Patent Publication Number: US-2022233762-A1

Title: Syringe-based microbubble generator with an aerator

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of U.S. patent application Ser. No. 17/566,079, titled, “SYRINGE-BASED MICROBUBBLE GENERATOR WITH AN AERATOR” filed on Dec. 30, 2021, which is a continuation-in-part of U.S. application Ser. No. 17/542,386, titled “SYRINGE-BASED MICROBUBBLE GENERATOR,” filed on Dec. 4, 2021, which is a continuation of U.S. patent application Ser. No. 17/158,396, titled “SYRINGE-BASED MICROBUBBLE GENERATOR,” filed on Jan. 26, 2021, now U.S. Pat. No. 11,191,888. This application incorporates the entire contents of the foregoing applications herein by reference. 
    
    
     TECHNICAL FIELD 
     Various implementations relate generally to generating microbubbles for use in various diagnostic and therapeutic procedures. 
     BACKGROUND 
     Echocardiography refers to the use of ultrasound to study the heart. Echocardiography is a widely used diagnostic test in the field of cardiology and may be used in the diagnosis, management, and follow-up of patients with suspected or known heart diseases. The results from an echocardiography test may provide much helpful information, including the size and shape of the heart&#39;s components (e.g., internal chamber size quantification), pumping function, and the location and extent of any tissue damage. An echocardiogram may also give physicians other estimates of heart function, such as a calculation of the cardiac output, ejection fraction (the percentage of blood volume of the left ventricle that is pumped out with each contraction), diastolic function (how well the heart relaxes), etc. 
     Echocardiography may be performed in one of multiple ways. Least invasively, an ultrasound transducer may be placed on a patient&#39;s chest, and imaging may be done through the patient&#39;s chest wall, in a transthoracic echocardiogram (TTE). If a higher fidelity image is required, a more invasive transesophageal echocardiogram (TEE) may be performed, in which an ultrasound transducer disposed on a thin tube is placed down the patient&#39;s throat and into the esophagus. Because the esophagus is so close to the heart, this procedure can be employed to obtain very clear images of heart structures and valves. 
     During either a TTE or TEE procedure, a contrast agent may be employed to enhance the imaging of the procedure. This contrast agent may be injected into the patient&#39;s vein, such that it quickly reaches the chambers of the heart and is detected by ultrasound to give greater definition to structures of the heart. In some procedures, the contrast agent employed is a saline solution comprising tiny air bubbles, and the procedure may be referred to as an agitated saline contrast study or “bubble study.” 
     SUMMARY 
     In some implementations, a device for generating microbubbles includes a syringe having a barrel and a syringe tip, a plurality of aerator components and a housing. Each aerator component may have (i) a generally cylindrical exterior body that is characterized by a longitudinal axis; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end, which tapered outlet end may be defined by an outlet diameter that is less than a body diameter corresponding to the exterior body, and a taper near the outlet end; and (v) an interior cavity comprising (A) an input port section, (B) an inlet section, (C) a throat section, (D) an outlet section, and (E) a transverse vent that fluidly couples the throat section to an area outside and adjacent to the exterior body. The housing may (x) circumferentially surround an end of the barrel and the plurality of aerator components, (y) be characterized by a longitudinal axis, (z) have an interior surface, (aa) form a circumferential gas pocket between the interior surface and the exterior body of each of the plurality of aerator components, and (bb) have a housing discharge tip. The input port section of each aerator component may be configured to accommodate the syringe tip or a tapered outlet port of one of the other aerator components in the plurality, and the housing discharge tip may be configured to accommodate the tapered outlet port of one of the plurality of aerator components, such that the syringe tip, a first aerator component, a second aerator component, and the housing can be coupled together in a coaxial manner relative to their respective longitudinal axes. 
     In some implementations, each of the aerator components further includes one or more alignment tabs, and the housing includes an alignment groove, such that when the syringe tip, the first aerator component, the second aerator component, and the housing are coupled together, the one or more alignment tabs and the alignment groove cooperate to radially fix the housing and each of the plurality of aerator components relative to each other. 
     In some implementations, a device for generating microbubbles includes a syringe having a barrel and a syringe tip that are characterized by a longitudinal axis, an aerator and a housing. The aerator may have (i) a generally cylindrical exterior body that is also characterized by a longitudinal axis; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end; and (v) an interior cavity having (A) an input port section, (B) a converging section, (C) a throat section, (D) a diverging section, (E) an outlet section, (F) a first vent that fluidly couples at least one of the throat section or the diverging section to an area outside and adjacent to the exterior body, and (G) a second vent that fluidly couples the outlet section to the area. The housing may (x) circumferentially surround an end of the barrel and the aerator, (y) be characterized by a longitudinal axis, (z) have an interior surface, (aa) form a circumferential gas pocket between the interior surface and the exterior body, and (bb) have a housing discharge tip. The input port section may be configured to accommodate the syringe tip, and the housing discharge tip may be configured to accommodate the tapered outlet port, such that the syringe tip, the aerator component, and the housing can be coupled together in a coaxial manner relative to their respective longitudinal axes. 
     In some implementations, the housing seals against the barrel, thereby preventing fluid communication between the area and a region exterior to the housing, except through the housing discharge tip, the first vent or the second vent. The first vent may be characterized by a first vent diameter, the second vent may be characterized by a second vent diameter, and the first vent diameter may be greater than the second vent diameter. In some implementations, the first vent diameter is about 1.0 mm, and the second vent diameter is about 0.5 mm. 
     In some implementations, a capacity of the barrel is about 30 mL, and a volume of the circumferential gas pocket is about 5 to 15 mL. The outlet section may be substantially cylindrical in shape. A diameter of the converging section may range between about 3.5 mm and about 0.5 mm. A diameter of the diverging section may range between about 0.65 mm and about 2.1 mm. The aerator may comprise a material having a surface energy that is greater than or equal to about 35 mN/m. 
     In some implementations, the device includes a body-compatible solution that is disposed in the barrel. In some implementations, the device further includes a cap that encloses a portion of the housing discharge tip and a sealing pin that occludes a portion of the interior cavity. 
     In some implementations, a method for generating microbubbles includes providing a microbubble generator. The microbubble generator may include (a) a syringe having a barrel and a syringe tip and being characterized by a longitudinal axis, wherein the barrel is filled with a body-compatible fluid; (b) an aerator having (i) a generally cylindrical exterior body that is also characterized by a longitudinal axis; (ii) an inlet end; (iii) an outlet end; (iv) a tapered outlet port at its outlet end; and (v) an interior cavity having (A) an input port section, (B) a converging section, (C) a throat section, (D) a diverging section, (E) an outlet section, (F) a first vent that fluidly couples at least one of the throat section or the diverging section to an area outside and adjacent to the exterior body, and (G) a second vent that fluidly couples the outlet section to the area; and (c) a housing that (x) circumferentially surrounds an end of the barrel and the aerator, (y) is characterized by a longitudinal axis, (z) has an interior surface, (aa) forms a circumferential gas pocket between the interior surface and the exterior body, and (bb) has a housing discharge tip. The input port section may be configured to accommodate the syringe tip, and the housing discharge tip may be configured to accommodate the tapered outlet port, such that the syringe tip, the aerator component, and the housing can be coupled together in a coaxial manner relative to their respective longitudinal axes. 
     The method may further include coupling the housing discharge tip to an intravenous line disposed in a patient undergoing a procedure. The method may further include generating microbubbles by forcing the body-compatible fluid out of the syringe, through the interior cavity, and through the housing discharge tip. 
     In some implementations, the aerator comprises a material having a solid surface energy of about 35 mN/m or more. In some implementations, the aerator comprises polycarbonate. In some implementations, the aerator comprises one of polycarbonate, polymethacrylate, polyvinyl chloride, polyamide, acrylonitrile butadiene styrene, acetal or polyethylene terephthalate glycol. 
     In some implementations, the body-compatible fluid comprises dextrose. In some implementations, the body-compatible fluid comprises saline and polysorbate. In some implementations, the body-compatible fluid comprises saline and dextrose or a body-compatible surfactant. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is an exploded perspective view of an exemplary microbubble generator. 
         FIG. 2A  is a longitudinal cross section of an exemplary syringe, converging nozzle, and aerator, as they are assembled, in one implementation. 
         FIG. 2B  is a longitudinal cross section of the converging nozzle, O-ring, and aerator shown in  FIG. 2A . 
         FIG. 2C  is another longitudinal cross section of the converging nozzle, O-ring and aerator shown in  FIG. 2A . 
         FIG. 2D  is a perspective, cross-sectional view of the configuration shown in  FIG. 2C . 
         FIG. 2E  is a perspective cross-sectional view of another exemplary converging nozzle and aerator. 
         FIG. 2F  is a longitudinal cross-sectional view of the converging nozzle and aerator shown in  FIG. 2E . 
         FIGS. 3A, 3B and 3C  depict operation of an exemplary microbubble generator. 
         FIG. 4  illustrates an exemplary microbubble generating system. 
         FIG. 5  illustrates a portion of an overall human circulatory system. 
         FIG. 6A  is a perspective cross-sectional view of another exemplary microbubble generator. 
         FIG. 6B  is a perspective view of an aerator component that may be included in the exemplary microbubble generator of  FIG. 6A . 
         FIG. 6C  is a perspective cross-sectional view of the aerator component of  FIG. 6B . 
         FIG. 6D  is a side view of the aerator component of  FIG. 6B . 
         FIG. 6E  is a side cross section of the aerator component of  FIG. 6B . 
         FIG. 6F  is a perspective cross-sectional view of a plurality of aerator components that may be coupled together and included in the exemplary microbubble generator of  FIG. 6A . 
         FIG. 6G  is a perspective cross-sectional view of the exemplary microbubble generator of  FIG. 6A , including a cap and sealing pin. 
         FIG. 7A  is a perspective cross-sectional view of another exemplary microbubble generator. 
         FIG. 7B  is a side cross section of an aerator component that may be included in the exemplary microbubble generator of  FIG. 7A . 
         FIG. 8A  is a perspective view of an exemplary aerator component. 
         FIG. 8B  is a cross section of the aerator component of  FIG. 8A . 
         FIG. 8C  is a cross section of the aerator component of  FIG. 8A , with a sealing pin disposed therein. 
         FIGS. 9A-9C  illustrate microbubbles formed with an exemplary multi-stage polypropylene aerator and saline, dextrose and saline with polysorbate, respectively. 
         FIGS. 10A-10C  illustrate microbubbles formed with an exemplary multi-stage polycarbonate aerator and saline, dextrose and saline with polysorbate, respectively. 
         FIGS. 11A-11C  illustrate microbubbles formed with an exemplary single-stage polypropylene aerator and saline, dextrose and saline with polysorbate, respectively. 
         FIGS. 12A-12C  illustrate microbubbles formed with an exemplary single-stage polycarbonate aerator and saline, dextrose and saline with polysorbate, respectively. 
         FIGS. 13A-13C  illustrate microbubbles formed with an exemplary single-stage acetal aerator and saline, dextrose and saline with polysorbate, respectively. 
         FIG. 14A  illustrates a TEE procedure in a porcine model in which microbubbles were produced using a current standard-of-care procedure. 
         FIG. 14B  illustrates a TEE procedure in a porcine model in which microbubbles were produced using an exemplary aerator with saline and polysorbate at a 0.1% concentration. 
         FIG. 14C  illustrates a TEE procedure in a porcine model in which microbubbles were produced using an exemplary aerator with saline and polysorbate at a 0.01% concentration. 
         FIG. 14D  illustrates a TEE procedure in a porcine model in which microbubbles were produced using an exemplary aerator with saline and polysorbate at a 0.005% concentration. 
         FIG. 14E  illustrates a TEE procedure in a porcine model in which a 20-gauge needle was employed to deliver microbubbles, rather than an intravenous line. 
