Biodegradable tubular implants

Abstract

In this field, there is a need for medical implants that do not harm the host when they are disassembled, compared to existing products. [Solution] The implantable medical device has a zone with high in vivo stability and an adjacent zone with relatively low in vivo stability. As a result, when these medical devices are implanted in a host, the zone with low in vivo stability decomposes first, allowing the formation of a relatively intact, highly in vivo stable band, which is small enough to pass through the host in a harmless state and is an independent segment.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 610,055, filed on 22 December 2017 under 35 U.S.C. § 119(e), which is incorporated herein by reference in its entirety for all purposes.

[0002] This invention generally relates to biodegradable medical implants, as well as their manufacture and use. [Background technology]

[0003] Some medical implants need to be present in the host for only a limited period. After that period, the implant may be physically removed, but this often requires additional medical intervention. Alternatively, the implant may be left permanently in place. This option is suitable when the long-term presence of the implant is not harmful. As another alternative, the implant may be formed from a bioabsorbable material. Bioabsorbable materials are broken down and / or absorbed within the host, and their components and metabolites are eventually excreted. While bioabsorbable implants are increasingly desired by healthcare providers, these implants can cause undesirable consequences, such as the host being unable to tolerate the breakdown products. [Overview of the project] [Problems that the invention aims to solve]

[0004] In this field, there is a need for medical implants that do not harm the host when they are disassembled, compared to existing products. This invention relates to fulfilling that need. [Means for solving the problem]

[0005] This disclosure relates, in one aspect, to medical implants that degrade in a host, wherein the degradation is controlled to occur in a particularly desirable manner by physical or chemical characteristics incorporated into the implant. The implantable medical devices of this disclosure have a zone of relatively high in vivo stability and an adjacent zone of relatively low in vivo stability. As a result, when these medical devices are implanted in a host, the low in vivo stability zone degrades first, allowing the formation of a relatively intact, high in vivo stability band, which is small enough to pass through the host harmlessly. The low in vivo stability band is considered to have lower in vivo stability compared to the high in vivo stability band also present in the medical device. Thus, "low" and "high" are interpreted as being relative to each other, and the low in vivo stability zone has lower in vivo stability than the high in vivo stability band. The low in vivo stability band or zone degrades faster than the high in vivo stability band or zone.

[0006] For example, in one embodiment, a medical implant includes a hollow, overall tubular structure having a longitudinal axis running along the center of the lumen of the overall tubular structure and side walls defining the lumen of the structure. This tubular structure is composed of multiple bands, also called rings, zones, or annular strips, each surrounding the longitudinal axis. These multiple bands include relatively high in vivo stability (HIVS) bands separated from each other by relatively low in vivo stability (LIVS) bands. The low in vivo stability bands degrade more quickly than the high in vivo stability bands once the implant is implanted in a host. Since two LIVS bands can be positioned on either side of an HIVS band, when the implant is placed in a host, the two LIVS bands degrade first, leaving the HIVS band in between.

[0007] The overall tubular structure described herein may be identified as -(LIVS-HIVS)n-LIVS-, or the overall tubular structure may be identified as -(HIVS-LVS)n-HVS-. In either case, n refers to the number of LIVS-HIVS repeating units and is an integer from at least 1 to about 100. Optionally, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 4, 5, 6, 7, 8, 9, or 10. In addition to the overall tubular hollow structure, the medical implant may, and usually, include other features that make it useful for its intended purpose.

[0008] Accordingly, the overall tubular structure according to this disclosure may include, as three examples, the following parts: HIVS1-LIVS1-HIVS2-LIVS2-HIVS3, or HIVS1-LIVS1-HIVS2-LIVS2-HIVS3-LIVS3-HIVS4, or HIVS1-LIVS1-HIVS2-LIVS2-HIVS3-LIVS3-HIVS4-LIVS4-HIVS5. In these specifications, LIVS1, LIVS2, LIVS3, and LIVS4 are each bands with low in vivo stability, and HIVS1, HIVS2, HIVS3, HIVS4, and HIVS5 are each bands with high in vivo stability. When an implant of such a structure is placed in a host, the LIVS1, LIVS2, LIVS3, and LIVS4 bands degrade relatively quickly, while the HIVS2 and HIVS3 bands are released from the medical implant and will later degrade or be removed.

[0009] Accordingly, the overall tubular structure according to this disclosure may include, as three examples, the following parts: LIVS1-HIVS1-LIVS2-HIVS2-LIVS3, or LIVS1-HIVS1-LIVS2-HIVS2-LIVS3-HIVS3-LIVS4, or LIVS1-HIVS1-LIVS2-HIVS2-LIVS3-HIVS3-LIVS4-HIVS4-LIVS5. In these examples, LIVS1, LIVS2, LIVS3, LIVS4, and LIVS5 are each bands with low in vivo stability, and HIVS1, HIVS2, HIVS3, and HIVS4 are each bands with high in vivo stability. When an implant of such a structure is placed in a host, the LIVS bands degrade relatively quickly, and the HIVS bands between them can be separated from the medical device and later completely degraded or removed from the implant site.

[0010] Furthermore, the overall tubular structure according to this disclosure may include, as three examples, the following parts: LIVS1-HIVS1-LIVS2-HIVS2, or LIVS1-HIVS1-LIVS2-HIVS2-LIVS3-HIVS3, or LIVS1-HIVS1-LIVS2-HIVS2-LIVS3-HIVS3-LIVS4-HIVS4. In these examples, LIVS1, LIVS2, LIVS3, and LIVS4 are each bands with low in vivo stability, and HIVS1, HIVS2, HIVS3, and HIVS4 are each bands with high in vivo stability. When an implant of such a structure is placed in a host, the LIVS bands degrade relatively quickly, and the HIVS bands between them can be separated from the medical device and later completely degraded or removed from the implant site.

[0011] When a tubular structure according to this disclosure having alternating HIVS and LIVS bands is placed in a host, the degradation of the implant is predetermined in part by specifying the length of the HIVS bands separated by the LIVS bands (the length is defined as the distance along the longitudinal axis of the structure; sometimes also called the band width). If it is desirable that the degradation product of the implant be, for example, 5 cm or less, the structure may incorporate multiple HIVS bands of 5 cm or less in length, with LIVS bands of less than 1 cm in length incorporated alongside each HIVS band. For example, the LIVS bands may be as short as 1 cm or 0.5 cm in length, and each HIVS band may be 4 cm in length.

[0012] In another example, in one embodiment, the medical implant includes a hollow structure that is generally tubular, having a longitudinal axis along the center of the lumen of the overall tubular structure and side walls defining the lumen of the structure. This tubular structure may be further described as having a proximal end and a distal end. In this example, one end (either the proximal or distal end) disintegrates faster in vivo than the other end. This structure allows one end to disintegrate while the other end is effectively fixed in place. Such a structure can incorporate the aforementioned LIVS and HIVS bands. For example, if the implant structure includes proximal end-HIVS1-LIVS1-HIVS2-LIVS2-HIVS3-LIVS3-HIVS4-distal end, then LIVS3 disintegrates first, then LIVS2 disintegrates, separating HIVS3 from the implant, then LIVS1 disintegrates, separating HIVS2 from the implant. This structure allows the proximal end of the implant to remain embedded longer than the distal end, and furthermore, the length of the HIVS band can be controlled. Such a structure may be useful, for example, when the implant is a urethral stent and the proximal end of the implant is inserted into the kidney.

[0013] In another embodiment, the proximal end of a medical implant comprising a generally tubular hollow structure having a longitudinal axis along the center of the lumen of the generally tubular structure and side walls defining the lumen of the structure has a coating (referred to as an additional coating) that is not present on the distal end of the implant. The coating, or additional coating, is resistant to biodegradation and therefore prevents in vivo degradation of the implant. For example, the implant may be a urethral stent, and the proximal end of the stent, which is the end inserted into the host kidney, has a coating or additional coating that is not present on the distal end of the implant. In this way, the proximal end degrades more slowly in vivo than the distal end of the stent. This is an example of an apparatus according to the present disclosure having a composition vector, meaning that the composition of the implant varies along the dimensions of the implant, for example, there may be more coating present on the proximal end of the implant than on the distal end. Coating, or additional coating, may be applied to the presence of HIVS and LIVS bands in medical implants, thereby allowing the HIVS and LIVS bands to selectively achieve preferential decomposition at one end of the implant compared to the other (another approach to achieving a constructive vector).

[0014] In one embodiment, the HIVS and LIVS bands do not provide any functional advantage to the device; for example, the bands do not make the device stronger or more functional, but are present only to affect the implant's disintegration profile.

[0015] In one embodiment, an overall tubular structure is formed, and the structure is then treated to partially modify its structure to produce one or more HIVS and / or LIVS bands. For example, a structure inherently possessing a specific in vivo stability may be treated by methods disclosed herein, e.g., base or ultraviolet treatment, thereby converting the treated portion of the structure (e.g., a band) into a less in vivo stable portion, i.e., a portion that is less stable (degrades faster) when the structure is placed or implanted in a host (e.g., when a stent is implanted in a human), compared to the in vivo stability of the portion / band of the structure that has not been treated to alter the degradation rate. For example, a specific band of an overall tubular structure may be exposed to a degradation environment to produce a low in vivo stability (LIVS) band. Exemplary treatment conditions for producing LIVS bands include exposure to basic conditions, i.e., high pH aqueous conditions, and exposure to radiation, e.g., ultraviolet light. Since only the specific band of an overall tubular structure is exposed to these degradation environments, the exposed band is a LIVS band, and the unexposed band is an HIVS band. For example, looking at coil (10) in Figure 6A, bands A, C, and E are exposed to the decomposition environment, and LIVS bands are generated at the positions of A, C, and E, while bands B, D, and F are not exposed to the decomposition environment, and therefore HIVS bands are generated at the positions of B, D, and E.

[0016] The processing conditions, as described above, can generate LIVS bands or HIVS bands. For example, referring again to coil (10) in Figure 6A for illustrative purposes, a protective coating can be applied to a selected area to slow the rate of decomposition of coil (10). Thus, by applying the protective coating to bands A, C, and E, HIVS bands can be generated at positions A, C, and E, and LIVS bands can be provided at positions B, D, and F.

[0017] Optionally, the implant may include a containment layer surrounding a portion of the implant, the containment layer being configured to degrade the implant in a different manner than if the containment layer were absent. Also, optionally, the implant may include heterogeneity in composition, where the heterogeneous portion is more or less prone to degradation than the homogeneous portion of the adjacent implant. For example, the implant may include particles dispersed in a polymer, where the polymer is homogeneous and the particles provide heterogeneity that makes the polymer more susceptible to degradation than the polymer, or act as initiation sites for polymer degradation. Optionally, the medical device and / or the overall tubular structure may not include a containment layer that restricts the movement of fragments formed during in vivo degradation of the overall tubular structure.

[0018] In another embodiment, the Disclosure provides a method for fabricating a medical device. This method comprises providing a bioabsorbable medical device, which includes a generally tubular structure having a lumen running through the center of the generally tubular structure within the side walls of the generally tubular structure. In other words, a generally tubular hollow structure such as a stent. The bioabsorbable medical device may, if necessary, be fabricated from a biodegradable polyester. Bands along the generally tubular structure of the provided medical device are exposed to an ex vivo degradation environment, thereby generating bands with low in vivo stability (LIVS) from the exposed bands. Furthermore, bands adjacent to the exposed bands are not exposed to the same ex vivo degradation environment and therefore become bands with high in vivo stability (HIVS) adjacent to the LIVS bands. The Disclosure also provides medical devices prepared by this process and other processes described herein.

[0019] In each of the foregoing aspects and embodiments, the overall tubular structure can be a stent, such as a ureteral stent. A stent, such as a ureteral stent, can include a central coil, a mesh, and a coating. The central coil can be a coiled monofilament. The mesh can be disposed around the central coil. The coating is provided not only between the coil and the mesh but also on the surface of the mesh.

[0020] These are examples of controlled degradation according to the present disclosure, whereby a medical implant that degrades within a host is constructed and degradation occurs in a particularly desirable manner by physical or chemical characteristics incorporated into the construction of the implant.

[0021] The present disclosure discloses several medical devices, where any of the disclosed medical devices can be modified to exhibit controlled degradation by the means disclosed herein. For example, any of the medical devices can be modified to include slits or to have polymeric components that selectively degrade to have a molecular weight gradient, thereby providing a degradation profile of the device that occurs in a particularly desirable manner by physical or chemical characteristics incorporated into the implant based on the present disclosure.

[0022] This brief summary is provided to introduce, in simplified form, specific concepts that will be further described in detail below in the detailed description. Unless specifically stated otherwise, this brief summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.

[0023] Details of one or more embodiments are set forth in the following description. Features illustrated or described in connection with an exemplary embodiment may be combined with features of other embodiments. Accordingly, various combinations of the embodiments described herein can be provided to form further embodiments. Where it is necessary to adopt the ideas of various patents, applications, and publications as specified herein to provide further embodiments, aspects of the embodiments can be modified. Other features, objects, and advantages will be apparent from the description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Exemplary features, their nature, and various advantages of the present disclosure will become apparent from the accompanying drawings and the following detailed description of various embodiments. Non-limiting and non-exhaustive embodiments are described with reference to the accompanying drawings, and like labels or reference numbers refer to like parts throughout the various figures unless otherwise indicated. The sizes and relative positions of elements in the drawings are not necessarily drawn to scale. For example, the shapes of various elements are selected, enlarged, and arranged to improve the readability of the drawings. The particular shapes of the elements depicted are selected to facilitate recognition in the drawings. One or more embodiments are described below with reference to the accompanying drawings.

[0025] [Figure 1] An exemplary overall tubular structure is shown. [Figure 2] An exemplary overall tubular structure is shown. [Figure 3] An exemplary overall tubular structure is shown. [Figure 4] An exemplary overall tubular structure is shown. [Figure 5] An exemplary medical device incorporating an overall tubular structure is shown. [Figure 6A] Exemplary bands A - F of an overall tubular structure are shown. [Figure 6B] Exemplary bands A - F of an overall tubular structure are shown, with band A particularly emphasized. [Figure 6C]The example shows bands A-F with an overall tubular structure, with band C being particularly emphasized. [Figure 7A] This is a schematic diagram of a medical device according to the present disclosure, having positions A, B, C, D, and E located on an overall tubular portion of the medical device. [Figure 7B] This is a schematic diagram of a medical device according to the present disclosure, having positions A, B, C, and D located on an overall tubular portion of the medical device. [Figure 8] This graph shows the buckling strength of a tubular structure as a function of UV treatment and base treatment. [Figure 9] This graph shows the results of deflection tests on an overall tubular structure as a function of UV treatment and base treatment. [Figure 10A] This graph shows the results of tensile strength tests on an overall tubular structure as a function of the degree of base treatment. [Figure 10B] This graph shows the results of tensile strength tests on a generally tubular structure as a function of UV treatment time. [Modes for carrying out the invention]

[0026] The present invention can be more readily understood by referring to the following detailed description of preferred embodiments of the invention and the examples contained herein. It should be understood that the terms used herein are intended solely to describe specific embodiments and are not intended to be limiting. Furthermore, unless specifically defined herein, terms used herein should be given their traditional meanings known in the relevant art. Headings used herein are provided solely for the convenience of the reader and should not be construed as limiting the invention or the claims in any way.

[0027] Where used herein, including in the claims, the singular forms "a," "an," and "the" also include the plural unless otherwise indicated. For example, "a" polymer includes one or more polymers. As another example, "a" layer refers to one or more layers.

[0028] In the context of biodegradable medical devices, "degradation" means that the medical device, once placed in the host at its intended location, decomposes or deteriorates in a chemical or structural sense. For example, a device that breaks into pieces, such as splitting in half or crumbling into many fragments, is structurally biodegradable. If a device softens while implanted, it is also structurally biodegradable. If part or all of a device dissolves in the biological fluids it is in contact with, it is chemically biodegradable. Chemical biodegradation includes the occurrence of decomposition reactions such as hydrolysis, oxidation, and enzymatic bond cleavage. Absorbable or bioabsorbable medical devices are devices that decompose within the host. A biodegradable implantable medical device is one in which the manufacturer and / or healthcare provider recommends limiting its lifespan within the host. In other words, one reason the manufacturer and / or healthcare provider manufactures and / or selects the device is that it will naturally decompose within the host and not become a permanent fixture. Disintegration includes situations in which a complete mass loss occurs, but also situations in which a partial mass loss occurs, or situations in which structural weakening occurs in a location of the medical device, such as a band. For example, a less stable area of ​​the device of this disclosure may disintegrate to the extent that the mechanical and / or physical properties of the area are impaired, causing the area to crack and adjacent areas to no longer be in indirect contact with each other.

[0029] A “decomposition profile” refers to a description of how an implant decomposes. The decomposition profile provides a time course of implant decomposition and a geometric description of the decomposition over time. For example, an implant may have a decomposition profile, thereby decomposing from top to bottom along its length over a specified number of days. For example, in the case of a ureteral stent of this disclosure, which includes an overall tubular structure including multiple HIVS and LIVS bands, the stent can maintain patency and remain at the application site for at least two weeks, be removed, or be repositioned as a single piece within the ureter up to seven days post-implantation. The stent begins to fragment one to four weeks post-implantation, and the fragments can be excreted. More preferably, fragmentation may occur two to three weeks post-implantation. At five months, no portion of the stent remains at the application site. This is an exemplary decomposition profile of the medical device of this disclosure.

[0030] "Host" refers to mammals, such as humans, dogs, cats, and livestock. The host may also be referred to as a patient or subject. The host accepts the implantable medical device of this disclosure.

[0031] As used herein, implantable medical devices refer to devices such as instruments or equipment intended to be placed or implanted in the body of a host by a healthcare provider. Implants can be placed in the host in any suitable manner, such as intramuscular, subcutaneous, or intradermal, and can be placed in any suitable location, such as an opening, body cavity, or cavity of the host. Medical devices provide a medical purpose or benefit (as opposed to, for example, purely cosmetic) and improve the host's health through one or more of the following: diagnosis, prevention, treatment, or cure of an undesirable medical condition, such as a disease. Medical devices may provide therapeutic effects. Medical devices may provide preventive benefits. Medical devices may perform one or more of the following: supporting the performance of a parent medical device by enabling or facilitating the parent medical device to function according to its intended use; enhancing the performance of a parent medical device by adding a new function or a new way of using the parent medical device without changing the intended use of the parent medical device; or enhancing the performance of a parent medical device by enabling the device to perform its intended use more safely or effectively. Medical devices do not achieve their purpose solely by chemical action in the body, nor by metabolism.

[0032] The medical devices of this disclosure include an overall tubular structure as a component of the device. The overall tubular structure can be described as including a hollow lumen extending through the center of the tubular structure, where the hollow lumen is surrounded by the side walls of the overall tubular structure. In other words, the medical devices include a pipe-like component. The side walls of the medical devices of this disclosure may be solid, like the side walls of a pipe used to transport liquids or gases. However, unlike conventional pipes that transport fluids and have solid, impermeable side walls, the overall tubular structures of this disclosure do not necessarily have solid side walls. Figures 1 and 2 illustrate exemplary overall tubular structures of this disclosure that do not have solid, impermeable side walls. In Figure 1, the side walls are in the shape of a coil (10), so the overall tubular structure looks like a spring including a lumen (12). In Figure 2, the side walls are a more complex mesh-like structure (14) surrounding the lumen (12). In both the overall tubular structures of Figure 1 and Figure 2, the lumen (12) of the structure can be observed by viewing through the side walls (10) or (14), i.e., the side walls have openings so as not to be solid.

[0033] The sidewall may comprise more than a single component. For example, Figure 3 shows that a coil (10) as shown in Figure 1 has a sheath or blanket (16) wrapped around a portion of the coil (10). In Figure 3, for illustrative purposes, the blanket (16) is shown wrapped around only a portion of the coil (10), and such a structure is the overall tubular structure of the present disclosure. However, the blanket (16) can be wrapped around the entire perimeter of the overall tubular structure such that the coil (10) and lumen (12) are completely enclosed by the blanket (16). In Figure 3, the bracket appears solid, i.e., without holes. However, a bracket like (16) does not necessarily have to be solid and may have perforations. In fact, the blanket may be in the form of a mesh with multiple openings. For illustrative purposes, Figure 3 shows the blanket (16) as being combined with a coiled sidewall; however, according to this disclosure, the blanket may be combined with a supportive, overall tubular sidewall configuration, such as the structure (14) shown in Figure 2.

