Patent Publication Number: US-2022233760-A1

Title: Syringe-based microbubble generator

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. application Ser. No. 17/158,396, titled “SYRINGE-BASED MICROBUBBLE GENERATOR,” filed on Jan. 26, 2021, now U.S. Pat. No. 11,191,888, the entire contents of which are hereby incorporated 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 secure 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, a plunger and a syringe tip; a unitary component having a converging nozzle and aerator; and a housing surrounding the unitary component. The housing may form an air chamber between an interior surface of the housing and an exterior surface of the unitary component. 
     The converging nozzle may have a coupling end, a converging tip opposite the coupling end, and an interior channel that fluidly couples the coupling end and converging tip. The interior channel may have a diameter that progressively decreases from the coupling end to the converging tip. The converging nozzle may be coupled to the syringe tip at its coupling end. The aerator may have an inlet that is axially aligned with the interior channel and a discharge channel that is fluidly coupled to the inlet. The unitary component may further include one or more air channels that fluidly couple the air chamber and a region adjacent the converging tip and the inlet. 
     The device may further include one or more seals that isolate the air chamber from a region exterior to the housing from ingress or egress of gas or liquid via any path other than through the one or more air channels. In some implementations, the one or more seals are one or more O-rings. The syringe may be a medical-grade syringe having a capacity of 1 mL, 2 mL, 3 mL, 5 mL, 10 mL or 20 mL. At least one of a dimension, a geometry or a surface treatment of the one or more air channels, the converging tip or the inlet may be configured to facilitate creation of microbubbles having a surface tension or charge that minimizes coalescence of microbubbles after they are generated. 
     In some implementations, at least one of a dimension, a geometry or a surface treatment of the one or more air channels, the converging tip or the inlet may be configured to facilitate creation of microbubbles having an average diameter of about 40 μm or less or about 100 μm or less; or an average diameter of about 5 μm to about 10 μm; or an average diameter of about 2 μm or less. 
     In some implementations, a device for generating microbubbles (e.g., for use as a contrast agent) includes a syringe having a barrel, a plunger and a syringe tip; a converging nozzle; and an aerator. The converging nozzle may have a coupling end, a converging tip opposite the coupling end, an exterior mating surface adjacent the converging tip, and an interior channel that fluidly couples the syringe tip and converging tip. The interior channel may have a diameter that progressively decreases from the coupling end to the converging tip. The converging nozzle may be coupled to the syringe tip at its coupling end. The aerator may have a retention end, a discharge end, an interior air chamber, an interior circumferential lip, and a discharge channel at the discharge end. The retention end may be coupled to the converging nozzle. The interior circumferential lip may abut the exterior mating surface. The interior circumferential lip may be disposed adjacent the exterior mating surface. One or more air channels may fluidly couple the discharge channel and the interior air chamber. 
     In some implementations, each of the one or more air channels is parallel to the exterior mating surface. At least one of a dimension, a geometry or a surface treatment of the one or more air channels may be configured to facilitate creation of microbubbles having an average diameter of about 5 μm to about 10 μm, in some implementations. In other implementations, at least one of a dimension, a geometry or a surface treatment of the one or more air channels may configured to facilitate creation of microbubbles having an average diameter of about 2 μm or less; in still other implementations, at least one of a dimension, a geometry or a surface treatment of the one or more air channels may be configured to facilitate creation of microbubbles having a surface tension or charge that minimizes coalescence of microbubbles after they are generated. 
     The converging nozzle and aerator may each comprise O-ring retention channels, and the aerator and converging nozzle may be coupled by an O-ring seated in the O-ring retention channels. The converging nozzle and aerator may be coupled with an adhesive or by an ultrasonic weld. The syringe and converging nozzle may be coupled with an adhesive or by an ultrasonic weld. The syringe and converging nozzle may be co-molded together. The syringe tip and coupling end may include mating Luer fittings. 
     The device may further include a removable retention pin that, when seated, prevents fluid communication between the interior air chamber and the discharge channel or interior channel. The removable retention pin may provide a sterile seal that protects the discharge channel. 
     In some implementations, a method of generating microbubbles may include providing a microbubble generator having (a) a syringe with a barrel that is filled with a body-compatible fluid, a plunger and a syringe tip; (b) a converging nozzle; and (c) an aerator; coupling the discharge end to an intravenous line disposed in a patient undergoing a procedure; and generating microbubbles by forcing the body-compatible fluid out of the syringe and through the converging nozzle and aerator, into a discharge channel. The method may further include extracting a removable retention pin from the discharge channel. 
     The converging nozzle may have a coupling end, a converging tip opposite the coupling end, an exterior mating surface adjacent the converging tip, and an interior channel that fluidly couples the syringe tip and converging tip. The interior channel may have a diameter that progressively decreases from the coupling end to the converging tip. The converging nozzle may be coupled to the syringe tip at the coupling end. The aerator may include a retention end, a discharge end, an interior air chamber, an interior circumferential lip, and a discharge channel at the discharge end. The retention end may be coupled to the converging nozzle. The interior circumferential lip may abut the exterior mating surface. The interior circumferential lip may be disposed adjacent the exterior mating surface. One or more air channels may fluidly couple the discharge channel and the interior air chamber. 
