HK1172811A - Methods and devices for sonographic imaging - Google Patents

Description

Method and apparatus for ultrasound examination imaging

RELATED APPLICATIONS

The present application claims priority from U.S. patent application serial No. 12/245,265 filed on 3/10/2008, PCT application number PCT/US2009/059370 filed on 2/10/2009, and U.S. provisional patent application serial No. 61/411,856 filed on 9/11/2010, each of which is incorporated herein in its entirety.

Technical Field

The present invention relates to methods and apparatus for ultrasonic inspection imaging of lumens and conduits, such as organs, tubes and other lumens. In particular, the method and apparatus of the present invention uses detectable acoustic changes in alternating patterns of gas and liquid phases (alternating patterns) that pass through the channels.

Background

Non-surgical diagnostic methods for examining the tubes and cavities of the body, in particular the uterus and fallopian tubes, are well known. One method, known as hysterosalpingography, employs contrast agents (contrast agents) and diagnostic fluorescence imaging techniques to visualize the uterus and fallopian tubes. A safer, cheaper and easier method is utero-salpingography or Sono HSG, where ultrasound is used as the imaging modality. Ultrasound imaging also allows the use of saline as an alternative method to assess the uterine cavity, but does not assess tubal patency. Patency of the fallopian tubes and occlusion of the fallopian tubes can only be assessed under ideal ultrasonographic conditions, which limits their clinical utility.

Currently, no contrast agents are available in the united states that are designed for contrast enhancement during ultrasound assessment of the uterine cavity and fallopian tubes. Other ultrasound contrast agents are available which are widely used, but are limited to use in the heart and blood vessels. Most of the currently available vascular contrast agents are stable against dissolution and fusion due to the presence of other substances, such as an elastic solid shell to enhance stability or a surfactant or a combination of two or more surfactants.

Contrast agents can improve the image quality of ultrasound examinations by reducing the refractive index of unwanted interfaces, or by increasing the backscattered echo from the desired region. In the former method, the contrast agent is taken orally and, for the latter effect, is introduced through the blood vessels. The diameter of the microbubbles in the vascular contrast agent should be less than 10 microns (average 2-5 microns for most newer contrast agents) in order to pass through the pulmonary capillaries and into the systemic circulation. Stability and durability are major problems with these small microbubbles, and bubbles in this size range can only last for a short time in solution. Thus, for systemic vascular applications the gas bubbles must be stabilized to allow the agent to last long enough and withstand pressure changes in the heart. Thus, the availability of contrast agents, procedural challenges (particularly during preparation of the patient and contrast material), and expense are disadvantages associated with known contrast agents used in ultrasound examinations.

While conventional contrast agents function adequately, the disadvantages inherent in conventional agents also create a need for better contrast agents. One disadvantage with currently used contrast agents is that they are very expensive and difficult for some physicians to obtain. Another disadvantage is that conventional contrast agents must be shaken to mix the components or create air bubbles prior to injection, thereby making the overall diagnostic procedure very cumbersome and potentially somewhat subjective. A third disadvantage is that the contrast agent composition, once prepared for use in a patient, has a very short shelf life due to its unstable nature.

Microbubbles in a liquid have previously been used as contrast agents (contrast media). Microbubbles can be generated by methods such as a combination of back and forth syringe motion with air and dispersant, or ultrasonic cavitation devices. Such microbubbles are known to be stable only for a short time. Preformed microparticles using short or long lasting polymeric films have been used to address the problem of short stability lifetimes. Pressurized systems have been used to generate microbubbles in solution. The technique includes means for generating a focused jet of gas to aerate the fluid with microbubbles. These microbubbles may fuse if there is a lag time between generation and application to the structure to be visualized, and therefore these methods employ high velocity flow of liquid. Also, the limitation of this method is that microbubbles introduced into the fluid may fuse into a few large bubbles or one large gas pocket, the formed microbubbles must be stable for a sufficient time to perform visualization, and it is difficult to establish reproducible conditions for comparative visualization due to instability of the microbubbles.

Accordingly, there is a need for devices and methods that produce contrast agents that can address the problems that currently exist. In particular, there is a need for methods and devices for the visualization of organ structure and function, such as the visualization of the uterus and fallopian tubes.

Disclosure of Invention

The present invention includes methods and apparatus for making and using contrast agents. The method of the invention comprises the use of a device for producing a contrast agent for ultrasound observation of an organ or body structure, for example for observation of the uterus and fallopian tubes. The contrast device may include a container assembly, and optionally a catheter assembly fluidly connected to the container assembly. The container assembly may include a first container for providing a liquid solution (e.g., saline), and a second container for providing a gas (e.g., air), and an element for forming an alternating pattern of gas and fluid (alternatingpattern) for direct delivery through the catheter assembly to the organ or structure. The container assembly may include one or more containers. The container assembly may include an element for providing the contained substance from the container to the conduit.

The methods of the present invention comprise ultrasonically viewing a body part, such as the uterus and its associated fallopian tubes, using the devices disclosed herein. The method includes placing a catheter delivery end in close proximity to a structure to be observed and providing a fluid/gas mixture to the structure. For example, in a method of viewing a fallopian tube, a delivery device comprising at least one catheter is placed in the uterus, the at least one catheter is provided through the delivery device and extends to the uterine horn of the uterus, and the delivery end of the catheter is held in place, for example by an end structure such as a balloon. Once the one or more catheters are held in place, a liquid/gas mixture, contrast agent is provided from a contrast agent device into the catheters and into one or more fallopian tubes. Ultrasound imaging is started and one or both fallopian tubes are examined. Depending on the delivery device used to provide the contrast agent, the fallopian tubes may be examined simultaneously or sequentially. If it is desired to visualize the entire uterus, for example after imaging the fallopian tubes, the catheter is withdrawn from the uterine horn and retracted until the end structures of the individual catheter are in place at the uterine entry. End structures, such as balloons, are enlarged to provide a liquid seal to the uterus, and a liquid/gas contrast agent is introduced into the uterus. Ultrasound imaging begins and may continue until a sufficient amount of liquid/gas contrast agent is present in the uterus.

The method includes providing a contrast agent to the uterus and fallopian tubes by providing a catheter delivery end within the uterus and delivering the contrast agent to the uterus. For example, in a method of evaluating the uterus and at least one fallopian tube, the contrast device comprises a catheter, wherein the delivery end of the catheter is positioned within the uterus. The catheter may optionally include an element for preventing backflow of fluid provided to the uterus by the catheter or outflow from the uterus through the cervix. For example, an expandable balloon is an element used to prevent reflux from the uterus to the vagina. Once the catheter or catheters are in place, contrast media, such as a liquid/gas mixture, is provided from the contrast media device through the catheter and into the uterus. Ultrasound imaging is initiated and optionally the uterus is imaged and one or both fallopian tubes are imaged. The fallopian tubes may be examined simultaneously or sequentially. The contrast device may be filled and refilled one or more times to provide an effective amount of contrast to the uterus and fallopian tubes, or to provide one or more visualizations of the uterus and/or the first or second fallopian tubes. The body structure of a human or animal, or inanimate object, can be readily observed with the contrast agent of the present invention. Providing contrast agent directly to the structure to be observed with the catheter assembly helps maintain the structure of the gas and liquid segments (segments) of the liquid/gas mixture. The method of the invention facilitates the reproduction of visualization methods and comparison results from said methods.

Drawings

Fig. 1 is a schematic diagram of an exemplary embodiment of the present invention.

Fig. 2 is a schematic diagram of an exemplary embodiment of the present invention.

Fig. 3 is a schematic diagram of an exemplary embodiment of the present invention.

Fig. 4 is a schematic diagram of an exemplary embodiment of the present invention.

Figure 5 is a schematic representation of the pattern of contrast material in a fallopian tube.

Fig. 6 is a schematic illustration of the pattern of contrast agent observed in the uterus and fallopian tubes provided by an exemplary device of the present invention.

Fig. 7 is a diagram of the internal components, container assembly, of an exemplary device of the present invention.

Fig. 8 is a diagram of an exemplary device of the present invention.

Fig. 9 is a diagram of an exemplary device of the present invention.

Fig. 10 is a diagram of an exemplary device of the present invention.

Fig. 11 is a graph of pressure readings from experiments with an example device including a pressure relief mechanism.

Detailed Description

The present invention includes methods and apparatus for making and using contrast agents for ultrasound or ultrasound inspection visualization of structures. Such structures may be present in the body of a human or animal, or may be inanimate structures. As discussed herein, the methods and devices are used for ultrasound imaging of the uterus and one or more fallopian tubes of a mammal. It will be appreciated that the method and apparatus are not limited to this application but may be used for the visualization of tubes or structures, whether in living beings or inanimate structures.

The present invention includes an apparatus for preparing a contrast agent composition. As used herein, contrast agent (contrast agent) and contrast medium (contrast medium) refer to compositions that can be visualized or visualized by methods known to those skilled in the art, including but not limited to ultrasound, radiography, or other detection methods, and the terms are used interchangeably. The method of the present invention includes the use of a contrast agent device for generating and delivering contrast agents for ultrasonically examining organs or body structures, such as the uterus and fallopian tubes. The method of the invention comprises the use of a contrast agent device for generating a contrast agent for ultrasound examination of an organ or body structure, for example, at least one fallopian tube.

The contrast media device includes a container assembly and, optionally, a catheter assembly fluidly connected to the container assembly. Exemplary embodiments of the container assembly of the present invention are illustrated in fig. 1-4 and 7-10. The container assembly may be provided with a packaging (not shown) enclosing at least a portion of the container assembly. For example, a package may enclose the components of the container assembly, and optionally the outlet end, the actuator, and/or the two plunger ends may be present outside of the package.

The contrast media device includes a container assembly and, optionally, a catheter assembly fluidly connected to the container assembly, and, optionally, a pressure control element. The container assembly may comprise at least one container for fluid. The fluid may be a liquid or a gas. The container assembly may comprise a first container for a liquid, such as saline, and a second container for a gas, such as air, and an element for generating an alternating pattern of gas and fluid. The container assembly may include a connection element (such as a tube or fluid conduit) for providing the contained fluid from the container to the contrast pattern generation chamber and to the catheter assembly, or from outside the container assembly to the contrast pattern generation chamber and to the container. The connecting element may be used to provide fluid from outside the device to the container. The container may include one or more outlets through which fluid (such as gas or liquid) exits the container, or the outlets may be used to provide fluid (liquid or gas) into the container. The container assembly may include means for providing a force on the fluid contained in the container to move the fluid into or out of the container. For example, the container may be a syringe body or barrel and the means for providing a force on the fluid is a syringe plunger. The container assembly may include means for actuating the means for providing a force. For example, the container may be a syringe body or barrel, the means for providing a force on the contained fluid is a syringe plunger, and the means for actuating the plunger may be a pump, or an operator's hand. One aspect of the present invention includes embodiments in which the contrast media device includes two containers, such as two syringe bodies, and the syringe plungers move together in that the two plunger ends are secured together by a component (such as an actuator) such that the syringe plungers move through the interior of the syringe barrel at the same rate, speed and distance. The syringe plungers move at the same rate, speed, and distance because the proximal ends of the plungers are connected together, such as by an element (actuator).

The container assembly may further include a fluid connection between elements that are in fluid connection with each other, such as one or more containers and an imaging pattern generation chamber. Such fluid connections include, but are not limited to, tubing, pipes, or needles. The container assembly may include a contrast-type generation chamber in which a gas phase and a liquid phase are mixed, and a composition exiting the contrast-type generation chamber, the contrast composition characterized by alternating phases of gas and liquid forming a contrast composition type. The container assembly may include a fluid connection that provides the contrast media composition to the catheter assembly or directly to the structure to be imaged.

In one embodiment, the contrast media device may include a container that may function as a contrast pattern generation chamber, wherein the contrast media is manufactured within the container, the contrast pattern generation chamber is absent, and the contrast media composition (e.g., including gas and liquid phases) is provided to the exterior of the contrast media device.

