Syringe-type microbubble generator with aerator

Abstract

The device includes a syringe having a barrel and a syringe tip; and an aerator having (i) a generally cylindrical exterior body characterized by a longitudinal axis, (ii) an inlet end, (iii) an outlet end, (iv) a tapered outlet port at the outlet end, and (v) an interior cavity having (A) an input port section, (B) a converging section, (C) a throat section, (D) a diverging section, (E) an outlet section, and (F) a first vent, adjacent at least one of the throat section or the diverging section exterior to the exterior of the exterior body. an aerator having an internal cavity with (x) a first vent fluidly connecting to an area, and (g) a second vent, the second vent fluidly connecting the outlet section to the area; and a housing, (x) circumferentially surrounding an end of the barrel and the plurality of aerator components, (z) having an inner surface, (aa) forming a circumferential gas pocket between the outer casing and the inner surface of each of the plurality of aerator components, and (bb) having a housing discharge tip.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application is a continuation of U.S. Patent Application Serial No. 17 / 584,826, filed on January 26, 2022, entitled "Syringe - Type Microbubble Generator with Aerator", and U.S. Patent Application No. 17 / 584,826 is a partial continuation of U.S. Patent Application Serial No. 17 / 566,079, filed on December 30, 2021, entitled "Syringe - Type Microbubble Generator with Aerator", and U.S. Patent Application No. 17 / 566,079 is a partial continuation of U.S. Application Serial No. 17 / 542,386, filed on December 4, 2021, entitled "Syringe - Type Microbubble Generator", and U.S. Application No. 17 / 542,386 is a continuation of U.S. Patent Application No. 17 / 158,396, filed on January 26, 2021, entitled "Syringe - Type Microbubble Generator", which is now U.S. Patent No. 11,191,888. This application incorporates the entire contents of the aforementioned applications herein by reference.

[0002] Various implementations generally relate to the generation of microbubbles for use in various diagnostic and therapeutic procedures.

Background Art

[0003] Echocardiography refers to the use of ultrasound to examine the heart. Echocardiography is a diagnostic test widely used in the field of cardiology and can be used for the diagnosis, management, and follow - up of patients known or suspected to have heart disease. The results of an echocardiography test can provide a lot of useful information, including the size and shape of the components of the heart (e.g., quantification of internal chamber size), pump function, and the location and extent of tissue damage. Echocardiograms can also provide other estimates of cardiac function to physicians, such as calculation of cardiac output, ejection fraction (the proportion of blood volume in the left ventricle ejected per contraction), diastolic function (how well the heart relaxes), etc.

[0004] Echocardiography can be performed using one of several methods. The least invasive method involves placing an ultrasound transducer in the patient's chest and imaging through the chest wall to obtain transthoracic echocardiography (TTE). If higher-fidelity images are required, a more invasive transesophageal echocardiogram (TEE) can be performed, in which an ultrasound transducer placed in a thin tube is lowered from the patient's throat into the esophagus. Because the esophagus is very close to the heart, this procedure allows for very clear images of the heart's structure and valves.

[0005] During either TTE or TEE, a contrast agent may be applied to enhance imaging of the procedure. This contrast agent can be injected intravenously into the patient so that it can quickly reach the cardiac chambers and be detected by ultrasound to more clearly visualize the cardiac structure. In some procedures, the contrast agent used is saline solution containing small bubbles, and the procedure may be referred to as a stirred saline contrast study or "bubble study." [Overview of the project]

[0006] In several implementations, a device for generating microbubbles includes a syringe having a barrel and a syringe tip, a plurality of aerator components, and a housing. Each aerator component may have an internal cavity comprising: (i) a generally cylindrical casing characterized by its longitudinal axis; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at the outlet end, the tapered outlet port being defined by an outlet diameter smaller than the body diameter corresponding to the casing and a taper near the outlet end; and (v) an internal cavity comprising: (A) an input port section; (B) an inlet section; (C) a throat section; (D) an outlet section; and (E) a lateral vent that fluidly connects the throat section to an adjacent region outside the casing. The housing may (x) surround the end of the barrel and the plurality of aerator components in the circumferential direction, be characterized by (y) a longitudinal axis, have (z) an inner surface, (aa) form a circumferential gas pocket between the outer casing and the inner surface of each of the plurality of aerator components, and (bb) have a housing discharge tip. The input port section of each aerator component may be configured to accommodate one tapered outlet port of one of the plurality of aerator components or the syringe tip, and the housing discharge tip may 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 light-flow element and the housing are coaxially connected with respect to their respective longitudinal axes.

[0007] In several implementation configurations, each of the aerator components further includes one or more alignment tabs, and the housing includes alignment grooves, so that when the syringe tip, the first aerator component, the second aerator component, and the housing are integrally connected, the one or more alignment tabs and the alignment grooves cooperate to fix the housing and each of the plurality of aerator components radially to each other.

[0008] In several implementations, a device for generating microbubbles includes a syringe having a barrel and a syringe tip and characterized by its longitudinal axis, an aerator, and a housing. The aerator may have (i) a generally cylindrical casing, also characterized by its longitudinal axis, (ii) an inlet end, (iii) an outlet end, (iv) a tapered outlet port at the outlet end, and (v) an internal cavity having (A) an input port section, (B) a converging section, (C) a throat section, (D) a diverging section, (E) an outlet section, (F) a first vent that fluidly connects at least one of the throat section or the diverging section to an adjacent region outside the casing, and (G) a second vent that fluidly connects the outlet section to the region. The housing may (x) surround the end of the barrel and the aerator in the circumferential direction, be characterized by (y) a longitudinal axis, have (z) an inner surface, (aa) form a circumferential gas pocket between the outer casing and the inner surface, and (bb) have a housing discharge tip. The input port section may be configured to accommodate the syringe tip, and the housing discharge tip may be configured to accommodate the tapered outlet port, so that the syringe tip, the aerator component, and the housing are coaxially integrated with respect to their respective longitudinal axes.

[0009] In some implementations, the housing prevents fluid communication between the region and the outer region of the housing by sealing against the barrel, except when passing through the housing discharge tip, the first vent, or the second vent. The first vent may be characterized by a first vent diameter, and the second vent may be characterized by a second vent diameter, the first vent diameter being larger than the second vent diameter. In some implementations, the diameter of the first vent is approximately 1.0 mm, and the diameter of the second vent is approximately 0.5 mm.

[0010] In some implementations, the barrel capacity is approximately 30 mL, and the volume of the circumferential gas pocket is approximately 5 mL to 15 mL. The outlet section may be substantially cylindrical in shape. The diameter of the converging section may be in the range of approximately 3.5 mm to approximately 0.5 mm. The diameter of the diverging section may be in the range of approximately 0.65 mm to approximately 2.1 mm. The aerator may contain a material having a surface energy of approximately 35 mN / m or more.

[0011] In some implementations, the device includes a biocompatible solution disposed within the barrel. In some implementations, the device further includes a sealing pin that closes off a portion of the internal cavity, and a cap that surrounds a portion of the housing discharge tip.

[0012] In several implementations, a method for generating microbubbles includes the step of preparing a microbubble generator. The microbubble generator comprises (a) a syringe having a barrel and a syringe tip, characterized by its longitudinal axis, the barrel being filled with biocompatible fluid, and (b) an aerator, which comprises (i) a generally cylindrical casing also characterized by its longitudinal axis, (ii) an inlet end, (iii) an outlet end, (iv) a tapered outlet port at the outlet end, and (v) an internal cavity, which comprises (A) an input port section, (B) a converging section, (C) a throat section, (D) a diverging section, (E) an outlet section, and (F) a first vent, wherein the throat section or the diverging section The aerator has an internal cavity comprising (G) a first vent, which fluidly connects at least one of the two sections between it to an adjacent region outside the outer casing, and (G) a second vent, which fluidly connects the outlet section to the region; and (C) a housing, which (X) surrounds the end of the barrel and the aerator in the circumferential direction, is characterized by (Y) a longitudinal axis, (Z) has an inner surface, (Aa) forms a circumferential gas pocket between the outer casing and the inner surface, and (B) has a housing discharge tip. The input port section may be configured to accommodate the syringe tip, and the housing discharge tip may be configured to accommodate the tapered outlet port, so that the syringe tip, the aerator components, and the housing are coaxially integrated with respect to their respective longitudinal axes.

[0013] The method may further include the step of connecting the housing dispensing tip to the venous system of the patient being treated. The step of connecting the housing dispensing tip to the venous system of the patient may include the steps of connecting the housing dispensing tip to a needle and positioning the needle in the patient's venous system. The step of connecting the housing dispensing tip to the venous system of the patient may also include the steps of connecting the housing dispensing tip to a venous line and positioning the venous line in the patient's venous system. The method may further include the step of generating microbubbles by pushing the biocompatible fluid out of the syringe through the internal cavity and the housing dispensing tip.

[0014] In some implementations, the aerator comprises a material having a solid surface energy of approximately 35 mN / m or more. In some implementations, the aerator comprises polycarbonate. In some implementations, the aerator comprises one of polycarbonate, polymethacrylate, polyvinyl chloride, polyamide, acrylonitrile butadiene styrene, acetal, or polyethylene terephthalate glycol.

[0015] In some implementations, the biocompatible fluid contains glucose. In some implementations, the biocompatible fluid contains saline solution and polysorbate. The biocompatible fluid may contain polysorbate at a concentration of 0.1% or less, the biocompatible fluid may contain polysorbate at a concentration of 0.01% or less, and the biocompatible fluid may contain polysorbate at a concentration of 0.005% or less. In some implementations, the biocompatible fluid contains saline solution and glucose or a biocompatible surfactant. [Brief explanation of the drawing]

[0016] [Figure 1] Figure 1 is an exploded perspective view of an exemplary microbubble generator.

[0017] [Figure 2A] Figure 2A is a longitudinal cross-sectional view of an exemplary syringe, converging nozzle, and aerator assembled in one implementation.

[0018] [Figure 2B] Figure 2B is a longitudinal cross-sectional view of the converging nozzle, O-ring, and aerator shown in Figure 2A.

[0019] [Figure 2C] Figure 2C is another longitudinal cross-sectional view of the converging nozzle, O-ring, and aerator shown in Figure 2A.

[0020] [Figure 2D] Figure 2D is a cross-sectional perspective view of the configuration shown in Figure 2C.

[0021] [Figure 2E] Figure 2E is a cross-sectional perspective view of another exemplary converging nozzle and aerator.

[0022] [Figure 2F] Figure 2F is a longitudinal cross-sectional view of the converging nozzle and aerator shown in Figure 2E.

[0023] [Figure 3] Figures 3A, 3B, and 3C depict the operation of an exemplary microbubble generator.

[0024] [Figure 4] Figure 4 shows an exemplary microbubble generation system.

[0025] [Figure 5] Figure 5 shows a part of the entire human circulatory system.

[0026] [Figure 6A] Figure 6A is a cross-sectional perspective view of another exemplary microbubble generator.

[0027] [Figure 6B] Figure 6B is a perspective view of an aerator component that may be included in the exemplary microbubble generator shown in Figure 6A.

[0028] [Figure 6C] Figure 6C is a cross-sectional perspective view of the aerator components shown in Figure 6B.

[0029] [Figure 6D] Figure 6D is a side view of the aerator components shown in Figure 6B.

[0030] [Figure 6E] Figure 6E is a side cross-sectional view of the aerator components shown in Figure 6B.

[0031] [Figure 6F] Figure 6F is a cross-sectional perspective view of multiple aerator components that may be integrally connected and included in the exemplary microbubble generator shown in Figure 6A.

[0032] [Figure 6G] Figure 6G is a cross-sectional perspective view of the exemplary microbubble generator shown in Figure 6A, including the cap and sealing pin.

[0033] [Figure 7A] Figure 7A is a cross-sectional perspective view of another exemplary microbubble generator.

[0034] [Figure 7B] Figure 7B is a side cross-sectional view of an aerator component that may be included in the exemplary microbubble generator shown in Figure 7A.

[0035] [Figure 8A] Figure 8A is a perspective view of an exemplary aerator component.

[0036] [Figure 8B]Figure 8B is a cross-sectional view of the aerator components shown in Figure 8A.

[0037] [Figure 8C] Figure 8C is a cross-sectional view of the aerator component shown in Figure 8A, with a sealing pin located inside.

