipitation
which exhibits color.
[0434] The fluorescent substance for labeling the target protein
may induce a color reaction in a region in which the target protein
is located. In this case, the tissue diagnosis according to the
present embodiment may be performed by performing colorimetric
measurement according to the color reaction and obtaining
information on a presence of target proteins, distribution of
target proteins, and the like.
[0435] The providing of the fluorescent substance to the tissue
sample SA by using the patch PA may include providing a fluorescent
substance for detecting a DNA from the tissue sample SA. The
fluorescent substance may be a fluorescent substance for labeling a
DNA or a specific genetic sequence included in the tissue sample
SA. The patch PA may contain a fluorescent substance for labeling a
DNA (or a specific base sequence) included in the tissue sample SA
and provide the fluorescent substance to the tissue sample SA or
the reaction region.
[0436] The fluorescent substance may be a substance for labeling a
DNA included in the tissue sample SA. The fluorescent substance may
bind to a DNA included in the tissue sample SA and facilitate
obtaining of a distribution of DNA (that is, a distribution of
nuclei) and the morphology of nuclei from the tissue sample SA. The
fluorescent substance may be 4',6-diamidino-2-phenylindole
(DAPI).
[0437] The fluorescent substance for labeling the target base
sequence may be for detecting the target base sequence by in situ
hybridization. The fluorescent substance for labeling the target
sequence may use a nucleic acid probe to detect a target base
sequence. Specifically, the fluorescent substance for labeling the
target base sequence may include a probe that binds specifically
(or complementarily) to the target base sequence and generates a
color precipitation substance. The detecting of the target base
sequence may be performed using fluorescence in situ hybridization
(FISH).
[0438] The providing of the fluorescent substance to the reaction
region may be performed by contacting a patch PA which contains the
fluorescent substance with the reaction region and separating the
patch PA from the reaction region. According to a
fluorescence-labeling method according to the present application,
in comparison to a conventional method in which fluorescence
labeling is performed by applying a large amount of fluorescence
staining reagent, a significantly smaller amount of staining
reagent is required.
[0439] In this case, the providing of the fluorescent substance may
be performed by contacting the patch PA with the reaction region so
that the fluorescent substance becomes movable to the reaction
region, and the fluorescent substance binding to a labelling target
substance TS included in the reaction region. In this case, when
the patch PA is separated from the reaction region, a fluorescent
substance that has not bound to the labelling target substance TS
of the fluorescent substance that has moved to the reaction region
may be absorbed into the patch PA.
[0440] Specifically, the providing of the fluorescent substance may
be performed by contacting the patch PA with the reaction region so
that, through a water film WF formed in the vicinity of a contact
region, the fluorescent substance becomes movable to the reaction
region and binds to the labelling target substance TS included in
the reaction region. In this case, when the patch PA is separated
from the reaction region, a fluorescent substance that has not
bound to the labelling target substance TS of the fluorescent
substance that has moved to the reaction region may be captured in
the water film WF and absorbed into the patch PA.
[0441] A conventional method of labeling fluorescence to a sample
SA essentially requires a process in which a separate washing
solution is poured to rinse the sample SA in order to remove a
fluorescent substance that has not bound to a labelling target
substance TS from a sample SA. In contrast, when the fluorescent
substance is provided using the patch PA as in the present
application, the fluorescent substance that has not bound to the
labelling target substance TS may be removed from the sample SA
just by separating the patch PA from the reaction region.
Therefore, fluorescence may be labeled to a tissue sample SA by a
more economical and convenient procedure in comparison to the
conventional method.
[0442] The acquiring of the fluorescence image of the tissue sample
SA may include acquiring an image in which target substances TS,
which are bases of the tissue diagnosis, are fluorescence-labeled.
The fluorescence image may be an image in which some elements which
are a basis of the morphological analysis of cells that constitute
the tissue sample SA are fluorescence-labeled. The fluorescence
image may be an image in which a target protein included in the
tissue sample SA is fluorescence-labeled. The fluorescence image
may be an image in which a DNA or target base sequence included in
the tissue sample SA is fluorescence-labeled.
[0443] The acquiring of the fluorescence image of the tissue sample
SA may be performed using a fluorescent microscope. The acquiring
of the fluorescence image may include making light which is in a
specific wavelength band incident on the reaction region or the
tissue sample SA and detecting the light in the specific wavelength
band emitted from the reaction region or the tissue sample SA to
acquire the fluorescence image. In this case, a filter that allows
only light in a suitable wavelength band to pass therethrough may
be used. The detecting of the fluorescence may be performed by a
method in which light is made incident on the plate PL and
fluorescence emitted from the plate PL is measured.
[0444] The acquiring of the fluorescence image of the tissue sample
SA may be performed using an imaging module such as a CMOS image
sensor and a CCD image sensor. The acquiring of the fluorescence
image may include acquiring a single image including an entire
region of the tissue sample SA, or acquiring a plurality of unit
images for each unit region and combining the plurality of acquired
unit images.
[0445] In the measuring of the fluorescence, preferably, an opaque
black plate or an opaque white plate may be used as the plate PL
when measuring the fluorescence.
[0446] The tissue diagnosis according to the present embodiment may
further include analyzing the acquired fluorescence image.
[0447] The analyzing of the acquired image may include performing
morphological analysis.
[0448] For example, the analyzing of the acquired image may be
performed to determine whether cancer has developed from the sample
SA. Specifically, a presence of an irregular morphology of a
nucleus may be determined from morphologies of nuclei included in
the tissue sample SA, an adhesiveness between cells may be
determined from a binding state between cells included in the
tissue sample SA, or whether the arrangement of cells included in
the tissue sample SA is uniform may be determined to determine
whether cancer has developed from the tissue sample SA. However,
the above subjects of determination are merely examples, and
various other morphological aspects may be applied to determine a
presence of tumor cells in the tissue sample SA.