     
    
    
     DETAILED DESCRIPTION 
     Agitated saline contrast studies (or “bubble studies”) are a useful adjunct to many ultrasound examinations, particularly cardiac ultrasound (echocardiography). Injection of agitated saline into a vein combined with echocardiography is a validated method to detect shunts which may be within the heart such as a patent foramen ovale (PFO) or an atrial septal defect (ASD)—two types of holes in the heart—or external to the heart (e.g., in the lungs) known as pulmonary arteriovenous malformations (pAVM). Agitated saline can also be used with echocardiography to confirm catheter placement in fluid around the heart (pericardiocentesis), detect anomalous connections within the heart, visualize the right side of the heart and accentuate right sided blood flow for the purpose of quantitation. 
     Agitated saline contrast echocardiography takes advantage of the increased reflection that results when ultrasound waves meet a liquid/gas interface. This allows for visualization of otherwise poorly reflective areas such as fluid-filled cavities by the ultrasound machine. Applications in which this has been clinically useful include echocardiography where agitated saline can be used to define the structural integrity of the interatrial septum or infer the presence of a transpulmonary shunt. Agitated saline can also be combined with Doppler echocardiography to assess blood flow through the tricuspid valve. An alternative method to detect atrial defects uses ultrasound of the brain vessels (transcranial Doppler) to detect bubbles that have crossed from the right heart to the left heart and entered the cerebral circulation. 
     At present, it may be difficult to generate agitated saline for these studies, and this can result in varying levels of quality and safety. Current bubble studies may have considerable variability in the amount, size, and quantity of bubbles generated. Such imprecise mixtures of saline and air can result in risk to patients and false-negative studies. In addition, few individuals may be properly trained to safely perform bubble studies. The productivity of an echocardiography lab may be substantially slowed by this lack of trained personnel; and even trained personnel who do not routinely perform agitated saline studies may be reluctant to do so because of concerns about comfort or safety of the procedure. 
     Described herein are devices and methods for producing bubbles (e.g., for an ultrasound-based bubble study). Advantages of the devices and methods described herein may include the production of more uniform and consistently dimensioned bubbles with minimal training. This may result in greater patient safety and comfort as well as studies with improved diagnostic benefit. 
       FIG. 1  is an exploded perspective view of an exemplary microbubble generator  100 , according to one implementation. As shown, the microbubble generator  100  includes a syringe  103 , a converging nozzle  115 , and an aerator  133 . In operation, the microbubble generator  100  can be coupled to an intravenous (IV) line disposed in a patient undergoing a procedure (e.g., a diagnostic bubble study), and the microbubble generator  100  can be employed to generate microbubbles as a contrast agent. 
     In some implementations, the syringe  103  portion of the microbubble generator  100  is a standard medical-grade syringe (e.g., 1 mL, 2 mL, 3 mL, 5 mL, 10 mL, 20 mL) having a barrel  106 , plunger  109  and tip  112 . The syringe  103  may be pre-filled with saline or another solution that is suitable for intravenous injection, which can provide a vehicle for microbubbles generated by the microbubble generator  100  to be delivered to a target region of a patient&#39;s body. The tip  112  can include a Luer lock connector suitable for coupling to needles, catheters, IV lines, etc. 
     Saline is referenced with respect to various implementations. In some implementations, this could be “NSS,” or 0.9% normal saline solution; in other implementations, “45NS,” or 0.45% normal saline may be used; in other implementations, phosphate-buffered saline (PBS) may be used. In still other implementations, liquids other than saline may be used, such as dextrose in water solution (e.g., “D5W,” or 5% dextrose in water; “D10W,” or 10% dextrose in water; “D50,” or 50% dextrose in water) or other solutions commonly used in intravenous applications at sites that are suitable for diagnostic studies or therapeutic procedures. 
     The converging nozzle  115 , in the implementation shown, has a coupling end  118  that is configured to engage the tip  112  of the syringe  103 . In some implementations, the coupling end  118  includes mating Luer lock threads to facilitate a twist-on engagement with the syringe  103 . Opposite the coupling end  118  is a converging tip  121 . An interior channel  127 , which will be described in greater detail with reference to the following figures, is configured to fluidly couple an interior of the syringe  103  to the aerator  133 . 
     The aerator  133 , as shown, includes a retention end  136  that is configured to mechanically mate with the converging nozzle  115 ; and a discharge end  139 . In some implementations, the aerator  133  can be coupled to the converging nozzle  115  via a compression-fit coupling facilitated by an O-ring  134  and grooves in the converging nozzle  115  and aerator  133 . A discharge channel  147  fluidly couples the interior channel  127  of the converging nozzle  115  to a discharge end  139 , which can be configured to engage a catheter or IV port or line used in a bubble study. 
     In  FIG. 1 , the syringe  103 , converging nozzle  115  and aerator  133  are shown as separate components. In other implementations, however, one or more components may have other arrangements. For example, the converging nozzle  115  and aerator  133  may be ultrasonically welded together, joined with adhesive, snap-fit, etc.; and the converging nozzle  115  or a singular converging nozzle/aerator structure could be coupled to the syringe  103  in one of the foregoing ways or co-molded with and as part of the syringe  103 . Additional detail of the exemplary syringe  103 , converging nozzle  115  and aerator  133  is now provided with reference to  FIGS. 2A, 2B and 2C . 
       FIG. 2A  illustrates a longitudinal cross-section of the syringe  103 , converging nozzle  115  and aerator  133 , as they could be assembled in some implementations. As shown, the converging nozzle  115  is disposed on the syringe  103  via a Luer lock fitting  218 , and the aerator  133  is compression-fit onto the converging nozzle  115  by an O-ring and corresponding grooves in each of the converging nozzle  115  and aerator  133  (see  FIG. 2B  for detail). In other implementations, connections maybe made differently. For example, other threaded or press-fit connections may replace Luer lock fittings. Similarly, the O-ring and grooves could be replaced by a threaded, adhesive-based or welded connection. 
       FIG. 2B  illustrates an exemplary longitudinal cross section of the converging nozzle  115 , O-ring  134 , and aerator  133 . The interior channel  127  fluidly couples to an interior of the mating syringe  103  (see  FIGS. 1, 2A ) and a throat  230 —a portion of the interior channel  127  whose diameter progressively decreases. In operation, the progressively decreasing diameter of the throat  230  changes dynamics of fluid flowing from the syringe  103  and through the converging nozzle  115 , as will be described with reference to  FIG. 2C . 
     As shown, the converging nozzle  115  includes grooves  235 A for receiving the O-ring  134  and facilitating a compression-fit coupling; and the aerator  133  includes corresponding grooves  235 B for the same purpose. This structure allows the O-ring  134  to be slipped into the grooves  235 A, and for the retention end  236  of the aerator  133  to be slid over the converging tip  121  and for the grooves  235 B to engage and be retained by the O-ring  134 . In such an implementation, the O-ring  134  may be made of an elastic material that has sufficient elasticity and compressibility to facilitate engagement of the converging nozzle  115  and aerator  133 , and sufficient resilience to securely couple the converging nozzle  115  and aerator  133  once the grooves  235 A and  235 B of these components  115  and  133  are aligned as described. In some implementations, the O-ring  134  and grooves  235 A and  235 B may provide an air-tight, sterile seal. 
     The converging nozzle  115  further includes an external mating surface  224  at the converging tip  121 , which is configured to mechanically fit adjacent to a corresponding circumferential lip  244  on the aerator  133 . In some implementations, the circumferential lip  244  circumferentially envelopes the external mating surface  224  and abuts the external mating surface  224  at least at one point; in other implementations, the circumferential lip  244  and external mating surface  224  are disposed adjacent and in close proximity to each other. When the converging nozzle  115  and aerator  133  are coupled (e.g., by the grooves  235 A and  235 B and O-ring  134 ), the external mating surface  224  and circumferential lip  244  align and facilitate fluid coupling between the interior fluid channel  127  and throat  230 , and the discharge channel  147 . In some implementations, specific dimensions and geometries of the external mating surface  224  and circumferential lip  244  further facilitate passage of air into the discharge channel  147 , from an interior air chamber  241 , which is formed by the outer wall  245  of the aerator  133 —as will be further described with reference to  FIG. 2C . 
       FIG. 2C  is a longitudinal cross section of the converging nozzle  115  and aerator  133 , shown in a coupled configuration, and a magnified view of a portion of that cross section. As shown, the interior air chamber  241  is formed by the outer wall  245  of the aerator. A small fluid coupling exists between this interior air chamber  241  and the passageway formed by the interior channel  127 , throat  230  and discharge channel  147 —specifically by an air channel  246  (see magnified inset) that is configured to exist between the exterior mating surface  224  and the circumferential lip  244 . This air channel  246  allows air or other gas in the interior air chamber  241  to be drawn into the aforementioned passageway (throat  230  and discharge channel  147 —referred to as the “ 230 / 147  passageway”). In addition, this air channel  246  may permit some fluid that is passing through the  230 / 147  passageway to enter the interior air chamber  241 , thereby displacing some of the air there and increasing the pressure in the interior air chamber  241  (e.g., in cases in which there may be a non-negligible back pressure at the discharge channel  147 ). 
       FIG. 2D  is a perspective, cross-sectional view of the converging nozzle  115  shown in  FIG. 2C , with the cross section taken along section line A-A (shown in  FIG. 2C ).  FIG. 2D  illustrates the air channel  246  (or series of air channels  246 ) that fluidly couple the interior air chamber  241  to the throat  230 -discharge channel  147  passageway. Visible in  FIG. 2D  is the throat  230  itself, in the center of the converging nozzle  115 , as well as a series of air channels  246  that are disposed radially about throat. 
     In some implementations, the exterior mating surface  224  and circumferential lip  244  (see  FIG. 2C ) are in mechanical contact and provide a fluid seal, except at the air channels  246 . That is, in such implementations, a fluid coupling between the interior air chamber  241  and the  230 / 147  passageway only exists at the air channels  246 . In some implementations, fewer air channels  246  are provided than shown—for example, some implementations may only include one, two, three or four air channels  246 . 
     Referring back to  FIG. 2C , dimensions and geometries of the air channels  246  may be configured to facilitate passage of air from the interior air chamber  241  into the  230 / 147  passageway only when certain pressure differentials exist therebetween. For example, some implementations may include air channels  246  with very small dimensions and with geometries that promote greater surface tension of any liquid that is disposed in the air channels  246 . Specific contours of either or both of the exterior mating surface  224  and the circumferential lip  244  may further promote an increased surface tension of liquid in the air channels  246 , to, for example, promote communication of air (and correspondingly, formation of microbubbles) in certain scenarios. Surface treatments to either or both of the exterior mating surface  224  and the circumferential lip  244  (e.g., hydrophobic or hydrophilic coatings) may be employed to further control communication of air or other gas from the interior air chamber  241  to the  230 - 147  passageway. 
     In some implementations, a vent (not shown) between the interior air chamber  141  and the exterior of the aerator  133  may be provided to enable more air to be drawn into the fluid than may otherwise be possible. In other implementations, a port or valve (not shown) may be provided to facilitate coupling of an exterior air supply for a similar purpose. In still other implementations, a valve (e.g., a reducing valve—not shown) may be provided to allow fluid to be drained from the air chamber  241  and again be replaced with air—for example, to facilitate an equilibrium relative to back pressure, and to enable the microbubble generator  100  to “recharge” its ability to generate microbubbles. 
       FIG. 2E  illustrates a perspective cross-sectional view of an exemplary implementation  260  of a unitary converging nozzle  263  and aerator  266 ; and  FIG. 2F  illustrates a longitudinal cross-section of the same device  260 . As shown in this implementation, the converging nozzle  263  and aerator  266  are fabricated as a unitary component (e.g., co-molded), rather than as two separate components. In such a configuration, it may be possible to precisely configure dimensions of one or more air channels  268  and their alignment to a stream of fluid traveling from an interior channel  269 , through a section  270  having a progressively decreasing diameter (e.g., a “Venturi section”), out an outlet  271 , into an inlet  273  of the aerator  266  and through and out a discharge channel  275 . 
