Syringe-based microbubble generator with aerator

Abstract

A device includes a syringe having a barrel and a syringe tip; an aerator having (i) a generally cylindrical outer body; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end; and (v) an internal chamber including (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 fluidically connects at least one of the throat section or the diverging section to an area outside and adjacent to the outer body, and (G) a second vent that fluidly connects the outlet section to the area; and a shell that (x) circumferentially surrounds the end of the barrel and the aerator, (z) has an inner surface, (aa) forms a circumferential air pocket between the inner surface and the outer body, and (bb) has a shell discharge tip.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a continuation-in-part of U.S. patent application serial number 17 / 584,826, filed on January 26, 2022, entitled “SYRINGE-BASED MICROBUBBLE GENERATORWITH AN AERATOR”, which is a continuation-in-part of U.S. patent application serial number 17 / 566,079, filed on December 30, 2021, entitled “SYRINGE-BASED MICROBUBBLE GENERATORWITH AN AERATOR”, which is a continuation-in-part of U.S. application serial number 17 / 542,386, filed on December 4, 2021, entitled “SYRINGE-BASED MICROBUBBLE GENERATOR”, which is a continuation-in-part of U.S. application serial number 17 / 542,386, filed on January 26, 2021, entitled “SYRINGE-BASED MICROBUBBLE GENERATOR" is a continuation-of-patent application of U.S. Patent No. 17 / 158,396, now a continuation-of-patent application of U.S. Patent No. 11,191,888. The entire contents of the aforementioned application are incorporated herein by reference. Technical Field

[0003] Various embodiments are generally directed to generating microvesicles for use in various diagnostic and therapeutic procedures. Background Art

[0004] An echocardiogram is the study of the heart using ultrasound. Echocardiograms are a widely used diagnostic test in the field of cardiology and are useful in the diagnosis, management, and follow-up of patients with suspected or known heart disease. The results of an echocardiogram test can provide a lot of useful information, including the size and shape of the heart's components (e.g., quantification of the size of the internal chambers), pumping function, and the location and extent of any tissue damage. An echocardiogram can also provide the doctor with other estimates of heart function, such as calculations of cardiac output, ejection fraction (the percentage of blood pumped out with each contraction of the left ventricle), diastolic function (how well the heart relaxes), and more.

[0005] An echocardiogram can be performed in one of several ways. Minimally invasively, an ultrasound transducer can be placed on the patient's chest and imaging can be performed through the patient's chest wall in a transthoracic echocardiogram (TTE). If a higher fidelity image is needed, a more invasive transesophageal echocardiogram (TEE) can be performed, in which an ultrasound transducer set 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 used to obtain very clear images of the heart's structures and valves.

[0006] During 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 so that it quickly reaches the chambers of the heart and is detected by ultrasound, giving greater clarity to the heart's structures. In some procedures, the contrast agent employed is a saline solution containing tiny bubbles, and the procedure may be called an oscillating saline contrast study or a "bubble study." Summary of the invention

[0007] In some embodiments, 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 outer body including a longitudinal axis feature; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end, the tapered outlet end may be defined by an outlet diameter less than the body diameter corresponding to the outer body and a tapered portion near the outlet end; and (v) an internal chamber including (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 outer body. The housing may (x) circumferentially surround the end of the barrel and the plurality of aerator components, (y) include a longitudinal axis feature, (z) have an inner surface, (aa) form a circumferential air pocket between the inner surface and the outer body of each of the plurality of aerator components, and (bb) have a housing discharge tip. The input port section of each aerator component can be configured to accommodate the tapered outlet port of the syringe tip or one of the other aerator components in the plurality of aerator components, and the housing discharge tip can be configured to accommodate the tapered outlet port of one of the plurality of aerator components, so that the syringe tip, the first aerator component, the second aerator component and the housing can be coupled together in a coaxial manner relative to their respective longitudinal axes.

[0008] In some embodiments, 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 secure the housing and each of the plurality of aerator components relative to each other.

[0009] In some embodiments, a device for generating microbubbles includes a syringe, an aerator, and a housing, the syringe having a barrel and a syringe tip including a longitudinal axis feature. The aerator may have (i) a generally cylindrical outer body, which also includes a longitudinal axis feature; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end; and (v) an internal chamber 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 outer body, and (G) a second vent that fluidly couples the outlet section to the area. The housing may (x) circumferentially surround the end of the barrel and the aerator, (y) include a longitudinal axis feature, (z) have an inner surface, (aa) form a circumferential air pocket between the inner surface and the outer body, and (bb) have a housing discharge tip. The input port section may be configured to receive the syringe tip, and the housing discharge tip may be configured to receive the tapered outlet port, such that the syringe tip, aerator component, and housing may be coupled together in a coaxial manner relative to their respective longitudinal axes.

[0010] In some embodiments, the housing seals against the cartridge to prevent fluid communication between the region and a region outside the housing except through the housing discharge tip, the first vent, or the second vent. The first vent includes a first vent diameter characteristic, the second vent includes a second vent diameter characteristic, and the first vent diameter may be greater than the second vent diameter. In some embodiments, the first vent diameter is about 1.0 mm, and the second vent diameter is about 0.5 mm.

[0011] In some embodiments, the capacity of the cartridge is about 30 mL, and the volume of the circumferential air pocket is about 5 to 15 mL. The outlet section may be substantially cylindrical. The diameter of the converging section may be in the range between about 3.5 mm and about 0.5 mm. The diameter of the diverging section may be in the range between about 0.65 mm and about 2.1 mm. The aerator may include a material with a surface energy greater than or equal to about 35 mN / m.

[0012] In some embodiments, the device includes a body-compatible solution disposed in the cartridge. In some embodiments, the device also includes a cap closing a portion of the discharge tip of the housing and a sealing pin blocking a portion of the interior chamber.

[0013] In some embodiments, 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 including a longitudinal axis feature, wherein the barrel is filled with a body-compatible fluid; (b) an aerator having (i) a generally cylindrical outer body including a longitudinal axis feature; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end; and (v) an internal chamber having (A) an input port section, (B) a converging section,

[0014] (C) a throat section, (D) a diverging section, (E) an outlet section, (F) a first vent fluidly coupling at least one of the throat section or the diverging section to an area outside and adjacent to the outer body, and (G) a second vent fluidly coupling the outlet section to the area; and (c) a housing that (x) circumferentially surrounds the end of the cartridge and the aerator, (y) includes a longitudinal axis feature, (z) has an inner surface, (aa) forms a circumferential air pocket between the inner surface and the outer body, and (bb) has a housing discharge tip. The input port section can be configured to accommodate a syringe tip, and the housing discharge tip can be configured to accommodate a 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.

[0015] The method may also include coupling the housing discharge tip to the venous system of a patient undergoing a procedure. Coupling the housing discharge tip to the patient's venous system may include coupling the housing discharge tip to a needle and placing the needle in the patient's venous system. Coupling the housing discharge tip to the patient's venous system may include coupling the housing discharge tip to an intravenous line and placing the intravenous line in the patient's venous system. The method may also include generating microbubbles by forcing a body-compatible fluid out of a syringe, through the interior chamber and through the housing discharge tip.

[0016] In some embodiments, the aerator comprises a material having a solid surface energy of about 35 mN / m or greater. In some embodiments, the aerator comprises polycarbonate. In some embodiments, the aerator comprises one of polycarbonate, polymethacrylate, polyvinyl chloride, polyamide, acrylonitrile butadiene styrene, acetal, or polyethylene terephthalate.

[0017] In some embodiments, the body compatible fluid comprises glucose. In some embodiments, the body compatible fluid comprises saline and polysorbate. The body compatible fluid may include polysorbate at a concentration of 0.1% or less; the body compatible fluid may include polysorbate at a concentration of 0.01% or less; the body compatible fluid may include polysorbate at a concentration of 0.005% or less. In some embodiments, the body compatible fluid comprises saline and glucose or a body compatible surfactant. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is an exploded perspective view of an exemplary microbubble generator.

[0019] Figure 2A is a longitudinal cross-section of an exemplary assembled injector, converging nozzle, and aerator, in one embodiment.

[0020] Figure 2B yes Figure 2A A longitudinal section of the converging nozzle, O-ring and aerator is shown in FIG.

[0021] Figure 2C yes Figure 2A Another longitudinal cross-section of the converging nozzle, O-ring and aerator shown in .

[0022] Figure 2D yes Figure 2C A perspective cross-sectional view of the configuration shown in FIG.

[0023] Figure 2E is a perspective cross-sectional view of another exemplary converging nozzle and aerator.

[0024] Figure 2F yes Figure 2E A longitudinal cross-section of the converging nozzle and aerator shown in FIG.

[0025] Figure 3A , Figure 3B and Figure 3C The operation of an exemplary microbubble generator is depicted.

[0026] Figure 4 An exemplary microbubble generating system is illustrated.

[0027] Figure 5 Diagram showing a portion of the entire human circulatory system.

[0028] Fig. 6A is a perspective cross-sectional view of another exemplary microbubble generator.

[0029] Figure 6B Can be included in Fig. 6A A perspective view of an aerator component in an exemplary microbubble generator.

[0030] Figure 6C yes Figure 6B A perspective cross-sectional view of the aerator components.

[0031] Fig.6D yes Figure 6B A side view of the aerator components.

[0032] Fig. 6E yes Figure 6B A side cross-sectional view of an aerator component.

[0033] Fig. 6F are connectable and included in Fig. 6A A perspective cross-sectional view of multiple aerator components in an exemplary microbubble generator.

[0034] Figure 6G Includes cap and sealing pin Fig. 6A A perspective cross-sectional view of an exemplary microbubble generator.

[0035] Fig. 7A is a perspective cross-sectional view of another exemplary microbubble generator.

[0036] Figure 7B Can be included in Fig. 7A A side cross-sectional view of an aerator component in an exemplary microbubble generator.

[0037] Fig. 8A is a perspective view of exemplary aerator components.

[0038] Figure 8B yes Fig. 8A Cross section of an aerator component.

[0039] Figure 8C yes Fig. 8A A cross section of an aerator component in which a sealing pin is provided.

[0040] 9A to 9C illustrate microbubbles formed using an exemplary multi-stage polypropylene aerator with saline, glucose, and saline containing polysorbate, respectively.

[0041] 10A to 10C illustrate microbubbles formed using an exemplary multi-stage polycarbonate aerator with saline, glucose, and saline containing polysorbate, respectively.

[0042] 11A to 11C illustrate microbubbles formed using an exemplary single-stage polypropylene aerator with saline, glucose, and saline containing polysorbate, respectively.

[0043] 12A to 12C illustrate microbubbles formed using an exemplary single-stage polycarbonate aerator with saline, glucose, and saline containing polysorbate, respectively.

[0044] 13A to 13C illustrate microbubbles formed using an exemplary single-stage acetal aerator with saline, glucose, and saline containing polysorbate, respectively.

[0045] Fig.14A Schematic representation of the TEE procedure in a porcine model, in which microbubbles are generated using current standard of care procedures.

[0046] Fig. 14B Schematic representation of the TEE procedure in a porcine model using an exemplary aerator to generate microbubbles with saline and a 0.1% concentration of polysorbate.

[0047] Fig. 14C Schematic representation of the TEE procedure in a porcine model using an exemplary aerator to generate microbubbles with saline and a 0.01% concentration of polysorbate.

[0048] Fig.14D Schematic representation of the TEE procedure in a porcine model using an exemplary aerator to generate microbubbles with saline and a 0.005% concentration of polysorbate.

