HK1069097B - A microcatheter for use with endoscopic embryo implantations - Google Patents

Description

Micro catheter for embryo transplantation under endoscope

Technical Field

The present invention relates generally to an intrauterine device comprising a hysteroscope and related devices for microsurgery, such as in the field of embryo transfer.

Background

Improving the success rate of in vitro egg fertilization (IVF) depends on a number of factors, one of which is the delivery or transfer of the embryo to the endometrium of the uterus and successful transfer of the embryo to the endometrium. It is known from the prior art that the attachment or transfer of an embryo to a predetermined area of the endometrium of the uterine wall, rather than simply releasing the embryo into the uterus, will increase the success rate of fertilization of an in vitro ovum.

One method of facilitating embryo transfer is shown in U.S. Pat. No.6,010,448 to Thompson. Where delivery of the embryo is performed through a flexible catheter using an endoscopic device, to the endometrium and secured in place by an adhesive.

Another method for transferring embryos is described in U.S. Pat. No.5,360,389 to Chenete, in which pressurized CO is used₂After the gas distends the uterine wall, the endoscope is used to select the implantation site. The embryos are then forced into the endometrium using a catheter.

Although these prior art embryo transfer methods are generally satisfactory for the intended purpose, damage to delicate embryos by injection or "attachment" can lead to less than optimal results and reduced success rates of fertilization of in vitro ova. Accordingly, it would be highly desirable to improve devices for use in intrauterine procedures such as in vitro ovum fertilization, and to improve methods of embryo transfer.

Disclosure of Invention

The present invention provides a catheter, an endoscope (hysteroscope), and a method for introducing at least one embryo into a uterus of a human. The purpose of ejecting the device and/or the method is to propose a simple method that can be used for procedures performed in utero, such as embryo transfer and transplantation. To achieve simple delivery, an improved microcatheter with an angled tip is proposed. The microcatheter may be used as a microsurgical instrument, and as an embryo recipient within the endometrium of the recipient uterus in the described method, and as a delivery vehicle to deliver an embryo to the recipient. It has been observed that by smoothly fixing the embryo in the endometrial receptor, the risk of fertilization of the test tube ovum, such as tubal pregnancy, misplacement of the embryo, and embryo dropout, can be reduced. For example, tubal pregnancy can be significantly reduced according to this method.

An additional benefit of efficient transfer of embryos to the endometrium ("intrauterine method") is that stale embryos (e.g. 2 to 7 days after fertilization) can be used and thus longer observation times can be made, allowing selection of the most likely surviving embryo. A higher accuracy in selecting the most likely surviving embryos will lead to the additional benefit that fewer embryos need to be transferred to ensure reliable conception, thus reducing the high risk of adulteration with conventional IVF procedures. Common IVF procedures place a large number of immature embryos into the uterus. For information see the article "Blastocyst Transfer (blast Transfer cultures Risk)" published by Doug Brunk in "ob. Gyn. News" (Vol. 35, No. 23, pages 1-3).

The intrauterine procedure preferably involves direct visual observation of the graft site or site through an endoscope. To enhance the scope of the endoscope and to increase the maneuverability of the endoscope within the uterus, the uterine wall may be distended by pressurizing the uterus with an inert, harmless gas, such as nitrogen. Other gases may be used, but pure CO is used₂The gas is limited because of toxicity. Reference may be made to "Gynecologic" published in 1997&Obstetrics exploration volume 43(2) article "Assisted exploration" at pages 73-75: direct intracolonic embryotransfer ". This article describes the introduction of CO₂Gas access to the uterus can distend the uterine wall and improve endoscopic vision (as claimed in U.S. patent No.5,360,389), but increases the risk of endometrial acidification, thus reducing the viability of the transplanted embryo. In addition, CO₂And air are generally unsafe because of the fear of fatal air embolism.

To improve the positioning of the microcatheter at the implantation site, a hysteroscope may be used which serves as an endoscope for intrauterine use. Hysteroscopes can provide direct visualization into the uterus, and guide and support microcatheters.

Specifically, the invention provides a microcatheter for endoscopic embryo transfer, comprising: a flexible hollow shaft with proximal and distal ends and a distal portion; characterized by a beveled tip at the distal end; a curved portion having an outer diameter smaller than an outer diameter of the hollow shaft proximate the distal end portion; and a bevel or a pyramidal cut formed around at least a portion of the periphery of the beveled tip.

