U.S. patent application number 12/918625 was filed with the patent office on 2010-12-30 for intelligent tissue mimicking ultrasonic phantom and method of preparing the same.
This patent application is currently assigned to CHONGQING HAIFU (HIFU) TECHNOLOGY CO., LTD.. Invention is credited to Yunbo Tian, Fangwei Ye.
Application Number | 20100330545 12/918625 |
Document ID | / |
Family ID | 40985062 |
Filed Date | 2010-12-30 |
United States Patent
Application |
20100330545 |
Kind Code |
A1 |
Tian; Yunbo ; et
al. |
December 30, 2010 |
INTELLIGENT TISSUE MIMICKING ULTRASONIC PHANTOM AND METHOD OF
PREPARING THE SAME
Abstract
An intelligent tissue mimicking ultrasonic phantom, which is a
temperature-sensitive polymer gel having the following acoustic
properties and other physical characteristics: acoustic velocity:
1500-1550 m/s; acoustic impedance: (1.50-1.60).times.10.sup.6
Pas/m; density: 1.01-1.06 g/cm.sup.3; and a denaturation
temperature, namely, a Lower Critical Solution Temperature (LCST)
or a Volume Phase Transition Temperature at which the volume of the
phantom changes, adjustable by changing the ratio of raw materials,
around which there is a reversible phase transformation between the
opaque phase and the transparent phase. Said gel can be a polymer
of isopropylacrylamide (NIPA). Said ultrasonic phantom has a
transparent appearance, and an adjustable thermal denaturation
temperature; the thermal denaturation region of the ultrasonic
phantom is distinct and has a well-defined boundary; the material
of the phantom is stable and deterioration-resistant, and can
ensure the consistency of the quality; the phantom is thermal
denaturable with the appearance thereof turning white, while the
phantom recovers when the heat is removed, such that it can be used
repeatedly.
Inventors: |
Tian; Yunbo; (Chongqing,
CN) ; Ye; Fangwei; (Chongqing, CN) |
Correspondence
Address: |
Stephen B. Salai, Esq.;Harter Secrest & Emery LLP
1600 Bausch & Lomb Place
Rochester
NY
14604-2711
US
|
Assignee: |
CHONGQING HAIFU (HIFU) TECHNOLOGY
CO., LTD.
Chongqing
CN
|
Family ID: |
40985062 |
Appl. No.: |
12/918625 |
Filed: |
February 17, 2009 |
PCT Filed: |
February 17, 2009 |
PCT NO: |
PCT/CN2009/000161 |
371 Date: |
August 20, 2010 |
Current U.S.
Class: |
434/267 |
Current CPC
Class: |
C08F 220/56 20130101;
C08F 220/56 20130101; C08L 33/26 20130101; G09B 23/286 20130101;
A61N 7/02 20130101; C08F 220/56 20130101; A61B 17/00 20130101; A61B
2017/00716 20130101; G01D 18/00 20130101; C08F 222/385 20130101;
A61B 2017/00707 20130101; C08F 22/385 20130101 |
Class at
Publication: |
434/267 |
International
Class: |
G09B 23/28 20060101
G09B023/28 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 21, 2008 |
CN |
200810007970.9 |
Claims
1. An intelligent tissue mimicking ultrasonic phantom,
characterized in that said phantom is a temperature-sensitive
polymer gel having the following acoustic properties and other
physical characteristics: acoustic velocity: 1500-1550 m/s;
acoustic impedance: (1.50-1.60).times.10.sup.6 Pas/m; density:
1.01-1.06 g/cm.sup.3; and a denaturation temperature, namely, a
Lower Critical Solution Temperature (LCST) or a Volume Phase
Transition Temperature at which the volume of the phantom changes,
adjustable by changing ratios of raw materials, around which there
is a reversible phase transformation between an opaque phase and a
transparent phase.
2. The intelligent tissue mimicking ultrasonic phantom according to
claim 1, characterized in that said temperature-sensitive polymer
gel is a isopropylacrylamide polymer hydrogel, a poly N-vinyl
caprolactam hydrogel, or a .beta.-hydroxypropyl
acrylate-N-cinnamoyloxymethacrylamide copolymer hydrogel.
3. The intelligent tissue mimicking ultrasonic phantom according to
claim 2, characterized in that said isopropylacrylamide polymer
hydrogel used for the intelligent tissue mimicking ultrasonic
phantom comprises isopropylacrylamide, water; an initiating
reductant, a crosslinking agent, an initiating oxidant; and a
denaturation temperature regulator, wherein the weight percentage
of each component is: 8-15% of isopropylacrylamide monomer, 0-4% of
the denaturation temperature regulator, 0.02-0.05% of the
initiating reductant, 0.1-0.15% of the crosslinking agent,
0.03-0.07% of the initiating oxidant, and 91.85-80.73% of water,
and the denaturation temperature is between 30.degree. C. and
70.degree. C.
4. The intelligent tissue mimicking ultrasonic phantom according to
claim 3, characterized in that said water is deionized and degassed
water, said crosslinking agent is N,N'-methylene bisacrylamide
(BIS), said initiating oxidant is ammonium persulfate (APS), and
said initiating reductant is sodium metabisulfite.
5. The intelligent tissue mimicking ultrasonic phantom according to
claim 3, characterized in that said denaturation temperature
regulator is acrylamide.
6. The intelligent tissue mimicking ultrasonic phantom according to
claim 3, characterized in that said isopropylacrylamide polymer
hydrogel further comprises a preservative with weight percentage of
0-0.4%.
7. A method of making an isopropylacrylamide polymer hydrogel for
an intelligent tissue mimicking ultrasonic phantom, including steps
of: (1) determining a formulation of a isopropylacrylamide (NIPA)
polymer hydrogel, weight percentage of each component being: 8-15%
of isopropylacrylamide, 0-4% of denaturation temperature (LCST)
regulator, 0.02-0.05% of initiating reductant, 0.1-0.15% of
crosslinking agent, 0.03-0.07% of initiating oxidant, and
91.85-80.73% of water; (2) dissolving an isopropylacrylamide
monomer in a portion of the water; (3) adding a crosslinking agent
to the solution obtained in step 2, and dissolving the same by
stirring; (4) dissolving the initiating reductant and the
initiating oxidant in portions of the water, respectively; (5)
mixing aqueous solutions of the isopropylacrylamide monomer, the
crosslinking agent, and the initiating reductant uniformly in a
container; (6) replacing the air at the surface of and around the
container with nitrogen; (7) adding the aqueous solution of the
initiating oxidant to the container, and mixing sufficiently while
replacing the air at the surface of and around the liquid with
nitrogen continuously; (8) sealing the container in a pure nitrogen
environment after adding the aqueous solution of the initiating
oxidant is completed, allowing the solution to react for 3 to 24
hours, the temperature being controlled at 15.degree. C.-25.degree.