The container assembly may be fluidly connected to a catheter assembly. The catheter assembly may comprise a single or dual lumen catheter. The catheter may include an end structure, such as a balloon on the delivery end of the catheter, where the delivery end of the catheter is distal to the contrast device and the connecting end is proximal to the contrast device. The opposite end (connection end) of the catheter may have a connection element for connecting the catheter to, for example, a contrast agent device. A connecting element, such as a luer lock, may be used to connect the catheter to the contrast device, and connecting devices are known. The catheter may include other components such as wires, sensors, cutting elements, retrieval elements such as clips or forceps. Such catheters are known in the art and one skilled in the art can select an appropriate catheter for the intended operation.

The present invention includes a device for delivering a contrast agent to a structure. Embodiments of the present invention contemplate that the contrast agent is provided by the catheter assembly substantially directly to the structure to be visualized. In one aspect of the invention, for example, directly delivered to the fallopian tubes, the amount of contrast agent used per fallopian tube assessment may be small, such as less than 20mL, less than 15mL, less than 10mL, less than 8mL, less than 5mL, less than 4mL, less than 3mL, less than 2mL, less than 1mL, less than 0.5 mL. The amount of contrast fluid may be any amount sufficient to provide accurate visualization of the structure. The contrast fluid may substantially fill the visualized structure, or may be present only at specific locations within the structure.

The present invention includes a contrast agent device for delivering contrast agent to one or more structures, such as a plurality of lumens, organs, or conduits, fluidly connected to one another. Embodiments of the invention encompass the provision of a contrast agent to at least one structure to be imaged by the catheter assembly, and optionally, by providing a contrast agent to one structure, the contrast agent may also flow into a second, third or more structures to be imaged. In one aspect of the invention, for example, salpingography may first involve providing a sufficient amount of contrast agent to the uterus so that fluid fills the uterus to a certain extent, and then the fluid moves into one or more fallopian tubes that are fluidly connected to the uterus. The fluid may be further moved into and through the fallopian tubes to enter the abdominal cavity. The amount of contrast agent used in a procedure to observe the uterus and at least one fallopian tube may be from about 5mL to about 100mL, from about 10mL to about 100mL, from about 15mL to about 90mL, from about 10mL to about 80mL, from about 20mL to about 70mL, from about 30mL to about 60 mL. The amount of contrast agent generated and delivered to the patient may be about 5mL, about 10mL, about 20mL, about 30mL, about 40mL, about 50mL, about 60mL, about 70mL, about 80mL, about 90mL, or about 100mL, or greater than 100mL, if imaging of the uterus and fallopian tubes is desired or for multiple imaging. For example, a large lumen or a lumen connected to several tubes may require more than 100mL for visualization of the entire lumen and/or tube. The amount of contrast fluid used may be any amount sufficient to provide an accurate visualization of the structure to be examined. The contrast fluid may substantially fill the visualized structure, or may be present only at specific locations within the structure.

For example, a contrast device capable of producing about 20mL of contrast composition uses two containers (syringe bodies), each 10mL, and transfers some or all of the contrast to a catheter system with the delivery end in the uterus. The contrast agent may enter the uterus and flow directly into the fallopian tubes where it is imaged (e.g., by ultrasound examination). Five to ten mL of contrast agent may be used for such visualization of both fallopian tubes. At which time the flow of contrast agent may be halted or terminated. If a second visualization is desired, the flow of contrast agent may be continued and the visualization of the body structure by the presence of contrast agent may be performed.

An advantage of the present invention is that the flow of contrast agent is controlled so that some or all of the contrast agent composition may be provided to the body structure. The flow of contrast out of the device and/or out of the catheter, and to the body structure, may be controlled so that the flow of contrast provided may be continuous or intermittent, such as providing some contrast, stopping the flow, providing contrast, stopping the flow, and so forth. During operation, the container(s) of the contrast media device may be refilled one or more times. The flow of contrast agent to the structure may be controlled automatically or by an operator. The delivery rate of the contrast agent can be controlled. The delivery rate may range from fast to slow and is controlled primarily by the rate of force applied to the component(s) used to provide the force acting on the fluid contained in the container(s). In one embodiment, wherein the contrast media device comprises two containers, such as two syringe bodies, and the means for providing a force on the fluid contained within each container is a plunger, the rate of force applied to the fluid in each container is the same when the plunger is actuated with the same applied force, thereby providing the same rate of delivery of contrast media from the device.

Embodiments of the invention include visualization of at least one fallopian tube using a catheter placed at or near the tubal opening. Any device that provides a catheter to the fallopian tubes may be used. The catheter may be connected to an imaging device that includes a container assembly as described herein. One specific device used in methods for providing a catheter to a body structure, such as a fallopian tube, and which may be used to visualize the fallopian tube, is U.S. patent application serial No. 11/065,886, U.S. patent application serial No. 12/240,738, and U.S. patent application serial No. 12/240,791, now the devices taught in U.S. patent nos. ____, ____ and ____, each of which is incorporated herein by reference in its entirety. Generally these applications disclose devices that include a housing and an introducer rod for entering and passing through the uterus until the tip of the rod reaches or touches the fundus of the uterus. Once the distal end of the introducer rod is in the fundus of the uterus, the device can be stabilized. One or more catheters (such as two) are fed through the introducer rod and out into the uterine cavity. Placement of the introducer rod allows for three-dimensional alignment of the catheter(s) with the uterine horn. The catheter(s) is advanced until the delivery end(s) of the catheter(s) is in place in the uterine horn. An end structure, such as a balloon, is inflated or used to stabilize the catheter(s) in place and may prevent or minimize backflow of material out of the delivery end of the catheter. Once the tip structure is used, the catheter(s) are ready for delivery of a substance or other activity.

In the method of the present invention, the catheter placed through the introducer rod comprises a catheter assembly. The end of the catheter opposite the delivery end, referred to herein as the proximal end or connection end, is connected to the contrast media device of the present invention. Contrast is generated by the action of the container assembly and is provided into the catheter(s) and through and out of the catheter into the uterine horn and into the fallopian tube(s). The imaging technique is initiated when the contrast agent enters the fallopian tube(s) and, if possible, flows through the fallopian tube(s) and out of the fallopian tube into the peritoneal cavity. If the fallopian tube is occluded, the contrast agent will not flow into the fallopian tube and may flow into the second, contralateral fallopian tube if the second fallopian tube is not occluded. The pressure caused by the occlusion may or may not displace an end structure (such as a balloon) on the catheter in an attempt to relieve the pressure, but if the end structure of the catheter is moved, flow will be directed to the uterus or the uninhibited fallopian tube.

If the catheter-providing device uses only one catheter, one fallopian tube visualization occurs, whereupon rotation of the device, such as the introducer rod, is readjusted, as taught in the referenced patent application, and the steps are repeated to provide contrast to the other fallopian tube. The contrast agent provided may be any presently known contrast agent that may be provided to a site via a catheter.

Embodiments of the invention include providing a contrast agent to a uterus using a contrast agent device and a catheter for imaging at least one fallopian tube, or imaging at least a portion of a uterus and at least one fallopian tube. When the structure to be imaged is at least one fallopian tube, or the uterus and/or at least one fallopian tube, an imaging agent device of the present invention in combination with a catheter may be used. A catheter having an element that prevents retrograde fluid flow from the uterus may be connected to a contrast media device that includes the container assembly described herein. Catheters having element(s) that prevent retrograde flow are known in the art, and the selection of a catheter to connect to a contrast device of the present invention for use in the methods taught herein is within the skill of one of ordinary skill in the art.

In the method of the present invention, the catheter (such as a balloon catheter) is a catheter assembly. In this method, the delivery end of the catheter is placed in the uterus, and optionally, a structure that prevents retrograde flow to the cervix is used, such as balloon inflation of a balloon catheter. The end of the catheter opposite the delivery end, referred to herein as the proximal end or connection end, is connected to the contrast media device of the present invention. Contrast agent is generated by the action of the device and is provided into and through the catheter(s) and out of the catheter into the uterus. Providing a desired amount of contrast agent and initiating an imaging technique and may be used to image movement of the contrast agent to the uterus for imaging at least a portion of a uterine structure, for example, by providing the contrast agent, and/or imaging entry, transport and/or exit of the contrast agent in at least one fallopian tube. If the fallopian tube is occluded, the contrast agent will not flow through the occlusion, but may flow into the contralateral fallopian tube (if not occluded). The increase in pressure caused by the blockage may or may not be detected by an element of the contrast media device designed to detect a fluid backpressure created by the lack of continuous flow of fluid through the structure and/or tubing. If the desired pressure is reached, contrast flow may be stopped, such as by a medical professional providing contrast stopping the application of pressure to the contrast device and stopping the supply of fluid to the uterus through the catheter. The contrast agent provided may be any presently known contrast agent that may be provided to a site via a catheter, or may be a liquid/air contrast agent as disclosed herein.

The contrast media device of the present invention may provide a container that is filled with fluid(s), or may provide an empty container that must be filled with fluid(s) prior to generation and delivery of contrast media. If all of the fluids in the contrast media device are used in a procedure and more contrast media is needed, the contrast media device of the present invention may be refilled, e.g., the container of the device is filled with the respective fluid(s). In using pre-filled containers, the original container may be removed and a new container inserted into the device. In using a refillable container, the container may be refilled without having to remove the delivery end of the catheter from the patient. The contrast device may be removed from the proximal end of the catheter and the container refilled with more of the same type of fluid or a different fluid (if needed) as used in the first delivery of contrast.

In contrast media devices using the present invention, once a volume of contrast media has been provided and the container is depleted of contrast media, the container may be refilled one or more times to provide an effective volume of contrast media to structures of the body and/or to the catheter. For example, in embodiments where the contrast agent comprises air and saline segments in a pattern, the pattern may be produced by a contrast agent device of the present invention having two containers, one container providing saline and a second container providing air. For example, the container may be a 10mL syringe, wherein the first container contains 10mL of saline and the second container contains 10mL of air or gas. The contrast media is generated or produced by simultaneously removing saline and air from each container, such as by applying pressure to a plunger in each container, or by a pump or other means for moving fluid from a syringe or similar container. Air and saline are moved into the contrast pattern generation chamber. The contrast pattern generation chamber may include a static mixer or similar structure for mixing air and liquid fluid, creating a dispersed saline section and an air section, thereby generating a contrast agent comprising saline with air bubbles or air sections contained therein. The static mixer may comprise elements, such as helical elements, which simultaneously produce a pattern of flow dispersion and radial mixing of the air and brine fluids. Static mixers are known in the art and typically comprise a mixer element, such as a cylindrical tube, contained in a tube or jacket. The static mixer elements may comprise a series of baffles made of metal or a variety of plastics. Static mixers work by continuously mixing two fluids as a fluid stream through the static mixer. Other mixing elements may be used in the present invention and such elements are known to those skilled in the art. Alternatively, the contrast generation chamber may include only one conduit into which both a gas conduit from the gas container and a liquid conduit from the liquid container enter, and no static mixer or other mixing element is included. Because gas and liquid are simultaneously provided to the contrast generating chamber conduit, a segment of gas is created in the fluid to generate the contrast composition.

When the container of the contrast media device is empty, e.g., before the process begins, or substantially all of the fluid in the container is absent, as in the process, in one embodiment of the present invention, the container may be simultaneously filled or refilled without the need to disassemble the contrast media device or remove the container from the device housing. For example, when the contrast media apparatus includes two containers, wherein a first container contains saline and a second container contains air, the first and second containers may be filled or refilled with saline and air, respectively, without requiring disassembly of the contrast media apparatus or removal of the containers. If the catheter is connected to the outlet of the contrast device, it may optionally be removed when filling the container and left in place on the patient. The outlet end of the contrast media device may be immersed in the saline solution prior to being connected to the catheter or prior to being connected to the catheter. If a plunger, such as a syringe plunger or similar operatively movable seal in the container body, is present in the container, the plunger is pulled up in the proximal direction inside the syringe barrel and away from the outlet, creating a reduced pressure in the syringe barrel which allows saline and air to enter the respective container (syringe). Typically, the plungers are controlled simultaneously so that both plungers are pulled up inside the syringe cylinder at the same rate so that both syringes are refilled simultaneously with air in the air cylinder and with saline in the saline cylinder. The air cylinder is in fluid communication with at least one inline check valve connected to the air syringe barrel, and optionally an inline air filter that enables filling of the air syringe barrel in one direction.

