Crosslinked radiopaque bioabsorbable polymers and devices made therefrom - Patents.com

Abstract

The present application provides polymeric materials having desirable properties for implantation in the human or animal body, particularly biocompatibility, biodegradability, radiopacity, and mechanical properties. Methods for making such polymeric materials, compositions or devices containing such polymeric materials, and uses of such polymeric materials, compositions, and devices are also disclosed. [Selected figure] Figure 2

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 715,928, filed August 8, 2018, and U.S. Provisional Application No. 62 / 754,234, filed November 1, 2018, each of which is incorporated by reference in its entirety.

[0002] The present invention relates to methods, materials and devices for medical devices, particularly medical devices for implantation into the human or animal body, and related materials and methods.Embodiments relate to materials that provide mechanical properties such as toughness, elasticity, structural strength combined with crush recovery, and properties such as biodegradability and radiopacity. [Background technology]

[0003] There are many areas of medical and therapeutic practice that have a need for devices, particularly implantable devices, with structures and materials that provide any or all of the following properties: high strength, high elasticity, and crush recovery (the ability to return to original shape and size after mechanical deformation). Additionally, the use of implantable devices within the body often creates a need for devices that are biocompatible, biodegradable, and / or radiopaque. Among these therapeutic areas that use implantable devices are interventions for diseases or conditions that affect body lumens, such as arteries, veins, various organ tracts, gastrointestinal, urinary, etc. Additionally, treatments that involve or surround joints require devices that can withstand the complex forces associated with these unique body regions.

[0004] For example, a particular area of ​​therapeutic delivery using implantable devices includes vascular disease, which includes diseases of the arteries and veins (see, for example, https: / / en.wikipedia.ORg / wiki / VasCulaR_disease by Wikipedia contributors). Subcategories include peripheral arterial disease (PAD), which is associated with reduced flow of blood in the arteries of the circulation outside the heart or brain.

[0005] In other examples, the implantable device may be used for treatment in areas of the body that characteristically undergo substantial movement. In such areas, properties such as fracture resistance and fracture recovery may be required to prevent damage or alteration of the structure of the implantable device due to the patient's activity. Applications may be relevant in areas such as orthopedics and localized drug delivery.

[0006] It has been common in prior art implantable medical devices to use Nitinol or similar elastic or "shape memory" metal alloys. For example, Nitinol stents have been used for the treatment of peripheral vascular disease, e.g., where an implant is required to restore and maintain patency in arteries or veins, particularly in areas subject to physical motion. Another aspect of the prior art use of Nitinol is for self-expanding implant structures, such as self-expanding stents.

[0007] However, a notable limitation of Nitinol is that it is not biodegradable, which results in clinical limitations including difficulty in retreatment in the area of ​​Nitinol stents and potential long-term fatigue fracture of the device, leading to poor clinical outcomes.

[0008] Implantable devices have also been made from conventional biodegradable polymers such as PLLA, and claims have been made for the crush recovery of certain designs. However, such devices offer very limited fracture resistance or are designed with inherently weak raw material formulations to prevent fracture. Furthermore, such conventional biodegradable polymers are not radiopaque, and in clinical applications, heavy metal marker bands have generally been required to achieve minimal visibility under fluoroscopy.

[0009] There is a need for materials for implantation within the body, and related devices and methods, that have properties to handle high stress environments in parts of the body that are exposed to tension, compression, bending, and other similar physical challenges, and that are also radiopaque and biodegradable. The mechanical challenges that need to be maintained in these applications require high scaffold performance in (a) extension / contraction, (b) compression, (C) bending, (d) bending, and (e) torsion. Figure 1 illustrates such physical challenges, using the upper limb and knee region as an example.

[0010] Additionally, various areas of the body are routinely or potentially subjected to substantial forces from impact or weight bearing.

[0011] High performance demands in such body regions require devices with high resilience to withstand complex fields of stress. This spectrum of properties can include crush recoverability, i.e., the ability to re-expand and recover following mechanical impact.

[0012] Similarly, significant advantages exist for devices that are biodegradable in vivo, for example, to avoid complications resulting from permanent placement and to allow maximum opportunity for retreatment at the implant site at a later time point. The device desirably provides an initial period of structural strength and integrity (e.g., about 1-6 months), followed by rapid degradation and excretion (e.g., within about 6-36 months).

[0013] Additionally, the materials and devices of the present invention can be radiopaque, allowing for precise fluoroscopic visualization during delivery and deployment. Summary of the Invention

[0014] As described herein, the disclosed embodiments address the need for medical devices and materials with high strength, high elasticity, and / or crush recovery, particularly where material embodiments allow for construction that is biocompatible, biodegradable, and / or radiopaque. In certain instances, embodiments having aspects of the invention have properties suitable for use in challenging bodily environments that are subject to high stress environments. Examples include implant devices for use in anatomical structures or soft tissues that undergo bodily motion. Implant devices requiring strength and toughness properties are applicable in orthopedics, drug delivery, and treatment of bodily lumens such as arteries, veins, tubes, and the like.

[0015] The embodiment includes a potentially crosslinkable polymeric material that can be preformed into a shape that is oriented to the requirements of a desired medical device. Such a preformed shape can then be crosslinked, starting with the crosslinkable polymeric material. One result of carrying out such a crosslinking reaction is to form a sufficient number or density of these crosslinks within the material, which enhances the properties to produce a strong, tough, elastic and / or crush-recoverable material with the preformed shape. Optional subsequent steps can be used to produce the final medical device.