     As shown, the exemplary device  260  includes a housing  278  that surrounds the unitary converging nozzle  263  and aerator  266 . In some implementations, as shown, the housing  278  can be sealed to the converging nozzle  263  and aerator  266  by O-rings  281 A and  281 B. In such implementations, an air chamber  283  is formed (e.g., by an interior surface  284  of the housing  278  and an exterior surface  285  of the unitary component that includes the converging nozzle  263  and aerator  266 ). When the O-rings  281 A and  281 B form an airtight and liquid-tight seal (of the air chamber  283 , isolating the air chamber  283  from a region exterior to the housing  278  from ingress or egress of gas or liquid via any path other than through the one or more air channels), air (or other gas) in the air chamber  283  can be drawn into a stream of liquid passing through the device  260 , in the form of microbubbles. 
     In some implementations, the exemplary device  260  can operate to produce microbubbles even in the presence of not-insignificant back pressure at the discharge channel  275 . Specifically, in the presence of back pressure at the discharge channel  275  (with a robust seal provided by O-rings  281 A and  281 B), fluid may pass through the interior channel  269 , section  270  and into the discharge channel  275 . However, no significant volume of fluid may flow out of the discharge channel  275  (e.g., into a downstream intravenous or needle-based system associated with a therapeutic or diagnostic procedure) until pressure is equalized between the device  260  and the back pressure. That is, rather than flowing out of the discharge channel  275 , the fluid may initially flow through the air channels  268  and into the interior air chamber  283 . Such fluid may displace the air in the air chamber  283 , causing an increase in pressure in the air chamber  283 . 
     Once this air pressure increases to the level of the back pressure, fluid may then flow through the device  260 , out of the discharge channel  275 , and into a connected patient diagnostic or therapeutic system (not shown). In this phase of operation, where the pressure inside the air chamber  283  is nearly equal to the back pressure seen at the discharge channel  275 , some air from the air chamber  283  may be drawn into the fluid stream, in the form of microbubbles—via an aspiration effect caused by the pressure drop in the fluid stream itself that is brought about by the increase in speed of flow of that fluid through the Venturi section  270 . 
     Over time, the aspiration of air into the fluid stream may cause the pressure in the air chamber  283  to again drop below a back pressure seen at the discharge channel  275 . At this point, some additional fluid may enter the air chamber  283 , again displacing air and increasing the pressure inside the air chamber  283 . Once equilibrium is reestablished, or nearly reestablished (e.g., within some small percentage, given the dynamic nature of the system, turbulence of the fluid, dynamically varying back pressure, variation in speed of fluid, etc.), air may again be aspirated into the fluid stream in the form of microbubbles. 
     In some implementations, a one-way reducing valve (not shown) may be provided between the air chamber  283  and an exterior of the housing  278 , to enable fluid to be periodically drained from the air chamber  283 . Allowing some fluid to be drained from the air chamber  283  may allow, in some implementations, air to be continuously available for aspiration into the fluid stream. In such an implementation, microbubbles may be produced and delivered out of the discharge channel  275  for as long as incoming fluid is supplied through the interior channel  269 . 
     In the implementation shown in  FIGS. 2E and 2F , dimensions, geometries and surface treatments (e.g., hydrophobic or hydrophilic coatings) of the air channels  268 , the outlet  271  (or interior channel  269  or section  270 ), the inlet  273  or the discharge channel  275  may be configured to facilitate creation of microbubbles having a specific average size or range of sizes (e.g., an average diameter of less than 2 μm; an average diameter of between about 5 μm and about 10 μm; an average diameter of about 40 μm or less; an average diameter of about 100 μm or less). Such implementations may employ dimensions, geometries or surface treatments to produce regions of turbulent or laminar flow that entrap or aspirate air in a particular manner. In other implementations, specific dimensions, geometries or surface treatments may be employed to create microbubbles with surface tensions or charges that minimize coalescence of microbubbles after they are generated. 
     Operation of an overall exemplary microbubble generator  300  are now described with respect to  FIGS. 3A, 3B and 3C , in one implementation. As shown in  FIG. 3A , a microbubble generator  300  that includes a syringe  303 , a converging nozzle  315  and an aerator  333  may be prefilled with a saline solution. That is, saline (or another suitable solution) may be prefilled in an interior  302  of the barrel  306  of the syringe portion  303 . To preserve the sterile nature of the saline, and to prevent fluid ingress into an interior chamber  341  of the aerator portion  333 , a sealing pin  353  may be provided to seal the saline in the syringe  303 , to seal the interior channel  327  and throat  330  of the converging nozzle  315  and to isolate the channel  327  from the interior chamber  341 . In operation, such a pin  353  may be removed immediately prior to use of the microbubble generator  300 . 
     The pin  353  may be made of a corrosion-resistant metal or resilient elastic material that seals off the tip of the throat  330  and a discharge channel  347 . The pin  353  may be adhesively sealed to the discharge end  339  of the aerator, such that some amount of twisting or pulling force is required by a user to dislodge the pin  353  prior to use of the microbubble generator  300 . Such an adhesive seal may further protect the sterile nature of the microbubble generator  300 , particularly at the discharge end  339 . 
     In some implementations, the pin  353  may be replaced with an internal membrane (not shown) that retains the saline (or other body-compatible fluid) in the interior  302  of the syringe or in the interior  302  of the syringe and the throat  330  of the converging nozzle  315 . In such implementations, a user may be required to depress the plunger  309  in order to generate an internal pressure that is sufficient to overcome the holding force of such a membrane. In some implementations, an internal membrane (not shown) may be configured to be broken when the converging nozzle  315  is affixed to the syringe  303  (e.g., in implementations in which the components are provided separately). 
     However the contents of the syringe are sealed prior to use, the appropriate seal can be released and the plunger  309  can be depressed slightly to flush microbubble generator  300 —as depicted in  FIG. 3B . In some instances, this can be done prior to the discharge end  339  being coupled to IV tubing  356  or another connection that may be made to a system used to diagnose or treat a patient (e.g., a needle, catheter, or other apparatus disposed in the patient (not shown)). In other instances, the discharge end  339  may be coupled to IV tubing  356  first, such that the tubing can also be flushed during this initial process. 
       FIG. 3C  depicts the process by which the microbubble generator  300  can generate microbubbles, in one implementation. In particular, after necessary seals are removed, and the microbubble generator  300  is flushed and coupled to a downstream IV system  356  associated with a patient undergoing a diagnostic or therapeutic procedure, the plunger  309  can be further depressed to force fluid from the interior  302  of the syringe  303 , into the interior channel  327 . In the interior channel  327 , the pressure of the fluid is relatively high, and its speed is relatively low (proportional to a speed at which the plunger is depressed). The progressively decreasing diameter of the throat  230  causes the speed of the fluid to increase there, thereby lowering its fluid pressure (through the Venturi effect). This lower pressure of the fluid at the throat  330  draws air into the fluid path traveling from the throat  330  to the discharge channel  347 , specifically from the interior chamber  341 , via one or more air channels  346 —thereby forming microbubbles. 
     In some implementations, the geometry, dimensions and/or surface treatment of the material forming the air channels  346  is correlated to microbubble size. Thus, in such implementations, configuration of converging nozzle  315  and aerator  333  can cause microbubbles to be created having different sizes and characteristics. In some implementations, microbubbles having a diameter of approximately 5 μm may be created; in other implementations, microbubbles having a diameter of approximately 10 μm or less may be created; in other implementations, microbubbles having a diameter of about 1-2 μm or less may be created; in other implementations, microbubbles having a diameter of about 40 μm may be created; in other implementations, microbubbles having a diameter up to about 100 μm may be created. 
     Different sized microbubbles may have different purposes in diagnostic or therapeutic procedures. For example, in certain diagnostic heart procedures, it may be advantageous to create microbubbles of approximately 5 μm to approximately 10 μm in average diameter. As used herein, “about” or “approximately” or “substantially” may mean within 1%, or 5%, or 10%, or 20%, or 50% of a nominal value; and “average” may mean that a significant number (e.g., 25%, 50%, 75%, 80%, 85%, 90%, 95%) of microbubbles have this diameter, or in some implementations, have a diameter that is within one or two standard deviations of the specified diameter. As another example, in diagnosing certain pulmonary conditions, it may be advantageous to create smaller-diameter microbubbles (e.g., 1-2 μm or less). In some implementations, microbubble size may be correlated with coalescence properties of the microbubbles. For example, surface tension and charge of microbubbles of specific sizes (in certain solutions, or in the blood) may inhibit their coalescence; and minimizing such coalescence of microbubbles may be advantageous (e.g., to minimize risk of an air embolism). 
     In some implementations, it may be advantageous to generate microbubbles of varying sizes. For example, in a procedure to diagnose the existence of a defect in the septum of a patient&#39;s heart, it may be advantageous to initially look for the presence of a septum defect with smaller microbubbles; then shift to larger microbubbles to determine whether a closure procedure is warranted. To facilitate procedures in which it may be advantageous to employ microbubbles of varying sizes, multiple microbubble generators may be employed; and in some implementations, they may be coupled together in advance. 
       FIG. 4  illustrates an exemplary microbubble generating system  400  that employs multiple microbubble generators  401 A,  401 B and  401 C. As shown, each microbubble generator  401 A,  401 B and  401 C can be coupled to a manifold  461  by corresponding fluid lines  456 A,  456 B and  456 C. The manifold can include multi-way valves  464 A,  464 B and  464 C that couple or isolate each fluid line to a main line  465  of the manifold  461 ; and that main line  465  of the manifold  461  can be coupled to an IV line  458  that is associated with a patient undergoing a diagnostic or therapeutic procedure. In this manner, individual microbubble generators  401 A,  401 B or  401 C can be alternately coupled to the IV line  458  to generate diagnostic or therapeutic microbubbles; or, multiple microbubble generators  401 A,  401 B or  401 C can be simultaneously connected to facilitate delivery of a large volume of fluid with minimal manipulation of valves. Some implementations employ three-way stopcocks  464 A,  464 B and  464 C, as shown, to isolate or fluidly couple one, two or three paths. Other implementations may employ different valve arrangements. 
     In some implementations, each microbubble generator  401 A,  401 B or  401 C, in a microbubble generating system  400  may be similarly configured to generate microbubbles of the same size. Such implementations may be employed to generate a larger volume of microbubbles, over a longer period of time than would be otherwise possible with a single microbubble generator. In other implementations, each microbubble generator  401 A,  401 B and  401 C may be configured to generate microbubbles of different sizes. For example, microbubble generator  401 A may be configured to generate microbubbles having an approximate diameter of 5 μm; microbubble generator  401 B may be configured to generate microbubbles having an approximate diameter of 1 μm; and microbubble generator  401 C may be configured to generate microbubbles having an approximate diameter of 10 μm. In this manner, complex diagnostic procedures requiring microbubbles of various sizes may be performed with minimal change in equipment. 
     The exemplary manifold  461  may include a port  468  for flushing out the manifold and/or overall system  400 . In some implementations, each microbubble generator  401 A,  401 B and  401 C may have an internal membrane to isolate fluid within a corresponding syringe barrel or syringe barrel/converging nozzle; and discharge channels of each microbubble generator and the manifold itself may be flushed and prefilled with fluid prior to a procedure being performed, through the port  468 . 
     In other implementations, the system  400  may be packaged in a manner in which the syringes, tubing and manifold are all pre-filled with fluid, such that a final connection between a main manifold line  465  and patient IV tubing  458  need be made at the time of a procedure. In such implementations, internal membranes may still be employed in individual microbubble generators  401 A,  401 B and  401 C to prevent egress of fluid into interior air chambers of an aerator component (e.g., air chamber  441 A in aerator  433 A). 
