US 10,809,331 B2

1

LIQUID CRYSTAL THERMOMETER FOR
MRI

STATEMENT REGARDING FEDERALLY
SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under
grant numbers 70NANB14H297 awarded by the National
Institute of Standards and Technology. The government has
certain rights in the invention.

BACKGROUND OF THE INVENTION

Magnetic resonance imaging (MRI) is a powerful plat-
form that enables non-invasive medical imaging with high
resolution. MRI enables the diagnosis and assessment of
various conditions such as cancer, neurodegenerative and
musculoskeletal diseases. However, for MRI to be effective
as a diagnostic tool, the measurement protocols must yield
consistent results across different MRI systems. Differences
in MRI hardware, software platforms and user implemen-
tation of imaging protocols produce variability in measure-
ments across different systems or even at different time
points for the same system. Such variability can lead to
misdiagnosis or inconclusive findings

Accordingly, there is a need to standardize measurements
across various systems. This can be achieved by the use of
MRI phantoms, which are objects that act as a surrogate for
different body sections or tissue types. Such phantoms will

typically contain solutions or materials that are ground truth 3

standards having fixed and known values for various MRI
parameters such as T1, T2, T2*, Tirho relaxation times;
Proton Density; and Apparent Diffusion Coefficient. The use
of such standards enables systems to be characterized and

standardized, and facilitates comparisons of images across 3

different machines and time points.

One factor that creates variability across systems and
across measurements at different times is temperature. Vari-
ous MRI parameters such as T1 and T2 relaxation time can
be temperature dependent. Apparent Diffusion Coeflicient is
inherently temperature dependent. Therefore, variations in
MRI bore temperatures, which can span from 15° C. to 25°
C., will render the use of phantoms as ground truth standards
irrelevant if not accurately corrected for temperature.

‘Temperature measurement in MRI has been achieved
using various methods and devices. Currently, digital, alco-
hol, or fiber optic thermometers are used to assess tempera-
ture. These methods are problematic for various reasons.
Fiber-optic thermometers are expensive, require laborious
set-up and tear down to implement. Other temperature
sensors are invasive and require human interface with the
phantom before and after the scan, and potentially compro-
mise the MRI phantom integrity by introducing unwanted
microorganisms into the phantom.

There has been significant effort over the last few decades
to develop a non-invasive Nuclear Magnetic Resonance
(NMR) thermometer. A well-known experimental method to
determine temperature is to image the chemical shift
observed between the NMR signal produced by a hydrogen
atom bonded to an oxygen atom (O—H) and a hydrogen
atom bonded to a carbon atom (C—H) in a molecule.
‘Typical chemicals used in such a thermometer include, but
are not limited to, alcohols and glycols which contain both
types of hydrogen atoms. As the temperature changes, the
O—H peak resonance frequency shows a pronounced shift,
while the C—H peak resonance frequency remains constant.
The separation in frequency between these peaks can be

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directly correlated to an absolute temperature. Such chemi-
cal shift thermometers work well in an NMR environment
where the main magnetic field is homogeneous, and other
spatial dependencies can be ignored since the samples are
small. However, for MRI, where the sample sizes and fields
of view are large, variations in the magnetic field strength
will introduce errors in the chemical shift based thermom-
eter, prohibiting accurate temperature measurement if the
thermometer is not reproducibly placed in the exact position,
and if variations of the main magnetic field exist between
scanners.

Previously, the use of liquid crystals has been proposed
for monitoring temperature in an MRI context. Liquid
crystals undergo temperature-specific phase changes that
can be detected by MRI. In Canadian Patent Number 1,288,
812, entitled “Thermometry using phase transitions in
encapsulated liquid crystals and magnetic resonance detec-
tion methods,” by McRae et al., it was proposed to use liquid
crystals and their temperature-dependent phase shifts as an
indicator of temperature, in the context of in vivo hyper-
thermia treatment of tumors. Temperatures in the range 42°
C. to 45° C, were assessed by NMR spectra of microencap-
sulated liquid crystals, where temperature-dependent liquid

5 crystal phase transitions, from nematic phase to isotropic

phase, were monitored by NMR spectra, wherein a single
peak was observed in the spectrum for the nematic phase and
a multitude of peaks were observed for the isotropic phase.

The methods disclosed by McRae et al., while useful in
the hyperthermic treatment regimen to which they were
applied, are insufficient for calibration of phantoms. Few
MRI scanners are equipped with the capability to do the
spectroscopic analysis needed for McRae’s technique, and
obtaining MR spectra is a time consuming process that
would not integrate well with the process used to charac-
terize or standardize an MRI using a ground truth tissue
mimicking standards. Furthermore, the signal obtained
using McRae’s methods is inadequate for the error assess-
ment needs addressed herein due to the much smaller
magnetic field used. Additionally, McRae’s implementation
required the use of the fluorine 19 to produce measurable
signal; such material is expensive and toxic. Additionally,
McRae’s method requires the liquid crystals to be microen-
capsulated, making the transition temperature too broad for
the accuracy needed for an MRI calibration thermometer

Accordingly, there remains a need in the art for novel
temperature sensing methods for the facile characterization
of MRI systems.

