Medical device introducer, method for manufacturing same, and method for sterilizing same

Abstract

Disclosed herein is an introducer for a medical device, comprising: an elongate tube comprising a first polymeric layer forming an outer surface of the introducer having an outer diameter d1 and a second polymeric layer forming an inner surface of the introducer and defining a lumen having a diameter d2, where the second layer is much more hydrophobic than the first layer; wherein the elongated tube has a length h wherein the ratio of l1 / d1 is greater than about 120 and the ratio of l1 / d2 is greater than about 200 to about 2,000; and wherein the introducer is configured to be sufficiently sterilized along substantially the entire l1 and substantially the entire d1 and d2.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 369,328, filed on July 25, 2022, the contents of which are incorporated by reference in their entirety. Technical Field

[0003] The present application relates to aspects of introducers for medical devices, methods of manufacturing the same, and methods of sterilizing the same. Background Art

[0004] The human heart may suffer from various valvular diseases. These valvular diseases may lead to significant dysfunction of the heart and ultimately require replacement of the natural valve with an artificial valve. There are many known artificial valves and many known methods of implanting these artificial valves in the human body.

[0005] When replacing a native valve, surgical implantation of a prosthetic valve typically requires an open-chest surgery during which the heart is stopped and the patient is placed on cardiopulmonary bypass (a so-called "heart-lung machine"). In one common surgical procedure, the diseased native valve leaflets are excised and the prosthetic valve is sutured to the surrounding tissue at the valve annulus. Due to the trauma associated with the surgery and the resulting duration of extracorporeal blood circulation, some patients do not survive the surgery or die shortly thereafter. It is well known that the risk to the patient increases with the amount of time required for extracorporeal circulation. Due to these risks, a large number of patients with defective native valves are considered inoperable because their condition is too frail to withstand the procedure. According to some estimates, more than 50% of subjects over the age of 80 who suffer from valvular stenosis are unable to undergo valve replacement surgery.

[0006] Due to the disadvantages associated with conventional open heart surgery, percutaneous and minimally invasive surgical approaches have received strong attention. In one technique, a prosthetic valve is configured to be implanted by catheterization in a much less invasive procedure. For example, U.S. Patent Nos. 5,411,522 and 6,730,118 (which are incorporated herein by reference) describe a collapsible transcatheter heart valve that can be introduced percutaneously in a compressed state on a catheter and expanded in a desired position by balloon inflation or by utilizing a self-expanding frame or stent.

[0007] In order to deliver the valve to the implantation site, a specially designed delivery system is adopted. One of the important parts of such a system is a medical device introducer. The introducer is configured to help deliver the prosthetic valve and remove the guidewire from the implantation site. In order to easily deliver the valve with minimal invasion, the introducer usually has a length of more than 30 inches. However, in order to prevent air embolism, it is necessary to keep the inner diameter of the introducer very small (less than about 0.05 inch) along the entire length of the device. However, such a high aspect ratio device is difficult to sterilize efficiently. In order to ensure the desired sterilization level, the current introducer is constructed to have an inner diameter of about 0.150 inch along most of the length of the introducer, and only has an inner diameter of less than about 0.05 inch in the far end of the device. However, such a structure is less desirable because air embolism still poses a substantial threat to patient health.

[0008] Therefore, there is a need for new introducers and methods of making the same, as well as methods of sterilizing the introducers, that substantially eliminate these problems and improve patient safety. The present disclosure at least partially satisfies these needs and other needs. Summary of the invention

[0009] Aspects of the present disclosure relate to prosthetic valves. Some aspects relate to an introducer for a medical device, comprising: an elongated tube comprising a first polymer layer forming an outer surface of the introducer having an outer diameter d1 and a second polymer layer forming an inner surface of the introducer and defining an inner cavity having a diameter d2. In some embodiments, the second layer is much more hydrophobic than the first layer. In some embodiments, the elongated tube has a length l1, and the ratio of l1 / d1 is greater than about 120, and the ratio of l1 / d2 is greater than about 200 to about 2,000. In still other embodiments, the introducer is configured to be fully sterilized along substantially the entire l1 and throughout substantially the entire d1 and d2.

[0010] Also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the second polymer layer comprises one or more of polypropylene, polyethylene, graft-modified polyethylene, or graft-modified polypropylene.

[0011] Also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the second polymer layer comprises one or more of low density polyethylene (LDPE), medium density polyethylene, ultra low density polyethylene (ULDPE), high density polyethylene (HDPE), heterogeneously branched linear low density polyethylene (LLDPE), grafted modified ethylene polymer, grafted modified polypropylene or ethylene vinyl acetate (EVA) or any combination thereof.

[0012] Also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the graft-modified polyethylene or graft-modified polypropylene is maleic anhydride graft-modified or acrylic acid graft-modified.

[0013] In some embodiments, there is also disclosed an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer comprises polyurethane, polyether block amide, polyethylene oxide, or any combination thereof.

[0014] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer is thermoplastic polyurethane.

[0015] In some embodiments, an introducer for a medical device of any aspect disclosed herein is also disclosed, wherein the first polymer layer is a composite comprising greater than 0 wt % to less than 100 wt % of a polyether-based thermoplastic polyurethane and about 5 wt % to about 50 wt % of polyethylene oxide.

[0016] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the polyurethane has a Shore D hardness of about 50D to about 75D.

[0017] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the polyurethane has a Shore A hardness of about 25A to about 95A.

[0018] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer is a polyether block amide.

[0019] In some embodiments, an introducer for a medical device of any aspect disclosed herein is also disclosed, wherein the first polymer layer is a composite comprising greater than 0 wt % to less than 100 wt % of a polyether block amide and about 5 wt % to about 50 wt % of polyethylene oxide.

[0020] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the polyether block amide has a Shore hardness of about 25D to about 72D.

[0021] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the polyethylene oxide (PEO) has a molecular weight of about 100,000 to about 7,000,000.

[0022] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer has a thickness of about 0.005 inches to about 0.150 inches.

[0023] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the second polymer layer has a thickness of about 0.005 inches to about 0.035 inches.

[0024] In some embodiments, an introducer for a medical device according to any aspect disclosed herein is also disclosed, comprising a third polymer layer located between the first polymer layer and the second polymer layer.

[0025] In some embodiments, there is also disclosed an introducer for a medical device of any aspect disclosed herein, wherein the third polymer layer is a tie layer and comprises graft-modified polyethylene or graft-modified polypropylene.

[0026] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the third polymer layer has a thickness of about 0.001 inches to about 0.025 inches.

[0027] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer and / or the second polymer layer comprises a filler.

[0028] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the third polymer layer comprises a filler.

[0029] In some embodiments, an introducer for a medical device of any aspect disclosed herein is also disclosed, wherein the filler comprises bismuth oxychloride, barium sulfate, bismuth subcarbonate, calcium carbonate, aluminum trihydrate, barite, kaolin, limestone, titanium oxide, or any combination thereof.

[0030] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer and the second polymer layer are co-extruded.

[0031] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer and / or the second polymer layer and / or the third layer are coextruded.

[0032] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer and / or the second polymer layer is at least partially cross-linked.

[0033] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the cross-linking is achieved by exposure to an energy source, wherein the energy source is selected from electron beam radiation, X-ray radiation, gamma radiation, or electromagnetic radiation.

[0034] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the cross-linking is achieved by exposure to an energy source at a dose of about 25 kGrey to about 100 kGrey.

[0035] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the first polymer layer and / or the second polymer layer is substantially cross-linked.

[0036] In some embodiments, there is also disclosed an introducer for a medical device of any aspect disclosed herein, wherein the inner diameter d2 is substantially the same along the entire length l1.

[0037] In some embodiments, there is also disclosed an introducer for a medical device of any aspect disclosed herein, wherein the introducer has a proximal portion and a distal portion.

[0038] In some embodiments, there is also disclosed an introducer for a medical device of any aspect disclosed herein, wherein the proximal portion is coupled with a hub or an adapter to connect the medical device.

[0039] In some embodiments, an introducer for a medical device of any aspect disclosed herein is also disclosed, wherein the distal portion is tapered such that the outer diameter d1 decreases toward the distal end of the introducer while the inner diameter d1 remains substantially the same along the entire length l1.

[0040] In some embodiments, an introducer for a medical device of any aspect disclosed herein is also disclosed, wherein the introducer is configured to receive a guidewire for deploying the medical device.

[0041] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the sterilization is ethylene oxide based.

