U.S. patent application number 17/566079 was filed with the patent office on 2022-07-28 for syringe-based microbubble generator with an aerator.
This patent application is currently assigned to Agitated Solutions Inc.. The applicant listed for this patent is Agitated Solutions Inc.. Invention is credited to Benjamin Arcand, Carl Lance Boling.
Application Number | 20220233761 17/566079 |
Document ID | / |
Family ID | 1000006062662 |
Filed Date | 2022-07-28 |
United States Patent
Application |
20220233761 |
Kind Code |
A1 |
Arcand; Benjamin ; et
al. |
July 28, 2022 |
SYRINGE-BASED MICROBUBBLE GENERATOR WITH AN AERATOR
Abstract
A device includes a syringe having a barrel and a syringe tip;
an aerator having (i) a generally cylindrical exterior body; (ii)
an inlet end; (iii) an outlet end; (iv) a tapered outlet port at
its outlet end; and (v) an interior cavity comprising (A) an input
port section, (B) a converging section, (C) a throat section, (D) a
diverging section, (E) an outlet section, (F) a first vent that
fluidly couples at least one of the throat section or the diverging
section to an area outside and adjacent to the exterior body, and
(G) a second vent that fluidly couples the outlet section to the
area; and a housing that (x) circumferentially surrounds an end of
the barrel and the aerator, (z) has an interior surface, (aa) forms
a circumferential gas pocket between the interior surface and the
exterior body, and (bb) has a housing discharge tip.
Inventors: |
Arcand; Benjamin;
(Minneapolis, MN) ; Boling; Carl Lance; (San Jose,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Agitated Solutions Inc. |
Oakdale |
MN |
US |
|
|
Assignee: |
Agitated Solutions Inc.
Oakdale
MN
|
Family ID: |
1000006062662 |
Appl. No.: |
17/566079 |
Filed: |
December 30, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17542386 |
Dec 4, 2021 |
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17566079 |
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17158396 |
Jan 26, 2021 |
11191888 |
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17542386 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 49/223 20130101;
A61M 5/1408 20130101; A61M 5/1452 20130101; A61M 5/007 20130101;
A61M 5/00 20130101 |
International
Class: |
A61M 5/00 20060101
A61M005/00; A61K 49/22 20060101 A61K049/22; A61M 5/145 20060101
A61M005/145 |
Claims
1. A device for generating microbubbles, the device comprising: a
syringe having a barrel and a syringe tip; a plurality of aerator
components, each aerator component having (i) a generally
cylindrical exterior body and being characterized by a longitudinal
axis; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet
port at its outlet end, which tapered outlet end is defined by an
outlet diameter that is less than a body diameter corresponding to
the exterior body, and a taper near the outlet end; and (v) an
interior cavity comprising (A) an input port section, (B) an inlet
section, (C) a throat section, (D) an outlet section, and (E) a
transverse vent that fluidly couples the throat section to an area
outside and adjacent to the exterior body; and a housing that (x)
circumferentially surrounds an end of the barrel and the plurality
of aerator components, (y) is characterized by a longitudinal axis,
(z) has an interior surface, (aa) forms a circumferential gas
pocket between the interior surface and the exterior body of each
of the plurality of aerator components, and (bb) has a housing
discharge tip; wherein the input port section of each aerator
component is configured to accommodate the syringe tip or a tapered
outlet port of one of the other aerator components in the
plurality, and the housing discharge tip is configured to
accommodate the tapered outlet port of one of the plurality of
aerator components, such that the syringe tip, a first aerator
component, a second aerator component, and the housing can be
coupled together in a coaxial manner relative to their respective
longitudinal axes.
2. The device of claim 1, wherein each of the aerator components
further comprises one or more alignment tabs, and the housing
comprises an alignment groove, such that when the syringe tip, the
first aerator component, the second aerator component, and the
housing are coupled together, the one or more alignment tabs and
the alignment groove cooperate to radially fix the housing and each
of the plurality of aerator components relative to each other.
3. A device for generating microbubbles, the device comprising: a
syringe having a barrel and a syringe tip and being characterized
by a longitudinal axis; an aerator having (i) a generally
cylindrical exterior body that is also characterized by a
longitudinal axis; (ii) an inlet end; (iii) an outlet end; (iv) a
tapered outlet port at its outlet end; and (v) an interior cavity
comprising (A) an input port section, (B) a converging section, (C)
a throat section, (D) a diverging section, (E) an outlet section,
(F) a first vent that fluidly couples at least one of the throat
section or the diverging section to an area outside and adjacent to
the exterior body, and (G) a second vent that fluidly couples the
outlet section to the area; and a housing that (x)
circumferentially surrounds an end of the barrel and the aerator,
(y) is characterized by a longitudinal axis, (z) has an interior
surface, (aa) forms a circumferential gas pocket between the
interior surface and the exterior body, and (bb) has a housing
discharge tip; wherein the input port section is configured to
accommodate the syringe tip, and the housing discharge tip is
configured to accommodate the tapered outlet port, such that the
syringe tip, the aerator component, and the housing can be coupled
together in a coaxial manner relative to their respective
longitudinal axes.
4. The device of claim 3, wherein the housing seals against the
barrel, thereby preventing fluid communication between the area and
a region exterior to the housing, except through the housing
discharge tip, the first vent or the second vent.
5. The device of claim 3, wherein the first vent is characterized
by a first vent diameter, and the second vent is characterized by a
second vent diameter, the first vent diameter being greater than
the second vent diameter.
6. The device of claim 5, wherein the first vent diameter is about
1.0 mm and the second vent diameter is about 0.5 mm.
7. The device of claim 3, wherein a capacity of the barrel is about
30 mL, and a volume of the circumferential gas pocket is about 5 to
15 mL.
8. The device of claim 3, wherein the outlet section is
substantially cylindrical in shape.
9. The device of claim 3, wherein a diameter of the converging
section ranges between about 3.5 mm and about 0.5 mm.
10. The device of claim 3, wherein a diameter of the diverging
section ranges between about 0.65 mm and about 2.1 mm.
11. The device of claim 3, wherein the aerator comprises a material
having a surface energy that is greater than or equal to about 35
mN/m.
12. The device of claim 3, further comprising a body-compatible
solution that is disposed in the barrel.
13. The device of claim 12, further comprising a cap that encloses
a portion of the housing discharge tip and a sealing pin that
occludes a portion of the interior cavity.
14. A method for generating microbubbles, comprising: providing a
microbubble generator having: (a) a syringe having a barrel and a
syringe tip and being characterized by a longitudinal axis, wherein
the barrel is filled with a body-compatible fluid; (b) an aerator
having (i) a generally cylindrical exterior body that is also
characterized by a longitudinal axis; (ii) an inlet end; (iii) an
outlet end; (iv) a tapered outlet port at its outlet end; and (v)
an interior cavity comprising (A) an input port section, (B) a
converging section, (C) a throat section, (D) a diverging section,
(E) an outlet section, (F) a first vent that fluidly couples at
least one of the throat section or the diverging section to an area
outside and adjacent to the exterior body, and (G) a second vent
that fluidly couples the outlet section to the area; and (c) a
housing that (x) circumferentially surrounds an end of the barrel
and the aerator, (y) is characterized by a longitudinal axis, (z)
has an interior surface, (aa) forms a circumferential gas pocket
between the interior surface and the exterior body, and (bb) has a
housing discharge tip; wherein the input port section is configured
to accommodate the syringe tip, and the housing discharge tip is
configured to accommodate the tapered outlet port, such that the
syringe tip, the aerator component, and the housing can be coupled
together in a coaxial manner relative to their respective
longitudinal axes; coupling the housing discharge tip to an
intravenous line disposed in a patient undergoing a procedure; and
generating microbubbles by forcing the body-compatible fluid out of
the syringe, through the interior cavity, and through the housing
discharge tip.
15. The method of claim 14, wherein the aerator comprises a
material having a solid surface energy of about 35 mN/m or
more.
16. The method of claim 14, wherein the aerator comprises
polycarbonate.
17. The method of claim 14, wherein the aerator comprises one of
polycarbonate, polymethacrylate, polyvinyl chloride, polyamide,
acrylonitrile butadiene styrene, acetal or polyethylene
terephthalate glycol.
18. The method of claim 14, wherein the body-compatible fluid
comprises dextrose.
19. The method of claim 14, wherein the body-compatible fluid
comprises saline and polysorbate.
20. The method of claim 14, wherein the body-compatible fluid
comprises saline and dextrose or a body-compatible surfactant.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 17/542,386, titled "SYRINGE-BSED MICROBUBBLE
GENERATOR," filed on Dec. 4, 2021, which is a continuation of U.S.
patent application Ser. No. 17/158,396, titled "SYRINGE-BASED
MICROBUBBLE GENERATOR," filed on Jan. 26, 2021, now U.S. Pat. No.
11,191,888. This application incorporates the entire contents of
the foregoing application herein by reference.
TECHNICAL FIELD
[0002] Various implementations relate generally to generating
microbubbles for use in various diagnostic and therapeutic
procedures.
BACKGROUND
[0003] Echocardiography refers to the use of ultrasound to study
the heart. Echocardiography is a widely used diagnostic test in the
field of cardiology and may be used in the diagnosis, management,
and follow-up of patients with suspected or known heart diseases.
The results from an echocardiography test may provide much helpful
information, including the size and shape of the heart's components
(e.g., internal chamber size quantification), pumping function, and
the location and extent of any tissue damage. An echocardiogram may
also give physicians other estimates of heart function, such as a
calculation of the cardiac output, ejection fraction (the
percentage of blood volume of the left ventricle that is pumped out
with each contraction), diastolic function (how well the heart
relaxes), etc.
[0004] Echocardiography may be performed in one of multiple ways.
Least invasively, an ultrasound transducer may be placed on a
patient's chest, and imaging may be done through the patient's
chest wall, in a transthoracic echocardiogram (TTE). If a higher
fidelity image is required, a more invasive transesophageal
echocardiogram (TEE) may be performed, in which an ultrasound
transducer disposed on a thin tube is placed down the patient's
throat and into the esophagus. Because the esophagus is so close to
the heart, this procedure can be employed to obtain very clear
images of heart structures and valves.
[0005] During either a TTE or TEE procedure, a contrast agent may
be employed to enhance the imaging of the procedure. This contrast
agent may be injected into the patient's vein, such that it quickly
reaches the chambers of the heart and is detected by ultrasound to
give greater definition to structures of the heart. In some
procedures, the contrast agent employed is a saline solution
comprising tiny air bubbles, and the procedure may be referred to
as an agitated saline contrast study or "bubble study."
SUMMARY
[0006] In some implementations, a device for generating
microbubbles includes a syringe having a barrel and a syringe tip,
a plurality of aerator components and a housing. Each aerator
component may have (i) a generally cylindrical exterior body that
is characterized by a longitudinal axis; (ii) an inlet end; (iii)
an outlet end; (iv) a tapered outlet port at its outlet end, which
tapered outlet end may be defined by an outlet diameter that is
less than a body diameter corresponding to the exterior body, and a
taper near the outlet end; and (v) an interior cavity comprising
(A) an input port section, (B) an inlet section, (C) a throat
section, (D) an outlet section, and (E) a transverse vent that
fluidly couples the throat section to an area outside and adjacent
to the exterior body. The housing may (x) circumferentially
surround an end of the barrel and the plurality of aerator
components, (y) be characterized by a longitudinal axis, (z) have
an interior surface, (aa) form a circumferential gas pocket between
the interior surface and the exterior body of each of the plurality
of aerator components, and (bb) have a housing discharge tip. The
input port section of each aerator component may be configured to
accommodate the syringe tip or a tapered outlet port of one of the
other aerator components in the plurality, and the housing
discharge tip may be configured to accommodate the tapered outlet
port of one of the plurality of aerator components, such that the
syringe tip, a first aerator component, a second aerator component,
and the housing can be coupled together in a coaxial manner
relative to their respective longitudinal axes.