     The exemplary system  400  is shown with three microbubble generators  401 A,  401 B and  401 C; but other numbers of microbubble generators could be included—such as, for example, two, four, or five. The microbubble generators  401 A,  401 B and  401 C are shown coupled to the manifold  461  with tubing  456 A,  456 B, and  456 C. In some implementations, various components of the system  400  may be provided and coupled together immediately prior to a patient procedure. 
     Various implementations described herein may be employed to generate microbubbles for various diagnostic and therapeutic studies. Many such studies involve the human circulatory system. Thus, for reference, portions of a human circulatory system are now briefly described. 
       FIG. 5  illustrates a portion of an overall human circulatory system  500 . At its core, is the heart  502 , and a system of arteries that extend from the heart, and veins that return to the heart. Blood is returned to the heart  502  from throughout the body via the vena cava, which is divided into the superior vena cava  505 , which collects blood from the upper portion of the body, and the inferior vena cava  508 , which collects blood from the lower portion of the body. Blood flows through the superior vena cava  505  and inferior cava  108  on its way to the right atrium. 
     To facilitate studies whereby microbubbles are to be introduced into the heart and lungs, one must get the bubbles into the venous system and ultimately into the superior vena cava  505  or inferior vena cava  508 . With reference to  FIG. 5 , there are several common access points through which microbubbles can be introduced. Common among them is intravenous introduction of bubbles via the median cubital vein  530  of the right arm. From here, blood flows through the basilic vein  531 , axillary vein  532 , subclavian vein  510 , brachiocephalic vein  537  and into the superior vena cava  505 . 
     Alternative paths to the superior vena cava  513  are the external jugular vein  533  or internal jugular vein  536 , both of which drain into a brachiocephalic vein  537  prior to reaching the superior vena cava  505 . An alternative route includes the femoral vein  539 , which flows into the inferior vena cava  508 . Other routes to the superior vena cava  505  and inferior vena cava  508  are possible. 
       FIG. 6A  is a perspective cross-sectional view of another exemplary microbubble generator  600 . As shown, the exemplary microbubble generator  600  includes a syringe  603  having a barrel  606 , a plunger  609 , and a syringe tip  612 . In some implementations, as shown, the syringe tip  612  includes a Luer lock  613  or other fitting. 
     A plurality of aerator components  616   a ,  616   b  and  616   c  may be coupled to the syringe tip  612 , and a housing  619  may circumferentially surround an end of the barrel  606  and the plurality of aerator components  616   a ,  616   b  and  616   c . The housing  619  may have a longitudinal axis  622 , which, in some implementations, aligns coaxially with a longitudinal axis  623  of the syringe  603  and longitudinal axes of the aerator components  616   a ,  616   b , and  616   c.    
     The housing  619  has an interior surface  625  and a discharge tip  628 . In some implementations, the housing  619  is configured to fluidly seal against the barrel  606 , and the plurality of aerator components  616   a ,  616   b , and  616   c  may be sealed against each other, to the syringe tip  612 , and to the discharge tip  628 , such that any fluid that is ejected from the syringe  603  (e.g., by a user of the syringe  603  depressing the plunger  609 ) is ejected through the syringe tip  612 , into an interior channel  673  (see  FIG. 6F ) of each of the aerator components  616   a ,  616   b  and  616   c , through the discharge tip  628 . A circumferential gas pocket  631  may be created by the interior surface  625 ; the plurality of aerator components  616   a ,  616   b  and  616   c ; the syringe tip  612 ; and the discharge tip  628 . In some implementations, the circumferential gas pocket  631  comprises at least approximately 10% of the volume of the corresponding syringe barrel  606 ; in other implementations, the circumferential gas pocket  631  comprises approximately 30-35% of the volume of the corresponding syringe barrel  606  (e.g., 3-3.5 mL for a 10 mL syringe); in still other implementations, the circumferential gas pocket  631  comprises 50% or more of the volume of the corresponding syringe barrel  606 . 
     Regardless of the precise 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  may be precisely controlled to a fail-safe value. Specifically, in medical applications, such as those described herein, this precise value may be set to a level that would prevent harm to a patient—even if all gas or air in the circumferential gas pocket  631  were directly injected into the patient (e.g., through some device failure). Such a safety feature that is inherent in the design of implementations described herein may be absent from other implementations (e.g., current standard-of-care implementations, such as the one described below in Example 16)—where a volume of air or gas that is mixed with a body-compatible fluid may be controlled only by a specific clinician performing a corresponding procedure (possibly resulting in significant variation from one clinician to another with implementations other than those described herein). 
       FIG. 6B  is a perspective view of an aerator component  616   b  that may be included in the exemplary microbubble generator  600  of  FIG. 6A . As shown the aerator component  616   b  has an exterior body  630 , which, in some implementations is cylindrical and characterized by a longitudinal axis  624 . One or more alignment tabs, such as alignment tab  632 , may protrude from the exterior body  630 ; and such alignment tab  632  may be configured to interface with one or more alignment grooves  633  in the housing  619  (see  FIG. 6A )—such that when the aerator components  616   a ,  616   b  and  616   c  and housing  619  are coupled together, the one or more alignment tabs  632  and the one or more alignment grooves  633  cooperate to radially fix the housing and each of the plurality of aerator components relative to each other. 
     As indicated above, when disposed in the microbubble generator  600 , the longitudinal axis  624  of the aerator component  616   b  may align coaxially with the longitudinal axis  622  of the housing  619  and the longitudinal axis  623  of the syringe  603 . The aerator component  616   b  has an inlet end  634  and an outlet end  637 . As will be described in more detail with reference to  FIGS. 6D and 6E , the aerator component  616   b  may include a tapered output port  640  and a transverse vent hole  643 . 
       FIG. 6C  is a perspective cross-sectional view of the aerator component  616   b ;  FIG. 6D  illustrates a side view of the aerator component  616   b ; and  FIG. 6E  illustrates a side cross section of the aerator component  616   b . As illustrated in  FIG. 6D , the tapered output port  640  may have a diameter  646  that is less than a diameter  649  of the exterior body  630 , as well as a taper  652  that narrows the diameter  646  from its start at the exterior body  630  to its distal end. 
     With reference to  FIG. 6E , in the implementation shown, the aerator component  616   b  includes an interior cavity  655  that has four discrete sections—an input port section  658 , an inlet section  661 , a throat section  664 , and an outlet section  667 . The input port section  658  is configured to receive a tapered output port of another aerator component (e.g., the tapered output port  640  of aerator component  616   b ) or of the syringe tip  612 —that is, the input port section  658  may have a diameter  670  that is only slightly larger than the diameter  646  of the tapered output port  640 , and that diameter  670  may decrease from outside to inside the input port section  658 , corresponding to the taper  652  of the tapered output port  640 . 
     As shown, the inlet section  661  has a progressively decreasing diameter that constricts flow of a gas or liquid through the aerator component  616   b  as that gas or liquid flows from the input port section  658  to a subsequent throat section  664 . As described above with respect to other implementations, this constriction of flow increases the corresponding velocity of the gas or liquid and lowers its pressure. This lowering of pressure allows gas or liquid in the circumferential air pocket  631  (see  FIG. 6A ) to be drawn into the flow, through the transverse vent hole  643 , in the throat section  664 . In some implementations, the progressively decreasing diameter ranges from about 3.5 mm to about 0.5 mm. 
     In some implementations, as shown, an outlet section  667  follows the throat section  664 . In the outlet section  667 , a diameter of the interior cavity  655  increases from the throat section  664  toward the tapered output port  640 . In some implementations, the increasing diameter of the outlet section  667  ranges from about 0.5 mm to 3.5; more preferentially, the diameter may range from about 0.65 mm to about 2.1 mm. 
     In some implementations, a boundary between the inlet section  661  and throat section  664  may be rounded and/or smooth (e.g., to minimize turbulence). In some implementations, the throat section  664  may have a slight taper (e.g., to facilitate a clean molding process). In some implementations, a boundary between the throat section  664  and outlet section  667  may by rounded and/or smooth (e.g., to minimize turbulence). In some implementations, various surfaces and boundaries may have a rough surface treatment, or edges may be sharp, rather than rounded or smooth (e.g., to increase turbulence). 
       FIG. 6F  is a perspective cross-sectional view of a plurality  616  of aerator components  616   a ,  616   b  and  616   c  that may be coupled together and included in the exemplary microbubble generator  600 . As shown, each component  616   a ,  616   b  and  616   c  is tightly coupled to the next, such that a channel  673  is formed from the input port section of the aerator component  616   a  to the outlet section of the aerator component  616   c . In some implementations, the channel  673  is fluid-tight from end-to-end, except at the transverse vent holes in each aerator component  616   a ,  616   b , and  616   c —that is, each aerator component may be tightly sealed to the next, such that fluid (e.g., liquid or gas) cannot leak out of the channel  673  at the intersection of the tapered output port of one aerator component and the input port section of another aerator component. 
     As depicted in  FIG. 6F , some variation may exist in the diameter of each throat section  664   a ,  664   b  or  664   c  in the plurality  616  of aerator components. That is, the diameter of throat section  664   c  of aerator component  616   c  may be larger than the diameter of throat section  664   b , which may be larger than the diameter of throat section  664   a . Similarly, there may be variation in the diameters of the transverse vent holes  643   a ,  643   b  and  643   c . In some implementations, diameters of the throat sections  664   a ,  664   b  and  664   c  may range from 0.4 mm or less to 2.0 mm or more. For example, one implementation may include aerator components with diameters of 0.45 mm, 2 mm and 2 mm; another implementation may include aerator components with diameters of 0.45 mm, 1 mm and 2 mm; yet another implementation may include aerator components with diameters of 1 mm, 1 mm and 2 mm. In some implementations, it may be advantageous to arrange aerators such that diameters are increasing from proximal end (e.g., the syringe end) to the distal end; in other implementations, a different arrangement may be advantageous. 
     In some implementations, the diameters of transverse vent holes  643   a ,  643   b  and  643   c  may range from 0.3 mm or less to 1.0 mm or more. For example, in some implementations, the proximal-most vent hole  643   a  may be approximately 1.0 mm, and the distal-most vent hole  643   c  may be approximately 0.6 mm; in other implementations, the proximal-most vent hole  643   a  may be approximately 0.3 mm, and the distal-most vent hole  643   c  may be approximately 0.6 mm. 
       FIG. 6G  is a perspective cross-sectional view of the exemplary microbubble generator  600 , including a cap  676  and sealing pin  679 . In some implementations, as shown, the cap  676  is threaded to engage with a Luer lock  680  or other threaded fitting at the discharge tip  628 . The cap  676  may include a sealing pin  679 , which, in some implementations, is configured to seal off the smallest-diameter throat section (e.g., throat section  664   a , as shown). In such implementations, the cap  676  may seal off the channel  673  and the circumferential gas pocket  631  (through the transverse vent holes (not visible in  FIG. 6G )); and the sealing pin may seal off the throat  664   a , thereby sealing off the inlet section  661   a  of aerator  616   a  and everything fluidly coupled thereto (e.g., an interior of the syringe tip  612  and of the barrel  606 ). In these implementations, the cap  676  and sealing pin  679  may maintain sterility of the contents of the syringe  603  and may prevent liquid or gas in the syringe  603  from leaking into the circumferential gas pocket  631  before the cap  676  and sealing pin  679  are removed. 
       FIG. 7A  is a perspective cross-sectional view of another exemplary microbubble generator  700 . As shown, the exemplary microbubble generator  700  includes a syringe  703  having a barrel  706 , a plunger  709 , and a syringe tip  712 . The syringe tip  712  may include a Luer lock fitting  713  having corresponding threads. 