[0016] In one purely illustrative, non-limiting example, polymeric materials having aspects of the invention may be used in creating scaffolds or other devices to restore and / or maintain patency or treat body lumens such as arteries, veins, various organ tracts, the gastrointestinal tract, and the like. Embodiments may include polymers that have high elasticity and crush recovery, providing the necessary strength to effectively support the vessel at the lesion site, followed by degradation and clearance, among other things, to allow retreatment of the vascular region. Additionally, polymers and devices having aspects of the invention may be radiopaque, allowing for accurate and convenient visualization by fluoroscopy during and after deployment.

[0017] Another illustrative example includes implants configured for controlled release of therapeutic agents, including localized delivery of drugs and / or biologics. Polymeric material embodiments of the present invention are particularly suited to target areas where bodily movements may apply high stresses to the delivery implant, resulting in undesirable fracture, movement, and / or risk of damage to the device. The elasticity, strength, and crush recovery of polymeric material embodiments allow the delivery implant to be able to withstand such dysfunction.

[0018] Such targeted implant delivery may include sustained release of a drug or other substance for a selected period of time, release in a preselected profile, and / or sequential release of two or more drugs or substances. The radiopacity of the polymeric material embodiments supports precise, minimally invasive placement of such implants. Subsequent biodegradation can remove residual material after the delivery function is completed.

[0019] Polymeric materials are disclosed herein. Various embodiments of the polymeric materials are described herein by utilizing chemical formulas to describe the materials or their components. Those skilled in the art will understand that such variables are generally defined consistently throughout the disclosure. Thus, if the description of a particular embodiment does not explicitly define a particular variable of such a chemical formula within the immediate context of that embodiment, those skilled in the art will understand that any description of that variable defined elsewhere herein may be applied to define that variable within the context of that embodiment. The polymeric materials include one or more of polymers, homogeneous polymers, copolymers, block copolymers, and / or blends or mixtures thereof, where the biocompatible polymeric materials are optionally inherently radiopaque and / or bioabsorbable; The polymeric material, as initially prepared, comprises at least one polymeric component having a potentially crosslinkable state such that the polymeric component contains functional groups configured to react when subjected to at least one crosslink-initiating treatment to crosslink the polymer; wherein the polymeric material, as initially prepared, comprises at least one polymeric component that has a rubbery or partially rubbery state at a temperature below 37°C; wherein the polymeric material has properties that enable it to be formed into a selected structural shape without initiating crosslinking, prior to being subjected to at least one crosslink initiating treatment; wherein the polymeric material has a crosslinked state such that, after being subjected to at least one crosslink initiating treatment, it has a sufficient number and / or density of crosslinks between polymer chains within the material to enhance the material properties to produce a tough, resilient material such that a selected shape comprised of the crosslinked polymeric material has crush recoverable properties that allow it to substantially return to the selected shape after mechanical deformation.

[0020] In some embodiments of the polymeric material of the preceding paragraph, the material is in a crosslinked state, and the material has undergone at least one initial treatment. In some embodiments, the at least one polymeric component having a rubbery or partially rubbery state when initially prepared comprises one or more of PCL (polycaprolactone), PTMO (polytetramethylene oxide), PTMC (polytrimethylene carbonate), PEG (polyethylene glycol), polydioxanone, polyglycolide, polylactide, and any comacromers thereof. In some embodiments, the at least one polymeric component having a potentially crosslinkable polymeric material comprises an essentially radiopaque biocompatible bioresorbable polymer, the polymer comprising one or more repeat units having the following structure:

[0021] [ka]

[0022] wherein each of a, b, and c, if present, is independently present in an amount ranging from about 1% to about 5%, from about 1% to about 10%, from about 1% to about 15%, from about 1% to about 20%, from about 1% to about 25%, from about 1% to about 30%, from about 1% to about 35%, from about 1% to about 40%, from about 1% to about 45%, from about 1% to about 50%, from about 5% to about 10%, from about 5% to about 15%, from about 5% to about 20%, from about 5% to about 25%, from about 5% to about 30%, from about 5% to about 35%, from about 5% to about 40%, from about 5% to about 45%, or from about 5% to about 50% by weight of the polymer; The polymer is a random or block copolymer; X 1 , X 2 , X 3 and X 4 are each independently Br or I; Each of y1, y2, y3, and y4 is independently 0, 1, 2, 3, or 4; a, b and c are weight percentages ranging from 0 to 100%, and a+b+c=100%, and A1, A2 and A 1 is as follows

[0023] [ka]

[0024] provided that the linking group to the adjacent oxygen atom is independently selected from the group consisting of A1, A2 or A 1 By the linkage, an OO or ON bond is implied, where there is no adjacent oxygen atom; B is at least one polymeric component that has a rubbery or partially rubbery state when initially prepared; R X , R y , R 3 are each independently H or C1-C6 alkyl; R 4 and R 4a are each independently C1-C 10 is alkylene; R1, R2, R3 and R4 are each independently a linear or branched, saturated or unsaturated C1-C12 alkylene, 2-15 membered heteroalkylene, or 2-15 membered heteroalkenylene, each optionally containing 1-3 heteroatoms independently selected from O, NR, and S; R is H or C1-C6 alkyl; Each of R1, R2, R3 and R4 optionally includes a pendant Z group that optionally includes a functional group that can react to crosslink the polymer after it has been fabricated into the desired shape, either by an elimination reaction or a free radical mechanism.

[0025] In some embodiments, the polymeric material comprises a polymer that includes one or more repeat units having the following structure:

[0026] [ka]

[0027] During the ceremony, M is a low Tg macromer comprising PTMC, PTMO, PCL, PEG, or any co-macromer thereof, optionally further comprising one or more of PLLA, PGA, and polydioxane; Z=O or NH; and X is a single bond or a linear or branched alkylene, alkenylene, or phenylene, each of which may be substituted with one or more substituents selected from alkyl, halogen, -OH, and -C(O)OH; and The polymer is a random or block copolymer; Here, at least one crosslinking initiation treatment comprises heating the potentially crosslinkable polymeric material to induce transesterification.