[0049] Fig.14E Schematic representation of the TEE procedure in a porcine model, where a 20-gauge needle rather than an intravenous line was used to deliver microbubbles. DETAILED DESCRIPTION

[0050] Oscillating saline contrast studies (or "bubble studies") are a useful adjunct to many ultrasound examinations, especially ultrasound of the heart (echocardiogram). Injecting an oscillating saline into a vein combined with echocardiography is an effective method for detecting shunts that may be located within the heart, such as a patent foramen ovale (PFO) or atrial septal defect (ASD)—two types of holes in the heart—or outside the heart, such as in the lungs, called a pulmonary arteriovenous malformation (pAVM). Oscillating saline can also be used with echocardiography to detect shunts. Figure 1 It is used together to confirm catheter placement in the fluid surrounding the heart (pericardiocentesis), detect abnormal connections within the heart, visualize the right side of the heart, and emphasize right-sided blood flow for quantification.

[0051] Oscillating saline contrast echocardiography takes advantage of the enhanced reflections produced when ultrasound waves encounter a liquid / gas interface. This allows visualization of otherwise poorly reflective areas, such as fluid-filled cavities, by the ultrasound machine. Clinically useful applications of this include echocardiography, where oscillating saline can be used to define the structural integrity of the atrial septum or infer the presence of a transpulmonary shunt. Oscillating saline can also be combined with Doppler echocardiography to assess blood flow through the tricuspid valve. An alternative method for detecting atrial defects is to use cerebral vascular ultrasound (transcranial Doppler) to detect gas bubbles that pass from the right heart through the left heart and into the cerebral circulation.

[0052] Currently, it can be difficult to generate the oscillating saline used for these studies, and this can result in varying levels of quality and safety. Current bubble studies can have considerable variability in the amount, size, and number of bubbles generated. This imprecise saline-to-air mixture can pose risks to patients and result in false-negative studies. Additionally, few personnel are properly trained to safely perform bubble studies. Productivity in echocardiography laboratories can be significantly slowed by the lack of trained personnel; and even trained personnel who do not routinely perform oscillating saline studies may be reluctant to do so due to concerns about the comfort or safety of the procedure.

[0053] Devices and methods for generating bubbles (e.g., for ultrasound-based bubble studies) are described herein. Advantages of the devices and methods described herein may include generating bubbles of more uniform and consistent size with minimal training. This may result in greater patient safety and comfort, as well as studies with improved diagnostic benefits.

[0054] Figure 1 is an exploded perspective view of an exemplary microbubble generator 100 according to one embodiment. 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 that is placed in a patient undergoing a procedure (e.g., a diagnostic bubble study), and the microbubble generator 100 can be used to generate microbubbles as a contrast agent.

[0055] In some embodiments, 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, a plunger 109, and a tip 112. The syringe 103 can be pre-filled with saline or another solution suitable for intravenous injection, which can provide a vehicle for the microbubbles generated by the microbubble generator 100 to be delivered to a target area of ​​the patient's body. The tip 112 can include a Luer lock connector suitable for coupling to a needle, catheter, IV tube, etc.

[0056] Reference is made to saline with respect to various embodiments. In some embodiments, this may be "NSS," or 0.9% normal saline solution; in other embodiments, "45NS," or 0.45% normal saline solution may be used; in other embodiments, phosphate buffered saline (PBS) may be used. In other embodiments, liquids other than saline may be used, such as dextrose in water (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 suitable for diagnostic studies or therapeutic procedures.

[0057] In the illustrated embodiment, the converging nozzle 115 has a coupling end 118 configured to engage the tip 112 of the syringe 103. In some embodiments, the coupling end 118 includes mating Luer lock threads to facilitate twist-on engagement with the syringe 103. Opposite the coupling end 118 is a converging tip 121. An internal passage 127, which will be described in more detail with reference to the following figures, is configured to couple the internal fluid of the syringe 103 to the aerator 133.

[0058] As shown, the aerator 133 includes a retaining end 136 and a discharge end 139, with the retaining end 136 being configured to mechanically mate with the converging nozzle 115. In some embodiments, 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 the aerator 133. The discharge passage 147 fluidly couples the internal passage 127 of the converging nozzle 115 to the discharge end 139, which can be configured to engage a catheter or IV port or tube used in bubble studies.

[0059] exist Figure 1 , the syringe 103, the converging nozzle 115, and the aerator 133 are shown as separate components. However, in other embodiments, one or more of the components may have other arrangements. For example, the converging nozzle 115 and the aerator 133 may be ultrasonically welded together, attached with an adhesive, snap-fitted, etc.; and the converging nozzle 115 or a single converging nozzle / aerator structure may be coupled to the syringe 103 in one of the aforementioned ways, or co-molded with the syringe 103 and as part of the syringe 103. Now referring to Figure 2A , Figure 2B and Figure 2C Additional details of an exemplary injector 103, converging nozzle 115, and aerator 133 are provided.

[0060] Figure 2A The diagram shows a longitudinal cross-section of the injector 103, the converging nozzle 115, and the aerator 133 as they may be assembled in some embodiments. As shown, the converging nozzle 115 is disposed on the injector 103 via a Luer lock fitting 218, and the aerator 133 is press-fitted to the converging nozzle 115 via an O-ring and corresponding groove in each of the converging nozzle 115 and the aerator 133 (see Figure 2B ). In other embodiments, the connection may be made in different ways. For example, other threaded or press-fit connections may replace the Luer lock fittings. Similarly, the O-ring and groove may be replaced with a threaded, adhesive-based or welded connection.

[0061] Figure 2BAn exemplary longitudinal cross-section of the converging nozzle 115, the O-ring 134, and the aerator 133 is shown. The internal passage 127 is fluidly coupled to the interior of the mating syringe 103 (see FIG. Figure 1 , Figure 2A ) and throat 230 - a portion of the internal passage 127 that gradually decreases in diameter. In operation, the gradually decreasing diameter of throat 230 changes the dynamics of the fluid flowing from syringe 103 and through converging nozzle 115, as will be seen in reference Figure 2C Just as described.

[0062] As shown, the converging nozzle 115 includes a groove 235A for receiving the O-ring 134 and facilitating a compression fit coupling; and the aerator 133 includes a corresponding groove 235B for the same purpose. This structure allows the O-ring 134 to slide into the groove 235A, and allows the retaining end 236 of the aerator 133 to slide over the converging tip 121, and allows the groove 235B to engage and be retained by the O-ring 134. In such an embodiment, the O-ring 134 can be made of an elastic material that has sufficient elasticity and compressibility to facilitate the engagement of the converging nozzle 115 with the aerator 133, and has sufficient resilience to securely couple the converging nozzle 115 and the aerator 133 once the grooves 235A and 235B of these components 115 and 133 are aligned as described. In some embodiments, the O-ring 134 and the grooves 235A and 235B can provide an airtight sterile seal.

[0063] The converging nozzle 115 also includes an outer mating surface 224 at the converging tip 121 that is configured to mechanically mate adjacent to a corresponding circumferential lip 244 on the aerator 133. In some embodiments, the circumferential lip 244 circumferentially encloses the outer mating surface 224 and abuts the outer mating surface 224 at least at one point; in other embodiments, the circumferential lip 244 and the outer mating surface 224 are disposed adjacent to and in close proximity to each other. When the converging nozzle 115 and the aerator 133 are coupled (e.g., via the grooves 235A and 235B and the O-ring 134), the outer mating surface 224 and the circumferential lip 244 align and facilitate fluid coupling between the internal fluid passage 127 and the throat 230 and the discharge passage 147. In some embodiments, the specific dimensions and geometry of the outer mating surface 224 and the peripheral lip 244 further facilitate the passage of air from the internal air chamber 241 formed by the outer wall 245 of the aerator 133 into the exhaust passage 147. Figure 2C Further described.

[0064] Figure 2C1 is a longitudinal section of the converging nozzle 115 and the aerator 133, shown in a coupled configuration, and an enlarged view of a portion of the section. As shown, an internal air chamber 241 is formed by an outer wall 245 of the aerator. There is a small fluid connection between the internal air chamber 241 and the passage formed by the internal passage 127, the throat 230 and the discharge passage 147 - specifically, through an air passage 246 (see enlarged inset), which is configured to exist between the external mating surface 224 and the circumferential lip 244. This air passage 246 allows air or other gas in the internal air chamber 241 to be drawn into the aforementioned passage (the throat 230 and the discharge passage 147 - referred to as the "230 / 147 passage"). In addition, this air passage 246 can allow some of the fluid passing through the 230 / 147 passage to enter the internal air chamber 241, thereby displacing some of the air there and increasing the pressure in the internal air chamber 241 (for example, in the case where there may be non-negligible back pressure at the discharge passage 147).

[0065] Figure 2D yes Figure 2C , wherein the section is taken along the section line AA ( Figure 2C ) as shown in . Figure 2D An air passage 246 (or series of air passages 246) is shown fluidly coupling the internal air chamber 241 to the throat 230 - discharge passage 147 pathway. Figure 2D Visible in FIG. 1 is the throat 230 itself, which is located at the center of the converging nozzle 115, and a series of air passages 246 disposed radially about the throat.

[0066] In some embodiments, the outer mating surface 224 and the circumferential lip 244 (see Figure 2C ) and provide a fluid seal except at air passage 246. That is, in this embodiment, the fluid connection between the interior air chamber 241 and the 230 / 147 passage exists only at the air passage 246. In some embodiments, fewer air passages 246 are provided than shown - for example, some embodiments may include only one, two, three, or four air passages 246.

[0067] Return to reference Figure 2C, the size and geometry of the air passage 246 can be configured to promote the flow of air from the interior air chamber 241 into the 230 / 147 passage only when a certain pressure differential exists between the interior air chamber 241 and the 230 / 147 passage. For example, some embodiments may include an air passage 246 having a very small size and a geometry that promotes greater surface tension of any liquid disposed in the air passage 246. The specific contours of one or both of the exterior mating surface 224 and the circumferential lip 244 can further promote an increase in the surface tension of the liquid in the air passage 246, such as to promote the communication of air (and correspondingly, the formation of microbubbles) in certain circumstances. Surface treatments (e.g., hydrophobic or hydrophilic coatings) of one or both of the exterior mating surface 224 and the circumferential lip 244 can be used to further control the communication of air or other gases from the interior air chamber 241 to the 230-147 passage.

[0068] In some embodiments, 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 would otherwise be possible. In other embodiments, a port or valve (not shown) may be provided to facilitate connection to an external air supply for similar purposes. In other embodiments, a valve (e.g., a pressure relief valve—not shown) may be provided to allow fluid to be exhausted from the air chamber 241 and replaced again by air—e.g., to facilitate balancing relative to back pressure and enable the microbubble generator 100 to “recharge” its ability to generate microbubbles.

[0069] Figure 2E illustrates a perspective cross-sectional view of an exemplary embodiment 260 of an integrated converging nozzle 263 and aerator 266; and Figure 2F A longitudinal cross section of the same device 260 is shown. As shown in this embodiment, the converging nozzle 263 and the aerator 266 are manufactured as an integral component (e.g., co-molded), rather than as two separate components. In this configuration, the size of one or more air passages 268 and their alignment with the fluid flow can be precisely configured, and the fluid flow passes from the internal passage 269 through the section 270 with a gradually decreasing diameter (e.g., a "Venturi section"), out of the outlet 271, into the inlet 273 of the aerator 266, and through and out of the discharge passage 275.

[0070] As shown, the exemplary device 260 includes a housing 278 surrounding an integral converging nozzle 263 and an aerator 266. In some embodiments, as shown, the housing 278 can be sealed to the converging nozzle 263 and the aerator 266 by O-rings 281A and 281B. In such an embodiment, an air chamber 283 is formed (e.g., formed by an inner surface 284 of the housing 278 and an outer surface 285 of the integral component including the converging nozzle 263 and the aerator 266). When the O-rings 281A and 281B form an air-tight and liquid-tight seal (a seal of the air chamber 283 that isolates the air chamber 283 from areas outside the housing 278, preventing gas or liquid from entering or leaving via any path other than through one or more air channels), the air (or other gas) in the air chamber 283 can be drawn into the liquid flow passing through the device 260 in the form of microbubbles.

