Controlled biodegradation tubular implants

Abstract

Implantable medical devices have a zone of high in vivo stability adjacent to a zone of relatively low in vivo stability, such that when these medical devices are implanted in a host, the zone of low in vivo stability degrades first, allowing the formation of a relatively intact band of high in vivo stability, a separate segment small enough to pass harmlessly from the host.

Description

[Technical Field]

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

[0002] The present invention relates generally to biodegradable medical implants and their manufacture and use. [Background technology]

[0003] Some medical implants only need to be present in the host for a limited period of time. After that period, the implant may be physically removed, often requiring additional medical intervention. Alternatively, the implant may be left in place permanently. This option is appropriate when the implant's long-term presence 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 metabolic products are eventually excreted. While bioabsorbable implants are increasingly desired by healthcare providers, these implants can sometimes cause undesirable consequences, such as the host being unable to tolerate the degradation products. Summary of the Invention [Problem to be solved by the invention]

[0004] There is a need in the art for medical implants that are less harmful to the host upon degradation than existing products. The present invention is directed to filling that need. [Means for solving the problem]

[0005] In one aspect, the present disclosure relates to medical implants that degrade within a host, where the degradation is controlled to occur in a specifically desired manner by physical or chemical features incorporated into the implant. The implantable medical devices of the present disclosure have a relatively high in vivo stability zone adjacent to a relatively low in vivo stability zone. This allows the low in vivo stability zone to degrade first when these medical devices are implanted into a host, forming a relatively intact high in vivo stability band, a separate segment small enough to pass harmlessly from the host. The low in vivo stability band is considered to have lower in vivo stability than the high in vivo stability band also present in the medical device. Thus, "low" and "high" are meant to be interpreted relative to each other, with a low in vivo stability zone having lower in vivo stability than a 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 generally tubular, hollow structure having a longitudinal axis along the center of the lumen of the generally tubular structure and sidewalls defining the lumen of the structure. The tubular structure is comprised of a plurality of bands, also referred to as rings, zones, or annular strips, each surrounding the longitudinal axis. The plurality of bands includes bands of relatively high in vivo stability (HIVS) separated from one another by bands of relatively low in vivo stability (LIVS). The low in vivo stability bands degrade more quickly when the implant is implanted in a host compared to bands of high in vivo stability. Two LIVS bands can be positioned on either side of the HIVS band, so that when the implant is placed in a host, the two LIVS bands degrade first, leaving behind the HIVS band between them.

[0007] A generally tubular structure according to the present disclosure may be identified as -(LIVS-HIVS)n-LIVS-. Alternatively, the generally 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 generally tubular hollow structure, a medical implant may, and usually does, include other features that make it useful for its intended purpose.

[0008] Thus, a generally tubular structure according to the present disclosure may include three exemplary segments identified below: 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 segments, LIVS1, LIVS2, LIVS3, and LIVS4 are bands with low in vivo stability, and HIVS1, HIVS2, HIVS3, HIVS4, and HIVS5 are 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 can subsequently be degraded or removed.

[0009] Thus, a generally tubular structure according to the present disclosure may include the following identified segments, as three example segments: 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, allowing the intervening HIVS bands to separate from the medical device and later degrade completely or be removed from the implant site.

[0010] Furthermore, a generally tubular structure according to the present disclosure may include the following identified segments, as three example segments: LIVS1-HIVS1-LIVS2-HIVS2, or LIVS1-HIVS1-LIVS2-HIVS2-LIVS3-HIVS3, 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, allowing the intervening HIVS bands to separate from the medical device and later degrade completely or be removed from the implant site.

[0011] When a tubular structure according to the present 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 (length is defined as the distance along the longitudinal axis of the structure, sometimes referred to as the width of the bands). If it is desired that the degradation product of the implant be, for example, 5 cm or less, the structure can incorporate multiple HIVS bands of 5 cm or less in length, with each HIVS band flanked by LIVS bands of less than 1 cm in length. For example, the LIVS bands can be only 1 cm or 0.5 cm in length, and the HIVS bands can each be 4 cm in length.

[0012] In another example, in one embodiment, a medical implant includes a generally tubular, hollow structure having a longitudinal axis along the center of the lumen of the generally tubular structure and sidewalls defining the lumen of the structure. The 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) degrades faster in vivo than the other end. This structure allows one end to degrade while the other end is effectively fixed in place. Such a structure may incorporate the LIVS and HIVS bands described above. For example, if the implant structure includes the following structure: proximal end - HIVS1 - LIVS1 - HIVS2 - LIVS2 - HIVS3 - LIVS3 - HIVS4 - distal end, LIVS3 will degrade first, followed by LIVS2, causing HIVS3 to separate from the implant, followed by LIVS1, causing HIVS2 to separate from the implant. This configuration allows the proximal end of the implant to remain implanted longer than the distal end, further controlling the length of the HIVS band. Such a configuration 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, which includes a generally tubular, hollow structure having a longitudinal axis along the center of the lumen of the generally tubular structure and sidewalls defining the lumen of the structure, has a coating (referred to as an additional coating) that is not present at the distal end of the implant. The coating, or additional coating, is resistant to biodegradation and therefore prevents the implant from degrading in vivo. For example, the implant may be a urethral stent, and the proximal end of the stent, the end inserted into the host's kidney, has a coating, or additional coating, that is not present at 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 a device according to the present disclosure having a composition vector, meaning that the composition of the implant varies along the dimension of the implant; for example, there may be more coating at the proximal end of the implant than at the distal end. Coatings, or additional coatings, can be added to the HIVS and LIVS bands present on the medical implant, whereby the HIVS and LIVS bands can be selected to achieve preferential degradation at one end of the implant compared to the other end (another approach to achieving structural vectors).

[0014] In one embodiment, the HIVS and LIVS bands do not provide a functional benefit to the device, e.g., the bands do not make the device stronger or more functional, but are only present to affect the degradation profile of the implant.

[0015] In one embodiment, a generally tubular structure is formed, and then the structure is treated to modify portions of the structure and generate one or more HIVS and / or LIVS bands. For example, a structure that inherently has a particular in vivo stability can be treated by a method disclosed herein, e.g., base or UV treatment, whereby the treated portions of the structure (e.g., bands) are converted to less stable portions in vivo (i.e., portions that degrade 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 portions / bands of the structure that have not been treated to modify their degradation rate. For example, certain bands of the generally tubular structure can be exposed to a degradation environment to create less stable (LIVS) bands in vivo. Exemplary processing conditions for generating LIVS bands include exposure to basic conditions, i.e., aqueous conditions with a high pH, ​​and exposure to radiation, e.g., UV light. Because only certain bands of the generally tubular structure are exposed to these degradation environments, the exposed bands are LIVS bands, and the unexposed bands are HIVS bands. For example, looking at coil (10) in Figure 6A, bands A, C, and E are exposed to a degradation environment, generating LIVS bands at positions A, C, and E, while bands B, D, and F are not exposed to a degradation environment, generating HIVS bands at positions B, D, and E.

[0016] The processing conditions, as described above, can produce LIVS bands or can produce HIVS bands. For example, referring again to coil 10 in FIG. 6A for illustrative purposes, a protective coating can be applied to selected areas to mitigate the rate of degradation of coil 10. Thus, a protective coating can be applied to bands A, C, and E to produce HIVS bands at locations A, C, and E, and LIVS bands at locations B, D, and F.

[0017] Optionally, the implant can include a containment layer surrounding a portion of the implant, the containment layer configured to cause the implant to degrade in a different manner than would occur if the containment layer were not present. Also, optionally, the implant can include compositional heterogeneity, where areas of heterogeneity are more susceptible or less susceptible to degradation than adjacent homogeneous areas of the implant. For example, the implant can include particles dispersed in a polymer, where the polymer is homogeneous and the particles provide a heterogeneity that is more susceptible to degradation than the polymer or act as initiation sites for degradation of the polymer. Optionally, the medical device and / or generally tubular structure does not include a containment layer that restricts the movement of fragments formed during in vivo degradation of the generally tubular structure.

[0018] In another embodiment, the present disclosure provides a method of making a medical device. The method includes providing a bioabsorbable medical device, the bioabsorbable medical device comprising a generally tubular structure having a lumen through the center of the generally tubular structure within a sidewall of the generally tubular structure. In other words, a generally tubular hollow structure such as a stent. The bioabsorbable medical device may optionally be made 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 of 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, resulting in bands of high in vivo stability (HIVS) adjacent to the LIVS bands. The present disclosure also provides medical devices prepared by this process and other processes described herein.

[0019] In each of the foregoing aspects and embodiments, the generally tubular structure may be a stent, e.g., a ureteral stent. The stent, e.g., a ureteral stent, may include a central coil, a mesh, and a coating. The central coil may be a monofilament in the shape of a coil. The mesh may be disposed over the central coil in a surrounding manner. The coating may be disposed between the coil and the mesh, as well as on the surface of the mesh.

[0020] These are examples of controlled degradation according to the present disclosure, whereby medical implants are constructed that degrade within the host and are controlled to cause degradation in a particularly desirable manner due to physical or chemical features incorporated by the construction of the implant.

[0021] The present disclosure discloses several medical devices, wherein 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 have polymer components that are selectively degraded to contain slits or have a molecular weight gradient, thereby providing a degradation profile for the device that is controlled to occur in a particularly desirable manner by physical or chemical features that are incorporated into the implant according to the present disclosure.

[0022] This brief summary is provided to introduce certain concepts in a simplified form that are described in more detail below in the detailed description. Unless otherwise specified, 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 description below. Features illustrated or described in connection with one exemplary embodiment may be combined with features of other embodiments. Accordingly, any of the various embodiments described herein may be combined to provide further embodiments. Aspects of the embodiments may be modified as necessary to adopt the teachings of the various patents, applications, and publications as identified herein to provide further embodiments. Other features, objects, and advantages will be apparent from the description and claims. [Brief explanation of the drawings]

[0024] Exemplary features of the present disclosure, its nature and various advantages 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, in which like labels or reference numbers refer to like parts throughout the various views 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 have been selected, enlarged, and arranged to improve the readability of the drawings. The particular shapes of the depicted elements have been selected for ease of recognition in the drawings. One or more embodiments are described below with reference to the accompanying drawings.

[0025] [Figure 1] 1 illustrates an exemplary generally tubular structure. [Figure 2] 1 illustrates an exemplary generally tubular structure. [Figure 3] 1 illustrates an exemplary generally tubular structure. [Figure 4] 1 illustrates an exemplary generally tubular structure. [Figure 5] 1 illustrates an exemplary medical device incorporating a generally tubular structure. [Figure 6A] Exemplary generally tubular structure bands A-F are shown. [Figure 6B] An exemplary generally tubular structure, bands A-F, is shown, with band A being particularly highlighted. [Figure 6C]Exemplary generally tubular structures, bands A-F, are shown, with band C particularly highlighted. [Figure 7A] 1 is a schematic diagram of a medical device according to the present disclosure with locations A, B, C, D, and E identified on a generally tubular portion of the medical device. [Figure 7B] 1 is a schematic diagram of a medical device according to the present disclosure with locations A, B, C, and D identified on a generally tubular portion of the medical device. [Figure 8] 1 is a graph showing buckling strength as a function of UV and base treatment of a generally tubular structure. [Figure 9] 1 is a graph showing the results of a flexure test on a generally tubular structure as a function of UV and base treatment. [Figure 10A] 1 is a graph showing the results of tensile strength tests on generally tubular structures as a function of the degree of base treatment. [Figure 10B] 1 is a graph showing the results of tensile strength tests on generally tubular structures as a function of UV treatment time. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention may be more readily understood by reference to the following detailed description of preferred embodiments of the invention and the examples contained herein. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Furthermore, it should be understood that, unless specifically defined herein, terms used herein should be given their traditional meanings as known in the relevant art. The headings used herein are used solely for the reader's convenience and should not be construed as limiting the scope of the invention or the claims in any way.

[0027] As used herein, including the claims, the singular forms "a," "an," and "the" 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] "Degradation" in the context of a degradable medical device means that the medical device breaks down or deteriorates in a chemical or structural sense upon placement within the host at the device's intended location within the host. For example, a device that breaks apart, such as breaking in half or crumbling into many pieces, is a structurally degrading device. If a device softens while implanted, it also degrades structurally. A device chemically degrades if some or all of the device dissolves in the biological fluids with which it is in contact. Chemical degradation also includes the occurrence of degradation reactions such as hydrolysis, oxidation, and enzymatic bond cleavage. An absorbable or bioabsorbable medical device is a device that degrades within the host. A degradable implantable medical device refers to an implantable medical device for which the manufacturer and / or healthcare provider recommends a desired limited lifespan within the host. In other words, one of the reasons the manufacturer and / or healthcare provider manufactured and / or selected the device is so that it will naturally degrade within the host and will not become a permanent fixture within the host. Degradation includes situations in which complete mass loss occurs, but also situations in which partial mass loss occurs or where structural weakening of a location on the medical device, such as a band, occurs. For example, less stable regions of the devices of the present disclosure may only degrade to the extent that the mechanical and / or physical properties of the region are compromised, causing the region to fracture and adjacent regions to no longer be in indirect contact with each other.

[0029] A "degradation profile" refers to a description of how an implant degrades. The degradation profile provides a time course of the implant's degradation and a geometric description of the degradation over time. For example, an implant can have a degradation profile whereby the implant degrades from top to bottom along its length over a specified number of days. For example, in the case of a ureteral stent of the present disclosure, which includes an overall tubular structure containing multiple HIVS and LIVS bands, the stent can remain patent and remain at the application site for at least two weeks, and can be removed or repositioned as a single piece within the ureter up to seven days after implantation. The stent begins to fragment one to four weeks after implantation, and the fragments can be expelled. More preferably, fragmentation can occur two to three weeks after implantation. At five months, no portion of the stent remains at the application site. This is an exemplary degradation profile for a medical device of the present disclosure.

[0030] "Host" refers to a mammal, such as a human, dog, cat, or livestock. A host may also be referred to as a patient or subject. A host receives an implantable medical device of the present disclosure.

[0031] As used herein, an implantable medical device refers to a device, such as an implement or instrument, intended to be placed or implanted into the body of a host by a healthcare provider. An implant can be placed in a host in any suitable manner, such as intramuscularly, subcutaneously, or intradermally, and can be placed in any suitable location, such as an orifice, cavity, or cavity of the host. A medical device provides a medical purpose or benefit (e.g., as opposed to being purely cosmetic) to improve the health of the host through one or more of the diagnosis, prevention, treatment, or cure of an undesirable condition, such as a disease. A medical device can provide a therapeutic effect. A medical device can provide a preventative benefit. A medical device can be an accessory device that does one or more of the following: supports the performance of a parent medical device by enabling or facilitating the parent medical device to function according to its intended use; augments the performance of a parent device by adding new functionality or new methods of use of the parent device without changing the intended use of the parent device; or enhances the performance of a parent device by enabling the device to perform its intended use more safely or effectively. A medical device does not achieve its purpose solely through chemistry or metabolism in the body.

[0032] The medical device of the present disclosure includes a generally tubular structure as a component of the device. The generally 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 sidewall of the generally tubular structure. In other words, the medical device includes a pipe-like component. The sidewall of the medical device of the present disclosure can be solid, like the sidewall of a pipe used to carry liquids or gases. However, unlike traditional pipes that carry fluids and have solid, impermeable sidewalls, the generally tubular structure of the present disclosure does not necessarily have a solid sidewall. Figures 1 and 2 illustrate exemplary generally tubular structures of the present disclosure that do not have solid, impermeable sidewalls. In Figure 1, the sidewall is in the shape of a coil (10), so the generally tubular structure appears like a spring containing a lumen (12). In Figure 2, the sidewall is a more complex mesh-like structure (14) that surrounds the lumen (12). In both the generally tubular structures of Figures 1 and 2, the lumen (12) of the structure can be observed by looking through the sidewall (10) or (14), i.e., the sidewall has openings so that it is not solid.