C., so as to obtain a gel product.
8. The method according to claim 7, further comprising the
following step: (9) washing the obtained gel product with water for
a plurality of times at room temperature, wherein every washing
comprises a cycle of soaking its surface with deionized and
degassed water for several hours and drying for another several
hours after discarding the water, the cycle is repeated for a
plurality of times to remove residual monomers and initiators on
the surface, so as to eliminate toxicity; (10) after the gel is
washed in step (9), adding a preservative solution prepared with
distilled water to wet the surface of the gel.
9. The method according to claim 7, characterized in that, in step
(1), a denaturation temperature regulator is acrylamide; and in
step (2), acrylamide is added to the aqueous solution of the
isopropylacrylamide monomer.
10. The method according to claim 7, characterized in that, when
molar ratio of isopropylacrylamide to acrylamide varies between
(100.about.70):(0.about.30), denaturation temperature can be
adjusted in a range of 30.degree. C.-70.degree. C.
11. The method according to claim 7, characterized in that, in step
(2), the mixture can be properly heated to help the dissolution of
the isopropylacrylamide monomer, but the temperature should not
exceed 40.degree. C., and the solution upon heating should be
cooled to below 25.degree. C. before subsequent operations.
12. The method according to claim 7, characterized in that, in step
(1), the water used is deionized and degassed water.
13. The method according to claim 7, characterized in that, the
isopropylacrylamide polymer hydrogel in step (1) further comprises
a preservative at a weight percentage of 0-0.4%., in step (3), the
preservative added to the solution in step (2) is also included,
and the preservative is dissolved in the solution in step (2)
together with the crosslinking agent by stirring.
14. The method according to claim 7, characterized in that, an
elasticity of the gel can be changed by adjusting the content of
the crosslinking agent according to usage requirements, and
N,N'-methylene bisacrylamide can be used as the crosslinking
agent.
15. The method according to claim 7, characterized in that, said
initiating oxidant is ammonium persulfate, and said initiating
reductant is sodium metabisulfite.
16. The method according to claim 7, characterized in that, in step
(8), the reaction in the sealed container is carried out under
nitrogen atmosphere to exclude the oxygen in the air from the
polymerization reaction to ensure smooth polymerization and quality
of the gel.
17. The method according to claim 8, characterized in that, in step
(10), said preservative is Kathon, formaldehyde, or Nipagin series,
and concentration of the preservative solution prepared with
distilled water is: 40-100 .mu.g/mL for a Kathon solution, 0.5-1
mg/mL for a formaldehyde solution, and 5-10 mg/mL for a Nipagin
solution.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a biological tissue model.
Specifically, the present invention relates to an intelligent
tissue mimicking ultrasonic phantom and a method of preparing the
same.
BACKGROUND OF THE INVENTION
[0002] Phantom is the abbreviation of biological tissue mimicking
model. Currently, there are various ultrasonic phantoms, most of
which are for applications of ultrasonic diagnosis, and for
microwave hyperthermia and HIFU (High Intensity Focused Ultrasound)
studies. However, the purpose of a phantom for ultrasound therapy
is completely different from that of a phantom for ultrasound
diagnosis. HIFU is applied in the treatment of tumor by causing
coagulate tissue necrosis. Ultrasonic phantom for diagnosis is
typically opaque, and cannot generate a macroscopic coagulation
necrosis after HIFU radiation, although it has acoustic properties
similar to those of a soft tissue.
[0003] HIFU is a newly immerging technology for treating tumor by a
non-invasive, conformal thermal ablation method guided by
ultrasound or MRI (Magnetic Resonance Imaging). During clinical
treatment using a HIFU system, the HIFU system must be quality
tested, i.e., effectiveness, safety, and reliability, wherein the
most crucial test is the evaluation of the focusing performance of
the HIFU treating applicator. The focusing performance of the HIFU
treating applicator on the tissues is directly related to
effectiveness, safety, and reliability of HIFU during clinical
application. However, it is thus far difficult to evaluate the
focusing performance of the HIFU treating applicator with a
non-standardized biological tissue, and compare focusing
performances of different HIFU treating applicators. Therefore, it
is very important to establish a standardized, reusable transparent
tissue mimicking phantom.
[0004] At present, the phantoms used in HIFU studies both in China
and abroad are transparent tissue mimicking phantoms formed by a
mixture mainly comprising polyacrylamide and protein (bovine serum
or fresh egg white) that serves as a temperature-sensitive
indicator. Upon HIFU radiation, protein undergoes thermal
denaturation, and the appearance of the phantom turns cloudy or
white, thereby revealing the focal region of the focused ultrasound
(See Fa-qi L I, Ping M A, Xiao-qin K O U, et al, A transparent
tissue-mimicking phantom for evaluating the focusing performance of
HIFU, Chinese Journal of Medical Imaging Technology, 2006, 22(8):
1261-1265). However, this protein phantom has many disadvantages:
[0005] (1) The cloudy region is not stable, the boundary is not
well-defined, and the properties are much inferior to those of BFR
(Biological focal region, i.e., the coagulation necrosis region
visible by naked eyes and confirmed by a microscope, which appears
at the location of the acoustic focus in the biological tissue
where HIFU radiation is applied. Reference: Yong-chang Z H O U,
Wan-xue G U O. Ultrasound Medicine [M]. Fourth Edition. Beijing:
Science Press, 2002.1780.) produced in biological tissues,
therefore, this protein phantom is not very suitable for studying
the focusing performance of HIFU in biological tissues. [0006] (2)
If bubbles are contained therein, the white region will become
irregular. [0007] (3) As a temperature-sensitive indicator, once
protein is denatured by heat, its appearance then turns white and
cannot be restored. Therefore, it can only be used once associated
with high cost. [0008] (4) Although additives such as preservatives
and foam inhibitors can be incorporated therein, the main material
(i.e., protein) is prone to deterioration, and therefore, the
stability of the phantom and the effectiveness to eliminate the
impact of bubbles in the preparation process are limited. [0009]
(5) As the source of transparent protein, bovine serum or fresh egg
white cannot assure the consistency of its quality, therefore the
consistency of the phantom also cannot be assured, and
standardization of the phantom cannot be realized. [0010] (6)
Restricted by factors such as the nature of protein, visible change
in the appearance can only be seen at a temperature of 70.degree.
