JP7642532B2 - Polymer tubes with controlled orientation - Google Patents

Description

This application relates to polymer tubes with specific molecular orientation that are used in a variety of fields.

Polymer tubes are widely used for many applications. In particular, bioabsorbable polymer tubes can be designed for implantation within the body (e.g., intravascular and intraarterial) to function as a scaffolding to replace traditional metal stents. Some bioabsorbable polymer tubes are used as nerve guide tubes and/or as placeholders within the body for regeneration of nerve tissue. Other bioabsorbable polymer tubes can be designed as drainage tubes to evacuate fluids and/or gases from body cavities or wounds, for example to promote healing. Advantageously, bioabsorbable polymer tubes are made of biodegradable polymer(s), which can dissolve or be absorbed by the body over time, eliminating the need to surgically remove the tube after use.

Biodegradable polymer tubes generally include one or more biodegradable polymers, including, but not limited to, poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(D,L-lactide) (PDLLA), poly(ε-caprolactone) (PCL), polyglycolic acid (PGA), poly(para-dioxanone) (PDO), poly(trimethylene carbonate) (PTMC), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethyl carbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and copolymers, blends, and derivatives thereof. The choice of polymer(s) for producing the bioabsorbable polymer tube can affect both the biocompatibility/toxicity properties of the resulting tube and the physical/mechanical properties of the resulting tube, such as degradation rate, strength (e.g., radial strength), and recoil rate.

One common means of producing such polymer tubes (and particularly single layer thick wall polymer tubes) includes extrusion and annular expansion processes. Using such methods, a polymer is extruded into a tubular shape and the resulting tubular shape is concentrically stretched/expanded to produce a polymer tube. The molecular orientation within the polymer tube wall obtained by concentric expansion is generally advantageous as it provides increased strength and/or heat shrink properties. However, known extrusion and annular expansion processes are inherently limited in the degree of molecular orientation possible throughout the wall thickness of the polymer tube. Furthermore, due to the tubular structure, a gradient of molecular orientation may exist throughout the wall thickness since the inner diameter of the tube generally undergoes greater stretching/molecular orientation than the outer diameter of the tube due to concentric expansion. It would therefore be beneficial to provide a method of controlling molecular orientation within a polymer tube wall and to provide a polymer tube having walls that exhibit such controlled molecular orientation.

The present invention generally relates to methods of making polymer tubes, and polymer tubes made by such methods. Polymer tubes used, for example in biomedical applications, are typically expanded/stretched in some manner to induce molecular orientation within the tube wall, resulting in increased strength (e.g., resistance to radial compression). The novel methods disclosed herein, which include making a polymer tube and molecularly orienting the polymer therein to obtain an oriented polymer tube, advantageously use a planar stretching process and/or a multilayer concentric expansion process. As disclosed herein, by modifying the process of molecular orientation within the polymer tube (relative to the typical extrusion/concentric expansion method of obtaining such oriented polymer tubes), tubes may be provided that exhibit modified crystallinity characteristics and, in some embodiments, corresponding enhanced strength (e.g., enhanced resistance to radial compression) and/or controlled heat shrink properties.

In one aspect, the present disclosure provides a method of making an oriented polymer tube, the method comprising: subjecting a polymeric material having a first dimension, the polymeric material including a crystallizable biodegradable polymer, to planar stretching to increase the first dimension to obtain an oriented polymeric material exhibiting at least partial molecular orientation; and forming the oriented polymeric material and the adhesive polymeric material into a tubular shape, which may also be referred to as a tube or an oriented polymeric tube. As an example, the adhesive polymeric material bonds adjacent layers of the oriented polymeric material to themselves or to other layers within the tubular shape. The polymeric material may be a polymeric film in some embodiments, and may be a polymeric profile in some embodiments.

In certain embodiments, the polymeric material has a second dimension, and the step of subjecting to planar stretching further comprises stretching the polymeric material to increase the second dimension to obtain a biaxially oriented polymeric material. The adhesive polymeric material may be associated with a crystallizable biodegradable polymer at various stages of the disclosed method. For example, in one embodiment, the method further comprises compounding the adhesive polymeric material with a crystallizable biodegradable polymer prior to the step of subjecting to planar stretching to obtain a polymeric material that is a composite polymeric material having a crystallizable biodegradable polymer and an adhesive polymeric material in a layered form. In another embodiment, the method further comprises compounding the adhesive polymeric material with a stretched polymeric material prior to the forming step.

The forming step, in certain embodiments, includes wrapping the polymeric material and the adhesive polymeric material around a cylindrical shape. In some embodiments, such wrapping includes wrapping the polymeric material and the adhesive polymeric material multiple times around the cylindrical shape to obtain a tube that includes multiple layers of the stretched polymeric material and multiple layers of the adhesive polymeric material. The cylindrical shape can vary and can be, for example, a mandrel. The method further includes removing the tube from the mandrel. In some embodiments, the cylindrical shape includes a device.

In another aspect, the present disclosure provides a method of producing an oriented polymer tube, the method comprising obtaining at least two polymer tubes, each polymer tube comprising a crystallizable biodegradable polymer, concentrically expanding the at least two polymer tubes to produce at least two oriented polymer tubes, and compounding the at least two oriented polymer tubes and one or more adhesive polymer materials into a multi-layer tubular article. In some embodiments, the concentrically expanding step occurs before the compounding step. In some embodiments, the compounding step occurs before the concentrically expanding step, and in some embodiments, the compounding step occurs during the concentrically expanding step (i.e., the at least two oriented polymer tubes and the adhesive polymer materials are compounded during the concentrically expanding of the at least two polymer tubes).

The method, in some embodiments, may further include compounding the adhesive polymeric material with one or more of the at least two polymer tubes prior to the concentric expansion step to obtain one or more polymer tubes that are composite polymer tubes having a crystallizable biodegradable polymer and an adhesive polymeric material in a layered form. The method, in some embodiments, may further include compounding the adhesive polymeric material with one or more of the at least two polymer tubes (before or after the concentric expansion step) to obtain one or more polymer tubes that are composite polymer tubes having a crystallizable biodegradable polymer and an adhesive polymeric material in a layered form. In certain embodiments, the aforementioned method, described in more detail herein below, further includes fusing the multi-layer tubular shape by applying heat, pressure, or both heat and pressure to the multi-layer tubular shape. The pressure may be either positive or negative, including, for example, drawing a vacuum (such as by applying a vacuum through a perforated mandrel) to form the tube. The fusing step may include, for example, applying a shrink tube or shrink film around the tubular shape to obtain a layered structure, followed by applying heat, pressure, or both heat and pressure to the tubular shape/layered structure. The composition of the shrink tube or shrink film may vary and may include, for example, one or more materials selected from the group consisting of fluoropolymers (e.g., poly(tetrafluoroethylene)), polyolefins (e.g., low density polyethylene (LLDPE)), polyurethanes, and/or silicone polymers (e.g., polydimethylsiloxane, PDMS), and combinations thereof.

In the context of any of the methods disclosed herein, in certain embodiments, the crystallizable biodegradable polymer is selected from the group consisting of poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(ε-caprolactone) (PCL), polyglycolic acid (PGA), poly(para-dioxanone) (PDO), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethylcarbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and copolymers, blends and derivatives thereof. The adhesive polymeric material may, for example, be selected from the group consisting of poly(ε-caprolactone), poly(trimethylene carbonate), poly(D,L-lactide) (PDLLA), poly(L-lactide-co-ε-caprolactone), poly(L-lactide-co-trimethylene carbonate), poly(ε-caprolactone-co-trimethylene carbonate), poly(ethylene glycol), poly(L-lactide-co-poly(ethylene glycol)), and copolymers and derivatives and combinations thereof. It should be noted that this list is not intended to be exhaustive, i.e., the same polymer(s) may be present as both the crystallizable biodegradable polymer and the adhesive polymer within a given product, which may differ in terms of molecular orientation (e.g., a polymer may have greater molecular orientation as the crystallizable biodegradable polymer component and less molecular orientation as the adhesive polymer component). Thus, the present disclosure encompasses, in certain embodiments, methods and products in which the crystallizable biodegradable polymer and the adhesive polymeric material comprise differently oriented (e.g., different amounts of orientation) of the same polymer.

The present disclosure further provides an oriented polymer tube made according to any of the methods disclosed herein. Some such oriented polymer tubes comprise primarily a crystallizable biodegradable polymer with a minimal amount of adhesive polymeric material. In some embodiments, such oriented polymer tubes are characterized by a substantially consistent molecular orientation of the crystallizable biodegradable polymer throughout the wall of the oriented polymer tube.

A further aspect provides a method of producing an oriented polymer tube, the method including: determining a desired shape and molecular orientation profile for the oriented polymer tube; selecting one or more polymer tube precursors comprising a crystallizable biodegradable polymer; disposing the one or more polymer tube precursors; and forming the one or more polymer tube precursors into an oriented polymer tube exhibiting a desired final tube shape and molecular orientation profile. The shape and molecular orientation profile may be determined based on, for example, one or more of (i) desired mechanical properties of the oriented polymer tube to be formed, (ii) desired thermodynamic properties of the oriented polymer tube to be formed, and (iii) desired chemical properties of the oriented polymer tube to be formed.

In some embodiments, at least one of the one or more polymer precursors is selected based at least in part on (i) the composition of the one or more polymer precursors, (ii) the shape of the one or more polymer precursors, (iii) the mechanical properties of the one or more polymer precursors, (iv) the thermodynamic properties of the one or more polymer precursors, (v) the chemical properties of the one or more polymer precursors, (vi) the degree of molecular orientation of the one or more polymer precursors, (vii) the molecular orientation profile about one or more axes of the one or more polymer precursors, (viii) the intended method of forming the final polymer tube from the one or more polymer precursors, and any combination thereof. In some embodiments, the one or more polymer precursors are selected from the group consisting of (i) one or more films, (ii) one or more tubes, and (iii) one or more profiles.

In certain embodiments, the one or more polymer precursors are one or more films or one or more tubes that are specifically selected to impart to the oriented polymer tube one or more of: (i) one or more specific mechanical properties, (ii) one or more specific thermodynamic properties, (iii) one or more specific chemical properties, and (iv) one or more specific degradation rates. In other certain embodiments, the one or more polymer precursors are one or more profiles having cross-sectional shapes including, but not limited to, circular, rectangular, triangular, elliptical, and tubular. In some embodiments, the one or more polymer precursors are one or more profiles that are specifically selected to impart to the oriented polymer tube one or more of: (i) one or more specific mechanical properties, (ii) one or more specific thermodynamic properties, (iii) one or more specific chemical properties, and (iv) one or more specific degradation rates. Advantageously, in some of these embodiments, the one or more polymer precursors further include a bonding layer.

