WO2002047744A2

WO2002047744A2 - Method and catheter for aerating fluids for medical uses

Info

Publication number: WO2002047744A2
Application number: PCT/US2001/047834
Authority: WO
Inventors: Reid M. Rubsamen; Alfonso Ganan-Calvo
Original assignee: Flow Focusing, Inc.
Priority date: 2000-12-13
Filing date: 2001-12-11
Publication date: 2002-06-20
Also published as: WO2002047744A3; AU2002230748A1

Abstract

A gas (23) such as air or oxygen is forced into an aqueous fluid such as blood, plasma, blood extender fluids, or an imaging medium to form very small microbubbles (31) on the order or about 10 microns or less. The aqueous fluid within the microbubbles (31) therein is administered to the circulatory system of an animal. A catheter which allows for the infusion of the microbubbles containing fluid into the circulatory system of an animal is also disclosed.

Description

METHOD AND CATHETER FOR AERATING FLUIDS FOR MEDICAL USES

FIELD OF THE INVENTION The invention relates generally to the introduction of microbubbles into fluids where it is important to create gas microbubbles which are very small and uniform in size. More particularly, the invention relates generally to a method of aerating a fluid, e.g., a method of introducing a gas such as air or oxygen into a fluid such as blood, plasma or blood extender designed for infusion into a subject's circulatory system.

BACKGROUND OF THE INVENTION The transfer of oxygen to tissue locations in humans and other vertebrate animals has been defined as being functionally dependent upon erythrocyte flux associated with the tissue, specifically the flow rate and hematocrit of the erythrocytes, and upon the difference in oxygen content between arterial and venous erythrocytes. Normally, erythrocytes contain about 98% of the arterial oxygen content. Thus, a condition leading to a localized, regionalized and/or systemic reduction in the circulation of erythrocytes (e.g., blood vessel constriction or occlusion), or from a reduced number of erythrocytes in the cardiovascular system, can result in local, regional or systemic tissue hypoxia, tissue death and possibly even in the death of the human or other vertebrate. The brain is the organ most sensitive to such cell death, followed by the heart, the abdominal organs, and the extremities. The brain will usually not tolerate lack of oxygen for very long (e.g. 3 to 5 minutes depending on the age, condition and temperature of the patient) without massive neuron death. In such situations, it is imperative to restore oxygen quickly and safely to the affected region. Traditional therapy of acute stroke has been limited to the delivery of supportive measures. Newer treatments for stroke attempt to relieve or bypass vessel occlusion before neuron death occurs. In the life threatening emergency of acute stroke, there is a time-limited window of opportunity for treatment after the onset of symptoms. After this treatment window has closed, there is minimal opportunity for recovery of neuronal function. Furthermore, restoring blood perfusion late in the therapeutic window can cause cerebral hemorrhage or edema and progression of symptoms, referred to as the "reperfusion syndrome." For this reason, recent emphasis has been placed on the early treatment of patients, usually within six hours of the onset of symptoms, and on relieving the area of obstruction e.g. by administration of an anticoagluant.

A number of techniques have been proposed which employ site-specific administration of thrombolytic drugs and/or mechanical means, laser or ultrasound energy sources to remove thrombus. Angioplasty, atherectomy and stent placement are employed to relieve atherosclerotic stenoses. These methods all require positioning catheter based devices at or near the site of the arterial obstruction. The primary objective is to restore blood flow as quickly as possible. Such devices, however, require significant time to position and use. There are also risks of damaging the obstructed artery, of dislodging and embolizing blood thrombus or atherosclerotic plaque, of inducing intracerebral hemorrhage or other serious complications. Directed thrombolysis using currently available catheters and guidewires often takes many hours to complete. While excellent technical results are feasible, many patients cannot tolerate the wait and their condition can deteriorate during the procedure. Surgical bypass does not work as well as standard medical therapy in preventing stroke recurrence and is only rarely performed. For these reasons, it would be desirable to provide improved methods and apparatus for treating acute ischemic conditions, such as stroke. It would be further desirable if such methods and apparatus were also useful for treating chronic ischemia in other portions of a patient's vasculature, including the coronary vasculature and the peripheral and mesenteric vasculature. Current methods for treating many causes of tissue hypoxia, particularly hypoxia resulting from a reduction in erythrocyte flow, are typically ineffectual and/or require long, time-consuming procedures before restoring adequate oxygen delivery to the hypoxic tissue. Thus, there is a need for devices and methods to increase the delivery of oxygen to tissues that are in need of such delivery. The present methods and apparatus address this need.

SUMMARY OF THE INVENTION A method of producing bubbles in a uniform and regular fashion is disclosed. The method may be applied to a variety of different applications including providing bubbles of air or oxygen to the circulatory system of a patient, injecting inert gas into the circulatory system of other area to be subj ected to ultrasound in order to provide for contrast imaging using ultrasound or related imaging devices. The method involves forcing a gas through a feeding tube in a manner such that the gas exits the tube from a tube exit opening. The tube may have any configuration but is preferably cylindrical having a circular cross-section at its opening. However, in some configurations an hourglass configuration at the opening or a funnel shaped opening is desired. The exit opening of the feeding tube is held inside of a pressure chamber and a first liquid is forced into a pressure chamber around the exit opening of the tube. The liquid exits the pressure chamber at an exit orifice positioned downstream from the flow of the gas exiting the tube exit opening. The exit orifice of the pressure chamber is preferably directly aligned with the flow of gas out of the tube exit but may be positioned out of alignment with the gas flow stream in that the liquid will focus and direct the flow of the gas out of the exit opening of the chamber. As the liquid contacts the gas the liquid forces the gas into a compressed gas stream which is substantially narrower than the exit opening from the tube from which the gas is expelled. The narrowed gas stream exits the exit orifice of the pressure chamber surrounded by the liquid into an outside environment comprised of a second liquid which may be the same as or different from the first liquid. The system is designed such that the narrowed gas stream then disassociates and the disassociated portions form uniform shaped bubbles and the bubbles flow outward in an extremely regular pattern one after another in an extremely regular size relative to each other. The regular size is desirable in many applications as is the regular emission of bubbles so as to prevent the bubbles from colliding with each other and forming larger bubbles which are undesirable in many applications. However, the essence of the invention is to produce very small very regularly shaped and spaced bubbles which are present in a solution which is thereafter placed in the circulatory system of a living animal in order to provide for oxygenation or to provide a contrast agent for use in imaging technology.

