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

Abstract

An introducer for a medical device is disclosed that includes an elongate tube having a first polymer layer that forms an outer surface of the introducer having an outer diameter d1 and a second polymer layer that forms an inner surface of the introducer and defines a lumen having a diameter d2, wherein the second layer is substantially more hydrophobic than the first layer, the elongate tube has a length l1, the ratio of l1 / d1 is greater than about 120, the ratio of l1 / d2 is greater than about 200 to about 2,000, and the introducer is configured to be substantially sterilized throughout substantially all of l1, substantially all of d1, and substantially all of d2.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 369,328, filed on July 25, 2022, the content of which is incorporated herein by reference in its entirety.

[0002] This application relates to aspects of introducers for medical devices, methods of manufacturing the same, and methods of sterilizing the same.

Background Art

[0003] The human heart is susceptible to various valvular diseases. These valvular diseases can cause severe heart dysfunction and ultimately may require replacement of the natural valve with an artificial valve. Numerous artificial valves are known, and numerous methods for implanting these artificial valves into the human body are also known.

[0004] When the natural valve is replaced, surgical implantation of an artificial valve typically requires open - chest surgery, during which the heart is stopped and the patient is put on cardiopulmonary bypass (so - called "heart - lung machine"). In one common surgical procedure, the diseased natural valve leaflets are excised and the artificial valve is sutured to the tissue around the valve annulus. Due to trauma associated with the procedure and the time of extracorporeal blood circulation involved, some patients cannot withstand the surgical procedure or die immediately. It is well - known that the risk to the patient increases with the time required for extracorporeal circulation. Due to these risks, a significant number of patients with defects in their natural valves are considered inoperable because their condition is too fragile to withstand the procedure. Some estimates suggest that over 50% of subjects over 80 years old suffering from valvular stenosis cannot undergo valve replacement surgery.

[0005] Due to the drawbacks associated with traditional open-heart surgery, percutaneous and minimally invasive surgical approaches have received strong attention. In one technique, an artificial valve is configured to be implanted by a much less invasive procedure via catheterization. For example, Patent Documents 1 and 2 (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 at a desired location by balloon inflation or by utilization of a self-expanding frame or stent.

[0006] To deliver the valve to the implantation site, a specially designed delivery system is utilized. One important component of such a system is a medical device introducer. The introducer is configured to assist in the delivery of the artificial valve and to remove the guide wire from the implantation site. To easily deliver the valve with minimal invasiveness, the introducer often has a length exceeding 30 inches. However, to prevent air embolism, it is desirable to keep the inner diameter of the introducer very small (less than about 0.05 inches) along the entire length of the device. However, such high aspect ratio devices are difficult to sterilize efficiently. To ensure a desired sterilization level, current introducers are constructed to have an inner diameter of about 0.150 inches along most of the length of the introducer and an inner diameter of less than about 0.05 inches at the distal end of the device. However, since air embolism still poses a substantial threat to the patient's health, such a structure is not very desirable.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

[0008] Therefore, there is a need for a new introducer, a method for manufacturing the same, and a method for sterilizing the introducer that substantially eliminate these problems and improve patient safety. These needs and other needs are at least partially satisfied by the present disclosure. [Means for Solving the Problems]

[0009] Aspects of the present disclosure relate to artificial valves. Some aspects include an elongate tube comprising a first polymer layer forming an outer surface of an introducer having an outer diameter d1, and a second polymer layer forming an inner surface of the introducer and defining a lumen having a diameter d2. In some implementations, the second layer is substantially more hydrophobic than the first layer. In some implementations, the elongate tube has a length l1, 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 further some implementations, the introducer is configured to be substantially sterilized along substantially the entire l1 and through substantially the entire d1 and d2.

[0010] Also disclosed is an introducer for a medical device according to any of the aspects 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 according to any of the aspects 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), graft-modified ethylene polymer, graft-modified polypropylene, or ethylene vinyl acetate (EVA), or any combination thereof.

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

[0013] Also disclosed is an introducer for a medical device according to any of the aspects disclosed herein, wherein the first polymer layer comprises polyurethane, polyether block amide, polyethylene oxide, or any combination thereof.

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

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

[0016] In some implementations, an introducer for a medical device according to any of the aspects disclosed herein is also disclosed, wherein the polyurethane has a durometer shore D of from about 50D to about 75D.

[0017] In some implementations, an introducer for a medical device according to any of the aspects disclosed herein is also disclosed, wherein the polyurethane has a shore A of from about 25A to about 95A.

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

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

[0020] In some implementations, an introducer for a medical device according to any of the aspects disclosed herein is also disclosed, wherein the polyether block amide has a shore hardness of from about 25D to about 72D.

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

[0022] In some implementations, an introducer for a medical device in any of the aspects disclosed herein is also disclosed, where the first polymer layer has a thickness of from about 0.005 inches to about 0.150 inches.

[0023] In some implementations, an introducer for a medical device in any of the aspects disclosed herein is also disclosed, where the second polymer layer has a thickness of from about 0.005 inches to about 0.035 inches.

[0024] In some implementations, an introducer for a medical device in any of the aspects disclosed herein is also disclosed, which includes a third polymer layer positioned between the first polymer layer and the second polymer layer.

[0025] In some implementations, an introducer for a medical device in any of the aspects disclosed herein is also disclosed, where the third polymer layer is a tie layer and includes graft-modified polyethylene or graft-modified polypropylene.

[0026] In some implementations, an introducer for a medical device in any of the aspects disclosed herein is also disclosed, where the third polymer layer has a thickness of from about 0.001 inches to about 0.025 inches.

[0027] In some implementations, an introducer for a medical device in any of the aspects disclosed herein is also disclosed, where the first polymer layer and / or the second polymer layer includes a filler.

[0028] In some implementations, an introducer for a medical device in any of the aspects disclosed herein is also disclosed, where the third polymer layer includes a filler.

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

[0030] In some implementations, an introducer for a medical device of any of the aspects disclosed herein, wherein the first polymer layer and the second polymer layer are coextruded, is also disclosed.

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

[0032] In some implementations, an introducer for a medical device of any of the aspects disclosed herein, wherein the first polymer layer and / or the second polymer layer are at least partially crosslinked, is also disclosed.

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

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

[0035] In some implementations, an introducer for a medical device of any of the aspects disclosed herein, wherein the first polymer layer and / or the second polymer layer are substantially crosslinked, is also disclosed.

[0036] In some implementations, an introducer for any of the medical devices disclosed herein is also disclosed, where the inner diameter d2 is substantially the same along the entire length l1.

[0037] In some implementations, an introducer for any of the medical devices disclosed herein is also disclosed, where the introducer has a proximal portion and a distal portion.

[0038] In some implementations, an introducer for any of the medical devices disclosed herein is also disclosed, where the proximal portion is coupled to a hub or adapter for connecting a medical device.