     The progressively decreasing diameter may cause, via the Venturi effect, air to be extracted from the interior air chamber, via the one or more air channels, thereby creating microbubbles. The body-compatible fluid may be saline or dextrose. The removable retention pin, prior to its removal, may prevent fluid communication between the interior air chamber and the discharge channel or interior channel. 
     In some implementations, a method of generating microbubbles includes providing a microbubble generator having (a) a syringe having a barrel filled with a body-compatible fluid, a plunger and a syringe tip; (b) a converging nozzle and aerator; and (c) a housing surrounding the converging nozzle and aerator to form an air chamber between an interior surface of the housing and exterior surfaces of the converging nozzle and aerator. The converging nozzle may have a coupling end, a converging tip opposite the coupling end, and an interior channel that fluidly couples the coupling end and converging tip and has a diameter that progressively decreases from the coupling end to the converging tip. The converging nozzle may be coupled to the syringe tip at its coupling end. The aerator may have an inlet that is axially aligned with the interior channel and a discharge channel that is fluidly coupled to the inlet. The aerator may further include one or more air channels that fluidly couple the air chamber and a region adjacent the converging tip and the inlet. The method may further include coupling the discharge channel to an intravenous line disposed in a patient undergoing a procedure; and generating microbubbles by forcing the body-compatible fluid out of the syringe and through the converging nozzle and aerator, into the discharge channel. 
     In some implementations, the diameter that progressively decreases may cause, via the Venturi effect, air to be extracted from the air chamber, via the one or more air channels, thereby creating microbubbles. In some implementations, the body-compatible fluid may be saline or dextrose. 
     In some implementations, a system for generating microbubbles includes a plurality of microbubble generators and a manifold having at least as many inlet ports as microbubble generators in the plurality of microbubble generators. Each of the plurality of microbubble generators may be coupled to an inlet port in the manifold. The manifold may further include an outlet port configured for coupling to an intravenous line associated with a patient undergoing a procedure. The manifold may include a valve for each inlet port that is configured to permit fluid coupling to or isolation from a corresponding microbubble generator and the outlet port. 
     Each microbubble generator may have (a) a syringe with a barrel that is filled with a body-compatible fluid, a plunger and a syringe tip; (b) a converging nozzle; and (c) an aerator. The converging nozzle may have a coupling end, a converging tip opposite the coupling end, an exterior mating surface adjacent the converging tip, and an interior channel that fluidly couples the syringe tip and converging tip. The interior channel may have a diameter that progressively decreases from the coupling end to the converging tip. The converging nozzle may be coupled to the syringe tip at the coupling end. The aerator may include a retention end, a discharge end, an interior air chamber, an interior circumferential lip, and a discharge channel at the discharge end. The retention end may be coupled to the converging nozzle. The interior circumferential lip may abut the exterior mating surface. The interior circumferential lip may be disposed adjacent the exterior mating surface. One or more channels fluidly may couple the discharge channel and the interior air chamber. 
     In some implementations, at least one of the plurality of microbubble generators is configured to generate microbubbles having a first average diameter, and at least another one of the plurality of microbubble generators is configured to generate microbubbles having a second average diameter, wherein the first average diameter is larger than the second average diameter. 
    
    
     
       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-section view of another exemplary converging nozzle and aerator. 
         FIG. 2F  is a longitudinal cross-section 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. 
     
    
    
     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 production of 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 citing concerns about comfort with the procedure. 
     Described herein is a device and method of 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 fluid 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 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 5% 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.  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  241  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 , and to seal the interior channel  327  and throat  330  of the converging nozzle  315 . 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 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 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. 2B . 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 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” 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 (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 by 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. 
     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, or central venous catheter placement in the right atrium and during interventional radiology procedures. In the field of gynecologic ultrasound/infertility, 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, or other body-compatible fluid; 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; a continuous source of saline or other fluid may replace a syringe; a syringe may be automatically or manually operated. 
     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.