[0007] In some implementations, each of the aerator components
further includes one or more alignment tabs, and the housing
includes an alignment groove, such that when the syringe tip, the
first aerator component, the second aerator component, and the
housing are coupled together, the one or more alignment tabs and
the alignment groove cooperate to radially fix the housing and each
of the plurality of aerator components relative to each other.
[0008] In some implementations, a device for generating
microbubbles includes a syringe having a barrel and a syringe tip
that are characterized by a longitudinal axis, an aerator and a
housing. The aerator may have (i) a generally cylindrical exterior
body that is also characterized by a longitudinal axis; (ii) an
inlet end; (iii) an outlet end; (iv) a tapered outlet port at its
outlet end; and (v) an interior cavity having (A) an input port
section, (B) a converging section, (C) a throat section, (D) a
diverging section, (E) an outlet section, (F) a first vent that
fluidly couples at least one of the throat section or the diverging
section to an area outside and adjacent to the exterior body, and
(G) a second vent that fluidly couples the outlet section to the
area. The housing may (x) circumferentially surround an end of the
barrel and the aerator, (y) be characterized by a longitudinal
axis, (z) have an interior surface, (aa) form a circumferential gas
pocket between the interior surface and the exterior body, and (bb)
have a housing discharge tip. The input port section may be
configured to accommodate the syringe tip, and the housing
discharge tip may be configured to accommodate the tapered outlet
port, such that the syringe tip, the aerator component, and the
housing can be coupled together in a coaxial manner relative to
their respective longitudinal axes.
[0009] In some implementations, the housing seals against the
barrel, thereby preventing fluid communication between the area and
a region exterior to the housing, except through the housing
discharge tip, the first vent or the second vent. The first vent
may be characterized by a first vent diameter, the second vent may
be characterized by a second vent diameter, and the first vent
diameter may be greater than the second vent diameter. In some
implementations, the first vent diameter is about 1.0 mm, and the
second vent diameter is about 0.5 mm.
[0010] In some implementations, a capacity of the barrel is about
30 mL, and a volume of the circumferential gas pocket is about 5 to
15 mL. The outlet section may be substantially cylindrical in
shape. A diameter of the converging section may range between about
3.5 mm and about 0.5 mm. A diameter of the diverging section may
range between about 0.65 mm and about 2.1 mm. The aerator may
comprise a material having a surface energy that is greater than or
equal to about 35 mN/m.
[0011] In some implementations, the device includes a
body-compatible solution that is disposed in the barrel. In some
implementations, the device further includes a cap that encloses a
portion of the housing discharge tip and a sealing pin that
occludes a portion of the interior cavity.
[0012] In some implementations, a method for generating
microbubbles includes providing a microbubble generator. The
microbubble generator may include (a) a syringe having a barrel and
a syringe tip and being characterized by a longitudinal axis,
wherein the barrel is filled with a body-compatible fluid; (b) an
aerator having (i) a generally cylindrical exterior body that is
also characterized by a longitudinal axis; (ii) an inlet end; (iii)
an outlet end; (iv) a tapered outlet port at its outlet end; and
(v) an interior cavity having (A) an input port section, (B) a
converging section, (C) a throat section, (D) a diverging section,
(E) an outlet section, (F) a first vent that fluidly couples at
least one of the throat section or the diverging section to an area
outside and adjacent to the exterior body, and (G) a second vent
that fluidly couples the outlet section to the area; and (c) a
housing that (x) circumferentially surrounds an end of the barrel
and the aerator, (y) is characterized by a longitudinal axis, (z)
has an interior surface, (aa) forms a circumferential gas pocket
between the interior surface and the exterior body, and (bb) has a
housing discharge tip. The input port section may be configured to
accommodate the syringe tip, and the housing discharge tip may be
configured to accommodate the tapered outlet port, such that the
syringe tip, the aerator component, and the housing can be coupled
together in a coaxial manner relative to their respective
longitudinal axes.
[0013] The method may further include coupling the housing
discharge tip to an intravenous line disposed in a patient
undergoing a procedure. The method may further include generating
microbubbles by forcing the body-compatible fluid out of the
syringe, through the interior cavity, and through the housing
discharge tip.
[0014] In some implementations, the aerator comprises a material
having a solid surface energy of about 35 mN/m or more. In some
implementations, the aerator comprises polycarbonate. In some
implementations, the aerator comprises one of polycarbonate,
polymethacrylate, polyvinyl chloride, polyamide, acrylonitrile
butadiene styrene, acetal or polyethylene terephthalate glycol.
[0015] In some implementations, the body-compatible fluid comprises
dextrose. In some implementations, the body-compatible fluid
comprises saline and polysorbate. In some implementations, the
body-compatible fluid comprises saline and dextrose or a
body-compatible surfactant.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is an exploded perspective view of an exemplary
microbubble generator.
[0017] FIG. 2A is a longitudinal cross section of an exemplary
syringe, converging nozzle, and aerator, as they are assembled, in
one implementation.
[0018] FIG. 2B is a longitudinal cross section of the converging
nozzle, 0-ring, and aerator shown in FIG. 2A.
[0019] FIG. 2C is another longitudinal cross section of the
converging nozzle, 0-ring and aerator shown in FIG. 2A.
[0020] FIG. 2D is a perspective, cross-sectional view of the
configuration shown in FIG. 2C.
[0021] FIG. 2E is a perspective cross-sectional view of another
exemplary converging nozzle and aerator.
[0022] FIG. 2F is a longitudinal cross-sectional view of the
converging nozzle and aerator shown in FIG. 2E.
[0023] FIGS. 3A, 3B and 3C depict operation of an exemplary
microbubble generator.
[0024] FIG. 4 illustrates an exemplary microbubble generating
system.
[0025] FIG. 5 illustrates a portion of an overall human circulatory
system.
[0026] FIG. 6A is a perspective cross-sectional view of another
exemplary microbubble generator.
[0027] FIG. 6B is a perspective view of an aerator component that
may be included in the exemplary microbubble generator of FIG.
6A.
[0028] FIG. 6C is a perspective cross-sectional view of the aerator
component of FIG. 6B.
[0029] FIG. 6D is a side view of the aerator component of FIG.
6B.
[0030] FIG. 6E is a side cross section of the aerator component of
FIG. 6B.
[0031] FIG. 6F is a perspective cross-sectional view of a plurality
of aerator components that may be coupled together and included in
the exemplary microbubble generator of FIG. 6A.
[0032] FIG. 6G is a perspective cross-sectional view of the
exemplary microbubble generator of FIG. 6A, including a cap and
sealing pin.
[0033] FIG. 7A is a perspective cross-sectional view of another
exemplary microbubble generator.
[0034] FIG. 7B is a side cross section of an aerator component that
may be included in the exemplary microbubble generator of FIG.
7A.
[0035] FIG. 8A is a perspective view of an exemplary aerator
component.
[0036] FIG. 8B is a cross section of the aerator component of FIG.
8A.
[0037] FIG. 8C is a cross section of the aerator component of FIG.
8A, with a sealing pin disposed therein.
[0038] FIGS. 9A-9C illustrate microbubbles formed with an exemplary
multi-stage polypropylene aerator and saline, dextrose and saline
with polysorbate, respectively.
[0039] FIGS. 10A-10C illustrate microbubbles formed with an
exemplary multi-stage polycarbonate aerator and saline, dextrose
and saline with polysorbate, respectively.
[0040] FIGS. 11A-11C illustrate microbubbles formed with an
exemplary single-stage polypropylene aerator and saline, dextrose
and saline with polysorbate, respectively.
[0041] FIGS. 12A-12C illustrate microbubbles formed with an
exemplary single-stage polycarbonate aerator and saline, dextrose
and saline with polysorbate, respectively.
[0042] FIGS. 13A-13C illustrate microbubbles formed with an
exemplary single-stage acetal aerator and saline, dextrose and
saline with polysorbate, respectively.
DETAILED DESCRIPTION
[0043] Agitated saline contrast studies (or "bubble studies") are a
useful adjunct to many ultrasound examinations, particularly
cardiac ultrasound (echocardiography). Injection of agitated saline
into a vein combined with echocardiography is a validated method to
detect shunts which may be within the heart such as a patent
foramen ovale (PFO) or an atrial septal defect (ASD)--two types of
holes in the heart--or external to the heart (e.g., in the lungs)
known as pulmonary arteriovenous malformations (pAVM). Agitated
saline can also be used with echocardiography to confirm catheter
placement in fluid around the heart (pericardiocentesis), detect
anomalous connections within the heart, visualize the right side of
the heart and accentuate right sided blood flow for the purpose of
quantitation.
[0044] Agitated saline contrast echocardiography takes advantage of
the increased reflection that results when ultrasound waves meet a
liquid/gas interface. This allows for visualization of otherwise
poorly reflective areas such as fluid-filled cavities by the
ultrasound machine. Applications in which this has been clinically
useful include echocardiography where agitated saline can be used
to define the structural integrity of the interatrial septum or
infer the presence of a transpulmonary shunt. Agitated saline can
also be combined with Doppler echocardiography to assess blood flow
through the tricuspid valve. An alternative method to detect atrial
defects uses ultrasound of the brain vessels (transcranial Doppler)
to detect bubbles that have crossed from the right heart to the
left heart and entered the cerebral circulation.
[0045] At present, it may be difficult to generate agitated saline
for these studies, and this can result in varying levels of quality
and safety. Current bubble studies may have considerable
variability in the amount, size, and quantity of bubbles generated.
Such imprecise mixtures of saline and air can result in risk to
patients and false-negative studies. In addition, few individuals
may be properly trained to safely perform bubble studies. The
productivity of an echocardiography lab may be substantially slowed
by this lack of trained personnel; and even trained personnel who
do not routinely perform agitated saline studies may be reluctant
to do so because of concerns about comfort or safety of the
procedure.
[0046] Described herein are devices and methods for producing
bubbles (e.g., for an ultrasound-based bubble study). Advantages of
the devices and methods described herein may include the production
of more uniform and consistently dimensioned bubbles with minimal
training. This may result in greater patient safety and comfort as
well as studies with improved diagnostic benefit.
[0047] FIG. 1 is an exploded perspective view of an exemplary
microbubble generator 100, according to one implementation. As
shown, the microbubble generator 100 includes a syringe 103, a
converging nozzle 115, and an aerator 133. In operation, the
microbubble generator 100 can be coupled to an intravenous (IV)
line disposed in a patient undergoing a procedure (e.g., a
diagnostic bubble study), and the microbubble generator 100 can be
employed to generate microbubbles as a contrast agent.
[0048] In some implementations, the syringe 103 portion of the
microbubble generator 100 is a standard medical-grade syringe
(e.g., 1 mL, 2 mL, 3 mL, 5 mL, 10 mL, 20 mL) having a barrel 106,
plunger 109 and tip 112. The syringe 103 may be pre-filled with
saline or another solution that is suitable for intravenous
injection, which can provide a vehicle for microbubbles generated
by the microbubble generator 100 to be delivered to a target region
of a patient's body. The tip 112 can include a Luer lock connector
suitable for coupling to needles, catheters, IV lines, etc.
[0049] Saline is referenced with respect to various
implementations. In some implementations, this could be "NSS," or
0.9% normal saline solution; in other implementations, "45NS," or
0.45% normal saline may be used. In still other implementations,
liquids other than saline may be used, such as dextrose in water
solution (e.g., "D5W," or 5% dextrose in water; "D10W," or 10%
dextrose in water; "D50," or 50% dextrose in water) or other
solutions commonly used in intravenous applications at sites that
are suitable for diagnostic studies or therapeutic procedures.