[0038] [Figure 9] Figures 9A to 9C show, respectively, an exemplary multi-stage polypropylene aerator and microbubbles formed with saline solution, glucose, and saline solution containing polysorbate.

[0039] [Figure 10] Figures 10A to 10C show, respectively, an exemplary multi-stage polycarbonate aerator and microbubbles formed with saline solution, glucose, and saline solution containing polysorbate.

[0040] [Figure 11] Figures 11A to 11C show, respectively, an exemplary single-stage polypropylene aerator and microbubbles formed with saline solution, glucose, and saline solution containing polysorbate.

[0041] [Figure 12] Figures 12A to 12C show, respectively, an exemplary single-stage polycarbonate aerator and microbubbles formed with saline solution, glucose, and saline solution containing polysorbate.

[0042] [Figure 13] Figures 13A to 13C show, respectively, an exemplary single-stage acetal aerator using polysorbate, and microbubbles formed with physiological saline, glucose, and physiological saline containing polysorbate.

[0043] [Figure 14A]Figure 14A shows TEE treatment in a pig model in which microbubbles were produced using current standard treatment procedures.

[0044] [Figure 14B] Figure 14B shows TEE treatment in a pig model in which microbubbles were produced using an exemplary aerator containing physiological saline and 0.1% polysorbate.

[0045] [Figure 14C] Figure 14C shows TEE treatment in a pig model in which microbubbles were produced using an exemplary aerator containing physiological saline and 0.01% polysorbate.

[0046] [Figure 14D] Figure 14D shows TEE treatment in a pig model in which microbubbles were produced using an exemplary aerator containing physiological saline and 0.005% polysorbate.

[0047] [Figure 14E] Figure 14E shows a TEE procedure in a pig model where a 20-gauge needle was applied instead of an intravenous line to deliver microbubbles. Detailed explanation

[0048] Stirred saline contrast studies (or "bubble studies") are a useful adjunct to many ultrasound examinations, particularly cardiac ultrasound (echocardiography). Intravenous injection of stirred saline in combination with echocardiography is a validated method for detecting two types of holes in the heart, such as patent foramen ovale (PFO) or atrial septal defect (ASD), or shunts that may be outside the heart (e.g., in the lungs), known as pulmonary arteriovenous malformations (pAVM). Stirred saline can also be used in echocardiography 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 highlight right-side blood flow for quantitative purposes.

[0049] Stirred saline echocardiography utilizes the increased reflection that occurs when ultrasound waves encounter a liquid / gas interface. This allows for the visualization of areas that would otherwise have low reflectivity by an ultrasound device, such as fluid-filled cavities. Clinically useful applications of this include echocardiography using stirred saline to define the structural integrity of the atrial septum or to infer the presence of a transpulmonary shunt. Stirred saline can also be combined with Doppler echocardiography to assess blood flow through the tricuspid valve. Another method for detecting atrial defects is to use ultrasound of the cerebral blood vessels (transcranial Doppler) to detect air bubbles entering the cerebral circulation from the right to the left heart.

[0050] Currently, producing stirred saline for these studies can be difficult, potentially leading to variability in quality and safety levels. Current bubble studies can exhibit significant variability in the amount, size, and quantity of bubbles generated. Such inaccurate mixtures of saline and air can lead to patient risks and false-negative results. In addition, few people may be adequately trained to safely perform bubble studies. The productivity of echocardiography laboratories can be significantly reduced by this lack of trained personnel, and even trained personnel may hesitate to perform stirred saline studies due to concerns about the safety and comfort of the procedure if they are not routinely performing them.

[0051] This specification describes apparatus and methods for producing bubbles (for example, for ultrasonic bubble surveys). The advantages of the apparatus and methods described herein may include the production of more uniform and consistent bubble sizes with minimal training. This can lead to improved patient safety and comfort, as well as improved diagnostic effectiveness of the survey.

[0052] Figure 1 is an exploded perspective view of an exemplary microbubble generator 100 in one implementation configuration. As shown, the microbubble generator 100 includes a syringe 103, a converging nozzle 115, and an aerator 133. During operation, the microbubble generator 100 can be connected to an intravenous (IV) line placed in a patient undergoing a procedure (e.g., a diagnostic bubble survey), and the microbubble generator 100 can be applied to generate microbubbles as a contrast agent.

[0053] In several implementations, the syringe 103 portion of the microbubble generator 100 is a standard medical-grade syringe (e.g., 1 mL, 2 mL, 3 mL, 5 mL, 10 mL, 20 mL) and has a barrel 106, a plunger 109, and a tip 112. The syringe 103 may be pre-filled with saline solution or another solution suitable for intravenous injection, providing a vehicle for delivering the microbubbles generated by the microbubble generator 100 to a target area of ​​the patient's body. The tip 112 may include a Luer locking connector suitable for connection to needles, catheters, IV lines, etc.

[0054] Physiological saline is referred to in various forms. In some forms, this may be "NSS," or 0.9% normal physiological saline; in other forms, "45NS," or 0.45% normal physiological saline may be used; and in still other forms, phosphate-buffered saline (PBS) may be used. In yet other forms, liquids other than physiological saline may be used, such as glucose solutions (e.g., "D5W," or 5% glucose solution; "D10W," or 10% glucose solution; "D50," or 50% glucose solution) or other solutions commonly used for intravenous applications at sites suitable for diagnostic investigation or therapeutic procedures.

[0055] The converging nozzle 115 has a connecting end 118 configured to engage with the tip 112 of the syringe 103 in the shown configuration. In some configurations, the connecting end 118 includes a mating luer locking thread to facilitate twist-on engagement with the syringe 103. On the opposite side of the connecting end 118 is the converging tip 121. An internal channel 127, which will be described in more detail with reference to the following drawings, is configured to fluidly connect the inside of the syringe 103 to the aerator 133.

[0056] The aerator 133 includes a retaining end 136 configured to mechanically engage with the converging nozzle 115, and a discharge end 139, as shown. In some implementations, the aerator 133 can be connected to the converging nozzle 115 via a compression-fit connection facilitated by an O-ring 134 and grooves in the converging nozzle 115 and the aerator 133. The discharge channel 147 fluidly connects the internal channel 127 of the converging nozzle 115 to the discharge end 139, although the discharge end 139 may be configured to engage with a catheter or IV port or line used for bubble investigation.

[0057] In Figure 1, the syringe 103, the converging nozzle 115, and the aerator 133 are shown as separate components. However, in other configurations, one or more components may have other arrangements. For example, the converging nozzle 115 and the aerator 133 may be ultrasonically welded together, or joined by adhesive, snap fitting, etc., and the converging nozzle 115 or a single converging nozzle / aerator structure may be connected to the syringe 103 by one of the aforementioned methods, or co-formed as part of the syringe 103. Further details of the exemplary syringe 103, converging nozzle 115, and aerator 133 are provided here with reference to Figures 2A, 2B, and 2C.

[0058] Figure 2A shows a longitudinal cross-sectional view of the syringe 103, converging nozzle 115, and aerator 133, which may be assembled in several configurations. As shown, the converging nozzle 115 is positioned on the syringe 103 via a Luer locking joint 218, and the aerator 133 is compression-fitted onto the converging nozzle 115 by an O-ring and corresponding grooves in the converging nozzle 115 and aerator 133, respectively (see Figure 2B for details). In other configurations, the connections may differ. For example, other threaded or press-fit connections may replace the Luer locking joint. Similarly, the O-ring and grooves may be replaced by threaded, adhesive, or welded connections.

[0059] Figure 2B shows an exemplary longitudinal cross-sectional view of the converging nozzle 115, O-ring 134, and aerator 133. The internal channel 127 is fluidically connected to the inside of the fitted syringe 103 (see Figures 1 and 2A) and the throat 230, i.e., the portion of the internal channel 127 where the diameter gradually decreases. During operation, the gradually decreasing diameter of the throat 230 alters the dynamics of the fluid flowing from the syringe 103 through the converging nozzle 115, as will be explained with reference to Figure 2C.

[0060] As shown in the figure, the converging nozzle 115 includes a groove 235A for receiving an O-ring 134 and facilitating 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 groove 235A, the retaining end 236 of the aerator 133 to slide on the converging tip 121, and groove 235B to engage with and hold the O-ring 134. In such a configuration, the O-ring 134 may be made of an elastic material having sufficient elasticity and compressibility to facilitate engagement of the converging nozzle 115 and the aerator 133, and sufficient restoring force to ensure that the converging nozzle 115 and the aerator 133 are securely coupled once grooves 235A and 235B of these components 115 and 133 are aligned as described. In some configurations, the O-ring 134 and grooves 235A and 235B may provide an airtight and sterile seal.

[0061] The converging nozzle 115 further includes an outer mating surface 224 configured to mechanically fit adjacent to a corresponding circumferential lip 244 on the aerator 133 at the converging tip 121. In some configurations, the circumferential lip 244 wraps around the outer mating surface 224 in the circumferential direction and abuts against the outer mating surface 224 at at least one point, while in other configurations, the circumferential lip 244 and the outer mating surface 224 are adjacent and positioned close to each other. When the converging nozzle 115 and the aerator 133 are connected (for example by grooves 235A, 235B and O-ring 134), the outer mating surface 224 and the circumferential lip 244 are aligned, facilitating fluid connection between the internal fluid channel 127 and the throat 230 and the discharge channel 147. In several implementations, the specific dimensions and configuration of the outer fitting surface 224 and the circumferential lip 244, which will be further described with reference to Figure 2C, further facilitate the passage of air from the internal air chamber 241 formed by the outer wall 245 of the aerator 133 to the discharge channel 147.

[0062] Figure 2C is a longitudinal cross-sectional view showing the convergence nozzle 115 and aerator 133 in a connected configuration, and an enlarged view of a portion of that cross-sectional view. As shown, the internal air chamber 241 is formed by the outer wall 245 of the aerator. Between this internal air chamber 241 and the passage formed by the internal channel 127, throat 230 and discharge channel 147, there is a small fluid connection, specifically an air channel 246 (see enlarged inset) configured to exist between the outer fitting surface 224 and the circumferential lip 244. This air channel 246 allows air or other gases in the internal air chamber 241 to be drawn into the aforementioned passage (throat 230 and discharge channel 147, referred to as the "230 / 147 passage"). In addition, the air channel 246 can increase the pressure in the internal air chamber 241 by allowing some of the fluid passing through the 230 / 147 passage to enter the internal air chamber 241, thereby replacing some of the air there (for example, if there may be a non-negligible back pressure in the discharge channel 147).

[0063] Figure 2D is a cross-sectional perspective view of the converging nozzle 115 shown in Figure 2C, and has a cross-section along the cutting line AA (shown in Figure 2C). Figure 2D shows the air channels 246 (or a series of air channels 246) that fluidly connect the internal air chamber 241 to the throat 230-discharge channel 147 passage. What is visible in Figure 2D is the throat 230 itself, the center of the converging nozzle 115, and the series of air channels 246 arranged radially around the throat.

[0064] In some configurations, the outer mating surface 224 and the circumferential lip 244 (see Figure 2C) are in mechanical contact and provide a fluid seal, except for the air channel 246. That is, in such configurations, the fluid connection between the internal air chamber 241 and the 230 / 147 passage is present only in the air channel 246. In some configurations, fewer air channels 246 than those shown may be provided; for example, some configurations may include only one, two, three, or four air channels 246.

[0065] Referring back to Figure 2C, the dimensions and configuration of the air channel 246 may be configured to facilitate the passage of air from the internal air chamber 241 to the 230 / 147 passage only when a specific pressure difference is present. For example, some implementations may include an air channel 246 having very small dimensions and a configuration that promotes a greater surface tension of any liquid placed within the air channel 246. Certain contours of either or both of the outer mating surface 224 and the circumferential lip 244 may further promote the increase in the surface tension of the liquid in the air channel 246 to facilitate air communication (and the formation of microbubbles accordingly) in certain scenarios. Surface treatments (e.g., hydrophobic or hydrophilic coatings) on either or both of the outer mating surface 224 and the circumferential lip 244 may be applied to further control the communication of air or other gases from the internal air chamber 241 to the 230-147 passage.

