Patent Application
20200261707
This application relates to a system and method for delivering therapeutic agents to a patient and, more specifically, to delivering agents to a body cavity such as a uterine cavity for endometrial ablation.
Heavy Menstrual Bleeding (HMB) is excessive bleeding from the vagina of over 80 mL of blood per period. Heavy periods can cause pain and discomfort and increase the risk of iron-deficiency anemia. Acute excessive bleeding can lead to hemodynamic instability, requiring hospitalization for fluid volume management, blood transfusion, and/or intravenous estrogen. This condition has a significant negative impact on woman's sexual functioning, mental well-being and overall health.
Studies have shown that Heavy Menstrual Bleeding affects approximately 1 in 3 women in their lifetime. This is over 200 million women worldwide. In the U.S. alone, there are ten million women suffering from HMB with 200,000 newly diagnosed women each year. The conservatively estimated annual direct economic cost of HMB in the US is approximately $1-1.55 billion and indirect cost is $12-36 billion.
There are four groups of treatment options that are currently available for treating HMB: 1) Dilatation and Curettage (D&C); 2) Hysterectomy; 3) Intrauterine device (IUD) and 4) Global endometrial ablation (GEA) devices. Each of these treatments has significant disadvantages. Dilation and Curettage offers a short-term relief and has a high risk of perforations. This option is not in wide use. Hysterectomy is a surgical removal of the uterus, which involves major surgery done under general anesthesia. Due to its invasive nature, high costs and risks, the number of these procedures has dropped over 50% in the last decade. Intrauterine devices, such as the Bayer HealthCare′ “Mirena” IUD, are not highly effective and have significant hormonal side effects. Yet, use of the Mirena IUD to control heavy menstrual bleeding in women seeking contraception has increased in popularity due to ease-of-use and relatively low cost of this treatment option. Global Endometrial Ablation devices, such as the Hologic “NovaSure” and the Boston Scientific “Genesys HTA”, are currently being utilized to ablate endometrium. The procedure can be done in a hospital setting or in the office. The procedure has demonstrated high efficacy, but is rather complex for in-office use and relatively expensive. Thus, GEA and IUD devices are the primary options for HMB treatment that are currently offered.
Endometrial ablation techniques, which have evolved as an alternative to hysterectomy, (e.g., laser, resecting loop with electric current, electric rollerball, thermal fluid-filled balloon, radiofrequency, freezing, heated saline) remove some of the lining of the uterus in an attempt to control excessive bleeding. After endometrial ablation, pregnancy is not likely to occur.
The early techniques of endometrial ablation, introduced in the 1980s and still used today (although much less commonly) involve the use of a hysteroscope with either a “rollerball” or wire loop through which electrical heat travels to remove (resection) the endometrial lining. After the uterus is filled with fluid to enlarge it for better viewing, the surgeon moves the rollerball back and forth across the lining or uses the wire loop to shave off the tissue. Potential risks of this ablation method include infection, perforation of the uterus, cervical laceration, and fluid overload.
In 1997, the Food and Drug Administration (FDA) approved ThermaChoice, the first non-hysteroscopic ablation device to treat excessive uterine bleeding (menorrhagia) due to benign (non-cancerous) causes. The Gynecare ThermaChoice Uterine Balloon Therapy System has a balloon that is inserted through the neck of the cervix and into the uterus. Through a catheter connected to a controller console, the balloon is inflated with fluid and heated to 188° F. (87° C.) for 8 minutes to destroy the uterine lining.
In 2001, the FDA approved three more similar devices. These devices are to be used only in women who have not yet reached menopause and whose child-bearing is completed. The BEI Medical Systems Hydro ThermAblator delivers heated saline solution into the uterus. The heated saline solution is delivered using hysteroscopic guidance. The heated solution destroys the uterine lining in about ten minutes. The CryoGen Her Option Uterine Cryoblation Therapy System uses a cryoprobe capable of producing temperatures down to minus 148° F. (minus 100° C.) at the tip. This extreme cold is applied to the tissue for ten minutes to freeze and destroy the uterine lining. Ultrasound is used to guide and monitor the procedure.
Currently available GEA treatment options are expensive and complex. As a result, only 15.8% of patients received a therapeutic procedure within twelve months, post diagnosis. Studies also show that 38% of women with HMB undergo a hysterectomy, which is a major surgery, without even being offered less invasive alternatives. These results show that physicians and patients are well-aware of these limitations and reluctant to use these treatment options.
There is a need for a non-invasive, easy-to-use (short learning curve), and effective device for treating HMB. It would further be advantageous to provide such treatment with a low cost device and low procedural costs. This would enable treatment of the patient population that currently remains untreated due to clinical and economic limitations of the current options. It would also be advantageous if such device ensured that the therapeutic agent is safely delivered to the endometrium in the uterine cavity.
The present invention overcomes the deficiencies and disadvantages of the prior art. The present invention advantageously provides in preferred embodiments an apparatus for endometrial ablation that is easy to use, economical and controls the pressure of therapeutic agent applied to the endometrium. The apparatus of the present invention also in preferred embodiments apply a pre-check of the uterine cavity to ensure it is sealed before application of the therapeutic agent, thereby preventing exposure to the agent in other areas of the body. The therapeutic agent is preferably injected to maximize the surface of exposure of the endometrium to the agent (preferably the entire surface of the endometrium will be exposed) to the agent while preventing leakage from the uterine cavity to other areas of the body.
In accordance with one aspect of the present invention, an apparatus for delivering an agent, such as a therapeutic agent, to a body cavity of a patient, such as a uterine cavity, is provided comprising a first passage for passage of the agent into the cavity of the patient, the first passage having an opening for exit of the agent, and a second passage for aspirating the agent from the cavity. The agent in these embodiments is injected at an increased pressure and is injected simultaneously with aspiration of the cavity.
In some embodiments, the second passage has a plurality of perforations to provide a plurality of entrance openings for passage of the agent into the apparatus during aspiration of the cavity. In some embodiments, the second passage aspirates gas, such as air bubbles/air pockets from the body cavity prior to injection of the agent and/or during injection of the agent.
In some embodiments, a distal portion of the second passage has a looped configuration, the loop having a first condition for delivery and a second expanded condition for placement (use) within the body cavity. In some embodiments, a tubular structure extends through a lumen of an elongated member of the apparatus and forms the looped configuration distal of the elongated member, wherein the tubular structure extends from the lumen and forms the loop terminating at an end which is distal of or alternatively aligned with a distalmost edge of the elongated member.
