Note: Descriptions are shown in the official language in which they were submitted.
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MULTILAYERED TISSUE PHANTOMS, FABRICATION METHODS, AND USE
FIELD OF THE INVENTION
[0001] The present invention relates in general to phantoms for biomedical
applications, their fabrication and their use, more specifically, the
invention
relates to phantoms targeting endoscopic applications of biomedical optics,
including optical techniques that characterize the detailed structure of
tissues as
a function of depth.
BACKGROUND OF THE INVENTION
[0002] An optical phantom is a fabricated sample that provides an optical
response similar to biological tissues for examination by one or more optical
imaging system. In many cases, the interaction of electromagnetic (EM)
radiation
(herein "light") with a tissue is described by the scattering and the
absorption
processes. In a scattering process, light is essentially redirected in a
different
direction. In the absorption process, light is absorbed and energy is
converted
into a different form. Therefore, phantoms are often made of scattering and/or
absorbing materials or mixtures that can produce the desired response. In the
literature, one can find a variety of phantom fabrication processes with
different
materials that provide optical responses somewhat similar to tissues. The main
differences between the resulting phantoms are often in terms of other
important
properties, like mechanical properties or durability.
[0003] Many phantom compositions are made of liquid or gel. These phantoms
suffer from a conservation period limited to months in the best cases due to
perishing or water evaporation (US Patent 7,288,759 to Frangioni et al.). A
housing is sometimes used to increase durability but can be inconvenient in
use
because such housings are known to influence measurements (US Patent
6,675,035 to Grable et al.).
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[0004] Phantoms that are durable for years can be obtained with polymeric
matrices such as polyester, epoxy resins or dried poly(vinyl alcohol) mixed
with
inorganic components (US Patents 6,083,008 to Yamada et at., and 6,224,969 to
Steenbergen). However, these matrices are hard and do not provide mechanical
properties similar to soft tissues. This limits some uses of phantoms, for
example
in training surgeons on operations, as haptic and tactile responses are not
similar, especially for procedures like endoscopy.
[0005] Phantoms with elastomeric matrices, like silicone, combine durability
with
mechanical properties somewhat similar to soft tissues. These were presented
in
a number of publications reviewed by Pogue and Patterson, in Journal of
Biomedial Optics, 11 (4), 041102, (2006). The mechanical properties can also
be
adjusted by modifying the silicone formulation (Oldenburg et at. in Optic
Letters,
30 (7), 747, (2005) and US Patent 7,419,376 to Sarvazyan). Some optical
properties can be obtained by introducing inorganic powders in the silicone
matrix. An experimental calibration can be conducted to relate the powder
concentrations and the optical properties, like by Beck et al. in Lasers in
Medical
Science, 13 (3), 160 (1998) and by Lualdi et al. in Lasers in Surgery and
Medicine, 28, 237, (2001). Some slab shape phantoms using different mixtures
representing multiple skin layers and lesions have also been published, for
example by Urso et al, in Physics in Medicine and Biology, 52 (10), N229,
(2007).
[0006] Very few phantoms have been designed for endoscopic applications.
Endoscopic optical applications are increasing with the development of
specialized optical probes that are able to deliver light to internal organs
using
optical fibers. Many of these organs, like blood vessels, bronchi, the
esophagus,
the colon, etc. have openings of somewhat cylindrical or tubular geometries,
or
define somewhat closed cavities. Herein a lumen is used to refer to a tubular
or
a closed cavity that is formed of walls on two or three sides. Such walls
generally
include tissues built up in layers, each of which having different
composition,
function, and optical and mechanical properties.
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[0007] Silicone-based phantoms with complex geometries have been molded in
various shapes (US Patent 6,807,876 and Bays et al. in Lasers in Surgery and
Medicine, 21(3), 227, (1997)) but do not show a detailed layered structure. A
molding process limits the shapes and the dimensions of the phantoms to the
ones of the available molds. Furthermore molding of very thin layers, less
than
about 25 pm for example, can be exceedingly difficult, generally requires high
pressure (which can damage other delicately formed features) and is prone to
failure.
[0008] Further still, it is generally desired to provide phantoms that contain
inclusions such as features that optically and/or mechanically represent
lesions,
tumors, scar tissues, inclusions, herniations etc. While highly planar
features can
be readily provided, even between layers of a phantom, by application of paint
or
powder prior to a subsequent overmolding step, the embedding of solid objects
within a mold can be exceedingly difficult. A general failure to provide
precise
localization of the object within a mold and numerous defects are recurring
problems with solid objects in molds. These problems may be exacerbated by
subsequent overmolding steps.
[0009] Finally it is very difficult to produce very uniform thickness layers,
or to
provide a very high measure of control of thickness as a function of position
of
the layer, unless the phantom is molded. With multilayered structures, the
costs
and tolerances of many molds that fit inside one-another is prohibitive for
many
applications.
[0010] There remains a need for multilayer optical phantoms representing
animal tissues and organs containing lumens, and for methods of fabricating
same, especially for fabrication methods that permit precise control of the
layer
thicknesses, down to layers of the order of 10 pm, and permitting solid body
inclusions between the layers.
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BRIEF SUMMARY OF THE INVENTION
[0011] In accordance with the present invention a method is provided for
fabrication of tissue-like phantoms that represent animal tissues and organs
containing lumens, with tissue details like multiple layers. Each layer of the
phantom has independently controlled optical properties that mimic the
optical/infrared response of the targeted tissue layers. The layers may have
controlled mechanical properties to mimic the behavior of the tissue. The
first
layer of a phantom is created by the application of the layer material on a
supporting element, which effectively forms the lumen of the phantom.
Subsequent layers are formed on top of previous layers, generally while the
first
layer is supported by the supporting element. The forming of the layer
involves
depositing a viscous flowable material and, before it completely solidifies,
selectively redistributing the material to control a thickness distribution of
the
layer. A desired thickness distribution of the layer is preferably obtained by
relative rotational motion between the supporting element and a wiper which
contacts the material. The wiper may substantially remove material (e.g. if it
is
sharp and meets the material at a steep angle), or may substantially only
spread
the material (e.g. if it is dull or meets the material at a shallow angle),
and may
both spread and remove material at any given point in time.
[0012] The supporting element can be any structure that will form the lumen in
a
desired shape. It can be, but is not limited to, a shaft, a rod, a mandrel or
an
inflated balloon that could be deflated for removal. The shape of the
supporting
element is not restricted to one with rotational or translational symmetry,
but is
preferably defined with respect to a single axis of rotation.
[0013] It is an aspect of the invention to be able to adjust the optical
properties
of the phantom layers. Different optical properties are obtained with
different
concentrations of one or more powders that scatter and/or absorb light, in a
polymer matrix. Control is obtained by establishing a relationship between the
concentrations of said products and the optical properties of the phantoms or
the
signal they produce when measured with a certain system. Such a relation can
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be wavelength dependent. In a preferred embodiment, highly stable inorganic
powders and pigments are used as the products that scatter and/or absorb light
to ensure high durability. The preferred inorganic powders and pigments are
aluminum oxide (A12O3), titanium oxide (TiO2), and carbon black.
[0014] It is another aspect of the invention to be able to control the
mechanical
properties of the phantom layers while approaching those of tissue. This is
particularly useful in providing lifelike response to endoscopic probing,
stent
deployment, balloon dialation, and numerous other procedures within lumens of
animals, which require significant training, as they must be performed without
any
cues other than tactile, and those provided by imaging.