[0449] The determination of the presence of tumor cells may be
similar to that described above with reference to FIG. 42 in the
embodiment of staining diagnosis. In other words, as illustrated in
FIG. 42, using the differences between characteristics of normal
cells and tumor cells in terms of cytoplasm, nucleus, chromatin,
and the like, the presence of tumor cells may be determined or a
distribution of tumor cells may be obtained from an image of a
tissue sample SA.
[0450] The analyzing of the obtained image may include obtaining a
distribution of a target substance to be detected TS. For example,
a distribution of target proteins may be obtained. In other words,
a presence of a target antigen related to a disease to be diagnosed
or positions at which the antigen is distributed in the tissue
sample SA may be obtained. Alternatively, a distribution of a
target base sequence may be obtained. For example, whether a target
base sequence related to a disease to be diagnosed is included in
the tissue sample SA and a distribution of the target base sequence
in the tissue sample SA may be obtained from the tissue sample
SA.
[0451] The above-described image analysis may be performed by
artificial intelligence. In other words, the above-described
detection of a basis of diagnosis from an image or acquisition of a
diagnosis result by analyzing the image may be performed by
machine-learned artificial intelligence.
[0452] The acquired image is not only used in diagnosis of cancer
or tumor but may also be used in observing a cell organelle,
predicting a disease with likelihood of development, and managing a
disease that developed in the past.
[0453] The tissue diagnosis according to the present embodiment may
include measuring an amount of target substance TS included in the
tissue sample SA. The target substance TS may include a substance
such as a target protein and a target base sequence which is a
basis of diagnosis.
[0454] The measuring of the amount of target substance TS may be
performed by measuring an amount of fluorescence generated in
accordance with the amount of target substance TS. Alternatively,
the measuring of the amount of the target substance TS included in
the tissue sample SA may be performed using an electrochemical
method. In other words, in the measuring of the amount of target
substance TS, the amount of substance provided from the patch PA to
the reaction region may vary in accordance with the amount of
target substance TS included in the tissue sample SA in providing
of the staining substance or fluorescent substance to the tissue
sample SA or the reaction region by using the patch PA. In this
case, the measuring of the amount of target substance TS included
in the tissue sample SA may be performed by measuring a change in
an electrical characteristic of the patch PA or the plate PL on
which the reaction region is placed that occurs due to the
providing of substance from the patch PA to the reaction
region.
[0455] However, the measuring of the amount of target substance TS
included in the tissue sample SA is not necessarily performed
independently from the above-described acquisition of the
fluorescence image, and the acquiring of the image to diagnose the
sample SA and the measuring of the amount of target substance TS
included in the sample SA may also be simultaneously performed.
4.2.3 Image Acquisition for Multiple Targets
[0456] Hereinafter, a tissue diagnosis method for detecting a
plurality of target substances TS will be described with reference
to FIGS. 39 to 41.
[0457] Referring to FIG. 39, a tissue diagnosis method for
detecting a plurality of target substances TS, which is a tissue
diagnosis method according to an embodiment of the present
application, may include placing a tissue sample SA in a reaction
region (S20), providing a first fluorescent substance to the tissue
sample SA (S30), and providing a second fluorescent substance to
the tissue sample SA (S40).
[0458] The placing of the tissue sample SA in the reaction region
(S20) may be performed similarly as in the above-described
embodiments.
[0459] The providing of the first fluorescent substance to the
tissue sample SA (S30) may be performed using a patch PA that
contains a first fluorescence labeling substance for specifically
labeling a first target substance.
[0460] The providing of the second fluorescent substance to the
tissue sample SA (S40) may be performed using a patch PA that
contains a second fluorescence labeling substance for specifically
labeling a second target substance.
[0461] Referring to FIG. 40, the tissue diagnosis method for
detecting a plurality of target substances TS according to the
present embodiment may further include detecting a first target
substance TS and a second target substance TS (S50). The detecting
of the first target substance TS and the second target substance TS
(S50) may be performed after the providing of the second
fluorescence labeling substance to the tissue sample SA.
[0462] In this case, a wavelength band from which fluorescence
emitted from the first fluorescence labeling substance is detected
and a wavelength band from which fluorescence emitted from the
second fluorescence labeling substance is detected may be different
from each other, and the detecting of the first target substance TS
and the second target substance TS (S50) may include detecting the
first target substance TS and the second target substance TS which
are included in the tissue sample SA (S50).
[0463] Referring to FIG. 41, the tissue diagnosis method for
detecting a plurality of target substances TS according to the
present embodiment may include placing a tissue sample SA in a
reaction region (S20), providing a first fluorescent substance to
the tissue sample SA (S30), detecting a first target substance TS
(S51), providing a second fluorescent substance to the tissue
sample SA (S40), and detecting a second target substance TS
(S53).
[0464] The placing of the tissue sample SA in the reaction region
(S20), the providing of the first fluorescent substance to the
tissue sample SA (S30), and the providing of the second fluorescent
substance to the tissue sample SA (S40) may be similarly performed
as those in the above-described embodiments.
[0465] The detecting of the first target substance TS (SM) may be
performed after the providing of the first fluorescence labeling
substance to the tissue sample SA, and may include detecting the
first target substance TS included in the tissue sample SA by
detecting fluorescence emitted from the first fluorescence labeling
substance.