In some embodiments, a fluid is injected into the body cavity prior to injection of the agent to conduct a cavity integrity check to assess the presence or absence of leakage from (out of) the cavity, and the agent is injected at a pressure less than or equal to the pressure of injection of the fluid.
In some embodiments, the fluid for the cavity integrity check has a surface tension less than or equal to a surface tension of the agent and/or a viscosity less than or equal to a viscosity of the agent.
In some embodiments, the apparatus includes a line connectable to a module, the module controlling a time period of injection of the agent so the agent is injected for a preset period of time. In some embodiments, the injection module and catheter can be all-in-one, e.g., part of the catheter.
An injection module can be provided in some embodiments as a separate unit for use with the apparatus rather than integral or part of the apparatus. The injection module can include one or more of a pressure controller to control pressure, a pressure controller to control aspiration, a pressure measurement device, a flow controller to control flow and a timer to indicate/control a time period of aspiration and injection. In some embodiments, the injection module automatically transitions to aspiration of the cavity and/or injection of the agent if the absence of a leakage is assessed.
In accordance with another aspect of the present invention, an apparatus for delivering an agent, such as a therapeutic agent, to a body cavity, such as a uterine cavity, of a patient is provided comprising an elongated member having a channel for passage of the agent into the cavity of the patient, the channel having a distal opening. An expanding member extends distally of the elongated member, the expanding member having a first condition for delivery and a second expanded condition for placement (use) within the cavity. The expanding member has a plurality of perforations to provide a plurality of entrance openings for passage therein during aspiration of the cavity.
In some embodiments, the expanding member comprises a tubular structure forming a loop distal of the elongated member in the second condition.
In some embodiments, a fluid is injected into the cavity prior to injection of the agent to assess the presence or absence of leakage in the cavity, and the agent is injected at a pressure less than or equal to the pressure of injection of the fluid.
In some embodiments, aspiration of the cavity aspirates gas bubbles and/or gas pockets prior to injection of the agent and aspirates the agent after injection into the cavity.
In accordance with another aspect of the present invention, a method for injecting a therapeutic agent into a cavity of a patient, such as a uterine cavity, is provided comprising:
In some embodiments, the agent is injected into the cavity for a pre-set period of time.
In some embodiments, the method further comprises the steps of a) leaving the agent in the cavity for a preset period after injection into the cavity (a dwell period); and b) after the pre-set period evacuating the agent from the body cavity.
In some embodiments, if no leakage is assessed by checking the integrity of the cavity, the injection of the agent is automatically initiated. In other embodiments, if no leakage is determined by checking the integrity of the cavity, a user actuates a valve to open a fluid line for injection of the agent.
In accordance with another aspect of the present invention, an apparatus for delivering a therapeutic agent to the uterine cavity of the patient is provided having an elongated member having a fluid channel for passage of the agent into a uterine cavity of a patient into contact with the endometrium. The fluid channel has an opening. An expandable member extends distally of the elongated member and has a plurality of perforations to provide entrance openings for passage of the agent from the uterine cavity into the expandable member. In preferred embodiments, the therapeutic agent is a chemical agent for endometrial ablation.
In some embodiments, the injection and suction, e.g. inflow and outflow, can be through the same passage/channel/expandable member. An automated controller can control/regulate the inflow and outflow to reverse the flow.
In some embodiments, the expanding member has a tubular looped structure having a first condition for delivery having a first transverse dimension and a second condition for placement within the uterine cavity having a second transverse dimension greater than the first transverse dimension.
In accordance with another aspect of the present invention, an apparatus for delivering a therapeutic agent to the uterine cavity of the patient is provided with an elongated member having a fluid channel for passage of the therapeutic agent into the uterine cavity into contact with the endometrium. The fluid channel has a distal opening. An expandable member extends distally of the elongated member and has at least one perforation to provide for aspiration of the therapeutic agent from the uterine cavity. An infusion line passes a fluid into the uterine cavity to assess leakage to determine integrity of the uterine cavity prior to passage of the therapeutic agent into the uterine cavity. The fluid and the agent are injected at a controlled pressure. In preferred embodiments, the therapeutic agent is a chemical agent for endometrial ablation.
In some embodiments, the expandable member is a tubular looped structure having a first transverse dimension in a first condition for insertion into the uterine cavity and a second transverse dimension in a second condition for use (placement) within the uterine cavity, the second transverse dimension being greater than the first transverse dimension.
In accordance with another aspect of the present invention, a system for delivering a therapeutic agent to the uterine cavity of the patient is provided having an elongated member having a fluid channel for passage of the agent into contact with the endometrium and an expandable member extending distally of the elongated member. The expandable member has a plurality of perforations to provide entrance openings for passage of the agent from the uterine cavity during aspiration through the entrance openings. A module controls the pressure of the agent and aspiration and the time period of injection. The module can also control the pressure of fluid injected through the elongated member into the uterine cavity to assess the presence or absence of leakage in the uterine cavity. A flow control mechanism such as a valve in the module or on the handle from which the elongated member extends can be provided to open and close the lines for the pressurized agent, aspiration and pressurized fluid. A pump that turns on and off to effect aspiration could alternatively be provided. Transition from injection of the fluid to assess leakage and injection of the agent can be user controlled or alternatively automatic. Pressure gauge(s), relief valves, flow meter(s) and/or timer(s) can be provided in the module. The module can be part of the catheter or a separate unit.
In some embodiments, the expandable member is formed from a tubular structure which forms a looped configuration when expanded.
In accordance with another aspect of the present invention, a module for controlling fluid flow to a uterine cavity for an endometrial ablation procedure is provided, the module comprising a pressure controller, a pressure gauge and a timer. The module can be part of the catheter or a separate unit. The pressure controller controls the pressure of the therapeutic agent injected into the cavity. The timer ensures the agent is injected into the cavity for a pre-set period of time. In some embodiments, the module includes a control to transition from a cavity integrity check (to assess the presence of absence of leakage from the uterine cavity) to agent injection. The module can also control a pump for aspiration of the uterine cavity for aspirating gas, e.g., air bubbles or pockets, and/or agent from the cavity. The timer can in some embodiments ensure that after the agent remains in the uterine cavity for a pre-set period of time after injection, the vacuum is turned on to evacuate the agent from the cavity.