[0033] The sidewall may comprise more than a single component. For example, in FIG. 3, a coil 10 such as that shown in FIG. 1 is shown with a sheath or blanket 16 wrapped around a portion of the coil 10. In FIG. 3, for illustrative purposes, the blanket 16 is shown wrapped only partially around the coil 10; such a structure is a generally tubular structure of the present disclosure. However, the blanket 16 could be wrapped completely around a generally tubular structure, such that the coil 10 and lumen 12 are completely surrounded by the blanket 16. In FIG. 3, the bracket appears solid, i.e., has no holes. However, brackets such as 16 need not necessarily be solid and may have perforations. In fact, the blanket could be in the form of a mesh with multiple openings. For illustrative purposes, blanket (16) is shown in FIG. 3 as being combined with a coiled sidewall, however, in accordance with the present disclosure, the blanket may be combined with a supportive, generally tubular sidewall configuration, such as structure (14) shown in FIG. 2.

[0034] Another exemplary sidewall component of the generally tubular structure of the present disclosure is a coating. For example, as shown in Figure 4, the generally tubular structure of Figure 3, including the coil (10), lumen (12), and blanket (16), may be sprayed with or dipped into a solution of an organic polymer, resulting in a coating (18) being deposited on the exterior and / or interior surfaces of the sidewall. In Figure 4, the coating (18) is shown as the darkened surface of the blanket (16) relative to the equivalent surface of the blanket (16) in Figure 3 (the blanket (16) in Figure 3 is uncoated and therefore does not have a darkened surface), and is present on the interior surface of the blanket (16). That is, the coating (18) is on the surface of the blanket that abuts the coil (10) and faces the lumen (12). Generally, the sidewall coating is on and / or in the blanket 16 (particularly when the blanket 16 is in the form of a mesh and the coating is applied by dipping or spraying a coating solution onto the blanket 16). As another example, the coil 10 of FIG. 1 or the mesh 14 of FIG. 2 can have a coating on some or all of the surface of the structure to provide a sidewall that includes the coating.

[0035] Thus, the medical devices of the present disclosure have a generally tubular structure with an open lumen extending substantially through the center of the structure and defined by adjacent sidewalls, which may be single-component, as shown in Figures 1 and 2, or multi-component, as shown in Figures 3 and 4.

[0036] The structures of the present disclosure are described as generally tubular to clarify that the invention is not limited to perfectly symmetrical structures. The diameter of the lumen may vary somewhat, for example, along the longitudinal axis of the structure. As another example, a generally tubular structure need not necessarily be strictly linear, but may be somewhat tortuous or curved. Typically, a generally tubular structure has a lumen that has an average diameter determined by the distance between points on the sidewall (where that distance passes through the center point of the lumen), and that average diameter is less 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 known medical device having a generally tubular structure is a stent, and in one embodiment, the medical device of the present disclosure is a stent. Thus, in one aspect, the medical device is a stent useful for maintaining or creating patency of a duct, e.g., a duct or blood vessel, within a host. Exemplary ducts and blood vessels are found, for example, along the gastrointestinal (GI) tract of a host, e.g., the esophagus, the intestine 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 a ureter, i.e., a tube that carries urine from the kidney to the bladder. In another embodiment, the medical implant is designed to be placed in a urethra, i.e., a tube that transports urine from the bladder to the outside of the host. In another embodiment, the medical implant is designed to be placed in a blood vessel, for example, the medical implant is a coronary stent or a peripheral stent intended to be placed in a peripheral artery. Other exemplary ducts and blood vessels are found in organs such as the heart, pancreas, prostate, and kidney. Another location where a duct or blood vessel exists in a host and where a medical implant may be placed in accordance with the present disclosure is the mammary duct, which transports milk from the lobule (milk-producing gland) to the nipple. Other locations for tubular medical implants include the ear, tear duct, and paranasal sinuses. Such medical implants are referred to herein as stents.

[0039] Generally tubular structures may be components of the medical devices of the present disclosure. For example, as shown in FIG. 5, medical device 20 may include a generally tubular structure identified by enclosed region 22, and also includes proximal end region 24 and distal end region 26, which may or may not be generally tubular structures. Device 20 is an example of a ureteral stent that includes curled region 24 at the proximal end of the device, which may be inserted into a host's kidney, and curled region 26 at the distal end of the device, which may be inserted into a host's bladder.

[0040] In one aspect, the medical device is formed at least in part from one or more thermoplastic, thermoset, or elastomeric polymers. Optionally, the entire tubular structure is made entirely from polyester, where the term polyester is meant to include one or more polyester polymers. Optionally, the entire tubular structure is made in part from polyester, where the term polyester is meant to include one or more polyester polymers.

[0041] In one aspect, the medical device is sterile. Optionally, the medical device is sterilized using gamma radiation or electron beam radiation. In one aspect, the medical device is sterilized using 23-45 kGy of gamma radiation. In another aspect, the medical device is sterilized using 25-40 kGy of gamma radiation. In yet another embodiment, the medical device is placed in a heat-sealed foil pouch prior to sterilization.

[0042] In one aspect, the medical device is intended to be fully implanted in the host, i.e., fully beneath the host's skin, as opposed to, for example, a hearing aid that sits in the ear, a dental prosthesis that sits in the host's mouth, or a contact lens that sits in the host's eye. In one aspect, the implantable medical device is intended to be placed in a body passageway, such as a duct or blood vessel. Examples of implantable medical devices that may be degradable include stents, shunts, sutures, and surgical meshes. Implantable medical devices are also described in the following patent documents: US 8,753,387; US 8,101,104; US 7,594,928; and US 2014 / 0288636.

[0043] Briefly, the present invention provides medical implants with controlled degradation after implantation in a host. During the process of bioabsorption within the host, the medical devices of the present disclosure degrade, i.e., exhibit in vivo degradation. To control this degradation process, for example, to control the timing, type, and extent of degradation, and the movement of the degraded medical device and its portions within the host, the medical implant can include multiple high in vivo stability (HIVS) and low in vivo stability (LIVS) bands. As these names suggest, HIVS bands are relatively stable in vivo (post-implantation) compared to LIVS bands.

[0044] FIG. 6A illustrates a generally tubular structure in the form of a coil (10). In FIG. 6A, the generally tubular structure is divided into bands identified as A, B, C, D, E, and F. Each of these bands A-F occupies a certain length of the generally tubular structure. Although shown as equal in length in FIG. 6A, bands generally need not be equal in length. To clarify the portion of the coil (10) located in band A, a dashed box (30) has been added to the illustration in FIG. 6A to provide the illustration in FIG. 6B. As shown in FIG. 6B, band A generally surrounds the first two coils of the generally tubular structure.

[0045] As another illustration of a band structure, a box (32) is superimposed over the region of the coil (10) corresponding to band C of the generally tubular structure shown in FIG. 6C. FIG. 6C shows the lumen 12 of the generally tubular structure, through which a longitudinal axis (34) extends from the distal end (36) to the proximal end (38) of the generally tubular structure. The side of a band, such as band (32) shown in FIG. 6C, may be characterized in part by having a distal side and a proximal side, such as distal side (40) and proximal side (42) of band C (32) in FIG. 6C. In FIG. 6C, feature (44) refers to the generally tubular structure including the coil (10) providing the sidewall of the generally tubular structure and the lumen (12) extending within the sidewall from the distal end (36) to the proximal end (38) of the generally tubular structure (44). In Figure 6C, the length of a band, e.g., 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 present disclosure provides a bioabsorbable implantable medical device including a generally tubular structure having a sidewall surrounding a lumen and 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 includes a plurality of bands, each band surrounding the longitudinal axis and having a distal side and a proximal side. The plurality of bands includes some 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 present 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 rapidly degrade, leaving behind the HIVS bands. The HIVS bands are selected to have a maximum length that will not harm the host when they are threaded through a conduit in the location where the medical device is to be placed. If the HIVS band is too long, it may clog the host's ducts, causing problems until the HIVS band degrades. On the other hand, if the HIVS band is short enough, it will easily pass through the ducts even before it completely degrades, facilitating removal from the host. It is desirable for the HIVS band to be long enough to allow relatively large portions of the tubular medical device to be excreted from the host even before they completely degrade. In this mechanism, the degradation of a bioabsorbable implant does not depend entirely on the rate of biodegradation profile of the polymer that makes up the implant. Instead, the implant breaks into small pieces (each piece is an HIVS band) that can be easily removed from the ducts by the host's natural biological processes, such as fluid 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 a break in the overall tubular structure, releasing the HIVS bands.

[0047] A medical device of the present disclosure may include a generally tubular structure, which may be identified as: proximal end of tubing-(LIVS-HIVS)n-LIVS-distal end of tubing; or proximal end of tubing-(HIVS-LVS)n-HVS-distal end of tubing. 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 and relatively low in vivo stability. Optionally, the tubular structure comprises X LIVS bands and X+1 HIVS bands, thereby providing one more HIVS band relative to the number of LIVS bands. Alternatively, the tubular structure comprises Y HIVS bands and Y+1 LIVS bands, thereby providing one more LIVS band relative to the number of HIVS bands in the tubular structure overall. Either X or Y can be selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and combinations thereof, such as 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 the LIVS band are arranged alternately along the length of the medical device. For example, optionally, the device has exactly one HIVS band and two LIVS bands, with one LIVS band on either side of the HIVS band, i.e., a configuration represented as LIVS-HIVS-LIVS. This configuration allows the two LIVS bands to degrade relatively quickly, releasing the HIVS band (which is not fully degraded due to its relatively high in vivo stability compared to the LIVS band) from the rest of the medical implant and allowing the HIVS band to pass through the host by natural biological processes.

[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 exactly 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 quickly, releasing the two HIVS bands (which are not completely degraded due to their relatively high in vivo stability compared to the LIVS bands) from the rest of the medical implant and allowing the HIVS band to pass through the host by natural biological action.

[0050] In some embodiments, the medical device has at least two bands of relatively high in vivo stability and at least three bands of 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 exactly 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 quickly, freeing the HIVS bands from the rest of the medical implant and allowing the HIVS bands to pass by natural biological action from the location where the device is placed within the host.

[0051] In some embodiments, the medical device has at least three bands of relatively high in vivo stability and at least four bands of 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 exactly 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 quickly, freeing the HIVS bands from the rest of the medical implant and allowing the HIVS bands to pass by natural biological action from the location where the device is placed within the host.

[0052] HIVS and LIVS bands can have a particular length, as measured along the longitudinal axis of the tubular structure. This dimension may alternatively be referred to as the width of the band, in which case the band length and width refer to the same dimension. In one embodiment, the LIVS band of the disclosed medical device has a shorter length than the HIVS band of the medical device. For example, the HIVS band may be greater than 1 cm in length, or greater than 1.1 cm in length, or greater than 1.2 cm in length, or greater than 1.3 cm in length, or greater than 1.4 cm in length, or greater than 1.5 cm in length. In contrast, the LIVS band may be less than 1 cm in length, or less than 0.9 cm in length, or less than 0.8 cm in length, or less than 0.7 cm in length, or less than 0.6 cm in length, or less than 0.5 cm in length. Thus, the relatively small LIVS band degrades relatively quickly. The larger HIVS bands are left behind and degrade more slowly and / or are expelled from the conduit in which the device is placed according to the host's natural mechanisms (e.g., fluid flow through the conduit causes free HIVS bands (i.e., HIVS bands that are no longer attached to the medical device) to leave the conduit).

[0053] Stated differently, in one embodiment, the HIVS band is longer (wider) than the LIVS band. Thus, the HIVS band extends further 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 stability bands, each having a width of 1-6 cm, separated from one another by relatively low in vivo stability bands having a width of less than 1 cm. In this embodiment, the length of the tubular structure is primarily occupied by the HIVS bands separated by the LIVS bands. Such a structure may be identified as (LIVS-HIVS)n-LIVS, where n refers to the number of LIVS-HIVS repeat units and 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 HIVS bands are each 1 cm or greater in width.

[0054] Optionally, the device has at least two HIVS bands, each HIVS band having a length of 2-6 cm. A LIVS band is located between the two HIVS bands, and the LIVS band is less than 1 cm long. Such a structure may be identified as (LIVS-HIVS)n-LIVS, where n refers to the number of LIVS-HIVS repeating units and 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 HIVS bands are each 1 cm or greater in width.

[0055] Optionally, the device has at least two HIVS bands, each HIVS band having a length of 3-6 cm. A LIVS band is located between the two HIVS bands, and the LIVS bands are less than 1 cm long. Such a structure may be identified as (LIVS-HIVS)n-LIVS, where n refers to the number of LIVS-HIVS repeating units and 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 HIVS bands are each 1 cm or greater in width.

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

[0057] Optionally, the medical device has at least three relatively high in vivo stability bands, each of the HIVS bands having a length of 3-6 cm. Additionally, the device has at least four LIVS bands seated on either side of the HIVS band. Each LIVS band is less than 1 cm wide. Such a configuration 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 HIVS band having a length of 3-6 cm, and the four HIVS bands are separated by three relatively low in vivo stability bands, each having a length of less than 1 cm. Such a structure may be identified as HIVS-LIVS-HIVS-LIVS-HIVS-LIVS.

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

[0060] In one embodiment, all LIVS bands degrade faster than HIVS bands present in a medical device of the present disclosure. Thus, in one embodiment, the present disclosure provides a medical device comprising a generally tubular structure, wherein the tubular structure comprises at least two relatively high in vivo stability bands (separated by one relatively low in vivo stability band), and the relatively low in vivo stability band degrades at least two times faster in vivo than the at least one relatively high in vivo stability band.

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

[0062] Optionally, all of the LIVS bands degrade at substantially the same rate in vivo, such that in vivo degradation of the medical device produces multiple, independent HIVS bands substantially simultaneously. Accordingly, the present disclosure provides a medical device comprising a generally tubular structure, wherein the tubular structure comprises at least two bands of relatively high in vivo stability (separated by a band of relatively low in vivo stability), wherein the at least two relatively high in vivo stability bands have substantially the same in vivo stability. Further, the present disclosure provides a medical device comprising a generally tubular structure, wherein the tubular structure comprises at least two bands of relatively low in vivo stability (separated by a band of relatively high in vivo stability), wherein the at least two relatively low in vivo stability bands have substantially the same in vivo stability.

[0063] However, as another option, the LIVS bands do not all degrade at the same rate. For example, a medical device of the present disclosure can include a tubular structure including bands of relatively low in vivo stability flanked by bands of relatively high in vivo stability, where the two bands of relatively low in vivo stability have unequal in vivo stabilities. This option can be useful when it is desired that degradation of the medical device occur preferentially from one end of the device compared to the other end. For example, if it is desired that the proximal end of the device degrade faster than the distal end, a structure including: proximal end - LIVS1 - HIVS1 - LIVS2 - HIVS2 - LIVS3 - HIVS3 - LIVS4 - distal end can be manufactured. In this case, LIVS1 is designed to degrade faster than LIVS2, which is designed to degrade faster than LIVS3, which is designed to degrade faster than LIVS4. In this situation, LIVS1 degrades first, providing a free end for HIVS1. When LIVS2 degrades, HIVS1 is completely released from the rest of the medical device, allowing it to later degrade or be expelled from the conduit in which the medical device is placed. LIVS3 then degrades, allowing HIVS2 to be completely released from the medical device and be expelled from the conduit. LIVS4 then degrades, allowing HIVS3 to be completely released from the medical device and be expelled from the conduit.

[0064] In one embodiment, the present disclosure provides a medical device comprising a generally 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 a higher in vivo stability than the second relatively in vivo stability band.

[0065] In one embodiment, the present disclosure provides a medical device comprising a generally tubular structure, wherein the tubular structure includes a plurality of bands of relatively low in vivo stability separated by bands of relatively high in vivo stability extending from a distal end to a 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, a generally tubular structure is formed, and then the structure is processed to produce one or more HIVS and / or LIVS bands. For example, certain bands of the generally tubular structure can be exposed to a degradative environment to produce bands with low in vivo stability (LIVS). Exemplary processing conditions for producing LIVS bands include exposure to basic conditions, i.e., aqueous conditions with a high pH, ​​and exposure to radiation, e.g., ultraviolet light. Because only certain bands of the generally tubular structure are exposed to these degradative environments, the exposed bands become LIVS bands, while the unexposed bands are relatively stable in vivo, i.e., become HIVS bands. For example, looking at the coil (10) in FIG. 6A , bands A, C, and E are exposed to a degradative environment, producing LIVS bands at positions A, C, and E, while bands B, D, and F are not exposed to a degradative environment, resulting in HIVS bands at positions B, D, and F. As noted above, LIVS and HIVS are relative terms. The high in vivo stability (HIVS) band is more stable in vivo than the low in vivo stability (LIVS) band.

