Methods and devices for Fallopian tube diagnostics

Methods and devices for performing minimally invasive procedures useful for Fallopian tube diagnostics are disclosed. In at least one embodiment, the proximal os of the Fallopian tube is accessed via an intrauterine approach; an introducer catheter is advanced to cannulate and form a fluid tight seal with the proximal os of the Fallopian tube; a second catheter inside the introducer catheter is provided to track the length of the Fallopian tube and out into the abdominal cavity; a balloon at the end of the second catheter is inflated and the second catheter is retracted until the balloon seals the distal os of the Fallopian tube; irrigation is performed substantially over the length of the Fallopian tube; and the irrigation fluid is recovered for cytology or cell analysis.

FIELD OF THE INVENTION

The present invention in general relates to Fallopian tube diagnostics and in particular to a catheter and diagnostic collection devices that accommodate the anatomical difficulties associated with navigation within the Fallopian tube.

BACKGROUND OF THE INVENTION

Ovarian cancer is a significant disease in women; 1 out of 72 women in the U.S. is diagnosed with ovarian cancer sometime during her lifetime. In 2012, 22,280 women in the U.S. were diagnosed with this illness, and 15,500 women died of this malignancy. Ovarian cancer is disproportionately deadly because this type of cancer lacks any clear early detection or screening test, meaning that most cases of ovarian cancer are not diagnosed until they have reached advanced stages. Thus, ovarian cancer screening is of high clinical interest because the disease is not typically detectable at its early stages, when it is the most curable.

Definitive detection of ovarian cancer presently requires a surgical procedure to obtain cell samples for diagnosis. Since the ovaries are intra-abdominal, laparoscopic or open surgery (laparotomy) must be performed to access the ovaries for evaluation. Furthermore, biopsy of the ovary is not generally recommended by medical guidelines as there exists a risk of spreading the cancer further.

Anatomically, the ovaries are in close proximity of the fimbria at the region of the distal opening or os of the Fallopian tube. Eggs released by the ovary are gathered by the fimbria and transported through the Fallopian tube to the uterus. In ovarian cancer, cells may be deposited in the Fallopian tube; a few of these cells may find their way into the uterus. Cell samples obtained from the uterus may detect ovarian malignancy; however, the incidence of migration of ovarian cancer cells into the uterus is too low to render uterine sampling a reliable diagnostic test for ovarian malignancy. A higher number of ovarian cancer cells migrate to the Fallopian tube; this number increases in the distal portion of the tube, near the distal os. The ability to test cells in the Fallopian tube for malignancy would be of considerable clinical value for the early detection and treatment of such cancers, if such could be performed without concern about spreading cancerous cells. Additionally, a need exists to distinguish ovarian cancers from Fallopian tube cancers based on the finding of abnormal cells in the Fallopian tubes for several reasons including the varying treatment regimens therebetween.

However, the introduction of a diagnostic device into the Fallopian tube is problematic since the Fallopian tube is extremely fragile and prone to perforation during passage of most devices. Perforation generally occurs at the uterotubal junction (UTJ), a constriction that occurs approximately 1 cm distal to the proximal os (opening) of the Fallopian tube in the uterus. The lumen size at this constriction may be as small as 0.3 mm or 0.5 mm, while the lumen size of the Fallopian tube adjacent to the uterotubal junction is approximately 1 mm.FIG. 1depicts a cross-sectioned view of the Fallopian tube1with the uterotubal junction (UTJ)2that connects the uterus4to the ovaries6.

Thus, there exists a need for a device and process to allow cell samples to be obtained from Fallopian tube for evaluation of ovarian cancer in a minimally invasively fashion and, particularly without the need for a skin incision. There further exists a need for securing a sample of representative cells from the Fallopian tube with a catheter to screen for early stage cancers

SUMMARY OF THE INVENTION

Methods and devices for performing minimally invasive procedures useful for Fallopian tube diagnostics are disclosed. In at least one embodiment, the proximal os of the Fallopian tube is accessed via an intrauterine approach; an introducer catheter is advanced to cannulate and form a fluid tight seal with the proximal os of the Fallopian tube; a second catheter inside the introducer catheter is provided to track the length of the Fallopian tube and out into the abdominal cavity; a balloon at the end of the second catheter is inflated and the second catheter is retracted until the balloon seals the distal os of the Fallopian tube; irrigation is performed substantially over the length of the Fallopian tube; and the irrigation fluid is recovered for cytology or cell analysis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention has utility in engaging the interior wall of the Fallopian tube and effectively removing cells therefrom for diagnostic purposes. A device and process is provided for collecting such cells in a minimally invasive procedure that in some embodiments occurs without cutaneous incision.

It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a balloon” includes a plurality of such balloons and reference to “the channel” includes reference to one or more channels and equivalents thereof known to those skilled in the art, and so forth.

Embodiments of an inventive catheter for Fallopian tube diagnostics are provided for the performance of minimally invasive procedures including (1) Access to the proximal os of the Fallopian tube via an intrauterine approach; (2) Advance of an introducer catheter to cannulate and form a fluid tight seal with the proximal os; (3) Use of a second catheter inside the introducer catheter to track the length of the Fallopian tube and out into the abdominal cavity; (4) Inflation of a balloon at the end of the second catheter with retraction of the second catheter until the balloon seals the distal os of the Fallopian tube. Retraction of the second catheter produces contact with the intraluminal surface of the Fallopian tube to dislodge cells for improved sampling; and (5) and provisions to irrigate the Fallopian tube and recover the irrigation fluid for cytology or cell analysis.