[0039] In some implementations, a distal portion is tapered such that the outer diameter d1 decreases towards the distal end of the introducer while the inner diameter d1 remains substantially the same along the entire length l1.

[0040] In some implementations, an introducer for any of the medical devices disclosed herein is also disclosed, where the introducer is configured to receive a guidewire used to deploy a medical device.

[0041] In some implementations, an introducer for any of the medical devices disclosed herein is also disclosed, where the sterilization is ethylene oxide-based.

[0042] In some implementations, an introducer for any of the medical devices disclosed herein is also disclosed, where a substantial sterilization that occurs substantially along all of l1 and substantially across all of d2 is defined by achieving effective inactivation of biological indicators with a fractional cycle of less than about 1 CFU.

[0043] In some implementations, the sterility assurance level is about 10 -6 and an introducer for any of the medical devices disclosed herein is also disclosed.

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

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

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

[0047] In some implementations, a delivery system is disclosed that includes an introducer for a medical device according to any of the examples herein, particularly Examples 1 - 38, a delivery sheath, and an artificial valve.

[0048] In some implementations, a method of making an introducer for a medical device according to any of the examples herein, particularly Examples 1 - 38, is disclosed. The method includes forming an elongate tube that includes a first polymer layer that forms an outer surface of the introducer having an outer diameter d1, and a second polymer layer that forms an inner surface of the introducer and defines a lumen having a diameter d2. The second layer is substantially more hydrophobic than the first layer. The elongate tube has a length l1, 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. The introducer is configured to be substantially sterilized along substantially the entire length l1 and through substantially the entire d1 and d2.

[0049] In some implementations, a method according to any of the aspects disclosed herein is disclosed, wherein the forming step includes co - extruding the first polymer layer and the second polymer layer.

[0050] In some implementations, any of the methods of the aspects disclosed herein are disclosed, where an elongated tube further comprises a third polymer layer positioned between a first polymer layer and a second polymer layer.

[0051] In some implementations, any of the methods of the aspects disclosed herein are disclosed, where the third polymer layer is co-extruded with the first polymer layer and the second polymer layer.

[0052] In some implementations, a method of delivering an artificial valve is disclosed, comprising the steps of placing a guide wire, introducing an introducer of any one of Examples herein, particularly Examples 1 - 38, removing the guide wire, and placing the artificial valve at the implantation site.

[0053] In some implementations, a method is disclosed that includes exposing an introducer for a medical device of any example herein, particularly Examples 1 - 38, to ethylene oxide gas containing from about 20% to about 70% humidity at a predetermined temperature for a predetermined time.

[0054] In some implementations, any of the methods of the aspects disclosed herein are disclosed, where the exposing step includes one or more cycles of exposure to ethylene oxide gas.

[0055] In some implementations, any of the methods of the aspects disclosed herein are disclosed, where the exposing step achieves effective inactivation of biological indicators with a fractional cycle of less than about 1 CFU.

[0056] In some implementations, the exposing step is about 10 -6 of achieving a sterility assurance level, and any of the methods of the aspects disclosed herein are disclosed.

[0057] In some implementations, any of the methods of the aspects disclosed herein are disclosed, where the first polymer layer, the second polymer layer, and the third polymer layer do not substantially show degradation after the exposing step.

[0058] The above method can be carried out on a patient or a living animal, or on a simulation (such as on a cadaver, a cadaver heart, an anthropomorphic ghost, or a simulator (e.g., where a part of the body, the heart, tissue, etc. is simulated)).

[0059] "Any of the various systems, instruments, devices, etc. in the present disclosure can be sterilized (e.g., using heat, radiation, ethylene oxide, hydrogen peroxide, etc.) to ensure safety for use on a patient, and the methods described herein may include sterilization of the related systems, instruments, devices, etc. (e.g., using heat, radiation, ethylene oxide, hydrogen peroxide, etc.)."

[0060] The foregoing and other features and advantages of the present disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying drawings.

Brief Description of the Drawings

[0061]

Figure 1A

Figure 1B

Figure 2

Figure 3

Figure 4A

Figure 4B

Figure 5

[0062] This disclosure can be more readily understood by reference to the following detailed description, examples, drawings, and claims, as well as the foregoing and following descriptions thereof. However, prior to the disclosure and description of the articles, systems, and / or methods, this disclosure is not limited to the specific or exemplary aspects of the articles, systems, and / or methods disclosed, unless otherwise specified, and thus, it should be understood that it can naturally vary. It should also be understood that the terms used herein are for the purpose of describing only specific aspects and are not intended to be limiting.

[0063] Those skilled in the relevant art will recognize and understand that many changes can be made to the various aspects of this disclosure described herein while still obtaining the beneficial results of this disclosure. It will also be apparent that some of the desired benefits of this disclosure can be obtained by selecting some of the features of this disclosure without using other features. Therefore, those skilled in the relevant art will recognize that many modifications and adaptations to this disclosure are possible and may even be desirable in certain circumstances and are part of this disclosure. Accordingly, the following description is provided again as an illustration, not a limitation, of the principles of this disclosure. Definitions

[0064] As used in this application and the claims, the singular forms "a", "an", and "the" include the plural unless the context clearly dictates otherwise. Thus, for example, references to "introducer" include aspects having two or more such introducers unless the context clearly indicates otherwise.

[0065] Also, it should be understood that the terms used in this specification are for the purpose of describing only specific embodiments and are not intended to be limiting. When used in this specification and the claims, the term "comprising" can include the "consisting of" and "consisting essentially of" embodiments. In addition, the term "includes" means "comprises".

[0066] For the terms "for example" and "such as", and their grammatical equivalents, it is understood that the phrase "although not limited to" follows, unless explicitly stated otherwise. It should be further understood that these terms are used for illustrative purposes only. The term "exemplary", as used in this specification, means "an example of" and is not intended to suggest a preferred or ideal embodiment.

[0067] The term "or" means "and / or". The recitation of numerical ranges is intended solely as a convenient method of referring individually to each separate numerical value falling within the range, unless otherwise indicated herein, and each separate numerical value is incorporated herein as if it were individually recited herein. All endpoints of the ranges are included within the range and are combinable independently. All methods described herein can be performed in a suitable order, unless otherwise indicated herein or otherwise clearly contradicted by the context.

[0068] Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, some implementations include from one particular value and / or to another particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about", it will be understood that the particular value forms another embodiment. It should be further understood that each endpoint of each range is important both in relation to the other endpoint and independently of the other endpoint.