C. or higher (i.e., the denaturation temperature of protein), and
this temperature is higher than that at which coagulation necrosis
occurs in real biological body tissues (typically 60-65.degree.
C.), and different biological body tissues may have different
temperatures at which coagulation necrosis occurs. The denaturation
temperature of the protein phantom is thus fixed, and the
requirements of different denaturation temperatures cannot be
satisfied. Therefore, a phantom that has a denaturation temperature
below 70.degree. C. and can be used at different denaturation
temperatures are desired by those skilled in the art (See: Sam
Howard, Jonathan Yuen, Paul Wegner, et al. Characterization and FEA
Simulation for a HIFU Phantom Material. 2003 IEEE International
Ultrasonics Symposium, 2003, Vol. 2: 1270-1272).
SUMMARY OF THE INVENTION
[0011] The technical problem to be solved by the present invention
is directed to the above problems in the prior art. This invention
provides an intelligent tissue mimicking ultrasonic phantom and a
method of preparing the same, wherein the thermal denaturation
temperature of the ultrasonic phantom is adjustable; the thermal
denaturation region of the ultrasonic phantom is visibly distinct
and has a well-defined boundary; the material of the phantom is
stable and resists deterioration, and can ensure the consistency of
the quality; the phantom is denatured by heat with the appearance
thereof turning white, while the phantom recovers when the heat is
removed, such that it can be used repeatedly.
[0012] To achieve the above objects, the present invention provides
an intelligent tissue mimicking ultrasonic phantom which is a
temperature-sensitive polymer gel having the following acoustic
property and other physical characteristics (which are
substantially the same as those of a biological tissue).
acoustic velocity: 1500-1550 m/s; acoustic impedance:
(1.50-1.60).times.10.sup.6
Pas/m; density: 1.01-1.06 g/cm.sup.3; and a denaturation
temperature, namely, a Lower Critical Solution Temperature (LCST)
or a Volume Phase Transition Temperature at which the volume of the
phantom changes, that is adjustable in the range of 30-70.degree.
C. by changing the ratio of raw materials, around which there is a
reversible phase transformation between the opaque phase and the
transparent phase in the gel. When radiated by focused ultrasound,
the tissue mimicking ultrasonic phantom in the focal region of the
focused ultrasound changes from a colorless and transparent
appearance to a opaque white appearance when the temperature of the
focal region reaches the denaturation temperature due to an
accumulation of ultrasonic energy, such that the morphology of the
focal region of the focused ultrasound is clearly shown. And when
the irradiation with focused ultrasound is stopped, the temperature
of the focal region turns below the denaturation temperature due to
local heat dissipation, and the white region gradually recovers to
the colorless and transparent state.
[0013] Intelligent polymer gel is a new functional material having
a sensitive response to external stimulations such as, typically,
temperature, pH, solvent, concentration of salt, light, electric
field, chemical substances, and etc. Temperature-sensitive polymer
gel is an intelligent gel having a sensitive response to the
stimulation of temperature.
[0014] Preferably, the temperature-sensitive polymer gel is an
isopropylacrylamide (NIPA) polymer hydrogel, a poly N-vinyl
caprolactam (PNVCL) hydrogel, or a .beta.-hydroxypropyl
acrylate-N-cinnamoyloxymethacrylamide (CMMAM) copolymer hydrogel,
etc.
[0015] More preferably, isopropylacrylamide (NIPA) polymer hydrogel
used for the intelligent tissue mimicking ultrasonic phantom
comprises isopropylacrylamide, water; an initiating reductant, a
crosslinking agent, an initiating oxidant; and a lower critical
solution temperature conditioner that is a denaturation temperature
regulator, wherein the weight percentage of each component is:
isopropylacrylamide of 8-15%, denaturation temperature regulator of
0-4%, initiating reductant of 0.02-0.05%, crosslinking agent of
0.1-0.15%, initiating oxidant of 0.03-0.07%, and 91.85-80.73% of
water, and the denaturation temperature is between 30.degree. C.
and 70.degree. C. When the content of the denaturation temperature
regulator is 0, the lower critical solution temperature (i.e., the
denaturation temperature) of the intelligent tissue mimicking
ultrasonic phantom of this invention is 30.degree. C. The
denaturation temperature varies from 30.degree. C. to 70.degree. C.
by adjusting the amount of the regulator according to different
needs.
[0016] In order to prevent microbiological contamination during
storage and use, it is preferable that the isopropylacrylamide
(NIPA) polymer hydrogel further comprises a preservative of 0-0.4%
weight percentage. The preservative used is one selected from the
group comprising Kathon (chemical name: mixture of
5-chloro-2-methyl-4-isothiazoline-3-one and
2-methyl-4-isothiazoline-3-one, molecular formula:
C.sub.4H.sub.4ClNOS+C.sub.4H.sub.5NOS, molecular weight:
149.56+115.06, Cas No.: 55965-84-9), sodium benzoate (molecular
formula: C.sub.7H.sub.5NaO.sub.2, molecular weight: 144.1, Cas No.:
532-32-1), Nipagin ester/Methylparaben (chemical name: methyl
p-hydroxybenzoate, molecular formula: C.sub.8H.sub.8O.sub.3,
molecular weight: 152.2, Cas No.: 99-76-3), phenoxyethanol
(molecular formula: C.sub.8H.sub.10O.sub.2, molecular weight:
138.16, Cas No.: 122-99-6). It is more preferable that the
preservative used is phenoxyethanol in the present invention.