The invention further comprises a catheter adapted to be inserted into the circulatory system of a living mammal. The catheter device is comprised of a first tube which supplies a liquid and a second tube which is present within the first tube (e.g. concentrically or on one internal surface of the first tube) for supplying a gas. The first tube connects to a pressure chamber component with an exit orifice adapted to be inserted into the circulatory system of an animal. The first tube is connected to a feeding tube which has an exit opening positioned inside a pressure chamber and which allows gas to flow out in a direction which is aligned with the exit orifice of the pressure chamber. When the patient is to be oxygenated then the gas is oxygen or air. Alternatively, the gas may be an inert gas such as nitrogen when the result to be obtained is imaging. The liquid may be blood, plasma, blood extenders, normal saline or any solution adapted for injection into the circulatory system of the animal.

A gas such as air or oxygen is forced into a pharmaceutically acceptable, injectable aqueous fluid (e.g., blood, plasma, normal saline, blood extender fluids, imaging fluids and the like) to form very small microbubbles on the order of about 12 microns or less depending upon the desired application. The microbubbles can be created by various types of systems and devices disclosed herein. The device includes a primary source of a stream of gas which is forced through a liquid introduced under pressure in a pressure chamber. The pressure chamber has an exit opening through which the stream is allowed to flow surrounded by the surrounding liquid of the pressure chamber. As the stream flows toward the exit opening it forms a gas stream which disassociates upon exiting the chamber. When certain parameters are correctly chosen the microbubbles formed are all substantially uniform in size with a very small degree of deviation, e.g., 3% to 10%. The microbubbles are produced using a relatively small amount of energy compared with the amount of energy used to produce such in comparable systems.

In one embodiment, the aqueous fluid with the microbubbles therein is administered to the circulatory system of an animal where the oxygen in the microbubbles is allowed to diffuse into an animal's circulatory fluid. A catheter which allows for the infusion of the microbubbles containing fluid into the circulatory system of an animal is also disclosed. In another embodiment, the aqueous fluid with the microbubbles therein is introduced into a subject via a catheter device comprising a device of the invention for production of microbubbles. The device may be fixedly attached to the catheter, or may be attached in a manner that allows for detachment of the catheter portion from the device.

In yet another embodiment, the fluid with microbubbles therein is introduced to the circulatory system of an animal where the microbubbles act as a contrast agent to allow for imaging procedures, e.g., ultrasound imaging.

These and other objects, advantages, features and embodiments of the invention will become apparent to those skilled in the art upon reading this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a cross-sectional planar view of extrusion from a feeding tube without a surrounding pressure chamber.

Figure 2 is a cross-sectional planar view of extrusion from a feeding tube with a surrounding pressure chamber.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Before the present device and method for producing bubbles is described, it is to be understood that this invention is not limited to the particular components and steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a microbubble" includes a plurality of microbubbles and reference to

"a fluid " includes reference to a mixture of fluids, and equivalents thereof known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application and/or a parent application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior applications and/or prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

DEFINITIONS

The term "aeration" as used herein refer to the introduction of a gas, including but not limited to air, oxygen, nitrogen, other inert gases and mixtures thereof and the like, as microbubbles into a liquid using the methods and devices of the present invention. The term

"aeration" as used herein is intended to encompass introduction of bubbles that remain intact in the liquid (e.g., microbubbles introduced into an imaging contrast medium) as well as introduction of microbubbles that dissolve into the liquid (e.g., oxygen microbubbles introduced into blood or a blood extender).

The term "aerated" as used herein refers to a liquid to which has been introduced microbubbles according to the invention. Such microbubbles can be composed of any gas or gas mixture, including but not limited to air, oxygen, nitrogen and other inert gases, and the like. Aerated liquids may contain intact microbubbles, or may have dissolved therein the components of the microbubble.

The term "ultrasound contrast medium" as used herein refers to a liquid medium containing at least one agent that enhances the contrast in an ultrasound image generated for use in medical diagnosis. In one embodiment of the present invention, the agent is a gas or combination of gases introduced into the medium in the form of a plurality of microbubbles.

DEVICE IN GENERAL The present invention provides a new technique for generating a focused jet of a gas, e.g., oxygen, for introduction into fluids having biological applications, such as blood, blood substitutes, blood extenders, plasma, imaging solutions used in medical imaging technologies such as ultrasound, and the like. The production of these microbubbles is based on fluid mechanics, and requires very little energy.

Different embodiments are shown and described herein (see Figure 2) which could be used in producing microbubbles which are substantially uniform in size. Although various embodiments are part of the invention, they are merely provided as exemplary devices which can be used to convey the essence of the invention, which is the formation of a uniform dispersion of microbubbles.