[0050] The converging nozzle 115, in the implementation shown, has
a coupling end 118 that is configured to engage the tip 112 of the
syringe 103. In some implementations, the coupling end 118 includes
mating Luer lock threads to facilitate a twist-on engagement with
the syringe 103. Opposite the coupling end 118 is a converging tip
121. An interior channel 127, which will be described in greater
detail with reference to the following figures, is configured to
fluidly couple an interior of the syringe 103 to the aerator
133.
[0051] The aerator 133, as shown, includes a retention end 136 that
is configured to mechanically mate with the converging nozzle 115;
and a discharge end 139. In some implementations, the aerator 133
can be coupled to the converging nozzle 115 via a compression-fit
coupling facilitated by an O-ring 134 and grooves in the converging
nozzle 115 and aerator 133. A discharge channel 147 fluidly couples
the interior channel 127 of the converging nozzle 115 to a
discharge end 139, which can be configured to engage a catheter or
IV port or line used in a bubble study.
[0052] In FIG. 1, the syringe 103, converging nozzle 115 and
aerator 133 are shown as separate components. In other
implementations, however, one or more components may have other
arrangements. For example, the converging nozzle 115 and aerator
133 may be ultrasonically welded together, joined with adhesive,
snap-fit, etc.; and the converging nozzle 115 or a singular
converging nozzle/aerator structure could be coupled to the syringe
103 in one of the foregoing ways or co-molded with and as part of
the syringe 103. Additional detail of the exemplary syringe 103,
converging nozzle 115 and aerator 133 is now provided with
reference to FIGS. 2A, 2B and 2C.
[0053] FIG. 2A illustrates a longitudinal cross-section of the
syringe 103, converging nozzle 115 and aerator 133, as they could
be assembled in some implementations. As shown, the converging
nozzle 115 is disposed on the syringe 103 via a Luer lock fitting
218, and the aerator 133 is compression-fit onto the converging
nozzle 115 by an O-ring and corresponding grooves in each of the
converging nozzle 115 and aerator 133 (see FIG. 2B for detail). In
other implementations, connections maybe made differently. For
example, other threaded or press-fit connections may replace Luer
lock fittings. Similarly, the O-ring and grooves could be replaced
by a threaded, adhesive-based or welded connection.
[0054] FIG. 2B illustrates an exemplary longitudinal cross section
of the converging nozzle 115, O-ring 134, and aerator 133. The
interior channel 127 fluidly couples to an interior of the mating
syringe 103 (see FIGS. 1, 2A) and a throat 230--a portion of the
interior channel 127 whose diameter progressively decreases. In
operation, the progressively decreasing diameter of the throat 230
changes dynamics of fluid flowing from the syringe 103 and through
the converging nozzle 115, as will be described with reference to
FIG. 2C.
[0055] As shown, the converging nozzle 115 includes grooves 235A
for receiving the 0-ring 134 and facilitating a compression-fit
coupling; and the aerator 133 includes corresponding grooves 235B
for the same purpose. This structure allows the O-ring 134 to be
slipped into the grooves 235A, and for the retention end 236 of the
aerator 133 to be slid over the converging tip 121 and for the
grooves 235B to engage and be retained by the O-ring 134. In such
an implementation, the O-ring 134 may be made of an elastic
material that has sufficient elasticity and compressibility to
facilitate engagement of the converging nozzle 115 and aerator 133,
and sufficient resilience to securely couple the converging nozzle
115 and aerator 133 once the grooves 235A and 235B of these
components 115 and 133 are aligned as described. In some
implementations, the O-ring 134 and grooves 235A and 235B may
provide an air-tight, sterile seal.
[0056] The converging nozzle 115 further includes an external
mating surface 224 at the converging tip 121, which is configured
to mechanically fit adjacent to a corresponding circumferential lip
244 on the aerator 133. In some implementations, the
circumferential lip 244 circumferentially envelopes the external
mating surface 224 and abuts the external mating surface 224 at
least at one point; in other implementations, the circumferential
lip 244 and external mating surface 224 are disposed adjacent and
in close proximity to each other. When the converging nozzle 115
and aerator 133 are coupled (e.g., by the grooves 235A and 235B and
O-ring 134), the external mating surface 224 and circumferential
lip 244 align and facilitate fluid coupling between the interior
fluid channel 127 and throat 230, and the discharge channel 147. In
some implementations, specific dimensions and geometries of the
external mating surface 224 and circumferential lip 244 further
facilitate passage of air into the discharge channel 147, from an
interior air chamber 241, which is formed by the outer wall 245 of
the aerator 133--as will be further described with reference to
FIG. 2C.
[0057] FIG. 2C is a longitudinal cross section of the converging
nozzle 115 and aerator 133, shown in a coupled configuration, and a
magnified view of a portion of that cross section. As shown, the
interior air chamber 241 is formed by the outer wall 245 of the
aerator. A small fluid coupling exists between this interior air
chamber 241 and the passageway formed by the interior channel 127,
throat 230 and discharge channel 147--specifically by an air
channel 246 (see magnified inset) that is configured to exist
between the exterior mating surface 224 and the circumferential lip
244. This air channel 246 allows air or other gas in the interior
air chamber 241 to be drawn into the aforementioned passageway
(throat 230 and discharge channel 147--referred to as the "230/147
passageway"). In addition, this air channel 246 may permit some
fluid that is passing through the 230/147 passageway to enter the
interior air chamber 241, thereby displacing some of the air there
and increasing the pressure in the interior air chamber 241 (e.g.,
in cases in which there may be a non-negligible back pressure at
the discharge channel 147).
[0058] FIG. 2D is a perspective, cross-sectional view of the
converging nozzle 115 shown in FIG. 2C, with the cross section
taken along section line A-A (shown in FIG. 2C). FIG. 2D
illustrates the air channel 246 (or series of air channels 246)
that fluidly couple the interior air chamber 241 to the throat
230-discharge channel 147 passageway. Visible in FIG. 2D is the
throat 230 itself, in the center of the converging nozzle 115, as
well as a series of air channels 246 that are disposed radially
about throat.
[0059] In some implementations, the exterior mating surface 224 and
circumferential lip 244 (see FIG. 2C) are in mechanical contact and
provide a fluid seal, except at the air channels 246. That is, in
such implementations, a fluid coupling between the interior air
chamber 241 and the 230/147 passageway only exists at the air
channels 246. In some implementations, fewer air channels 246 are
provided than shown--for example, some implementations may only
include one, two, three or four air channels 246.
[0060] Referring back to FIG. 2C, dimensions and geometries of the
air channels 246 may be configured to facilitate passage of air
from the interior air chamber 241 into the 230/147 passageway only
when certain pressure differentials exist therebetween. For
example, some implementations may include air channels 246 with
very small dimensions and with geometries that promote greater
surface tension of any liquid that is disposed in the air channels
246. Specific contours of either or both of the exterior mating
surface 224 and the circumferential lip 244 may further promote an
increased surface tension of liquid in the air channels 246, to,
for example, promote communication of air (and correspondingly,
formation of microbubbles) in certain scenarios. Surface treatments
to either or both of the exterior mating surface 224 and the
circumferential lip 244 (e.g., hydrophobic or hydrophilic coatings)
may be employed to further control communication of air or other
gas from the interior air chamber 241 to the 230-147
passageway.
[0061] In some implementations, a vent (not shown) between the
interior air chamber 141 and the exterior of the aerator 133 may be
provided to enable more air to be drawn into the fluid than may
otherwise be possible. In other implementations, a port or valve
(not shown) may be provided to facilitate coupling of an exterior
air supply for a similar purpose. In still other implementations, a
valve (e.g., a reducing valve--not shown) may be provided to allow
fluid to be drained from the air chamber 241 and again be replaced
with air--for example, to facilitate an equilibrium relative to
back pressure, and to enable the microbubble generator 100 to
"recharge" its ability to generate microbubbles.
[0062] FIG. 2E illustrates a perspective cross-sectional view of an
exemplary implementation 260 of a unitary converging nozzle 263 and
aerator 266; and FIG. 2F illustrates a longitudinal cross-section
of the same device 260. As shown in this implementation, the
converging nozzle 263 and aerator 266 are fabricated as a unitary
component (e.g., co-molded), rather than as two separate
components. In such a configuration, it may be possible to
precisely configure dimensions of one or more air channels 268 and
their alignment to a stream of fluid traveling from an interior
channel 269, through a section 270 having a progressively
decreasing diameter (e.g., a "Venturi section"), out an outlet 271,
into an inlet 273 of the aerator 266 and through and out a
discharge channel 275.
[0063] As shown, the exemplary device 260 includes a housing 278
that surrounds the unitary converging nozzle 263 and aerator 266.
In some implementations, as shown, the housing 278 can be sealed to
the converging nozzle 263 and aerator 266 by O-rings 281A and 281B.
In such implementations, an air chamber 283 is formed (e.g., by an
interior surface 284 of the housing 278 and an exterior surface 285
of the unitary component that includes the converging nozzle 263
and aerator 266). When the O-rings 281A and 281B form an airtight
and liquid-tight seal (of the air chamber 283, isolating the air
chamber 283 from a region exterior to the housing 278 from ingress
or egress of gas or liquid via any path other than through the one
or more air channels), air (or other gas) in the air chamber 283
can be drawn into a stream of liquid passing through the device
260, in the form of microbubbles.
[0064] In some implementations, the exemplary device 260 can
operate to produce microbubbles even in the presence of
not-insignificant back pressure at the discharge channel 275.
Specifically, in the presence of back pressure at the discharge
channel 275 (with a robust seal provided by O-rings 281A and 281B),
fluid may pass through the interior channel 269, section 270 and
into the discharge channel 275. However, no significant volume of
fluid may flow out of the discharge channel 275 (e.g., into a
downstream intravenous or needle-based system associated with a
therapeutic or diagnostic procedure) until pressure is equalized
between the device 260 and the back pressure. That is, rather than
flowing out of the discharge channel 275, the fluid may initially
flow through the air channels 268 and into the interior air chamber
283. Such fluid may displace the air in the air chamber 283,
causing an increase in pressure in the air chamber 283.
[0065] Once this air pressure increases to the level of the back
pressure, fluid may then flow through the device 260, out of the
discharge channel 275, and into a connected patient diagnostic or
therapeutic system (not shown). In this phase of operation, where
the pressure inside the air chamber 283 is nearly equal to the back
pressure seen at the discharge channel 275, some air from the air
chamber 283 may be drawn into the fluid stream, in the form of
microbubbles--via an aspiration effect caused by the pressure drop
in the fluid stream itself that is brought about by the increase in
speed of flow of that fluid through the Venturi section 270.
[0066] Over time, the aspiration of air into the fluid stream may
cause the pressure in the air chamber 283 to again drop below a
back pressure seen at the discharge channel 275. At this point,
some additional fluid may enter the air chamber 283, again
displacing air and increasing the pressure inside the air chamber
283. Once equilibrium is reestablished, or nearly reestablished
(e.g., within some small percentage, given the dynamic nature of
the system, turbulence of the fluid, dynamically varying back
pressure, variation in speed of fluid, etc.), air may again be
aspirated into the fluid stream in the form of microbubbles.
[0067] In some implementations, a one-way reducing valve (not
shown) may be provided between the air chamber 283 and an exterior
of the housing 278, to enable fluid to be periodically drained from
the air chamber 283. Allowing some fluid to be drained from the air
chamber 283 may allow, in some implementations, air to be
continuously available for aspiration into the fluid stream. In
such an implementation, microbubbles may be produced and delivered
out of the discharge channel 275 for as long as incoming fluid is
supplied through the interior channel 269.