[0067] As an illustration of a medical device of the present disclosure, FIG. 7A provides a schematic image of a ureteral stent having a renal curl at one end, providing a renal-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 in FIG. 7A identifies locations A, B, C, D, and E on a generally tubular structure located between the renal curl and the bladder curl. In this schematic diagram, each of locations A, B, C, D, and E is the midpoint of a band (e.g., a LIVS band) approximately 0.1-0.5 cm wide. The area between the bands with their midpoints at locations A-E is the HIVS band. In summary, A, B, C, D, and E each represent the location of the LIVS band, while the areas between A and B, B and C, C and D, and D and E each represent the location of the HIVS band. To achieve this degradation gradient, the band at location E is exposed to a relatively harsh degradation environment, the band at location D is exposed to a slightly less harsh degradation environment, and the band at location C is further exposed to a degradation environment less harsh than that used to generate the band at location D. Similarly, for bands at locations B and A. Thus, the band at location A is exposed to the least harsh degradation environment, with the severity of the degradation environments increasing in the order A, B, C, D, and E. In FIG. 7A , location E, for example, is subjected to a degradation treatment with 1.5 M NaOH, location D is subjected to a degradation treatment with 1.25 M NaOH, location C is subjected to a degradation treatment with 1.0 M NaOH, location B is subjected to a degradation treatment with 0.75 M NaOH, and location A is subjected to a degradation treatment with 0.5 M NaOH. The exposure times for these different locations to the degradation environments are constant; the only difference is the strength of the base solution to which the bands are exposed. Alternatively, the same strength of base can be used to resolve each band, generating LIVS bands, but the band at position E is exposed to the base solution for the longest time, the band at position A for the shortest time, and the intermediate bands for an intermediate time.

[0068] According to this degradation gradient, the LIVS band at position E degrades faster than the other bands. After the band at position E degrades to the point of destruction, 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 fastest. Therefore, the next LIVS band to degrade is the LIVS band at position D, thereby releasing the HIVS band between the LIVS bands with midpoints at positions D and E from the medical device. Without a containment layer or equivalent feature, this detached HIVS band could be excreted from the host's body. The LIVS band at position C degrades faster than the LIVS bands at positions B or A. Once the LIVS band at position C degrades and destroys, the HIVS band between positions C and D is released from the medical device and can be excreted from the host's body. This degradation gradient allows for the safe management of the degradation of medical implants without relying on a containment layer. By appropriately selecting the location of the LIVS band, the fragments formed upon degradation of the overall tubular structure of the medical implant are small enough that the detached HIVS bands are excreted from the host's body and do not pose a health risk to the host.

[0069] FIG. 7B incorporates the schematic diagram shown in FIG. 7A, but illustrates different positions A, B, C, and D. In FIG. 7B, a decomposition gradient can be generated by exposing the bands at positions A, B, C, and D to decomposition radiation, such as ultraviolet radiation, for progressively longer periods of time. With this approach, the LIVS band at position D decomposes before the LIVS band at position C, the LIVS band at position B decomposes slower than the LIVS band at position C, and of the bands at positions A, B, C, and D, the LIVS band at position A decomposes the slowest. For example, the band at position D can be exposed to ultraviolet radiation for 15 seconds, the band at position C can be exposed to the same intensity of ultraviolet radiation for 12 seconds, the band at position B can be exposed to ultraviolet radiation for 9 seconds, and the band at position A can be exposed to ultraviolet radiation for 6 seconds.

[0070] In one embodiment, the present disclosure provides a method of fabricating a medical device. The method includes providing a medical device comprising a bioabsorbable generally tubular structure. Next, a degradation environment is applied to at least two bands of the generally tubular structure, thereby producing at least two low in vivo stability (LIVS) bands. One or more high in vivo stability (HIVS) bands are between any two LIVS bands. The degradation environment achieves degradation of the bands of the generally tubular structure to which it is applied. The degradation environment can be, for example, aqueous base. Alternatively, the degradation conditions can be ultraviolet light. The generally tubular structure can be made in whole or in part from a bioabsorbable polyester, and the base or ultraviolet radiation achieves partial degradation of the polyester.

[0071] The processing conditions, as described above, can produce LIVS bands or can produce HIVS bands. For example, referring again to coil (10) in FIG. 6A for illustrative purposes, a protective coating can be applied to selected areas of the generally tubular structure to mitigate the rate of degradation of coil (10). Thus, a protective coating can be applied to bands A, C, and E to produce HIVS bands at locations A, C, and E, and LIVS bands at locations B, D, and F. In one embodiment, the coating is a bioabsorbable polyester.

[0072] In one embodiment, the present disclosure provides a method of fabricating a medical device. The method includes providing a medical device comprising a bioabsorbable generally tubular structure. Next, a degradation environment is applied to at least two bands of the generally tubular structure, thereby producing at least two low in vivo stability (LIVS) bands. One or more high in vivo stability (HIVS) bands are between any two LIVS bands. The degradation environment achieves degradation of the bands of the generally tubular structure to which it is applied. The degradation environment can be, for example, aqueous base. Alternatively, the degradation conditions can be ultraviolet light. The generally tubular structure can be made in whole or in part from a bioabsorbable polyester, and the base or ultraviolet radiation achieves partial degradation of the polyester.

[0073] The present disclosure also provides a method of making a medical device, including providing a bioabsorbable medical device. The bioabsorbable medical device includes a generally tubular structure having a lumen through the center of the generally tubular structure within a sidewall of the generally tubular structure. In other words, a generally tubular hollow structure, such as a stent. The bioabsorbable medical device may optionally be made 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 of 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, resulting in bands of high in vivo stability (HIVS) adjacent to the LIVS bands. The present disclosure also provides medical devices prepared by this process and other processes described herein.

[0074] In one embodiment, the degradative environment is or includes ultraviolet radiation. Moderate ultraviolet radiation is applied to a portion of the generally tubular structure, causing the ultraviolet radiation to impinge on that portion of the generally tubular structure and alter the structure of that portion, resulting in a higher rate of in vivo degradation in the affected portion compared to adjacent portions of the generally tubular structure not exposed to ultraviolet radiation. To achieve selective exposure of the generally tubular structure to ultraviolet radiation, bands or other shaped portions are shielded from exposure to ultraviolet radiation, while adjacent bands or other portions are not. Shielding can be achieved by masking the generally tubular structure. The mask has holes that allow ultraviolet radiation to pass through and contact the generally tubular structure, but also has radiopaque areas that do not allow ultraviolet radiation to pass through. Shielding can also be achieved by placing the generally tubular structure within a metal block having a lumen into which the generally tubular structure can be inserted and seated in a resting position. The metal block can have holes that extend through the metal, i.e., between the exterior surface of the metal block and the lumen of the metal block. Ultraviolet light can be directed from the exterior surface of the block into the holes so that the radiation passes through the holes and into the lumen of the metal block, where it then strikes that portion of the generally tubular structure that is exposed to the ultraviolet radiation. 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 likewise selected. For example, if the diameter of the holes is 5 mm, the length of the generally tubular structure that is exposed to the ultraviolet radiation will likewise be about 5 mm.

[0075] The generally tubular structure may or may not have a solid support (e.g., an opaque rod) passing through the lumen of the generally tubular structure while the structure is exposed to ultraviolet radiation. In particular, when an opaque rod passes through the lumen of the generally tubular structure, the rod may block exposure of some portions of the generally tubular structure to the incoming ultraviolet radiation. To overcome radiation blockage caused by the opaque solid support, the generally tubular structure is periodically rotated about its longitudinal axis, thereby exposing all portions of that band of the generally tubular structure to the incoming ultraviolet radiation. The rotation may occur constantly, i.e., the generally tubular structure is gradually rotated about its longitudinal axis at a constant speed, thereby exposing the band of the structure to ultraviolet radiation. Alternatively, rotation can be performed incrementally; for example, a portion of the generally tubular structure (i.e., a portion adjacent to the hole in the block through which the UV light passes) is exposed to UV radiation for a desired period of time, then the structure is rotated, for example, 60 degrees about its longitudinal axis, after which the generally tubular structure is again exposed to UV radiation for a desired period of time. The structure is then rotated another 60 degrees in the same direction and then exposed to UV radiation again. This process continues until the generally tubular structure has received six doses of UV radiation, producing LIVS bands. While the above example uses six doses of UV radiation spaced 60 degrees apart on the stent, other processes can be used instead, such as rotating the stent 90 degrees after each dose for a total of four doses, or rotating the stent 120 degrees after each dose for a total of three doses. In addition to rotating the generally tubular structure about its longitudinal axis, the generally tubular structure can also be translated along its longitudinal axis, resulting in a helical pattern of LIVS bands.

[0076] To create a generally tubular structure with multiple LIVS bands, rows of holes may be drilled into the block. For example, two holes create two LIVS bands, or three holes create three LIVS bands. The holes are typically aligned in a row and spaced apart by the desired length of the LIVS bands. As previously mentioned, the diameter of each hole will be 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 inner lumen of the block. The holes can be spaced 4 cm apart. In this manner, a generally tubular structure having an HIVS-LIVS-HIVS-LIVS-HIVS-LIVS-HIVS pattern can be created, where the three LIVS bands are each approximately 5 mm long and the two intervening HIVS bands are each approximately 4 cm long, so the structure can be represented as HIVS-LIVS(5 mm)-HIVS(4 cm)-LIVS(5 mm)-HIVS(4 cm)-LIVS(5 mm)-HIVS. If the generally tubular structure includes both a kidney 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-kidney curl).

[0077] Rather than creating multiple holes in the block, the block can have only a single hole, where the generally tubular structure is moved through the lumen a desired distance, thereby exposing another band of the structure to ultraviolet radiation. For example, after a first LIVS band is created, the generally tubular structure can be offset by a distance of, e.g., 5 cm, whereby a new (second) band of the generally tubular structure can be exposed to ultraviolet radiation passing through the hole in the metal block, creating a second LIVS band.

[0078] Ultraviolet radiation can be generated by standard means. For example, a BLUEWAVE™ 200 UV spot lamp (Dymax Corporation, Torrington, Connecticut, USA) or equivalent is a suitable source of ultraviolet radiation. A suitable intensity of ultraviolet radiation is about 10 W / cm. 2 For example, 9 to 11 W / cm 2 The range is approximately 10-60 seconds. A suitable time for exposing a portion of the overall tubular structure to UV radiation is approximately 10-60 seconds, so that that portion of the overall tubular structure has a suitably low in vivo stability. Different bands can be exposed to UV radiation for different times and / or at different light intensities and / or different exposure times, thereby achieving unique degradation and mechanical properties at different locations on the stent, thereby varying the rate of degradation of different portions when the overall tubular structure is deployed in vivo. For example, to create a generally tubular structure in which the band closest to the bladder curl degrades first and the band closest to the kidney curl degrades last, this generally tubular structure can be represented as follows: (kidney curl-HIVS)-LIVS(5mm; each portion of this band of the generally tubular structure is exposed to UV radiation for 20 seconds)-HIVS(4cm)-LIVS(5mm; each portion of this band of the generally tubular structure is exposed to UV radiation for 30 seconds)-HIVS(4cm)-LIVS(5mm; each portion of this band of the generally tubular structure is exposed to UV radiation for 40 seconds)-(HIVS-bladder curl).

[0079] As previously mentioned, medical devices of the present disclosure may be or include a generally tubular structure that is hollow. Optionally, such medical devices are or include mesh tubes, i.e., tubes formed from mesh, i.e., the sidewalls of the generally tubular structure have a mesh structure and the interior of the tube is open space. Optionally, the tubular structure is characterized by its length and / or its width, where width refers to the cross-sectional diameter of the generally tubular structure. The generally tubular structure may have 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 may be 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, a medical device of the present disclosure includes a generally tubular structure having a sidewall, where the sidewall includes a monofilament coil surrounding an (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 sidewall includes three components: the monofilament coil, the mesh, and the coating. This structure can be used to create a stent, which is a representative medical device of the present disclosure. If the stent is a urethral stent, the stent may further include a kidney retention structure at the proximal end of the device and a bladder retention structure at the distal end of the device. The kidney retention structure is inserted into the host's kidney and secures the proximal end of the stent to the kidney. The bladder retention structure is inserted into the host's bladder and secures the distal end of the stent to the bladder. Optionally, the kidney retention structure may be in the form of a curl at the proximal end of the device, and the bladder retention structure may be in the form of a curl at the distal end of the device.

[0081] When a device includes a coating as part of its generally tubular structure, the coating may or may not have a uniform thickness along the length of the generally tubular structure. In one embodiment, the coating thickness is uniform along the length of the generally tubular structure. In another embodiment, the coating thickness is non-uniform along the length of the generally tubular structure. The non-uniformity in coating thickness can be used to influence the rate of biodegradation of the generally tubular structure. For example, if a thicker coating is present at the proximal end of the device, all other factors being equal, biodegradation will occur preferentially at the distal end of the device. 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, the device including 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. The medical device may include HIVS and LIVS bands as described above.

[0082] Generally, medical devices of the present disclosure can be made from biostable or non-biostable materials, where non-biostable materials are referred to herein as degradable materials and may be understood in the art as biodegradable, absorbable, erodable, soluble, or biodissolvable. Degradable polymers are completely eroded or absorbed upon exposure to bodily fluids, such as blood, and are gradually resorbed, absorbed, and / or eliminated by the body. Some degradable materials absorb 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 due to chemical reactions between the material and the bodily fluid or substances within the bodily fluid. Chemical degradation can be the result of hydrolysis, oxidation, enzymatic degradation, and / or metabolic processes, among others. 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 a material. Degradation of a material's mechanical properties reduces the ability of a medical device made therefrom to function optimally in a host. For example, if the device is a stent, the stent reduces mechanical support within the blood vessel as it degrades. Additionally, some degradable materials are water-soluble. Water-soluble materials refer to materials that can be dissolved in water in addition to (or without) chemical degradation of the material.

[0083] In one embodiment, a degradable medical device is formed in whole or in part from a degradable organic polymer. The organic polymer can be, for example, a thermoplastic polymer, a thermosetting polymer, or an elastomeric polymer. The organic polymer can also be a copolymer, where the copolymer is made from two or more different monomers to provide properties not readily achievable from a homopolymer. The organic polymer can also be a mixture of one or more different polymers, such as one or more different organic polymers. Thus, the various degradable organic monomers identified herein can be used in concert to prepare homopolymers or copolymers, and the various organic polymers identified herein can be used in combination to prepare blends. The medical devices of the present disclosure are at least partially, and optionally completely, degradable, and thus include some degradable components. In one embodiment, the medical device is made entirely from degradable materials, and thus the medical device is fully degradable. In another embodiment, the medical device is made predominantly from degradable materials, and thus at least 50% by weight of the medical device is degradable. In another embodiment, the medical device is made from both degradable and biostable materials, and thus less than 100% of the medical device degrades. In various embodiments, 100%, or up to 95%, or up to 90%, or up to 85%, or up to 80%, or up to 75%, or up to 70%, or up to 65%, or up to 60%, or up to 55%, or up to 50%, or up to 45%, or up to 40%, or up to 35%, or up to 30%, or up to 25% of the medical device is made from degradable materials, where these percentages are wt% based on the weight of the implantable medical device.