A basic device comprises a means for supplying a gas, e.g., air, nitrogen or oxygen and a pressure chamber supplied with a liquid which flows out of an exit opening in the pressure chamber. The exit opening of the pressure chamber is aligned with the flow path of the means for supplying the gas. The embodiment of Figure 2 shows a means for supplying the gas. Other means for supplying a gas stream including multiple gas feed tubes into a single pressure chamber will occur to those skilled in the art upon reading this disclosure. Further, other configurations for forming the pressure chamber around the means for supplying the gas will occur to those skilled in the art upon reading this disclosure. Such other embodiments are intended to be encompassed by the present invention provided the basic conceptual results disclosed here are obtained, i.e., the gas stream is focused to a narrow stream and a dispersion of microbubbles highly uniform in size is formed. Further description provided below shows that a plurality of uniform microbubbles can be obtained when parameters are adjusted correctly.

To simplify the description of the invention, the means for supplying the gas into the liquid is often referred to as a cylindrical tube (see Figure 1) and the gas to be introduced to the fluid, be it air, oxygen, etc., is generally referred to as a gas. The liquid can be any liquid for which it is desirable to introduce microbubbles of a gas.

Formation of the focused gas and ultimate microbubble formation are based on the abrupt pressure drop associated with the steep acceleration experienced by the gas on passing through an exit orifice of the pressure chamber which holds the second fluid (i.e. the liquid). On leaving the chamber the flow undergoes a large pressure difference between the liquid and the gas, which in turn produces a curved zone on the gas surface near the exit port of the pressure chamber and in the formation of a cuspidal point, provided the amount of the gas withdrawn through the exit port of the pressure chamber is replenished. Thus, in the same way that a glass lens or a lens of the eye focuses light to a given point, the flow of the liquid surrounds and focuses the gas. The focusing effect of the surrounding flow of liquid creates a stream of gas which is substantially smaller in diameter than the diameter of the exit orifice of the pressure chamber. This is particularly desirable because it is difficult to precisely engineer holes which are very small in diameter. Further, in the absence of the focusing effect the flow of gas out of an opening will result in microbubbles which have about twice the diameter of the exit opening. An additional advantage is that the microbubbles are not prone to agglomeration following exit from the chamber and avoiding such is particularly important when the aerated liquid is to be introduced into a living being.

These advantages are all obtained with a system which uses a very small amount of energy as compared to other systems for creating a monodispersion of microbubbles in a liquid. More specifically, a given ideal minimum amount of energy is needed to move a stream of gas through a liquid. Further energy is needed (based on characteristics such as surface tensions) to form small spherical microbubbles. By using methodology disclosed here a supercritical flow is obtained and used to move the flow stream and create the microbubbles using an amount of energy which is substantially closer to the minimum amount of energy required in an ideal system, i.e. it is closer to the ideal minimum amount of energy needed in other systems for obtaining such results. The smaller the microbubbles and the greater the number of microbubbles the more energy that is required. However, smaller microbubbles present a greater surface area to the water resulting in greater diffusion of gas (e.g. oxygen) into the liquid (e.g. blood plasma) . Further, smaller microbubbles rise less quickly when administered in a container outside the body and thereby provide contact between the gas and liquid for a greater period of time - further enhancing the oxygenation of the fluid (e.g., blood or blood extender). Figure 1 shows a feeding tube 1 supplied with gas from a gas supply source 2. A gas stream 3 is extruded from the exit 4 of the tube 1 and the exit 4 may have any configuration (e.g. oval, square, rectangular, conical) but is preferably circular with a diameter d. The stream 4 disassociates into segments 5, which form bubbles 6 and result in spherical bubbles 7. The bubbles 7 have a diameter which is larger than the diameter d of the exit 4 and are approximately twice the diameter d of the exit 4. Thus, in order to make the bubbles small the exit 4 must be engineered to have a diameter approximately half that of the desired bubble diameter. For example, if it is desirable to produce bubbles of about 12 micrometers in diameter the exit 4 should have a diameter of about 6 micrometers. The bubbles 7 enter the liquid 8. However, the liquid 8 is not in motion and the resistance created by the liquid 8 against the stream 3, disassociated segments 5 and bubbles 7 causes bubbles to join together. Any two bubbles joining will have twice the volume. Further, a plurality of bubbles may join together. The joining of bubbles creates at least two problems. First, the bubbles are larger and it is generally desirable to make smaller bubbles. Secondly, bubble size is not predictable because the number of bubbles joining together and regularity of such joining can not be controlled. Accordingly, bubble size is not predictable and there is considerable variation in the size of bubbles created. This is particularly problematic when the bubbles are being introduced into the circulatory system of a living animal such as a human where it is critical to know the bubble size within a very narrow range. Figure 2 illustrates the interaction of a liquid and a gas to form microbubbles using the method of the invention. The feeding needle 21 has a circular exit opening with a diameter D and an internal radius R₀ which feeds a gas 23 out of the end, forming a stream 24 with a radius in the range of Ro to Ro plus the thickness of the wall of the needle 21. The exiting gas stream 24 forms an infinite amount of gas streamlines that interact with and are focused by the surrounding liquid 26 to form a stable cusp at an interface of the gas 23 and liquid 26 from the liquid source 27. The surrounding liquid 26 also forms an infinite number of liquid streamlines 26, which interact with the exiting gas to create a virtual focusing funnel which creates the narrow gas stream 25. The exiting gas is focused by the focusing funnel resulting in a stable lens formation, which remains stable in the stream 25 until it exits the opening 29 of the pressure chamber 28. After exiting the pressure chamber 28, the narrow gas stream 25 begins to breakup, forming microbubbles 31. The liquid flow, which affects the gas withdrawal and its subsequent acceleration following focusing, should be very rapid but also uniform in order to avoid perturbing the fragile gas-liquid interface (the surface of the gas that emerges from the jet).