[0066] In some implementations, a vent (not shown) may be provided between the internal air chamber 141 and the outside of the aerator 133 to allow more air to be drawn into the fluid than would otherwise be possible. In other implementations, a port or valve (not shown) may be provided to facilitate connection of an outside air supply for a similar purpose. In yet another implementation, a valve (e.g., a pressure reducing valve; not shown) may be provided to allow the fluid to be discharged from the air chamber 241 and replaced with air again, for example, to facilitate equilibrium with back pressure, and to allow the microbubble generator 100 to "recharge" its ability to generate microbubbles.

[0067] Figure 2E shows a cross-sectional perspective view of an exemplary configuration 260 of a single converging nozzle 263 and aerator 266, and Figure 2F shows a longitudinal cross-sectional view of the same device 260. As shown in this configuration, the converging nozzle 263 and aerator 266 are manufactured (e.g., co-molded) as a single component rather than as two separate components. In such a configuration, it may be possible to precisely configure the dimensions of one or more air channels 268, as well as their alignment with respect to a fluid flow that travels through a section 270 (e.g., a "venturi section") having a progressively decreasing diameter from an internal channel 269, exiting the outlet 271 and entering the inlet 273 of the aerator 266, and passing through the discharge channel 275.

[0068] As shown, the exemplary apparatus 260 includes a housing 278 surrounding a single converging nozzle 263 and an aerator 266. In some implementations, as shown, the housing 278 can be sealed to the converging nozzle 263 and aerator 266 by O-rings 281A and 281B. In such implementations, an air chamber 283 is formed (for example, by the inner surface 284 of the housing 278 and the outer surface 285 of the integral component including the converging nozzle 263 and aerator 266). Once the O-rings 281A and 281B form an airtight and liquidtight seal (of the air chamber 283, isolating it from areas outside the housing 278 and from the inflow or outflow of gas or liquid through any path other than through one or more air channels), air (or other gas) within the air chamber 283 can be drawn into the liquid flow passing through the apparatus 260 in the form of microbubbles.

[0069] In several implementations, the exemplary device 260 can be operated to produce microbubbles even in the presence of a non-negligible back pressure in the discharge channel 275. Specifically, in the presence of back pressure in the discharge channel 275 (with a robust seal provided by O-rings 281A and 281B), fluid can pass through the internal channel 269, section 270, to the discharge channel 275. However, the amount of fluid that may flow out of the discharge channel 275 (e.g., into a needle system associated with a therapeutic or diagnostic procedure or downstream of a vein) before the pressure between the device 260 and the back pressure becomes equal is not significant. That is, the fluid may first flow into the air chamber 283 through the air channel 268 rather than flowing out of the discharge channel 275. Such fluid may displace the air in the air chamber 283, causing an increase in the pressure within the air chamber 283.

[0070] Once this air pressure rises to the level of back pressure, the fluid can then flow through the device 260 and out of the discharge channel 275 into a patient connected to a diagnostic or therapeutic system (not shown). During this operating phase, the pressure in the air chamber 283 is approximately equal to the back pressure found in the discharge channel 275, and some of the air from the air chamber 283 is drawn into the fluid flow in the form of microbubbles via a suction effect caused by a pressure drop in the fluid flow itself, resulting from the increased velocity of the fluid flow through the Venturi section 270.

[0071] Over time, the suction of air into the fluid flow may again reduce the pressure in the air chamber 283 to below the back pressure observed in the discharge channel 275. At this point, some additional fluid may enter the air chamber 283 and replace the air again, increasing the pressure in the air chamber 283. Once equilibrium is re-established or nearly re-established (for example, by a small percentage, taking into account the dynamic properties of the system, fluid turbulence, dynamic changes in back pressure, fluid velocity changes, etc.), air may again be drawn into the fluid flow in the form of microbubbles.

[0072] In some implementations, a one-way pressure reducing valve (not shown) may be provided between the air chamber 283 and the outside of the housing 278 to allow periodic discharge of fluid from the air chamber 283. By allowing some fluid to be discharged from the air chamber 283, in some implementations, air can be continuously used for suction into the fluid flow. In such implementations, as long as fluid is supplied entering through the internal channel 269, microbubbles can be produced and delivered from the discharge channel 275.

[0073] In the configurations shown in Figures 2E and 2F, the dimensions, morphology, 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 discharge channel 275 may be configured to facilitate the creation of microbubbles having a specific average size or size range (e.g., average diameter less than 2 μm, average diameter between approximately 5 μm and approximately 10 μm, average diameter of approximately 40 μm or less, average diameter of approximately 100 μm or less). In such configurations, dimensions, morphology, or surface treatments may be applied to produce turbulent or laminar flow regions that trap or draw in air in a specific manner. In other configurations, specific dimensions, morphology, or surface treatments may be applied to create microbubbles with surface tension or charge that minimizes the accretion of microbubbles after generation.

[0074] The overall operation of an exemplary microbubble generator 300 will be described here with reference to Figures 3A, 3B, and 3C in one implementation configuration. As shown in Figure 3A, the microbubble generator 300 includes a syringe 303, a converging nozzle 315, and an aerator 333, which may be pre-filled with saline solution. That is, saline solution (or another suitable solution) may be pre-filled into the interior 302 of the barrel 306 of the syringe section 303. To maintain the sterility of the saline solution and to prevent fluid from entering the internal chamber 341 of the aerator section 333, a sealing pin 353 may be provided to seal the saline solution in the syringe 303, seal the throat 330 and internal channel 327 of the converging nozzle 315, and isolate the channel 327 from the internal chamber 341. During operation, such a pin 353 may be removed immediately before use of the microbubble generator 300.

[0075] The pin 353 may be made of a corrosion-resistant metal or a resilient elastic material that seals the throat 330 and the tip of the discharge channel 347. The pin 353 may be adhesively sealed to the discharge end 339 of the aerator, and some twisting or pulling force may be required by the user to remove the pin 353 before use of the microbubble generator 300. Such an adhesive seal may further protect the sterility of the microbubble generator 300, particularly at the discharge end 339.

[0076] In some implementations, the pin 353 may be replaced by an internal membrane (not shown) that holds saline solution (or other biocompatible fluid) within the interior 302 of the syringe, or within the interior 302 of the syringe and the throat 330 of the converging nozzle 315. In such implementations, it may be necessary for the user to push down the plunger 309 to generate sufficient internal pressure to overcome the retaining force of such a membrane. In some implementations (for example, in implementations where the components are provided separately), the internal membrane (not shown) may be configured to break when the converging nozzle 315 is attached to the syringe 303.

[0077] However, the contents of the syringe can be sealed before use, and the proper seal can be released, and the plunger 309 can be slightly pushed down to flush out the microbubble generator 300, as shown in Figure 3B. In some examples, this may be done before the discharge end 339 is connected to the IV tube 356 or to another connection that may be made in a system used to diagnose or treat a patient (e.g., a needle, catheter, or other device placed in the patient (not shown)). In other examples, the discharge end 339 may be connected to the IV tube 356 first so that the tube can also be flushed out during this initial process.

[0078] Figure 3C illustrates the process by which the microbubble generator 300 can generate microbubbles in one implementation configuration. In particular, after the necessary seals are removed, the microbubble generator 300 is flushed out and connected to a downstream IV system 356 associated with a patient undergoing a diagnostic or therapeutic procedure, the plunger 309 can be further pushed down to push the fluid from the interior 302 of the syringe 303 into the internal channel 327. In the internal channel 327, the fluid pressure is relatively high and its velocity is relatively low (proportional to the speed at which the plunger is pushed). As the diameter of the throat 230 gradually decreases, the fluid velocity increases there, and the fluid pressure decreases (via the Venturi effect). This low pressure of the fluid in the throat 330 draws air from the throat 330 into the discharge channel 347, specifically into a fluid path moving from the internal chamber 341 through one or more air channels 346, thereby forming microbubbles.

[0079] In some implementation configurations, the form, dimensions, and / or surface treatment of the material forming the air channel 346 correlate with the microbubble size. Therefore, in such implementation configurations, microbubbles of different sizes and characteristics can be created by the configuration of the converging nozzle 315 and the aerator 333. In some implementation configurations, microbubbles with a diameter of approximately 5 μm can be created; in other configurations, microbubbles with a diameter of approximately 10 μm or less can be created; in other configurations, microbubbles with a diameter of approximately 1 to 2 μm or less can be created; in other configurations, microbubbles with a diameter of approximately 40 μm can be created; and in other configurations, microbubbles up to approximately 100 μm in diameter can be created.

[0080] Microbubbles of different sizes may serve different purposes in diagnostic or therapeutic procedures. For example, in certain cardiac diagnostic procedures, it may be advantageous to create microbubbles with an average diameter of approximately 5 μm to 10 μm. As used herein, "approximately," "about," or "about" means within 1%, 5%, 10%, 20%, or 50% of the nominal value, and "average" may mean a significant number (e.g., 25%, 50%, 75%, 80%, 85%, 90%, 95%) of microbubbles have this diameter, or in some implementations, have a diameter that is 1 standard deviation of or within the specified diameter. In another embodiment, it may be advantageous to create microbubbles with a smaller diameter (e.g., 1-2 μm or less) when diagnosing a particular lung condition. In some implementations, microbubble size may correlate with the cohesive properties of the microbubbles. For example, the surface tension and charge of microbubbles of a certain size (in a particular solution or in blood) can inhibit their coalescence, and minimizing such coalescence of microbubbles may be advantageous (for example, to minimize the risk of air embolism).

[0081] In some implementations, it may be advantageous to generate microbubbles of various sizes. For example, in a procedure to diagnose the presence of a defect in the septum of a patient's heart, it may be advantageous to first search for the defect with smaller microbubbles, and then move on to larger microbubbles to determine whether a closure procedure should be performed. To facilitate procedures where applying microbubbles of various sizes may be advantageous, multiple microbubble generators may be used, and in some implementations, they may be pre-connected together.

[0082] Figure 4 shows an exemplary microbubble generation system 400 with multiple microbubble generators 401A, 401B, and 401C applied. As shown, each microbubble generator 401A, 401B, and 401C may be connected to a manifold 461 by corresponding fluid lines 456A, 456B, and 456C. The manifold may include multi-directional valves 464A, 464B, and 464C that connect or isolate each fluid line to or from the main line 465 of the manifold 461, and the main line 465 of the manifold 461 may be connected to an IV line 458 associated with a patient undergoing diagnostic or therapeutic treatment. In this way, individual microbubble generators 401A, 401B, and 401C can be alternately connected to the IV line 458 to generate diagnostic or therapeutic microbubbles, or multiple microbubble generators 401A, 401B, and 401C can be connected simultaneously to facilitate the delivery of large volumes of fluid while minimizing valve operation. In some implementations, three-way stopcocks 464A, 464B, and 464C are applied, as shown, to isolate or fluidly connect one, two, or three pathways. In other implementations, different valve arrangements may be applied.

[0083] In several implementations, each microbubble generator 401A, 401B, and 401C may be similarly configured to generate microbubbles of the same size in the microbubble generation system 400. Such an implementation can be applied to generate a larger volume of microbubbles over a longer period than would otherwise be possible with a single microbubble generator. In other implementations, each microbubble generator 401A, 401B, and 401C may be configured to generate microbubbles of different sizes. For example, microbubble generator 401A may be configured to generate microbubbles with a diameter of approximately 5 μm, microbubble generator 401B may be configured to generate microbubbles with a diameter of approximately 1 μm, and microbubble generator 401C may be configured to generate microbubbles with a diameter of approximately 10 μm. In this way, complex diagnostic procedures requiring microbubbles of various sizes can be performed with minimal equipment changes.

[0084] An exemplary manifold 461 may include a port 468 for flushing the manifold and / or the entire system 400. In some implementations, each microbubble generator 401A, 401B, 401C may have an internal membrane for isolating the fluid in the corresponding syringe barrel or syringe barrel / converging nozzle, and each microbubble generator may have a discharge channel, and the manifold itself may be flushed and pre-filled with fluid via port 468 before the procedure is performed.

[0085] In other implementations, the system 400 may be packaged such that the syringe, tubing, and manifold are all pre-filled with fluid, and that at the time of treatment, the main manifold line 465 and the patient's IV tube 458 need to be finally connected. In such implementations, internal membranes may be applied to the individual microbubble generators 401A, 401B, and 401C to prevent fluid from leaking into the air chambers of the aerator components (e.g., the air chamber 441A of aerator 433A).