[0017] The above mentioned initiator is a substance containing weak
bond, which produce an active centre for free radical
polymerization. Under the action of the decomposition activation
energy, covalent bond breaks to generate free radicals. In a
general free radical polymerization system, the polymerization
temperature is between 40.degree. C. and 100.degree. C. to provide
sufficient activation energy. The initiators used in the present
invention are an initiating reductant and an initiating oxidant,
which is formed by adding a reductant to a peroxide initiator to
generate free radicals by oxidation-reduction reactions. Such a
system is called oxidation-reduction initiating system, or
oxidation-reduction initiator. The decomposition activation energy
can be reduced by using an oxidation-reduction initiator, so that
the polymerization can be conducted at low temperatures
(15-25.degree. C.), which is beneficial in improving the quality of
the polymer and reducing the requirements on the reaction
environment for convenient operation.
[0018] The aforesaid crosslinking agent is a compound comprising a
plurality of non-conjugated double bonds, which serves to convert
the linear crosslinked structure of isopropylacrylamide formed by
free radicals initiation to a three-dimensional network structure,
so as to shape the gel.
[0019] Preferably, the water used is deionized and degassed water,
the crosslinking agent is N,N'-methylene bisacrylamide, the
initiating oxidant is ammonium persulfate, and the initiating
reductant is sodium metabisulfite.
[0020] Preferably, the denaturation temperature regulator is
acrylamide.
[0021] In the present invention, acrylamide is hydrophilic while
isopropylacrylamide monomer is hydrophobic, therefore, the
hydrophilicity of the entire system can be enhanced by adding
acrylamide to the gel formed by polymerization of
isopropylacrylamide, which increases the number of hydrogen bonds
in the system. Since the thermal phase transition of a gel is
caused by the breaking up of hydrogen bonds in the system, an
increase in hydrogen bonds would increase the phase transition
temperature of the system. Therefore, the denaturation temperature
regulator is used to adjust the lower critical solution temperature
(LCST) of the temperature-sensitive gel.
[0022] The applicant filed a patent application with the title
"Method for Preparing Monomer of a Temperature-sensitive
Poly(isopropylacrylamide)" at the Chinese Patent Office on Feb. 7,
2007, the application number being 200710003153.1. The
isopropylacrylamide used in the present invention may be the
monomer of poly(isopropylacrylamide) prepared according to this
patent application "Method for Preparing Monomer of a
Temperature-sensitive Poly(isopropylacrylamide)".
[0023] Test results shows that acoustic property and other physical
characteristics of the intelligent tissue mimicking ultrasonic
phantom according to the present invention are substantially the
same as those of a biological tissue: acoustic velocity: 1500-1550
m/s; acoustic impedance: (1.50-1.60).times.10.sup.6 Pas/m; density:
1.01-1.06 g/cm.sup.3; and a denaturation temperature, i.e., a Lower
Critical Solution Temperature (LCST) or a Volume Phase Transition
Temperature at which the volume of the phantom changes, adjustable
in the range of 30-70.degree. C. by changing the ratio of the raw
materials. When radiated with focused ultrasound, the tissue
mimicking ultrasonic phantom, i.e. the isopropylacrylamide (NIPA)
polymer hydrogel, in the focal region of the focused ultrasound
changes from a colorless and transparent appearance to a opaque
white appearance when the temperature of the focal region reaches
the denaturation temperature due to an accumulation of ultrasonic
energy, such that the morphology of the focal region of the focused
ultrasound is clearly shown. When the focused ultrasonic radiation
stops, the white region gradually reverts back to the colorless and
transparent state as the temperature of the focal region becomes
lower than the denaturation temperature due to local heat
dissipation.
[0024] The mechanism of using the intelligent tissue mimicking
ultrasonic phantom according to the present invention in showing
the focal region of the focused ultrasound is as follows: [0025]
(1) As the intelligent tissue mimicking ultrasonic phantom is an
intelligent polymer material, such has substantially the same
acoustic property and other physical characteristics as those of a
biological tissue. Acoustic velocity: 1500-1550 m/s; acoustic
impedance: (1.50-1.60).times.10.sup.6 Pas/m; density: 1.01-1.06
g/cm.sup.3. [0026] (2) At the focus of the focused ultrasound, the
ultrasonic intelligent phantom is strongly stimulated by the
overall effect of mechanical effects, thermal effects and cavity
effects, particularly thermal effects, of the ultrasound. When the
energy of the focused ultrasound reaches a certain intensity
threshold causing that the temperature of the focus point reaches
the denaturation temperature, the internal molecular structure of
the ultrasonic intelligent phantom changes in its spatial
arrangement (conformation), leading to a change in the appearance
from colorless and transparent to white opaque (an emulsion).
(Note: conformational change is phase transition which is also
called phase separation.) [0027] (3) With the deposition and
diffusion of ultrasonic energy at the focal point, the area with
change of the spatial conformation of phantom changes
correspondingly, and the area with white (or opaque) appearance
increases accordingly. This change is reversible within a certain
range of ultrasonic intensity. With the disappearance of the
ultrasound irradiation, the dissipation of heat, and the decrease
in temperature, the changed spatial conformation restores the
original state by self-absorption of water, that is, the white (or
opaque) region reverts to the colorless and transparent state. That
is why such a phantom is called an intelligent phantom. [0028] (4)
The denaturation temperature designed for this ultrasonic
intelligent phantom is close to the coagulation necrosis
temperature of a biological tissue, and the white (or opaque)
region shown corresponds to the biological focal region induced by
HIFU on the biological tissue. The denaturation temperature can
also be adjusted by changing the ratio of the raw materials, so as
to be applicable for different research purposes.