Specific embodiments of an inventive catheter for Fallopian tube diagnostics are also provided for the performance of minimally invasive procedures including (1) Access to the proximal os of the Fallopian tube via an intrauterine approach; (2) Advance of an introducer catheter to cannulate the proximal os; (3) Use of a second catheter inside the introducer catheter to track inside the Fallopian tube; An inflated balloon at the end of the second catheter is advanced across the proximal portion of the Fallopian tube and is everted further into the Fallopian tube; (4) The balloon contacts the intraluminal surface of the Fallopian tube and dislodges cells for improved sampling; and (5) the balloon is removed and inserted into a vial for cell collection and subsequently processed

Embodiments of the inventive catheter are configured to be inserted into the Fallopian tube, which is typically very difficult. The Fallopian tube is curved, and the soft tissue of the tube collapses, resulting in multiple constrictions as passage is attempted. This is particularly true of the uterotubal junction (UTJ), which is prone to perforation when medical instruments are inserted in the constriction that occurs approximately 1 cm distal to the proximal os (opening) of the Fallopian tube in the uterus. The UTJ also typically presents a downward bend with a lumen size at the constriction that may be as small as 0.3 mm or 0.5 mm, while the lumen size of the Fallopian tube adjacent to the uterotubal junction is approximately 1 mm.

In at least one embodiment of the present invention, an elongated balloon that is initially inverted into a catheter lumen is deployed. The balloon everts upon pressurization inside the catheter, and the unrolling mechanism of the eversion creates a path through the Fallopian tube, regardless of tortuosity or constriction in the Fallopian tube. The great majority of the length of the balloon should be substantially inelastic, such that the balloon does not substantially expand and dilate the Fallopian tube as it everts, preferably so the Fallopian tube does not expand or dilate as the balloon everts. Balloon expansion may burst or injure the Fallopian tube. However, the design also incorporates an elastic distal balloon end that expands to allow sealing of the distal os upon balloon retraction.

An inventive process common to the various embodiments of inventive devices includes the deployment of the distal end of a catheter. In some inventive embodiments, an inventive catheter distal end is delivered to a proximal end of the Fallopian tube with resort to a conventional hysteroscope. Regardless of the mode of deployment, a retracted portion of an inventive catheter is extended into contact with the interior wall of the Fallopian tube. It has been surprisingly found that the act of extending the portion abrades sufficient cells from the Fallopian tube wall to perform histological evaluation. This is observed for planar surfaces of seemingly non-abrasive character. While an abrasive is present on the tube contacting surfaces in some embodiments, such an abrasive is found not to be necessary. It has also been surprisingly found that withdrawal of the extended portion removes still more cells. In other inventive processes the extended portion is retracted prior to catheter removal so as to preclude dispersal of dislodged Fallopian tube cells to surrounding tissue. Upon catheter removal contacting the exposed portion, now covered in cells with a microscope slide or other diagnostic substrate, is sufficient to test for abnormal cells and in particular cancerous cells.

Referring now to the figures, inFIGS. 2A-2Dan introduction catheter10with an inverted inelastic sleeve12and an attached distal elastic balloon14is (A) inserted through an introduction catheter10that resides in the working channel22of an operative hysteroscope20(FIG. 3), and used to cannulate the proximal os of the Fallopian tube1; (B) inflated to evert the sleeve12the length of the Fallopian tube1and distend the distal elastic balloon14; and (C) retracted slightly to seal the distal os18of the Fallopian tube1with the inflation of the elastic balloon14upon full advancement of the inverted elastic sleeve12.FIG. 2Dillustrates the introduction of saline to irrigate the length of the Fallopian tube1between the introducer catheter10and the everted sleeve12with the retraction of the inflated elastic balloon14that seals the opening of the distal os, and the subsequent collection of the irrigation fluid to obtain cell samples from substantially the entire length of the Fallopian tube1for cell analysis in the detection of ovarian cancer or other medical condition inFIG. 2D.

The catheter10described above, and in greater detail below may be introduced into the uterus of a patient using an operating hysteroscope20, an example of which is shown inFIG. 3. An operating hysteroscope contains an endoscope and multiple channels; one channel may provide irrigation to distend the uterus and allow endoscopic visualization, and one or more additional channels22may allow instruments and/or catheters to be advanced distal to the hysteroscope. A Proximal Introducer Catheter10(seeFIG. 2AandFIG. 4) may be advanced through the working channel of the operating hysteroscope, and used to cannulate the proximal os of a Fallopian tube. The balloon14on the proximal introducer catheter10is inflated to occlude the proximal os, and the everting balloon catheter is advanced through the proximal introducer catheter10into the proximal portion of the Fallopian tube. The sleeve/balloon element14is fully everted, and the inflated balloon tip pulled back to seal the distal os. Irrigation may be introduced via a port11, and aspirated via the irrigation port11on the proximal introducer catheter10, to collect the sample. Irrigation may also be introduced through both the everting balloon catheter and the proximal introducer catheter, followed by aspiration through one or both ports (11,13).