[0015] Therefore, in many cases, the possible materials for the phantoms are
elastic materials. In a preferred embodiment, the chosen elastic materials are
also highly stable, so that their properties vary minimally in time. Such
materials
include silicones and thermoplastics that have mechanical properties that
depend
on the polymer formulation and possibly also on polymerization conditions.
[0016] In certain embodiments, the phantoms can also have other solid
structures integrated to mimic pathologies, etc. The structures can be added
during or after the process of the layer formation. They can be internal or
external
to the layers. The structures can be solid, liquid or gaseous. In the case of
a
liquid or gas, a void can be created by first adding a temporary material,
crafting
the phantom, removing the temporary material, and then filling the void with
the
desired product. In addition, phantoms can be attached (welded, glued, fused,
stitched, etc.) together to create more complex structures.
[0017] The invention provides various ways of using the phantoms. The
phantoms can be used to calibrate a system. A calibration procedure consists
in
measuring the phantom with a specific system, and then quantifying the
performances, for example using previously ascertained properties of the
phantom. The measurements can also be compared with images of the phantom
taken with different imaging systems. Qualitative or quantitative differences
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between the images may be used to evaluate, compare or test the imaging
systems.
[0018] Another way to use the phantoms is to use them as a convenient and
cost-effective replacement of real tissue for the training of medical staff on
the
use of imaging systems. A collection of phantoms that mimic a variety of
tissue
conditions, including normal tissues and pathological tissues, may have
further
value for such training or for the evaluation of imaging systems.
[0019] The phantom may be integrated in a setup that recreates realistic
conditions such as contact with circulating fluids, with a range of
temperatures or
pulsating pressure. The phantoms preserve their properties after having been
exposed to measurements in realistic conditions. For example, a blood vessel
phantom will maintain its integrity after being exposed to a liquid such as
saline
solution or blood, either static or in circulation, either with pulsating
pressure for
simulating heart beats or not. That property is useful because it can be used
to
quantify the performances of different instruments operating under realistic
conditions and then to compare those performances.
[0020] It would then be possible to test medical procedures. The medical
procedure can be a normal procedure such as the deployment of a stent or a
balloon angioplasty; it can also be a new medical procedure, tool, or implant
that
is being developed or improved.
[0021] Phantoms fabricated using our method can be used as a reference
standard. With some materials such as alumina and carbon black in silicone the
phantoms retain their optical and mechanical properties over a very long
period.
They can therefore be used to evaluate and quantify the optical performance of
an instrument over time. The results of those evaluations can be compared for
a
given instrument, at different times to ensure that there is no degradation
and
quantify any differences. It is of strategic importance for a medical team to
be
able to verify the performance of an instrument before its use in an operating
room.
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[0022] The phantoms, having some known or selected optical and mechanical
properties can be reproduced with substantially the same properties. Such a
phantom, available in multiple, substantially identical copies, can be
distributed to
various users, (medical teams, commercial users, research teams or to other
users) and serve as a reference standard. Such a reference can then be
compared, with different real tissue conditions (normal, abnormal but healthy,
or
pathological).
[0023] Our phantom can be used as a replacement for real tissue for the
development or testing of various procedures. The procedure may be a medical
procedure such as the deployment of a stent, angioplasty, a blood flushing
technique, like removal of plaque from a lumen, or another procedure where the
measurement of the condition of the tissue may be involved.
[0024] For example, an OCT device operated at a typical wavelength of 1300nm
can not see through blood. The blood is therefore displaced temporarily and
generally replaced by a liquid transparent at 1300nm such as a saline
solution.
The liquid may be inside a compliant balloon and the probe is used inside the
balloon that must be inflated to the dimension of the artery. Another approach
consists in injecting the saline solution directly into the artery. If the
volume is
large enough, over a short period of time the blood would be almost entirely
replaced by the saline. The OCT probe can be used efficiently during a few
seconds. The flushing procedure may be initially developed using a phantom.
The OCT probe would be used to quantify the effectiveness of the method.
[0025] Optical measurements within an artery are often complicated by the
geometrical deformation, like diameter size fluctuations, that are caused by
blood
pressure changes. Our phantom has mechanical properties that mimic the
mechanical properties of a vessel. Therefore, it is possible to reproduce the
geometrical deformations caused by the heart beats. Using that realistic
model, it
becomes easier to develop robust algorithms that would be able to recognize
the
target features even in the presence of heart beats and like factors that
complicate measurements in living tissues.
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[0026] The phantoms may mimic mechanical properties of tissue structures
sufficiently to permit surgeons to learn how to operate on the tissues with
the
phantoms. Concurrently the phantoms can be used with new or old tools,
devices, implants etc. and can teach the user how to use the same, with or
without the functions of the imaging system. A surgeon may train on the
phantom to use an imaging device and 3D volume visualization software to find
pathological features, like obstructing plaques in arteries. Phantoms can be
produced, stored, and disposed of, far more effectively and at less expense
than
an animal, or human cadaver tissues, especially given ethical considerations.
Additionally necrotic tissue has properties that are difficult or expensive to
reproduce in order to mimic living tissue. Abnormal tissues that are not very
common can be reproduced using phantoms, once characterized making it easier
to train someone to identify a larger set of possible tissue conditions.
[0027] In a specific embodiment, the phantoms represent blood vessels. Blood
vessels typically have three distinct layers, the intima, the media, and the
adventitia. Each of these layers can be affected by diseases like
atherosclerosis,
which can take several forms. The choice among available materials to mimic
the
optical and mechanical properties of the layers and diseases permits high
durability, in the range of years. The present invention includes the
fabrication of
blood vessel phantoms with morphological details representing the tissue
layers
and various forms of blood vessel diseases. As the intima is typically less
than 25
pm thick, molding such phantoms is impractical.
[0028] Specifically, in accordance with the invention there is provided:
A method for producing a multilayer tissue phantom, the method comprising:
successively forming at least two layers, each layer formed by:
depositing a viscous flowable material to encircle at least a portion of a
supporting element or over a previously formed layer of the phantom
supported by the supporting element;
selectively redistributing the material while material is solidifying to
control a thickness distribution of the layer; and
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allowing the material to solidify sufficiently to apply a next layer,
wherein at least neighbouring layers are of different composition, and
wherein the compositions and thickness distributions of the layers are
chosen to provide desired optical properties and mechanical properties of
the phantom.
The above method wherein selectively redistributing the material comprises
contacting the material with a wiper while the wiper is in relative rotational
motion
with respect to the material.
The above method further comprising successively forming a third layer.
The above method wherein selectively redistributing:
is performed by the wiper that extends a length of the phantom and bears a
desired profile across that length whereby different thicknesses of the
deposited layers may be deposited relative to the previously deposed layer,
or the supporting surface;
is performed by the wiper, which extends a fraction of the length of the
phantom, the wiper moving axially across the length of the phantom during
the relative rotational motion, wherein radial motion of the wiper imparts a
desired profile to the layer;
is performed in part by contacting the material with a wiper while rotating
the
supporting element along an axis wherein control over a radial position of
the wiper is faster than the relative rotational motion and the layer has
different thicknesses at different angles; or
is performed by the wiper which consists of a blade, an edge, a sharp point,
or a rubber wiper.