[0028] In some embodiments, the polymeric material comprises a polymer that includes one or more repeat units having the following structure:

[0029] [ka]

[0030] During the ceremony, M is a low Tg macromer comprising PTMC, PTMO, PCL, PEG or any co-macromer thereof, optionally further comprising one or more of PLLA, PGA, and polydioxane; and Z=O or NH; and the polymer is a random or block copolymer; At least one crosslink initiation treatment involves a free radical initiated chain reaction of the polymer in the presence of a free radical initiator.

[0031] In some embodiments, the polymeric material comprises a polymer that includes one or more repeat units having the following structure:

[0032] [ka]

[0033] During the ceremony, M is a low Tg macromer comprising PTMC, PTMO, PCL, PEG, or any co-macromer thereof, optionally further comprising one or more of PLLA, PGA, and polydioxane; and Z=O or NH; and At least one crosslink initiation treatment involves a free radical initiated chain reaction of a polymer in the presence of a free radical initiator.

[0034] In some embodiments, the moiety in bracket "b" has the following structural formula:

[0035] [ka]

[0036] is replaced by the t-butyl ester of the diphenolic acid.

[0037] In some embodiments of the polymeric material, R=H. In some embodiments, R is a straight or branched chain alkyl group. In some embodiments, R is CH3 or C2H5.

[0038] In some embodiments, when the polymeric material has cross-linking functionality on the side chains of an essentially rubbery PTMC, it comprises a polymer that includes one or more repeat units having the following structure:

[0039] [ka]

[0040] In the formula, each of X and y is independently an integer ranging from about 1 to about 50.

[0041] In some embodiments, the polymeric material comprises a polymer comprising at least two distinct types of repeat units, each such type of repeat unit having a different type of potentially crosslinkable functional group; One such repeat unit is a structural radiopaque component that includes a crosslinkable acryloyl or methacryloyl moiety on a pendant group; Another such repeating unit is an essentially rubbery component which contains crosslinkable acryloyl or methacryloyl moieties in pendant groups.

[0042] In some embodiments, the polymeric material comprises a polymer that includes one or more repeat units having the following structure:

[0043] [ka]

[0044] In the formula, Z is O, S or NH.

[0045] Also disclosed herein is a medical device. The medical device comprises at least one structural portion; Here, the structural portions are preformed from a potentially crosslinkable polymeric material to have a preformed shape, the potentially crosslinkable polymeric material comprising one or more polymers or copolymers that are inherently radiopaque, biocompatible, and / or bioabsorbable.

[0046] Following formation of the preformed shape of the structural portion, the potentially crosslinkable polymeric material of the structural portion is subjected to at least one crosslink initiation treatment to form a sufficient number and / or density of crosslinks between polymer chains within the material to enhance the material properties to create a strong, tough, resilient, and / or crush recoverable material having the preformed shape, and optionally, the crosslinked preformed shape is further processed to make a medical device.

[0047] In some embodiments of the medical devices described herein, the potentially crosslinkable polymeric material comprises an inherently radiopaque biocompatible bioresorbable polymer, the polymer comprising one or more repeat units having the following structure:

[0048] [ka]

[0049] wherein each of a, b, and c, if present, is independently present in an amount ranging from about 1% to about 5%, from about 1% to about 10%, from about 1% to about 15%, from about 1% to about 20%, from about 1% to about 25%, from about 1% to about 30%, from about 1% to about 35%, from about 1% to about 40%, from about 1% to about 45%, from about 1% to about 50%, from about 5% to about 10%, from about 5% to about 15%, from about 5% to about 20%, from about 5% to about 25%, from about 5% to about 30%, from about 5% to about 35%, from about 5% to about 40%, from about 5% to about 45%, or from about 5% to about 50% by weight of the polymer; the polymer is a random or block copolymer; X 1 , X 2 , X 3 and X 4each independently is BR or I; Each of y1, y2, y3, and y4 is independently 0, 1, 2, 3, or 4; a, b and c are weight percentages ranging from 0 to 100%, and a+b+c=100%, and A1, A2 and A 1 is as follows

[0050] [ka]

[0051] provided that the linking group to the adjacent oxygen atom is independently selected from the group consisting of A1, A2 or A 1 By the connection, an OO or ON bond is implied, in which case there is no adjacent oxygen atom, B is at least one polymer component having a rubbery or partially rubbery state when initially prepared; R X , R y , R 3 are each independently H or C1-C6 alkyl; R 4 and R 4a are each independently C1-C 10 is alkylene, R1, R2, R3 and R4 are each independently a linear or branched, saturated or unsaturated C1-C 12 alkylene, 2-15 membered heteroalkylene, or 2-15 membered heteroalkenylene, each optionally containing 1-3 heteroatoms independently selected from O, NR, and S; R is H or C1-C6 alkyl; Each of R1, R2, R3 and R4 optionally comprises a pendant Z group; The pendant Z groups optionally contain functional groups that can react, either by elimination reactions or free radical mechanisms, to crosslink the polymer after it has been fabricated into the desired shape.

[0052] In some embodiments of the medical devices described herein, the potentially crosslinkable polymeric material comprises the following structure:

[0053] [ka]

[0054] During the ceremony, M comprises a low Tg macromer and further comprises PTMC, PTMO, PCL, PLLA, PGA, polydioxane, or any co-macromer thereof; Z=O or NH, and X is a linear or branched alkylene, alkenylene, or substituted or unsubstituted phenylene; Here, at least one crosslink initiation treatment involves a free radical initiated chain reaction of a polymer in the presence of a free radical initiator.