[0069] The detailed description of numerical ranges in this specification is merely intended to serve as a convenient way of referring individually to each separate numerical value detailed or included within that range, without further instruction in this specification, and each separate numerical value is incorporated into this specification as if it were individually detailed. The ranges provided in this specification are to be understood as being all inclusive of the numerical values within those ranges. For example, a range of 1 to 50 is understood to include any number or combination of numbers selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, or sub-ranges selected from the group consisting of 10 to 40, 20 to 50, 5 to 35, etc. Similarly, a numerical range detailed in this specification by its endpoints includes sub-ranges subsumed within that range (e.g., 1 to 5 includes 1 to 1.5, 1.5 to 2, 2 to 2.75, 2.75 to 3, 3 to 3.90, 3.90 to 4, 4 to 4.24, 4.24 to 5, 2 to 5, 3 to 5, 1 to 4, and 2 to 4).

[0070] Furthermore, the terms "connected" and "associated" generally mean electrically, electromagnetically, and / or physically (e.g., mechanically or chemically) connected or linked, and do not exclude the presence of intermediate elements between the connected or associated items.

[0071] As used in this specification, the term or phrase "effective", "effective amount", or "conditions effective to" refers to an amount or condition such that the function or property represented by the effective amount or condition can be carried out. As pointed out below, the exact amount or specific conditions required will vary by aspect depending on recognized variables such as the materials employed and the processing conditions observed. Thus, it is not always possible to specify an exact "effective amount" or "conditions effective to". However, it should be understood that an appropriate effective amount can be readily determined by one of ordinary skill in the art using only routine experimentation.

[0072] As used herein, the term "substantially" means that the event or situation described later occurs completely, or that the event or situation described later generally, typically, or approximately occurs.

[0073] Still further, in some embodiments, the term "substantially" characterizes or otherwise quantifies the amount in which it is used, and 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 the described characteristics, components, compositions, or other conditions.

[0074] In some implementations, as used herein, the term "substantially free of" is intended to refer to an amount of the described material of less than about 1% by weight, such as less than about 0.5% by weight, less than about 0.1% by weight, less than about 0.05% by weight, or less than about 0.01% by weight, based on the total weight of the composition, when used in the context of a composition or a component of a composition that is substantially absent.

[0075] Aspects of the present disclosure may be described and claimed in a particular statutory field such as the system statutory field, but this is for convenience only, and those skilled in the art will understand that each aspect of the present disclosure may be described and claimed in any statutory field. Unless explicitly stated otherwise, it is never intended that any method or aspect described herein be construed as requiring that its steps be performed in a specific order. Thus, when method claims do not specifically recite in the claims or the description that the steps are limited to a specific order, it is never intended that the order be inferred with respect to any aspect. This is valid for any possible implicit basis for interpretation, including the arrangement or flow of steps, the plain meaning derived from grammatical construction or punctuation, or logical issues regarding the number or type of aspects described herein.

[0076] The operations of the exemplary aspects of the disclosed method may be described in a particular sequential order for convenience of presentation, but it should be understood that the disclosed aspects may include operation orders other than the particular sequential order disclosed. For example, operations described sequentially may, in some cases, be rearranged or performed simultaneously. Further, the description and disclosure provided in relation to one particular aspect are not limited to that aspect and may be applied to any of the disclosed aspects.

[0077] Furthermore, for simplicity, the accompanying figures may not show various ways (easily recognizable by those skilled in the art based on the present disclosure) in which the disclosed systems, methods, and devices can be used in combination with other systems, methods, and devices. In addition, the description sometimes uses terms such as "produce" and "provide" to describe the disclosed method. These terms are high-level abstractions of the actual operations that may be performed. The actual operations corresponding to these terms may vary depending on the specific implementation and are easily recognizable by those skilled in the art based on the present disclosure.

[0078] Treatment techniques, methods, steps, etc. described or suggested in this specification or reference materials incorporated herein can be implemented on patients, live animals, or non-living simulations (such as on cadavers, cadaver hearts, anthropomorphic ghosts, simulators (e.g., where parts of the body, tissues, etc. are simulated), etc.).

[0079] In the present disclosure, any of the various systems, instruments, devices, etc. can be sterilized (e.g., using heat, radiation, ethylene oxide, hydrogen peroxide, etc.) to ensure safety for use on patients, and the methods described herein may include sterilization of the related systems, instruments, devices, etc. (e.g., using heat, radiation, ethylene oxide, hydrogen peroxide, etc.).

[0080] The present disclosure can be more readily understood by reference to the following detailed description of various aspects of the invention, as well as the examples contained therein, and the figures and their previous and subsequent descriptions. Introducer

[0081] In one aspect, an introducer for a medical device is disclosed herein. The medical device may comprise an elongate tube having a length l1. The tube may comprise a first polymer layer forming the outer surface of the introducer having an outer diameter d1, and a second polymer layer forming the inner surface of the introducer and defining a lumen having a diameter d2. In some aspects, the second layer is substantially more hydrophobic than the first layer. In some aspects, the length l1 may be in the range of about 30 inches to about 50 inches, including exemplary values of 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 is understood that the introducer disclosed herein may also be longer than 50 inches.

[0082] In some implementations, the diameter d1 can range from 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 0.250 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.

[0083] In some implementations, d2 can be from about 0.01 inches to about 0.07 inches, including exemplary values of about 0.0125 inches, about 0.015 inches, about 0.0175 inches, about 0.020 inches, about 0.0225 inches, about 0.0250 inches, about 0.0275 inches, about 0.030 inches, about 0.0325 inches, about 0.0350 inches, about 0.0375 inches, about 0.040 inches, about 0.0425 inches, about 0.0450 inches, about 0.0475 inches, about 0.05 inches, about 0.0525 inches, about 0.0550 inches, about 0.0575 inches, about 0.06 inches, about 0.0625 inches, about 0.0650 inches, and about 0.0675 inches.

[0084] In some implementations, the ratio of l1 to 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, 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 implementations, the ratio of l1 to d1 (l1 / d1) can be from 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.

[0085] In some implementations, the l1 / d2 ratio 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.

[0086] One problem in medicine is the ability to efficiently sterilize high aspect ratio instruments. Generally, ethylene oxide gas is used to sterilize medical instruments. Most medical instruments are hygroscopic and can rapidly absorb moisture from the ethylene oxide gas mixture during the sterilization process. As a result, sterilization becomes inefficient. More specifically, efficient sterilization in very narrow lumens over the long length of the instrument is a problem. As a result, sterilization is not uniform and is insufficient for surgical procedures, as it can lead to risks to the patient's health during surgery.

[0087] One approach for longer instruments is to increase the inner diameter to the highest acceptable value and have a narrow inner diameter only over a short portion of the instrument, for example, over the distal end or the proximal end of the instrument, as needed. However, this approach is not desirable. For example, undesirable side effects such as air embolisms can still occur with instruments having a larger diameter.

[0088] The introducer disclosed herein overcomes the challenges of the sterilization process and is configured to be substantially sterilized throughout substantially all of d1 and d2 along substantially all of l1. 。

[0089] An exemplary introducer 100 for a medical instrument is shown in FIG. 1A. The introducer has the l1, outer diameter d, disclosed above. 1、and has either an inner diameter d2. In some implementations, the inner diameter d2 can be substantially the same along the entire length l1. In some implementations, the inner diameter d2 can vary along the length l1 according to a particular application. However, it is understood that the overall value of d2 falls within the ranges disclosed above.