Gas flows out of the end of a tube 21 and forms a small microbubble at the end. The tube has an internal radius Ro. The microbubble has a radius in a range of from R_o to R_o plus the structural thickness of the tube 21 as the gas stream 24 exits the tube 21, and thereafter the stream narrows in circumference of the narrow gas stream 25.

The exit opening of the tube 21 is positioned close to an exit opening 29 in a planar surface of a pressure chamber 28. The exit opening of the tube 21 has a minimum diameter D. The diameter D is referred to as a minimum diameter because the opening may have a conical configuration with the narrower end of the cone positioned closer to the source of liquid flow. Thus, the exit opening of the tube 21 may be a funnel-shaped nozzle although other opening configurations are also possible, e.g. an hour glass configuration. Liquid 26 in the pressure chamber 28 continuously flows out of the exit opening 29. The flow of the liquid causes the gas drop expelled from the tube 21 to decrease in circumference as the gas moves away from the end of the tube 21 in a direction toward the exit opening 29 of the pressure chamber 28.

In actual use, it can be understood that the opening shape which provokes maximum liquid acceleration (and consequently the most stable cusp with a given set of parameters) is a conically shaped opening in the pressure chamber. The conical opening is positioned with its narrower end toward the source of gas flow.

The distance between the end of the tube 21 and the beginning of the exit opening 29 is H. The chamber 28 has a wall thickness L at the point of the exit 29. At this point it is noted that R_o, D, H and L are all preferably on the order of hundreds of microns. For example, R_o = 400μm, D = 150μm, H = 1mm, L = 300μm. However, each could be 1/100 to lOOx these sizes. The description provided here generally indicates that the gas 23 leaves the pressure chamber 28 through an exit orifice 29 surrounded by the liquid 26 and thereafter enters into a liquid either in vivo or ex vivo. The need for the formation of very small highly uniform microbubbles into a fluid occurs in a variety of different applications. Those skilled in the art will recognize that variations on and different embodiments will be useful in obtaining particularly preferred results.

The device and method of Figure 2 have at least two important advantages over the device and method of Figure 1. First, the gas stream 24 is focused to a very narrow stream 25 which is 1/10 or less, preferably 1/50 or less and still more preferably 1/100 or less the diameter of the stream 24. This narrow stream 25 forms bubbles 31 which are about twice the diameter of the stream 25 but which are only a fraction of the diameter of the stream 24. Second, the stable gas/liquid interfaced is formed and the narrow gas stream 25 exits the exit 29 surrounded by the liquid 26 moving in the same direction into the liquid 31. The liquids 26 and 31 may be the same or different e.g. liquid 26 is plasma and liquid 31 is blood. The movement of the liquid 26 and the stable gas/liquid interfaces prevents the bubbles 31 from joining together. Thus, the bubbles 31 created are very uniform in size.

Although the device can be configured in a variety of designs, the different designs will preferably include the components shown in Figure 2 or components which perform an equivalent function and obtain the desired results. Specifically, a device of the invention will preferably be comprised of at least one source of a gas (e.g., a feeding needle 21 with an opening) into which the desired gas 23 can be fed and an exit opening from which the gas can be expelled. The feeding needle 21, or at least its exit opening, is encompassed by a pressure chamber 28. The chamber 28 has inlet opening which is used to feed the liquid into the chamber 28 and an exit opening 29 through which liquid 20 from the pressure chamber and gas 23 from the feeding needle 21 are expelled.

In Figure 2, the feeding needle and pressure chamber are configured to obtain a desired result of producing microbubbles 31 which are small and uniform in size. The microbubbles have a size which is in a range of 0.1 to 100 microns. The microbubbles will all have about the same diameter with a relative standard deviation of 10% to 30% or less more preferably 3% to 10% or less. Stating that microbubbles have a diameter in a range of 1 to 5 microns does not mean that different microbubbles will have different diameters and that some will have a diameter of 1 micron while others of 5 microns. The microbubbles in a given microbubble monodispersion will all (preferably about 90% or more) have the same diameter 3% to 30%. For example, the microbubbles of a given monodispersion will consist essentially of microbubbles having a diameter of 2 microns 3% to 10%.

The fact that the liquid is much more viscous and that the gas is much less dense virtually equalize the fluid and gas velocities. The gas microthread (e.g. narrow stream 25) formed has a rupture zone almost invariably located in a laminar flowing stream, and dispersion in the size of the microbubbles formed is almost always small. The diameter d_g of the gas stream (e.g. the narrow gas stream 25) is given by

p_g is the density of the gas;

is the change in pressure of the liquid on exiting the pressure chamber at a given point A; and ≡ means approximately equal with a degree of error of ±10 % or less, preferably ±5% or less and more preferably ±1% or less, and Q_g is the volumetric velocity of the gas. The low liquid velocity and the absence of relative velocities between the liquid and gas lead to the Rayleigh relation between the diameter d_g of the microthread and the diameter d of the microbubbles 31 (t.e. d= \.89d_g).

In general, the gas flow rate is about O._g=20t/², where d is the microbubble diameter in microns, and Q_g is the gas flow rate measured at the exit of the feeding tube. Owing to gas expansion, the gas flow rate will be about twice after the exit. The liquid flow rate is about

O,_/=10H , where D is the orifice diameter in microns, and Q_\ is the liquid flow rate measured in nanoliters per second.

The gas-to-liquid flow rate ratio Q^Qi- 2(d/D) , is independent of units and can be chosen at will. In a preferred embodiment, 0.3D<d< 1.5D. It is assumed that the surface tension between the gas and the liquid is not larger than about 55 mN/m. The orifice diameter should be the minimum possible one to minimize the liquid flow rate needed to focus and convey the gas. A microbubble monodisperion is created using the components and configuration as described above. However, other components and configurations will occur to those skilled in the art. The object of each design will be to supply gas which is accelerated and stabilized by tangential viscous stress exerted by the surrounding liquid. The focused narrow gas stream is focused by the surrounding liquid as the liquid leaves the pressurized area (e.g., leaves the pressure chamber and exits the pressure chamber orifice) and splits into microbubbles which have the desired size and uniformity.