Drawings

FIG. 1 is a side view of an embodiment of a microcatheter of the present invention;

FIG. 2 is a perspective front view of the tip of the microcatheter of FIG. 1;

FIG. 3 is a partially cut-away side view of the tip of the microcatheter of FIG. 1;

FIG. 4 is a schematic cross-sectional side view of one embodiment of a hysteroscope;

FIG. 5 is a cross-sectional side view of a portion of the hybrid insertion arm of the hysteroscope of FIG. 4;

FIG. 6 is a cross-sectional view of the hysteroscope of FIG. 4 taken along line A-A' of FIG. 5;

FIG. 7 is a schematic cross-sectional side view of another embodiment of a hysteroscope;

FIG. 8 is a partial cross-sectional view of the hysteroscope of FIG. 7 taken along line A-A';

FIG. 9 is a cross-sectional side view of a portion of the hybrid insertion arm of the hysteroscope of FIG. 7;

FIG. 10 is a cross-sectional view of the hysteroscope of FIG. 7 taken along line B-B' of FIG. 9;

FIG. 11 is a cut-away side view of the tip of the microcatheter of FIG. 1 containing an embryo to be transferred;

FIG. 12 is a first continuous action diagram of one embodiment of a method of performing embryo transfer; showing the view of the endometrium to select the implantation site;

FIG. 13 is a second sequential action diagram of a method of performing embryo transfer, illustrating the formation of an embryo recipient at a selected transfer site;

FIG. 14 is a third sequential action diagram of a method of performing embryo transfer, showing embryo transfer being performed in the embryo recipient of FIG. 13;

FIG. 15 is a fourth series of plots of continuous operations for a method of performing embryo transfer showing closure of an embryo recipient to an embryo.

Detailed Description

Referring now to the drawings, figures 1 to 3 show one embodiment of a microcatheter, in this embodiment, microcatheter 10 includes a movable syringe 20 with a plunger 21 attached to the proximal end 22 of a flexible hollow shaft 25, the distal end of which forms a contoured end 30, and in one embodiment, the proximal end 22 may be attached to a smooth locking mount.

Shaft 25 defines a lumen therethrough, the typical use being to introduce one or more embryos into the uterus of a human. In one embodiment, shaft 25 is made of an extruded polymer plastic. Suitable polymers for shaft 25 are preferably polycarbonates (e.g., transparent polycarbonates). Tetrafluoroethylene (e.g. TEFLON)^TM) Materials are also well suited. The outer diameter of the proximal portion of the shaft 25 is on the order of 1 millimeter or less, and the shaft 25 includes a distal portion having a shaped end 30.

The contoured tip 30 of microcatheter 10 includes a base region 31 having a diameter similar to the diameter of flexible hollow shaft 25 (e.g., 1 mm or less than 1 mm), connected by a taper 32 that is 1 to 3 mm long, to a narrower distal end 33, preferably between 10 and 15 mm long, and having a typical outer diameter of 0.8 mm or less. In one embodiment, the inner diameter of distal end 33 is about 400 to 500 microns. Distal end 33 includes a curved portion 39 that is inclined at an angle α of between 5 and 45 degrees, preferably about an axis defined proximally relative to axis 25 of between 10 and 15 degrees (in this case inclined upwardly as shown). The microcatheter also includes a beveled tip (beveled opening) 34 that is beveled 10 to 45 degrees (angle γ), which in the illustrated embodiment is at the angle α described above. The angled tip 34 is a transport means for transporting embryos to a transfer site and may also be a microsurgical instrument for forming a transfer recipient within the endometrium, as shown in figures 12 to 15 and elsewhere herein. Beveled and tapered edges 35 may be provided to the beveled tip 34 to create a more precise cut.