[0466] The detecting of the second target substance TS (S53) may be
performed after the providing of the second fluorescence labeling
substance to the tissue sample SA, and may include detecting the
second target substance TS included in the tissue sample SA by
detecting fluorescence emitted from the second fluorescence
labeling substance.
[0467] In this case, a wavelength band from which fluorescence
emitted from the first fluorescence labeling substance is detected
and a wavelength band from which fluorescence emitted from the
second fluorescence labeling substance is detected may at least
partially overlap each other, and the detecting of the fluorescence
emitted from the second fluorescence labeling substance may be
performed by comparing fluorescence detected from the tissue sample
SA after the second fluorescence labeling substance is provided to
the tissue sample SA and fluorescence detected from the tissue
sample SA before the second fluorescence labeling substance is
provided to the tissue sample SA.
[0468] The tissue diagnosis according to the present application
may be used to detect a plurality of targets. The tissue diagnosis
method for detecting a plurality of targets may be performed using
a plurality of patches PA.
[0469] A target to be detected may refer to a target substance TS
that becomes a basis of tissue diagnosis. For example, the target
may refer to a DNA included in the tissue sample SA, a specific
base sequence, a specific protein, a cellular component, or the
like. In the tissue diagnosis, a plurality of targets may be
detected through a single process. The single process may refer to
using a single plate PL. The single process may refer to using a
single sample SA.
[0470] In the tissue diagnosis according to the present
application, a plurality of targets may be detected from a process
of acquiring a single bright-field image. In other words, according
to the tissue diagnosis according to the present application, a
plurality of targets may be detected from a single bright-field
image. In this case, a single image may refer to an image of an
entire region of the tissue sample SA placed on the plate PL, or an
image formed by combining a plurality of unit images respectively
acquired for a plurality of unit regions included to the plate
PL.
[0471] The plurality of targets may be displayed in different
colors in the bright-field image. For example, a nucleus included
in the tissue sample SA may be displayed in blue color, and a
cytoplasm may be displayed in red color.
[0472] In the tissue diagnosis according to the present
application, a plurality of targets may be detected by a process of
acquiring a single fluorescence image. The plurality of targets may
be detected from a single fluorescence image. The plurality of
targets may be detected from a plurality of fluorescence images
acquired in a single process. Fluorescences detected from similar
wavelength bands may be labeled to the plurality of targets.
[0473] Fluorescences detected from different wavelength bands may
be labeled to the plurality of targets. For example, a nucleus
included in the tissue sample SA may be displayed with blue
fluorescence, and a microtubule may be displayed with green
fluorescence.
[0474] In the present embodiment, the plurality of targets may be a
plurality of target proteins. In other words, according to an
embodiment of the present application, a plurality of target
proteins may be detected by a process of acquiring a single
fluorescence image.
[0475] As an example of tissue diagnosis for detecting a plurality
of targets according to the present application, tissue diagnosis
in which a plurality of target proteins are detected using an
immunological method will be described below.
[0476] As an example of tissue diagnosis according to the present
application, a tissue diagnosis method for detecting a plurality of
target proteins may include fixating a sample SA on a plate PL,
providing multiple types of fluorescence labeling substances that
bind specifically to the plurality of target proteins to the plate
PL, and detecting the plurality of target proteins. In the present
embodiment, the fluorescence labeling substance may refer to an
antibody to which a fluorescence label is attached. The
fluorescence labeling substance may refer to an antibody to which
an enzyme, which reacts with a substrate SU and generates
fluorescence, is attached.
[0477] The fixating of the sample SA on the plate PL may be similar
as that in the above-described embodiments.
[0478] The providing of the multiple types of fluorescence labeling
substances that bind specifically to the plurality of target
proteins to the plate PL may include providing a first fluorescence
labeling substance and a second fluorescence labeling substance. In
other words, the plurality of target proteins may include a first
target protein and a second target protein, and the multiple types
of fluorescence labeling substances may include a first
fluorescence labeling substance that binds specifically to the
first target protein and a second fluorescence labeling substance
that binds specifically to the second target protein. In this case,
a wavelength band from which fluorescence emitted from the first
fluorescence labeling substance is detected and a wavelength band
from which the second fluorescence labeling substance is detected
may be different from each other.
[0479] The detecting of the plurality of targets may include
acquiring an image in which a region in which each target is
distributed in the tissue sample SA is displayed. Alternatively,
the detecting of the plurality of targets may include measuring an
amount of the plurality of targets included in the tissue sample
SA.
[0480] The detecting of the plurality of target proteins may
include acquiring a fluorescence image of the tissue sample SA. The
detecting of the plurality of target proteins may include
performing quantitative analysis on the plurality of target
proteins.
[0481] The above-described method of detecting the plurality of
target proteins may be performed using a plurality of patches PA.
For example, the plurality of patches PA may include a first patch
PA that contains the first fluorescence labeling substance and a
second patch PA that contains the second fluorescence labeling
substance.
[0482] Specifically, the method of detecting targets using the
plurality of patches PA may include fixating a sample SA on a plate
PL, providing a first fluorescence labeling substance which reacts
specifically with a first target protein to the plate PL by using
the first patch PA that contains the first fluorescence labeling
substance, and providing the second fluorescence labeling substance
which reacts specifically with a second target protein to the plate
PL by using the second patch PA that contains the second
fluorescence labeling substance. A wavelength band from which
fluorescence which labels the first fluorescence labeling substance
is detected and a wavelength band from which fluorescence which
labels the second fluorescence labeling substance is detected may
be different from each other.