[0055] In some embodiments of the medical devices described herein, the potentially crosslinkable polymeric material comprises the following structure:

[0056] [ka]

[0057] In some embodiments of the medical devices described herein, the potentially crosslinkable polymeric material comprises the following structure:

[0058] [ka]

[0059] In some embodiments of the medical devices described herein, the preformed shape of the structural portion is tubular. In some embodiments, the tubular preformed shape of the structural portion is laser cut to form at least a portion of the vascular scaffold device, either before or after crosslinking of the polymeric material.

[0060] Also provided herein is a method of making a medical device, the medical device having a structure essentially comprising a radiopaque, biocompatible, and / or bioabsorbable polymeric material, the structure having at least one of the following properties: toughness, elasticity, impact resistance, and / or crush recovery upon deformation, the method comprising the steps of, in any functional order: (a) preparation of a potentially crosslinkable polymeric material comprising a polymer or copolymer that is inherently radiopaque, biocompatible and / or bioabsorbable and capable of subsequently forming crosslinks between polymer chains when subjected to at least one crosslink initiation treatment; (b) forming at least one preformed structural feature portion, the preformed structural feature portion comprising a potentially crosslinkable polymeric material; (c) subsequent to forming step (b), subjecting the preformed structural feature portion to at least one crosslink initiating treatment to form crosslinks between polymer chains, resulting in the formation of a crosslinked structural feature portion having at least one of the following properties: toughness, elasticity, impact resistance, and / or crush recovery upon deformation; (d) optionally carrying out forming, treating and / or conditioning steps after the treatment step (c) to modify the crosslinked structural features; and (e) manufacturing a medical device to include a cross-linked structural feature;

[0061] In some embodiments, a medical device is made using all or some of the steps of the methods disclosed herein, in any order.

[0062] In some embodiments, the device comprises a vascular scaffold.

[0063] In some embodiments, the medical device comprises a polymer comprising one or more repeat units having the following structure:

[0064] [ka]

[0065] In the formula, X and y each independently represent an integer of about 1 to 50.

[0066] In some embodiments, the device comprises a polymer comprising one or more repeat units having the following structure:

[0067] [ka]

[0068] In the formula, Z is O, S or NH.

[0069] In some embodiments, the medical device comprises a coating that includes a drug and / or agent. These and other embodiments are described in more detail below. [Brief description of the drawings]

[0070] The above and other features of the embodiments of the present invention will now be described with reference to the drawings of the embodiments. The illustrated embodiments are intended to be illustrative and not limiting. The drawings include the following figures: [Figure 1] FIG. 1 depicts various mechanical challenges experienced by specific body regions due to body movement, as exemplified by the leg and knee regions. [Diagram 2] 1 is a flow chart outlining an exemplary approach for making a medical device having aspects of the present invention (Scheme I). [Diagram 3] FIG. 2 shows an example of a reaction scheme for preparing a potentially crosslinkable polymer via transesterification (Scheme II). [Figure 4] FIG. 1 shows an example of a reaction scheme for preparing a potentially crosslinkable polymer via free radical polymerization (Scheme III). [Diagram 5]FIG. 4 shows another example of a reaction scheme for preparing a potentially crosslinkable polymer via free radical polymerization (Scheme IV). [Figure 6] FIG. 1 shows a reaction scheme for preparing a potentially crosslinkable polymer via free radical polymerization using trimethylene carbonate oligomer diol with HEMA-like double bonds in the side chain (Scheme V). [Figure 7] FIG. 6 shows a reaction scheme for preparing potentially crosslinkable polymers in which several different types of potentially crosslinkable functional groups are present (Scheme VI). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0071] In accordance with aspects of the present invention, the use of implantable devices within the body often creates a need for devices that are biocompatible, biodegradable, and / or radiopaque. Among these therapeutic areas that use implantable devices are interventions for diseases or conditions that affect body lumens, such as arteries, veins, various organ ducts, gastrointestinal, urinary, etc. Additionally, treatments at or surrounding joints require devices that can withstand the complex forces associated with these unique body regions.

[0072] Certain embodiments include bioabsorbable polymer scaffolds suitable for use in diseased vessels of the circulatory system, particularly those affected by peripheral arterial disease. Certain aspects of certain embodiments of the present invention include the use of cross-linked (X-linked) polymeric materials, which provide a tough, elastic framework.

[0073] The formation of a sufficient number or density of these crosslinks within a material enhances properties to create a tough, resilient, generally crush recoverable material.

[0074] Examples of polymer embodiments having aspects of the present invention may include copolymers that, when initially synthesized and isolated, have a rubbery or partially rubbery state, for example, copolymers having a Tg (glass transition temperature) of less than 37° C. In certain examples, this desired property can be achieved by incorporating macromers such as PCL (polycaprolactone), PTMO (polytetramethylene oxide), PTMC (polytrimethylene carbonate), PEG (polyethylene glycol), polydioxanone, and co-macromers thereof into the copolymer.

[0075] In an embodiment of a method having aspects of the present invention, a partially rubbery polymeric stock can be prepared that has moieties or functional groups incorporated along the polymer chain that have the potential (in the initial or uncrosslinked stock state) of crosslinking by reaction with sites on adjacent polymer chains. Such materials can be described as potentially crosslinkable polymeric materials.

[0076] The polymeric material in its initial unconsolidated material state may be formed into a physical configuration suitable for a desired device or product (preform). It is noted that such preform configuration may closely resemble the desired final product or device, or may have an intermediate form suitable for subsequent processing.