Referring now to the drawings, one embodiment of a hysteroscope is shown in Figs. 4-6. Hysteroscope 100 is constructed in two parts, an operative portion 111 at one end and a hybrid insertion arm 112 at the other end. The operating section 111 is grasped by the operator during the performance of the intrauterine procedure and the section 112 of the hybrid insertion arm is inserted into the uterus of the human body. An eyepiece 113 supported at the operation portion 111 for observing the inside of the uterus, and a control knob 114 for controlling a control structure such as one or more twisted wires extending to the hybrid insertion arm 112 to actuate the hybrid insertion arm 112 (the actuation result is shown by a dotted line); and a series of ports 115 and 117 extending from the handle portion 111 through one or more lumens in the proximal portion 118 and the distal portion 119 forming the hybrid insertion arm 112. Hybrid insertion arm 112 is tubular in this embodiment and includes a proximal portion 118 of a rigid material and a distal portion 119 of a relatively flexible material (e.g., a polymeric material).

One or more lumens defined by ports 115 through 117 extend through proximal portion 118 and distal portion 119, terminating at distal end 130 of distal portion 119 by a guide surface. An operative channel or lumen 120 is located between the one or more lumens. Working channel 120 generally extends between distal end 130 and port 116. The diameter of the working channel 120 is suitable for insertion of a microcatheter for performing microsurgical procedures.

In one embodiment, the distal end 130 of the hybrid insertion arm 112 has a chamfer radius 132 (i.e., a radius) to facilitate gradual and smooth insertion into the uterus of a human. Instruments with a chamfer radius may produce less damage than blunt-ended instruments and generally enter smaller openings more easily than blunt-ended instruments. To further assist the operator in performing the insertion, a series of positioning marks may be provided on the exterior of hybrid insertion arm 112 to assist the operator in positioning the position of hybrid insertion arm 112 within the human uterus.

Prior hysteroscopes having fully flexible insertion portions are often difficult to control accurately in performing an intrauterine procedure. In the case of an intrauterine microsurgical procedure, the hybrid insertion arm 12, in one embodiment, has a rigid tubular proximal portion 118, preferably made of a smooth material such as stainless steel, seamlessly attached/bonded to a flexible tubular polymer (e.g., plastic) distal portion 119 so that it can be more easily manipulated within the uterus. A more stable platform may be provided for microsurgery and/or embryo transfer than a fully flexible hysteroscope insertion arm.

Hybrid insertion arm 112 with rigid proximal portion 118 and flexible distal portion 119 can be attached to different hysteroscopic instruments and is not limited to being attached to or supported by operative portion 111 as described in detail herein.

During the performance of intrauterine procedures, it is often desirable to insufflate the uterus. Referring to fig. 4, hysteroscope 100 is shown with gas port 115 leading to working port 116 and working channel 120. By utilizing working channel 116 in conjunction with the instrument and insufflation gas, the diameter of insertion arm 112 can be reduced while still providing the desired functionality of the hysteroscope.

Illumination within the uterus of the human body may be provided by an illumination train extending within lumen 135 of hysteroscope 100. In one embodiment shown in fig. 4-6, lumen 135 extends between operative portion 111 and hybrid insertion arm 112. The lumen 135 is accessible through the optical port 117 and the light source is preferably remotely connected to the optical port 117 so as not to interfere with the operation of the device by the operator. Typically, one or more illumination fibers 121 may extend proximally from port 117 a sufficient distance to connect to the proximal end of light source 145 so that light source 145 may remain stationary (e.g., on the top of a table) while hysteroscope 100 is moved. In one embodiment, one or more illumination fibers 121 may be inserted into the lumen 135 and terminate at the distal end 130. In one embodiment, the one or more illumination fibers 121 include ground glass at the distal end, the ground glass having a perpendicular cross-section that is obtuse as shown. The distal ends of the one or more illumination fibers 121 are preferably flush (coextensive) with the distal end. Thus, in embodiments where the distal end 130 has rounded corners, these rounded corners do not include the entire cross-section of the distal end 130. Referring to fig. 5 and 6, the guide surface 131 has an obtuse vertical shape (β is 90 °) as shown. In this embodiment, the operation channel 120 and the lumen 135 are provided in a section of the guide surface 131.