[0483] According to an embodiment, the method of detecting targets
using the plurality of patches PA may include, after the providing
of the first fluorescence labeling substance to the plate PL or
before the providing of the second fluorescence labeling substance
to the plate PL, detecting the first target protein included in the
tissue sample SA. Also, the method of detecting targets using the
plurality of patches PA may include, after the providing of the
second fluorescence labeling substance to the plate PL, detecting
the second target protein included in the tissue sample SA. In
other words, the first target protein may be detected when the
first fluorescence labeling substance is provided to the plate PL,
and the second target protein may be detected when the second
fluorescence labeling substance is provided to the plate PL.
[0484] According to another embodiment, the method of detecting
targets using the plurality of patches PA may further include,
after the providing of the second fluorescence labeling substance
to the plate PL, detecting the first target protein and the second
target protein which are included in the tissue sample SA. In other
words, the first target protein and the second target protein may
be detected after the first fluorescence labeling substance and the
second fluorescence labeling substance are provided to the plate
PL.
[0485] When a plurality of target proteins are detected using a
plurality of patches PA as in the present embodiment, a wavelength
band from which fluorescence labeled to the first target protein is
detected and a wavelength band from which fluorescence labeled to
the second target protein is detected may be similar to each other.
In this case, while the first target protein is detected when the
first fluorescence labeling substance is provided to the plate PL
and the second target protein is detected when the second
fluorescence labeling substance is provided to the plate PL, the
detecting of the second target protein may be performed by
comparing fluorescence acquired upon the detection of the first
target protein and fluorescence obtained for the detection of the
second target protein.
[0486] FIGS. 43 and 44 schematically illustrate a part of a method
of detecting a plurality of target substances TS, as an example of
a tissue diagnosis method according to the present application.
Referring to FIGS. 43 and 44, the tissue diagnosis method according
to the present application may be used when it is desired to detect
a first target substance TS1 and a second target substance TS2
which are included in a tissue sample SA. Description with
reference to FIG. 41 will be given below.
[0487] A tissue diagnosis method of the present application may
include placing a sample SA in a reaction region (S20), providing a
first fluorescence labeling substance to the tissue sample SA
(S30), and detecting a first target substance TS1 (SM) (see FIG.
43). Also, after the detecting of the first target substance TS1
(S51), the tissue diagnosis method of the present application may
include providing a second fluorescence labeling substance to the
tissue sample SA (S40), and detecting a second target substance TS2
(S53) (see FIG. 44). In the present embodiment, when a wavelength
band from which first fluorescence emitted from the first target
substance TS, which is fluorescence-labeled by the first
fluorescence labeling substance, overlaps with a wavelength band
from which second fluorescence emitted from the second target
substance TS, which is fluorescence-labeled by the second
fluorescence labeling substance, during the detecting of the second
target substance TS2 (S53), differentiation between the second
target substance TS2 and the first target substance TS1 may be
difficult due to the fluorescence labeled to the first target
substance TS1. In this case, the detecting of the second target
substance TS may be performed by comparing fluorescence detected
from the tissue sample SA after the second fluorescence labeling
substance is provided to the tissue sample SA and fluorescence
detected from the tissue sample SA before the second fluorescence
labeling substance is provided to the tissue sample SA. For
example, when, as in FIGS. 43 and 44, the first target substance
TS1 is detected together with the second target substance TS2 upon
the detection of the second target substance TS2, the second target
substance TS2 may be detected by comparing fluorescence labels
detected before and after the providing of the second fluorescence
labeling substance to the plate PL. By detecting each of the first
target substance TS1 and the second target substance TS2 as
described above, a position at which each target substance TS is
distributed in the tissue sample SA and the amount of each target
substance TS included in the tissue sample SA may be obtained.
[0488] FIGS. 45 to 47 schematically illustrate a part of a method
of detecting a plurality of target substances TS, as another
example of the tissue diagnosis method according to the present
application. Referring to FIGS. 45 to 47, the tissue diagnosis
method according to the present application may be used when it is
desired to detect a third target substance TS3 and a fourth target
substance TS4 which are included in the tissue sample SA.
Description with reference to FIG. 41 will be given below.
[0489] A tissue diagnosis method of the present application may
include placing a sample SA in a reaction region (S20), providing a
first fluorescence labeling substance FL1 to the tissue sample SA
(S30), and detecting a third target substance TS3 (S51) (see FIG.
45). Also, after the detecting of the third target substance TS3
(S51), the tissue diagnosis method of the present application may
include providing a second fluorescence labeling substance FL2 to
the tissue sample SA (S40), and detecting a fourth target substance
TS4 (S53) (see FIG. 46). In the present embodiment, when a
wavelength band from which first fluorescence emitted from the
third target substance TS3, which is fluorescence-labeled by the
first fluorescence labeling substance FL1, overlaps with a
wavelength band from which second fluorescence emitted from the
fourth target substance TS4, which is fluorescence-labeled by the
second fluorescence labeling substance FL2, during the detecting of
the fourth target substance TS4 (S53), identification of the fourth
target substance TS4 may be difficult due to the fluorescence
labeled to the third target substance TS3. In this case, the
detecting of the fourth target substance TS4 may be performed by
comparing fluorescence detected from the tissue sample SA after the
second fluorescence labeling substance FL2 is provided to the
tissue sample SA and fluorescence detected from the tissue sample
SA before the second fluorescence labeling substance FL2 is
provided to the tissue sample SA. For example, when, as in FIGS. 45
and 46, the third target substance TS3 is detected together with
the fourth target substance TS4 upon the detection of the fourth
target substance TS4, the fourth target substance TS4 may be
detected by comparing fluorescence labels detected before and after
the providing of the second fluorescence labeling substance FL2 to
the plate PL (see FIG. 47). By detecting each of the third target
substance TS3 and the second target substance TS4 as described
above, a position at which each target substance TS is distributed
in the tissue sample SA and the amount of each target substance TS
included in the tissue sample SA may be obtained.