The placement of the one or more polymer precursors, in some embodiments, includes one or more of (i) placing the one or more polymer precursors around a mandrel (or other support as described herein below) and (ii) placing the one or more polymer precursors inside a mold (which in certain embodiments may be expandable, e.g., including a balloon). The placement around the mandrel may include, for example, placing around the mandrel using a technique selected from the group consisting of wrapping, sheathing, rolling, braiding, and combinations thereof. The mandrel may, in some embodiments, include a device. The placement of the one or more polymer precursors inside a mold may include (i) placing the one or more polymer precursors on the mandrel, then inserting the one or more polymer precursors on the mandrel into the mold and removing the mandrel, (ii) placing the one or more polymer precursors on the mandrel, then removing the mandrel and inserting the one or more polymer precursors into the mold, or (iii) placing the one or more polymer precursors inside a mold during one or more manufacturing steps of the precursor.

The one or more manufacturing steps may be selected from the group consisting of, for example, tube expansion, blow molding, injection stretch blow molding, die drawing, and mandrel drawing. The disposing may include disposing two or more polymer precursors, for example, simultaneously or sequentially disposing each polymer precursor. The forming may further include fusing the one or more polymer precursors by applying heat, pressure, or both heat and pressure to the one or more polymer precursors, in certain embodiments. Such fusing may include, for example, applying a shrink tube or shrink film around the one or more polymer precursors before applying heat, pressure, or both heat and pressure to the one or more polymer precursors. Such fusing may include, for example, applying heat, pressure, or both heat and pressure to the one or more polymer precursors using a mold and a balloon. In some such embodiments, the mold is lined with one or more polymer precursors, and a portion of the balloon will form part of the final polymer tube. In such embodiments, the forming step may occur, for example, during or after the disposing step. In some embodiments, the two or more disposing steps and the two or more forming steps occur simultaneously or sequentially. Advantageously, in some embodiments, the one or more polymer precursors comprise a biocompatible, biodegradable polymer, such as, but not limited to, a polymer comprising one or more polymers selected from the group consisting of poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(ε-caprolactone) (PCL), polyglycolic acid (PGA), poly(para-dioxanone) (PDO), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethylcarbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and copolymers, blends, and derivatives thereof.

The present disclosure further provides an oriented polymer tube made according to any of the methods outlined herein. A tube according to the present disclosure may be characterized, for example, by a molecular orientation profile that is substantially consistent through the wall of the oriented polymer tube, a molecular orientation profile that is substantially consistent through a predetermined portion of the wall of the oriented polymer tube, a molecular orientation profile characterized by various orientation levels through a predetermined portion of the wall of the oriented polymer tube, a molecular orientation profile characterized by various orientation axes through a predetermined portion of the wall of the oriented polymer tube, a molecular orientation profile characterized by an increase in molecular orientation gradient through the wall from the inner diameter to the outer diameter of the oriented polymer tube, a molecular orientation profile characterized by a decrease in molecular orientation gradient through the wall from the inner diameter to the outer diameter of the oriented polymer tube, a molecular orientation profile that is substantially consistent through the length of the oriented polymer tube, a molecular orientation profile that is substantially consistent through a predetermined portion of the length of the oriented polymer tube, a molecular orientation profile characterized by various orientation levels through a predetermined portion of the length of the oriented polymer tube, and/or a molecular orientation profile characterized by various orientation axes through a predetermined portion of the length of the oriented polymer tube.

Tubes according to the present disclosure may be characterized, for example, by a composition profile that is substantially consistent through a wall of the oriented polymer tube, a composition profile that is substantially consistent through a predetermined portion of the wall of the oriented polymer tube, a composition profile characterized by a range of compositions through a predetermined portion of the wall of the oriented polymer tube, a composition profile that is substantially consistent through a length of the oriented polymer tube, a composition profile that is substantially consistent through a predetermined portion of the length of the oriented polymer tube, and/or a composition profile characterized by a range of compositions through a predetermined portion of the length of the oriented polymer tube. Tubes according to the present disclosure may be characterized, for example, by a degradation rate profile that is substantially consistent through the wall of the oriented polymer tube, a degradation rate profile that is substantially consistent through a predetermined portion of the wall of the polymer tube, a degradation rate profile characterized by a range of degradation rates through a predetermined portion of the wall of the oriented polymer tube, a degradation rate profile characterized by an increasing degradation rate gradient through the wall from the inner diameter to the outer diameter of the polymer tube, a degradation rate profile characterized by a decreasing degradation rate gradient through the wall from the inner diameter to the outer diameter of the oriented polymer tube, a degradation rate profile that is substantially consistent through the length of the oriented polymer tube, a degradation rate profile that is substantially consistent through a predetermined portion of the length of the oriented polymer tube, a degradation rate profile characterized by a range of degradation rates through a predetermined portion of the length of the oriented polymer tube, and/or a degradation rate profile characterized by a degradation rate gradient along the length of the oriented polymer tube.

The present disclosure further provides a method of manufacturing an oriented polymer tube, the method including determining a desired tube shape and at least one of a desired composition profile and a desired molecular orientation profile, selecting one or more polymer precursors, disposing the one or more polymer precursors, and forming the one or more polymer precursors into an oriented polymer tube exhibiting the desired tube shape and at least one of the desired composition profile and the desired molecular orientation profile.

A particular embodiment is as follows:

Embodiment 1: A method of manufacturing an oriented polymer tube, comprising: obtaining at least one stretched polymer material exhibiting at least partial molecular orientation, wherein obtaining the at least one stretched polymer material comprises stretching the at least one polymer material, the at least one polymer material having a first dimension and comprising at least one crystallizable biodegradable polymer material, and the at least one polymer material is stretched to increase the first dimension; and forming an oriented polymer tube using the at least one stretched polymer material.

Embodiment 2: The method of the above embodiment, in which the stretching includes planar stretching.

Embodiment 3: The method of any of the above embodiments, wherein one or more of the at least one polymeric material is one or more of a polymer film, a polymer monofilament, a polymer ribbon, a polymer tape, and a polymer rod.

Embodiment 4: The method of any of the above embodiments, wherein the at least one polymeric material has a second dimension and stretching the at least one polymeric material comprises stretching the at least one polymeric material to increase the second dimension, and the at least one stretched polymeric material comprises a biaxially stretched polymeric material.

Embodiment 5: The method of any of the above embodiments, wherein the forming includes using the at least one stretched polymeric material and at least one adhesive polymeric material.

Embodiment 6: The method of any of the above embodiments, further comprising obtaining the at least one polymeric material at least in part based on compounding the at least one adhesive polymeric material with the at least one crystallizable biodegradable polymeric material.

Embodiment 7: The method of the above embodiment, wherein the at least one polymeric material is a composite polymeric material comprising the at least one crystallizable biodegradable polymeric material and the at least one adhesive polymeric material in a layered form.

Embodiment 8: The method of embodiment 6, wherein the at least one adhesive polymeric material and the at least one crystallizable biodegradable polymeric material are combined before, during, or after stretching the at least one polymeric material.

Embodiment 9: The method of embodiment 6, wherein forming the tube includes wrapping the at least one stretched polymeric material and the at least one adhesive polymeric material around a support.

Embodiment 10: The method of the above embodiment, wherein the support has one or more of the following shapes: cylindrical, circular, rectangular, triangular, elliptical, polygonal, and tubular.

Embodiment 11: The method of embodiment 9 or 10, wherein the wrapping comprises wrapping the at least one stretched polymeric material and the at least one adhesive polymeric material around the support multiple times such that the tube comprises multiple layers of the at least one stretched polymeric material and multiple layers of the at least one adhesive polymeric material.

Embodiment 12: The method of any of embodiments 9-11, wherein the at least one stretched polymeric material comprises a plurality of units of stretched polymeric material, the plurality of units of stretched polymeric material comprising different polymeric materials or the same polymeric materials, and the forming comprises arranging the plurality of units of stretched polymeric material in at least one of a stacked and staggered manner and winding the arranged plurality of units of stretched polymeric material at a bias angle.

Embodiment 13: The method of any of embodiments 9-12, wherein the support is a mandrel and the method further includes removing the tube from the mandrel.

Embodiment 14: The method of any of embodiments 9 to 12, wherein the support includes a device.

Embodiment 15: The method of embodiment 14, further comprising forming a resultant composite based at least in part on the oriented polymer tube and the substrate, the resultant composite being a medical device.

Embodiment 16: The method of any of the above embodiments, further comprising forming a medical device based at least in part on the oriented polymer tube.

Embodiment 17: The method of any of the above embodiments, wherein forming the medical device includes cutting the tube into a stent.

Embodiment 18: The method of any of the above embodiments, further comprising applying one or more of a therapeutic agent, covering, and coating to the stent.

Embodiment 19: The method of any of the above embodiments, wherein the forming includes applying at least one of heat and pressure to the at least one stretched polymeric material.

Embodiment 20: The method of any of the above embodiments, comprising forming a layered structure, the forming including applying a shrink tube or shrink film around at least a portion of the at least one stretched polymeric material to obtain a layered structure, and applying at least one of heat and pressure to the layered structure.

Embodiment 21: The method of any of the above embodiments, wherein the forming includes inserting at least a portion of the at least one stretched polymeric material into a mold, disposing the at least one stretched polymeric material on an expandable support, and applying at least one of heat and pressure to the at least one stretched polymeric material.

Embodiment 22: The method of any of the above embodiments, wherein one or more of the at least one crystallizable biodegradable polymeric material is selected from the group consisting of poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(ε-caprolactone) (PCL), polyglycolic acid (PGA), poly(para-dioxanone) (PDO), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethylcarbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and copolymers and derivatives and combinations thereof.

Embodiment 23: The method of any of the above embodiments, wherein the forming includes using the at least one stretched polymeric material and at least one adhesive polymeric material, the adhesive polymeric material being selected from the group consisting of poly(ε-caprolactone), poly(trimethylene carbonate), poly(D,L-lactide), poly((L-lactide)-co-ε-caprolactone), poly(L-lactide-co-trimethylene carbonate), poly(ε-caprolactone-co-trimethylene carbonate), poly(ethylene glycol), poly(L-lactide-co-poly(ethylene glycol)), and copolymers and derivatives and combinations thereof.