The path of the air or gas during filling of the container placed in the contrast agent device is as follows. When the air syringe barrel is pulled proximally inside the syringe, away from the outlet, while the outlet of the device is immersed in the saline solution, air flows through the optional air filter, through the fluid connection with the at least one-way check valve, through the connector connecting the at least one check valve and the syringe (container) outlet, and into the air syringe barrel. When the plunger reaches the proximal end of the syringe barrel, and/or is pulled to a desired extent, such as the entire length of the syringe barrel, the syringe is filled with, for example, 10mL of air.

The fluid syringe plunger is pulled from the fluid syringe barrel at the same time and rate as the air syringe plunger is pulled from the air syringe. When the outlet of the contrast media device is immersed in saline, movement of the fluid injector plunger in a proximal direction away from the outlet causes the saline to enter the outlet of the device and move through a fluid connection with the fluid injector receptacle. When the plunger reaches the proximal end of the fluid syringe barrel, and/or is pulled up to a desired extent, e.g., the entire length of the syringe barrel, the syringe is filled with, e.g., 10mL of fluid, e.g., saline. When the plungers stop moving, e.g., each plunger is positioned at a desired location in the syringe barrel, the air reservoir and the fluid reservoir contain substantially the same amount of air and saline in the respective reservoirs. The contrast agent device is now filled or refilled. In a continuous visualization process, the catheter may be re-coupled to one or more connecting elements of the outlet of the device and, with the reverse action of the plunger, moved down the syringe barrel toward the outlet, fluid (saline) and air are forced out of the respective fluid and air reservoirs. The contrast agent is generated in the contrast agent generation chamber, for example, by a fluid/air flow through a mixer, such as a static mixer, or the fluid is mixed in the mixing chamber without mixing elements, and the contrast agent composition comprising air and liquid segments exits the contrast agent device, for example, into and through a connected catheter. The contrast agent may be passed into a body cavity, such as the uterus, and at least one fallopian tube, where imaging of the contrast agent in the structure is performed, such as by an ultrasound examination method, and the tissues of the body are examined.

The disclosure herein relates to fluids such as air or saline, but it is contemplated that the invention is not limited to air and/or saline, and that one skilled in the art may substitute air and/or saline for other suitable fluids such as other liquids, other gases, or known contrast media compositions. The method of the present invention includes preparing or generating a contrast agent and delivering the contrast agent to the bodily structure. The contrast agent device of the present invention is used for preparing a contrast agent. For example, one embodiment of a contrast media device comprising a fluid reservoir may comprise a container comprising a flexible porous mass in the reservoir. An example of a container is described in which the container is a syringe body, as shown in fig. 4. The present invention is not limited to this design, but contemplates other containers that will function in a similar manner. The syringe is primarily filled with a flexible porous substance. The flexible porous material includes, but is not limited to, strips or sheets of woven or non-woven material, open-cell material such as sponge or sponge chips, or any material that contains gas and acts upon it (e.g., by a squeezing force) to release the gas. For example, the flexible, porous substance is an open-cell sponge. The sponge is placed in a container and a liquid is added, but the liquid does not replace all of the gas in the sponge. A syringe plunger is applied to the larger open end of the syringe and the other end of the syringe is fluidly connected to the catheter assembly. When the plunger is depressed into the syringe, the sponge is compressed and air is forced out into the liquid, creating a bubble or air segment (air segment). Bubbles and fluid, air and fluid segments enter the conduit and pass through the conduit into the structure. The structure can then be visualized. See fig. 5 for an example of tubal visualization.

The present invention includes contrast media devices comprising more than one container. For example, the contrast media device may include two containers, such as the containers shown in fig. 1 and 7-10, where an example of a container containing a syringe body is also referred to herein as a syringe barrel or syringe container. Optionally, the plunger element may pass through the interior of the syringe barrel. The plunger element may be moved through the interior of the syringe container, such as by a manipulator, from a proximal position within the barrel (where proximal refers to the end of the device closest to the manipulator and away from the outlet of the device) to a distal position (where distal refers to the end of the device closest to the patient and closer to the outlet), and from a distal position within the barrel to a proximal position within the barrel. The plunger element may comprise a piston and a fluid seal (fluid seal) having two surfaces, wherein the piston is connected to one surface, a proximal surface, and the other surface, a distal surface, of the fluid seal towards and in contact with the deliverable fluid. The standard syringe plunger is the plunger element. A liquid seal having two surfaces forms a liquid seal within the container to maintain or contain the deliverable fluid on the distal surface (first surface) of the plunger surface and the absence of the deliverable fluid on the proximal surface (second surface). The deliverable fluid is the fluid contained in the container and will be provided to the structure to be imaged and/or inspected. As a plunger containing a piston and a liquid seal, movement by the syringe creates air or a slight vacuum on the proximal side of the plunger, but is not intended to provide air on the proximal side of the seal, and therefore, is not a deliverable fluid. The invention is not limited to this design, but contemplates other containers that will function in a similar manner. One container, which may be a pre-filled syringe, contains the liquid. The liquid may be any of those disclosed herein, such as saline or water, or a known contrast fluid. The second container, which may be a pre-filled syringe, contains a gas. The gas may be any of those disclosed herein, such as air, carbon dioxide, oxygen, nitrogen, or halocarbon gases, other gases, or known contrast agent gases. The plungers of the two syringes are simultaneously compressed, either manually or mechanically, and the mixture of gas and liquid forms an alternating pattern of gas and liquid phases, which are the contrast agent composition. The contrast agent composition then enters, passes through the attached catheter and exits into a structure, such as the fallopian tube. The structure can be visualized by ultrasound techniques.

Alternatively, the device of the present invention may comprise two containers, such as two syringes, which are provided without the inclusion of fluid. In applying the device, each plunger is depressed to a position at the distal end of each container, such as a syringe. And the outlet of the device was placed in saline. When each plunger is simultaneously moved to a desired proximal position in the container, air is introduced into the first container and fluid is introduced into the second container. Substantially simultaneous filling of dual container devices is disclosed herein. Once the container is filled, the plunger may be depressed, moving the liquid-tight surface to a more distal position, and dispensing the fluid from the container. The fluids are mixed and the gas and liquid are mixed to form a contrast agent composition comprising air and liquid segments, and the contrast agent composition flows out of an outlet of the device, optionally into a catheter placed in the structure to be examined. An embodiment of the invention may include movement of a plunger and filling a container with fluid or providing fluid from a container.

The compositions of the present invention comprise a contrast agent prepared using the methods taught herein. The contrast agents of the present invention comprise a gas phase in a liquid carrier. The gas phase may be a bubble or may be a liquid-free, gas-filled region adjacent to a liquid phase region, and the alternating gas-filled and liquid regions may be repeated multiple times. The size of the gas-filled region or the liquid-filled region may or may not be uniform in size. The present invention contemplates aspects in which the application provides the contrast agent in a reduced volume, which may be 20mL or more, compared to the amounts currently used, and primarily in or very near the structure to be imaged (i.e., the fallopian tube).

The present invention contemplates providing an amount of contrast agent effective to visualize structure. For example, an effective amount of contrast agent may comprise 5mL to 200mL, depending on the volume of the structure to be examined and the number of structures to be examined. For example, if contrast media is provided to the uterus and fallopian tubes using the device of the present invention, an effective amount of contrast media to be provided to those structures may be greater than the amount used to provide contrast media directly to the fallopian tubes. The present invention controls the amount of gas and liquid used in combination to form a mixed gas/liquid composition into the structure. The contrast agent composition may be in a form ranging from a predominantly gas phase (air or other gas) to a predominantly liquid phase (saline or other liquid), and may be provided in a regular or irregular pattern. The ratio of gas to liquid can be determined by the size of each syringe. The larger the air injector, the larger the air section in the composition version. The use of porous structures can produce more random or irregular patterns. The amount of contrast agent delivered may be controlled by the amount of syringe plunger displacement or by refilling the container one or more times.

The contrast agent device of the present invention produces and delivers reproducible and reliable alternating air and fluid patterns that are visible by detection methods, such as ultrasound examination. The air/liquid pattern produced by the composition produced by the device of the invention is reproducible in that a substantially regular repeating pattern of alternating air and liquid is produced when the contrast agent composition is provided to the body structure by the device and is visible, for example, in relation to the fallopian tubes. This pattern continues to be produced by the device, such as the contrast agent composition produced in the device of the present invention, where the distance between the air/saline interfaces is sufficiently short and regularly repeated so that the composition is visible through movement of the structure, such as by ultrasonic examination. The sustained pattern in the uterus as well as in the open, non-occluded fallopian tubes can be observed by detection methods such as ultrasonography. The present invention contemplates that the distance between the contrast agent interfaces of the present invention need not be the same for each pair of interfaces, but that the distance is of a size similar enough so that a repeating pattern of light and dark can be perceived by a detection means, such as an ultrasound examination, and a body structure, such as a fallopian tube, can be observed under a detection means, such as an ultrasound examination, by the movement of the light and dark pattern produced by the interfaces.

For example, to assess the patency of a fallopian tube to determine if the tube is open and not occluded or closed, it is desirable to deliver saline and air compositions having an air/saline interface that exists in a frequently regular alternating pattern at different intervals. Saline alone appears black when viewed by ultrasound examination, and thus long intervals of saline may present problems for the user to visualize body structures such as the fallopian tubes, because saline reflects less of an acoustic echo to the probe. Air appears white, as bones appear, because air reflects more of the acoustic echo to the probe, so long intervals of air can be misinterpreted and easily confused with other body tissue, leading to uncertainty in diagnosing tubal patency. As described in the present invention, the movement of the interface between the brine and the air with a frequent, regular and alternating repetitive pattern allows an effect called reverberation to occur, which is caused by the sound of interaction with two structures with sufficiently different reflection properties (interfering with). The invention also allows a comet-tail effect, a type of reverberation caused by many small, highly reflective interfaces (such as air bubbles in a fluid). If the pattern is too unstable, as observed in the historical literature and previously described methods, a determination and accurate diagnosis of the structure or patency of the fallopian tube cannot be assessed, and must not be easy and reliable. The complexity of the sonohysterography procedure, if of an unstable and irregular type, increases considerably, questioning the reliability of the procedure and making the learning curve for the medical professional to learn and perform the procedure very steep. In particular, unstable patterns consisting of small frequent patterns of long segments producing air or saline may lead to misinterpretation, as there appears to be no movement of the contrast agent, which is necessary for a medical professional to assess the fallopian tube, perceiving movement of the contrast agent in and through the structure.

In addition, in ultrasound examination methods that examine the uterus and fallopian tubes, obtaining an optimal ultrasound examination probe position/location in the correct plane can be challenging due to different patients having different uterus and fallopian tube anatomical locations. Thus, a continuous movement of the contrast agent in a frequent, regular alternating pattern as produced by the device of the invention will increase the likelihood that the physician (medical professional) will observe the body structure for an intended assessment. In this method, the physician may have difficulty observing one fallopian tube, such as in situations where flow is readily observed in one fallopian tube, while the other fallopian tube is blocked, in situations where positioning is difficult, or in situations where a spasm of the fallopian tube has occurred. In this and other similar situations, the user may need to deliver additional saline and air to the patient to clear or confirm the obstruction in the unobserved fallopian tubes, so aspects of the invention that enable quick and easy refilling of the device with fluids (e.g., air and saline) facilitate easy and convenient performance of the method. Patient discomfort or the decision to extend the procedure for minutes to relax the fallopian tubes and thereby challenge difficult fallopian tube assessments may also require delayed delivery of saline and air, thereby extending the overall time of the procedure. Thus, it is an advantage of the present invention over previous devices to provide a contrast media composition that provides a regularly repeating pattern of interfaces of air and liquid sections, such as after a procedure interruption, or after refilling of the device container.

The compositions of the present invention also comprise liquids and gases, and optionally, surfactants, emulsifiers or other stabilizers. The liquid that can be considered a carrier for the gas phase can be any liquid that is substantially free of solids and that flows at normal or body temperature. For example, the liquid may be water or a physiologically acceptable aqueous solution including, but not limited to, a physiological electrolyte solution, a physiological saline solution, a ringer's solution, or a solution of sodium chloride, calcium chloride, sodium bicarbonate, sodium citrate, sodium acetate or sodium tartrate, a glucose solution, or a solution of a monohydric or polyhydric alcohol, such as ethanol, n-butanol, ethylene glycol, polyvinylpyrrolidone, or a mixture or combination of these. In addition, the liquid carrier may comprise a physiologically acceptable non-aqueous solution including, but not limited to, anhydrous or substantially anhydrous carrier liquids, alcohols, glycols, polyglycols, synthetic perfluorinated hydrocarbons, or mixtures or combinations with other non-aqueous or aqueous liquids.