[0068] In the implementation shown in FIGS. 2E and 2F, dimensions,
geometries and surface treatments (e.g., hydrophobic or hydrophilic
coatings) of the air channels 268, the outlet 271 (or interior
channel 269 or section 270), the inlet 273 or the discharge channel
275 may be configured to facilitate creation of microbubbles having
a specific average size or range of sizes (e.g., an average
diameter of less than 2 .mu.m; an average diameter of between about
5 .mu.m and about 10 .mu.m; an average diameter of about 40 .mu.m
or less; an average diameter of about 100 .mu.m or less). Such
implementations may employ dimensions, geometries or surface
treatments to produce regions of turbulent or laminar flow that
entrap or aspirate air in a particular manner. In other
implementations, specific dimensions, geometries or surface
treatments may be employed to create microbubbles with surface
tensions or charges that minimize coalescence of microbubbles after
they are generated.
[0069] Operation of an overall exemplary microbubble generator 300
are now described with respect to FIGS. 3A, 3B and 3C, in one
implementation. As shown in FIG. 3A, a microbubble generator 300
that includes a syringe 303, a converging nozzle 315 and an aerator
333 may be prefilled with a saline solution. That is, saline (or
another suitable solution) may be prefilled in an interior 302 of
the barrel 306 of the syringe portion 303. To preserve the sterile
nature of the saline, and to prevent fluid ingress into an interior
chamber 341 of the aerator portion 333, a sealing pin 353 may be
provided to seal the saline in the syringe 303, to seal the
interior channel 327 and throat 330 of the converging nozzle 315
and to isolate the channel 327 from the interior chamber 341. In
operation, such a pin 353 may be removed immediately prior to use
of the microbubble generator 300.
[0070] The pin 353 may be made of a corrosion-resistant metal or
resilient elastic material that seals off the tip of the throat 330
and a discharge channel 347. The pin 353 may be adhesively sealed
to the discharge end 339 of the aerator, such that some amount of
twisting or pulling force is required by a user to dislodge the pin
353 prior to use of the microbubble generator 300. Such an adhesive
seal may further protect the sterile nature of the microbubble
generator 300, particularly at the discharge end 339.
[0071] In some implementations, the pin 353 may be replaced with an
internal membrane (not shown) that retains the saline (or other
body-compatible fluid) in the interior 302 of the syringe or in the
interior 302 of the syringe and the throat 330 of the converging
nozzle 315. In such implementations, a user may be required to
depress the plunger 309 in order to generate an internal pressure
that is sufficient to overcome the holding force of such a
membrane. In some implementations, an internal membrane (not shown)
may be configured to be broken when the converging nozzle 315 is
affixed to the syringe 303 (e.g., in implementations in which the
components are provided separately).
[0072] However the contents of the syringe are sealed prior to use,
the appropriate seal can be released and the plunger 309 can be
depressed slightly to flush microbubble generator 300--as depicted
in FIG. 3B. In some instances, this can be done prior to the
discharge end 339 being coupled to IV tubing 356 or another
connection that may be made to a system used to diagnose or treat a
patient (e.g., a needle, catheter, or other apparatus disposed in
the patient (not shown)). In other instances, the discharge end 339
may be coupled to IV tubing 356 first, such that the tubing can
also be flushed during this initial process.
[0073] FIG. 3C depicts the process by which the microbubble
generator 300 can generate microbubbles, in one implementation. In
particular, after necessary seals are removed, and the microbubble
generator 300 is flushed and coupled to a downstream IV system 356
associated with a patient undergoing a diagnostic or therapeutic
procedure, the plunger 309 can be further depressed to force fluid
from the interior 302 of the syringe 303, into the interior channel
327. In the interior channel 327, the pressure of the fluid is
relatively high, and its speed is relatively low (proportional to a
speed at which the plunger is depressed). The progressively
decreasing diameter of the throat 230 causes the speed of the fluid
to increase there, thereby lowering its fluid pressure (through the
Venturi effect). This lower pressure of the fluid at the throat 330
draws air into the fluid path traveling from the throat 330 to the
discharge channel 347, specifically from the interior chamber 341,
via one or more air channels 346--thereby forming microbubbles.
[0074] In some implementations, the geometry, dimensions and/or
surface treatment of the material forming the air channels 346 is
correlated to microbubble size. Thus, in such implementations,
configuration of converging nozzle 315 and aerator 333 can cause
microbubbles to be created having different sizes and
characteristics. In some implementations, microbubbles having a
diameter of approximately 5 .mu.m may be created; in other
implementations, microbubbles having a diameter of approximately 10
.mu.m or less may be created; in other implementations,
microbubbles having a diameter of about 1-2 .mu.m or less may be
created; in other implementations, microbubbles having a diameter
of about 40 .mu.m may be created; in other implementations,
microbubbles having a diameter up to about 100 .mu.m may be
created.
[0075] Different sized microbubbles may have different purposes in
diagnostic or therapeutic procedures. For example, in certain
diagnostic heart procedures, it may be advantageous to create
microbubbles of approximately 5 .mu.m to approximately 10 .mu.m in
average diameter. As used herein, "about" or "approximately" or
"substantially" may mean within 1%, or 5%, or 10%, or 20%, or 50%
of a nominal value; and "average" may mean that a significant
number (e.g., 25%, 50%, 75%, 80%, 85%, 90%, 95%) of microbubbles
have this diameter, or in some implementations, have a diameter
that is within one or two standard deviations of the specified
diameter. As another example, in diagnosing certain pulmonary
conditions, it may be advantageous to create smaller-diameter
microbubbles (e.g., 1-2 .mu.m or less). In some implementations,
microbubble size may be correlated with coalescence properties of
the microbubbles. For example, surface tension and charge of
microbubbles of specific sizes (in certain solutions, or in the
blood) may inhibit their coalescence; and minimizing such
coalescence of microbubbles may be advantageous (e.g., to minimize
risk of an air embolism).
[0076] In some implementations, it may be advantageous to generate
microbubbles of varying sizes. For example, in a procedure to
diagnose the existence of a defect in the septum of a patient's
heart, it may be advantageous to initially look for the presence of
a septum defect with smaller microbubbles; then shift to larger
microbubbles to determine whether a closure procedure is warranted.
To facilitate procedures in which it may be advantageous to employ
microbubbles of varying sizes, multiple microbubble generators may
be employed; and in some implementations, they may be coupled
together in advance.
[0077] FIG. 4 illustrates an exemplary microbubble generating
system 400 that employs multiple microbubble generators 401A, 401B
and 401C. As shown, each microbubble generator 401A, 401B and 401C
can be coupled to a manifold 461 by corresponding fluid lines 456A,
456B and 456C. The manifold can include multi-way valves 464A, 464B
and 464C that couple or isolate each fluid line to a main line 465
of the manifold 461; and that main line 465 of the manifold 461 can
be coupled to an IV line 458 that is associated with a patient
undergoing a diagnostic or therapeutic procedure. In this manner,
individual microbubble generators 401A, 401B or 401C can be
alternately coupled to the IV line 458 to generate diagnostic or
therapeutic microbubbles; or, multiple microbubble generators 401A,
401B or 401C can be simultaneously connected to facilitate delivery
of a large volume of fluid with minimal manipulation of valves.
Some implementations employ three-way stopcocks 464A, 464B and
464C, as shown, to isolate or fluidly couple one, two or three
paths. Other implementations may employ different valve
arrangements.
[0078] In some implementations, each microbubble generator 401A,
401B or 401C, in a microbubble generating system 400 may be
similarly configured to generate microbubbles of the same size.
Such implementations may be employed to generate a larger volume of
microbubbles, over a longer period of time than would be otherwise
possible with a single microbubble generator. In other
implementations, each microbubble generator 401A, 401B and 401C may
be configured to generate microbubbles of different sizes. For
example, microbubble generator 401A may be configured to generate
microbubbles having an approximate diameter of 5 .mu.m; microbubble
generator 401B may be configured to generate microbubbles having an
approximate diameter of 1 .mu.m; and microbubble generator 401C may
be configured to generate microbubbles having an approximate
diameter of 10 .mu.m. In this manner, complex diagnostic procedures
requiring microbubbles of various sizes may be performed with
minimal change in equipment.
[0079] The exemplary manifold 461 may include a port 468 for
flushing out the manifold and/or overall system 400. In some
implementations, each microbubble generator 401A, 401B and 401C may
have an internal membrane to isolate fluid within a corresponding
syringe barrel or syringe barrel/converging nozzle; and discharge
channels of each microbubble generator and the manifold itself may
be flushed and prefilled with fluid prior to a procedure being
performed, through the port 468.
[0080] In other implementations, the system 400 may be packaged in
a manner in which the syringes, tubing and manifold are all
pre-filled with fluid, such that a final connection between a main
manifold line 465 and patient IV tubing 458 need be made at the
time of a procedure. In such implementations, internal membranes
may still be employed in individual microbubble generators 401A,
401B and 401C to prevent egress of fluid into interior air chambers
of an aerator component (e.g., air chamber 441A in aerator
433A).
[0081] The exemplary system 400 is shown with three microbubble
generators 401A, 401B and 401C; but other numbers of microbubble
generators could be included--such as, for example, two, four, or
five. The microbubble generators 401A, 401B and 401C are shown
coupled to the manifold 461 with tubing 456A, 456B, and 456C. In
some implementations, various components of the system 400 may be
provided and coupled together immediately prior to a patient
procedure.
[0082] Various implementations described herein may be employed to
generate microbubbles for various diagnostic and therapeutic
studies. Many such studies involve the human circulatory system.
Thus, for reference, portions of a human circulatory system are now
briefly described.
[0083] FIG. 5 illustrates a portion of an overall human circulatory
system 500. At its core, is the heart 502, and a system of arteries
that extend from the heart, and veins that return to the heart.
Blood is returned to the heart 502 from throughout the body via the
vena cava, which is divided into the superior vena cava 505, which
collects blood from the upper portion of the body, and the inferior
vena cava 508, which collects blood from the lower portion of the
body. Blood flows through the superior vena cava 505 and inferior
cava 108 on its way to the right atrium.
[0084] To facilitate studies whereby microbubbles are to be
introduced into the heart and lungs, one must get the bubbles into
the venous system and ultimately into the superior vena cava 505 or
inferior vena cava 508. With reference to FIG. 5, there are several
common access points through which microbubbles can be introduced.
Common among them is intravenous introduction of bubbles via the
median cubital vein 530 of the right arm. From here, blood flows
through the basilic vein 531, axillary vein 532, subclavian vein
510, brachiocephalic vein 537 and into the superior vena cava
505.
[0085] Alternative paths to the superior vena cava 513 are the
external jugular vein 533 or internal jugular vein 536, both of
which drain into a brachiocephalic vein 537 prior to reaching the
superior vena cava 505. An alternative route includes the femoral
vein 539, which flows into the inferior vena cava 508. Other routes
to the superior vena cava 505 and inferior vena cava 508 are
possible.
[0086] FIG. 6A is a perspective cross-sectional view of another
exemplary microbubble generator 600. As shown, the exemplary
microbubble generator 600 includes a syringe 603 having a barrel
606, a plunger 609, and a syringe tip 612. In some implementations,
as shown, the syringe tip 612 includes a Luer lock 613 or other
fitting.
[0087] A plurality of aerator components 616a, 616b and 616c may be
coupled to the syringe tip 612, and a housing 619 may
circumferentially surround an end of the barrel 606 and the
plurality of aerator components 616a, 616b and 616c. The housing
619 may have a longitudinal axis 622, which, in some
implementations, aligns coaxially with a longitudinal axis 623 of
the syringe 603 and longitudinal axes of the aerator components
616a, 616b, and 616c.