[0077] Such preforms can then be subjected to conditions suitable to activate latent crosslinking moieties on the polymer to produce a crosslinked polymeric device or product comprising the polymeric material in a crosslinked material state to provide desired properties (such as toughness, elasticity, and / or crush recovery). In an exemplary embodiment, the initially unlinked potentially crosslinkable copolymer material may be preformed into a tubular shape (e.g., by sheet rolling, dip coating, extrusion / blow molding, etc.). The tubular preform is then exposed to conditions suitable to activate the crosslinkable moieties (e.g., heat treatment, radiation, chemical or solvent application).

[0078] Embodiments of polymeric materials having aspects of the present invention can be made according to a number of schemes, examples of which are described below.

[0079] Scheme I - Potentially crosslinkable pendant groups on monomers / macromers Scheme I includes a general exemplary approach for making crosslinked bioabsorbable polymeric devices. Figure 2 is a flow chart showing the steps of Scheme I, which can be outlined as follows:

[0080] A. A first component having a pendant functional group A polymeric material is prepared having a first biodegradable (and optionally radiopaque) monomer or macromer component ("latently crosslinkable component") that has pendant moieties or functional groups suitable for eventual crosslinking reactions, but is protected or sequestered from internal crosslinking reactions. Examples include I2DTtBu (I2-desaminotyrosyl-tyrosine tert-butyl ester) and its macromers, or components with acryloyl or methacryloyl moieties in the pendant groups, and the like, and mixtures thereof. The protected functional groups on the side chains are converted to crosslinkable groups after the polymer is prepared. The crosslinkable groups should remain unreacted during the preforming process by various means, for example, heat treatment, solvent casting, or 3-D printing. Crosslinking then occurs only in the next stage of initiation, for example, by heating, radiation, or other means. The first component may be made of one or more compounds.

[0081] B. A second component that has "rubbery" or elastic properties The polymeric material also includes a second, generally rubbery, biodegradable component (macromer or monomer) that serves to affect the thermal / mechanical properties of the copolymer, such as the Tg or glass transition temperature (the "rubbery component"). Examples include, but are not limited to, PCL (polycaprolactone), PTMO (polytetramethylene oxide), PTMC (polytrimethylene carbonate), PEG (polyethylene glycol), polydioxanone and the like, and their co-macromers.

[0082] It should be noted that in this example, the component having pendant functional groups ("A") and the component having "rubbery" properties ("B") are described as separate components, and in alternative embodiments, the component having "rubbery" properties may have pendant functional groups suitable for crosslinking, as described below.

[0083] C. Polymerization reactions to produce potentially crosslinkable copolymers The first potentially crosslinkable component is copolymerized with the second rubbery component to form a copolymer material. The pendant moieties are non-reactive during the copolymerization process (e.g., tert-butyl esters). Thus, the copolymer can be isolated without inducing crosslinking. Note that in certain embodiments, either or both components may contain potentially crosslinkable groups.

[0084] After the copolymerization process, the pendant moieties are converted to activated forms, such as methacryloyl moieties or other moieties that can react via nucleophilic substitution (for free radical crosslinking). However, during the preform process, these activated moieties remain inactive. The crosslinking process is carried out on the preform.

[0085] D. A preformed version of the desired device The latent X-linked copolymers can be formed into the desired functional form and / or shape using methods that do not initiate X-linking of the pendant functional groups ("preforms"). Such preform versions of the desired device can have a form that is a selected approximation of the final device form. Exemplary vascular scaffold preforms can use methods such as dip coating, sheet pressing and rolling, blow molding, and the preforms thus produced can be in a tubular shape with dimensions suitable for a subsequent laser cutting operation. The tube (or other preform) can then be adapted as desired for a particular purpose. For example, a tube preform can be cut by laser into a predetermined pattern of rings and interconnections to form a series of rings of a stent or scaffold, such as for vascular support.

[0086] E. Preforms subjected to crosslinking-inducing conditions The preform containing potentially X-bondable copolymeric material can then be subjected to conditions to induce crosslinking reactions between polymer chains. Examples include esterification reactions, etc., or free radical polymerization of available methacryloyl moieties. Inducing conditions include incorporation of heat, radiation, solvents or free radical initiators, such as by thermal treatment or radiation. Crosslinking results in substantial changes to the thermomechanical properties of the preform material, for example, creating toughness, elasticity, impact resistance, and / or a crush-recoverable structure.

[0087] It should be noted that the preform version of the desired device for step E may have a form that is a selected approximation of the final device form. Thus, in certain embodiments, the preform may have a form and shape that is intended to be used in its final form after crosslinking in step E, while in other embodiments the preform may have a size and / or shape suitable for any subsequent steps, such as machining, etching, coating, etc. (not shown in FIG. 2), prior to use.

[0088] While the preform may consist solely of the potentially crosslinkable copolymer material of step E, in still further embodiments, the preform may include other components or materials as well. For example, the preform may include an assembly of interconnected portions, some portions including the potentially X-bondable copolymer material of step E and other portions including materials that are not potentially crosslinkable (e.g., metal components).

[0089] Scheme II - Crosslinking by transesterification One exemplary embodiment of an aspect of the present invention is a method for producing crosslinked biodegradable radiopaque polymeric materials and related devices by means of transesterification.

[0090] FIG. 3 shows the chemical reactions and steps of Scheme II step by step.

[0091] A. Formation of Copolymers with Protected Functional Groups In certain exemplary embodiments illustrated, the precursor group includes I2DTE (diiodized deaminotyrosine ethyl ester), a component with a protected functional group that can be converted to I2DTtBu (tert-butyl substituted I2DTE)-X linkable group, and a diol or hydroxy terminated macromer of the structure HO-M-OH, where M is a low Tg macromer selected from the group including PTMC, PTMO, PCL, PEG, PLLA, PGA, PLGA, polydioxane, etc., and copolymers thereof. The precursor components can be linked via phosgenation, as exemplified by the description in Example 2 herein. The functional sites on the precursor group can be protected from reaction during polymerization, such as by the tert-butyl group of I2DTEtBu. Note that in the illustrated example, a, b, and c indicate the percent composition of each precursor, and each precursor can vary from 0% to 100%, such that a+b+c=100%.