When the stationary, steady interface is created, the gas that emerges from the end of the gas stream at the outlet of the feeding point is concentrically withdrawn into the nozzle.

After the gas emerges from the gas stream, the gas is accelerated by tangential sweeping forces exerted by the liquid stream flowing on its surface. Stated differently the liquid flow acts as a lens and focuses and stabilizes the gas as it moves toward and into the exit orifice of the pressure chamber. The forces exerted by the liquid flow on the gas surface should be steady enough to prevent irregular surface oscillations. Therefore, any turbulence in the liquid motion should be avoided; even if the liquid velocity is high, the characteristic size of the orifice should ensure that the gas motion is laminar (similar to the boundary layers formed on the jet and on the inner surface of the nozzle or hole).

The gas and liquid can be dispensed by any type of continuous delivery system (e.g. a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter). If multiplexing (a plurality of feeding tubes 21 ) is needed, the liquid flow-rate should be as uniform as possible among tubes and chambers; this may entail propulsion through several capillary needles, porous media or any other medium capable of distributing a uniform flow among different feeding points.

Each individual device should consist of a feeding point (a capillary needle, a point with an open microchannel, a microprotuberance on a continuous edge, etc.) 0.002-2 mm (but, preferentially 0.01-0.4 mm) in diameter, where the bubble emerging from the gas stream can be anchored, and a small orifice 0.002-2 mm (preferentially 0.01-0.25 mm) in diameter facing the drop and separated 0.01-2 mm (preferentially 0.2-0.5 mm) from the feeding point. The orifice communicates the liquid around the gas stream, at an increased pressure, with the zone where the microbubbles are produced, at a decreased pressure. The device can be made from a variety of materials (metal, polymers, ceramics, glass). Figure 2 is a schematic, cross-sectional view of a tested prototype where the gas is inserted from the source 22 and the focusing liquid 26 is introduced from the liquid source 27 into the pressure chamber 28. Depending on the pressure drop in the needle and the liquid feeding system, the pressure difference (Pj - PQ > 0) and the flow-rate of the gas, Q_g, are linearly related provided the flow is laminar - which is indeed the case with this prototype. The critical dimensions are the distance from the tube 21 end to the opening 29 (H), the needle (tube 21) diameter (Do), the diameter of the orifice 29 through which the gas and liquid are discharged (do) and the axial length, e, of the orifice (i. e. the thickness of the plate where the orifice 29 is made).

In this prototype, H was varied from 0.3 to 0.7 mm on constancy of the distances (Do = 0.45 mm, do - 0.2 mm) and e = 0.5 mm. The quality of the resulting microbubbles 31 did not vary appreciably with changes in H provided the operating regime was maintained. PHYSICAL PROPERTIES OF MICROBUBBLES The physical properties of the systems that feature gas microbubbles or gases dissolved in liquid solutions have been investigated in detail including the diffusion of air microbubbles formed in the cavitating flow of a liquid and the scatter of light and sound in water by gas microbubbles. The stability of gas microbubbles in liquid-gas solution has been investigated both theoretically, Epstein P. S. and Plesset M. S., On the Stability of Gas microbubbles in Liquid-Gas Solutions, J. Chem. Phys. 18:1505-1509 (1950) and experimentally, Yang W J, Dynamics of Gas microbubbles in Whole Blood and Plasma, J. Biomech 4:119-125 (1971); Yang W J, Echigo R, Wotton DR, and Hwang J B, Experimental Studies of the Dissolution of Gas microbubbles in Whole Blood and Plasma-I. Stationary microbubbles. J. Biomech 3:275-281 (1971); Yang W J, Echigo R., Wotton D R, Hwang J B, Experimental Studies of the Dissolution of Gas microbubbles in Whole Blood and Plasma-II. Moving microbubbles or Liquids. J. Biomech 4:283-288 (1971). The physical and chemical properties of the liquid and the gas determine the kinetic and thermodynamic behavior of the system. The chemical properties of the system which influence the stability of a microbubble, and accordingly the life time, are the rate and extent of reactions which either consume, transform, or generate gas molecules.

The behavior of microbubbles in solution can be described mathematically based on certain parameters and characteristics of the gas of which the microbubble is formed and the solution in which the microbubble is present. Depending on the degree to which a solution is saturated with the gas of which the microbubbles are formed, the survival time of the microbubbles can be calculated. P. S. Epstein, M. S. Plesset, "On the Stability of Gas microbubbles in Liquid-Gas Solutions," The Journal of Chemical Physics, Vol. 18, n. 11, 1505 (1950). Based on calculations, as the size of the microbubble decreases, the surface tension between microbubble and surrounding solution increases. As the surface tension increases, the rate at which the microbubble dissolves into the solution increases rapidly and, therefore, the size of the microbubble decreases more and more rapidly. Thus, the rate at which the microbubble shrinks increases as the size of the microbubble decreases. The ultimate effect of this is that a population of small free gas microbubbles composed of ordinary air dissolves so rapidly that the contrast-enhancing effect is extremely short lived. Using known mathematical formula, one can calculate that a microbubble of air that is 8 microns in diameter, which is small enough to pass through the lungs, will dissolve in between 190 and 550 milliseconds depending on the degree of saturation of the surrounding solution. In order to prevent the microbubbles' expansion, the liquid 28 used to create the microbubbles should not be injected into a warmer liquid 32 to prevent (i) gas expansion itself, and (ii) gas precipitation, i.e. the ejection of dissolved gas from the liquid when the temperature increases. For example, when a liquid having microbubbles is to be injected into a mammal, the liquid is preferably introduced at the same temperature as the mammal=s body temperature. This temperature may vary, however, based on the biochemical kinetics between the O₂, the oxygen carrier (e.g., hemoglobin) and the CO₂. It is also preferred that the pH and the ionic equilibrium of the animal (Na+, K+, etc.) should be minimally disturbed to prevent potential adverse effects. For example, a well known reaction that is observed between a gas and a liquid takes place when carbon dioxide gas is present in water. As the gas dissolves into the aqueous solution, carbonic acid is created by hydration of the carbon dioxide gas. Because carbon dioxide gas is highly soluble in water, the gas diffuses rapidly into the solution and the microbubble size diminishes rapidly. The presence of the carbonic acid in the solution alters the acid-base chemistry of the aqueous solution and, as the chemical properties of the solution are changed by dissolution of the gas, the stability of the carbon dioxide gas microbubbles changes as the solution becomes saturated. In this system, the rate of dissolution of a gas microbubble depends in part on the concentration of carbon dioxide gas that is already dissolved in solution.