[0086] An exemplary system 400 is shown, comprising three microbubble generators 401A, 401B, and 401C, but it may also include other numbers of microbubble generators (e.g., two, four, or five). The microbubble generators 401A, 401B, and 401C are shown connected to a manifold 461 by tubes 456A, 456B, and 456C. In some implementations, the system 400 may be provided with various components that are connected together immediately before patient treatment.

[0087] The various implementations described herein can be applied to generate microbubbles for various diagnostic and therapeutic investigations. Many of these investigations relate to the human circulatory system. Therefore, for reference, a brief description of some aspects of the human circulatory system is provided.

[0088] Figure 5 shows a portion of the entire human circulatory system 500. At its core is the heart 502, which consists of arteries extending from the heart and veins returning blood to the heart. Blood returns to the heart 502 from the entire body via the superior vena cava, but the superior vena cava is divided into the superior vena cava 505, which collects blood from the upper body, and the inferior vena cava 508, which collects blood from the lower body. Blood flows towards the right atrium through the superior vena cava 505 and the inferior vena cava 108.

[0089] To facilitate studies introducing microbubbles into the heart and lungs, the bubbles need to be introduced into the venous system, ultimately into the superior vena cava 505 or inferior vena cava 508. Referring to Figure 5, there are several common access points from which microbubbles can be introduced. Common to them is the venous introduction of bubbles through the median cubital vein 530 in the right arm. From here, blood flows through the ulnar cutaneous vein 531, axillary vein 532, subclavian vein 510, and brachiocephalic vein 537 to the superior vena cava 505.

[0090] 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 drains into the inferior vena cava 508. Other routes to the superior vena cava 505 and inferior vena cava 508 are also possible.

[0091] Figure 6A is a cross-sectional perspective view of another exemplary microbubble generator 600. As shown, the exemplary microbubble generator 600 includes a syringe 603 having a barrel 606, a plunger 609, and a syringe tip 612. In some implementations, as shown, the syringe tip 612 includes a Luer locking fitting 613 or other fitting.

[0092] Multiple aerator components 616a, 616b, 616c may be connected to the syringe tip 612, and the housing 619 may circumferentially surround the end of the barrel 606 and the multiple aerator components 616a, 616b, 616c. The housing 619 may have a longitudinal axis 622, which in some implementations is coaxial with the longitudinal axis 623 of the syringe 603 and the longitudinal axis of the aerator components 616a, 616b, 616c.

[0093] The housing 619 has an inner surface 625 and a dispensing tip 628. In some implementations, the housing 619 is configured to fluidically seal to the barrel 606, and the multiple aerator components 616a, 616b, 616c are sealed to each other by the syringe tip 612 and the dispensing tip 628, so that any fluid discharged from the syringe 603 can be discharged (for example, by the user of the syringe 603 pushing down the plunger 609) through the syringe tip 612 and the dispensing tip 628 into the respective internal channels 673 (see Figure 6F) of the aerator components 616a, 616b, 616c. A circumferential gas pocket 631 can be created by the inner surface 625, the multiple aerator components 616a, 616b, 616c, the syringe tip 612, and the dispensing tip 628. In some implementations, the circumferential gas pocket 631 comprises at least approximately 10% of the volume of the corresponding syringe barrel 606; in other implementations, the circumferential gas pocket 631 comprises approximately 30-35% of the volume of the corresponding syringe barrel 606 (for example, 3-3.5 mL for a 10 mL syringe); and in yet another implementation, the circumferential gas pocket 631 comprises 50% or more of the volume of the corresponding syringe barrel 606.

[0094] Regardless of the exact volume of the circumferential gas pocket 631 relative to the volume of the syringe barrel 606, one advantage is that this overall volume of the circumferential gas pocket 631 can be precisely controlled to a fail-safe value. Specifically, in medical applications such as those described herein, this exact value can be set to a level that prevents harm to the patient even if all the gas or air in the circumferential gas pocket 631 is injected directly into the patient (e.g., through some device malfunction). Such safety characteristics inherent in the design of the implementations described herein may not be present in other implementations (e.g., current standard therapeutic implementations such as those described in Example 16 below), in which the amount of air or gas mixed with the biocompatible fluid can only be controlled by the specific clinician performing the corresponding procedure (in implementations other than those described herein, significant variation may occur between one clinician and another).

[0095] Figure 6B is a perspective view of an aerator component 616b that may be included in the exemplary microbubble generator 600 of Figure 6A. As shown, the aerator component 616b has an outer casing 630 that is cylindrical in some implementations and characterized by a longitudinal axis 624. One or more alignment tabs, such as alignment tabs 632, may protrude from the outer casing 630, and such alignment tabs 632 may be configured to align with one or more alignment grooves 633 of the housing 619 (see Figure 6A), so that when the aerator components 616a, 616b, 616c are integrally connected to the housing 619, the one or more alignment tabs 632 and the one or more alignment grooves 633 may cooperate to radially fix the housing and each of the aerator components to each other.

[0096] As shown above, when placed within the microbubble generator 600, the longitudinal axis 624 of the aerator component 616b may be aligned coaxially with the longitudinal axis 622 of the housing 619 and the longitudinal axis 623 of the syringe 603. The aerator component 616b has an inlet end 634 and an outlet end 637. As will be described in more detail with reference to Figures 6D and 6E, the aerator component 616b may also include a tapered output port 640 and a lateral vent hole 643.

[0097] Figure 6C is a cross-sectional perspective view of the aerator component 616b, Figure 6D is a side view of the aerator component 616b, and Figure 6E is a side cross-sectional view of the aerator component 616b. As shown in Figure 6D, the tapered output port 640 may have a diameter 646 smaller than the diameter 649 of the outer casing 630, and a taper 652 that narrows the diameter 646 from its starting point to its distal end in the outer casing 630.

[0098] Referring to Figure 6E, in the shown implementation, the aerator component 616b includes an internal cavity 655 having four separate sections: an input port section 658, an inlet section 661, a throat section 664, and an outlet section 667. The input port section 658 is configured to receive a tapered output port of another aerator component (e.g., the tapered output port 640 of aerator component 616b) or a syringe tip 612, i.e., the input port section 658 may have a diameter 670 that is slightly larger than the diameter 646 of the tapered output port 640, and the diameter 670 may decrease from the outside to the inside of the input port section 658, corresponding to the taper 652 of the tapered output port 640.

[0099] As shown, the inlet section 661 has a progressively decreasing diameter that restricts the flow of gas or liquid through the aerator component 616b so that the gas or liquid flows from the input port section 658 to the subsequent throat section 664. As described above with respect to other implementations, this flow constriction increases the corresponding velocity of the gas or liquid and decreases its pressure. This pressure reduction allows the gas or liquid in the circumferential air pocket 631 (see Figure 6A) to be drawn into the flow in the throat section 664 through the lateral vent hole 643. In some implementations, the progressively decreasing diameter ranges from about 3.5 mm to about 0.5 mm.

[0100] In some implementations, as shown, the exit section 667 is followed by the throat section 664. In the exit section 667, the diameter of the internal cavity 655 increases from the throat section 664 toward the tapered output port 640. In some implementations, the increasing diameter of the exit section 667 is in the range of approximately 0.5 mm to 3.5 mm, and more preferably, the diameter may be in the range of approximately 0.65 mm to 2.1 mm.

[0101] In some implementations, the boundary between the inlet section 661 and the throat section 664 may be rounded and / or smooth (for example, to minimize turbulence). In some implementations, the throat section 664 may have a slight taper (for example, to facilitate a clean molding process). In some implementations, the boundary between the throat section 664 and the outlet section 667 may be rounded and / or smooth (for example, to minimize turbulence). In some implementations, various surfaces and boundaries may be roughened, or edges may be sharp rather than rounded or smooth (for example, to increase turbulence).

[0102] Figure 6F is a cross-sectional perspective view of aerator components 616a, 616b, and 616c of a plurality of aerator components 616 that may be integrally connected and included in an exemplary microbubble generator 600. As shown, each component 616a, 616b, and 616c are tightly connected to the adjacent components 616a, 616b, and 616c such that a channel 673 is formed from the input port section of aerator component 616a to the outlet section of aerator component 616c. In some implementations, the channel 673 may be fluidly tight from end to end, except for the lateral vent holes in each aerator component 616a, 616b, and 616c, i.e., each aerator component may be tightly sealed to the adjacent component so that fluid (e.g., liquid or gas) does not leak out of the channel 673 at the overlapping portion between the tapered output port of one aerator component and the input port section of another aerator component.

[0103] As shown in Figure 6F, there may be some variation in the diameters of the throat sections 664a, 664b, and 664c in the multiple aerator components 616. That is, the diameter of throat section 664c of aerator component 616c may be larger than the diameter of throat section 664b, and the diameter of throat section 664b may be larger than the diameter of throat section 664a. Similarly, there may be variation in the diameters of the lateral vent holes 643a, 643b, and 643c. In some implementation configurations, the diameters of throat sections 664a, 664b, and 664c may range from 0.4 mm or less to 2.0 mm or more. For example, one implementation may include aerator components with diameters of 0.45 mm, 2 mm, and 2 mm; another implementation may include aerator components with diameters of 0.45 mm, 1 mm, and 2 mm; and yet another implementation may include aerator components with diameters of 1 mm, 1 mm, and 2 mm. In some implementations, it may be advantageous to arrange the aerators so that the diameter increases from the proximal end (e.g., syringe end) to the distal end, while in other implementations, a different arrangement may be advantageous.

[0104] In some mounting configurations, the diameters of the lateral vent holes 643a, 643b, and 643c may range from 0.3 mm or less to 1.0 mm or more. For example, in some mounting configurations, the nearest vent hole 643a may be approximately 1.0 mm and the farthest vent hole 643c may be approximately 0.6 mm, while in other mounting configurations, the nearest vent hole 643a may be approximately 0.3 mm and the farthest vent hole 643c may be approximately 0.6 mm.

[0105] Figure 6G is a cross-sectional perspective view of an exemplary microbubble generator 600, including a cap 676 and a sealing pin 679. In some implementations, as shown, the cap 676 is screwed onto the discharge tip 628 to engage with a Luer locking fitting 680 or other threaded fitting. The cap 676 may also include a sealing pin 679, which in some implementations is configured to seal the smallest diameter throat section (e.g., the throat section 664a shown). In such implementations, the cap 676 may also seal the channel 673 and the circumferential gas pocket 631 (through a lateral vent hole (not visible in Figure 6G)), and the sealing pin may seal the throat 664a to seal the inlet section 661a of the aerator 616a and everything fluidically connected thereto (e.g., the syringe tip 612 and the inside of the barrel 606). In these configurations, the cap 676 and sealing pin 679 maintain the sterility of the contents of the syringe 603 and prevent the liquid or gas inside the syringe 603 from leaking into the circumferential gas pocket 631 until the cap 676 and sealing pin 679 are removed.

[0106] Figure 7A is a cross-sectional perspective 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 locking fitting 713 having a corresponding thread.

[0107] The aerator 716 may be connected to the syringe tip 712, and the housing 719 may surround the end of the barrel 706 and the aerator 716 in the circumferential direction. The housing 719 may have a longitudinal axis 722, which in some mounting configurations is coaxial with the longitudinal axis 723 of the syringe 703 and the longitudinal axis 724 of the aerator 716.

[0108] As shown, the housing 719 has an inner surface 725 and a dispensing tip 728. In some implementations, the housing 719 may be configured to fluidically seal to the barrel 706, and the aerator 716 may be sealed to the syringe tip 712 and the dispensing tip 728 so that any fluid discharged from the syringe 703 (for example, by the user of the syringe 703 pushing down the plunger 709) passes through the syringe tip 712 and through the dispensing tip 728 to the internal cavity 755 of the aerator 716 (see Figure 7B). A circumferential gas pocket 731 may be created by the inner surface 725, the aerator 716, the syringe tip 712, and the dispensing tip 728.

[0109] Referring to Figure 7B, in the shown implementation, the aerator 716 includes an internal cavity 755 having five distinct sections: an input port section 758, an inlet section 761, a throat section 764, a diffusion section 765, and an outlet section 767. The input port section 758 may be configured to receive a syringe tip 712, i.e., the input port section 758 may have a diameter slightly larger than the diameter of the syringe tip 712, and its diameter may decrease from the outside to the inside.