[0490] The tissue diagnosis method in which the plurality of target
substances TS are detected is not applicable only to the case in
which fluorescence labels are used as in the above-described
embodiments. The tissue diagnosis method in which the plurality of
target substances TS are detected may be widely applied to cases in
which identification labels for specifically identifying different
target substances TS are the same type of labels. In other words,
the method of detecting the plurality of target substances TS of
the present application may be applied to various cases in which a
first label which reacts specifically with a first target substance
TS and a second label which reacts specifically with a second
target substance TS generate similar signals.
4.3 Patches Used in Tissue Diagnosis
[0491] Embodiments of a patch PA that may be used in immunoassay
according to the present embodiment will be described below. Each
patch PA will be described as containing a few components, and each
component may be understood as the above-described base substance
or additive substance. However, the components described below as
being able to be contained in each patch PA may not be all
components contained in each patch PA, and each patch PA may also
contain other unspecified components.
[0492] According to an embodiment of the present application, a
patch PA may include a labeling substance for binding to a target
substance TS included in a tissue sample SA and a mesh structural
body which has a mesh structure forming micro-cavities in which the
labeling substance is contained that is configured to come into
contact with the tissue sample SA and provide the labeling
substance to a reaction region in which the target substance TS is
located. The labeling substance may be a fluorescence labeling
substance or color labeling substance (for example, staining
substance).
[0493] When tissue diagnosis is performed using the patch, applying
a large amount of reagent on a tissue sample to stain a tissue or
label some substances of the tissue in conventional biopsy methods
may be performed just by contacting a patch that contains a reagent
with a tissue and separating the patch therefrom, and in this way,
an amount of reagent being used may be saved.
[0494] When a reagent is provided using the patch, since, as
described above, a reagent that has not bound to a target substance
may easily be removed from a tissue in addition to being able to
perform diagnosis economically, accuracy of diagnosis may be
significantly improved. Also, by a method of applying a different
patch for each diagnosis, an effect of preventing
cross-contamination is also expected. Since the patch is easy to
keep in comparison to a liquid specimen, it may be easier to
prevent a specimen from being exposed to harmful substances.
4.3.1 Staining Patch (Hematoxylin&Eosin (H&E) Patch)
[0495] A staining patch PA which stains parts of a tissue sample SA
in various colors and intensities to facilitate observation of the
parts will be described below. The patch may contain a staining
substance and provide the staining substance to the tissue sample.
The staining substance may be a color labeling substance.
[0496] The staining substance contained in the staining patch PA
may be an additive substance contained in the patch PA. The patch
PA may contain a solution including the staining substance. Also,
in addition to the staining substance, the patch PA may contain a
separate base substance or additive substance that allows the
staining substance to easily bind to an object to be stained.
[0497] The patch PA according to the present application may
contain a staining substance that exhibits acidity or basicity. The
staining substance which exhibits acidity or basicity may
selectively bind to ionized parts present in the tissue sample SA
so that the parts exhibit color.
[0498] For example, for the patch PA according to the present
application, a method of staining the tissue sample SA by using
hematoxylin and eosin may be used. Tissue staining using
hematoxylin and eosin is one staining method that is widely used to
observe a tissue. For example, to diagnose cancer, a section of
tissue provided through pre-processing may be stained using
hematoxylin and eosin, and the morphology of the section of tissue
may be observed to determine whether cancer has developed.
[0499] The patch PA according to an embodiment of the present
application may contain a staining substance for staining a nucleus
included in the tissue sample SA. The patch PA may contain
hematoxylin and provide hematoxylin to the tissue sample SA.
Hematoxylin is a basic substance that binds to a basophilic (that
is, acidic or anionic) substance to stain the basophilic substance
blue, and may stain a basophilic DNA (or a nucleus including the
same) dark blue or violet. However, embodiments are not limited
thereto, and the patch PA for staining the nucleus according to the
present embodiment may also contain methylene blue, toluidine blue,
or the like and provide the same to the sample SA.
[0500] The patch PA according to another embodiment may contain a
staining substance for staining a cytoplasm included in the tissue
sample SA. The patch PA may contain eosin and provide eosin to the
tissue sample SA. Eosin may bind to an acidophilic (that is, basic
or cationic) substance to stain the acidophilic substance reddish.
Therefore, eosin may stain proteins, muscle cells, and the like
which exhibit basicity red or pink. Particularly, most cytoplasms
are basic, i.e., eosinophilic. However, the patch PA for staining
the cytoplasm may contain acid fuchsin, orange G, and the like
instead of eosin.
[0501] The patch PA according to yet another embodiment may also
contain a staining substance that exhibits neutrality. For example,
the patch PA may contain a staining substance that simultaneously
has a part exhibiting positivity and a part exhibiting negativity.
In this case, the part exhibiting positivity and the part
exhibiting negativity of the tissue sample SA may be stained to
exhibit different colors.
4.3.2 Antibody Patch
[0502] An antibody patch PA used in immunological tissue diagnosis
will be described below.
[0503] The antibody may be an additive substance contained in the
patch PA. The patch PA may contain a solution including the
antibody. Also, in addition to the antibody, the patch PA may
contain a separate base substance or additive substance that allows
the antibody to easily bind specifically.