In inventive embodiments of the catheter, the sleeve12of the everting sleeve catheter is preferably a flexible, elongated, substantially inelastic tube with an elastic balloon tip14attached to its distal end, seeFIGS. 5A and 5B. The inelastic tube12may have multiple ridges15along its length that extend externally of the tube when the tube has been extended/deployed, such as illustrated inFIG. 5B. Prior to deployment, the ridges extend inwardly, as the tube is inverted, as illustrated inFIG. 5A. With the ridges extending externally, as inFIG. 5B, the ridges are exposed to the luminal surface of the Fallopian tube when the sleeve is fully everted. These ridges increase the ability of the sleeve to gather cells upon balloon retraction. Alternatively, the outer surface of the everted inelastic tube may be covered with fabric or otherwise textured, to increase cell dislodgment during balloon retraction.

FIGS. 6A-6Cillustrate an embodiment of an everting sleeve catheter10A which provides greater protection of the bond between the balloon and the sleeve of the everting sleeve catheter10A during deployment, relative to that provided in the embodiment ofFIGS. 5A and 5B. The construction of the embodiment ofFIGS. 6A-6Cinvolves attachment of an elongated, elastic balloon to the distal tip of the everting sleeve catheter. A substantially inelastic sleeve17, slightly shorter in length than the elastic balloon14, is attached to the elastic balloon14at the distal tip of the catheter, and inverted so that it lies inside the elastic balloon. Upon eversion of the balloon/sleeve combination14A, the inelastic sleeve emerges from a double wall19of the catheter10A, and lies on the outside of the elastic balloon and constricts the elastic balloon along the majority of its length, to prevent the elastic balloon from expanding and potentially rupturing the Fallopian tube during the time that the everting sleeve is being advanced through the Fallopian tube. Upon full balloon/sleeve eversion, the distal elastic balloon inflates to 3×-5× the diameter of the sleeve, for occlusion of the distal os upon retraction of the catheter with concomitant pullback of the inflated balloon. The catheter may contain a port11to allow irrigation to occur between the balloon and the outer sleeve, if desired.

FIGS. 7A-7Cillustrate an embodiment of an everting sleeve catheter10B where a concentric double walled catheter is provided, and the eversion of three layers are attached to the distal catheter tip: (1) an elongated inelastic balloon21is attached to the distal tip of the inner catheter23, and the balloon lies within the inner catheter lumen25; (2) an elongated elastic balloon14B equal in length to the inelastic balloon21is attached to the distal tip of the outer wall27catheter10B, and it resides inside the inelastic balloon21; and (3) an inelastic sleeve29shorter in length than the elastic balloon14B is attached to the distal tip of the outer catheter wall27, and it lies inside the elastic balloon14B. Pressurization of the inner catheter23everts the inelastic balloon21, which delivers the elastic balloon14B and outer constricting sleeve29. Following full eversion of all three layers, pressurization between the walls of the inner catheter and outer catheter inflates the elastic balloon. The inelastic sleeve29constricts the elastic balloon14B along the majority of its length, and the distal, un-constricted tip of the balloon14T expands to form the occlusion element. The potential advantage of this design is a decrease in frictional characteristics during the eversion process. In this embodiment, the inelastic balloon21delivers the elastic balloon and constricting sleeve. The elastic balloon does not undergo expansion until it has been fully everted, and therefore does not increase friction with the wall of an everting sleeve during eversion, as in previous embodiments, which can be a significant advantage in facilitating deployment, particularly when working with small diameter catheters required for traversing the Fallopian tube.

FIGS. 8A and 8Billustrate an embodiment of an everting sleeve catheter10C with an inelastic sheath29A that has a small lumen31for irrigation, with the lumen29A connected to a third port11A used for fluid irrigation and aspiration to obtain cytology samples.

A modified design is shown inFIGS. 9A-9E. An elongated balloon32with an expandable member34attached to the distal end of the balloon32is inverted into the lumen36of a catheter30. Upon inversion, the expandable member34lies inside the elongated balloon32. In certain inventive embodiments, the expandable portion34is a spiral of multiple loops38of filament. The filament that forms the expandable member34is readily formed from a variety of materials illustratively including monofilament plastic material such as Nylon or polypropylene, fluoropolymers, or polylactic acid; metal such as stainless steel titanium, or platinum; or a superelastic metal such as Nitinol. In some embodiments a fiducial marker is present (not shown) to facilitate subsequent return to the situs of cell sampling. It is appreciated that the expanding portion may also have alternative configurations. For example, the expanding portion34may contain multiple outwardly oriented bristles40of plastic or metal (FIG. 18); or the expanding portion34is present as an elongated strand of material that curls38, spreads or fans out42, balls up44to a predetermined shaped when released from being constrained inside the catheter (FIGS. 11A-11BorFIGS. 14A-14B); or it may be compressed plastic foam that expands upon release into a wet environment (FIGS. 12A-12B). Upon pressurizing the catheter adjacent to the distal os, the balloon32everts so as to urge the inverted portion outward into the extended position and into contact with the Fallopian tube inner wall cells. In certain inventive embodiments, upon full balloon eversion, the extending portion34is delivered out of the distal os of the Fallopian tube, into the abdominal cavity. The extending portion34in some embodiments has to an outer diameter of approximately 15-20 mm.

An advantage of the extending portion34having multiple bristles is that there is a lot of surface area on which cells can be collected, including areas that are not likely to be exposed to shear forces when the device is pulled back in. This approach can maximize cell collection and minimize the amount of cells that are wiped off when the device is pulled through the Fallopian tube or into a sheath, as seen inFIGS. 18-20. In those embodiments in which the extending portion has greater surface area, the cell collection typically increases per linear unit of Fallopian tube so engaged under like pressurization conditions, as compared to a contourless extending portion.