[0034] Another exemplary sidewall component of the overall tubular structures of this disclosure is a coating. For example, as shown in Figure 4, the overall tubular structure of Figure 3 comprises a coil (10), a lumen (12), and a blanket (16), which may be sprayed with or immersed in a solution of an organic polymer, resulting in a coating (18) being deposited on the outer and / or inner surfaces of the sidewalls. In Figure 4, the coating (18) is shown as a dark surface of the blanket (16) relative to the equivalent surface of the blanket (16) in Figure 3 (the blanket (16) in Figure 3 is not coated and therefore its surface is not dark), and is present on the inner surface of the blanket (16). That is, the coating (18) is on the surface of the blanket that is in contact with the coil (10) and facing the lumen (12). Generally, the sidewall coating is on and / or within the blanket (16) (especially when the blanket (16) is in the form of a mesh and the coating is applied by dipping or spraying the blanket (16) with a coating solution). As another example, the coil (10) in Figure 1 or the mesh (14) in Figure 2 may have a coating on part or all of the surface of the structure in order to provide a sidewall with a coating.

[0035] Accordingly, the medical device of this disclosure has an overall tubular structure having an open lumen that extends substantially through the center of the structure and is defined by adjacent side walls. The side walls may be a single component, as shown in Figures 1 and 2, or they may be multiple components, as shown in Figures 3 and 4.

[0036] The structures of the present disclosure are described as being generally tubular in order to clarify that the present invention is not limited to perfectly symmetrical structures. The diameter of the lumen may vary somewhat along the longitudinal axis of the structure, for example. As another example, a generally tubular structure does not necessarily have to be strictly linear and may be bent or curved to some extent. Typically, a generally tubular structure has a lumen, the lumen having an average diameter determined by the distance between points on the side walls (the distance passing through the center point of the lumen), and the average diameter is shorter than the length of the lumen along the longitudinal axis extending from the proximal end to the distal end of the generally tubular structure.

[0037] One well-known medical device having an overall tubular structure is a stent, and in one embodiment, the medical device of this disclosure is a stent. Thus, in one aspect, the medical device is a stent useful for maintaining or creating patency of tubes, such as conduits or blood vessels, within a host. Exemplary conduits and blood vessels are found, for example, along the gastrointestinal (GI) tract of the host, including the esophagus, the intestines including the transverse colon, the descending colon, the ascending colon, the sigmoid colon, and the small intestine. The small intestine includes the duodenum, jejunum, ileum, cecum, and rectum.

[0038] In one embodiment, the medical implant is designed to be placed in the ureter, i.e., the tube that carries urine from the kidney to the bladder. In another embodiment, the medical implant is designed to be placed in the urethra, i.e., the tube that carries urine from the bladder to the outside of the host. In yet another embodiment, the medical implant is designed to be placed within a blood vessel; for example, the medical implant is a coronary artery stent or a peripheral stent intended to be placed within a peripheral artery. Other exemplary conduits and blood vessels are found in organs such as the heart, pancreas, prostate, and kidneys. Another location where conduits or blood vessels exist within the host and where medical implants may be placed according to this disclosure is the mammary duct that carries milk from the lobules (milk-producing glands) to the nipple. Other locations for tubular medical implants include the ear, lacrimal duct, and sinuses. Such medical implants are referred to herein as stents.

[0039] A generally tubular structure may be a component of the medical device of this disclosure. For example, as shown in Figure 5, the medical device 20 may include a generally tubular structure identified by an enclosed region 22, and also include a proximal end region 24 and a distal end region 26, which may or may not be generally tubular. Device 20 is an example of a ureteral stent, including a curled region 24 at the proximal end of the device which can be inserted into the host's kidney, and a curled region 26 at the distal end of the device which can be inserted into the host's bladder.

[0040] In one aspect, the medical device is formed at least partially from one or more thermoplastic, thermosetting, or elastomer polymers. Optionally, the overall tubular structure is made entirely from polyester, where the term polyester means including one or more polyester polymers. Optionally, the overall tubular structure is made partially from polyester, where the term polyester means including one or more polyester polymers.

[0041] In one aspect, the medical device is sterile. Optionally, the medical device is sterilized using gamma rays or electron beams. In one aspect, the medical device is sterilized using gamma rays at 23–45 kGy. In another aspect, the medical device is sterilized using gamma rays at 25–40 kGy. In yet another embodiment, the medical device is placed in a heat-sealed foil pouch before sterilization.

[0042] In one aspect, medical devices are intended to be completely embedded in the host, i.e., entirely beneath the host's skin, in contrast to, for example, hearing aids that are seated in the ear, dental prostheses that are seated in the host's mouth, or contact lenses that are seated in the host's eye. In another aspect, implantable medical devices are intended to be placed in internal passages such as conduits or blood vessels. Examples of implantable medical devices that may be disassemblable include stents, shunts, sutures, and surgical meshes. Implantable medical devices are also described in the following patent documents: US8,753,387; US8,101,104; US7,594,928; and US2014 / 0288636.

[0043] In short, the present invention provides a medical implant whose degradation is controlled after it is implanted in a host. During the process of bioresorption within the host, the medical device of this disclosure degrades, i.e., exhibits in vivo degradation. To control this degradation process, for example, to control the timing, type, degree of degradation, and movement of the degraded medical device and its parts within the host, the medical implant may include multiple high in vivo stability (HIVS) bands and low in vivo stability (LIVS) bands. As these names suggest, the HIVS band is relatively stable in vivo (post-implant) compared to the LIVS band.

[0044] Figure 6A shows the overall tubular structure of the coil (10). In Figure 6A, the overall tubular structure is divided into bands identified as A, B, C, D, E, and F. Each of these bands A through F occupies a certain length of the overall tubular structure. In Figure 6A, the lengths are shown as equal to one another, but generally, the bands do not need to be equal to one another in terms of length. To clarify the portion of the coil (10) located in band A, a box (30) formed from dashed lines is added to the diagram in Figure 6A to provide the illustration in Figure 6B. As shown in Figure 6B, band A surrounds roughly the first two coils of the overall tubular structure.

[0045] As another illustration of the band structure, a box (32) is superimposed on the region of a coil (10) corresponding to band C of the overall tubular structure shown in Figure 6C. Figure 6C is the lumen 12 of the overall tubular structure, through which the longitudinal axis (34) extends from the distal end (36) to the proximal end (38) of the overall tubular structure. The sides of the band, for example, band (32) shown in Figure 6C, may be partially characterized by having a distal side and a proximal side, such as the distal side (40) and proximal side (42) of band C (32) in Figure 6C. In Figure 6C, feature (44) refers to the overall tubular structure, which includes a coil (10) providing the sidewall of the overall tubular structure and a lumen (12) extending within the sidewall from the distal end (36) to the proximal end (38) of the overall tubular structure (44). In Figure 6C, the length of a band, for example, band C, is measured as the distance between the distal side of the band (e.g., side (40) in Figure 6C) and the proximal side of the band (e.g., side (42) in Figure 6C).

[0046] In one embodiment, the Disclosure provides a bioabsorbable implantable medical device comprising an overall tubular structure, the overall tubular structure comprising side walls surrounding a lumen, with a longitudinal axis extending along the length of the lumen from the distal end to the proximal end of the structure. The tubular structure further comprises a plurality of bands, each surrounding the longitudinal axis and having a distal and a proximal end. The plurality of bands include several bands having relatively high in vivo stability (HIVS), and these HIVS bands are separated from each other by relatively low in vivo stability (LIVS) bands. This structure allows the medical device of the Disclosure to undergo in vivo degradation such that the LIVS bands degrade faster than the HIVS bands. This provides an efficient means for the entire tubular structure to degrade, as the LIVS bands degrade rapidly, leaving the HIVS bands behind. The HIVS bands are selected to have the maximum length that will not harm the host when these HIVS bands are passed through a conduit located at the site where the medical device is installed. If the HIVS bands are too long, they can clog the host's ducts, causing problems until the HIVS bands degrade. On the other hand, if the HIVS bands are short enough, they can easily pass through the ducts even before they have completely degraded, making removal from the host easier. It is desirable that the HIVS bands be long enough so that parts of the tubular medical device can be excreted from the host even before relatively large portions have completely degraded. In this mechanism, the degradation of the bioabsorbable implant does not depend entirely on the rate of biodegradation of the polymers that make up the implant. Instead, the implant breaks down into small fragments (each fragment being an HIVS band) that can be easily removed from the ducts by the host's natural biological processes, such as fluids flowing through the ducts. In one embodiment, the HIVS bands are selected to have a relatively short length so that when the device is placed in vivo, they effectively create breaks in the tubular structure as a whole, and these breaks release the HIVS bands.

[0047] The medical device of this disclosure may include an overall tubular structure, which can be identified as the proximal end of a tube - the distal end of a (LIVS-HIVS)n-LIVS tube, or the proximal end of a tube - the distal end of a (HIVS-LVS)n-HVS tube. In either case, n refers to the number of LIVS-HIVS repeating units and is an integer from at least 1 to about 100. Optionally, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 4, 5, 6, 7, 8, 9, or 10. In this embodiment, the tubular structure includes alternating bands of relatively high in vivo stability and relatively low in vivo stability. Optionally, the tubular structure contains X LIVS bands and X+1 HIVS bands, resulting in one more HIVS band than the number of LIVS bands. Alternatively, the tubular structure contains Y HIVS bands and Y+1 LIVS bands, resulting in one more LIVS band overall compared to the number of HIVS bands in the tubular structure. X or Y can be selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and any combination thereof, for example, 1 or 2 or 3, or 1, 2, 3 or 4; or 2, 3 or 4, etc.

[0048] In some embodiments, the medical device has at least one band with relatively high in vivo stability and at least two bands with relatively low in vivo stability. Optionally, the HIVS band and LIVS band are arranged alternately along the length of the medical device. For example, optionally, the device has just one HIVS band and two LIVS bands, with one LIVS band on each side of the HIVS band, i.e., a configuration represented as LIVS-HIVS-LIVS. This configuration allows the two LIVS bands to degrade relatively rapidly, freeing the HIVS band (which does not degrade completely due to its relatively higher in vivo stability compared to the LIVS band) from the rest of the medical implant, allowing the HIVS band to pass through the host by natural biological action.

[0049] In some embodiments, the medical device has at least two bands with relatively high in vivo stability and at least one band with relatively low in vivo stability. Optionally, the HIVS bands and LIVS bands are arranged alternately along the length of the medical device. For example, optionally, the device has just two HIVS bands and one LIVS band, with one HIVS band on each side of the LIVS band, i.e., a configuration represented as HIVS-LIVS-HIVS. This configuration allows one LIVS band to degrade relatively rapidly, freeing the two HIVS bands (which are relatively more in vivo stable than the LIVS bands and therefore not completely degraded) from the rest of the medical implant, allowing the HIVS bands to pass through the host by natural biological action.

[0050] In some embodiments, the medical device has at least two relatively high in vivo-stable bands and at least three relatively low in vivo-stable bands. Optionally, the HIVS bands and LIVS bands are arranged alternately along the length of the medical device. For example, optionally, the device has just two HIVS bands and three LIVS bands, resulting in a configuration represented as LIVS-HIVS-LIVS-HIVS-LIVS. This configuration allows the LIVS bands to degrade relatively rapidly, freeing the HIVS bands from the rest of the medical implant, and enabling the HIVS bands to pass through the host from where the device is placed by natural biological action.

[0051] In some embodiments, the medical device has at least three relatively high in vivo-stable bands and at least four relatively low in vivo-stable bands. Optionally, the HIVS bands and LIVS bands are arranged alternately along the length of the medical device. For example, optionally, the device has just three HIVS bands and four LIVS bands, resulting in a configuration represented as LIVS-HIVS-LIVS-HIVS-LIVS-HIVS-LIVS. This configuration allows the LIVS bands to degrade relatively rapidly, freeing the HIVS bands from the rest of the medical implant, and enabling the HIVS bands to pass through the host from where the device is placed by natural biological action.

[0052] HIVS and LIVS bands may have a specific length when their dimensions are measured along the longitudinal axis of the tubular structure. This dimension is sometimes referred to as the band width instead, in which case the band length and width refer to the same dimension. In one embodiment, the LIVS band of the medical device of this disclosure has a shorter length than the HIVS band of the medical device. For example, the HIVS band is longer than 1 cm, or longer than 1.1 cm, or longer than 1.2 cm, or longer than 1.3 cm, or longer than 1.4 cm, or longer than 1.5 cm. On the other hand, the LIVS band is shorter than 1 cm, or shorter than 0.9 cm, or shorter than 0.8 cm, or shorter than 0.7 cm, or shorter than 0.6 cm, or shorter than 0.5 cm. Thus, a relatively small LIVS band decomposes relatively quickly. Relatively large HIVS bands remain, decompose more slowly, and / or are discharged from the conduit in which the device is installed, according to the host's natural mechanisms (e.g., the flow of fluid through the conduit causes the free HIVS bands (i.e., HIVS bands that are no longer attached to the medical device) to exit the conduit).

[0053] In other words, in one embodiment, the HIVS band is longer (wider) than the LIVS band. Thus, the HIVS band extends longer along the longitudinal axis of the tubular structure than the LIVS band. For example, in one embodiment, the medical device includes at least two relatively high in vivo-stable bands, each having a width of 1 to 6 cm, and these bands are separated from each other by a relatively low in vivo-stable band having a width of less than 1 cm. In this embodiment, the length of the tubular structure is mainly occupied by the HIVS bands separated by the LIVS bands. Such a structure may be specified as (LIVS-HIVS)n-LIVS, where n refers to the number of LIVS-HIVS repeating units, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, the width of each LIVS band is less than 1 cm, or less than 0.8 cm, or less than 0.6 cm, or less than 0.4 cm, or less than 0.2 cm, or less than 1 cm, and the width of each HIVS band is 1 cm or more.

[0054] Optionally, the device has at least two HIVS bands, each HIVS band having a length of 2–6 cm. A LIVS band lies between the two HIVS bands, and the length of the LIVS band is less than 1 cm. Such a structure may be specified as (LIVS-HIVS)n-LIVS, where n refers to the number of LIVS-HIVS repeating units, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, the width of each LIVS band is less than 1 cm, or less than 0.8 cm, or less than 0.6 cm, or less than 0.4 cm, or less than 0.2 cm, or less than 1 cm, and each HIVS band is at least 1 cm wide.

[0055] Optionally, the device has at least two HIVS bands, each HIVS band having a length of 3–6 cm. A LIVS band lies between the two HIVS bands, and the length of the LIVS band is less than 1 cm. Such a structure may be specified as (LIVS-HIVS)n-LIVS, where n refers to the number of LIVS-HIVS repeating units, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, the width of each LIVS band is less than 1 cm, or less than 0.8 cm, or less than 0.6 cm, or less than 0.4 cm, or less than 0.2 cm, or less than 1 cm, and each HIVS band is at least 1 cm wide.

[0056] Optionally, the medical device has at least three relatively high in vivo stability bands, each of which is 3–6 cm long. These three HIVS bands are separated by two relatively low in vivo stability bands, each less than 1 cm long. Such a structure can be identified as HIVS-LIVS-HIVS-LIVS-HIVS.

[0057] Optionally, the medical device has at least three relatively high in vivo stable bands, with each HIVS band having a length of 3–6 cm. Furthermore, the device has at least four LIVS bands seated on either side of the HIVS bands. Each LIVS band is less than 1 cm wide. Such a structure may be identified as LIVS-HIVS-LIVS-HIVS-LIVS-HIVS-LIVS.

[0058] Optionally, the medical device has at least four relatively high in vivo stability bands, each of which is 3–6 cm long. These four HIVS bands are separated by three relatively low in vivo stability bands, each less than 1 cm long. Such a structure can be identified as HIVS-LIVS-HIVS-LIVS-HIVS-LIVS.

[0059] Optionally, the medical device has at least three relatively high in vivo stability bands, each HIVS band being 2–5 cm long and separated by two relatively low in vivo stability bands, each less than 1 cm long. Alternatively, the medical device has at least three relatively high in vivo stability bands, each HIVS band being 3–6 cm long and separated by two relatively low in vivo stability bands, each less than 1 cm long.

[0060] In one embodiment, all LIVS bands degrade faster than the HIVS bands present in the medical device of the Disclosure. Thus, in one embodiment, the Disclosure provides a medical device comprising an overall tubular structure, wherein the tubular structure comprises at least two relatively high in vivo stable bands (separated by one relatively low in vivo stable band), the relatively low in vivo stable band degrades at least twice as fast in vivo compared to at least one relatively high in vivo stable band.

[0061] Optionally, all HIVS bands degrade at substantially the same rate in vivo. Accordingly, the present disclosure provides a medical device comprising an overall tubular structure, wherein the tubular structure comprises multiple bands having substantially identical and relatively high in vivo stability.

[0062] Optionally, all LIVS bands degrade at substantially the same rate in vivo, thereby generating multiple independent LIVS bands substantially simultaneously by in vivo decomposition of the medical device. Accordingly, the present disclosure provides a medical device comprising an overall tubular structure, wherein the tubular structure comprises at least two relatively high in vivo stable bands (separated by one relatively low in vivo stable band), and the at least two relatively high in vivo stable bands have substantially identical in vivo stability. Furthermore, the present disclosure provides a medical device comprising an overall tubular structure, wherein the tubular structure comprises at least two relatively low in vivo stable bands (separated by one relatively high in vivo stable band), and the at least two relatively low in vivo stable bands have substantially identical in vivo stability.

[0063] However, as an alternative, the LIVS bands do not all disintegrate at the same rate. For example, the medical device of this disclosure may include a tubular structure containing two bands with relatively low in vivo stability located on either side of one band with relatively high in vivo stability, the two bands with relatively low in vivo stability having different in vivo stabilities. This option may be useful when it is desirable that the disintegration of the medical device preferentially occurs from one end of the device compared to the other. For example, if it is desirable that the proximal end of the device disintegrate faster than the distal end, a structure can be manufactured that includes proximal end-LIVS1-HIVS1-LIVS2-HIVS2-LIVS3-HIVS3-LIVS4-distal end. In this case, LIVS1 is designed to disintegrate faster than LIVS2, LIVS2 is designed to disintegrate faster than LIVS3, and LIVS3 is designed to disintegrate faster than LIVS4. In this situation, LIVS1 disintegrates first, providing the free end of HIVS1. When LIVS2 decomposes, HIVS1 is completely released from the remaining medical device and can subsequently decompose or be discharged through the conduit to which the medical device is installed. Subsequently, LIVS3 decomposes, completely releasing HIVS2 from the medical device and making it possible to discharge HIVS2 through the conduit. Subsequently, LIVS4 decomposes, completely releasing HIVS3 from the medical device and making it possible to discharge HIVS3 through the conduit.

[0064] In one embodiment, the disclosure provides a medical device having an overall tubular structure, wherein the tubular structure includes a first relatively low in vivo stability band located distal to a first relatively high in vivo stability band, and a second relatively low in vivo stability band located proximal to the first relatively high in vivo stability band, wherein the first relatively low in vivo stability band has higher in vivo stability than the second relatively low in vivo stability band.

[0065] In one embodiment, the disclosure provides a medical device having an overall tubular structure, wherein the tubular structure includes a plurality of relatively low in vivo stability bands separated by a relatively high in vivo stability band extending from the distal end to the proximal end of the structure, the in vivo stability of the plurality of relatively low in vivo stability bands increasing from the distal end to the proximal end of the structure.

[0066] In one embodiment, an overall tubular structure is formed, and then the structure is processed to generate one or more HIVS and / or LIVS bands. For example, specific bands of the overall tubular structure may be exposed to a degradation environment to generate low in vivo stability (LIVS) bands. Exemplary processing conditions for generating LIVS bands include exposure to basic conditions, i.e., high pH aqueous conditions, and exposure to radiation, such as ultraviolet light. Since only specific bands of the overall tubular structure are exposed to these degradation environments, the exposed bands become LIVS bands, while the unexposed bands remain relatively stable in vivo, i.e., HIVS bands. For example, looking at coil (10) in Figure 6A, when bands A, C, and E are exposed to a degradation environment, LIVS bands are generated at the positions of A, C, and E, while bands B, D, and F are not exposed to a degradation environment, so the positions of B, D, and F become HIVS bands. As mentioned above, LIVS and HIVS are relative terms. The high in vivo stability (HIVS) band indicates higher in vivo stability than the low in vivo stability (LIVS) band.