Embodiment 24: The method of any of embodiments 5-23, wherein the forming includes using the at least one stretched polymeric material and at least one adhesive polymeric material, and the at least one crystallizable biodegradable polymeric material and the at least one adhesive polymeric material include the same polymeric material.

Embodiment 25: The method of any of the above embodiments, wherein the at least one stretched polymeric material is stretched by at least 10 percent of the maximum stretch ratio corresponding to each of the at least one polymeric material.

Embodiment 26: The method of any of the above embodiments, wherein stretching the at least one polymeric material includes controlling one or more of the mechanical properties, thermodynamic properties, chemical properties, electrical properties, and degradation rate of the at least one polymeric material during stretching.

Embodiment 27: The method of any of the above embodiments, wherein the at least one polymeric material is stretched between 300 percent and 1000 percent of the original dimension of the at least one polymeric material.

Embodiment 28: A method comprising obtaining at least one stretched polymeric material exhibiting at least partial molecular orientation, wherein the at least one stretched polymeric material has a first dimension and corresponds to at least one polymeric material including at least one crystallizable biodegradable polymeric material, and wherein the at least one polymeric material has been stretched such that the first dimension is increased; and forming a tube using the at least one stretched polymeric material.

Embodiment 29: A tube comprising at least one stretched polymeric material exhibiting at least partial molecular orientation, at least in part obtained based on stretching at least one polymeric material, the at least one polymeric material having a first dimension and comprising at least one crystallizable biodegradable polymeric material, and the at least one polymeric material being stretched such that the first dimension is increased.

Embodiment 30: A tube, the tube comprising at least one crystallizable biodegradable polymeric material and having an outer surface with a normal perpendicular to the length of the tube, the tube exhibiting a maximum stress value of about 20 MPa or more measured based on a first compression cycle, and the tube being deformed by at least 17% of a first dimension or less after the first compression cycle.

Embodiment 31: The tube of the above embodiment, wherein the first compression cycle includes obtaining an initial distance between two parallel plates between which the tube is disposed, the two parallel plates being in contact with the outer surface of the tube such that the two parallel plates do not substantially load the tube; compressing the plates to a distance of 50% of the initial distance of the two parallel plates at a rate of 50% of the initial distance of the two parallel plates per minute, the compression of the plates causing a deformation of the tube in a first direction, the first direction being a direction in which the plates are compressed; and releasing the pressure of the plates on the tube at a rate of 50% of the initial distance of the two parallel plates per minute.

Embodiment 32: The tube of embodiment 30 or 31, wherein the total energy value under the engineering stress-strain curve corresponding to the tube after the first compression is at least 138 kgf mm/cm.

Embodiment 33: The tube of any of the above embodiments, wherein the tube has one or more of a therapeutic agent, covering, and coating applied thereon.

Embodiment 34: A tube comprising at least one crystallizable biodegradable polymeric material and having an outer surface with a normal perpendicular to the length of the tube, the tube exhibiting a maximum stress value of about 20 MPa or more measured based on a first compression cycle, and a total energy value under an engineering stress-strain curve corresponding to the tube after the first compression of at least 138 kgf mm/cm.

These and other features, aspects and advantages of the present disclosure may become apparent from the following detailed description taken in conjunction with the accompanying drawings, which are briefly described below. The present invention includes any combination of two, three, four or more of the above-described embodiments, as well as any combination of two, three, four or more features or elements described in the present disclosure, regardless of whether such features or elements are specifically combined in the description of a specific embodiment herein. The present disclosure is intended to be read holistically, and therefore in any of its various aspects and embodiments, it is considered that any separable features or elements of the disclosed invention are intended to be combinable, unless otherwise indicated by the context. Other aspects and advantages of the present invention will become apparent hereinafter.

For an understanding of embodiments of the present invention, reference is made to the accompanying drawings, which are not necessarily drawn to scale and in which reference characters represent components of exemplary embodiments of the present invention. The drawings are merely illustrative and are not to be construed as limiting the present invention.

FIG. 1 is a background (prior art) schematic diagram of a typical extrusion/expansion process for producing a single layer oriented polymer tube. FIG. 1 is a schematic diagram of the method disclosed herein for producing oriented polymer tubes via planar orientation and concentric placement. 1A-1D are schematic diagrams of various techniques for wrapping polymer films to form polymer tubes. 1A-1D are schematic diagrams of various techniques for wrapping polymer films to form polymer tubes. 1A-1D are schematic diagrams of various techniques for wrapping polymer films to form polymer tubes. 1 is a schematic diagram of a method for aligning adjacent polymer films to form a polymer tube. 1 is a schematic diagram of a method for aligning adjacent polymer films to form a polymer tube. 1 is a schematic diagram of certain methods disclosed herein for producing oriented polymer tubes via multi-layer concentric orientation and concentric placement. 1 is a schematic diagram of certain methods disclosed herein for producing oriented polymer tubes via multi-layer concentric orientation and concentric placement. FIG. 13 shows maximum stress from cyclic compression tests for tubes according to Examples 3 and 4 compared to a control tube. FIG. 13 shows normalized energy from cyclic compression tests for tubes according to Examples 3 and 4 compared to a control tube. FIG. 13 shows X-sections from cyclic compression tests on tubes according to Examples 3 and 4 compared to a control tube. FIG. 1 shows maximum stress from cyclic compression tests for tubes according to Examples 1, 3, 5, and 7. FIG. 1 shows normalized energy from cyclic compression tests on tubes according to Examples 1, 3, 5, and 7. FIG. 1 shows X-sections from cyclic compression tests on tubes according to Examples 1, 3, 5, and 7. FIG. 1 shows maximum stress from cyclic compression tests for tubes according to Examples 2, 4, 6, and 8. FIG. 1 shows normalized energy from cyclic compression tests on tubes according to Examples 2, 4, 6, and 8. FIG. 1 shows X-sections from cyclic compression tests on tubes according to Examples 2, 4, 6, and 8.

The present invention is described in more detail below with reference to the accompanying drawings, some, but not all, embodiments of the invention. Indeed, these inventions may be embodied in many different forms and are not to be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Like numbers refer to like elements throughout.

The present disclosure relates to methods of making polymer tubes (e.g., biodegradable polymer tubes) and the polymer tubes made thereby. In particular, the present disclosure relates to methods of making polymer tubes comprising a crystallizable polymer, the methods including a molecular orientation step that aligns/orients at least a portion of the molecules of the crystallizable polymer within the wall of the tube (thus resulting in an oriented polymer tube). In various embodiments, the methods disclosed herein provide control over the crystalline molecular orientation within the polymer tube wall, e.g., with respect to all three axes of a cylindrical coordinate system. The methods disclosed herein include, in certain embodiments, selecting a predetermined final tube shape and an associated predetermined molecular orientation profile, and selecting materials and process steps accordingly, e.g., by arranging and forming one or more precursors to achieve the desired final tube shape and molecular orientation profile. The disclosed methods can advantageously provide oriented polymer tubes that exhibit sufficient strength/resistance to radial compression to be useful for a wide range of applications, including, but not limited to, biomedical applications. The disclosed methods can also advantageously provide oriented polymer tubes that exhibit more controlled and improved heat shrink properties relative to tubes (e.g., oriented polymer tubes) produced by conventional extrusion and concentric expansion.

As mentioned above, a conventional method for producing oriented polymer tubes includes extrusion and concentric expansion to obtain a single layer tube. In such a method, as shown diagrammatically in FIG. 1 (PRIOR ART), a polymer tube is extruded by a conventional method and then subjected to concentric expansion. As shown in FIG. 1, an extruded tube 10 is produced having a given inner diameter (ID) related to the inner radius (denoted as r _i1 ) through the equation OD=2×r _i1 and a given outer diameter (OD) related to the outer radius (denoted as r _o1 ) through the equation OD=2×r _o1 . The extruded tube 10 is expanded (optionally under conditions of heat and pressure denoted by T and P, respectively) to produce a polymer tube 12 having a larger ID (related to r _i2 according to the above equation) and a larger OD (related to r _o2 according to the above equation). In such an expansion process, the ID of the extruded tube is subjected to a greater degree of stretch than the OD of the extruded tube. The difference in the rate and amount of expansion experienced by the ID and OD during this process leads to an unequal degree of molecular orientation through the tube wall (i.e., from the ID to the OD). As noted above, a typical concentric expansion process is limited in the degree of orientation throughout the final wall thickness, resulting in a decreasing orientation gradient from the ID to the OD.

According to the present disclosure, various methods are provided for producing oriented polymer tubes comprising a crystallizable polymer (e.g., a crystallizable biodegradable polymer, resulting in a biodegradable oriented polymer tube). In some embodiments, such tubes may exhibit modified molecular orientation characteristics relative to oriented polymer tubes produced by conventional extrusion and concentric expansion, as well as corresponding modified mechanical and/or thermodynamic properties. Modified molecular orientation characteristics in this regard may refer to a greater percentage of molecular orientation in the crystalline regions of the oriented polymer tube and/or greater regularity in the distribution of molecular orientation within the crystalline regions of the oriented polymer tube. For example, in some embodiments, the molecular orientation throughout the wall thickness of the disclosed oriented polymer tubes is more uniform (leading to such improved mechanical and thermodynamic properties) than the molecular orientation of the walls of the oriented polymer tubes produced by conventional methods as shown in FIG. 1. Modified mechanical properties may refer to higher strength, higher modulus, higher toughness, and/or greater elasticity. Modified thermodynamic properties may refer to modified heat shrink properties, including, but not limited to, controlled shrink activation temperature, shrink force, and shrink ratio.

Planar and Concentric Alignment One method presented herein involves using uniaxially or biaxially oriented polymer films as oriented precursors to form oriented polymer tubes (herein referred to as "planar and concentric alignment"). Orienting the polymer molecules by drawing them into uniaxially or biaxially oriented films is known to improve properties such as tensile strength and toughness. See, e.g., "Understanding biaxially and monoaxially oriented films", Packaging World, October 20, 2013.

One embodiment of the method disclosed herein is shown generally in Figure 2. According to this method, a polymer film comprising a crystallizable polymer having a given dimension _x1 (here considered to be the film length) is stretched in a planar direction to obtain a stretched polymer film having a corresponding dimension _x2 that is greater than _x1 (i.e., the stretched polymer film increases in length). The stretched polymer film is referred to herein as an "oriented" polymer film because the stretching process imparts at least some degree of molecular orientation within the crystalline regions of the polymer film.