SUMMARY OF THE INVENTION

Disclosed herein are novel implementations of liquid
crystal temperature sensing techniques. The novel thermom-
eters and techniques of the invention employ liquid crystals
in an innovative way to achieve consistent temperature
assessment and the accurate use of standards. The novel
liquid crystal thermometers of the invention provide the art
with an inexpensive and facile means of accurately measur-
ing temperature when characterizing equipment against
ground state standards.

BRIEF DESCRIPTION OF THE DRAWINGS.

FIGS. 1A and 1B depict vessels of the invention used to
encase liquid crystals. FIG. 1A is a drawing depicting the
cylindrical vessel (101), with top protrusion (102) and
bottom receiving indent (103). FIG. 1B is a cutaway view of


US 10,809,331 B2

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two or more liquid crystal compositions, wherein each of
the two or more liquid crystal compositions is enclosed
in a separate container and wherein each composition
has a phase transition temperature between an ordered
state and a liquid state, and wherein the ordered state
and liquid state of the liquid crystal compositions
produce distinct signals when imaged by a selected
MRI scan technique.

2. The thermometer of claim 1, wherein

the two or more liquid crystal compositions comprise
cholesteric liquid crystals

3. The thermometer of claim 1, wherein

the two or more liquid crystal compositions have phase
transition temperatures between 15 and 25° C.

4. The thermometer of claim 1, wherein

the two or more liquid crystal compositions have phase
transition temperatures that vary by a fixed increment.

5. The thermometer of claim 4, wherein

the increment is 0.1, 0.5, or 1.0° C.

6. The thermometer of claim 1, wherein

each container comprises a material that does not generate
a substantial signal when imaged by the selected MRI
scan technique.

7. The thermometer of claim 6, wherein

the material is selected from the group consisting of
polychlorotriflouroetheylene; polytetrafluoroethylene;
a fluoropolymer; polycarbonate: polypropylene: poly-
ethylene terephthalate; glycol modified polyethylene
terephthalate; polylactic acid; acrylonitrile butadiene;

high density polyethylene, low density polyethylene; 3

polyvinylchloride; and

polyurethane.

8. The thermometer of claim 7, wherein

the container comprises an opening sealed by a sphere.

9. The thermometer of claim 1, wherein

the selected scan technique is selected from the group
consisting of a spin echo, gradient echo and spoiled
gradient echo scans.

10. The thermometer of claim 1, wherein

the containers containing the two or more liquid crystal
compositions comprise complementary interlocking
features and wherein the containers are configured in an
assembly of interlocked containers.

11. A method of assessing temperature of an Mill bore,

comprising

acquiring an image of a thermometer by a selected Mill

scan technique;

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wherein the thermometer is in the MRI bore;

wherein the thermometer comprises two or more liquid
crystal compositions, wherein each of the two or more
liquid crystal compositions is enclosed in a separate
container and wherein each composition has a phase
transition temperature between an ordered state and a
liquid state, and wherein the ordered state and liquid
state of the liquid crystal compositions produce distinct
signals when imaged by the selected MM scan tech-
nique:

by the acquired image, assessing the break point between.
a first liquid crystal composition being that with the
lowest phase transition temperature which is in the
liquid state and a second liquid crystal composition,
being that with the highest phase transition temperature
that is in the solid state;

wherein the Mill bore temperature is determined as a
being in a range intermediate between the phase tran-
sition temperatures of first and second liquid crystal
compositions.

12. The method of claim 11, wherein

the liquid crystal compositions comprise cholesteric lig-
uid crystals.

13. The method of claim 11, wherein

the two or more liquid crystal compositions have phase
transition temperatures between 15 and 25° C.

14. The method of claim 11, wherein

each container comprises a material selected from the
group consisting of polychlorotriflouroetheylene: poly-
tetrafluoroethylene; a fluoropolymer; polycarbonate;
polypropylene; polyethylene terephthalate; glycol
modified polyethylene terephthalate; polylactic acid;
acrylonitrile butadiene; high density polyethylene, low
density polyethylene; polyvinylchloride; and polyure-
thane.

15. The method of claim 11, wherein

the containers containing the two or more liquid crystal
compositions comprise complementary interlocking
features and wherein the containers are configured in an
assembly of interlocked containers.

16. The method of claim 11, wherein

the selected scan technique is selected from the group
consisting of a spin echo, gradient echo and spoiled
gradient echo scans.