The above method wherein the viscous flowable material deposited:
comprises a polymer resin selected for durability;
comprises at least 40 wt. % molten polymer resin;
comprises at least 40 wt. % curable polymer resin;
comprises at least 40 wt. % dissolved polymer in a volatile solvent;
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comprises a silicone;
comprises a silicone with a poly(dimethyl siloxane);
comprises, for each layer, a proportion of resin of silicone to poly(dimethyl
siloxane) chosen to obtain a desired mechanical property for the layer.
comprises a same polymer resin in the composition of all layers;
comprises a selected amount of 0.0001-100 mg/mI of an optical attenuating
additive;
comprises a selected amount of 0.0001-100 mg/ml of an optical scattering
additive;
comprises an amount of an optical scattering and optical attenuating powder
additives selected to provide:
a backscattering amplitude for the layer proportional to a square root of
a sum of the squared backscattering amplitudes of each of the powder
additives for given concentrations; and
an attenuation coefficient for the layer equal to a sum of attenuation
coefficients of each of the powder additives for given concentrations;
comprises a selected amount of 0.0001-100 mg/mI of at least one of the
following: carbon black, titania, and alumina, in powdered form;
comprises a selected amount of 0.0001-100 mg/ml of carbon black; or
comprises a selected amount of 0.0001-100 mg/ml of alumina.
The above method wherein throughout the forming, the phantom is supported by
the support element, which:
consists of a shaft, a rod, a tapered mandrel, or an inflated balloon;
is substantially covered by the phantom in 2 dimensions;
is substantially covered by the phantom in 3 dimensions;
has a profile corresponding to a cavity within an organ of an animal;
The above method wherein depositing the viscous flowable material comprises:
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applying the material through a conduit that is translated axially over a
length of the phantom said supporting element or the said previous layer;
applying the material through a conduit connected to the wiper;
applying the material through a conduit that is positioned with respect to an
axis of the relative rotational motion that is at a substantially fixed angle
with
respect to the wiper;
applying the material at a part of a surface of the support element or the
previously formed layer, and allowing a viscous flow under gravity to at least
substantially coat the surface;
applying the material at a part of the surface that is rotating at a rate that
is
fast enough to prevent the material from dripping under the force of gravity,
and slow enough to prevent ejection of the material by centrifugal force; or
concurrently applying the material at one location while contacting
previously deposited material at another location to selectively redistribute
the material.
The above method wherein allowing the material to solidify to a desired degree
comprises controlling a temperature distribution of the layer and selecting a
composition of the material that solidifies at a temperature higher than an
ambient temperature.
The above method:
wherein forming one of the layers further comprises embedding a feature at
a location on the outer layer after the selective redistributing;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing;
wherein forming one of the layers further comprises applying a compound at
a location on the outer layer after the selective redistributing;
wherein forming one of the layers further comprises spraying a compound at
a location on the outer layer after the selective redistributing;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing,
and
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further comprising, after one or more subsequent layers are formed,
penetrating the one or more subsequent layers to inject or remove material
in contact with the solid feature;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing,
and
further comprising after one or more subsequent layers are formed,
penetrating the one or more subsequent layers to inject a fluid to dissolve
the solid feature, followed by removing the fluid and solute;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing,
and
further comprising after one or more subsequent layers are formed,
penetrating the one or more subsequent layers to inject a fluid to dissolve
the solid feature, followed by removing the fluid and solute and refilling a
pocket formed within the phantom with another material;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing,
and
further comprising after one or more subsequent layers are formed, locally
heating the solid feature until it exceeds a critical temperature, and
penetrating the one or more subsequent layers to remove a fluidized part of
the solid feature;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing,
and
further comprising after one or more subsequent layers are formed, locally
heating the solid feature until it exceeds a critical temperature, penetrating
the one or more subsequent layers to remove a fluidized part of the solid
feature, and refilling a void created by the removal of the fluidized part
with
another material;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing,
and
further comprising after one or more subsequent layers are formed, locally
heating the solid feature until it exceeds a critical temperature, penetrating
the one or more subsequent layers to remove a fluidized part of the solid
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feature, refilling a void created by the removal of the fluidized part with
another material, and repairing a hole in the phantom produced by the
penetration;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing,
and
further comprising after one or more subsequent layers are formed, locally
heating the solid feature until it exceeds a critical temperature, penetrating
the one or more subsequent layers to remove a fluidized part of the solid
feature, and refilling a pocket formed within the phantom with a fluid;
wherein forming one of the layers further comprises embedding a solid
feature at a location on the outer layer after the selective redistributing,
and
further comprising after one or more subsequent layers are formed, locally
heating the solid feature until it exceeds a critical temperature, penetrating
the one or more subsequent layers to remove a fluidized part of the solid
feature, refilling a pocket formed within the phantom with a fluid, and
repairing a hole in the phantom produced by the penetration;
further comprising applying a non-covering material in a liquid form on one
of a part of an inner surface of an inner layer and a part of an outer surface
of an outer layer and directing a flow of the non-covering material under the
action of gravity to cover the part of the inner or outer surface without
covering the whole of the inner or outer surface;
further comprising applying a non-covering material in a liquid form on one
of a part of an inner surface of an inner layer and a part of an outer surface
of an outer layer and directing a flow of the non-covering material under the
action of gravity to cover the part of the inner or outer surface without
covering the whole of the inner or outer surface, the non-covering material
having a same composition as the inner layer or outer layer; or
further comprising producing a hole in one of a part of an inner surface of an
inner layer and a part of an outer surface of an outer layer and depositing a
non-covering material in a liquid form in the hole, the non-covering material
being of different composition than the inner or outer layer.
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A collection of phantoms obtained by applications of the above method to serve
as standard samples representative of a single tissue in abnormal healthy,
normal healthy and/or pathological states.
A use of a phantom produced according to the above method comprising
inserting the phantom into the optical imaging system and imaging a portion of
the phantom.
The above use further comprising:
placing the phantom in contact with other tissue-like structures or liquids;
submitting the phantom to temperature variations or pressure variations that
can be found normally or exceptionally in an animal;
testing a tool, process or implant on the phantom;
attaching a second phantom fabricated according to the method of claim 1
to the phantom such that lumens are coupled
The above use further comprising comparing independently characterized
parameters of phantom to calibrate the system.
The above use further comprising inserting the phantom into a second optical
imaging system, imaging the phantom using the second system, and comparing
the image data from the system and second system to compare the two.
The above use further comprising operating the system in a training mode to
provide the user with feedback on the operation of the system.
A phantom consisting of a chamber covered by a structure having at least 2
polymer-based layers having different compositions exhibiting different
scattering
and attenuation values within optical and infrared regions of the
electromagnetic
spectrum wherein one of the at least two polymer-based layers has a thickness
of
less than 25 pm. and
A phantom consisting of a chamber covered by a structure having at least 2
polymer-based layers having different compositions exhibiting different
scattering
and attenuation values within optical and infrared regions of the
electromagnetic
spectrum wherein a solid object is embedded.