In addition to the illumination train, hysteroscope 100 also includes an imaging train. The imaging series includes a lumen 136 extending between the operative portion 111 and the hybrid insertion arm 112. At the operative portion end, eyepiece 113 is disposed in or connected to lumen 136. Alternatively, a camera may be coupled to lumen 136 to provide a photographic image of the uterus. At the hybrid insertion arm end, one or more lenses 37 are disposed in or connected to the lumen 136. In the embodiment shown in fig. 4-6, a lumen 136 including one or more lenses 137 is disposed within a cross-section of the guide surface 131. The optical fiber disposed in the lumen 136 may be positioned between a viewing device (e.g., eyepiece 113) and one or more lenses 137.

Fig. 7 shows a schematic cross-sectional view of another embodiment of a hysteroscope. In this embodiment, hysteroscope 200 includes an operative portion 211 at one end (proximal) and a hybrid insertion arm 212 at a second end (distal). Hybrid insertion arm 212 is generally tubular (with one or more lumens formed therein), and includes a proximal portion 218 of a rigid material, such as stainless steel, and a distal portion 219 of a relatively flexible material (e.g., a polymeric material, polycarbonate). Typically, proximal portion 218 has a length on the order of 8 to 19 centimeters and an outer diameter of about 3 to 4 millimeters. Distal portion 219 is typically 3 to 10 cm in length, and typically has an outer diameter of 2.5 to 4 mm, preferably 3 to 3.5 mm, with a preferred diameter (at least toward distal end 230) that is slightly smaller than proximal portion 218.

Referring to fig. 7, the operating portion 211 includes a grip portion 227 which is preferably knurled for better grip and feel. Attached to the distal end of the handle portion 227 is a lever handle 228. Disposed within the lever handle 228 is a hinge bar 229, which connects a wire member (e.g., a twisted wire member) to a distal end 229 thereof. Typically, deflection of the hinge rod 229 about the lever handle 228 may deflect the distal end portion 219 of the hybrid insertion arm 212 to the same extent. In one embodiment, the hinge bar 229 rotates 60 ° in both directions (i.e., clockwise and counterclockwise) about a single axis, with a full range of rotation of 120 °. The protruding stop 213 on the lever handle 228 may limit the articulation of the articulation rod 229.

FIG. 8 shows a cross-sectional view of the lever handle 228 taken along section A-A' of FIG. 7. In this embodiment, the control rod handle 228 includes a hinged rod 229 that is connected to a C-shaped wire fixation member 263 in the main lumen 225. As shown, two wire members 262, such as twisted wire members, are attached to wire mount 263 on opposite sides thereof (at the 12 o 'clock and 6 o' clock positions, respectively, as shown). The wire mount 263 is connected to the hinge bar 229 by a bar handle 266.

Referring again to fig. 7, proximal to the handle portion 227 of hysteroscope 200 is port 216. An operative channel or lumen 220 is accessible through the port 216. An operating channel 220 extends from operating portion 211 through the device to hybrid insertion arm 212, terminating in a distal tip 230. In this embodiment, port 216 is axially aligned with working channel 220. In one aspect, axial alignment may aid in the insertion of instruments, such as microcatheters, into working channel 220.

Also at the proximal end of handle portion 227 of hysteroscope 200 is an illumination train 240 that includes an illumination fixture 244. A plurality of illumination fibers (e.g., glass fibers) are disposed in illumination fixture 244 and are connected to working channel 220 in handle portion 227. As best shown in fig. 10 below, in one embodiment, working channel 220 and the plurality of illumination fibers are axially aligned and disposed in a main lumen extending from working portion 211 to hybrid insertion arm 212. The light post 242 is disposed at the distal end of the illumination fixture 244 and may itself be a light source connected to an illumination fiber or connected to a light source. For example, the light source 245 may be remotely located so as not to interfere with the use of the appliance by an operator. At the proximal end of the illumination fixture 244, the illumination fiber is surrounded by a tube or catheter that is attached to the handle portion 227.

Referring again to fig. 7, at the proximal end of handle portion 227 is an imaging series 255 including an eyepiece 256. Eyepiece 256 is connected to lumen 236 (see fig. 9 and 10) which is connected to working channel 220 in handle portion 227 and is axially aligned with the main lumen extending from working portion 211 to hybrid insertion arm 212.