     An aerator  716  may be coupled to the syringe tip  712 , and a housing  719  may circumferentially surround an end of the barrel  706  and the aerator  716 . The housing  719  may have a longitudinal axis  722 , which, in some implementations, aligns coaxially with a longitudinal axis  723  of the syringe  703  and a longitudinal axis  724  of the aerator  716 . 
     As shown, the housing  719  has an interior surface  725  and a discharge tip  728 . In some implementations, the housing  719  is configured to fluidly seal against the barrel  706 , and the aerator  716  may be sealed to the syringe tip  712  and the discharge tip  728 , such that any fluid that is ejected from the syringe  703  (e.g., by a user of the syringe  703  depressing the plunger  709 ) is ejected through the syringe tip  712 , into an interior cavity  755  (see  FIG. 7B ) of the aerator  716 , through the discharge tip  728 . A circumferential gas pocket  731  may be created by the interior surface  725 , the aerator  716 , the syringe tip  712 , and the discharge tip  728 . 
     With reference to  FIG. 7B , in the implementation shown, the aerator  716  includes an interior cavity  755  that has five discrete sections—an input port section  758 , an inlet section  761 , a throat section  764 , a diffusing section  765 , and an outlet section  767 . The input port section  758  may be configured to receive the syringe tip  712 —that is, the input port section  758  may have a diameter that is only slightly larger than the diameter of the syringe tip  712 , and that diameter of the input port section  758  may decrease from outside to inside the input port section  758 . 
     As shown, the inlet section  761  has a progressively decreasing diameter that constricts flow of a gas or liquid through the aerator  716  as that gas or liquid flows from the input port section  758  to a subsequent throat section  764 . As described above with respect to other implementations, this constriction of flow of the gas or liquid increases its corresponding velocity and lowers its pressure. This lowering of pressure allows gas to be drawn into the flow through the first vent hole  743 . 
     In some implementations, as shown, a diffusing section  765 , having a progressively increasing diameter, follows the throat section  764 ; and an outlet section  767  follows the diffusing section  765 , which outlet section  767  may be cylindrical in structure. In other implementations, the diffusing section  765  and outlet section  767  may be a single section whose diameter progressively increases from the throat section  764  to a tapered outlet port  740 . 
     In some implementations, as shown, a second vent  744  may be disposed in the outlet section  767  (or, in some implementations, the diffusing section  765 ). In operation, the first vent  743  and second vent  744  may cooperate to increase efficiency at which fluid moving through the throat section  764  aspirates gas, through the first vent hole  743 , from the circumferential gas pocket  731  (see  FIG. 7A ). For example, in some implementations, an initial quantity of fluid passing through the interior cavity  755  may displace air or other gas in the interior cavity  755  primarily through the second vent hole  744 , rather than through the first vent hole  743 —thereby (i) more quickly pressurizing the circumferential gas pocket  731  and allowing gas in the circumferential gas pocket  731  to be aspirated into the fluid stream moving through the interior cavity  755 ; and (ii) minimizing the simultaneous movement of a quantity of liquid from the interior cavity  755  into the circumferential gas pocket  731  and movement of gas from the circumferential gas pocket  731  into the interior cavity  755 —which simultaneous movement of liquid in one direction and gas in the opposite direction, through the same first vent hole  743 , may create turbulence and result in larger bubbles of air being aspirated or formed than would otherwise be the case in implementations that include the second vent hole  744 . 
     In some implementations, the second vent hole  744  is larger than the first vent hole  743 . In such implementations, this difference in size, coupled with the difference in pressure of gas, liquid, or a combination thereof in the throat section  764  relative to the outlet section  767 , may result in both the liquid itself, and gas that is initially displaced from the interior cavity  755  (e.g., as an initial quantity of fluid flows through said interior cavity  755 ), flowing from the interior cavity  755  into the circumferential gas pocket  731  primarily through the second vent hole  744 . 
     Regardless of the mechanism of action for any specific implementation, Applicant surprisingly found that a single aerator  716  with both a first vent hole  743  and a second vent hole  744  (e.g., in the outlet section  767 , as shown, or in the diffusing section  765 ) significantly outperformed a single aerator  716  having only a single vent hole  743 . 
     In this context, “performance” may be quantified in terms of (i) production of a significant quantity of very small bubbles (e.g., bubbles having an average diameter of about 300 μm or less; or bubbles having an average diameter of about 250 μm or less; or bubbles having an average diameter of about 200 μm or less; or bubbles having an average diameter of about 100 μm or less; or more preferably, bubbles having an average diameter of less than about 50 μm; or still more preferably, bubbles having an average diameter of less than about 20 μm; or bubbles having an average diameter of less than about 10 μm; or bubbles having an average diameter of less than about 2 μm—note that in some implementations, it may be advantageous to produce bubbles on the higher end of the example ranges provided (e.g., to be more echogenic); whereas in other implementations, it may be advantageous to produce bubbles on the lower end of the example ranges provided (e.g., to more precisely outline internal anatomic features under ultrasound)); and/or (ii) a substantially heterogeneous size distribution of the bubbles produced (e.g., 50% or more of the bubbles falling within one standard deviation of an average bubble size; or 95% of the bubbles falling within one or two standard deviations of an average bubble size; or 99% of the bubbles falling within one, two or three standard deviations of an average bubble size); and/or (iii) with substantially no (or very minimal) production of larger bubbles (e.g., bubbles larger than about 100 μm in diameter, or larger than about 200 μm in diameter, or larger than about 250 μm in diameter, or larger than about 300 μm in diameter). 
     In some implementations, a boundary between the inlet section  761  and throat section  764  may be rounded and/or smooth (e.g., to minimize turbulence). Similarly, a boundary between the throat section  764  and diffusing section  765  or a boundary between the diffusing section  765  and outlet section  767  may by rounded and/or smooth (e.g., to minimize turbulence). In some implementations, the throat section  764  may have a slight taper (e.g., to facilitate a clean molding process). In some implementations, various surfaces and boundaries may have a rough surface treatment, or edges may be sharp, rather than rounded or smooth (e.g., to increase turbulence). 
       FIG. 8A  is a perspective view of an exemplary aerator component  816 . In some implementations, the aerator component  816  may replace the aerator component  716  shown in  FIG. 7A . As shown, the aerator component includes threads  814  that may directly interface with mating threads on a corresponding syringe component (e.g., the threads of the Luer lock fitting  713  shown in  FIG. 7A ). In such implementations, the threads  814  may facilitate a secure, direct connection between the aerator component  816  and a corresponding syringe (e.g., without reliance on a housing component to facilitate that connection). 
     As shown, the aerator component  816  has an exterior body  830 , which, in some implementations, is cylindrical and characterized by a longitudinal axis  824 . In other implementations, the exterior body  830  may have other shapes (e.g., rectangular, cubical, triangular, etc.). One or more alignment tabs, such as alignment tab  832 , may protrude from the exterior body  830 ; and such alignment tab(s)  832  may be configured to interface with one or more alignment grooves in a corresponding housing (e.g., alignment grooves  633  in the housing  619 , shown in  FIG. 6A )—such that when the aerator  816  and corresponding housing are coupled together, the alignment tab(s)  832  and corresponding alignment grooves cooperate to radially fix the housing and aerator component  816  together. When so coupled, the longitudinal axis  824  may align coaxially with longitudinal axes of a corresponding housing and syringe. 
     With reference to  FIG. 8B , in the implementation shown, the aerator  816  includes an interior cavity  855  that has five discrete sections, each fluidly coupled to the next to form a flow path  873  through an interior of the aerator  816 . The five discrete sections shown include an input port section  858 , an inlet section  861 , a throat section  864 , a diffusing section  865 , and an outlet section  867 . The input port section  858  may be configured to receive a syringe tip (like the input port  758  of  FIG. 7B ); and, as noted, threads  814  may be provided to secure the aerator  816  to the syringe tip. The input port section  858  may have a diameter that is only slightly larger than the exterior diameter of the syringe tip, and that diameter of the input port section  858  may decrease from outside to inside the input port section  858  such that the input port section seals against an end of a corresponding syringe tip. 
     As shown, the inlet section  861  has a progressively decreasing diameter that constricts flow of a gas or liquid through the aerator  816  as that gas or liquid flows from the input port section  858  to a subsequent throat section  864 . As described above with respect to other implementations, this constriction of flow of the gas or liquid increases its corresponding velocity and lowers its pressure, which can allow gas to be drawn in through a vent hole  843  in or near the throat section  864 . 
     In the implementation shown, the vent hole  843  is positioned just outside the throat section  864 , in a subsequent diffusing section  865 , rather than in the throat section  864  itself. As shown, the diffusing section has a progressively increasing diameter and follows the throat section  864 ; and an outlet section  867  follows the diffusing section  865 . In other implementations, the diffusion section  865  and outlet section  867  may be a single section whose diameter progressively increases from the throat section  864  to an outlet port  840 . 
     Although the vent hole  843  is not in the throat section  864  itself, as it is in other implementations illustrated and described herein, the vent hole  843  is disposed close enough to the throat section  864  that the pressure of gas or liquid flowing through the aerator  816 , along path  873 , is lower at the point of the vent hole  843  than at other portions along the path  873 ; and this lower pressure allows gas to be drawn into a fluid stream flowing along the path  873 , through the vent hole  843 . 
     Disposition of the vent hole  843  just outside of the throat section  843 , in the diffusing section  865 —rather than in the throat section  834 —can have certain advantages. For example, such an arrangement can facilitate a seal between a sealing pin (such as the sealing pin  679  shown in  FIG. 6G ) and the vent hole  843 , while enabling the sealing pin itself to be larger and more robustly manufactured than would otherwise be possible if such a sealing pin were required to be accommodated by the throat section  864 . In some implementations, this may both simplify the manufacturing process and improve the yield on sealing pins; and it may minimize risk of a fragment of a sealing pin breaking off inside the aerator  816  and possibly being introduced into a stream of fluid that is ultimately injected into a patient.  FIG. 8C  illustrates an exemplary sealing pin  879  and how it may be accommodated by the outlet section  867  and diffusing section  865 . 
     Returning to  FIG. 8A , some implementations may include a second vent  844 . In the implementation shown, the second vent  844  is disposed at a distal end of the aerator component  816 , at an outlet port  840 . The second vent  844  may be formed as a notch in a wall of the outlet port  840 , and the vent  844  may be fluidly coupled to an area adjacent to the exterior body  830  (e.g., when the aerator component  816  is disposed in a corresponding housing, as in the implementations shown in  FIGS. 6A and 7A ) via one or more grooves in the exterior body  830 , such as the groove  845 . In some implementations, implementation of a groove  845  to form the second vent  844  may simplify a manufacturing process, relative to other methods for forming the vent  844 . For example, a groove  845  may simplify a mold and molding process, and obviate, in some implementations, the need for a separate pin in the mold to form the vent. In some implementations, a similar approach (e.g., a groove in place of a hole) may be employed for the vent hole  843 . 
     In some implementations, a groove  845  at the outlet port  840  may provide other advantages. For example, when, in a procedure, the device  700  is disposed vertically, with the outlet port  840  directed downward, the groove  845  is positioned at the lowest point of the adjacent gas pocket  731 . When fluid in the syringe  703  is nearly expelled, any remaining pressurized air or gas in the gas pocket  731  may expel the last bit of fluid—before the pressure between the gas pocket  731  and the path  873  is equalized—such that no (or very few) bubbles are introduced into the final fluid exiting the outlet port  840 . This can be advantageous, because bubbles that are otherwise produced in the last bit of fluid, as that fluid is expelled, may be significantly larger than those created at the vent hole  843 . Similar advantages may result from a second vent  744  that is disposed very near the outlet port  740 . 