In accordance with another aspect of the present invention, a method for injecting a therapeutic agent into the uterine cavity of the patient is provided comprising the steps of a) checking the integrity of a uterine cavity to determine if there is leakage from the uterine cavity; b) if the integrity of the uterine cavity is confirmed, subsequently injecting the therapeutic agent into the uterine cavity under controlled pressure; and c) aspirating the cavity during injection of the agent. In some embodiments, the integrity of the uterine cavity is checked by injection of pressurized fluid and a) determining if the pressure remains constant after injection of the pressurized fluid is terminated and/or b) determining if flow of the pressurized fluid ceases prior to being turned off. In some embodiments, the pressurized fluid is used to inject the therapeutic agent. In some embodiments, the therapeutic agent is a chemical ablation agent.
In some embodiments, valves are controlled by the user to open the fluid, aspiration and agent lines. In other embodiments, valves are automatically actuated to open the fluid, aspiration and agent lines.
So that those having ordinary skill in the art to which the subject invention appertains will more readily understand how to make and use the apparatus disclosed herein, preferred embodiments thereof will be described in detail hereinbelow with reference to the drawings, wherein:
The present invention in preferred embodiments provides a chemical global endometrium ablation apparatus for the treatment of Heavy Menstrual Bleeding (HMB). The apparatus (also referred to herein as the device, catheter, or delivery catheter) advantageously performs one or more multiple functions including: 1) expanding an expandable member inside the uterine cavity; 2) providing a cavity integrity checking feature to ensure absence of perforations, that the fallopian tubes are closed and the cervical canal of the uterine cavity is sealed prior to injection of the chemical agent and/or 3) injecting at sufficient pressure the chemical agent at a desired controlled pressure for application of the agent to the endometrium (the tissue layer that lines the inside of the uterus wall). The agent in some embodiments is injected through the expandable member; in other embodiments it is injected through the catheter out of a distal opening. Further, in some embodiments, the agent is injected during application of suction to the body cavity. The various embodiments are discussed in detail below.
The therapeutic agent is preferably injected at a pressure to maximize the surface of exposure of the endometrium to the agent (preferably the entire surface will be exposed) while preventing leakage to other areas. In the absence of perforations, and when the cervical canal is sealed by the device, the uterine cavity should be sealed as long as injection pressure will remain below the pressure that is necessary to push fluids into fallopian tubes. Therefore, in these embodiments there are two pressure limits: 1) the upper limit to prevent leakage and 2) the lower limit to assure complete exposure.
Further, to ensure that the therapeutic agent does not leak into the fallopian tubes, a cavity integrity check is conducted in some embodiments to inject a fluid at a given pressure. If the integrity check detects no leakage, then the therapeutic agent is injected at an equal or lower pressure. Moreover, the fluid for the integrity check can be selected so its properties enable easier passage into the fallopian tubes than the therapeutic agent. This is discussed in more detail below.
The apparatus can also include one or more sealing members to seal the cavity from leaks of the chemical agent or air through the cervix and/or into the fallopian tubes.
In some embodiments of the present invention, the apparatus includes a control which is operable by the clinician to achieve the foregoing functions in the single device, as discussed in more detail below.
The present invention in alternative embodiments also includes systems that instead of a manifold include separate devices, e.g., syringes, connectable to the apparatus downstream of the handle to inject fluid and gas through the fluid channel in the apparatus for agent delivery and/or cavity integrity checking. These embodiments are also discussed in detail below.
The systems of the present invention can also include a console or injection module that controls pressure and/or measures pressure flow and other parameters, discussed in detail below.
The apparatus is designed in preferred embodiments to deliver the therapeutic agent in the form of a liquid chemical agent (substance) for a chemical endometrial ablation procedure. One cauterizing agent which can be used is an acid such as trichloroacetic acid (TCA). Derivatives of trichloroacetic such as bichloroacetic acid, and other substances such as silver nitrate, and derivatives of silver nitrate can also be utilized in certain embodiments. TCA is a chemical agent that denatures on contact with protein and causes chemical cauterization on contact with tissue, but does not spread beyond where it is directly applied. Additionally, instead of chemical agents, other therapeutic agents can be delivered, the devices/systems herein not being limited to chemical endometrial ablation as for example a specially formulated substance, such as a therapeutic agent in the form of a drug with a pharmaceutical formula that is specially formulated for this application can be utilized. The therapeutic agent could also be in the form of a gas, gel, powder or granules that are mixed or dissolved in the cavity. Additionally, the apparatus can be used to inject a diagnostic fluid, for example saline or sterile water, in procedures such as genomic lavage.
Additionally, although disclosed for use within the uterine cavity for endometrial ablation, the apparatus and systems disclosed herein are not so limited and can be used for treatment of other conditions and/or for treatment in other body areas or body spaces (cavities lumnes) of the patient.
As used herein, the term ‘proximal” denotes the portion of the device closer to the user and the term “distal” denotes the portion of the device further from the user. Also, the terms apparatus and device are used herein interchangeably.
As used herein, the term “about” and the term “substantially” means±(plus and minus) 20% of the stated numeric value.
As used herein, as is convention, the term “fluid” includes a liquid or gas.
Turning now to the expandable (expanding) member (element/component) of the apparatus of the present invention, various embodiments are shown in
It should be appreciated that the “dispensing members” in
The embodiments of
The dispensing member in these embodiments of
When an agent such as TCA utilized, it is in preferred embodiments is intended to completely ablate the endometrium and also not only to contact the endometrium but to penetrate deeper into the myometrium. The application of TCA as disclosed herein can be controlled, e.g., timed, as disclosed herein, to assure the TCA doesn't penetrate myometrium to deep so as to come too close to serosa.
Referring now in detail to the drawings wherein like reference numerals identify similar or like components throughout the several views, a first embodiment of the expandable member is shown in
Note that as an alternative to the balloon 11, as well as an alternative to the other embodiments of balloons disclosed herein, a foam material, sponge, or other material that expands and has perforations or pores to enable application of the agent to the lining of the uterus (endometrium) can be utilized. Additionally, the balloon can be filled with a foam. In any of these embodiments, the size of the holes of the balloon (or foam material, sponge, etc.) can be varied to control the flow and volume of the agent in different areas of the balloon.