The proximal end of working channel 220 is connected to a valve or plug 226 that seals or blocks working channel 220 in one position and allows inflation gas or instruments, such as microcatheters, to pass through working channel 220 in another position. In another embodiment, the plug 226 may have three positions, for example, to provide respective inlet ports for the appliance and inflation gas. In one embodiment, plug 226 is sterilizable, removable, and replaceable. In one embodiment, microcatheters and/or inflation gas may be alternately introduced to working channel 220 through inlet port 216. As shown in FIG. 4, in one embodiment, the proximal end of the handle 127 has a concave shape with the inlet port 216 on about the centerline of the end of the handle 127, the illumination series 240 and the imaging series being radially disposed in different directions relative to the axis.

Fig. 9 shows a schematic cross-sectional side view of the distal end of hybrid insertion arm 212. Fig. 10 shows a cross-sectional view of section B-B' of fig. 9. The figures show a main channel 225 extending through hybrid insertion arm 212 to a distal end 230. In one embodiment, the primary channel 225 is made of a polymeric material and has a diameter on the order of 1.3 millimeters. In this embodiment, working channel 220 and illumination lumen 236 are disposed in main channel 225. In a preferred embodiment, working channel 220 has an Inner Diameter (ID) of about 1.5 millimeters or less, preferably 1.3 millimeters. A plurality of illumination fibers 280 (each having a representative 0.12 millimeter diameter) are disposed in the main channel 225 forming a portion of the illumination train 240 extending to the illumination fixture 244, the light pillar 242, and the operative portion 211. In this embodiment, the illumination fiber 280 surrounds the operative channel and the imaging lumen 236. Also disposed in working channel 220 is an imaging lumen 236, which may form part of an imaging series 255, which in one embodiment is connected to an eyepiece 256 on working portion 211. An imaging fiber 257, such as a 10K imaging fiber available from Fujikura America, Marietta, Georgia, USA, may be disposed in the imaging lumen 236 and connected to the eyepiece 256. At the distal end of the imaging lumen 236 are one or more lenses 237, such as GRIN, ILH-5-WD15 lenses available from NSG America, Somerset, N.J..

Located outside the main channel 225, and preferably also within a separate lumen or catheter, is a coaxially disposed dumbbell 275 attached (e.g., by adhesive) to the distal end 230 of the mixing insertion arm 212. The wire member 262 is connected to the dumbbell 275 to provide hinged rotation of the distal end portion 219 of the hybrid insertion arm 212 via the hinge bar 229.

Referring to fig. 9, the distal end 230 of the hybrid insertion arm 12 has a rounded corner 232 and a blunt (e.g., perpendicular) guide surface 231. Thus, the guide surface 231 has a smaller diameter than the outer diameter of the distal end portion 219 of the hybrid insertion arm 212. It should be understood that edge 232 need not be rounded and may be a linear slope. The main channel 225 is disposed within the blunt guide surface 231 so that the illumination fiber 280 (see fig. 7) may terminate at the blunt edge of the guide surface 231. Rounded edge 232 facilitates insertion into the body.

Fig. 11 to 15 show the continuous operation of an embryo transfer procedure using the microcatheter 10 and hysteroscope 200. The organisms involved in embryo selection and optimization of the body undergoing transplantation, timing and biochemistry are not the subject of the present invention. It is clear to the skilled person how to harvest and fertilize eggs, and how to select for active embryos. When choosing the appropriate time to perform embryo transfer, a large body of scientific and technical literature on hormones, drugs, and other chemical factors should also be integrated, reviewed, and considered. Thus, these information are omitted.

Prior to any intrauterine procedure, the embryo must be placed inside the microcatheter 10. The microcatheter 10 will be used to prepare the site for implantation and to deliver the embryo E to that site. As shown in FIG. 11, the embryo E is immersed in the culture medium CM near the distal end 33 of the microcatheter 10. The culture medium CM plays an important role in maintaining the health and viability of the embryo E during the procedure. In this example, the culture medium CM used was "modified human oviduct fluid" manufactured by Irvine Scientific, Irvine, Calif. In view of the space for rapid growth of in vitro egg fertilization, new and different media will no doubt be developed or become a reality. Thus, the described methods should not be limited to the described media, but rather any suitable media that can function to maintain embryo viability during the transfer procedure can be used.