     Regardless of their precise construction, the vents  843  and  844  may cooperate to increase efficiency at which fluid moving along the path  873  aspirates gas, through the vent hole  843 , from a circumferential gas pocket (e.g., like the gas pocket  731  illustrated in  FIG. 7A ). For example, in some implementations, an initial quantity of fluid passing through the interior cavity  855  may displace air or other gas in the interior cavity  855  primarily through the second vent hole  844 , rather than through the vent hole  843 —thereby (i) more quickly pressurizing a corresponding circumferential gas pocket and allowing gas in the circumferential gas pocket to be aspirated into the fluid stream moving through the interior cavity  855 ; and (ii) minimizing the simultaneous movement of a quantity of liquid from the interior cavity  855  into the circumferential gas pocket and movement of gas from the circumferential gas pocket into the interior cavity  855 —which simultaneous movement of liquid in one direction and gas in the opposite direction, through the same vent hole  843 , may create turbulence and result in larger bubbles of air or other gas being aspirated or formed than would otherwise be the case in implementations that include the second vent hole  844 . 
     In some implementations, the second vent hole  844  is larger than the vent hole  843 . In such implementations, this difference in size (coupled with the difference in pressure of gas, liquid, or a combination thereof) in the throat and diffusing sections,  864  and  865 , respectively, relative to the outlet section  867 , may result in both the liquid itself, and gas that is initially displaced from the interior cavity  855  (e.g., as an initial quantity of fluid flows through said interior cavity  855 ), flowing from the interior cavity  855  into the circumferential gas pocket primarily through the second vent hole  844 . 
     In some implementations, materials for one or more of the components of the exemplary implementations described herein may be selected based on (a) suitability for use with human patients (i.e., suitable for contact with body-compatible solutions that are to be injected into human patients); (b) solid surface energy (SFE) (e.g., of various components); and (c) interfacial tension (e.g., of the body-compatible solution). The various components described herein may be further selected from materials that are commonly used for the construction of medical devices. Such materials may be selected by virtue of widespread acceptance in the medical device field and/or ability to be sterilized or inherent sterile and/or antimicrobial or antibacterial properties. 
     With respect to SFE, the material used (e.g., in particular for the aerator or aerator components, such as aerator components  616   a ,  616   b  and  616   c  in  FIGS. 6A-6G , aerator  716  in  FIG. 7A , or aerator  816  in  FIG. 8A ) may be selected from among thermoplastics or other materials that may be injection molded and that are accepted for use in medical devices—including, for example, polyethylene (in high or low densities), polypropylene, polymethyl methacrylate (PMMA), polyvinyl chloride (PVC), polyamide, acrylonitrile butadiene styrene (ABS), polycarbonate, acetal, polyethylene terephthalate glycol (PETG), or other suitable materials. 
     More preferentially, in some implementations, the material used may be further selected based on the SFE of the material. For example, in some implementations, it may be advantageous to have a material with an SFE of greater than about 30 millinewtons/meter (“mN/m”) (sometimes expressed alternatively as dynes/cm, where 1 mN/m=1 dyne/cm)—in such implementations, a PVC (with an SFE of about 35 mN/m, in some forms), ABS (with an SFE of about 35 mN/m, in some forms), acetal (with an SFE of about 36 mN/m, in some forms), PMMA (with an SFE of about 41 mN/m, in some forms), polycarbonate (with an SFE of about 46 mN/m, in some forms) or PETG (with an SFE of about 47 mN/m, in some forms) may be selected over polypropylene (with an SFE of about 30 mN/m, in some forms) or a polyethylene (with an SFE of about 30 mN/m, in some forms). In other implementations, it may be advantageous to have a material with an SFE of greater than about 35 mN/m. In still other implementations, it may be advantageous to have a material with an SFE of greater than about 40 mN/m—in such implementations, a PMMA, polycarbonate or PETG may be employed. 
     In some implementations, a material may be treated to raise, lower or otherwise control its SFE (e.g., the surface may be roughened to increase its surface energy, it may be treated chemically, it may be coated with another material, it may be plasma treated or plasma activated, etc.). In many implementations, the practical effect on wettability of the fundamental or treated SFE may matter more than the actual effective value of the SFE—that is, wettability (and specifically, a more wettable, rather than less wettable material) may be more important in certain implementations than the specific SFE value. 
     In some implementations, the body-compatible solution includes a surfactant that lowers an interfacial tension of the solution; or alternatively, the body-compatible solution is one that has an inherently low interfacial tension relative to other body-compatible solutions. For example, in some implementations, the body-compatible solution is dextrose (e.g., D5W, D10W or D50). As another example, in some implementations, the body-compatible solution includes a surfactant such as polysorbate (e.g., 0.001% polysorbate in a saline solution, 0.005% polysorbate in a saline solution, 0.01% polysorbate in a saline solution, 0.1% polysorbate in a saline solution, 1% polysorbate in a saline solution, 10% polysorbate in a saline solution, etc.). In other implementations, other body-compatible surfactants may be used (e.g., nonionic, anionic, cationic, amphoteric surfactants, generally; specific examples may include, among others, propanediol, polyethylene glycol, lecithin, poloxamer, glycerin, hypertonic saline, hydrophobic hydrocarbon chains with hydrophilic heads, caseins, certain proteins, etc.). 
     Various implementations were tested with respect to microbubble production capability in a benchtop setup, and images captured of each test. Those images appear as  FIGS. 9A-9C, 10A-10C, 11A-11C, 12A-12C and 13A-13C . In each test, a device was employed like one of the devices illustrated in and described with reference to  FIG. 6A, 7A or 8A —each device included a syringe body and plunger, a housing, and one or more aerator components within the housing; in addition, a 20-gauge needle was disposed on the end of the housing. For each test, the syringe component was filled with approximately 10 mL of a body-compatible solution, and the device was oriented with the needle disposed in a beaker of tap water. Approximately 3-3.5 mL of room air was enclosed by the housing, in the circumferential air pocket. A black backdrop was placed behind the beaker, and lighting was positioned on the side to illuminate microbubbles formed by the device. 
     In each test, once the syringe was filled and positioned, the plunger of the syringe was manually depressed using a substantially consistent force/speed to force the body-compatible solution through the aerator component(s) and needle, into the beaker of tap water. Depression of the plunger continued until the body-compatible solution was substantially expelled from the syringe. 
     Each of  FIGS. 9A-9C, 10A-10C, 12A-12C, and 13A-13C  includes four panels. In these figures, the left-most panel corresponds to a time approximately 0.5 seconds after the plunger was initially depressed; the left-middle panel corresponds to a time approximately 2.5 seconds after the plunger was initially depressed; the right-middle panel corresponds to a time approximately 6.0 seconds after plunger was initially depressed; and the right-most panel corresponds to a time at which the body-compatible solution was substantially expelled.  FIGS. 11A-11C  include three panels, because in the corresponding examples, the body-compatible solution was expelled from the syringe more rapidly than in the other examples, such that the total time was less than 6.0 seconds after the plunger was initially depressed. In  FIGS. 11A-11C , the left and middle panels remain the same as in  FIGS. 9A-9C, 10A-10C, 12A-12C , and  13 A- 13 C—namely, these panels correspond to times of approximately 0.5 and 2.5 seconds after the plunger was initially depressed; the right panel corresponds to a time at which the body-compatible solution was substantially expelled (prior to 6.0 seconds). 
     Each test (“example”) and the results thereof are now described in detail. In the descriptions that follow, subjective descriptions of bubble size are provided (e.g., “microbubbles,” “very small” bubbles, “small” bubbles, “medium-sized” bubbles and “large” bubbles); these qualitative descriptions are provided to facilitate qualitative comparison. In some implementations, “large” bubbles may be 1 mm or more in diameter (e.g., 1 mm, 2 mm, 3 mm, 5 mm, etc.); “medium-sized” bubbles may have diameters ranging from about 0.5 mm to about 1 mm; “small” bubbles may have diameters ranging from about 0.1 mm (100 μm) to about 0.5 mm; “very small” bubbles may have diameters ranging from about 10 μm to about 100 μm; and “microbubbles” may have diameters ranging from about 1 μm to about 10 μm. In other implementations, different ranges may apply—for example, in some implementations, “microbubbles” may have diameters less than 1 μm (and may include what could be referred to as “nanobubbles”); as another example, “microbubbles” may include bubbles having diameters of about 1 μm to about 25 μm; as another example, “very small” bubbles may have diameters ranging from 2 μm to about 50 μm. Many specific ranges are possible; and as stated, the primary point of the bubble size references is for qualitative comparison. 
     Example 1 (Multi-Stage, Polypropylene, Saline) 
     In a first example, illustrated in  FIG. 9A , a device having multiple aerator components (e.g., like the exemplary microbubble generator  600  shown in  FIG. 6 ), each made of polypropylene, was employed; and the syringe was filled with saline. As captured in the left-most panel, initial expulsion of the saline resulted in production of a minimal volume of small to medium-sized bubbles. Bubble production continued to be intermittent and minimal as the saline was expelled from the syringe (note that some small and medium-sized bubbles are visible in solution in the left-middle and right-middle panels). After about 8.5 seconds (see right-most panel), when the saline was substantially expelled, a significant volume of large bubbles was produced. 
     Example 2 (Multi-stage, Polypropylene, Dextrose) 
     In a second example, illustrated in  FIG. 9B , a device having multiple aerator components, each made of polypropylene, was employed; and the syringe was filled with D50 dextrose (e.g., a solution comprising 50% dextrose). As captured in the left-most panel, initial expulsion of the dextrose resulted in production of a minimal volume of small to medium-sized bubbles. Bubble production was more continuous with the dextrose than with pure saline, and more small bubbles were produced (with medium-sized bubbles also being produced throughout—see left-middle and right-middle panels). A greater quantity of bubbles was produced with dextrose than with saline, but the overall volume remained relatively low. After about 10 seconds (see right-most panel), when the dextrose was substantially expelled, a significant volume of large bubbles was produced. 
     Example 3 (Multi-Stage, Polypropylene, Saline/Polysorbate) 
     In a third example, illustrated in  FIG. 9C , a device having multiple aerator components, each made of polypropylene, was employed; and the syringe was filled with saline with a small quantity of polysorbate added (approximately 1% by volume). As illustrated in the left-most panel, initial expulsion of the saline/polysorbate resulted in production of a quantity of very small bubbles and microbubbles (as illustrated by the “cloud-like” pattern). After an initial production of very small bubbles, bubble production tapered off with only intermittent production of very small, small and medium-sized bubbles being produced (see left-middle and right-middle panels). After about 9 seconds (see right-most panel), when the saline/polysorbate was substantially expelled, a significant volume of large bubbles was produced. 
     Example 4 (Multi-Stage, Polycarbonate, Saline) 
     In a fourth example, illustrated in  FIG. 10A , a device having multiple aerator components, each made of polycarbonate, was employed; and the syringe was filled with saline. As illustrated in the left-most panel, initial expulsion of the saline resulted in production of a volume of large bubbles. Steady production of large bubbles continued for approximately two seconds, after which, a steady but minimal stream of small and medium-sized bubbles continued (see left-middle and right-middle panels). After about 11 seconds (see right-most panel), when the saline was substantially expelled, bubble production simply stopped—no large bubbles were produced at the end, as they had been in the previous examples. 
     Example 5 (Multi-stage, Polycarbonate, Dextrose) 
     In a fifth example, illustrated in  FIG. 10B , a device having multiple aerator components, each made of polycarbonate, was employed; and the syringe was filled with D50 dextrose. As illustrated in the left-most panel, initial expulsion of the dextrose resulted in production of a smooth stream of microbubbles (appearing as a bright cloud). Large bubbles initially accompanied the microbubbles for about two seconds, after which point bubble production slowed slightly (but remained consistent throughout—see left-middle and right-middle panels), and bubble size shifted to mostly very small bubbles. After about 13 seconds (see right-most panel), when the dextrose was substantially expelled, bubble production simply stopped, and no large bubbles were produced at the end. 