Balloon 11 may also include a support wire 14 which expands the balloon 11, i.e., forces the balloon 11 open. The wire 14 facilitates expansion to maximize the exposure area of the balloon with respect to the endometrium. The wire 14 can be made of material with sufficient springiness or of shape memory material so that when deployed from the outer tube or sheath 19, it moves from its collapsed or compressed condition inside sheath 19 to an expanded position of larger transverse dimension shown in
The balloon 11 and supporting/expanding wire 14 are supported, e.g., attached, at a distal end on shaft 18 which is movable relative to sheath 19. That is, for delivery to the uterus, the wire 14 and balloon 11 are retained inside the sheath 19 as the shaft 18 is retracted within the sheath 19. To deploy the balloon 11 and wire 14, the sheath 19 is retracted, the shaft 18 is advanced distally or both the sheath 19 and shaft 18 are moved relative to one another so that the balloon 11 and wire 14 are distal of the sheath 19 and exposed from the confines of the sheath wall, the term “relative movement” or “movement relative to” encompassing these three alternatives. Exposure of the balloon 11 and wire 14 from the confines of sheath 19 enables expansion of the balloon 11 due to expansion of the wire 14. The agent is injected through channel or lumen 18a in shaft 18, the channel 18a having a distal opening in communication with the interior of balloon 11 so the agent (e.g., chemical ablative substance/agent) flows through the channel, exiting the distal opening into the interior of balloon 11. In addition to the channel for delivery of the agent to the dispensing member, additional channels could be provided for use for other purposes, such as a separate channel for inflation of the balloon, insertion of other instruments, tools, scope, camera, etc.
Markings can be provided on sheath 19 to indicate the depth of insertion of the apparatus 10 into the uterine cavity. Markings can also be provided on shaft 18 to indicate the extent of exposure from the sheath 19. Such marking on the sheath and/or shaft can also be provided in the other embodiments disclosed herein. The outer sheath 19 is configured for ease of insertion through the cervix and in some embodiments is sized such that it would require no or minimum dilation of the cervix prior to insertion.
The structural wire 14 as shown in
In some embodiments utilizing a structural wire to expand the balloon, the balloon expansion is independent of the therapeutic agent. In this manner, the agent dosage can be determined solely by the clinical need to effectively perform ablation or other treatment rather than requiring sufficient injection to first inflate the balloon, followed by passage through the balloon. In other words, in such embodiments, the agent is not used for balloon inflation but only for dispensing through the balloon, independent of the expansion by the internal wire. By relying on mechanical expansion, it also enables agent pressure to be minimized so excessive pressure is not applied. The balloons can be made for example of a non-compliant elastomeric material such as PET (polyethylene terephthalate), although other materials are also contemplated.
It is also contemplated that in alternate embodiments, instead of a wire to expand the balloon in the various embodiments disclosed herein, the balloon can be expanded by the pressure of the injection fluid.
In the alternate embodiment of
The balloons disclosed herein can include welded areas, such as areas 43 of balloon (dispensing member) 41 of device 40 shown in
In the embodiments disclosed herein, the shaft (elongated member) could have additional perforations to maximize exposure in cases where the length of the cavity exceeds the length of the dispensing member. This is shown for example in
One possible way to form the balloon 61 is shown in
As mentioned above, as an alternative to a balloon, sponge, foam or other porous or perforated material, the dispersing/dispensing member can include one or more perforated tubes. In
The foregoing apparatus can include in some embodiments a feature that allows users to confirm that the dispensing member has opened and see how wide it has opened. This is shown in
Any of the devices disclosed herein can include protective plugs to prevent or minimize the flow of the therapeutic agent into the fallopian tubes/and or into the cervix. An example of such plugs is shown in
In some embodiments, the perforated dispensing member is configured and dimensioned so that when expanded its outer wall is close to but not necessarily in contact with the endometrium. However, it is also contemplated that the dispensing member can be configured and dimensioned so that when expanded it conforms to the contour of the uterus, thereby expanding to be in contact (abutment) with the endometrium. An example of such oversized perforated dispensing member for passage of the therapeutic agent is shown in
The apparatus of
Turning now to the various systems of the present invention which include the fluid and suction lines,
Turning first to the system of
The syringe 130 can be similar to syringe 140 and could be equipped with a pressure gauge and an injection line 132 which is in fluid communication with the channel 18a of shaft 18 via attachment to side port 17b of outer tube 19. Movement of the plunger 134 forces the therapeutic agent, e.g. chemical ablative agent, out of barrel 136 and into injection line (tube or shaft) 132 for passage into channel 18a and into the balloon 11, where it exits through the balloon perforations 12 into the uterine cavity to ablate the endometrium. The syringe 130 is actuated after the syringe 140 confirms the uterine cavity is sealed to ensure that the chemical ablation substance or other agent being injected does not exit the uterine cavity and damage the fallopian tubes or other areas of the body. If the syringe 130 is equipped with the pressure gauge, the injection pressure is maintained at the level equal or below the pressure level at which the integrity of the uterine cavity was tested.
The slidable actuator 122 is operatively connected to outer tube (sheath) 19 so that movement of the actuator 122 retracts outer tube 19 so the balloon 11 and internal wire 14 attached to shaft 18 are exposed from outer sheath 19 so the balloon 11, via the radial force of the wire 14, expands to the expanded position shown in the same manner as described with respect to
In use, the balloon (dispensing/dispersing) member 11 is expanded by proximal movement of the sheath 19 via actuator 122. After expansion of the balloon 11 and prior to injection of the chemical ablative agent (or other therapeutic agent), the syringe 140 is operated to inject gas (or liquid) though line 142 and through the channel 18a and out the distal opening of channel 18a into the uterine cavity to conduct the cavity integrity check. If the integrity of the uterine cavity is confirmed, i.e., there is no leakage into the fallopian tubes or other parts of the body from the uterus, the injected gas (or liquid) is evacuated by the syringe 140, and then the syringe 130 is actuated to advance the agent though line 132 and through the perforations 12 in expanded balloon 11 to contact, e.g., chemically ablate the endometrium (or in alternate embodiments like the
Turning first to the embodiment of
With continued reference to the diagram of
The manifold is in the form of a control such as a switch 170 which has three positions: 1) a neutral position (Position A) wherein the selector switch 170 is in the off position; 2) a second position (Position B) wherein the selector switch 170 is in a cavity integrity checking position; and 3) a third position (Position C) wherein the selector switch 170 is in a therapeutic agent (e.g. TCA) injection position. In Position A, the fluid line 164 from the pressure source is not in fluid communication with the tube connecting to the fluid channel within the shaft so there is no injection of pressurized fluid into the uterine cavity. In Position A, the fluid line is also not in fluid communication with the fluid line 166 for injection of the therapeutic agent so there is no injection of agent. In Position B, the fluid line 164 is fluidly connected to the tube connecting to the fluid channel so the pressurized fluid can be injected into the uterine cavity to perform the integrity check. In Position B, the fluid line is not in communication with the line 166 for injection of the therapeutic agent so there is no injection of the agent. In Position C, the fluid line 164 is in fluid communication with line 166 not line 164 for injection of pressurized fluid into the therapeutic agent storage device 172 to inject the agent under pressure into body cavity (preferably relatively low pressure but greater than if not pressurized) through the dispensing member and the perforations in the dispensing member into contact with the endometrium or through a distal opening in the catheter shaft in alternate embodiments. Note switching mechanisms (switches or other controls) can be provided with additional positions for purging, filling the cavity, dwell time, etc., for use with the systems of
The system as noted above also includes a pressure gauge 162 (or 174), positioned distal/downstream of the manifold to measure the pressure within the uterine cavity. This ensures the pressure within the cavity does not exceed a maximum level that could cause outflow from the cavity or damage to the cavity. The pressure gauge measures the pressure for injection of the therapeutic agent. That is, the pressure level is preset (e.g., at or below 50 mm Hg) for the cavity integrity check at a level where there is no leakage (to provide a Go or No-Go test), so it informs the user that the agent can be injected into the cavity at a pressure equal to or less than the measured fluid pressure (from the cavity check) without leakage or damage due to excess pressure. That is, the integrity cavity check also ensures the agent is applied at a safe pressure. Stated another way, the cavity checking feature applies the gas or liquid at a pressure where it is determined there is no leakage through perforations in the uterine wall or into the fallopian tubes or back via the cervical canal that is not fully plugged. With knowledge of this pressure, the therapeutic agent can be applied at the same pressure (or a lower pressure) to ensure no leakage of the agent.