In still other embodiments of an inventive catheter, the extending portion, upon deployment defines: multiple filaments42attached to the distal end of the balloon32that splay out upon balloon eversion to form a brush42(FIGS. 11A-11B); a plastic foam structure46that is compressed inside the balloon32and expands on balloon32eversion and exposure to a fluid environment (FIGS. 12A-12B); an elastic or inelastic balloon48on the distal end of the inelastic sleeve balloon32(FIGS. 13A-13B), an everting balloon with a superelastic wire coil (FIGS. 14A-14B), a spiral everting balloon50(FIGS. 15A-15B), an everting distal arc balloon52FIGS. 16A-16B); or a long elastic filament of plastic or metal that gathers into a three-dimensional structure upon balloon eversion, such as an inner lumen54(FIGS. 17A-17B), and expanding portion34with multiple outwardly oriented bristles40(FIG. 18). It is appreciated that any of these embodiments of an inventive catheter extending portion are readily fitting with a fiducial marker that can be used to navigate back to the Fallopian tube as needed. Such markers are known to the art and illustratively include radio-opacity markers, isotopic markers, and radiofrequency markers. In still other embodiments, a biodegradable extending portion or a permanent extending portion are severed from the catheter. In still other embodiments, the extending portion delivers a therapeutic agent such as a chemotherapeutic drug, antibiotic, anti-inflammatory, or combinations thereof of the Fallopian tube tissue.

When the catheter is pulled into the working channel of the hysteroscope, cells are dislodged from the entire length of the inner surface of the Fallopian tube. In some embodiments, the extending portion is inverted through reduced the gas pressure with the balloon so as to shield collected cells with the catheter tip region internal bore (FIG. 19).

Without intending to be bound by a particular theory, the expanding portion creates friction between the outer surface of the expanding portion and the inner lining of the Fallopian tube sufficient to dislodge cells and adhere such cells to the expanding portion, even in certain instances on a contourless expanding portion. The expanded spiral at the distal end of the balloon contacts the fimbria at the distal end of the Fallopian tube, gathering cell samples as it is withdrawn. Since the Fallopian tube increases in inner diameter as it proceeds from its proximal to its distal end, the expanding portion ensures that cell samples are obtained at the distal end of the tube (fimbrial portion of the Fallopian tube). The elongated balloon and the distal expanding portion are in certain procedural embodiments retracted into the working channel of the hysteroscope, to avoid loss of cell samples as the hysteroscope is removed from the patient. An elastomer seal at the proximal end of the working channel of the hysteroscope seals against the outer surface of the catheter. A mark on the catheter body indicates the length of retraction necessary to ensure that the elongated balloon and distal spiral lay within the hysteroscope working channel. Upon removal of the hysteroscope from the patient, in some embodiments, a syringe containing saline solution is attached to the Luer fitting at the proximal end of the working channel, and the saline is used to flush cells gathered by the elongated balloon and expanding spiral into a test tube. It is appreciated that the cells decorating the extending portion are readily collected for testing by conventional techniques and are prepared for cytological, molecular or genetic examination.

An alternative embodiment of that shown inFIGS. 17A-17Bin which a coil is attached to the end of the inverting balloon, an inner lumen formed of the exemplary material polyethylene terephthalate (PET) is attached. The eversion process follows that of the aforementioned embodiments. This alternative embodiment also includes an inflation sideport and a proximal seal that allow the balloon to be inverted while maintaining an orifice through the inner lumen in fluid communication between the hysteroscope and the patient body tissue. Once everted, the inner lumen provides a pathway through which a separate extending portion is passed or a surgical instrument package is passed. An example of such a collection device is the spiral shown inFIG. 19andFIG. 20. It is appreciated that cells can be collected from a specific portion of the Fallopian tubes, for example the fimbria, and then pulled back into the inner lumen so as to avoid the potential for distal cells to be wiped off by the inner surface of the proximal Fallopian tube as the device is removed.

FIGS. 21A and 21Bare schematic, cross-sectional views of a ball tip everting balloon catheter120in accordance with at least one embodiment of the present invention. A spherical ball122is attached to the distal end of a spring tip124that is affixed to a catheter126and is provided to negotiate through a patient's UTJ without penetration through the UTJ sidewalls. The spring tip124and spherical ball122have an open lumen128that extends through the spring tip124and the spherical ball122. The spherical ball122on the spring tip124is approximately 0.8-1.0 mm in diameter, and the hollow spring tip124has a length of approximately 1.5 cm, and an outer diameter of approximately 0.6 mm. The hollow spring tip124may be a metal (stainless steel or superelastic metal, e.g., Nitinol) coil spring sheathed on the outside with thin walled plastic heat shrink tubing, made of nylon, PET (polyethylene teraphthalate), or similar material. In a specific inventive embodiment, the spring tip124may be a metal coil spring co-extruded into a tubular plastic body. The hollow spring tip124may also be a flexible plastic tube, made of nylon, Polyethylene terephthalate (PET), polyether block amide (PEBAX), or similar materials. A long everting balloon130lies inside the hollow spring tip124. The everting balloon130extends proximally inside the main lumen132of the introduction catheter126(a generally flexible tubular structure) or cannula (a generally rigid tubular structure), and the proximal end of the everting balloon130is attached to a push rod134that passes through a seal136on the proximal end of the catheter126or cannula. In operational use on a patient, the flexible ball tip122is manually advanced through the uterotubal junction. Once passage of the flexible ball tip122and spring tip124through the uterotubal junction is successful, the push rod134is advanced through the seal136of the previously pressurized introduction catheter126or cannula. Advancement of the push rod134causes a controlled eversion of the balloon130out of the hollow spring tip124, through the length of the Fallopian tube.