     Example 6 (Multi-Stage, Polycarbonate, Saline/Polysorbate) 
     In a sixth example, illustrated in  FIG. 10C , a device having multiple aerator components, each made of polycarbonate, was employed; and the syringe was filled with saline with a small quantity of polysorbate added (approximately 1% by volume). As illustrated in the left-most panel, initial expulsion of the saline/polysorbate resulted in production of a smooth stream of microbubbles (in a significant quantity, relative to the other examples) with a minimal number of small and very small bubbles (and virtually no medium-sized or large bubbles forming). Steady production of microbubbles continued for about two seconds, after which the volume of bubbles decreased slightly, and the bubbles appeared to increase in size slightly, to very small bubbles (see left-middle and right-middle panels). After about 10.5 seconds (see right-most panel), when the saline/polysorbate was substantially expelled, bubble production tapered off without the production of any large bubbles. 
     Example 7 (Single-Stage, Polypropylene, Saline) 
     In a seventh example, illustrated in  FIG. 11A , a device having a single aerator component (e.g., like the exemplary microbubble generator  700  shown in  FIG. 7 ) made of polypropylene was employed; and the syringe was filled with saline. As illustrated in the left-most panel, initial expulsion of the saline resulted in production of a quantity of small, medium-sized and large bubbles. Production of these bubbles remained consistent for about one second, after which bubble production diminished, and bubble size decreased (see middle panel). After about 3.5 seconds (see right panel), when the saline was substantially expelled, a significant volume of large bubbles was produced. As evident from the existence of only three panels in  FIG. 11A  (and  FIGS. 11B and 11C ), the duration during which bubbles were produced was much shorter in example seven (and examples eight and nine) than in the other examples provided. 
     Example 8 (Single-Stage, Polypropylene, Dextrose) 
     In an eighth example, illustrated in  FIG. 11B , a device having a single aerator component made of polypropylene was employed; and the syringe was filled with D50 dextrose. As illustrated in the left panel, initial expulsion of the dextrose resulted in production of a quantity of small and medium-sized bubbles. Production of these bubbles remained consistent for about one second, after which bubble production diminished, and bubble size decreased (see middle panel). After about four seconds (see right panel), when the dextrose was substantially expelled, a significant volume of large bubbles was produced. 
     Example 9 (Single-Stage, Polypropylene, Saline/Polysorbate) 
     In a ninth example, illustrated in  FIG. 11C , a device having a single aerator component made of polypropylene was employed; and the syringe was filled with saline with a small quantity of polysorbate added (approximately 1% by volume). As illustrated in the left panel, initial expulsion of the saline/polysorbate resulted in production of a quantity of microbubbles, with some small and medium-sized bubbles also present. Production of these bubbles remained consistent for about one second, after which bubble production diminished (see middle panel). After about four seconds (see right panel), when the saline/polysorbate was substantially expelled, a significant volume of large bubbles was produced. 
     Example 10 (Single-Stage, Polycarbonate, Saline) 
     In a tenth example, illustrated in  FIG. 12A , a device having a single aerator component made of polycarbonate was employed; and the syringe was filled with saline. As illustrated in the left-most panel, initial expulsion of the saline resulted in production of a quantity of small, medium-sized and large bubbles. Production of these bubbles remained consistent for about four seconds (see left-middle panel), after which bubble production nearly ceased (see right-middle panel). After about seven seconds (see right-most panel), when the saline was substantially expelled, a significant volume of large bubbles was produced. 
     Example 11 (Single-Stage, Polycarbonate, Dextrose) 
     In an eleventh example, illustrated in  FIG. 12B , a device having a single aerator component made of polycarbonate was employed; and the syringe was filled with D50 dextrose. As illustrated in the left-most panel, initial expulsion of the dextrose resulted in production of a quantity of small and very small bubbles, with a few medium-sized and large bubbles also present. Production of small and very small bubbles continued for approximately three seconds (see left-middle panel), after which bubble production tapered off somewhat but remained consistent, with small and very small bubbles being produced (see right-middle panel). After about 7.5 seconds (see right-most panel), when the dextrose was substantially expelled, a volume of large bubbles was produced. 
     Example 12 (Single-Stage, Polycarbonate, Saline/Polysorbate) 
     In a twelfth example, illustrated in  FIG. 12C , a device having a single aerator component made of polycarbonate was employed; and the syringe was filled with saline with a small quantity of polysorbate added (approximately 1% by volume). As illustrated in the left-most panel, initial expulsion of the saline/polysorbate resulted in production of a quantity of small and very small bubbles and microbubbles, with a few medium-sized and large bubbles also present. Production of very small bubbles and microbubbles continued for approximately three seconds (see left-middle panel), after which bubble production tapered off somewhat but remained consistent, with very small bubbles and microbubbles being produced (see right-middle panel). After about 7.0 seconds (see right-most panel), when the saline/polysorbate was substantially expelled, a volume of large bubbles was produced. 
     Example 13 (Single-Stage, Acetal, Saline) 
     In a thirteenth example, illustrated in  FIG. 13A , a device having a single aerator component made of acetal was employed; and the syringe was filled with saline. As illustrated in the left-most panel, initial expulsion of the saline/polysorbate resulted in production of a quantity of bubbles ranging greatly in size—including large, medium-sized, small and some very small bubbles. Production of bubbles ranging greatly in size continued for approximately three seconds (see left-middle panel), after which bubble production tapered off considerably, with only a small quantity of small and very small bubbles being produced (see right-middle panel). After about 6.5 seconds, medium-sized bubbles were again produced; and at about 8.0 seconds, when the saline was substantially expelled, a volume of large bubbles was produced. 
     Example 14 (Single-Stage, Acetal, Dextrose) 
     In a fourteenth example, illustrated in  FIG. 13B , a device having a single aerator component made of acetal was employed; and the syringe was filled with D50 dextrose. As illustrated in the left-most panel, initial expulsion of the dextrose resulted in production of a quantity of bubbles ranging greatly in size—including large, medium-sized and small bubbles and some very small bubbles and microbubbles. Production of bubbles ranging greatly in size continued for approximately 3.5 seconds (see left-middle panel), after which bubble production tapered off, with primarily very small bubbles and microbubbles being produced (see right-middle panel). After about 9.0 seconds, when the dextrose was substantially expelled, a volume of large bubbles was produced. 
     Example 15 (Single-Stage, Acetal, Saline/Polysorbate) 
     In a fifteenth example, illustrated in  FIG. 13C , a device having a single aerator component made of acetal was employed; and the syringe was filled with saline with a small quantity of polysorbate added (approximately 1% by volume). As illustrated in the left-most panel, initial expulsion of the saline/polysorbate resulted in production of small and very small bubbles and microbubbles. Steady production of bubbles in these ranges continued for approximately 4.0 seconds (see left-middle panel), after which bubble quantity tapered slightly but size remained relatively consistent (see right-middle panel). After about 6.5 seconds, when the saline/polysorbate was substantially expelled, a volume of large bubbles was produced. 
     Analysis of Examples 1-15 
     As these examples show, Applicant found that, with respect to aerator material and bubble formation, polycarbonate aerators generally outperformed polypropylene aerators—in one or more of length of time over which bubbles were produced (and, by extension, quantity of bubbles) and quality of bubbles (where “higher quality” here corresponds to a distribution that primarily includes small and very small bubbles and microbubbles and that minimizes medium-sized and large bubbles). With single-stage aerators, acetal seemed to perform comparably to polycarbonate. With respect to the solution used in the aerators, dextrose outperformed saline across all examples, though the differences between dextrose and saline were less pronounced with polypropylene aerators. Saline with a small quantity of added polysorbate generally outperformed dextrose across all examples; though, again, differences between saline/polysorbate and dextrose were less pronounced with polypropylene aerators. In contrast to single-staged aerators with either dextrose or polysorbate, multi-staged aerators with either dextrose or polysorbate did not produce large bubbles at the end, when the solution was substantially expelled from the syringe. 
     Surprisingly, Applicant found that the combination of polycarbonate and dextrose, or polycarbonate and saline/polysorbate very significantly outperformed (e.g., in bubble quantity and quality, as described above) implementations involving only saline or implementations with polypropylene aerators. Compare, for example,  FIG. 10C  to the other multi-stage implementations depicted in  FIGS. 9A-9C , and  FIGS. 10A-10B ; further compare  FIG. 12C  to the other single-stage implementations depicted in  FIGS. 11A-11C  and  FIGS. 12A-12B . Applicant found that acetal and saline/polysorbate performed similar to polycarbonate and saline/polysorbate (see  FIG. 13C  and  FIG. 12C ). 
     Applicant determined that variations in performance in the various examples are related to (1) the surface energy of the material (polypropylene, polycarbonate or acetal in these examples) from which the aerator components are formed—and perhaps more precisely, the corresponding level of hydrophobicity or hydrophilicity that results from said surface energy of the material; and (2) the presence of a surfactant in the body-compatible solution (both dextrose and polysorbate act as surfactants in solution). 
     Examining these properties independently of each other, various forms of polypropylene have surface energies of about 30 mN/m (milli-Newtons per meter—the International System of Units&#39; standard units for measuring surface energy), whereas various forms of polycarbonate have surface energies of about 46 mN/m. (Various forms of acetal have surface energies of about 36 mN/m—between the surface energies of polypropylene and polycarbonate.) It is believed that the higher surface energy of polycarbonate (and, to a lesser extent, acetal) allows greater spreading of a given solution on the surfaces of the aerator components (e.g., along the channel  773  shown in  FIG. 7B  or the channel  673  shown in  FIG. 6F ) than does the lower surface energy of polypropylene—resulting in more efficient operation of the venturi and corresponding vent in introducing air or other gas into the stream of solution flowing past). Put another way, the difference in surface energies is believed to allow less beading of a given solution on polycarbonate (or acetal) than on polypropylene This greater spreading, or less beading, is believed to facilitate greater uptake of air or gas into a stream of solution flowing through the venturi. 
     Surfactants in solution tend to reduce the interfacial tension between molecules of the solution (independent of effects on interfacial tension that surface energies of materials in contact with the solution may have at the contact surface). That is, in the absence of a surfactant, the intermolecular forces holding individual molecules of the solution to each other may be relatively strong, whereas addition of a surfactant reduces the intermolecular attractive forces, or interfacial tension. It is understood that this reduction of interfacial tension, caused by the presence of a surfactant (e.g., dextrose or polysorbate), increases a solution&#39;s ability to attract air or gas, in the form of microbubbles (e.g., in or near the venturi throat, when the solution is moving through said venturi throat). 
     Surprisingly, Applicant found that variations in these two parameters (surface energy and interfacial tension) combine in a seemingly multiplicative manner rather than merely an additive manner. That is, implementations involving both a higher material surface energy of the aerator components and the presence of a surfactant in the solution facilitated creation of microbubbles that were far superior to bubbles formed in an implementation in which only surface energy was optimized, or only interfacial tension was optimized. For example, with respect to surface energy only, a greater quantity of bubbles were produced by multi-stage aerators having higher surface energies (e.g., more bubbles were produced in example 4 ( FIG. 10A ) than in example 1 ( FIG. 9A )); similarly, a greater quantity of bubbles were produced by single-stage having higher surface energies (e.g., more bubbles were produced in examples 10 and 13 ( FIGS. 12A and 13A ) than in example 7 ( FIG. 11A )). With respect to surfactant only, examples involving dextrose or polysorbate outperformed those involving only saline. However, when these parameters were combined, the differences were very significant—with a multi-stage aerator, bubbles were produced in example 6 ( FIG. 10C ) in much greater quantity and at much higher quality than those produced in example 3 ( FIG. 9C ); and with a single-stage aerator, bubbles were produced in examples 12 and 15 ( FIG. 12C  and  FIG. 13C ) in much greater quantity and at much higher quality than those produced in example 9 ( FIG. 11C ). Thus, Applicant surprisingly found that aerator components made of a high surface energy material (e.g., polycarbonate or acetal), combined with a body-compatible solution having a surfactant (e.g., dextrose or polysorbate), produced greater quantities of higher-quality bubbles than other implementations. 