[0042] In some embodiments, an introducer for a medical device of any aspect disclosed herein is also disclosed, wherein being sufficiently sterilized along substantially the entire l1 throughout substantially the entire d2 is defined by achieving effective inactivation of biological indicators to less than about 1 CFU in a short cycle.

[0043] In some embodiments, an introducer for a medical device of any aspect disclosed herein is also disclosed, wherein the sterility assurance level is about 10 -6 .

[0044] In some embodiments, there is also disclosed an introducer for a medical device of any aspect disclosed herein, wherein the outer surface of the introducer is substantially lubricious and exhibits a coefficient of friction (COF) of about 0.05 to about 0.5.

[0045] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the outer surface of the introducer does not include a hydrophilic coating.

[0046] In some embodiments, also disclosed is an introducer for a medical device of any aspect disclosed herein, wherein the introducer is configured to substantially not generate insoluble particulate material.

[0047] In some embodiments, a delivery system is disclosed, comprising: an introducer for a medical device of any of the examples herein, particularly examples 1-38; a delivery sheath; and a prosthetic valve.

[0048] In some embodiments, a method of manufacturing an introducer for a medical device of any of the examples herein, particularly Examples 1-38, is disclosed, comprising: forming an elongated tube comprising a first polymer layer forming an outer surface of the introducer having an outer diameter d1, and a second polymer layer; forming an inner surface of the introducer and defining an inner cavity having a diameter d2, wherein the second layer is much more hydrophobic than the first layer; wherein the elongated tube has a length l1, wherein the ratio of l1 / d1 is greater than about 120 and the ratio of l1 / d2 is greater than about 200 to about 2,000; and wherein the introducer is configured to be fully sterilized along substantially the entire l1 and throughout substantially the entire d1 and d2.

[0049] In some embodiments, a method of any aspect disclosed herein is disclosed, wherein the forming step comprises coextruding the first polymer layer and the second polymer layer.

[0050] In some embodiments, a method of any aspect disclosed herein is disclosed, wherein the elongated tube further comprises a third polymer layer located between the first polymer layer and the second polymer layer.

[0051] In some embodiments, a method of any aspect disclosed herein is disclosed, wherein the third polymer layer is coextruded with the first polymer layer and the second polymer layer.

[0052] In some embodiments, a method of delivering a prosthetic valve is disclosed, comprising: placing a guidewire; introducing the introducer of any of the examples herein, particularly examples 1-38, removing the guidewire; and placing the prosthetic valve in an implantation site.

[0053] In some embodiments, a method is disclosed comprising: exposing an introducer for a medical device of any of the examples herein, particularly examples 1-38, to ethylene oxide gas containing about 20% to about 70% humidity at a predetermined temperature for a predetermined time.

[0054] In some embodiments, there is disclosed a method of any aspect disclosed herein, wherein the exposing step comprises one or more cycles of exposure to ethylene oxide gas.

[0055] In some embodiments, the method of any aspect disclosed herein is disclosed, wherein the exposing step achieves effective inactivation of the biological indicator to less than about 1 CFU in a short period of time.

[0056] In some embodiments, a method of any aspect disclosed herein is disclosed, wherein the exposing step is performed for about 10 -6 Sterility assurance level.

[0057] In some embodiments, the method of any aspect disclosed herein is disclosed, wherein the first polymer layer, the second polymer layer, and the third polymer layer exhibit substantially no degradation after the exposing step.

[0058] The above methods may be performed on a patient or a living animal, or on a simulator, such as a cadaver, a cadaver heart, an anthropomorphic artifact, or a phantom (eg, having simulated body parts, hearts, tissues, etc.).

[0059] “Any of the various systems, devices, apparatuses, etc. of the present disclosure may be sterilized (e.g., using heat, radiation, ethylene oxide, hydrogen peroxide, etc.) to ensure that they are safe for use with patients, and the methods herein may include sterilizing (e.g., using heat, radiation, ethylene oxide, hydrogen peroxide, etc.) the associated systems, devices, apparatuses, etc..”

[0060] The foregoing and other features and advantages of the present disclosure will become more apparent from the following detailed description made with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1A-1B A schematic diagram of an exemplary introducer in one aspect is shown. Figure 1A A schematic diagram of the entire introducer is shown. Figure 1B A schematic diagram of a tapered portion of an introducer in one aspect is shown.

[0062] Figure 2 A schematic diagram of the various layers of an introducer in one aspect is shown.

[0063] Figure 3 A schematic diagram showing the various layers of an introducer in one aspect of the various aspects.

[0064] Figure 4A-4B An exemplary introducer and delivery system is shown. Figure 4A The introduction of the introducer into the delivery sheath is shown. Figure 4B A general representation of a delivery system with an introducer is shown.

[0065] Figure 5 A schematic diagram is shown of one of the steps of an implantation procedure in one aspect. DETAILED DESCRIPTION

[0066] The present disclosure may be more readily understood by reference to the following detailed description, examples, drawings, and claims, as well as the descriptions preceding and following them. However, before disclosing and describing the articles, systems, and / or methods of the present disclosure, it should be understood that, unless otherwise stated, the present disclosure is not limited to the specific or exemplary aspects of the disclosed articles, systems, and / or methods, and thus may certainly vary. It should also be understood that the terms used herein are only for the purpose of describing specific aspects and are not intended to be limiting.

[0067] Those skilled in the relevant art will recognize and appreciate that many changes can be made to the various aspects of the disclosure described herein while still obtaining the beneficial results of the disclosure. It is also apparent that some desired benefits of the disclosure can be obtained by selecting some features of the disclosure without utilizing other features. Therefore, those of ordinary skill in the relevant art will recognize that many modifications and changes to the disclosure are possible, and may even be desirable in some cases, and are a part of the disclosure. Therefore, the following description is again provided as an illustration of the principles of the disclosure, rather than a limitation thereof.

[0068] definition

[0069] As used in this application and in the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an introducer" includes aspects having two or more such introducers unless the context clearly dictates otherwise.

[0070] It should also be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. As used in the specification and claims, the term "comprising" may include aspects of "consisting of" and "consisting essentially of." In addition, the term "include" means "comprise."

[0071] With respect to the terms "for example" and "such as" and their grammatical equivalents, the phrase "and not limited to" should be understood to follow unless expressly stated otherwise. It should also be understood that these phrases are used for explanation purposes only. It should also be understood that, as used herein, the term "exemplary" means "an example of..." and is not intended to convey an indication of a preferred or ideal aspect.

[0072] The term "or" means "and / or". Unless otherwise indicated herein, recitation of ranges of values ​​is intended merely to serve as a shorthand method of individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included in the ranges and are independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0073] Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When expressing such ranges, some embodiments include from a particular value and / or to another particular value. Similarly, when numerical values ​​are expressed as approximations by using the antecedent "about," it will be understood that the particular values ​​constitute another aspect. It will also be understood that the endpoints of each range are important both relative to the other endpoint and independently of the other endpoint.

[0074] Unless otherwise indicated herein, recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value recited or falling within the range, and each individual value is incorporated into the specification as if it were individually recited. Ranges provided herein should be understood as shorthand for all values ​​within the range. 45, 46, 47, 48, 49, or 50, or a sub-range from the group consisting of 10-40, 20-50, 5-35, etc. Similarly, numerical ranges recited herein by endpoints include sub-ranges contained within that range (eg, 1 to 5 includes 1-1.5, 1.5-2, 2-2.75, 2.75-3, 3-3.90, 3.90-4, 4-4.24, 4.24-5, 2-5, 3-5, 1-4, and 2-4).

[0075] Additionally, the terms “coupled” and “associated” generally mean electrical, electromagnetic, and / or physical (eg, mechanically or chemically) connections or links, and do not exclude the presence of intervening elements between the coupled or associated items.

[0076] As used herein, the term or phrase "effective", "effective amount" or "conditions effective for" refers to such an amount or condition that is capable of achieving the function or property represented by the effective amount or condition. As will be noted below, the exact amount or specific conditions required will vary from aspect to aspect, depending on recognized variables such as the materials used and the processing conditions observed. Therefore, it is not always possible to specify an exact "effective amount" or "conditions effective for". However, it should be understood that a person of ordinary skill in the art can readily determine a suitable effective amount using only routine experimentation.

[0077] As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs, or that the subsequently described event or circumstance will generally, usually, or approximately occur.

[0078] Still further, in some aspects, the term "substantially" can refer to at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of a stated property, component, composition, or other condition used to characterize or otherwise quantify an amount.