[0067] As an example of a medical device of the present disclosure, Figure 7A provides a schematic image of a ureteral stent having a renal curl at one end providing a kidney-retaining end and a bladder curl at the other end providing a bladder-retaining end at the other end of the stent. The schematic diagram of Figure 7A identifies positions A, B, C, D, and E, which are located between the renal curl and the bladder curl, and are in a generally tubular structure. In this schematic diagram, each of positions A, B, C, D, and E is the midpoint of a band (such as a LIVS band) with a width of approximately 0.1 to 0.5 cm. The region between the bands with midpoints A to E is the HIVS band. In summary, A, B, C, D, and E each represent the position of the LIVS band, and the regions between A and B, between B and C, between C and D, and between D and E each represent the position of the HIVS band. To achieve a degradation gradient, the band at position E is exposed to a relatively harsh degradation environment, the band at position D to a slightly less harsh environment, and the band at position C to an even less harsh environment than the one used to generate the band at position D. The same applies to the bands at positions B and A. Thus, the band at position A is exposed to the least harsh degradation environment, and the harshness of the degradation environment increases in the order of A, B, C, D, and E. In Figure 7A, position E is subjected to degradation with, for example, 1.5 M NaOH, position D to 1.25 M NaOH, position C to 1.0 M NaOH, position B to 0.75 M NaOH, and position A to 0.5 M NaOH. The exposure time for these different positions to the degradation environment is constant, the only difference being the strength of the base solution to which the bands are exposed. Alternatively, one could use a base of the same strength to decompose each band and generate LIVS bands, but the band at position E would be exposed to the base solution for the longest time, the band at position A for the shortest time, and the intermediate band for an intermediate time.

[0068] According to this gradient of degradation, the LIVS band at position E degrades the fastest compared to the other bands. Even after the band at position E degrades to its breakdown point, the HIVS region between positions E and D remains part of the overall tubular structure. However, of the remaining LIVS bands D-A, the LIVS band at position D degrades the fastest. Therefore, the next LIVS band to break is the LIVS band at position D, thus releasing the HIVS band between the LIVS bands with midpoints at positions D and E from the medical device. In the absence of a containment layer or equivalent function, this separated HIVS band can be expelled from the host's body. The LIVS band at position C degrades faster than the LIVS bands at positions B or A, and once the LIVS band at position C degrades and breaks down, the HIVS band between positions C and D is released from the medical device and can be expelled from the host's body. This gradient of degradation environment allows for safe control of the degradation of medical implants without the need to rely on a containment layer. By appropriately selecting the location of the HIVS band, the fragments formed during the breakdown of the overall tubular structure of the medical implant are small enough that the isolated HIVS band is expelled from the host's body, thus preventing the isolated HIVS band from posing a health risk to the host.

[0069] Figure 7B is based on the schematic diagram shown in Figure 7A, but with different positions A, B, C, and D. In Figure 7B, the resolution gradient can be generated by progressively exposing the bands at positions A, B, C, and D to resolving radiation, such as ultraviolet radiation, for progressively longer periods of time. In this approach, the LIVS band at position D resolves before the LIVS band at position C, the LIVS band at position B resolves later than the LIVS band at position C, and among the bands at positions A, B, C, and D, the LIVS band at position A resolves the slowest. For example, the band at position D may be exposed to ultraviolet radiation for 15 seconds, the band at position C for 12 seconds, the band at position B for 9 seconds, and the band at position A for 6 seconds.

[0070] In one embodiment, the present disclosure provides a method for fabricating a medical device. The method includes providing a medical device comprising a bioabsorbable, overall tubular structure. A degradation environment is then applied to at least two bands of the overall tubular structure, thereby generating at least two low in vivo stability (LIVS) bands. One or more high in vivo stability (HIVS) bands are located between any two LIVS bands. The degradation environment achieves the degradation of the bands of the overall tubular structure to which it is applied. The degradation environment may be, for example, an aqueous base. Alternatively, the degradation condition may be ultraviolet light. The overall tubular structure may be made entirely or partially from a bioabsorbable polyester, and the base or ultraviolet radiation achieves partial degradation of the polyester.

[0071] The processing conditions, as described above, can generate LIVS bands or HIVS bands. For example, referring again to coil (10) in Figure 6A for illustrative purposes, the rate of decomposition of coil (10) can be slowed by applying a protective coating to selected areas of the overall tubular structure. Thus, by applying the protective coating to bands A, C and E, HIVS bands can be generated at positions A, C and E, and LIVS bands can be provided at positions B, D and F. In one embodiment, the coating is a bioabsorbable polyester.

[0072] In one embodiment, the present disclosure provides a method for fabricating a medical device. The method includes providing a medical device comprising a bioabsorbable, overall tubular structure. A degradation environment is then applied to at least two bands of the overall tubular structure, thereby generating at least two low in vivo stability (LIVS) bands. One or more high in vivo stability (HIVS) bands are located between any two LIVS bands. The degradation environment achieves the degradation of the bands of the overall tubular structure to which it is applied. The degradation environment may be, for example, an aqueous base. Alternatively, the degradation condition may be ultraviolet light. The overall tubular structure may be made entirely or partially from a bioabsorbable polyester, and the base or ultraviolet radiation achieves partial degradation of the polyester.

[0073] This disclosure also provides a method for fabricating a medical device, including providing a bioabsorbable medical device, wherein the bioabsorbable medical device includes a generally tubular structure having a lumen running through the center of the generally tubular structure within the side walls of the generally tubular structure. In other words, it is a generally tubular hollow structure such as a stent. The bioabsorbable medical device may, if necessary, be fabricated from a biodegradable polyester. Bands along the generally tubular structure of the provided medical device are exposed to an ex vivo degradation environment, thereby generating bands with low in vivo stability (LIVS) from the exposed bands. Furthermore, bands adjacent to the exposed bands are not exposed to the same ex vivo degradation environment and therefore become bands with high in vivo stability (HIVS) adjacent to the LIVS bands. This disclosure also provides medical devices prepared by this process and other processes described herein.

[0074] In one embodiment, the decomposition environment is or includes ultraviolet radiation. Moderate ultraviolet radiation is applied to a portion of the overall tubular structure, and the ultraviolet radiation strikes that portion of the overall tubular structure, altering its structure so that the affected portion has a higher in vivo decomposition rate compared to adjacent portions of the overall tubular structure that are not exposed to ultraviolet radiation. To achieve selective exposure of the overall tubular structure to ultraviolet radiation, a band or other shaped portion is shielded from exposure to ultraviolet radiation, while adjacent bands or other portions are not shielded. Shielding can be achieved by masking the overall tubular structure. The mask has holes through which ultraviolet radiation can pass and come into contact with the overall tubular structure, but also radiopaque areas through which ultraviolet radiation cannot pass. Shielding can also be achieved by placing the overall tubular structure within a metal block having a lumen into which the overall tubular structure can be inserted and seated in a resting position. The metal block may have holes that penetrate the metal, i.e., holes that extend between the outer surface of the metal block and the lumen of the metal block. Since ultraviolet light can be guided from the outer surface of the block into the holes, the radiation enters the lumen of the metal block through the holes, and then the ultraviolet light strikes that portion of the overall tubular structure that is exposed to this ultraviolet light. By adjusting or selecting the diameter of the holes, the size of the portion of the tubular structure that is struck by the ultraviolet radiation is also selected. For example, if the diameter of the holes is 5 mm, the length of the overall tubular structure that is exposed to the ultraviolet radiation will also be approximately 5 mm.

[0075] The tubular structure may or may not have a solid support (e.g., an opaque rod) passing through its lumen while the structure is exposed to ultraviolet radiation. In particular, when an opaque rod passes through the lumen of the tubular structure, this rod may prevent some parts of the tubular structure from being exposed to incoming ultraviolet radiation. To overcome the radiation interference caused by the opaque solid support, the tubular structure is periodically rotated about its longitudinal axis, thereby exposing all parts of the band of the tubular structure to incoming ultraviolet radiation. The rotation may always occur, i.e., the tubular structure rotates gradually at a constant speed around its longitudinal axis, thereby exposing the band of the structure to ultraviolet radiation. Alternatively, the rotation may be performed progressively. For example, a portion of the overall tubular structure (i.e., the portion adjacent to the block's pores through which the ultraviolet light passes) may be exposed to ultraviolet radiation for a desired period, then the structure may be rotated, for example, 60 degrees around its longitudinal axis, and then the overall tubular structure may be exposed to ultraviolet radiation again for a desired period. Next, the structure may be rotated another 60 degrees in the same direction and then exposed to ultraviolet radiation. This is continued until the overall tubular structure has received six doses of ultraviolet radiation and the LIVS bands are generated. In the above example, six doses of ultraviolet radiation were used at 60-degree intervals in the stent, but other processing methods may be used instead. For example, the stent may be rotated 90 degrees after each dose for a total of four doses, or the stent may be rotated 120 degrees after each dose for a total of three doses. In addition to rotating the overall tubular structure around its longitudinal axis, the overall tubular structure may also be moved along its longitudinal axis, resulting in the generation of a helical pattern of LIVS bands.

[0076] To create an overall tubular structure with multiple LIVS bands, rows of holes may be drilled into the block. For example, two holes can be used to create two LIVS bands, or three holes can be used to create three LIVS bands. The holes are usually arranged in a row, spaced apart from each other by the desired length of the LIVS bands. As mentioned above, the diameter of each hole is approximately equal to the desired length of the LIVS bands. For example, three holes can be arranged in a row, each with a diameter of 5 mm, and each hole extending from the outer surface of the block to the lumen of the block. The holes can be spaced 4 cm apart. In this way, an overall tubular structure with an HIVS-LIVS-HIVS-LIVS-HIVS-LIVS-HIVS pattern can be created, where the lengths of the three LIVS bands are each about 5 mm and the lengths of the two HIVS bands in between are each about 4 cm, so this structure can be represented as HIVS-LIVS(5 mm)-HIVS(4 cm)-LIVS(5 mm)-HIVS(4 cm)-LIVS(5 mm)-HIVS. If the overall tubular structure includes both a renal curl at one end and a bladder curl at the other end, the structure can be represented as (bladder curl-HIVS)-LIVS(5 mm)-HIVS(4 cm)-LIVS(5 mm)-HIVS(4 cm)-LIVS(5 mm)-(HIVS-renal curl).

[0077] Aside from creating multiple holes in the block, the block can have only a single hole, where the overall tubular structure moves through the lumen by a desired distance, thereby exposing another band of the structure to ultraviolet radiation. For example, after the first LIVS band is created, the overall tubular structure is offset by a distance of, say, 5 cm, thereby exposing a new (second) band of the overall tubular structure to ultraviolet radiation passing through the hole in the metal block, generating a second LIVS band.

[0078] Ultraviolet radiation can be generated by standard means. For example, the BLUEWAVE® 200 UV spot lamp (Dymax Corporation, Torrington, Connecticut, USA) or equivalent is a suitable light source for ultraviolet radiation. A suitable intensity of ultraviolet radiation is approximately 10 W / cm². 2 For example, 9-11 W / cm² 2 It is within the range. The appropriate time for a portion of the overall tubular structure to be exposed to ultraviolet radiation is about 10 to 60 seconds, so that the portion of the overall tubular structure has appropriately low in vivo stability. Different bands can be exposed to ultraviolet radiation for different times and / or different light intensities and / or different number of exposures, thereby achieving unique decomposition and mechanical properties at different locations of the stent, thereby allowing the rate of decomposition of different parts to be varied when the overall tubular structure is installed in vivo. For example, to create an overall tubular structure where the band closest to the bladder curl breaks down first and the band closest to the kidney curl breaks down last, this overall tubular structure can be represented as follows: (kidney curl - HIVS) - LIVS (5mm; each part of this band of the overall tubular structure is exposed to UV radiation for 20 seconds) - HIVS (4cm) - LIVS (5mm; each part of this band of the overall tubular structure is exposed to UV radiation for 30 seconds) - HIVS (4cm) - LIVS (5mm; each part of this band of the overall tubular structure is exposed to UV radiation for 40 seconds) - (HIVS - bladder curl).

[0079] As stated above, the medical devices of this disclosure are or may include a hollow, overall tubular structure. Optionally, such a medical device is a mesh tube, i.e., a tube formed from mesh, i.e., the side walls of the overall tubular structure have a mesh structure and the interior of the tube is an open space. Optionally, the tubular structure is characterized by its length and / or width, where the width refers to the diameter of the cross-section of the overall tubular structure. The overall tubular structure has a length of at least 5 cm, or at least 6 cm, or at least 7 cm, or at least 8 cm, or at least 9 cm, or at least 10 cm, and 30 cm or less, or 28 cm or less, or 26 cm or less, or 24 cm or less, or 22 cm or less, or 20 cm or less.

[0080] In one embodiment, the medical device of the present disclosure includes a generally tubular structure having a side wall, wherein the side wall includes a monofilament coil surrounding the (open) lumen of the generally tubular structure, a mesh covering the monofilament coil, and a coating deposited on the coil and mesh. In this structure, the side wall includes three components: a monofilament coil, a mesh, and a coating. This structure can be used to fabricate a stent, which is a typical medical device of the present disclosure. If the stent is a urethral stent, the stent may further include a kidney-retaining structure at the proximal end of the device and a bladder-retaining structure at the distal end of the device. The kidney-retaining structure is inserted into the host kidney and fixes the proximal end of the stent to the kidney. The bladder-retaining structure is inserted into the host bladder and fixes the distal end of the stent to the bladder. Optionally, the kidney-retaining structure may be in the form of a curl at the proximal end of the device, and the bladder-retaining structure may be in the form of a curl at the distal end of the device.

[0081] If the device includes a coating as part of an overall tubular structure, the coating may or may not have a uniform thickness along the overall length of the tubular structure. In one embodiment, the thickness of the coating is uniform along the overall length of the tubular structure. In another embodiment, the thickness of the coating is non-uniform along the overall length of the tubular structure. Non-uniformity of the coating thickness can be used to influence the rate of biodegradation of the overall tubular structure. For example, if a thicker coating is present at the proximal end of the device, biodegradation will preferentially occur at the distal end of the device, all other equal. In one embodiment, the present disclosure provides a ureteral stent having a kidney-retaining structure at the proximal end of the device and a bladder-retaining structure at the distal end of the device, wherein the device includes a coating on the outer surface of the device, where the proximal end of the device includes more coating, e.g., a thicker coating, compared to the distal end of the device. This medical device may include the aforementioned HIVS and LIVS bands.

[0082] In general, the medical devices of this disclosure may be made from biostable or non-biostable materials, where non-biostable materials are referred to herein as biodegradable materials, and in the art they may be understood as biodegradable, absorbable or bioabsorbable, erosive or bioerosive, soluble or biosoluble. Biodegradable polymers are completely eroded or absorbed when exposed to bodily fluids such as blood, and are gradually reabsorbed, absorbed, and / or removed by the body. Some biodegradable materials are absorbed by chemical degradation that occurs in the material upon exposure to bodily fluids, such as those found in the host's vascular environment. Chemical degradation refers to the breakdown of a material by chemical reactions between the material and bodily fluids or substances within bodily fluids. Chemical degradation may be the result of hydrolysis, oxidation, enzymatic degradation, and / or metabolic processes. Chemical degradation can result in, for example, a decrease in molecular weight, a decrease in mechanical properties, and a decrease in mass due to erosion. Mechanical properties may correspond to the strength and modulus of elasticity of the material. Degradation of the mechanical properties of a material reduces the ability of a medical device made from it to function optimally in the host. For example, if the device is a stent, the stent will reduce its mechanical support within the blood vessel as it degrades. Furthermore, some biodegradable materials are water-soluble. Water-soluble materials are those that can dissolve in water in addition to (or without) chemical degradation of the material.

[0083] In one embodiment, a biodegradable medical device is formed from a whole or partially biodegradable organic polymer. The organic polymer may be, for example, a thermoplastic polymer, a thermosetting polymer, or an elastomer polymer. The organic polymer may also be a copolymer, where the copolymer is made from two or more different monomers to provide properties that cannot be readily achieved from a homopolymer alone. The organic polymer may also be a mixture of one or more different polymers, such as one or more different organic polymers. Thus, the various biodegradable organic monomers specified herein may be used in cooperation to prepare a homopolymer or copolymer, and the various organic polymers specified herein may be used in combination to prepare a mixture. The medical devices of this disclosure are at least partially, optionally completely, biodegradable, and therefore include several biodegradable components. In one embodiment, the medical device is made from a completely biodegradable material, and therefore the medical device is completely biodegradable. In another embodiment, the medical device is made from a majority of a biodegradable material, and therefore at least 50% by weight of the medical device is biodegradable. In yet another embodiment, the medical device is made from both a biodegradable material and a biostable material, and therefore less than 100% of the medical device is biodegradable. In various embodiments, 100%, up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, or up to 25% of the medical device is made from biodegradable materials. These percentage values ​​are wt% based on the weight of the implantable medical device.

[0084] Examples of biodegradable polymers that may be used to fabricate the medical devices of this disclosure include poly(alpha-hydroxy acid) polymers and copolymers. For example, polymers and copolymers of glycosides, including polyglycolide (PGA), poly(glycolide-co-lactide) (PGLA), and poly(glycolide-co-trimethylene carbonate) (PGA / TMC); polymers and copolymers of polylactide (PLA), including poly-L-lactide (PLLA), poly-D-lactide (PDLA), poly-DL-lactide (PDLLA), poly(lactide-co-tetramethyleneglycolide), poly(lactide-co-trimethylene carbonate), poly(lactide-co-delta-valerolactone), poly(lactide-co-epsilon-caprolactone), poly(glycine-co-DL-lactide), and poly(lactide-co-ethylene oxide); and poly(asymmetric 3,6-substituted poly-1,4-dioxan-2,5-dione, etc. Dioxanone polymers; poly(beta-hydroxybutyrate) (PHBA) and its copolymers, such as poly(beta-hydroxybutyrate-co-beta-hydroxyvalerate); polygluconates; poly(beta-hydroxypropionate) (PHPA); poly(beta-dioxanone) (PDS); poly(delta-valerolactone); poly(ε-caprolactone); methyl methacrylate-N-vinylpyrrolidone copolymer; polyesteramides; oxalic acid polyesters; polydihydropyrans; poly(alkyl-2-cyanoacrylate); polyvinyl alcohol (PVA); polypeptides; poly(beta-maleic acid) (PMLA); poly(beta-alkanoic acid); poly(ethylene oxide) (PEO); polyanhydrides, polyphosphoesters, and chitin polymers.

[0085] In one embodiment, the organic polymer is a polyester, and the overall tubular structure is made mostly or entirely from a bioabsorbable polyester. For example, the polymer may be a polyester selected from poly(α-hydroxy acid) homopolymers, poly(α-hydroxy acid) copolymers, and blends thereof. Furthermore, or alternatively, the polyester may be selected from polyglycolides, poly-L-lactides, poly-D-lactides, poly-DL-lactides, and blends thereof. The polyester can be selected from polymers and copolymers of polylactides (PLA), including poly-L-lactide (PLLA), poly-D-lactide (PDLA), and poly-DL-lactide (PDLLA).

[0086] In one embodiment, the organic polymer is semi-crystalline, or can form fibers, or is both semi-crystalline and fiber-forming. In one embodiment, the medical device is made using an organic polymer that is semi-crystalline and fiber-forming. In one embodiment, the biodegradable stent is prepared from an organic polymer that is semi-crystalline and fiber-forming. Furthermore, glycosides can be used as a monomer or one of the monomers used to form the organic polymer in order to rapidly degrade the organic polymer, i.e., to lower its in vivo stability. Paradioxanes (PDOs) (the corresponding homopolymer is known as poly(PDO)) are another suitable monomer for forming rapidly biodegradable (LIVS) organic polymers. Since poly(PDO) typically degrades more slowly than glycoside-based polymers, it is preferable to have a glycoside-rich monomer input in order to prepare a very rapidly biodegradable organic polymer.