[0029] A method of making an isopropylacrylamide (NIPA) polymer
hydrogel for an intelligent tissue mimicking ultrasonic phantom,
including the following steps:
[0030] 1. determining the formulation of the isopropylacrylamide
(NIPA) polymer hydrogel, the weight percentage of each component
being: 8-15% of isopropylacrylamide, 0-4% of denaturation
temperature (LCST) regulator, 0.02-0.05% of initiating reductant,
0.1-0.15% of crosslinking agent, 0.03-0.07% of initiating oxidant,
and 91.85-80.73% of water;
[0031] 2. dissolving the isopropylacrylamide monomer in a portion
of the water, and mass ratio of the monomer to water can be
(0.1-0.2): 1;
[0032] 3. adding a crosslinking agent to the solution obtained in
step 2, and dissolving the same by stirring;
[0033] 4. dissolving the initiating reductant and the initiating
oxidant in a portion of the water, respectively, and the
concentration can be 1-20%;
[0034] 5. mixing the aqueous solutions of the isopropylacrylamide
monomer, the crosslinking agent, and the initiating reductant
uniformly in a container;
[0035] 6. replacing the air at the surface of and around the
container with nitrogen, which can be for 1 to 3 minutes;
[0036] 7. adding the initiating oxidant aqueous solution to the
container, mixing sufficiently and replacing the air at the surface
of and around the liquid with nitrogen continuously;
[0037] 8. sealing the container in a pure nitrogen environment
after the addition of the initiating oxidant aqueous solution is
completed. The solution in the container reacts for 3 to 24 hours,
the temperature being controlled at 15.degree. C.-25.degree. C., so
as to obtain a gel product;
[0038] 9. washing the obtained gel product with water repeatedly at
room temperature, wherein every washing comprises a cycle of
soaking the surface with deionized and degassed water for several
hours and drying for another several hours after discarding the
water, and the cycle is repeated to remove toxicities of residual
monomers and initiators on the surface which react
incompletely.
[0039] In the whole process, the operation temperature is
controlled in the range of 15.degree. C.-25.degree. C. If the
temperature is too high, polymerization will occur during operation
(explosive polymerization); if the temperature is too low, by
contrast, it is difficult for polymerization to occur.
[0040] Preferably, in step 1, the denaturation temperature
regulator of the isopropylacrylamide (NIPA) polymer gel composition
is acrylamide with weight percentage of 0-4% in the polymer gel; in
step 2, acrylamide can be added to the aqueous solution of the
isopropylacrylamide monomer to change the LCST for fulfilling
requirements of different uses. The change of the LCST can be
achieved by adjusting the ratio of isopropylacrylamide to
acrylamide. The LCST increases with the decrease of the molar ratio
of isopropylacrylamide to acrylamide. When the molar ratio of
isopropylacrylamide to acrylamide varies between
(100.about.70):(0.about.30), the LCST can be adjusted in a range of
30.degree. C.-70.degree. C. Specifically, if acrylamide is not
added, the LCST is maintained at 30.degree. C., i.e., the LCST of
poly(N-isopropylacrylamide) (PNIPA) hydrogel; if the molar ratio of
isopropylacrylamide to acrylamide is 95:5, the LCST is 40.degree.
C.; if the molar ratio of isopropylacrylamide to acrylamide is
80:20, the LCST is 60.degree. C.; and if the molar ratio of
isopropylacrylamide to acrylamide is 70:30, the LCST is 70.degree.
C.
[0041] The water used is preferred to be double distilled deionized
water. Deionized water is suitable for chemical reactions; however,
water deionized by merely osmosis filtration through ion exchange
column still cannot remove microorganisms in the water. Double
distilled deionized water is advantageous in that, it is suitable
for a chemical reaction, and it is free of microbial contamination.
Therefore, changes resulted from microbial contamination in the gel
is avoided. More preferably, the water used in the synthesis is
degassed water.
[0042] Preferably, in step 1, the isopropylacrylamide polymer
hydrogel further comprises a preservative with weight percentage of
0 to 0.4%; simultaneously, in step 3, the preservative added to the
solution in step 2 is also included, and the preservative is
dissolved in the solution in step 2 together with the crosslinking
agent by stirring.
[0043] Preferably, in step 2, the mixture can be properly heated to
assist in dissolving the isopropylacrylamide monomer, but the
temperature should not exceed 40.degree. C., and the solution upon
heating should be cooled to below 25.degree. C. before the
subsequent operations.
[0044] Preferably, the elasticity of the gel can be adjusted by
changing the amount of the crosslinking agent, that is, the
elasticity of the gel can be changed by changing the amount of the
crosslinking agent. It is preferable to use N,N'-methylene
bisacrylamide as the crosslinking agent.
[0045] It is preferable to use ammonium persulfate as the
initiating oxidant, and sodium metabisulfite as the initiating
reductant.
[0046] Preferably, in step 8, the reaction in the sealed container
is carried out under nitrogen atmosphere to exclude oxygen in the
air from the polymerization reaction to ensure the smooth
polymerization and the quality of the gel. The container containing
the well-mixed raw materials is sealed in a commonly available
plastic bag with good sealing performance, the air in the bag is
then replaced by nitrogen, and the bag is then tied to maintain the
pure nitrogen environment inside.
[0047] The container may be a glass beaker or other transparent
containers. The nitrogen quality is of general industry standard,
and the nitrogen may be supplied by a compressed gas cylinder.
[0048] Preferably, in step 9, the gel is washed for 5 cycles, each
with double distilled deionized water soaking the surface for 12
hours, and then dried for another 12 hours after discarding the
water. It is cumbersome if there are too many cycles; if there are
too few cycles, the residual monomers on the surface cannot be
effectively removed. For each cycle, there is an immersion in water
step for 12 hours and a drying step for 12 hours. The desired
effect cannot be achieved if the time is too short; if the time is
too long, there will be a significant expansion in the volume of
the gel.
[0049] Preferably, the method further includes the following
step:
[0050] 10. In step 9, after the gel is washed, a small amount of
preservative solution prepared with distilled water is added to wet
the surface of the gel, wherein the preservative can be Kathon,
formaldehyde, or Nipagin series, and the concentration of the
preservative solution prepared with distilled water is: 40-100
.mu.g/mL for a Kathon solution, 0.5-1 mg/mL for a formaldehyde
solution, and 5-10 mg/mL for a Nipagin solution.
[0051] More preferably, a small amount of Kathon solution prepared
with distilled water is added to wet the surface of the gel for
antisepsis purpose. Using formaldehyde in the antiseptic material
will affect the transparency of the gel. Nipagin is not readily
soluble in water, which affects the antisepsis effect.
[0052] The intelligent tissue mimicking ultrasonic phantom
according to the present invention has the following advantages:
[0053] 1. The ultrasonic intelligent phantom is highly transparent.