[0110] As shown, the inlet section 761 has a progressively decreasing diameter that restricts the flow of gas or liquid through the aerator 716 so that the gas or liquid flows from the input port section 758 to the subsequent throat section 764. As described above with respect to other implementations, this narrowing of the gas or liquid flow increases its corresponding velocity and decreases its pressure. This pressure reduction makes it possible to draw gas into the flow through the first vent hole 743.

[0111] In some implementations, as shown, a diffusion section 765 having a progressively increasing diameter follows a throat section 764, and an outlet section follows the diffusion section 765, the outlet section 767 of which may have a cylindrical structure. In other implementations, the diffusion section 765 and the outlet section 767 may be a single section whose diameter progressively increases from the throat section 764 to a tapered outlet port 740.

[0112] In some implementations, the second vent 744 may be located in the outlet section 767 (or, in some implementations, in the diffusion section 765), as shown. During operation, the first vent 743 and the second vent 744 may cooperate to increase the efficiency of the fluid moving through the throat section 764 in drawing gas from the circumferential gas pocket 731 (see Figure 7A) through the first vent hole 743. For example, in some implementations, the initial amount of fluid passing through the internal cavity 755 may displace air or other gases within the internal cavity 755 primarily through the second vent hole 744 rather than through the first vent hole 743, thereby (i) pressurizing the circumferential gas pocket 731 more rapidly and drawing the gas within the circumferential gas pocket 731 into the fluid flow moving through the internal cavity 755, and (ii) minimizing the movement of gas from the circumferential gas pocket 731 to the internal cavity 755 simultaneously with the movement of a certain amount of liquid from the internal cavity 755 to the circumferential gas pocket 731, that is, the simultaneous movement of liquid in one direction and gas in the opposite direction through the same first vent hole 743 may create turbulence, resulting in the drawing in or formation of larger air bubbles in implementations including the second vent hole 744 than in other cases.

[0113] In some implementations, the second vent hole 744 is larger than the first vent hole 743. In such implementations, this size difference, combined with the pressure difference of the gas, liquid, or combination thereof in the throat section 764 relative to the outlet section 767, can result in both the liquid itself and the gas initially displaced from the internal cavity 755 flowing from the internal cavity 755 into the circumferential gas pocket 731 primarily through the second vent hole 744 (for example, so that an initial amount of fluid flows through the internal cavity 755).

[0114] Regardless of the mechanism of action for any specific implementation, the applicant has surprisingly found that a single aerator 716 having both a first vent hole 743 and a second vent hole 744 (for example, within the outlet section 767 or within the diffusion section 765 as shown) exhibits significantly better performance than a single aerator 716 having only a single vent hole 743.

[0115] In this context, "performance" can be quantified in the following respects: (i) a significant number of very small bubbles (e.g., bubbles with an average diameter of about 300 μm or less, or about 250 μm or less, or about 200 μm or less, or about 100 μm or less, or more preferably about 50 μm or less, or even more preferably about 20 μm or less, or about 10 μm or less, or about 2 μm or less, where in some implementations it may be advantageous to produce bubbles at the upper end of the specified range examples (e.g., more echogenic), while in other implementations it may be advantageous to produce bubbles at the upper end of the specified range examples) It should be noted that producing bubbles within the lower limit of the range of examples may be advantageous (for example, to more accurately outline internal anatomical features under ultrasound); and / or (ii) a substantially non-uniform size distribution of the produced bubbles (e.g., 50% or more of bubbles within a standard deviation of 1 of the mean bubble size, or 95% of bubbles within a standard deviation of 1 or 2 of the mean bubble size, or 99% of bubbles within a standard deviation of 1, 2, or 3 of the mean bubble size); and / or (iii) the production of larger bubbles (e.g., bubbles with a diameter greater than approximately 100 μm, or greater than approximately 200 μm, or greater than approximately 250 μm, or greater than approximately 300 μm) is substantially zero (or very minimal).

[0116] In some implementations, the boundary between the inlet section 761 and the throat section 764 may be rounded and / or smooth (for example, to minimize turbulence). Similarly, the boundary between the throat section 764 and the diffusion section 765, or the boundary between the diffusion section 765 and the outlet section 767, may be rounded and / or smooth (for example, to minimize turbulence). In some implementations, the throat section 764 may have a slight taper (for example, to facilitate a clean molding process). In some implementations, various surfaces and boundaries may be roughened, or the edges may be sharp rather than rounded or smooth (for example, to increase turbulence).

[0117] Figure 8A is a perspective view of an exemplary aerator component 816. In some implementations, the aerator component 816 may be replaced with the aerator component 716 shown in Figure 7A. As shown, the aerator component includes a thread 814 that can be directly matched with the mating threads of the corresponding syringe component (e.g., the threads of the Luer locking fitting 713 shown in Figure 7A). In such implementations, the thread 814 can facilitate a secure and direct connection between the aerator component 816 and the corresponding syringe (e.g., without relying on a housing component to facilitate this connection).

[0118] As shown, the aerator component 816 has an outer casing 830, which in some configurations is cylindrical and characterized by a longitudinal axis 824. In other configurations, the outer casing 830 may have other shapes (e.g., rectangle, cube, triangle, etc.). One or more alignment tabs, such as an alignment tab 832, may protrude from the outer casing 830, and such an alignment tab 832 may be configured to align with one or more alignment grooves of the corresponding housing (e.g., alignment groove 633 of housing 619 shown in Figure 6A), so that when the aerator 816 and the corresponding housing are integrally connected, the alignment tab 832 and the corresponding alignment grooves may cooperate to radially fix the housing and the aerator component 816 together. When connected in this manner, the longitudinal axis 824 may be aligned coaxially with the longitudinal axis of the corresponding housing and syringe.

[0119] Referring to Figure 8B, in the shown implementation, the aerator 816 includes an internal cavity 855 having five separate sections, each fluidly connected to its neighbor to form a flow path 873 through the interior of the aerator 816. The five separate sections shown include an input port section 858, an inlet section 861, a throat section 864, a diffusion section 865, and an outlet section 867. The input port section 858 may be configured to receive a syringe tip (as input port 758 in Figure 7B), and as noted, a thread 814 may be provided for securing the aerator 816 to the syringe tip. The input port section 858 may have a diameter slightly larger than the outer diameter of the syringe tip, and the diameter of the input port section 858 may decrease from the outside to the inside of the input port section 858 so that the input port section seals against the end of the corresponding syringe tip.

[0120] As shown, the inlet section 861 has a progressively decreasing diameter that restricts the flow of gas or liquid through the aerator 816 so that the gas or liquid flows from the input port section 858 into the subsequent throat section 864. As described above with respect to other implementations, this narrowing of the gas or liquid flow can increase its corresponding velocity and decrease its pressure, allowing the gas to be drawn into or near the throat section 864 through the vent hole 843.

[0121] In the implementation shown, the vent hole 843 is located not in the throat section 864 itself, but in the subsequent diffusion section 865, just outside the throat section 864. As shown, the diffusion section follows the throat section 864 with a progressively increasing diameter, and the outlet section 867 follows the diffusion section 865. In other implementations, the diffusion section 865 and the outlet section 867 may be a single section whose diameter progressively increases from the throat section 864 to the outlet port 840.

[0122] Although the vent hole 843 is not located in the throat section 864 itself, as in other implementations shown and described herein, the vent hole 843 is located close enough to the throat section 864 that the pressure of the gas or liquid flowing through the aerator 816 along the path 873 is lower at the location of the vent hole 843 than at other parts along the path 873, and this lower pressure allows the gas to be drawn through the vent hole 843 into the fluid flow along the path 873.

[0123] The placement of the vent hole 843 in the diffusion section 865, just outside the throat section 843, rather than within the throat section 834, can have certain advantages. For example, such an arrangement can facilitate sealing between the sealing pin (such as the sealing pin 679 shown in Figure 6G) and the vent hole 843, and at the same time, it can be manufactured to be larger and more robust than would otherwise be possible if such a sealing pin were required to be housed in the throat section 864. In some implementations, this can simplify the manufacturing process, improve the yield of sealing pins, and minimize the risk that broken pieces of the sealing pin inside the aerator 816 could be introduced into the fluid flow that is ultimately injected into the patient. Figure 8C shows an exemplary sealing pin 879 and how it may be housed in the outlet section 867 and the diffusion section 865.

[0124] Returning to Figure 8A, several implementations may include a second vent 844. In the shown implementations, the second vent 844 is located at the distal end of the aerator component 816, at the outlet port 840. The second vent 844 may be formed as a notch in the wall of the outlet port 840, and the vent 844 may be fluidly connected to an area adjacent to the casing 830 via one or more grooves in the casing 830, such as groove 845, when the aerator component 816 is positioned in the corresponding housing (for example, when the aerator component 816 is positioned in the corresponding housing, as shown in the implementations in Figures 6A and 7A). In some implementations, the implementation of groove 845 forming the second vent 844 may simplify the manufacturing process compared to other methods of forming the vent 844. For example, groove 845 may simplify the mold and molding process, and in some implementations, may eliminate the need for separate pins in the mold to form the vent. In some implementations, a similar approach (e.g., groove instead of hole) may be applied to the vent hole 843.

[0125] In some implementations, the groove 845 at the outlet port 840 may offer other advantages. For example, if the device 700 is positioned vertically in a procedure with the outlet port 840 facing downwards, the groove 845 is located at the lowest point of the adjacent gas pocket 731. When the fluid in the syringe 703 is almost completely released, the pressurized air or gas remaining in the gas pocket 731 may release the last drop of fluid before the pressure between the gas pocket 731 and the path 873 becomes equal, so that no (or very few) bubbles are introduced into the final fluid exiting the outlet port 840. This may be advantageous because otherwise, the bubbles produced in the fluid when the last drop of fluid is released could be significantly larger than those created at the vent hole 843. Similar advantages may also arise from a second vent 744 located very close to the outlet port 740.

[0126] Regardless of their exact structure, the vents 843, 844 can cooperate to enhance the efficiency of the fluid moving along the path 873 in drawing gas through the vent holes 843 from circumferential gas pockets (such as the gas pocket 731 shown in Figure 7A). For example, in some implementations, the initial amount of fluid passing through the internal cavity 855 may displace air or other gases within the internal cavity 855 primarily through the second vent hole 844 rather than through the vent hole 843, thereby (i) enabling more rapid pressurization of the corresponding circumferential gas pocket to draw the gas within the circumferential gas pocket into the fluid flow moving through the internal cavity 855, and (ii) minimizing the movement of gas from the circumferential gas pocket to the internal cavity 855 simultaneously with the movement of a certain amount of liquid from the internal cavity 855 to the circumferential gas pocket. In other words, the simultaneous movement of liquid in one direction and gas in the opposite direction through the same vent hole 843 creates turbulence, which may result in the drawing in or formation of larger air or other gas bubbles in implementations including the second vent hole 844 than would otherwise occur.

[0127] In some implementations, the second vent hole 844 is larger than the vent hole 843. In such implementations, this size difference can result in both the liquid itself and the gas initially displaced from the internal cavity 855 flowing from the internal cavity 855 into the circumferential gas pocket primarily through the second vent hole 844 (for example, so that an initial amount of fluid flows through the internal cavity 855), in conjunction with the pressure difference of the gas, liquid, or combination thereof in the throat section 864 and the diffusion section 865, respectively, relative to the outlet section 867.

[0128] In some implementation configurations, materials for one or more components of the exemplary implementation configurations described herein may be selected based on (a) suitability for use in human patients (i.e., suitability for contact with biocompatible solutions injected into human patients), (b) solid surface energy (SFE) (e.g., of various components), and (c) interfacial tension (e.g., of biocompatible solutions). The various components described herein may further be selected from materials commonly used in the construction of medical devices. Such materials may be selected because they are widely accepted in the medical device field and / or because of their sterility or inherent sterility and / or antimicrobial or antimicrobial properties.

[0129] With respect to SFE, the material used (for example, in particular for aerators or aerator components such as aerator components 616a, 616b, 616c in Figures 6A to 6G, aerator 716 in Figure 7A, or aerator 816 in Figure 8A) may be selected from thermoplastics or other materials that are injection moldable and accepted 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.