However, depending on the particular gas or liquid present in the system, the gas may be substantially insoluble in the liquid and dissolution of a gas microbubble will be slower. In this situation, it has been discovered that it is possible to calculate microbubble stability in a gas-liquid system by examining certain physical parameters of the gas.

The end of the liquid stream develops a cusp-like shape at a critical distance from the exit opening 29 of the pressure chamber 28 when the applied pressure drop ΔP_g across the exit opening 29 overcomes the liquid-gas surface tension stresses γ/R appearing at the point of maximum curvature C e.g. 1/R from the exit opening. A steady state is then established if the rate Q ejected from the cusp is steadily supplied from the tube. This is the stable cusp which is a very preferred characteristic of the invention.

Pressure increment should be kept to 0.8 bar ±10% for most experiments and industrial applications when the outside liquid is at 1 bar. This is to in part avoid the formation of micro-shock waves and supersonic regimes at the micro-jet. The pressure increment recommended for an optimum output (i.e. maximum gas flow rate for a given microbubble diameter) is preferably constant in time and preferably kept equal to 0.8 times the outside pressure (i.e. ambient pressure) independently of the desired microbubble diameter and liquid flow rate. For example, a recommended increment in pressure should be 0.8 bars if the outside pressure is 1 bar.

AERATION OF BLOOD AND BLOOD PRODUCTS, SUBSTITUTES AND EXTENDERS

The methods and device of the invention can be use to introduce microbubbles comprising any gas (e.g. air, nitrogen, oxygen) into biological fluids, such as blood, blood products, plasma, or artificial blood extenders including saline solutions and blood substitutes or into synthetic fluids for administration to a subject. Blood extenders that can be aerated according to the methods of the present invention, include, but are not limited to, U. S . Pat Nos. 5,968,726; 5,945,272; 5,899,846; 5,747,071 ;5,733,894; 5,723,281; 5,702,880; 5,698,536; 5,688,246; 5,613,944; 5,574,019; 5,571,801; 5,514,536; 5,484,417; 5,407,428; 5,405,742; 5,374,624; 5,274,001; 5,210,083; 5,130,230; 5,084,377; 5,082,831; 4,927,806; 4,923,442; 4,908,350; 4,812,310; 4,769,318; 3,897,550; 4,663, 166;3,937,821; and 1,313,164. The liquid to be aerated may also be a physiologically accepted liquid such as saline, which may further contain any electrolytes such as potassium chloride. The smaller size of the microbubbles, and in particular microbubbles smaller than 10 microns in diameter, and more preferably 3-8 microns, even more preferably 5 microns, allows oxygen to dissolve into the fluid. Such aerated biological fluids can be produced ex vivo and later introduced into a subject, or may be produced in an in vivo environment for oxygen delivery directly to a subject.

In one embodiment, the aqueous fluid will comprise an oxygen carrier, either naturally occurring or synthetic, such as hemoglobin. A number of various hemoglobins or hemoglobin substitutes can be used in the aerated fluids of the invention. A number of such molecules are disclosed in U.S. Pat Nos. 5,621,144; 5,753,616;5,905,141; 5,945,272; 5,962,651; 5,985,825; 6,072,072; 6,083,909; and 6, 133,425; each of which are incorporated by reference herein in their entirety.

IMAGE CONTRAST MEDIUM

Materials that are useful as ultrasound contrast agents operate by having an effect on ultrasound waves as they pass through the body and are reflected to create the image from which a medical diagnosis is made. Microbubbles are readily detected in an image produced using standard ultrasound imaging techniques. When infused into the bloodstream or a particular site in the body, microbubbles enhance the contrast between the region containing the microbubbles and the surrounding tissue. A critical parameter that must be satisfied by a microbubble used as a contrast-enhancing agent is size.

The methods of the present invention can also be used to introduce microbubbles into imaging medium to increase the quality of the image. The ability of the methods of the invention to introduce microbubbles of a very specific size can allow the introduction of gas microbubbles into the circulatory system of an individual at a size determined to have a calculated dissolution time. Microbubbles larger than 8 microns are removed from a typical human circulatory system when blood flows through the lungs. Medical researchers have reported in the medical literature that microbubbles small enough to pass through the lungs will dissolve so quickly that contrast enhancement of left heart images is not possible with a free gas microbubble. Meltzer, R. S., Tickner, E. G., Popp, R. L., "Why Do the Lungs Clear Ultrasonic Contrast?" Ultrasound in Medicine and Biology, vol. 6, p.263, 267 (1980). Thus the microbubbles for use in imaging are preferably larger than 8 microns, preferably between 8-12 microns, even more preferably 10 microns, but small enough to avoid impeding blood flow or occluding vascular beds depending on the desired area of use of the imaging medium.