The polymer film may be of various sizes and thicknesses, and the amount of stretching (associated with the _x1 and _x2 values) may be determined in some embodiments based on the desired thickness (z, not shown in FIG. 2) of the stretched/oriented film relative to the initial thickness of the (unstretched/unoriented) film. In some embodiments, the amount of stretching (associated with the _x1 and _x2 values) may be determined based on the desired mechanical and/or thermodynamic properties of the stretched/oriented film. While the embodiment shown in FIG. 2 results in uniaxial stretching (stretching/increasing only the x dimension), in some embodiments, the disclosed method includes biaxial stretching (stretching/increasing both the x and y dimensions, i.e., length and width). In such embodiments, the stretching rate and/or amount in both the x and y directions may be modified independently of each other. Planar stretching (either in one dimension only, i.e. uniaxially, or in two dimensions, i.e. biaxially) is advantageously carried out in a controlled manner such that the stretching rate, indicated by "k" or dx/dt (FIG. 2), is constant and the resulting stretched/oriented polymer film is substantially uniform (e.g., in terms of thickness). As shown in FIG. 2, when the planar stretching is uniaxial, it is understood that the stretching rate for the other axis (here, along the y-axis) dy/dt is equal to 0 (i.e., there is no stretching along the y-axis). Those skilled in the art will recognize that when there is stretching along the y-axis, dy/dt is non-zero.

The polymeric film subjected to stretching may be produced by any of a number of methods, including, but not limited to, extrusion, extrusion coating, injection/blow molding, melt casting, solvent casting, or compression molding (the last two methods allow the use of higher molecular weight polymers than extrusion). In some embodiments, materials such as fillers may be dispersed in the polymeric film prior to the stretching step. In certain embodiments, as described in more detail below, the tie layer material is associated with the polymeric film prior to stretching (so that both the polymeric film and the tie layer material are stretched together). It should be noted that although the present application is specifically described in the context of stretched polymeric films (and polymeric shapes, as described below), the present disclosure is not intended to be limited thereto. For example, in other embodiments, polymeric materials in the form of polymeric monofilaments, polymeric ribbons, polymeric tapes, or polymeric rods are used. Those skilled in the art are familiar with these terms and will understand, for example, that a polymer monofilament is a thread-like synthetic fiber (these fibers may have a variety of diameters), a polymer tape is a flat strip of polymer material (these tapes may have a variety of lengths and widths), and a polymer rod is a three-dimensional structure (but is not limited to being diametrically circular). As an example, a polymer rod may be a cylindrical structure. As another example, a polymer rod may be a tubular structure.

There are many methods known in the art for stretching polymeric materials in one or two dimensions as described above. In machine direction (MD) stretching, the extruded film is cast onto a chill roll, then reheated and stretched by passing the material through a nip and over a tension roller at a speed above the extrusion casting speed. Subsequent transverse direction (TD) stretching can be achieved by gripping the sides of the film with clamps and pulling the clamps perpendicular to the machine direction through a heated oven in a tenter frame. Alternatively, MD and TD stretching can be achieved simultaneously in a tenter frame capable of simultaneous biaxial orientation, such as the LISIM line manufactured by Brueckner. The line speed, temperature, and stretching rate are controlled so that the desired degree of stretching is achieved without tearing the film. Simultaneous stretching of the polymeric material can also be achieved by using a blown film line, which stretches the material in both the TD and MD directions by extruding the polymeric material through an annular die and then inflating the extrudate with air to create a bubble. If additional MD or TD stretching is required, the blown film line can be modified to provide a second bubble to achieve a higher degree of stretching in either or both MD and TD. There are numerous manufacturers of industrial blown film and double bubble lines, such as Hosokawa Alpine, GAP srl., or Kuhne Group. In addition to the continuous methods outlined herein, in some embodiments, batch stretching can be achieved by clamping the polymer film on all sides and stretching it in an oven in either or both MD and TD, either sequentially or simultaneously. The Karo IV stretcher manufactured by Brueckner represents an example of a batch film stretcher.

As previously mentioned, the degree to which the polymeric film is stretched can vary. In some embodiments, the polymeric film is stretched at least 10 percent of the maximum stretch ratio corresponding to at least one respective polymeric material. As used herein, "maximum stretch ratio" is intended to mean the maximum possible stretch before tearing of the material occurs.

Using the stretched oriented polymer film as a precursor for the formation of a tubular object, the stretched oriented polymer film is arranged in a concentric configuration (e.g., by rolling or wrapping the stretched oriented polymer film) and optionally further processed to obtain an oriented polymer tube (e.g., a biodegradable oriented polymer tube). While the present disclosure focuses on arranging the stretched oriented polymer film in a concentric configuration by rolling/wrapping the film to obtain a tubular object, other arrangement means are encompassed herein.

Optionally, the stretched oriented polymer film can be further processed prior to this step, for example, by cutting the film to individual desired sizes and/or by associating a bonding layer with the film, as described in more detail below. Without intending to be limiting, one means of arranging the stretched oriented polymer film in a concentric configuration includes wrapping/rolling the film around a forming mandrel. It is noted that the shape of the forming mandrel is not particularly limited. Thus, it is understood that a polymer "tube" as used herein is not limited to a cylindrical tube. Rather, a polymer "tube" produced according to the disclosed method is any hollow elongated structure, where the cross-sectional shape of the hollow elongated structure can be, but is not limited to, circular.

Additionally, the disclosed methods are not limited to wrapping/rolling the film around a mandrel, but rather the film can be wrapped around various types of supports. Suitable supports include, but are not limited to, supports having one or more of a cylindrical, circular, rectangular, triangular, elliptical, polygonal, and tubular shape. In some embodiments, the support is a device or device component (e.g., including but not limited to, a stent). In certain such embodiments, the methods disclosed herein provide a composite that may be in the form of a medical device, including the support and the disposed oriented polymer film. Particularly when the support is a device and the disclosed methods provide a medical device, in some embodiments, the composite may be further processed. For example, in some embodiments, one or more of a therapeutic agent, a covering, and a coating are applied to the composite. In some embodiments, the composite is cut to a size appropriate for a stent. Various methods are known for cutting stents, including but not limited to laser cutting.

In some embodiments, the oriented polymer film can be arranged by rolling/wrapping as described above to obtain a single layer oriented polymer tube in which one end of the polymer film has little to no overlap with the opposite end of the film (e.g., there is only a small seam where the ends of the two films meet) or a multi-layer tube can be produced by rolling/wrapping the film multiple times. More preferably, a multi-layer tube having any number of layers (e.g., a tube having a "layered structure") is formed, where the number of layers is not particularly limited. An exemplary such multi-layer tube preferably has 2 to 20 layers of oriented polymer film, including a single oriented polymer film that is rolled/wrapped to obtain a desired number of layers (e.g., to achieve a desired wall thickness of the resulting multi-layer oriented polymer tube). In such embodiments, it is understood that a larger number of layers/wraps will result in a polymer tube with a thicker wall (assuming that oriented polymer films having the same thickness are used). Thus, the number of layers/wraps can dictate the wall thickness of the resulting oriented polymer tube. As shown in Figures 3A-3C, the axis about which the polymer film is rolled/wrapped can vary with respect to the axis(es) about which the polymer film is stretched/oriented. The circular arrows indicate the direction of wrapping.

Typically, in order to provide sufficient adhesion between adjacent layers of oriented polymer films of such multi-layer polymer tubes (e.g., produced by arranging and forming multiple wraps of one or more films), a bonding layer (e.g., "adhesive polymer material"), as described herein below, is included in the oriented polymer tube. In some embodiments, the bonding layer is incorporated by associating the bonding layer material with the (non-stretched/non-oriented) polymer film described herein above to obtain a composite polymer film and subjecting the composite polymer film to planar expansion as described above. This association can be performed, for example, by aligning a film of the bonding layer material with the (non-stretched/non-oriented) polymer film or by coating the (non-stretched/non-oriented) polymer film with the bonding layer material, for example, by extrusion coating or solution coating the bonding layer material onto the polymer film. This method provides both the crystallizable polymer film and the bonding layer in a stretched form (and in some such embodiments, this method can provide molecular orientation in the bonding layer as well as in the polymer film).

In another embodiment, the tie layer is incorporated by associating the tie layer material with the stretched/oriented polymer film. In such an embodiment, the composite film is obtained by associating the tie layer material with the stretched oriented polymer film after subjecting the crystallizable polymer film to stretching/orientation. This association can be done, for example, by aligning a film of the tie layer material with the (stretched/oriented) polymer film or by coating the (stretched/oriented) polymer film with the tie layer material, for example by extrusion coating or solution coating the tie layer material onto the polymer film. The composite polymer film obtained according to this embodiment comprises a crystallizable polymer film in stretched/oriented form, while the tie layer is in non-stretched/non-oriented form. Other modifications to these embodiments are also encompassed, for example the polymer film and the tie layer can be stretched independently to obtain a stretched/oriented polymer film and a stretched or stretched/oriented tie layer, which can then be combined to obtain a composite polymer film.

As briefly discussed herein above, the composition of the oriented polymer film(s) and the composition of the bonding layer(s) may be the same or different. Thus, in certain embodiments, the composition of one or more oriented polymer films is the same as the composition of one or more bonding layers, but the degree of polymer orientation is different (e.g., the oriented polymer film(s) has a greater degree of orientation than the bonding layer(s)).

The composite polymer film is then formed into an oriented polymer tube as described herein above, so that the bonding layer material associates with each "layer" (or wrap) of the oriented polymer film to bond adjacent layers of the polymer film together. This bonding may require, in some embodiments, processing the polymer tube by applying heat and/or pressure to the final polymer tube. In some embodiments, the pressure is negative, i.e., application of a vacuum to the tube, such as by pulling a vacuum through a mandrel around which the polymer tube is wrapped. In some embodiments, the heat and (positive) pressure are provided by wrapping the polymer tube with a shrink material (e.g., shrink tubing or shrink wrap containing linear low density polyethylene, or LLDPE) and heating the wrapped polymer tube (e.g., by placing the tube in an oven). The oven temperature, forming time, and applied forming pressure may depend on the composition of the polymer tube, and each of these processing variables may be controlled to tailor the final oriented polymer tube properties. In some embodiments, other bonding techniques may be used to replace or supplement the heat/pressure method. For example, in some embodiments, bonding can use contact with one or more solvents (e.g., chloroform), and in some embodiments, bonding can include the use of radio frequency welding.