[0090] In some implementations, the outer diameter d1 of the introducer can be substantially the same over the entire length l1, while in some implementations, the diameter d1 can vary according to a particular application. As shown in FIG. 1B, at least a portion of the disclosed introducer can be tapered.

[0091] It is understood that the introducers disclosed herein have a proximal portion and a distal portion. In some aspects, the distal portion of the introducer can be tapered with a length l2. Such a tapered portion can enable a more atraumatic use of the introducer during a surgical procedure. In certain aspects, l2 extends from the distal end of the introducer towards the proximal end of the introducer and can be from about 0.1 inch to about 3 inches, including exemplary values of 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. In such aspects, the outer diameter d3 of the distal end of the tapered portion is substantially smaller than d1. Still, in some implementations, the outer diameter d3 of the distal end of the tapered portion is only gradually larger than d2. For example, d3 can be from 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.

[0092] In some implementations, the distal portion is tapered such that the outer diameter d1 decreases towards the distal end of the introducer while the inner diameter d1 remains substantially the same along the entire length l1.

[0093] In some implementations, the introducer 200 disclosed herein can comprise at least two layers, such as a first polymer layer 204 that forms the outer surface 202 of the introducer and a second polymer layer 208 that forms the lumen 206 (and that defines the inner surface of the introducer), as shown in FIG. 2.

[0094] In the aspects disclosed herein, it is understood that the second polymer layer is more hydrophobic than the first polymer layer. Such a configuration allows ethylene oxide gas to penetrate into the inner lumen of the introducer and sterilize without being immediately absorbed by the polymer layer.

[0095] In some aspects, the second polymer layer can include one or more of polypropylene, polyethylene, graft-modified polyethylene, or graft-modified polypropylene. Further, in some implementations, the second polymer layer can 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 implementations, the second polymer layer can include LLDPE. In some implementations, the second polymer layer can include HDPE or LDPE.

[0096] In some implementations, 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 is also understood that the second polymer layer can include a copolymer of any of the polymers disclosed above. Further, in some implementations, the second polymer can be formulated from two or more polymers selected from any of the polymers disclosed above.

[0097] In some implementations, the thickness of the second polymer layer 208 can be from 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.

[0098] In some implementations, the first polymer layer can include polyurethane, polyether block amide, polyethylene oxide, or any combination thereof. In some aspects, the first polymer layer may be a thermoplastic polyurethane. In some implementations, the first polymer layer may be a composite material including polyurethane and polyether block amide. In some implementations, the first polymer layer may be a composite material including polyurethane and polyethylene oxide. In still some implementations, the first polymer layer may be a composite material including polyether block amide and polyethylene oxide. In still some implementations, the first polymer layer may be a composite material including polyurethane, polyether block amide, and polyethylene oxide.

[0099] Further, in some implementations, the first polymer layer may be a compound including more 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.

[0100] In such embodiments, the polyether-based thermoplastic material can be present in an amount greater than 0 wt% and 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-based thermoplastic polyurethane can be present in any amount between any two of the aforementioned values. In some implementations, the polyether-based thermoplastic polyurethane can be based on an aromatic polyether or an aliphatic polyether. In some embodiments, the polyether-based thermoplastic polyurethane used in the present disclosure can be those sold under the trade names Tecothane™ or TecoFlex™. In some implementations, the polyurethanes disclosed herein can include Pellethane® or Texin®.

[0101] In some implementations, polyethylene oxide can be present in an amount of about 5 wt% to about 80 wt%, including exemplary values of 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%. Polyethylene oxide can be present in any amount between any two of the aforementioned values.

[0102] In some implementations, the polyurethanes disclosed herein can have a durometer Shore D of about 50D to about 75D, including exemplary values of about 55D, about 60D, or about 70D. In some implementations, the polyurethanes disclosed herein can have a Shore A 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.

[0103] Furthermore, in some implementations, the first polymer layer is a polyether block amide. In certain embodiments, the polyether block amide can be PEBAX. In still some implementations, other polyamides such as Vestamid® and Nylon® can also be utilized.

[0104] In some implementations, the first polymer layer can be a compound comprising greater than 0 wt% to less than 100 wt% of a polyether block amide and from about 5 wt% to about 50 wt% of polyethylene oxide.

[0105] In such exemplary embodiments, the polyether block amide can be present 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 aforementioned values.

[0106] In some implementations, the polyethylene oxide can be present in an amount from about 5 wt% to about 80 wt%, including exemplary values of 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%. The polyethylene oxide can be present in any amount between any two of the aforementioned values.

[0107] In some implementations, the polyether block amide has a Shore hardness of from 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.

[0108] In some implementations, the polyethylene oxide (PEO) that can be used for the first polymer layer disclosed herein can have a molecular weight of from about 100,000 Daltons to about 7,000,000 Daltons, including exemplary values of 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 2,500,000 Daltons, about 2,750,000 Daltons, about 3,000,000 Daltons, about 3,250,000 Daltons, about 3,500,000 Daltons, about 3,750,000 Daltons, about 4,000,000 Daltons, about 4,250,000 Daltons, about 4,500,000 Daltons, about 4,750,000 Daltons, 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.

[0109] In some implementations, the thickness of the first polymer layer is from 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.

[0110] In some implementations, 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, as shown in FIG. 3. In such an embodiment, the third polymer layer 304 may be disposed between the first polymer layer 302 and the second polymer layer 306. In some implementations, the third layer can function as a tie layer that can bond the first polymer layer and the second polymer layer together. In certain embodiments, the third polymer layer can include any polymer disclosed herein, or it can include any polymer configured to function as a tie layer. In some implementations, the third polymer layer can include graft-modified polyethylene or graft-modified polypropylene. In some implementations, the third polymer layer may include Orevac®.

[0111] In embodiments where a third polymer layer is present, this polymer layer can have a thickness of from about 0.001 inches to about 0.025 inches, including exemplary values of about 0.0015 inches, about 0.002 inches, about 0.0025 inches, about 0.003 inches, about 0.0035 inches, about 0.004 inches, about 0.0045 inches, about 0.005 inches, about 0.0055 inches, about 0.006 inches, about 0.0065 inches, about 0.007 inches, about 0.0075 inches, 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.

[0112] In some implementations, the first polymer layer and / or the second polymer layer may include a filler. Further, in some implementations, if a third polymer layer is present, the third polymer layer may also include a filler. In some implementations, if a third polymer layer is present, this layer may be substantially free of filler.