[0088] The housing 619 has an interior surface 625 and a discharge
tip 628. In some implementations, the housing 619 is configured to
fluidly seal against the barrel 606, and the plurality of aerator
components 616a, 616b, and 616c may be sealed against each other,
to the syringe tip 612, and to the discharge tip 628, such that any
fluid that is ejected from the syringe 603 (e.g., by a user of the
syringe 603 depressing the plunger 609) is ejected through the
syringe tip 612, into an interior channel 673 (see FIG. 6F) of each
of the aerator components 616a, 616b and 616c, through the
discharge tip 628. A circumferential gas pocket 631 may be created
by the interior surface 625; the plurality of aerator components
616a, 616b and 616c; the syringe tip 612; and the discharge tip
628. In some implementations, the circumferential gas pocket 631
comprises at least approximately 10% of the volume of the
corresponding syringe barrel 606; in other implementations, the
circumferential gas pocket 631 comprises approximately 30-35% of
the volume of the corresponding syringe barrel 606 (e.g., 3-3.5 mL
for a 10 mL syringe); in still other implementations, the
circumferential gas pocket 631 comprises 50% or more of the volume
of the corresponding syringe barrel 606.
[0089] FIG. 6B is a perspective view of an aerator component 616b
that may be included in the exemplary microbubble generator 600 of
FIG. 6A. As shown the aerator component 616b has an exterior body
630, which, in some implementations is cylindrical and
characterized by a longitudinal axis 624. One or more alignment
tabs, such as alignment tab 632, may protrude from the exterior
body 630; and such alignment tab 632 may be configured to interface
with one or more alignment grooves 633 in the housing 619 (see FIG.
6A)--such that when the aerator components 616a, 616b and 616c and
housing 619 are coupled together, the one or more alignment tabs
632 and the one or more alignment grooves 633 cooperate to radially
fix the housing and each of the plurality of aerator components
relative to each other.
[0090] As indicated above, when disposed in the microbubble
generator 600, the longitudinal axis 624 of the aerator component
616b may align coaxially with the longitudinal axis 622 of the
housing 619 and the longitudinal axis 623 of the syringe 603. The
aerator component 616b has an inlet end 634 and an outlet end 637.
As will be described in more detail with reference to FIGS. 6D and
6E, the aerator component 616b may include a tapered output port
640 and a transverse vent hole 643.
[0091] FIG. 6C is a perspective cross-sectional view of the aerator
component 616b; FIG. 6D illustrates a side view of the aerator
component 616b; and FIG. 6E illustrates a side cross section of the
aerator component 616b. As illustrated in FIG. 6D, the tapered
output port 640 may have a diameter 646 that is less than a
diameter 649 of the exterior body 630, as well as a taper 652 that
narrows the diameter 646 from its start at the exterior body 630 to
its distal end.
[0092] With reference to FIG. 6E, in the implementation shown, the
aerator component 616b includes an interior cavity 655 that has
four discrete sections--an input port section 658, an inlet section
661, a throat section 664, and an outlet section 667. The input
port section 658 is configured to receive a tapered output port of
another aerator component (e.g., the tapered output port 640 of
aerator component 616b) or of the syringe tip 612--that is, the
input port section 658 may have a diameter 670 that is only
slightly larger than the diameter 646 of the tapered output port
640, and that diameter 670 may decrease from outside to inside the
input port section 658, corresponding to the taper 652 of the
tapered output port 640.
[0093] As shown, the inlet section 661 has a progressively
decreasing diameter that constricts flow of a gas or liquid through
the aerator component 616b as that gas or liquid flows from the
input port section 658 to a subsequent throat section 664. As
described above with respect to other implementations, this
constriction of flow increases the corresponding velocity of the
gas or liquid and lowers its pressure. This lowering of pressure
allows gas or liquid in the circumferential air pocket 631 (see
FIG. 6A) to be drawn into the flow, through the transverse vent
hole 643, in the throat section 664. In some implementations, the
progressively decreasing diameter ranges from about 3.5 mm to about
0.5 mm.
[0094] In some implementations, as shown, an outlet section 667
follows the throat section 664. In the outlet section 667, a
diameter of the interior cavity 655 increases from the throat
section 664 toward the tapered output port 640. In some
implementations, the increasing diameter of the outlet section 667
ranges from about 0.5 mm to 3.5; more preferentially, the diameter
may range from about 0.65 mm to about 2.1 mm.
[0095] In some implementations, a boundary between the inlet
section 661 and throat section 664 may be rounded and/or smooth
(e.g., to minimize turbulence). In some implementations, the throat
section 664 may have a slight taper (e.g., to facilitate a clean
molding process). In some implementations, a boundary between the
throat section 664 and outlet section 667 may by rounded and/or
smooth (e.g., to minimize turbulence). In some implementations,
various surfaces and boundaries may have a rough surface treatment,
or edges may be sharp, rather than rounded or smooth (e.g., to
increase turbulence).
[0096] FIG. 6F is a perspective cross-sectional view of a plurality
616 of aerator components 616a, 616b and 616c that may be coupled
together and included in the exemplary microbubble generator 600.
As shown, each component 616a, 616b and 616c is tightly coupled to
the next, such that a channel 673 is formed from the input port
section of the aerator component 616a to the outlet section of the
aerator component 616c. In some implementations, the channel 673 is
fluid-tight from end-to-end, except at the transverse vent holes in
each aerator component 616a, 616b, and 616c--that is, each aerator
component may be tightly sealed to the next, such that fluid (e.g.,
liquid or gas) cannot leak out of the channel 673 at the
intersection of the tapered output port of one aerator component
and the input port section of another aerator component.
[0097] As depicted in FIG. 6F, some variation may exist in the
diameter of each throat section 664a, 664b or 664c in the plurality
616 of aerator components. That is, the diameter of throat section
664c of aerator component 616c may be larger than the diameter of
throat section 664b, which may be larger than the diameter of
throat section 664a. Similarly, there may be variation in the
diameters of the transverse vent holes 643a, 643b and 643c. In some
implementations, diameters of the throat sections 664a, 664b and
664c may range from 0.4 mm or less to 2.0 mm or more. For example,
one implementation may include aerator components with diameters of
0.45 mm, 2 mm and 2 mm; another implementation may include aerator
components with diameters of 0.45 mm, 1 mm and 2 mm; yet another
implementation may include aerators components with diameters of 1
mm, 1 mm and 2 mm. In some implementations, it may be advantageous
to arrange aerators such that diameters are increasing from
proximal end (e.g., the syringe end) to the distal end; in other
implementations, a different arrangement may be advantageous.
[0098] In some implementations, the diameters of transverse vent
holes 643a, 643b and 643c may range from 0.3 mm or less to 1.0 mm
or more. For example, in some implementations, the proximal-most
vent hole 643a may be approximately 1.0 mm, and the distal-most
vent hole 643c may be approximately 0.6 mm; in other
implementations, the proximal-most vent hole 643a may be
approximately 0.3 mm, and the distal-most vent hole 643c may be
approximately 0.6 mm.
[0099] FIG. 6G is a perspective cross-sectional view of the
exemplary microbubble generator 600, including a cap 676 and
sealing pin 679. In some implementations, as shown, the cap 676 is
threaded to engage with a Luer lock 680 or other threaded fitting
at the discharge tip 628. The cap 676 may include a sealing pin
679, which, in some implementations, is configured to seal off the
smallest-diameter throat section (e.g., throat section 664a, as
shown). In such implementations, the cap 676 may seal off the
channel 673 and the circumferential gas pocket 631 (through the
transverse vent holes (not visible in FIG. 6G)); and the sealing
pin may seal off the throat 664a, thereby sealing off the inlet
section 661a of aerator 616a and everything fluidly coupled thereto
(e.g., an interior of the syringe tip 612 and of the barrel 606).
In these implementations, the cap 676 and sealing pin 679 may
maintain sterility of the contents of the syringe 603 and may
prevent liquid or gas in the syringe 603 from leaking into the
circumferential gas pocket 631 before the cap 676 and sealing pin
679 are removed.
[0100] FIG. 7A is a perspective cross-sectional view of another
exemplary microbubble generator 700. As shown, the exemplary
microbubble generator 700 includes a syringe 703 having a barrel
706, a plunger 709, and a syringe tip 712. The syringe tip 712 may
include a Luer lock fitting 713 having corresponding threads.
[0101] An aerator 716 may be coupled to the syringe tip 712, and a
housing 719 may circumferentially surround an end of the barrel 706
and the aerator 716. The housing 719 may have a longitudinal axis
722, which, in some implementations, aligns coaxially with a
longitudinal axis 723 of the syringe 703 and a longitudinal axis
724 of the aerator 716.
[0102] As shown, the housing 719 has an interior surface 725 and a
discharge tip 728. In some implementations, the housing 719 is
configured to fluidly seal against the barrel 706, and the aerator
716 may be sealed to the syringe tip 712 and the discharge tip 728,
such that any fluid that is ejected from the syringe 703 (e.g., by
a user of the syringe 703 depressing the plunger 709) is ejected
through the syringe tip 712, into an interior cavity 755 (see FIG.
7B) of the aerator 716, through the discharge tip 728. A
circumferential gas pocket 731 may be created by the interior
surface 725, the aerator 716, the syringe tip 712, and the
discharge tip 728.
[0103] With reference to FIG. 7B, in the implementation shown, the
aerator 716 includes an interior cavity 755 that has five discrete
sections--an input port section 758, an inlet section 761, a throat
section 764, a diffusing section 765, and an outlet section 767.
The input port section 758 may be configured to receive the syringe
tip 712--that is, the input port section 758 may have a diameter
that is only slightly larger than the diameter of the syringe tip
712, and that diameter of the input port section 758 may decrease
from outside to inside the input port section 758.
[0104] As shown, the inlet section 761 has a progressively
decreasing diameter that constricts flow of a gas or liquid through
the aerator 716 as that gas or liquid flows from the input port
section 758 to a subsequent throat section 764. As described above
with respect to other implementations, this constriction of flow of
the gas or liquid increases its corresponding velocity and lowers
its pressure. This lowering of pressure allows gas to be drawn into
the flow through the first vent hole 743.
[0105] In some implementations, as shown, a diffusing section 765,
having a progressively increasing diameter, follows the throat
section 764; and an outlet section 767 follows the diffusing
section 765, which outlet section 767 may be cylindrical in
structure. In other implementations, the diffusing section 765 and
outlet section 767 may be a single section whose diameter
progressively increases from the throat section 764 to a tapered
outlet port 740.
[0106] In some implementations, as shown, a second vent 744 may be
disposed in the outlet section 767 (or, in some implementations,
the diffusing section 765). In operation, the first vent 743 and
second vent 744 may cooperate to increase efficiency at which fluid
moving through the throat section 764 aspirates gas, through the
first vent hole 743, from the circumferential gas pocket 731 (see
FIG. 7A). For example, in some implementations, an initial quantity
of fluid passing through the interior cavity 755 may displace air
or other gas in the interior cavity 755 primarily through the
second vent hole 744, rather than through the first vent hole
743--thereby (i) more quickly pressurizing the circumferential gas
pocket 731 and allowing gas in the circumferential gas pocket 731
to be aspirated into the fluid stream moving through the interior
cavity 755; and (ii) minimizing the simultaneous movement of a
quantity of liquid from the interior cavity 755 into the
circumferential gas pocket 731 and movement of gas from the
circumferential gas pocket 731 into the interior cavity 755--which
simultaneous movement of liquid in one direction and gas in the
opposite direction, through the same first vent hole 743, may
create turbulence and result in larger bubbles of air being
aspirated or formed than would otherwise be the case in
implementations that include the second vent hole 744.
[0107] In some implementations, the second vent hole 744 is larger
than the first vent hole 743. In such implementations, this
difference in size, coupled with the difference in pressure of gas,
liquid, or a combination thereof in the throat section 764 relative
to the outlet section 767, may result in both the liquid itself,
and gas that is initially displaced from the interior cavity 755
(e.g., as an initial quantity of fluid flows through said interior
cavity 755), flowing from the interior cavity 755 into the
circumferential gas pocket 731 primarily through the second vent
hole 744.