[0071] In some embodiments, the exemplary device 260 can be operated to generate microbubbles even in the presence of non-negligible back pressure at the exhaust channel 275. Specifically, in the presence of back pressure at the exhaust channel 275 (with a strong seal provided by the O-rings 281A and 281B), the fluid can pass through the internal channel 269, the section 270, and into the exhaust channel 275. However, no significant volume of the fluid can flow out of the exhaust channel 275 (e.g., into a downstream intravenous or needle-based system associated with a therapeutic or diagnostic procedure) before the pressure between the device 260 and the back pressure is equalized. That is, the fluid can initially flow through the air channel 268 and into the internal air chamber 283, rather than out of the exhaust channel 275. Such fluid can displace the air in the air chamber 283, resulting in an increase in the pressure in the air chamber 283.

[0072] Once this air pressure increases to the level of the back pressure, the fluid can then flow through the device 260, out of the exhaust passage 275, and into a connected patient diagnostic or treatment system (not shown). At this stage of operation, where the pressure within the air chamber 283 is nearly equal to the back pressure seen at the exhaust passage 275, some of the air from the air chamber 283 can be drawn into the fluid stream in the form of microbubbles - via a suction effect caused by the pressure drop in the fluid stream itself, which is caused by the increase in the flow rate of the fluid flowing through the venturi section 270.

[0073] Over time, drawing air into the fluid flow may cause the pressure in air chamber 283 to again drop below the back pressure at exhaust passage 275. At this point, some additional fluid may enter air chamber 283, again displacing the air and increasing the pressure inside air chamber 283. Once equilibrium is reestablished or nearly reestablished (e.g., within some small percentage, taking into account the dynamic nature of the system, turbulence of the fluid, dynamically changing back pressure, changes in fluid velocity, etc.), air may again be drawn into the fluid flow in the form of microbubbles.

[0074] In some embodiments, a one-way pressure relief valve (not shown) can be disposed between the air chamber 283 and the exterior of the housing 278 to allow fluid to be periodically exhausted from the air chamber 283. In some embodiments, allowing some fluid to be exhausted from the air chamber 283 can allow air to be continuously available for suction into the fluid stream. In such embodiments, microbubbles can be generated and delivered out of the exhaust passage 275 as long as incoming fluid is supplied through the internal passage 269.

[0075] exist Figure 2E and Figure 2F In the embodiment shown in , the size, geometry, and surface treatment (e.g., hydrophobic or hydrophilic coating) of the air channel 268, outlet 271 (or internal channel 269 or section 270), inlet 273, or exhaust channel 275 can be configured to facilitate the formation of microbubbles having a specific average size or size range (e.g., an average diameter of less than 2 μm; an average diameter between about 5 μm and about 10 μm; an average diameter of about 40 μm or less; an average diameter of about 100 μm or less). Such an embodiment can use size, geometry, or surface treatment to create turbulent or laminar flow areas that capture or draw air in a specific manner. In other embodiments, specific size, geometry, or surface treatment can be used to form microbubbles with surface tension or charge that minimizes the aggregation of microbubbles after they are generated.

[0076] In one embodiment, reference is now made to Figure 3A , Figure 3B and Figure 3C The operation of the overall exemplary microbubble generator 300 is described. Figure 3AAs shown in , the microbubble generator 300 including the syringe 303, the converging nozzle 315 and the aerator 333 can be pre-filled with a saline solution. That is, saline (or another suitable solution) can be pre-filled in the interior 302 of the barrel 306 of the syringe portion 303. In order to maintain the sterile nature of the saline, and to prevent fluid from entering the internal chamber 341 of the aerator portion 333, a sealing pin 353 can be provided to seal the saline in the syringe 303, to seal the internal channel 327 and the throat 330 of the converging nozzle 315, and to isolate the channel 327 from the internal chamber 341. In operation, such a pin 353 can be removed just before the microbubble generator 300 is to be used.

[0077] The pin 353 can be made of a corrosion resistant metal or a resilient elastomeric material that seals the tip of the throat 330 and the discharge passage 347. The pin 353 can be adhesively sealed to the discharge end 339 of the aerator so that before using the microbubble generator 300, the user needs to have some amount of twisting or pulling force to remove the pin 353. This adhesive seal can further protect the sterile nature of the microbubble generator 300, particularly at the discharge end 339.

[0078] In some embodiments, the pin 353 can be replaced with an inner membrane (not shown) that retains 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 embodiments, the user may need to depress the plunger 309 in order to generate an internal pressure sufficient to overcome the retaining force of such a membrane. In some embodiments, the inner membrane (not shown) can be configured to be broken when the converging nozzle 315 is attached to the syringe 303 (e.g., in embodiments where the components are provided separately).

[0079] However, the contents of the syringe are sealed prior to use, the proper seal may be released, and the plunger 309 may be slightly depressed to flush the microbubble generator 300 - e.g. Figure 3B In some cases, this can be done before drain 339 is coupled to IV tubing 356 or another connection that can be connected to a system for diagnosing or treating a patient, such as a needle, catheter, or other device placed in the patient's body (not shown). In other cases, drain 339 can be coupled to IV tubing 356 first so that the tube can also be flushed during this initial process.

[0080] Figure 3CDescribe the process that microbubble generator 300 can generate microbubbles in one embodiment.Specifically, after removing necessary seal, microbubble generator 300 is rinsed and connected to the downstream IV system 356 associated with the patient receiving diagnosis or treatment procedure, and plunger 309 can be further pressed down to force fluid to enter internal channel 327 from the inside 302 of syringe 303.In internal channel 327, the pressure of fluid is relatively high, and its speed is relatively low (proportional to the speed at which plunger is pressed down).The gradually decreasing diameter of throat 230 causes the speed of fluid to increase there, thereby reduces its fluid pressure (by venturi effect).This lower pressure of the fluid at throat 330 place sucks air (specifically from internal chamber 341) via one or more air passages 346 and advances to the fluid path of discharge passage 347 from throat 330--thereby forming microbubbles.

[0081] In some embodiments, the geometry, size, and / or surface treatment of the material forming the air passage 346 is related to the size of the microbubbles. Thus, in such embodiments, the configuration of the converging nozzle 315 and the aerator 333 can result in the generation of microbubbles of different sizes and characteristics. In some embodiments, microbubbles with a diameter of about 5 μm can be generated; in other embodiments, microbubbles with a diameter of about 10 μm or less can be generated; in other embodiments, microbubbles with a diameter of about 1-2 μm or less can be generated; in other embodiments, microbubbles with a diameter of about 40 μm can be generated; in other embodiments, microbubbles with a diameter of up to about 100 μm can be generated.

[0082] Microbubbles of different sizes may have different purposes in diagnostic or therapeutic procedures. For example, in some diagnostic cardiac procedures, it may be advantageous to produce microbubbles with an average diameter of about 5 μm to about 10 μm. As used herein, "approximately" or "approximately" or "substantially" may refer to within 1%, or 5%, or 10%, or 20% or 50% of the nominal value; and "average" may mean that a large number (e.g., 25%, 50%, 75%, 80%, 85%, 90%, 95%) of microbubbles have the diameter, or in some embodiments, have a diameter within one or two standard deviations of the specified diameter. As another example, when diagnosing certain lung diseases, it may be advantageous to produce microbubbles with smaller diameters (e.g., 1-2 μm or less). In some embodiments, the size of microbubbles may be related to the aggregation properties of microbubbles. For example, the surface tension and charge of microbubbles of a specific size (in certain solutions, or in blood) may inhibit their aggregation; and minimizing such aggregation of microbubbles may be advantageous (e.g., minimizing the risk of air embolism).

[0083] In some embodiments, it may be advantageous to generate microbubbles of different sizes. For example, in the process of diagnosing the presence of a defect in the septum of a patient's heart, it may be advantageous to initially use a microbubble with smaller size to look for the presence of the septum defect; then switch to larger microbubbles to determine if a sealing procedure is needed. To facilitate procedures that may advantageously employ microbubbles of different sizes, multiple microbubble generators may be employed; and in some embodiments, they may be pre-coupled together.

[0084] Figure 4 An exemplary microbubble generating system 400 employing a plurality of microbubble generators 401A, 401B, and 401C is illustrated. As shown, each microbubble generator 401A, 401B, and 401C can be coupled to a manifold 461 by corresponding fluid tubes 456A, 456B, and 456C. The manifold may include multi-way valves 464A, 464B, and 464C that couple each fluid tube to or isolate the main line 465 of the manifold 461; and the main line 465 of the manifold 461 can be coupled to an IV tube 458 associated with a patient undergoing a diagnostic or therapeutic procedure. In this manner, each microbubble generator 401A, 401B, or 401C can be alternately coupled to an IV tube 458 to generate diagnostic or therapeutic microbubbles; or, multiple microbubble generators 401A, 401B, or 401C can be connected simultaneously to facilitate delivery of large amounts of fluid with minimal valve manipulation. As shown, some embodiments employ three-way stopcocks 464A, 464B, and 464C to isolate or fluidly connect one, two, or three paths. Other embodiments may employ different valve arrangements.

[0085] In some embodiments, each microbubble generator 401A, 401B or 401C in the microbubble generating system 400 can be similarly configured to generate microbubbles of the same size. Compared with a single microbubble generator, this embodiment can be used to generate a larger amount of microbubbles in a longer period of time. In other embodiments, each microbubble generator 401A, 401B and 401C can be configured to generate microbubbles of different sizes. For example, microbubble generator 401A can be configured to generate microbubbles with a diameter of about 5 μm; microbubble generator 401B can be configured to generate microbubbles with a diameter of about 1 μm; and microbubble generator 401C can be configured to generate microbubbles with a diameter of about 10 μm. In this way, complex diagnostic procedures requiring microbubbles of various sizes can be carried out when the equipment changes minimally.

[0086] The exemplary manifold 461 may include a port 468 for flushing the manifold and / or the entire system 400. In some embodiments, each microbubble generator 401A, 401B, and 401C may have an inner membrane to isolate the fluid within the corresponding syringe barrel or syringe barrel / converging nozzle; the exhaust channel of each microbubble generator and the manifold itself can be flushed and pre-filled with fluid through port 468 before performing a procedure.

[0087] In other embodiments, the system 400 can be packaged such that the syringes, tubing, and manifold are all pre-filled with fluids such that a final connection is required when the procedure is performed between the main manifold line 465 and the patient IV line 458. In such embodiments, an inner membrane can still be used in the individual microbubble generators 401A, 401B, and 401C to prevent fluid from flowing out into the internal air chambers of the aerator components (e.g., air chamber 441A in aerator 433A).

[0088] An exemplary system 400 having three microbubble generators 401A, 401B, and 401C is shown; however, other numbers of microbubble generators, such as two, four, or five, may also be included. Microbubble generators 401A, 401B, and 401C are shown coupled to manifold 461 via tubes 456A, 456B, and 456C. In some embodiments, the various components of system 400 may be provided and coupled together immediately prior to a patient procedure.

[0089] The various embodiments described herein can be used to generate microbubbles for various diagnostic and therapeutic studies. Many such studies involve the human circulatory system. Therefore, as a reference, parts of the human circulatory system are now briefly described.