The contrast agent composition of the present invention may contain a surfactant or a compound that stabilizes the gas-liquid interface. The surfactant may be provided in the liquid phase of the contrast agent. For example, if the contrast agent composition comprises air and a liquid, such as saline, one or more surfactants may be added to the saline. The surfactant composition may be useful when providing contrast media to tissue larger than the size of the catheter used to deliver the contrast media. Surfactants include surfactants such as lecithin; esters and ethers of fatty acids and fatty alcohols with polyoxyethylene and polyoxyethylated polyols such as sorbitol, ethylene glycol and glycerol, cholesterol; and polyethylene oxide-polypropylene oxide polymers, viscosity-increasing and stabilizing compounds, mono-and polysaccharides (glucose, lactose, sucrose, dextran, sorbitol); polyols, for example, glycerol, polyethylene glycol; and polypeptides such as proteins, gelatin, oxidized poly-gelatin, plasma proteins, amphiphilic compounds capable of forming stable membranes in the presence of water and gas, such as lecithin (phosphatidylcholine) and other phospholipids, in particular Phosphatidic Acid (PA), phosphatidylinositol, Phosphatidylethanolamine (PE), Phosphatidylserine (PS), Phosphatidylglycerol (PG), Cardiolipin (CL), sphingomyelin, protoplasm, cerebroside, natural lecithins such as egg lecithin or soybean lecithin, or synthetic lecithins such as saturated synthetic lecithins such as dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine or distearoylphosphatidylcholine, or unsaturated synthetic lecithins such as dioleylphosphatidylcholine or linoleoylphosphatidylcholine, free fatty acids, esters of fatty acids with polyoxyalkylene compounds such as polyoxypropylene glycol and polyoxyalkylene glycol; ethers of fatty alcohols with polyoxyalkylene glycols; esters of fatty acids with polyoxyalkylene sorbitan; a soap; glycerol stearate-polyalkylene esters; ricinoleic acid glycerol-polyethylene oxide esters; homopolymers and copolymers of polyalkylene glycols; polyethoxylated soya and castor oils and their hydrogenated derivatives; ethers and esters of sucrose or other carbohydrates with fatty acids, fatty alcohols, which may optionally be polyoxyalkylated; mono-, di-and triglycerides of saturated or unsaturated fatty acids; glycerol esters of soybean oil and sucrose, block copolymers of polyoxypropylene and polyoxyethylene (poloxamer) polyoxyethylene sorbitan, sorbitol, glycerol-polyalkylene stearate, glycerol polyethylene oxide ricinoleate, homo-and copolymers of polyalkylene glycols, soybean oil and its hydrogenated derivatives, esters and ethers of sucrose or other carbohydrates with fatty acids, fatty alcohols, glycerol esters of soybean oil, dextran, sucrose and carbohydrates. The surfactants may be film-forming and non-film-forming and may include the following types of polymerizable amphiphilic compounds: linoleyl-lecithin or polyethylene dodecanoate, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, cardiolipin, sphingomyelin, and biocompatible amphiphiles capable of forming stable membranes in the presence of liquid and gas, phospholipids including Phosphatidylcholine (PC) with both saturated and unsaturated lipids; including phosphatidylcholines such as dioleylphosphatidylcholine; dimyristoyl phosphatidylcholine (DMPC), dipentanoyl phosphatidylcholine-, dilauroyl phosphatidylcholine (DLPC), dipalmitoyl phosphatidylcholine (DPPC); distearoyl phosphatidylcholine (DSPC); and Dianhydroacylphosphatidylcholine (DAPC); phosphatidylethanolamines (PE), such as dioleylphosphatidylethanolamine, Dipalmitoylphosphatidylethanolamine (DPPE) and Distearoylphosphatidylethanolamine (DSPE); phosphatidylserines (PS) such as Dipalmitoylphosphatidylserine (DPPS), Distearoylphosphatidylserine (DSPS); phosphatidylglycerol (PG), such as Dipalmitoylphosphatidylglycerol (DPPG), Distearoylphosphatidylglycerol (DSPG); and phosphatidylinositol. Surfactants, emulsifiers or other stabilizers may be aerosolized in the gas phase.

The contrast agent composition may comprise a gas, and any physiologically acceptable gas may be present in the composition of the invention. The term "gas" as used herein includes any substance that is in substantially gaseous form in the normal human body (37 ℃.) (Including mixtures). Approximately 200 different gases have been identified as potentially useful for making ultrasound contrast agents, and include oxygen, air, nitrogen, carbon dioxide or mixtures thereof, helium, argon, xenon, krypton, CHClF₂Or dinitrogen monoxide, sulfur hexafluoride, tetrafluoromethane, chlorotrifluoromethane, dichlorodifluoromethane, bromotrifluoromethane, bromochlorodifluoromethane, dibromodifluoromethane, dichlorotetrafluoroethane, chloropentafluoroethane, hexafluoroethane, hexafluoropropylene, octafluoropropane, hexafluorobutadiene, octafluoro-2-butene, octafluorocyclobutane, decafluorobutane, perfluorocyclopentane, didedecafluoropentane, the fluorinated gas comprising a substance containing at least one fluorine atom, such as SF₆Freon (organic compounds containing one or more carbon atoms and fluorine, i.e. CF)₄、C₂F₆、C₃F₈、C₄F₈、C₄F₁₀、CBrF₃、CCl₂F₂、C₂ClF₅And CBrClF₂And perfluorocarbons. The term perfluorocarbon refers to compounds containing only carbon and fluorine atoms and includes saturated, unsaturated and cyclic perfluorocarbons such as perfluoroalkanes like perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutene (e.g. perfluoron-butane, optionally in mixture with other isomers such as perfluoroisobutane), perfluoropentane, perfluorohexane and perfluoroheptane; perfluoroolefins such as perfluoropropene, perfluorobutene (e.g., perfluorobut-2-ene), and perfluorobutadiene; perfluoroalkynes such as perfluorobut-2-yne, and perfluorocycloalkanes such as perfluorocyclobutane, perfluoromethylcyclobutane, perfluorodimethylcyclobutane, perfluorotrimethylcyclobutane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclopentane, perfluorocyclohexane, perfluoromethylcyclohexane, and perfluorocycloheptane. ). The generally preferred saturated perfluorocarbons have the formula C_nF_n+2Where n is from 1 to 12, preferably from 2 to 10, most preferably from 3 to 8 and even more preferably from 3 to 6. Suitable perfluorocarbons include, for example, CF₄、C₂F₆、C₃F₈、C₄F₈、C₄F₁₀、C₅F₁₂、C₆F₁₂、C₇F₁₄、C₈F₁₈And C₉F₂₀。

The invention includes contrast media devices and systems. The system of the present invention may include separable components; a contrast device comprising a container assembly, and a catheter assembly providing a contrast composition within, near, or in a target vessel or lumen, a fluid output of the device. Alternatively, the system of the present invention may be a unitary, one-piece construction in which the contrast media device includes a container assembly adjacent to a catheter assembly. The contrast media apparatus may include a container assembly that provides contrast media comprising a gas phase and a liquid phase. The contrast media device may include a container assembly that includes an improved conventional multi-syringe pump, i.e., a mechanically or manually operated device capable of receiving syringes of different sizes. The syringe output is directed into a mixing chamber or tube where a properly formed gas (i.e., air) and liquid (i.e., saline) train is then pushed into the input of the catheter assembly. For example, targeted delivery of contrast agents near or within the tube (i.e., fallopian tube) should allow for ultrasonic examination of the structure. The contrast agent composition may be provided directly to the fallopian tube by which is meant that the contrast agent composition is delivered only to the fallopian tube, or only first to the fallopian tube, and not by filling the uterus with fluid and spilling the fluid into the fallopian tube. The contrast agent composition may be provided directly to the uterus, which allows for visualization of the uterus, and by providing a sufficient amount of contrast agent, the contrast agent may flow to one or more fallopian tubes. The contrast agent may or may not enter and flow through the fallopian tube, depending on the patency of the fallopian tube. Directly providing a composition to a structure herein means providing the composition at or near the opening of the structure to be evaluated such that the composition enters the structure and does not flow into the structure from a remote site where the composition is delivered.

One aspect of the present invention includes the use of the device of the present invention with known hysterosalpingography procedures. Such a procedure may be performed, for example, before or after use of the apparatus of the invention. The procedure may include providing saline only to the uterine cavity until at least partially filling or distending the uterus. The uterus may be visualized by detection methods, such as ultrasonography. The saline is then released from the uterus, such as by a balloon used to seal the uterus near the cervix, or by withdrawing a catheter that provides saline to the uterus. Alternatively, saline may flow out of the fallopian tubes. After such a pre-treatment procedure, the contrast agent device of the invention can be used by: the device is connected to a catheter having its discharge end (delivery end) inside the uterus, a contrast agent composition is produced and provided to the uterus and at least one fallopian tube. After providing the contrast agent composition, post-treatment may also be provided to the uterus or fallopian tubes. For example, the therapeutic or embryonic composition can then be provided to the uterus or fallopian tubes. While not wishing to be bound by any particular theory, such theories are proposed: providing a contrast agent composition of the invention using a device of the invention is helpful for the fertility of a patient who has undergone the methods described herein. It is believed that there is a higher incidence of pregnancy in women who have undergone a procedure involving the use of the contrast media device of the present invention and an air/saline contrast media composition. The present invention includes a method for providing pregnancy in a female, assisting or obtaining a pregnant condition in a female, or increasing female fertility, the method comprising providing a contrast media generation and delivery device comprising a container assembly comprising at least one container for holding a fluid, means for initiating movement of the fluid from the container, and a connection for fluidly connecting the at least one container to a contrast media generation chamber, such as the device disclosed herein, filling the at least one container with the fluid; moving the fluid from the at least one container to a contrast generating container to generate a contrast composition; and delivering the contrast agent composition to a female bodily structure. Visualization by detection methods such as ultrasound examination may or may not be performed.

In the methods of the invention, one or both fallopian tubes may be viewed simultaneously, sequentially, or in separate procedures. In some cases, it may not be possible to view both fallopian tubes in the same plane as the ultrasound examination imaging. One or both fallopian tubes may not fill at the same time, for example, a spasm should constrict an opening or a portion of a fallopian tube.

One aspect of the invention includes a contrast media apparatus comprising a container assembly including a contrast media pattern generation chamber having a ratio of a diameter to a diameter of a structure to be visualized in a ratio range of 0.3-1.8. The diameter of the contrast-type generation chamber may be in the ratio of 0.1 to 100 diameters of the structure to be imaged. The contrast agent type generation chamber may have a diameter ratio of 0.5: 1 of the structure to be imaged, a diameter ratio of 1: 1.5 of the structure to be imaged, and a diameter ratio of 1: 2 of the structure to be imaged. One aspect of a contrast media apparatus includes a container assembly including a contrast media pattern generation chamber having a diameter substantially equal to a diameter of a structure to be visualized, wherein the diameter ratio is 1.

One aspect of the present invention includes a contrast media apparatus comprising a container assembly including a contrast media pattern generation chamber including a static mixer for mixing two or more fluids provided by the container. The static mixer mixes two or more fluids as they enter the static mixer, which is placed in series (in-line) or fluidly connected to two or more vessels and before the outlet. For example, in an embodiment of the contrast media device of the present invention, the fluid of one container is saline and the fluid of the second container is air. Air bubbles or portions of air and brine are formed in the brine by the static mixer as the brine and air move from the respective containers into the static mixer. When exiting the static mixer and exiting the contrast agent device via the outlet, and optionally entering the catheter, the mixture of air and saline, observed primarily as a sequence of patterns of air bubbles in saline in an open space (open space) such as the uterus or portions of air and saline entering the tube, is a contrast agent that may be used to visualize structures.