When phase transition occurs at the denaturation temperature point
upon radiation with focused ultrasound, the focal region formed
therein has a clear morphology with well-defined boundary. That is,
when the temperature is above the denaturation temperature, the
opaque phase resulted can clearly show the morphology of the focal
region of focused ultrasound. [0054] 2. With ultrasonic radiation
ceases, the temperature is reduced, and the denatured region
(appearance changed to white) can be reverted to be transparent
(when the temperature is lower than the denaturation temperature,
the time of phase transition depends on the volume, where the phase
transition occurs most rapidly in 1 second), therefore, the phantom
is intelligent, and can be used repeatedly. [0055] 3. The
denaturation temperature of the phantom can be adjusted in the
range of 30.degree. C.-70.degree. C. by changing the ratio of the
raw materials or by adding an appropriate modifier. By contrast,
protein phantoms only have a single and higher denaturation
temperature, while the denaturation temperature of the ultrasonic
intelligent phantom can be adjusted in the range of 30.degree.
C.-70.degree. C. The ultrasonic intelligent phantom has more
applications as such can be prepared to have a same denaturation
temperature with that of simulation of biological tissues, which is
based on the requirement of the tissue to be mimicked and different
biological tissues have different coagulation necrosis
temperatures. [0056] 4. With the unique formulation technology, the
synthesis of the phantom can be carried out at room temperature,
and the production of the phantom is simple. [0057] 5. The phantom
is prepared using deionized and degassed water, which almost
contains no air therein, which minimizes the effect of bubbles
generated by cavity effects upon the focal region during ultrasonic
radiation. [0058] 6. Not only the raw materials but also the
preparation process of the ultrasonic intelligent phantom can be in
strict uniformity. Besides, the phantom is a polymer and is free of
bioactive substances such as proteins, resulting in good stability.
A preservative can be added during the synthesis if necessary,
which further ensures the stability of the phantom. [0059] 7. The
quality of all the raw materials and the ratio according to the
formulation can be consistent, and thereby ensuring the consistency
of the properties of the ultrasonic intelligent phantom, and
achieving standardization of the phantom.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0060] Specific but non-limiting working examples for preparing
isopropylacrylamide (NIPA) polymer hydrogels as the intelligent
tissue mimicking ultrasonic phantoms of the present invention are
illustrated as follows.
Example 1
An Intelligent Tissue Mimicking Ultrasonic Phantom Having a
Denaturation Temperature, i.e., LCST, of 30.degree. C.
[0061] Ratio of Raw Materials:
TABLE-US-00001 Isopropylacrylamide 100.0 g Initiating reductant,
sodium metabisulfite 0.5 g Crosslinking agent, N, N'-methylene
bisacrylamide 1 g Initiating oxidant, ammonium persulfate 0.5 g
water (deionized and degassed water) 898 g
[0062] Steps:
[0063] 1) dissolving the isopropylacrylamide monomer in a portion
of the water, and mass ratio of the monomer to water is 0.15:1;
[0064] 2) adding a crosslinking agent to the solution obtained in
step 1), and dissolving the same by stirring;
[0065] 3) dissolving the initiating reductant and the initiating
oxidant in portions of the water, respectively, the concentrations
of the two solutions thus obtained both being 10%;
[0066] 4) mixing the aqueous solutions of the isopropylacrylamide
monomer, the crosslinking agent, and the initiating reductant
uniformly in a container;
[0067] 5) packaging the container within a freshness protection
plastic bag having good sealing performance, and replacing the air
at the surface of and around the container with nitrogen for 4
minutes;
[0068] 6) adding the aqueous solution of the initiating oxidant to
the container, and mixing sufficiently while replacing the air in
the bag with nitrogen for 3 minutes; then fastening the bag to
maintain the internal pure nitrogen environment;
[0069] 7) sealing the container for reacting for further 5 hours,
the temperature being controlled at 20.degree. C., so as to obtain
a gel product;
[0070] 8) washing the gel with water for five times, each wash
comprising soaking the surface with deionized and degassed water
for 12 hours and drying for another 12 hours after discarding the
water; a small amount of Kathon solution (with a concentration of
60 .mu.g/mL) prepared with distilled water can be added to wet the
surface of the gel.
[0071] Test results of the prepared isopropylacrylamide (NIPA)
polymer hydrogel, i.e., the intelligent tissue mimicking ultrasonic
phantom, according to the present invention show a denaturation
temperature, i.e., a Lower Critical Solution Temperature (LCST), of
30.degree. C., and acoustic and physical characteristics: acoustic
velocity: 1528 m/s; acoustic impedance: 1.56.times.10.sup.6 Pas/m;
and density: 1.02 g/cm.sup.3. When JC type focused ultrasound tumor
therapy system (produced by Chongqing Haifu (HIFU) Technology Co.,
Ltd.) is used to focus ultrasound at the phantom, the spatial
arrangement (conformation) of the internal molecular structure of
the tissue mimicking ultrasonic phantom changes, i.e., phase
transition, leading to a change in appearance from colorless and
transparent to opaque white when the temperature of the focal
region goes above the denaturation temperature of 30.degree. C.,
due to an accumulation of ultrasonic energy. With the deposition
and diffusion of ultrasonic energy at the focal point, the area in
which a change of the spatial conformation of the phantom takes
place expands, and the white area expands accordingly, and the
focal region of the white area formed therein has a clear
morphology with well-defined boundary. When the focused ultrasound
radiation stops, with the disappearance of ultrasound irradiation,
the temperature of the focal region of the focused ultrasound
decreases correspondingly, and the changed spatial conformation
reverts to the original state when the temperature turns below the
denaturation temperature of 30.degree. C., that is, the white
region reverts to the colorless and transparent state. That is, at
a certain range of ultrasonic intensity, the phase transition of
the intelligent tissue mimicking ultrasonic phantom according to
the present invention is reversible, and the white region can
revert to the transparent state, therefore, the phantom is
intelligent, and can be used repeatedly. Comparing with disposable
protein phantom of the prior art, the phantom according to the
present invention reduces costs of use, saves resources, and
benefits the environment.
Example 2
An Intelligent Tissue Mimicking Ultrasonic Phantom Having a
Denaturation Temperature, i.e., LCST, of 40.degree. C.