[0090] Figure 5 A portion of the entire human circulatory system 500 is illustrated. At its core is the heart 502, and a system of arteries extending from the heart and veins returning to the heart. Blood returns to the heart 502 from the entire body via the vena cava, which is divided into the superior vena cava 505, which collects blood from the upper part of the body, and the inferior vena cava 508, which collects blood from the lower part of the body. Blood flows through the superior vena cava 505 and the inferior vena cava 108 to the right atrium.

[0091] In order to facilitate the introduction of microbubbles into the heart and lungs for research, the bubbles must be introduced into the venous system and ultimately into the superior vena cava 505 or the inferior vena cava 508. Figure 5 There are several common access points through which microbubbles can be introduced. A common one is the intravenous introduction of bubbles via the median cubital vein 530 in the right arm. From here, blood flows through the basilic vein 531, the axillary vein 532, the subclavian vein 510, the brachiocephalic vein 537 and into the superior vena cava 505.

[0092] Alternative routes to the superior vena cava 513 are the external jugular vein 533 or the internal jugular vein 536, both of which drain into the brachiocephalic vein 537 before reaching the superior vena cava 505. Alternative routes include the femoral vein 539 which flows into the inferior vena cava 508. Other routes to the superior vena cava 505 and the inferior vena cava 508 are also possible.

[0093] Fig. 6A 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 embodiments, as shown, the syringe tip 612 includes a Luer lock 613 or other fitting.

[0094] A plurality of aerator components 616a, 616b, and 616c can be coupled to the syringe tip 612, and a housing 619 can circumferentially surround the end of the barrel 606 and the plurality of aerator components 616a, 616b, and 616c. The housing 619 can have a longitudinal axis 622 that, in some embodiments, is coaxially aligned with a longitudinal axis 623 of the syringe 603 and the longitudinal axes of the aerator components 616a, 616b, and 616c.

[0095] The housing 619 has an inner surface 625 and a discharge tip 628. In some embodiments, the housing 619 is configured to fluidly seal against the cartridge 606, and the plurality of aerator components 616a, 616b, and 616c can be sealed against each other to the syringe tip 612, and to the discharge tip 628, such that any fluid 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 to the internal passage 673 of each of the aerator components 616a, 616b, and 616c (see Fig. 6F ) in the syringe barrel 606. The circumferential air pocket 631 can be created by the inner surface 625, the plurality of aerator components 616a, 616b, and 616c; the syringe tip 612; and the discharge tip 628. In some embodiments, the circumferential air pocket 631 comprises at least about 10% of the volume of the corresponding syringe barrel 606; in other embodiments, the circumferential air pocket 631 comprises about 30-35% of the volume of the corresponding syringe barrel 606 (e.g., 3-3.5 mL for a 10 mL syringe); in other embodiments, the circumferential air pocket 631 comprises 50% or more of the volume of the corresponding syringe barrel 606.

[0096] Regardless of the precise volume of the circumferential air pocket 631 relative to the volume of the syringe barrel 606, one advantage is that the total volume of the circumferential air pocket 631 can be precisely controlled to a fail-safe value. Specifically, in medical applications, such as those described herein, the precise value can be set to a level that prevents harm to the patient - even if all of the gas or air in the circumferential air pocket 631 is injected directly into the patient (e.g., through some device failure). This safety feature inherent in the design of the embodiments described herein may not be present in other embodiments (e.g., current standard of care embodiments, such as those described below in Example 16) - where the volume of air or gas mixed with the body compatible fluid can be controlled only by the specific clinician performing the corresponding procedure (which may result in significant variation between different clinicians than the embodiments described herein).

[0097] Figure 6B Can be included in Fig. 6A 616b in an exemplary microbubble generator 600. As shown, the aerator component 616b has an outer body 630, which in some embodiments is cylindrical and includes a longitudinal axis 624 feature. One or more alignment tabs, such as alignment tab 632, can protrude from the outer body 630; and such alignment tab 632 can be configured to dock with one or more alignment grooves 633 in the housing 619 (see Fig. 6A ) - so that when the aerator components 616a, 616b and 616c are coupled to the housing 619, the one or more alignment tabs 632 cooperate with the one or more alignment grooves 633 to radially secure the housing and each of the plurality of aerator components relative to each other.

[0098] As indicated above, when disposed in the microbubble generator 600, the longitudinal axis 624 of the aerator component 616b can be coaxially aligned with the longitudinal axis 622 of the housing 619 and the longitudinal axis 623 of the injector 603. The aerator component 616b has an inlet end 634 and an outlet end 637. Fig.6D and Fig. 6E Described in greater detail, the aerator component 616b may include a tapered output port 640 and a transverse vent 643 .

[0099] Figure 6C is a perspective cross-section of aerator component 616b; Fig.6D illustrates a side view of aerator component 616b; and Fig. 6E A side cross-section of aerator component 616b is shown. Fig.6DAs shown in , the tapered output port 640 can have a diameter 646 that is smaller than a diameter 649 of the outer body 630, and a taper 652 that narrows the diameter 646 from its origin at the outer body 630 to its distal end.

[0100] refer to Fig. 6E In the illustrated embodiment, the aerator component 616b includes an interior chamber 655 having 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 the aerator component 616b) or a 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 the diameter 670 may decrease from the outside of the input port section 658 to the inside, corresponding to the taper 652 of the tapered output port 640.

[0101] As shown, the inlet section 661 has a gradually decreasing diameter that restricts the flow of gas or liquid through the aerator component 616b as the gas or liquid flows from the input port section 658 to the subsequent throat section 664. As described above with respect to other embodiments, this restriction of flow increases the corresponding velocity of the gas or liquid and reduces its pressure. This reduction in pressure allows the circumferential gas pocket 631 (see Fig. 6A ) is drawn into the fluid in the throat section 664 through the transverse vents 643. In some embodiments, the tapered diameter ranges from about 3.5 mm to about 0.5 mm.

[0102] In some embodiments, as shown, the outlet section 667 is downstream of the throat section 664. In the outlet section 667, the diameter of the internal chamber 655 increases from the throat section 664 toward the tapered output port 640. In some embodiments, the increasing diameter of the outlet section 667 ranges from about 0.5 mm to 3.5 mm; more preferably, the diameter can be in the range of about 0.65 mm to about 2.1 mm.

[0103] In some embodiments, the border between the inlet section 661 and the throat section 664 can be rounded and / or smoothed (e.g., to minimize turbulence). In some embodiments, the throat section 664 can have a slight taper (e.g., to facilitate a clean molding process). In some embodiments, the border between the throat section 664 and the outlet section 667 can be rounded and / or smoothed (e.g., to minimize turbulence). In some embodiments, various surfaces and borders can have a rough surface finish, or the edges can be sharp rather than rounded or smooth (e.g., to increase turbulence).

[0104] Fig. 6F 616 is a perspective cross-sectional view of a plurality of 616 aerator components 616a, 616b, and 616c that can be coupled together and included in an exemplary microbubble generator 600. As shown, each component 616a, 616b, and 616c is tightly coupled to the next component so 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 embodiments, the channel 673 is fluid-tight from end to end, except at the transverse vents in each aerator component 616a, 616b, and 616c - that is, each aerator component can be tightly sealed to the next so that a 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.

[0105] like Fig. 6F As depicted in , in the plurality of aerator components 616, there may be some variation in the diameter of each throat segment 664a, 664b, or 664c. That is, the diameter of the throat segment 664c of the aerator component 616c may be greater than the diameter of the throat segment 664b, and the diameter of the throat segment 664b may be greater than the diameter of the throat segment 664a. Similarly, the diameters of the transverse vents 643a, 643b, and 643c may vary. In some embodiments, the diameters of the throat segments 664a, 664b, and 664c may range from 0.4 mm or less to 2.0 mm or more. For example, one embodiment may include aerator components having diameters of 0.45 mm, 2 mm, and 2 mm; another embodiment may include aerator components having diameters of 0.45 mm, 1 mm, and 2 mm; and yet another embodiment may include aerator components having diameters of 1 mm, 1 mm, and 2 mm. In some embodiments, it is advantageous to arrange the aerator so that the diameter increases from the proximal end (eg, the syringe end) to the distal end; in other embodiments, different arrangements may be advantageous.

[0106] In some embodiments, the diameters of the lateral vents 643a, 643b, and 643c can range from 0.3 mm or less to 1.0 mm or more. For example, in some embodiments, the most proximal vent 643a can be about 1.0 mm and the most distal vent 643c can be about 0.6 mm; in other embodiments, the most proximal vent 643a can be about 0.3 mm and the most distal vent 643c can be about 0.6 mm.

[0107] Figure 6G 676 and sealing pin 679. In some embodiments, 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 embodiments is configured to seal the throat segment of the smallest diameter (e.g., throat segment 664a, as shown). In this embodiment, the cap 676 can seal the channel 673 and the circumferential air pocket 631 (via the transverse vent (at Figure 6G and the sealing pin can seal the throat 664a, thereby sealing the inlet section 661a of the aerator 616a and everything fluidly connected thereto (e.g., the syringe tip 612 and the interior of the barrel 606). In these embodiments, the cap 676 and the sealing pin 679 can maintain the sterility of the contents of the syringe 603 and can prevent liquid or gas in the syringe 603 from leaking into the circumferential air pocket 631 before the cap 676 and the sealing pin 679 are removed.

[0108] 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.

[0109] Aerator 716 can be coupled to syringe tip 712, and housing 719 can circumferentially surround the end of cartridge 706 and aerator 716. Housing 719 can have a longitudinal axis 722 that is coaxially aligned with a longitudinal axis 723 of syringe 703 and a longitudinal axis 724 of aerator 716 in some embodiments.

[0110] As shown, the housing 719 has an inner surface 725 and a discharge tip 728. In some embodiments, the housing 719 is configured to be fluid-tight against the barrel 706, and the aerator 716 can be sealed to the syringe tip 712 and the discharge tip 728 so that any fluid 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 the interior chamber 755 of the aerator 716 (see Figure 7B ) and through the discharge tip 728. The circumferential air pocket 731 can be formed by the inner surface 725, the aerator 716, the syringe tip 712 and the discharge tip 728.

[0111] Reference Figure 7B In the illustrated embodiment, the aerator 716 includes an interior chamber 755 having five discrete sections—an input port section 758, an inlet section 761, a throat section 764, a diffuser section 765, and an outlet section 767. The input port section 758 can be configured to receive the syringe tip 712—that is, the input port section 758 can have a diameter that is only slightly larger than the diameter of the syringe tip 712, and the diameter of the input port section 758 can decrease from the outside of the input port section 758 to the inside.

[0112] As shown, the inlet section 761 has a gradually decreasing diameter, which restricts the flow of gas or liquid through the aerator 716 as it flows from the input port section 758 to the subsequent throat section 764. As described above with respect to other embodiments, this restriction of the flow of gas or liquid increases its corresponding velocity and reduces its pressure. This reduction in pressure allows gas to be drawn into the fluid through the first vent 743.

[0113] In some embodiments, as shown, a diffuser section 765 having a gradually increasing diameter is downstream of the throat section 764; and an outlet section 767 is downstream of the diffuser section 765, which outlet section 767 can be cylindrical in structure. In other embodiments, the diffuser section 765 and the outlet section 767 can be a single section, whose diameter gradually increases from the throat section 764 to the tapered outlet port 740.

[0114] In some embodiments, as shown, the second vent 744 can be disposed in the outlet section 767 (or in some embodiments, the diffuser section 765). In operation, the first vent 743 and the second vent 744 can cooperate to increase the efficiency of the fluid moving through the throat section 764 to draw gas from the circumferential gas pocket 731 through the first vent 743 (see Fig. 7A). For example, in some embodiments, an initial amount of fluid passing through the interior chamber 755 can displace air or other gas in the interior chamber 755 primarily through the second vents 744 rather than through the first vents 743, thereby (i) more quickly pressurizing the circumferential air pockets 731 and allowing the gas in the circumferential air pockets 731 to be drawn into the fluid flow moving through the interior chamber 755; and (ii) minimizing the simultaneous movement of a certain amount of liquid from the interior chamber 755 into the circumferential air pockets 731 and gas from the circumferential air pockets 731 into the interior chamber 755 - the simultaneous movement of liquid in one direction and gas in an opposite direction through the same first vent 743 can create turbulence and cause larger bubbles to be drawn or formed than in embodiments including the second vents 744.