If a tube (duct), tube (tube) or structure is to be visualized by the contrast agent, the interface of the alternating gas and liquid phases must be present in sufficient quantity and both phases must be present in the observation zone during the observation time. Providing contrast in the image is the presence of two phases across the viewing area. For example, if only one phase (liquid or gas) is visible within the viewing zone at a given time, then evaluation is very difficult or impossible. By forming a plurality of interfaces between two phases in the contrast agent, it is possible to carry out an observation of the structure due to the flow of the contrast agent of the interface comprising said phases.

One aspect of the invention includes a contrast media device comprising a contrast media-type generation chamber having a diameter similar to a diameter of a structure being viewed. For example, if a gas phase is formed that is smaller than the diameter of the structure to be observed, the gas will rise to the upper portion of the tube and combine with another gas phase and fill the diameter of the structure. One aspect of the invention includes a contrast media device comprising a contrast media-type generation chamber having a diameter that is larger or smaller than the diameter of the structure being viewed. For example, if a very small gas phase forms in the contrast agent pattern generation chamber, the small gas phase may be maintained in the larger diameter structure using dispersants, surfactants, or other similarly acting components in the liquid or gas phase. Such a small gas phase can be obtained by a vibrating operation of the container assembly. The higher the frequency of vibration, the smaller the gas bubbles released.

One aspect of the invention includes a contrast media device that includes a contrast-type generation chamber having a configuration that allows mixing of two or more fluids. For example, the contrast media-type generation chamber may include a static mixer. Static mixers and similar elements that can mix two or more fluids are known to those skilled in the art and the present invention is not limited to the examples used herein. By the term mixing, it is understood mixing two or more fluids, but maintaining an interface between the two or more fluids in the mixed composition. The interface between the fluids provides contrast for the visualization of the structure. The interface may be maintained by the use of dispersants, surfactants, or other similar acting agents in the liquid or gas phase. The contrast agents of the present invention comprise an interface between air and a fluid, such as saline, wherein the interface is provided by an air bubble or air portion and a saline portion in saline and the interface is maintained for a time sufficient to determine a physical aspect of a structure, such as the uterus and/or at least one fallopian tube, or both fallopian tubes. For example, the physical aspect may include a shape of the lumen, a polyp within the lumen, patency of the catheter, and/or blockage of the catheter. The cavity herein may comprise any cavity of the body, such as the uterus. The catheter herein may comprise any catheter of the body, for example, a fallopian tube.

The manual means of forming the contrast media may be accomplished by using a contrast media device that includes a container assembly that includes a single syringe or a porous substance, such as an open cell foam, sponge, or woven or non-woven fabric or fiber or a combination thereof. The syringe is filled with one or more of these substances in a loose-fill manner and then the plunger is repositioned to the fully retracted position. The contrast media is then injected or otherwise fed or drawn into the injector chamber containing the porous mass. When the syringe plunger is controlled down (depression), fluid and air or other gases exit in a manner similar to the dual syringe system described above. The catheter assembly delivers a contrast agent into the structure being evaluated.

A use of the device disclosed herein is to deliver a contrast agent composition to a structure to be imaged. A diagnostic or therapeutic treatment may be provided to a human or animal by delivering a composition, such as a contrast agent composition, or a composition comprising a therapeutic agent to a structure using a contrast agent device and catheter assembly as described herein. For example, a therapeutic agent can be provided to the fallopian tube in combination with an alternating phase interface (which is provided by introducing a gas to a composition comprising the therapeutic agent) and used to treat the fallopian tube. Such agents include, but are not limited to, methotrexate (methotrexate), hormones, fertility enhancing compounds (fertility interfering compounds), fertility interfering compounds (fertility interfering compounds), motility enhancing compounds (motility interfering compounds), compounds that affect the cilia/cilia cycle, cilia growth enhancing or interfering compounds (cilia growth interfering compounds), follicle treating compounds (follicle stimulating compounds), antibacterial, antimicrobial, antifungal, antiviral, anti-mycoplasma (antimycotopmal), or anti-parasitic (anti-parasitic) compounds, compounds that reduce inflammation or scar tissue formation, compounds that include one or more anti-biotic compounds, anti-viral compositions, or anti-pathogenic agents; compositions comprising mucins, electrolytes or enzymes that enhance or inhibit fertility, progestins, estrogens, adrenergic active compounds, norepinephrine active compounds, nonsteroidal anti-inflammatory drugs, prostaglandins, other compounds that can treat or prevent conditions associated with the fallopian tubes, uterus, ovaries, or other organs or coverings reached by the fallopian tube basal process (cornua) or mating pore (ostia) outflow composition, or combinations thereof. The therapeutic composition includes a hormone for fertility, a fertility enhancing compound, a gamete (gamete), a sperm, an ovum, a combination of sperm and ovum, one or more fertilized eggs, or one or more embryos, or a combination thereof. In methods in which delivery of the diagnostic or therapeutic agent composition is provided by providing the composition directly to a structure, the composition may further comprise mixing a gas with the composition comprising the diagnostic or therapeutic agent, and delivery of the composition may be monitored by techniques such as ultrasound. Compositions comprising a therapeutic agent in combination with an interface formed by combining a gas and a therapeutic composition using the contrast media device of the present invention provide both treatment and diagnosis of structural disorders in a one-step delivery composition. Alternatively, the combined therapeutic agent composition and interface from the gas/liquid phase may be used to confine or localize the drug in the target structure with the support of ultrasound examination imaging, allowing diagnosis and treatment to occur simultaneously or sequentially.

Fig. 1 shows a schematic view of an embodiment of a contrast media apparatus 100 including a container assembly 101 and shows a portion of a conduit assembly 102 fluidly connected to container assembly 101 for forming an alternating and repeating interface of a gas phase and a liquid phase. The container assembly 100 may be connected to a catheter assembly comprising a catheter 1. The dimensions of the contrast-type generation chamber 3 and/or the conduit may be of such a diameter that a distinct gas/liquid phase is maintained and thus the merging of similar phases is minimized. In some embodiments, the contrast-generating chamber and catheter may have a diameter in the range of about 0.5mm to about 5.0 mm. The pressure relief valve 2 may minimize excessive pressure buildup in structures, such as the fallopian tubes, if the structures are blocked, such as if the fallopian tubes are not open. Such valves may be used in series (not shown) in other locations in the device or embodiments may not have valves. The valve may also act as a secondary pressure relief (second daryrelief) to a tip structure on the catheter, such as a balloon, and the tip structure acts to hold the catheter in place when the catheter is positioned in an access channel to the fallopian tube, the basal process.

The contrast agent pattern generation chamber 3 forms a phase having an interface between a liquid (e.g., saline) phase 14 and a gas (e.g., air) phase 13. The formation of an interface between the gas and liquid phases occurs as the two media enter the contrast-type generation chamber as it is advanced by the dual syringe pump 7. Rubber septum 4 allows needle 9 to be inserted into contrast-type generation chamber 3 under an air-tight seal. The liquid phase is introduced into the contrast agent pattern generation chamber 3 via a connection 10, which connection 10 may be a tube. The gas or liquid may be provided from either container. The valves may be added in series, such as to prevent flow along the path of least resistance possible, and a one-way check valve 12 may be placed at the rear of the needle 9. The aforementioned check valve is an in-line sterile filtration device 5 having a porosity of about 0.2, such a filter can be used in series with either or both media. Embodiments of the invention may include an apparatus of such a valve that does not include a filter. Syringes 11a and 11b may be preloaded with their respective media, liquids or gases, and placed and locked in the dual syringe pump 7. The syringe pump drive block 8 advances each of the gas and liquid syringe plungers 6a and 6b in a simultaneous manner. A junction 15 is formed between the contrast generating chamber and the catheter. The vibrator 16 is an optional element for creating vibrations through the needle 9, thereby creating a phase out of the needle 9, a smaller phase of gas or liquid, such as a foam.

An alternative embodiment includes a dual pump, wherein the drive block includes two separate drives for two separate syringes. This allows the interface pattern, or gas/liquid phase, to be varied to provide one phase that is shorter or longer than the section of the other phase. This may be achieved by one plunger delivering a slower (or faster) rate of delivery than the other plunger.

The needle 9 diameter may be slightly smaller or slightly smaller than the diameter of the contrast-type generation chamber to allow the phase delivered via the needle 9 to be affected by another phase in the contrast-type generation chamber 3, thereby dispersing the phase delivered through the needle 9 in discrete amounts. For example, the surface tension of the liquid delivered via the needle 9 may cause a determined amount of liquid to separate from the needle tip and form a liquid phase in the gas within the contrast media pattern generation chamber. For example, the gauge of the needle may be in the range of 10-30 gauge.

Figure 2 is similar to figure 1 except that contrast device 200 has a contrast-type generation chamber with a larger diameter than the delivery catheter. Fig. 2, which is numbered similarly to fig. 1, shows a container assembly 201 fluidly connected to a catheter assembly 202.

Fig. 3 is similar to fig. 1, except that contrast device 300 has a contrast-type generation chamber with a larger diameter than the delivery catheter, and needle 9 is not present. Fig. 3, which is numbered similarly to fig. 1, shows a container assembly 301 fluidly connected to a catheter assembly 302.

Fig. 4 is a schematic diagram of an embodiment of a container assembly 200 for forming and delivering an alternating gas/liquid contrast agent to a catheter assembly or similar device.

The syringe 10 is filled with a porous substance 20. The porous mass 20 is partially saturated with a liquid 30. This may be accomplished by withdrawing the plunger 40, and submerging the syringe in the liquid, injecting the liquid through the syringe opening 50, or other suitable means of placing the liquid in the void of the porous mass 20. For example, the porous mass may be provided in a wet state, wherein the liquid has been combined with the porous mass prior to being placed in the container. The syringe opening 50 is suitably connected, with or without a sterile filter component, to a catheter assembly or similar delivery component to deliver the contrast media to the desired site. The plunger 40 is gradually advanced to cause the liquid and gas phases to alternatively exit the syringe opening to the catheter assembly and be delivered to the desired site to be imaged.

Figure 5 is a schematic representation of a visualization of a fallopian tube using a contrast agent composition of the present invention, and a delivery device of U.S. patent application serial nos. 12/240,738 and 12/240,791. The introducer rod (introducershaw) 60 is shown positioned within uterus 120. The catheter assembly 70 extends from the introducer rod 60 and positions the delivery end of the catheter 80 in the uterine horn. A contrast agent 130 is present in the fallopian tube 90 and includes the contrast agent 130 having a liquid phase 100 and a gas phase 110.

Figure 6 illustrates the delivery of an air/saline contrast agent composition by a device of the present invention wherein the air/saline composition is delivered directly to the uterus of a female mammal. The delivery end of the catheter 1 with the balloon element for blocking reflux is placed inside the uterus 2 of a mammal. A gas/liquid contrast agent 3 is generated and delivered via the catheter 1 and into the uterus. The contrast agent flows through the uterus and enters the fallopian tubes 4, which tubes 4 are visible due to the alternating pattern formed by the gas/liquid portion of the contrast agent.

Fig. 7 illustrates a container assembly of a contrast media device 20 that includes a dual container embodiment of the present invention. The housing that may enclose the components shown in the figures is not shown, but optionally may not enclose the air and outlet port 6, and/or the plunger end. Starting from the proximal end of the figure, the elements of the device are described. Plunger ends 7a and 7b are connected to syringe plungers (not shown) retained in syringe bodies 4a and 4 b. The element connecting the two plunger ends is not shown so that the plunger ends 7a and 7b can be pushed simultaneously. See fig. 8 for actuator 35 as an example of an element connecting the two plunger ends. The full length of each plunger is not shown, where each plunger end may be connected to a piston and fluid seal that are moved into position within the syringe body. The syringe body (container) 4b is hollow and can contain a liquid, such as saline, and is in fluid connection with the conduit for fluid, the connector 3 b. The connector 3b is connected to a contrast generating chamber 8, said contrast generating chamber 8 comprising a conduit (connectors 11a and 11b) and a mixing chamber 1 in fluid connection with each container, respectively, and a static mixer 12. The syringe body (container) 4a is hollow and can contain gas and is connected in series and in gas connection with a non-return valve 2a, said non-return valve 2a being connected in series with a connection piece 10 in the gas path from the vent opening 5. The connection 10 is in series and in fluid connection with an air filter 9, said air filter 9 being in series and in fluid connection with the vent opening 5. To fill the container 4a, air can be drawn through the vent opening 5 into and through the filter 9, through the connector 10, through the check valve 2a, through the connector 3a, through the container outlet 14a and into the container 4 a. To provide air to the contrast generating chamber 8, air is moved from the container 4a through the outlet 14a and into the connector 3a by applying pressure to the plunger end 7a, which moves the plunger piston and fluid seal through the inner body of the container 4 a. Check valve 2b is in fluid (gas) communication with contrast generating chamber 8 such that gas from container 4a begins to move from container 4a, through container outlet 14a, through connector 3a, through check valve 2b, to the proximal end of contrast generating chamber 8 at connector 11a in contrast generating chamber 8 and to mixing chamber 1, which may include static mixer 12. A contrast generating chamber 8 is fluidly connected to the outlet port 6. A connector, connector 7, is shown and may be used to connect the catheter and contrast device as shown. A connecting element, such as a connector 22, such as a luer lock or other tube or catheter connector, may be used to connect the separate elements of the device.