[0130] More preferably, in some implementation configurations, the materials used may be further selected based on the material's SFE (Surface-to-Energy Fit). For example, in some implementations, it may be advantageous to have a material with an SFE (Surface Filtration Efficiency) greater than approximately 30 millinewtons / meter ("mN / m") (sometimes expressed as dynes / cm, where 1 mN / m = 1 dyne / cm), in such implementations, PVC (SFE approximately 35 mN / m in some implementations), ABS (SFE approximately 35 mN / m in some implementations), acetal (SFE approximately 36 mN / m in some implementations), PMMA (SFE approximately 41 mN / m in some implementations), polycarbonate (SFE approximately 46 mN / m in some implementations), or PETG (SFE approximately 47 mN / m in some implementations) may be preferred over polypropylene (SFE approximately 30 mN / m in some implementations) or polyethylene (SFE approximately 30 mN / m in some implementations). In other implementations, it may be advantageous to have a material with an SFE greater than approximately 35 mN / m. Furthermore, in other implementation configurations, it may be advantageous to have a material with an SFE exceeding approximately 40 mN / m, in which case PMMA, polycarbonate, or PETG may be used.

[0131] In some implementations, materials may be treated to increase, decrease, or otherwise control their SFE (for example, the surface may be roughened to increase its surface energy, chemically treated, coated with another material, or subjected to plasma treatment or plasma activation). In many implementations, the practical effect of the intrinsic or treated SFE on wettability may be more important than the actual RMS value of the SFE; that is, in certain implementations, wettability (and specifically, high-wettability materials rather than low-wettability materials) may be more important than the specific SFE value.

[0132] In some implementations, the biocompatible solution contains a surfactant that reduces the interfacial tension of the solution, or the biocompatible solution has inherently lower interfacial tension compared to other biocompatible solutions. For example, in some implementations, the biocompatible solution is glucose (e.g., D5W, D10W, or D50). In another example, in some implementations, the biocompatible solution contains a surfactant such as polysorbate (e.g., saline solution containing 0.001% polysorbate, saline solution containing 0.005% polysorbate, saline solution containing 0.01% polysorbate, saline solution containing 0.1% polysorbate, saline solution containing 1% polysorbate, saline solution containing 10% polysorbate, etc.). Other implementations may use other biocompatible surfactants (for example, nonionic, anionic, cationic, and amphoteric surfactants in general, including, in particular, propanediol, polyethylene glycol, lecithin, poloxamer, glycerin, hypertonic saline, hydrophobic hydrocarbon chains with hydrophilic heads, casein, certain proteins, etc.).

[0133] Regarding the microbubble production capability in a tabletop setup, various implementation configurations were tested, and images were captured from each test. These images are shown as Figures 9A-9C, 10A-10C, 11A-11C, 12A-12C, and 13A-13C. Each test used an apparatus such as one of the devices shown in Figure 6A, 7A, or 8A, which were described with reference to these drawings. Each apparatus included a syringe body and plunger, a housing, and one or more aerator components within the housing, and further included a 20-gauge needle positioned at the end of the housing. In each test, approximately 10 mL of biocompatible solution was filled into the syringe components, and the apparatus was pointed at a needle placed in a beaker of tap water. Approximately 3-3.5 mL of room air was sealed in the circumferential air pocket of the housing. A black background was placed behind the beaker, and lighting was placed on the side to illuminate the microbubbles formed by the apparatus.

[0134] In each test, the syringe was filled and positioned, and the plunger was manually pushed down with approximately constant force / speed to push the biocompatible solution through the aerator components and needle into a beaker of tap water. The plunger was continued until the biocompatible solution was approximately released from the syringe.

[0135] Figures 9A–9C, 10A–10C, 12A–12C, and 13A–13C each contain four panels. In these drawings, the leftmost panel corresponds to approximately 0.5 seconds after the plunger is first pressed down, the center-left panel corresponds to approximately 2.5 seconds after the plunger is first pressed down, the center-right panel corresponds to approximately 6.0 seconds after the plunger is first pressed down, and the rightmost panel corresponds to the point when the biocompatible solution has been almost released. Figures 11A–11C contain three panels because, in the corresponding embodiment, the biocompatible solution was released from the syringe more rapidly than in the other embodiments, resulting in a total time of less than 6.0 seconds from the initial pressing down of the plunger. In Figures 11A to 11C, the left and center panels are the same as those in Figures 9A to 9C, 10A to 10C, 12A to 12C, and 13A to 13C, meaning these panels correspond to approximately 0.5 seconds and 2.5 seconds after the plunger is first pushed down, respectively, while the right panel corresponds to the point in time when the biocompatible solution has been released (before 6.0 seconds).

[0136] Here, we will describe each test ("Examples") and its results in detail. In the following descriptions, subjective descriptions of bubble size are given (e.g., "microbubbles," "very small" bubbles, "small" bubbles, "medium-sized" bubbles, and "large" bubbles), but these qualitative descriptions are provided to facilitate qualitative comparisons. In some implementations, "large" bubbles may have a diameter of 1 mm or more (e.g., 1 mm, 2 mm, 3 mm, 5 mm, etc.), "medium-sized" bubbles may have a diameter in the range of approximately 0.5 mm to approximately 1 mm, "small" bubbles may have a diameter in the range of approximately 0.1 mm (100 μm) to approximately 0.5 mm, "very small" bubbles may have a diameter in the range of approximately 10 μm to approximately 100 μm, and "microbubbles" may have a diameter in the range of approximately 1 μm to approximately 10 μm. In other implementations, different ranges may apply. For example, in some implementations, "microbubbles" may have a diameter of less than 1 μm (which may include what could be called "nanobubbles"), in another embodiment, "microbubbles" may include bubbles with a diameter of about 1 μm to about 25 μm, and in yet another embodiment, "very small" bubbles may have a diameter ranging from 2 μm to about 50 μm. Many specific ranges are possible, and as stated, the main point of mentioning bubble size is for qualitative comparison. Example 1 (Multi-stage, polypropylene, physiological saline solution)

[0137] In Example 1, shown in Figure 9A, an apparatus having multiple aerator components, each made of polypropylene (for example, the exemplary microbubble generator 600 shown in Figure 6), was applied, and a syringe was filled with saline solution. As captured in the leftmost panel, the initial discharge of saline solution produced a minimal amount of small to medium-sized bubbles. Bubble production remained intermittent and minimal as the saline solution was released from the syringe (note that some small to medium-sized bubbles are visible in the solution in the center left and center right panels). After approximately 8.5 seconds (see the rightmost panel), as the saline solution was almost completely discharged, a significant amount of large bubbles were produced. Example 2 (Multi-stage, polypropylene, glucose)

[0138] In Example 2, shown in Figure 9B, an apparatus having multiple aerator components, each made of polypropylene, was applied, and a syringe was filled with D50 glucose (e.g., a solution containing 50% glucose). As captured in the leftmost panel, the initial discharge of glucose produced a minimum amount of small to medium-sized bubbles. Bubble production was more continuous with glucose than with pure saline, and more small bubbles were produced (medium-sized bubbles were also produced throughout; see the center left and center right panels). Although more bubbles were produced with glucose than with saline, the overall amount remained relatively small. After about 10 seconds (see the rightmost panel), as the glucose was almost completely discharged, a significant amount of large bubbles were produced. Example 3 (Multi-stage, polypropylene, physiological saline / polysorbate)

[0139] In Example 3, shown in Figure 9C, an apparatus having multiple aerator components, each made of polypropylene, was applied, and a syringe was filled with saline solution to which a small amount (approximately 1 vol%) of polysorbate had been added. As shown in the leftmost panel, the initial discharge of saline solution / polysorbate produced a certain amount of very small bubbles and microbubbles (as shown by the "cloud-like" pattern). After the initial production of very small bubbles, only very small bubbles were produced intermittently, and the production of small and medium-sized bubbles tapered off (see the center left and center right panels). After approximately 9 seconds (see the rightmost panel), as the saline solution / polysorbate was almost completely discharged, a significant amount of larger bubbles were produced. Example 4 (Multi-stage, polycarbonate, physiological saline)

[0140] In Example 4, shown in Figure 10A, an apparatus having multiple aerator components, each made of polycarbonate, was applied, and saline solution was filled into a syringe. As shown in the leftmost panel, the initial discharge of saline solution produced a certain amount of large bubbles. The stable production of large bubbles continued for approximately 2 seconds, followed by a stable but minimal flow of small and medium-sized bubbles (see the center left and center right panels). After approximately 11 seconds (see the rightmost panel), when the saline solution was almost completely discharged, bubble production simply stopped, and no large bubbles were produced at the end, as in the previous example. Example 5 (Multi-stage, polycarbonate, glucose)

[0141] In Example 5, shown in Figure 10B, an apparatus having multiple aerator components, each made of polycarbonate, was applied and D50 glucose was filled into a syringe. As shown in the leftmost panel, the initial discharge of glucose produced a smooth microbubble flow (appearing like a bright cloud). Large bubbles accompanied the microbubbles for the first approximately 2 seconds, after which bubble production slowed slightly (though remained constant throughout; see the center left and center right panels), and the bubble size transitioned mostly to very small bubbles. After approximately 13 seconds (see the rightmost panel), when the glucose was almost completely discharged, bubble production simply stopped, and no large bubbles were produced at the end. Example 6 (Multi-stage, polycarbonate, physiological saline / polysorbate)

[0142] In Example 6, shown in Figure 10C, an apparatus having multiple aerator components, each made of polycarbonate, was applied, and a syringe was filled with saline solution to which a small amount (approximately 1 vol%) of polysorbate had been added. As shown in the leftmost panel, the initial discharge of saline solution / polysorbate produced a smooth microbubble stream (a significant amount compared to other examples) containing a minimum number of small and very small bubbles (virtually no medium or large bubbles were formed). Stable microbubble production continued for approximately 2 seconds, after which the amount of bubbles slightly decreased and the size of the bubbles slightly increased, appearing to become very small (see the center left and center right panels). After approximately 10.5 seconds (see the rightmost panel), as the saline solution / polysorbate was almost discharged, bubble production tapered off, and no large bubbles were produced. Example 7 (Single-stage, polypropylene, physiological saline)

[0143] In Example 7, shown in Figure 11A, a device having a single aerator component made of polypropylene (for example, the exemplary microbubble generator 700 shown in Figure 7) was applied, and saline solution was filled into a syringe. As shown in the leftmost panel, the initial discharge of saline solution produced a certain amount of small, medium, and large bubbles. The production of these bubbles remained constant for about 1 second, after which the bubble production decreased and the bubble size decreased (see the center panel). After about 3.5 seconds (see the right panel), as the saline solution was almost completely discharged, a significant amount of large bubbles were produced. As is evident from the presence of only three panels in Figure 11A (and Figures 11B and 11C), the duration of bubble production in Example 7 (and Examples 8 and 9) was much shorter than in the other examples provided. Example 8 (Single-stage, polypropylene, glucose)

[0144] In Example 8, shown in Figure 11B, an apparatus having a single aerator component made of polypropylene was applied, and D50 glucose was filled into a syringe. As shown in the left panel, the initial discharge of glucose produced a certain amount of small and medium-sized bubbles. The production of these bubbles remained constant for about 1 second, after which the production of bubbles decreased and the size of the bubbles became smaller (see the center panel). After about 4 seconds (see the right panel), as the glucose was almost completely discharged, a significant amount of large bubbles were produced. Example 9 (Single-stage, polypropylene, physiological saline / polysorbate)

[0145] In Example 9, shown in Figure 11C, an apparatus with a single polypropylene aerator component was used, and a syringe was filled with saline solution to which a small amount (approximately 1 vol%) of polysorbate had been added. As shown in the left panel, the initial discharge of saline solution / polysorbate produced a certain amount of microbubbles, with some small and medium-sized bubbles also present. The production of these bubbles remained constant for about 1 second, after which the production of bubbles decreased (see the center panel). After about 4 seconds (see the right panel), as the saline solution / polysorbate was almost completely discharged, a significant amount of large bubbles were produced. Example 10 (Single-stage, polycarbonate, physiological saline)

[0146] In Example 10, shown in Figure 12A, an apparatus having a single polycarbonate aerator component was used, and saline solution was filled into a syringe. As shown in the leftmost panel, the initial discharge of saline solution produced a certain amount of small, medium, and large bubbles. The production of these bubbles remained constant for approximately 4 seconds (see the center left panel), after which bubble production almost ceased (see the center right panel). After approximately 7 seconds (see the rightmost panel), as the saline solution was almost completely discharged, a significant amount of large bubbles were produced. Example 11 (Single-stage, polycarbonate, glucose)