[0079] In some embodiments, as used herein, the term "substantially free," when used in the context of a composition or a substantially absent component of a composition, is intended to refer to an amount of about 1 wt %, e.g., less than about 0.5 wt %, less than about 0.1 wt %, less than about 0.05 wt %, or less than about 0.01 wt %, of the recited material based on the total weight of the composition.

[0080] Although aspects of the present disclosure may be described and claimed in specific statutory categories (such as the system statutory category), this is for convenience only, and one of ordinary skill in the art will understand that each aspect of the present disclosure may be described and claimed in any statutory category. Unless otherwise expressly stated, it is by no means intended that any method or aspect set forth herein be interpreted as requiring that its steps be performed in a particular order. Therefore, in the absence of a method claim specifically stating in the claim or description that the steps are restricted to a particular order, it is by no means intended that an order be inferred in any respect. This applies to any possible non-explicit basis for interpretation, including logical matters regarding the arrangement of steps or operational flows, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0081] Although the operations of the exemplary aspects of the disclosed methods may be described in a particular sequential order for ease of presentation, it should be understood that the disclosed aspects may encompass orders of operations other than the disclosed particular sequential order. For example, the operations described in sequence may be rearranged or performed simultaneously in some cases. In addition, the description and disclosure provided in conjunction with a particular aspect are not limited to that aspect and may apply to any aspect of the disclosure.

[0082] In addition, for simplicity, the accompanying drawings may not show the various ways in which the disclosed systems, methods, and devices can be used in conjunction with other systems, methods, and devices (based on this disclosure, it is easy for a person of ordinary skill in the art to discern). In addition, this specification sometimes uses terms such as "produce" and "provide" to describe the disclosed methods. These terms are high-level abstractions of actual operations that can be performed. The actual operations corresponding to these terms can vary depending on the specific implementation, and based on this disclosure, it is easy for a person of ordinary skill in the art to discern.

[0083] The therapeutic techniques, methods, steps, etc. described or suggested herein or in references incorporated herein may be performed on patients, living animals, or on non-living simulators, such as cadavers, cadaver hearts, anthropomorphic artifacts, simulated bodies (e.g., having simulated body parts, tissues, etc.), and the like.

[0084] Any of the various systems, devices, equipment, etc. in the present disclosure may be sterilized (e.g., using heat, radiation, ethylene oxide, hydrogen peroxide, etc.) to ensure that they are safe for use with patients, and the methods herein may include sterilizing (e.g., using heat, radiation, ethylene oxide, hydrogen peroxide, etc.) the associated systems, devices, equipment, etc.

[0085] The present disclosure may be understood more readily by reference to the following detailed description of various aspects of the invention and the examples included therein, and by reference to the drawings and their preceding and following descriptions.

[0086] Introducer

[0087] In one aspect, an introducer for a medical device is disclosed herein. The medical device may include an elongated tube with a length l1. The tube may include a first polymer layer forming the outer surface of the introducer with an outer diameter d1 and a second polymer layer forming the inner surface of the introducer and defining an inner cavity with a diameter d2. In some aspects, the second layer is far more hydrophobic than the first layer. In some aspects, the length l1 can be any value between about 30 inches and about 50 inches, including about 31 inches, about 32 inches, about 33 inches, about 34 inches, about 35 inches, about 36 inches, about 37 inches, about 38 inches, about 39 inches, about 40 inches, about 41 inches, about 42 inches, about 43 inches, about 44 inches, about 45 inches, about 46 inches, about 47 inches, about 48 inches and about 49 inches. It should be understood that the introducer disclosed herein may also be longer than 50 inches.

[0088] In some embodiments, the inner diameter d1 can be about 0.150 inches to about 0.5 inches, including exemplary values ​​of about 0.155 inches, about 0.200 inches, about 0.225 inches, about 250 inches, about 0.275 inches, about 0.300 inches, about 0.325 inches, about 0.350 inches, about 0.375 inches, about 0.400 inches, about 0.425 inches, about 0.450 inches, and about 0.475 inches.

[0089] In some embodiments, d2 can be from about 0.01 inch to about 0.07 inch, including exemplary values ​​of about 0.0125 inch, about 0.015 inch, about 0.0175 inch, about 0.020 inch, about 0.0225 inch, about 0.0250 inch, about 0.0275 inch, about 0.030 inch, about 0.0325 inch, about 0.0350 inch, about 0.0375 inch, about 0.040 inch, about 0.0425 inch, about 0.0450 inch, about 0.0475 inch, about 0.05 inch, about 0.0525 inch, about 0.0550 inch, about 0.0575 inch, about 0.06 inch, about 0.0625 inch, about 0.0650 inch, and about 0.0675 inch.

[0090] In some embodiments, the ratio between l1 and d1 (l1 / d1) is greater than about 120, greater than about 130, greater than about 140, greater than about 150, greater than about 160, greater than about 170, greater than about 180, greater than about 190, greater than about 200, greater than about 210, greater than about 220, greater than about 230, greater than about 240, greater than about 250, greater than about 260, greater than about 270, greater than about 280, greater than about 290, 0, greater than about 300, greater than about 310, greater than about 320, greater than about 330, greater than about 340, greater than about 350, greater than about 360, greater than about 370, greater than about 380, greater than about 390, greater than about 400, greater than about 410, greater than about 420, greater than about 430, greater than about 440, greater than about 450, greater than about 460, greater than about 470, greater than about 480, greater than about 490, or even greater than about 500. In some embodiments, the ratio between l1 and d1 (l1 / d1) can be about 100 to about 500, including exemplary values ​​of about 120, about 150, about 180, about 200, about 220, about 250, about 280, about 300, about 320, about 350, about 380, about 300, about 320, about 350, about 380, about 400, about 420, about 450, and about 480.

[0091] In some embodiments, the ratio of l1 / d2 is greater than about 200 to about 2,000, including exemplary values ​​of about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 800, about 900, about 1,000, about 1,100, about 1,200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, and about 1,900.

[0092] One of the problems in the medical field is the ability to efficiently sterilize high aspect ratio devices. Typically, medical devices are sterilized using ethylene oxide gas. Most medical devices are hygroscopic and will quickly absorb moisture from the ethylene oxide gas mixture during the sterilization procedure. Therefore, sterilization becomes inefficient. More specifically, efficient killing of microorganisms in a very narrow lumen over a large length of the device becomes problematic. Therefore, sterilization is uneven and is unsatisfactory for surgical procedures as it may pose a risk to the patient's health during surgery.

[0093] For longer devices, one approach is to increase the inner diameter to the highest acceptable value and only have a narrow inner diameter on shorter portions of the device as needed, such as a narrow inner diameter on the distal end of the device or the proximal end of the device. However, this approach is not preferred. For example, undesirable side effects such as air embolism may still occur in devices with larger diameters.

[0094] The introducers disclosed herein overcome challenges in the sterilization process and are configured to be fully sterilized along substantially all of l1 and throughout substantially all of d1 and d2.

[0095] Figure 1A An exemplary introducer 100 for a medical device is shown in FIG. The introducer has any of the above disclosed l1, outer diameter d1, and inner diameter d2. In some embodiments, the inner diameter d2 may be substantially the same along the entire l1. However, in some embodiments, depending on the specific application, the inner diameter d2 may vary along the length l1. However, it should be understood that the overall value of d2 falls within the above-disclosed range.

[0096] In some embodiments, the outer diameter d1 of the introducer can be substantially the same throughout the length l1, while in some embodiments, the diameter d1 can vary depending on the specific application. Figure 1B As shown in , at least a portion of the disclosed introducer can be tapered.

[0097] It should be understood that the introducer disclosed herein has a proximal portion and a distal portion. In some respects, the distal portion of the introducer can be tapered at length 12. Such a tapered portion can allow the introducer to be used more atraumatically during surgery. In some respects, extending from the distal end of the introducer toward the proximal end of the introducer, 12 can be about 0.1 inch to about 3 inches, including about 0.2 inches, about 0.5 inches, about 0.8 inches, about 1.0 inches, about 1.2 inches, about 1.5 inches, about 1.8 inches, about 2.0 inches, about 2.2 inches, about 2.5 inches and about 2.8 inches of exemplary values. In such respects, the outer diameter d3 at the distal end of the tapered portion is fully less than d1. However, in some embodiments, the outer diameter d3 at the distal end of the tapered portion is only slightly larger than d2. For example, d3 can be about 0.05 inches to about 0.3 inches, including exemplary values ​​of about 0.055 inches, about 0.065 inches, about 0.07 inches, about 0.075 inches, about 0.080 inches, about 0.085 inches, about 0.090 inches, about 0.095 inches, about 0.10 inches, about 0.15 inches, about 0.20 inches, and about 0.25 inches.