In providing saline or any other fluid into contrast generation chamber 8, the saline (or other fluid) is set in motion from container 4b by applying pressure to plunger end 7b, through container outlet end 14b and into connector 3b, which moves the plunger piston and fluid seal through the inner body of container 4 b. Beginning with connection 3b, saline enters the proximal end of contrast generation chamber 8, which includes connection 11b, which is in series and fluidly connected to mixing chamber 1. The distal end of contrast generating chamber 8 is fluidly connected to static mixer 12 and outlet port 6.

In filling the apparatus of fig. 7 with a liquid, such as brine, the outlet port 6 is immersed in a fluid, such as brine, present in a container, such as a bowl or other fluid container. The piston and fluid seal of the plunger 7b are placed in a remote position of the container 4b and a force is applied to move the plunger end, and the piston and fluid seal, away from the outlet end 6 and towards the extreme end of the container 4 b. As the fluid seal moves in a proximal direction through the container, saline is drawn into and through the outlet port 6, through the contrast generating chamber 8 and the connections 11a and 11b, with the flow of saline being prevented further than the 11a connection by the check valve 2b (one-way valve), and the saline continuously flows through the connection 3b, the container outlet port 14b and into the container 4 b.

Fig. 8 illustrates an alternative embodiment of a contrast media device in which the static mixer 12 (shown in fig. 7) is shortened or absent and the outlet port 6 is connected to the mixing chamber 1 of the contrast media generation chamber 8. The other elements are similar to those of fig. 7.

Fig. 9 illustrates the internal components (container assembly) of the contrast media device of the present invention with the presence of a pressure management element. The structures are numbered as in fig. 7. The distal end of the connector 7 is in series and fluidly connected with a channel 21a of a pressure relief mechanism comprising at least elements 21a, 21b, 22, 16 and 17. The channel 21a of the pressure relief mechanism is in fluid connection with the connector 19, which optionally includes a stopcock valve that can be placed in an open or closed position by use of the stopcock handle 15, and is in series and fluid connection with the connector 18 and the outlet 20. The pressure relief valve 21b of the pressure relief mechanism is in a closed position and opens when the fluid pressure on the valve exceeds the allowable pressure. When the allowable pressure is exceeded, the pressure relief valve 21b opens and fluid starts from passage 21a (or from connection 19 to passage 21a), flows through the pressure relief valve 21b and into and through the connector 16, which is connected to the pressure relief valve 21b by the pipe connection 22. The connector 16 is a connecting element for connecting a container, bag or collection device (not shown) with respect to the fluid flowing through the outlet 17. If the pressure relief valve 21b is open, the stopcock 15 may be turned to close the connection 19 to stop fluid flow to the pressure relief valve 21 b.

Fig. 10 illustrates the internal components of the device of the present invention and shows an actuator 35 which moves both plunger ends 7a and 7b simultaneously (partially obscured in the drawing of the actuator 35) when moving towards or away from the outlet 20. The actuator may be external to a housing enclosing internal elements of the device.

The method of the invention comprises observing the structure by ultrasound techniques using a contrast agent. The present invention includes the use of the contrast agent device described herein to prepare contrast agents comprising a liquid phase and a gas phase in one format. The contrast agent is delivered directly to or in a structure visualized by ultrasound examination. For example, if a fallopian tube is to be examined, a contrast agent may be delivered through a catheter to the uterine horn or at the ostium of the fallopian tube. Alternatively, a sufficient amount of contrast agent may be provided to the uterus and fallopian tubes so that the entire organ system, i.e., the uterus and fallopian tubes, can be evaluated by imaging techniques. One or both fallopian tubes may be evaluated without requiring the entire uterine cavity to be inflated. In contrast, other known systems require filling the entire uterus with a liquid (e.g., saline), then adding the mixed gas/liquid composition to the saline filled uterus, and waiting until the gas/liquid mixture reaches the fallopian tubes. Using such a method is procedural limited because it requires filling the uterus with saline sufficient to inflate the uterus before introducing air and saline to visualize the tubal passageway, the presence of air in the uterus or tube may create air pockets that alter fluid flow, and the patient may need to be controlled into an odd position to allow gas to flow in an effective direction. The physician has to perform a number of transformation steps of a complex nature. The present invention may include a one-step procedure using a simple automated contrast device or a hand-held contrast device.

The method of the present invention includes providing a contrast media device comprising first and second containers, e.g., each container capable of holding 10mL of liquid and each container containing a plunger, wherein each container is fluidly connected to an outlet and the second container is connected to a vent via at least one check valve; both containers are filled simultaneously by placing the outlet end within the saline container and passing the two containers and withdrawing the plunger away from the outlet end. One container is filled with saline and the second container is filled with air. When the plunger is withdrawn to a determined position, the first reservoir contains saline and the second reservoir contains air. When the plungers are simultaneously depressed to move each plunger through its container toward the outlet end, saline and air move from the respective container and into and through separate fluid connections to a contrast generating chamber that includes a mixing chamber with a static mixer or, alternatively, to a contrast generating chamber that includes a mixing chamber that is fluidly connected to two separate connections from each container and functions as a container space, a conduit in which the two separate connections from the containers join together (conduit mixing chamber) and in which no static mixer is present. The contrast agent composition is produced by the contrast agent generation chamber and moves therefrom into the catheter and into the body structure. In the static mixer, air and saline are mixed to form a contrast agent composition that includes an air/saline interface. Alternatively, in embodiments where the contrast-generating chamber does not include a static mixer but rather a tube mixing chamber, when fluid-flow mixing is performed in the mixing chamber through separate connections, air and saline flow out of their respective tubes and disperse and mix to form air segments (bubbles) within the fluid. Such an air/brine interface may be the result of air bubbles surrounded by or within the brine section or the air and brine sections. The contrast agent composition flowing out of the static mixer or tube mixing chamber optionally flows through an outlet tube and out the outlet end. The catheter may be connected to a catheter and the contrast agent composition flows into the catheter. After dispersing the fluid in the container, the container may be refilled one or more times to prepare and deliver a sufficient amount of contrast agent. Alternatively, containers pre-filled with fluid (e.g., air and saline) may be provided to initially provide contrast media, and the first pre-filled container replaced with a new pre-filled container containing fluid (e.g., air and saline), or the first pre-filled container, now empty, may be refilled in the steps described above.

With the present invention, delivery of contrast agent containing an air/liquid interface pattern from a contrast agent device to the fallopian tube may determine patency of the tube by unobstructed flow during visualization and may not result in unnecessary material accumulation in the blind path. The delivery volume may be defined as the possible volume of the egg transport conduit, i.e. about 2ml, for a single assessment, and may include larger amounts to verify initial observations. Oviduct imaging can include using a combined liquid/gas phase composition of about 0.5mL to about 20mL, about 1mL to about 15mL, about 1mL to about 5mL, about 1mL to about 10mL, about 10mL to about 20mL, about 1mL to about 3mL, about 15mL to about 20 mL. Imaging the uterus and the at least one fallopian tube may comprise using a combined liquid/gas phase contrast agent composition of about 10mL to about 150mL, about 10mL to about 100mL, about 10mL to about 50mL, about 20mL to about 100mL, about 10mL to about 80mL, about 10mL to about 90mL, about 20mL to about 90 mL. The blockage of the tube may be visualized by the lack of movement of the contrast agent along the fallopian tube into the abdominal cavity. The ensuing pressure relief may be provided by a pressure relief valve in the device or by moving an end structure on the delivery catheter from its position into the uterine horn. The device of the present invention lends itself to automation when a syringe is inserted into the pumping system or to activation by manual delivery when a syringe is inserted into or connected to the hand-held device.

One embodiment of the present invention contemplates a contrast delivery device that does not require a supplemental system, such as a fluid reservoir or valve control of fluid flow from the fluid reservoir connected to the device. Simplified devices and methods, such as those of the present invention that include a refillable container, make it more likely that successful operation and results will be achieved. Furthermore, the device is capable of maintaining the pattern of alternating phases for a period of time effective for ultrasound examination. This allows the user to be free to correctly place the structure and reposition the patient or structure, or catheter, during the procedure. Generally, there is no coalescence of individual phases. The gas/liquid phase or interface pattern produced by the contrast agent device is initially visible to the naked eye, and each segment of contrast agent and the rate of delivery can be controlled to suit the needs of the user.

The mixing of the fluids (air and saline) results in a consistency of the alternating air/liquid interface pattern and is ideal for optimally observing the migration of the imaging agent in the fallopian tubes. Due to the size of the tubes, an alternating pattern of continuity is required to allow visualization with flow ultrasound. Other devices that attempt to deliver saline and air do not consistently perform and procedures are considered too difficult to perform by medical personnel for evaluation of the fallopian tubes and/or uterus. With previous devices, the procedure required extensive practice and technical learning to use the device and obtain sufficient visualization for diagnosis, whereas with the consecutive alternating patterns produced by the present invention, most physicians can master the device and routinely obtain sufficient good data after only a few applications and patients. One example of a contrast generating chamber is commercially available from Micromedics (parts: mixing connectors with static mixers), and is an example of an alternating pattern of components that can bring liquids and gases together in a coherent fashion to create an easy visualization. Micromedics parts have a static mixer made of Keptal F30, which adopts a configuration that produces turbulence of liquid and gas. Other materials, such as foam or any porous material, will be used for similar purposes to generate turbulence and mix the liquid and gas. Alternatively, where the contrast generation chamber comprises a mixing chamber without a static mixer, such as a contrast generation chamber comprising a space (conduit mixing chamber) where the mixing chamber is a junction of two single connectors, the alternating pattern may or may not be consistent with the contrast generation chamber with a static mixer. The diameter of the individual connections, the contrast generating chamber, the mixing chamber and the outlet end to the conduit affect the spacing of the produced saline and air and may be optimised to ensure a coherent alternating pattern. Under ultrasound, the liquid appears black, while the gas appears white. The alternating pattern of black and white, moving along the lumen or duct, allows for the evaluation of small diameter tubes, such as fallopian tubes or ducts. In some structural pathways of greater volume and diameter, two phases of the fluid may be maintained by additives or surfactants (such as those disclosed herein). The contrast media device may include a container larger than the syringes shown herein. For example, one container may be used and the container may contain a frothed liquid. The foam may be generated by shaking, adding a foaming agent, by ultrasound or agitation. The foam is delivered to the cavity to be visualized by transporting the foam from the container assembly through the catheter assembly into the structure to be evaluated. Obviously, other methods of creating dispersion are possible and may include mechanized means of creating dispersion. The phases produced by these methods allow the size of the foam produced to be adjusted by controlling the shaking or agitation and the type and concentration of the dispersing agent.

The method of the present invention allows for the assessment of pathways, such as the fallopian tubes and uterine cavity, by ultrasound and provides a simple, safe and inexpensive outpatient method. The methods of the present invention comprise ultrasonically examining a site of a body, such as the uterus and its associated fallopian tubes, using the devices and compositions disclosed herein.

In general, the invention includes methods and apparatus for imaging structures by providing a contrast agent composition to the structures, and imaging techniques, such as ultrasound. The imaging of the contrast agent in or around the structure provides information to the viewer and the method and apparatus may be used for diagnosis and treatment of conditions associated with the structure being viewed. The methods and devices of the present invention are useful for the diagnosis and treatment of disorders associated with the uterus and/or fallopian tubes of humans and animals.