[0108] Regardless of the mechanism of action for any specific
implementation, Applicant surprisingly found that a single aerator
716 with both a first vent hole 743 and a second vent hole 744
(e.g., in the outlet section 767, as shown, or in the diffusing
section 765) significantly outperformed a single aerator 716 having
only a single vent hole 743.
[0109] In this context, "performance" may be quantified in terms of
(i) production of a significant quantity of very small bubbles
(e.g., bubbles having an average diameter of about 300 .mu.m or
less; or bubbles having an average diameter of about 250 .mu.m or
less; or bubbles having an average diameter of about 200 .mu.m or
less; or bubbles having an average diameter of about 100 .mu.m or
less; or more preferably, bubbles having an average diameter of
less than about 50 .mu.m; or still more preferably, bubbles having
an average diameter of less than about 20 .mu.m; or bubbles having
an average diameter of less than about 10 .mu.m; or bubbles having
an average diameter of less than about 2 .mu.m--note that in some
implementations, it may be advantageous to produce bubbles on the
higher end of the example ranges provided (e.g., to be more
echogenic); whereas in other implementations, it may be
advantageous to produce bubbles on the lower end of the example
ranges provided (e.g., to more precisely outline internal anatomic
features under ultrasound)); and/or (ii) a substantially
heterogeneous size distribution of the bubbles produced (e.g., 50%
or more of the bubbles falling within one standard deviation of an
average bubble size; or 95% of the bubbles falling within one or
two standard deviations of an average bubble size; or 99% of the
bubbles falling within one, two or three standard deviations of an
average bubble size); and/or (iii) with substantially no (or very
minimal) production of larger bubbles (e.g., bubbles larger than
about 100 .mu.m in diameter, or larger than about 200 .mu.m in
diameter, or larger than about 250 .mu.m in diameter, or larger
than about 300 .mu.m in diameter).
[0110] In some implementations, a boundary between the inlet
section 761 and throat section 764 may be rounded and/or smooth
(e.g., to minimize turbulence). Similarly, a boundary between the
throat section 764 and diffusing section 765 or a boundary between
the diffusing section 765 and outlet section 767 may by rounded
and/or smooth (e.g., to minimize turbulence). In some
implementations, the throat section 764 may have a slight taper
(e.g., to facilitate a clean molding process). In some
implementations, various surfaces and boundaries may have a rough
surface treatment, or edges may be sharp, rather than rounded or
smooth (e.g., to increase turbulence).
[0111] FIG. 8A is a perspective view of an exemplary aerator
component 816. In some implementations, the aerator component 816
may replace the aerator component 716 shown in FIG. 7A. As shown,
the aerator component includes threads 814 that may directly
interface with mating threads on a corresponding syringe component
(e.g., the threads of the Luer lock fitting 713 shown in FIG. 7A).
In such implementations, the threads 814 may facilitate a secure,
direct connection between the aerator component 816 and a
corresponding syringe (e.g., without reliance on a housing
component to facilitate that connection).
[0112] As shown, the aerator component 816 has an exterior body
830, which, in some implementations, is cylindrical and
characterized by a longitudinal axis 824. In other implementations,
the exterior body 830 may have other shapes (e.g., rectangular,
cubical, triangular, etc.). One or more alignment tabs, such as
alignment tab 832, may protrude from the exterior body 830; and
such alignment tab(s) 832 may be configured to interface with one
or more alignment grooves in a corresponding housing (e.g.,
alignment grooves 633 in the housing 619, shown in FIG. 6A)--such
that when the aerator 816 and corresponding housing are coupled
together, the alignment tab(s) 832 and corresponding alignment
grooves cooperate to radially fix the housing and aerator component
816 together. When so coupled, the longitudinal axis 824 may align
coaxially with longitudinal axes of a corresponding housing and
syringe.
[0113] With reference to FIG. 8B, in the implementation shown, the
aerator 816 includes an interior cavity 855 that has five discrete
sections, each fluidly coupled to the next to form a flow path 873
through an interior of the aerator 816. The five discrete sections
shown include an input port section 858, an inlet section 861, a
throat section 864, a diffusing section 865, and an outlet section
867. The input port section 858 may be configured to receive a
syringe tip (like the input port 758 of FIG. 7B); and, as noted,
threads 814 may be provided to secure the aerator 816 to the
syringe tip. The input port section 858 may have a diameter that is
only slightly larger than the exterior diameter of the syringe tip,
and that diameter of the input port section 858 may decrease from
outside to inside the input port section 858 such that the input
port section seals against an end of a corresponding syringe
tip.
[0114] As shown, the inlet section 861 has a progressively
decreasing diameter that constricts flow of a gas or liquid through
the aerator 816 as that gas or liquid flows from the input port
section 858 to a subsequent throat section 864. As described above
with respect to other implementations, this constriction of flow of
the gas or liquid increases its corresponding velocity and lowers
its pressure, which can allow gas to be drawn in through a vent
hole 843 in or near the throat section 864.
[0115] In the implementation shown, the vent hole 843 is positioned
just outside the throat section 864, in a subsequent diffusing
section 865, rather than in the throat section 864 itself. As
shown, the diffusing section has a progressively increasing
diameter and follows the throat section 864; and an outlet section
867 follows the diffusing section 865. In other implementations,
the diffusion section 865 and outlet section 867 may be a single
section whose diameter progressively increases from the throat
section 864 to an outlet port 840.
[0116] Although the vent hole 843 is not in the throat section 864
itself, as it is in other implementations illustrated and described
herein, the vent hole 843 is disposed close enough to the throat
section 864 that the pressure of gas or liquid flowing through the
aerator 816, along path 873, is lower at the point of the vent hole
843 than at other portions along the path 873; and this lower
pressure allows gas to be drawn into a fluid stream flowing along
the path 873, through the vent hole 843.
[0117] Disposition of the vent hole 843 just outside of the throat
section 843, in the diffusing section 865--rather than in the
throat section 834--can have certain advantages. For example, such
an arrangement can facilitate a seal between a sealing pin (such as
the sealing pin 679 shown in FIG. 6G) and the vent hole 843, while
enabling the sealing pin itself to be larger and more robustly
manufactured than would otherwise be possible if such a sealing pin
were required to be accommodated by the throat section 864. In some
implementations, this may both simplify the manufacturing process
and improve the yield on sealing pins; and it may minimize risk of
a fragment of a sealing pin breaking off inside the aerator 816 and
possibly being introduced into a stream of fluid that is ultimately
injected into a patient. FIG. 8C illustrates an exemplary sealing
pin 879 and how it may be accommodated by the outlet section 867
and diffusing section 865.
[0118] Returning to FIG. 8A, some implementations may include a
second vent 844. In the implementation shown, the second vent 844
is disposed at a distal end of the aerator component 816, at an
outlet port 840. The second vent 844 may be formed as a notch in a
wall of the outlet port 840, and the vent 844 may be fluidly
coupled to an area adjacent to the exterior body 830 (e.g., when
the aerator component 816 is disposed in a corresponding housing,
as in the implementations shown in FIGS. 6A and 7A) via one or more
grooves in the exterior body 830, such as the groove 845. In some
implementations, implementation of a groove 845 to form the second
vent 844 may simplify a manufacturing process, relative to other
methods for forming the vent 844. For example, a groove 845 may
simplify a mold and molding process, and obviate, in some
implementations, the need for a separate pin in the mold to form
the vent. In some implementations, a similar approach (e.g., a
groove in place of a hole) may be employed for the vent hole
843.
[0119] Regardless of their precise construction, the vents 843 and
844 may cooperate to increase efficiency at which fluid moving
along the path 873 aspirates gas, through the vent hole 843, from a
circumferential gas pocket (e.g., like the gas pocket 731
illustrated in FIG. 7A). For example, in some implementations, an
initial quantity of fluid passing through the interior cavity 855
may displace air or other gas in the interior cavity 855 primarily
through the second vent hole 844, rather than through the vent hole
843--thereby (i) more quickly pressurizing a corresponding
circumferential gas pocket and allowing gas in the circumferential
gas pocket to be aspirated into the fluid stream moving through the
interior cavity 855; and (ii) minimizing the simultaneous movement
of a quantity of liquid from the interior cavity 855 into the
circumferential gas pocket and movement of gas from the
circumferential gas pocket into the interior cavity 855--which
simultaneous movement of liquid in one direction and gas in the
opposite direction, through the same vent hole 843, may create
turbulence and result in larger bubbles of air or other gas being
aspirated or formed than would otherwise be the case in
implementations that include the second vent hole 844.
[0120] In some implementations, the second vent hole 844 is larger
than the vent hole 843. In such implementations, this difference in
size (coupled with the difference in pressure of gas, liquid, or a
combination thereof) in the throat and diffusing sections, 864 and
865, respectively, relative to the outlet section 867, may result
in both the liquid itself, and gas that is initially displaced from
the interior cavity 855 (e.g., as an initial quantity of fluid
flows through said interior cavity 855), flowing from the interior
cavity 855 into the circumferential gas pocket primarily through
the second vent hole 844.
[0121] In some implementations, materials for one or more of the
components of the exemplary implementations described herein may be
selected based on (a) suitability for use with human patients
(i.e., suitable for contact with body-compatible solutions that are
to be injected into human patients); (b) solid surface energy (SFE)
(e.g., of various components); and (c) interfacial tension (e.g.,
of the body-compatible solution). The various components described
herein may be further selected from materials that are commonly
used for the construction of medical devices. Such materials may be
selected by virtue of widespread acceptance in the medical device
field and/or ability to be sterilized or inherent sterile and/or
antimicrobial or antibacterial properties.
[0122] With respect to SFE, the material used (e.g., in particular
for the aerator or aerator components, such as aerator components
616a, 616b and 616c in FIGS. 6A-6G, aerator 716 in FIG. 7A, or
aerator 816 in FIG. 8A) may be selected from among thermoplastics
or other materials that may be injection molded and that are
accepted for use in medical devices--including, for example,
polyethylene (in high or low densities), polypropylene, polymethyl
methacrylate (PMMA), polyvinyl chloride (PVC), polyamide,
acrylonitrile butadiene styrene (ABS), polycarbonate, acetal,
polyethylene terephthalate glycol (PETG), or other suitable
materials.
[0123] More preferentially, in some implementations, the material
used may be further selected based on the SFE of the material. For
example, in some implementations, it may be advantageous to have a
material with an SFE of greater than about 30 millinewtons/meter
("mN/m") (sometimes expressed alternatively as dynes/cm, where 1
mN/m=1 dyne/cm)--in such implementations, a PVC (with an SFE of
about 35 mN/m, in some forms), ABS (with an SFE of about 35 mN/m,
in some forms), acetal (with an SFE of about 36 mN/m, in some
forms), PMMA (with an SFE of about 41 mN/m, in some forms),
polycarbonate (with an SFE of about 46 mN/m, in some forms) or PETG
(with an SFE of about 47 mN/m, in some forms) may be selected over
polypropylene (with an SFE of about 30 mN/m, in some forms) or a
polyethylene (with an SFE of about 30 mN/m, in some forms). In
other implementations, it may be advantageous to have a material
with an SFE of greater than about 35 mN/m. In still other
implementations, it may be advantageous to have a material with an
SFE of greater than about 40 mN/m--in such implementations, a PMMA,
polycarbonate or PETG may be employed.
[0124] In some implementations, a material may be treated to raise,
lower or otherwise control its SFE (e.g., the surface may be
roughened to increase its surface energy, it may be treated
chemically, it may be coated with another material, it may be
plasma treated or plasma activated, etc.). In many implementations,
the practical effect on wettability of the fundamental or treated
SFE may matter more than the actual effective value of the
SFE--that is, wettability (and specifically, a more wettable,
rather than less wettable material) may be more important in
certain implementations than the specific SFE value.