     Additional Examples 
     One implementation was further tested to assess ultrasound echogenicity of microbubbles produced and introduced into a live porcine model. Specifically, a multi-stage aerator implementation was employed to produce microbubbles in saline or in a saline/polysorbate solution; the saline or saline/polysorbate solution with microbubbles was injected into the venous system of a live porcine model; and ultrasound images were captured using a transesophageal echocardiogram (TEE). These images appear as  FIGS. 14A-14E . Each of these figures comprises a left panel and a right panel. The left panel illustrates the TEE image prior to injection of the solution with microbubbles; and the right panel illustrates the TEE image following injection of the solution with microbubbles. 
     Example 16 (Current Standard of Care) 
       FIG. 14A  illustrates a TEE taken of a procedure in which microbubbles produced using a current standard-of-care procedure were injected into the venous system of the porcine model. Specifically, two 10 mL syringes were coupled together and to an intravenous line using a three-way stop cock. The intravenous line was disposed in the venous system of the porcine model such that any fluid injected therethrough would be carried to the right atrium of the porcine model. Initially, the stop cock was adjusted to isolate the intravenous line and to couple the two syringes. The first syringe initially contained 9 mL of saline, and the second syringe initially contained 1 mL of room air. The syringe plungers were actuated back and forth 30 times to mix the saline and air and form microbubbles, with all of the saline and air (in the form of microbubbles) ending in one syringe. Then, the stop cock was moved to couple that one syringe to the intravenous line, and the corresponding plunger for that syringe was actuated to inject the saline/microbubble mix into the intravenous line. 
     The left panel of  FIG. 14A  illustrates the TEE just prior to the injection. The right atrium is labeled as “RA” in this left panel and in the subsequent panels of  FIGS. 14A-14E . For additional anatomical reference, the left atrium and left ventricle are also labeled (“LA” and “LV,” respectively) in the left panel of  FIG. 14A . In the left panel of  FIG. 14A , the “RA” region initially appears dark—indicating a hypoechogenic or anechogenic response associated with blood flowing through the right atrium; in contrast, the tissue forming the wall of the right atrium (and the other tissue structures of the heart) appears lighter in color—indicating a hyperechogenic response that is generally associated with tissue. 
     The right panel of  FIG. 14  illustrates the TEE following the injection. In this panel, the right atrium appears lighter in color—resulting from the hyperechogenic microbubbles appearing in the right atrium following the injection. 
     Example 17 (Multi-Stage Aerator; Saline with 0.1% Polysorbate) 
       FIG. 14B  illustrates a TEE taken of a procedure in which microbubbles produced using a multi-stage aerator implementation, such as the one illustrated in and described with reference to  FIG. 6A . In this example, the input end of a multi-stage aerator was coupled to a 10 mL syringe filled with saline and a 0.1% polysorbate mixture; and the output end of the multi-stage aerator was coupled to the intravenous line disposed in the venous system of the porcine model (again, such that any fluid injected therethrough would be carried to the right atrium of the porcine model). 
     As in  FIG. 14A , the left panel of  FIG. 14B  illustrates the TEE prior to the injection of the saline/polysorbate/microbubble mixture, and the right atrium is again labeled. After this reference image was captured, the contents of the syringe were injected through the multi-stage aerator and into the intravenous line with a single, steady actuation of the syringe plunger. In contrast to a current standard-of-care procedure captured in and described with reference to  FIG. 14A , no agitation of air and saline between multiple syringes was required. By employing the multi-stage aerator, much user-variability associated with creating microbubbles using the current standard-of-care procedure was eliminated. 
     As shown in the right panel of  FIG. 14B , the right atrium again appears lighter in color resulting from hyperechogenic microbubbles appearing in the right atrium following the injection. A comparison of the right panels of  FIG. 14A  and  FIG. 14B  reveals a nearly identical ultrasound image. That is, a multi-stage aerator as described herein produces microbubbles of the same quality as those produced using a current standard-of-care procedure, but without user-dependent preparation of air and saline using multiple syringes and a three-way stop cock. 
     Example 18 (Multi-Stage Aerator; Saline with 0.01% Polysorbate) 
       FIG. 14C  illustrates a TEE taken of a procedure in which microbubbles produced using a multi-stage aerator implementation, such as the one illustrated in and described with reference to  FIG. 6A . In this example, the input end of a multi-stage aerator was coupled to a 10 mL syringe filled with saline and a 0.01% polysorbate mixture; and the output end of the multi-stage aerator was coupled to the intravenous line disposed in the venous system of the porcine model (again, such that any fluid injected therethrough would be carried to the right atrium of the porcine model). 
     Again, the left panel of  FIG. 14C  illustrates the TEE prior to the injection of the saline/polysorbate/microbubble mixture. After this reference image was captured, the contents of the syringe were injected through the multi-stage aerator and into the intravenous line with a single, steady actuation of the syringe plunger. As shown in the right panel of  FIG. 14C , after the injection, the right atrium again appears lighter in color—resulting from hyperechogenic microbubbles appearing in the right atrium following the injection. The ultrasound image quality is comparable to that in Examples 16-17—again equaling that of a current standard-of-care procedure. 
     Example 19 (Multi-Stage Aerator; Saline with 0.005% Polysorbate) 
       FIG. 14D  illustrates a TEE taken of a procedure in which microbubbles produced using a multi-stage aerator implementation, such as the one illustrated in and described with reference to  FIG. 6A . In this example, the input end of a multi-stage aerator was coupled to a 10 mL syringe filled with saline and a 0.005% polysorbate mixture; and the output end of the multi-stage aerator was coupled to the intravenous line disposed in the venous system of the porcine model (again, such that any fluid injected therethrough would be carried to the right atrium of the porcine model). 
     Again, the left panel of  FIG. 14D  illustrates the TEE prior to the injection of the saline/polysorbate/microbubble mixture. After this reference image was captured, the contents of the syringe were injected through the multi-stage aerator and into the intravenous line with a single, steady actuation of the syringe plunger. As shown in the right panel of  FIG. 14D , after the injection, the right atrium again appears lighter in color—resulting from hyperechogenic microbubbles appearing in the right atrium following the injection. The ultrasound image quality is comparable to that in Examples 16-18—again equaling that of a current standard-of-care procedure. 
     Example 20 (Multi-Stage Aerator; Saline with 0.005% Polysorbate) 
       FIG. 14E  illustrates a TEE taken of a procedure in which microbubbles produced using a multi-stage aerator implementation, such as the one illustrated in and described with reference to  FIG. 6A . In this example, the input end of a multi-stage aerator was coupled to a 10 mL syringe filled with saline and a 0.005% polysorbate mixture; and the output end of the multi-stage aerator was coupled to a 20-gauge needle, which was directly disposed (without any intervening intravenous line) in the venous system of the porcine model (again, such that any fluid injected therethrough would be carried to the right atrium of the porcine model). 
     The left panel of  FIG. 14E  illustrates the TEE prior to the injection of the saline/polysorbate/microbubble mixture. After this reference image was captured, the contents of the syringe were injected through the multi-stage aerator and 20-gauge needle with a single, steady actuation of the syringe plunger. As shown in the right panel of  FIG. 14E , after the injection, the right atrium again appears lighter in color—resulting from hyperechogenic microbubbles appearing in the right atrium following the injection. The ultrasound image quality is comparable to that in Examples 16-19—again equaling that of a current standard-of-care procedure. As illustrated in this example, there was no perceptible difference in ultrasound image quality between saline/polysorbate/microbubbles being injected through an intravenous line or through a 20-gauge needle. 
     Analysis of Examples 16-20 
     As Examples 16-20 illustrate, aerators such as those described herein can produce microbubbles with application for echocardiogram studies and other studies of anatomical structures, such as those utilizing ultrasound and a contrast agent. Moreover, aerators can produce microbubbles from solutions of saline and polysorbate in various concentrations for use in studies of living patients. 
     Variation in polysorbate concentration may produce effects that are not captured in  FIGS. 14B-14E . For example, in some implementations, microbubbles may be smaller with concentrations of polysorbate of approximately 0.1%; and microbubbles in such implementations may be useful in imaging very small anatomic structures (e.g., PFOs, ASDs, or pAVMs). In some implementations, the concentration of polysorbate may influence the time required for microbubbles to dissipate within the circulatory system. Some concentrations may require greater clearance time than other concentrations; thus, by adjusting the polysorbate concentration, one may be able to control clearance time. Polysorbate concentration may also influence precise echogenicity of microbubbles. In some implementations, it may be advantageous to produce microbubbles having greater hyperechogenicity (e.g., to clearly outline a structure); whereas in other implementations, it may be advantageous to produce microbubbles that are merely echogenic (e.g., to facilitate better imaging of adjacent structures). 
     CONCLUSION 
     While many implementations are described with reference to heart studies, contrast studies may have other useful applications. For example, microbubbles combined with ultrasound or other imaging technology may be clinically useful in documenting proper catheter placement during pericardiocentesis, central venous catheter placement in the right atrium, and during interventional radiology procedures. In the field of gynecology, for example with ultrasound/infertility procedures, microbubbles may be used to assess patency of the fallopian tubes. Other applications could include imaging of abdominal spaces, portions of the gastrointestinal tract, and joints or other interstitial spaces of a human body. Microbubbles may also be employed in veterinary procedures in a similar manner as described herein. 
     Several implementations have been described with reference to exemplary aspects, but it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the contemplated scope. For example, syringes of various sizes may be employed; a converging nozzle may be integral to the syringe; an aerator may be integral to the converging nozzle; converging nozzles and aerators may be an integral assembly; components may be adhesively joined, ultrasonically welded or molded as unitary parts; some implementations may employ O-rings and compression fittings to join components while other implementations may employ different techniques; different size air channels and geometries may be employed within a converging nozzle; syringes may be prefilled or filled on-site, immediately prior to a procedure; microbubbles may be generated in saline, dextrose, plasma, saline/polysorbate, saline with some other surfactant, or some other body-compatible fluid or combination of fluids; microbubbles may be employed in the context of ultrasound or with other imaging technology; microbubbles may be employed for diagnostic or therapeutic purposes; kits may be provided with any number of microbubble generators, coupled together with a manifold or provided with a manifold for coupling prior to a procedure; different membranes, caps or seals may be employed to contain pre-filled fluid within certain portions of a microbubble generator or microbubble generation system; various numbers of air channels may be employed to facilitate generation of a greater or smaller number of microbubbles per unit of fluid; the air channels may have various dimensions, geometries and/or surface treatment to control size of generated microbubbles; in place of “air” throughout, another gas may be employed (e.g., oxygen, nitrogen, carbon dioxide, some mixture thereof, another biologically compatible gas, etc.); a continuous source of saline or other fluid may replace a syringe; a syringe may be automatically or manually operated; microbubbles may include “nanobubbles” or bubbles of various sizes and distributions; aerator components may vary in dimension (e.g., throat diameter, vent diameter); different numbers of aerator components may be deployed (e.g., one, two, three or more); aerator components may be staged in sequence with different sequences of dimensions (e.g., throats ranging from smaller to larger or in some other sequence); a single-aerator implementation may include different numbers of vent holes (e.g., one, two, three or more); vent holes may be transverse holes that are generally perpendicular to a longitudinal axis of a corresponding channel or flow path; vent holes may be angled relative to a longitudinal axis of a corresponding channel or flow path; vent holes may comprise grooves or other paths that fluidly couple an area exterior to an aerator body to a flow path interior to the aerator body. 
     Many other variations are possible, and modifications may be made to adapt a particular situation or material to the teachings provided herein without departing from the essential scope thereof. Therefore, it is intended that the scope include all aspects falling within the scope of the appended claims.