The contrast media device of the present invention comprises a container assembly comprising at least one container for containing a fluid, means for running the fluid from the container, means for connecting said at least one container with said container assembly, and optionally a catheter assembly in fluid connection with said container means. In an embodiment of the invention, the container is a syringe and the means for handling fluid from the container is a syringe plunger. Embodiments may further comprise means for actuating the syringe plunger, and the means is a mechanical pump or manual operation. The device may further comprise fluidic connections to various parts of the device, valves, needles, filters, vibrators, pumps and other component connection elements.

Embodiments include devices wherein at least one container further comprises a porous mass and a gas. The porous substance may be any substance that may contain a gas and a liquid and easily release the gas and the liquid when a squeezing or physical force is applied to the porous substance. For example, the porous substance may be a sponge, such as an open-cell polyurethane sponge, which is compressible. For example, the porous mass may be a rigid material containing gas and liquid, but which collapses upon compression to release the gas and liquid. A porous mass may be provided in a dry state into a container, wherein the porous mass comprises a gas, and a liquid may be added to the container such that the porous mass comprises both a gas and a liquid. Alternatively, the porous mass may be wet, contain both liquid and gas, and as such be provided into a container. After the wet porous mass is inserted, more liquid may be added to the container, or not. In theory, a porous mass comprises within its pores a gas and a liquid associated with the porous mass. The liquid and gas may be present in the pores or associated with the porous material in a manner that is readily releasable, such as by surface tension, hydrogen bonding, or other weak bonding association.

The liquid provided to the container or porous mass may further include a surfactant, emulsion, other stabilizer, or other dispersing agent. The liquid provided to the container or porous mass may further comprise a frothed liquid. The liquid may be foamed by methods known in the art.

Embodiments of the present invention include a contrast media apparatus comprising a container assembly comprising two containers and a patterned contrast generating chamber fluidly connected to the containers. For example, the containers may be syringes, each syringe comprising a means for moving fluid from the container, the means being a syringe plunger. The embodiments may further comprise means for actuating the syringe plunger, and the means is a mechanical pump or manual operation. In a two-vessel device, one vessel contains a gas and the other a liquid. For example, when the container is a syringe, one contains a gas and the other contains a liquid. In the present invention, when two or more containers are used in one device, the containers may be of the same or different size, volume, diameter, length or made of the same or different materials.

The method of the present invention comprises the use of ultrasound techniques known to those skilled in the art to visualize structures. A method of ultrasonically inspecting an imaging structure includes generating a contrast agent comprising alternating phases of a gas and a liquid in a contrast agent arrangement including at least one container; providing the contrast agent into a catheter assembly, wherein the catheter assembly comprises a catheter delivery end that is placed at or near a structure to be visualized; delivering the contrast agent directly to a structure to be imaged; and the contrast agent in the structure is visualized by ultrasound. Methods of ultrasonically inspecting an imaging structure include observing a structure in which a contrast agent of the present invention is contained, or through which the contrast agent flows. The method of the present invention comprises preparing a contrast agent comprising mixing a gas and a liquid in a contrast agent device, thereby producing alternating phases of gas and liquid, said phases having a visible interface therebetween, said interface forming a pattern that is visible by ultrasound, thereby forming a contrast agent composition.

The present invention includes ultrasound to image contrast agents within a structure. Procedures using ultrasound typically use a transvaginal probe, wherein the probe can be placed proximal to the fallopian tube. Placement of the probe to obtain a radial view enables the use of an in situ catheter to visualize the ultrasound imaging agent within the uterine cavity, verifying forward flow into the uterine cavity and no reverse flow into the vagina. Placement of a probe capable of obtaining a lateral view can visualize the ultrasound imaging agent from the uterine cavity to the fallopian tubes, which can allow viewing of both or each tube in a particular plane.

Any structure that can be imaged using ultrasound can be imaged with the contrast agent compositions of the present invention and contrast agent compositions prepared by the contrast agent device taught herein. For example, the structure to be visualized is at least one fallopian tube of a human or animal.

The contrast agent composition of the present invention may be made of a flowing liquid and form a discrete liquid phase upon contact with a gas. The contrast fluid may or may not include a visualization fluid. The contrast agent composition may further comprise a therapeutic composition. Therapeutic compositions include therapeutic agents including, but not limited to, methotrexate (methotrexate), hormones, fertility enhancing compounds, fertility impeding compounds, motility enhancing compounds, motility impeding compounds, compounds that affect the ciliary/detoxification cycle, compounds that enhance or impede ciliary growth, follicular therapeutic compounds, antibacterial agents, bactericidal agents, antifungal agents, antiviral agents, anti-mycoplasma agents, or anti-parasitic compounds, compounds that reduce inflammation or scar tissue formation, compositions comprising one or more antibiotics, anti-mycoplasma agents, or antiviral compounds; compositions comprising mucin, electrolytes or enzymes that enhance or inhibit fertility, progesterone, estrogen, adrenal active compounds, norepinephrine active compounds, nonsteroidal anti-inflammatory drugs, prostaglandins, other compounds that can treat or prevent conditions associated with the fallopian tubes, uterus, ovaries, or other organs or coverings reached by compositions that flow from the uterine horn or ostium, or any combination thereof, or combinations thereof. The therapeutic composition includes a hormone for fertility, a compound that enhances fertility, a gamete, a sperm, an ovum, a combination of sperm and ovum, one or more zygotes, or one or more embryos, or a combination thereof.

The method of imaging a structure may comprise using a composition prepared by a contrast agent device of the present invention. In embodiments, the contrast media device comprises a container comprising a porous mass and a fluid. The porous mass further comprises a gas, and the liquid may comprise a surfactant, emulsion, other stabilizer, or other dispersant. The liquid may be foamed.

The method of the invention comprises delivering the contrast agent composition of the invention directly into the structure. For example, the contrast agent composition may be delivered directly to the fallopian tube. The composition may be delivered by a catheter, and the catheter may be provided to the site by means known in the art and by those taught herein. For example, the catheter may be provided such that the catheter delivery end is placed in the uterine horn. The contrast agent composition is provided through the catheter and exits the catheter into the tubal opening and, if possible, flows along the fallopian tube. The contrast agent composition is visualized by ultrasound and the condition of the fallopian tube can be determined by the visualization, a diagnosis can be provided or a treatment of the fallopian tube or other structure can be provided. For example, when the at least one fallopian tube is imaged by ultrasound, patency or occlusion of the at least one fallopian tube is determined. The methods of the invention include using small amounts of the contrast agent composition to evaluate or treat a structure, such as a fallopian tube, and the amount of contrast agent to be provided into the structure is below 20mL for a single evaluation. The contrast media generation and delivery apparatus of the present invention includes a container assembly including at least one container for holding a fluid, means for moving the fluid from the container, and a connection for fluidly connecting the at least one container to a contrast media generation chamber. The contrast media generation and delivery apparatus of the present invention may include two containers, each container having means for moving fluid from the container. In one aspect, each container is a syringe and the means for moving fluid from the container is a syringe plunger. The contrast media generation and delivery device of the present invention may further include a means for simultaneously actuating the two syringe plungers, referred to herein as an actuator. The actuating member is connected to the end of the syringe plunger such that the operating members simultaneously move the plunger in the same direction, at the same rate, and at the same distance. The contrast media generation and delivery apparatus of the present invention may include a contrast media generation chamber with a static mixer. The contrast media generation and delivery apparatus of the present invention may include a contrast media generation chamber including a tubing mixing chamber. The contrast media generation and delivery devices of the present invention may include a container fluidly connected to a vent of an atmosphere or other gas source. The contrast media generation and delivery apparatus of the present invention may include at least one check valve in fluid connection with a container in fluid connection with the vent. The contrast media generation and delivery device of the present invention may include at least two check valves in fluid connection with a container in fluid connection with a vent. The contrast media generation and delivery devices of the present invention may include a pressure relief mechanism. The pressure relief mechanism may include a pressure relief valve. The contrast media generation and delivery apparatus of the present invention may include a contrast media generation chamber that includes a mixing chamber and does not include a static mixer. The contrast media generation and delivery apparatus of the present invention may include an outlet in fluid connection with the contrast media generation chamber. The contrast media generation and delivery apparatus of the present invention may include a catheter connected to the outlet end.

The method of the present invention comprises a method of ultrasonically imaging a body structure, the method comprising providing a contrast agent generating and delivery device comprising a container assembly comprising at least one container for holding a fluid, means for running the fluid from the container, and a connection for fluidly connecting the at least one container to a contrast agent generation chamber; filling at least one container with a fluid; running fluid from the at least one container into a contrast-producing container, thereby producing a contrast composition; providing the contrast composition to a bodily structure through a catheter comprising a catheter delivery tip disposed in the same or a different bodily structure; the contrast agent composition in one or more body structures is visualized by ultrasound. The method of the present invention may comprise at least one container pre-filled with a fluid. The method of the present invention may include a contrast media device comprising two containers, wherein a first container is filled with air and a second container is filled with saline. The method of the present invention may comprise providing saline and air to a contrast generating chamber, wherein the saline and air are mixed, thereby forming a contrast composition comprising air segments and saline segments having a pattern with a regular frequency. The methods of the invention may comprise providing a contrast agent composition to the uterus and fallopian tubes, which may be visualized using ultrasonography.

The method of the present invention includes diagnosing patency of a fallopian tube, comprising, providing a contrast agent generation and delivery device comprising a container assembly comprising at least one container for containing a fluid, means for running the fluid from the container, and a connection for fluidly connecting the at least one container with the contrast agent generation chamber; filling at least one container with a fluid; running fluid from the at least one container into a contrast-producing container, thereby producing a contrast composition; providing the contrast composition to a bodily structure through a catheter comprising a catheter delivery tip disposed in the same or a different bodily structure; the contrast agent composition in one or more body structures is visualized by ultrasound. The method of the present invention may comprise wherein the contrast agent production and delivery device comprises two containers, wherein the containers are connected together such that a simultaneous action is applied, wherein a first container is filled with air, a second container is filled with saline, and the saline and air are provided to the contrast agent generation chamber, wherein the saline and air are mixed, thereby forming a contrast agent composition comprising a pattern of air segments and saline segments having a regular frequency. The method of the invention may comprise providing a contrast agent composition to the uterus and at least one fallopian tube, and wherein the uterus and/or at least one fallopian tube is imaged using ultrasonography.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

All patents, patent applications, and references included herein are specifically incorporated by reference in their entirety.

It should be understood, of course, that the foregoing relates only to preferred embodiments of the present invention and that numerous modifications or alterations may be made therein without departing from the spirit and scope of the invention as described in the disclosure thereof.

The present invention is further illustrated by the following examples, which should not be construed as in any way limiting its scope. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

Examples

Example 1

Preparation of contrast agents using dual syringe pumps

As shown generally in fig. 1, a container assembly including a dual pump is manufactured to have two syringes, one of which has a volume of 6cc and the other of which has a volume of 20 cc. The 6cc syringe was completely filled with saline and the 20cc was filled with air. Since sterile technology is required, a sterile 0.2 μm filter (Sartorius Minisart or Whatman Syrfil-MF) is attached to the syringe. A 27 gauge, 3.5 "long spinal needle was used to inject a gas phase into the liquid phase in the contrast-type generation chamber to create alternating gas and liquid phase interfaces. A PICC-nature catheter T-port extension (T-port extension) and two lengths of extension tubing are used in the device.

Variations in syringe ID, pump volume, pump rate, and pump delay settings are evaluated and acceptable contrast is produced, as seen in the catheter assembly in front of the container assembly. The contrast agent is delivered into a clear PVC tube that mimics the dimensions of the fallopian tube. The user can change the pattern created with the gas and liquid phases by adjusting the pump settings to increase the volume of gas or liquid and the rate of contrast delivery. A rather regular pattern of gas/liquid phase interfaces is generated by the contrast agent device.