[0113] It is understood that the filler, if present in the first polymer layer and / or the second polymer layer and / or the third polymer layer, may be the same or different. In some implementations, the filler may include bismuth oxychloride, barium sulfate, bismuth subcarbonate, calcium carbonate, aluminum trihydrate, barite, kaolin clay, limestone, titanium oxide, or any combination thereof. In some implementations, the filler may include a radiopaque material.

[0114] In some implementations, the first layer and the second layer (and the third layer, if present) may be formed by any method known in the art. For example, each layer may be extruded separately and then assembled together. Further, in some implementations, the first polymer layer and the second polymer layer may be co-extruded. In some implementations, if a third polymer layer is present, this layer may be co-extruded with the first polymer layer and the second polymer layer. Still further, in some implementations, if a third polymer layer is present, it may be co-extruded with the first polymer layer and then assembled with the second polymer layer extruded separately. Still yet, in some implementations, if a third polymer layer is present, this layer may be co-extruded with the second polymer layer and then assembled with the first polymer layer extruded separately. It is understood that these are exemplary and an introducer can be formed using any of the methods disclosed above.

[0115] Still further, in some implementations, each or all of the polymer layers present in the introducer may be at least partially crosslinked. For example, the first polymer layer containing any of the polymers or compounds disclosed above may be at least partially crosslinked. Similarly, the second polymer layer (and / or even the third polymer layer) containing any of the polymers or compounds disclosed above may be at least partially crosslinked. In some implementations, the first polymer layer may be substantially crosslinked. In some implementations, the second polymer layer (and / or the third polymer layer) may be substantially crosslinked.

[0116] In some implementations, crosslinking can be achieved by exposing any or all of the layers to an energy source, which can be selected from electron beam radiation, X-ray radiation, gamma ray radiation, or electromagnetic radiation. In certain embodiments, crosslinking is achieved by exposing the 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.

[0117] In some implementations, when a compound containing polyurethane and PEO, or a compound containing polyether block amide and PEO, is used to form the outer surface of the introducer, this outer surface of the introducer is substantially lubricious and 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 is understood that this coefficient of friction can be measured by any method known in the art. In some exemplary and non-limiting embodiments, the COF can be measured against a silicone pad. In such exemplary and non-limiting embodiments, the COF of the compounds of the present disclosure remains low compared to other polymers commonly used to form the outer surface of the introducer. In some implementations, the COF remains low and does not substantially change over at least 10 cycles of friction testing.

[0118] In some implementations where a compound containing polyurethane and PEO, or a compound containing polyether block amide and PEO, is used to form the outer surface of the introducer, the outer surface of the introducer demonstrates lubricious properties. In such exemplary and non-limiting embodiments, it is understood that due to the lubricious properties of the outer surface, there is no need to apply an additional hydrophilic coating to the surface. In such embodiments, the outer surface of the introducer does not include a hydrophilic coating.

[0119] In some implementations, when a compound containing polyurethane and PEO, or a compound containing polyether block amide and PEO, is used to form the outer surface of the introducer, such an introducer substantially generates no insoluble particulate matter that can be released into the patient's body. This feature of the introducers disclosed herein is particularly beneficial for further minimizing potential side effects, such as the release of nanoparticles into the patient's body, that can accumulate in the patient's organs and affect recovery and lifespan.

[0120] In some implementations, the proximal portion (FIG. 1A) of the introducer 100 is coupled to the hub 150 or an adapter to connect to a medical device. Still, the introducer 502 shown in FIG. 5, as disclosed herein, can be configured to receive a guidewire 508 used to deploy a medical device (not shown).

[0121] In some implementations, the sterilization process can be any sterilization process known in the art that can provide the desired level of sterilization for the medical device. In some aspects, the sterilization treatment is ethylene oxide-based. Ethylene oxide (also known as EO or EtO) is a low-temperature gas process widely used to sterilize various medical devices. Ethylene oxide sterilization is vacuum-based. EO sterilization is known to be able to efficiently penetrate the surfaces of most medical devices and is an ideal process for a wide variety of materials because of its lower temperature. Ethylene oxide sterilization can be controlled by controlling the gas concentration, humidity, temperature, and time. Generally, the humidity of the ethylene oxide gas used for sterilization is up to about 70%, including exemplary values of about 10%, about 20%, about 30%, about 40%, about 50%, and about 60%.

[0122] Ethylene oxide is an alkylating agent. It inhibits the cell metabolism and reproductive processes of microorganisms, and as a result, it can remove live microorganisms from instruments. Ethylene oxide can penetrate through breathable packages and various parts of instruments, enabling contact with all accessible surfaces of the product and providing the required sterility assurance level (SAL).

[0123] The introducers disclosed herein are designed to allow ethylene oxide gas, or other sterilizing fluids, such as gaseous fluids, to move and penetrate through the narrow inner diameter of the introducer and to minimize or eliminate ethylene oxide absorption on the surface of the introducer. For example, the presence of a hydrophobic second polymer layer allows ethylene oxide to move through the lumen without being substantially absorbed within the second polymer layer.

[0124] The effectiveness of sterilization can be evaluated by a validation process to ensure the sterility assurance level. Validation is performed by placing biological indicators (BIs) within the range of positions of the introducer where achievement of the sterilization conditions is most difficult. In some exemplary and non-limiting embodiments, the biological indicators are placed at various positions within 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 utilized. For example, without limitation, the biological indicator can include Geobacillus species or Bacillus species.

[0125] In some implementations, the introducer disclosed herein is configured to be substantially sterilized along substantially all of l1, through substantially all of d1 and d2, where substantial sterilization is defined by achieving effective inactivation of biological indicators in a fractional cycle of 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.

[0126] In some implementations, the introducer disclosed herein can achieve a sterilization assurance level of about 10 -6 in ethylene oxide sterilization.

[0127] Also disclosed herein is a delivery system comprising any of the introducers for medical devices disclosed herein, a delivery sheath, and an artificial valve. FIG. 4A shows the insertion of an exemplary introducer 402 into a delivery sheath 404. FIG. 4B shows the introducer 402 fully inserted into the delivery sheath 404 such that the tapered portion of the introducer extends beyond the distal end of the delivery sheath.

[0128] It is understood that any delivery sheath known in the art may be used. Some exemplary and non-limiting examples of delivery sheaths can be found in Patent Documents 3-14, the contents of which are hereby incorporated by reference in their entirety.

[0129] In yet some implementations, the artificial valve can be a mitral valve. Methods

[0130] Aspects of the present disclosure also relate to a method of making an introducer for a medical device disclosed herein, the method comprising forming an elongate 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 a lumen having a diameter d2, wherein the second layer is substantially more hydrophobic than the first layer, the elongate tube has a length l1, the ratio of l1 / d1 is greater than about 120, the ratio of l1 / d2 is greater than about 200 and less than about 2,000, and the introducer is configured to be substantially sterilized along substantially the entire length l1 and through substantially the entire d1 and d2.