Although the planar orientation/concentric placement methods outlined herein above are disclosed as including three separate steps (planar orientation, e.g., stretching a polymer film; concentric placement, e.g., placing an oriented polymer film in a concentric position; and forming, e.g., forming the placed oriented polymer film into an oriented polymer tube), the disclosed methods can be modified such that two or all three of these steps are performed substantially simultaneously. For example, in some embodiments, a polymer film can be provided in an unstretched form and can be stretched (and oriented) by pneumatic and/or hydraulic pressure against a cylindrical forming surface to form an oriented polymer tube.

In some embodiments, rather than utilizing a stretched polymer film as the polymer tube precursor, an oriented composite polymer profile may be positioned and formed into a tube, which may serve as the polymer tube precursor. The method includes positioning the oriented composite polymer profile according to a desired orientation profile with respect to all three cylindrical axes. Positioning the composite profile may include, but is not limited to, wrapping, sheathing, rolling, or braiding. Pressure and/or temperature are applied to the positioned composite profile such that the bonding layer(s) adhere to adjacent layers of the composite profile, thereby forming a coalesced multi-layer oriented polymer tube.

A polymeric shape is a shaped polymeric form (rather than a polymeric film as previously described) that includes a crystallizable polymer as disclosed herein. Exemplary polymeric shapes include, but are not limited to, square, rectangular, polygonal, oval, or other geometric cross-sectional shapes that may or may not have regular or intermittent features on one or more surfaces of the shape. A composite shape is a polymeric shape that further includes a bonding layer material (including a crystallizable polymer as previously described).

In certain embodiments, tubes produced by forming the oriented film or oriented profile arrangements outlined in this section exhibit a degree of molecular orientation across the tube wall thickness that is more consistent than that of extruded, radially expanded, single-layer tubes (produced as shown generally in FIG. 1, as previously described). Using a cylindrical coordinate system and assuming that two surfaces in full contact (except for a bonding layer of negligible thickness) are geometrically continuous, such a tube formed from a circular profile arranged for maximum density would be geometrically discontinuous along all three axes. In terms of molecular orientation and implied geometric continuity, such a tube would be continuous along the θ axis and discontinuous along the r and z axes. Such a tube formed from a rectangular profile arranged for maximum density would be geometrically discontinuous along all three axes. In terms of molecular orientation and implied geometric continuity, such a tube would be continuous along all three axes.

The planar orientation/concentric placement methods disclosed herein provide many advantages over traditional extrusion/concentric expansion. For example, according to the disclosed methods, each polymer film (or profile) can be uniaxially or biaxially oriented to the desired extent and as desired. In some embodiments, multiple polymers can be combined as individual layers in a composite structure and stretched (and oriented) together. In some embodiments, multiple polymers can be provided independently in the form of films or profiles and stretched (and oriented) to various degrees, after which the oriented films and/or oriented profiles can be combined prior to or during the formation of a polymer tube.

The manner in which different polymer films (or profiles) may be combined can be modified to achieve different composite structures and different properties. For example, in some embodiments, multiple films can be stacked at a bias angle during the tube forming process (e.g., on a forming mandrel) to meet key application requirements. Various configurations of component layers can be obtained during manufacturing. For example, individual layers can be staggered or stacked with respect to each other. In this context, a stacked configuration (e.g., as shown in FIG. 4A) includes different films directly on top of each other, and a staggered configuration (e.g., as shown in FIG. 4B) includes different films that are staggered such that when rolled (or otherwise formed into a tubular shape), the first layer(s) is a single material, followed by one or more layers of a composite film (or profile), followed by one or more layers of a final material. A given oriented polymer tube may further include a stacked series of layers and a staggered series of layers.

In some embodiments, individual films/layers can be selected for very specific properties such as strength, toughness, drug encapsulation/elution, adhesion, surface functionality, degradability, etc. to impart such properties to the resulting polymer tube. Additional components, including but not limited to braids, fibers, wovens, nonwovens, and/or inserts, can be incorporated into the final tube at various stages of the manufacturing methods outlined herein (e.g., between films that are subsequently encapsulated by the bonding layer(s) before or during the forming process). In some embodiments, the oriented polymer tubes obtained via the methods disclosed herein can be further modified in subsequent processes (e.g., by laser cutting, crimping, expansion, etc.) to produce medical devices.

Multi-layered concentric orientation and concentric arrangement Another aspect of the present disclosure relates to a method including multi-layered concentric orientation and concentric arrangement, and an oriented polymer tube produced by the method. As mentioned above, one disadvantage of the concentric expansion process is that the degree of orientation throughout the final tube wall thickness is limited, resulting in a decreasing orientation gradient from ID to OD. This concern can be addressed by using a concentric orientation approach, but minimizing the wall thickness, since the limit to the degree of orientation that can be achieved approaches zero as the wall thickness approaches zero. Thus, when the wall thickness of the precursor becomes additive in forming the wall thickness of the final formed oriented polymer tube, the multi-layered tube formed from the concentrically oriented tube precursor shows a higher degree of orientation throughout the tube wall thickness and a decreasing orientation gradient from ID to OD of the final formed polymer tube.

In this multi-layer concentric orientation and concentric placement approach, multiple polymer tubes (which may be of the same or different compositions) are made and subjected to concentric expansion to produce an oriented tube precursor having at least some degree of molecular orientation, as shown in FIG. 5A (step 14 or step 18). Such polymer tubes may be made by any method, for example, via extrusion, extrusion coating, and/or injection molding. In one embodiment, the individual oriented tube precursors are nested as shown in step 16. In another embodiment, the oriented tube precursors are nested as shown in step 20 and then subjected to additional concentric expansion (simultaneously) as shown in step 22. The placement of the oriented tube precursors in such an embodiment is completed via the concentric expansion step. The formation of the final tubular shape (resulting in an oriented multi-layer polymer tube) may be completed via or subsequent to the concentric expansion step.

In another embodiment, the concentric expansion of the polymer tubes is performed sequentially, one inside the other, as shown in FIG. 5B. Following the concentric expansion of the first tube (constituting the outer oriented tube precursor), the concentric expansion of each subsequent tube places the additional oriented tube precursor within the ID of the preceding oriented tube precursor, resulting in a concentric arrangement of all oriented tube precursors. The formation of the final tubular shape (resulting in an oriented multilayer polymer tube) can be completed via the concentric expansion of one or more tube precursors or following the concentric expansion of one or more tube precursors. The concentric expansion of any of these embodiments can be performed by any known method of concentrically expanding a tube.

Compounding multiple unstretched/unoriented polymer tube precursors or stretched/oriented tube precursors using this method can be performed in a variety of ways, such as by forming an oriented polymer tube on a mandrel (optionally with the application of heat and/or pressure) or by forming an oriented polymer tube in a mold (again, optionally with the application of heat and/or pressure). It should be noted that such forming mandrels and molds need not be circular in cross section, and thus the resulting multi-layer oriented polymer tube can be in the form of a hollow elongated structure that may be, but is not limited to, circular in cross section.

In the multi-layer concentric orientation and concentric arrangement methods, since multiple individual layers are included, again a bonding layer is typically incorporated between adjacent layers to provide sufficient adhesion therebetween. In these embodiments, the inclusion of a bonding layer may be achieved, for example, by associating a bonding layer material with one or more polymer tube precursors (thus resulting in a composite polymer tube precursor), so that when the polymer tube precursor is expanded/oriented and composited with other precursors (or expanded/oriented after composited with other precursors), the bonding layer is also subjected to such a process. Thus, in some embodiments, the bonding layer is also subjected to concentric expansion/orientation. In other embodiments, the bonding layer is applied after the individual polymer tubes are expanded/oriented, and in such embodiments, the bonding layer is not subjected to concentric expansion/orientation. Again, bonding adjacent layers (resulting from composite of multiple tube precursors or multiple individually expanded/oriented tubes) to form the final oriented polymer tube may require processing the final oriented polymer tube by applying heat and/or pressure to the multi-layer oriented polymer tube. In some embodiments, the heat and pressure are provided by wrapping the oriented polymer tube with shrink tubing or shrink wrap and heating the wrapped oriented polymer tube, for example by placing the wrapped oriented polymer tube in an oven. The oven temperature and applied forming pressure can each be controlled to tailor the properties of the final tube.

Thus, in certain embodiments (e.g., as illustrated by steps 16 and 22 in FIG. 5A), at least two oriented tubes, each of which may include one crystallizable polymer layer and optionally one bonding layer (thus resulting in a composite oriented tube), are positioned according to a desired orientation profile with respect to all three cylindrical axes. The positioned tubes are subjected to elevated pressure and/or temperature such that the bonding layer adheres to the adjacent layers (i.e., the oriented polymer layers on either side thereof), thereby forming a coalesced multilayer oriented polymer tube. In some embodiments, the stretched and oriented composite tube is positioned against an outer and/or inner expanded/oriented tube (which may or may not include a bonding layer) that includes a crystallizable polymer.

In some embodiments (e.g., as shown in FIG. 5B), the non-oriented composite tube (containing both the crystallizable polymer and the tie layer material) is expanded concentrically (e.g., under conditions of elevated temperature and pressure) to orient at least a portion of the crystallizable polymer. Through this concentric expansion process, the tie layer material may, in some embodiments, adhere to any adjacent layers. For example, in this embodiment, one adjacent layer may be a crystallizable polymer of the same non-oriented composite tube precursor, and the other adjacent layer may be an already oriented tube of a second crystallizable polymer (which may be the same or different from the crystallizable polymer in the composite tube precursor), thereby forming a coalesced multi-layer oriented polymer tube. In such an embodiment, the individual layers are positioned according to a desired orientation profile with respect to all three cylindrical axes. The composite tube precursor may also be positioned with respect to an inner tube precursor containing a crystallizable polymer.

There are many methods known in the art for concentrically expanding a polymer tube as described above. In conventional blow molding, an extruded polymer tube is placed in a mold, heated to a rubber-like state, and pressure is applied to expand the tube into the mold. In some methods, the extruded polymer tube is also stretched in the machine direction by applying tension. The machine direction stretching is completed before or during the concentric expansion. The shape of the final expanded tube is generally determined by the mold geometry and process parameters such as temperature and pressure. The properties of the final expanded tube are generally determined by process parameters such as concentric expansion ratio, concentric expansion rate, machine direction stretch ratio, machine direction stretch rate, temperature, and pressure.