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[0029] The above and other features of the present invention will become
apparent in the following description. However, it is to be understood that
the
scope of the invention is not limited to the specific embodiment described in
this
document.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] In order that the invention may be more clearly understood, embodiments
thereof will now be described in detail by way of example, with reference to
the
accompanying drawings, in which:
FIG. 1 schematically illustrates a setup used in the formation of a layer of a
phantom in accordance with a first embodiment of the invention in which a
wiper
is used that covers an extent of the phantom;
FIG. 2 schematically illustrates a setup used in the formation of a layer of a
phantom in accordance with a second embodiment of the invention in which a
wiper is used and is translated axially to cover an extent of the phantom;
FIG. 3 is a graph of average backscattered amplitude as a function of depth
for a
calibration sample, and the curve resulting from its fit with a mathematical
equation;
FIG. 4 is a graph of backscattered amplitude coefficients as a function of
concentration for twelve (12) calibration samples of alumina powder in
silicone;
FIG. 5 is a graph of total attenuation coefficients as a function of
concentration for
twelve (12) calibration samples of alumina powder in silicone;
FIG. 6 is a graph of backscattered amplitude coefficients as a function of
concentration for eight (8) calibration samples of carbon black powder in
silicone;
FIG. 7 is a graph of total attenuation coefficients as a function of
concentration for
eight (8) calibration samples of carbon black powder in silicone;
FIG. 8 is a graph of true stress as a function of elongation ratio of five (5)
examples formed of PDMS, Sylgard 184 resin, and Sylgard 184 reactive in
different proportions;
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FIG. 9 is a graph comparing true stress as a function of elongation ratio for
a
sheet formed of 22.5 : 15 : 1 ratio of PDMS : Sylgard 184 resin : Sylgard 184
reactive, and for a porcine coronary artery;
FIG. 10 is a graph of average backscattered amplitude as a function of depth
for
a porcine coronary artery and that of a curve resulting from the fit of the
three
tissue layers with a mathematical equation;
FIG. 11 is an OCT image showing the backscattered amplitude as a function of
depth for a phantom produced as an example of the invention;
FIG. 12 is a schematic cross-sectional view of a coronary artery phantom with
an
added volumetric structure mimicking intimal thickening;
FIG. 13 is a schematic cross-sectional view of a coronary artery phantom with
an
added volumetric structure mimicking a calcification in a thickened intima;
and
FIG. 14 is a schematic cross-sectional view of a coronary artery phantom with
an
added volumetric structure mimicking a lipid pool in a thickened intima.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The invention provides a fabrication method and uses for phantoms that
mimic the optical response and/or the mechanical behavior of tissue structures
that at least partially enclose lumina within walls having multiple tissue
layers.
One aspect of the method involves a controlled process for fabricating layers
of a
specified geometry when one or more of the layers is/are thin, or contain(s)
embedded solid objects. Applicant further provides a method for controlling an
optical response of the phantom layers to match the response of the tissue
structure. Applicant further provides a method to fabricate phantoms that have
mechanical response similar to those of actual tissues.
Layer fabrication
(0032] A process for fabricating a multi-layer structure of a desired geometry
involves forming successive layers of the phantom. Herein a layer is taken to
be
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a macroscopically homogeneous composition (although exogenous features may
be attached or embedded in separate steps, and microscopic inclusions may not
be uniformly enough distributed to be homogeneous at some scales, and may
vary somewhat in density such as in graded deposition) that is substantially
continuous around the lumen of the phantom, throughout at least 50% of a
transverse length of the phantom. Herein the "lumen" is a volume of an
internal
passage surrounded by a tissue structure (or the phantom which mimics the
same).
[0033] The layer formation process involves the deposition, redistribution and
solidification of material that is initially in a viscous liquid state.
Throughout this
forming, the deposed layer is supported by a supporting element. The
supporting
element defines the shape the lumen of the tissue structure modeled by the
phantom. It can be in the shape of a shaft, a rod, a mandrel, or an inflated
balloon, and may or may not be rotationally, axially, or otherwise symmetric.
The
supporting element may be designed to receive the material only along a
fraction
of its length, and this fraction may include an end (in which case the lumen
is a
chamber closed at one end), or not (in which case the lumen is tubular). The
supporting element may have a generally cylindrical shape, but doesn't
necessarily have the radial or the longitudinal regularity of an exact
cylinder.
[0034] The deposition may be performed by pushing the viscous liquid material
through a conduit held over the supporting element, although in alternate
embodiments the material may be poured, dipped, or sprayed onto the
supporting element (or phantom thus far produced). This may be performed
manually, or by pushing the material through a number of holes spaced axially
along the supporting element, by a scanning arm that moves the conduit axially
across the supporting element, or manually, for example, through a syringe.
The
supporting element may be rotating during the supply of the material, or only
after
the supply of the material is complete, depending on a viscosity of the liquid
material, a solidification rate of the material, and a desired thickness of
the layer.
It is usually preferable for the material to remain in a viscous liquid state
until at
least the material is spread all around the supporting element (or the
previously
18
CA 02668114 2009-06-02
deposited layer supported thereon) so that a seam is not formed of solidified
material, resulting in a weaker joint and non-uniform material properties.
[0035] Furthermore, the material may be supplied while a wiper (or other
shaping element) redistributes the material deposited, or may be applied
before
wiping commences. If a wiper used extends the length of the phantom, and the
supply of the liquid operates over the entire length, an angular offset
(relative to
the axis) between the wiper and the number of holes to provide a desired dwell
time between when the material is applied to a surface (of the supporting
element
or the previously deposited layer) before the wiper is encountered. Similarly
if the
conduit applied the material from a point and a relatively narrow wiper is
used to
shape the deposited material, they may be scanned together while the
supporting
element is in rotation, and a fixed axial and/or angular offset between the
wiper
and supporting element may be chosen to provide the desired dwell time.
Applicant has continuously rotated the supporting element during the forming
which includes deposition, redistribution, and solidification phases. The
deposition of the layer may continue with the same material being deposited
over
the same material to produce a layer that is thicker than can be applied
without
dripping and wastage to produce a monolithic material layer, and a wiper may
be
only applied sparingly throughout the majority of the deposition, as will be
appreciated.
[0036] An element, located in the vicinity of the supporting element, shapes
the
layer by removing excess liquid material, preferably before the complete
solidification. To ensure control of a thickness distribution all around the
tubular
structure for each layer, the supporting element and the shaping element
(preferably a wiper) are in relative rotational motion. It is also possible to
have the
supporting and the shaping element in relative translational motion
synchronized
with the rotation to obtain uneven but controlled thickness at any point.
Multiple
layers are obtained by successive deposition and solidification of viscous
liquid
material of different compositions leading to different optical and/or
mechanical
properties. For each layer, the distance between the supporting element and
shaping element is adjusted to obtain the desired thickness. It is also
possible to
19
CA 02668114 2009-06-02
use external means for precisely monitoring the layer thickness during the
action
of the shaping element, and further properties may be monitored throughout
deposition.
[0037] To create a new layer, the material that is deposited is replaced by a
material of a different composition. Enough time, and thermal conditions are
provided to solidify the previously applied material to enable the present
surface
of the phantom to support the application of a new layer. The different
composition may be a blend of the same components in different proportions, or
different compounds. The compounds envisaged are principally thermoplastics
and elastomers, but may contain various additives, including those that alter
the
optical properties of the material, such as colour, absorption (at given
frequencies), and scattering. Advantageously by changing concentrations of
some formulations, different mechanical properties (e.g. Young's modulus) can
be changed, while providing excellent bonding of adjacent layers. It will be
appreciated that certain graduated properties can be provided within a same
nominal layer by continuously varying a density of an additive during the
coating.
[0038] FIG. 1 is a schematic illustration of an apparatus in accordance with
an
embodiment of the present invention. The apparatus consists of a supporting
element shown as a cylindrical shaft 1. The shaft 1 is coupled to a motor 2
through a reducer 3 to rotate at a controlled speed. The circular arrow 4
indicates
a direction of rotation of the shaft around its longitudinal axis. The
preferred
rotation speed is of the order of one rotation per second for usual
viscosities and
temperatures of the materials used, but in any case should be maintained
within
a certain range. The lower limit of the range is somewhat higher than a speed
where the viscous liquid would fall by gravity and drip. The higher limit of
the
range is somewhat lower than a speed where the viscous liquid would be ejected
by centrifugal force. At a balanced speed the action of gravity is
counterbalanced
by a flow rate of the material permitting continuous, even coating of the
material
to build up.