[0131] In aspects disclosed herein, the first polymer layer can comprise any of the polymers disclosed above. Further, in some implementations, the second polymer layer can comprise any of the polymers disclosed above.

[0132] It is understood that any method known in the art for forming an elongate tube can be utilized. In certain aspects, the elongate tube can be extruded. In some aspects, each layer is extruded separately and then assembled together to form the desired configuration. Still, in some implementations, the forming step comprises co-extruding the first polymer layer and the second polymer layer. In some implementations, the elongate tube can further comprise a third polymer layer positioned between the first polymer layer and the second polymer layer. In such aspects, the third layer can comprise any of the polymers disclosed above. In some implementations, the third polymer layer can be co-extruded with the first polymer layer and the second polymer layer. In certain exemplary aspects, the third polymer layer can be co-extruded with the first polymer layer and then assembled with the second polymer layer. Still, in some implementations, the third polymer layer can be co-extruded with the second polymer layer and then assembled with the first polymer layer. In some implementations, all three polymer layers can be co-extruded.

[0133] In some implementations, any or all of the polymer layers present in the introducer configuration may be at least partially crosslinked. Further, in some implementations, any or all of the polymer layers present in the introducer configuration may be substantially crosslinked. In some implementations, crosslinking can be achieved by exposing any or all of the layers to an energy source, which can be selected from electron beam radiation, X-ray radiation, gamma ray radiation, or electromagnetic radiation. In certain embodiments, crosslinking is achieved by exposing the energy source at a dose of from 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.

[0134] Also disclosed herein is a method of delivering an artificial valve, including the steps of placing a guidewire, introducing any of the introducers disclosed herein, removing the guidewire, and placing the artificial valve at the implantation site. Exemplary treatment steps are shown in FIG. 5. The implantation site is prepared with an exemplary 23Fr guidewire 508. The delivery sheath 516 penetrates the septum 510 and moves the introducer 502 from the right atrium 514 to the left atrium 512. It can be seen that the introducer tip (or the distal tapered portion of the introducer disclosed herein) 502 extends from the upper part of the guide sheath 504.

[0135] It is understood that the above methods can be performed on a patient, on a living animal, or on a simulation (such as on a cadaver, a cadaver heart, an anthropomorphic dummy, a simulator (e.g., where a part of the body, the heart, tissue, etc. are simulated)).

[0136] Also disclosed herein is a method of exposing an introducer for a medical device to ethylene oxide gas containing from about 20% to about 70% moisture, including exemplary values of about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, and about 65% at a predetermined temperature for a predetermined time. It is understood that the predetermined time can be any time necessary to achieve the desired sterilization level. It is further understood that the sterilization level can be evaluated by placing a biological indicator (BI) within the introducer at the location that is most difficult to achieve the sterilization conditions. In some exemplary and non-limiting embodiments, the biological indicator can be placed at various positions within 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 utilized. For example, but not limited to, the biological indicator can include Geobacillus species or Bacillus species.

[0137] In some implementations, the method disclosed herein performs substantial sterilization substantially throughout l1 and substantially throughout d1 and d2, and the substantial sterilization is defined by achieving effective inactivation of the biological indicator in a fractional cycle of 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.

[0138] In still further implementations, the introducer disclosed herein can achieve a sterilization assurance level of about 10 -6 in ethylene oxide sterilization.

[0139] In some implementations, the exposing step includes one or more cycles of exposing to ethylene oxide gas. In some implementations, the first polymer layer, the second polymer layer, and the third polymer layer (if present) do not exhibit substantial degradation after the exposing step. [Examples]

[0140] Disclosed herein are introducers manufactured in accordance with 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, where 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 of the most distal end of the introducer is about 0.065 ± 0.003 inches.

[0141] The following table shows the sterilization results obtained for the introducers of the present invention compared to a reference introducer. The control is a reference introducer having the dimensions disclosed above and constructed from a single polymer layer of Shore 93A polyurethane such as Tecoflex® 93A. Example 1 is an introducer having the dimensions disclosed above and having polyurethane and high density polyethylene (HDPE) coextruded as the first and second layers, respectively. In this example, the thickness of the first layer is 0.128 inches and the thickness of the second layer is 0.005 inches. The first layer of this example has a composition of aliphatic polyether-based Tecoflex® 93A containing 40 wt% barium sulfate. The second layer of this example has a composition of HDPE.

[0142] Example 2 is an introducer having a first layer having dimensions disclosed herein and comprising a composite material of polyurethane and PEO, and a second layer comprising HDPE, wherein both the first layer and the second layer are coextruded. In this example, the thickness of the first layer is 0.128 inches and the thickness of the second layer is 0.005 inches. The first layer of this example has a composition of aromatic polyether-based polyurethane Pellethane® 55D containing 30 wt% poly(ethylene oxide) and 20 wt% barium sulfate. The second layer of this example has a composition of HDPE.

[0143] The D value is Stumbo Murphy Cochran:

Number

Number

Table 1

[0144] Example 1: An elongate 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 a lumen having a diameter d2, wherein the second layer is substantially more hydrophobic than the first layer, the elongate tube has a length l1, the ratio of l1 / d1 is greater than about 120, the ratio of l1 / d2 is greater than about 200 to about 2,000, and the introducer is configured to be substantially sterilized along substantially the entire length l1 and through substantially the entire d1 and d2, an introducer for a medical device.

[0145] Example 2: An introducer for a medical device according to any example herein, particularly Example 1, wherein the second polymer layer comprises one or more of polypropylene, polyethylene, graft-modified polyethylene, or graft-modified polypropylene.

[0146] Example 3: An introducer for a medical device according to any example herein, particularly 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), graft-modified ethylene polymers, graft-modified polypropylene, or ethylene vinyl acetate (EVA), or any combination thereof.

[0147] Example 4: An introducer for a medical device according to any example herein, particularly Example 2 or 3, wherein the graft-modified polyethylene or graft-modified polypropylene is maleic anhydride graft-modified or acrylic acid graft-modified.

[0148] Example 5: An introducer for a medical device according to any example herein, particularly Examples 1 to 4, wherein the first polymer layer comprises polyurethane, polyether block amide, polyethylene oxide, or any combination thereof.

[0149] Example 6: An introducer for a medical device according to any example herein, particularly Examples 1 to 5, wherein the first polymer layer is thermoplastic polyurethane.

[0150] Example 7: An introducer for a medical device according to any example herein, particularly Examples 1 to 5, wherein the first polymer layer is a compound comprising more 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.

[0151] Example 8: An introducer for a medical device according to any example herein, particularly Examples 1-7, wherein the polyurethane has a durometer Shore D of from about 50D to about 75D.

[0152] Example 9: An introducer for a medical device according to any example herein, particularly Examples 1-7, wherein the polyurethane has a Shore A of from about 25A to about 95A.

[0153] Example 10: An introducer for a medical device according to any example herein, particularly Examples 1-5, wherein the first polymer layer is a polyether block amide.

