Foam generation

Abstract

The mixing and delivery system may include a syringe having a barrel, a plunger assembly, and a tip. The plunger assembly may include (i) a plunger stem having a cap end and a distal end, (ii) a plunger cylinder having a handle end and a tip end, (iii) a plunger head having a front face, a rear face, and a circumferential sealing edge, (iv) an elastic membrane, and (v) a screen. The plunger head may be disposed at the tip end of the plunger cylinder, with the circumferential sealing edge configured to seal against the inside of the barrel, and may include an orifice therethrough. The plunger stem may be disposed inside the plunger cylinder, with its cap end connected to the handle end of the plunger cylinder. The elastic membrane may be disposed around the plunger stem, and the screen may be disposed within the orifice.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation-in-part of U.S. patent application Ser. No. 18 / 131,326, entitled "Foam Generating Device and Method," filed April 5, 2023, and claims the benefit of U.S. Provisional Application Ser. No. 63 / 415,733, entitled "Foam Generating Device and Method," filed October 13, 2022, and U.S. Provisional Application Ser. No. 63 / 540,657, entitled "Intra-Stem Elastic Membrane and Graduated Syringe," filed September 27, 2023. This application incorporates the foregoing applications herein by reference.

[0002] Various implementations generally relate to devices and methods for producing foams for use in medical and / or veterinary applications. Various implementations generally relate to mixing two components of a medical or diagnostic agent (e.g., two liquids, a liquid and a gas, a liquid and a solid). In some implementations, the mixing may occur immediately prior to use of the medical or diagnostic agent. [Background technology]

[0003] Some implementations may be advantageous for preparing foams for use in medical and / or veterinary applications. The foams may be generated immediately prior to use and may be generated from one or more components. These components may include liquids, gases, solids, or combinations thereof. Summary of the Invention

[0004] A method for creating and providing a therapeutic foam may include providing (i) a syringe and (ii) a mixing device. The syringe may have a barrel, a plunger, a tip, and a foamable therapeutic agent disposed within the barrel. The mixing device may have: (A) a syringe body, a mixing tip fluidly connected to the interior of the syringe body, and a plunger and a spring disposed within the syringe body; (B) a mixing channel, a supply channel, and a delivery channel, wherein one end of the mixing channel is connected to the mixing tip and one end of the supply channel includes a connector for removably connecting to the syringe; (C) a three-way valve configured to selectively connect the other end of the mixing channel, the other end of the supply channel, and the delivery channel to one or more of the others; and (D) a mixing element disposed within the mixing channel. The method may further include the steps of connecting a syringe to the connector; activating the three-way valve to connect the supply channel to the mixing channel but not to the delivery channel; a pushing step of pushing the plunger of the syringe to force the foamable therapeutic agent through the supply channel, the mixing channel and the mixing element into the mixing device, thereby compressing the spring; a releasing step of releasing the force on the plunger of the syringe to allow the spring to push the foamable therapeutic agent back into the syringe through the mixing channel, the mixing element and the supply channel, thereby creating a foamed therapeutic agent; and a step of operating the three-way valve to connect the supply channel to the delivery channel but not to the mixing channel; and a step of pushing the plunger to expel the foamed therapeutic agent.

[0005] The method may further include repeating the pushing and releasing steps one or more times. In some implementations, the mixing element includes a mesh screen characterized by openings of about 100 μm to 500 μm, in some implementations, the mixing element includes a mesh screen characterized by openings of about 10 μm to 25 μm, in some implementations, the mixing element includes a sintered or porous material.

[0006] The kit may include a syringe and a mixing device. The syringe may have a barrel, a plunger, a tip, and a foamable therapeutic agent disposed within the barrel. The mixing device may have: (A) a syringe body, a mixing tip fluidly connected to the interior of the syringe body, and a plunger and a spring disposed within the syringe body; (B) a mixing channel, a supply channel, and a delivery channel, where one end of the mixing channel is connected to the mixing tip and one end of the supply channel includes a connector for detachably connecting to the syringe; (C) a three-way valve configured to selectively connect the other end of the mixing channel, the other end of the supply channel, and the delivery channel to one or more of the others; and (D) a mixing element disposed within the mixing channel. The kit may be configured to allow (x) removably connecting a syringe to the connector, (y) actuating the three-way valve to connect the supply channel to the mixing channel but not to the delivery channel, (z) depressing the plunger to force the foamable therapeutic agent through the supply channel, mixing channel and mixing element into the mixing device, thereby compressing the spring, (aa) releasing the plunger to allow the spring to push the foamable therapeutic agent back through the mixing channel, mixing element and supply channel into the syringe, thereby creating a foamed therapeutic agent, (bb) actuating the three-way valve to connect the supply channel to the delivery channel but not to the mixing channel, and (cc) depressing the plunger to expel the foamed therapeutic agent.

[0007] A method for producing a therapeutic foam may include providing a syringe having a plunger, a housing connected to the syringe, and a container. The housing may have a first inlet port connected to the syringe, a second inlet port having a first needle and a second needle, an outlet port, a mixing chamber, a first check valve that allows fluid connection from the second inlet port to the mixing chamber but not from the mixing chamber to the second inlet port, a second check valve that allows fluid connection from the mixing chamber to the outlet port but not from the outlet port to the mixing chamber, and at least one screen disposed between the first check valve and the mixing chamber, between the second check valve and the mixing chamber, or between the first inlet port and the mixing chamber. The container may include a vessel having an opening at one end sealed with a pierceable membrane. The vessel may contain a biocompatible gas and a therapeutic agent that can be combined to form a foam. The method for creating a therapeutic foam may further include connecting the container to a syringe by piercing the pierceable membrane at the second inlet port so that the first needle extends beyond the therapeutic agent to an area containing the biocompatible gas and the second needle extends into the therapeutic agent; withdrawing the syringe to draw the biocompatible gas and therapeutic agent from the container into the mixing chamber and syringe, thereby forming a therapeutic foam; and pushing the syringe to expel the therapeutic foam from the housing.

[0008] In some implementations, the first and second needles may comprise dual-lumen needles, with the second needle concentrically disposed around the first needle and extending beyond the second needle. The therapeutic agent may be in a liquid state within the container. The pierceable membrane may be a self-healing pierceable membrane. The container may be made of glass. The container may include a coated material that inhibits gas diffusion into and out of the container. The at least one screen may include a mesh with openings of approximately 25 μm. The at least one screen may include a mesh with openings of approximately 10 μm.

[0009] The container may further include a pressure equalization channel fluidly connected to the expandable pressure equalization chamber and configured to be connected to a pressure equalization passage in the housing. The pressure equalization passage may have one end open to the exterior of the housing and a needle at the other end, configured to pierce the pierceable membrane and be connected to the pressure equalization channel when the container is placed on the housing. The interior of the expandable pressure equalization chamber may be isolated from the therapeutic agent and biocompatible gas in the container. The expandable pressure equalization chamber may include an expandable balloon structure configured to be inflated by gas entering the interior through its one end, the pressure equalization passage, and the pressure equalization channel whenever negative pressure exists inside the container, such that the inflation and resulting volume increase displaces the therapeutic agent and biocompatible gas drawn from the container.

[0010] The mixing and delivery device may include a syringe, a mixing channel, a seal, and a stopcock. The syringe may include a barrel, a plunger, and a tip. The barrel may have a sidewall that, together with the plunger, defines an interior space. The interior space may contain a first fluid component and be fluidically connected to an outlet port of the tip. The mixing channel may have a channel wall characterized by a thickness, defining an interior volume, and having an exterior surface. The mixing channel may have an inlet end, an outlet end, and a plurality of through-holes disposed through the thickness to fluidly connect the interior volume to an exterior space adjacent to the mixing channel. The mixing channel may further include a flexible membrane circumferentially surrounding the exterior surface and sealed to the exterior surface at the inlet end and the outlet end. The interior volume may contain a second fluid component. A seal may be disposed at the inlet end to initially separate the first and second fluid components. The stopcock may include an inlet, an outlet, and a valve, the inlet being coupled to the outlet end, and the valve may have an open configuration that facilitates fluid communication between the inlet and outlet, and a closed configuration that prevents fluid communication between the inlet and outlet.

[0011] In some implementations, the seal may be a sealing membrane that is configured to rupture when the plunger is depressed to allow mixing of the first and second fluid components.

[0012] The flexible membrane may be configured to expand when the plunger is depressed to facilitate transport of fluid from the internal space and the internal volume through the plurality of through-holes to the mixing space. The flexible membrane may be elastic and exert a force on the fluid in the mixing space when the flexible membrane is in an expanded state, and push the fluid back into the internal volume through the through-holes when the force exceeds the balancing pressure of the fluid.