[0115] In some embodiments, the second vent 744 is larger than the first vent 743. In such embodiments, this size difference, coupled with the pressure difference of the gas, liquid, or combination thereof in the throat section 764 relative to the outlet section 767, can cause the liquid itself and the gas initially displaced from the internal chamber 755 (e.g., when an initial amount of fluid flows through the internal chamber 755) to flow from the internal chamber 755 into the circumferential gas pocket 731 primarily through the second vent 744.

[0116] Regardless of the mechanism of action of any particular embodiment, applicants have surprisingly discovered that a single aerator 716 having both a first vent 743 and a second vent 744 (e.g., in outlet section 767 , as shown, or in diffuser section 765 ) performs significantly better than a single aerator 716 having only a single vent 743 .

[0117] In this context, "performance" may be quantified in terms of (i) producing a large number of very small bubbles (e.g., bubbles having an average diameter of about 300 μm or less; or bubbles having an average diameter of about 250 μm or less; or bubbles having an average diameter of about 200 μm or less; or bubbles having an average diameter of about 100 μm or less; or more preferably, bubbles having an average diameter of less than about 50 μm; or even more preferably, bubbles having an average diameter of less than about 20 μm; or bubbles having an average diameter of less than about 10 μm; or bubbles having an average diameter of less than about 2 μm) - note that in some embodiments, it may be advantageous to produce bubbles at the higher end of the example range provided (e.g., to make the echo stronger). In other embodiments, it may be advantageous to generate bubbles at the lower end of the example range provided (e.g., to more accurately delineate internal anatomical features under ultrasound); and / or (ii) generate bubbles with a substantially non-uniform size distribution (e.g., 50% or more of the bubbles fall within one standard deviation of the mean bubble size; or 95% of the bubbles fall within one or two standard deviations of the mean bubble size; or 99% of the bubbles fall within one, two, or three standard deviations of the mean bubble size) for quantification; and / or (iii) generate essentially no (or very few) larger bubbles (e.g., bubbles with a diameter greater than about 100 μm, or with a diameter greater than about 200 μm, or with a diameter greater than about 250 μm, or with a diameter greater than about 300 μm) for quantification.

[0118] In some embodiments, the boundary between the inlet section 761 and the throat section 764 can be rounded and / or smoothed (e.g., to minimize turbulence). Similarly, the boundary between the throat section 764 and the diffuser section 765 or the boundary between the diffuser section 765 and the outlet section 767 can be rounded and / or smoothed (e.g., to minimize turbulence). In some embodiments, the throat section 764 can have a slight taper (e.g., to facilitate a clean molding process). In some embodiments, various surfaces and boundaries can have a rough surface finish, or the edges can be sharp, rather than rounded or smooth (e.g., to increase turbulence).

[0119] Fig. 8A is a perspective view of an exemplary aerator component 816. In some embodiments, the aerator component 816 may replace Fig. 7A As shown, the aerator component 716 includes threads 814 that can mate with mating threads on a corresponding syringe component (e.g., Fig. 7A In this embodiment, the threads 814 can facilitate a secure, direct connection between the aerator component 816 and the corresponding syringe (e.g., without relying on the housing component to facilitate the connection).

[0120] As shown, the aerator component 816 has an outer body 830, which in some embodiments is cylindrical and includes a longitudinal axis 824 feature. In other embodiments, the outer body 830 can have other shapes (e.g., rectangular, cubic, triangular, etc.). One or more alignment tabs, such as alignment tab 832, can protrude from the outer body 830; and such (one or more) alignment tabs 832 can be configured to align with one or more alignment grooves in a corresponding shell (e.g., alignment groove 633 in shell 619, in Fig. 6A ) docking - so that when the aerator 816 and the corresponding housing are coupled together, the (one or more) alignment tabs 832 and the corresponding alignment grooves cooperate to radially secure the housing and the aerator component 816 together. When so coupled, the longitudinal axis 824 can be coaxially aligned with the longitudinal axis of the corresponding housing and the syringe.

[0121] refer to Figure 8B In the illustrated embodiment, the aerator 816 includes an internal chamber 855 having five discrete sections, each section being fluidly coupled to the next section to form a flow path 873 through the 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 diffuser section 865, and an outlet section 867. The input port section 858 may be configured to receive a syringe tip (similar to Figure 7B and, as described above, threads 814 may be provided to secure the aerator 816 to the syringe tip. The diameter of the input port segment 858 may be only slightly larger than the outer diameter of the syringe tip, and the diameter of the input port segment 858 may decrease from the outside to the inside of the input port segment 858 so that the input port segment seals against the end of the corresponding syringe tip.

[0122] As shown, the inlet section 861 has a gradually decreasing diameter that restricts the flow of gas or liquid through the aerator 816 as it flows from the input port section 858 to the subsequent throat section 864. As described above with respect to other embodiments, this restriction of the flow of gas or liquid increases its corresponding velocity and reduces its pressure, which can allow gas to be drawn in through the vent 843 in or near the throat section 864.

[0123] In the illustrated embodiment, the vent 843 is located just outside of the throat section 864, in the subsequent diffuser section 865, rather than in the throat section 864 itself. As shown, the diffuser section has a gradually increasing diameter and is downstream of the throat section 864; and the outlet section 867 is downstream of the diffuser section 865. In other embodiments, the diffuser section 865 and the outlet section 867 can be a single section with a gradually increasing diameter from the throat section 864 to the outlet port 840.

[0124] Although the vent 843 is not in the throat section 864 itself, as in other embodiments illustrated and described herein, the vent 843 is positioned sufficiently close to the throat section 864 so that the pressure of the gas or liquid flowing through the aerator 816 along the path 873 is lower at the point of the vent 843 than at other portions along the path 873; and this lower pressure allows gas to be drawn into the fluid flow flowing along the path 873 through the vent 843.

[0125] Placing vent 843 just outside of throat section 843, in diffuser section 865, rather than in throat section 834, may have certain advantages. For example, such an arrangement may facilitate the sealing of a sealing pin (such as Figure 6G 843, while making the sealing pin itself larger and made stronger than it would be if such a sealing pin needed to be accommodated by the throat section 864. In some embodiments, this can both simplify the manufacturing process and increase the yield of sealing pins; and it can minimize the risk of fragments of the sealing pin breaking off within the aerator 816 and being introduced into the fluid stream that is ultimately injected into the patient. Figure 8C An exemplary sealing pin 879 is illustrated and how it is received by the outlet section 867 and the diffuser section 865 .

[0126] return Fig. 8A , some embodiments may include a second vent 844. In the illustrated embodiment, the second vent 844 is disposed at the distal end of the aerator component 816, at the outlet port 840. The second vent 844 can be formed as a recess in the wall of the outlet port 840, and the vent 844 can be fluidly coupled to an area adjacent to the outer body 830 (e.g., when the aerator component 816 is disposed in a corresponding housing, such as in Fig. 6A and Fig. 7AIn some embodiments, the use of grooves 845 to form second vent 844 can simplify the manufacturing process relative to other methods for forming vent 844. For example, grooves 845 can simplify the mold and molding process, and in some embodiments, avoid the need for separate pins in the mold to form the vent. In some embodiments, similar methods (e.g., grooves instead of holes) can be used for vent 843.

[0127] In some embodiments, the groove 845 at the outlet port 840 may provide other advantages. For example, when the device 700 is positioned vertically during a procedure with the outlet port 840 pointing downward, the groove 845 is positioned at the lowest point of the adjacent air pocket 731. When the fluid in the syringe 703 is almost exhausted, any remaining pressurized air or gas in the air pocket 731 can be expelled from the last bit of fluid - before the pressure between the air pocket 731 and the path 873 is equalized - so that no (or very few) bubbles are introduced into the final fluid exiting the outlet port 840. This can be advantageous because the bubbles that would have been created in the last bit of fluid as the fluid was exhausted may be significantly larger than the bubbles created at the vent 843. Similar advantages may be brought about by a second vent 744 that is positioned very close to the outlet port 740.

[0128] Regardless of their precise configuration, vents 843 and 844 can cooperate to improve efficiency, in which fluid moving along path 873 is removed from a circumferential air pocket (e.g., similar to Fig. 7A For example, in some embodiments, an initial amount of fluid passing through the interior chamber 855 can displace air or other gas in the interior chamber 855 primarily through the second vent 844 rather than through the vent 843 - thereby (i) more quickly pressurizing the corresponding circumferential air pocket and allowing the gas in the circumferential air pocket to be drawn into the fluid flow moving through the interior chamber 855; and (ii) minimizing the simultaneous movement of a certain amount of liquid from the interior chamber 855 into the circumferential air pocket and gas from the circumferential air pocket into the interior chamber 855 - compared to the situation in an embodiment including the second vent 844, the simultaneous movement of liquid in one direction and gas in the opposite direction through the same vent 843 can generate turbulence and cause the suction or formation of larger air or other gas bubbles than in an embodiment including the second vent 844.

[0129] In some embodiments, the second vent 844 is larger than the vent 843. In such embodiments, this size difference in the throat section 864 and the diffuser section 865, respectively, relative to the outlet section 867 (combined with pressure differences of the gas, liquid, or a combination thereof) can cause the liquid itself and the gas initially displaced from the internal chamber 855 (e.g., when an initial amount of fluid flows through the internal chamber 855) to flow from the internal chamber 855 primarily through the second vent 844 into the circumferential gas pocket.

[0130] In some embodiments, the materials used for one or more of the components of the exemplary embodiments described herein can be selected based on (a) suitability for use in human patients (i.e., suitable for contact with a body-compatible solution to be injected into a human patient); (b) solid surface energy (SFE) (e.g., the surface energy of the various components); and (c) interfacial tension (e.g., the interfacial tension of a body-compatible solution). The various components described herein can be further selected from materials commonly used to construct medical devices. Such materials can be selected based on wide acceptance in the medical device field and / or sterilization capabilities or inherent sterility and / or antimicrobial or antibacterial properties.

[0131] With regard to SFE, the materials used (e.g., in particular for aerators or aerator components, such as FIG. 6A to FIG. 6G aerator components 616a, 616b and 616c, Fig. 7A Aerator 716 or Fig. 8A The aerator 816 in the figure can be selected from thermoplastics or other materials that can be injection molded and are acceptable for use in medical devices, including, for example, polyethylene (high density or low density), polypropylene, polymethyl methacrylate (PMMA), polyvinyl chloride (PVC), polyamide, acrylonitrile butadiene styrene (ABS), polycarbonate, acetal, polyethylene terephthalate glycol (PETG), or other suitable materials.

[0132] More preferably, in some embodiments, the material used can be further selected based on the SFE of the material. For example, in some embodiments, a material having an SFE greater than about 30 millinewtons / meter ("mN / m") (sometimes alternatively expressed as dynes / cm, where 1 mN / m=1 dyne / cm) may be advantageous - in these embodiments, PVC (having an SFE of about 35 mN / m in some forms), ABS (having an SFE of about 35 mN / m in some forms), acetal (having an SFE of about 36 mN / m in some forms), PMMA (having an SFE of about 41 mN / m in some forms), polycarbonate (having an SFE of about 46 mN / m in some forms) or PETG (having an SFE of about 47 mN / m in some forms) can be selected instead of polypropylene (having an SFE of about 30 mN / m in some forms) or polyethylene (having an SFE of about 30 mN / m in some forms). In other embodiments, a material having an SFE greater than about 35 mN / m may be advantageous. In other embodiments, materials having a SFE greater than about 40 mN / m may be advantageous - in these embodiments, PMMA, polycarbonate, or PETG may be employed.