[0092] B. Removal of Protective Pendant Groups and Formation of Potentially Linkable Functional Groups The copolymer material can then be esterified with a potentially linkable group. This method can first include removing a protective pendant group, such as the tert-butyl protective group in the example shown. In a particular embodiment illustrated, the linkable group has the structure HZCH2-X-CH2-OH, where Z is selected from the group consisting of O, S, and NH; X is selected from the group consisting of a bond, an alkylene group, or an alkenylene group having 1-10 carbon atoms, and a substituted or unsubstituted phenylene group. Example 4 below describes esterification with 1,3-propanediol as a potentially linkable group. Example 6 below describes esterification with ethanolamine as a potentially linkable group (i.e., Z=NH).

[0093] C(1) Formation of device on preform A preform having a selected size and shape (eg, of a medical device such as a stent) may be formed containing the copolymer material of Step B.

[0094] C(2) Heating to induce transesterification Heat can be applied to induce or induce transesterification in which bondable groups (e.g., 1,3-propanediol) are attached to adjacent weak sites on the polymer chains of the copolymer material, for example, as described in Example 5.

[0095] Scheme III - Crosslinking via free radical addition Another exemplary embodiment having aspects of the present invention is a scheme for making crosslinked biodegradable radiopaque polymeric materials and related devices, where crosslinking can be achieved by means of free radical addition.

[0096] FIG. 4 shows the chemical reactions and steps of Scheme III step by step.

[0097] A. Formation of copolymers with protected functional groups In certain exemplary embodiments exemplified, the precursor groups include I2DTE (diiodinated deaminotyrosine ethyl ester), I2DTtBu (tert-butyl substituted I2DTE) - a component having a protected functional group that can be subsequently converted to an X-linking group, and a diol or hydroxy terminated macromer of the structure HO-M-OH, where M is a low Tg macromer selected from the group including PTMC, PTMO, PCL, PEG, PLLA, PLGA, polydioxane and co-macromers thereof, and where a, b and c represent the percent composition of each precursor, each of which can be from 0 to 100%, so that a+b+c=100%.

[0098] As in Scheme II above, the precursor components can be linked via phosgenation, and functional sites on the precursor side chains can be protected from reaction during polymerization, for example, by the tert-butyl group of I2DTtBu.

[0099] B. Removal of pendant groups and formation of potentially linkable functional groups As in Scheme II, the copolymer material can then be esterified with a potentially linkable group. In the embodiment shown in FIG. 4, this group is a HEMA-like group, e.g., when Z=O, the group comprises 2-hydroxyethyl methacrylate (HEMA). In other embodiments, the HEMA-like group can be 2-aminoethyl methacrylate hydrochloride (AEMA). In this regard, see Examples 9, 12, 13, and 14. This method can first include removal of a protecting pendant group, e.g., the tert-butyl protecting group in the example shown. The HEMA-like group can be attached to the COOH group, e.g., using the procedure described in Example 9 below for AEMA as the HEMA-like group.

[0100] C(1) Formation of device on preform A preform having a selected size and shape can be made as described in Scheme II above.

[0101] C(2) Heat with a free radical initiator to induce crosslinking A free radical initiator such as AIBN can be applied in conjunction with heat treatment to induce crosslinking such as the method described in Example 19 below.

[0102] It should be noted that one or more free radical initiators (e.g., AIBN) can be introduced and distributed within the potentially crosslinkable polymeric material during the device fabrication process, as described below in Examples 21 and 22. Examples include spray casting / coating and dip casting, where the initiator can be dissolved or suspended in a solvent along with the potentially crosslinkable copolymer.

[0103] Alternative Monomers in Schemes II and III In both Schemes II and III, DTtBu can be replaced with the t-butyl ester of a diphenolic acid, the structure of which is shown below.

[0104] [ka]

[0105] Additionally, glycerol, trifunctional polycaprolactone, trifunctional PTMC, etc., with appropriate modifications, can be used for cross-linking purposes.

[0106] Scheme IV - Using PRD-diI2DAT instead of I2DTE FIG. 5 shows the chemical reactions and steps of formula IV step by step. In this particular example, the method is similar to that of Scheme III. In this embodiment, one precursor comprises propane-1,3-diylbis(3-(4-hydroxy-3,5-diiodophenyl)propanoate, also known as PRD-diI2DAT, in place of (or in combination with) I2DTE. The meanings of the terms are otherwise as described for Scheme III.

[0107] Scheme V - Polymer with crosslinkable groups in the rubber component FIG. 6 shows the steps of Scheme V, including preparing a potentially crosslinkable polymer. In this particular example, a crosslinked polymer device is made from a potentially crosslinkable polymer including a TMC oligomer diol having a pendant group (HEMA-like group) containing a double bond, where the TMC oligomer diol is copolymerized with a series of different oligomer or macromer diols, and the particular diol is selected to impart the desired properties to the resulting polymeric structural material. Embodiments having aspects of the invention herein are suitable for use in implantable devices requiring elasticity and crush recovery capabilities. Examples of such devices include stents for peripheral artery treatment, such as SFA (superficial femoral artery) stents, etc.