17. The method of claim 11, wherein

the break point is assessed by an automated analysis.

+ * RR Oe


US 10,809,331 B2

chemicals is removed by either vacuum degassing, sonica-
tion, and/or passing the chemical stream through a nonme-
tallic oxygen scavenger such as ascorbic acid, ascorbate
salts, or catechol prior to sealing it within a container or
compartment.

In the thermometer of the invention, each of the two or
more aliquots of liquid crystals are encased in a container.
The container which contains each liquid crystal composi-
tion must be composed of a material that does not generate
substantial MRI signal itself. Exemplary materials that may
be utilized include polytetrafluoroethylene, e.g. TEFLONTM
or other fluoropolymers; polycarbonate (PC); polypropylene
(PP); polyethylene terephthalate (PET); glycol modified
polyethylene terephthalate (PETG); polylactic acid (PLA);
acrylonitrile butadiene (ABS); high and Low density poly-
ethylene (HDPE/LDPE); polyvinylchloride (PVC); and
polyurethane. An especially suitable material is polychloro-
triflouroetheylene (aka PCTFE, KEL-FTM, and NEOF-
LONTM). As set forth below, this material has particularly
low perfusion and can advantageously be welded, which
eliminates the need for glued seams or joints, increasing
robustness. Flouroethylene based plastics are ideal, but also
extremely difficult to glue due to the low surface energy of
the material. In addition, the high thermal expansion coef-
ficient of liquid crystals can produce large stresses on glued
joints that can cause failure of the glued joints. Chemical
compatibility and stability of the glue when in contact with
liquid crystals and water simultaneously limits the selection
of glues that can be used. For example, an aliphatic amine

such as n-Heptane adhesive may be used, for example 3

LOCLITE 770 TM (Ellesworth Adhesives, Gemantown,
Wis., USA)

critical factor in the design of the container is the liquid
crystal aliquot size. An aliquot that is too large will act as a

heat reservoir, and the temperature thereof will display 3

hysteresis with the surrounding environment, i.e. it will not
respond quickly to changes in the surrounding temperature
and therefore cannot act as an accurate thermometer. For
example, in some applications, a thermal time constant of 1
minute or less is desirable, to ensure rapid equilibration to
the surrounding environment. Conversely, an aliquot that is
too small cannot generate sufficient signal to be visualized in
an MRI scan. The inventors of the present disclosure have
determined that a minimal aliquot size of 65 mm? liquid
crystals and a maximum size of 3,500 mm? liquid crystals
provides a sufficient signal while being sufficiently respon-
sive to bore temperature. For example, aliquots of 120-700
mm? may be used.

Another critical container factor is the shape or geometry
of the container. The shape of the container must be designed
for image capture in one or more planes of the MRI system.
Generally, the containers of the invention will comprise a
volume having a regular shape, such as a cube, cuboid, or
cylinder. For example, as depicted in FIG. 1A, the container
may comprise a regular cylinder of 7 mm inner diameter,
and 8 mm height. The wall thickness of the vessel is an
important consideration as well, as an overly thick encase-
meant will slow the equilibration of the liquid crystals with
the MRI bore or MRI phantom. For example, a vessel wall
thickness of 0.2-0.7 mm, for example, 0.5 mm, may be used.

The volume and container shapes are selected to ensure
visualization of a cross section of the liquid crystals in one
plane of the MRI system. For example, the volume of
material in the vessel should be at least one voxel in width,
as determined by the settings and capabilities of the selected
system. For example, the volume may comprise at least two,
three, or four voxel widths. For example, in one implemen-

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tation, it would be desirable to capture at least four voxels
of the liquid crystal to ensure visualization of at least two
identical adjacent voxels of the liquid crystals. If the volume
of the liquid crystals is too small, ie. sufficient voxels
comprising primarily the liquid crystal material are not
imaged, the material will be undersampled. Worse, if there
are not sufficient voxels comprising primarily the liquid
crystal material, it is possible the signal would be averaged
with the wall of the vessel or even worse the neighboring
liquid crystal. This would result in signal averaging across
liquid crystal vessel units, greatly increasing the uncertainty
on the temperature measurement.

Thermometer Assembly.

In a preferred implementation, the thermometer of the

5 invention will comprise an assembly comprising multiple

containers arranged in a linear or flat configuration, enabling
imaging of the containers of the assembly in a single plane.
The multiple containers will comprise aliquots of liquid
crystals from the aforementioned series of liquid crystal
solutions, for example 2, 3, 4, 5, 6, 7. 8, or more containers
having liquid crystals with phase transition temperatures at
regular increments, e.g. 0.1, 0.25, 0.5, or 1.0 degrees.