[0098] In some embodiments, the distal portion is tapered such that the outer diameter d1 decreases toward the distal end of the introducer while the inner diameter d1 remains substantially the same along the entire length l1.

[0099] In some embodiments, the introducer 200 disclosed herein may include at least two layers, such as Figure 2 As shown in FIG. 2 , a first polymer layer 204 forms an outer surface 202 of the introducer and a second polymer layer 208 forms an inner lumen 206 (also defining an inner surface of the introducer).

[0100] It should be understood that in aspects disclosed herein, the second polymer layer is more hydrophobic than the first polymer layer. Such a configuration allows ethylene oxide gas to penetrate and sterilize the lumen of the introducer without being immediately absorbed by the polymer layer.

[0101] In some aspects, the second polymer layer may include one or more polypropylene, polyethylene, graft-modified polyethylene, or graft-modified polypropylene. However, in some embodiments, the second polymer layer may include one or more of low-density polyethylene (LDPE), medium-density polyethylene, ultra-low-density polyethylene (ULDPE), high-density polyethylene (HDPE), heterogeneously branched linear low-density polyethylene (LLDPE), graft-modified ethylene polymers, graft-modified polypropylene, or ethylene-vinyl acetate (EVA), or any combination thereof. In some embodiments, the second polymer layer may include LLDPE. However, in some embodiments, the second polymer layer may include HDPE or LDPE.

[0102] In some embodiments, the graft modified polyethylene or graft modified polypropylene is maleic anhydride graft modified or acrylic acid graft modified. For example, graft modified polyolefins sold under the trade name Orevac can be used. It should also be understood that the second polymer layer can include a copolymer of any of the polymers disclosed above. However, in some embodiments, the second polymer can be compounded by two or more polymers selected from any of the polymers disclosed above.

[0103] In some embodiments, the second polymer layer 208 can have a thickness of about 0.005 inches to about 0.035 inches, including exemplary values ​​of about 0.006 inches, about 0.007 inches, about 0.008 inches, about 0.009 inches, about 0.01 inches, about 0.012 inches, about 0.015 inches, about 0.017 inches, about 0.02 inches, about 0.022 inches, about 0.025 inches, about 0.027 inches, about 0.030 inches, and about 0.032 inches.

[0104] In some embodiments, the first polymer layer may include polyurethane, polyether block amide, polyethylene oxide, or any combination thereof. In some aspects, the first polymer layer may be a thermoplastic polyurethane. But in some embodiments, the first polymer layer may be a composite material comprising polyurethane and polyether block amide. In some embodiments, the first polymer layer may be a composite material comprising polyurethane and polyethylene oxide. In still other embodiments, the first polymer layer may be a composite material comprising polyether block amide and polyethylene oxide. In still other embodiments, the first polymer layer may be a composite material comprising polyurethane, polyether block amide, and polyethylene oxide.

[0105] However, in some embodiments, the first polymer layer may be a composite including greater than 0 wt % to less than 100 wt % of a polyether-based thermoplastic polyurethane and about 5 wt % to about 50 wt % of polyethylene oxide.

[0106] In such aspects, the thermoplastic material based on polyether can be present in an amount greater than 0 wt % to less than 100 wt %, including about 1 wt %, about 5 wt %, about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt %, about 50 wt %, about 55 wt %, about 60 wt %, about 65 wt %, about 70 wt %, about 75 wt %, about 80 wt %, about 85 wt %, about 90 wt % and about 95 wt % exemplary values. Thermoplastic polyurethane based on polyether can be present in any amount between any two aforementioned values. In some embodiments, thermoplastic polyurethane based on polyether can be based on aromatic polyether or aliphatic polyether. In some aspects, the thermoplastic polyurethane based on polyether used in the present disclosure can be a thermoplastic polyurethane with trade name Tecothane TM or TecoFkex TM Thermoplastic polyurethane for sale.

[0107] In some embodiments, the polyurethanes disclosed herein may include or

[0108] In some embodiments, the polyethylene oxide can be present in an amount of about 5% to about 80% by weight, including exemplary values ​​of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%. The polyethylene oxide can be present in any amount between any two of the aforementioned values.

[0109] In some embodiments, the polyurethanes disclosed herein may have a Shore D hardness of about 50D to about 75D, including exemplary values ​​of about 55D, about 60D, or about 70D. In some embodiments, the polyurethanes disclosed herein may have a Shore A hardness of about 25A to about 95A, including exemplary values ​​of about 30A, about 35A, about 40A, about 45A, about 50A, about 55A, about 60A, about 65A, about 70A, about 75A, about 80A, about 85A, and about 90A.

[0110] However, in some embodiments, the first polymer layer is a polyether block amide. In some aspects, the polyether block amide can be PEBAX. In still other embodiments, other polyamides such as and

[0111] In some embodiments, the first polymer layer may be a composite including greater than 0 wt % to less than 100 wt % of a polyether block amide and about 5 wt % to about 50 wt % of polyethylene oxide.

[0112] In such exemplary aspects, the polyether block amide can be present and in an amount greater than 0 wt % to less than 100 wt %, including exemplary values ​​of about 1 wt %, about 5 wt %, about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt %, about 50 wt %, about 55 wt %, about 60 wt %, about 65 wt %, about 70 wt %, about 75 wt %, about 80 wt %, about 85 wt %, about 90 wt %, and about 95 wt %. The polyether block amide can be present in any amount between any two of the foregoing values.

[0113] In some embodiments, the polyethylene oxide can be present in an amount of about 5% to about 80% by weight, including exemplary values ​​of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%. The polyethylene oxide can be present in any amount between any two of the aforementioned values.

[0114] In some embodiments, the polyether block amide has a Shore hardness of about 25D to about 72D, including exemplary values ​​of about 30D, about 35D, about 40D, about 45D, about 50D, about 55D, about 60D, about 65D, and about 70D.

[0115] In some embodiments, the polyethylene oxide (PEO) that can be used in the first polymer layer disclosed herein can have a molecular weight of about 100,000 Daltons to about 7,000,000 Daltons, including about 200,000 Daltons, about 300,000 Daltons, about 400,000 Daltons, about 500,000 Daltons, about 600,000 Daltons, about 700,000 Daltons, about 800,000 Daltons, about 900,000 Daltons, about 1,000,000 Daltons, about 1,250,000 Daltons, about 1,500,000 Daltons, about 1,750,000 Daltons, about 2,000,000 Daltons, about 2,250,000 Daltons, about 3,400,000 Daltons, about 5,600,000 Daltons, about 6,700,000 Daltons, about 700,000 Daltons, about 800,000 Daltons, about 900,000 Daltons, about 1 Exemplary values ​​include about 5,000,000 Daltons, about 5,250,000 Daltons, about 5,500,000 Daltons, about 5,750,000 Daltons, about 6,000,000 Daltons, about 6,250,000 Daltons, about 6,500,000 Daltons, and about 6,750,000 Daltons.

[0116] In some embodiments, the first polymer layer has a thickness of about 0.005 inches to about 0.150 inches, including exemplary values ​​of about 0.0075 inches, about 0.01 inches, about 0.05 inches, about 0.075 inches, about 0.100 inches, about 0.105 inches, about 0.110 inches, about 0.115 inches, about 0.120 inches, about 0.125 inches, about 0.130 inches, about 0.135 inches, about 0.140 inches, and about 0.145 inches.