[0072] Ratio of Raw Materials:
TABLE-US-00002 Isopropylacrylamide 100.0 g Denaturation temperature
regulator, acrylamide 3.31 g Initiating reductant, sodium
metabisulfite 0.34 g Crosslinking agent, N, N'-methylene
bisacrylamide 1 g Initiating oxidant, ammonium persulfate 0.5 g
water (deionized and degassed water) 895 g
[0073] Steps:
[0074] 1) dissolving the isopropylacrylamide monomer and acrylamide
in a portion of the water, and mass ratio of the monomer to water
is 0.15:1;
[0075] 2) adding a crosslinking agent to the solution obtained in
step 1), and dissolving the same by stirring;
[0076] 3) dissolving the initiating reductant and the initiating
oxidant in portions of the water, respectively, the concentrations
of the two solutions thus obtained both being 1%;
[0077] 4) mixing the aqueous solutions of the isopropylacrylamide
monomer, the crosslinking agent, and the initiating reductant
uniformly in a container;
[0078] 5) packaging the container within a freshness protection
plastic bag having good sealing performance, and replacing the air
at the surface of and around the container with nitrogen for 5
minutes;
[0079] 6) adding the aqueous solution of the initiating oxidant to
the container, and mixing sufficiently while replacing the air in
the bag with nitrogen for 3 minutes; then fastening the bag to
maintain the internal pure nitrogen environment;
[0080] 7) sealing the container for reacting for further 24 hours,
the temperature being controlled at 15.degree. C., so as to obtain
a gel product;
[0081] 8) washing the gel with water for five times, each wash
comprising soaking the surface with deionized and degassed water
for 12 hours and drying for another 12 hours after discarding the
water; a small amount of Kathon solution (with a concentration of
80 .mu.g/mL) prepared with distilled water can be added to wet the
surface of the gel.
[0082] Test results of the prepared isopropylacrylamide (NIPA)
polymer hydrogel, i.e., the intelligent tissue mimicking ultrasonic
phantom, according to the present invention show a denaturation
temperature, i.e., a Lower Critical Solution Temperature (LCST), of
40.degree. C., and acoustic and other physical characteristics:
acoustic velocity: 1522 m/s; acoustic impedance:
1.54.times.10.sup.6 Pas/m; and density: 1.01 g/cm.sup.3. Other
properties are the same as those of Example 1.
Example 3
An Intelligent Tissue Mimicking Ultrasonic Phantom Having a
Denaturation Temperature, i.e., LCST, of 60.degree. C.
[0083] Ratio of Raw Materials:
TABLE-US-00003 Isopropylacrylamide 100.0 g Denaturation temperature
regulator, acrylamide 15.7 g Initiating reductant, sodium
metabisulfite 0.4 g Crosslinking agent, N, N'-methylene
bisacrylamide 1.2 g Initiating oxidant, ammonium persulfate 0.6 g
water (deionized and degassed water) 882 g
[0084] Steps:
[0085] 1) dissolving the isopropylacrylamide monomer and acrylamide
in a portion of the water, and mass ratio of the monomer to water
is 0.18:1;
[0086] 2) adding a crosslinking agent to the solution obtained in
step 1), and dissolving the same by stirring;
[0087] 3) dissolving the initiating reductant and the initiating
oxidant in portions of the water, respectively, the concentrations
of the two solutions thus obtained both being 20%;
[0088] 4) mixing the aqueous solutions of the isopropylacrylamide
monomer, the crosslinking agent, and the initiating reductant
uniformly in a container;
[0089] 5) packaging the container within a freshness protection
plastic bag having good sealing performance, and replacing the air
at the surface of and around the container with nitrogen for 3
minutes;
[0090] 6) adding the aqueous solution of the initiating oxidant to
the container, and mixing sufficiently while replacing the air in
the bag with nitrogen for 1 minute; then fastening the bag to
maintain the internal pure nitrogen environment;
[0091] 7) sealing the container for reacting for further 10 hours,
the temperature being controlled at 18.degree. C., so as to obtain
a gel product;
[0092] 8) washing the gel with water for five times, each wash
comprising soaking the surface with double distilled deionized
water for 12 hours and drying for another 12 hours after discarding
the water; a small amount of Kathon solution (with a concentration
of 50 .mu.g/mL) prepared with distilled water can be added to wet
the surface of the gel.
[0093] Test results of the prepared isopropylacrylamide (NIPA)
polymer hydrogel, i.e., the intelligent tissue mimicking ultrasonic
phantom, according to the present invention show a denaturation
temperature, i.e., a Lower Critical Solution Temperature (LCST), of
60.degree. C., and acoustic and other physical characteristics:
acoustic velocity: 1530 m/s; acoustic impedance:
1.55.times.10.sup.6 Pas/m; and density: 1.01 g/cm.sup.3. Other
properties are the same as those of Example 1.
Example 4
An Intelligent Tissue Mimicking Ultrasonic Phantom Having a
Denaturation Temperature, i.e., LCST, of 70.degree. C.
[0094] Ratio of Raw Materials:
TABLE-US-00004 Isopropylacrylamide 100.0 g Denaturation temperature
regulator, acrylamide 27 g Initiating reductant, sodium
metabisulfite 0.4 g Crosslinking agent, N, N'-methylene
bisacrylamide 1.2 g Initiating oxidant, ammonium persulfate 0.5 g
water (deionized and degassed water) 871 g
[0095] Steps:
[0096] 1) dissolving the isopropylacrylamide monomer and acrylamide
in a portion of the water, and mass ratio of the monomer to water
is 0.15:1;
[0097] 2) adding a crosslinking agent to the solution obtained in
step 1), and dissolving the same by stirring;
[0098] 3) dissolving the initiating reductant and the initiating
oxidant in portions of the water, respectively, the concentrations
of the two solutions thus obtained both being 15%;
[0099] 4) mixing the aqueous solutions of the isopropylacrylamide
monomer, the crosslinking agent, and the initiating reductant
uniformly in a container;
[0100] 5) packaging the container within a freshness protection
plastic bag having good sealing performance, and replacing the air
at the surface of and around the container with nitrogen for 5
minutes;
[0101] 6) adding the aqueous solution of the initiating oxidant to
the container, and mixing sufficiently while replacing the air in
the bag with nitrogen for 3 minutes; then fastening the bag to
maintain the internal pure nitrogen environment;
[0102] 7) sealing the container for reacting for further 20 hours,
the temperature being controlled at 25.degree. C., so as to obtain
a gel product;
[0103] 8) washing the gel with water for five times, each wash
comprising soaking the surface with double distilled deionized
water for 12 hours and drying for another 12 hours after discarding
the water; a small amount of Kathon solution (with a concentration
of 40-100 .mu.g/mL) prepared with distilled water can be added to
wet the surface of the gel.