[0013] In some implementations, the mixing and delivery system includes a syringe having a barrel, a plunger assembly, and a tip. The plunger assembly may include (i) a plunger stem having a cap end and a distal end, (ii) a plunger cylinder having a handle end and a tip end, (iii) a plunger head having a front surface, a rear surface, and a circumferential sealing edge, (iv) an elastic membrane, and (v) a screen. The plunger head may be disposed at the tip end of the plunger cylinder, with the circumferential sealing edge configured to seal against the inside of the barrel. The plunger head may further include an orifice disposed therethrough from the front surface to the rear surface. The plunger stem may be disposed inside the interior of the plunger cylinder, with its cap end coupled to the handle end of the plunger cylinder. The elastic membrane may be disposed around the plunger stem. The elastic membrane may be configured to be retained by the cap end of the plunger stem and the handle end of the plunger cylinder. The screen may be disposed within the orifice.

[0014] The mixing and delivery system may further include a stopcock assembly having an inlet, an outlet, and a valve. The inlet may be coupled to the tip of the syringe, and the valve may have an open configuration that facilitates fluid communication between the inlet and the outlet, and a closed configuration that prevents fluid communication between the inlet and the outlet.

[0015] The syringe barrel may include a first portion having a first diameter and a second portion having a second, smaller diameter. A first indicator may be disposed on the first portion and a second indicator, different from the first indicator, may be disposed on the second portion. The first indicator and the second indicator may be configured to facilitate accurate drawing of the first and second components into the syringe such that an excess of the first component is drawn relative to an excess of the second component.

[0016] The mixing and delivery system may further include an adjustable lockout stem disposed within the plunger stem and configured to be adjustable between an unobstructed position and an obstructed position. In the unobstructed position, the first side of the screen may be fluidly coupled to the second side of the screen. In the obstructed position, the first side of the screen is fluidly isolated from the second side of the screen. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows an exemplary device for generating therapeutic foam having a syringe, a housing, and a container.

[0018] [Figure 2A] FIG. 2A shows the device of FIG. 1 with the container disposed on the housing.

[0019] [Figures 2B-2D] 2B-2D show the device of FIG. 1 forming a therapeutic foam by withdrawing the plunger of the syringe, drawing the contents of the container into the housing and syringe.

[0020] [Figure 2E] FIG. 2E shows the device of FIG. 1 with the plunger of the syringe depressed to expel the therapeutic foam from the housing.

[0021] [Figure 3A] FIG. 3A shows another exemplary device for generating therapeutic foam.

[0022] [Figure 3B] FIG. 3B shows the device of FIG. 3A with a needle attached, illustrating an exemplary therapeutic foam that can be produced therefrom.

[0023] [Figure 4] FIG. 4 illustrates another exemplary device for generating therapeutic foam.

[0024] [Figure 5] FIG. 5 illustrates an exemplary method for generating therapeutic foam.

[0025] [Figure 6A] FIG. 6A shows another exemplary device for generating therapeutic foam, including a syringe, a housing, a container, and a pressure equalization system.

[0026] [Figure 6B] FIG. 6B shows the device of FIG. 6A with the container positioned on the housing.

[0027] [Figure 6C] FIG. 6C shows the device of FIGS. 6A and 6B with the plunger of the syringe withdrawn to draw the contents of the container into the housing and syringe, thereby forming a therapeutic foam and activating the pressure equalization system.

[0028] [Figure 6D] FIG. 6D illustrates another exemplary pressure equalization system.

[0029] [Figure 6E] FIG. 6E shows the pressure equalization system of FIG. 6D in operation.

[0030] [Figures 7A-7B] 7A-7B show an embodiment of an exemplary mixing device.

[0031] [Figures 8A-8M]8A-8M illustrate the operation of an exemplary mixing device and the accompanying expansion and contraction of a flexible membrane within the device.

[0032] [Figure 8N-8Q] 8N-8Q illustrate the dispensing of a mixture formed within an exemplary mixing device.

[0033] [Figure 9] FIG. 9 shows another exemplary mixing device.

[0034] [Figure 10A] FIG. 10A shows an exemplary mixing kit that includes a syringe and a mixing device.

[0035] [Figure 10B] FIG. 10B shows the mixing kit after the syringe has been connected to the mixing device.

[0036] [Figure 10C] FIG. 10C shows a portion of the mixing operation where force is applied to the syringe plunger to force the effervescent therapeutic agent into the mixing device.

[0037] [Figure 10D] FIG. 10D shows a portion of the mixing operation, where a spring within the mixing device pushes the foamable therapeutic agent back through the mixing channel and mixing element and into the syringe, creating a foam.

[0038] [Figure 10E] FIG. 10E shows the therapeutic foam being expelled.

[0039] [Figure 11A] FIG. 11A shows an exemplary mixing and delivery system.

[0040] [Figure 11B] FIG. 11B is an exploded view showing further details of the exemplary mixing and delivery system of FIG. 11A.

[0041] [Figures 12A-12L] 12A-12L illustrate an exemplary operation of the mixing and delivery system.

[0042] [Figure 13A] FIG. 13A shows another exemplary mixing and delivery system with a lockout feature.

[0043] [Figure 13B] FIG. 13B shows the mixing and delivery system of FIG. 13A with the lockout feature in the closed position.

[0044] [Figure 13C] FIG. 13C is an exploded view showing further details of the exemplary mixing and delivery system of FIG. 13A.

[0045] [Figure 14] FIG. 14 shows an exemplary graduated syringe. Detailed Description

[0046] 1 illustrates an apparatus 101 that, in some implementations, can be used to prepare a therapeutic foam. As illustrated, the apparatus 101 includes a syringe 110, a container 130 (e.g., a vial or other container), and a housing 150. The container 130 may be coupled to the housing 150, and the syringe 110 may be actuated (e.g., pulled) to draw a therapeutic agent 131 (e.g., in liquid form) and a biocompatible gas 132 from the container 130 and mix the therapeutic agent 131 and the biocompatible gas 132 within the housing 150 and / or syringe 110 to prepare a therapeutic foam. The therapeutic agent may include a drug, a biologic, a vehicle and excipients, or a combination thereof. The syringe 110 may then be actuated (e.g., pushed) to expel the therapeutic foam.

[0047] Syringe 110 may be a standard medical-grade syringe having a barrel 111, a plunger 112, and an exit port 113. In some implementations, as shown, syringe 110 includes a luer lock 114 (or other coupling member) at exit port 113 for coupling syringe 110 to another device (e.g., a needle or, as shown, housing 150). In some implementations, syringe 110 is a 10 mL, 20 mL, 30 mL, or 40 mL syringe, and in other implementations, syringe 110 has other suitable volumes.

[0048] The container 130 may include a vessel wall 133 that is open at an end, and the open end may be sealed with a membrane 134. In some implementations, the membrane 134 is a pierceable, self-healing membrane configured to accommodate a needle for accessing its contents. In some implementations, the vessel wall 133 comprises glass to inhibit gas diffusion into and out of the container 130, while in other implementations, the vessel wall 133 comprises a coated material that inhibits gas diffusion, and the membrane 134 may be configured to inhibit gas diffusion as well.

[0049] As shown, the housing 150 includes a first inlet port 151, a second inlet port 152, and an outlet port 153. The first inlet port 151 may be configured to couple to the syringe 110, for example, via a corresponding luer lock fitting 154. The second inlet port 152 may be configured to couple to the container 130. For example, the second inlet port 152 may include a first needle 155 and a second needle 156. In some implementations, the second needle 156 may be concentrically disposed around the first needle 155, as shown, while in other implementations, the second needle 156 may be a separate needle that is not concentrically disposed around the first needle 155. The first needle 155 may be longer than the second needle 156. Both the needle 155 and the needle 156 may be configured to pierce the membrane 134 of the container 130. In some implementations, the needle may have a sharp and / or angled edge (eg, like needle tip 687 shown in FIG. 6D).

[0050] The housing 150 may enclose a mixing chamber 157, which may be fluidly connected to a first inlet port 151, a second inlet port 152, and an outlet port 153. In some implementations, as shown, a first check valve 158 is disposed between the mixing chamber 157 and the second inlet port 152, allowing fluid communication from the second inlet port 152 to the mixing chamber 157, but not from the mixing chamber 157 to the second inlet port 152. A second check valve 159 is disposed between the mixing chamber 157 and the outlet port 153, allowing fluid communication from the mixing chamber 157 to the outlet port 153, but not from the outlet port 153 to the mixing chamber 157. In other implementations, other check valves may be included, or the placement of the check valve 158 or the check valve 159 may be different.

[0051] As shown, a screen 160a may be disposed between the first check valve 158 and the mixing chamber 157. In some implementations, the screen 160a expedites the formation of a therapeutic foam by promoting mixing of components (e.g., liquid and gaseous components) passing through the screen 160a from the first inlet port 152. In some implementations, the screen 160a comprises a mesh with openings of a particular size, such as about 10 μm or about 25 μm. As used herein, "about" or "approximately" or "substantially" can mean within 1%, within 5%, within 10%, within 20%, within 50%, or within 100% of a nominal value.