[0084] Examples of degradable polymers that can be used to fabricate the medical devices of the present disclosure include poly(alpha-hydroxy acid) polymers and copolymers. For example, polymers and copolymers of glycolide, 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-tetramethylene glycolide), poly(lactide-co-trimethylene carbonate), poly(lactide-co-delta-valerolactone), poly(lactide-co-epsilon-caprolactone), poly(glycine-co-DL-lactide), poly(lactide-co-ethylene oxide); polysimilar polymers such as asymmetric 3,6-substituted poly-1,4-dioxane-2,5-diones. 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 copolymers; polyesteramides; polyesters of oxalic acid; polydihydropyran; poly(alkyl-2-cyanoacrylate); polyvinyl alcohol (PVA); polypeptides; poly(beta-maleic acid) (PMLA); poly(beta-alkanoic acids); 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 fabricated predominantly or entirely from a bioabsorbable polyester. For example, the polymer can be a polyester selected from poly(α-hydroxy acid) homopolymers, poly(alpha-hydroxy acid) copolymers, and blends thereof. Additionally or alternatively, the polyester may be selected from polyglycolide, poly-L-lactide, poly-D-lactide, poly-DL-lactide, and blends thereof. The polyester can be selected from polymers and copolymers of polylactide (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 be formed into fibers, or is both semi-crystalline and fiber-forming. In one embodiment, the medical device is fabricated using an organic polymer that is at least one of semi-crystalline and fiber-forming. In one embodiment, a degradable stent is prepared with a semi-crystalline and fiber-forming organic polymer. Furthermore, to rapidly degrade the organic polymer, i.e., to reduce in vivo stability, glycolide can be used as the monomer or one of the monomers used to form the organic polymer. Paradioxane (PDO) (the corresponding homopolymer is known as poly(PDO)) is another suitable monomer for forming rapidly degrading (LIVS) organic polymers. Because poly(PDO) typically degrades more slowly than glycolide-based polymers, a glycolide-rich monomer input is preferred to prepare very fast-degrading organic polymers.

[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, in a block of a block copolymer. Another option is for the organic polymer to be a semi-crystalline, fiber-forming, segmented polyaxial and glycolide-based, ensuring rapid degradation, i.e., low in vivo stability (LIVS). Yet another option is to use linear copolymers in either or both diblock, triblock, and pentablock copolymers, with the exception of the pentablock, where the central block is amorphous and the other blocks are semi-crystalline. This could be a PEG central block with amorphous segments connected to the outer crystalline segments (forming a symmetric pentablock polymer, which is a polyetherester; all other polymers mentioned are aliphatic polyesters). Linear block copolymers may be composed of semi-crystalline blocks in all cases, and the absence of amorphous blocks results in polymers that can be oriented after fiber formation to produce different alternating crystalline structures and percentage patterns within the fiber, resulting in slight differences in the degradation profiles of the alternating blocks that form the fiber (because the fiber is oriented, horizontal strips of crystalline regions form and align blocks that make up the polymer chain). Alternatively, linear copolymers without blocks can be substituted. In one embodiment, these organic polymers are used to form fibers, and the fibers are used to form coatings on or as part of the sidewalls of generally tubular structures that are components of the medical devices of the present disclosure. In another embodiment, these organic polymers are not formed into fibers, but rather are used to form coatings on medical devices, for example, by spraying a solution of the polymer onto the medical device or dip-coating the device into an organic polymer solution.

[0088] Medical devices can be made from a base polymer that is amorphous, flexible, and elastic. It can be crystalline, but too much crystallinity typically reduces the flexibility of the polymer. If a highly crystalline material is selected for use, it is recommended to combine the crystalline material with a plasticizer, such as PEG, to reduce the final crystallinity of the polymer (e.g., the final crystallinity of the coating applied to the medical device). As noted above, the polymer can be multiaxial or linear, block or segmented, or random. For highly flexible and conformable coatings, the organic polymer can be minimally crystalline or amorphous.

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

[0090] Suitable degradable organic polymers other than polyesters include polyether-esters, polyether-ester-urethanes (bioabsorbable urethanes), polyether-urethanes and polyether-urethane-ureas, the latter examples of which degrade very slowly and typically incompletely.

[0091] In various embodiments, the medical device is made from any of the following polymers: MG-5 (Poly-Med, Anderson, SC): A semi-crystalline multiaxial block copolyester prepared in a two-step reaction from an amorphous prepolymer and a crystalline endograft, with at least 65% glycolide in the endograft; MG-9 (Poly-Med, Anderson, SC): A semi-crystalline multiaxial block copolyester prepared in a two-step reaction from an amorphous prepolymer and a crystalline endograft, with at least 80% glycolide; A semi-crystalline, multiaxial segmented copolyester prepared in a one-step reaction (no prepolymer); A semi-crystalline linear block copolyester prepared in a two-step reaction from an amorphous prepolymer and a crystalline endograft; A triblock copolymer with a crystalline endograft; A diblock copolymer; A semi-crystalline linear segmented copolyester prepared in a one-step reaction (i.e., no prepolymer). SVG-12 (Poly-Med, Anderson, South Carolina): Intrinsic viscosity greater than 1.0 with crystalline endografts. Multiaxial block copolymers. Polymers prepared from amorphous prepolymers and amorphous endografts. Linear block copolymers (triblock, diblock, pentablock). Linear segmented copolymers. Linear random copolymers that are amorphous and therefore flexible and malleable. The foregoing are merely exemplary of organic polymers that may be used to fabricate suitable medical devices, or components thereof (e.g., coating layers).

[0092] Another suitable polymer for making the medical devices of the present disclosure is a mixture comprising: (a) a bioerodible polyester network formed by the reaction between reactive species including a polyol and a polycarboxylate, where at least one of the polyol and the polycarboxylate has a functionality of three or greater; and (b) a bioerodible thermoplastic polymer. Optionally, the composition can be further characterized by one or more of the following: the polyol is selected from a non-polymeric diol, a polymeric diol, a non-polymeric triol, and a polymeric triol; the polycarboxylate is selected from a non-polymeric dicarboxylate, a polymeric dicarboxylate, a non-polymeric tricarboxylate, and a polymeric tricarboxylate; the reactive species includes a triol, a tricarboxylate, or both; the reactive species includes (a) a non-polymeric tricarboxylate and (b) a polyester polyol; the reactive species includes (a) citric acid and (b) a polycaprolactone diol, a polycaprolactone triol, or both; the bioerodible thermoplastic polymer has a melting point above body temperature; the bioerodible thermoplastic polymer has a glass transition temperature below room temperature; and the bioerodible thermoplastic polymer is a bioerodible thermoplastic polyester. See, for example, U.S. Patent Publication No. 20160166739.

[0093] In one aspect, the implantable medical device of the present disclosure includes a coating as a component of the medical device. The location of the coating relative to the medical device and the properties of the coating, with respect to physical and chemical properties, contribute to managing the degradation and / or removal of the medical implant from the host. In particular, the coating contributes, in part, to managing the degradation and / or removal of the medical device from the host. The properties of the coating can be selected to manage the degradation and / or removal of the coated medical device from the host.

[0094] The medical devices present in the medical implants of the present disclosure are degradable, at least to some extent. In other words, the medical device degrades once placed in a host. The degradation can be physical or chemical. Physical degradation refers to a change in the physical or mechanical properties of the medical device. For example, the device may fall apart and lose integrity. As another example, the device may become softer and malleable. As yet another example, the device may absorb fluid and swell. In each of these cases, the device undergoes a change in its physical or mechanical properties. Chemical degradation refers to a change in chemical composition. For example, organic polymers from which the device is made may undergo hydrolytic bond cleavage or enzyme-induced bond cleavage, thereby losing molecular weight. As another example, 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 degradation results in a change in the chemical properties of the medical device. In one embodiment, the degradation of a medical implant occurs through both physical and chemical degradation. The coating of the medical implant may play a role in influencing this degradation, either partially or entirely. Thus, the properties of the coating can be used to manage the degradation and / or removal of the medical implant from the host.

[0095] In one aspect, a medical device includes a coating on a portion of the medical 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 a device degrades by breaking down into fragments and it is desired to manage the dispersion or propagation of those fragments. For example, in one embodiment, the containment layer can be relatively long-lasting compared to the medical device, such that when the medical device breaks down into fragments, the containment layer maintains sufficient structural integrity to retain those fragments within the containment layer. Such a containment layer is useful when the medical device is placed in the kidney, where it is undesirable for debris from the medical device to come into contact with the interior of the kidney and calcify. In a related embodiment, the containment layer is also relatively long-lasting compared to a medical device that is an esophageal stent. In this case, when the esophageal stent breaks down into fragments, the containment layer located on and surrounding the luminal wall of the stent prevents those fragments from entering the stomach. Thus, in either instance, the containment layer effectively limits debris migration of the medical device.

[0096] In another aspect, the medical device does not have a containment layer. In this case, the medical device lacks a feature, such as a containment layer, that would limit the movement of fragments, such as the HIVS band, formed upon degradation of the medical device (e.g., degradation of the LIVS band adjacent to the HIVS band). Optionally, a generally tubular structure that is part of the medical device does not include a containment layer that would limit the movement of fragments, such as the HIVS band, formed upon degradation of the generally tubular structure. In the absence of a containment layer or equivalent feature, fragments formed during in vivo degradation of the disclosed medical device or generally tubular structure are free to separate from the medical device and leave the vicinity of the implanted medical device. It is possible for the medical device, or any portion thereof, to lack a containment layer.

[0097] In another aspect, the containment layer provides a physical or chemical barrier between the degradation-inducing fluid from the host and the medical device. This layer can be used to spatially and temporally influence the degradation of the medical device. For example, in one embodiment, the containment layer is a discontinuous layer such that it covers some, but not all, of the medical device. In this case, the containment layer effectively acts as a barrier between the portion of the medical device and the degradation-inducing fluid from the host, limiting contact between the portion of the medical device and the fluid. In this way, the containment layer allows the exposed portions of the medical device to degrade faster than the unexposed portions of the medical device. In this way, the containment layer can be used to control where the device degrades first.

[0098] In another embodiment, a gradient containment layer is used to manage the spatial and temporal degradation and / or removal of a medical device. For example, a medical device may have a single coating layer covering a first portion of the device, a double coating layer covering a second portion of the device, and optionally a triple coating layer covering a third portion of the device. Assuming the composition of the coating layers is the same at each location, the first portion of the medical device will degrade before the second and third portions of the device. Depending on the relative thickness at each location, the first portion may significantly degrade and be removed from the host, while the second and third portions of the device may still be fully intact. Depending on the layer arrangement, the degradation and removal of the first portion of the medical device may increase biological fluid access to the second portion of the medical device, resulting in the degradation of the second portion (which may still be covered by the coating). The degradation and removal of the second portion of the device is followed by the degradation and removal of the third portion of the device. In this example, the coating manages the rate at which the various portions of the medical device degrade and are removed from the host. However, it should be noted that the coating may also function as a containment layer to manage the dispersion or propagation of these fragments, ie, to limit the movement of these fragments within the host.

[0099] Medical implants, including the medical device itself and / or the coating thereon, may contain a therapeutic agent. The amount of therapeutic agent incorporated into the implant will depend on the nature of the implant, the actual therapeutic agent, the condition of the subject, etc. The amount can be determined appropriately by one of ordinary skill in the art. Exemplary therapeutic agents include antithrombotic agents, antiproliferative agents, anti-inflammatory agents, anti-migratory agents, antitumor agents, antimitotic agents, anesthetic agents, and anticoagulants. Further, suitable therapeutic agents include agents that affect the production and organization of the extracellular matrix and the growth of vascular cells (either promoters or inhibitors), cholesterol-lowering agents, vasodilators, and agents that interfere with endogenous vasoactive mechanisms.

[0100] In various embodiments of the present invention, the medical device can be a ureteral stent. Medical devices, such as ureteral stents, can be designed to release one or more drugs, representative examples of which include one or more of the following: alpha-adrenergic blockers, analgesics, anti-cancer agents, anti-tumor agents, anti-inflammatory agents, antibacterial agents, anti-proliferative 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 the like, as well as 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 stimulators, heat shock protein 90 antagonists, HMGCoA reductase inhibitors, hydroorotate dehydrogenase inhibitors, IKK2 inhibitors, IL-1, ICE and IRAK antagonists, IL-4 agonists, immunomodulators, inosine monophosphate dehydrogenase inhibitors, and the like. Anti-inflammatory drugs, leukotriene inhibitors, MCP-1 antagonists, MMP inhibitors, NF-kappa B inhibitors, NO agonists, P38 MAP kinase inhibitors, phosphodiesterase inhibitors, TGF-β 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, antifungals, bisphosphonates, phospholipase A1 inhibitors, histamine H1 / H2 / H3 receptor antagonists, macrolide antibiotics, GPIIbIIIa receptor antagonists, endothelin receptor antagonists, peroxisome proliferator-activated 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, enkephalin kinase inhibitors, peroxisome proliferator-activated 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, amosulalol, arotinilol, dapiprazole, doxazosin, ergoloids, fenspiride, idazoxan, indoramin, labetalol, manotepir, mesylate, naftopidil, nicergoline, prazosin, tamsulosin, terazosin, tolazoline, trimazosin, and yohimbine.

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

[0104] Examples of β-adrenergic agonists include albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, chlorprenaline, denopamine, ephedrine, epinephrine, etafedrine, ethylnorepinephrine, fenoterol, formoterol, hexoprenaline, ibopamine, isoetharine, isoproterenol, mabuterol, metaproterenol, methoxyphenamine, oxyfedrine, pirbuterol, prenalterol, procaterol, protokylol, reproterol, rimiterol, ritodrine, salmelterol, soterenol, terbutaline, tretoquinol, tulobuterol, and xamoterol.

[0105] Examples of anti-cancer, anti-proliferative and anti-tumor agents include: drugs that affect microtubule dynamics (e.g., colchicine, Epo D, epothilones, paclitaxel, vinblastine, vincristine, etc.), alkyl sulfonates, 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, flavopiridol, limus drugs (e.g., everolimus, sirolimus, tacrolimus, zotarolimus, etc.), methotrexate, nitrogen mustards, nitrosoureas, proteasome inhibitors, and suramin.

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

[0107] Examples of bronchodilators include: (a) ephedrine derivatives, such as albuterol, bambuterol, bitolterol, carbuterol, clenbuterol, chlorenaline, dioxedrine, ephedrine, epinephrine, eprozinol, etafedrine, ethylnorepinephrine, fenoterol, formoterol, hexoprenaline, isoetharine, isoproterenol, mabuterol, metaproterenol, n-methylephedrine, pirbuterol, procaterol, protokylol, reproterol, rimiterol, salmeterol, soterenol, terbutaline, and tulobuterol; (b) quaternary ammonium compounds. (c) xanthine derivatives such as acefylline, acefylline piperazine, ambuphylline, aminophylline, bamifylline, choline theophylline acid, doxofylline, dyphylline, etamiphylline, etophylline, guaitiline, proxyphylline, theobromine, 1-theobromine acetate, theophylline, and (d) other bronchodilators such as fenspiride, medivadine, methoxyphenamine, tretoquinol, and the like, as well as combinations of the foregoing and pharmaceutically acceptable salts, esters, and other derivatives thereof.

[0108] Examples of calcium channel blockers include: arylalkylamines (including phenylalkylamines) such as bepridil, clentiazene, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, and benzothiazepines such as diltiazem; calcium channel blockers such as bencyclane, etafenone, fantofarone, monatepir, and perhexiline, among other calcium channel blockers; dihydropyridine derivatives (including 1,4-dihydropyridine derivatives) such as amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, and nitrendipine; and piperazine derivatives such as cinnarizine, dotalizine, flunarizine, lidoflazine, and lomerizine.

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

[0110] Examples of nitric oxide donor / releasing molecules include: inorganic nitrates / nitrites such as amyl nitrite, isosorbide dinitrate, nitroglycerin, inorganic nitroso compounds such as sodium nitroprusside, sydnoimines such as linsidomine and molsidomine, nonoates such as diazeniumdiolates, NO adducts of alkanediamines, S-nitroso compounds including low molecular weight compounds (e.g., S-nitroso derivatives of captopril, glutathione, 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 analogs thereof for use in the present disclosure may be selected from the following suitable items: prostaglandins such as PGE1 and PGI2, prostacyclin analogs such as beraprost, carbacyclin, ciprostene, epoprostenol, iloprost, etc.

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

[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, meclofenamate, meloxicam, nabumetone, naproxen, naproxen indomethacin, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, and valdecoxib.

[0114] The medical devices of the present disclosure, such as ureteral stents, can be manufactured to contain and release one or more of these or other therapeutic agents. In addition to the drugs listed herein, pharmaceutically acceptable salts, esters, and other derivatives of the drugs can also be utilized. The drugs provided herein can be loaded, for example, into polymeric components of the medical device. When the medical device is a stent, the drug can be incorporated into the coil, the knit structure adjacent to the coil, or a coating impregnated into the knit structure.