[0504] The antibody used in the immunological tissue diagnosis of
the present application may be: 1) an antibody that has a property
of binding specifically to a target protein and has an
identification label attached thereto; or 2) a primary antibody
having a property of binding specifically to a target protein and a
secondary antibody having a property of binding specifically to the
primary antibody and having an identification label attached
thereto.
4.3.2.1 Immunostaining Patch
[0505] The patch PA according to the present application may
contain an immunostaining substance that facilitates observation of
parts of the tissue sample SA through an antigen-antibody reaction.
The patch PA may contain the immunostaining substance and provide
the immunostaining substance to the reaction region or the tissue
sample SA. The tissue diagnosis according to the present
application may include acquiring an image in which the target
protein is labeled from the tissue sample SA by using the
immunostaining patch PA.
[0506] The immunostaining substance may include an antibody that
binds specifically to a target protein by an antigen-antibody
reaction. The antibody that binds specifically to the target
protein may indicate a region in which the target protein is
distributed. The antibody may be a color labeling substance. The
antibody may have an enzyme attached thereto. The antibody having
the enzyme attached thereto may catalyze a chemical reaction of a
substrate SU. A product PD generated due to the chemical reaction
may color-label the target protein.
[0507] The target protein may be an antigen related to a specific
disease, and the providing of the staining substance may include
providing an antibody, which binds specifically to the antigen and
has an enzyme attached thereto, and a substrate SU, which is
catalyzed by the enzyme and generates a precipitation which
exhibits color. The immunostaining substance may induce a color
reaction in a region in which the target protein is located. In
other words, the patch PA which contains the immunostaining
substance may generate a precipitation which exhibits color in the
region in which the target protein is located or induce a color
reaction in the region to stain the region.
4.3.2.2 Immunofluorescence Patch/Immunochemical Fluorescence
Patch
[0508] The patch PA according to the present application may
contain a fluorescence labeling substance that allows fluorescence
to be detected from a target protein through an antigen-antibody
reaction, and provide the fluorescence labeling substance to the
tissue sample SA. The tissue diagnosis according to the present
application may include acquiring an image in which the target
protein is fluorescence-labeled from the tissue sample SA by using
the patch PA that contains the fluorescence labeling substance.
Alternatively, the tissue diagnosis may include measuring an amount
of fluorescence with which the target protein is labeled from the
tissue sample SA.
[0509] The fluorescence labeling substance may include, as the
antibody which binds specifically to the target protein, an
antibody to which a fluorescence label is attached. The antibody to
which the fluorescence label is attached may bind specifically to a
target protein to be detected. The fluorescence labeling substance
may include, as the antibody which binds specifically to the target
protein, an antibody to which an enzyme for emitting fluorescence
through a reaction of a substrate SU is attached.
[0510] In this case, in the present embodiment, for the
fluorescence emission, a substrate patch that contains a substrate
SU for forming fluorescence by a chemical reaction catalyzed by the
enzyme attached to the antibody may be provided.
4.3.3 ISH Patch
[0511] An ISH patch PA that includes a probe which binds
specifically to a target base sequence and is used in detecting the
target base sequence will be described below. The tissue diagnosis
according to the present application may include acquiring an image
in which a distribution of the target base sequence is labeled from
the tissue sample SA by using the ISH patch PA.
[0512] The probe may be an additive substance contained in the
patch PA. The patch PA may contain a solution including the probe.
Also, in addition to the probe, the patch PA may contain a separate
base substance or additive substance that allows the probe to
easily bind specifically.
4.3.3.1 FISH Patch
[0513] The patch PA according to the present application may
contain a fluorescence labeling substance for labeling a target
base sequence and provide the fluorescence labeling substance to
the tissue sample SA. The tissue diagnosis according to the present
application may include acquiring an image in which the target base
sequence is fluorescence-labeled from the tissue sample SA by using
the patch PA that contains the fluorescence labeling substance for
labeling the target base sequence. Alternatively, the tissue
diagnosis may include measuring an amount of fluorescence labeled
to the target base sequence from the tissue sample SA.
[0514] The fluorescence labeling substance according to the present
embodiment may be a probe that binds specifically to the target
base sequence. The fluorescence labeling substance may include, as
the probe that binds specifically to the target base sequence, a
probe to which a fluorescence label is attached. The fluorescence
labeling substance may include, as the probe that binds
specifically to the target base sequence, a probe to which an
enzyme for emitting fluorescence through a reaction of a substrate
SU is attached.
[0515] In this case, in the present embodiment, for the
fluorescence emission, a substrate SU patch PA that contains a
substrate SU for forming fluorescence by a chemical reaction
catalyzed by the enzyme attached to the probe may be separately
provided.
4.3.3.2 CISH Patch
[0516] The patch PA according to the present application may
contain a staining substance for labeling a target base sequence
and provide the staining substance to the tissue sample SA. The
tissue diagnosis according to the present application may include
acquiring an image in which the target base sequence is labeled
from the tissue sample SA by using the patch PA that contains the
staining substance for labeling the target base sequence.
[0517] The staining substance according to the present embodiment
may include a probe that binds specifically to the target base
sequence. The staining substance may include, as the probe that
binds specifically to the target base sequence, a probe to which a
color substance is attached.
4.3.4 DAPI Staining Patch
[0518] The patch PA according to the present application may
contain a fluorescence labeling substance for labeling a DNA and
provide the fluorescence labeling substance to the tissue sample
SA. The tissue diagnosis according to the present application may
include obtaining the morphology and distribution of DNA included
in the tissue sample SA by using the patch PA that contains the
fluorescence labeling substance for labeling the DNA.