[0052] In other implementations, the mesh openings may have other sizes, such as, for example, about 25 μm to 100 μm, or about 0.5 μm to 500 μm. In some mesh-based implementations, the "pore density" (e.g., the percentage of the total space occupied by the mesh that constitutes the pore openings (as opposed to the space occupied by the material that constitutes the mesh itself)) may vary. In still other implementations, the mesh may be replaced with other media, such as, for example, a sintered disk, other sintered element, porous disk, other porous element, etc.

[0053] In some implementations, elements (e.g., screens, meshes, sintered elements, porous elements) may be arranged in series with one another to provide a gradual mixing of the liquid and gas components; for example, some implementations may use multiple screens, each with a different mesh size; as another example, some implementations may use a screen arranged in series with a sintered element.

[0054] In general, the pore size and pore density can be tailored to optimize the formation of therapeutic foams with particular properties (e.g., particular density, particular component ratios, average bubble size, minimum half-life, etc.) Additionally, the pore size and pore density can be tailored to optimize (e.g., minimize in some implementations) the backpressure generated by the corresponding porous element.

[0055] 2A shows the device 101 in a configuration in which the container 130 is disposed on the housing 150. As shown, a first needle 155 is disposed through the membrane 134, with its opening in contact with the biocompatible gas 132 in the container 130. A second needle 156 is also disposed through the membrane 134, with its opening in contact with the therapeutic agent 131 in the container 130. In some implementations, as shown, the membrane seals around the needles 155 and 156, such that the gas 132 and therapeutic agent 131 from within the container 130 exit the container 130 only through the internal lumens of the needles 155 and 156 (and do not leak out of the opening between the needles 155 and 156 and the membrane).

[0056] In the illustrated implementation, the opening of needle 156 contacts medicament 131, allowing medicament 131 to pass through needle 156 and reach check valve 158. Plunger 112 is shown in its initial, fully depressed position, and mixing chamber 157 is at atmospheric pressure, so check valve 158 and check valve 159 both remain closed.

[0057] 2B shows plunger 112 being slightly withdrawn, creating a negative pressure within mixing chamber 157. As shown, this negative pressure overcomes the retaining force of check valve 158, causing drug 131 and gas 132 to be drawn through their respective needles 156 and 155, through check valve 158, and through screen 160a into mixing chamber 157. As drug 131 and gas 132 are drawn through screen 160a, gas 132 aerates drug 131, forming bubbles 170 as shown.

[0058] 2C shows that as the plunger 112 is further withdrawn, the negative pressure in the mixing chamber 157 is maintained and / or increased, and additional medicament 131 and gas 132 are drawn through the screen 160a and into the mixing chamber 157, forming additional bubbles 170. In some implementations, the bubbles may be drawn through the second screen 160b as they are drawn into the interior of the barrel 111 of the syringe 110. As shown in FIG. 2D, as the plunger 112 is further withdrawn, more medicament 131 and gas 132 are drawn into the mixing chamber 157, forming more bubbles 170.

[0059] 2E shows plunger 112 being depressed, creating a positive pressure inside barrel 111 and mixing chamber 157. As shown, this positive pressure closes check valve 158 and opens check valve 159, allowing foam 170 to exit housing 150 via outlet port 153.

[0060] In some implementations, the pushing action of the plunger 112 forces the foam 170 through the screen 160b, breaking down larger bubbles within the foam 170 into smaller bubbles, further agitating the foam 170 and incorporating air, allowing the gas 172 inside the barrel 111 to mix with the foam 170.

[0061] In some implementations, the gas within housing 150 and syringe 110 may be controlled. For example, referring to FIG. 2A , gas 172 within syringe 110 and gas 173 within mixing chamber 157 may be the same or similar biocompatible gas as gas 132 within container 130. To maintain such gas 172 and gas 173 and to keep atmospheric gases outside syringe 110 or housing 150 prior to use, syringe 110 and housing 150 may be pre-assembled and pre-filled with the desired biocompatible gas. Additional internal seals (not shown) may then be provided (e.g., at outlet port 113 and / or first inlet port 151).

[0062] Another implementation of mixing device 301 is shown in Figure 3A, which includes a housing 350 with a first needle 355, a second needle 356, and an exit port 353, and a syringe 310. Figure 3B shows mixing device 301 with a container 330 disposed on housing 350 (e.g., needles 355 and 356 disposed through a membrane (not shown) of container 330) and needle 375 disposed at exit port 353, and a quantity of foam 370 produced by mixing device 301.

[0063] FIG. 4 shows another implementation of a mixing device 401 that includes a syringe 410 , a container 430 , and a housing 450 .

[0064] 5 illustrates an exemplary method 500 for preparing a therapeutic foam using a mixing device. Method 500 may include providing (502) a mixing device having a syringe, a mixing chamber, and an exit port, and a container containing a biocompatible gas and a therapeutic agent. For example, method 500 may include providing (502) device 101 having syringe 110, mixing chamber 157, and exit port 153 as shown in and described with reference to FIGS. 1 and 2A-2E, and further providing container 130 containing biocompatible gas 132 and therapeutic agent 131.

[0065] Method 501 may further include the step of coupling (505) the container to the mixing device. For example, referring to FIG. 2A , container 130 may be coupled (505) to device 101. More specifically, container 130 is coupled (505) to device 101 on housing 150, with second inlet port 152 (comprising first needle 155 and second needle 156) disposed through membrane 134 of container 130. In some implementations, membrane 134 seals around second inlet port 152 such that there is substantially no fluid connection between the interior of container 130 and the exterior of container 130, except for second inlet port 152. Furthermore, membrane 134 may be self-repairing, such that if container 130 becomes dislodged from housing 150 and second inlet port 152, the interior of container 130 is resealed from the exterior of container 130, thereby preventing leakage of biocompatible gas 132 or therapeutic liquid 131 from container 130 and preventing gases, liquids, or solids outside container 130 from entering container 130.

[0066] Method 501 may further include withdrawing (508) the syringe to draw the biocompatible gas and therapeutic agent from the container into the mixing chamber, thereby forming a therapeutic foam. For example, with reference to FIG. 2B , plunger 112 may be withdrawn (508) (e.g., from a fully depressed, neutral, initial position). As shown, the withdrawal (508) action creates a negative pressure within mixing chamber 157, opening first check valve 158 and allowing therapeutic agent 131 to be drawn into mixing chamber 157 through second needle 156 and biocompatible gas 132 to be drawn into mixing chamber 157 through first needle 155. As biocompatible gas 132 and therapeutic agent 131 are drawn into mixing chamber 157, they mix within first check valve 158, with further mixing facilitated by screen 160a, forming a therapeutic foam 170 within mixing chamber 157. As the plunger 112 continues to be withdrawn (508), additional therapeutic liquid 131 and biocompatible gas 132 are drawn into the mixing chamber 157 and the interior of the barrel 111 of the syringe 110 to form additional therapeutic foam 170. In some implementations, the therapeutic foam 170 is drawn through the screen 160b as it passes from the mixing chamber 157 to the syringe 110.

[0067] Method 501 may further include the step of depressing 511 the syringe to expel the therapeutic foam through the outlet port. For example, with reference to FIG. 2E, plunger 112 may be depressed to create a positive pressure within syringe 110 and mixing chamber 157. Such positive pressure closes first check valve 158 and opens second check valve 159, allowing therapeutic foam 170 to be expelled through outlet port 153.

[0068] As shown, the therapeutic foam 170 within the syringe 110 is forced back through the screen 160b. In some implementations, passing the therapeutic foam 170 through the screen 160b a second time may further agitate the therapeutic foam 170, more thoroughly mixing the gas and liquid components and breaking down larger gas bubbles into smaller bubbles. Passing the therapeutic foam through the second check valve 159 may achieve a similar effect of further agitating the bubbles, further mixing the gas and liquid components and breaking down larger gas bubbles into even smaller gas bubbles. Additionally, a portion of the gas 172 within the syringe 110 may be introduced into the therapeutic foam 170 by positive pressure and / or by the therapeutic foam 170 and gas 172 passing through the screen 160b and the second check valve 159.

[0069] 6A shows another implementation of a mixing device 601 including a syringe 610, a housing 650, and a container 630. In the illustrated implementation, the container 630 includes a pressure equalization channel 680 and an expandable pressure equalization chamber 681 within the container 630, and further includes a vessel wall 633 and a membrane 634 capable of enclosing a therapeutic agent 631 and a biocompatible gas 632. As shown, the housing 650 includes a pressure equalization passage 682 that fluidly connects an open end 683 (e.g., the end of the passage 682 that is open to the atmosphere) to a needle 684.