[0154] Example 11: An introducer for a medical device according to any example herein, particularly Examples 1-5, wherein the first polymer layer is a compound comprising greater than 0 wt% to less than 100 wt% polyether block amide and from about 5 wt% to about 50 wt% polyethylene oxide.

[0155] Example 12: An introducer for a medical device according to any example herein, particularly Examples 1-5 or 10-11, wherein the polyether block amide has a Shore hardness of from about 25D to about 72D.

[0156] Example 13: An introducer for a medical device according to any example herein, particularly Examples 7-9 or 11-12, wherein the molecular weight of the polyethylene oxide (PEO) is from about 100,000 to about 7,000,000.

[0157] Example 14: An introducer for a medical device according to any example herein, particularly Examples 1-13, wherein the first polymer layer has a thickness of from about 0.005 inches to about 0.150 inches.

[0158] Example 15: An introducer for a medical device according to any example herein, particularly Examples 1-14, wherein the second polymer layer has a thickness of from about 0.005 inches to about 0.035 inches.

[0159] Example 16: An introducer for a medical device according to any example herein, particularly Examples 1 to 15, further comprising a third polymer layer positioned between a first polymer layer and a second polymer layer.

[0160] Example 17: An introducer for a medical device according to any example herein, particularly Example 16, wherein the third polymer layer is a tie layer and comprises graft-modified polyethylene or graft-modified polypropylene.

[0161] Example 18: An introducer for a medical device according to any example herein, particularly Example 16 or 17, wherein the third polymer layer has a thickness of from about 0.001 inches to about 0.025 inches.

[0162] Example 19: An introducer for a medical device according to any example herein, particularly Examples 1 to 18, wherein the first polymer layer and / or the second polymer layer comprises a filler.

[0163] Example 20: An introducer for a medical device according to any example herein, particularly Examples 16 to 19, wherein the third polymer layer comprises a filler.

[0164] Example 21: An introducer for a medical device according to any example herein, particularly Example 20, wherein the filler comprises bismuth oxychloride, barium sulfate, bismuth subcarbonate, calcium carbonate, aluminum trihydrate, barite, kaolin clay, limestone, titanium oxide, or any combination thereof.

[0165] Example 22: An introducer for a medical device according to any example herein, particularly Examples 1 to 21, wherein the first polymer layer and the second polymer layer are coextruded.

[0166] Example 23: An introducer for a medical device according to any example herein, particularly Examples 16 to 22, wherein the first polymer layer and / or the second polymer layer and / or the third layer are coextruded.

[0167] Example 24: An introducer for a medical device according to any example herein, particularly Examples 1 to 23, wherein the first polymer layer and / or the second polymer layer is at least partially cross-linked.

[0168] Example 25: An introducer for a medical device according to any example herein, particularly Example 24, wherein cross-linking is achieved by exposure to an energy source selected from electron beam radiation, X-ray radiation, gamma ray radiation, or electromagnetic radiation.

[0169] Example 26: An introducer for a medical device according to any example herein, particularly Example 25, wherein cross-linking is achieved by exposing to an energy source at a dose of about 25 kGrey to about 100 kGrey.

[0170] Example 27: An introducer for a medical device according to any example herein, particularly Examples 1 to 26, wherein the first polymer layer and / or the second polymer layer is substantially cross-linked.

[0171] Example 28: An introducer for a medical device according to any example herein, particularly Examples 1 to 27, wherein the inner diameter d2 is substantially the same along the entire length l1.

[0172] Example 29: An introducer for a medical device according to any example herein, particularly Examples 1 to 28, wherein the introducer has a proximal portion and a distal portion.

[0173] Example 30: An introducer for a medical device according to any example herein, particularly Example 29, wherein the proximal portion is connected to a hub or an adapter to connect to a medical device.

[0174] Example 31: An introducer for a medical device according to any example herein, particularly Example 29 or 30, wherein the distal portion is tapered such that the outer diameter d1 decreases towards the distal end of the introducer while the inner diameter d1 remains substantially the same along the entire length l1.

[0175] Example 32: An introducer for a medical device according to any embodiment of the present specification, particularly embodiments 1 to 31, configured to receive a guide wire used to deploy a medical device.

[0176] Example 33: An introducer for a medical device according to any embodiment of the present specification, particularly embodiments 1 to 32, where sterilization is ethylene oxide-based.

[0177] Example 34: An introducer for a medical device according to any embodiment of the present specification, particularly embodiments 1 to 33, defined by achieving effective inactivation of biological indicators with a fractional cycle of less than about 1 CFU by substantial sterilization carried out substantially throughout l1 and substantially throughout d2.

[0178] Example 35: An introducer for a medical device according to any embodiment of the present specification, particularly embodiment 34, where the sterilization assurance level is about 10 -6 .

[0179] Example 36: An introducer for a medical device according to any embodiment of the present specification, particularly embodiments 7 to 9 or 11 to 35, where the outer surface of the introducer is substantially lubricious and exhibits a coefficient of friction (COF) of about 0.05 to about 0.5.

[0180] Example 37: An introducer for a medical device according to any embodiment of the present specification, particularly embodiments 7 to 9 or 11 to 36, where the outer surface of the introducer does not include a hydrophilic coating.

[0181] Example 38: An introducer for a medical device according to any embodiment of the present specification, particularly embodiments 7 to 9 or 11 to 37, configured to substantially not generate insoluble particulate matter.

[0182] Example 39: A delivery system comprising an introducer for a medical device according to any embodiment of the present specification, particularly embodiments 1 to 38, a delivery sheath, and an artificial valve.

[0183] Example 40: A method comprising the step of forming an elongated tube comprising a first polymer layer forming an outer surface of an introducer having an outer diameter d1 and a second polymer layer forming an inner surface of the introducer and defining a lumen having a diameter d2, wherein the second layer is substantially more hydrophobic than the first layer, the elongated tube has a length l1, the ratio of l1 / d1 is greater than about 120, the ratio of l1 / d2 is greater than about 200 to about 2,000, and the introducer is configured to be substantially sterilized along substantially the entire l1 and through substantially the entire d1 and d2, a method of making an introducer for a medical device according to any embodiment herein, particularly embodiments 1-38.

[0184] Example 41: A method according to any embodiment herein, particularly the method described in Example 40, wherein the forming step comprises co-extruding the first polymer layer and the second polymer layer.

[0185] Example 42: A method according to any embodiment herein, particularly the method described in Example 40 or 41, wherein the elongated tube further comprises a third polymer layer positioned between the first polymer layer and the second polymer layer.

[0186] Example 43: A method according to any embodiment herein, particularly the method described in Example 42, wherein the third polymer layer is co-extruded with the first polymer layer and the second polymer layer.