[0519] The fluorescence labeling substance according to the present
embodiment may include a DAPI reagent that infiltrates into the
DNA. The patch PA may provide the fluorescence labeling substance
including the DAPI to the tissue sample SA, and the distribution of
DNA included in the tissue sample SA to which the DAPI is provided
may be obtained by detecting blue fluorescence. Therefore, the
distribution or morphology of a nucleus included in the tissue
sample SA may be obtained by detecting blue fluorescence.
[0520] The identification of nucleus by DAPI may be solely used or
used together with other techniques in observing the tissue sample
SA. For example, when it is desired to observe an endothelial
tissue, in addition to the patch PA that contains DAPI, a separate
patch PA that contains an isothiocyanate derivative (TRITC) that
labels a microfiber with red fluorescence, a fluorescein
isothiocyanate (FITC) that labels a microtubule with green
fluorescence, or the like may be used to label multiple parts
included in the tissue sample SA and observe the parts.
[0521] The DAPI may be an additive substance contained in the patch
PA. In addition to the DAPI, the patch PA may contain a separate
base substance or additive substance that allows the DAPI to easily
infiltrate into the DNA.
[0522] As the DAPI reagent is contained in the patch according to
the present application and provided to a tissue, only an optimal
amount of reagent required for staining a nucleus may be provided
to a reaction region, and residual DAPI that has not bound to a
nucleus may be re-absorbed into the patch just by separating the
patch from the tissue. This may allow a fluorescence process to be
more conveniently and promptly performed.
4.3.5 Buffer Patch
[0523] The patch PA of the present application may contain a
substance that facilitates performance of the tissue diagnosis,
come into contact with a reaction space, and provide a
predetermined environment to the reaction space or the tissue
sample SA.
[0524] The patch PA according to an embodiment of the present
application may contain a buffer solution that allows a staining
substance to easily bind to a staining target substance TS and
provide an environment that facilitates the binding to the reaction
region.
[0525] For example, according to an embodiment of the present
application, the patch PA may contain a buffer solution at a pH of
7.0, and provide an environment suitable for binding between a DAPI
stain and a DNA included in the sample SA. The providing of the
environment to the reaction region may be performed by contacting
the patch PA with the reaction region. Since the DAPI stain is
sensitive to light. The patch PA may have a light shielding
function.
4.3.6 Washing Patch
[0526] The tissue diagnosis according to the present application
may be performed using a washing patch PA that absorbs a residue.
In other words, the tissue diagnosis method according to the
present embodiment may include absorbing a residue by contacting
the washing patch with the plate PL and separating the washing
patch from the plate PL. The residue may include a fluorescence
labeling substance (e.g., an antibody) that has not bound to a
target protein.
[0527] The washing patch may contain a washing solution. The
washing solution may include a tris buffered saline (TBS) or
phosphate buffered saline (PBS) with Tween 20. In accordance with a
residue to be absorbed, the washing solution may be provided as a
solution in which the residue may be dissolved.
[0528] According to the present embodiment, a washing patch may
allow residual substance that is nonspecifically placed on the
plate PL to be easily removed. Accordingly, in comparison to a
conventional method which essentially requires, before and after
applying each reagent used in detecting a specific reaction, a
process in which a large amount of washing solution is sprayed onto
the plate PL to wash off residual substance, a more precise
detection result may be derived.
[0529] In addition to the washing solution, the washing patch may
contain a separate base substance or additive substance that
improves the washing efficiency.
[0530] FIGS. 59 to 61 briefly illustrate removing a residue from a
reaction region using the washing patch PA, as an embodiment of a
tissue diagnosis method according to the present application. Here,
the residue may refer to a substance that has not participated in a
reaction for detecting a target substance TS. The residue may be
residual substance (e.g., residual labeling substance) that has not
participated in a specific reaction for detecting the target
substance TS.
[0531] Referring to FIGS. 59 to 61, the washing patch PA may absorb
a residue from the plate PL. According to the present embodiment,
by contacting the washing patch PA with the tissue sample SA and
separating the washing patch PA from the tissue sample SA, the
residue may be removed from the reaction region. When the washing
patch PA is in contact with the tissue sample SA, a water film WF
may be formed in the vicinity of a contact region, and the residue
may be dissolved in the water film WF. When the washing patch PA is
separated from the tissue sample SA, the water film WF may move
along with the patch PA, and an antibody AB2, which is the residue,
may be captured in the water film WF and absorbed into the patch
PA. In this case, an antibody AB1, which has bound to a target
protein TP, may not be absorbed into the patch.
[0532] Although an antibody that has not bound to a target protein
has been given as an example of a residue in the present
embodiment, the residue is not limited thereto. The residue may
include a probe that has not bound to a target base sequence, a
staining substance that has not bound to a target substance TS, and
the like.
[0533] By performing washing of a reaction region using the washing
patch as described above, a washing process used in conventional
tissue diagnosis may be replaced. Conventionally, applying a large
amount of washing solution on a sample to wash off a residue is
essentially required to perform washing, and the large amount of
washing solution is consumed in this process. When washing of a
tissue is performed using the washing patch according to the
present application instead of the above-described conventional
method, an amount of washing solution being used may be
significantly saved.
4.3.7 Plurality of Patches
[0534] The tissue diagnosis according to the present application
may be performed using a plurality of patches PA.
[0535] The tissue diagnosis using the plurality of patches may be
used to detect a plurality of target substances. For example, when
detecting a plurality of target proteins, a plurality of patches PA
may be used.