In one implementation of the invention, each container
comprises a pair of complementary interlocking elements
that enable different containers to be snapped together in a
linear configuration or other configuration. Such comple-
mentary elements may comprise, for example, tongue and
groove elements, rib and debossed groove elements, or other
complementary structures that interlock, or which can serve
as attachment sites joined by adhesives or welding of the
container material. The thermometer may comprise an
assembly of interlocked or connected containers. For
example, interlocking elements are depicted in FIG. 1A and
an assembly comprising multiple interlocked or connected
containers is depicted in FIG. 2. Alternatively, the thermom-
eter may comprise a housing or other body wherein multiple
containers are held in place or otherwise contained in the
housing or body. The thermometer assembly may comprise
a linear configuration or any other configuration that allows
for separate imaging of the multiple containers in the same
plane.

Thermometer assemblies can be designed for compatibil-
ity with MRI phantom components.

Novel Container Design.

The unique requirements of the present invention led to
the development of a novel container design which includes
many features that facilitate successful operation of the
thermometer. As depicted in FIG. 1A, the novel container of
the invention comprises a cylindrical body which can be
filled with a liquid crystal solution. In one embodiment, the
container of the invention comprises polychlorotriflouroeth-
eylene. This fluoropolymer is chemically inert and has
among the lowest permeability of water and other com-
pounds. Generally, chemically inert plastics are difficult to
glue, however PCTFE is somewhat unique as a fluoropoly-
mer in that it can be welded, enabling construction of a
vessel without glue joints that might interfere with MRI
signals due to the chemical makeup of adhesives. The
container of the invention comprises two pieces of PCTFE
welded together to form a vessel having an opening, for
example, a circular opening. The opening may comprise a
proximal narrow section, an intermediate wider section, and
distal narrow section. This opening enables the vessel to be
filled to the top without any airspace, and it can then be
sealed by forcing a hard plastic or glass sphere or bead into
the opening, wherein the diameter of the sphere is slightly
larger than that of the intermediate section of the opening. A


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the vessel, showing the top opening (104) sealed by an
inserted hard plastic sphere, such as PMMA (105).

FIG. 2 depicts a thermometer assembly of the invention
(201) comprising six individual vessels (202) snapped
together end to end.

FIG. 3 represents a thermometer assembly of the inven-
tion which has been read by an appropriate MRI scan to
determine whether liquid crystals are in the ordered or liquid
phase.

DETAILED DESCRIPTION OF THE
INVENTION

The liquid crystal MRI thermometers of the invention
comprise a collection of different liquid crystal composi-
tions, wherein each of the liquid crystal compositions has a
unique phase transition temperature. A series of liquid
crystal compositions having phase transitions spanning the
range of typical MRI bore temperatures, e.g. 15-25° C., may
be used. The assemblies of the invention are compatible with
MRI phantoms and can be included therein. Temperature
can be assessed quickly using T1-weighted, T2-weighted, or
other scan protocols, wherein phase changes are readily
assessed by distinct visual signals.

The concept of the invention is demonstrated by the
exemplary embodiment depicted in FIG. 2. FIG. 2 depicts an
illustrative implementation of the invention comprising vari-
ous elements:

a plurality of containers;

wherein each container contains a unique liquid crystal 3

composition having a unique phase transition tempera-
ture;

wherein the liquid crystal compositions have phase tran-
sition temperatures that span the selected range of
interest;

3

wherein liquid crystals in the isotropic, liquid phase and

in the crystalline, ordered phase yield distinct signals in
a selected MRI scan; and

wherein the temperature of the MRI phantom can be
determined by observing which compositions in the
series are in the ordered phase, which are in the
transition phase, and which are in the isotropic phase.

Each element of the invention is described in detail next.

Liquid Crystals.

The devices and methods of the invention encompass the
use of various liquid crystal compositions. The liquid crystal
compositions will be selected and/or formulated such that
each has a phase transition temperature at a selected value of
interest. The liquid crystals may comprise any thermotropic
liquid crystal composition known in the art, wherein an
MRI-detectable phase transition occurs within a selected
temperature range, for example, in the range of 15-25° C.
For example, sterol-based liquid crystals, such as cholesteric
liquid crystals may be used.

Exemplary liquid crystals that may be used in the practice
of the invention include those described in U.S. Pat. No.
5,422,033, entitled “Phase transition-type liquid crystal
composition,” by Mochiziki et al.; U.S. Pat. No. 5,508,068,
entitled “Cholesteric liquid crystal composition, color-form-
ing liquid crystal composite product, method for protecting
liquid crystal and color-forming liquid crystal picture lami-
nated product,” by Nakano et al.; and in Brown and Wolken,
Liquid Crystals and Biological Systems, Academic Press,
NY, 1979.