[0133] In some embodiments, a material may be treated to increase, decrease, or otherwise control its SFE (e.g., the surface may be roughened to increase its surface energy, it may be chemically treated, it may be coated with another material, it may be plasma treated or plasma activated, etc.). In many embodiments, the actual effect on wettability of a base or treated SFE may be more important than the actual effective value of the SFE - that is, in certain embodiments, wettability (and specifically, a more wettable material, rather than a less wettable material) may be more important than a specific SFE value.

[0134] In some embodiments, the body-compatible solution includes a surfactant that reduces the interfacial tension of the solution; or alternatively, the body-compatible solution is a solution that has an inherently low interfacial tension relative to other body-compatible solutions. For example, in some embodiments, the body-compatible solution is glucose (e.g., D5W, D10W, or D50). As another example, in some embodiments, the body-compatible solution includes a surfactant, such as a polysorbate (e.g., 0.001% polysorbate in saline solution, 0.005% polysorbate in saline solution, 0.01% polysorbate in saline solution, 0.1% polysorbate in saline solution, 1% polysorbate in saline solution, 10% polysorbate in saline solution, etc.). In other embodiments, other body-compatible surfactants may be used (e.g., generally nonionic, anionic, cationic, amphoteric surfactants; specific examples may include, among others, propylene glycol, polyethylene glycol, lecithin, poloxamers, glycerol, hypertonic saline, hydrophobic hydrocarbon chains with hydrophilic heads, casein, certain proteins, etc.).

[0135] Various embodiments of microbubble generation capabilities were tested in a benchtop setting, and images of each test were captured. These images are shown in Figures 9A-9C, 10A-10C, 11A-11C, 12A-12C, and 13A-13C. In each test, a similar method to that of reference Fig. 6A , Fig. 7A or Fig. 8A A device of one of the devices illustrated and described in the drawings and examples of the invention was used - each device comprising 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 in a circumferential air pocket by the housing. A black background was placed behind the beaker and lighting was positioned on the side to illuminate the microbubbles formed by the device.

[0136] 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 the needle into the beaker of tap water. The plunger was continued to be depressed until the body-compatible solution was substantially expelled from the syringe.

[0137] Each of Figures 9A to 9C, Figures 10A to 10C, Figures 12A to 12C, and Figures 13A to 13C includes four frames. In these figures, the leftmost frame corresponds to a time of approximately 0.5 seconds after the plunger is initially depressed; the left-center frame corresponds to a time of approximately 2.5 seconds after the plunger is initially depressed; the right-center frame corresponds to a time of approximately 6.0 seconds after the plunger is initially depressed; and the rightmost frame corresponds to a time when the body-compatible solution is substantially expelled. Figures 11A to 11C include three frames because in the corresponding embodiments, the body-compatible solution is expelled from the syringe faster than in other embodiments, such that the total time after the plunger is initially depressed is less than 6.0 seconds. In Figures 11A to 11C, the left and middle frames remain the same as Figures 9A to 9C, Figures 10A to 10C, Figures 12A to 12C, and Figures 13A to 13C, that is, these frames correspond to times of approximately 0.5 seconds and 2.5 seconds after the plunger is initially depressed; the right frame corresponds to the time when the body-compatible solution is substantially discharged (before 6.0 seconds).

[0138] Each test ("Example") and its results are now described in detail. In the following description, 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 embodiments, the diameter of a "large" bubble can be 1 millimeter or larger (e.g., 1 mm, 2 mm, 3 mm, 5 mm, etc.); a "medium-sized" bubble can have a diameter ranging from about 0.5 mm to about 1 mm; a "small" bubble can have a diameter ranging from about 0.1 mm (100 μm) to about 0.5 mm; a "very small" bubble can have a diameter ranging from about 10 μm to about 100 μm; and a "microbubble" can have a diameter ranging from about 1 μm to about 10 μm. In other embodiments, different ranges may apply—for example, in some embodiments, "microbubbles" may have a diameter of less than 1 μm (and may include what may be referred to as "nanobubbles"); as another example, "microbubbles" may include bubbles with a diameter of about 1 μm to about 25 μm; as another example, "very small" bubbles may have diameters ranging from 2 μm to about 50 μm. Many specific ranges are possible; and as stated, the main point of bubble size reference is for qualitative comparison.

[0139] Example 1 (multi-stage, polypropylene, brine)

[0140] In a first embodiment illustrated in FIG. 9A , a device having multiple aerator components (e.g., similar to the exemplary microbubble generator 600 shown in FIG. 6 ) is employed, each of which is made of polypropylene; and a syringe is filled with saline. As captured in the leftmost frame, the initial discharge of the saline results in the generation of a minimal volume of small to medium-sized bubbles. As the saline is discharged from the syringe, bubble generation continues to be intermittent and minimal (note that some small and medium-sized bubbles can be seen in the solution in the left-center and right-center frames). After approximately 8.5 seconds (see the rightmost frame), when the saline is substantially discharged, a large number of large bubbles are generated.

[0141] Example 2 (multi-stage, polypropylene, glucose)

[0142] In a second embodiment illustrated in FIG. 9B , an apparatus having multiple aerator components is employed, each of which is made of polypropylene; and a syringe is filled with D50 glucose (e.g., a solution containing 50% glucose). As captured in the leftmost frame, the initial expulsion of glucose results in the generation of small to medium-sized bubbles of minimal volume. Bubble generation with glucose is more continuous and produces more small bubbles (medium-sized bubbles are also generated throughout the process—see left-center and right-center frames) than with pure saline. A greater amount of bubbles is generated with glucose than with saline, but the total amount is still relatively low. After approximately 10 seconds (see rightmost frame), when the glucose is substantially expelled, a larger amount of large bubbles is generated.

[0143] Example 3 (Multi-stage, polypropylene, saline / polysorbate)

[0144] In the third embodiment illustrated in FIG. 9C , a device having multiple aerator components is used, each of which is made of polypropylene; and the syringe is filled with saline to which a small amount of polysorbate (about 1% by volume) is added. As illustrated in the leftmost frame, the initial discharge of the saline / polysorbate results in the generation of a large number of very small bubbles and microbubbles (as illustrated by the "cloud-like" pattern). After the initial generation of very small bubbles, the generation of bubbles gradually decreases, with only intermittent generation of very small, small and medium-sized bubbles (see the left-center frame and the right-center frame). After about 9 seconds (see the rightmost frame), when the saline / polysorbate is substantially discharged, a large number of large bubbles are generated.

[0145] Example 4 (multi-stage, polycarbonate, brine)

[0146] In the fourth embodiment illustrated in FIG. 10A , a device having a plurality of aerator components is employed, each of which is made of polycarbonate; and a syringe is filled with saline. As illustrated in the leftmost frame, the initial discharge of the saline results in the generation of a certain amount of large bubbles. The steady generation of large bubbles lasts for about two seconds, after which the stream of small and medium-sized bubbles continues at a steady but lower rate (see the left-center frame and the right-center frame). After about 11 seconds (see the rightmost frame), when the saline is substantially discharged, the bubble generation simply stops—finally no large bubbles are generated, as in the previous embodiment.

[0147] Example 5 (multi-stage, polycarbonate, glucose)

[0148] In the fifth embodiment illustrated in FIG. 10B , a device with multiple aerator components is used, each of which is made of polycarbonate; a syringe is filled with D50 glucose. As illustrated in the leftmost frame, the initial discharge of glucose results in a smooth stream of microbubbles (looking like a bright cloud). Large bubbles initially accompany the microbubbles for about two seconds, after which the bubble generation slows down slightly (but remains continuous throughout - see the left and right middle frames), and the bubble size changes to mostly very small bubbles. After about 13 seconds (see the rightmost frame), when the glucose is substantially discharged, the bubble generation simply stops, and no large bubbles are generated at the end.

[0149] Example 6 (Multi-stage, polycarbonate, saline / polysorbate)

[0150] In the sixth embodiment illustrated in FIG. 10C , a device having a plurality of aerator components is used, each of which is made of polycarbonate; and a syringe is filled with saline to which a small amount of polysorbate (about 1% by volume) is added. As illustrated in the leftmost frame, the initial discharge of the saline / polysorbate results in a smooth stream of microbubbles (significant in number relative to the other embodiments), with a smaller number of small and very small bubbles (and almost no formation of medium-sized or large bubbles). The stable production of microbubbles lasts for about two seconds, after which the total amount of bubbles decreases slightly, and the size of the bubbles appears to increase slightly, becoming very small bubbles (see the middle left and middle right frames). After about 10.5 seconds (see the rightmost frame), when the saline / polysorbate is substantially discharged, the bubble production gradually decreases, without producing any large bubbles.

[0151] Example 7 (single stage, polypropylene, brine)

[0152] In the seventh embodiment illustrated in FIG. 11A , a device having a single aerator component made of polypropylene (e.g., similar to the exemplary microbubble generator 700 shown in FIG. 7 ) is employed; and the syringe is filled with saline. As illustrated in the leftmost frame, the initial discharge of saline results in the generation of a certain amount of small, medium-sized, and large bubbles. The generation of these bubbles remains continuous for about one second, after which the bubble generation weakens and the bubble size decreases (see the middle frame). After about 3.5 seconds (see the right frame), when the saline is substantially discharged, a larger amount of large bubbles is generated. It is apparent from the presence of only three frames in FIG. 11A (as well as FIGS. 11B and 11C ) that the duration of bubble generation in Example 7 (as well as Examples 8 and 9) is much shorter than in the other embodiments provided.

[0153] Example 8 (single stage, polypropylene, glucose)

[0154] In the eighth embodiment illustrated in FIG. 11B , a device having a single aerator component made of polypropylene is employed; and the syringe is filled with D50 glucose. As illustrated in the left panel, the initial discharge of glucose results in the generation of a certain amount of small and medium-sized bubbles. The generation of these bubbles continues for about one second, after which the bubble generation weakens and the bubble size decreases (see the middle panel). After about four seconds (see the right panel), when the glucose is substantially discharged, a larger amount of large bubbles is generated.

[0155] Example 9 (single stage, polypropylene, saline / polysorbate)

[0156] In the ninth embodiment illustrated in FIG. 11C , a device having a single aerator component made of polypropylene is used; and the syringe is filled with saline to which a small amount of polysorbate (about 1% by volume) has been added. As illustrated in the left panel, the initial discharge of the saline / polysorbate results in the generation of a certain amount of microbubbles, and there are also some small and medium-sized bubbles. The generation of these bubbles continues for about one second, after which the bubble generation subsides (see the middle panel). After about 4 seconds (see the right panel), when the saline / polysorbate is substantially discharged, a larger amount of large bubbles is generated.

[0157] Example 10 (single stage, polycarbonate, brine)

[0158] In the tenth embodiment illustrated in FIG. 12A , a device having a single aerator component made of polycarbonate is used; and the syringe is filled with saline. As illustrated in the leftmost frame, the initial discharge of the saline results in the generation of a certain amount of small, medium-sized, and large bubbles. The generation of these bubbles continues for about four seconds (see the middle left frame), after which the bubble generation almost stops (see the middle right frame). After about 7 seconds (see the rightmost frame), when the saline is substantially discharged, a relatively large amount of large bubbles is generated.