[0117] In some embodiments, the introducer 300 may include a first polymer layer 302 disclosed herein, a second polymer layer 306 disclosed herein, and an optional third polymer layer 304, such as Figure 3In such aspects, the third polymer layer 304 can be disposed between the first polymer layer 302 and the second polymer layer 306. In some embodiments, the third layer can be used as a tie layer, which can bond the first polymer layer and the second polymer layer together. In certain aspects, the third polymer layer can include any polymer disclosed herein, or it can include any polymer configured to be used as a tie layer. In some embodiments, the third polymer layer can include grafted modified polyethylene or grafted modified polypropylene. In some embodiments, the third polymer layer can include

[0118] In aspects where a third polymer layer is present, the polymer layer can have a thickness of about 0.001 inch to about 0.025 inch, including about 0.0015 inch, about 0.002 inch, about 0.0025 inch, about 0.003 inch, about 0.0035 inch, about 0.004 inch, about 0.0045 inch, about 0.005 inch, about 0.0055 inch, about 0.006 inch, about 0.0065 inch, about 0.007 inch, about 0.0075 inch, about 0.0085 inch, about 0.010 inch, about 0.0115 inch, about 0.0125 inch, about 0.0135 inch, about 0.0145 inch, about 0.015 inch, about 0.0165 inch, about 0.0175 inch, about 0.0185 inch, about 0.0195 inch, about 0.0200 inch, about 0.0215 inch, about 0.0235 inch, about 0.0240 inch, about 0.0250 inch, about 0.0260 inch, about 0.0275 inch, about 0.0280 inch, about 0.0290 inch, about 0.0315 inch, about 0.0335 inch, about 0.0345 inch, about 0.0350 inch, about 0.0360 inch, about 0.0375 inch, about 0.0385 inch, about 0.0390 inch, about 0.0415 inch, about 0.0435 inch, about 0.044 Exemplary values ​​include about 0.008 inches, about 0.0085 inches, about 0.009 inches, about 0.0095 inches, about 0.01 inches, about 0.011 inches, about 0.012 inches, about 0.013 inches, about 0.014 inches, about 0.015 inches, about 0.016 inches, about 0.017 inches, about 0.018 inches, about 0.019 inches, about 0.02 inches, about 0.021 inches, about 0.022 inches, about 0.023 inches, and about 0.024 inches.

[0119] In some embodiments, the first polymer layer and / or the second polymer layer may contain fillers. However, in some embodiments, if a third polymer layer is present, it may also contain fillers. However, in some embodiments, if a third polymer layer is present, the layer is substantially free of fillers.

[0120] It should be understood that the filler, if present in the first polymer layer and / or the second polymer layer and / or the third polymer layer, can be the same or different. In some embodiments, the filler can include bismuth oxychloride, barium sulfate, bismuth subcarbonate, calcium carbonate, aluminum trihydrate, barite, kaolin, limestone, titanium oxide, or any combination thereof. In some embodiments, the filler can include a radiopaque material.

[0121] In some embodiments, the first layer and the second layer (and the third layer, if present) can be formed by any method known in the art. For example, each layer can be extruded separately and then assembled together. However, in some embodiments, the first polymer layer and the second polymer layer can be coextruded. In some embodiments, if there is a third polymer layer, it can be coextruded with the first polymer layer and the second polymer layer. In some other embodiments, if there is a third polymer layer, it can be coextruded with the first polymer layer and then assembled with the second polymer layer extruded separately. However, in some embodiments, if there is a third polymer layer, it can be coextruded with the second polymer layer and then assembled with the first polymer layer extruded separately. It should be understood that these aspects are exemplary, and any method disclosed above can be used to form the introducer.

[0122] In some other embodiments, each or all of the polymer layers present in the introducer can be at least partially cross-linked. For example, a first polymer layer comprising any of the polymers disclosed above or a composite can be at least partially cross-linked. Similarly, a second polymer layer (and / or even a third polymer layer) comprising any of the polymers disclosed above or a composite can be at least partially cross-linked. In some embodiments, the first polymer layer can be fully cross-linked. In some embodiments, the second polymer layer (and / or the third polymer layer) can be fully cross-linked.

[0123] In some embodiments, crosslinking can be achieved by exposing any or all of the layers to an energy source, wherein the energy source can be selected from electron beam radiation, X-ray radiation, gamma radiation, or electromagnetic radiation. In some aspects, crosslinking is achieved by exposure to an energy source at a dose of about 25 kGrey to about 100 kGrey, including exemplary values ​​of about 30 kGrey, about 35 kGrey, about 40 kGrey, about 45 kGrey, about 50 kGrey, about 55 kGrey, about 60 kGrey, about 65 kGrey, about 70 kGrey, about 75 kGrey, about 80 kGrey, about 85 kGrey, about 90 kGrey, and about 95 kGrey.

[0124] In some embodiments where a compound comprising polyurethane and PEO or a compound comprising polyether block amide and PEO is used to form the outer surface of an introducer, the introducer outer surface is fully lubricated and wherein exhibits a coefficient of friction (COF) of about 0.05 to about 0.5, including exemplary values ​​of about 0.075, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4 and 0.45. It should be understood that the coefficient of friction can be measured by any method known in the art. In some exemplary and non-limiting aspects, COF can be measured relative to a silicone pad. In such exemplary and non-limiting aspects, the COF of the disclosed compound remains lower than other polymers that are commonly used to form the outer surface of an introducer. In some embodiments, COF remains lower and is substantially unchanged in at least 10 friction test cycles.

[0125] In some embodiments where a composite comprising polyurethane and PEO or a composite comprising polyether block amide and PEO is used to form the outer surface of the introducer, the outer surface of the introducer exhibits lubricating properties. It should be understood that in such exemplary and non-limiting aspects, due to the lubricating properties of the outer surface, it is not necessary to apply an additional hydrophilic coating to the surface. In such aspects, the outer surface of the introducer does not include a hydrophilic coating.

[0126] In some embodiments where a composite comprising polyurethane and PEO or a composite comprising polyether block amide and PEO is used to form the outer surface of the introducer, such an introducer generates substantially no insoluble particulate material that can be released into the patient's body. This characteristic of the introducer disclosed herein is particularly beneficial because it further minimizes potential side effects, such as the release of nanoparticles into the patient's body, which may accumulate in the patient's organs and affect recovery and life span.

[0127] In some embodiments, the introducer 100 ( Figure 1A ) is connected to the hub 150 or adapter to connect with the medical device. However, as disclosed herein and as Figure 5 The introducer 502 shown in FIG. 5 may be configured to receive a guidewire 508 for deploying a medical device (not shown).

[0128] In some embodiments, the sterilization process can be any sterilization process known in the art that can provide a desired sterilization level for medical devices. In some respects, the sterilization procedure is based on ethylene oxide. Ethylene oxide (also referred to as EO or EtO) is a low-temperature gaseous method widely used in sterilizing various medical devices. Ethylene oxide sterilization is based on vacuum. As is well known, EO sterilization can efficiently penetrate the surface of most medical devices, and its lower temperature makes it an ideal method for a wide range of materials. Ethylene oxide sterilization can be controlled by controlling gas concentration, humidity, temperature and time. Typically, the humidity of the ethylene oxide gas used in sterilization is up to about 70%, including exemplary values ​​of about 10%, about 20%, about 30%, about 40%, about 50% and about 60%.

[0129] Ethylene oxide is an alkylating agent. It can disrupt the cellular metabolism and reproduction processes of microorganisms, resulting in the elimination of viable microorganisms from the device. Ethylene oxide can penetrate gas permeable packaging and various parts of the device, allowing contact with all accessible surfaces of the product to deliver the required sterility assurance level (SAL).

[0130] The introducers disclosed herein are designed to allow ethylene oxide gas or other sterilizing fluids (e.g., gaseous fluids) to travel and permeate through the narrow inner diameter of the introducer, while the introducer surface has no substantial absorption, little absorption or no absorption of ethylene oxide. For example, the presence of a hydrophobic second polymer layer allows ethylene oxide to travel through the lumen without being substantially absorbed into the second polymer layer.

[0131] The effect of sterilization can be evaluated by the validation process to ensure the sterility assurance level. Validation is carried out by placing a biological indicator (BI) in the introducer position where the sterilization condition is most difficult to achieve. In some exemplary and non-limiting aspects, the biological indicator can be placed in different positions in the narrow lumen to ensure that all lumens along the entire length of the introducer are sterilized to the desired level. Any biological indicator known in the art can be used. For example, and without limitation, the biological indicator can include Bacillus or Bacillus species.

[0132] In some embodiments, the introducers disclosed herein are configured to be sufficiently sterilized along substantially the entire l1 throughout substantially the entire d1 and d2, wherein being sufficiently sterilized is defined by achieving effective inactivation of biological indicators in a short cycle to less than about 1 CFU, less than about 0.9 CFU, less than about 0.8 CFU, less than about 0.7 CFU, less than about 0.6 CFU, less than about 0.5 CFU, less than about 0.4 CFU, less than about 0.3 CFU, less than about 0.2 CFU, less than about 0.1 CFU, less than about 0.09 CFU, less than about 0.08 CFU, less than about 0.07 CFU, less than about 0.06 CFU, less than about 0.05 CFU, less than about 0.04 CFU, less than about 0.03 CFU, less than about 0.02 CFU or less than about 0.01 CFU.

[0133] In some embodiments, the introducers disclosed herein can be sterilized in ethylene oxide to achieve about 10 -6 Sterility assurance level.