[0087] In one embodiment, the organic polymer has a polyaxial structure, while in another embodiment, the organic polymer is linear. The polyaxial structure may be part of the organic polymer, for example, present within a block copolymer. Another option is for the organic polymer to be semi-crystalline, fiber-forming, segmented polyaxial, and glycolide-based to ensure rapid degradation, i.e., low in vivo stability (LIVS). Yet another option is to use a linear copolymer in one or both of the diblock, triblock, and pentablock, where, except for the pentablock, the central block is amorphous and the other blocks are semi-crystalline. This could be a case where the central block is PEG, with amorphous segments connected to the outer crystalline segments (forming a symmetric pentablock polymer that is a polyether ester; all other polymers mentioned are aliphatic polyesters). The linear block copolymer may in all cases consist of semicrystalline blocks, and because there are no amorphous blocks, the polymer can be oriented after fiber formation, resulting in a polymer that can alternately generate different crystalline structures and percentage patterns within the fiber, thereby resulting in slight differences in the decomposition profile of the alternating blocks forming the fiber (because the fiber is oriented, horizontal strips of crystalline regions form and align the blocks that make up the polymer chain). Alternatively, a linear copolymer without blocks can be substituted. In one embodiment, these organic polymers are used to form fibers, and these fibers are used to form a coating on or as part of the sidewalls of an overall tubular structure that is a component of the medical device of this disclosure. In another embodiment, these organic polymers are not formed into fibers, but the organic polymers are used to form a coating on the medical device, for example, by spraying a solution of the polymer onto the medical device or by dipping the device into an organic polymer solution.

[0088] Medical devices can be fabricated from a base polymer that is amorphous, flexible, and elastic. While crystalline, excessive crystallinity typically reduces the polymer's flexibility. When choosing a highly crystalline material, it is recommended to combine the crystalline material with a plasticizer such as PEG to lower the final crystallinity of the polymer (e.g., the final crystallinity of the coating applied to the medical device). As described above, the polymer can be multiaxial or linear, blocky or segmented, or random. For highly flexible and adaptable coatings, the organic polymer can be minimally crystalline or amorphous.

[0089] The organic polymer, if it is a block copolymer, may be prepared from a prepolymer and an end graft, or it may not be prepared from a prepolymer. In one embodiment, one or more monomers used to prepare the polymer are selected from caprolactone, trimethylene carbonate, and / or L-lactide. Incorporating these monomers into the monomer input used to prepare the polymer, particularly when glycolide is also used as a monomer, extends the degradation time beyond the degradation time limit of polymers made from glycolide alone.

[0090] Other suitable biodegradable organic polymers besides polyester include polyether-esters, polyether-ester-urethanes (bioabsorbable urethanes), polyether-urethanes, and polyether-urethane-ureas, the latter of which decompose very slowly and typically incompletely.

[0091] In various embodiments, medical devices are fabricated from one of the following polymers: MG-5 (Poly-Med, Anderson, South Carolina): A semi-crystalline multiaxial block copolyester prepared in a two-step reaction from an amorphous prepolymer and a crystalline endgraft, with more than 65% glycolide in the endgraft. MG-9 (Poly-Med, Anderson, South Carolina): A semi-crystalline multiaxial block copolyester prepared in a two-step reaction from an amorphous prepolymer and a crystalline endgraft, with more than 80% glycolide. Semi-crystalline, multiaxial segmented copolyester prepared in a one-step reaction (no prepolymer used). Semi-crystalline linear block copolyester prepared in a two-step reaction from an amorphous prepolymer and a crystalline endgraft. Triblock copolymer with crystalline endgrafts. Diblock copolymer. Semi-crystalline linear segmented copolyester prepared in a one-step reaction (i.e., no prepolymer used). SVG-12 (Poly-Med, Anderson, South Carolina): Has an intrinsic viscosity greater than 1.0 and possesses crystalline endgrafts. Multiaxial block copolymer. Polymer prepared from amorphous prepolymer and amorphous endgraft. Linear block copolymer (triblock, diblock, pentablock). Linear segmented copolymer. Amorphous, and therefore flexible and adaptable linear random copolymer. The foregoing are merely examples of organic polymers that may be used to fabricate suitable medical devices or their components (e.g., coating layers).

[0092] Another suitable polymer for fabricating the medical devices of the present disclosure is a mixture comprising: (a) a bio-erosive polyester network formed by a reaction between a polyol and a polycarboxylate, wherein at least one of the polyol and the polycarboxylate has three or more functional groups; and (b) a bio-erosive thermoplastic polymer. If necessary, one or more of the following may further characterize this composition: the polyol is selected from nonpolymeric diols, polymeric diols, nonpolymeric triols, and polymeric triols; the polycarboxylate is selected from nonpolymeric dicarboxylates, polymeric dicarboxylates, nonpolymeric tricarboxylates, and polymeric tricarboxylates; the reactant includes a triol, a tricarboxylate, or both; the reactant includes (a) a nonpolymeric tricarboxylate and (b) a polyester polyol; the reactant includes (a) citric acid and (b) a polycaprolactone diol, a polycaprolactone triol, or both; the bio-erosive thermoplastic polymer has a melting point higher than body temperature; the bio-erosive thermoplastic polymer has a glass transition temperature lower than room temperature; and the bio-erosive thermoplastic polymer is a bio-erosive thermoplastic polyester. See, for example, U.S. Patent Publication No. 20160166739.

[0093] In one embodiment, the implantable medical device of the present disclosure includes a coating as a component of the medical device. The location of the coating on the medical device and the properties of the coating with respect to its physical and chemical characteristics contribute to the control of disassembly and / or removal of the medical implant from the host. In particular, the coating contributes, in part, to the control of disassembly and / or removal of the medical device from the host. The properties of the coating may be selected for the purpose of controlling the disassembly and / or removal of the coated medical device from the host.

[0094] The medical devices present in the medical implants of this disclosure are, at least to some extent, decomposable. In other words, the medical devices decompose once they are placed in a host. This decomposition can be physical or chemical. Physical decomposition refers to a change in the physical or mechanical properties of the medical device. For example, the device may fall apart and lose its integrity. Another example is that the device may become soft and pliable. Yet another example is that the device may absorb fluid and expand. In each of these cases, the device undergoes a change in its physical or mechanical properties. Chemical decomposition refers to a change in chemical composition. For example, the organic polymers from which the device is made may undergo hydrolytic bond cleavage or enzyme-induced bond cleavage, thereby losing molecular weight. Another example is that water-soluble components of the medical device may dissolve in water and leave the vicinity of the medical device. In each of these examples, chemical decomposition results in a change in the chemical properties of the medical device. In one embodiment, the decomposition of a medical implant occurs by both physical and chemical decomposition. The coating of the medical implant may play a role in influencing this decomposition, either partially or entirely. Thus, the properties of the coating can be used to control the decomposition and / or removal of the medical implant from the host.

[0095] In one embodiment, the medical device includes a coating on a portion of the device, which functions as a containment layer. This containment layer provides a physical barrier between the host tissue and the medical device. Such a barrier is useful, for example, when it is desired to control the dispersion or propagation of the fragments when the device breaks down into fragments. For example, in one embodiment, the containment layer can last relatively longer than the medical device, and as a result, when the medical device breaks down into fragments, the containment layer maintains sufficient structural integrity to keep the fragments contained within the containment layer. Such a containment layer is useful when the medical device is placed in the kidney, where it is undesirable for fragments from the medical device to come into contact with the inside of the kidney and calcify. In a related embodiment, the containment layer also lasts relatively longer than the medical device, which is an esophageal stent. In this case, when the esophageal stent breaks down into fragments, the containment layer located on the inner wall of the stent and surrounding it prevents these fragments from entering the stomach. Therefore, in both examples, the containment layer effectively restricts the movement of medical device fragments.

[0096] In another respect, the medical device does not have a containment layer. In this case, the medical device does not have features such as a containment layer that restrict the movement of fragments, such as HIVS bands, that are formed when the medical device is disassembled (e.g., disassembly of a LIVS band adjacent to an HIVS band). Optionally, a generally tubular structure that is part of the medical device does not include a containment layer that restricts the movement of fragments, such as HIVS bands, that are formed when the generally tubular structure is disassembled. In the absence of a containment layer or equivalent features, fragments formed during in vivo disassembly of the medical device or generally tubular structure of this disclosure are freely separated from the medical device and away from the vicinity of the implanted medical device. In each embodiment disclosed herein, the medical device or any part thereof does not have a containment layer.

[0097] In another embodiment, the containment layer provides a physical or chemical barrier between the disintegration-inducing fluid from the host and the medical device. This layer can be used to have a spatial and temporal influence on the disintegration of the medical device. For example, in one embodiment, the containment layer is a discontinuous layer that covers part but not all of the medical device. In this case, the containment layer effectively functions as a barrier between the part of the medical device and the disintegration-inducing fluid from the host, limiting contact between the part of the medical device and the fluid. This allows the containment layer to disintegrate the exposed part of the medical device faster than the unexposed part of the medical device. Thus, the containment layer is used to control where the device disintegrates first.

[0098] In another embodiment, a gradient containment layer is used to control the spatial and temporal decomposition and / or removal of a medical device. For example, a medical device may have a single coating layer covering a first part of the device, a double coating layer covering a second part of the device, and optionally a triple coating layer covering a third part of the device. Assuming the composition of the coating layers is the same at each location, the first part of the medical device decomposes before the second and third parts of the device. Depending on the relative thickness at each location, the second and third parts of the device may still be largely intact even if the first part has decomposed and been removed from the host. Depending on the arrangement of the layers, the decomposition and removal of the first part of the medical device may increase access of biological fluids to the second part of the medical device, resulting in the decomposition of the second part (which may still be covered by the coating). Once the second part of the device has decomposed and been removed, the third part of the device is subsequently decomposed and removed. In this example, the coating controls the rate at which the different parts of the medical device decompose and are removed from the host. However, it should be noted that the coating can also function as a containment layer to manage the dispersion or propagation of these fragments, i.e., to restrict their movement within the host.

[0099] Medical implants, including either the medical device itself or a coating thereon, may contain therapeutic agents. The amount of therapeutic agent incorporated into an implant depends on the nature of the implant, the actual therapeutic agent, the condition of the target, etc. The amount may be appropriately determined by those skilled in the art. Exemplary therapeutic agents include antithrombotic agents, antiproliferative agents, anti-inflammatory agents, anti-migration agents, antitumor agents, antimitotic agents, anesthetic agents, and anticoagulants. Furthermore, appropriate therapeutic agents include agents that affect the generation and organization of the extracellular matrix or the growth of vascular cells (either promoters or inhibitors), cholesterol-lowering agents, vasodilators, and agents that interfere with intrinsic vasoactive mechanisms.

[0100] In various embodiments of the present invention, the medical device may be a ureteral stent. A medical device such as a ureteral stent may be designed to release one or more drugs, and typical examples of drugs include one or more of the following: alpha-adrenergic blockers, analgesics, anticancer agents, antitumor agents, anti-inflammatory agents, antibacterial agents, antiproliferative agents, anticonvulsants, beta-adrenergic agonists, bronchodilators (e.g., for muscle relaxant properties), calcium channel blockers, corticosteroids, anesthetics, narcotic analgesics, nitric oxide donors, nitric oxide-releasing compounds, non-narcotic analgesics, prostaglandins, and combinations thereof.

[0101] Further representative examples of drugs include one or more of the following: angiogenesis inhibitors, 5-lipoxygenase inhibitors and antagonists, chemokine receptor antagonists CCR(1, 3, and 5), cell cycle inhibitors, cyclin-dependent protein kinase inhibitors, EGF (epidermal growth factor) receptor kinase inhibitors, elastase inhibitors, factor Xa inhibitors, farnesyltransferase inhibitors, fibrinogen antagonists, guanylate cyclase stimulants, heat shock protein 90 antagonists, HMG-CoA reductase inhibitors, hydroorotate dehydrogenase inhibitors, IKK2 inhibitors, IL-1, ICE, and IRAK antagonists, IL-4 agonists, immunomodulators, and inosine phosphate dehydrogenase inhibitors. Harmful agents, leukotriene inhibitors, MCP-1 antagonists, MMP inhibitors, NF kappa B inhibitors, NO agonists, P38 MAP kinase inhibitors, phosphodiesterase inhibitors, TGFβ inhibitors, TNFα antagonists and TACE inhibitors, tyrosine kinase inhibitors, vitronectin inhibitors, fibroblast growth factor inhibitors, protein inhibitors, PDGF receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, retinoic acid receptor antagonists, platelet-derived growth factor receptor kinase inhibitors, fibronogin antagonists, antifungal agents, bisphosphonates, phospholipase A1 inhibitors, histamine H1 / H2 / H3 receptor antagonists, macrolide antibiotics, GPIIbIIIa receptor antagonists, endothelin receptor antagonists, peroxisome proliferator-responsive receptor agonists, estrogen receptor agents, somatostatin analogs, neurokinin 1 antagonists, neurokinin 3 antagonists, neurokinin antagonists, VLA-4 antagonists, osteoclast inhibitors, DNA topoisomerase ATP hydrolysis inhibitors, angiotensin I-converting enzyme inhibitors, angiotensin II antagonists, enkephali Nase inhibitors, peroxisome proliferator-responsive receptor gamma agonists, insulin sensitizers, protein kinase C inhibitors, CXCR3 inhibitors, Itk inhibitors, cytosolic phospholipase A2α inhibitors, PPAR agonists, immunosuppressants, Erb inhibitors, apoptosis agonists, lipocortin agonists, VCAM-1 antagonists, collagen antagonists, α2 integrin antagonists, TNFα inhibitors, nitric oxide inhibitors, and cathepsin inhibitors.

[0102] Examples of alpha-adrenergic blockers include alfuzosin, amosulol, arotinirol, dapiprazole, doxazosin, ergoloid, fenspiride, idazoxane, indramine, labetalol, manotepil, mesylate, naphtopidil, nicergoline, prazosin, tamsulosin, terazosin, trazoline, trimazosin, and yohimbine.

[0103] Examples of anesthetics include benzocaine, cocaine, lidocaine, mepivacaine, and novacaine.

[0104] Examples of β-adrenergic agonists include albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, chloreprenaline, denopamine, ephedrine, epinephrine, etahedrine, ethylnorepinephrine, fenoterol, formoterol, hexoprenaline, ivopamine, isoetaline, isoproterenol, mabuterol, metaproterenol, methoxyphenamine, oxyphedrine, pirbuterol, prenalterol, procaterol, protochlor, reproterol, limiterol, ritodrine, salmelterol, soterenol, terbutaline, tretokinol, tulobuterol, and xamoterol.

[0105] Examples of anticancer, antiproliferative, and antitumor agents include: agents that affect microtubule dynamics (e.g., colchicine, Epo D, epothirone, paclitaxel, vinblastine, vincristine, etc.), alkyl sulfons, angiogenesis inhibitors (e.g., angiostatin, endostatin, squalamine, etc.), antimetabolites such as purine analogs (e.g., 6-mercaptopurine or cladribine (chlorinated purine nucleoside analogs), pyrimidine analogs (e.g., 5-fluorouracil, cytarabine, etc.) and antibiotics (e.g., daunorubicin, doxorubicin, etc.), caspase activators, cerivastatin, cisplatin, ethyleneimine, flavopyridol, limus drugs (e.g., everolimus, sirolimus, tacrolimus, zotarolimus, etc.), methotrexate, nitrogen mustard, nitrosourea, proteasome inhibitors, and suramin.

[0106] Examples of antimicrobial agents include benzalkonium chloride, chlorhexidine, nitrofurazone, silver particles, silver salts, metallic silver, and antibiotics such as gentamicin, minocycline, rifampin, and triclosan.

[0107] Examples of bronchodilators include: (a) ephedrine derivatives, e.g., albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, chlorenaline, dioxedrine, ephedrine, epinephrine, eprodinol, etahedrine, ethylnorepinephrine, fenoterol, formoterol, hexoprenaline, isoetaline, isoproterenol, mabuterol, metaproterenol, n-methylephedrine, pyrbuterol, procaterol, protochlor, reproterol, limiterol, salmeterol, soterenol, terbutaline, tulobuterol; (b) quaternary ammonium compounds (c) substances such as bevonium methylsulfate, flutropium bromide, ipratropium bromide, oxytropium bromide, tiotropium bromide; (d) xanthine derivatives such as acephyrin, acephyrin piperazine, ambuphyllin, aminophyllin, bamiphyllin, choline theophylline, doxophyllin, diphyllin, etamiphyllin, etophyllin, guaicylin, proxiphyllin, theobromine, 1-theobrominacetate, theophylline, and (e) other bronchodilators such as fenspiride, medibazine, methoxyphenamine, tretokinol, and the aforementioned combinations and pharmaceutically acceptable salts, esters, and other derivatives.

[0108] Examples of calcium channel blockers include: arylalkylamines (including phenylalkylamines) such as bepridil, clentiazen, fendiline, garopamil, mibefladil, prenylamine, semothiazil, telodiline, and verapamil; benzothiazepines such as diltiazem; and other calcium channel blockers, particularly those such as bencyclan, etafenone, fantofalon, monatepir, and perhexylline; dihydropyridine derivatives (including 1,4-dihydropyridine derivatives) such as amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, ergodipine, felodipine, isradipine, lasidipine, relcanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, and nitrendipine; and piperazine derivatives such as cinnarizine, dotarizine, flunarizine, lidoflazine, and lomerizine.

[0109] Examples of corticosteroids include: betamethasone, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and combinations thereof, as well as pharmaceutically acceptable salts, esters, and other derivatives.

[0110] Examples of nitric oxide donors / releasing molecules include: inorganic nitrates / nitrites such as amyl nitrite, isosorbide dinitrate, and nitroglycerin; inorganic nitroso compounds such as sodium nitroprusside; sidnoimines such as lincidomin and morcidomin; nonoates such as diazenium diolate; NO adducts of alkanediamines; S-nitroso compounds including low molecular weight compounds (e.g., S-nitroso derivatives of captopril, glutathione, and N-acetylpenicillamine); and high molecular weight compounds (e.g., S-nitroso derivatives of natural polymers / oligomers, oligosaccharides, peptides, polysaccharides, proteins, and synthetic polymers / oligomers); as well as C-nitroso compounds, L-arginine, N-nitroso compounds, and O-nitroso compounds.

[0111] Examples of prostaglandins and their analogues for use in this disclosure can be selected from the following appropriate items: prostaglandins such as PGE1 and PGI2, and prostacyclin analogues such as beraprost, carbacycline, cyprosten, epoprostenol, and iloprost.

[0112] Examples of narcotic analgesics include: codeine, fentanyl, hydromorphoneine, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyfen, pentazocine, and combinations thereof, as well as pharmaceutically acceptable salts, esters, and other derivatives.

[0113] Examples of non-narcotic analgesics include: analgesics such as acetaminophen, and nonsteroidal anti-inflammatory drugs such as aspirin, celecoxib, diflunisal, diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, meclofenamete, meloxicam, nabumetone, naproxen, naproxen-indomethacin, oxaprozin, piroxicam, sarsalate, sulindac, tolmetine, and valdecoxib.

[0114] The medical devices of this disclosure, for example, ureteral stents, may be manufactured to contain and release one or more of these or other therapeutic agents. In addition to the drugs enumerated herein, pharmaceutically acceptable salts, esters, and other derivatives of the drugs may also be available. The drugs provided herein may, for example, be loaded into polymer components of the medical device. If the medical device is a stent, the drug may be incorporated into a coil, a knit structure adjacent to the coil, or a coating impregnated into the knit structure.

[0115] Urologically beneficial drugs can be attached to drug-release stents in a variety of ways, including, in particular: (a) loaded into the interior (bulk) of stent components (e.g., monofilament coils, multifilament knit structures, or coatings, sleeves, or sheaths); (b) bonded to the surface of the stent (e.g., the surface of a monofilament coil, the surface of a multifilament knit structure, or coating, sleeve, or sheath that forms part of the stent), where the drug is bonded to the surface by either covalent and / or non-covalent interactions (e.g., van der Waals forces, hydrophobic interactions, and / or electrostatic interactions, e.g., charge-charge interactions, charge-dipole interactions, dipole-dipole interactions including hydrogen bonds); (c) applied as a coating covering all or part of the stent or its components; (d) loaded into surface features (e.g., recesses) of the stent or its components; and (e) any combination thereof.

[0116] The amount of urologically beneficial drug adhering to the drug-release stent should be a therapeutically or prophylactically effective amount, which may range from less than 1% by weight to ~2% by weight, ~5% by weight, ~10% by weight, ~25% by weight, ~50% by weight, or more, depending on the specific drug and the desired effect.