Microbubbles can also be created in viscous and/or non-aqueous imaging liquids that are then injected or infused into the body while the ultrasound diagnosis is in progress. The use of viscous fluids can reduce the rate at which the gas dissolves into the liquid and, in so doing, provide a more stable chemical environment for the microbubbles so that their lifetime is extended.

The primary physical and chemical properties of gases can also produce stable microbubbles at a size that would allow contrast-enhanced ultrasound imaging. A number of different gases may be used to aerate imaging contrast medium, such as those described in U.S. Patent Nos. 6,156,292; 5,733,572; 5,730,955; 5,730,9554; 5,720,938; 5,718,884; 5,714,529; 5,716,597; 5,573,751; 5,558,094; 5,558,094 are incorporated in their entirety here by reference.

TREATMENT OF ISCHEMIA OR INFARCTION In one embodiment of the present invention, patients suffering from acute stroke resulting from a sudden, catastrophic blockage of a cerebral artery are treated by introduction of an oxygenated fluid. The present invention, however, will also be useful for treating acute blockages in other portions of the vasculature as well as for treating chronic occlusions in the cerebral, cardiac, peripheral, mesenteric, and other vasculature. Optionally, the methods of the present invention may be used to facilitate dissolving or removing the primary obstruction responsible for the ischemia, e.g., by drug delivery, mechanical intervention, or the like, while perfusion is maintained to relieve the ischemia.

Methods according to the present invention comprise penetrating a perfusion conduit through the blockage and subsequently pumping an oxygenated medium through the conduit at a rate or pressure sufficient to relieve ischemia downstream from the blockage. Usually, the oxygenated medium is blood, more usually being blood obtained from the patient being treated. In some instances, however, it will be possible to use other oxygenated media, such as perfluorocarbons or other synthetic blood substitutes. In a preferred aspect of the present invention, the pumping step comprises drawing oxygenated blood from the patient, and pumping the blood back through the conduit at a controlled pressure and/or rate for humans, typically a pressure within the range from 50 mmHg to 300 mmHg, preferably at a mean arterial pressure in the range from 50 mmHg to 150 mmHg, and at a rate in the range from 30 cc/min to 360 cc/min, usually from 30 cc/min to 240 cc/min, and preferably from 30 cc/min to 180 cc/min, for the cerebral vasculature. Usually, pressure and flow rate will both be momtored. Pressure is preferably monitored using one or more pressure sensing element(s) on the catheter which may be disposed distal and/or proximal to the obstruction where the blood or other oxygenated medium is being released. Flow rate is easily monitored on the pumping unit in a conventional manner. Conveniently, the blood may be withdrawn through a sheath which is used for percutaneously introducing the perfusion conduit. It will usually be desirable to control the pressure and/or flow rate of the oxygenated medium being delivered distally to the occlusion. Usually, the delivered pressure of the oxygenated medium should be maintained below the local peak systolic pressure and/or mean arterial blood pressure of the vasculature at a location proximal to the occlusion. It will generally be undesirable to expose the vasculature distal to the occlusion to a pressure above that to which it has been exposed prior to the occlusion. Pressure control of the delivered oxygenated medium will, of course, depend on the manner in which the medium is being delivered. In instances where the oxygenated medium is blood which is being passively perfused past the occlusion, the delivered pressure will be limited to well below the inlet pressure, which is typically the local pressure in the artery immediately proximal to the occlusion. Pressure control may be necessary, however, when the oxygenated medium or blood is being actively pumped. In such cases, the pump may have a generally continuous (non-pulsatile) output or in some cases may have a pulsatile output, e.g., being pulsed to mimic coronary output. In the case of a continuous pump output, it is preferred that the pressure being released distally of the occlusion be maintained below the mean arterial pressure immediately distal to the occlusion, usually being below 150 mmHg, often being below 100 mmHg. In the case of a pulsatile pump output, the peak pressure should be maintained below the peak systolic pressure upstream of the occlusion, typically being below 200 mmHg, usually being below 150 mmHg. Control may be based on the measured pressure proximal of the occlusion or could be based on an average value of the mean arterial pressure or peak systolic pressure expected for most patients.

In some instances, it will be desirable to initiate the flow of blood or other oxygenated medium slowly and allow the flow rate and pressure to achieve their target values over time. For example, when actively pumping the oxygenated medium, the pumping rate can be initiated at a very low level, typically less than 30 cc/min, often less than 10 cc/min, and sometimes beginning at essentially no flow and can then be increased in a linear or non-linear manner until reaching the target value. Rates of increase can be from 1 cc/min/min to 360 cc/min/min, usually being from 5 cc/min/min to 100 cc/min/min.

CATHETER ELEMENTS

In certain embodiments, it may be desirable to provide the aeration device of the invention via use of a catheter. The catheter is generally a substantially hollow elongate member having a first end (or "proximal" end) associated with the exit orifice of the aeration device, and a second end (or "distal" end) for delivery of the aerated liquid to a desired delivery site. Where a catheter is used, a first end of the catheter is associated with or attached to the aeration device so that the lumen of the catheter is in communication with the exit orifice of the aeration device, so that the aerated liquid can move into the catheter, and out a delivery outlet of the catheter which is positioned at the desired delivery site.