[0070] 6B , when container 630 is coupled to housing 650 (e.g., by needles 655 and 656 piercing membrane 634 to fluidly couple biocompatible gas 632 and therapeutic agent 631, respectively, as in other implementations), pressure equalization passage 682 may be coupled to pressure equalization channel 680 (e.g., by needle 684 piercing membrane 634 and aligning with and coupling pressure equalization channel 680). In this manner, the interior of expandable pressure equalization chamber 681 may be coupled to the atmosphere (e.g., to the exterior of both container 630 and housing 650 via open end 683 of pressure equalization passage 682). Furthermore, in some embodiments, the interior of the expandable pressure equalization chamber 681 may be isolated from the interior of the container 630 by a wall of the expandable pressure equalization chamber 681 itself (which in some embodiments may take the form of a flexible balloon or similar volume-expandable structure), thereby preventing contamination of the therapeutic agent 631 and biocompatible gas 632.

[0071] 6C , when plunger 612 of syringe 610 is withdrawn, this creates a negative pressure within syringe 610 and mixing chamber 657 of housing 650, drawing therapeutic agent 631 and biocompatible gas 632 into mixing chamber 657 to form therapeutic compound 670, such that the resulting negative pressure within container 630 (e.g., from the aspiration of a quantity of therapeutic agent 631 and biocompatible gas 632) can be offset by the expansion of expandable pressure equalization chamber 681. That is, the negative pressure within container 630 allows air at atmospheric pressure to enter open end 683 of pressure equalization passage 682, flow through pressure equalization channel 680 and into expandable pressure equalization chamber 681, increasing its volume and offsetting the loss of volume associated with the amount of therapeutic agent 631 and biocompatible gas 632 that was aspirated.

[0072] In another implementation, as shown in FIG. 6D , an expandable pressure equalization chamber 681′ may be disposed on the housing 650 (e.g., around a needle 684′ that forms the pressure equalization channel 680′). The needle 684′ may include a tip 687 with a sharp and / or angled edge to facilitate piercing the membrane 634 on the container 630. As shown in one implementation, the needle 684′ may also include a protrusion 688 to facilitate passage of the material that forms the pressure equalization chamber 681′ through an opening that the needle 684′ creates in the membrane 634 (e.g., by temporarily creating an opening in the membrane 634 that is larger than the pressure equalization channel 680′).

[0073] 6E , when plunger 612 of syringe 610 is retracted, thereby creating a negative pressure within syringe 610 and mixing chamber 657 of housing 650, therapeutic agent 631 and biocompatible gas 632 are drawn into mixing chamber 657 to form therapeutic compound 670, such that the resulting negative pressure within container 630 (e.g., from the aspiration of a quantity of therapeutic agent 631 and biocompatible gas 632) can be counteracted by the expansion of expandable pressure equalization chamber 681′. That is, the negative pressure within container 630 allows air at atmospheric pressure to enter expandable pressure equalization chamber 681′ through open end 683 of pressure equalization passage 682, increasing its volume and counteracting the loss of volume associated with the amount of therapeutic agent 631 and biocompatible gas 632 drawn in.

[0074] In such implementations, the volume and pressure balance may reduce the resistance force acting through the plunger 612 as it is withdrawn. Thus, a user of the syringe 610 may more easily actuate (e.g., withdraw) the syringe 610 to form the therapeutic foam 670 compared to implementations without a pressure equalization system. In some implementations, a machine, rather than a human user, may actuate the syringe to form the therapeutic foam. In such implementations, the device 601 shown in and described with reference to FIGS. 6A-6C may have the advantage of requiring a linear or near-linear force to actuate the plunger 612.

[0075] In other implementations, the devices and methods may be used to mix two components of a medical or diagnostic agent (e.g., immediately prior to use). In some implementations, a liquid component and a gas component are combined to prepare an agent for use in a diagnostic or therapeutic procedure, such as may require ultrasound imaging. In other implementations, two liquid components are combined to prepare an agent for use, for example, as a sclerosing agent in a sclerotherapy procedure or as a clotting agent in a diagnostic or surgical procedure. In other implementations, a liquid component and a solid component are combined to prepare an agent for use, for example, in one of the aforementioned applications or other applications.

[0076] 7A illustrates an exemplary mixing device 701. As shown, the exemplary mixing device 701 includes a syringe 704, a mixing channel 720, and a stopcock 740. The syringe 704 includes a barrel 705, a plunger 706, and a tip 707. The barrel 705 has a sidewall 708 that cooperates with the plunger 706 to form an interior space 710. The interior space 710 is fluidly connected to an outlet port 712 at the tip 707.

[0077] 7B provides an enlarged view of a portion of exemplary mixing device 701. As shown, mixing channel 720 has channel walls 721 characterized by a thickness 722, which define an interior volume 723. Mixing channel 720 has an inlet end 724 and an outlet end 725. Disposed through thickness 722 are a plurality of through-holes 726 that fluidly connect interior volume 723 with an exterior space adjacent to mixing channel 720. Channel wall 721 has an exterior surface 728. Circumferentially surrounding exterior surface 728 is a flexible membrane 729.

[0078] As described in more detail with reference to the implementation shown in Figures 8A-8M, the flexible membrane 729 may be configured to expand when pressure increases within the internal volume 723, forcing liquid or gas within the internal volume 723 through the multiple through pores 726 into an expandable space defined by the inner surface of the flexible membrane 729 and the outer surface 728 of the channel wall 721.

[0079] Stopcock 740 has an inlet 741, an outlet 742, and a valve 743. The inlet 741 of stopcock 740 is coupled to the outlet end 725 of the mixing channel 720. The valve 743 has an open configuration that facilitates fluid communication between the inlet 741 and the outlet 742 and a closed configuration that prevents fluid communication between the inlet 741 and the outlet 742. In some implementations, the valve 743 is a cylinder with a lateral hole 744 disposed therethrough. In the open configuration (not shown in FIG. 7B ), the lateral hole 744 is aligned with the longitudinal axis of the channel connecting the inlet 741 and the outlet 742, allowing fluid communication between the inlet 741 and the outlet 742, while in the closed configuration (shown in FIG. 7B ), the lateral hole is aligned perpendicular to the longitudinal axis, preventing fluid communication between the inlet 741 and the outlet 742.

[0080] As shown in one exemplary configuration, syringe 704 may be coupled to mixing channel 720 by a coupling 715, such as a Luer taper fitting. Mixing channel 720 may be coupled to stopcock 740 by a similar coupling 733, such as another Luer taper fitting. Other styles of couplings 715 and 733 are possible, such as, for example, threaded couplings, press-fit couplings, etc. In some implementations, the various parts may be integrally molded or adhesive welding may be used to join the various parts.

[0081] In operation, the mixing device 701 may be used to mix the first component 713 with the second component 730 and then expel the mixture from the mixing device 701. In some implementations, the first component 713 is a fluid component and the second component 730 is a second liquid component. In other implementations, the first component 713 is a fluid component and the second component 730 is a gas component. In other implementations, the first component 713 is a fluid component and the second component 730 is a solid component.

[0082] 7B , in an initial configuration, the first component 713 may be disposed in the interior space 710, and the second component 730 may be disposed in the interior volume 723. (In other implementations (not shown), the first component 713 may be disposed in the interior volume 730, and the second component 730 may be disposed in the interior space 710.) A sealing membrane 714 disposed on the tip 707 may initially contain the first component 713 within the interior space 710. Optionally, in some implementations, a second sealing membrane 731 and / or a third sealing membrane 732 may contain the second component 730 within the interior volume 723. In other implementations, the second sealing membrane 731 and the third sealing membrane 732 are not present. Instead, a stopcock 740 may contain the second component 730 at the outlet end 725 of the mixing channel 720, and the sealing membrane 714 may initially separate the first component 713 and the second component 730. Whatever the configuration, sealing membrane 714 and optional second sealing membrane 731 can prevent mixing of first component 713 and second component 730 in the initial configuration.

[0083] The sealing membrane 714 (and optional second sealing membrane 731 and / or third sealing membrane 732) may be configured to rupture when pressure acting thereon exceeds a certain threshold point. In such implementations, the sealing membrane 714, sealing membrane 731, and / or sealing membrane 732 may contain the first component 713 and the second component 730 separately in an initial configuration (e.g., when the mixing device 701 is shipped and prepared for use). When pressure is applied to the sealing membrane 714 (e.g., by actuation of the mixing device's plunger 706), the sealing membrane 714 ruptures, forcing the first component 713 out of the interior space 710, through the discharge port 712, and into the mixing channel 720. Similarly, if present, the second sealing membrane 731 is also configured to easily rupture, allowing the first component 713 and the second component 730 to mix in the mixing channel 720 when the plunger 706 is actuated.