[0134] Also disclosed herein is a delivery system comprising: any introducer for a medical device disclosed herein; a delivery sheath; and a prosthetic valve. Figure 4A Insertion of an exemplary introducer 402 into a delivery sheath 404 is shown. Figure 4B The introducer 402 is shown fully inserted into a delivery sheath 404 such that the tapered portion of the introducer extends beyond the distal end of the delivery sheath.

[0135] It should be understood that any delivery sheath known in the art can be used. Some exemplary and non-limiting examples of delivery sheaths can be found in U.S. Patent No. 9,987,134, U.S. Patent No. 10,792,150, U.S. Patent No. 10,524,905, U.S. Patent No. 10,517,720, U.S. Patent No. 10,254,906, U.S. Patent No. 10,254,907, U.S. Patent No. 11,045,317, U.S. Patent No. 11,273,062, International Patent Application Publication No. PCT / US2021 / 019514, International Patent Application Publication No. PCT / US2021 / 050006, or Provisional Application Nos. 63 / 230,631 and 63 / 324,436, the contents of which are incorporated herein by reference in their entirety.

[0136] In yet other embodiments, the prosthetic valve can be a mitral valve.

[0137] method

[0138] Aspects of the present disclosure also relate to a method for manufacturing an introducer for a medical device disclosed herein, wherein the method includes: forming a slender tube, the slender tube including a first polymer layer forming an outer surface of the introducer having an outer diameter d1, and a second polymer layer; forming an inner surface of the introducer and defining an inner cavity having a diameter d2, wherein the second layer is much more hydrophobic than the first layer; wherein the slender tube has a length l1, wherein the ratio of l1 / d1 is greater than about 120 and the ratio of l1 / d2 is greater than about 200 to about 2,000; and wherein the introducer is configured to be fully sterilized along substantially the entire l1 and throughout substantially the entire d1 and d2.

[0139] In aspects disclosed herein, the first polymer layer can include any of the polymers disclosed above. Also in some embodiments, the second polymer layer can include any of the polymers disclosed above.

[0140] It should be understood that any method of forming an elongated tube known in the art can be adopted. In some aspects, the elongated tube can be extruded. In some aspects, each layer is extruded separately and then assembled together to form a desired configuration. However, in some embodiments, the forming step includes coextruding the first polymer layer and the second polymer layer. In some embodiments, the elongated tube may also include a third polymer layer between the first polymer layer and the second polymer layer. In such aspects, the third layer may include any polymer disclosed above. In some embodiments, the third polymer layer may be coextruded with the first polymer layer and the second polymer layer. In some exemplary aspects, the third polymer layer may be coextruded with the first polymer layer and then assembled with the second polymer layer. However, in some embodiments, the third polymer layer may be coextruded with the second polymer layer and then assembled with the first polymer layer. In some embodiments, all three polymer layers may be coextruded.

[0141] In some embodiments, any layer or all layers in the polymer layer present in the guide configuration can be at least partially cross-linked. In some other embodiments, any layer or all layers in the polymer layer present in the guide configuration can be fully cross-linked. In some embodiments, cross-linking can be achieved by exposing any layer or all layers in the layer to an energy source, wherein the energy source can be selected from electron beam radiation, X-ray radiation, gamma radiation or electromagnetic radiation. In some aspects, cross-linking is achieved by an energy source exposed to a dosage of about 25kGrey to about 100kGrey, including about 30kGrey, about 35kGrey, about 40kGrey, about 45kGrey, about 50kGrey, about 55kGrey, about 60kGrey, about 65kGrey, about 70kGrey, about 75kGrey, about 80kGrey, about 85kGrey, about 90kGrey and about 95kGrey exemplary values.

[0142] Also disclosed herein are methods of delivering a prosthetic valve comprising: placing a guidewire; introducing any introducer disclosed herein; removing the guidewire; and placing the prosthetic valve in an implantation site. Figure 5 . An exemplary 23Fr guidewire 508 is prepared at the implantation site. The delivery sheath 516 penetrates the septum 510 and transfers the introducer 502 from the right atrium 514 to the left atrium 512. The introducer tip (or the distal tapered portion of the introducer disclosed herein) 502 can be seen extending from the guide sheath top 504.

[0143] It should be understood that the above methods can be performed on patients, living animals, or on a simulator, such as a cadaver, a cadaver heart, an anthropomorphic artifact, a phantom body (e.g., having simulated body parts, hearts, tissues, etc.).

[0144] Also disclosed herein is a method comprising: exposing the introducer for medical device disclosed herein to ethylene oxide gas containing about 20% to about 70% humidity at a predetermined temperature for a predetermined time, the humidity including exemplary values ​​of about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60% and about 65%. It should be understood that the predetermined time can be any time required to achieve the desired sterilization level. It should also be understood that the sterilization level can be evaluated by placing a biological indicator (BI) at a position where the sterilization condition is most difficult to achieve in the introducer. In some exemplary and non-limiting aspects, the biological indicator can be placed at different positions in the narrow lumen to ensure that all lumens along the entire length of the introducer are sterilized to the desired level. Any biological indicator known in the art can be used. For example, and without limitation, the biological indicator can include Bacillus or Bacillus species.

[0145] In some embodiments, the methods disclosed herein provide sufficient sterilization along substantially the entire l1 throughout substantially the entire d1 and d2, wherein sufficient sterilization is defined by achieving effective inactivation of biological indicators in a short cycle to less than about 1 CFU, less than about 0.9 CFU, less than about 0.8 CFU, less than about 0.7 CFU, less than about 0.6 CFU, less than about 0.5 CFU, less than about 0.4 CFU, less than about 0.3 CFU, less than about 0.2 CFU, less than about 0.1 CFU, less than about 0.09 CFU, less than about 0.08 CFU, less than about 0.07 CFU, less than about 0.06 CFU, less than about 0.05 CFU, less than about 0.04 CFU, less than about 0.03 CFU, less than about 0.02 CFU or less than about 0.01 CFU.

[0146] In still other embodiments, the introducers disclosed herein can be sterilized in ethylene oxide to achieve about 10 -6 Sterility assurance level.

[0147] In some embodiments, the exposing step comprises one or more cycles of exposure to ethylene oxide gas. In some embodiments, the first polymer layer, the second polymer layer, and the third polymer layer (if present) exhibit no substantial degradation after the exposing step.

[0148] Examples

[0149] Disclosed herein are introducers manufactured according to aspects of the present disclosure. For example, disclosed herein is an introducer having an l1 of about 40.44 ± 0.10 inches, a d1 of about 0.305 ± 0.003 inches, and a d2 of about 0.039 ± 0.001 inches, wherein d2 is substantially the same along the entire length l1. The distal portion of the outer diameter is tapered. The tapered portion has a length l2 of about 1.37 ± 0.03 inches. The outer diameter at the most distal end of the introducer is about 0.065 ± 0.003 inches.

[0150] The following table shows the sterilization results obtained for the introducer of the present invention as compared to a reference introducer. The control is a polyurethane having the dimensions disclosed above and made of a polyurethane comprising Shore 93A such as for example Example 1 is a guide having the dimensions disclosed above and having coextruded polyurethane and high density polyethylene (HDPE) as the first and second layers, respectively. In this example, the thickness of the first layer is 0.128", and the thickness of the second layer is 0.005". The first layer in this example has aliphatic polyether-based The second layer in this example has a composition of HDPE.

[0151] Example 2 is an introducer having dimensions disclosed herein and having a first layer of a composite material comprising polyurethane and PEO and a second layer comprising HDPE, wherein the first layer and the second layer are coextruded. In this example, the thickness of the first layer is 0.128", and the thickness of the second layer is 0.005". The first layer in this example has a polyurethane based on an aromatic polyether. A composition of 55D with 30 wt% poly(ethylene oxide) and 20 wt% barium sulfate. The second layer in this example has a composition of HDPE.

[0152] The D value is calculated according to Stumbo Murphy Cochran, where

[0153] Where U is the exposure time, N0 is the starting spore population, and Nu is the most likely number of surviving spores. u It can be calculated as follows:

[0154] Where n is the number of exposed units and r is the number of sterile (negative) units.

[0155] Table 1.

[0156]

[0157] Exemplary Aspects

[0158] Example 1: An introducer for a medical device, comprising: an elongated tube comprising a first polymer layer forming an outer surface of the introducer having an outer diameter d1 and a second polymer layer forming an inner surface of the introducer and defining an inner cavity having a diameter d2, wherein the second layer is much more hydrophobic than the first layer; wherein the elongated tube has a length l1, wherein the ratio of l1 / d1 is greater than about 120 and the ratio of l1 / d2 is greater than about 200 to about 2,000; and wherein the introducer is configured to be fully sterilized along substantially the entire l1 and throughout substantially the entire d1 and d2.