CA 02668114 2009-06-02
[0039] The viscous liquid material 5 is deposited by manually translating a
syringe 6 along the shaft axis while the shaft I is rotating and is
substantially
concurrently shaped by a knife blade 7. The blade 7 has a square profile that
extends the length of the phantom and is suited to create a layer with a
cylindrical
or a conic outer surface, regardless of the shape of the previous layer.
Naturally
the blade 7 can be switched with one having a variety of profiles.
[0040] The blade 7 is mounted on a support 8 that allows the precise
adjustment
of the distance (d) and the angular position between the blade and the shaft.
The
distance from the axis to the blade 7 in the illustrated embodiment is
provided by
rotational movement of the blade 7 relative to the axis, although it could
equally
be provided by other motion having a radial component, such as tangential
motion. The blade 7 is in a horizontal plane that passes through the axis. The
angle (4) created by the blade 7 and the axis in the horizontal plane can be
adjusted.
[0041] A heating element 9 may be located in the vicinity of the shaft 1,
particularly if the material has accelerated solidification at higher
temperature.
The blade's position d can be changed, in a controlled manner as layer
material
is deposited or between successive depositions, either manually, as shown, or
using automated equipment known in the art. A different syringe can be used
for
the new material. Initial viscosity of the liquid polymer and cure
temperature,
which impacts on the time of curing, can both be used to control, to some
extent,
the spreading of the liquid mixture. This allows limited control on the shape
of the
layer. Applicant has found that excellent control of thicknesses at every
point can
be provided with the use of a wiper.
[0042] FIG. 2 schematically illustrates a second embodiment of the invention
that incorporates axial translation of a smaller shaping element to produce a
desired layer profile with a radial component of motion. This allows
controlling
the thickness of a layer at every location on the surface of the phantom,
meaning
all axial positions along the phantom, and all positions around the phantom,
if the
radial motion is faster than the cycle rate of the rotation. The principal
differences
21
CA 02668114 2009-06-02
between the embodiment of FIG. 2 with that of FIG. 1 is the inclusion of a
scanning dispenser, and machining of the shaft 20, both of which are
considered
to be well within the scope of one skilled in the art to produce.
[0043] The supporting element is a cylindrical shaft 20 that is machined with
a
flat groove 21 to obtain a d-shape on a short section of the shaft 20. The
shaft 20
is coupled to a motor 22 through a reducer 23 to rotate at a controlled speed,
as
in the embodiment of FIG. 1. Arrow 24 indicates a direction of rotation of the
shaft
around its longitudinal axis. Viscous liquid material 25 is deposited through
a
conduit 26 in translation along the axis. The flow of material through the
conduit 26 does not entrain air bubbles or cause splattering or spraying, and
ranges from 0.01-50 ml/min. The conduit is controlled to release the material
25
(via a pump and a viscous liquid mixing chamber well known in the art and not
shown) at a desired rate that can be varied during translation to assist in
the
shaping of the layer. The material 25 is shaped by a narrow rubber wiper 27.
The
wiper 27 is mounted on a biaxial translation stage 28. The biaxial translation
stage 28 is connected to a programmable controller 29 that receives a signal
for
synchronization with the rotational motion. The programmable controller 29
allows the rubber wiper to follow any desired pattern that determinates the
layer
thickness at all locations. Programmable controller 29 may further control the
release of material by volume and the axial motion of the conduit 26. While
the
translation of the conduit 26 along the axis is shown schematically as
separate
from the wiper, it will be appreciated that there may be a single stage for
moving
both the conduit 26 and the wiper 27, which may have a fixed, configurable
offset
from each other in the axial and/or radial (relative to the axis) directions
as
desirable for the material 25 to be in a desired condition upon encountering
the
wiper.
[0044] At a change in layer, different material will be deposited through the
conduit 26, or through a different conduit. If a same conduit 26 is used for
depositing different layers the process may involve switching supplies,
evacuating the supply conduit 26 and purging the supply conduit 26 as well
known in the art. The subsequent material may be mixed in a same hopper that
22
CA 02668114 2009-06-02
was previously used with the addition of material to change relative
concentrations of components, in which case the conduit 26 may simply be
purged.
[0045] It is well known how to produce a variety of materials for use in the
present invention. Numerous methods of producing a viscous fluid that is
polymerizable, settable, gelable, curable or vitrifiable under chosen
thermodynamic conditions are fully applicable. The process may involve melting
a resin that will cure under controlled thermal conditions, or dissolving the
polymer in a volatile solvent that evaporates to form the polymer. Evaporation
may be expedited by vacuum or forced air.
[0046] The material may be prepared in a conventional manner by weighing the
needed amounts of additives for producing desired properties of the layer,
selecting mechanical properties for the layer by selecting a formulation for
the
polymer matrix, and then adding the necessary volume of the selected resin in
with the additives. In some cases, a viscosity of the material can be
decreased
with the addition of a thinner in a suitable volume. The mixture preferably
undergoes extended mixing, to homogenize the material. Afterwards, if needed,
the thinner may be evaporated in vacuum for a few hours. Finally a reactive
may
be added and dispersed by manual mixing prior to deposition through the
conduit.
[0047] The choice of product and composition of the polymer matrix mostly
impacts on the mechanical properties of the phantoms, which is discussed
further, as there are a wide variety of polymers that are substantially
transparent
and can retain the additives.
Optical properties
[0048] Applicant has used the following methods to produce layers that have
optical properties similar to those of tissue layers. Dyes may be added to
match
chromatic response of the tissues. These may be omitted if the phantom is
going
23
CA 02668114 2009-06-02
to be imaged only with narrowband light. The materials used in layer
fabrication
may principally mimic the optical response of a tissue layer as detected with
a
specific optical characterization or imaging technique. In order for a phantom
to
mimic the tissue response, not all optical properties need to be reproduced.
[0049] In some cases, off-the-shelf materials having optical properties close
to
the target tissue may be used. In order to gain better control on the optical
properties of the phantoms, one can mix materials in concentrations selected
according to known relationships. The relationship can be obtained either
theoretically, using the material parameters and a model of the system, or
experimentally by fabricating sets of samples with different concentrations
and
measuring the response of the system. Such a technique therefore allows
mimicking tissues exhibiting a wide range of optical properties.
[0050] In one embodiment of current interest, phantoms are fabricated to mimic
the response of tissues to optical coherence tomography (OCT) systems. To
mimic an OCT response, a phantom must provide backscattering, attenuation,
and a speckle structure. An OCT system collects a portion of the light that is
backscattered along the depth of the tissue. In a phantom, scattering
materials
provide backscattering. The amplitude of backscattering decreases with depth
from attenuation due to scattering, including backscattering, and due to
absorption. This backscattering and attenuation can be mimicked by adding
various materials that scatter and/or absorb light into the polymer matrix
Optical
properties of tissues constituents are wavelength dependent. Therefore, in
general, as is cost effective, a phantom will be designed to mimic a tissue
over a
limited wavelength range. In a tissue, a dense assembly of structures (nuclei,
mitochondria, cell membrane, etc) scatters light, and since OCT is a coherent
imaging technique, resulting images contain speckle. In a phantom, this
speckle
can be obtained by using a dense assembly of scatterers the size of which
being
on the order of or smaller than the wavelength of the OCT imaging.