[0084] 8A-8M, the operation of exemplary mixing device 801 will now be described. As shown in FIG. 8A, exemplary mixing device 801 includes a syringe 804, a mixing channel 820, and a stopcock 840. Mixing channel 820 includes a lumen 834 having a plurality of through-holes 826 along its circumference and length, and a flexible membrane 829 circumferentially surrounding lumen 834.

[0085] In the initial configuration, plunger 806 in syringe 804 is not actuated and first sealing membrane 814 contains first component 813 in interior space 810 of syringe 804. Second component 830 is contained in mixing channel 820 by second sealing membrane 831 and stopcock 840, as shown, with valve 843 of stopcock 840 closed to prevent fluid communication between inlet 841 and outlet 842.

[0086] 8B shows a configuration in which plunger 806 has been actuated (e.g., by a user partially depressing plunger 806). The pressure that plunger 806 applies to first component 813 causes first component 813 to impact and rupture both sealing membrane 814 and second sealing membrane 831, allowing first component 813 and second component 830 to begin mixing to create mixture 835. The resulting pressure of mixture 835 then forces mixture 835 through through-hole 826, initiating the expansion or dilation of flexible membrane 829.

[0087] 8C-8D, continued actuation of plunger 806 forces more mixture 835 through through-hole 826, causing further expansion or dilation of flexible membrane 829. In some implementations, as the mixture passes through through-hole 826, further mixing occurs, and mixture 835 formed by the mixing of first component 813 and second component 830 becomes more homogeneous.

[0088] 8A-8M, housing 836 surrounds mixing channel 820, which includes flexible membrane 829. Housing 836 may provide an airtight seal around mixing channel 820, and as flexible membrane 829 expands, pressure increases in air space 837 (see FIG. 8D ) defined by housing 836 and flexible membrane 829. Because the pressure in air space 837 may oppose the force exerted by plunger 806 (e.g., when air space 837 is sealed), it may become more difficult to actuate plunger 806 when flexible membrane 829 expands and compresses the air (or other gas) in air space 837.

[0089] In implementations that include a sealed housing 836, when the user releases the force on the plunger 806, the flexible membrane 829 can contract, forcing the mixture 835 back through the through-hole 826 and into the syringe lumen 834 and interior space 810 (which, in some implementations, pushes back the plunger 806). As the mixture 835 passes through the through-hole 826, mixing continues, and the mixture 835 may become more homogenous. The contraction of the flexible membrane 829 is shown in Figures 8E, 8F, and 8G.

[0090] As shown in Figures 8H-8J, plunger 806 can be actuated again (e.g., the user of syringe 804 can again press plunger 806, which has been reset to its initial position as described above), and the mixture is again forced out through through-hole 826. After flexible membrane 829 has again expanded (e.g., as shown in Figure 8J), the user may again release the force on plunger 806, causing flexible membrane 829 to again contract (as shown in Figures 8K-8M).

[0091] In some implementations, this process of actuating and releasing plunger 806 (pushing the mixture back and forth through through-hole 826) is repeated multiple times so that the mixture has a desired homogeneity or other property. In some implementations (e.g., implementations in which the components of the curing agent are chemically mixed), the desired property may include the formation of a homogeneous foam. In still other implementations, other properties may be obtained.

[0092] Whatever the specific properties desired for mixture 835, when mixture 835 is ready to be dispensed, valve 843 of stopcock 840 can be opened, as shown in FIG. 8N. In some implementations, such valve 843 is a cylindrical member having a transverse through-hole 844 that, in its open configuration (shown in FIG. 8N, where through-hole 844 is shown in longitudinal cross-section), is aligned with inlet 841 and outlet 842 of stopcock 840, thereby fluidly connecting the inlet 841 and outlet 842 through a channel; alternatively, transverse through-hole 844 is positioned perpendicular to said channel (shown in FIG. 8M, where through-hole 844 is shown in cross-section), thereby preventing fluid connection between inlet 841 and outlet 842. Once valve 840 is opened, plunger 806 can again be actuated to force mixture 835 out outlet 842, as shown in FIGS. 8P and 8Q.

[0093] In some implementations, it may be advantageous to create mixture 835 from first component 813 and second component 830 (e.g., as shown and described with reference to FIGS. 8A-8M), dispense a portion of mixture 835 (e.g., as shown and described with reference to FIGS. 8N-8Q), and then "reactivate" mixture 835 before continuing to dispense. In such implementations, to reactivate mixture 835, a user may close valve 843, re-actuate plunger 806 as shown and described with reference to FIGS. 8A-8M, and then open valve 843 to continue dispensing mixture 835. Reactivating mixture 835 may be advantageous if certain desired parameters of mixture 835 change over a period of time, and the procedure of creating and dispensing mixture 835 exceeds that period. For example, in some implementations, mixing device 801 may be used to create a homogenous effervescent agent, but the effervescent agent may degrade over time (e.g., microbubbles within the bubbles may collapse or coalesce), and desirable bubble qualities may be restored by reactivating mixture 835. In some implementations, first component 713 and second component 730 are mixed to provide a useful diagnostic or therapeutic mixture.

[0094] 9 illustrates another exemplary mixing device 901. In the exemplary mixing device 901, a mixing element 920 may be disposed within a barrel 905 of a syringe 904. As shown, the mixing element 920 may separate the syringe 904 into a first compartment 910 that may hold a first component 913 and a second compartment 923 (e.g., a cylindrical compartment) that may hold a second component 930.

[0095] The mixing component 920 itself may include various other components, including, for example, an internal plunger 906 (which may be associated with another plunger (not shown) that is actuated by the user), a mixing tube 950, and a mixing body 962.

[0096] In an initial, neutral position, mixing body 962 includes a circumferential protrusion 965 that seals against a corresponding lip 968 of mixing tube 950. The space between mixing body 962 and the interior lumen of mixing tube 950 defines a circumferential channel 971. A flexible membrane 929 is disposed around a portion of mixing tube 950, with through-hole pores 926 extending through the wall of the mixing tube to connect the space between the outer surface of the wall forming the interior lumen of mixing tube 950 and the inner surface of flexible membrane 929 with circumferential channel 971.

[0097] The indexing shaft 953 is mechanically coupled to the mixing body 962 via a first ratchet mechanism 956. The indexing shaft 953 is further coupled to the mixing tube 950 via a second ratchet mechanism 959.

[0098] In operation, the first component 913 may be placed in the first compartment 910 (e.g., inside the barrel 905 of the syringe) and the second component 930 may be placed in the second compartment 923. The protrusion 965 and lip 968 may initially keep the first component 913 and the second component 930 separated.

[0099] A user may actuate the primary plunger (not shown), which may actuate the internal plunger 906. This actuation (and the resulting vertical translation of the mixture 962) breaks the seal created by the protrusion 965 and lip 968, allowing fluid communication between the compartment 910, the channel 971, and the compartment 930, thereby allowing mixing of the first component 913 and the second component 923. Further actuation of the plunger and internal plunger 906 forces the mixture in the compartment 923 out of the through-hole 926, causing the flexible membrane 929 to expand.

[0100] In some implementations, region 977 is filled with a gas (e.g., air or other compressible gas) and sealed to exert a force against flexible membrane 929 as it expands. Spring tab 974 exerts additional force against internal plunger 906, and when the user releases the force on the plunger, flexible membrane 929 may return to its original position against the wall of mixing tube 950, pushing the mixture back into compartment 930 and forcing mixture 962 upward. This action may advance one or both of first ratchet mechanism 956 and second ratchet mechanism 959.

[0101] When the user applies additional force to the plunger, it again acts on inner plunger 906, translating the plunger downward and repeating the above process, further mixing first component 913 and second component 923 and forcing the resulting mixture further out through-hole 926, again expanding flexible membrane 929. In this manner, mixing device 901 can provide mechanical agitation and mixing of first component 913 and second component 930, similar to mixing device 801, but within barrel 905 of syringe 904.

[0102] The first ratchet mechanism 956 and the second ratchet mechanism 959 provide the additional benefit of facilitating a specific number of actuations before the second ratchet mechanism 959 drives the indexing shaft 953, drawing the lower seal 981 of the second ratchet mechanism 959 above the corresponding lip 984 and allowing the mixture at the tip 907 to be expelled from the mixing device 901. In some implementations, by varying the number of teeth and spring force associated with the first ratchet mechanism 956 and the second ratchet mechanism 959, it may be possible to control the number of actuations of the internal syringe 906 before the mixture of the first component 913 and the second component 930 is expelled from the mixing device 901. In such implementations, the uniformity of the resulting mixture may be more precisely controlled compared to other implementations that do not provide the ability to adjust the mixing volume.