In inventive embodiments, when the elongated balloon that is initially everted into a catheter lumen is deployed, the balloon everts upon pressurization inside the catheter, and the unrolling mechanism of the eversion tracks through the Fallopian tube, regardless of tortuosity or constriction in the Fallopian tube. The great majority of the length of the balloon should be substantially inelastic, such that the balloon does not substantially expand and dilate the Fallopian tube as it everts, preferably so the Fallopian tube does not expand or dilate as the balloon everts. Balloon expansion may burst or injure the Fallopian tube.

An inventive process common to the various embodiments of inventive devices includes the deployment of the distal end of a catheter. In some inventive embodiments, an inventive catheter distal end is delivered to a proximal end of the Fallopian tube with resort to a conventional hysteroscope. Regardless of the mode of deployment, a retracted portion of an inventive catheter is extended into contact with the interior wall of the Fallopian tube. It has been surprisingly found that the act of extending the portion abrades sufficient cells from the Fallopian tube wall to perform histological evaluation. This is observed for planar surfaces of seemingly non-abrasive character. While an abrasive is present on the tube contacting surfaces in some embodiments, such an abrasive is found not to be necessary. It has also been surprisingly found that withdrawal of the extended portion removes still more cells. In other inventive processes the extended portion is retracted prior to catheter removal so as to preclude dispersal of dislodged Fallopian tube cells to surrounding tissue. Upon catheter removal contacting the exposed portion, now covered in cells with a microscope slide or other diagnostic substrate, is sufficient to test for abnormal cells and in particular cancerous cells.

The catheter126described above, and in greater detail below may be introduced into the uterus of a patient using an operating hysteroscope40, an example of which is shown inFIG. 3. An operating hysteroscope contains an endoscope and multiple channels; one channel may provide irrigation to distend the uterus and allow endoscopic visualization, and one or more additional channels may allow instruments and/or catheters to be advanced distal to the hysteroscope. The catheter126(seeFIGS. 21A and 21B) may be advanced through the working channel of the operating hysteroscope, and used to cannulate the proximal os of a Fallopian tube. The everting balloon130is advanced through the proximal catheter126into the proximal portion of the Fallopian tube.

FIGS. 22A-22Care a series of photographs of the everting balloon130exiting from a nylon flexible tip152with a spherical ball122in accordance with an embodiment of the invention. The nylon flexible tip152and spherical ball122are configured to pass through the patient UTJ for the deployment of the everted balloon130in the Fallopian tube. In a specific inventive embodiment of the nylon ball tip everting balloon catheter150is configured with a 0.9 mm ball tip on 0.66 mm dia.×18 mm long nylon tip; 4 Fr catheter with a 0.64 mm dia. manual balloon that everts through and beyond the tip (24 atm).

FIG. 23Ais a schematic, cross-sectional side view that depicts a sheathed everted balloon tip catheter160or cannula, which is shown in the photograph ofFIG. 23B, in accordance with an embodiment of the invention. A long inverted balloon130, with an outer diameter of approximately 0.8-1.0 mm, is everted a length of approximately 1-3 cm, most preferably 1.2-1.5 cm out of the distal end of the catheter126or cannula. The balloon130is inflated with fluid to a pressure of approximately 14-24 atm (206-353 psi). The pressurized balloon130has a rounded end, a degree of flexibility along the balloon130length, while possessing sufficient column strength to allow the balloon130to be manually advanced through the uterotubal junction. In a specific embodiment, the balloon130is constructed of a thin-walled plastic material, such as polyethylene terephthalate (PET), polyethylene, Nylon, or a similar material, and the balloon30has a wall thickness of approximately 0.25 mil (0.00025″). The balloon may be an opaque color to enhance visibility during use. The length of the fully everted balloon130extends approximately 7 cm, such that when fully everted, the balloon130extends through the patient Fallopian tube, following the successful advancement of the 1.5 cm length of everted balloon through the uterotubal junction. Eversion of the balloon130is performed in a controlled manner, by advancing a push rod134through a fluid tight seal136at the proximal end of the catheter126. At least a portion of the catheter126is preferred to be transparent (167), so that movement of the balloon130can be viewed through the hysteroscope through which the catheter is inserted, thereby providing the user with a direct view of the insertion procedure. The catheter126may be constructed of polymers such as Nylon (preferred), Pebax, polyurethane PET (polyethylene terephthalate), polyethylene, or polyvinyl chloride (PVC) plastic, with or without polymer or metal coil or braid reinforcement.