[0536] The plurality of target proteins may include a first target
substance TS and a second target substance TS, and the plurality of
patches PA may include a first patch PA that contains a first
labeling substance and a second patch PA that contains a second
labeling substance. In this case, the first labeling substance may
bind specifically to the first target substance TS and provide an
identification label thereto. The second labeling substance may
bind specifically to the second target substance TS and provide an
identification label thereto. In this case, the identification
label provided from the first labeling substance and the
identification label provided from the second substance may be
different from each other.
[0537] For example, the plurality of target proteins may include a
first target protein and a second target protein, and the plurality
of patches PA may include a first patch PA that contains a first
fluorescence labeling substance and a second patch PA that contains
a second fluorescence labeling substance. In this case, the first
fluorescence labeling substance may bind specifically to the first
target protein and emit fluorescence. The second fluorescence
labeling substance may bind specifically to the second target
protein and emit fluorescence. A wavelength band from which the
fluorescence emitted from the first fluorescence labeling substance
is detected and a wavelength band from which the fluorescence
emitted from the second fluorescence labeling substance is detected
may be different from each other. The wavelength band from which
the fluorescence emitted from the first fluorescence labeling
substance is detected and the wavelength band from which the
fluorescence emitted from the second fluorescence labeling
substance is detected may be similar to each other.
[0538] By using the plurality of patches as described above, a
plurality of target substances may be simultaneously detected.
Here, the simultaneous detection includes detection of a plurality
of target substances in a single diagnostic process as well as
detection of a plurality of target substances at the same point in
time. In this case, the plurality of target substances which are
simultaneously detected using the plurality of patches may include
a mixture of proteins, base sequences, cellular components, and the
like. Fluorescence detection, colorimetric detection, radiation
detection, and the like may be used in combination as a method of
detecting a plurality of target substances.
4.4 Tissue Culture
[0539] A tissue sample SA may be cultured using a patch PA
according to the present application. Particularly, by culturing
the tissue sample SA, whether the tissue sample SA is a malignant
tumor may be determined. Specifically, properties of a tumor may be
determined by observing the growth of cells.
[0540] Culturing a tissue sample SA by using the patch PA according
to the present application may include placing a sample SA on a
plate PL, contacting a culture patch which includes a nutrient
substance for culturing the tissue sample SA, with the sample SA,
and acquiring an image of the tissue sample SA. In this case, a
living body may be used as the sample SA placed on the plate
PL.
[0541] The culture patch for culturing the tissue sample SA may
include a substance required for the growth of tissue. For example,
the culture patch may include some of a carbon source, an energy
source, a nitrogen source, mineral salts, vitamins, microelements,
growth factors, buffers, and serums.
[0542] The acquiring of the image of the tissue sample SA may be
similar to the acquiring of the image of the reaction region, the
plate PL, or the tissue sample SA in the above-described
embodiments.
[0543] The acquired image, i.e., an image of the cultured tissue
sample SA, may be used in morphological diagnosis. For example,
morphological characteristics of tumor cells may be detected, and
whether tumor cells are included in the tissue sample SA may be
determined. In this case, the cultured tissue sample SA may be
stained to facilitate identification of parts constituting the
tissue sample SA.
4.5 Tissue Diagnosis Device
[0544] Referring to FIG. 62, a tissue diagnosis device 10 according
to the present application may include a controller 100, a plate
supporter 200, a patch controller 300, and a target substance
detector 400. The tissue diagnosis device 10 may detect a target
substance TS from a tissue sample SA by using a patch PA which
includes a mesh structural body forming micro-cavities and is
configured to contain a substance in the micro-cavities.
[0545] The controller 100 may perform tissue diagnosis in which a
target substance is detected from a tissue sample by using the
patch which includes the mesh structural body forming
micro-cavities and is configured to contain a substance in the
micro-cavities.
[0546] The controller 100 may place a tissue sample in a reaction
region. The controller may provide a fluorescence labeling
substance for specifically labeling a target substance to the
tissue sample by using a patch that contains the fluorescence
labeling substance. The controller 100 may detect a
fluorescence-labeled target substance from the tissue sample. The
controller 100 may provide a staining substance to the tissue
sample by using a patch that contains a color labeling substance
for assigning color to the target substance. The controller 100 may
detect a color-assigned target substance.
[0547] The plate supporter 200 may support a plate on which a
reaction region is placed and the tissue sample SA is placed in the
reaction region.
[0548] The patch controller 300 may support a patch PA that
contains a labeling substance for specifically labeling the target
substance TS, and control a position of the patch PA relative to
the reaction region so that the patch PA is in contact with the
reaction region and provides the labeling substance to the reaction
region.
[0549] The target substance detector 400 may detect the labeling
substance and detect the target substance TS included in the tissue
sample SA.
[0550] Referring to FIG. 63, in the tissue diagnosis device 10
according to the present application, the target substance TS
detector 400 may include an imaging module 410 and a measurement
module 430.
[0551] The imaging module 410 may acquire an image of the reaction
region in which the tissue sample SA is located. The measurement
module 430 may measure the amount of target substance TS included
in the tissue sample SA.
[0552] The above description is merely illustrative of the
technical spirit of the present disclosure, and those of ordinary
skill in the art to which the present disclosure pertains should be
able to make various modifications and changes within a scope not
departing from essential characteristics of the present disclosure.
Therefore, the above-described embodiments of the present
disclosure may also be implemented separately or in
combination.
[0553] The embodiments disclosed herein are for describing the
technical spirit of the present disclosure instead of limiting the
same, and the scope of the technical spirit of the present
disclosure is not limited by such embodiments. The scope of the
present disclosure should be interpreted on the basis of the claims
below, and all technical spirits within the equivalent scope should
be interpreted as belonging to the scope of the present
disclosure.
* * * * *