[0103] In other implementations, a device may be provided for creating foam on demand, such as, for example, a therapeutic foam for use in administering a treatment (e.g., sclerotherapy) to a patient. With reference to FIG. 10A , a mixing kit 1001 may be provided that includes a mixing device 1004 and a syringe 1007 that may contain a foamable therapeutic agent 1010. The mixing device 1004 may include a syringe body 1013 having a plunger 1016 and a spring 1019 within its interior 1015. The spring 1019 may be made of metal, plastic, or may include other devices, such as an air shock, that can convert kinetic energy to potential energy and back to kinetic energy.

[0104] In the illustrated implementation, the syringe body 1013 is fluidly coupled to a mixing channel 1022 via a mixing tip 1024. This coupling may be achieved by a luer lock connector 1025, other coupling, or an adhesive or molded connection. The mixing channel 1022 is coupled to a supply channel 1028 and a delivery channel 1031. A three-way valve 1034 (e.g., a stopcock) may selectively isolate the supply channel 1028 from both the mixing channel 1022 and the delivery channel 1031 (as shown in FIG. 10A ), couple the supply channel 1022 to the mixing channel 1022, and couple the supply channel 1029 to the delivery channel 1031.

[0105] In some implementations, removable seals 1037a and 1037b may be provided on the mixing device 1004 to maintain a sterile environment within the mixing channel 1022, the supply channel 1028, the delivery channel 1031, and the syringe body 1013. In some implementations, the mixing device 1004 is provided with a quantity of gas 1038 (e.g., sterile room air, oxygen, carbon dioxide, etc.) that is mixed with the effervescent therapeutic agent 1010. In some implementations, the gas 1038 is sterile, and in other implementations, it is not sterile.

[0106] A mixing screen or other mixing element 1040 may be provided to create turbulence within the mixing channel 1022 as the fluid or gas flow traverses the mixing channel 1022. In some implementations, multiple (e.g., serial) mixing elements may be provided. For example, two or more screens having mesh openings of approximately 10 μm or 25 μm, or 100 μm or 500 μm, may be provided. As another example, screens of different sizes may be provided (e.g., an outer 500 μm mesh screen with a central 100 μm mesh screen). As with other implementations described herein, materials other than screens (e.g., sintered or porous elements) may be used to create turbulence during bubble creation and / or to break up large bubbles into smaller ones.

[0107] In some implementations, the resistance to fluid flow created by the mixing element 1040 may be controlled to allow for rapid exchange of fluid between the mixing device 1004 and the syringe 1007. For example, some implementations may use a smaller mesh size, which provides a larger surface area for the mesh itself (and a larger cavity 1043 to hold the mesh). Other implementations may use a larger mesh size, which provides a smaller surface area. Many modifications are possible.

[0108] Syringe 1007 includes an actuation handle 1012 and plunger 1011 and may be initially sealed by a seal 1046. Syringe 1007 may also have a luer lock connector 1049 (or other connector) configured to mate with a corresponding connector 1052 on mixing device 1004.

[0109] To use the mixing kit 1001, a user removes seals 1037a and 1046 and couples the syringe 1007 to the mixing device 1004 (e.g., by threading the syringe 1007 onto the mixing device 1004 using corresponding luer locks 1049 and 1052 (or other connectors)). In some implementations, the syringe 1007 may be provided with the mixing device 1004 or may already be coupled to the mixing device 1004. In such implementations, removable or breakable seals may isolate the effervescent therapeutic agent 1010 from the various channels 1022, 1028, 1031 of the mixing device 1004. In other implementations, the syringe 1007 may be supplied by the end user and filled with the effervescent therapeutic agent on-site.

[0110] FIG. 10B shows the mixing kit 1001 after seals 1037a and 1046 have been removed, the syringe 1007 is connected to the mixing device 1004, the three-way valve 1034 is adjusted to allow fluid connection between the supply channel 1028 and the mixing channel 1022 (but not fluid connection with the delivery channel 1031), and a small amount of pressure is applied to the handle 1012 to inject a portion of the foamable therapeutic agent 1010 into the supply channel 1028 and the mixing channel 1022.

[0111] 10C shows that additional force is applied to the plunger 1011 (e.g., by a user actuating the handle 1012), injecting more of the effervescent therapeutic agent 1010 into the mixing device 1004. As shown, some of the gas 1038 initially remains as a gas within the mixing device 1004, but as the effervescent therapeutic agent 1010 is injected, some of this gas may begin to dissolve into the effervescent therapeutic agent 1010 (shown as bubbles 1055). As more effervescent therapeutic agent is injected into the mixing device 1004, the spring 1019 is compressed, thereby converting the movement of the effervescent therapeutic agent 1010 into the mixing device 1004 into potential energy. When the force is removed from the handle 1012 and plunger 1011, the potential energy stored in the spring 1019 is converted back into kinetic energy; specifically, the force of the spring pushes the plunger 1016, forcing the effervescent therapeutic agent out of the mixing device 1004, through the mixing channel 1022 and screen 1040, through the delivery channel 1028, and back into the syringe 1007 (see FIG. 10D).

[0112] In some implementations, the spring force of the spring 1019 may be configured to achieve a particular fluid velocity or fluid pressure passing through the mixing element 1040. The particular pressure or velocity of the fluid passing through the mixing element 1040 may provide sufficient turbulence to foam the foamable therapeutic agent 1010 (e.g., by causing the gas 1038 to mix into the foamable therapeutic agent in the form of very small bubbles). The mixing element 1040 may break down large bubbles into smaller bubbles, and this mixing and foaming process may be repeated as the foamable therapeutic agent passes back and forth through the mixing element 1040.

[0113] In some implementations, the design shown and described immediately above may provide two potential advantages. First, the pressure exerted by the spring 1019 on the effervescent therapeutic agent (e.g., related to the energy stored in the spring 1019 and the flow resistance created by the mixing element 1040) may be more consistent, regardless of variations in the speed at which a user actuates the handle 1012 (which may depend on hand strength or the force intentionally applied by the user). Thus, even if a particular user with weaker hand strength is less efficient than another user with stronger hand strength in forcing the effervescent therapeutic agent from the syringe 1007 through the mixing element 1040 to create a foam, the efficiency with which foam is formed in the opposite direction (from the mixing element 1004 to the syringe 1007) may be more consistent. Second, the mixing kit 1001 may be operable by a user with only one hand. This is a significant advantage over other designs that require a user to hold and operate multiple components (e.g., two syringes). The mixing kit 1001 allows the user to keep their other hand free for other aspects of the procedure (e.g., to operate the ultrasound probe or attend to other aspects of the therapeutic procedure). In some implementations, this single-handed operation allows the procedure to be performed with fewer clinicians or technicians, or more quickly and easily.

[0114] The process of applying force to the handle 1012 and plunger 1011 may be repeated multiple times to create a foam containing very small and stable air bubbles (which, in some implementations, are less likely to aggregate over time). Once a therapeutic foam with the desired properties is formed, the three-way valve 1034 may be actuated to fluidly connect the syringe 1007, the flexible channel 1028, and the delivery channel 1031. The still-present seal 1037b may be configured to rupture upon application of an ejection force from actuation of the handle 1012 and plunger 1011 (or the seal 1037b may be removed prior to ejection). The newly foamed therapeutic agent may then be ejected (see FIG. 10E). In some implementations, the connector 1036 may be connected to a line or needle (tip not shown) for application of the foamed therapeutic agent to the treatment site.

[0115] 11A shows an exemplary mixing and delivery system 1101. As shown, the system 1101 includes a syringe 1104 having a barrel 1107, a plunger assembly 1110, and a tip 1113. In some implementations, the system 1101 further includes a stopcock assembly 1116 having an inlet 1119, an outlet 1122, and a valve 1125. The valve may have a closed configuration (as shown) in which the inlet 1119 is fluidly isolated from the outlet 1122, and an open configuration (not shown in FIG. 11A) in which the inlet 1119 is fluidly coupled to the outlet 1122. In some implementations, the stopcock assembly 1116 may be disposed on the syringe 1104 (e.g., the inlet 1119 may be disposed on the tip 1113 using a connector, such as a Luer connector or other fitting or coupling mechanism).

[0116] 11B is an exploded view showing further details of the plunger assembly 1110 according to some implementations. As shown, the plunger assembly 1110 includes a plunger stem 1128 having a cap end 1131 and a distal end 1134, a plunger cylinder 1137 having a handle end 1140 and a tip end 1143, a plunger head 1146 having a front face 1149, a rear face 1152, and a circumferential sealing edge 1155, an elastic membrane 1158, and a screen 1161.