It is also contemplated that the manual manifold (switch) described herein could be replaced by an automated system that switches the connection from one line to another or switches the opening and closing of the lines. Additionally, it is contemplated that the suction line can be designed to be controlled by the manifold or an automated system.
The system of
In use of the systems of
The injection module can be powered by a CO2 source, such a standard CO2 tank, CO2 line or a disposable CO2 cartridge to provide injection of the fluid at an increased pressure. Medical grade CO2 cartridges of different sizes can be utilized, for example 16 grams. Alternative sources of pressure, such as electrical, mechanical or manual pumps and syringes are also contemplated to inject pressurized fluid. Examples of these various power sources are shown in the block diagram of
In some clinical applications, it is advantageous that only the targeted tissue is exposed to the gas/liquid agent that is delivered by the system. For such applications, specifically for those that deliver the agent to a body cavity, a cavity integrity test is initially performed to confirm there is no leakage out of the cavity. Such integrity test is discussed above and is also utilized in the systems of
The systems of
The systems of the present invention provide a safe, effective, and easy-to-use cGEA therapeutic procedure by tightly controlling the TCA delivery and providing features that prevent accidental leakage, spillage or unintended exposure of healthy tissue. As noted above, the area of particular concern is leakage of TCA via a possible full-thickness uterine wall perforation or via the fallopian tubes. The system of the present invention prevents such leakage by testing the integrity of the uterine cavity before the TCA injection. By way of example, a typical pressure that would inject liquids into fallopian tubes is known to be 60+ mm Hg. If a user injects TCA at the pressure above the threshold that is patient specific, other areas could unintentionally be exposed to TCA.
One way to ensure the TCA pressure does not exceed the threshold pressure which would cause unwanted leakage in most of the patients is the provision in some embodiments of a pressure control system that includes components that regulate flow rates and/or pressure levels. The pressure control system can also include a source of pressure. In some embodiments, the injection module includes more than one pressure control system. For example, the module can include one pressure control system for the cavity integrity test and a separate pressure control system for the TCA injection. (The module can also include a separate control system for aspiration). In other embodiments, the system can use a single pressure control system for the cavity integrity check and the TCA injection. Once the body cavity is insufflated with CO2 at the predetermined pressure, the flow meter (or, alternatively, a flow sensor) provided in the system confirms that CO2 flow stops. This is a confirmation of the cavity integrity, i.e., there is no leakage of CO2 via a possible uterine wall perforation, fallopian tubes or into a vaginal cavity via a cervical canal. Another test to confirm cavity integrity is a pressure sensor to assess pressure within the cavity as discussed above. Once the cavity integrity is confirmed, TCA is injected at the same pressure. If CO2 doesn't leak, then TCA will not leak either at the same pressure. This assures that the injected TCA will only fill the uterine cavity, which is the target tissue of the proposed therapy. Note that the TCA can also be injected at a lower pressure than the C02 since if the CO2 doesn't leak at the higher pressure, the TCA won't leak at the lower pressure.
Another aspect of the cavity integrity check depends on the fluids used for the integrity check and for treatment (fluid meaning a liquid or gas). In preferred embodiments the fluid for the integrity check (referred to herein the “integrity check fluid”) has properties that make it easier to get into openings or perforations than the therapeutic or diagnostic agent. This prevents a situation where the integrity check detects no flow because the integrity check fluid cannot enter the openings but the fluid for the agent is able to pass through the openings and therefore leak through a uterine perforation or into the fallopian tubes or vaginal cavity. In some embodiments, to ensure this, the integrity check fluid utilized has a viscosity less than or equal to the viscosity of the agent and/or a surface tension less than or equal to the surface tension of the agent. Consequently, in these embodiments, by ensuring properties of the integrity check fluid and the agent are such that the agent does not more easily pass through perforations, an additional check is provided.
Preferably, the surface area of endometrial ablation should be greater than or equal to 90% of the total endometrial surface. This means it is desirable that TCA fills the cavity as much as possible and come in contact with at least 90% of its surface. A presence of air/gas bubbles/pockets inside of the cavity during the treatment might prevent proper tissue contact with and exposure to TCA. These bubbles or pockets could form from the air/gas that is present inside of the cavity itself and/or inside of the delivery catheter lines. To mitigate this, the system in preferred embodiments includes venting and/or aspiration capabilities to allow the air/gas bubbles to evacuate while TCA is being injected. Thus, aspiration and agent injection occur simultaneously in preferred embodiments. The air/gas bubbles can also be evacuated before TCA injection commences. In some embodiments, after purging bubbles during injection of the agent (TCA), aspiration is turned off and the agent is injected without aspiration for a pre-set period of time.