[0051] Optical backscattering and attenuation needs to be mimicked only on a
length scale larger than the speckle size. For each layer of a given tissue,
OCT
24
CA 02668114 2009-06-02
measurements are averaged over many speckles to provide target values for
backscattering and attenuation. Consequently, to obtain optical properties for
a
tissue layer or a phantom layer, the OCT signal is averaged for each depth
over
many speckles. The resulting OCT profile is fitted to a mathematical
expression
to extract parameters.
[0052] In a tissue, the different layers can have a wide range of optical
properties. When dispersing a single additive to scatter and absorb light in a
polymer matrix, the signal profiles that can be mimicked are limited to pairs
of
backscattered amplitude and attenuation values of the additives available.
Using
a combination of additives that scatter and/or absorb light differently
provides
more liberty on the properties that can be obtained.
[0053] These additives can be fine particles in the form of powders added to a
substantially transparent polymer matrix. Powders with particle dimensions on
the
order of the wavelength of light (to be used to examine and image the phantom)
can be introduced in high enough concentration to provide a speckle field.
Furthermore, by using powders, the concentration of scatterers in the phantom
is
directly known from the mass of powder put in a specific transparent matrix
volume.
[0054] The choice of materials used to scatter and/or absorb light also has a
certain impact on how the properties of the phantom evolve in time. To
fabricate
phantoms that keep the same properties over a long period, the preferred
powders are inorganic, like metal oxides and inorganic pigments. Such powders
are highly stable.
[0055] A preferred mixture is one that uses a first powder that mostly
provides
the backscattered amplitude, and a second powder that mostly provides
attenuation. Our preferred choice of materials to match the response of
various
tissues to OCT systems working at a center wavelength of 1.3 pm is alumina and
carbon black powders mixed in a transparent matrix. These powders do not
CA 02668114 2009-06-02
degrade in time. When mixed in a stable matrix, they yield highly durable
phantoms.
[0056] To determine the concentration of powders, knowledge of the
relationships between the optical properties of the system and the
concentration
of components is required. For a powder in transparent matrix, the
backscattered
amplitude of OCT signal is proportional to the square root of the
concentration of
powder, and the total attenuation is directly proportional to the
concentration. A
more detailed description can be found our paper: Bisaillon et al, Physics in
Medicine and Biology, 53 (13), (2008). When mixing different powders, the
resulting backscattered amplitude measured by OCT (Atot) is obtained by the
quadratic addition of the amplitudes produced by the respective concentrations
(C1) of each powder (having backscattered amplitude (A1), the backscattered
amplitude being proportional to the square root of the concentration). The
total
attenuation (atot) is obtained by the linear combination of the attenuation
produced by each powder (at) as a function of relative concentration. These
relations are expressed by eq. 1 and eq. 2:
with Aoc (eq. 1)
Atot = XA ,
atot = a(Ci ). (eq. 2)
(0057] OCT systems provide interference measurements on an arbitrary linear
or logarithmic scale that maps the momentary intensity to the scale
representing
a dynamic range of signal intensities that can be measured. The relationship
between the backscattered amplitude measured and the concentrations is
system-dependent, varying by a constant of proportionality from one system to
another. Therefore, to fabricate a phantom based on these relationships, the
target values for the tissues must have been obtained with the same system.
The
system dependency is only required for the fabrication process. The
relationship
between the optical response of the resulting phantoms and the tissue is
nevertheless system-independent. This means that the resulting phantom will
26
CA 02668114 2009-06-02
mimic the tissue when measured with any OCT system operating in the same
wavelength range.
[0058] The specific relationships between optical properties and concentration
for certain compositions were obtained by producing sets of calibration
samples
and analyzing their signal profiles. A set of calibration samples can consist
of
cured mixtures that all have a different concentration of one single powder in
the
matrix.
[0059] Mixtures are prepared by weighing the needed amounts of alumina and
carbon black, and then adding the necessary volume of the silicone resin. In
some cases, the mixture viscosity was decreased with the addition of hexane in
a
volume that can be around half the volume of the resin. The alumina used in
the
present studies is a 1 pm de-agglomerated powder obtained from Struers
(Mississauga, Canada). The carbon black is a product from Cabot (Boston, MA)
called Monarch 700TH, having a size distribution of about 40 to 100 nm. Both
powders have small enough sizes to provide a speckle field. The silicone used
was a mixture of pure poly(dimethyl siloxane) (Dow Corning 200R 50 cSt
viscosity PDMS) and of Sylgard 184TM resin and reactive. The proportion of
PDMS : Sylgard resin : Sylgard reactive was 15:15: 1.
[0060] The mixture was sufficiently homogenized with at least 5 hours of
sonication in an ultrasonic bath (Branson 1510), interrupted every hour by
manual mixing. Afterwards, if needed, the hexane was evaporated in vacuum for
a few hours. Finally the reactive is added and dispersed by manual mixing.
[0061] The mixture was then cured to form a layer by pouring the mixture into
slab-shaped molds. The curing occurred at 70 C in an oven during approximately
one hour. The samples were imaged (B-scan) with a proprietary time domain
OCT system as described in US Patent 7,428,086 performing 353 depth scans
per second, with a depth resolution of about 15 pm and a transverse spot size
of
about 40 pm. The image is averaged in the transverse direction at each depth.
The average depth profile is then fitted mathematically with an exponential
decay
27
CA 02668114 2009-06-02
that includes a correction for the incident beam and the collection of
scattered
light. This correction is obtained using a model according to Gaussian beam
propagation theory. The fitting model has the form of eq. 3:
A
exp[- 2az]
1 + (z/z,(eq. 3)
where the fitted parameters A and a are the backscattered amplitude and the
total attenuation, respectively. The variable z is the location in depth and
z, is
determined from the optical configuration of the OCT system.
[0062] The analysis of the signal profile is illustrated in FIG. 3. It shows
the
average profile of a sample containing 20.5 mg/ml of alumina in the silicone
matrix. The fitted exponential decay curve (according to the model) is also
plotted
over the data and the resulting fitting values (A =1440, a = 2mm-1) obtained
are
also displayed.
[0063] After measuring all the samples from a set and after fitting their OCT
profile, the needed relationships between concentration, and backscattering
and
attenuation coefficients, are obtained. FIGs. 4-7 show plots of backscattered
amplitude or attenuation as a function of concentration for alumina and carbon
black. The differences between these powders demonstrate clearly that the
carbon black is a relatively good attenuator with less backscattering, whereas
the
alumina is a relatively good backscatterer with less attenuation. This permits
various relative concentrations of these two components to span the range of
attenuation and backscattering coefficients between these. Substantially
alumina
can be used to obtain a target level of the backscattering, and carbon black
can
be used to increase the attenuation with weak impact on the resulting
backscattered amplitude.
[0064] FIG. 4 shows a plot of the backscattered amplitude coefficients as a
function of the concentration obtained from twelve samples of alumina in
silicone.
The relationship follows the expected square root dependency with a
28
CA 02668114 2009-06-02
proportionality factor of about 320. Likewise, FIG. 5 shows the plot of the
attenuation of the signal as a function of concentration. At low
concentration, the
linear dependency is respected, with a slope of about 0.098. FIG. 6 shows a
plot
of the backscattered amplitude coefficients as a function of the concentration
obtained from eight samples of carbon black in silicone. The relationship
somewhat follows the expected square root dependency with a proportionality
factor of 430. FIG. 7 shows the plot of the attenuation of the signal as a
function
of the concentration. The linearity dependency is respected, with a slope of
2.61.