[0115] Urologically beneficial drugs can be attached to drug-releasing stents in a variety of ways, including, among others: (a) loaded internally (in the bulk) on a stent component (e.g., a monofilament coil, a multifilament knit structure, or a coating, sleeve, or sheath); (b) bound to the surface of the stent (e.g., the surface of a monofilament coil, a multifilament knit structure, or a coating, sleeve, or sheath forming part of the stent), where the drug is bound to the surface by either covalent and / or non-covalent interactions (e.g., interactions such as van der Waals forces, hydrophobic interactions, and / or electrostatic interactions, e.g., charge-charge interactions, charge-dipole interactions, dipole-dipole interactions including hydrogen bonding); (c) applied as a coating covering all or a portion of the stent or its components; (d) loaded into surface features (e.g., depressions) of the stent or its components; and (e) combinations of the foregoing.

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

[0117] In one embodiment of a drug-containing medical device, the present disclosure provides a medical device for placement within the body of a mammal, comprising: a polymeric matrix forming the device and defining a lumen therethrough, the matrix comprising polymer macromolecules and defining spaces between the polymer macromolecules; a drug contained within at least some of the spaces of the matrix; and a material contained within at least some of the spaces of the matrix for affecting diffusion of the drug from the polymeric matrix when the medical device is placed within the body of a mammal. Optionally, one or more of the following may further characterize the medical device of the present disclosure: the polymeric material and the drug each have a molecular weight, and the molecular weight of the drug is smaller than the molecular weight of the polymeric material; the amount of drug attached to the device is 0.1 to 50% by weight of the device; the medical device is a ureteral stent or catheter; the polymeric component comprises a degradable polyester; the polymeric component is hydrophobic; at least a portion of the space containing the drug also comprises a polymeric material; the drug comprises oxybutynin chloride or ketorolac; the material to which the drug is attached comprises polyethylene glycol (PEG); the drug is attached to a biodegradable material; the drug is attached to a material from which the drug must dissociate before diffusing out of the polymer matrix; or the polymeric matrix is ​​coated onto the device.

[0118] Thus, medical devices can be used as vehicles for delivering one or more drugs to a patient's body. Urinary stents, catheters, and / or other medical devices can be used to deliver drugs by placing the device completely or partially within a patient's body. By using specific materials and drugs in a polymer matrix, the diffusion of the drug from the matrix can be controlled in a manner not previously achievable. One or more drugs can thereby be administered to a patient's body at relatively constant therapeutic levels over a sustained period of time (e.g., ranging from days to months).

[0119] Drug delivery medical devices according to the present disclosure may be formed, in whole or in part, 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, a catheter, a dialysis tubing, a cannula, a urethral stent, a suture, or other medical device designed to be placed (in whole or in part) inside the body. Devices according to the present disclosure may optionally be coated, in whole or in part, with such a loaded polymer matrix. For example, a hydrophobic polymer matrix may coat all or part of a lead wire, stent, or catheter.

[0120] In another embodiment, the present disclosure provides a ureteral stent comprising an elongate stent body, a deployable retention structure, and a drug release member, wherein the drug release member is selected from: (i) a sleeve of drug release material disposed over at least a portion of the deployable retention structure, (ii) a sheet of drug release material attached to the deployable retention structure, and (iii) a sheet of drug release material connected to a sleeve of material disposed over at least a portion of the deployable retention structure. Optionally, one or more of the following features may further describe this drug-releasing ureteral stent: a sleeve of drug-releasing material is disposed over at least a portion of the expandable retention structure, and optionally, the sleeve is a biodegradable sleeve, and / or the sleeve is a heat-shrinkable sleeve, and / or the sleeve has an inner diameter in the range of 1-4 mm, a length in the range of 2-500 mm, and a thickness in the range of 50-200 μm; the stent comprises a sheet of drug-releasing material attached to the expandable retention structure, and optionally, the sheet is a biodegradable sheet, and / or the sheet is an elastic sheet, and / or the sheet has a width in the range of 2-20 mm, a length in the range of 2-500 mm, and a thickness in the range of 50-200 μm; the stent comprises a retention structure in the form of a coil or loop; The sheet of drug-releasing material spans the majority of the coil or loop region upon deployment of the retention structure; the stent comprises a sheet of drug-releasing material connected to a sleeve of material disposed over at least a portion of the expandable retention structure; the stent comprises a retention structure that is a renal retention structure configured to be delivered through the ureter and deployed in the kidney, and optionally the retention structure is adapted to be reduced to a sufficiently small profile during deployment so that the retention structure can be delivered to the kidney; the stent has a retention structure comprising a plurality of elongated elements to which the sheet of drug-releasing material is attached and between which the sheet of drug-releasing material is positioned upon deployment of the retention structure; the stent body and the expandable retention structure comprise a biostable polymer.

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

[0122] Materials can be added to the polymer composition to specifically influence the release of the drug from the polymer. Such materials include, but are not limited to, styrene-butylene-styrene (SIBS), collagen, alginate, carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), dextrin, plasticizers, lipophilic materials and other fatty acid salts, pore-forming agents, chelating agents including sugars, glucose, starch, hyaluronic acid (HA), ethylenediaminetetraacetic acid (EDTA), polyethylene glycol (PEG), polyethylene oxide (PEO), and copolymers thereof. Multiple materials with different 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 present disclosure provides a bioabsorbable medical implant partially covered by an outer containment layer, which is non-bioabsorbable or at least partially bioabsorbable but does not degrade as rapidly as the medical implant. In one embodiment, in vivo, the medical implant breaks down into fragments, while the outer layer retains sufficient structural integrity to provide a barrier through which the debris from the implant cannot pass. In this way, the debris is confined to a localized area where it cannot harm the host. Indeed, as the fragments break down, the resulting smaller fragments, and the final molecular components of the implant, all remain within the outer containment layer and are guided together to a location safe for removal.

[0124] [gradient] In one aspect, a medical device is characterized as having a gradient. A gradient refers to the variation in some property, e.g., composition, of a medical device as a function of direction. This gradient provides for a change in degradation along the gradient. For example, the average molecular weight of the polymer forming the medical device may vary along the direction of the medical device, such that the polymer at the distal end of the medical device or portion thereof has a higher average molecular weight than the polymer at the proximal end of the medical device or portion thereof. In this manner, the proximal end of the medical device or portion thereof may degrade faster than the distal end, where the polymer has a higher initial average molecular weight. The provision of a gradient in the medical devices of the present disclosure provides a mechanism for controlled degradation of the device. In one embodiment, the gradient does not affect or have an effect on the function of the medical device, but only affects the degradation profile of the device. Such heterogeneity in a medical device may be referred to herein as a gradient in the medical device, and a medical device having such a gradient may be referred to as a gradient medical device.

[0125] Optionally, coatings or containment layers of the present disclosure may be characterized in that they have a gradient, whereby a coating or containment layer covering one portion of a medical device is different from a coating or containment layer covering another portion of the medical device. Such non-uniformity in a coating or containment layer is referred to herein as a coating or containment layer gradient, 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 a variety of ways. For example, different compositions with different degradation rates can be used to form different portions of a medical device. Thus, a composition with a relatively high degradation rate can be used to form a first portion of the medical device, and a composition with a relatively slow degradation rate can be used to form a second portion of the medical device. In this way, the device will degrade faster in some areas than in other areas.

[0127] As another example, a single composition can be used to form a gradient coating or containment layer. For example, a single composition can be coated to a first thickness on a first portion of a medical device, and the same composition can be used to create a coating having a second thickness on a second portion of the medical device. Generally, thicker coatings will remain on the medical device longer than thinner coatings; that is, all other factors being equal, thicker coatings will degrade more slowly than thinner coatings. Thicker coatings can be formed, for example, by repeatedly coating areas of the containment layer where a greater coating thickness is desired.

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

[0129] The amount of the coating or encapsulation layer can vary throughout the medical implant. In one aspect, in addition to, or instead of, specifying the thickness of the coating or encapsulation layer, the coating or encapsulation 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 can be expressed per square centimeter (cm) of the medical device. 2) In various embodiments, the amount of 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 is.

[0130] Thus, in one embodiment, the present disclosure provides a medical implant including a medical device and a gradient coating or gradient containment layer covering a portion of the medical device. Optionally, the gradient coating or containment layer can include multiple thicknesses, e.g., two, three, four, five, or more than five different thicknesses at different locations. A gradient coating or containment layer having multiple thicknesses at different locations can be formed by having varying numbers of coating layers of a polymer composition at different locations and can thus be said to include multiple layers of a coating composition. Optionally, the gradient coating or containment layer can also include multiple compositions, e.g., two, three, four, five, or more than five different compositions at different locations. Optionally, the gradient coating or containment layer can include variations in two or more properties, e.g., multiple thicknesses and multiple compositions.

[0131] While thickness and composition are examples of variations that may be present in a coating or containment layer, these are merely illustrative. Other variations, such as variations in texture, hydrophilicity, thermal stability, tensile strength, and fiber density when fibers are included in the coating or containment layer, can be used to create a gradient coating or containment layer according to the present disclosure.

[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 degrades at a slower rate than the medical device. In this way, when the medical device breaks down into fragments, the containment layer maintains its structural integrity and holds the fragments together within a limited space for a sufficient time for the fragments to break down into smaller fragments that are harmless to the host and / or to degrade into the polymeric and / or monomeric components of the medical device.

[0133] In one embodiment, the containment layer is a coating on the medical device. The coating can be present on the position-maintaining end of the medical device. The coating can be completely non-biodegradable. However, in another embodiment, the coating is biodegradable, but degrades at a slower rate than the medical device. In this way, when the medical device breaks down into fragments, the coating maintains its structural integrity and holds the position-maintaining end fragments together within a limited space for a sufficient time for the fragments to break down into smaller fragments that are harmless to the host and / or degrade into polymeric and / or monomeric 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: a higher concentration of polymer tends to deposit more polymer on the surface of the medical device when the device is dipped, drawn, or otherwise coated with the polymer to form a coating or encapsulation layer.

[0135] The containment layer is positioned on portions of the medical device where it is desired to protect the host from damage, injury, or trauma caused by device debris formed during biodegradation. For example, in the case of a stent implanted in a host, since the stent is positioned partially within the host's kidney and partially outside the kidney, it is desirable to prevent disintegrating stent fragments from dissolving into the kidney and causing kidney stones. Thus, the portion of the stent positioned within the kidney may be coated to provide a containment layer, while the portion of the stent positioned outside the kidney, e.g., the generally tubular structure forming the main central tube of the stent, may not have a containment layer. In this way, the containment layer is present on only a portion of the medical device.

[0136] The present disclosure proposes that a containment layer can be provided for any medical device that degrades through a disintegration process, i.e., by breaking down the device 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 of time. However, after this period, the stent begins to break down into smaller fragments. To prevent migration of these fragments (especially if these fragments form part of the position-maintaining end of the stent), the position-maintaining end of the stent is at least partially encased by a containment layer. The layer retains sufficient integrity to contain the small fragments as they form and subsequently disintegrate into harmless fragments or polymeric or molecular components. Thus, the containment layer functions to protect the host from the small fragments formed during the stent's degradation. The containment layer also protects the host from contact with rigid fragments that cannot be easily excreted from the body.

[0137] In one embodiment, the present disclosure provides a ureteral stent having varying properties at different locations on the stent, although the stent and its components are not assembled from multiple segments. Rather, the stent is assembled from a single, uniform construct, which is then modified to provide varying properties at different locations on the construct. The varying properties can be one or more properties, including biodegradability, radiopacity, stiffness or flexibility, and therapeutic drug loading. The varying properties are created by methods such as those disclosed herein, for example, by selectively degrading the stent or its components before implantation in a host, and by other methods disclosed herein. In this manner, bands can be created that have higher in vivo stability (HIVS) or lower in vivo stability (LIVS) compared to unmodified portions of the medical device. 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 producing LIVS bands. In another embodiment, bands of unmodified material are treated to induce them to have increased in vivo stability (HIVS) relative to adjacent unmodified bands, thereby producing HIVS bands.

[0138] In one embodiment, the medical device is a stent, the stent being a fiber-reinforced elastomeric film construction designed with at least one position-retaining end, the fiber reinforcement being (a) a combination of monofilament coil and weft-knitted tubular multifilament yarn; (b) a combination of monofilament coil and braided multifilament yarn; (c) a tube comprising braided or weft-knitted monofilament yarn; or (d) a tubular weft-knitted or braided monofilament yarn.

[0139] In yet another embodiment, the stent is a construction of a fiber-reinforced elastomeric film designed with at least one position-maintaining end, wherein the fiber reinforcement is a combination of monofilament and knitted or braided multifilament yarns, and wherein the fiber-reinforced elastomeric film is in the form of a tube having a central main component with a diameter smaller than that of the patient's ureter, and each position-maintaining end defines two freely laterally deformable components formed by the initial partially overlapping double tubular ends of the main central component and the laterally fused tubes, which are cut radially and axially to form two overextended flaps attached to intact semi-cylindrical extensions of the main central component.

[0140] In yet another embodiment, the stent is a construction of fiber-reinforced elastomeric film designed with at least one position-maintaining end, wherein the fiber reinforcement is monofilament yarn or a combination with knitted or braided multifilament yarn, and the fiber-reinforced elastomeric 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-maintaining end, the position-maintaining end being an angled portion of the main tube having a length equivalent to the patient's ureter and including a flexible hinge that maintains an angle of greater than 30 degrees relative to the main tube in the absence of deforming stress.

[0141] In another embodiment, the stent includes a retention portion configured to help retain the stent in place within the patient's body; and an elongate portion extending from the retention portion, the elongate portion having a sidewall defining a lumen, the sidewall having a first section and a second section, the first section of the sidewall having a first thickness and the second section of the sidewall having a second thickness different from the first thickness. Optionally, the stent may be further characterized by one or more of the following: the retention portion is configured to be positioned within the patient's kidney; the retention portion is a first retention portion and the stent further includes a second retention portion configured to help retain the stent in place within the patient's body; the first section of the sidewall forms an annular ring; the first section of the sidewall forms a helix; the first section of the sidewall forms a dimple; the sidewall has a third portion and the second portion of the sidewall is disposed between the first portion of the sidewall and the third portion of the sidewall; the sidewall has a third portion and the third portion is The stent may have a thickness different from the second thickness, and the second portion of the sidewall is disposed between the first portion of the sidewall and the third portion of the sidewall; the sidewall has a third portion, and the second portion of the sidewall is disposed between the first portion of the sidewall and the third portion of the sidewall, the third portion having a third thickness, the second thickness being greater than the first thickness, and the second thickness being greater than the third thickness; the first portion of the sidewall has a first section and a second section, and the first section of the first section forms a helix that rotates in a first direction, and the second section of the first section forms a helix that rotates in a second direction that is different from the first direction. This stent, including any of its embodiments, can be modified by the techniques disclosed herein to exhibit controlled degradation when the stent is deployed in a host. For example, slits can be formed in the slits to provide sites that promote degradation.

[0142] In another embodiment, a stent includes a retention portion configured to help retain the stent in place within a patient; and an elongate portion extending from the retention portion, the elongate portion having a first member and a second member, the first member lacking a lumen, the second member lacking a lumen, and the first member and the second member being intertwined. In another embodiment, a stent includes a retention portion configured to help retain the stent in place within a patient; and an elongate portion extending from the retention portion, the elongate portion having an expanded configuration and a nominal configuration, the elongate portion having a sidewall defining a lumen extending from a first end portion of the elongate portion to a second end portion of the elongate portion, the sidewall defining a chamber, the chamber configured to receive a fluid and position the elongate portion in its expanded configuration. Again, any of these stents can be modified by the techniques disclosed herein to exhibit controlled degradation when the stent is deployed within a host.

[0143] In another embodiment, the stent is a fiber-reinforced elastomeric film construction designed with at least one position-maintaining end, where the fiber reinforcement is a combination of monofilament and knitted or braided multifilament yarns, and the fiber-reinforced elastomeric film is tubular with a central main component having a diameter smaller than the diameter of the patient's ureter and has at least one position-maintaining end, where the position-maintaining end is a highly flexible extension of the central main tube that is neck-like after insertion into the patient's ureter but can be made collinear with the central main tube during insertion using an applicator.