[0108] A. Preparation of Oligomeric TMC Diols with Pendant HEMA-like Groups In the first step, an oligomer is prepared from glyceryl monomethacrylate (commercially available, for example, from PolySciences Inc.) and TMC (trimethylene carbonate) using a suitable catalyst (see Example 15 below). The resulting oligomer is hydroxy-terminated, diol, and comprises chains of polymerized TMC containing at least one pendant HEMA-like group derived from the glyceryl monomethacrylate moiety. For convenience, this resulting oligomer (or a mixture of similar oligomers) may be referred to as "OligoTMC / HEMA," although the TMC oligomer diol may be referred to as the "chain extender" and the HEMA-like pendant may be referred to as the "bridging group."

[0109] B. Copolymerization with Selected Monomer, Macromer, or Oligomer Diols The "OligoTMC / HEMA" from step A can be reacted with other diols to produce copolymers of selected composition. For example, the diols may be selected from PTMC, PTMO, PCL, PEG, PLLA, PG, polydioxanes and their co-macromers, etc. In embodiments, the diols can include monomers, macromers or oligomers including the compounds described below: I2DTE, PRD-diI2DAT, etc.

[0110] Polymerization can be accomplished using reactants such as triphosgene (TP), oxalyl chloride, and the like, and mixtures thereof, which form linkages (eg, carbonate linkages and / or oxalyl ester linkages) between adjacent diols.

[0111] In certain embodiments, the copolymer material may have a portion of oxalyl ester linkages in the polymer chain in the sequence with carbonate linkages. Such a mixture of linkage types may be used to "tune" the biodegradation properties of the polymer material. It should be noted that the copolymerization process may be carried out in various modes of reaction sequence, such as simultaneous reaction mixtures, sequential reactions, alternating reactants (e.g., alternating addition of TP and oxalyl chloride to the reaction mixture), etc.

[0112] C. Formation of a device preform incorporating a free radical initiator and a crosslinker for device formation These steps can be carried out as described above for Schemes III and IV.

[0113] Scheme VI - Polymers with multiple crosslinkable groups Whereas in Schemes II, III and IV the crosslinkable functionality was present on the structural non-rubbery component of the copolymer, in Scheme V the crosslinkable functionality is present on the rubbery component. Copolymerization of a component containing a tert-butyl group (I2DTtBu) and a component similar to "OligoTMC / HEMA" results in the incorporation of two different types of potentially crosslinkable functional groups.

[0114] Figure 7 shows the process of Figure 6 in which an exemplary copolymer "structural" portion similar to Figure 5 (with protecting groups) is polymerized with an exemplary copolymer "rubbery" portion similar to Figure 6 (comprising oligomeric TMC with HEMA-like pendant groups). Using methods described herein, the protecting groups are removed from the structural portion and the HEMA-like functional groups are attached.

[0115] The resulting multifunctional copolymer feedstock can then be formed into a device preform and subsequently cross-linked by activation of a free radical initiator as described herein. It should be noted that such cross-links can be formed between either "rubber to rubber", "structure to structure" or "rubber to structure" components.

[0116] Non-iodized embodiments It should be noted that while the various diagrams and schemes depicted herein may include certain halogenated (iodized) versions of the chemical structures and moieties described, various embodiments of polymeric materials having aspects of the present invention may also include non-halogenated (non-iodized) embodiments of these structures and schemes. For example, non-iodized potentially non-crosslinkable or crosslinked polymeric materials may be suitable for use in medical devices where radiographic visualization is not required.

[0117] Additional Alternatives It should be noted that other monomers may be substituted for the I2DTE and PRD-diDAT shown above. Methods for making and using these are described in U.S. Patent and Application Nos.: 6,284,862; 6,475,477; 6,475,477; 8,685,367; 7,473,417; 8,008,528; 8,461,289; 8,551,511; 8,252,887; 8,415,449; 9,080,015; 8,765,161; 9,605,112; 8,883,861; 9,416,090; 2015-0045,451; and 2016-0177,028, among many others, which are incorporated herein by reference.

[0118] [ka]

[0119] For example, the above-referenced US Pat. No. 6,475,477 describes the following as Formula I:

[0120] [ka]

[0121] wherein Formula I represents a diphenol compound substituted with at least one bromine or iodine atom, where each X1 and X2 is independently an iodine or bromine atom, Y1 and Y2 are independently 0 to 2, and R9 is an alkyl, aryl, or alkylaryl group having up to 18 carbon atoms.

[0122] Further description of both Formula I and various other monomers and polymers from U.S. Patent No. 6,475,477 is incorporated herein by reference. Such monomers and polymers may be included in the polymeric materials of the embodiments herein by those skilled in the art without departing from the spirit of the invention described herein.

[0123] Drugs and Drug Coatings The devices made from the embodiments of the polymeric materials described herein can be implantable devices with drug or pharmaceutical agent content. For example, the devices can include stents or scaffolds suitable for vascular implantation and can include drugs / drugs in the coating. Drug-eluting stents (DES) include drug coatings on all or part of the structure, which include drugs such as anti-restenosis drugs (e.g., sirolimus, paclitaxel, everolimus, etc.) in a carrier polymer. Various other therapeutic agents or drugs have been suggested (see, for example, European Patent EP1789097). The coating of drug-eluting stents can include coating polymers that are biodegradable so that the coating releases the drug as it degrades. EXAMPLES

[0124] Further embodiments are disclosed in further detail in the following schemes and examples, which are not intended to limit the scope of the claims in any way.

[0125] Example 1 Preparation of poly(trimethylene carbonate) PTMC8.5K The following example illustrates the preparation of 8.5 KDa PTMC macromer: To a 500 mL, 2-neck flask equipped with an overhead stirrer and nitrogen inlet was added trimethylene carbonate (250 g, 2.45 mol), ethylene glycol (1.5 g, 0.025 mol).