The body of the catheter defines a lumen, which lumen is to have a diameter (generally less than 0.5 cm and more preferably less than 0.25 cm) compatible with providing leak-proof delivery of liquid upon exiting the aeration device. The body of the catheter can be of any of a variety of dimensions and geometries (e.g. , curved, substantially straight, tapered, etc.) that can be selected according to their suitability for the intended site for delivery of the liquid. The distal end of the catheter can provide a distinct opening for delivery of the liquid, or a series of openings.

In one embodiment, the catheter device comprises a component for introducing a gas supply having an opening with a diameter of about 50 microns or less, a component for introducing a focusing liquid positioned downstream of the gas supply component, and a circulatory infusion component with an exit opening positioned downstream of the liquid supply component opening.

The catheter may be produced from any of a variety of suitable materials, and may be manufactured from the same or different material as the aeration device. Exemplary materials from which the catheter can be manufactured include, but are not necessarily limited to, polymers; metals; glasses; polyolefins (high mass polyethylene (HDPE), low mass polyethylene (LDPE), linear low mass polyethylene (LLDPE), polypropylene (PP), and the like); nylons; polyethylene terephtholate; silicones; urethanes; liquid crystal polymers; PEBAX⁷; HYTREL⁷; TEFLON ; perflouroethylene (PFE) perflouroalkoxy resins (PFA); poly(methyl methacrylate) (PMMA); multilaminates of polymer, metals, and/or glass; nitinol; and the like.

The catheter can comprise additional materials or agents (e.g. , coatings on the external or internal catheter body surface(s)) to facilitate placement of the catheter and/or to provide other desirable characteristics to the catheter. For example, the catheter inner and/or outer walls can be coated with silver or otherwise coated or treated with antimicrobial agents, thus further reducing the risk of infection at the site of implantation and drug delivery.

In one embodiment, the catheter is primed with an anticoagulant, e.g., the internal surfaces of the catheter are coated with an anticoagulant prior to introduction of a liquid into the lumen of the catheter is substantially pre-filled with drug prior to implantation. This will prevent potential clotting in the catheter based on contact of the lumen surface with a fluid such as a blood or a blood product.

Methods for implanting or otherwise positioning the aeration device of the invention into the body are well known in the art. In general, placement of aeration devices will be accomplished using methods and tools that are well known in the art, and performed under aseptic conditions with at least some local or general anesthesia administered to the subject. Removal of the catheter portion following placement of the aeration device, if necessary, can also be accomplished using tools and methods that are readily available.

While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

What is claimed is:

1. A method, comprising the steps of: forcing a gas through a feeding tube in a manner such that the gas exits the tube from a tube exit opening; forcing a first liquid into a pressure chamber positioned around the tube exit opening whereby the liquid exits the pressure chamber from a chamber exit orifice positioned downstream from the gas forced from the tube exit opening in a manner such that a gas stream exiting the mbe open is compressed in size by the liquid in the pressure chamber to a narrow gas stream which flows out of the chamber exit orifice and forms bubbles in a second liquid; wherein the bubbles are introduced to a circulatory system of a living mammal.

2. The method of claim 1, wherein the bubbles in the second fluid are first placed in a container prior to introduction into the circulatory system of the living mammal.

3. The method as claimed in claim 1, wherein the bubbles are directly introduced to the circulatory system of the living mammal.

4. The method of claim 1, wherein the gas is selected from the group consisting of air, oxygen and nitrogen.

5. The method of claim 1 , wherein the first liquid is an aqueous solution selected from the group consisting of a blood extender, blood, plasma, and a blood substitute.

6. The method as claimed in claim 1, wherein the bubbles have a diameter of 12 micrometers or less.

7. The method of claim 3, wherein the second fluid is blood present in a living mammal.

8. The method of claim 3, wherein the first liquid is an imaging fluid, the second liquid is blood in a living mammal, the method further comprising: applying ultrasound to the mammal at an area where the bubbles are in the mammal and creating an ultrasound image.

9. A method comprising the steps of: creating microbubbles of a gas in an aqueous fluid, wherein the microbubbles have a diameter of about 12 microns or less in diameter; administering the aqueous fluid with microbubbles therein into a circulatory system of an animal.

10. The method of claim 9, wherein the gas comprises oxygen, and further wherein the oxygen is allowed to diffuse into circulatory fluid in the animal's circulatory system.

11. The method of claim 10, wherein the microbubbles have a diameter of about 8 microns or less in diameter.

12. The method of claim 10, wherein the aqueous fluid comprises hemoglobin and further wherein oxygen from the microbubbles oxygenates the hemoglobin.

13. The method of claim 9, wherein the gas consists essentially of oxygen.

14. The method of claim 9, wherein the aqueous fluid comprises electrolyte dissolved therein, wherein the electrolyte is selected from the group consisting of sodium chloride and potassium chloride.

15. The method of claim 9, wherein the microbubbles have a diameter in a range of from about 8 to about 12 microns.

16. The method of claim 9, wherein the aqueous fluid comprises blood plasma.

17. A catheter for injecting gas bubbles into an animal's circulatory system, comprising: a first tube; a second tube positioned in the first tube; a pressure chamber having a first opening connected to the first tube and a second opening positioned downstream of the first opening in alignment with flow through the first tube; a feeding tube having a first opening connected to the second mbe and an exit opening positioned inside the pressure chamber and positioned in a manner such that gas flowing out of the exit opening of the second tube exits the exit opening of the pressure chamber; wherein the exit opening of the feeding tube is positioned at a distance from the exit opening of the pressure chamber such that gas flowing out of the feeding tube is focused by liquid flowing out of the pressure chamber in order to emit uniform bubbles at a regular rate upon disassociation of the gas stream upon exiting the pressure chamber.

18. The catheter as claimed in claim 17, wherein the pressure chamber has a pointed needle- like configuration adapted for introduction into the circulatory system of an animal.