Example 2

Preparation of contrast media using a handheld dual injector

Following the assembly of example 1 is the use of a housing to support the dual syringe. A Block (Block) was placed behind the plunger of a 6cc syringe containing saline to align with the plunger distance of a 20cc syringe containing air. When it is desired to deliver contrast media into a catheter, the generation of the contrast media and its delivery to the catheter is controlled and manipulated by applying force by hand on the plunger of the dual syringe. The contrast agent pattern is uniform when both plungers of the syringe are pushed simultaneously, with substantially equal amounts of gas and saline phases alternating in the conduit. When pushing one plunger followed by the other of the syringe, the pattern is sometimes regular and sometimes irregular, depending on the actuation of the respective plungers. Although the dimensions of the individual sections of the gas and brine phases are not uniform, the liquid/air phases are repeated enough to be easily observed. The contrast agent is delivered into a clear PVC tube that mimics the dimensions of the fallopian tube.

Example 3

Preparation of contrast agent using syringe containing porous substance

A sterile Optipore cleaning sponge was cut longitudinally into two equal sections. The plunger of the 60cc syringe was removed and the two sponge halves were inserted, one half behind the other. The plunger was reinserted into the syringe and depressed to the 15cc mark. The syringe needle tip was submerged in saline in a sterile container and the plunger was withdrawn to 30cc mark. The container assembly is now fully assembled and loaded. The container assembly is connected to a catheter assembly and the plunger is depressed to produce a composition of air and saline, i.e., a contrast agent composition for ultrasound examination imaging. The contrast agent is delivered into a clear PVC tube that mimics the dimensions of the fallopian tube. When the user controls the delivery of the contrast agent, an irregular pattern or a random pattern is visualized. Although the dimensions of the individual sections of the gas and brine phases are not consistent, the liquid/air phases are repeated enough to be easily observed.

Example 4

Study of contrast agent produced by dual syringe pumps in a simulation model

In an ultrasound simulation model (ultrasounded Phantom model) (available from Advanced medical technologies, LLC, division Blue Phantom, Kirkland, Washington), the contrast agent device of fig. 1 and example 1 was used to deliver contrast agent produced by the device as saline in liquid phase and air in gas phase into a channel simulating the dimensions of a human fallopian tube. The delivery end of the catheter assembly is placed within the simulated fallopian tube. The contrast device pump is activated, the contrast agent is generated, and the contrast agent is delivered into the model fallopian tube and in a similar fashion to that shown in figure 5. Ultrasound equipment (model: Voluson 730Pro, manufactured by GE Medical Systems) is used to visualize the generated contrast agent that travels down the channel or simulated fallopian tube in real time while the gas/liquid phase contrast is visualized with an ultrasound probe.

Example 5

Study of contrast agent produced by dual syringe pump in human subjects

The contrast agent device of fig. 1 and example 1 is used to deliver contrast agent into the fallopian tubes of a human subject. The contrast agent composition is produced by a device that uses saline as the liquid phase and air as the gas phase, each of which passes through a sterile filter of about 0.2 microns in size to ensure sterility. The catheter assembly was provided to a patient using a delivery system described in U.S. patent application serial No. 11/065,886, placed at the uterine horn of each subject. The contrast agent is delivered through the catheter of the delivery system and visualized using an ultrasound device (manufacturer: GEmedical Systems, model: Logic 500). Tubal patency is evidenced by contrast passing through the fallopian tube and into the abdominal cavity. This evaluation is done in real time by evaluating the apparent contrast agent flow after the delivery system is properly positioned.

Example 6

Studying contrast agent produced by an injector comprising a porous substance in a simulation model

In an ultrasound simulation model (ultrasounded Phantom model) (available from Advanced medical technologies, LLC, division Blue Phantom, Kirkland, Washington), a contrast agent device similar to the one shown in fig. 4 and example 3 was used to deliver contrast agent produced by the device into a channel simulating the size of a human fallopian tube, where saline is the liquid phase and air is the gas phase. The porous mass used is a highly porous polyurethane open-cell foam designed for protective packaging materials. The delivery end of the catheter assembly is placed in the simulated fallopian tube and the contrast device is manually actuated, thereby producing contrast that is less regular in pattern than that shown in fig. 5. An ultrasound instrument (manufactured by GE Medical Systems, model: Voluson 730Pro) is used to visualize the generated contrast agent that travels down the channel or simulated fallopian tube in real time while the gas/liquid phase contrast agent composition is visualized with an ultrasound probe.

Example 7

Studying contrast agent produced by an injector comprising a porous substance in a human subject

A contrast agent device similar to the one shown in fig. 4 and example 3 was used to deliver contrast agent produced by the device into the oviduct of a human subject by means of a catheter assembly incorporated in a delivery system as described in U.S. patent application serial No. 11/065,886, where saline is the liquid phase and air is the gas phase. The delivery device is placed in the uterus of a human subject and the delivery end of one or both catheters is placed within the uterine horn of the uterus. A3X 2 "sterile Optipore wound cleansing sponge (manufacturer: E.R. Squibb & Sons, Inc., ConvaTec, Princeton, N.J., Branch of LLC) was inserted into a 60cc sterile syringe. The sponge is made of polyurethane and is highly porous in nature. Saline is drawn into the syringe so as to fill the syringe, but air trapped in the syringe is not removed. Connecting the syringe to the connection end of one or both conduits of the delivery device. When the plunger of the syringe is depressed, the contrast agent is formed and delivered through the catheter assembly and out into one or both fallopian tubes. The contrast agent is visible under ultrasound (manufacturer: Philips, model: HD 3). This evaluation is done in real time by evaluating the apparent contrast agent flow after the delivery system is properly positioned.

Example 8

Investigation of contrast agents produced by four channel configurations in a small model (bench model)

A contrast agent device similar to that shown in fig. 7 was modified to produce the following four configurations to assess contrast agent spacing:

a) the contrast device (with static mixer) as shown in fig. 7, where each flow channel has an ID (inner diameter) of 0.022 "up to an ID of 0.100" inside the static mixer.

b) A contrast agent device (without a static mixer) as shown in fig. 8, where each fluid channel has an ID of 0.022 ".

c) A contrast media device similar to that of fig. 8, wherein each fluid channel has an ID of 0.045 ".

d) A contrast media device similar to that of fig. 8, wherein each fluid channel has an ID of 0.017 ".

All contrast devices were connected to a 2.2mm tube simulating the diameter of the fallopian tube to assess the spacing of the fluids produced. It was found that with these inner diameters of the fluid channels and with or without a static mixer, the length of the brine was essentially the same compared to the length of the air space generated, with an average length of about 5 mm.

Example 9

Analyzing saline and air pattern frequency and zone length differences at different delivery rates

A system was created for simulating the female reproductive system including cervix, uterine cavity and fallopian tubes to enable analysis of the possible effects of different delivery rates of the device depicted in fig. 7, as well as the frequency of air and saline patterns and the length of the respective segments. The length and delivery rate of the air sections used for several experiments are shown in table 1.

The test equipment consisted of a transparent soft elastomer material sandwiched between two transparent acrylic plates. The base plate has a similarly sized recess representing the uterine cavity, and the elastomer is placed over the recess. The acrylic panels are latched together to create a water tight seal. The top plate is composed of: a) an inlet fitted with a short length elastomeric tube to simulate a 2mm bore of the internal cervical orifice, sufficient to accommodate a standard intrauterine balloon catheter, and b) two outlets fitted with two 2mm bore elastomeric tubes to simulate the internal diameter of each fallopian tube. Each tube is approximately 400mm long to enable multiple data readings. The test equipment was fixed to a standard desktop tensile tester (Instron). The carriage was made to secure the device to the Instron but allowed to move when refilling with saline and air was required. The device is connected to a testing apparatus comprising a standard intrauterine catheter. The crosshead of the Instron is placed against the plunger of the fully filled device and advanced forward at a set rate to simulate delivery.

TABLE 1

Example 10

Saline and air delivery by devices incorporating pressure relief mechanisms

The apparatus depicted in FIG. 9 includes a 3.0PSI (155mmHg) pressure relief valve. A test device consisting of the device described in connection with a disposable pressure transducer (Utah Medical P/N DPT-100) which is then connected to a pressure monitor (pendot technical mat 3Plus) which is then connected to a standard digital computer, is used to measure the pressure achieved when delivering saline and air. A fluid-containing pocket is connected to a pressure relief port of the pressure relief valve to capture excess fluid discharged from the pressure relief valve when actuated.

The device of this embodiment is designed to limit the injection pressure of saline and air poured into the closed system to 200mm Hg or values below 200mm Hg. When the in-line pressure reaches or exceeds a pressure level of 3.0PSI (155mmHg), the valve opens and fluid is discharged from the pressure relief port of the pressure relief valve.

Fluid injection pressure measurements of the device were captured in a simulated closed system, obtained by placing a cap (cap) over a port at the opposite end of the sensor. The sensor was started with saline and visually checked for the absence of air bubbles near the sensing portion of the sensor before pressure measurements were obtained to ensure accurate fluid pressure readings. The test was repeated 6 times, and the results are shown in the graph shown in fig. 11.

Claims (21)

1. A contrast agent generation and delivery apparatus, comprising: a container assembly comprising at least one container for containing a fluid; means for moving fluid from the container; and a connector for fluidly connecting the at least one container with the contrast-generating chamber.

2. The apparatus of claim 1 comprising two containers, each container having means for moving fluid from the container.

3. The device of claim 2, wherein each container is a syringe and the means for moving fluid from the container is a syringe plunger.

4. The device of claim 2, further comprising means for simultaneously driving two syringe plungers.

5. The apparatus of claim 1, further comprising a contrast agent generation chamber, the contrast agent generation chamber comprising a static mixer.

6. The device of claim 5, further comprising a container in fluid connection with a vent to atmosphere or other gas source.

7. The device of claim 6, wherein at least one check valve is in fluid connection with the container, which is in fluid connection with the vent.

8. The device of claim 6, wherein at least two check valves are in fluid connection with the container, the container being in fluid connection with the vent.

9. The device of claim 1, further comprising a pressure relief mechanism.

10. The apparatus of claim 9, wherein the pressure relief mechanism comprises a pressure relief valve.

11. The apparatus of claim 1, wherein the contrast generation chamber comprises a mixing chamber and does not contain a static mixer.

12. The apparatus of claim 1, further comprising an outlet port fluidly connected to the contrast-producing chamber.

13. The apparatus of claim 12, further comprising a conduit connected to the outlet end.

14. A method of ultrasound imaging of a body structure, comprising,

a) providing a contrast agent generation and delivery apparatus comprising: a container assembly comprising at least one container for containing a fluid, means for moving the fluid from the container, and a connection for fluidly connecting the at least one container with the contrast generating chamber;

b) filling at least one container with a fluid;

c) moving the fluid from the at least one container to a contrast generating container to generate a contrast composition;

d) providing the contrast composition to a bodily structure through a catheter comprising a catheter delivery tip disposed in the same or a different bodily structure; and

e) observing the contrast agent composition in one or more body structures by ultrasound.

15. The method of claim 14, wherein step b is omitted because at least one container is prefilled with the fluid.

16. The method of claim 14, wherein the contrast media device comprises two containers, wherein a first container is filled with air and a second container is filled with saline.

17. The method of claim 16, wherein step c) comprises providing saline and air to a contrast agent generation chamber where the saline and air are mixed to form a contrast agent composition comprising a pattern of air segments and saline segments having a regular frequency.

18. The method of claim 14, wherein the contrast agent composition is provided to the uterus and the fallopian tubes are observed using ultrasonography.

19. A method of diagnosing patency of a fallopian tube comprising

a) Providing a contrast agent generation and delivery apparatus comprising: a container assembly comprising at least one container for containing a fluid, means for moving the fluid from the container, and a connection for fluidly connecting the at least one container with the contrast generating chamber;

b) filling at least one container with a fluid;

c) moving the fluid from the at least one container to a contrast generating container to generate a contrast composition;

d) providing the contrast composition to a bodily structure through a catheter comprising a catheter delivery tip disposed in the same or a different bodily structure; and

e) the contrast agent composition is observed in one or more body structures by ultrasound.

20. The method of claim 19, wherein the contrast agent generation and delivery device comprises two containers, wherein the containers are joined to achieve simultaneous action, wherein a first container is filled with air and a second container is filled with saline, and wherein step c) comprises providing saline and air to a contrast agent generation chamber where the saline and air are mixed to form a contrast agent composition comprising air segments and saline segments having a pattern of regular frequency.

21. The method of claim 19, wherein the contrast agent composition is provided to the uterus and at least one fallopian tube is observed using ultrasonography.