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

[0145] In another embodiment, the medical device is a ureteral stent and includes: an elongate member having a first portion and a second portion, the second portion having a substantially solid cylindrical shape, the first portion coupled to the second portion, the first portion configured to be disposed within a kidney of a patient, the first portion having a length such that the first portion terminates in at least one of the patient's kidney and ureter, the second portion of the elongate member configured to deliver fluid from a first location in the second portion to a second location in the second portion via at least one of capillary action and wicking, the second portion of the elongate member configured to be disposed within at least one of the patient's bladder and the patient's ureter. This stent can be modified to exhibit managed degradation in accordance with the present disclosure.

[0146] In another embodiment, a stent includes at least one filament having a longitudinal axis and formed from a material including a bioabsorbable polymer material. The polymer molecules within the bioabsorbable polymer material can have a helical orientation aligned with the longitudinal axis of the filament. The stent is at least partially bioabsorbed by a patient upon implantation or insertion of the stent into a patient. For example, the stent can include: a braided or woven construction; a flared end portion at one of the proximal or distal ends of the stent; and at least one filament having a longitudinal axis and comprising an oriented bioabsorbable polymer material, where the polymer molecules within the bioabsorbable polymer material have a helical orientation aligned with 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 includes a plurality of filaments, optionally, the plurality of filaments is helically wound along at least a portion of the length of the stent, and further optionally, a first portion of the plurality of filaments is helically wound along a first direction and a second portion of the plurality of filaments is helically wound in a direction opposite the first direction; the plurality of filaments is braided and helically wound along at least a portion of the length of the stent; the stent includes stainless steel or nitinol filaments.The stent comprises 12 to 36 helical filaments; optionally, 6 to 18 filaments are helical and axially displaced from one another, the helices extending in a first direction and an equal number of filaments comprising helices extending in a second direction opposite the first direction, the filaments being uniformly arranged around the longitudinal axis of the stent; the oriented bioabsorbable polymer material comprises a single bioabsorbable polymer or a blend of bioabsorbable polymers; the oriented bioabsorbable polymer material comprises a polymer selected from poly(α-hydroxy acid) homopolymers, poly(α-hydroxy acid) copolymers and blends thereof; the oriented bioabsorbable polymer material comprises a polymer selected from poly(α-hydroxy acid) homopolymers, poly(α-hydroxy acid) copolymers and blends thereof; the oriented bioabsorbable polymer material comprises polyglycolide, poly-L-lactide, poly-D-lactide, poly-DL- the oriented bioabsorbable polymer material has a crystallinity in the range of 0.1 to 20%; at least one filament comprises a core of oriented bioabsorbable polymer material; at least one filament comprises a coating of oriented bioabsorbable polymer material; the stent comprises a plurality of oriented filaments arranged to form a pattern of geometric diamond-shaped cells; the plurality of filaments are interwound to form an interlocking joint; at least one filament comprises a therapeutic agent; the stent is selected from coronary stents, peripheral stents, urethral stents, ureteral stents, biliary stents, tracheal stents, gastrointestinal stents, and esophageal stents.

[0147] Another optional embodiment provides a stent constructed of a fiber-reinforced elastomeric film designed with at least one position-maintaining edge. The fiber reinforcement is a monofilament yarn or a combination with a knitted or braided multifilament yarn, and the fiber-reinforced elastomeric film is in the form of a tube with at least one position-maintaining edge. The retaining edge is an inverted cone with a diameter greater than the diameter of the main vessel at its widest cross section, and upon application of a radial compression force with an applicator, it reversibly compresses to match the diameter of the main vessel (which is also smaller than the diameter of the patient's ureter). The inverted cone is preferably partially slit, resulting in a cone wall with at least two leaflets, preferably three to five leaflets, to facilitate radial compression during insertion with an applicator.

[0148] Yet another embodiment provides a fiber-reinforced elastomeric film construction designed with at least one position-maintaining edge, where the fiber reinforcement is a combination of monofilament yarns and knitted or braided multifilament yarns, the elastomeric film is tubular with a central main component having a diameter smaller than the diameter of the patient's ureter, and the at least one position-maintaining edge is an axially slit asymmetric inverted cone with a teardrop-shaped cross section (at the apex of the teardrop, the average diameter in the widest cross section exceeds the average diameter of the main canal), and the slit asymmetric cone reversibly compresses to match the diameter of the central main canal upon application of a radial compressive force by an applicator.

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

[0150] Optionally, the fiber-reinforced elastomeric film is formed from a segmented copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group represented by the following: 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 elastomeric swellable film composition is a crystalline copolymer of high molecular weight (20-35 kDa) polyethylene glycol (PEG) and a 95 / 5 (molar) mixture of epsilon-caprolactone / glycolide, where the weight percentage of the PEG component of the copolymer is about 10%.

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

[0152] Optionally, a film may be prepared from electrospun fibers. Also optionally, the fiber-reinforced elastomeric film may include or contain a monofilament yarn (optionally combined with a knitted or braided multifilament yarn), where the reinforced monofilament yarn is formed from a segmented copolymer made from at least two cyclic monomers selected from the group consisting of L-lactide, epsilon-caprolactone, trimethylene carbonate, glycolide, morpholine-dione, p-dioxanone, and 1,5-dioxapan-2-one. Optionally, the copolymer is a relatively slow-degrading composition formed from L-lactide, epsilon-caprolactone, and trimethylene carbonate. Optionally, the copolymer is a relatively fast-degrading composition formed from glycolide, epsilon-caprolactone, and trimethylene carbonate.

[0153] The monofilament reinforcing yarn may also be a composite of a dispersed inorganic particulate phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass, and an absorbable 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 morpholinedione. Further, the monofilament reinforcing yarn may be a composite of a dispersed inorganic particulate phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass, and an absorbable polymer matrix of a crystalline segmented copolymer of polyethylene glycol and at least one cyclic monomer selected from the group consisting of L-lactide, epsilon-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepan-2-one, and morpholinedione.

[0154] In yet another optional embodiment, the present disclosure provides a bioabsorbable, disintegrable, multicomponent intraureteral stent constructed of a fiber-reinforced elastomeric film designed with at least one position-retaining edge. Here, 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 a copolymer is a triaxial copolymer made in two steps. The first step involves the formation of an amorphous or low-melting triaxial prepolymer using epsilon-caprolactone and / or trimethylene carbonate in the presence of trimethylolpropane and stannous octoate 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 making knitted or braided multifilament yarns, the copolymer being a crystalline copolymer made from polyethylene glycol and at least one cyclic monomer selected from the group consisting of 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 is made from glycolide and trimethylene carbonate to provide the yarn with a relatively fast degradation profile.

[0155] Thus, in one embodiment, the present invention provides an absorbable, disintegrable, multicomponent intraureteral stent constructed of a fiber-reinforced elastomeric film designed with at least one position-retaining edge, wherein 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 morpholinedione. 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 morpholinedione.

[0156] The present invention further provides an absorbable, disintegrable, multicomponent intraureteral stent that is constructed of a fiber-reinforced elastomeric film designed with at least one position-retaining edge, where the fiber reinforcement is a combination of monofilament coils and braided multifilament yarns, the monofilament yarns 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, morpholinedione, p-dioxanone, and 1,5-dioxapan-2-one. Alternatively, the monofilament reinforcing yarn is a composite of a dispersed inorganic particulate phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass, and an absorbable 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 morpholinedione. The monofilament reinforcing yarn may be a composite of a dispersed inorganic particulate phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass, and an absorbable 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 morpholinedione.

[0157] Accordingly, the present disclosure also provides optional embodiments of an absorbable, disintegrable, multicomponent intraureteral stent that is constructed of a fiber-reinforced elastomeric film designed with at least one position-retaining edge, wherein the fiber reinforcement is a combination of monofilament coils and braided multifilament yarns, and the braided multifilament reinforcing fibers 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, trimethylene carbonate, ε-caprolactone, glycolide, p-dioxanone, morpholinedione, and 1,5-dioxapan-2-one. Alternatively, the braided multifilament reinforcing 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-dioxepan-2-one, and morpholinedione.

[0158] In another embodiment, the present disclosure provides a stent constructed of a fiber-reinforced elastomeric film designed with at least one position-maintaining edge, where the fiber reinforcement is a tube of braided or weft-knitted monofilament yarn, the fiber-reinforced film is tubular, has a central main component smaller in diameter than the patient's ureter, and has at least one position-maintaining edge. The position-maintaining edge is a highly flexible extension of the central main component that, after insertion into the patient's ureter, assumes a loop shape with an open end parallel to the axis of the central main component, but which can be aligned with the central main component during insertion using an applicator. The film component of the assembled stent 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 morpholinedione. 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 and 1,5-dioxepan-2-one, and morpholinedione.

[0159] In another embodiment, the present disclosure provides a stent constructed of a fiber-reinforced elastomeric film designed with at least one position-retaining edge, 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, morpholinedione, p-dioxanone, and 1,5-dioxepan-2-one. Alternatively, the reinforcing braided or weft-knitted 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-dioxepan-2-one. The reinforcing braided or weft-knitted monofilament yarns are also composites of an inorganic particulate dispersed phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass, and an absorbable 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 morpholinedione. Additionally, the reinforcing braided or weft-knitted monofilament yarn may be a composite of an inorganic particulate dispersed phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass, and an absorbable 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 morpholinedione.

[0160] Optionally, the stent is a fiber-reinforced elastomeric film construction designed with at least one position-maintaining edge, where the fiber reinforcement is a weft- or weft-knit monofilament backbone from which the reinforcing structure is in the form of a tube including a central main component having a diameter smaller than that of the patient's ureter and at least one position-maintaining edge. The position-maintaining edge is an inverted cone with a series of diameters designed to provide cross sections progressively wider than that of the central main component, and is reversibly compressed to radially conform to the central main component upon application of a radial compression force during insertion into the urogenital tract using a tubular applicator. 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 morpholinedione. 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, and 1,5-dioxepan-2-one, and morpholinedione. The reinforcing weft knitted or braided monofilament yarn is optionally 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, morpholinedione, p-dioxanone, and 1,5-dioxepan-2-one. Alternatively, the reinforcing braided 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-dioxepan-2-one.

[0161] In another optional embodiment, the stent is a fiber-reinforced elastomeric film construction designed with at least one position-maintaining end, the fiber reinforcement being a weft-knitted or braided monofilament backbone from which the reinforcing structure is in the form of a tube including a central main component having a diameter smaller than that of the patient's ureter, and at least one position-maintaining end, the position-maintaining end being an inverted cone with a series of diameters designed to provide progressively wider cross sections than that of the central main tube, and which reversibly compresses to radially conform to the central main tube upon application of a radial compressive force during insertion into the urogenital tract using a tubular applicator. The reinforcing weft knit or braided monofilament is a composite of an inorganic particulate dispersed phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass, and an absorbable 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 morpholinedione. Alternatively, the reinforcing braided or weft-knitted monofilament yarn is a composite of an inorganic particulate dispersed phase of at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass, and an absorbable 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 morpholinedione.

[0162] In another embodiment, the present disclosure provides an absorbable, disintegrable, multicomponent intraureteral stent constructed of a fiber-reinforced elastomeric film designed with at least one position-maintaining end. The fiber reinforcement is a weft-knit monofilament yarn, and the reinforcing structure is 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-maintaining end. The position-maintaining end is a highly flexible extension of the central main component that, after insertion into the patient's ureter, assumes a loop shape with an open end parallel to the axis of the central main component, but can be made collinear with the central main component upon insertion using an applicator. The film is formed from a crystalline, segmented, elastomeric, high L-lactide copolymer, and the monofilament is formed from a segmented L-lactide copolymer with at least one cyclic monomer selected from the group consisting of glycolide, ε-caprolactone, and morpholinedione. The monofilament contains a particulate inorganic filler selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass.

[0163] In one embodiment, the medical device is a stent including a filament having a longitudinal axis and an oriented bioabsorbable polymer material, wherein polymer molecules within the bioabsorbable polymer material have a helical orientation aligned with the longitudinal axis of the filament, and wherein the stent is at least partially bioabsorbed by the patient upon implantation or insertion of the stent into a 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 includes a plurality of said filaments, optionally, the plurality of filaments is helically wound along at least a portion of the length of the stent, optionally, a plurality of said filaments is helically wound along a first direction and a plurality of said filaments is helically wound in an opposite direction; c) the filament is a braided filament; a plurality of said 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 comprises either a single bioabsorbable polymer or a blend of bioabsorbable polymers; f) the oriented bioabsorbable polymer material comprises a polymer selected from poly(alpha-hydroxy acid) homopolymers, poly(alpha-hydroxy acid) copolymers, and blends thereof; g) the oriented bioabsorbable polymer material comprises a polymer selected from polyglycolide, poly-L-lactide, poly-D-lactide, poly-DL-lactide, and blends thereof; h) the oriented bioabsorbable polymer material has a crystallinity in the range of 0.1 to 20%; i) the filaments comprise a core of 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 two days after implantation, or two to three weeks after implantation, or degrade after seven weeks at the implant site, or largely degrade after 90 days, or completely degrade after four months. Optionally, the medical device, e.g., a ureteral stent, remains intact for at least the first 48 hours after placement within the host. Preferably, the medical device can be reinstalled or removed from the host as a single unit within seven days after implantation. Approximately one week after implantation, the medical device may begin to generate HIVS fragments, although fragmentation may occur more or less quickly in some patients. Typically, HIVS fragments are formed between two and three weeks after implantation and are separated from the medical device, for example, by excretion if the medical device is a ureteral stent. Fragmentation may continue for several more weeks (e.g., between four and six weeks after implantation). Optionally, the majority of the medical implant is expelled from the patient by about 90 days (approximately 12 to 13 weeks) after placement. Portions of the medical device may remain within the host for up to about 120 days.

[0165] The present disclosure provides the following additional exemplary embodiments.

[0166] In one embodiment, the medical device is a biodegradable intraureteral stent. The stent includes a tubular elastomeric film and a tubular fiber reinforcement, the tubular elastomeric film being a single tube encasing the tubular fiber reinforcement. The stent optionally has at least one position-maintaining end. The device has a central main tube having a diameter smaller than the diameter of the patient's ureter, and the at least one position-maintaining end, if present, is an extension of the central main tube. The central main tube is a generally tubular structure including a sidewall surrounding a lumen and 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 includes a plurality of bands, each surrounding the longitudinal axis and having a distal side and a proximal side. The plurality of bands include relatively high in vivo stability bands separated from one another by relatively low in vivo stability bands. The stent is configured to be placed within a patient's ureter, extending from the patient's kidney to the bladder, and optionally held in place by at least one position-maintaining end. In one configuration, the film is reinforced and impregnated with a fiber reinforcement, which comprises a monofilament coil disposed on a knitted or braided tube of monofilament or multifilament yarns, which together form a sidewall surrounding the lumen of the generally tubular structure. The film and fiber reinforcement may each comprise an absorbable, crystalline, segmented copolymer comprising at least one cyclic monomer. The film and fiber reinforcement alone are capable of maintaining patency of the ureter.

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

[0168] As described above, the biodegradable intraureteral stent of the present disclosure includes multiple bands, each surrounding a longitudinal axis and having a distal side and a proximal side. The multiple bands include relatively high in vivo stability bands separated by relatively low in vivo stability bands. The generally tubular structure, also referred to as the central main duct, may be identified as: proximal end of duct-(LIVS-HIVS)n-LIVS-distal end of duct, or as proximal end of duct-(HIVS-LVS)n-HVS-distal end of duct. 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 comprises alternating bands of relatively high and relatively low in vivo stability.