A phase transition temperature, as known in the art, is a
temperature point, or range of temperature values, wherein
a volume of liquid crystals will transition between a liquid

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or isotropic phase and an ordered or crystalline phase such
as the nematic, cholesteric, or smectic phase. At tempera-
tures above the phase transition temperature, the composi-
tion will switch from an ordered (“crystalline”) phase to an
isotropic (“liquid”) phase due to the kinetic energy/molecu-
lar motion of the molecules being too much to support the
lower-energy ordered phase.

An MRI-detectable phase transition means a phase tran-
sition that is detectable by a selected MRI scanning tech-
nique wherein an image is generated and wherein crystals in
the liquid or isotropic phase generate a different signal, ie.
imaged differentially, from crystals in the ordered phase (e.g.
nematic, cholesteric, or smectic). Liquid molecules in the
crystalline state align with magnetic field and proton dipolar

5 interactions cause rapid transitions that cause line broaden-

ing and shortening of the T2, and hence do not produce any
MR signal. In the isotropic phase, they are fully liquid and
contribute to the image signal intensity. Thus, the phase
transition is MRI-detectable.

The liquid crystal assemblages of the invention will
comprise two or more separately contained aliquots of liquid
crystals, wherein each separate aliquot comprises a unique
composition having a unique phase transition temperature.
The two or more aliquots of liquid crystals will define a
temperature range, defined by the lowest transition phase
temperature of the two or more liquid crystal compositions
and the highest transition phase temperature of the two or
more liquid crystal compositions, and encompassing inter
mediate phase transition temperature values, if any.

Ina preferred implementation, the temperature range is a
range typically found within the bore of an MRI system,
which will typically encompass room temperatures, for
example within the range of 15-25° C. It will generally be
preferred that the liquid crystal compositions have phase
transition temperatures separated at regular intervals, for
example 0.1, 0.25, 0.5 or 1.0 degree Celsius increments.

A series of liquid crystal compositions having phase
transition temperatures separated by regular intervals can be
formulated by mixing two miscible liquid crystal composi-
tions having divergent phase transition temperatures in
different proportions to arrive at different intermediate phase
transition temperature values. For example, as described in
Example 1, two liquid crystal compositions having phase
transition temperatures of 11° C. and 42.5° C. were admixed
in different proportions to create a series of seven compo-
sitions with phase transition temperatures in the range of
17-23° C.

The liquid crystal compositions can be used in the pure or
native form, but can also be diluted in an organic solvent to
achieve different temperature change characteristics, for
example, as described in U.S. Pat. No. 5,508,068.

Containers.

Each aliquot of the two or more liquid crystal composi-
tions will be enclosed in a separate container or a separate
compartment of a body comprising multiple containers,
separated from each other and from the atmosphere or
surrounding liquid, to prevent loss, oxidation, evaporation of
solvents, and contamination by microbes. For clarity, enclo-
sure or encasement of liquid crystals, as used herein, refers
to containing or enclosing the materials in a macroscale
vessel, and does not refer to microencapsulation techniques,
such as those utilized in McRae, wherein microscopic aggre-
gates of crystals were coated with biocompatible coatings.

Oxidative attack on unsaturated bonds of the liquid crys-
tals will broaden the temperature range of the phase transi-
tion by 0.1° C. to 1° C. or more. To prevent oxidation of the
enclosed composition, oxygen in the native liquid crystal


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determine temperature. In another embodiment, the scan is
analyzed by automated means, wherein an analysis algo-
rithm or other technique is used to determine the break point
between liquid and ordered crystals states in the series of
liquid crystal solutions forming the thermometer. Such auto-
mated analysis techniques for determining light, dark, and/or
gray can be readily implemented by one of skill in the art,
for example, using computer aided detection algorithms.

When analyzing a phantom or other target comprising
ground state standard for purposes of characterizing an MRI
system, a single temperature scan may be performed or
multiple temperature scans may be performed. For example,
a temperature scan at the beginning of phantom assessment
and at the end of phantom assessment may be performed and
the average temperature of the two scans may be used to
designate temperature of the ground state standards. Alter-
natively, the data acquired at an earlier timepoint would use
the first temperature assessment and the data acquired at a
timepoint closer to the end of the scan would use the last
temperature assessment. Ideally, the temperature would be
measured at several time intervals to provide an adequate
assessment of the temperature change over time.

In a related embodiment, the scope of the invention
comprises a method of characterizing an MRI system,
comprising the steps of:

determining MRI bore temperature or the temperature of

ground state standards by means of a liquid crystal
thermometer of the invention;

measuring one or more temperature-dependent properties *

of the ground state standard; and
correcting or adjusting the measure of the one or more
temperature-dependent properties of the ground state

standard based on the temperature measured by the

liquid crystal thermometer of the invention.

By this method, a correction factor can be applied to MRI
assessments of ground state standards based on the known
relationship between ground state standard properties and
temperature.