[0147] In Example 11, shown in Figure 12B, an apparatus having a single polycarbonate aerator component was used, and D50 glucose was filled into a syringe. As shown in the leftmost panel, the initial discharge of glucose produced a certain amount of small and very small bubbles, with a small amount of medium and large bubbles also present. The production of small and very small bubbles continued for approximately 3 seconds (see the center left panel), after which bubble production remained constant, albeit tapering slightly, producing small and very small bubbles (see the center right panel). After approximately 7.5 seconds (see the rightmost panel), as the glucose was almost completely discharged, a certain amount of large bubbles were produced. Example 12 (Single-stage, polycarbonate, physiological saline / polysorbate)

[0148] In Example 12, shown in Figure 12C, an apparatus having a single polycarbonate aerator component was used, and a syringe was filled with saline solution to which a small amount (approximately 1 vol%) of polysorbate had been added. As shown in the leftmost panel, the initial discharge of saline solution / polysorbate produced a certain amount of small bubbles, very small bubbles, and microbubbles, with some medium and large bubbles also present. The production of very small bubbles and microbubbles continued for approximately 3 seconds (see the center left panel), after which bubble production was maintained at a constant rate, albeit tapering slightly, producing very small bubbles and microbubbles (see the center right panel). After approximately 7.0 seconds (see the rightmost panel), as the saline solution / polysorbate was almost completely discharged, a certain amount of large bubbles were produced. Example 13 (Single-stage, acetal, physiological saline)

[0149] In Example 13, shown in Figure 13A, an apparatus having a single aerator component made of acetal was applied, and a syringe was filled with saline solution. As shown in the leftmost panel, the initial discharge of saline solution / polysorbate produced a certain amount of large bubbles, including large and medium-sized bubbles, small bubbles, and some very small bubbles. The production of large bubbles continued for approximately 3 seconds (see the center left panel), after which bubble production tapered significantly, producing only a small amount of small and very small bubbles (see the center right panel). After approximately 6.5 seconds, medium-sized bubbles were produced again, and then at approximately 8.0 seconds, as the saline solution was almost discharged, a certain amount of large bubbles were produced. Example 14 (Single-stage, acetal, glucose)

[0150] In Example 14, shown in Figure 13B, an apparatus having a single aerator component made of acetal was applied, and D50 glucose was filled into a syringe. As shown in the leftmost panel, the initial discharge of glucose produced a certain amount of large-sized bubbles, including large, medium, small, and some very small bubbles and microbubbles. The production of large-sized bubbles continued for approximately 3.5 seconds (see the center left panel), after which bubble production tapered off, mainly producing very small bubbles and microbubbles (see the center right panel). After approximately 9.0 seconds, as the glucose was almost completely discharged, a certain amount of large bubbles were produced. Example 15 (Single-stage, acetal, physiological saline / polysorbate)

[0151] In Example 15, shown in Figure 13C, an apparatus with a single aerator component made of acetal was used, and a syringe was filled with saline solution to which a small amount (approximately 1 vol%) of polysorbate had been added. As shown in the leftmost panel, the initial discharge of saline solution / polysorbate produced small bubbles, very small bubbles, and microbubbles. Stable production of bubbles in this range continued for approximately 4.0 seconds (see the center left panel), after which the bubble volume tapered slightly, but the size remained relatively constant (see the center right panel). After approximately 6.5 seconds, as the saline solution / polysorbate was almost completely discharged, a constant amount of larger bubbles were produced. Analysis of Examples 1-15

[0152] As these examples demonstrate, the applicant found that polycarbonate aerators generally performed better than polypropylene aerators in terms of aerator material and bubble formation, specifically in terms of the length of time (and therefore the amount of bubbles) and bubble quality (where "higher quality" corresponds to a distribution that mainly consists of small bubbles, very small bubbles and microbubbles, with medium and large bubbles minimized). In single-stage aerators, acetal appeared to perform comparably to polycarbonate. Regarding the solutions used in the aerators, glucose performed better than saline in all examples, although the difference between glucose and saline was not as pronounced in polypropylene aerators. Saline with a small amount of polysorbate added generally performed better than glucose in all examples, but again, the difference between saline / polysorbate and glucose was not as pronounced in polypropylene aerators. In contrast to single-stage aerators using either glucose or polysorbate, multi-stage aerators using either glucose or polysorbate did not produce large bubbles when the solution was almost completely released from the syringe.

[0153] Surprisingly, the applicant found that combinations of polycarbonate and glucose, or polycarbonate and saline / polysorbate, exhibited significantly superior performance compared to configurations containing saline alone or configurations using polypropylene aerators. For example, Figure 10C is compared with other multi-stage configurations depicted in Figures 9A-9C and 10A-10B, and Figure 12C is compared with other single-stage configurations depicted in Figures 11A-11C and 12A-12B. The applicant found that acetal and saline / polysorbate exhibited similar performance to polycarbonate and saline / polysorbate (see Figures 13C and 12C).

[0154] The applicant determined that the variations in performance in various embodiments were related to (1) the surface energy of the material on which the aerator components are formed (in these examples, polypropylene, polycarbonate, or acetal), that is, more precisely, probably the corresponding level of hydrophobicity or hydrophilicity arising from the said surface energy of the material, and (2) the presence of surfactants in the biocompatible solution (glucose and polysorbate both act as surfactants in solution).

[0155] When these properties are examined independently, various forms of polypropylene have a surface energy of approximately 30 mN / m (millineutons per meter, the standard unit of the International System of Units for measuring surface energy), while various forms of polycarbonate have a surface energy of approximately 46 mN / m. (Various forms of acetal have a surface energy of approximately 36 mN / m, which is between that of polypropylene and polycarbonate.) The higher surface energy of polycarbonate (and to a lesser extent, acetal) allows for better spreading of a given solution onto the surface of the aerator components (e.g., along channel 773 shown in Figure 7B, or channel 673 shown in Figure 6F) than the lower surface energy of polypropylene, resulting in more efficient operation of the venturi and corresponding vent when introducing air or other gases into the flowing solution stream. In other words, the difference in surface energy is thought to allow for reduced beading of a given solution on polycarbonate (or acetal) than on polypropylene. This better spreading and reduced beading is thought to facilitate better intake of air or gas into the solution stream flowing through the venturi.

[0156] Surfactants in a solution tend to decrease the interfacial tension between molecules in the solution (regardless of the effect of the surface energy of the material in contact with the solution on the interfacial tension that may exist at the contact surface). That is, in the absence of a surfactant, the intermolecular forces holding individual molecules of the solution together can be relatively strong, while the addition of a surfactant decreases the intermolecular attractive forces or interfacial tension. This decrease in interfacial tension caused by the presence of a surfactant (e.g., glucose or polysorbate) is understood to increase the solution's ability to attract air or gas (e.g., in or near the venturi throat as the solution moves through the venturi throat) in the form of microbubbles.

[0157] Surprisingly, the applicant found that variations in these two parameters (surface energy and interfacial tension) combine not simply additively, but seemingly multiplicatively. That is, in implementations containing both aerator components with high material surface energy and surfactants present in the solution, it was easier to create microbubbles far superior to those formed in implementations optimized only for surface energy or only for interfacial tension. For example, with respect to surface energy alone, multi-stage aerators with higher surface energy produced a larger volume of bubbles (e.g., Example 4 (Figure 10A) produced more bubbles than Example 1 (Figure 9A)), and similarly, single-stage aerators with higher surface energy produced a larger volume of bubbles (e.g., Examples 10 and 13 (Figures 12A and 13A) produced more bubbles than Example 7 (Figure 11A)). With respect to surfactant alone, examples containing glucose or polysorbate showed superior performance compared to examples containing only physiological saline. However, when these parameters are combined, the difference becomes very significant. Specifically, in the multi-stage aerator, Example 6 (Figure 10C) produced a much larger quantity of higher-quality bubbles than the bubbles purified in Example 3 (Figure 9C), and in the single-stage aerator, Examples 12 and 15 (Figures 12C and 13C) produced a much larger quantity of higher-quality bubbles than the bubbles produced in Example 9 (Figure 11C). Thus, the applicant has surprisingly found that combining aerator components made of high-surface-energy materials (e.g., polycarbonate or acetal) with a biocompatible solution containing a surfactant (e.g., glucose or polysorbate) produces a larger quantity of higher-quality bubbles than other implementations. Other examples

[0158] One implementation was further tested in a live pig model to evaluate the ultrasound echogenicity of the produced microbubbles. Specifically, a multi-stage aerator implementation was applied to produce microbubbles in saline or saline / polysorbate solution. The saline or saline / polysorbate solution containing the microbubbles was then injected into the venous system of a live pig model, and ultrasound images were acquired using transesophageal echocardiography (TEE). These images are shown as Figures 14A to 14E. Each of these figures includes a left panel and a right panel. The left panel shows the TEE image before injection of the solution containing microbubbles, and the right panel shows the TEE image after injection of the solution containing microbubbles. Example 16 (Current Standard Treatment)

[0159] Figure 14A shows a TEE (Technical Examination) of a procedure in which microbubbles produced using current standard treatment procedures were injected into the venous line of a pig model. Specifically, two 10 mL syringes were connected together using a three-way stopper and then connected to the venous line. The venous line was positioned in the venous system of the pig model so that the fluid injected through it would be delivered to the right atrium of the pig model. First, the stopper was adjusted to isolate the venous line, and the two syringes were connected. The first syringe initially contained 9 mL of saline solution, and the second syringe initially contained 1 mL of room air. The syringe plungers were operated back and forth 30 times to mix the saline solution and air to form microbubbles, until one syringe was completely filled with saline solution and air (in the form of microbubbles). Next, the stopper was moved to connect one syringe to the venous line, and the corresponding plunger was operated to inject the saline solution / microbubble mixture into the venous line.

[0160] The left panel of Figure 14A shows the TEE immediately before infusion. The right atrium is labeled "RA" in this left panel and in the subsequent panels of Figures 14A–14E. For additional anatomical reference, the left atrium and left ventricle are also labeled ("LA" and "LV," respectively) in the left panel of Figure 14A. In the left panel of Figure 14A, the "RA" region initially appears dark, indicating a hypoechoic or anechoic response associated with the blood flowing through the right atrium. In contrast, the tissues forming the wall of the right atrium (and other tissue structures of the heart) appear lighter, indicating a generally tissue-related hyperechoic response.

[0161] The right panel of Figure 14 shows the TEE after injection. In this panel, the right atrium appears bright, which is due to the appearance of hyperechoic microbubbles in the right atrium after injection. Example 17 (Multistage aerator; physiological saline containing 0.1% polysorbate)

[0162] Figure 14B shows a TEE (Technical Emission Examination) photographed during a procedure in which microbubbles are produced using a multistage aerator implementation configuration, such as the one shown in and described with reference to Figure 6A. In this embodiment, the input end of the multistage aerator was connected to a 10 mL syringe filled with a mixture of saline and 0.1% polysorbate, and the output end of the multistage aerator was connected to a venous line located in the venous system of a pig model (so that the injected fluid would be delivered to the right atrium of the pig model).

[0163] As shown in Figure 14A, the left panel of Figure 14B shows the TEE before injection of the saline / polysorbate / microbubble mixture, with the right atrium labeled. After capturing this reference image, the syringe plunger was stably activated once to inject the contents of the syringe into the venous line via a multistage aerator. In contrast to the current standard treatment procedure captured in Figure 14A and described with reference to Figure 14A, agitation of air and saline between multiple syringes was not required. By applying the multistage aerator, much of the user variability associated with microbubble creation using the current standard treatment procedure was eliminated.

[0164] As shown in the right panel of Figure 14B, the right atrium also appears bright, i.e., due to the color caused by the highly echogenic microbubbles that appear in the right atrium after infusion. Comparing Figure 14A and the right panel of Figure 14B reveals nearly identical ultrasound images. That is, the multistage aerator described herein produces microbubbles of the same quality as those produced using current standard treatment procedures with multiple syringes and three-way stoppers, without user-dependent preparation of air and saline. Example 18 (Multistage aerator; physiological saline containing 0.01% polysorbate)

[0165] Figure 14C shows a TEE (Technical Emission Examination) photographed during a procedure in which microbubbles are produced using a multistage aerator implementation configuration, such as the one shown in and described with reference to Figure 6A. In this embodiment, the input end of the multistage aerator was connected to a 10 mL syringe filled with a mixture of saline and 0.01% polysorbate, and the output end of the multistage aerator was connected to a venous line located in the venous system of a pig model (so that the injected fluid would be delivered to the right atrium of the pig model).