[0169] The following options may also further define the intraureteral stent of the present disclosure: a) the stent has at least one position-maintaining end, which is a flexible extension of the central main canal and which, after insertion into the patient's ureter, is neck-like but can be collinear with the central main canal upon insertion using an applicator; b) the tubular elastomeric film is a tubular elastomeric film selected from the group consisting of polyethylene glycol and L-lactide, epsilon-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxapan-2-one, and morpholino. c) the tubular elastomeric film 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, and 1,5-dioxepan-2-one; d) the monofilament coil comprises a crystalline segmented copolymer of L-lactide and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, glycolide, morpholinedione, p-dioxanone, and 1,5-dioxepan-2-one. e) the monofilament coil comprises a composite comprising a polymer matrix and an inorganic particulate dispersed phase contained within the matrix, the matrix comprising a crystalline segmented copolymer, the inorganic particulate dispersed phase comprising at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass; f) the monofilament coil comprises a composite comprising a polymer matrix and an inorganic particulate dispersed phase contained within the matrix, the matrix comprising 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 dispersed phase comprising at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass;g) the monofilament coil comprises a composite including a polymer matrix and an inorganic particulate dispersed phase contained within the matrix, the matrix comprising 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; h) the fiber reinforcement comprises a monofilament coil and a multifilament and a braided tube of yarns, wherein optionally, 1) the tubular elastomeric film 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; 2) the tubular elastomeric film 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, and morpholinedione. 1,5-dioxepan-2-one, and morpholinedione; 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, morpholinedione, p-dioxanone, 1,5-dioxepan-2-one; 4) the monofilament coil comprises a composite including a polymer matrix and an inorganic particulate 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, epsilon-caprolactone, trimethylene carbonate, glycolide, p-dioxanone, 1,5-dioxepan-2-one, and morpholinedione, and the inorganic particulate dispersed phase comprises at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass;5) The monofilament coil comprises a composite including a polymer matrix and an inorganic particulate dispersed phase contained within the matrix, the matrix comprising 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 particulate dispersed phase comprises at least one cyclic monomer selected from the group consisting of barium sulfate, zirconium oxide, and absorbable 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 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-dioxepan-2-one, and morpholinedione. j) a monofilament coil disposed over a tube of weft-knitted monofilament yarn, wherein, optionally, 1) the tubular elastomeric film 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; 2) the tubular elastomeric film 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; 3) the monofilament yarn comprises a crystalline segmented copolymer of L-lactide and at least one cyclic monomer selected from the group consisting of L-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and 1,5-dioxepan-2-one, and morpholinedione; 3) 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, morpholinedione, p-dioxanone, and 1,5-dioxepan-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, morpholinedione, and 1,5-dioxapan-2-one; 5) the monofilament yarn comprises a composite including a polymer matrix and an inorganic particulate dispersed phase contained within the matrix, the matrix comprising 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 morpholinedione, and the inorganic particulate dispersed phase comprises at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass; and 6) the monofilament yarn comprises a composite including a polymer matrix and an inorganic particulate dispersed phase contained within the matrix, the matrix comprising 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 morpholinedione, and the inorganic particulate dispersed phase comprising at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass; a composite including a stent matrix and an inorganic particulate 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 morpholinedione, and the inorganic particulate dispersed phase comprises at least one material selected from the group consisting of barium sulfate, zirconium oxide, and absorbable phosphate glass; k) the stent is capable of remaining patent and at the application site for at least 2 days; l) the stent is capable of remaining patent and at the application site for 2 to 4 months; and m) at least one position-retaining end comprises at least 4% by weight of at least one powdered radio-opacifying agent selected from the group consisting of barium sulfate, zirconium oxide, and bismuth subcarbonate;

[0170] The following are some specific embodiments of the present disclosure: (1) 1. A bioabsorbable implantable medical device comprising a generally tubular structure having a sidewall and a lumen surrounded by the sidewall, the lumen having a longitudinal axis extending along the length of the lumen from a distal end to a proximal end of the structure, the tubular structure further comprising a plurality of bands, each band surrounding the longitudinal axis and having a distal side and a proximal side, the plurality of bands including bands of relatively high in vivo stability separated by bands of relatively low in vivo stability. (2) 2. The medical device of embodiment 1, wherein the structure has at least one, or exactly one, band of relatively high in vivo stability and at least two, or exactly two, bands of relatively low in vivo stability. (3) 2. The medical device of embodiment 1, wherein the structure has at least two, or exactly two, bands of relatively high in vivo stability and at least three, or exactly three, bands of relatively low in vivo stability. (4) 2. The medical device of embodiment 1, wherein the structure has at least three, or exactly three, bands of relatively high in vivo stability and at least four, or exactly four, bands of relatively low in vivo stability. (5) 2. The medical device of embodiment 1, wherein at least two bands of relatively high in vivo stability each have a length of 1 to 6 cm and are separated by one band of relatively low in vivo stability having a length of less than 1 cm. (6) 2. The medical device of embodiment 1, wherein at least two bands of relatively high in vivo stability each have a length of 2-6 cm and are separated by one band of relatively low in vivo stability having a length of less than 1 cm. (7) 2. The medical device of embodiment 1, wherein at least two bands of relatively high in vivo stability each have a length of 3-6 cm and are separated by one band of relatively low in vivo stability having a length of less than 1 cm. (8) 2. The medical device of embodiment 1, wherein at least three bands of relatively high in vivo stability each have a length of 3-6 cm and are separated by two bands of relatively low in vivo stability each having a length of less than 1 cm. (9) 2. The medical device of embodiment 1, wherein at least four bands of relatively high in vivo stability each have a length of 3-6 cm and are separated by three bands of relatively low in vivo stability each having a length of less than 1 cm. (10) 2. The medical device of embodiment 1, wherein at least three bands of relatively high in vivo stability each have a length of 2-5 cm and are separated by two bands of relatively low in vivo stability each having a length of less than 1 cm. (11) 2. The medical device of embodiment 1, wherein at least three bands of relatively high in vivo stability each have a length of 3-6 cm and are separated by two bands of relatively low in vivo stability each having a length of less than 1 cm. (12) 2. The medical device of embodiment 1, wherein the tubular structure comprises alternating bands of relatively high and relatively low in vivo stability. (13) 2. The medical device of embodiment 1, wherein the tubular structure comprises at least two bands of relatively high in vivo stability separated by one band of relatively low in vivo stability, and wherein the band of relatively low in vivo stability degrades in vivo at least twice as fast as the at least one band of relatively high in vivo stability. (14) 2. The medical device of embodiment 1, wherein the tubular structure comprises at least two bands of relatively high in vivo stability separated by one band of relatively low in vivo stability, and wherein the at least two bands of relatively high in vivo stability have substantially identical in vivo stability. (15) 2. The medical device of embodiment 1, wherein the tubular structure includes bands of relatively low in vivo stability on either side of one band of relatively high in vivo stability, the two bands of relatively low in vivo stability having different in vivo stabilities. (16) 2. The medical device of 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, and the first relatively low in vivo stability band has higher in vivo stability than the second relatively in vivo stability band. (17) 2. The medical device of embodiment 1, wherein the tubular structure comprises a plurality of bands having substantially identical, relatively high in vivo stability. (18) A medical device as described in embodiment 1, wherein the tubular structure includes a plurality of bands of relatively low in vivo stability separated by bands of relatively high in vivo stability 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) 2. The medical device of embodiment 1, wherein the tubular structure is or comprises a mesh tube. (20) 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) 21. A medical device as described in any one of embodiments 1 to 20, wherein the side wall comprises a monofilament coil surrounding the lumen, a mesh covering the monofilament coil, and a coating deposited on the coil and the mesh. (twenty two) 22. The medical device of any of embodiments 1-21, further comprising a kidney-retaining structure at the proximal end of the device and a bladder-retaining structure at the distal end of the device. (twenty three) 23. The medical device of any one of embodiments 1 to 22, further comprising a curled kidney-retaining structure at a proximal end of the device, and a curled bladder-retaining structure at a distal end of the device. (twenty four) 24. The medical device according to any one of embodiments 1 to 23, which is a ureteral stent. (twenty five) 25. The medical device of any one of embodiments 1-24, comprising a coating on an exterior surface of the device, the coating having an average thickness. (26) 26. A medical device as described in any one of embodiments 1 to 25, comprising a coating on an exterior surface of the device, the coating having a non-uniform thickness throughout the device. (27) 27. A medical device according to any one of embodiments 1 to 26, comprising a coating on the outer surface of the device, the proximal end of the device comprising more coating than the distal end of the device. (28) A medical device described in any of embodiments 1 to 27, wherein the device is a ureteral stent having a kidney retention structure at a proximal end of the device and a bladder retention structure at a distal end of the device, and includes a coating on an outer surface of the device, and the proximal end of the device includes more coating than the distal end of the device. (29) 29. The medical device of any of embodiments 1-28, which does not include a containment layer that restricts movement of HIVS bands that detach from the medical device during in vivo degradation. (30) a. A method of making a medical device, comprising: providing a bioabsorbable medical device comprising a generally tubular structure having a lumen within a sidewall of the generally tubular structure and passing through a center of the generally tubular structure; b. exposing a band of generally tubular structures to an ex vivo degradation environment to generate a band of low in vivo stability (LIVS) from the exposed band, and not exposing a band of generally tubular structures adjacent to the exposed band of generally tubular structures to a similar degradation environment to generate a band of high in vivo stability (HIVS) adjacent to the LIVS band; A method comprising: (31) 31. A medical device made by a method comprising the method of embodiment 30. (32) 32. The medical device of embodiment 31, wherein the generally tubular structure comprises polyester.

[0171] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Further, it is to be understood that, unless specifically defined herein, terms used herein are to be given their traditional meanings known in the relevant art.

[0172] References throughout this specification to "one embodiment" or "an embodiment" and variations thereof mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Any of the medical device embodiments disclosed herein may include a drug, e.g., a therapeutic or prophylactic agent, as part of the medical device.

[0173] As used within this specification, including the claims, the singular forms "a," "an," and "the" include plural references, i.e., one or more, unless the content and context dictate otherwise. It should also be noted that "and" and "or" are generally used in their broadest sense to include "and / or," unless the content and context dictate otherwise, as the case may be, inclusiveness or exclusiveness. Thus, the use of an alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. Furthermore, the "and" or "or" configuration, when described herein as "and / or," is intended to encompass embodiments including all of the associated items or ideas, as well as one or more other alternative embodiments that do not include all of the associated items or ideas.

[0174] Unless the context dictates otherwise, throughout the specification and the appended claims, the word "comprises" and its cognates and variations, such as "having" and "comprising," as well as variations thereof (e.g., "having"), are to be interpreted in an open and inclusive sense, such as "including but not limited to...." The term "consisting essentially of" limits the scope of a claim to particular materials or steps, or those that do not materially affect the basic and novel characteristics of the claimed invention.

[0175] The headings used herein are for the reader's convenience only and should not be construed as limiting the scope of the invention or the claims in any way. Accordingly, the headings and abstracts of the disclosure provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

[0176] In the description, certain specific details are set forth to provide a thorough understanding of the various disclosed embodiments. However, one skilled in the art will recognize that the embodiments may be practiced without one or more of these specific details, or with other methods, components, materials, etc. [Example]

[0177] The examples and preparations provided below further describe 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 scope of the following examples and preparations. Indeed, unless the context dictates otherwise, when a specific polymer is used in the examples, this polymer is merely exemplary and may be substituted with alternative polymers in accordance with the present invention. Also, when degradation times and properties are exemplified, it should be understood that these values ​​are approximate and that other values ​​may be obtained using different starting materials. The starting materials and various reactants utilized or referenced in the examples can be obtained from commercial sources or are readily prepared from commercially available organic compounds using methods well known to those skilled in the art. Accordingly, the following examples are illustrative of embodiments of the present invention and should not be construed as limitations thereon.

[0178] [Example 1] [Making the coil] A 1-liter stainless steel kettle with a three-neck glass lid equipped with an overhead mechanical stirrer unit, a vacuum adapter, and a nitrogen inlet was assembled. The kettle was evacuated to approximately 0.5 mmHg pressure and then purged with nitrogen. 9.15 g of paxTMC-1, which had been 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 15:1 TMC:TMP molar ratio in the presence of a tin catalyst, stannous octoate, with 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 microparticles 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 temperature of the oil bath 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 solution of stannous octoate in toluene (2.576 mL, 5.152 × 10 -4mol of stannous octoate was added. The temperature of the oil bath was raised to 180°C and stirring was continued as long as possible. After stirring became impossible (due to high viscosity), the reaction mixture was maintained at 180°C for 7 hours.

[0179] The kettle was removed from the oil bath and allowed to cool to room temperature. The kettle was then placed in a cold bath to solidify the polymer. The solid polymer was removed from the kettle and crushed. The crushed 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. A vacuum was applied, achieving a vacuum of 0.25 mmHg, and the flask was then immersed in an oil bath. The temperature of the oil bath was increased to 40°C. After 2 hours at 40°C, the temperature of the oil bath was increased to 80°C. After 1 hour at 80°C, the temperature of the oil bath was increased to 110°C. The temperature of the oil bath 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 four-zone single-screw extruder. A 325 line / inch filter pack 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 / spin pack at 210°C. The metering pump was operated at 8 rpm while the take-up roll was set at 40-60 rpm. The polymer from Example 1 was extruded using a 0.4 mm die. The collected monofilament diameter was 0.48 mm to 0.54 mm. The fiber was stretched 4.5x at 55°C in the first stage and 0.5x at 70°C in the second stage, resulting in monofilaments with diameters of 0.25 mm to 0.30 mm. The free shrinkage was approximately 8.85% to 10.43% at 50°C. The fiber relaxed to one-half the free shrinkage plus 2% at 70°C. The resulting fibers had a maximum load of approximately 10-13 N and were dimensionally stable.

[0181] [Example 3] [Production of Coiled Skeleton (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 33-35 coils per inch to provide a coiled scaffold (CS), an exemplary generally tubular structure of the present disclosure.

[0182] [Example 4] Synthesis and characterization of triaxially segmented glycolide copolymers for use in the fabrication of knitted scaffolds. A reaction apparatus was assembled with a 1-liter stainless steel kettle with a three-neck glass lid equipped with an overhead mechanical stirrer unit, a vacuum adapter, and a nitrogen inlet. The reactor was evacuated. After a vacuum of 0.5 mm Hg was obtained, the apparatus was purged with nitrogen. An initial charge 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) was 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 completely dissolved in the molten monomer, a solution of stannous octoate (0.966 ml of a 0.2 M toluene solution of stannous octoate, 1.933 x 10 -4 (mol) was added to the reaction mixture. The temperature of the oil bath was increased to 180°C. The reaction mixture was stirred until the mixture became too viscous to stir. The reaction was maintained at 180°C for an additional 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 crushed into a powder. The crushed material was sieved. The sieved polymer was transferred to a 2-liter pear-shaped glass flask and placed in a Büchi rotavap. A vacuum was applied, and after achieving a vacuum of 0.5 mmHg, the flask was immersed in an oil bath. The temperature of the oil bath was increased to 40°C. After 2 hours at 40°C, the temperature of the oil bath was increased to 80°C. After 1 hour at 80°C, the temperature of the oil bath was increased to 110°C. The temperature of the oil bath was maintained at 110°C for 4 hours. The vacuum was released, and the material was removed from the flask.

[0183] [Example 5] [Melt spinning and properties of multifilament yarn using the polymer of Example 4] The polymer from Example 4 was extruded into multifilaments using a five-zone single-screw extruder. A 400 line / 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 / spin pack at 228°C. A 0.584 cc / rev Zenith metering pump was operated at 6.0 rpm while the denier control roll was set at a linear speed of 315 meters / min. The fibers were then oriented onto three high-speed godets traveling at 200 m / min, 480 m / min, and 480 m / min, heated to 45°C, 80°C, and 26°C, respectively. The polymer from Example 4 was extruded using a 20-hole die with 0.018-inch diameter holes. The collected multifilaments were then reoriented at a speed of 250 M / min to 280 M / min at a temperature of 100° C. The resulting fibers had a tenacity of about 3.26 and a denier of about 80.4.

[0184] [Example 6] [Fabrication of knit skeleton (KS)] The 20 filament yarn from Example 5 was twisted once to form a 40 filament yarn. This multifilament yarn was continuously weft knitted onto the coiled scaffold of Example 3 using a Ram circular knitting machine. A 7 / 8 inch knitting cylinder with 12 course gauge needles was used to form a knitted scaffold over the coiled scaffold. The resulting structure is an exemplary generally tubular structure of the present disclosure.