EXAMPLES
Example 1. Formulation of a Liquid Crystal Series

Asseries of seven cholesteric (sterol based) liquid crystal
formulations exhibiting a cholesteric to isotropic transition
between 17° C. and 23° C. was formulated by mixing
different proportions of two liquid crystal compositions. The
liquid crystal compositions were product number GB310
(LCR Hallerest, Glenview Ill, USA), having a phase tran-
sition temperature of 11° C. and GB320 (LCR Hallcrest,
Glenview IIl., USA), having a phase transition temperature
of 42.5° C. Table | lists the proportion of the two solutions
in each mixture.

‘Transition
‘Temperature % 115°C. LC % 42.5° C. LC
IPC. 83.6 16.4
18°C. 80.6 194
19°C. 71.6
20°C, 746
ec, 116
22°C. 68.7
BPC. 657

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3!

60

65

10
Example 2. Liquid Crystal Thermometer

A liquid crystal thermometer was constructed using mul-
tiple interlocking containers. Containers as depicted in FIG.
1A were constructed from PCTFE. Each container was filled
with a different solution of liquid crystal compositions of the
series of Example 1, by syringe, and was sealed by plugging
the opening with hard plastic ball. The opening diameter was
0.035 inches+1-0.001 inches, and the sphere had a diameter
of 0.0394 inches+/-0.002 inches. The interlocking contain-
ers were snapped together in order of increasing phase
transition temperature. The resulting assembly is depicted in
FIG. 2.

Example 3. Temperature Measurements

The liquid crystal thermometer of Example 2 was placed
in a Diffusion Standard (model number 128, QalibreMD
(High Precision Devices), Boulder Colo., USA). The phan-
tom was imaged on a 3 T clinical system (Siemens Prisma“)
before and after routine measurements of ground state
standards, with a scan duration of one hour. Using a 2D
FLASH sequence, the temperature at initial scan was
19-19.7° C. and at the end of scanning the temperature had
warmed to the 19.7-19.9° C., as determined by the light and
dark break point between liquid crystal aliquots. (A FLASH
sequence is a fast low angle shot sequence, also known as a
spoiled gradient-echo sequence using a flip angle of less
than 90 degrees.) A digital thermometer measured the tem-
perature prior to scanning at 18.6+0.2° C., and post-scanning
at 19.6#0.2° C. Differences between the initial temperature
as measured by the digital thermometer and the liquid
crystal thermometer are due to the 10 minute time difference
between when the phantom temperature was measured with
the digital thermometer and the first temperature scan was
taken.

Additional scans of the thermometer were performed in
both pre-clinical (Agilent) and clinical (Siemens) systems at
3 T using various scan parameters:

Pre-clinical gradient echo: flip angle 70°, TR 200 ms, TE

5.00 ms, 0.55 mm? acquisition time 51.2 s;

Pre-clinical spin-echo: flip angle 90°, TR 20.10 ms, TE

13.82 ms, 0.55 mm? acquisition time 41.2 s;
Pre-clinical spoiled gradient echo (SPGR): flip angle 20°,
TR 60.48 ms, TE 5.00 ms, 1.17 mm? acquisition time
1.9 s; and
Clinical spoiled gradient echo: flip angle 70°, TR 200 ms,
TE 2.47 ms, 0.625 mm’.
In each of the scans, the break point between liquid crystal
aliquots was readily ascertained, both by manual visual
examination of the scans and by computer aided detection
algorithms, and measured temperatures were within 0.5° C
of bore temperatures measured by digital thermometer.

All patents, patent applications, and publications cited in
this specification are herein incorporated by reference to the
same extent as if each independent patent application, or
publication was specifically and individually indicated to be
incorporated by reference. The disclosed embodiments are
presented for purposes of illustration and not limitation.
While the invention has been described with reference to the
described embodiments thereof, it will be appreciated by
those of skill in the art that modifications can be made to the
structure and elements of the invention without departing
from the spirit and scope of the invention as a whole.

What is claimed is:

1. A thermometer for monitoring bore temperature of an
MRI system, comprising



a2 United States Patent

Mirowski et al.

US010809331B2

(10) Patent No.:
(45) Date of Patent:

US 10,809,331 B2
Oct. 20, 2020

(54)

(71)

(72)

(73)
(*)

(21)

(22)
(65)

G1)

(52)

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LIQUID CRYSTAL THERMOMETER FOR

MRI

Applicants:QALIBRE MD, INC.., Boulder, CO
(US); NATIONAL INSTITUTE OF
STANDARDS AND TECHNOLOGY,

Inventors:

Assignee:

Notice:

Appl. No.:

Filed:

Gaithersburg, MD (US)

Elizabeth Mirowski, Nederland, CO
(US); Michael Snow, Erie, CO (US);
Kathryn Keenan, Boulder, CO (US)

QalibreMD, Boulder, CO (US)

Subject to any disclaimer, the term of this
patent is extended or adjusted under 35

USC. 154(b) by 102 days.
15/912,420
Mar. 5, 2018

Prior Publication Data

US 2019/0271750 Al Sep. 5, 2019
Int. Cl.