[0159] Example 11 (single stage, polycarbonate, glucose)

[0160] In the eleventh embodiment illustrated in FIG. 12B , a device having a single aerator component made of polycarbonate is used; and the syringe is filled with D50 glucose. As illustrated in the leftmost frame, the initial discharge of glucose results in the generation of a certain amount of small and very small bubbles, and there are also some medium-sized and large bubbles. The generation of small and very small bubbles lasts for about three seconds (see the left middle frame), after which the generation of bubbles gradually decreases, but remains continuous, with the generation of small and very small bubbles (see the right middle frame). After about 7.5 seconds (see the rightmost frame), when the glucose is substantially discharged, a certain amount of large bubbles is generated.

[0161] Example 12 (Single Stage, Polycarbonate, Saline / Polysorbate)

[0162] In the twelfth embodiment illustrated in FIG. 12C , a device having a single aerator component made of polycarbonate is used; and the syringe is filled with saline to which a small amount of polysorbate (about 1% by volume) has been added. As illustrated in the leftmost frame, the initial discharge of the saline / polysorbate results in the generation of a certain amount of small and very small bubbles and microbubbles, and there are also a few medium-sized and large bubbles. The generation of very small bubbles and microbubbles lasts for about three seconds (see the left middle frame), after which the generation of bubbles gradually decreases, but remains continuous, generating very small bubbles and microbubbles (see the right middle frame). After about 7.0 seconds (see the rightmost frame), when the saline / polysorbate is substantially discharged, a certain amount of large bubbles is generated.

[0163] Example 13 (single stage, acetal, brine)

[0164] In the thirteenth embodiment illustrated in FIG. 13A , a device having a single aerator component made of acetal is employed; and the syringe is filled with saline. As illustrated in the leftmost frame, the initial expulsion of the saline / polysorbate results in the generation of a certain amount of bubbles of a wide range of sizes - including large, medium, small, and some very small bubbles. The generation of bubbles of a wide range of sizes continues for about three seconds (see the middle left frame), after which the generation of bubbles decreases significantly, and only a small amount of small and very small bubbles are generated (see the middle right frame). After about 6.5 seconds, medium-sized bubbles are generated again; and at about 8.0 seconds, when the saline is substantially expelled, a certain amount of large bubbles are generated.

[0165] Example 14 (single-stage, acetal, glucose)

[0166] In the fourteenth embodiment illustrated in FIG. 13B , a device having a single aerator component made of acetal is employed; and the syringe is filled with D50 glucose. As illustrated in the leftmost frame, the initial expulsion of glucose results in the generation of a certain amount of bubbles of a wide range of sizes - including large, medium, small bubbles and some very small bubbles and microbubbles. The generation of bubbles of a wide range of sizes lasts for about 3.5 seconds (see the left middle frame), after which the generation of bubbles gradually decreases and mainly very small bubbles and microbubbles are generated (see the right middle frame). After about 9.0 seconds, when the glucose is substantially expelled, a certain amount of large bubbles is generated.

[0167] Example 15 (Single-stage, acetal, saline / polysorbate)

[0168] In the fifteenth embodiment illustrated in FIG. 13C , a device having a single aerator component made of acetal is employed; and the syringe is filled with saline to which a small amount of polysorbate (about 1% by volume) has been added. As illustrated in the leftmost frame, the initial discharge of the saline / polysorbate results in the generation of small and very small bubbles and microbubbles. The steady generation of bubbles within these ranges lasts for about 4.0 seconds (see the middle left frame), after which the amount of bubbles decreases slightly, but the size remains relatively consistent (see the middle right frame). After about 6.5 seconds, when the saline / polysorbate is substantially discharged, a certain amount of large bubbles is generated.

[0169] Analysis of Examples 1-15

[0170] As shown in these examples, applicants have found that, with respect to aerator materials and bubble formation, polycarbonate aerators are generally superior to polypropylene aerators - in one or more of the length of time bubbles are generated (and, by extension, the number of bubbles) and bubble quality (where "higher quality" corresponds to a distribution that includes primarily small and very small bubbles and microbubbles and minimizes medium-sized and large bubbles). For single-stage aerators, acetal appears to perform comparable to polycarbonate. With respect to the solutions used in the aerators, glucose was superior to saline in all examples, although the difference between glucose and saline was less pronounced for polypropylene aerators. Saline with a small amount of polysorbate added was generally superior to glucose in all examples; however, again, the difference between saline / polysorbate and glucose was less pronounced for polypropylene aerators. Compared to single-stage aerators using glucose or polysorbate, multi-stage aerators using glucose or polysorbate ultimately do not produce large bubbles when the solution is substantially discharged from the syringe.

[0171] Surprisingly, Applicants have found that the combination of polycarbonate and glucose or polycarbonate and saline / polysorbate is very significantly superior (e.g., in terms of bubble quantity and quality, as described above) to embodiments involving saline alone or embodiments with polypropylene aerators. For example, compare FIG. 10C with other multi-stage embodiments depicted in FIGS. 9A to 9C and 10A to 10B; further compare FIG. 12C with other single-stage embodiments depicted in FIGS. 11A to 11C and 12A to 12B. Applicants have found that acetal and saline / polysorbate perform similarly to polycarbonate and saline / polysorbate (see FIGS. 13C and 12C).

[0172] Applicants have determined that the variation in performance in the various embodiments is related to: (1) the surface energy of the material forming the aerator component (in these embodiments, polypropylene, polycarbonate, or acetal) - and perhaps more precisely, the corresponding level of hydrophobicity or hydrophilicity resulting from said surface energy of the material; and (2) the presence of a surfactant in the body-compatible solution (both glucose and polysorbate were used as surfactants in the solution).

[0173] Examining these properties independently of one another, various forms of polypropylene have a surface energy of about 30 mN / m (millinewtons per meter - the SI standard unit for measuring surface energy), while various forms of polycarbonate have a surface energy of about 46 mN / m. (Various forms of acetal have a surface energy of about 36 mN / m - intermediate 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 a given solution to flow over the surface of the aerator component (e.g., along the surface of the aerator component) compared to the lower surface energy of polypropylene. Figure 7B Channel 773 or Fig. 6F 673) is more diffused - resulting in more efficient operation of the venturi and corresponding vent in introducing air or other gas into the solution stream flowing therethrough. In other words, the difference in surface energy is believed to allow a given solution to bead up less on polycarbonate (or acetal) than on polypropylene. This greater diffusion or less beading is believed to facilitate greater absorption of air or gas into the solution stream flowing through the venturi.

[0174] Surfactants in a solution tend to reduce the interfacial tension between the molecules of the solution (independent of the effect that the surface energy of the material contacting the solution may have on the interfacial tension at the contacting surface). That is, in the absence of a surfactant, the intermolecular forces holding the individual molecules of the solution to each other may be relatively strong, whereas the addition of a surfactant reduces the intermolecular attractions or interfacial tension. It will be appreciated that this reduction in interfacial tension caused by the presence of a surfactant (e.g., glucose or polysorbate) increases the ability of the solution to attract air or gas in the form of microbubbles (e.g., within or near the venturi throat as the solution moves through the venturi throat).

[0175] Surprisingly, the applicant has found that the changes in these two parameters (surface energy and interfacial tension) combine in a manner that appears to be multiplicative, rather than merely additive. That is, embodiments involving higher material surface energies of aerator components and the presence of surfactants in the solution facilitate the generation of microbubbles that are far superior to bubbles formed in embodiments that optimize only surface energy or only interfacial tension. For example, with respect to surface energy alone, multi-stage aerators with higher surface energies produce a greater number of bubbles (e.g., more bubbles are produced in Example 4 (FIG. 10A) than in Example 1 (FIG. 9A)); similarly, single-stage aerators with higher surface energies produce a greater number of bubbles (e.g., more bubbles are produced in Examples 10 and 13 (FIGs. 12A and 13A) than in Example 7 (FIG. 11A)). With respect to surfactants alone, embodiments involving glucose or polysorbates are superior to embodiments involving only saline. However, when these parameters are combined, the differences are quite dramatic - using the multi-stage aerator, the bubbles produced in Example 6 (FIG. 10C) are much larger in number and higher in quality than those produced in Example 3 (FIG. 9C); and using the single-stage aerator, the bubbles produced in Examples 12 and 15 (FIG. 12C and 13C) are much larger in number and higher in quality than those produced in Example 9 (FIG. 11C). Thus, Applicants have surprisingly discovered that an aerator component made of a high surface energy material (e.g., polycarbonate or acetal), combined with a body-compatible solution having a surfactant (e.g., glucose or polysorbate), produces a greater number of bubbles of higher quality than other embodiments.

[0176] Additional Examples

[0177] One embodiment was further tested to evaluate the ultrasound echogenicity of the microbubbles generated and introduced into a live porcine model. Specifically, microbubbles were generated in saline or saline / polysorbate solution using a multi-stage aerator; the saline or saline / polysorbate solution containing the microbubbles was injected into the venous system of a live porcine model; and ultrasound images were captured using transesophageal echocardiography (TEE). These images, such as FIG. 14A to FIG. 14EEach of these figures includes a left frame and a right frame. The left frame illustrates a TEE image before the injection of a solution containing microbubbles; and the right frame illustrates a TEE image after the injection of a solution containing microbubbles.

[0178] Example 16 (Current Standard of Care)

[0179] Fig.14A The TEE of the procedure of injecting the microbubbles produced by the current standard nursing procedure into the venous system of the pig model is illustrated. Specifically, two 10mL syringes are connected together and connected to the intravenous tube using a three-way stopcock. The intravenous tube is arranged in the venous system of the pig model so that any fluid injected by it will be brought to the right atrium of the pig model. Initially, the stopcock is adjusted to isolate and connect two syringes to the intravenous tube. The first syringe initially contains 9mL saline, and the second syringe initially contains 1mL room air. The syringe plunger is actuated back and forth 30 times to mix saline and air and form microbubbles, and finally all saline and air (in the form of microbubbles) are located in a syringe. Then, the stopcock is moved to connect this syringe to the intravenous tube, and the corresponding plunger of the syringe is actuated to inject the saline / microbubble mixture into the intravenous tube.

[0180] Fig.14A The left panel of FIG. 1 shows a TEE immediately before injection. The right atrium is FIG. 14A to FIG. 14E The left atrium and left ventricle are also shown in the figure for additional anatomical reference. Fig.14A are marked in the left frame ("LA" and "LV" respectively). Fig.14A In the left frame of the image, the "RA" region initially appears dark - indicating a hypoechoic or anechoic response associated with blood flowing through the right atrium; in contrast, the tissue forming the right atrium wall (as well as other tissue structures of the heart) is lighter in color - indicating a hyperechoic response typically associated with tissue.

[0181] The right frame of Figure 14 illustrates the TEE after injection. In this frame, the right atrium is lighter in color—this is due to the hyperechoic microbubbles that appear in the right atrium after injection.

[0182] Example 17 (Multi-stage aerator; brine containing 0.1% polysorbate)

[0183] Fig. 14B The diagram shows a photograph of an embodiment using a multi-stage aerator (such as in Fig. 6A Figure and reference Fig. 6AThe multi-stage aerator embodiment described above was used to perform a TEE of a procedure to generate microbubbles. In this example, the input end of the multi-stage aerator was connected to a 10 mL syringe filled with a mixture of saline and 0.1% polysorbate; and the output end of the multi-stage aerator was connected to an intravenous line set in the venous system of a porcine model (again, so that any fluid injected therethrough would be delivered to the right atrium of the porcine model).