[0159] Example 2: The introducer for a medical device of any example herein, in particular Example 1, wherein the second polymer layer comprises one or more polypropylene, polyethylene, graft-modified polyethylene or graft-modified polypropylene.

[0160] Example 3: Any example of the present invention, in particular the introducer for a medical device of Example 2, wherein the second polymer layer comprises one or more of low-density polyethylene (LDPE), medium-density polyethylene, ultra-low-density polyethylene (ULDPE), high-density polyethylene (HDPE), heterogeneously branched linear low-density polyethylene (LLDPE), grafted modified ethylene polymers, grafted modified polypropylene or ethylene-vinyl acetate (EVA) or any combination thereof.

[0161] Example 4: The introducer for a medical device according to any example herein, in particular Example 2 or 3, wherein the graft-modified polyethylene or graft-modified polypropylene is maleic anhydride graft-modified or acrylic acid graft-modified.

[0162] Example 5: The introducer for a medical device of any of the examples herein, in particular examples 1-4, wherein the first polymer layer comprises polyurethane, polyether block amide, polyethylene oxide, or any combination thereof.

[0163] Example 6: The introducer for a medical device of any of the examples herein, in particular examples 1-5, wherein the first polymer layer is thermoplastic polyurethane.

[0164] Example 7: An introducer for a medical device according to any of the examples herein, in particular examples 1-5, wherein the first polymer layer is a composite comprising greater than 0 wt % to less than 100 wt % of a polyether-based thermoplastic polyurethane and about 5 wt % to about 50 wt % of polyethylene oxide.

[0165] Example 8: The introducer for a medical device of any of the examples herein, in particular examples 1-7, wherein the polyurethane has a Shore D hardness of about 50D to about 75D.

[0166] Example 9: The introducer for a medical device of any of the examples herein, in particular examples 1-7, wherein the polyurethane has a Shore A hardness of about 25A to about 95A.

[0167] Example 10: The introducer for a medical device of any of the examples herein, in particular examples 1-5, wherein the first polymer layer is a polyether block amide.

[0168] Example 11: The introducer for a medical device of any of the examples herein, particularly examples 1-5, wherein the first polymer layer is a composite comprising greater than 0 wt % to less than 100 wt % of polyether block amide and about 5 wt % to about 50 wt % of polyethylene oxide.

[0169] Example 12: The introducer for a medical device of any of the examples herein, particularly examples 1-5 or 10-11, wherein the polyether block amide has a Shore hardness of about 25D to about 72D.

[0170] Example 13: The introducer for a medical device of any of the examples herein, particularly examples 7-9 or 11-12, wherein the polyethylene oxide (PEO) has a molecular weight of about 100,000 to about 7,000,000.

[0171] Example 14: The introducer for a medical device of any of the examples herein, in particular examples 1-13, wherein the first polymer layer has a thickness of about 0.005 inches to about 0.150 inches.

[0172] Example 15: The introducer for a medical device of any of the examples herein, in particular examples 1-14, wherein the second polymer layer has a thickness of about 0.005 inches to about 0.035 inches.

[0173] Example 16: The introducer for a medical device of any of the examples herein, in particular examples 1-15, further comprising a third polymer layer located between the first polymer layer and the second polymer layer.

[0174] Example 17: The introducer for a medical device of any example herein, in particular Example 16, wherein the third polymer layer is a tie layer and comprises graft-modified polyethylene or graft-modified polypropylene.

[0175] Example 18: The introducer for a medical device of any example herein, in particular examples 16 or 17, wherein the third polymer layer has a thickness of about 0.001 inches to about 0.025 inches.

[0176] Example 19: The introducer for a medical device of any of the examples herein, in particular examples 1-18, wherein the first polymer layer and / or the second polymer layer comprises a filler.

[0177] Example 20: The introducer for a medical device of any of the examples herein, in particular examples 16-19, wherein the third polymer layer comprises a filler.

[0178] Example 21: The introducer for a medical device of any example herein, in particular Example 20, wherein the filler comprises bismuth oxychloride, barium sulfate, bismuth subcarbonate, calcium carbonate, aluminum trihydrate, barite, kaolin, limestone, titanium oxide, or any combination thereof.

[0179] Example 22: The introducer for a medical device of any of the examples herein, in particular examples 1-21, wherein the first polymer layer and the second polymer layer are coextruded.

[0180] Example 23: The introducer for a medical device of any of the examples herein, in particular examples 16-22, wherein the first polymer layer and / or the second polymer layer and / or the third layer are coextruded.

[0181] Example 24: The introducer for a medical device of any of the examples herein, in particular examples 1-23, wherein the first polymer layer and / or the second polymer layer is at least partially cross-linked.

[0182] Example 25: The introducer for a medical device of any example herein, in particular example 24, wherein the cross-linking is achieved by exposure to an energy source, wherein the energy source is selected from electron beam radiation, X-ray radiation, gamma radiation, or electromagnetic radiation.

[0183] Example 26: The introducer for a medical device of any example herein, in particular example 25, wherein the cross-linking is achieved by exposure to an energy source at a dose of about 25 kGrey to about 100 kGrey.

[0184] Example 27: The introducer for a medical device of any of the examples herein, in particular examples 1-26, wherein the first polymer layer and / or the second polymer layer is substantially cross-linked.

[0185] Example 28: An introducer for a medical device according to any of the examples herein, in particular examples 1-27, wherein the inner diameter d2 is substantially the same along the entire length l1.

[0186] Example 29: An introducer for a medical device according to any of the examples herein, in particular examples 1-28, wherein the introducer has a proximal portion and a distal portion.

[0187] Example 30: The introducer for a medical device of any example herein, in particular Example 29, wherein the proximal portion is coupled to a hub or an adapter to connect the medical device.

[0188] Example 31: An introducer for a medical device of any example herein, particularly examples 29 or 30, wherein the distal portion is tapered such that the outer diameter d1 decreases toward the distal end of the introducer while the inner diameter d1 remains substantially the same along the entire length l1.

[0189] Example 32: An introducer for a medical device according to any of the examples herein, in particular examples 1-31, wherein the introducer is configured to receive a guidewire for deploying the medical device.

[0190] Example 33: An introducer for a medical device according to any of the examples herein, in particular examples 1-32, wherein the sterilization is ethylene oxide based.

[0191] Example 34: An introducer for a medical device according to any of the examples herein, in particular examples 1-33, wherein being sufficiently sterilized along substantially all of l1 throughout substantially all of d2 is defined by achieving effective inactivation of biological indicators to less than about 1 CFU in a short cycle.

[0192] Example 35: The introducer for a medical device of any example herein, in particular example 34, wherein the sterility assurance level is about 10 -6 .

[0193] Example 36: An introducer for a medical device according to any of the examples herein, in particular examples 7-9 or 11-35, wherein the outer surface of the introducer is substantially lubricious and exhibits a coefficient of friction (COF) of about 0.05 to about 0.5.

[0194] Example 37: An introducer for a medical device according to any of the examples herein, in particular examples 7-9 or 11-36, wherein the outer surface of the introducer does not include a hydrophilic coating.

[0195] Example 38: An introducer for a medical device according to any of the examples herein, in particular examples 7-9 or 11-37, wherein the introducer is configured to generate substantially no insoluble particulate material.

[0196] Example 39: A delivery system comprising: an introducer for a medical device of any example herein, in particular Examples 1-38; a delivery sheath; and a prosthetic valve.

[0197] Example 40: A method for manufacturing an introducer for a medical device of any of the examples herein, in particular Examples 1-38, the method comprising: forming an elongated tube comprising a first polymer layer forming an outer surface of the introducer having an outer diameter d1, and a second polymer layer; forming an inner surface of the introducer and defining an inner cavity having a diameter d2, wherein the second layer is much more hydrophobic than the first layer; wherein the elongated tube has a length l1, wherein the ratio of l1 / d1 is greater than about 120 and the ratio of l1 / d2 is greater than about 200 to about 2,000; and wherein the introducer is configured to be fully sterilized along substantially the entire l1 and throughout substantially the entire d1 and d2.

[0198] Example 41: The method of any of the examples herein, in particular Example 40, wherein the forming step comprises coextruding the first polymer layer and the second polymer layer.