GOIR 33/48 (2006.01)
GOIK 15/00 (2006.01)
GOIR 33/56 (2006.01)
GOIR 33/28 (2006.01)
GOIN 24/08 (2006.01)

US. Cl.

CPC

Field of Classification Search

CPC

GOIR 33/4804 (2013.01); GOIK 15/005
(2013.01); GOIN 24/08 (2013.01); GOIR
33/28 (2013.01); GOIR 33/5601 (2013.01)

GOIR 33/4804; GOIR 33/28; GOIR
33/5601; GOIK 15/005; GOIN 24/08

See application file for complete search history.

WT

(56) References Cited
U.S. PATENT DOCUMENTS

4,859,360 A * 8/1989 Suzuki GOIK 11/165
252/299.7

5,810,888 A * 9/1998 Fenn AGIK 41/0028,
600/407

6,280,384 BL* 8/2001 Loefiler GOIK 7/38
374/E7.04

8,335,554 B2* 12/2012 Pananakis AGIN 1/403
600/411

9,852,705 B2* 12/2017 Kim G09G 3/3614
2004/0064031 Al* 4/2004 Dean GOIR 33/3804
600/410

2005/0136002 AL* 6/2005 Fossheim AGIB 5/01
424/111

2007/0197904 AL* 8/2007. Viglianti AGIB 5/055
600/420

(Continued)

FOREIGN PATENT DOCUMENTS,

CA 1288812 9/1991

Primary Examiner — Nathaniel T Woodward
Assistant Examiner — Philip L Cotey

(57) ABSTRACT

Provided herein are novel liquid crystal based devices for
the facile measurement of temperature in an MRI system.
The thermometers comprise a plurality of vessels wherein
each vessel contains a liquid crystal composition having a
unique phase transition temperature. By scanning with
appropriate techniques, the state of the liquid crystals in each
vessel can be assessed, and the temperature at the time of the
scan can be determined by the state of the liquid crystal
compositions. Also provided are novel vessels and assem-
blies of vessels that can be used as MRI thermometers and
which are compatible with MRI phantoms.

17 Claims, 2 Drawing Sheets

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7 302

308

SN

| 305

= 308

yo 307



US 10,809,331 B2

cross sectional diagram depicting an exemplary vessel and
sealing sphere of the invention is depicted in FIG. 1B.

The material of the container will comprise a material
with sufficient flexibility or give to enable the sphere, under
pressure to pass through the narrow section without cracking
or breaking the material and become lodged and held in
place in the intermediate wider space, creating an airtight
and liquid-proof seal, and to accommodate the pressure
forces exerted by the liquid when the sphere is forced into
the locked position. For example, an opening of sufficient
width to inject the liquid crystals by syringe may be used, for
example, to accommodate a 19 gauge needle may be used,
for example, a diameter of 1 mm.

Phantoms.

The thermometers of the invention may be placed within
an MRI calibration phantom, as known in the art, in order to
enable accurate characterization of the MRI system. The
phantom may comprise a body, wherein the body contains
an MRI thermometer of the invention and also contains one
or more containers containing ground state standard mate-
rials. In an alternative embodiment, the MRI thermometer is
immersed in a ground state material within the phantom.

Temperature Measurement.

The scope of the invention encompasses the afore-de-
scribed thermometers. The scope of the invention further
encompasses methods of using such thermometers to assess
MRI bore and/or MRI phantom temperature. The general
method encompasses the steps of:

acquiring an image of an MRI thermometer of the inven-

tion by a selected MRI scan technique;

wherein the thermometer is in the MRI bore;

by the acquired image, assessing the break point between.

a first liquid crystal composition being that with the
lowest phase transition temperature which is in the

liquid state and a second liquid crystal composition, 3

being that with the highest phase transition temperature
that is in the solid state;

wherein the MRI bore temperature is determined as a

being in a range intermediate between the phase tran-

sition temperatures of first and second liquid crystal

compositions.
In the broadest implementation, the method encompasses
performance of an MRI scan wherein the thermometer is
imaged using MRI methodologies that result in differential
signal of the liquid crystal aliquots when the liquid crystals
are in an isotropic phase vs. an ordered phase. For example,
the scan may result in an image wherein ordered crystals are
dark (no or little signal) and isotropic, liquid crystals are
imaged as bright (strong signal). In some implementations,
an intermediate phase may also be detectable, the interme-
diate phase being indicative of a temperature at or near the
phase transition temperature of the liquid crystals, for
example, showing as gray.