Prior to placing the embryo E in the catheter 10, a first volume of culture medium CM is placed in the microcatheter 10, followed by a post-placement volume of atmospheric air A2. Next, the embryo E immersed in the culture medium CM is drawn to the distal end 33 of the catheter 10, and then the pre-set amount of atmospheric air A is placed, sandwiching the embryo E between the first and second sets of atmospheric air A and A2. Once the embryo is placed in E, the microcatheter 10 is ready for the implantation procedure. The appropriate volume of each atmosphere of air is, for example, about 3 to 20 microliters.

A preferred implantation procedure is initiated, leading distal end 212 of hysteroscope 200 into uterus U (see fig. 12). During insertion of hysteroscope 200, nitrogen gas 101 is delivered into uterus U, pressurizing or distending uterus U, thus expanding uterine wall W. The gas 101 may be automatically maintained at a steady pressure or varied by the operator depending on the operator's needs and the human uterus. The expansion of the uterine wall W facilitates viewing of the interior of the uterus U using the hysteroscope 200.

Once the location I of the embryo transfer is selected, the distal end 30 of the microcatheter 10 is inserted into the endometrium L (see FIG. 13) and the beveled tip 34 is moved generally in the direction of arrow 300 to form a small incision 2 several millimeters deep in the endometrium L and a small flap F. Then, a proper amount of atmospheric air A in the microcatheter 30 is released, and the small skin F of the endometrium L is turned over.

FIG. 14 shows the embryo recipient P formed under the small skin piece F. The actual transfer of the embryo E into the embryo recipient P is performed by the same microcatheter 30 that forms the embryo recipient P and by depressing the plunger 21 of the syringe 20 (see FIG. 1), the embryo E and then a suitable amount of atmospheric air A2 can be smoothly removed from the microcatheter 30 and into the embryo recipient P.

The latter amount of atmospheric air A2 forms an air cushion around the embryo E, protecting the embryo as the microcatheter is moved (FIG. 15), returning the small skin piece F in the direction of arrow 201 to a position covering the embryo E. To accomplish this, the hysteroscope 200 is smoothly removed from the body and a late stage procedure and protocol for the fertilization of the in vitro ovum is performed. Another possible advantage of successfully transferring the embryo E in the endometrium L is that the time required for the late stage of fertilization of the in vitro ovum can be reduced.

Depending on the recipient, the number of viable embryos obtained and the aperture, a maximum of two embryos can be transplanted in a single recipient P. In the case of embryo transfer to multiple recipients, additional embryos immersed in culture medium are placed between the moderately atmospheric air in microcatheters, respectively transferred to separately formed recipients P.

Some preferred embodiments of the device and method for carrying out the invention have been described in detail herein, and some possible modifications and additions have been suggested. Other improvements, modifications, and additions not described herein can be made without departing from the principles of the present invention. For example, microcatheters (e.g., microcatheter 10) and hysteroscopes (e.g., hysteroscope 200) have been described with reference to in vitro egg fertilization procedures. It will be appreciated that the apparatus need not be limited in this manner and may be used for applications other than in vitro egg fertilization procedures. Typically, hysteroscopes may be used with other instruments, such as biopsy forceps, or for other procedures such as irrigation/aspiration.

Claims (5)

1. A microcatheter for endoscopic embryo transfer, comprising:

a flexible hollow shaft with a proximal end and a distal portion; it is characterized in that the preparation method is characterized in that,

a beveled tip at said distal end;

a curved portion having an outer diameter smaller than the outer diameter of the hollow shaft proximate the distal end portion; and

a bevel or a pyramidal cut formed around at least a portion of the periphery of the beveled tip.

2. The microcatheter of claim 1, wherein the curved portion of the hollow shaft is inclined at an angle of 5 to 45 degrees relative to an axis defined by the proximal end of the hollow shaft.

3. The microcatheter of claim 2, wherein the curved portion is inclined at an angle of 10 to 15 degrees relative to an axis defined by the proximal end of the hollow shaft.

4. The microcatheter of claim 1, wherein the curved portion further comprises a tapered region about 1.5 centimeters from the distal end where the diameter of the hollow shaft is reduced by about 20%.

5. The microcatheter of claim 1, wherein the hollow further comprises a tapered region about 1.5 centimeters from the distal end that reduces the diameter of the hollow shaft of about 1.0 millimeter to an angled tip diameter of about 0.8 millimeter.