[0185] [Example 7] [Synthesis and Characterization of Triaxially Segmented L-Lactide Copolymer (P1)] A reaction apparatus was assembled containing a 4-liter stainless steel reactor with an overhead mechanical stirrer unit, a vacuum adapter, and a nitrogen inlet. A vacuum was applied to the reactor, and after a vacuum of less than 0.5 mmHg was obtained, the apparatus was purged with nitrogen. The reaction temperature was controlled by circulating oil through the jacketed reactor. Glycolide (254.9 g, 2.1976 mol), trimethylene carbonate (348.7 g, 3.4185 mol), pre-dried triethanolamine (3.0319 g, 2.0348 x 10 mol), and ethanolamine (3.0319 g, 2.0348 x 10 mol) were added. -2 mol), stannous octoate (354.5 mg, 8.752 × 10 -4 An initial charge of glycolide (226.6 g, 1.9534 mol) and ε-caprolactone (974.3 g, 8.5463 mol) was 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 increased to 175 °C, and the contents were thoroughly mixed for 6.5 hours. The temperature was then reduced to allow for the addition of a final charge of glycolide (226.6 g, 1.9534 mol) and L-lactide (1195.5 g, 8.3021 mol). The oil temperature was then increased to 135 °C and maintained for 19 hours. The resulting polymer was removed from the vessel and dissolved at a concentration of 1 g per 4 mL of dichloromethane (DCM). The polymer was precipitated by slowly adding this polymer / DCM solution to a sufficient amount of cold isopropyl alcohol with mechanical stirring. The precipitated polymer was isolated by vacuum filtration. The filtered polymer was then added to a sufficient amount of cold isopropyl alcohol with mechanical stirring. The polymer was then isolated by vacuum filtration. Once the majority of the solvent was removed, the polymer was dried under vacuum to a constant weight.

[0186] [Example 8] [Assembly of the 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 bottle was sealed with a lid. The bottle was placed on a rolling mill-like device to continuously rotate the bottle. The solution was rolled until the PEG4600 and P1 were completely dissolved in the acetone.

[0187] The dried knit scaffold from Example 6 was impregnated with the above PEG4600 / P1 polymer solution using a continuous impregnation process involving continuous movement of the knit core material through a 0.75 liter bath of polymer solution. The scaffold was removed from the spool and fed into a bath of coating solution, where two in-line submerged pulleys kept the scaffold material submerged for the length of the bath. As 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, after which the impregnated material was spooled onto a final take-up spool. This coating process was repeated to provide a thicker coating of PEG4600 / P1 coating on the scaffold.

[0188] The impregnated knitted scaffold was wound onto a rack equipped with two parallel 0.5-inch diameter stainless steel bars, the separation distance of which could be adjusted to control the final stent length. The newly impregnated knitted scaffold was wound continuously 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 scaffolding material at the appropriate locations along the interior of the separating rods of the shape-forming rack. These stents still contained a Teflon core, but were modified by adding a UVJ marker 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 using an MTS Synergie (Models 100 and 200) test instrument, mechanically dipping the proximal end of the stent into the coating solution in a controlled manner using multiple cycles. The distal end of the stent was mounted in a vertical fixture on the MTS test instrument. The MTS test instrument 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 mark and then immediately lifted the stent from the cylinder. The MTS instrument held the stent above the coating solution for a sufficient time (approximately 30-300 seconds) to allow the coating to dry to a non-tacky state. The above immersion procedure was repeated, except the stent was lowered to the 40 mL mark. 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 a gradient outer coating layer, 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 so that it would not prematurely degrade.

[0191] The stents were dried by hanging the distal loop in a laminar flow hood. The Teflon™ PTFE core was removed from each stent by clamping one end of the Teflon core in a fixed-position vise-grip pliers and stretching the opposite end of the Teflon using a second set of vise-grip pliers. A clean slit was made in the stretched Teflon core at the fixed end, and the reduced-diameter Teflon core was then pulled through the stent and discarded. Each stent was then trimmed to the appropriate specifications.

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

[0193] This process was performed by preparing bands of low in vivo stability by treating the stents with basic solutions having NaOH concentrations of either 0.5 M, 0.75 M, 1.0 M, 1.25 M, or 3.0 M. Each stent was treated with only one of these base concentrations.

[0194] [Example 10] [Create multibands using base processing] Placing the stent between two 5 mm x 5 mm sponge pieces created bands with lower in vivo stability compared to the adjacent untreated portion of the stent. The sponges were clipped together to maintain circumferential contact between the sponges and the stent around the stent. A second set of sponges was attached to the stent in a similar manner, with a distance of approximately 4 cm 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 with these sponge sets touching 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. Bands of lower in vivo stability (LIVS) were created where each sponge set had been placed. This resulted in one LIVS band between the two LIVS bands.

[0195] This process was performed by preparing a band of low in vivo stability on each stent by treating the stent with a basic solution having an NaOH concentration of either 0.5 M, 0.75 M, 1.0 M, 1.25 M, or 3.0 M. That is, each stent was treated with either 0.5 M NaOH, 0.75 M NaOH, etc. in each sponge set.

[0196] [Example 11] [Generating multibands using base processing - generating gradients] By placing the stent between two 5 mm x 5 mm sponge pieces, a gradient of bands with progressively decreased in vivo stability compared to the adjacent untreated section of the stent was created. The sponges were clipped together to maintain circumferential contact between the sponges and the stent around the stent. The second, third, and fourth sponge sets were attached to the stent in a similar manner, with the distance between the edge of one sponge band and the edge of the sponge of the next closest band being approximately 4 cm. Next, approximately 1 mL of 0.5 M NaOH solution was pipetted onto each sponge in the set of sponges closest to the kidney-retaining portion of the stent. Next, approximately 1 mL of 0.75 M NaOH solution was pipetted onto each sponge in the second sponge set from the kidney-retaining portion of the stent. Next, approximately 1 mL of 1.0 M NaOH solution was pipetted onto each sponge in the third sponge set from the kidney-retaining portion of the stent. Next, approximately 1 mL of 1.25 M NaOH solution was pipetted onto each sponge in the fourth sponge set from the kidney-retaining portion of the stent. The stent was then left for 1 hour. The sponge was then removed and the stent was rinsed with deionized water for 15 seconds. The stent was then dried under vacuum.

[0197] [Example 12] [Band generation using UV light] The stent was placed in a holder that maintained the renal curl and had attachment points for insertion into a drill chuck. The holder was then inserted into the drill chuck, and the chuck was tightened to hold the stent. The body of the stent was then placed into a stainless steel stent band guide. The first band on the guide was 8 cm from the renal curl. A 5 mm UV spotlight was then applied to the guide hole 0.8 mm from the surface of the stent. The guide exposed a 5 mm section of the stent to the UV light. The motor attached to the drill chuck was turned on, rotating the stent at 20 RPM. The UV unit was then turned on for a specific time period to irradiate the first band with UV light. The light intensity was approximately 6 W / cm. 2 The exposure time varied from 3 to 18 seconds. This process was then repeated for each band along the length of the stent. The bands were spaced 4 cm apart, with an 8 cm "tail" at the renal end of the stent. For a 24 cm stent, four UV-treated (LIVS) bands were generated on the stent, and for a 30 cm long stent, five UV-treated (LIVS) bands were generated.

[0198] [Example 13] [Buckling test of treated stents] A buckling test was used to determine the effect of the band generation process on the mechanical properties of the treated stents. A 4 cm long stent, including the treated region, was used for the buckling test. The treated region was approximately the center of the sample (approximately 2 cm from either end). Two blocks, each with a short cylinder (approximately 0.5 cm high) attached to the center of the block, were mounted on an MTS instrument (force and motion measurement, models: MTS Synergie 100 and MTS Synergie 200). One block was attached to the base and the other to 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, compressing 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 treatment site. The force required to buckle data is shown in Table 1 and Figure 8. The control sample was not treated to generate LIVS bands.

[0199] [Table 1]

[0200] [Example 14] [Deflection test of processed stents] A flexure test was used to determine the effect of the LIVS band on the strength of the banded stent. A 4-cm-long stent segment was used for this test. The stent segment was mounted in a custom stainless steel fixture. This fixture consisted of two blocks with guide pins that held the two halves together securely. The top and bottom of the block had semicircular grooves machined into them, so that when the two halves were assembled, they formed a continuous cylinder. The stent was placed in the bottom groove, and the top half was placed on top of the stent, holding it firmly but not crushing it. The sample segment was positioned with the treatment site at the edge of the block, allowing it to bend at the treatment site. In effect, there was a 2-cm stent segment cantilevered out from the block. This block was placed in the base of an MTS instrument (force and motion measurement, models: MTS Synergie 100 and MTS Synergie 200), and the top of the three-point bending test fixture was attached to a load cell. The top half of the three-point bending fixture was then used to press down on the portion of the stent protruding from the block, and the force required to "deflect" the stent was measured. The data obtained for the various treatments used to produce the bands 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±1.0 g urea, 18.0±0.4 g NaCl, 5.0±0.1 g NaHPO, 15.0±0.3 g KHPO, 10.0±0.2 g NHCl, 3.0±0.1 g NaSO, 4.0±0.1 g creatinine, and 2 L of deionized water.

[0203] To determine the effect of each treatment intensity on the mechanical integrity of the stent, the stents were tested at the LIVS band site. Testing of base-treated samples was performed after 0 and 7 days of in vitro incubation in artificial urine pH 5.5-6.5 at 37°C. Testing of UV-treated samples was performed on stent samples after aging in artificial urine pH 8 for 5 days. For tensile strength testing, 5 cm sections of the stents were used as test specimens. Using vise-type grips, the samples were mounted in an MTS (Models: MTS Synergie 100 and MTS Synergie 200). 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 testing of fragmentation patterns Stents with LIVS and HIVS band sections were 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 at 37°C. Stent samples were placed in the simulated use model, and synthetic urine was continuously circulated through the system. The synthetic urine was changed weekly. The stents were observed over time to determine their degradation / fragmentation and migration behavior, as well as whether transient incontinence occurred during urination. The endpoint of this study was defined as complete expulsion of the stent.

[0205] For base-treated stents, no incontinence events were observed for all final base-treated stents (gradient application of 0.5M, 0.75M, 1.0M, and 1.25M NaOH treatments), confirming the weight distribution target that allowed relaxation of renal curl and desired movement into the bladder. All final stents exhibited fragmentation at the treatment site, which allowed for evacuation without incontinence, and final base-treated stent renal curl progressed into the bladder by 28–35 days.

[0206] No incontinence events were observed for UV-treated stents. An incontinence event was classified as when the stent or stent fragment became lodged in the hydrogel urethra.

[0207] [Example 17] [Stent packaging] In a nearly or completely dust-free environment, the stents were placed in a PET thermoform tray. The thermoform 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 under vacuum 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 preheated vacuum oven at 40±2°C. The oven was then closed and evacuated (<5 Torr). The stent remained under vacuum in the oven for at least 24 hours. The vacuum oven was then backflushed 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 with a nitrogen atmosphere using a vacuum / nitrogen purge cycle. A label was then affixed to the exterior of the foil pouch. The foil pouch was then sterilized with gamma radiation at 24-40 kGy.

[0208] [Example 18] [Packaging of stents with pushers] In a nearly or completely dust-free environment, the stents were placed in a PET thermoform tray. The thermoform 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 under vacuum 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 preheated vacuum oven at 40±2°C. The oven was then closed, and a vacuum (less than 5 Torr) was applied to the oven. The stent remained under vacuum in the oven for at least 24 hours. The vacuum oven was then backflushed with dry nitrogen. The stent / pusher within the foil pouch was removed from the vacuum oven. The foil pouch was then heat-sealed. For one set of samples, a nitrogen atmosphere was used to cover the stent. A label was then applied to the exterior of the foil pouch. The foil pouches were then sterilized with gamma radiation at 24-40 kGy.

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

[0210] Where a range of numerical values ​​is provided herein, unless the context clearly dictates otherwise, each intervening value (to the tenth of the unit of the lower limit) between the upper and lower limit of that range and any other stated value, as well as any other stated or intervening value within that stated range, is understood to be included within the invention. The upper and lower limits of these smaller ranges, which may be independently included in smaller ranges, are also included within the invention, subject to any specific excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0211] For example, any concentration range, percentage range, ratio range, or integer range provided herein should be understood to include any integer value within the recited range, and fractions thereof (e.g., tenths and hundredths of integers), where appropriate, unless otherwise indicated. Also, any numerical range recited herein relating to any physical characteristic, such as polymer subunits, size, or thickness, should be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term "about" means ±20% of the indicated range, value, or structure, unless otherwise indicated.

[0212] All publications and patents cited herein are incorporated by reference in their entirety for the purpose of describing and disclosing, for example, the materials and methodology described in the publications, which might be used in connection with the invention(s) of the present disclosure. This application incorporates by reference the disclosure of International Application No. PCT / US17 / 39130. The publications discussed above and throughout the text are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the inventors are not entitled to antedate the referenced publications by virtue of prior invention.

Claims

1. 1. A bioabsorbable implantable medical device comprising a generally tubular structure, the medical device is a ureteral stent; the generally tubular structure comprises a monofilament in the form of a coil, the coil comprising a sidewall, the sidewall enclosing a lumen, the lumen having a longitudinal axis extending along the length of the lumen from the distal end to the proximal end of the structure; the monofilament coil consisting essentially of bioabsorbable polyester; the tubular structure further includes a plurality of bands, each band surrounding the longitudinal axis and having a distal side and a proximal side; the plurality of bands comprises a plurality of relatively high in vivo stability bands separated by a plurality of relatively low in vivo stability bands, the plurality of relatively low in vivo stability bands undergoing gradient degradation in a degradation environment; Medical devices.

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

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

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

5. 2. The medical device of claim 1, wherein the tubular structure comprises at least two bands of relatively high in vivo stability separated by one band of relatively low in vivo stability, the band of relatively low in vivo stability degrading in vivo at least twice as fast as the at least one band of relatively high in vivo stability.

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

7. 10. The medical device of claim 1, wherein the tubular structure includes bands of relatively low in vivo stability on either side of a band of relatively high in vivo stability, the two bands of relatively low in vivo stability having different in vivo stabilities.

8. 2. The medical device of 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 a higher in vivo stability than the second relatively low in vivo stability band.

9. The medical device of claim 1 , wherein the tubular structure includes a plurality of high in vivo stability bands having substantially the same relatively high in vivo stability.

10. 2. The medical device of claim 1, wherein the tubular structure includes a plurality of bands of relatively low in vivo stability separated by bands of relatively high in vivo stability 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.

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

12. The medical device of claim 1 , wherein the sidewall comprises a mesh covering the monofilament coil and a coating deposited on the coil and the mesh.

13. 10. The medical device of claim 1, further comprising a kidney-retaining structure at a proximal end of the device and a bladder-retaining structure at a distal end of the device, the kidney-retaining structure being in a curled configuration at the proximal end of the device and the bladder-retaining structure being in a curled configuration at the distal end of the device.

14. 10. The medical device of claim 1, comprising a coating on an exterior surface of the device, wherein the coating satisfies any of the following: a) the coating has an average thickness; b) the coating has a non-uniform thickness across the device; c) the proximal end of the device includes more coating than the distal end of the device;

15. 10. The medical device of claim 1, wherein the device is a ureteral stent having a kidney retention structure at a proximal end of the device and a bladder retention structure at a distal end of the device, and includes a coating on an outer surface of the device, the proximal end of the device including more coating than the distal end of the device.

16. The medical device of any of claims 1 to 15, which does not include a containment layer that restricts movement of a high in vivo stability band that separates from the medical device during in vivo degradation.

17. A method for making a ureteral stent, comprising: providing a bioabsorbable ureteral stent comprising a generally tubular structure; and exposing a band of generally tubular structures to an ex vivo degradation environment to generate a plurality of low in vivo stability (LIVS) bands from the exposed band, and not exposing bands of generally tubular structures adjacent to the exposed band to a similar degradation environment to generate a plurality of high in vivo stability (HIVS) bands adjacent to the plurality of LIVS bands; Including, the generally tubular structure comprises a monofilament in the form of a coil, the coil comprising a sidewall, the sidewall enclosing a lumen, the lumen having a longitudinal axis extending along the length of the lumen from the distal end to the proximal end of the structure; the monofilament coil consisting essentially of bioabsorbable polyester; The method wherein the plurality of LIVS bands are subjected to gradient degradation in a degradation environment.

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