However, a balloon of the aforementioned dimensions when everted a 1.5 cm length out of the catheter126or cannula may not remain straight, rather the balloon130may assume a curved configuration, either a single “C” curve, or an “S” curve. However, it is difficult or nearly impossible to cannulate the proximal os of the Fallopian tube with a curved balloon, and to advance it through the uterotubal junction. The 1.5 cm length of everted balloon130may be straightened out by use of an outer plastic sheath162that lies coaxial to the catheter126or cannula, and covers the 1.5 cm everted balloon tip. At least a portion of sheath162is preferred to be transparent (167), so that movement of the balloon130can be viewed through the hysteroscope through which the catheter is inserted, thereby providing a user with a direct view of the insertion process. The sheath162may be constructed of polymers such as Nylon (preferred), Pebax, polyurethane, PET (polyethylene terephthalate), polyethylene, or polyvinyl chloride (PVC) plastic, with or without polymer or metal coil or braid reinforcement.

FIG. 35illustrates the linear eversion of a deploying balloon. In the cross-section example of an everting balloon, one end of the balloon is fixed at point X and the other end can be moved at point Y. The balloon everts from the position shown in Step1to the position shown in Step2to the position shown in Step3. In the inversion process, points A, B, and C move towards the left side of the diagram. As shown, as the balloon unrolls at the left side of the diagram, point A moves from the inside diameter of the balloon to the outside diameter. In practice, the balloon that has been everted during the preparation step is advanced into the proximal end of the Fallopian tube. Further eversion (extension) of the balloon (totaling up to 2-3 cm into the Fallopian tube) is accomplished by further rotation of the drive wheel204. The balloon130is then deflated by relieving pressure in the inflation device. The balloon130is then retracted from the Fallopian tube. Because the Fallopian tube is a potential space, the Fallopian tube tissue collapses around the balloon. Because the balloon fills the Fallopian tube, the balloon surface area is equivalent to the surface area inside the Fallopian tube. This matched surface area optimizes tissue collection from the inside of the Fallopian tube.

To further optimize tissue collection, wrinkles may be added to the surface of the balloon, where the wrinkles form as the balloon deflates to create multiple edges, which also aid in cell collection. These edges work in a manner similar to the edges of the curette of the U-Scope predicate device and the edges of the jaws in the biopsy forceps predicate device. Similar to these features on the predicate devices, the edges formed by the wrinkled balloon focus the contact force on the anatomical wall in order to collect cells. Because the collection surface is a polymer balloon, however, the contact with the endothelium is less traumatic than the stainless steel contact surfaces of prior art diagnostic devices. The less traumatic nature of the wrinkles on the balloon for collecting cell tissue, allows for cycling of the inflation/deflation of the balloon inside the Fallopian tube to scrap cells free. The inventive balloon deployment device is then removed from the working channel of the hysteroscope and from the patient. Once the device is removed from the patient, cells can be removed from the balloon by dipping the balloon into a cytopreservative and stirring in order to agitate the cells. Alternatively, both balloon and sheath can be cut off and placed into a cytological preservative. In a specific embodiment a sheath may extend and deploy over the balloon as the balloon is deflated and removed to protect tissue samples that are now resident on the balloon surface.

FIG. 24is a schematic, cross-sectional side view that depicts a sheathed everted balloon tip catheter160′ configured with a superelastic push rod175and spiral carrier176that eliminates the need to extend the push rod backwards for the full length of the push rod in accordance with embodiments of the invention. The push rod175is constructed of a superelastic material such as Nitinol (nickel-titanium compound) wire. The length of push rod175may then be coiled multiple times into a spiraling tubular carrier176made of polyethylene or polytetrafluoroethylene (Teflon). The outer spiral diameter of the carrier may be approximately 8 cm, rendering the proximal operating length much more compact. The plastic spiral carrier176may be attached to the proximal Tuohy-Borst fitting136on the catheter with a flexible strap177constructed of plastic or silicone rubber material. In a specific embodiment the superelastic push rod175has a diameter of approximately 0.025″, and it is difficult to grip this wire and push it forward through the Tuohy-Borst seal136. Therefore, a flexible grip178has been added, that slides freely on the push rod175, but upon compression between the thumb and forefinger, provides excellent grip for push rod175advancement. The flexible grip178may be an elliptical cross-section frame made of polyvinyl chloride, silicone rubber, or similar flexible compound whose inner dimensions are approximately 2 cm in length, 1 cm in width, and 3 mm in height, with a wall thickness of approximately 2 mm. Holes in the proximal and distal faces of the grip are a slip fit with the push rod175.

FIG. 25is a schematic side view that depicts an inventive embodiment of a sheathed everted balloon tip catheter200configured with handle202. Handle202has a drive wheel204which advances and retracts the push wire206that causes the balloon130to evert linearly (gradually unfold from the inside out.). The drive wheel204may be made of plastic illustratively including ABS. The outer edge of the wheel may have notches to facilitate gripping the wheel during operation of the catheter200. The top surface of the drive wheel204may have an arrow molded into it that indicates the correct direction in which to turn in order to evert the balloon. The opposite side of the drive wheel may have a square boss that inserts into a drive gear.

The catheter200holds the balloon130in a shaft210(which may be made up of a stainless steel tube and a Nylon tube), a sheath212, and a sheath knob214. The handle202also has an extension tube216that is attached to a luer218in the handle body. In order to enable balloon advancement, the balloon130and shaft210are pressurized with an inflation device (such as inflation device172ofFIG. 23C) that is attached to the extension tube216. Once the catheter device200is pressurized, a user rotates the drive wheel204, which causes a push wire206to advance.