[0104] Test results of the prepared isopropylacrylamide (NIPA)
polymer hydrogel, i.e., the intelligent tissue mimicking ultrasonic
phantom, according to the present invention show a denaturation
temperature, i.e., a Lower Critical Solution Temperature (LCST), of
70.degree. C., and acoustic and other physical characteristics:
acoustic velocity: 1549 m/s; acoustic impedance:
1.56.times.10.sup.6 Pas/m; and density: 1.01 g/cm.sup.3. Other
properties are the same as those of Example 1.
Example 5
An Intelligent Tissue Mimicking Ultrasonic Phantom Having a
Denaturation Temperature, i.e., LCST, of 57.degree. C.
[0105] Ratio of Raw Materials:
TABLE-US-00005 Isopropylacrylamide 85.0 g Denaturation temperature
regulator, acrylamide 9.5 g Initiating reductant, sodium
metabisulfite 0.2 g Crosslinking agent, N, N'-methylene
bisacrylamide 1 g Initiating oxidant, ammonium persulfate 0.3 g
water (deionized and degassed water) 898 g
[0106] Steps:
[0107] 1) dissolving the isopropylacrylamide monomer and acrylamide
in a portion of the water, and mass ratio of the monomer to water
is 0.15:1;
[0108] 2) adding a crosslinking agent to the solution obtained in
step 1), and dissolving the same by stirring;
[0109] 3) dissolving the initiating reductant and the initiating
oxidant in portions of the water, respectively, the concentrations
of the two solutions thus obtained both being 10%;
[0110] 4) mixing the aqueous solutions of the isopropylacrylamide
monomer, the crosslinking agent, and the initiating reductant
uniformly in a container;
[0111] 5) packaging the container within a freshness protection
plastic bag having good sealing performance, and replacing the air
at the surface of and around the container with nitrogen for 3-5
minutes;
[0112] 6) adding the aqueous solution of the initiating oxidant to
the container, and mixing sufficiently while replacing the air in
the bag with nitrogen for 2 minutes; then fastening the bag to
maintain the internal pure nitrogen environment;
[0113] 7) sealing the container for reacting for further 15 hours,
the temperature being controlled at 18.degree. C., so as to obtain
a gel product;
[0114] 8) washing the gel with water for five times, each wash
comprising soaking the surface with double distilled deionized
water for 12 hours and drying for another 12 hours after discarding
the water; a small amount of Kathon solution (with a concentration
of 90 .mu.g/mL) prepared with distilled water can be added to wet
the surface of the gel.
[0115] Test results of the prepared isopropylacrylamide (NIPA)
polymer hydrogel, i.e., the intelligent tissue mimicking ultrasonic
phantom, according to the present invention show a denaturation
temperature, i.e., a Lower Critical Solution Temperature (LCST), of
57.degree. C., and acoustic and other physical characteristics:
acoustic velocity: 1541 m/s; acoustic impedance:
1.57.times.10.sup.6 Pas/m; and density: 1.02 g/cm.sup.3. And other
properties are the same as those of Example 1.
Example 6
An Intelligent Tissue Mimicking Ultrasonic Phantom Having a
Denaturation Temperature, i.e., LCST, of 52.degree. C.
[0116] Ratio of Raw Materials:
TABLE-US-00006 Isopropylacrylamide 140.0 g Denaturation temperature
regulator, acrylamide 10 g Initiating reductant, sodium
metabisulfite 0.5 g Crosslinking agent, N, N'-methylene
bisacrylamide 1.5 g Initiating oxidant, ammonium persulfate 0.7 g
Preservative, phenoxyethanol 2 ml water (deionized and degassed
water) 846 g
[0117] Steps:
[0118] 1) dissolving the isopropylacrylamide monomer and acrylamide
in a portion of the water, and mass ratio of the monomer to water
is 0.15:1;
[0119] 2) adding a crosslinking agent and the preservative to the
solution obtained in step 1), and dissolving the same by
stirring;
[0120] 3) dissolving the initiating reductant and the initiating
oxidant in portions of the water, respectively, the concentrations
of the two solutions thus obtained both being 15%;
[0121] 4) mixing the aqueous solutions of the isopropylacrylamide
monomer, the crosslinking agent, and the initiating reductant
uniformly in a container;
[0122] 5) packaging the container within a freshness protection
plastic bag having good sealing performance, and replacing the air
at the surface of and around the container with nitrogen for 5
minutes;
[0123] 6) adding the aqueous solution of the initiating oxidant to
the container, and mixing sufficiently while replacing the air in
the bag with nitrogen for 3 minutes; then fastening the bag to
maintain the internal pure nitrogen environment;
[0124] 7) sealing the container for reacting for further 15 hours,
the temperature being controlled at 25.degree. C., so as to obtain
a gel product;
[0125] 8) washing the gel with water for five times, each wash
comprising soaking the surface with double distilled deionized
water for 12 hours and drying for another 12 hours after discarding
the water; a small amount of Kathon solution (with a concentration
of 40-100 .mu.g/mL) prepared with distilled water can be added to
wet the surface of the gel.
[0126] Test results of the prepared isopropylacrylamide (NIPA)
polymer hydrogel, i.e., the intelligent tissue mimicking ultrasonic
phantom, according to the present invention show a denaturation
temperature, i.e., a Lower Critical Solution Temperature (LCST), of
52.degree. C., and acoustic and other physical characteristics:
acoustic velocity: 1536 m/s; acoustic impedance:
1.58.times.10.sup.6 Pas/m; and density: 1.03 g/cm.sup.3. Other
properties are the same as those of Example 1.
* * * * *