The multi-layer concentric orientation and concentric placement methods disclosed herein provide many advantages over conventional extrusion/concentric extrusion. For example, each tube precursor can be uniaxially or biaxially oriented to a desired degree as desired prior to or during the formation of the multi-layer oriented polymer tube to meet application requirements. In some embodiments, multiple polymers can be compounded as individual layers in a composite structure and expanded/oriented together. In some embodiments, multiple polymers can be provided independently in the form of tubes and, for example, expanded (and thus oriented) to various degrees before compounding the resulting oriented tubes during placement and formation of the multi-layer oriented polymer tube. In some embodiments, the individual tubes and tube precursors can be selected for very specific properties such as strength, toughness, drug encapsulation/elution, adhesion, surface functionality, degradability, etc. to impart such properties to the resulting multi-layer polymer tube. Additional components, such as fillers, can be dispersed in one or more of the tube precursors prior to expansion. Additional components, including but not limited to braids, fibers, wovens, nonwovens, and/or inserts, can be incorporated into the final multilayer polymer tube at various stages of the manufacturing methods outlined herein (e.g., between layers of tubing that are subsequently encapsulated by a bonding layer(s) material). In some embodiments, the multilayer polymer tube obtained via the methods disclosed herein can be further modified in subsequent steps (i.e., by laser cutting, crimping, expansion, etc.) to produce a medical device.

Using a cylindrical coordinate system and assuming that two surfaces in full contact are geometrically continuous, such a tube (formed from the annular shape of the precursor) will be geometrically continuous along all three axes. With respect to molecular orientation and the implied geometric continuity, such a tube will be continuous along the z and θ axes, and discontinuous along the r axis.

The methods of making oriented polymer tubes disclosed herein are applicable to a range of crystallizable polymers. Such methods are particularly applicable (but not limited to) to biodegradable polymers. Thus, in preferred embodiments, the polymer(s) from which oriented polymer tubes are made according to the present disclosure are advantageously crystallizable biodegradable polymers, and can advantageously exhibit macromolecular orientation, strain-induced crystallization, and high strength.

Biodegradable (also commonly referred to as "bioresorbable" and/or "bioresorbable") polymers are polymers that undergo breakdown or degradation under certain biological conditions into compounds that are considered harmless/safe as part of normal biological processes. Advantageously, under the biological conditions to which they are exposed, they gradually degrade and/or erode and are absorbed or resorbed by the body. Typically, biodegradable polymers applicable in the context of the present disclosure are sufficiently stable under biological conditions to remain in the body for a period of time (e.g., including but not limited to, up to about one week, up to about one month, up to about three months, up to about six months, up to about twelve months, up to about eighteen months, up to about two years, or longer) before substantial degradation. Typically, such biodegradable polymers are also biocompatible.

Exemplary crystallizable polymers applicable in the context of the present invention include, but are not limited to, poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(ε-caprolactone) (PCL), polyglycolic acid (PGA), poly(para-dioxanone) (PDO), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethylcarbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), poly(propylene glycol), polydioxanone, polygluconate, and copolymers, blends, and derivatives thereof. Certain polymers that can be used according to the disclosed methods can be characterized as poly(alpha-hydroxy acids). Some polymers are modified cellulose polymers, collagen or other binding proteins, adhesive proteins, hyaluronic acid, polyanhydrides, polyphosphoesters, poly(amino acids), and copolymers and derivatives thereof. The molecular weight of the polymers processed according to the methods outlined herein can vary and can affect the properties of the resulting oriented polymer tube. It is generally understood that the mechanical properties (e.g., strength and modulus) of a polymer generally improve with increasing molecular weight, and degradation time generally increases with increasing molecular weight (i.e., a tube made of a low molecular weight polymer will typically degrade more quickly than a comparable tube made of a higher molecular weight polymer). Thus, the molecular weight of the polymer may be appropriately selected to balance these properties and may vary widely depending on the particular application.

As noted above, the oriented polymer tubes disclosed herein typically include, in addition to the oriented crystallizable polymer, one or more bonding layer materials (also referred to herein as "adhesive" layer materials) sufficient to bond the multiple layers together. Such multiple layers can include multiple layers of the same material (e.g., in the case of multi-layer materials produced by winding) and/or layers of different materials. Advantageously, in some embodiments, the bonding layers bond adjacent layers together such that the oriented polymer tube exhibits little to no delamination during use (e.g., sufficient that the adhesion between the layers does not cause the oriented polymer tube to exhibit delamination, even though the oriented polymer tube may at least partially degrade).

The composition of the bonding layer(s) in the final oriented polymer tube can vary. The bonding layer typically comprises one or more polymers capable of bonding two adjacent layers together, and therefore a variety of polymers with adhesive properties can be used. Typical adhesive polymers used as bonding layers exhibit some degree of flowability and/or tackiness. The polymer(s) comprising the bonding layer are preferably biocompatible, biodegradable polymers in some embodiments (e.g., where the final product is designed to be implanted in the body). The polymer(s) comprising the bonding layer are, in some embodiments, non-crystalline/substantially amorphous polymer(s). Exemplary polymers suitable for serving as (or being included in) a bonding layer according to the present disclosure include, but are not limited to, poly(ε-caprolactone), poly(trimethylene carbonate), poly(D,L-lactide), poly((L-lactide)-co-ε-caprolactone), poly(L-lactide-co-trimethylene carbonate), poly(ε-caprolactone-co-trimethylene carbonate), poly(ethylene glycol), poly(L-lactide-co-poly(ethylene glycol)), and copolymers and derivatives and combinations thereof.

The properties of the tubes produced by the above methods can vary. For example, the geometric and orientational continuity of oriented polymer tubes made by various methods are compared in Table 1 below.

The shapes and sizes of the oriented polymer tubes produced according to the disclosed methods can vary. As noted herein above, such tubes can be cylindrical, but are not limited thereto. The wall thickness of the oriented polymer tubes can vary as well, and can be adjusted based on, for example, the thickness of the polymer film (or profile) (for planar orientation and concentric arrangement methods), the thickness of the tube/tube precursor (for multi-layer concentric orientation and concentric arrangement methods), the amount of elongation force applied, and the number of layers (e.g., the number of wraps or the number of tube precursors or tubes combined to produce a multi-layer tube) that are combined to produce the final oriented polymer tube. The oriented polymer tubes provided by the present disclosure can be substantially homogeneous in composition (e.g., consisting primarily of a single oriented crystallizable polymer component), and the multiple layers can be bonded together with a relatively small amount of bonding layer material (forming an adhesive/bonding layer between adjacent layers of oriented polymer). Certain oriented polymer tubes provided by the present disclosure can be non-uniform. This is because compositions of films/profiles/tubes can be combined (e.g., tubes can include different crystallizable polymers and/or different tie layer materials (either oriented or unoriented), can include/exclude fillers or other ingredients, etc.). The methods outlined herein are broadly applicable to the creation of a wide range of oriented polymer tubes.

In some embodiments, oriented polymer tubes made according to the disclosed methods can be characterized by the degree of molecular orientation of the crystallizable polymer across the entire cross-section of the tube (i.e., from the ID to the OD of the tube). Preferably, the molecular orientation of the crystallizable polymer within the tube wall is substantially constant across the entire cross-section of the oriented polymer tube. For example, the molecular orientation is generally in the same direction and is present in approximately the same amount near the ID of an oriented polymer tube according to the present disclosure as near the OD. Such orientation characteristics can be evaluated using, for example, x-ray diffraction.

In particular, the molecular orientation profile in certain embodiments is substantially consistent through the wall of the oriented polymer tube or substantially consistent through a predetermined portion of the wall of the oriented polymer tube. In some embodiments, the tube has a molecular orientation profile characterized by different orientation levels through a predetermined portion of the wall of the oriented polymer tube and/or a molecular orientation profile characterized by different orientation axes through a predetermined portion of the wall of the oriented polymer tube. Some tubes provided herein exhibit other profiles, such as an increasing molecular orientation gradient through the wall from the inner diameter to the outer diameter of the oriented polymer tube, or a decreasing molecular orientation gradient through the wall from the inner diameter to the outer diameter of the oriented polymer tube. In some embodiments, the molecular orientation profile is substantially consistent along the length of the oriented polymer tube or substantially consistent along a predetermined portion of the length of the oriented polymer tube. In some embodiments, the tube has a molecular orientation profile characterized by different orientation levels along the length of the oriented polymer tube and/or a molecular orientation profile characterized by different orientation axes along the length of the oriented polymer tube.

The compositional profile of the oriented polymer tubes provided herein, in certain embodiments, is substantially consistent through the wall of the oriented polymer tube or is substantially consistent through a predetermined portion of the wall of the oriented polymer tube. In other embodiments, the compositional profile may be characterized by a range of compositions through a predetermined portion of the wall of the oriented polymer tube. Similarly, the compositional profile of the oriented polymer tubes provided herein, in certain embodiments, is substantially consistent along the length of the oriented polymer tube or is substantially consistent along the length of the oriented polymer tube. In other embodiments, the compositional profile may be characterized by a range of compositions along the length of the oriented polymer tube.

In certain embodiments, the degradation rate profile may be influenced by the particular method used to form the oriented polymer tube. For example, provided herein are oriented polymer tubes characterized by a degradation rate profile that is substantially consistent through the wall of the oriented polymer tube, including a degradation rate profile characterized by an increasing degradation rate gradient through the wall from the inner diameter to the outer diameter of the polymer tube and a degradation rate profile characterized by a decreasing degradation rate gradient through the wall from the inner diameter to the outer diameter of the oriented polymer tube, a degradation rate profile that is substantially consistent through a predefined portion of the wall of the polymer tube, or a degradation rate profile that is characterized by a variety of degradation rates through a predefined portion of the wall of the oriented polymer tube. In some embodiments, provided herein are oriented polymer tubes characterized by a degradation rate profile that is substantially consistent along the length of the oriented polymer tube, including a degradation rate profile characterized by a degradation rate gradient along the length of the oriented polymer tube, a degradation rate profile that is substantially consistent along the length of the oriented polymer tube, or a degradation rate profile that is characterized by a variety of degradation rates along the length of the oriented polymer tube.