FIG. 26Ais a cross-sectional view of the handle portion ofFIG. 25, andFIG. 26Bis a detail view that depicts the internal handle gear mechanism220. The drive wheel drive wheel204has a square boss (not shown) that is inserted into square hole222in the drive gear224. As the drive wheel204is rotated in a clockwise motion, the square boss causes drive gear224to spin. The drive gear224engages the idler gear226and gear one228, causing these gears to spin. Likewise, the idler gear80causes gear two230and then gear three232to spin. The push wire206runs between rubber conduction surfaces on and between each of the four large gears (224,228,230,232) and moves as shown inFIG. 26Bduring advancement of balloon130. The balloon130advances until the proximal end of the push wire206passes between the drive gear224and gear one228. The gear mechanism220allows for fine, precise, and controlled movement for the deployment and retraction of the balloon130.

The sequence of steps used to enter and track through the Fallopian tube may be described with the embodiment ofFIG. 23A. When it is desired to cross the uterotubal junction with the 15 mm length of everted balloon130, the outer plastic sheath162is placed in apposition with the proximal os of the Fallopian tube, without entering the proximal os. The outer plastic sheath162supports the 15 mm length of everted balloon130until it enters the proximal os, The short length of pressurized everted balloon130that exits the supportive outer sheath162contains sufficient column strength to be manually advanced through the uterotubal junction, whereas an unsupported 15 mm length of everted balloon130does not contain sufficient rigidity by itself, and buckles upon attempted advancement through the proximal os and uterotubal junction.

The sheath162has an outer diameter of 5 Fr (1.59 mm), and the proximal end of the sheath62is attached to a male luer lock fitting164with a Tuohy-Borst seal136connector. A Tuohy-Borst adapter is a medical device used for creating seals between devices and attaching catheters to various other devices. The Touhy-Borst seal36is tightened down so that it has a slip fit with the catheter or cannula holding the sheath162in place thereby covering the everted balloon tip. The male luer lock fitting164may mate with a female luer lock fitting, if present, on the working channel of the hysteroscope. When these respective luer fittings are connected, the tip of the outer sheath protrudes approximately 2-3 cm out of the distal end of the hysteroscope. The outer sheath also protects the 1.5 cm everted balloon tip from injury as the catheter or cannula is advanced through the working channel of the metallic hysteroscope. A stainless steel tube of dimensions 0.050″ OD×0.004″ wall is preferred for the inner cannula126, as it provides sufficient rigidity to prevent kinking of the portion protruding from the proximal end of the hysteroscope working channel.

FIG. 23Cis an image of the sheathed everted balloon tip catheter160ofFIG. 23Awith a high pressure tubing reservoir168and inflation device172in accordance with an embodiment of the invention. Pressurization of the balloon130using fluid injection may be performed using a threaded syringe device commonly known as an indeflator as the inflation device172. Rotation of a threaded plunger shaft through a releasable lock increases and maintains pressure in the inflation device172, while a pressure gauge174provided with the inflation device172allows control of input pressure. In a specific embodiment of the sheathed everted balloon tip catheter160provides for one person operation of the device. A length of high pressure tubing168is added between the inflation device172and the inflation port166on the device. The high pressure tubing168may be constructed of polymers such as polyurethane or polyvinyl chloride (PVC), with or without polymer or metal coil or braid reinforcement. The pressure tubing168contains an amount of intrinsic elasticity, while the everting balloon is generally inelastic. At full pressurization of the balloon130, the pressure tubing168imparts fluid capacitance to the system. A small volume of fluid is contained in the everted balloon, and this volume is further subtracted by the volume occupied by the push rod134(which moves into the balloon130as it is being everted). The resultant everted balloon volume is small compared with the larger volume in the pressure tubing168, which allows the balloon130to evert its full length without significant decrease in pressure, once the sheathed everted balloon tip catheter160has been pressurized. The stopcock valve170between the pressure tubing168and the inflation device172may be closed following pressurization, and the heavy inflation device172removed from the examination field, prior to insertion and eversion of the balloon130. The less cumbersome, one operator procedure is the result of the design embodiment as shown inFIG. 23C.

As described above forFIGS. 23A-23C, the everting balloon130extends a total distance of approximately 7 cm distal to the tip of the catheter, in order to pass through the entire length of the Fallopian tube. The everting balloon130assumes a toroidal shape as it exits the catheter tip, and the everted portion possesses a double walled configuration. Thus, the push rod134must advance forward a distance of 14 cm in order to yield an everted balloon length of 7 cm. This length of push rod initially extends backwards from the proximal end of the catheter126, directly into the face of the operator, making its use cumbersome. The length of the push rod134also makes the push rod susceptible to contamination of the sterile device, as the proximal end of the long push rod314may contact the physician's face or surgical mask during use. Therefore, it is desirable to provide a push rod system that does not have to extend backwards its full length. The superelastic push rod and carrier design ofFIG. 24and the sheathed everted balloon tip catheter200configured with handle202ofFIG. 25act to contain the push rod and avoids the need to extend the push rod back towards the user.

FIG. 27is a schematic, cross-sectional side view that depicts an everted balloon tip catheter180with a thin walled tube182with a diameter smaller than the inflated diameter of the everting balloon130for insertion into the patient's uterotubal junction in accordance with an embodiment of the invention. The thin walled tube182straightens a portion of the balloon tip163. The thin walled tube182may have an approximately 0.0005″-0.001″ wall thickness, and may extend 1.5 cm distal to the tip of the cannula. The thin walled tube extension182supports the balloon130and keeps the balloon tip163straight, but because thin walled tube diameter is smaller than the balloon diameter, this allows the balloon130to retain flexibility and compressibility, which are properties necessary to allow the balloon130to be advanced through the uterotubal junction. In a specific embodiment the balloon has a 0.040″ (1 mm) OD with a 0.033″ OD×0.001″ wall×1.5 cm long inner tube to support and straighten the balloon.