[0199] Example 42: The method of any example herein, in particular examples 40 or 41, wherein the elongated tube further comprises a third polymer layer located between the first polymer layer and the second polymer layer.

[0200] Example 43: The method of any of the examples herein, in particular Example 42, wherein the third polymer layer is coextruded with the first polymer layer and the second polymer layer.

[0201] Example 44: A method of delivering a prosthetic valve, the method comprising: placing a guidewire; introducing the introducer of any of the examples herein, particularly Examples 1-38, removing the guidewire; and placing the prosthetic valve in an implantation site.

[0202] Example 45: A method comprising: exposing the introducer for a medical device of any of the examples herein, particularly Examples 1-38, to ethylene oxide gas containing about 20% to about 70% humidity at a predetermined temperature for a predetermined time.

[0203] Example 46: The method of any example herein, particularly Example 45, wherein the exposing step comprises one or more cycles of exposure to the ethylene oxide gas.

[0204] Example 47: The method of any example herein, in particular examples 45 or 46, wherein the exposing step achieves effective inactivation of the biological indicator to less than about 1 CFU in a short period.

[0205] Example 48: The method of any example herein, in particular Example 47, wherein the exposing step is performed for about 10 -6 Sterility assurance level.

[0206] Example 49: The method of any of the examples herein, in particular Examples 45-48, wherein the first polymer layer, the second polymer layer, and the third polymer layer exhibit substantially no degradation after the exposing step.

[0207] In view of the many possible aspects to which the principles of the disclosed disclosure may be applied, it should be recognized that the illustrated aspects are merely examples of the disclosure and should not be considered as limiting the scope of the disclosure. Instead, the scope of the disclosure is defined by the following claims. We therefore claim as our disclosure all that is within the scope and spirit of these claims.

Claims

1. An introducer for a medical device, comprising: an elongated tube comprising a first polymer layer forming an outer surface of the introducer having an outer diameter d1 and a second polymer layer forming an inner surface of the introducer and defining an inner lumen having a diameter d2, wherein the second layer is much more hydrophobic than the first layer; wherein the elongated tube has a length l1, wherein the ratio of l1 / d1 is greater than about 120 and the ratio of l1 / d2 is greater than about 200 to about 2,000; And wherein the introducer is configured to be substantially sterilized along substantially all of l1 throughout substantially all of d1 and d2. 2 . The introducer for a medical device according to claim 1 , wherein the second polymer layer comprises one or more of polypropylene, polyethylene, graft-modified polyethylene or graft-modified polypropylene.

3. An introducer for a medical device according to claim 2, wherein the second polymer layer comprises one or more of low-density polyethylene (LDPE), medium-density polyethylene, ultra-low-density polyethylene (ULDPE), high-density polyethylene (HDPE), heterogeneously branched linear low-density polyethylene (LLDPE), grafted modified ethylene polymers, grafted modified polypropylene or ethylene-vinyl acetate (EVA) or any combination thereof.

4. The introducer for a medical device according to any one of claims 1 to 3, wherein the first polymer layer comprises polyurethane, polyether block amide, polyethylene oxide, or any combination thereof.

5. An introducer for a medical device according to any one of claims 1 to 4, wherein the first polymer layer is a composite comprising greater than 0 wt % to less than 100 wt % of a polyether-based thermoplastic polyurethane and about 5 wt % to about 50 wt % of polyethylene oxide.

6. An introducer for a medical device according to any one of claims 4-5, wherein the polyurethane has a Shore D hardness of about 50D to about 75D and / or a Shore A hardness of about 25A to about 95A.

7. The introducer for a medical device according to any one of claims 1 to 4, wherein the first polymer layer is a composite comprising greater than 0 wt% to less than 100 wt% of polyether block amide and about 5 wt% to about 50 wt% of polyethylene oxide.

8. The introducer for a medical device according to claim 7, wherein the polyether block amide has a Shore hardness of about 25D to about 72D.

9. An introducer for a medical device according to any one of claims 5-8, wherein the polyethylene oxide (PEO) has a molecular weight of about 100,000 Daltons to about 7,000,000 Daltons.

10. An introducer for a medical device according to any one of claims 1-9, wherein the first polymer layer has a thickness of about 0.005 inches to about 0.150 inches and / or wherein the second polymer layer has a thickness of about 0.005 inches to about 0.035 inches.

11. An introducer for a medical device according to any one of claims 1-10, the introducer also comprising a third polymer layer located between the first polymer layer and the second polymer layer, wherein the third polymer layer is a bonding layer and comprises grafted modified polyethylene or grafted modified polypropylene, and wherein the third polymer layer has a thickness of about 0.001 inches to about 0.025 inches.

12. An introducer for a medical device according to any one of claims 1 to 11, wherein the first polymer layer and / or the second polymer layer and / or the third polymer layer if present comprises a filler.

13. The introducer for a medical device according to claim 12, wherein the filler comprises bismuth oxychloride, barium sulfate, bismuth subcarbonate, calcium carbonate, aluminum trihydrate, barite, kaolin, limestone, titanium oxide, or any combination thereof.

14. An introducer for a medical device according to any one of claims 1 to 13, wherein the first polymer layer and / or the second polymer layer and / or the third layer if present are coextruded.

15. The introducer for a medical device according to any one of claims 1 to 14, wherein the first polymer layer and / or the second polymer layer is at least partially cross-linked.

16. An introducer for a medical device according to any one of claims 1 to 15, wherein the inner diameter d2 is substantially the same along the entire length l1.

17. An introducer for a medical device according to any one of claims 1-16, wherein the introducer has a proximal portion and a distal portion, wherein the proximal portion is coupled to a hub or an adapter to connect to the medical device, and wherein the distal portion is tapered so that the outer diameter d1 decreases toward the distal end of the introducer while the inner diameter d1 remains substantially the same along the entire length l1.

18. An introducer for a medical device according to any one of claims 1-17, wherein the introducer is configured to receive a guidewire for deploying the medical device.

19. An introducer for a medical device according to any one of claims 1-18, wherein the sterilization is based on ethylene oxide.

20. An introducer for a medical device according to any one of claims 1 to 19, wherein being substantially sterilized along substantially the entire l1 throughout substantially the entire d2 is defined by achieving effective inactivation of biological indicators to less than about 1 CFU in a short cycle and / or wherein the sterility assurance level is about 10 -6 .

21. An introducer for a medical device according to any one of claims 5-20, wherein the outer surface of the introducer is substantially lubricated and exhibits a coefficient of friction (COF) of about 0.05 to about 0.5, and wherein the outer surface of the introducer does not include a hydrophilic coating.

22. A delivery system, comprising: An introducer for a medical device according to any one of claims 1 to 21; Delivery sheath; as well as Prosthetic valve.

23. A method for manufacturing an introducer for a medical device according to any one of claims 1 to 21, the method comprising: forming an elongated tube comprising a first polymer layer forming an outer surface of the introducer having an outer diameter d1, and a second polymer layer; forming an inner surface of the introducer and defining an inner lumen having a diameter d2, wherein the second layer is substantially more hydrophobic than the first layer; wherein the elongated tube has a length l1, wherein the ratio of l1 / d1 is greater than about 120 and the ratio of l1 / d2 is greater than about 200 to about 2,000; And wherein the introducer is configured to be substantially sterilized along substantially all of l1 throughout substantially all of d1 and d2.

24. The method of claim 23, wherein the forming step comprises coextruding the first polymer layer and the second polymer layer.

25. The method of claim 223 or 24, wherein the elongated tube further comprises a third polymer layer located between the first polymer layer and the second polymer layer, and / or wherein the third polymer layer is co-extruded with the first polymer layer and the second polymer layer.

26. A method of delivering a prosthetic valve, the method comprising: Guidewire placement; Introducing an introducer according to any one of claims 1 to 21; removing the guidewire; and placing a prosthetic valve in an implantation site.

27. A method comprising: The introducer for a medical device according to any one of claims 1 to 21 is exposed to ethylene oxide gas containing about 20% to about 70% humidity at a predetermined temperature for a predetermined time.

28. The method of claim 27, wherein the exposing step comprises one or more cycles of exposure to the ethylene oxide gas, and wherein the exposing step achieves effective inactivation of the biological indicator to less than about 1 CFU in a short cycle and / or wherein the exposing step achieves about 10 -6 Sterility assurance level.

29. The method of any one of claims 27-28, wherein the first polymer layer, the second polymer layer, and the third polymer layer, if present, exhibit no substantial degradation after the exposing step.

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