[0117] In some implementations, the plunger head 1146 is disposed at the tip end 1143 of the plunger cylinder 1137, and the circumferential sealing edge 1155 is configured to seal against the inside of the barrel 1107 of the syringe 1104 (see FIG. 11A ). The plunger head 1146 may further include an orifice 1164 extending through the plunger head 1146 from the front surface 1149 to the rear surface 1152 to fluidly connect the opposite sides of the plunger head 1146. The screen 1161 and plunger head 1146 may be configured such that the screen 1161 is disposed within and retained by the orifice 1164. For example, the plunger head 1146 may be constructed of a stretchable, elastic material that can stretch to accommodate the screen 1161. The plunger head 1146 may further include features such as ribs or protrusions 1167 for retaining the screen 1161.

[0118] In some implementations, the screen 1161 has a mesh structure characterized by open pores (e.g., about 10 μm to 25 μm open pores, or about 100 μm to 500 μm open pores). (As used herein, "about" or "approximately" means within 1%, 5%, 10%, 20%, 50%, or 100% of a nominal value, and "substantially" means within 100%, 95%, 90%, 85%, 80%, 75%, or 50% of a nominal value.) Overall, the screen 1161 may be configured to induce turbulence in any fluid flowing therethrough, causing such fluid to mix with surrounding air or gas and create or enhance bubbles.

[0119] The plunger stem 1128 may be configured to be disposed inside the plunger cylinder 1137. In some implementations, a cap end 1131 of the plunger stem 1128 is configured to be coupled to a handle end 1140 of the plunger cylinder 1137. In some implementations, the cap end 1131 and the handle end 1140 may have cooperating threads as shown, while in other implementations, the cap end 1131 and the handle end 1140 may be coupled via other means such as a latch, fastener, compression fitting, adhesive, etc.

[0120] The elastic membrane 1158 may be configured to be disposed around the plunger stem 1128. In some implementations, as shown, the elastic membrane 1158 is coupled to or integrally formed with the plunger head 1146. The elastic membrane 1158 may also include a flange 1170 that may allow it to be held by (e.g., sandwiched between) the plunger stem 1128 and the plunger cylinder 1137.

[0121] In some implementations, the elastic membrane 1158 is thin and expands easily, while in other implementations, the elastic membrane 1158 is thick and expands relatively less easily. Regardless of the inherent force that the elastic membrane 1158 resists expansion, the plunger assembly 1110 may be configured such that fluid passing through the screen 1161 and plunger head 1146 causes the elastic membrane 1158 to expand radially away from the plunger stem 1128, as described with reference to Figures 12A-12L.

[0122] 12A-12L illustrate an exemplary operation of system 1101. As shown in FIG. 12A, exemplary system 1101 may include a syringe 1104 as described herein having an attached stopcock assembly 1116. Valve 1125 may be open, and when plunger assembly 1110 is withdrawn, fluid in communication with outlet 1122 is drawn into stopcock assembly 1116 and syringe 1104, as further shown in FIG. 12B.

[0123] In some implementations, both liquid and air (or other gas) may be drawn into the syringe, as shown in FIG. 12B. The air may be drawn in as a volume, and some of the air may be mixed with the liquid, for example, as bubbles of various sizes. In some implementations, the air and liquid are drawn in a specific ratio, for example, a 1:3 liquid-to-air ratio, while other implementations may use a 1:4 liquid-to-air ratio, and still other implementations may use a 1:5 liquid-to-air ratio, a 1:6 liquid-to-air ratio, a 1:7 liquid-to-air ratio, or a 1:10 liquid-to-air ratio. Various ratios may be used in different implementations.

[0124] As shown in FIG. 12C , the valve 1125 may be closed and the plunger assembly 1110 may be pushed to force a portion of the mixture 1173 through the screen 1161 into the space between the elastic membrane 1158 and the plunger stem 1128. In some implementations, forcing the mixture 1173 through the screen 1161 causes the elastic membrane 1158 to expand radially, as shown. The screen 1161 may break up large air bubbles into smaller bubbles and mix (or more thoroughly mix) the air and liquid, forming an air-laden bubble. As shown in FIG. 12D , the plunger assembly 1110 may be pushed further to force substantially all of the mixture 1173 into the space defined by the elastic membrane 1158.

[0125] As shown in FIG. 12E, plunger assembly 1110 may be withdrawn, causing mixture 1173 to pass through screen 1161 in the opposite direction from before, which causes mixture 1173 to become more aerated and breaks down larger bubbles into smaller ones, creating an overall less dense foam.

[0126] In some implementations, little or no force may be required to withdraw the plunger assembly 1110. Rather, the energy stored by the expansion of the elastic membrane 1158 forces the mixture back through the screen 1161 toward the tip 1113, withdrawing the syringe assembly 1110. This withdrawal process may continue until the elastic membrane 1158 returns to its starting position and substantially all of the mixture 1173 has been expelled from within the elastic membrane 1158, as shown in FIG.

[0127] 12G-12I, the pushing and pulling steps may be repeated. With each pushing and pulling cycle, the mixture 1173 may achieve a more uniform, lighter foam consistency and reach a steady-state consistency. In some implementations, such a steady-state consistency may be reached quickly (e.g., within one or two pushing / pulling cycles).

[0128] Once the mixture 1173 reaches a desired consistency, the valve 1125 may be opened and the plunger assembly 1110 may be depressed again to expel the mixture from the tip 1113 and outlet 1122, as shown in Figures 12J-12L.

[0129] 13A shows another exemplary mixing and delivery system 1301 with a lockout feature. As shown, the system 1301 includes a syringe 1304 having a barrel 1307, a plunger assembly 1310, and a tip 1313. In some implementations, the system 1301 further includes a stopcock assembly 1316 having an inlet 1319, an outlet 1322, and a valve 1325. The valve may have a closed configuration (as shown) in which the inlet 1319 is fluidly isolated from the outlet 1322, and an open configuration (not shown in FIG. 13A) in which the inlet 1319 is fluidly coupled to the outlet 1322. In some implementations, the stopcock assembly 1316 may be disposed on the syringe 1304 (e.g., the inlet 1319 may be disposed on the tip 1313 using a connector, such as a Luer connector or other fitting or coupling mechanism).

[0130] 13C is an exploded view illustrating another exemplary plunger assembly 1310 according to some implementations. As shown, the plunger assembly 1310 includes a plunger stem 1328 having a cap end 1331 and a distal end 1334, a plunger cylinder 1337 having a handle end 1340 and a tip end 1343, a plunger head 1346 having a front face 1349, a rear face 1352, and a circumferential sealing edge 1355, an elastic membrane 1358, and a screen 1361.

[0131] The plunger assembly 1310 may further include a lockout stem 1329, which may be adjustably disposed within the plunger stem 1328 at a depth settable by an adjustment mechanism 1330. As shown, the adjustment mechanism 1330 includes corresponding threads on the plunger stem 1328 and the lockout stem 1329, although other adjustment mechanisms (e.g., ratchets, springs, catches, breakable elements, deformable elements, etc.) may be used. Collectively, the lockout mechanism may facilitate fluid communication or isolation between the interior space 1332 (the interior of the plunger stem 1328 where the elastic membrane 1358 is located) and the exterior space 1332 (e.g., the space on the other side of the screen 1361). Placing the lockout stem 1329 in an unobstructed position may allow fluid to easily pass through the screen 1361 in either direction (e.g., when the fluid is being agitated into a foam, as shown in FIGS. 12B-12I), while placing the lockout stem 1329 in an obstructed position may prevent fluid from passing through the screen 1361, as shown in FIG. 13B. In some implementations, such an obstructed position may make the system 1301 easier to use in scenarios where there is significant backpressure from the environment into which the system 1301 is injecting. In some implementations, an obstructed position may also prevent foam reformation, which may be problematic in such implementations from a foam consistency, foam safety, or regulatory standpoint.

[0132] In some implementations, the lockout stem 1329 may cooperate with other components (not shown) that automatically actuate the lockout stem 1329 from the non-occluding position to the occluding position (e.g., with a spring, ratchet, catch, actuator, etc.) In other implementations, manual actuation (e.g., by a user rotating action in implementations that include threads corresponding to the adjustment mechanism) may be required to transition the lockout stem 1329 from the non-occluding position to the occluding position.

[0133] Because precise liquid-to-air ratios may be used to achieve a desired foam consistency, it may be advantageous to facilitate the drawing of a precisely metered amount of a liquid component followed by a precisely metered (but, depending on the implementation, significantly larger) amount of an air or gas component. Figure 13 illustrates an exemplary syringe 1304 that includes certain features that facilitate the precise metering of both a relatively small amount of a first component (e.g., a liquid component) and a relatively large amount of a second component (e.g., an air or gas component).

[0134] 14, a syringe 1404 may include a barrel 1407 having a first portion 1408 with a first diameter and a second portion 1409 with a second, smaller diameter. Each portion 1408, 1409 may have a corresponding indicia 1410, 1411, respectively, that indicate a particular volume. Using such a graduated syringe 1404 may allow a relatively large volume of air or gas to be drawn into the syringe 1404 first, and then a relatively small volume of liquid to be drawn into the syringe 1404, each accurately metered to achieve the desired air-to-liquid ratio.