Advantageously, the oriented polymer tubes provided by the present disclosure may exhibit sufficient strength for use, for example, in vivo. Such tubes may be characterized as having sufficient compressive strength/resistance to radial compression to function in desired situations. For example, in some embodiments, the oriented polymer tubes obtained by the disclosed methods may be used, for example, as stents or as components of stents. Stents are exposed to large loads, for example, when inserted and left in a blood vessel, and should exert sufficient radial force to ensure that the stent remains in a narrow spot and prevents the vessel from constricting. Oriented polymer tubes made by the above-mentioned methods were tested (e.g., evaluated for repeated compression), and relevant findings from this testing are described herein below. Certain oriented polymer tubes made according to the planar orientation/concentric placement method exhibited higher energy absorption (normalized to wall thickness) than comparative materials (made via the conventional extrusion/expansion method described herein). All tested oriented polymer tubes made according to the planar orientation/concentric placement method exhibited improved hysteresis behavior, as measured by the X-intercept at the beginning of each cycle period.

It has also been found that various parameters of the disclosed methods (and properties of the disclosed materials) can result in differences in the physical properties of the resulting oriented polymer tube, allowing for processing flexibility. For example, the physical properties of the oriented polymer tube can be altered based on the present disclosure, for example, by selecting polymers (including, for example, copolymers) having different molecular weights and/or compositions, by changing the orientation mode of the film in a planar orientation/concentric arrangement manner (e.g., uniaxial vs. biaxial), by wrapping the polymer film/shape at different angles around the forming mandrel (e.g., along the axis or at a bias angle), by using different polymer films/shapes wrapped together around the mandrel, by wrapping such polymer films/shapes in different ways (e.g., staggered vs. stacked), etc. In some embodiments, the disclosed method includes arranging a plurality of units of stretched polymeric material (e.g., stretched films/profiles, etc.) in at least one of a stacked and staggered fashion, and wrapping the arranged plurality of units of stretched polymeric material at a bias angle (where the bias angle can be varied (including 0°)).

The end uses of the tubes provided by the present disclosure may be varied. As previously described herein, the molecular orientation provided by the disclosed methods may advantageously result in tubes of relatively high strength (e.g., radial strength/compressive strength), making these tubes particularly useful where such high strength is important. One such use relates to medical implants such as stents. The size of the stents obtained by certain embodiments of the disclosed methods may vary and may be appropriately designed for one or more specific uses. For example, in some embodiments, the length L of the stent may be from about 20 mm to about 200 mm. For example, in some applications, the stent may have a length L of about 40 mm to 100 mm, or any value therebetween, such as at least about 50 mm, 60 mm, 70 mm, 80 mm, or 90 mm. In some applications, the stent may have a length L of about 25 mm to 150 mm, or any value therebetween, such as at least about 50 mm, 75 mm, 100 mm, or 125 mm. Stents may also be longer or shorter than these exemplary values in other stent applications. Similarly, in some embodiments, the strut thickness of a stent may be from about 0.7 mm to about 0.4 mm. For example, in some applications, a stent may have a strut thickness of from about 0.08 mm to 0.15 mm, or any value therebetween, such as at least about 0.09 mm, 0.1 mm, 0.12 mm, 0.13 mm, or 0.14 mm. In some applications, a stent may have a strut thickness of from about 0.15 mm to 0.4 mm, or any value therebetween, such as at least about 0.2 mm, 0.25 mm, 0.3 mm, or 0.35 mm. Stents may also have strut thicknesses greater or less than these exemplary values in other stent applications. Similarly, stents may be formed having a variety of diameters. In some embodiments, the mid-body diameter of the stent (the diameter of the stent at a point equidistant from each end) can be from about 1.5 mm to about 40 mm, for example, a mid-body inner diameter of about 2.5 mm to 16 mm, or any distance within this range, for example, between about 3 mm and 14 mm, or between about 5 mm and about 10 mm.

Stents are generally cylindrically shaped devices that are often used to treat arterial disease. Arterial disease involves the deposition of lipids within the arteries and the subsequent formation of plaque along the arterial walls. These plaque lesions may be soft or may become hard and calcify, reducing the luminal space within the blood vessel over time, a process known as stenosis. To treat stenosis, a stent is typically deployed at the treatment site to help maintain luminal patency in the affected area of the blood vessel. A stent must have adequate radial strength to provide adequate radial support to the blood vessel to maintain vascular patency.

Stents are typically manufactured by laser cutting tubing into a radially expandable shape that includes interconnected structural elements or struts. During conventional deployment, such as in angioplasty balloon catheters, the stent struts undergo high local deformation, so the material from which the stent is manufactured must be highly deformable while maintaining high strength and stiffness (e.g., the material must exhibit high toughness). In many clinical therapeutic applications, stents are only needed temporarily, for example to maintain patency during critical healing phases or to deliver active agents or drugs to a target site.

Thus, in various embodiments, the tubes described herein may be used in particular as stents, since they can exhibit high compressive/radial strength as well as biodegradability/bioabsorbability. As disclosed herein, the ability to tailor the composition and physical properties of the layers that make up each tube allows for the manufacture of tubes that exhibit sufficient compressive/radial strength as well as biodegradability, e.g., that may be fully absorbed after their clinical use is complete. The tubes disclosed herein may be correspondingly processed/modified to serve the desired purpose in this regard, e.g., by cutting to the appropriate size/shape.

In other embodiments, the tubes provided by the present disclosure may be used in other contexts, including, for example, but not limited to, being placed around other tubes/tubular structures to act as heat shrink tubing, for example, to aid in fusing components of such tubular structures. In some embodiments, such heat shrink tubing made according to the disclosed methods exhibits enhanced thermomechanical properties, including, but not limited to, improved heat shrink capabilities.

It should be noted that while the present disclosure focuses on embodiments that include at least one crystallizable (e.g., crystallizable and biodegradable) polymer, the principles described herein are not so limited. Although the techniques outlined herein are advantageously applied in the context of such crystallizable polymers to orient the molecules therein to enhance the strength of the resulting tubular shape, these principles may provide other benefits that are not limited to crystallizable polymers as well (and may be applicable to amorphous polymers, including, for example, but not limited to, biodegradable amorphous polymers). Thus, in some embodiments, the present disclosure provides methods for subjecting polymeric materials, including amorphous biodegradable polymers, to planar stretching and concentric orientation or multilayer concentric expansion and concentric arrangement as generally disclosed herein. Typically, such amorphous polymer-containing products do not exhibit the high strength values previously described herein relative to crystallizable polymer-containing products (e.g., reinforced by molecular orientation), and may be used, for example, in the fabrication of other tubes (including, for example, but not limited to, serving as heat shrink materials to fuse other multi-layer tubes previously described) and as components of various devices, for example, reinforced by one or more additional components.

Many modifications and other embodiments of the invention will come to mind to one skilled in the art to which this invention pertains having the benefit of the teachings presented in the foregoing description. It is to be understood, therefore, that the invention is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Example 1
Plaques made of PL32, a polylactide resin purchased from Corbion Purac, were made by compression molding using a Carver press to a thickness of 125 μm. The PL32 plaques were then uniaxially stretched in a Brueckner laboratory stretcher to obtain a final thickness of approximately 25 μm. Plaques made of PLC7015, a copolymer resin of lactide and caprolactone obtained from Corbion Purac, were made by compression molding using a Carver press to obtain a thickness of approximately 40 μm. The PLC7015 plaques were then biaxially stretched in a Brueckner laboratory stretcher to obtain a final thickness of approximately 15 μm.

A rectangle was cut from each of the two films, one placed on top of the other, and wrapped around a metal mandrel with OD=2.8 mm with the PL32 film in contact with the mandrel. The film was wrapped so that the stretch direction of the PL32 film was aligned circumferentially. The wrapped mandrel was then tightly covered with Cortuff™ shrink film, a linear low density polyethylene (LLDPE) film obtained from Sealed Air Corporation, and taped in place. The assembly was then placed in a hot air circulating oven set at 80° C. for 30 minutes. After removing the assembly from the oven, the shrink film was removed and the now fused composite tube was slid off the mandrel. The final average wall thickness of the composite tube was approximately 130 μm.

Example 2
The procedure of Example 1 was repeated starting with a 125 μm plaque made from PL65, a polylactide purchased from Corbion Purac, uniaxially stretched to a final thickness of approximately 30 μm and a 40 μm plaque made from PLC7015, biaxially stretched to a final thickness of approximately 15 μm. The compression molded tube had a wall thickness of approximately 140 μm.

Example 3
The procedure of Example 1 was repeated using an oven temperature of 120°C.

Example 4
The procedure of Example 2 was repeated using an oven temperature of 120°C.

Example 5
The procedure of Example 1 was repeated using an oven temperature of 160°C.

Example 6
The procedure of Example 2 was repeated using an oven temperature of 160°C.

Example 7
The procedure of Example 1 was repeated using an oven temperature of 180°C.

Example 8
The procedure of Example 2 was repeated using an oven temperature of 180°C.

Cyclic Compression Testing The composite tubes from Examples 1-8 were tested in compression with an Instron apparatus equipped with a 10 lb load cell. The tube was positioned with its length axis perpendicular to the jaw movement. During the test, a disk clamped to the jaws was lowered onto the surface of the tube. The tube was compressed at 50% of its initial diameter every minute until the tube was deformed to 50% of its initial diameter, after which the jaws moved at the same speed to rise back to their starting position. The force required to compress the sample was measured by the load cell and converted to stress. This procedure was repeated five times for each tube with no pause between cycles. Values reported were the maximum stress, the energy absorbed by the tube over five cycles normalized for wall thickness, and the recovery of the tube as a percentage of the degree of compression. This last quantity is a measure of the hysteresis between compression cycles of the tube.

6A, 6B, and 6C show the maximum stress, normalized energy, and X-intercept from cyclic compression tests for tubes from Examples 3 and 4 compared to the control tube. The control tube was produced by extruding and expanding an input tube of PL38, a PLLA from Corbion Purac, to a final dimension of 100 μm wall thickness with an ID of 2.8 mm. This tube was then annealed at 120° C. for 30 minutes to match the compression formation time of the composite tubes from Examples 3 and 4. According to FIGS. 6A, 6B, and 6C, the tube from Example 4 shows a clear advantage over the control tube in maximum stress, normalized energy, and cycle-to-cycle hysteresis for all compression cycles. The tube from Example 3 shows a lower maximum stress value, but an improvement in normalized energy and cycle-to-cycle hysteresis.

Figures 7A, 7B, and 7C show the maximum stress, normalized energy, and X-intercept from cyclic compression tests on tubes from Examples 1, 3, 5, and 7. The effect of forming temperature on these properties is immediately apparent. For the PL32/PLC7015 composite structures disclosed in the examples, the optimal forming temperature for maximizing maximum stress and energy is 160°C.