Mechanical properties
[0065] Another aspect of our method for phantom fabrication is to obtain a
resulting phantom that mechanically behaves, to a certain extent, like the
target
tissue. The mechanical behavior is the reaction to applied forces. Since a
force
can be applied in many different ways and strengths, the mechanical behavior
can be described by a large number of properties. When fabricating a phantom
for specific applications, one can specify how the forces are applied and
choose
to mimic specific mechanical properties of a tissue.
[0066] The method for fabricating multilayer phantoms is to form individual
layers with respective amounts of powder additives in an elastomer matrix. The
polymer matrix has the most impact on the mechanical properties. One very
important property of tissues is their elasticity. This can be determined by
measuring the force needed to stretch the material to a certain length.
Materials
that need smaller force to gain greater length have smaller elastic modulus.
The
variability of elastic modulus observed in tissues is accommodated by using
different matrix materials.
[0067] The polymer matrix also has the most impact on the durability of the
phantoms, and how it reacts to surrounding conditions. In the preferred
embodiment, the layers are composed of different formulations of silicone.
Each
formulation provides a different elastic modulus. Additionally, using
formulations
based on the same silicone ensures that layers are well attached one to the
29
CA 02668114 2009-06-02
other. Cured silicones are also highly stable. Phantoms of inorganic
scatterers
mixed in silicone have constant properties over many years. They also react
with
very few materials, and are especially stable in contact with materials that
are
compatible with a biomedical environment. Therefore, they are highly resistant
in
clinical conditions.
[0068] One specific silicone is Sylgard 184 which is sold as a kit composed of
a
resin and a reactive. The resin is a viscous liquid that allows the
incorporation of
powders. The addition of the reactive to the resin enables curing. Curing
occurs
within 48 hours at room temperature and within minutes at around 150 C. Curing
temperature influences the elasticity of the resulting silicone. The
elasticity is also
influenced by the ratio of resin to reactive volumes used. The elasticity can
be
further adjusted by initially mixing poly(dimethyl siloxane) (PDMS) in the
resin.
Increasing the proportion of PDMS decreases the elastic modulus.
[0069] FIG. 8 shows the results of stretch tests performed on different
formulations of silicone matrices. The true stress, defined as the stretch
force
divided by the area resulting from deformation, is plotted against the
elongation
ratio. The samples are made of Sylgard 184 resin and reactive, and Dow Corning
200R 50 cSt viscosity PDMS mixed in different ratios. Curves are identified on
the right above with their ratios of PDMS : Sylgard resin : Sylgard reactive.
A
formulation for a specific phantom matrix can therefore be chosen to mimic the
elasticity of the targeted tissue layer.
Additional structures
[0070] The invention also includes methods to add volumetric structures to the
phantoms. The volumetric structures can be located anywhere in the phantom,
including on the inner and outer surfaces. In many cases, they represent
pathologies like, for example, plaque in blood vessels. Their optical and
mechanical properties are known and can differ from those of the layers.
CA 02668114 2009-06-02
[0071] To obtain a phantom with an embedded volumetric structure, after the
formation of one or more layers by deposition and redistribution of the
material,
as described above the process is stopped. Prior to applying another layer, a
solid feature is embedded at a location on the outer layer after the selective
redistributing. This may be performed before the complete curing of the outer
layer to assist in bonding of the solid feature to the outer layer. During the
layer
fabrication process, the layer material passes from viscous liquid to solid
state. At
some point in that process, the solidifying liquid is highly viscous, sticky
in some
cases, and has enough strength to somewhat maintain its shape and to support
the incorporated solid material. At that point, the motions between the
supporting
and shaping elements may be stopped and the solid material is stuck on the
phantom at the desired location. In some cases, the location can be created by
altering the previously deposited layer or layers, for example by cutting a
hole to
receive the material. Subsequently additional layers of the phantom are formed
covering (or substantially covering) the solid feature. Positions between the
supporting element and the shaping element may need to be adjusted relative to
the solid material.
[0072] In some embodiments the solid feature has the desired properties of the
phantom. In other embodiments, the solid feature is later removed either by
fracturing the solid feature and removing the parts, or dissolving, melting or
vaporizing the solid feature, for example by penetrating the additional layers
to
inject a fluid to dissolve the feature and suction to remove the solution, or
by
pumping to remove the liquefied or gasified solid object, for example. The
removal of the solid feature may form a pocket within the phantom. This may be
filled with a liquid, gas, or any fluid which may set, and provide desired
mechanical and/or optical properties of a feature of the phantom. The
penetration may leave a hole that may be subsequently repaired.
[0073] The solid features can be located on the outer and/or inner surfaces
the
multilayer phantom. The solid features may be put into place and then, a
mixture
of liquid polymer deposited locally and cured to embed the said material, at
least
partially, and to fix it to the phantom.
31
CA 02668114 2009-06-02
Example: Blood vessel embodiment
[0074] In one embodiment, the method we provide is used to produce blood
vessel phantoms to be measured with OCT systems. Both types of blood
vessels, arteries and veins, are tubular organs composed of three distinct
tissue
layers: the intima, the media, and the adventitia.
[0075] In this embodiment, the layer materials are mixtures of powders in
silicone. In order to mimic the mechanical properties, the silicone is a
mixture of
Sylgard 184 and PDMS. The required OCT backscattered amplitude for each
layer is mainly provided by alumina powder. The optical attenuation is
adjusted
with carbon black as required. With such compositions, the blood vessel
phantoms are durable over many years and are highly resistant.
[0076] The ratio of PDMS : Sylgard resin : Sylgard reactive to approximate the
elasticity of the targeted tissue was determined experimentally. In this case,
the
mechanical behavior of a coronary artery is reproduced as a whole instead of
for
each layer separately. In FIG. 9, we show the result of traction tests
performed on
a porcine coronary artery and on a silicone material sample with a PDMS
Sylgard resin : Sylgard reactive ratio of 22.5:15:1. It shows that this
particular
formulation of silicone has an elastic modulus similar to that of the artery
for small
deformations, especially for upto 15% elongation where it is highly accurate.
Upto 38% elongation (-25 kPa) the response of the porcine coronary artery and
silicone material are similar. No effort was made to model at each layer the
elastic modulus according to the present example.
[0077] When measuring a porcine coronary artery with an OCT system, the
three layers are clearly discernable as a result of different optical
properties.
Therefore, three mixtures with different concentrations in alumina and carbon
black powders were used. To determine the required concentrations, the
backscattered amplitude and total attenuation were obtained for each layer.
The
coronary artery was cut longitudinally, unfolded, and laid on a flat surface.
It was
imaged with the OCT apparatus in a benchtop configuration. For each layer the
32
CA 02668114 2009-06-02
image is averaged at each depth. A profile is mathematically fitted for
amplitude
and total attenuation using eq. 3. A plot of the depth profile of a porcine
coronary
artery is presented in FIG. 10. The sections corresponding to each layer are
discernable. The first section is very thin (about 10 pm) and corresponds to
the
intima. The second section (about 0.55 mm) corresponds to the media, and the
third section, to the adventitia (about 0.45 mm). The fit curves are plotted
over the
amplitude and their corresponding values for the amplitude A and the total
attenuation a are shown on the graph. No attenuation value is obtained for the
intima because it is too thin.