It is also contemplated that the pressure levels and flow rates for inflow/injection and outflow/aspiration could be controlled independently. Both injection and aspiration could therefore be used simultaneously or separately. The pressure levels and flow rates could be adjusted independently to achieve a needed inflow/outflow balance between injection and aspiration to lead to a desired result. For example, to purge the entire system of TCA after the TCA has been delivered to the uterine cavity, the pressure levels and flow rates on the outflow/suction (aspiration) side could be controlled or set to exceed the pressure levels and flow rates on the inflow/injection side. Conversely, if the pressure levels and flow rates on the inflow/injection side are controlled or set to be higher than on the outflow/suction side, the uterine cavity could be filled with TCA even if the suction is still operational. Other possible flow effects based on the pressure level and flow rate parameters set for injection and aspiration could include swirling and liquid/gas circulation through the cavity. Simultaneous operation of inflow/injection and outflow/venting/suction allows for air/gas bubbles evacuation and assures that the exposure of the endometrial surface to TCA is optimized/maximized.
To effect aspiration in the system, a source of vacuum, such a vacuum/suction pump, is provided. In addition to venting/aspirating/evacuating bubbles/air pockets, the aspiration system could also be used to facilitate outflow (evacuation) from the body cavity of gases and liquids, for example remaining/unused TCA, at the end of the procedure. It could also be used to evacuate the fluid used for the cavity integrity check. An electrical, mechanical or manual vacuum pump or syringe can be utilized. Alternatively, a Venturi pump could be powered by a pressure control system. In some embodiments, the Venturi pump could be powered by the same CO2 source that powers the integrity test and/or TCA injection. It is contemplated that the source(s) of pressure and vacuum could be located within the injection module, or alternatively, outside the injection module, e.g., mounted to or adjacent the catheter handle.
The system in accordance with some embodiments includes an injection module or console that controls pressure levels and flow rates of gases and liquids. The module includes a pressure regulator(s) and can further include a flow control adjustable or fixed orifice to restrict flow through the fluid line, i.e., restrict the flow of the low viscosity CO2 during the cavity integrity check. For a more precise pressure control, multiple pressure regulators could be arranged in series, such that they are gradually reducing pressure starting with a high pressure level from the CO2 source and down to a very low pressure at the last stage that is responsible for injection of gases/liquids into the uterine cavity. The pressure regulators control the integrity fluid pressure and therapeutic agent pressure. The module can also include sensors for measuring pressure at one or multiple times during injections. Regulators for aspiration could also be provided in or separate from the module.
A system that includes an injection module and a delivery catheter that are configured for cGEA for HMB will now be described by way of example. In this system, the sequence of procedural steps listed below is executed using a number of pinch valves that are located in the handle of the catheter to open and close the input and output fluid lines. However, other mechanical valve designs are also considered. It should be understood that alternatively, this sequence could be executed by flow and pressure controls that could be located inside of the injection module instead of outside the module, e.g., in or adjacent the device handle. Further, these control components could be activated manually or using an automated control system, such as electronic.
In some embodiments, the flow lines are shared to achieve multiple functions. For example, the inflow of CO2 for the integrity test and inflow of TCA for treatment can be effected through a common channel in the catheter shaft. Alternatively, individual delivery channels in the catheter shaft could be used—one channel for the integrity test and the other for the TCA. Also, as described herein, the inflow of CO2 and TCA can be via an internal diameter of a main shaft (through a single, or alternatively, two independent channels), while outflow/suction can occur via a perforated tube that is located at the catheter's distal end. It should be understood that this could be reversed so the inflow of CO2 and/or TCA are through the perforated tube and outflow/suction occurs via an internal diameter of the main shaft or in alternate embodiments, inflow and outflow are through the same passage and components. The system could be equipped with features for both venting and suction.
The inflow and outflow are preferably balanced so that during simultaneous injection of TCA and aspiration, the outflow is not too excessive so as to aspirate too much of the TCA before it can perform its ablation function but is sufficient to evacuate bubbles. That is, if the agent pressure is too high relative to the aspiration pressure, the air bubbles won't be able to exit and complete coverage of the endometrium by the TCA might not be achieved. Conversely, if the agent pressure is too low compared to the aspiration pressure, too much agent will be evacuated so complete coverage might not be achieved and the TCA might not be left in the cavity long enough.
The entire system or just the catheter or just the module could be disposable. Alternatively, the catheter and/or module can be reusable. When reusable modules are used, it is preferred that their components are not exposed to liquids or TCA. In the system that is described below, the injection module can be made as a reusable component since it controls gas flow of CO2 and suction, but no TCA flows through it.
Turning now to
The perforated tube 214 is formed into a loop-shape at the distal end of the shaft assembly terminating at 235. As best shown in
The tube portions 214a, 214b which are exposed in the body cavity include a plurality of perforations (openings) 223 along the length. (Only a few of the openings 223 are labeled for clarity). The multiple perforations 223 allow inflow or outflow of liquids and gases to the uterine cavity. The number, size and spacing of the openings can vary from that shown so long as they are configured to achieve their functions as described herein.