[0117] In one embodiment of a medical device containing a drug, the Disclosure provides a medical device for placement in the body of a mammal, comprising: a polymer matrix forming the device and defining a lumen through the device, comprising polymer macromolecules and defining spaces between polymer macromolecules; a drug contained in at least some of the spaces of the matrix; and a material contained in at least some of the spaces of the matrix to influence the diffusion of the drug from the polymer matrix when the medical device is placed in the body of a mammal. Optionally, one or more of the following can further characterize the medical device of this disclosure: the polymer material and the drug each have molecular weights, and the molecular weight of the drug is smaller than that of the polymer material; the amount of drug adhering to the device is 0.1 to 50% by weight of the device; the medical device is a ureteral stent or catheter; the polymer component includes a biodegradable polyester; the polymer component is hydrophobic; at least a portion of the space containing the drug also includes polymer material; the drug includes oxybutynin chloride or ketorolac; the material to which the drug adheres includes polyethylene glycol (PEG); the drug adheres to a biodegradable material; the drug adheres to a material to which the drug must dissociate before it diffuses from the polymer matrix; the polymer matrix is ​​a coating on the device.

[0118] Therefore, medical devices can be used as vehicles for delivering one or more drugs to a patient's body. Drugs can be delivered by fully or partially implanting the device in the patient's body using ureteral stents, catheters, and / or other medical devices. By using specific materials and drugs in a polymer matrix, the diffusion of drugs from the matrix can be controlled in ways that were previously unattainable. This allows one or more drugs to be administered to the patient's body at a relatively constant therapeutic level over a certain duration (e.g., ranging from a few days to several months).

[0119] The drug delivery medical devices according to this disclosure may be formed entirely or partially from a polymer matrix loaded with a drug and a material that affects the diffusion of the drug out of the matrix when the device is placed in the body of a human or other mammal. The device may be a ureteral stent, catheter, dialysis tube, cannula, urethral stent, suture, or other medical device designed to be placed (whole or partially) in the body. The devices according to this disclosure may optionally be coated whole or partially with such loaded polymer matrix. For example, a hydrophobic polymer matrix may be used to coat all or part of a lead wire, stent, or catheter.

[0120] In another embodiment, the Disclosure provides a ureteral stent comprising a long stent body, a deployable retaining structure, and a drug release member, the drug release member being selected from: (i) a sleeve of drug release material disposed on at least a portion of the deployable retaining structure, (ii) a sheet of drug release material attached to the deployable retaining structure, and (iii) a sheet of drug release material connected to a sleeve of material disposed on at least a portion of the deployable retaining structure. If necessary, one or more of the following features can further describe this drug-releasing ureteral stent: a sleeve of drug-releasing material is positioned on at least part of a deployable retaining structure, optionally the sleeve is a biodegradable sleeve and / or the sleeve is a heat-shrinkable sleeve and / or the sleeve is in the range of an inner diameter of 1 to 4 mm, a length of 2 to 500 mm, and a thickness of 50 to 200 μm; the stent includes a sheet of drug-releasing material attached to a deployable retaining structure, optionally the sheet is a biodegradable sheet and / or the sheet is an elastic sheet and / or the sheet is in the range of a width of 2 to 20 mm, a length of 2 to 500 mm, and a thickness of 50 to 200 μm; the stent includes a retaining structure in the form of a coil or loop; A sheet of drug-releasing material spreads over most of the coil or loop area when the retaining structure is deployed; the stent includes a sheet of drug-releasing material connected to a sleeve of material positioned on at least a portion of the deployable retaining structure; the stent includes a retaining structure which is a renal retaining structure configured to be delivered through the ureter and deployed in the kidney, and optionally the retaining structure is fitted to shrink to a sufficiently small contour during deployment so that the retaining structure can be delivered to the kidney; the stent has a retaining structure which includes a plurality of elongated elements to which the sheet of drug-releasing material is attached, between which the sheet of drug-releasing material is positioned when the retaining structure is deployed; the stent body and the deployable retaining structure include a biostable polymer.

[0121] The loading of the drug onto the polymer can be about 0-20% by weight of the device, depending in particular on the properties of the material, the amount of polymer, the polymer release profile, the drug release profile, the desired drug diffusion effect, and the desired drug delivery period. In one embodiment, the drug loading is about 1-10% by weight of the device.

[0122] Materials can be added to polymer compositions to particularly influence the release of drugs from the polymer. Such materials include, but are not limited to, styrene-ethylene-butylene-styrene (SIBS), collagen, alginates, carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), dextrin, plasticizers, lipophilic materials and other fatty acid salts, pore-forming agents, sugars, glucose, starch, hyaluronic acid (HA), ethylenediaminetetraacetic acid (EDTA), polyethylene glycol (PEG), polyethylene oxide (PEO), and chelating agents including copolymers thereof. Multiple materials with various release profiles may be incorporated into the polymer composition along with the drug to achieve a desired drug release profile.

[0123] In one aspect, the disclosure provides a bioabsorbable medical implant partially covered by an outer containment layer, which is non-biobsorbable, or at least partially bioabsorbable, but does not degrade as rapidly as the medical implant. In one embodiment, in vivo, the medical implant degrades into fragments, while the outer layer maintains sufficient structural integrity to provide a barrier that prevents fragments from the implant from passing through. In this way, the fragments are restricted to remain in localized areas that cannot harm the host. Indeed, even as the fragments degrade, the resulting smaller fragments, and the final molecular components of the implant, all remain within the outer containment layer and are led together to a location where they can be safely removed.

[0124] [gradient] In one aspect, a medical device is characterized as having a gradient. The gradient refers to several properties of the medical device as a function of direction, such as variations in composition. This gradient provides a variation in decomposition along the gradient. For example, the average molecular weight of the polymers forming the medical device may vary along the direction of the medical device, thereby the polymers at the distal end of the medical device or part thereof have a higher average molecular weight than the polymers at the proximal end of the medical device or part thereof. In this way, the proximal end of the medical device or part thereof may decompose faster than the distal end where the polymers have a higher initial average molecular weight. The provision of a gradient in a medical device of this disclosure provides a mechanism for controlled decomposition of the device. In one embodiment, the gradient does not affect or have any effect on the function of the medical device, but only affects the decomposition profile of the device. Such heterogeneity in a medical device may be referred to herein as a gradient of the medical device, and a medical device having such a gradient may be referred to as a gradient medical device.

[0125] Optionally, the coatings or containment layers of this disclosure may be characterized in that they have a gradient, thereby differentiating a coating or containment layer covering one part of a medical device from a coating or containment layer covering another part of the medical device. Such non-uniformity in a coating or containment layer is referred to herein as a gradient of the coating or containment layer, a coating having such a gradient may be referred to herein as a gradient coating, and a containment layer having such a gradient may be referred to herein as a gradient containment layer.

[0126] The gradient can be formed in various ways. For example, different parts of a medical device can be formed using different compositions with different decomposition rates. Thus, a first part of the medical device can be formed using a composition with a relatively high decomposition rate, and a second part can be formed using a composition with a relatively slow decomposition rate. In this way, some parts of the device will decompose faster than others.

[0127] As another example, a single composition can be used to form a gradient coating or containment layer. For instance, a single composition can be used to coat a first part of a medical device with a first thickness, and the same composition can be used to create a coating of a second thickness on a second part of the medical device. Generally, thicker coatings remain on the medical device longer than thinner coatings; that is, assuming all other elements are identical, thicker coatings degrade more slowly than thinner coatings. Thicker coatings can be formed, for example, by repeatedly coating areas of a containment layer where a greater coating thickness is desired.

[0128] The thickness of the coating or containment layer may vary throughout the medical implant. However, at its thickest point, in various embodiments, the coating or containment layer may have a thickness of more than 10 μm, or more than 20 μm, or more than 30 μm, or more than 40 μm, or more than 50 μm, or more than 60 μm, or more than 70 μm, or more than 80 μm, or more than 90 μm, or more than 100 μm, or more than 110 μm, or more than 120 μm, or more than 130 μm, or more than 140 μm, or more than 150 μm, or more than 160 μm, or more than 170 μm, or more than 180 μm, or more than 190 μm, or more than 200 μm. The maximum thickness may be 500 μm, or 400 μm, or 300 μm, or 200 μm, or 150 μm, or 100 μm.

[0129] The amount of coating or containment layer can vary throughout the medical implant. In one aspect, in addition to, or instead of, specifying the thickness of the coating or containment layer, the coating or containment layer can be characterized in terms of the amount of organic polymer present over a given volume of the medical device. For example, the amount may be per square centimeter (cm) of the medical device. 2) It can be specified from the perspective of the mg of the surrounding organic polymer. In various embodiments, the amount of the coating or encapsulation layer covering the medical device is at least 10 mg / cm 2 ; or at least 15 mg / cm 2 ; or at least 20 mg / cm 2 ; or at least 25 mg / cm 2 ; or at least 30 mg / cm 2 ; or at least 35 mg / cm 2 ; or at least 40 mg / cm 2 ; or at least 45 mg / cm 2 ; or at least 50 mg / cm 2 .

[0130] Thus, in one embodiment, the present disclosure provides a medical implant comprising a medical device and a gradient coating or gradient encapsulation layer covering a part of the medical device. Optionally, the gradient coating or encapsulation layer can include a plurality of thicknesses, for example, 2, 3, 4, 5, or more than 5 different thicknesses at different locations. A gradient coating or encapsulation layer having a plurality of thicknesses at different positions can be formed by having different numbers of coating layers of the polymer composition at different positions, and thus can be said to include a plurality of layers of the coating composition. Also, optionally, the gradient coating or encapsulation layer can include a plurality of compositions, for example, 2, 3, 4, 5, or more than 5 different compositions at different locations. Optionally, the gradient coating or encapsulation layer may include two or more characteristics, for example, variations in a plurality of thicknesses and a plurality of compositions.

[0131] Thickness and composition are examples of variations that can exist in the coating or encapsulation layer, but these are merely illustrative. To create a gradient coating or encapsulation layer according to the present disclosure, other variations can be used, such as variations in texture, variations in hydrophilicity, variations in thermal stability, variations in tensile strength, and variations in fiber density when fibers are included in the coating or encapsulation layer.

[0132] In one embodiment, the containment layer is made from one or more organic polymers. The containment layer may be completely non-biodegradable. However, in another embodiment, the containment layer is biodegradable but decomposes at a slower rate than the medical device. In this way, as the medical device decomposes into fragments, the containment layer maintains its structural integrity and holds the fragments together in a confined space for a sufficient amount of time for the fragments to decompose into even smaller fragments that do not harm the host and / or into polymer and / or monomer components of the medical device.

[0133] In one embodiment, the containment layer is a coating on the medical device. The coating may be present on the position-holding end of the medical device. The coating may be completely non-biodegradable. However, in another embodiment, the coating is biodegradable but decomposes at a slower rate than the medical device. In this way, as the medical device decomposes into fragments, the coating maintains its structural integrity and holds the position-holding end fragments together in a limited space for a sufficient time for the fragments to decompose into even smaller fragments that do not harm the host and / or into polymer and / or monomer components of the medical device.

[0134] When a polymer solution is used to form a coating on a medical device, the concentration of the polymer in the solution is a factor to consider. If the device is dipped, drawn, or otherwise coated with the polymer to form a coating or containment layer, higher concentrations of polymer tend to deposit more polymer on the surface of the medical device.

[0135] The containment layer is located in the portion of the medical device where it is desired to protect the host from damage, injury, or trauma caused by fragments of the device formed during biodegradation. For example, in the case of a stent implanted in a host, it is desirable that the stent is partially located inside the host's kidney and partially outside the kidney so that disintegrating stent fragments do not disappear into the kidney and cause kidney stones. Therefore, the portion of the stent located inside the kidney may be coated to provide a containment layer, while the portion of the stent located outside the kidney, such as the overall tubular structure forming the main central canal of the stent, may not have a containment layer. In this way, the containment layer is present only in a portion of the medical device.

[0136] This disclosure presents that a containment layer can be provided for all medical devices that decompose by a disintegration process, i.e., by a process in which the device breaks down into fragments. An exemplary device of this type is an intraureteral stent, also known as a ureteral stent. The stent is biodegradable and disintegrable, initially maintaining optimal ureteral patency for a predetermined period. However, after this period, the stent begins to decompose into small fragments. To prevent the movement of these fragments (especially if these fragments form part of the stent's position-holding end), the stent's position-holding end is enclosed, at least partially, by a containment layer. The layer maintains sufficient integrity so that the containment layer contains the small fragments while they are formed and subsequently decompose into harmless fragments or polymer or molecular components. Thus, the containment layer functions to protect the host from the small fragments formed during the decomposition of the stent. The containment layer also protects the host from contact with rigid fragments that are not readily expelled from the body.

[0137] In one embodiment, the disclosure provides a ureteral stent having diverse properties at different locations within the stent, but the stent and its components are not assembled from multiple segments. Rather, the stent is assembled from a single, homogeneous component, which is then modified to provide diverse properties at different locations within the component. Diverse properties may include one or more properties, including biodegradability, radiopaqueness, rigidity or flexibility, and therapeutic agent loading. Diverse properties are created by methods such as those disclosed herein, for example, by selectively decomposing the stent or its components before implantation in a host, and by other methods disclosed herein. In this way, bands having higher in vivo stability (HIVS) or lower in vivo stability (LIVS) compared to the unmodified portion of the medical device can be created. In one embodiment, bands of unmodified material are treated to induce them to have lower in vivo stability (LIVS) compared to adjacent unmodified bands, thereby generating LIVS bands. In another embodiment, bands of the unmodified material are treated to induce them to have higher in vivo stability (HIVS) compared to adjacent unmodified bands, thereby generating HIVS bands.

[0138] In one embodiment, the medical device is a stent, which is a fiber-reinforced elastomer film component designed to have at least one position-holding end, wherein the fiber reinforcement is (a) a combination of monofilament coils and weft-knitted tube multifilament yarns; (b) a combination of monofilament coils and braided multifilament yarns; (c) a tube containing braided or weft-knitted monofilament yarns; or (d) a tubular weft-knitted or braided monofilament yarn.

[0139] In yet another embodiment, the stent is a fiber-reinforced elastomer film structure designed to have at least one position-holding end, where the fiber reinforcement is a combination of monofilament and knitted or braided multifilament yarn, and the fiber-reinforced elastomer film is in the form of a tube having a central main component having a diameter smaller than the diameter of the patient's ureter, and each position-holding end defines two freely laterally deformable components formed by the main central component and the first partially overlapping double tubular end of the lateral fusion tube, which are cut radially and axially and attach to an intact semi-cylindrical extension of the main central tube to form two overextended flaps.

[0140] In yet another embodiment, the stent is a fiber-reinforced elastomer film component designed to have at least one position-holding end, where the fiber reinforcement is a combination of monofilament yarn or knitted or braided multifilament yarn, and the fiber-reinforced elastomer film is in the form of a tube having a diameter smaller than the diameter of the patient's ureter and having at least one position-holding end, the position-holding end being an angled portion of the main tube including a flexible hinge that has a length equivalent to the patient's ureter and maintains an angle greater than 30 degrees with respect to the main tube when there is no deformation stress.

[0141] In another embodiment, the stent includes a retaining portion configured to help hold the stent in place within the patient's body; and an elongated portion extending from the retaining portion, the elongated portion having a lateral wall defining a lumen, the lateral wall having a first section and a second section, the first section of the lateral wall having a first thickness, and the second section of the lateral wall having a second thickness different from the first thickness. Optionally, the stent may be further characterized by one or more of the following: the retaining portion is configured to be positioned within the patient's kidney; the retaining portion is a first retaining portion, and the stent further includes a second retaining portion configured to help hold the stent in place within the patient's body; the first section of the lateral wall forms an annular ring; the first section of the lateral wall forms a helix; the first section of the lateral wall forms a dimple; the lateral wall has a third portion, the second portion of the lateral wall is positioned between the first portion of the lateral wall and the third portion of the lateral wall; the lateral wall has a third portion, the third portion The second portion of the sidewall has a thickness different from the second portion, and the second portion of the sidewall is positioned between the first portion of the sidewall and the third portion of the sidewall; the sidewall has a third portion, the second portion of the sidewall is positioned between the first portion of the sidewall and the third portion of the sidewall, and the third portion has a third thickness, the second thickness is greater than the first thickness, and the second thickness is greater than the third thickness; the first portion of the sidewall has a first section and a second section, the first section of the first portion forms a helix that rotates in a first direction, and the second section of the first portion forms a helix that rotates in a second direction different from the first direction. The stent, including any embodiment thereof, can be modified by the methods disclosed herein to exhibit controlled degradation when the stent is placed in a host. For example, slits can be formed in the slits to provide areas that promote degradation.

[0142] In another embodiment, the stent includes a retaining portion configured to help hold the stent in place within the patient's body; and an elongated portion extending from the retaining portion, the elongated portion having a first member and a second member, the first member lacking a lumen, the second member lacking a lumen, and the first and second members being intertwined. In another embodiment, the stent includes a retaining portion configured to help hold the stent in place within the patient's body, and an elongated portion extending from the retaining portion, having an extension configuration and a nominal configuration, the elongated portion having a side wall defining a lumen extending from a first end portion of the elongated portion to a second end portion of the elongated portion, the side wall defining a chamber, the chamber being configured to receive fluid and to position the elongated portion in its extension configuration. In this case as well, any of these stents may be modified by the methods disclosed herein to exhibit controlled degradation when the stent is placed in a host.

[0143] In another embodiment, the stent is a fiber-reinforced elastomer film structure designed to have at least one position-holding end, where the fiber reinforcement is a combination of monofilaments and knitted or braided multifilament yarns, and the fiber-reinforced elastomer film is tubular having a central main component having a diameter smaller than the diameter of the patient's ureter and having at least one position-holding end, where the position-holding end is a highly flexible extension of the central main tube, which becomes neck-shaped after insertion into the patient's ureter but can be made collinear with the central main tube when inserted using an applicator.

[0144] In another embodiment, the stent includes an elongated member having a first portion and a second portion, the second portion having a side wall defining a single lumen, the first portion being coupled to the second portion, the first portion being configured to be positioned within the patient's kidney, and the side wall of the second portion of the elongated member being configured to deliver fluid from a first position on the side wall of the second portion to a second position on the side wall of the second portion via at least one of capillary action and wicking. The second portion of the elongated member is configured to be positioned within at least one of the patient's bladder and the patient's ureter, and at least a portion of the first portion is positioned within the lumen. Optionally, the stent may be further characterized by one or more of the following features: a second portion of the elongated member is made of a multi-strand material; a second portion of the elongated member is made of yarn; a second portion of the elongated member has a configuration selected from the group consisting of braided tube configurations and long woven strip configurations; a second portion of the elongated member is made of melt-spun polypropylene heavily filled with barium sulfate; the stent further includes a proximal retention structure configured to be placed in the patient's bladder, the proximal retention structure being coupled to the second portion of the elongated member; the stent further includes a distal retention structure configured to be placed in the patient's kidney, the distal retention structure being coupled to the first portion of the elongated member; the first portion is coupled to the second portion via an interference fit; the second portion of the elongated member has a substantially solid tubular shape; the second portion of the elongated member is substantially flexible; the first portion of the elongated member is substantially rigid; the second portion of the elongated member is more flexible than the first portion of the elongated member. This stent, including any embodiment thereof, can be modified to exhibit controlled disassembly in accordance with this disclosure.

[0145] In another embodiment, the medical device is a ureteral stent and includes: a long member having a first part and a second part, the second part having a substantially solid cylindrical shape, the first part being coupled to the second part, the first part being configured to be positioned in the patient's kidney, the first part having a length such that the first part ends in at least one of the patient's kidney and ureter, the second part of the long member being configured to deliver fluid from a first location in the second part to a second location in the second part via at least one of capillary action and wicking, and the second part of the long member being configured to be positioned in at least one of the patient's bladder and the patient's ureter. The stent can be modified to exhibit controlled disintegration in accordance with this disclosure.