[0078] The concentrations of alumina needed in each mixture to provide the
respective backscattering values are obtained using the relationship between
backscattered amplitude and concentration of alumina given in FIG. 4. This
leads
to concentrations of approximately 15 mg/ml for the intima, 10 mg/ml for the
media, and 35 mg/ml for the adventitia. Using the relationship obtained in
FIG. 5,
we find that these concentrations produce total attenuations of 1.4 mm-1, 0.9
mm"
1, and 2.7 mm-1 respectively. For the media and the adventitia, the target
attenuation coefficients are 2.3 mm-' and 2.8 mm-' respectively. For the
adventitia, the target attenuation coefficient and the attenuation from
alumina are
sufficiently close. For the media, the attenuation needs to be increased by
the
addition of 0.5 mg/ml of carbon black powder. The required concentration of
carbon black is obtained with FIG. 6.
[0079] An apparatus according to FIG. 1 was used to produce a phantom in
accordance with an example of the invention. Three mixtures with the required
powder concentrations were prepared and deposited and cured successively.
The heating element provided a substantially uniform curing temperature of
about
70 C across the shaft throughout the layer forming. No hexane or other
additive
was used. The mixture ejected from the syringe as a rope which deformed slowly
to spread across the surface. The blade wiped a majority of the material off,
depending on a desired thickness of the layer.
33
CA 02668114 2009-06-02
[0080] A shaft with a 3 mm diameter was chosen and coupled to the rotation
motor via the reducer. The distance between the blade and the shaft was
adjusted to obtain the required layer thicknesses. The blade and the shaft
were
set to be parallel to obtain an even thickness all along the layers which had
cylindrical inner and outer surfaces. The length of the blade used for shaping
was
55 mm, and the length of the phantom was also 55 mm. Once the last layer has
cured, the shaft was removed from the setup and the phantom was carefully
detached from the shaft. The resulting coronary artery phantom was then ready
for use.
[0081] The structure produced is essentially monolithic, as cross-section
micrographs show that there is no boundary between the layers. This is
desirable for the durability of the phantom, but may not be desired in all
cases. If
not desired, different compounds such as incompatible polymers can be used for
different layers to reduce bonding, or complete curing with the application of
coatings can be applied before a next layer.
[0082] The vessel produced had a very uniform distribution of thicknesses as
was specifically desired in this instance. Control over the thickness to the
degree
produced was heretofore only obtained with molding, and molding of numerous
layers requires many dies of respective qualities. The uniformity of the
thicknesses of the 3 layers is advantageously controlled principally by
mechanical
devices (straightness of the blade, rectitude of the rotation, etc.) which can
be
produced for any desired measure of accuracy in a manner known in the art.
Shrinkage rates (empirically or theoretically derived) may be used to
predefine a
thickness sought for a point on the layer to compensate for shrinkage.
[0083] The specific layers of the phantoms produced were not of thicknesses
specifically chosen to emulate the porcine coronary artery, but rather were
chosen to ensure visibility of the three layers with OCT characterization.
[0084] FIG. 11 is a schematic OCT image of the phantom produced according to
the present example, and an enlarged view of a part thereof. The full image
was
34
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taken in a mock surgery using an endoscopic probe head. The probe is encased
in a protective guide catheter, encircled by a balloon. Inner and outer
surfaces of
the guide catheter are visible in a center of the complete image. The images
of
the phantom were taken with the balloon expanded.
[0085] These images show the intimal layer having a thickness of about 30 pm,
a medial layer having a thickness of about 220 pm, and an adventitia of about
100 pm. All of the measures were within at least an estimated 10 pm
uncertainty.
This example is one of several produced using the present invention. A radial
line
of signal on the inner lumen is attributed to an inflated compliant balloon on
which
the phantom was supported for imaging. The enlarged image is grainy because
of the angular step size between measurements.
[0086] Those of skill in the art will appreciate the similarity of the phantom
as
imaged with that of an artery, apart from the thicknesses of the layers being
not
drawn to scale.
[0087] The intimal layer of the phantom produced was not of a minimum
thickness that can be provided using the apparatus shown. The thickness was
made substantially thicker than in the porcine coronary artery to facilitate
imaging
of this layer. Applicant could reliably form layers of about 20 pm (-30 pm
optical
path length) or smaller using the present method.
[0088] In anticipated experiments, additional solid features will be added to
the
coronary artery phantoms to mimic diseases like, for example various features
found in the different stages of atherosclerosis. FIGs. 12-14 schematically
illustrate how these various features are expected to look, and below methods
that are expected to be used to produce them according to the present
knowledge.
[0089] FIG. 12 schematically illustrates a cross-section of a coronary artery
phantom 50 with its three initial layers: the adventitia 51, the media 52, and
the
intima 53. An occlusion is provided at an axial location on the lumen by the
CA 02668114 2009-06-02
deposition of liquid polymer, after the coronary artery phantom 50 is produced
according to the above method. The alumina and silicone mixture used for the
fabrication of the intima layer of the coronary artery phantom described above
is
deposited on the inner surface of the phantom with a syringe. The phantom with
the non-covering material is then cured at a temperature of 150 C in an oven
to
accelerate curing, and minimize the spreading. The deposition of the non-
covering material, having the same properties as the intima 53 layer, narrows
a
lumen 55 of the phantom 50, mimicking intimal thickening, a pathological
condition causing blood flow obstruction in a vessel.
[0090] FIG. 13 schematically illustrates a cross-section of another
pathological
coronary artery phantom 60 having an adventitia 61, media 62, and a thickened
intima 63. A solid feature 64 is embedded in the intima 63. The process for
forming the phantom is the same as before, except that the forming of the
intima 63 is interrupted after only about half of the material was deposited
and
redistributed. As the first half of the intima 63 is curing, the forming is
stopped.
While the applied material is still sticky, a solid feature is applied to the
surface.
Fine particles can be sprinkled or large particles can be put in place at the
desired location on the sticky outer surface. The solid feature may be formed
of
bone dust or calcium salt, which have high calcium concentrations and
therefore
mimic a calcification of a thickened intima. After the solid features were
deposited, the rotation is restarted and the rest of the intima layer material
is
applied to cover the solid features. The phantom is completed by the
fabrication
of the media and the adventitia layers.
[0091] FIG. 14 schematically illustrates a cross-section of a third
pathological
coronary artery phantom 70 having an adventitia 71, media 72, and an intima 73
produced again by the above method. Phantom 70 has a solid feature 74 placed
in the lumen of the phantom consisting of a solid material 76 shrouded by a
non-
covering material 75. The solid material 76 is put in place and removed to be
replaced by a liquid material. The solid material can be a salt crystal. It is
put at a
desired location in the lumen of the artery phantom and is completely
embedded 76 in the mixture used for the fabrication of the intima layer. The
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mixture is cured again at 1500C to avoid spreading. After curing, the intima
layer
was perforated to create an access point. The phantom is then put in water
overnight to completely dissolve the salt crystal. Then, the phantom is dried,
and
the void is filled with a liquid mixture of alumina and carbon black in
silicone resin,
without the reactive. Without the reactive, the mixture will not cure. The
hole is
then patched with the mixture mimicking the intima. Phantom 70 mimics a
pathological condition where a lipid pool is embedded in a thickened intima.
[0092] Other advantages that are inherent to the structure are obvious to one
skilled in the art. The embodiments are described herein illustratively and
are not
meant to limit the scope of the invention as claimed. Variations of the
foregoing
embodiments will be evident to a person of ordinary skill and are intended by
the
inventor to be encompassed by the following claims.
37