FIG. 28is a schematic, cross-sectional side view that depicts an everted balloon tip catheter190with one or more flexible plastic monofilament strands192attached to the distal end of the cannula126that extend into everting balloon tip163, thereby supporting and keeping the tip straight for insertion into the patient's uterotubal junction in accordance with an embodiment of the invention. In a specific embodiment the one or more flexible plastic monofilament strands192extend 1.5 cm into the balloon tip163. The monofilament may be formed of nylon, polypropylene, or other flexible plastic material. The monofilament strands may have a diameter of approximately 0.006″-0.012″. In a specific embodiment the balloon has a 0.033″ (.8 mm) OD with a 0.008″ diameter nylon monofilament inside a 1.5 cm long everted balloon tip

FIGS. 29A-29Care a series of side perspective views of a steerable balloon tip252for an everted balloon catheter250using guide wires in accordance with an embodiment of the invention. As shown inFIG. 29Aa steerable balloon tip252is controlled by a right direction guide wire254and a left direction guide wire256. InFIG. 29Bthe right guide wire204is pulled (as shown by the arrow) to steer the balloon202to the right. Conversely, inFIG. 29Cthe left guide wire206is pulled (as shown by the arrow) to steer the balloon202to the left. It is noted that additional guide wires may be added to provide movement in the Z-plane in addition to movement in the X-Y plane achieved with the pair of guide wires as shown.

FIG. 30is a side perspective view of a balloon catheter260with a smaller diameter lead balloon tip262at the distal end of the everted balloon130in accordance with an embodiment of the invention. The smaller diameter lead balloon tip262is dimensioned so as to gradually expand the opening at the constriction presented by the patient uterotubal junction, as well be flexible with blunted edges so as not to perforate the walls at the uterotubal junction.

FIG. 31is a side perspective view of a balloon catheter270with a flexible guide wire272on the tip of the balloon30in accordance with an embodiment of the invention. The flexible guide wire leads the balloon catheter220through the patient uterotubal junction.

In embodiments of the inventive everted balloon catheters a portion of the everted balloon may be treated with flouropolymer, silicone, and like material coatings that lubricate the surface at the lead portion of embodiments of the balloon catheters enter the constricted portions of the Fallopian tube.

FIG. 32is partial side perspective view of a striped balloon130S prior to inversion of the striped balloon130S into the catheter or cannula ofFIG. 32in accordance with an embodiment of the invention. The indicia131on the balloon provide a visual feedback indicator of the progress of the balloon eversion. In a specific embodiment, the indicia131may be approximately 1 mm wide and spaced at approximately 1 cm increments along the entire length of the balloon130S. Alternative spacing of the strips or other visual markers on the balloon may be spaced closer together for finer positional feedback, or further apart for coarser feedback. Other visual markers of length of eversion include a sinusoidal indicia with a known length of periodicity. It is also appreciated that indicia of length also include differently colorized segments of a known length.

FIG. 33is a schematic, cross-sectional side view that depicts a sheathed everted balloon tip catheter280configured with striped balloon130S in accordance with an embodiment of the invention. As shown inFIG. 33the indicia131of the striped everting balloon130S are coupled with a transparent distal section167of the cannula or catheter126to provide visual feedback of balloon eversion. In a specific embodiment the indicia131may be approximately 1 mm wide, spaced approximately in 1 cm increments along the entire length of the balloon and be pad printed or scribed with an indelible marker in a highly visible color. Pad printing (also called tampography) is a printing process that can transfer a 2-D image onto a 3-D object. Other patterns may be used instead of, or in addition to indicia131on the surface of the balloon130S. For example, indicia131on the balloon130S may be spaced 10 cm apart, and dots added in the remaining intervals between the indicia. Each indicia131that comes into view in the transparent distal section167indicates a successful eversion of a 5 cm length of balloon, as the push rod must be advanced a 10 cm length for a corresponding 5 cm of balloon eversion. Indicia of different thicknesses may be used, as well as different colored indicia, or a different number of indicia, in the same fashion described for the stripe and dot combination. In a specific embodiment color coded sections may be added to the balloon to indicate the extent of the balloon eversion.

Additional inventive embodiments of feedback markers, which are externally visible to the physician on the outside of the patient's body, for the extent of positive balloon eversion may include the use of a knotted string or sutures that may be spaced in known increments to provide tactile feedback as to the balloon eversion progress. The knots or sutures may be radio opaque. The string may have color coded zones for providing feedback to the operator.FIG. 34illustrates a string140with a series of knots or sutures142in accordance with an embodiment of the invention. The balloon130may be transparent to enhance visibility of string, knots, or sutures. In a specific embodiment the knots or sutures may also provide an additional cell collection surface.

Further inventive feedback mechanisms may include ultrasound saline—air marking, and a sinusoidal pattern for the balloon, where the distances between maximums of a sinusoidal wave define an incremental distance of balloon eversion.

Any patents or publications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The foregoing description is illustrative of particular embodiments of the invention, but is not meant to be a limitation upon the practice thereof.