[0184] like Fig.14A middle, Fig. 14B The left frame of illustrates the TEE before the injection of the saline / polysorbate / microbubble mixture, and the right atrium is again labeled. After capturing this reference image, the contents of the syringe were injected into the IV line through the multi-stage aerator with a single, steady actuation of the syringe plunger. Fig.14A Capture and reference Fig.14A Compared to the current standard of care procedure described, there is no need to agitate air and saline between multiple syringes. By employing a multi-stage aerator, much of the user variability associated with generating microbubbles using the current standard of care procedure is eliminated.

[0185] like Fig. 14B As shown in the right panel of the image, the right atrium appears lighter in color again—this is due to the hyperechoic microbubbles that appeared in the right atrium after the injection. Fig.14A and Fig. 14B Comparison of the right panel reveals nearly identical ultrasound images. That is, the multi-stage aerator described herein produces microbubbles of the same quality as those produced using current standard of care procedures, but without reliance on user preparation of air and saline using multiple syringes and a three-way stopcock.

[0186] Example 18 (Multi-stage aerator; saline containing 0.01% polysorbate)

[0187] Fig. 14C The diagram shows a photograph of an embodiment using a multi-stage aerator (such as in Fig. 6A Figure and reference Fig. 6A In this example, the input of the multi-stage aerator was connected to a 10 mL syringe filled with a mixture of saline and 0.01% polysorbate; and the output of the multi-stage aerator was connected to an IV line placed in the venous system of a porcine model (again, so that any fluid injected therethrough would be delivered to the right atrium of the porcine model).

[0188] Fig. 14C The left frame of FIG again illustrates the TEE before the injection of the saline / polysorbate / microbubble mixture. After capturing this reference image, the contents of the syringe were injected into the IV line through the multi-stage aerator by a single steady actuation of the syringe plunger. Fig. 14CAs shown in the right panel of , after injection, the color of the right atrium again appears lighter - this is due to the hyperechoic microbubbles that appear in the right atrium after injection. The ultrasound image quality is comparable to that of Examples 16-17 - again equal to the quality of the current standard of care procedure.

[0189] Example 19 (Multi-stage aerator; saline containing 0.005% polysorbate)

[0190] Fig.14D The diagram shows a photograph of an embodiment using a multi-stage aerator (such as in Fig. 6A Figure and reference Fig. 6A The multi-stage aerator embodiment described above was used to perform a TEE of a procedure for generating microbubbles. In this example, the input end of the multi-stage aerator was connected to a 10 mL syringe filled with a mixture of saline and 0.005% polysorbate; and the output end of the multi-stage aerator was connected to an intravenous line set in the venous system of a porcine model (again, so that any fluid injected therethrough would be delivered to the right atrium of the porcine model).

[0191] Fig.14D The left frame of FIG again illustrates the TEE before the injection of the saline / polysorbate / microbubble mixture. After capturing this reference image, the contents of the syringe were injected into the IV line through the multi-stage aerator by a single steady actuation of the syringe plunger. Fig.14D As shown in the right panel of , after injection, the color of the right atrium again appears lighter - this is due to the hyperechoic microbubbles that appear in the right atrium after injection. The ultrasound image quality is comparable to that of Examples 16-18 - again equal to the quality of the current standard of care procedure.

[0192] Example 20 (Multi-stage aerator; saline containing 0.005% polysorbate)

[0193] Fig.14E The diagram shows a photograph of an embodiment using a multi-stage aerator (such as in Fig. 6A Figure and reference Fig. 6A The TEE of the procedure for generating microbubbles using a multi-stage aerator embodiment described in the present invention (described in the present invention) was performed. In this example, the input end of the multi-stage aerator was connected to a 10 mL syringe filled with a mixture of saline and 0.005% polysorbate; and the output end of the multi-stage aerator was connected to a 20-gauge needle placed directly (without any intervening intravenous tubing) in the venous system of the pig model (again, so that any fluid injected therethrough would be delivered to the right atrium of the pig model).

[0194] Fig.14E The left frame of illustrates a TEE prior to injection of the saline / polysorbate / microbubble mixture. After this reference image was captured, the contents of the syringe were injected through the multi-stage aerator and 20-gauge needle with a single, steady actuation of the syringe plunger. Fig.14EAs shown in the right panel of , after injection, the color of the right atrium again appears lighter - this is due to the hyperechoic microbubbles that appear in the right atrium after injection. The ultrasound image quality is comparable to that in Examples 16-19 - again equal to that of the current standard of care procedure. As illustrated in this example, there is no perceptible difference in ultrasound image quality between saline / polysorbate / microbubbles injected through an IV line or through a 20-gauge needle.

[0195] Analysis of Examples 16-20

[0196] As shown in Examples 16-20, the aerators described herein can generate microbubbles for use in echocardiographic studies and other studies of anatomical structures, such as studies using ultrasound and contrast agents. In addition, the aerators can generate microbubbles from saline and polysorbate solutions of varying concentrations for use in studies of living patients.

[0197] Changes in polysorbate concentrations may produce FIG. 14B to FIG. 14E For example, in some embodiments, when the concentration of polysorbate is about 0.1%, the microbubbles can be smaller; and the microbubbles in such embodiments may be useful in imaging very small anatomical structures such as PFOs, ASDs, or pAVMs. In some embodiments, the concentration of polysorbate may affect the time required for the microbubbles to dissipate within the circulatory system. Some concentrations may require longer clearance times than other concentrations; therefore, by adjusting the concentration of polysorbate, it may be possible to control the clearance time. The concentration of polysorbate may also affect the precise echogenicity of the microbubbles. In some embodiments, it may be advantageous to produce microbubbles with higher echogenicity (e.g., to clearly outline the contours of a structure); while in other embodiments, it may be advantageous to produce microbubbles that are only echogenic (e.g., to facilitate better imaging of adjacent structures).

[0198] in conclusion

[0199] Although many embodiments are described with reference to cardiac studies, comparative studies can have other useful applications. For example, microbubbles combined with ultrasound or other imaging techniques can be used clinically to record the correct catheter placement during pericardiocentesis, right atrial central venous catheter placement, and interventional radiology procedures. In the field of gynecology, such as ultrasound / infertility procedures, microbubbles can be used to assess the patency of the fallopian tubes. Other applications can include imaging of the abdominal space, the portion of the gastrointestinal tract, and the joints or other interstitial spaces of the human body. Microbubbles can also be used in veterinary procedures in a similar manner as described herein.

[0200] Several embodiments 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 intended scope. For example, syringes of various sizes may be used; the converging nozzle may be integral to the syringe; the aerator may be integral to the converging nozzle; the converging nozzle and aerator may be an integral assembly; the components may be adhesively joined, ultrasonically welded, or molded as an integral part; some embodiments may use O-rings and compression fittings to join the components, while other embodiments may use different techniques; different sized air channels and geometries may be used within the converging nozzle; the syringe may be pre-filled or filled on-site immediately prior to the procedure; the microbubbles may be generated in saline, glucose, plasma, saline / polysorbate, saline with some other surfactant, or some other body-compatible fluid or combination of fluids; the microbubbles may be used in the context of ultrasound or other imaging techniques; the microbubbles may be used for diagnostic or therapeutic purposes; the kit may be equipped with any number of microbubble generators, coupled together with a manifold, or equipped with a manifold for coupling prior to the procedure; different membranes, caps, or seals may be used to contain pre-filled fluids within the microbubble generators or portions of the microbubble generating system; various numbers of air channels may be used to facilitate the generation of a greater or lesser number of microbubbles per unit of fluid; air channels may be used to facilitate the generation of a greater or lesser number of microbubbles per unit of fluid; and air channels may be used to facilitate the generation of a greater or lesser number of microbubbles per unit of fluid. The gas channels can have various sizes, geometries and / or surface treatments to control the size of the generated microbubbles; another gas (e.g., oxygen, nitrogen, carbon dioxide, some mixture thereof, another biocompatible gas, etc.) can be used throughout to replace "air"; a continuous source of saline or other fluid can replace the syringe; the syringe can be automatically or manually operated; the microbubbles can include "nanobubbles" or bubbles of various sizes and distributions; the aerator components can vary in size (e.g., throat diameter, vent diameter); different numbers of aerator components can be deployed (e.g., one aerator components may be sequentially graded in different size sequences (e.g., from smaller to larger range throats or in some other sequence); single aerator embodiments may include different numbers of vents (e.g., one, two, three, or more); the vents may be transverse holes that are generally perpendicular to the longitudinal axis of the corresponding channel or flow path; the vents may be angled relative to the longitudinal axis of the corresponding channel or flow path; the vents may include grooves or other paths that fluidly connect an area outside the aerator body to a flow path inside the aerator body.

[0201] Many other modifications 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, the scope is intended to include all aspects that fall within the scope of the appended claims.

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) an outer body having a cylindrical shape including a longitudinal axis feature; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end, the tapered outlet port being defined by an outlet diameter less than a body diameter corresponding to the outer body and a taper proximate the outlet end; and (v) an internal chamber including (A) an input port section, (B) an inlet section, (C) a throat section, (D) an outlet section, and (E) a transverse vent fluidly coupling the throat section to a region external to and adjacent to the outer body; as well as a housing, the housing (x) circumferentially surrounding the end of the cartridge and the plurality of aerator components, (y) including a longitudinal axis feature, (z) having an inner surface, (aa) forming a circumferential air pocket between the inner surface and the outer body of each of the plurality of aerator components, and (bb) having a housing discharge tip; The input port section of each aerator component is configured to accommodate the tapered outlet port of the syringe tip or one of the other aerator components among the multiple aerator components, and the shell discharge tip is configured to accommodate the tapered outlet port of one of the multiple aerator components, so that the syringe tip, the first aerator component, the second aerator component and the shell can be connected together in a coaxial manner relative to their respective longitudinal axes.

2. The device according to claim 1, characterized in that Each of the aerator components also 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 secure the housing and each of the multiple 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 including a longitudinal axis feature; An aerator having (i) a cylindrical outer body also including a longitudinal axis feature; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end; and (v) an internal chamber 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 fluidly coupling at least one of the throat section or the diverging section to the region outside of and adjacent to the outer body, and (G) a second vent fluidly coupling the outlet section to the region; a housing, the housing (x) circumferentially surrounding the ends of the cartridge and the aerator, (y) including a longitudinal axis feature, (z) having an inner surface, (aa) forming a circumferential air pocket between the inner surface and the outer body, and (bb) having a housing discharge tip; Wherein the input port section is configured to receive the syringe tip and the housing discharge tip is configured to receive the tapered outlet port such that the syringe tip, the aerator and the housing can be coupled together in a coaxial manner relative to their respective longitudinal axes.

4. The device according to claim 3, characterized in that The housing seals against the cartridge to prevent fluid communication between the region and a region external to the housing except through the housing discharge tip, the first vent, or the second vent.

5. The device according to claim 3, characterized in that The first vent includes a first vent diameter characteristic and the second vent includes a second vent diameter characteristic, the first vent diameter being greater than the second vent diameter.

6. The device according to claim 5, characterized in that The first vent has a diameter of 1.0 mm and the second vent has a diameter of 0.5 mm.

7. The device according to claim 3, characterized in that The capacity of the cylinder is 30 mL, and the volume of the circumferential air pocket is 5 to 15 mL.

8. The device according to claim 3, characterized in that The outlet section is cylindrical in shape.

9. The device according to claim 3, characterized in that The converging section has a diameter ranging between 3.5 mm and 0.5 mm.

10. The device according to claim 3, characterized in that The diameter of the diverging section ranges between 0.65 mm and 2.1 mm.

11. The device according to claim 3, characterized in that The aerator comprises a material having a surface energy greater than or equal to 35 mN / m.

12. The device according to claim 3, characterized in that Also included is a body compatible solution disposed in the cartridge.

13. The device according to claim 12, characterized in that Also included is a cap enclosing a portion of the housing discharge tip and a sealing pin blocking a portion of the interior chamber.

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