Temperature is assessed by determining the break point
within a series of liquid crystal temperature standards, i.e.
identifying a first liquid crystal composition in the series
having the lowest phase transition temperature which is in
the liquid state and a second liquid crystal composition in the
series having the highest phase transition temperature which
is in the solid state. Bore and/or phantom temperature can be
determined as a value or range intermediate between the
phase transition temperatures of the first and second com-
positions. Alternatively, identification of the liquid crystal
aliquot having an intermediate phase (gray) can be used to
determine the temperature value or range. For example, in a
liquid crystal thermometer having aliquots with phase tran-
sition temperatures at 1° C. increments between 17° C. and

S

40

8

23° C., if the aliquot having a phase transitions temperature
of 19° C. is observed to be in the crystalline, ordered phase
(e.g. dark in the scan) and the aliquot having a phase
transitions temperature of 20° C. is observed to be in the
liquid, isotropic phase (e.g. bright in the scan), the bore
temperature is assessed as being within the range of 19-20°
Cc

A drawing depiction of a scan of the thermometer assem-
bly of the invention is presented in FIG. 3. The thermometer
is an assembly (301) comprising multiple vessels (302, 303,
304, 305, 306, and 307), wherein each vessel contains a
liquid crystal composition with a unique phase transition
temperature, ordered from lowest phase transition tempera-
ture (302) to highest (307). At the time of the scan, the

5 temperature was intermediate between the phase transition

temperature of vessel 303 and that of 305. As the tempera-
ture at the time of the scan was higher than the phase
transition temperature of the liquid crystals in vessels 305,
306, and 307, these liquid crystals were in an isotropic state,
yielding a bright signal. The temperature at the time of the
scan was lower than the phase transition temperature of the
liquid crystals in vessels 302 and 303, and these liquid
crystals were in an ordered state, yielding a dark signal. The
temperature at the time of the scan was at about the phase

5 transition temperature of the liquid crystals in vessel 304,

with these liquid crystals were in a mixed state with some
ordered and some isotropic, yielding a gray signal
The scan may comprise any MRI imaging technique
capable of producing differential signals by liquid crystals in
the ordered and liquid states (and intermediate states, in
some embodiments). Exemplary scans include spin echo
(SE), gradient echo (GRE) and spoiled gradient echo
(SPGR). Preferably, the scan will be short, for example,
being on the order of 0.25-2.0 minutes, for example, 1
minute or less. This insures that a snapshot of current
temperature can be captured in the event of changing bore
and/or phantom temperatures and that the temperature data
acquisition does not significantly add to the duration of the
scan time, and subsequently the quality control process used
to evaluate and report the characteristics of the MRI
machine.
Exemplary scans include:
gradient echo, for example with parameters of; flip angle
70°, TR 200 ms, TE 5.00 ms, voxel size 0.55 mm? by
3 mm slice thickness, acquisition time 51.2 s;
spin-echo, for example with parameters of: flip angle 90°,
TR 20.10 ms, TE 13.82 ms, voxel size 0.55 mm? by 3
mum slice thickness, acquisition time 41.2 s;
spoiled gradient echo (SPGR), for example with param-
eters of: flip angle 20°, TR 60.48 ms, TE 5.00 ms, voxel
size 1.17 mm? by 3 mm slice thickness, acquisition
time 1.9 s; and
spoiled gradient echo, for example with parameters of:
flip angle 70°, TR 200 ms, TE 2.47 ms, voxel size 0.625
mm? by 3 mm slice thickness, acquisition time less than
sixty seconds,
The exemplary parameters presented above may be varied
by one of skill in the art to attain suitable measurements that
distinguish ordered and liquid crystal states for the selected
liquid crystal compositions used in a particular thermometer.
For example, the enumerated parameters of flip angle,
repetition time (TR), echo time (TE), voxel size, and acqui-
sition time listed above may be varied by up to 5%, up to
10%, or up to 25% in alternative implementations.
In one embodiment, the resulting scan is analyzed by
visual inspection of the image, wherein the break point in the
series of liquid crystal solutions is noted by an observer to



U.S. Patent Oct. 20, 2020 Sheet 2 of 2 US 10,809,331 B2

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U.S. Patent

Oct. 20, 2020 Sheet 1 of 2

US 10,809,331 B2

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US 10,809,331 B2

Page 2
(56) References Cited
U.S. PATENT DOCUMENTS
2009/0191131 Al* 7/2009 Fossheim AGIB 5/01
424/9.321
2009/0192383 Al* 7/2009 Pananakis GOIR 33/4804
600/411
2014/0005523 Al* 1/2014 Kohler AGIB 5/055
600/411
2015/0247908 Al* 9/2015 Liu GOLR 33/4804
324/309
2015/0273245 Al* 10/2015 Nurmilaukas AGIN 7/02
601/3
2016/0133204 Al* 5/2016 Kim G09G 3/3614
345/101

* cited by examiner