[0135] Numerous references have been written about foam-forming therapeutic agents. In some applications, the foam-forming therapeutic agent may be a composition suitable for sclerotherapy. Exemplary components include hypertonic saline, sodium tetradecyl sulfate (STS), polidocanol, and glyceryl chromate. One or more foam-stabilizing compounds may also be included. For example, proteins (e.g., albumin), glycerol, or proteoglycans may be added to extend the shelf life of the resulting foam. One or more surfactants (e.g., including polysorbates (e.g., PS-80) or ethanol) may also be added, for example, as wetting agents, emulsifiers, foaming agents, or dispersing agents. In general, the formulation may include an aqueous buffer containing water and one or more salts (e.g., saline or potassium chloride), at least one foam-stabilizing compound (e.g., a protein such as albumin), at least one surfactant, and a sclerosing agent (e.g., polidocanol or STS). Other variations are also contemplated.

[0136] While some implementations have been described with reference to exemplary embodiments, those skilled in the art will recognize that various modifications may be made and equivalents may be substituted for elements thereof without departing from the intended scope. For example, while needles are shown and described as concentric around a common axis to pierce the membrane of a container, separate needles may be used. The needle tips or edges may be sharp. While a liquid drug and a biocompatible gas are described, two liquid drugs having different densities may be used. Alternatively, with appropriate modifications (e.g., additional membranes or films to separate the drugs), a solid (e.g., powdered) drug may be used with a liquid, gas, or other solid drug, depending on the chemical interaction. Screens may be arranged differently than described, may have different design parameters, may have more or fewer screens, or may be replaced with sponges, porous elements, sintered elements, or other structures. Check valves may be arranged or configured differently from those described or illustrated, may have more or fewer check valves, or may be replaced with manually operated valves. Syringes may be manually actuated by a user, mechanically actuated (e.g., using a spring, pneumatic cylinder, electric solenoid, etc.), or actuated by a combination of mechanical and user mechanisms (e.g., a user may release a mechanical fastener that releases a spring, or a user may control a pneumatically or electrically operated mechanism). Certain components may be combined, components may be omitted, or components may be constructed of different materials. Components may be assembled in various ways, using threads, clips, adhesives, retaining rings, compression fittings, etc. Screens with different mesh characteristics may be used. Multiple screens may be used. Screens may be positioned in different locations and in different ways than those described. Multiple push / pull cycles or a single cycle may be used to prepare the desired mixture or foam. Syringes may have a uniform diameter or may include two or more sections with different diameters. Indicators may be provided in the form of a scale corresponding to the different sections with different diameters.One portion may have graduations that correspond to a multiple or an order of magnitude greater (e.g., 2x, 5x, 10x, etc.) than the graduations displayed on another portion. Alternative valve mechanisms may be used in place of stopcocks. Other springs or elastic elements may be used to reduce the force required to push or pull the syringe.

[0137] Many other modifications may be possible and modifications may be made to adapt a particular situation or material to the present disclosure without departing from the essential scope of the teachings disclosed herein. Accordingly, it is intended that the scope of the present invention include all embodiments that fall within the scope of the appended claims.

Claims

1. 1. A method of making and providing a therapeutic foam, comprising: (i) a syringe; and (ii) a mixing device, The syringe has a barrel, a plunger, a tip, and an effervescent therapeutic agent disposed within the barrel; The mixing device comprises: (A) a syringe body, a mixing tip fluidly connected to the interior of the syringe body, and a plunger and spring disposed within the syringe body; (B) a mixing channel, a supply channel, and a delivery channel, one end of the mixing channel being coupled to the mixing tip, and one end of the supply channel including a connector for detachably coupling to the syringe; (C) a three-way valve configured to selectively couple the other end of the mixing channel, the other end of the supply channel, and the delivery channel to one or more of the other; (D) a mixing element disposed within the mixing channel; Equipped with Providing (i) a syringe and (ii) a mixing device; connecting the syringe to the connector; actuating the three-way valve to connect the supply channel to the mixing channel but not to the delivery channel; a pushing step of pushing the plunger of the syringe to force the effervescent therapeutic agent through the delivery channel, the mixing channel, and the mixing element into the mixing device, thereby compressing the spring; releasing the force on the plunger of the syringe to allow the spring to push the foamable therapeutic agent back through the mixing channel, the mixing element, and the delivery channel and into the syringe, thereby creating a foamy therapeutic agent; actuating the three-way valve to connect the supply channel to the delivery channel but not to the mixing channel; depressing the plunger to expel the therapeutic foam; A method of making and providing a therapeutic foam, comprising:

2. The method of claim 1 , further comprising repeating the pushing and releasing steps one or more times.

3. The method of claim 1 , wherein the mixing element comprises a mesh screen characterized by openings of about 100 μm to 500 μm.

4. The method of claim 1 , wherein the mixing element comprises a mesh screen characterized by openings of about 10 μm to 25 μm.

5. The method of claim 1 , wherein the mixing element comprises a sintered or porous material.

6. 1. A mixing and delivery device comprising: a syringe having a barrel, a plunger, and a tip, the barrel having a sidewall defining an interior space with the plunger, the interior space containing a first fluid component, the syringe being fluidly connected to an outlet port of the tip; a mixing channel having a channel wall characterized by a thickness, the channel wall defining an interior volume and having an exterior surface, the mixing channel having an inlet end, an outlet end, and a plurality of through holes disposed through the thickness fluidly connecting the interior volume with an exterior space adjacent the mixing channel, the mixing channel further comprising a flexible membrane circumferentially surrounding the exterior surface and sealed to the exterior surface at the inlet end and the outlet end, the interior volume containing a second fluid component; a seal disposed at the inlet end for initially separating the first fluid component from the second fluid component; a stopcock having an inlet, an outlet, and a valve, the inlet coupled to the outlet end, the valve having an open configuration that facilitates fluid communication between the inlet and the outlet, and a closed configuration that prevents fluid communication between the inlet and the outlet; A mixing and delivery device comprising:

7. 7. The mixing and delivery device of claim 6, wherein the seal is a sealing membrane configured to rupture when the plunger is depressed to permit mixing of the first fluid component and the second fluid component.

8. 7. The mixing and delivery device of claim 6, wherein the flexible membrane is configured to expand when the plunger is depressed to facilitate transport of fluid from the interior space and through the plurality of through-holes to the mixing space.

9. 9. The mixing and delivery device of claim 8, wherein the flexible membrane has elasticity, and the elasticity exerts a force on the fluid in the mixing space when the flexible membrane is in an expanded state, and pushes the fluid back into the internal volume through the through-hole when the exerted force exceeds the balancing pressure of the fluid.

10. A mixing and delivery system comprising a syringe having a barrel, a plunger assembly, and a tip; The plunger assembly (i) a plunger stem having a cap end and a distal end; (ii) a plunger cylinder having a handle end and a tip end; (iii) a plunger head having a front face, a rear face, and a circumferential sealing edge; (iv) an elastic membrane; and (v) a screen; and Equipped with the plunger head is disposed at the tip end of the plunger cylinder such that the circumferential sealing edge seals against the inside of the barrel; the plunger head further comprising an orifice disposed through the plunger head from the front surface to the rear surface; the plunger stem is disposed inside the interior of the plunger cylinder, and the cap end of the plunger stem is connected to the handle end of the plunger cylinder; the elastic membrane is disposed around the plunger stem; The screen is disposed within the orifice. Mixing and delivery system.

11. 11. The mixing and delivery system of claim 10, wherein the elastic membrane is configured to be retained by the cap end of the plunger stem and the handle end of the plunger cylinder.

12. 11. The mixing and delivery system of claim 10, further comprising a stopcock assembly having an inlet, an outlet, and a valve, the inlet coupled to the tip of the syringe, the valve having an open configuration that facilitates fluid communication between the inlet and the outlet, and a closed configuration that prevents fluid communication between the inlet and the outlet.

13. 11. The mixing and delivery system of claim 10, wherein the barrel of the syringe comprises a first portion having a first diameter and a second portion having a second, smaller diameter.

14. 14. The mixing and delivery system of claim 13, further comprising a first indicia on the first portion and a second indicia on the second portion that is different from the first indicia.

15. 15. The mixing and delivery system of claim 14, wherein the first indicator and the second indicator are configured to facilitate precise drawing of the first component and the second component into the syringe such that an excess of the first component is drawn relative to an amount of the second component.

16. 11. The mixing and delivery system of claim 10, further comprising an adjustable lockout stem disposed within the plunger stem and configured to be adjustable between an unobstructed position and a blocked position, wherein in the unobstructed position a first side of the screen is fluidly coupled to a second side of the screen and wherein in the blocked position the first side of the screen is fluidly isolated from the second side of the screen.

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