[0146] In another embodiment, the stent comprises at least one filament having a longitudinal axis and formed from a material comprising a bioabsorbable polymer material. The polymer molecules in the bioabsorbable polymer material may have a helical orientation aligned with respect to the longitudinal axis of the filament. The stent is at least partially bioabsorbed by the patient upon implantation or insertion of the stent into the patient. For example, the stent may include: a braided or woven structure; a flared end portion at either the proximal or distal end of the stent; and at least one filament having a longitudinal axis and comprising an oriented bioabsorbable polymer material, wherein the polymer molecules in the bioabsorbable polymer material have a helical orientation aligned with respect to the longitudinal axis of the at least one filament. Optionally, the stent can be further described by one or more of the following: the proximal and distal ends include flared end portions; at least one filament is helically wound along at least a portion of the length of the stent; the stent comprises multiple filaments, optionally such multiple filaments are helically wound along at least a portion of the length of the stent, and further optionally such first portions of the multiple filaments are helically wound along a first direction and second portions of the multiple filaments are helically wound in the opposite direction to the first direction; the multiple filaments are braided and helically wound along at least a portion of the length of the stent; the stent comprises stainless steel or nitinol filaments.The stent contains 12 to 36 helical filaments; where optionally 6 to 18 filaments are helical and axially displaced from one another, the helices extending in a first direction, and the same number of filaments include helices extending in a second direction opposite to the first direction, and the filaments are uniformly arranged around the longitudinal axis of the stent; the oriented bioabsorbable polymer material includes a single bioabsorbable polymer or a blend of bioabsorbable polymers; the oriented bioabsorbable polymer material includes polymers selected from poly(α-hydroxy acid) homopolymers, poly(α-hydroxy acid) copolymers and blends thereof; the oriented bioabsorbable polymer material includes polyglycolide, poly-L-lactide, poly-D-lactide, poly-DL- The stent comprises polymers selected from lactides and blends thereof; the oriented bioabsorbable polymer material has a degree of crystallinity ranging from 0.1 to 20%; at least one filament comprises a core of the oriented bioabsorbable polymer material; at least one filament comprises a coating of the oriented bioabsorbable polymer material; the stent comprises multiple oriented filaments arranged to form a geometric rhomboid cell pattern; the multiple filaments are wound around each other to form an interlocking joint; at least one filament contains a therapeutic agent; the stent is selected from coronary stents, peripheral vascular stents, urethral stents, ureteral stents, biliary stents, tracheal stents, gastrointestinal stents and esophageal stents.

[0147] Another optional embodiment provides a stent which is a component of a fiber-reinforced elastomer film designed to have at least one position-retaining end. The fiber reinforcement is a combination of monofilament yarn or knitted or braided multifilament yarn, and the fiber-reinforced elastomer film is in the form of a tube having at least one position-retaining end. The retaining end is an inverted cone with a diameter exceeding the diameter of the main tube in a broad cross-section, and when radial compression is applied with an applicator, it is reversibly compressed to match the diameter of the main tube (which is also smaller than the diameter of the patient's ureter). Preferably the inverted cone is partially slit, which results in a cone wall having at least two lobules, preferably three to five lobules, to facilitate radial compression when inserted with an applicator.

[0148] Another embodiment provides a fiber-reinforced elastomer film structure designed to have at least one position-retaining end. The fiber reinforcement is a combination of monofilament yarn and knitted or braided multifilament yarn, and the elastomer film is tubular having a central main component with a diameter smaller than the diameter of the patient's ureter and having at least one position-retaining end, where the position-retaining end is an asymmetric inverted cone with an axially slit teardrop-shaped cross section (at the apex of the teardrop, having an average diameter greater than the average diameter of the main tube in the broader cross section), and this slit asymmetric cone is reversibly compressed to match the diameter of the central main tube when a radial compressive force is applied with an applicator.

[0149] In yet another optional embodiment, the stent is a component of a fiber-reinforced elastomer film, the fiber reinforcement being a combination of monofilament yarn or knitted or braided multifilament yarn, the reinforced elastomer film being tubular, with a central main component compressed unidirectionally longitudinally, the expandable tube having a circular cross-section smaller than the cross-section of the patient's ureter when expanded outward, and having at least one position-holding end. The position-holding end is compressed unidirectionally, expandable, and is an asymmetric inverted cone with a teardrop cross-sectional shape and a crimp at the apex of the teardrop (collinear with the crimp of the central main tube), the average diameter of the inverted cone exceeding the average diameter of the central main tube when expanded outward.

[0150] Optionally, the fiber-reinforced elastomer film is formed from a segmented copolymer made of polyethylene glycol and at least one cyclic monomer selected from the group represented by: L-lactide, epsilon-caprolactone, trimethylene carbonate, glycolide, morpholine-dione, p-dioxanone, and 1,5-dioxapan-2-one. Optionally, the film is formed from a mixture of epsilon-caprolactone and glycolide. Optionally, the film is formed from a mixture of L-lactide and glycolide. An exemplary composition of the elastomer swelling film composition is a crystalline copolymer of high molecular weight (20-35 kDa) polyethylene glycol (PEG) and a 95 / 5 (mol) mixture of epsilon-caprolactone / glycolide, where the weight percentage of the PEG component of the copolymer is approximately 10%.

[0151] Another exemplary composition of the elastomer film composition is a crystalline segmented copolymer prepared in two steps. The first step involves the formation of an amorphous or low-melting-point copolymer prepared from epsilon-caprolactone, trimethylene carbonate, and glycolide by polymerization in the presence of triethanolamine and stannous octanoate as initiator and catalyst, respectively. In the second step, the product from the first step is reacted with a mixture of L-lactide and epsilon-caprolactone to produce a crystalline triaxial final copolymer.

[0152] Optionally, the film may be prepared from electrospun fibers. Optionally, the fiber-reinforced elastomer film may contain or include monofilament yarns (optionally combined with knitted or braided multifilament yarns), where the reinforced monofilament yarns are formed from segmented copolymers made from at least two cyclic monomers selected from the group represented by L-lactide, epsilon-caprolactone, trimethylene carbonate, glycolide, morpholine-dione, p-dioxanone, and 1,5-dioxapan-2-one. Optionally, a composition formed from L-lactide, epsilon-caprolactone, and trimethylene carbonate that degrades relatively slowly. Optionally, a composition formed from glycolide, epsilon-caprolactone, and trimethylene carbonate that degrades relatively quickly.

[0153] The reinforcing monofilament yarn may also be a composite of an inorganic fine particle dispersion phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass, and an absorbent polymer matrix of a crystalline segmented copolymer made from at least two cyclic monomers selected from the group consisting of L-lactide, epsilon-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepan-2-one, and morpholindione. Furthermore, the reinforcing monofilament yarn may also be a composite of an inorganic fine particle dispersion phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass, and an absorbent polymer matrix of a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepan-2-one, and morpholindione.

[0154] In yet another optional embodiment, the disclosure provides a bioabsorbable and disintegrable multicomponent intraureteral stent, which is a component of a fiber-reinforced elastomer film designed to have at least one position-holding end, where the fiber reinforcement is a combination of monofilament yarn or knitted multifilament or braided yarn, and the reinforcing knitted or braided multifilament fibers are formed from a crystalline segmented copolymer. An exemplary composition of such copolymer is a triaxial copolymer prepared in two steps. The first step involves the formation of an amorphous or low-melting-point triaxial prepolymer using epsilon-caprolactone and / or trimethylene carbonate in the presence of trimethylolpropane and stannous octanoate as initiator and catalyst, respectively. The second step involves reacting the product of the first step with glycolide, or a mixture of glycolide and epsilon-caprolactone and / or trimethylene carbonate. Another exemplary composition is a copolymer for use in the manufacture of knitted or braided multifilament yarns, which is a crystalline copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group represented by L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, morpholine-dione, p-dioxanone, and 1,5-dioxapan-2-one (preferably from polyethylene glycol, L-lactide, and trimethylene carbonate, more preferably from a segmented copolymer of L-lactide and trimethylene carbonate). Optionally, the copolymer may be made from glycolide and trimethylene carbonate, providing the yarn with a relatively fast degradation profile.

[0155] Accordingly, in one embodiment, the present invention provides an absorbable and disintegrating multi-component intraureteral stent, which is a component of a fiber-reinforced elastomer film designed to have at least one position-holding end. Here, the fiber reinforcement is a combination of monofilament coils and braided multifilament yarns, and the film is formed from a crystalline segmented copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepan-2-one, and morpholindione. The film may also be formed from a crystalline segmented copolymer made from L-lactide and at least one cyclic monomer selected from the group consisting of glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepan-2-one, and morpholindione.

[0156] Furthermore, the present invention provides an absorbable and disintegrating multi-component intraureteral stent, which is a component of a fiber-reinforced elastomer film designed to have at least one position-holding end. Here, the fiber reinforcement is a combination of a monofilament coil and a braided multifilament yarn, the monofilament yarn being formed from a crystalline segmented copolymer made from at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, morpholine dione, p-dioxanone, and 1,5-dioxapan-2-one. Alternatively, the reinforcing monofilament yarn is a composite of an inorganic fine particle dispersion phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass, and an absorbent polymer matrix of a crystalline segmented copolymer made from at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepan-2-one, and morpholindione. The reinforcing monofilament yarn may also be a composite of an inorganic fine particle dispersion phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass, and an absorbent polymer matrix of a crystalline segmented copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepan-2-one, and morpholindione.

[0157] Accordingly, the disclosure also provides any embodiment of an absorbable and disintegrating multi-component intraureteral stent, which is a component of a fiber-reinforced elastomer film designed to have at least one position-holding end, wherein the fiber reinforcement is a combination of a monofilament coil and a braided multifilament yarn, and the reinforcing braided multifilament fiber is formed from a crystalline segmented copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, trimethylene carbonate, ε-caprolactone, glycolide, p-dioxanone, morpholinedione, and 1,5-dioxapan-2-one. Alternatively, the reinforcing braided multifilament tube is made from a crystalline segmented copolymer made from L-lactide and at least one cyclic monomer selected from the group consisting of glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxapan-2-one, and morpholinedione.

[0158] In another embodiment, the disclosure presents a stent comprising a fiber-reinforced elastomer film designed to have at least one position-retaining end, where the fiber reinforcement is a tube of braided or weft-knitted monofilament yarn, and the fiber-reinforced film is tubular, with a central main component smaller than the diameter of the patient's ureter and having at least one position-retaining end. The position-retaining end is a highly flexible extension of the central main tube, which, after insertion into the patient's ureter, forms a loop shape with an open end parallel to the axis of the central main tube, but this loop is collinear with the central main tube when inserted using an applicator. The film components of the assembled stent are formed from a crystalline segmented copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholindione. Alternatively, the film is formed from a crystalline segmented copolymer made from L-lactide and at least one cyclic monomer selected from the group consisting of glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepant-2-one, and morpholindione.

[0159] In another embodiment, the disclosure presents a stent as a component of a fiber-reinforced elastomer film designed to have at least one position-holding end, wherein the fiber reinforcement is a tube of braided or weft-knitted monofilament yarn, the reinforcing braided or weft-knitted monofilament yarn being formed from a crystalline segmented copolymer made from at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, morpholindione, p-dioxanone, and 1,5-dioxepan-2-one. Alternatively, the reinforcing braided or weft-knitted monofilament yarn being formed from a crystalline segmented copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, trimethylene carbonate, ε-caprolactone, glycolide, p-dioxanone, morpholindione, and 1,5-dioxepan-2-one. The reinforcing braided or weft-knitted monofilament yarn is also a composite of an inorganic fine particle dispersion phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass, and an absorbent polymer matrix of a crystalline segmented copolymer made from at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepant-2-one, and morpholindione. Furthermore, the reinforcing braided or weft-knitted monofilament yarn may be a composite of an inorganic fine particle dispersion phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass, and an absorbent polymer matrix of a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepant-2-one, and morpholindione.

[0160] Optionally, the stent is a component of a fiber-reinforced elastomer film designed to have at least one position-holding end, wherein the fiber reinforcement is a transversely or weftly knitted monofilament skeleton from which the reinforced structure is in the form of a tube comprising a central main component having a diameter smaller than the diameter of the patient's ureter and at least one position-holding end. The position-holding end is an inverted cone with a series of diameters designed to gradually provide a cross-section wider than the cross-section of the central main tube, and when radial compressive force is applied during insertion into the urogenital tract using a tubular applicator, it is reversibly compressed to radially coincide with the central main tube. The film is formed from a crystalline segmented copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholindione. Alternatively, the film may be formed from a crystalline segmented copolymer made from L-lactide and at least one cyclic monomer selected from the group consisting of glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepane-2-one, and morpholindione. The reinforcing weft or braided monofilament yarn may optionally be formed from a crystalline segmented copolymer made from at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, morpholindione, p-dioxanone, and 1,5-dioxapane-2-one. Alternatively, the reinforcing braid or weft-knit monofilament yarn is formed from a crystalline segmented copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, trimethylene carbonate, ε-caprolactone, glycolide, p-dioxanone, morpholinedione, and 1,5-dioxepant-2-one.

[0161] In another optional embodiment, the stent is a fiber-reinforced elastomer film component designed to have at least one position-holding end, the fiber reinforcement being a weft-knit or braided monofilament skeleton, the reinforced structure therefrom in the form of a tube including a central main component having a diameter smaller than the diameter of the patient's ureter and at least one position-holding end. The position-holding end is an inverted cone with a series of diameters designed to gradually provide a cross-section wider than the cross-section of the central main tube, and when a radial compressive force is applied during insertion into the urogenital tract using a tubular applicator, it is reversibly compressed to radially coincide with the central main tube. The reinforcing weft-knit or braided monofilament is a composite of an inorganic fine particle dispersion phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass, and an absorbent polymer matrix of a crystalline segmented copolymer made from at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepant-2-one, and morpholindione. Alternatively, the reinforcing braided or weft-knitted monofilament yarn is a composite of an inorganic fine particle dispersion phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass, and an absorbent polymer matrix of a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepant-2-one, and morpholindione.

[0162] In another embodiment, the disclosure provides an absorbable and disintegrable multi-component intraureteral stent, which is a component of a fiber-reinforced elastomer film designed to have at least one position-retaining end. Here, the fiber reinforcement is a weft-knitted monofilament yarn, and the reinforced structure is in the form of a tube comprising a central main component having a diameter smaller than the diameter of the patient's ureter, and at least one position-retaining end. The position-retaining end is a highly flexible extension of the central main tube, which, after insertion into the patient's ureter, forms a loop shape with an open end parallel to the axis of the central main tube, but this loop becomes collinear with the central main tube when inserted using an applicator. The film is formed from a crystalline segmented elastomer high-L-lactide copolymer, and the monofilaments are formed from segmented L-lactide copolymers with at least one cyclic monomer selected from the group consisting of glycolide, ε-caprolactone, and morpholindione. The monofilaments contain particulate inorganic fillers selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass.

[0163] In one embodiment, the medical device is a stent comprising a filament having a bioabsorbable polymer material oriented toward a longitudinal axis, wherein the polymer molecules in the bioabsorbable polymer material have a helical orientation aligned with the longitudinal axis of the filament, and the stent is bioabsorbed by the patient at least partially upon implantation or insertion of the stent into the patient. In any embodiment, one or more of the following features can further characterize the medical device: a) the filament is helically wound along at least a portion of the length of the stent; b) the stent comprises a plurality of such filaments, optionally the plurality of filaments helically wound along at least a portion of the length of the stent, optionally the plurality of such filaments helically wound in a first direction and the plurality of such filaments helically wound in the opposite direction; c) the filament is a braided filament; the plurality of such braided filaments are braided and helically wound along at least a portion of the length of the stent; d) the filament is a knitted filament; e) the plurality of filaments is a knitted filament; oriented bioabsorbable polymer material f) The bioabsorbable polymer material comprises either a single bioabsorbable polymer or a blend of bioabsorbable polymers; g) The oriented bioabsorbable polymer material comprises polymers selected from poly(alpha-hydroxy acid) homopolymers, poly(alpha-hydroxy acid) copolymers, and blends thereof; h) The oriented bioabsorbable polymer material comprises polymers selected from polyglycolides, poly-L-lactide, poly-D-lactide, poly-DL-lactide, and blends thereof; i) The oriented bioabsorbable polymer material has a degree of crystallinity in the range of 0.1 to 20%; i) The filament comprises a core of the oriented bioabsorbable polymer material; j) The stent is selected from coronary stents, peripheral vascular stents, urethral stents, ureteral stents, biliary stents, tracheal stents, gastrointestinal stents, and esophageal stents.

[0164] Optionally, the stent can maintain patency and remain at the application site for at least 2 days or 2-3 weeks after implantation, or decompose after 7 weeks at the implant site, or significantly decompose after 90 days, or completely decompose after 4 months. Optionally, the medical device, such as a ureteral stent, remains intact for at least the first 48 hours after placement in the host. For the first 7 days after implantation, it is preferable that the medical device can be re-implanted or removed from the host as a single unit. Approximately one week after implantation, the medical device may begin to generate HIVS fragments, although in some patients, the time until fragmentation occurs may vary slightly. Typically, HIVS fragments form between 2 and 3 weeks after implantation and are separated from the medical device by excretion, for example, if the medical device is a ureteral stent. Fragmentation may continue for several more weeks (e.g., 4-6 weeks after implantation). Optionally, most medical implants are excreted from the patient within approximately 90 days (about 12-13 weeks) after placement. Some medical devices may remain in the host for up to approximately 120 days.

[0165] This disclosure provides the following additional exemplary embodiments:

[0166] In one embodiment, the medical device is a biodegradable intraureteral stent. The stent comprises a tubular elastomer film and a tubular fiber reinforcement, the tubular elastomer film being a single tube covering the tubular fiber reinforcement. The stent optionally has at least one position-holding end. The device has a central main tube having a diameter smaller than the diameter of the patient's ureter, and at least one position-holding end, if present, is an extension of the central main tube. The central main tube is an overall tubular structure, the overall tubular structure includes side walls surrounding a lumen, and the longitudinal axis extends along the length of the lumen from the distal end to the proximal end of the structure. The tubular structure further comprises a plurality of bands, each surrounding the longitudinal axis and having a distal side and a proximal side. The plurality of bands have relatively high in vivo stability, separated from each other by relatively low in vivo stability bands. The stent is placed in the patient's ureter, extending from the patient's kidney to the bladder, and is configured to be held in place by optionally at least one position-holding end. In one structure, the film is reinforced and impregnated with a fiber-reinforced material, which includes monofilament coils placed on a knitted or braided tube of monofilament or multifilament yarn (which together form the side walls surrounding the lumen of the tubular structure). The film and fiber-reinforced material may each contain an absorbable crystalline segmented copolymer containing at least one cyclic monomer. The film and fiber-reinforced material alone can maintain ureteral patency.

[0167] In one embodiment, the intraureteral stent of the present disclosure can be placed by inserting a cystoscope through the patient's urethra into the patient's bladder. The clinician uses the cystoscope to locate the opening through which the ureter connects to the bladder. The clinician passes the intraureteral stent of the present disclosure through the cystoscope into the patient's ureter, ensuring that as one curl of the stent enters the patient's kidney, the other curl at the opposite end of the stent remains in the patient's bladder. After stent placement, the cystoscope is removed.

[0168] As described above, the biodegradable intraureteral stent of this disclosure comprises a plurality of bands, each surrounding a longitudinal axis and having distal and proximal ends. The plurality of bands comprises relatively high in vivo stability bands separated by relatively low in vivo stability bands. The overall tubular structure, also called the central main tube, may be identified as the proximal end of the tube-(LIVS-HIVS)n-LIVS-tube distal end, or the proximal end of the tube-(HIVS-LVS)n-HVS-tube distal end. In either case, n refers to the number of LIVS-HIVS repeating units and is an integer from at least 1 to about 100. Optionally, n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 3, 4, 5, 6, 7, 8, 9, or 10. Optionally, n is selected from 4, 5, 6, 7, 8, 9, or 10. In this embodiment, the tubular structure includes alternating bands of relatively high in vivo stability and relatively low in vivo stability.