[0166] The left panel of Figure 14C again shows the TEE before injection of the saline / polysorbate / microbubble mixture. After capturing this reference image, the syringe plunger was stably activated once to inject the contents of the syringe into the venous line via a multi-stage aerator. As shown in the right panel of Figure 14C, after injection, the right atrium also appears bright, i.e., due to the color caused by the hyperechoic microbubbles that appear in the right atrium after injection. The quality of the ultrasound image is comparable to that of Examples 16-17, i.e., it is also comparable to that of current standard treatment procedures. Example 19 (Multistage aerator; physiological saline containing 0.005% polysorbate)

[0167] Figure 14D shows a TEE (Technical Examination) taken during a procedure in which microbubbles are produced using a multistage aerator implementation configuration, such as the one shown in and described with reference to Figure 6A. In this embodiment, the input end of the multistage aerator was connected to a 10 mL syringe filled with a mixture of saline and 0.005% polysorbate, and the output end of the multistage aerator was connected to a venous line located in the venous system of a pig model (so that the injected fluid would be delivered to the right atrium of the pig model).

[0168] The left panel of Figure 14D again shows the TEE before injection of the saline / polysorbate / microbubble mixture. After capturing this reference image, the syringe plunger was stably activated once to inject the contents of the syringe into the venous line via a multi-stage aerator. As shown in the right panel of Figure 14D, after injection, the right atrium also appears bright, i.e., due to the color caused by the hyperechoic microbubbles that appear in the right atrium after injection. The quality of the ultrasound images is comparable to that of Examples 16-18, i.e., also comparable to that of current standard treatment procedures. Example 20 (Multistage aerator; physiological saline containing 0.005% polysorbate)

[0169] Figure 14E shows a TEE (Technical Examination) taken during a procedure in which microbubbles are produced using a multistage aerator implementation configuration, such as the one illustrated and described with reference to Figure 6A. In this embodiment, the input end of the multistage aerator was connected to a 10 mL syringe filled with a mixture of saline and 0.005% polysorbate, and the output end of the multistage aerator was connected to a 20-gauge needle placed directly into the venous system of a pig model (without the intervening of a venous line) (the fluid injected through the needle was delivered to the right atrium of the pig model).

[0170] The left panel of Figure 14E shows the TEE before injection of the saline / polysorbate / microbubble mixture. After capturing this reference image, the syringe plunger was stably activated once to inject the contents of the syringe through a multi-stage aerator and a 20-gauge needle. As shown in the right panel of Figure 14E, after injection, the right atrium also appears bright, i.e., due to the color caused by the hyperechoic microbubbles that appear in the right atrium after injection. The quality of the ultrasound images is comparable to that of Examples 16–19, i.e., also comparable to that of current standard treatment procedures. As shown in this example, there was no perceptible difference in ultrasound image quality between injecting the saline / polysorbate / microbubble mixture via an intravenous line and injecting it via a 20-gauge needle. Analysis of Examples 16-20

[0171] As shown in Examples 16 to 20, aerators as described herein can produce microbubbles that have applications for echocardiographic examinations and other examinations of anatomical structures, such as those utilizing ultrasound and contrast agents. Furthermore, aerators can produce microbubbles from solutions of saline and polysorbate at various concentrations for use in examinations of living patients.

[0172] Variations in polysorbate concentration can produce effects not captured in Figures 14B–14E. For example, in some implementations, microbubbles can become smaller at polysorbate concentrations of approximately 0.1%, and in such implementations, microbubbles may be useful for imaging very small anatomical structures (e.g., PFOs, ASDs, or pAVMs). In some implementations, the polysorbate concentration can affect the time required for microbubbles to dissipate into the circulatory system. Some concentrations may require longer clearance times than others, and the clearance time may be adjusted by adjusting the polysorbate concentration. The polysorbate concentration can also affect the precise echogenicity of the microbubbles. In some implementations, it may be advantageous to produce microbubbles with greater echogenicity (e.g., to clearly outline structures), while in other implementations, it may be advantageous to produce microbubbles that are simply echogenic (e.g., to facilitate good imaging of adjacent structures). conclusion

[0173] While many implementations are described with reference to cardiac studies, contrast-enhanced imaging may have other useful applications. For example, combining microbubbles with ultrasound or other imaging techniques can be clinically useful for recording proper catheter placement during pericardiocentesis, central venous catheter placement in the right atrium, and catheter placement during interventional radiological procedures. In the field of gynecology, e.g., ultrasound / sterilization, microbubbles can be used to assess the patency of the fallopian tubes. Other applications may include imaging of abdominal spaces, parts of the gastrointestinal tract, and joints or other interstitial spaces of the human body. Microbubbles can also be applied in veterinary procedures in a manner similar to that described herein.

[0174] While several implementations have been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various modifications can be made and those elements can be replaced with equivalents without deviating from the intended scope. For example, this could include: syringes of various sizes may be applied; the converging nozzle may be integrated with the syringe; the aerator may be integrated with the converging nozzle; the converging nozzle and aerator may be a single assembly; the components may be joined with adhesive, ultrasonically welded, or molded as a single part; in some implementations, O-rings or compression joints may be applied to join the components, while in other implementations, different techniques may be applied; different sizes and forms of air channels may be applied within the converging nozzle; the syringe may be pre-filled or filled in-situ immediately before treatment; microbubbles may be generated in saline, glucose, plasma, saline / polysorbate, saline with any other surfactant, or any other biocompatible fluid or combination of fluids; microbubbles may be applied in the context of ultrasound or in conjunction with other imaging techniques; microbubbles may be used for diagnostic or It may be applied for therapeutic purposes; the kit may include any number of microbubble generators, which may be integrated with a manifold, or a manifold may be provided for connection before treatment; different membranes, caps, or seals may be applied to seal pre-filled fluids within specific parts of the microbubble generator or microbubble generation system; various numbers of air channels may be applied to facilitate the generation of many or few microbubbles per unit of fluid; the air channels may have various dimensions, shapes, and / or surface treatments to control the size of the generated microbubbles; throughout, another gas (e.g., oxygen, nitrogen, carbon dioxide, mixtures thereof, another biocompatible gas, etc.) may be applied instead of "air"; a continuous supply source of saline or other liquid may be replaced with a syringe; the syringe may be operated automatically or manually; the microbubbles may include "nanobubbles" or bubbles of various sizes and distributions;Aerator components may vary in dimensions (e.g., throat diameter, vent diameter); different numbers (e.g., one, two, three, or more) of aerator components may be deployed; aerator components may be staged sequentially in different dimensional order (e.g., a range from smallest to largest, or some other order of throats); a single aerator implementation may include different numbers (e.g., one, two, three, or more) of vent holes; vent holes may be lateral holes approximately perpendicular to the longitudinal axis of the corresponding channel or flow path; vent holes may be angled with respect to the longitudinal axis of the corresponding channel or flow path; vent holes may include grooves or other paths that fluidically connect the area outside the aerator body to the flow path inside the aerator body.

[0175] Many other modifications are possible, and the teachings provided herein may be modified to suit specific circumstances or materials without departing from their essential scope. Therefore, the scope is intended to include all embodiments included in the appended claims.

Claims

1. A device for generating microbubbles, A syringe having a barrel and a syringe tip, characterized by its longitudinal axis, It is an aerator, (i) A generally cylindrical outer casing, which is also characterized by its longitudinal axis. (ii) an inlet end; (iii) an exit end; (iv) a tapered outlet port at its outlet end, and (v) an internal cavity, (A) Input port section, (B) Convergence interval, (C) Throat section, (D) Divergent interval, (E) Exit section, (F) A first vent that fluidly connects at least one of the throat section or the diverging section to an adjacent area outside the outer casing, and (G) An aerator having an internal cavity, comprising a second vent which fluidly connects the outlet section to the region, It is a housing, (x) Surrounding the end of the barrel and the aerator in the circumferential direction, Characterized by the (y) longitudinal axis, (z) Having an inner surface, (aa) A circumferential gas pocket is formed between the outer casing and the inner surface, and (bb) Housing has an ejection tip, The housing seals against the barrel, thereby preventing fluid communication between the region and the outer region of the housing, except when passing through the housing discharge tip, the first vent, or the second vent. Equipped with, The device is configured such that the input port section accommodates the syringe tip, and the housing discharge tip accommodates the tapered outlet port, so that the syringe tip, the aerator, and the housing are coaxially connected with respect to their respective longitudinal axes.

2. The apparatus according to claim 1, wherein the first vent is characterized by a first vent diameter, the second vent is characterized by a second vent diameter, and the first vent diameter is larger than the second vent diameter.

3. The apparatus according to claim 2, wherein the diameter of the first vent is approximately 1.0 mm and the diameter of the second vent is approximately 0.5 mm.

4. The apparatus according to claim 1, wherein the capacity of the barrel is approximately 30 mL, and the volume of the circumferential gas pocket is approximately 5 mL to 15 mL.

5. The apparatus according to claim 1, wherein the outlet section has a substantially cylindrical shape.

6. The apparatus according to claim 1, wherein the diameter of the convergence section is in the range of approximately 3.5 mm and approximately 0.5 mm.

7. The apparatus according to claim 1, wherein the diameter of the divergent section is in the range of about 0.65 mm to about 2.1 mm.

8. The apparatus according to claim 1, wherein the aerator comprises a material having a surface energy of about 35 mN / m or more.

9. The apparatus according to claim 1, further comprising a biocompatible solution disposed within the barrel.

10. The apparatus according to claim 9, further comprising a sealing pin that closes off a portion of the internal cavity, and a cap that surrounds a portion of the housing discharge tip.

11. A method for generating microbubbles, (a) A syringe having a barrel and a syringe tip, characterized by its longitudinal axis, wherein the barrel is filled with a biocompatible fluid, (b) an aerator, (i) This is also a generally cylindrical exterior body characterized by its longitudinal axis, (ii) an inlet end; (iii) an exit end; (iv) The tapered outlet port at its outlet end, (v) an internal cavity, (A) Input port section, (B) Convergence interval, (C) Throat section, (D) Divergent interval, (E) Exit section, (F) A first vent that fluidly connects at least one of the throat section or the diverging section to an adjacent area outside the outer casing, and (G) An aerator having an internal cavity, comprising a second vent which fluidly connects the outlet section to the region, (c) Housing, (x) Surrounding the end of the barrel and the aerator in the circumferential direction, Characterized by the (y) longitudinal axis, (z) Having an inner surface, (aa) A circumferential gas pocket is formed between the outer casing and the inner surface, and (bb) Housing has an ejection tip, The housing, by surrounding the aerator, prevents fluid communication between the region and the outer region of the housing, except when passing through the housing discharge tip, the first vent, or the second vent. It has, The steps include preparing a microbubble generator in which the input port section is configured to accommodate the syringe tip, the housing discharge tip is configured to accommodate the tapered outlet port, and the syringe tip, the aerator, and the housing are coaxially and integrally connected with respect to their respective longitudinal axes, and The steps include generating microbubbles by pushing the biocompatible fluid through the internal cavity and the housing discharge tip from the syringe, A method that includes [a certain feature].

12. The method according to claim 11, wherein the aerator comprises a material having a solid surface energy of about 35 mN / m or more.

13. The method according to claim 11, wherein the aerator comprises polycarbonate.

14. The method according to claim 11, wherein the aerator comprises one of polycarbonate, polymethacrylate, polyvinyl chloride, polyamide, acrylonitrile butadiene styrene, acetal, or polyethylene terephthalate glycol.

15. The method according to claim 11, wherein the biocompatible fluid contains glucose.

16. The method according to claim 11, wherein the biocompatible fluid comprises physiological saline and glucose or a biocompatible surfactant.

17. The method according to claim 11, wherein the biocompatible fluid comprises physiological saline and polysorbate.

18. The method according to claim 17, wherein the biocompatible fluid contains polysorbate at a concentration of 0.1% or less.

19. The method according to claim 17, wherein the biocompatible fluid contains polysorbate at a concentration of 0.01% or less.

20. The method according to claim 17, wherein the biocompatible fluid contains polysorbate at a concentration of 0.005% or less.

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