8A, 8B, and 8C show the maximum stress, normalized energy, and X-intercept from cyclic compression tests for tubes according to Examples 2, 4, 6, and 8. For the PL65/PLC7015 composite structures disclosed in the examples, the optimal forming temperature for maximizing maximum stress and energy is 120°C.

Example 9
The procedure of Example 3 was repeated starting with 125 μm plaques made from PL32, biaxially stretched to a final thickness of about 10 μm, and 40 μm plaques made from PLC7015, biaxially stretched to a final thickness of approximately 15 μm. The finished composite tubes had an average wall thickness of approximately 120 μm.

Example 10
The procedure of Example 3 was repeated starting with 125 μm plaques made from PL32, biaxially stretched to a final thickness of about 10 μm, and 125 μm plaques made from PLC8516, a polylactide-co-caprolactone copolymer purchased from Corbion Purac, biaxially stretched to a final thickness of about 7 μm. The finished composite tubes had an average wall thickness of approximately 50 μm.

Example 11
The procedure of Example 4 was repeated using 125 μm plaques made from PLC 8516, uniaxially stretched to a final thickness of about 25 μm, and 125 μm plaques made from PLC 8516, a polylactide-co-caprolactone copolymer purchased from Corbion Purac, that were biaxially stretched to a final thickness of about 7 μm. The finished composite tubes had an average wall thickness of approximately 95 μm.

Example 12
The procedure of Example 3 was repeated using 125 μm plaques made from PLC8516, biaxially stretched to a final thickness of about 7 μm, and 45 μm plaques made from PC12, a polycaprolactone purchased from Corbion Purac, biaxially stretched to a final thickness of about 25 μm. The finished composite tubes had an average wall thickness of approximately 100 μm.

Example 13
A 125 μm plaque made from PLC8516 was biaxially stretched to a final thickness of about 7 μm. A rectangle was cut from this film and wrapped around a metal mandrel with OD=2.8 mm. The wrapped mandrel was then tightly covered with LLDPE shrink film and taped in place. The assembly was subsequently placed in a hot air circulating oven set at 120° C. for 30 minutes. After removing the assembly from the oven, the shrink film was removed and the now fused composite tube was slid off the mandrel. The final average wall thickness of the composite tube was approximately 90 μm.

Example 14
A plaque made of PL32 was cast to a thickness of 125 μm and biaxially stretched in a Brueckner laboratory stretcher to obtain a final thickness of approximately 15 μm. A plaque made of PLC7015 was cast to a thickness of 40 μm and then biaxially stretched to obtain a final thickness of approximately 15 μm. A 125 μm plaque made of PLC8516 was biaxially stretched to a final thickness of approximately 7 μm. Rectangles were cut from each film, stacked in the order PL32/PLC7015/PLC8516, and wrapped around a metal mandrel with OD=2.8 mm. The PL32 film was in contact with the mandrel. The wrapped mandrel was then tightly covered with a LLDPE film and taped in place. The assembly was subsequently placed in a hot air circulating oven set at 120° C. for 30 minutes. After the assembly was removed from the oven, the shrink film was removed and the now fused composite tube was slid off the mandrel. The final average wall thickness of the composite tube was approximately 80 μm.

Example 15
A 30 μm wall, 2.8 mm ID extruded and expanded tube made from PL32 resin (PLA) was slid onto the mandrel and the biaxially stretched PL32 film from Example 9 and the PLC7015 film were wrapped around the PLA tube, with the PLC7015 film in contact with the outer circumference of the PLA tube. The wrapped mandrel was then tightly covered with an LLDPE film and taped in place. The assembly was then placed in a hot air circulating oven set at 120° C. for 30 minutes. After removing the assembly from the oven, the shrink film was removed and the now fused composite tube was slid off the mandrel. The final average wall thickness of the composite tube was approximately 130 μm.

Claims (28)

1. A method for producing a multi-layered tube of a crystallizable biodegradable polymer, comprising:
Obtaining at least one stretched polymeric material exhibiting at least partial molecular orientation;
wherein obtaining the at least one stretched polymeric material comprises stretching at least one polymeric material;
the at least one polymeric material has a first dimension;
the at least one oriented polymeric material comprises at least one crystallizable biodegradable polymeric material;
The stretching increases the first dimension and provides a controlled level of molecular orientation;
forming the tube using the at least one oriented polymeric material and at least one adhesive polymeric material;
Including,
the tube has an exterior surface with a normal perpendicular to a length of the tube;
The tube exhibits a maximum stress value between 15 MPa and 26 MPa measured on the first compression cycle;
wherein the first compression cycle includes placing the tube in the apparatus with the longitudinal axis of the tube perpendicular to the movement of the jaws, and lowering a disk clamped in the jaws to compress the tube at 50% of its initial diameter every minute until the tube is deformed to 50% of its initial diameter;
The tube exhibits improved hysteresis behavior between cycles of less than 20% as measured by total longitudinal displacement as a percentage of the original length axis at the start of a fifth compression cycle, the start of the fifth compression cycle being the point at which the first compression cycle has been repeated four times without a break between cycles. The method of claim 1, wherein the stretching includes planar stretching. The method of claim 1, wherein one or more of the at least one polymeric material is one or more of a polymeric film, a polymeric monofilament, a polymeric tape, and a polymeric rod. the at least one polymeric material has a second dimension; and
2. The method of claim 1, wherein stretching the at least one polymeric material comprises stretching the at least one polymeric material to increase the second dimension, such that the at least one stretched polymeric material comprises a biaxially stretched polymeric material. The method of claim 1 , wherein obtaining the at least one stretched polymeric material further comprises combining the at least one adhesive polymeric material with the at least one polymeric material. The method of claim 5, wherein the combining includes forming a composite polymeric material including the at least one polymeric material and the at least one adhesive polymeric material in a layered form. The method of claim 5 , wherein the at least one adhesive polymeric material and the at least one polymeric material are combined prior to stretching the at least one polymeric material. The method of claim 1, wherein forming the tube comprises wrapping the at least one stretched polymeric material and the at least one adhesive polymeric material around a support. The method of claim 8, wherein the support has one or more of the following shapes: cylindrical, circular, rectangular, triangular, elliptical, polygonal, and tubular. The method of claim 8, wherein the wrapping comprises wrapping the at least one stretched polymeric material and the at least one adhesive polymeric material multiple times around the support such that the tube comprises multiple layers of the at least one stretched polymeric material and multiple layers of the at least one adhesive polymeric material. the at least one stretched polymeric material comprises a plurality of units of stretched polymeric material;
the multiple units of stretched polymeric material comprise different polymeric materials or the same polymeric material; and
9. The method of claim 8, wherein forming the tube comprises arranging the multiple units of stretched polymeric material in at least one of a stacked and a staggered manner and winding the arranged multiple units of stretched polymeric material at a bias angle. The method of claim 8, wherein the support is a mandrel and the method further comprises removing the tube from the mandrel. The method of claim 8, wherein the support comprises a device. The method of claim 13, further comprising forming a resultant composite based at least in part on the tube and the support, the resultant composite being a medical device. The method of claim 1, further comprising forming a medical device based at least in part on the tube. The method of claim 15, wherein forming the medical device includes cutting the tube into a stent. 17. The method of claim 16, further comprising applying one or more of a therapeutic agent, a covering, and a coating to the stent. The method of claim 1, wherein forming the tube includes applying at least one of heat and pressure to the at least one stretched polymeric material. The formation of the tube comprises:
forming a layered structure, comprising applying a shrink tube or shrink film around at least a portion of the at least one oriented polymeric material to obtain a layered structure;
applying at least one of heat and pressure to the layered structure;
The method of claim 1 , comprising: The formation of the tube comprises:
Inserting at least a portion of the at least one stretched polymeric material into a mold;
disposing the at least one expanded polymeric material on an expandable support;
applying at least one of heat and pressure to the at least one stretched polymeric material;
The method of claim 1 , comprising: The method of claim 1, wherein one or more of the at least one crystallizable biodegradable polymeric material is selected from the group consisting of poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(ε-caprolactone) (PCL), polyglycolic acid (PGA), poly(para-dioxanone) (PDO), poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethylcarbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), and copolymers and derivatives and combinations thereof. The method of claim 1, wherein the adhesive polymeric material is selected from the group consisting of poly(ε-caprolactone), poly(trimethylene carbonate), poly(D,L-lactide), poly((L-lactide)-co-ε-caprolactone), poly(L-lactide-co-trimethylene carbonate), poly(ε-caprolactone-co-trimethylene carbonate), poly(ethylene glycol), poly(L-lactide-co-poly(ethylene glycol)), and copolymers and derivatives and combinations thereof. The method of claim 1, wherein forming the tube comprises using the at least one stretched polymeric material and the at least one adhesive polymeric material, and the at least one crystallizable biodegradable polymeric material and the at least one adhesive polymeric material comprise the same polymeric material. The method of claim 1, wherein the at least one stretched polymeric material is stretched at least 10 percent of the maximum stretch ratio corresponding to each of the at least one polymeric material. The method of claim 1, wherein stretching the at least one polymeric material includes controlling one or more of the mechanical properties, thermodynamic properties, chemical properties, electrical properties, and degradation rate of the at least one polymeric material during stretching. The method of claim 1, wherein the at least one polymeric material is stretched between 300 percent and 1000 percent of an original dimension of the at least one polymeric material. A tube comprising at least one stretched polymeric material exhibiting at least partial molecular orientation, at least in part based on stretching at least one polymeric material, said at least one polymeric material having a first dimension, said stretching increasing said first dimension to provide a controlled level of molecular orientation, said at least one stretched polymeric material comprising at least one crystallizable biodegradable polymeric material and at least one adhesive polymeric material;
the tube has an exterior surface with a normal perpendicular to a length of the tube;
the tube exhibits a maximum stress value between 15 MPa and 26 MPa measured based on a first compression cycle, the first compression cycle including placing the tube in an apparatus with the tube's length axis perpendicular to the jaw movement, and lowering a disk clamped in the jaws to compress the tube at 50% of its initial diameter per minute until the tube is deformed to 50% of its initial diameter;
The tube exhibits improved hysteresis behavior between cycles of less than 20%, measured in total longitudinal displacement as a percentage of the original length axis, at the start of the fifth compression cycle, where the start of the fifth compression cycle is the point at which the first compression cycle has been repeated four times without a break between cycles. The method of claim 1 , wherein obtaining the at least one stretched polymeric material further comprises combining the at least one adhesive polymeric material with the at least one stretched polymeric material during or after the stretching.