[0169] The following options may further define the intraureteral stent of this disclosure: a) the stent has at least one position-holding end, which is a flexible extension of the central main tube and becomes cancerous after insertion into the patient's ureter but can be made collinear with the central main tube when inserted using an applicator; b) the tubular elastomer film is made of polyethylene glycol and L-lactide, epsilon-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morphol a) The tubular elastomer film comprises a crystalline segmented copolymer of L-lactide and at least one cyclic monomer selected from the group consisting of morpholindione; d) The monofilament coil comprises L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, morpholindione, p-dioxanone; e) The monofilament coil comprises a composite comprising a polymer matrix and an inorganic fine particle dispersed phase contained within the matrix, wherein the matrix comprises a crystalline segmented copolymer of at least two cyclic monomers selected from the group consisting of oxanone and 1,5-dioxapan-2-one; f) The monofilament coil comprises a composite comprising a polymer matrix and an inorganic fine particle dispersed phase contained within the matrix, wherein the matrix comprises a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholindione, and the inorganic fine particle dispersed phase comprises at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass;g) The monofilament coil comprises a composite comprising a polymer matrix and an inorganic fine particle dispersed phase contained within the matrix, wherein the matrix comprises a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholindione; h) The fiber reinforcement comprises a monofilament coil and a multifilament The braided tube of yarn includes, optionally, 1) a tubular elastomer film comprising polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholindione; 2) a tubular elastomer film comprising L-lactone and glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and 1 1,5-Dioxepan-2-one and morpholindione; 3) The monofilament coil comprises a crystalline segmented copolymer of at least two cyclic monomers selected from the group consisting of L-lactide, epsilon-caprolactone, trimethylene carbonate, glycolide, morpholindione, p-dioxanone, and 1,5-dioxapan-2-one; 4) The monofilament coil comprises a composite comprising a polymer matrix and an inorganic fine particle dispersed phase contained within the matrix, wherein the matrix comprises a crystalline segmented copolymer of at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholindione, and the inorganic fine particle dispersed phase comprises at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass;5) The monofilament coil comprises a composite comprising a polymer matrix and an inorganic microparticle dispersion phase contained within the matrix, wherein the matrix comprises a crystalline segmented copolymer of polyethylene glycol and at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholinedione, and the inorganic microparticle dispersion phase comprises a small amount selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass. 6) The multifilament yarn comprises a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, trimethylene carbonate, ε-caprolactone, glycolide, p-dioxanone, morpholinedione, and 1,5-dioxapan-2-one; 7) The multifilament yarn comprises L-lactide and a monomer selected from the group consisting of glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxapan-2-one, and morpholinedione j) The monofilament coil is placed on a tube of weft-knitted monofilament yarn, where optionally, 1) the tubular elastomer film comprises polyethylene glycol and a crystalline segmented copolymer of at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholindione; 2) the tubular elastomer film, 3) The monofilament yarn comprises a crystalline segmented copolymer of L-lactide and at least one cyclic monomer selected from the group consisting of glycolide, ε-caprolactone, trimethylene carbonate, p-dioxanone, 1,5-dioxepane-2-one, and morpholindione; 4) The monofilament yarn comprises a crystalline segmented copolymer of at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, morpholindione, p-dioxanone, and 1,5-dioxapane-2-one;4) The monofilament yarn comprises a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, trimethylene carbonate, ε-caprolactone, glycolide, p-dioxanone, morpholine dione, and 1,5-dioxapan-2-one; 5) The monofilament yarn comprises a composite comprising a polymer matrix and an inorganic fine particle dispersed phase contained within the matrix, wherein the matrix comprises a crystalline segmented copolymer of at least two cyclic monomers selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholine dione, and the inorganic fine particle dispersed phase comprises at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass; and 6) The monofilament yarn is poly The composite comprises a matrix and an inorganic particulate dispersion phase contained within the matrix, wherein the matrix comprises a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholinedione, and the inorganic particulate dispersion phase comprises at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbent phosphate glass; k) the stent can maintain patency and remain in the application site for at least 2 days; l) the stent can maintain patency and remain in the application site for 2 to 4 months; and m) at least one position-holding end contains at least 4% by weight of at least one powder radiopaque agent selected from the group consisting of barium sulfate, zirconium oxide, and bismuth carbonate.

[0170] The following are some specific embodiments of this disclosure: (1) A bioabsorbable implantable medical device comprising an overall tubular structure, wherein the overall tubular structure comprises a side wall and a lumen surrounded by the side wall, the lumen having a longitudinal axis extending along the length of the lumen from the distal end to the proximal end of the structure, and the tubular structure further comprises a plurality of bands, each surrounding the longitudinal axis and having a distal side and a proximal side, wherein the plurality of bands comprises a relatively high in vivo stability band separated by a relatively low in vivo stability band. (2) The medical device according to Embodiment 1, wherein the structure has at least one or just one relatively high in vivo stability band and at least two or just two relatively low in vivo stability bands. (3) The medical device according to Embodiment 1, wherein the structure has at least two, or just two, relatively high in vivo stability bands and at least three, or just three, relatively low in vivo stability bands. (4) The medical device according to Embodiment 1, wherein the structure has at least three, or exactly three, relatively high in vivo stability bands and at least four, or exactly four, relatively low in vivo stability bands. (5) The medical device according to Embodiment 1, wherein at least two relatively high in vivo stability bands are separated by one relatively low in vivo stability band having a length of less than 1 cm, each having a length of 1 to 6 cm. (6) The medical device according to Embodiment 1, wherein at least two relatively high in vivo stability bands are separated by one relatively low in vivo stability band having a length of less than 1 cm, each having a length of 2 to 6 cm. (7) The medical device according to Embodiment 1, wherein at least two relatively high in vivo stability bands are separated by one relatively low in vivo stability band having a length of less than 1 cm, each having a length of 3 to 6 cm. (8) The medical device according to Embodiment 1, wherein at least three relatively high in vivo stability bands are each 3 to 6 cm in length and separated by two relatively low in vivo stability bands having a length of less than 1 cm. (9) The medical device according to Embodiment 1, wherein at least four relatively high in vivo stability bands are separated by three relatively low in vivo stability bands, each having a length of 3 to 6 cm. (10) The medical device according to Embodiment 1, wherein at least three relatively high in vivo stability bands are each 2 to 5 cm in length and separated by two relatively low in vivo stability bands having a length of less than 1 cm. (11) The medical device according to Embodiment 1, wherein at least three relatively high in vivo stability bands are each 3 to 6 cm in length and separated by two relatively low in vivo stability bands having a length of less than 1 cm. (12) The medical device according to Embodiment 1, wherein the tubular structure includes alternating bands with relatively high in vivo stability and relatively low in vivo stability. (13) The medical device according to Embodiment 1, wherein the tubular structure includes at least two relatively high in vivo stable bands separated by one relatively low in vivo stable band, the relatively low in vivo stable band decomposes in vivo at at least twice the rate of the at least one relatively high in vivo stable band. (14) The medical device according to Embodiment 1, wherein the tubular structure includes at least two relatively high in vivo stability bands separated by one relatively low in vivo stability band, the at least two relatively high in vivo stability bands having substantially identical in vivo stability. (15) The medical device according to Embodiment 1, wherein the tubular structure includes a band with relatively high in vivo stability on both sides of a band with relatively low in vivo stability, and the two bands with relatively low in vivo stability have different in vivo stabilities. (16) The medical device according to Embodiment 1, wherein the tubular structure includes a first relatively low in vivo stability band located distal to a first relatively high in vivo stability band, and a second relatively low in vivo stability band located proximal to the first relatively high in vivo stability band, the first relatively low in vivo stability band having higher in vivo stability than the second relatively in vivo stability band. (17) The medical device according to Embodiment 1, wherein the tubular structure comprises a plurality of bands having substantially identical and relatively high in vivo stability. (18) The medical device according to Embodiment 1, wherein the tubular structure includes a plurality of relatively low in vivo stability bands separated by a relatively high in vivo stability band extending from the distal end to the proximal end of the structure, and the in vivo stability of the plurality of relatively low in vivo stability bands increases from the distal end to the proximal end of the structure. (19) The medical device according to Embodiment 1, wherein the tubular structure is a mesh tube or includes a mesh tube. (20) The medical device according to any one of embodiments 1 to 19, wherein the tubular structure has a length of 10 to 30 cm. (twenty one) The medical device according to any one of embodiments 1 to 20, wherein the side wall includes a monofilament coil surrounding the lumen, a mesh covering the monofilament coil, and a coating deposited on the coil and the mesh. (twenty two) Furthermore, the medical device according to any one of Embodiments 1 to 21, further comprising a kidney-holding structure at the proximal end of the device and a bladder-holding structure at the distal end of the device. (twenty three) Furthermore, the medical device according to any one of embodiments 1 to 22, further comprising a curled kidney retaining structure at the proximal end of the device and a curled bladder retaining structure at the distal end of the device. (twenty four) A ureteral stent, a medical device according to any one of embodiments 1 to 23. (twenty five) A medical device according to any one of embodiments 1 to 24, wherein the device includes a coating on its outer surface, and the coating has an average thickness. (26) A medical device according to any one of embodiments 1 to 25, wherein the device includes a coating on its outer surface, and the coating has a non-uniform thickness over the entire device. (27) A medical device according to any one of embodiments 1 to 26, wherein the device includes a coating on its outer surface, and the proximal end of the device has more coating than the distal end of the device. (28) The device is a ureteral stent having a kidney-retaining structure at the proximal end of the device and a bladder-retaining structure at the distal end of the device, and the device includes a coating on its outer surface, wherein the proximal end of the device includes more coating than the distal end of the device, as described in any of Embodiments 1 to 27. (29) A medical device according to any one of embodiments 1 to 28, which does not include a containment layer that restricts the movement of HIVS bands that separate from the medical device during in vivo decomposition. (30) a. A method for manufacturing a medical device, To provide a bioabsorbable medical device including a generally tubular structure having a lumen passing through the center of the generally tubular structure within the side walls of the generally tubular structure, a bioabsorbable medical device, and b. Exposing a band with an overall tubular structure to an ex vivo degradation environment to generate a band with low in vivo stability (LIVS) from the exposed band, while not exposing bands adjacent to the exposed band with an overall tubular structure to the same degradation environment to generate a band with high in vivo stability (HIVS) adjacent to the LIVS band. A method that includes this. (31) A medical device manufactured by a method including the method described in Embodiment 30. (32) A medical device according to embodiment 31, in which the overall tubular structure contains polyester.

[0171] It should be understood that the terms used herein are intended solely to describe specific embodiments and are not intended to be limiting. Furthermore, unless specifically defined herein, terms used herein should be given their traditional meanings known in the relevant art.

[0172] Throughout this specification, any reference to “one embodiment” or “embodiment” and its variations means that a particular feature, structure, or characteristic described in relation to the embodiment is included in at least one embodiment. Therefore, the appearance of the terms “in one embodiment” or “in an embodiment” in various places throughout this specification does not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic can be combined in any suitable manner in one or more embodiments. Any embodiment of a medical device disclosed herein may include a drug, such as a therapeutic or prophylactic agent, as part of the medical device.

[0173] Where used herein, including in the claims, the singular forms "a," "an," and "the" include plural references, i.e., one or more, unless the content and context specifically indicate otherwise. It should also be noted that "and" and "or" are used most broadly to include "and / or" unless the content and context specifically indicate inclusiveness or exclusivity where applicable. Therefore, the use of an alternative (e.g., "or") should be understood to mean one of the alternatives, both, or any combination thereof. Furthermore, when described herein as "and / or," the "and" or "or" configuration is intended to encompass embodiments including all of the relevant items or ideas, and one or more other alternative embodiments not including all of the relevant items or ideas.

[0174] Unless otherwise indicated by the context, throughout the specification and the attached claims, the word “includes” and its synonyms and variations, e.g., “have” and “equip,” as well as variations of itself (e.g., “have”), should be interpreted in an open and comprehensive sense, e.g., “not limited to, but including, ….” The term “substantially consists of” does not limit the claims to specific materials or steps or to any extent that does not substantially affect the fundamental and novel features of the invention described in the claims.

[0175] The headings used herein are for the sole purpose of facilitating the reader's browsing and should not be construed in any way as limiting the scope of the invention or the claims. Accordingly, the headings and summaries of the disclosures provided herein are for convenience only and do not constitute any interpretation of the scope or meaning of the embodiments.

[0176] The description provides certain specific details to give a complete understanding of the various embodiments disclosed. However, those skilled in the art will recognize that embodiments may be carried out without one or more of these specific details, or using other methods, components, materials, etc. [Examples]

[0177] The examples and preparations provided below further illustrate and illustrate the medical devices of the present invention and methods for preparing such devices. It should be understood that the scope of the present invention is not limited in any way to the following examples and preparations. In fact, unless the context otherwise indicates, where a particular polymer is used in an example, this polymer is merely illustrative and may be replaced with an alternative polymer according to the present invention. Also, where decomposition time and properties are illustrated, these values ​​are approximate and other values ​​may be obtained using different starting materials. The starting materials and various reactants used or referenced in the examples can be obtained from commercial sources or readily prepared from commercially available organic compounds using methods well known to those skilled in the art. Therefore, the following examples illustrate embodiments of the present invention and should not be construed as limitations thereto.

[0178] [Example 1] [Coil fabrication] A 1-liter stainless steel kettle with a three-portion glass lid, equipped with an overhead mechanical stirrer unit, a vacuum adapter, and a nitrogen inlet, was assembled. The kettle was evacuated to a pressure of approximately 0.5 mmHg and then purged with nitrogen. 9.15 g of paxTMC-1, pre-dried by heating to 220°C, was placed in the kettle. paxTMC-1 was prepared by combining trimethylene carbonate (TMC) and trimethylolpropane (TMP) in a TMC:TMP molar ratio of 15:1 in the presence of a tin catalyst, stannous octanoate, while heating and stirring. Glycolide (313.8 g, 2.705 mol), ε-caprolactone (132.1 g, 1.159 mol), and a radiopaque agent (245 g barium sulfate particles with a diameter of 1-4 microns) were added to the reaction kettle. The kettle apparatus was immersed in an oil bath, and its contents were placed under vacuum at 40°C for 1 hour, after which the system was purged with nitrogen. The oil bath temperature was raised to 95°C, and the contents of the kettle were thoroughly mixed with an overhead stirrer. After a homogeneous fluid composition was obtained, a 0.2 M toluene solution of stannous octanoate (2.576 mL, 5.152 × 10⁻¹⁶) was added. -4Moles of stannous octanoate were added. The oil bath temperature was raised to 180°C, and stirring was continued for as long as possible. After stirring became impossible (due to high viscosity), the reaction product was maintained at 180°C for 7 hours.

[0179] The kettle was removed from the oil bath and allowed to cool to room temperature. Next, the kettle was placed in a cold bath to solidify the polymer. The solid polymer was removed from the kettle and pulverized. The pulverized material was sieved to obtain a powder. The sieved powder was transferred to a 2-liter pear-shaped glass flask and placed in a Buchi·rotavap. Vacuum was applied, and after obtaining a vacuum of 0.25 mmHg, the flask was immersed in the oil bath. The oil bath temperature was raised to 40°C. After 2 hours at 40°C, the oil bath temperature was raised to 80°C, and after 1 hour at 80°C, the oil bath temperature was raised to 110°C. The oil bath temperature was maintained at 110°C for 4 hours. The vacuum was released and the material was removed from the flask.

[0180] [Example 2] [Melt spinning and properties of radiopaque monofilaments using the polymer of Example 1] The polymer from Example 1 was extruded into monofilaments using a single-screw extruder with four zones. A filter pack with a 325 lines / inch capacity was used in the extruder. Zone 1 was maintained at 95°C, Zone 2 at 175°C, Zone 3 at 208°C, and Zone 4 / spinning pack at 210°C. The metering pump was operated at 8 rpm while the take-up roll was set to 40-60 rpm. The polymer from Example 1 was extruded using a 0.4 mm die. The diameter of the collected monofilaments was 0.48 mm to 0.54 mm. These fibers were stretched to 4.5 × at 55°C in the first stage and to 0.5 × at 70°C in the second stage, yielding monofilaments with a diameter of 0.25 mm to 0.30 mm. Free shrinkage was approximately 8.85% to 10.43% at 50°C. The fibers relaxed to half of the free shrinkage plus 2% at 70°C. The resulting fibers had a maximum load capacity of approximately 10-13 N and were dimensionally stable.

[0181] [Example 3] [Manufacturing of coiled skeletons (CS)] The radiopaque monofilament prepared in Example 2 was helically wound around a 0.047-inch diameter Teflon cord. The monofilament was wound around the Teflon cord at a rate of 33–35 coils / inch to provide a coiled skeleton (CS), which is an exemplary overall tubular structure of the present disclosure.

[0182] [Example 4] [Synthesis and characterization of triaxially segmented glycoside copolymers for use in the fabrication of knitted skeletons] A reaction apparatus was assembled with an overhead mechanical stirrer unit, a vacuum adapter, and a 1-liter stainless steel kettle with a three-necked glass lid and a nitrogen inlet. The reaction apparatus was evacuated. After a vacuum of 0.5 mmHg was achieved, the apparatus was purged with nitrogen. The initial amounts of paxTMC-1 (16.0 g, as described in Example 1), ε-caprolactone (38.6 g, 0.3382 mol), and glycolide (745.4 g, 6.4262 mol) were added to the kettle. The reaction apparatus was then immersed in an oil bath. The oil bath was then heated to 110°C and the reaction mixture was mixed under positive nitrogen pressure. Once the polymer initiator (pax-TMC) appeared to be completely dissolved in the molten monomer, a solution of stannous octanoate (0.966 ml of 0.2 M toluene solution of stannous octanoate, 1.933 × 10⁻⁶) was added. -4 A mole of the polymer was added to the reaction mixture. The oil bath temperature was increased to 180°C. The reaction mixture was stirred until the viscosity of the mixture increased and stirring was no longer possible. The reaction was maintained at 180°C for a further 5 hours. The reaction vessel was removed from the oil bath and allowed to cool until the polymer solidified. The cooled polymer was removed from the reaction kettle and ground into a powder. The ground material was sieved. The sieved polymer was transferred to a 2-liter pear-shaped glass flask and placed in a Buchi·rotavap. Vacuum was applied, and after obtaining a vacuum of 0.5 mmHg, the flask was immersed in the oil bath. The oil bath temperature was increased to 40°C. After 2 hours at 40°C, the oil bath temperature was increased to 80°C, and after 1 hour at 80°C, the oil bath temperature was increased to 110°C. The oil bath temperature was maintained at 110°C for 4 hours. The vacuum was released and the material was removed from the flask.

[0183] [Example 5] [Melting spinning and properties of multifilament yarn using the polymer of Example 4] The polymer from Example 4 was extruded into multifilaments using a single-screw extruder with five zones. A 400 lines / inch filter pack was used in the extruder. Zone 1 was maintained at 190°C, Zone 2 at 210°C, Zone 3 at 222°C, Zone 4 / pump at 228°C, and Zone 5 / spinning pack at 228°C. A Zenith metering pump with 0.584 cc / rpm was operated at 6.0 rpm while the denier control roll was set to a linear speed of 315 m / min. The fibers were then oriented onto three high-speed godets heated to 45°C, 80°C, and 26°C, respectively, moving at 200 m / min, 480 m / min, and 480 m / min. The polymer from Example 4 was extruded using a 20-hole die with holes having a diameter of 0.018 inches. Next, the collected multifilaments were reoriented at a rate of 250 M / min to 280 M / min at a temperature of 100°C. The resulting fibers had a tenacity of approximately 3.26 and a denier of approximately 80.4.

[0184] [Example 6] [Creation of a knitted skeleton (KS)] Twenty-filament yarns from Example 5 were twisted together once to form a 40-filament yarn. This multifilament yarn was continuously weft-knitted onto the coiled skeleton of Example 3 using a lamb's circular knitting machine. A knitted skeleton was formed on the coiled skeleton using a 7 / 8-inch knitting cylinder equipped with 12-cours gauge needles. The resulting structure is an exemplary overall tubular structure of the present disclosure.

[0185] [Example 7] [Synthesis and Characterization of Triaxially Segmented L-Lactidopolymer (P1)] A reactor apparatus was assembled, comprising an overhead mechanical stirrer unit, a vacuum adapter, and a 4-liter stainless steel reactor with a nitrogen inlet. Vacuum was applied to the reactor apparatus, and after a vacuum of less than 0.5 mmHg was achieved, the apparatus was purged with nitrogen. The reaction temperature was controlled by circulating oil through a jacketed reactor. The reaction ingredients were glycolide (254.9 g, 2.1976 mol), trimethylene carbonate (348.7 g, 3.4185 mol), and pre-dried triethanolamine (3.0319 g, 2.0348 × 10⁻⁶). -2 (moles), stannous octanoate (354.5 mg, 8.752 × 10⁻¹⁴) -4 Initial amounts of 1 mol (1.9534 mol) and ε-caprolactone (974.3 g, 8.5463 mol) were added to a 2 L flask and dried under high vacuum at 40°C for 1.25 hours. The contents of the flask were then added to a 4 L reactor. The system was then purged with nitrogen. The oil temperature was raised to 175°C and the contents were thoroughly mixed for 6.5 hours. The final amounts of glycolide (226.6 g, 1.9534 mol) and L-lactide (1195.5 g, 8.3021 mol) were added by lowering the temperature. The oil temperature was then raised to 135°C and maintained for 19 hours. The resulting polymer was removed from the container and dissolved at a concentration of 1 g per 4 ml of dichloromethane (DCM). The polymer / DCM solution was slowly added to a sufficient amount of cold isopropyl alcohol that was mechanically stirred to precipitate the polymer. The precipitated polymer was isolated by vacuum filtration. Next, the filtered polymer was added to a sufficient amount of cold isopropyl alcohol that was mechanically stirred. The polymer was then isolated by vacuum filtration. Once most of the solvent had been removed, the polymer was dried under vacuum until it reached a certain weight.