[0187] Example 44: A method of delivering an artificial valve, comprising the steps of placing a guidewire, introducing an introducer according to any one of Examples 1-38 herein, removing the guidewire, and placing the artificial valve at the implantation site.

[0188] Example 45: A method according to any embodiment herein, particularly the method described in Examples 1-38, comprising exposing an introducer for a medical device to ethylene oxide gas containing about 20% to about 70% moisture at a predetermined temperature for a predetermined time.

[0189] Example 46: The method according to any example herein, particularly Example 45, wherein the exposing step comprises one or more cycles of exposure to ethylene oxide gas.

[0190] Example 47: The method according to any example herein, particularly Example 45 or 46, wherein the exposing step achieves effective inactivation of the biological indicator in a fractional cycle of less than about 1 CFU.

[0191] Example 48: The method according to any example herein, particularly Example 47, wherein the exposing step achieves a sterility assurance level of about 10 -6 .

[0192] Example 49: The method according to any example herein, particularly Examples 45 - 48, wherein the first polymer layer, the second polymer layer, and the third polymer layer show substantially no degradation after the exposing step.

[0193] Considering the many possible aspects to which the disclosed principles may be applied, it should be recognized that the exemplified aspects are only some examples of the disclosure and should not be regarded as limiting the scope of the present disclosure. Rather, the scope of the present disclosure is defined by the following claims. Accordingly, the inventors claim as their disclosure all that comes within the scope and spirit of these claims.

Claims

Claim 1 An introducer for medical instruments, Outer diameter d １ A first polymer layer that forms the outer surface of the introducer having the same, and a second polymer layer that forms the inner surface of the introducer and defines a lumen having a diameter d ２ An elongated tube comprising the same, wherein the second polymer layer is substantially more hydrophobic than the first polymer layer The elongated tube has a length l １ and l １ / d １ The ratio of l １ / d ２ exceeds about 120, and the ratio of l The introducer is substantially l １ substantially d along the whole １ and d ２ An introducer configured to be substantially sterilized throughout the whole of d and d Claim 2 The introducer for medical instruments according to claim 1, wherein the second polymer layer contains one or more of polypropylene, polyethylene, graft-modified polyethylene, or graft-modified polypropylene. Claim 3 The introducer for medical instruments according to claim 2, wherein the second polymer layer contains 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 polymer, graft-modified polypropylene, or ethylene vinyl acetate (EVA), or any combination thereof. Claim 4 The introducer for medical instruments according to any one of claims 1 to 3, wherein the first polymer layer contains polyurethane, polyether block amide, polyethylene oxide, or any combination thereof. Claim 5 The introducer for medical instruments according to any one of claims 1 to 4, wherein the first polymer layer is a compound containing more than 0 wt% to less than 100 wt% of polyether-based thermoplastic polyurethane and about 5 wt% to about 50 wt% of polyethylene oxide. Claim 6 The introducer for medical instruments according to claim 4 or 5, wherein the polyurethane has a durometer Shore D of about 50D to about 75D and / or a Shore A of about 25A to about 95A. Claim 7 The introducer for medical instruments according to any one of claims 1 to 4, wherein the first polymer layer is a compound containing more than 0 wt% to less than 100 wt% of polyether block amide and about 5 wt% to about 50 wt% of polyethylene oxide. Claim 8 The introducer for medical instruments according to claim 7, wherein the polyether block amide has a Shore hardness of about 25D to about 72D. Claim 9 The introducer for medical instruments according to any one of claims 5 to 8, wherein the molecular weight of the polyethylene oxide (PEO) is about 100,000 daltons to about 7,000,000 daltons. Claim 10 The introducer for a medical device according to any one of claims 1 to 9, wherein the first polymer layer has a thickness of about 0.005 inches to about 0.150 inches and / or the second polymer layer has a thickness of about 0.005 inches to about 0.035 inches.

11. The introducer for a medical device according to any one of claims 1 to 10, further comprising a third polymer layer positioned between the first polymer layer and the second polymer layer, wherein the third polymer layer is a tie layer and includes graft-modified polyethylene or graft-modified polypropylene, and the third polymer layer has a thickness of about 0.001 inches to about 0.025 inches.

12. The 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) includes a filler.

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

14. The 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 co-extruded.

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 are at least partially crosslinked.

16. Inner diameter d ２ is substantially the same along the entire length l １ The introducer for medical instruments according to any one of claims 1 to 15

17. The introducer has a proximal portion and a distal portion, the proximal portion being connected to a hub or an adapter to connect to the medical device, and the distal portion having an outer diameter d １ that decreases towards the distal end of the introducer while having an inner diameter d １ that remains substantially the same along the entire length l １ and being tapered, the introducer for a medical device according to any one of claims 1 to 16.

18. The introducer for a medical device according to any one of claims 1 to 17, wherein the introducer is configured to receive a guide wire used to deploy the medical device.

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

20. Substantially l １ Substantially d along the whole ２ Substantial sterilization performed throughout is defined by achieving effective inactivation of biological indicators in a fractional cycle of less than about 1 CFU and / or the sterilization assurance level is about 10 －６ The introducer for medical instruments according to any one of claims 1 to 19, wherein the introducer is

21. The introducer for a medical device according to any one of claims 5 to 20, 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, and the outer surface of the introducer does not include a hydrophilic coating.

22. An introducer for a medical device according to any one of claims 1 to 21, a delivery sheath, and an artificial valve, comprising a delivery system.

23. A method of manufacturing an introducer for a medical device according to any one of claims 1 to 21, Outer diameter d １ Forming a first polymer layer that forms an outer surface of the introducer having the same, and an elongated tube having a second polymer layer forming an inner surface of the introducer and defining a lumen having a diameter d ２ including a step of defining a lumen having a diameter d, wherein the second polymer layer is substantially more hydrophobic than the first polymer layer The elongated tube has a length l １ and l １ / d １ The ratio of l １ / d ２ is greater than about 120, and the ratio of l The introducer is substantially l １ substantially d along the whole １ and d ２ A method configured to be substantially sterilized throughout the whole of d

24. The method according to claim 23, wherein the forming step includes a step of co-extruding the first polymer layer and the second polymer layer.

25. The method according to claim 23 or 24, wherein the elongated tube further comprises a third polymer layer positioned between the first polymer layer and the second polymer layer, and / or the third polymer layer is co-extruded with the first polymer layer and the second polymer layer.

26. A method of delivering an artificial valve, comprising the steps of placing a guide wire, introducing an introducer according to any one of claims 1 to 21, removing the guide wire, and placing the artificial valve at the implantation site.

27. Exposing an introducer for a medical device according to any one of claims 1 to 21 to ethylene oxide gas containing about 20% to about 70% moisture at a predetermined temperature for a predetermined time, a method.

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

29. The method according to claim 27 or 28, wherein the first polymer layer, the second polymer layer, and the third polymer layer (if present) do not substantially deteriorate after the exposing step.

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