[0125] In some implementations, the body-compatible solution
includes a surfactant that lowers an interfacial tension of the
solution; or alternatively, the body-compatible solution is one
that has an inherently low interfacial tension relative to other
body-compatible solutions. For example, in some implementations,
the body-compatible solution is dextrose (e.g., D5W, D10W or D50).
As another example, in some implementations, the body-compatible
solution includes a surfactant such as polysorbate (e.g., 0.1%
polysorbate in a saline solution, 1% polysorbate in a saline
solution, 10% polysorbate in a saline solution, etc.). In other
implementations, other body-compatible surfactants may be used
(e.g., nonionic, anionic, cationic, amphoteric surfactants,
generally; specific examples may include, among others,
propanediol, polyethylene glycol, lecithin, poloxamer, glycerin,
hypertonic saline, hydrophobic hydrocarbon chains with hydrophilic
heads, caseins, certain proteins, etc.).
[0126] Various implementations were tested with respect to
microbubble production capability, and images captured of each
test. Those images appear as FIGS. 9A-9C, 10A-10C, 11A-11C, 12A-12C
and 13A-13C. In each test, a device was employed like one of the
devices illustrated in and described with reference to FIG. 6A, 7A
or 8A--each device included a syringe body and plunger, a housing,
and one or more aerator components within the housing; in addition,
a 20-gauge needle was disposed on the end of the housing. For each
test, the syringe component was filled with approximately 10 mL of
a body-compatible solution, and the device was oriented with the
needle disposed in a beaker of tap water. Approximately 3-3.5 mL of
room air was enclosed by the housing, in the circumferential air
pocket. A black backdrop was placed behind the beaker, and lighting
was positioned on the side to illuminate microbubbles formed by the
device.
[0127] In each test, once the syringe was filled and positioned,
the plunger of the syringe was manually depressed using a
substantially consistent force/speed to force the body-compatible
solution through the aerator component(s) and needle, into the
beaker of tap water. Depression of the plunger continued until the
body-compatible solution was substantially expelled from the
syringe.
[0128] Each of FIGS. 9A-9C, 10A-10C, 12A-11C, and 13A-12C includes
four panels. In these figures, the left-most panel corresponds to a
time approximately 0.5 seconds after the plunger was initially
depressed; the left-middle panel corresponds to a time
approximately 2.5 seconds after the plunger was initially
depressed; the right-middle panel corresponds to a time
approximately 6.0 seconds after plunger was initially depressed;
and the right-most panel corresponds to a time at which the
body-compatible solution was substantially expelled. FIGS. 11A-11C
include three panels, because in the corresponding examples, the
body-compatible solution was expelled from the syringe more rapidly
than in the other examples, such that the total time was less than
6.0 seconds after the plunger was initially depressed. In FIGS.
11-11C, the left and middle panels remain the same as in FIGS.
9A-9C, 10A-10C, 12A-12C, and 13A-13C--namely, these panels
correspond to times of approximately 0.5 and 2.5 seconds after the
plunger was initially depressed; the right panel corresponds to a
time at which the body-compatible solution was substantially
expelled (prior to 6.0 seconds).
[0129] Each test ("example") and the results thereof are now
described in detail. In the descriptions that follow, subjective
descriptions of bubble size are provided (e.g., "microbubbles,"
"very small" bubbles, "small" bubbles, "medium-sized" bubbles and
"large" bubbles); these qualitative descriptions are provided to
facilitate qualitative comparison. In some implementations, "large"
bubbles may be 1 mm or more in diameter (e.g., 1 mm, 2 mm, 3 mm, 5
mm, etc.); "medium-sized" bubbles may have diameters ranging from
about 0.5 mm to about 1 mm; "small" bubbles may have diameters
ranging from about 0.5 mm to 0.1 mm (100 .mu.m); "very small"
bubbles may have diameters ranging from about 10 .mu.m and 100
.mu.m; and "microbubbles" may have diameters ranging from about 1
.mu.m to about 10 .mu.m. In other implementations, different ranges
may apply--for example, in some implementations, "microbubbles" may
have diameters less than 1 .mu.m (and may include what could be
referred to as "nanobubbles"); as another example, "microbubbles"
may include bubbles having diameters of about 1 .mu.m to about 25
.mu.m; as another example, "very small" bubbles may have diameters
ranging from 2 .mu.m to about 50 .mu.m. Many specific ranges are
possible; and as stated, the primary point of the bubble size
references is for qualitative comparison.
EXAMPLE 1
Multi-Stage, Polypropylene, Saline
[0130] In a first example, illustrated in FIG. 9A, a device having
multiple aerator components (e.g., like the exemplary microbubble
generator 600 shown in FIG. 6), each made of polypropylene, was
employed; and the syringe was filled with saline. As captured in
the left-most panel, initial expulsion of the saline resulted in
production of a minimal volume of small to medium-sized bubbles.
Bubble production continued to be intermittent and minimal as the
saline was expelled from the syringe (note that some small and
medium-sized bubbles are visible in solution in the left-middle and
right-middle panels). After about 8.5 seconds (see right-most
panel), when the saline was substantially expelled, a significant
volume of large bubbles was produced.
EXAMPLE 2
Multi-Stage, Polypropylene, Dextrose
[0131] In a second example, illustrated in FIG. 9B, a device having
multiple aerator components, each made of polypropylene, was
employed; and the syringe was filled with D50 dextrose (e.g., a
solution comprising 50% dextrose). As captured in the left-most
panel, initial expulsion of the dextrose resulted in production of
a minimal volume of small bubbles. Bubble production was more
continuous with the dextrose than with pure saline, and more small
bubbles were produced (with medium-sized bubbles also being
produced throughout--see left-middle and right-middle panels). A
greater quantity of bubbles was produced with dextrose than with
saline, but the overall volume remained relatively low. After about
10 seconds (see right-most panel), when the dextrose was
substantially expelled, a significant volume of large bubbles was
produced.
EXAMPLE 3
Multi-Stage, Polypropylene, Saline/Polysorbate
[0132] In a third example, illustrated in FIG. 9C, a device having
multiple aerator components, each made of polypropylene, was
employed; and the syringe was filled with saline with a small
quantity of polysorbate added (approximately 1% by volume). As
illustrated in the left-most panel, initial expulsion of the
saline/polysorbate resulted in production of a quantity of very
small bubbles and microbubbles (as illustrated by the "cloud-like"
pattern). After an initial production of very small bubbles, bubble
production tapered off with only intermittent production of very
small, small and medium-sized bubbles being produced (see
left-middle and right-middle panels). After about 9 seconds (see
right-most panel), when the saline/polysorbate was substantially
expelled, a significant volume of large bubbles was produced.
EXAMPLE 4
Multi-Stage, Polycarbonate, Saline
[0133] In a fourth example, illustrated in FIG. 10A, a device
having multiple aerator components, each made of polycarbonate, was
employed; and the syringe was filled with saline. As illustrated in
the left-most panel, initial expulsion of the saline resulted in
production of a volume of large bubbles. Steady production of large
bubbles continued for approximately two seconds, after which, a
steady but minimal stream of small and medium-sized bubbles
continued (see left-middle and right-middle panels). After about 11
seconds (see right-most panel), when the saline was substantially
expelled, bubble production simply stopped--no large bubbles were
produced at the end, as they had been in the previous examples.
EXAMPLE 5
Multi-Stage, Polycarbonate, Dextrose
[0134] In a fifth example, illustrated in FIG. 10B, a device having
multiple aerator components, each made of polycarbonate, was
employed; and the syringe was filled with D50 dextrose. As
illustrated in the left-most panel, initial expulsion of the
dextrose resulted in production of a smooth stream of microbubbles
(appearing as a bright cloud). Large bubbles initially accompanied
the microbubbles for about two seconds, after which point bubble
production slowed slightly (but remained consistent throughout--see
left-middle and right-middle panels), and bubble size shifted to
mostly very small bubbles. After about 13 seconds (see right-most
panel), when the dextrose was substantially expelled, bubble
production simply stopped, and no large bubbles were produced at
the end.
EXAMPLE 6
Multi-Stage, Polycarbonate, Saline/Polysorbate
[0135] In a sixth example, illustrated in FIG. 10C, a device having
multiple aerator components, each made of polycarbonate, was
employed; and the syringe was filled with saline with a small
quantity of polysorbate added (approximately 1% by volume). As
illustrated in the left-most panel, initial expulsion of the
saline/polysorbate resulted in production of a smooth stream of
microbubbles (in a significant quantity, relative to the other
examples) with a minimal number of small and very small bubbles
(and virtually no medium-sized or large bubbles forming). Steady
production of microbubbles continued for about two seconds, after
which the volume of bubbles decreased slightly, and the bubbles
appeared to increase in size slightly, to very small bubbles (see
left-middle and right-middle panels). After about 10.5 seconds (see
right-most panel), when the saline/polysorbate was substantially
expelled, bubble production tapered off without the production of
any large bubbles.
EXAMPLE 7
Single-Stage, Polypropylene, Saline
[0136] In a seventh example, illustrated in FIG. 11A, a device
having a single aerator component (e.g., like the exemplary
microbubble generator 700 shown in FIG. 7) made of polypropylene
was employed; and the syringe was filled with saline. As
illustrated in the left-most panel, initial expulsion of the saline
resulted in production of a quantity of small, medium-sized and
large bubbles. Production of these bubbles remained consistent for
about one second, after which bubble production diminished, and
bubble size decreased (see middle panel). After about 3.5 seconds
(see right panel), when the saline was substantially expelled, a
significant volume of large bubbles was produced. As evident from
the existence of only three panels in FIG. 11A (and FIGS. 11B and
11C), the duration during which bubbles were produced was much
shorter in example seven (and examples eight and nine) than in the
other examples provided.
EXAMPLE 8
Single-Stage, Polypropylene, Dextrose
[0137] In an eighth example, illustrated in FIG. 11B, a device
having a single aerator component made of polypropylene was
employed; and the syringe was filled with D50 dextrose. As
illustrated in the left panel, initial expulsion of the dextrose
resulted in production of a quantity of small and medium-sized
bubbles. Production of these bubbles remained consistent for about
one second, after which bubble production diminished, and bubble
size decreased (see middle panel). After about four seconds (see
right panel), when the dextrose was substantially expelled, a
significant volume of large bubbles was produced.
EXAMPLE 9
Single-Stage, Polypropylene, Saline/Polysorbate
[0138] In a ninth example, illustrated in FIG. 11C, a device having
a single aerator component made of polypropylene was employed; and
the syringe was filled with saline with a small quantity of
polysorbate added (approximately 1% by volume). As illustrated in
the left panel, initial expulsion of the saline/polysorbate
resulted in production of a quantity of microbubbles, with some
small and medium-sized bubbles also present. Production of these
bubbles remained consistent for about one second, after which
bubble production diminished (see middle panel). After about four
seconds (see right panel), when the saline/polysorbate was
substantially expelled, a significant volume of large bubbles was
produced.
EXAMPLE 10
Single-Stage, Polycarbonate, Saline
[0139] In a tenth example, illustrated in FIG. 12A, a device having
a single aerator component made of polycarbonate was employed; and
the syringe was filled with saline. As illustrated in the left-most
panel, initial expulsion of the saline resulted in production of a
quantity of small, medium-sized and large bubbles. Production of
these bubbles remained consistent for about four seconds (see
left-middle panel), after which bubble production nearly ceased
(see right-middle panel). After about seven seconds (see right-most
panel), when the saline was substantially expelled, a significant
volume of large bubbles was produced.
EXAMPLE 11
Single-Stage, Polycarbonate, Dextrose
[0140] In an eleventh example, illustrated in FIG. 12B, a device
having a single aerator component made of polycarbonate was
employed; and the syringe was filled with D50 dextrose. As
illustrated in the left-most panel, initial expulsion of the
dextrose resulted in production of a quantity of small and very
small bubbles, with a few medium-sized and large bubbles also
present. Production of small and very small bubbles continued for
approximately three seconds (see left-middle panel), after which
bubble production tapered off somewhat but remained consistent,
with small and very small bubbles being produced (see right-middle
panel). After about 7.5 seconds (see right-most panel), when the
dextrose was substantially expelled, a volume of large bubbles was
produced.