[0186] [Example 8] [Assembly of a composite ureteral stent configuration] A polymer solution was prepared by combining 16.0 grams of polyethylene glycol (PEG4600; MW=4600), 1600 milliliters of acetone, and 144.0 grams of purified P1 (Example 7) in a glass bottle. The glass bottle was sealed with a lid. The bottle was placed on an apparatus such as a rolling mill to continuously rotate the glass bottle. The solution was rotated until PEG4600 and P1 were completely dissolved in the acetone.

[0187] The dried knitted skeleton from Example 6 was impregnated with the PEG4600 / P1 polymer solution described above using a continuous impregnation process that included continuous transfer of the knitted core material through a bath of 0.75 liters of polymer solution. The skeleton was removed from the spool and fed into a bath of the coating solution, where two in-line submersible pulleys kept the skeleton material immersed for the length of the bath. Once the impregnated material exited the bath, it passed through an air-circulating drying tube heated to 40°C, then through a stainless steel element heated to 50°C, and then the impregnated material was spooled onto a final winding spool. This coating process was repeated to provide a thicker coating of PEG4600 / P1 coating on the skeleton.

[0188] The impregnated knitted skeleton was wound onto racks equipped with two parallel stainless steel bars, each 0.5 inches in diameter, allowing for adjustment of the separation distance to control the final stent length. Newly impregnated knitted skeletons were continuously wound onto these racks. The racks were annealed at 130°C for 30 minutes. After the annealing process, the racks were cooled to room temperature in a laminar flow hood.

[0189] Multiple stents were removed from each rack by cutting the skeletal material at the appropriate position along the internal position of the separation rod of the shaping rack. These stents still contained Teflon cores, but were altered by adding UVJ markers to the main trunk of each stent within 1 centimeter of what would eventually become the proximal loop of each stent.

[0190] An additional coating was applied to the proximal loop of the stent by mechanically immersing the proximal end of the stent in a controlled manner in the coating solution using MTS Synergie (Models 100 and 200) apparatus, using multiple cycles. The distal end of the stent was mounted in a vertical fixture of the MTS apparatus. The MTS apparatus was programmed to immerse the stent in a 100 mL graduated cylinder containing 100 mL of coating solution. The programmed procedure lowered the stent into the cylinder to the 20 mL marking and immediately lifted the stent out of the cylinder. The MTS apparatus held the stent above the coating solution for a sufficient time (approximately 30–300 seconds) to allow the coating to dry and become non-stick. The above immersion procedure was repeated, except that the stent was lowered to the 40 mL marking. The MTS program performed two final immersion cycles, in which the stent was lowered to 60 mL and then to 80 mL, respectively. This resulted in an outer coating layer with a thickness gradient, with the thickest layer of coating located on the proximal loop. This ensured that the proximal loop was reinforced with more coating material than the rest of the stent to prevent premature decomposition of the proximal loop.

[0191] The stents were dried in a laminar flow hood with the distal loop suspended. The Teflon® PTFE cores were removed from each stent by securing one end of the Teflon core with a fixed-position vise-grip pliers and stretching the other end of the Teflon using a second set of vise-grip pliers. A clean cut was made in the stretched Teflon core at the fixed end, and the reduced-diameter Teflon core was then passed through the stent and pulled out for discarding. Each stent was then trimmed to the appropriate specifications.

[0192] [Example 9] [Band creation using base treatment] By positioning a stent between two 5mm x 5mm sponge pieces, a band with lower in vivo stability was created on the stent compared to the adjacent untreated portion. The sponges were clipped together to maintain circumferential contact between the sponges and the stent. Approximately 1 mL of NaOH solution was then pipetted onto each sponge. The stent was then left in contact with the sponge pieces for 1 hour. The sponges were then removed, and the stent was rinsed with deionized water for 15 seconds. The stent was then dried under vacuum. This process created one low in vivo stability (LIVS) band on each stent, which was located between two high in vivo stability (HIVS) bands on the stent.

[0193] This process was carried out by treating the stents with a basic solution having one of the following NaOH concentrations: 0.5 M, 0.75 M, 1.0 M, 1.25 M, or 3.0 M, to prepare bands with low in vivo stability. Each stent was treated with only one of these basic concentrations.

[0194] [Example 10] [Creating multibands using base treatment] By positioning a stent between two 5mm x 5mm sponge pieces, a band with lower in vivo stability was created compared to the adjacent untreated portion of the stent. The sponges were clipped together to maintain circumferential contact between the sponges and the stent. A second set of sponges was attached to the stent in a similar manner, with a distance of approximately 4cm between the ends of the first and second sponge sets. Approximately 1 mL of NaOH solution was then pipetted onto each sponge. The stent was then left in contact with these sponge sets for 1 hour. The sponges were then removed, and the stent was rinsed with deionized water for 15 seconds. The stent was then dried under vacuum. A band of low in vivo stability (LIVS) was generated where each set of sponges had been positioned. This resulted in one LIVS band being generated between the two LIVS bands.

[0195] This process was carried out by treating the stents with a basic solution having one of the following NaOH concentrations: 0.5 M, 0.75 M, 1.0 M, 1.25 M, or 3.0 M, to prepare a low in vivo stability band for each stent. That is, each stent was treated with one of the following in each sponge set: 0.5 M NaOH, 0.75 M NaOH, etc.

[0196] [Example 11] [Multiband generation using base treatment - gradient generation] By positioning the stent between two 5mm x 5mm sponge pieces, a band gradient was created in which the in vivo stability of the stent gradually decreased compared to the adjacent untreated portion. The sponges were clipped together to maintain circumferential contact between the sponges and the stent. The second, third, and fourth sponge sets were attached to the stent in a similar manner, such that the distance from the end of one band's sponge to the end of the next nearest band's sponge was approximately 4cm. Next, approximately 1 mL of 0.5 M NaOH solution was pipettered onto each sponge in the sponge set closest to the kidney-holding portion of the stent. Next, approximately 1 mL of 0.75 M NaOH solution was pipettered onto each sponge in the second sponge set from the kidney-holding portion of the stent. Next, approximately 1 mL of 1.0 M NaOH solution was pipettered onto each sponge in the third sponge set from the kidney-holding portion of the stent. Next, approximately 1 mL of 1.25 M NaOH solution was pipettered onto each sponge in the fourth sponge set from the kidney-holding portion of the stent. Next, the stent was left for 1 hour. Then the sponge was removed and the stent was rinsed with deionized water for 15 seconds. Next, the stent was dried under vacuum.

[0197] [Example 12] [Generating bands using UV light] The stent was positioned in a holder that maintained the curl of the kidney and had an attachment point for insertion into a drill chuck. The holder was then inserted into the drill chuck, and the chuck was tightened to hold the stent. Next, the body of the stent was placed in a stainless steel stent band guide. The first band on the guide was 8 cm from the curl of the kidney. Next, a 5 mm UV spotlight was shone into the guide hole 0.8 mm from the surface of the stent. The guide exposed a 5 mm portion of the stent to the UV light. The motor attached to the drill chuck was turned on, and the stent rotated at 20 RPM. Next, the UV unit was turned on for a specified time to irradiate the first band with UV light. The light intensity was approximately 6 W / cm². 2 The irradiation time was then varied from 3 to 18 seconds. Next, this process was repeated for each band along the length of the stent. The bands were placed 4 cm apart, with an 8 cm "tail" at the kidney end of the stent. For a 24 cm stent, four UV-treated (LIVS) bands were generated on the stent, and for a 30 cm stent, five UV-treated (LIVS) bands were generated.

[0198] [Example 13] [Treated stents undergo buckling testing] Buckling tests were used to determine the effect of the band formation process on the mechanical properties of treated stents. A 4 cm long stent including the treated region was used for the buckling test. The treated region was approximately in the center of the sample (about 2 cm from both ends). Two blocks, each with a short cylinder (approximately 0.5 cm high) mounted in the center of each block, were mounted on an MTS instrument (force and motion measuring instrument, models: MTS Synergie 100 and MTS Synergie 200), with one block on the base and the other on the load cell of the MTS instrument. The stent sample was positioned so that it was held within these two cylinders when the MTS gauge length was set to 4 cm. The MTS was then turned on to compress the stent sample as a function of time. The force required to buckle the stent sample was measured. Buckling of each stent sample occurred at the treated area. The force required to buckle is shown in Table 1 and Figure 8. Control samples were not treated to generate LIVS bands.

[0199] [Table 1]

[0200] [Example 14] [Treated stents undergo deflection testing] A deflection test was used to determine the effect of the LIVS band on the strength of the band-shaped stent. A 4 cm long stent segment was used in this test. The stent segment was mounted in a custom stainless steel fixture. This fixture consisted of two blocks with guide pins that allowed the two halves to be joined together securely. Semicircular grooves were machined into the top and bottom of the blocks so that when the two halves were joined, they formed a continuous cylinder. The stent was placed in the lower groove, and the upper half was placed on top of the stent, holding it firmly without crushing it. The sample segment was positioned so that the processed area was at the edge of the block, allowing it to bend at the processed area. There was essentially a 2 cm stent segment protruding from the block like a cantilever. This block was mounted on the base of an MTS instrument (to measure force and motion, models: MTS Synergie 100 and MTS Synergie 200), and the top of the three-point bending test fixture was placed on a load cell. Next, the upper half of a three-point bending jig was used to press down on the portion of the stent protruding from the block, and the force required to "bend" the stent was measured. The data obtained for the various processes used to generate the band are shown in Table 2 and Figure 9.

[0201] [Table 2]

[0202] [Example 15] [Tensile strength test] Artificial urine was prepared by combining 50.0±1.0g of urea, 18.0±0.4g of NaCl, 5.0±0.1g of Na2HPO4, 15.0±0.3g of KH2PO4, 10.0±0.2g of NH4Cl, 3.0±0.1g of Na2SO3, 4.0±0.1g of creatinine, and 2L of deionized water.

[0203] To determine the effect of each treatment intensity on the mechanical integrity of the stent, the stent was tested at the LIVS band site. Base-treated samples were tested at 0 and 7 days after in vitro incubation in artificial urine pH 5.5–6.5 and 37°C. UV-treated samples were tested on stent samples after aging in artificial urine at pH 8 for 5 days. For tensile strength testing, a 5 cm section of the stent was used as the test specimen. The sample was placed on an MTS (models: MTS Synergie 100 and MTS Synergie 200) using a vice-type grip. Tensile testing was performed at a speed of 500 mm / min. The results are shown in Figures 10A and 10B.

[0204] [Example 16] [In vitro trials of fragmentation patterns] A stent with LIVS and HIVS band sections was placed in a simulated use model developed to meet physiologically relevant criteria. The simulated use model consisted of 3D-printed kidney and bladder components, a custom hydrogel ureter, and a custom hydrogel urethra. The system was placed in an oven set to 37°C. A stent sample was placed in this simulated use model, and artificial urine was continuously circulated through the system. The artificial urine was changed weekly. The stent was observed over time to assess its degradation / fragmentation and displacement behavior, as well as whether transient incontinence occurred during urination. The endpoint of this study was defined as the complete emptiness of the stent.

[0205] Regarding the base-treated stents, no incontinence events were observed in any of the final base-treated stents (gradient application of 0.5M, 0.75M, 1.0M, and 1.25M NaOH treatments), and weight distribution targets were confirmed that allowed for relaxation of the renal curl and desired bladder movement. All final stents showed fragmentation at the treatment site, and the fragmentation allowed for elimination without incontinence, with the final base-treated stent renal curl progressing to the bladder by days 28–35.

[0206] No incontinence events were observed with UV-treated stents. Incontinence events were classified as those caused by stent or stent fragment blockage in the hydrogel urethra.

[0207] [Example 17] [Stent packaging] The stent was placed in a PET thermoformed tray in a nearly or completely dust-free environment. The thermoformed tray was closed, and the tray with the stent was placed in a foil pouch. The foil pouch containing the stent was placed in a vacuum oven at room temperature for at least 14 hours. The vacuum oven was then purged with nitrogen, and the foil pouch containing the stent was placed in a vacuum oven preheated to 40±2°C. The oven was closed, and the oven was vacuumed (less than 5 Torr). The stent was maintained under vacuum in the oven for at least 24 hours. The vacuum oven was then backwashed with dry nitrogen. The stent in the foil pouch was removed from the vacuum oven. The foil pouch was then heat-sealed. For one set of samples, the stent was covered in a nitrogen atmosphere using a vacuum / nitrogen purge cycle. A label was then affixed to the outside of the foil pouch. The foil pouch was then sterilized with gamma rays at 24–40 kGy.

[0208] [Example 18] [Packaging of stent with pusher] The stent was placed in a PET thermoformed tray in a nearly or completely dust-free environment. The thermoformed tray was closed, and the tray with the stent was placed in a foil pouch. A stent pusher (New England Swaging Services) was placed in the foil pouch. The foil pouch containing the stent and pusher was placed in a vacuum oven at room temperature for at least 14 hours. The vacuum oven was then purged with nitrogen, and the foil pouch containing the stent was placed in the vacuum oven preheated to 40±2°C. The oven was closed, and the oven was vacuumed (less than 5 Torr). The stent was maintained under vacuum in the oven for at least 24 hours. The vacuum oven was then backwashed with dry nitrogen. The stent / pusher in the foil pouch was removed from the vacuum oven. The foil pouch was then heat-sealed. For one set of samples, the stent was covered in a nitrogen atmosphere using a vacuum / nitrogen purge cycle. The label was then affixed to the outside of the foil pouch. Next, the foil pouches were sterilized with gamma rays at 24-40 kGy.

[0209] Any methods and materials similar or equivalent to those described herein may also be used in carrying out or testing the present invention, but only a limited number of exemplary methods and materials are described herein. Generally, unless otherwise indicated, the materials and / or components for making the present invention may be selected from suitable materials such as biodegradable polymers.

[0210] Where numerical ranges are provided herein, unless the context explicitly indicates otherwise, each intermediate value between the upper and lower limits of that range and any other stated value (up to one-tenth of the lower limit), and any other stated or intermediate values ​​within that stated range, are understood to be included in the Invention. The upper and lower limits of these smaller ranges, which may be independently included within smaller ranges, are also included in the Invention and subject to any specific excluded limitations of the stated range. If a stated range includes one or both of the limitations, the range excluding either or both of those included limitations is also included in the Invention.

[0211] For example, any concentration range, percentage range, ratio range, or integer range provided herein should be understood, unless otherwise indicated, to include any integer value within the enumerated range, and, where appropriate, fractions thereof (e.g., one-tenth and one-hundredth of an integer). Similarly, any number range enumerated herein in relation to any physical characteristics such as polymer subunits, size, or thickness should be understood, unless otherwise indicated, to include any integer within the enumerated range. Where used herein, the term “about” means ±20% of the indicated range, value, or structure, unless otherwise indicated.

[0212] All publications and patents referenced herein are incorporated herein by whole reference for the purpose of explaining and disclosing, for example, materials and methodologies described in those publications that may be used in connection with the inventions of this disclosure. This application incorporates by whole reference the disclosures of International Application No. PCT / US17 / 39130. The publications discussed above and throughout this text are provided only for their disclosures prior to the filing date of this application. Nothing herein should be construed as the inventors acknowledging that they have no prior rights to the referenced publications by prior invention.

Claims

1. A bioabsorbable implantable medical device that includes a tubular structure overall, The overall tubular structure includes side walls and a lumen surrounded by the side walls, the lumen having a longitudinal axis that extends along the length of the lumen from the distal end to the proximal end of the structure. The tubular structure further includes a plurality of bands, each surrounding the longitudinal axis and having a distal side and a proximal side. The aforementioned multiple bands include bands with relatively high in vivo stability, separated by bands with relatively low in vivo stability. Medical device.

2. The medical device according to claim 1, wherein the structure has at least three bands with relatively high in vivo stability and at least four bands with relatively low in vivo stability.

3. The medical device according to claim 1, wherein at least two relatively high in vivo stability bands are each 1 to 6 cm in length and separated by one relatively low in vivo stability band having a length of less than 1 cm.

4. The medical device according to claim 1, wherein the tubular structure includes alternating bands of relatively high in vivo stability and relatively low in vivo stability.

5. The medical device according to claim 1, wherein the tubular structure comprises at least two relatively high in vivo stable bands separated by one relatively low in vivo stable band, the relatively low in vivo stable band decomposes in vivo at at least twice the rate of the at least one relatively high in vivo stable band.

6. The medical device according to claim 1, wherein the tubular structure includes at least two relatively high in vivo stability bands separated by one relatively low in vivo stability band, the at least two relatively high in vivo stability bands having substantially the same in vivo stability.

7. The medical device according to claim 1, wherein the tubular structure includes a band with relatively high in vivo stability on both sides of a band with relatively low in vivo stability, and the two bands with relatively low in vivo stability have different in vivo stabilities.

8. The medical device according to claim 1, wherein the tubular structure includes a first relatively low in vivo stability band located distal to a first relatively high in vivo stability band, and a second relatively low in vivo stability band located proximal to the first relatively high in vivo stability band, the first relatively low in vivo stability band having higher in vivo stability than the second relatively in vivo stability band.

9. The medical device according to claim 1, wherein the tubular structure comprises a plurality of bands having substantially identical and relatively high in vivo stability.

10. The medical device according to claim 1, wherein the tubular structure includes a plurality of relatively low in vivo stability bands separated by a relatively high in vivo stability band extending from the distal end to the proximal end of the structure, and the in vivo stability of the plurality of relatively low in vivo stability bands increases from the distal end to the proximal end of the structure.

11. The medical device according to claim 1, wherein the tubular structure includes a mesh tube.

12. The medical device according to claim 1, wherein the tubular structure has a length of 10 to 30 cm.

13. The medical device according to claim 1, wherein the side wall includes a monofilament coil surrounding the lumen, a mesh covering the monofilament coil, and a coating deposited on the coil and the mesh.

14. Furthermore, the medical device according to claim 1, further comprising a kidney-holding structure at the proximal end of the device and a bladder-holding structure at the distal end of the device.

15. The medical device according to claim 1, further comprising a curled kidney retaining structure at the proximal end of the device and a curled bladder retaining structure at the distal end of the device.

16. A medical device according to claim 1, which is a ureteral stent.

17. The medical device according to claim 1, wherein the device includes a coating on its outer surface, and the coating has an average thickness.

18. The medical device according to claim 1, wherein the device includes a coating on its outer surface, the coating having a non-uniform thickness over the entire device.

19. The medical device according to claim 1, wherein the device includes a coating on its outer surface, and the proximal end of the device includes more coating than the distal end of the device.

20. The medical device according to claim 1, wherein the device is a ureteral stent having a kidney-retaining structure at the proximal end of the device and a bladder-retaining structure at the distal end of the device, and the outer surface of the device includes a coating, the proximal end of the device includes more coating than the distal end of the device.

21. A medical device according to any one of claims 1 to 20, which does not include a containment layer that restricts the movement of HIV bands that separate from the medical device during in vivo decomposition.

22. A method for manufacturing medical devices, To provide a bioabsorbable medical device including a generally tubular structure having a lumen passing through the center of the generally tubular structure within the side walls of the generally tubular structure, a bioabsorbable medical device, and A band with an overall tubular structure is exposed to an ex vivo degradation environment to generate a band with low in vivo stability (LIVS) from the exposed band, while a band adjacent to the exposed band with an overall tubular structure is not exposed to the same degradation environment to generate a band with high in vivo stability (HIVS) adjacent to the LIVS band. A method that includes this.

23. A medical device manufactured by a method comprising the method described in claim 22.

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