Positioned inside of the tube 214 is a backbone wire 222. The wire 222 is preferably made from a shape memory material, such as Nitinol, although it can be made of alternative materials with sufficient spring like characteristics to expand the tube 214. It is pre-formed in a loop shape (its shape memorized state/condition) and acts as a spring forcing the compliant tube 214 to take the same shape. The wire 222 has two sections 222a and 222b. The end of the wire section 222a serves as a mechanical attachment of the end of the tube section 214b to the tube section 214a. The wire section 222a is mechanically attached, for example with a crimp ferrule 229a or welding, to the wire section 222b. The wire section 222b extends to the proximal section of the shaft assembly 212 where it is mechanically anchored to the fitting 218, for example, with a crimp ferrule 229b. In alternate embodiments, instead of the wire section 214b attached to the ferrule 229a at a distal region of the catheter, wire section 214b extends through the shaft lumen and is attached to wire section 214a at a proximal end. The spring action of the wire 222 effects opening of the loop of the tubular structure 214 when the sheath 215 is retracted to expose the loop from the confines of the wall of the sheath 215. The open loop facilitates delivery and distribution of liquid/gas throughout the uterine cavity and reduces dependence on pressure to achieve such distribution. When the loop opens, i.e., expands, its transverse dimension, defined as the distance across from tube section 214a to tube section 214b increases. The transverse dimension is represented by reference letter T in
In use, for delivery, the tube portions 214a, 214b are in a reduced profile position within the sheath 215 which is in a distal position. Sheath 215 facilitates ease of insertion of the distal portion of the catheter 200 into a uterine cavity C. When the sheath 215 is advanced over the tube 214 (or the tube 214 withdrawn into the sheath 215), the backbone wire 222 is deformed/compressed from its loop-shaped free state and the distal section of the tube 214 is collapsed. After delivery, the sheath 215 is retracted to expose the tube portions 214a and 214b (or the tube 214 is advanced from the sheath 215), enabling the tube 214 to expand to its loop configuration of
Note in the embodiment of
In the embodiment of
Pinch arms 237a, 237b, 237c have a guide surfaces 242a, 242b, 242c (collectively guide surface 242). Cam plate 236 (
The cam surfaces 236a, 236b and 236c can be located so that they can open and close the lines 233a, 233b and 233c and execute the sequence of procedural steps described herein. For example, they can be staggered so they open and close the lines in the desired sequence when the actuator, e.g., lever, 239, is advanced. Alternatively, separate cam plates can be provided with separate actuators for each cam plate to selectively open and close the lines. As an alternative to a slidable actuator, a push button, a lever or other type of actuator(s) can be utilized to effect opening and closing of the valves to open and close the lines. Additionally, valves other than pinch valves can be utilized to open and close the lines as the pinch valves disclosed herein are one example of a mechanism to open the lines to allow flow and close the lines to prevent flow. The valves are preferably normally in the closed position requiring actuation to open the lines, but, alternatively, the valves can be normally in an open position so the fluid lines are open requiring actuation to close the valves to close the fluid lines.
Various forms of valves can be provided at the handle portion of the catheter mechanically controlled by the user to selectively open and close the fluid lines such as the pinch valves described above. In alternate embodiments, control of opening and closing the fluid lines can be at the injection module rather than at the catheter. Such controls can be manually (mechanically) applied at the injection module or alternatively electronically controlled. For example, the control module can have a regulator and a valve controlled by a solenoid to control the CO2 source. A switch to the TCA line from the CO2 line can be effected by a mechanically actuated valve or an electronically activated valve at the module. Note an electronically controlled valve or a manually controlled valve can also alternatively be utilized in an assembly outside the injection module, e.g., mounted to or adjacent the handle portion of the catheter.
As shown in
In embodiments having vials fluidly connected to the fluid lines, the vials (bottles) containing the fluid (for inflow and outflow) can be mounted to the catheter, e.g., mounted to the handle 230, or alternatively stand-alone vials not mounted to the handle (e.g.,
As an alternative to the vial or bottle for collecting the TCA from the body cavity, a bag such as a propylene bag can be used. The bag would be connected via a connecting tube to a connection port on the catheter handle, e.g., handle 230. Thus, in these embodiments, the bag is not mounted on the handle housing. Note the bag or vial containing the evacuated TCA would include a material therein to absorb and neutralize the acid for disposing and protection of the user.
One embodiment of an injection module separate from the delivery module (catheter) is shown in
The module 270 is equipped with a CO2 source 280 that is connected to a primary pressure regulator 282 and a primary pressure gauge. This regulator reduces the pressure from the CO2 source, e.g., from a pressure level that might exceed 3,000 (three thousand) psi down to below 50 psi level for example. A secondary pressure regulator 283 can be provided to further reduce pressure to a level appropriate for injection of the CO2 into the cavity. Preferably, this pressure level is below 1 psi or 50 mm Hg, although other pressure levels are also contemplated. An adjustable orifice 284 can be provided to provide additional control over the flow rate by restricting the flow of the low viscosity CO2 to increase the viscosity. (The TCA is more viscous so there is not the same need to restrict its flow out of the bottle). To provide a safety backup system, a pressure relief valve (PRV) 295 can be provided. The valve 295 can be set at a pressure level just over the pressure setting of the secondary regulator 297. For example, if the regulator 283 is set to 25 mm Hg, the pressure relief valve 295 can be set to 27-30 mm Hg. A gas filter 291 can be provided to prevent passage of particles into the catheter lines. The gas filter 291 can be located within the injection module 270 or alternatively outside of the module and can be disposable. A flow meter 271 is provided for the cavity integrity test described above. A pressure gauge 272 is an indicator of the pressure setting that is used for injection. The connector 273 could be used for connection of CO2 source from the injection module 270 to the CO2 line 233a of the delivery catheter 200.
In this embodiment, the Venturi vacuum pump is powered by the same CO2 source 280 and the primary pressure regulator 282. A secondary pressure regulator 277 can be provided in some embodiments to reduce pressure that powers the Venturi pump. The output of this regulator 277 is connected to the connector 274, which will in turn connect to a catheter line 233c which provides for aspiration. This connector 274 could also act as a check valve. The catheter line is controlled by a pinch valve that will open it when suction function is desired. When this line is open, the pressure from the regulator 277 is delivered to the Venturi pump 278 that can also be equipped with an exhaust 279 to reduce noise. Other components that could be provided include the PRV valve 289, adjustable flow orifice 281, a gas filter 282 and a vacuum gauge 283. The Venturi pump generates vacuum and is connected to the connector 276. With the provision of the Venturi pump which converts pressure into vacuum, a fluid line extends from connector 275 into the catheter handle and a second fluid line extends from the catheter handle into connector 276. To open and close off suction, rather than using for example a pinch valve to close tube 294 or fluid line 218c within the catheter handle, the CO2 supply to the Venturi pump is closed off to control the vacuum (aspiration).
The line 294 is connected to the connector 274 and could have an optional check valve. The line 294 is controlled by a pinch valve 237c that opens and closes a pressure supply to the Venturi pump via line 233d. When open, the vacuum generated by the pump creates a suction force within the vial 300b via a line 294 and pulls liquid out of the cavity through the line 233c.