EXAMPLE 12
Single-Stage, Polycarbonate, Saline/Polysorbate
[0141] In a twelfth example, illustrated in FIG. 12C, a device
having a single aerator component made of polycarbonate was
employed; and the syringe was filled with saline with a small
quantity of polysorbate added (approximately 1% by volume). As
illustrated in the left-most panel, initial expulsion of the
saline/polysorbate resulted in production of a quantity of small
and very small bubbles and microbubbles, with a few medium-sized
and large bubbles also present. Production of very small bubbles
and microbubbles continued for approximately three seconds (see
left-middle panel), after which bubble production tapered off
somewhat but remained consistent, with very small bubbles and
microbubbles being produced (see right-middle panel). After about
7.0 seconds (see right-most panel), when the saline/polysorbate was
substantially expelled, a volume of large bubbles was produced.
EXAMPLE 13
Single-Stage, Acetal, Saline
[0142] In a thirteenth example, illustrated in FIG. 13A, a device
having a single aerator component made of acetal was employed; and
the syringe was filled with saline. As illustrated in the left-most
panel, initial expulsion of the saline/polysorbate resulted in
production of a quantity of bubbles ranging greatly in
size--including large, medium-sized, small and some very small
bubbles. Production of bubbles ranging greatly in size continued
for approximately three seconds (see left-middle panel), after
which bubble production tapered off considerably, with only a small
quantity of small and very small bubbles being produced (see
right-middle panel). After about 6.5 seconds, medium-sized bubbles
were again produced; and at about 8.0 seconds, when the saline was
substantially expelled, a volume of large bubbles was produced.
EXAMPLE 14
Single-Stage, Acetal, Dextrose
[0143] In a fourteenth example, illustrated in FIG. 13B, a device
having a single aerator component made of acetal was employed; and
the syringe was filled with D50 dextrose. As illustrated in the
left-most panel, initial expulsion of the dextrose resulted in
production of a quantity of bubbles ranging greatly in
size--including large, medium-sized and small bubbles and some very
small bubbles and microbubbles. Production of bubbles ranging
greatly in size continued for approximately 3.5 seconds (see
left-middle panel), after which bubble production tapered off, with
primarily very small bubbles and microbubbles being produced (see
right-middle panel). After about 9.0 seconds, when the dextrose was
substantially expelled, a volume of large bubbles was produced.
EXAMPLE 15
Single-Stage, Acetal, Saline/Polysorbate
[0144] In a fifteenth example, illustrated in FIG. 13C, a device
having a single aerator component made of acetal was employed; and
the syringe was filled with saline with a small quantity of
polysorbate added (approximately 1% by volume). As illustrated in
the left-most panel, initial expulsion of the saline/polysorbate
resulted in production of small and very small bubbles and
microbubbles. Steady production of bubbles in these ranges
continued for approximately 4.0 seconds (see left-middle panel),
after which bubble quantity tapered slightly but size remained
relatively consistent (see right-middle panel). After about 6.5
seconds, when the saline/polysorbate was substantially expelled, a
volume of large bubbles was produced.
Analysis
[0145] As these examples show, Applicant found that, with respect
to aerator material and bubble formation, polycarbonate aerators
generally outperformed polypropylene aerators--in one or more of
length of time over which bubbles were produced (and, by extension,
quantity of bubbles) and quality of bubbles (where "higher quality"
here corresponds to a distribution that primarily includes small
and very small bubbles and microbubbles and that minimizes
medium-sized and large bubbles). With single-stage aerators, acetal
seemed to perform comparably to polycarbonate. With respect to the
solution used in the aerators, dextrose outperformed saline across
all examples, though the differences between dextrose and saline
were less pronounced with polypropylene aerators. Saline with a
small quantity of added polysorbate generally outperformed dextrose
across all examples; though, again, differences between
saline/polysorbate and dextrose were less pronounced with
polypropylene aerators. In contrast to single-staged aerators with
either dextrose or polysorbate, multi-staged aerators with either
dextrose or polysorbate did not produce large bubbles at the end,
when the solution was substantially expelled from the syringe.
[0146] Surprisingly, Applicant found that the combination of
polycarbonate and dextrose, or polycarbonate and saline/polysorbate
very significantly outperformed (e.g., in bubble quantity and
quality, as described above) implementations involving only saline
or implementations with polypropylene aerators. Compare, for
example, FIG. 10C to the other multi-stage implementations depicted
in FIGS. 9A-9C, and FIGS. 10A-10B; further compare FIG. 12C to the
other single-stage implementations depicted in FIGS. 11A-11C and
FIGS. 12A-12B. Applicant found that acetal and saline/polysorbate
performed similar to polycarbonate and saline/polysorbate (see FIG.
13C and FIG. 12C).
[0147] Applicant determined that variations in performance in the
various examples are related to (1) the surface energy of the
material (polypropylene, polycarbonate or acetal in these examples)
from which the aerator components are formed--and perhaps more
precisely, the corresponding level of hydrophobicity or
hydrophilicity that results from said surface energy of the
material; and (2) the presence of a surfactant in the
body-compatible solution (both dextrose and polysorbate act as
surfactants in solution).
[0148] Examining these properties independently of each other,
various forms of polypropylene have surface energies of about 30
mN/m (milli-Newtons per meter--the International System of Units'
standard units for measuring surface energy), whereas various forms
of polycarbonate have surface energies of about 46 mN/m. (Various
forms of acetal have surface energies of about 36 mN/m--between the
surface energies of polypropylene and polycarbonate.) It is
believed that the higher surface energy of polycarbonate (and, to a
lesser extent, acetal) allows greater spreading of a given solution
on the surfaces of the aerator components (e.g., along the channel
773 shown in FIG. 7B or the channel 673 shown in FIG. 6F) than does
the lower surface energy of polypropylene--resulting in more
efficient operation of the venturi and corresponding vent in
introducing air or other gas into the stream of solution flowing
past). Put another way, the difference in surface energies is
believed to allow less beading of a given solution on polycarbonate
(or acetal) than on polypropylene This greater spreading, or less
beading, is believed to facilitate greater uptake or air or gas
into a stream of solution flowing through the venturi.
[0149] Surfactants in solution tend reduce the interfacial tension
between molecules of the solution (independent of effects on
interfacial tension that surface energies of materials in contact
with the solution may have at the contact surface). That is, in the
absence of a surfactant, the intermolecular forces holding
individual molecules of the solution to each other may be
relatively strong, whereas addition of a surfactant reduces the
intermolecular attractive forces, or interfacial tension. It is
understood that this reduction of interfacial tension, caused by
the presence of a surfactant (e.g., dextrose or polysorbate),
increases a solution's ability to attract air or gas, in the form
of microbubbles (e.g., in or near the venturi throat, when the
solution is moving through said venturi throat).
[0150] Surprisingly, Applicant found that variations in these two
parameters (surface energy and interfacial tension) combine in a
seemingly multiplicative manner rather than merely an additive
manner. That is, implementations involving both a higher material
surface energy of the aerator components and the presence of a
surfactant in the solution facilitated creation of microbubbles
that were far superior to bubbles formed in an implementation in
which only surface energy was optimized, or only interfacial
tension was optimized. For example, with respect to surface energy
only, a greater quantity of bubbles were produced by multi-stage
aerators having higher surface energies (e.g., more bubbles were
produced in example 4 (FIG. 10A) than in example 1 (FIG. 9A));
similarly, a greater quantity of bubbles were produced by
single-stage having higher surface energies (e.g., more bubbles
were produced in examples 10 and 13 (FIGS. 12A and 13A) than in
example 7 (FIG. 11A)). With respect to surfactant only, examples
involving dextrose or polysorbate outperformed those involving only
saline. However, when these parameters were combined, the
differences were very significant--with a multi-stage aerator,
bubbles were produced in example 6 (FIG. 10C) in much greater
quantity and at much higher quality than those produced in example
3 (FIG. 9C); and with a single-stage aerator, bubbles were produced
in examples 12 and 15 (FIG. 12C and FIG. 13C) in much greater
quantity and at much higher quality than those produced in example
9 (FIG. 11C). Thus, Applicant surprisingly found that aerator
components made of a high surface energy material (e.g.,
polycarbonate or acetal), combined with a body-compatible solution
having a surfactant (e.g., dextrose or polysorbate), produced
greater quantities of higher-quality bubbles than other
implementations.
Conclusion
[0151] While many implementations are described with reference to
heart studies, contrast studies may have other useful applications.
For example, microbubbles combined with ultrasound or other imaging
technology may be clinically useful in documenting proper catheter
placement during pericardiocentesis, central venous catheter
placement in the right atrium, and during interventional radiology
procedures. In the field of gynecology, for example with
ultrasound/infertility procedures, microbubbles may be used to
assess patency of the fallopian tubes. Other applications could
include imaging of abdominal spaces, portions of the
gastrointestinal tract, and joints or other interstitial spaces of
a human body. Microbubbles may also be employed in veterinary
procedures in a similar manner as described herein.
[0152] Several implementations have been described with reference
to exemplary aspects, but it will be understood by those skilled in
the art that various changes may be made and equivalents may be
substituted for elements thereof without departing from the
contemplated scope. For example, syringes of various sizes may be
employed; a converging nozzle may be integral to the syringe; an
aerator may be integral to the converging nozzle; converging
nozzles and aerators may be an integral assembly; components may be
adhesively joined, ultrasonically welded or molded as unitary
parts; some implementations may employ O-rings and compression
fittings to join components while other implementations may employ
different techniques; different size air channels and geometries
may be employed within a converging nozzle; syringes may be
prefilled or filled on-site, immediately prior to a procedure;
microbubbles may be generated in saline, dextrose, plasma,
saline/polysorbate, saline with some other surfactant, or some
other body-compatible fluid or combination of fluids; microbubbles
may be employed in the context of ultrasound or with other imaging
technology; microbubbles may be employed for diagnostic or
therapeutic purposes; kits may be provided with any number of
microbubble generators, coupled together with a manifold or
provided with a manifold for coupling prior to a procedure;
different membranes, caps or seals may be employed to contain
pre-filled fluid within certain portions of a microbubble generator
or microbubble generation system; various numbers of air channels
may be employed to facilitate generation of a greater or smaller
number of microbubbles per unit of fluid; the air channels may have
various dimensions, geometries and/or surface treatment to control
size of generated microbubbles; in place of "air" throughout,
another gas may be employed (e.g., oxygen, nitrogen, carbon
dioxide, some mixture thereof, another biologically compatible gas,
etc.); a continuous source of saline or other fluid may replace a
syringe; a syringe may be automatically or manually operated;
microbubbles may include "nanobubbles" or bubbles of various sizes
and distributions; aerator components may vary in dimension (e.g.,
throat diameter, vent diameter); different numbers of aerator
components may be deployed (e.g., one, two, three or more); aerator
components may be staged in sequence with different sequences of
dimensions (e.g., throats ranging from smaller to larger or in some
other sequence); a single-aerator implementation may include
different numbers of vent holes (e.g., one, two, three or more);
vent holes may be transverse holes that are generally perpendicular
to a longitudinal axis of a corresponding channel or flow path;
vent holes may be angled relative to a longitudinal axis of a
corresponding channel or flow path; vent holes may comprise grooves
or other paths that fluidly couple an area exterior to an aerator
body to a flow path interior to the aerator body.
[0153] Many other variations are possible, and modifications may be
made to adapt a particular situation or material to the teachings
provided herein without departing from the essential scope thereof.
Therefore, it is intended that the scope include all aspects
falling within the scope of the appended claims.
* * * * *