Some methods of the present invention using the injection module and delivery module include the following procedural steps. However, these steps are provided by way of example, as the procedure could include additional steps or omit some of the steps. The steps in one embodiment are as follows and are depicted in the diagrams of
The block diagram of
More specifically, the steps are as follows:
The system of the present invention in some embodiments can be conducted in a multi-step step timed process. In Step 1, a cavity integrity check is conducted by injection of pressurized fluid into the body cavity. The fluid is injected at a preselected pressure and the flow meter is checked to ensure flow stops. If flow stops, this indicates there is no leakage and the cavity is purged via application of aspiration/suction (Step 2) for a predetermined (preset) period of time. The time period for the purge can vary but for example can in some embodiments be between about 5 seconds to about 60 seconds and in more particular embodiments can be for example about 10 seconds to about 15 seconds (about or substantially as defined throughout this application means a deviation of (plus or minus) ±20%). The preset can include an indicator to prompt the user to terminate suction or alternatively there can be an automatic cutoff at the end of the pre-set time. In Step 3, pressurized TCA is applied to the cavity for a selected period of time. In some embodiments, the time is pre-set and can be for example between about 5 seconds to about 60 seconds and in more particular embodiments can be for example about 15 seconds to about 40 seconds. Other time periods for these various functions are also contemplated. In some embodiments it can be the same duration as the purge; in other embodiments it is a different duration. The time can be pre-set for a timed application of TCA, and the pre-set can include an indicator to prompt the user to terminate the TCA injection or alternatively there can be an automatic cutoff at the end of the pre-set time to terminate inflow of TCA. Step 4 is the “dwell step” or “dwell period” wherein the TCA is left in the cavity for a pre-set period of time for the ablation function. This preset can include an indicator to prompt the user to terminate the dwell period and initiate suction/evacuation or alternatively this suction/evacuation initiation can occur automatically at the end of preset time for the dwell step. In Step 5, the last step, the TCA is evacuated via suction from the cavity. This evacuation can be for a preset time period with either a prompt to terminate evacuation or an automatic cutoff of suction after a period of time.
In some embodiments, the foregoing steps in the procedure are user controlled, with the user determining when to move on to the next step. For example, the injection module can include a timer to provide an indication of the elapsed time for each step. The timer(s) can be on the handle, external of the catheter or on the injection module, and the output can be analog or digital. In such embodiments, the user watches the timer to determine when to end the step and initiate the next step in the procedure. In some embodiments, a visual indicator, such as a flashing light or an LED, and/or an audible indicator can indicate when the time has expired. In alternate embodiments, one or more of the steps are electronically controlled. That is, the timer(s) is electronically controlled such that at the expiration of the pre-set time, the system automatically terminates that step and initiates the next Step in the sequence without requiring human intervention. In such electronic systems, a digital flow meter can trigger an electric signal to launch the procedure sequence. If the flow equals zero, then the system automatically initiates/activates TCA injection. In some embodiments, launch of the TCA injection sequence is fully automatic; in other embodiments human intervention, e.g., pushing a button, initiates/activates the TCA injection.
Note a single source of pressure control can be utilized for the CO2 (integrity check) and the TCA (treatment agent). The CO2 goes into a pressure regulator and is split into a CO2 line and a TCA line. The advantage of a single line is it informs the user that there is no leakage at that pressure level. For example, if the calibration fails, the TCA will still be injected at the same level as the CO2.
In alternate embodiments two pressure regulators can be utilized. Associated with the CO2 cartridge would be one pressure regulator for the CO2 at a higher pressure, e.g., 25 mmHg and a second pressure regulator at a lower pressure for the TCA, e.g., at 20 mmHg.
In other alternate embodiments, two CO2 cartridges can be provided—one for the integrity check and one to inject pressurized TCA. More than two CO2 cartridges are also contemplated.
Although CO2 is described for the cavity check and pressurization of the agent, it is also contemplated that alternatively a pump, e.g., an air pump or a magnetic pump, can be utilized for the cavity check. Also, other fluids besides CO2 can be used for the cavity check such as sterile water.
The systems of the present invention could be used for various clinical applications where a controlled injection/insufflation of gas/liquid agents into a body space, for example a body cavity such as a uterine cavity, a lumen, a closed volume, etc. is required. One example of such application is a non-surgical lavage, which is washing out of a body cavity with water or other solutions, for example saline, antibiotics, chemotherapy agents, contrast agent, etc. In addition to the uterine cavity, this system could also be used for lavage of colon, stomach, or other body cavities. Another example is a wound irrigation for prevention of surgical site/wound infection and other gas/liquid agent delivery applications. Another application is an intravascular contrast agent injection.
Body cavity as used herein denotes a space in the body of a patient which includes a body lumen.
It is contemplated to add in some embodiments an element on the fluid input line that is not compatible with the chemical agent (e.g., TCA) so that it would degrade during the procedure to prevent reuse. For example, a cover or collar made of plastic can be positioned over a portion of the tube, for example, inside the handle, which plugs a side hole in the tube. As the plastic degrades, the side opening would become unplugged so that fluid would exit through the side opening. This would provide an indicator and prevent reuse of the system.
As noted above the apparatus described herein can provide a chemical global endometrium ablation device for the treatment of Heavy Menstrual Bleeding (HMB). The apparatus is a small profile non-invasive device that combines simplicity, cost effectiveness and ease-of-use of the IUD devices with the clinical efficacy of the global endometrial ablation (GEA) therapeutic approach making available for use in the office environment by OBGYN practitioners to treat HMB without learning any new skills. In some embodiments, the catheter can have an outer diameter of less than or equal to 4 mm, and is flexible and atraumatic and can eliminate the need for cervical dilations.
As noted above, the apparatus and systems disclosed herein are described by way of example for use for chemical ablation of the endometrium for endometrium ablation. However, the apparatus and systems disclosed herein can be used to apply other therapeutic agents to the uterine cavity as well as can also be used for injecting chemical ablative or other therapeutic agents to other regions or cavities of the body.
The apparatus and systems disclosed herein can also be used to inject diagnostic agents such as saline or sterile water for genomic language.
While the above description contains many specifics, those specifics should not be construed as limitations on the scope of the disclosure, but merely as exemplifications of preferred embodiments thereof. Those skilled in the art will envision many other possible variations that are within the scope and spirit of the disclosure as defined by the claims appended hereto.
This application is a continuation in part of application Ser. No. 16/523,989, filed Jul. 26, 2019, which is a continuation of application Ser. No. 15/803,415, filed on Nov. 3, 2017, now U.S. Pat. No. 10,485,962, which claims priority from provisional application Ser. No. 62/421,853, filed Nov. 14, 2016, and this application claims priority from provisional application Ser. No. 62/843,921 filed May 6, 2019, and provisional application Ser. No. 62/824,390, filed Mar. 27, 2019. The entire contents of each of these applications are incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62421853 | Nov 2016 | US | |
| 62824390 | Mar 2019 | US | |
| 62843921 | May 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15803415 | Nov 2017 | US |
| Child | 16523989 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16523989 | Jul 2019 | US |
| Child | 16818102 | US |