[0126] [ka]

[0127] The flask was placed in a 110°C oil bath under a dry nitrogen atmosphere with stirring using a stainless steel stirrer. After the solids had completely melted, the temperature of the oil bath was increased to 130°C. 0.15 g of Sn(II) octoate was then added to the reaction mixture using a pre-weighed 1 mL syringe. Stirring was continued for 3.5 hours and then cooled to room temperature. The viscous oil was transferred to a 1 L beaker with 200 mL of dichloromethane. The polymer was precipitated as a thick oil by adding 250 mL of heptane with stirring. The product was further purified by dissolving in 200 mL of dichloromethane and precipitating with 250 mL of heptane. The thick syrupy polymer was dried under vacuum at ambient temperature. 1 H NMR showed Mn at 8.5K.

[0128] Examples 2, 3, 4, and 5 below collectively illustrate examples suitable for preparing terpolymers with pendant propanediol functionality (potentially crosslinkable), which can then be thermally crosslinked.

[0129] Example 2 Preparation of poly(50% I2DTE-co-10% I2DTtBu-co-40% PTMC8.5K carbonate) To a 1 L 3-neck flask were added 25 g of I2DTE, 5 g of I2DTtBu, 20 g of PTMC8.5K prepared according to Example 1, and 265 mL of dichloromethane (DCM). The mixture was stirred with an overhead stirrer at 300 Rpm, and 16.25 mL of pyridine was added when all solids were in solution. Triphosgene (5.32 g) was dissolved in 15 ml of dichloromethane and transferred to a 25 ml syringe. Using a syringe pump, the contents of the syringe were added to the flask at a rate of 6.3 mL / min until the reaction mixture became viscous. The reaction was quenched by adding a mixture of 45 mL of THF and 5 mL of water. With stirring at 300 rpm, 450 mL of 2-propanol (IPA) was added to the flask to precipitate the polymer. Stirring was continued for 30 minutes and then allowed to settle. The supernatant was siphoned off and the residue was stirred with 225 mL of IPA for 30 min, after which the polymer had settled to the bottom of the flask and the supernatant was siphoned off. This was repeated with 100 mL of IPA. The product was isolated by filtration. The polymer was repurified by dissolving in 250 mL of DCM and precipitating with 375 mL of IPA. The precipitate was dried in a vacuum oven at 45° C. for 24 h. The polymer 1 1 H NMR was consistent with the composition.

[0130] Example 3 Removal of t-Bu protecting groups to form poly(50%I2DTE-co-10%I2DT-co-40%PTMC8.5K carbonate) The tert-Bu protecting groups are converted to COOH groups by using trifluoroacetic acid (TFA). Trifluoroacetic acid (100 mL) was placed in a 1 L flask and stirred with an overhead stirrer. The polymer from Example 2 was added to the flask and the solution became very viscous as the polymer dissolved. 100 mL of DCM was then added to the flask and stirred overnight, directing the fumes from the flask into the bottle containing the NaOH solution. The polymer was precipitated with 400 mL of IPA while stirring at 300 rpm. The polymer precipitated as fine particles. After removing the supernatant with a siphon, the polymer was stirred twice with 100 mL of IPA and filtered each time. The polymer was washed twice with 100 mL of heptane. It was dried in a vacuum oven at 45° C. for 4 hours and then at 55° C. for 2 days.

[0131] Example 4 Esterification of poly(50%I2DTE-co-10%I2DT-co-40%PTMC8.5K carbonate) with 1,3-propanediol The reaction was carried out with a large excess of 1,3-propanediol to ensure that all acid groups in the polymer were esterified and to prevent crosslinking at this stage.

[0132] A 500 mL round-bottom flask equipped with an overhead stirrer and a modified Dean-Stark trap for solvents heavier than water was charged with 8 g of the polymer from Example 3, 2.3 g of 1,3-propanediol, 0.5 g of p-toluenesulfonic acid monohydrate (PTSA), and 200 mL of 1,2-dichloroethane.

[0133] The flask was heated using an oil bath maintained at 108°C. Refluxing was carried out for 8 hours. Molecular sieves were placed in the side arm of the Dean-Stark trap to remove traces of water produced from the reaction. The reaction mixture was cooled to room temperature and the contents were added to a 1 L beaker. The polymer was precipitated by adding 750 mL of IPA while stirring with an overhead stirrer. The precipitate was washed with IPA and then dissolved in 80 mL of DCM and precipitated with heptane. The precipitate was washed with heptane and dried in a vacuum oven at 45°C for 24 hours. DSC of the sample gave a Tg of -12.5°C.

[0134] 1 H NMR showed three new peaks, corresponding to the three methylene groups of -O-CH2-CH2-CH2-OH of 1,3-propanediol at 4.2, 1.7, and 3.41 ppm, respectively.

[0135] Example 5 Preparation of polymer films and crosslinking of polymers (a) A film was prepared by compression molding 0.5 g of poly(50% I2DTE-co-10% I2DT-O-CH2CH2CH2OH-co-40% PTMC8.5K carbonate) prepared in Example 4 at 140° C. A strip of the film was wrapped around a tube and both ends were glued using DCM. The tube was dried in a vacuum oven at 45° C. for 5 hours.

[0136] (b) This tube was then placed inside a small culture tube immersed in an oil bath at 160°C. A Pasteur pipette was inserted into the polymer tube and nitrogen gas was passed through it at a slow rate. The polymer tube contracted and became rigid. Also, some bubbles were observed throughout the tube due to the evolution of ethanol vapor.

[0137] (c) After 15 min, the culture tube was removed from the oil bath and cooled to room temperature. A piece of polymer tubing was placed into another culture tube, to which some DCM was added and vortexed. The piece of tubing did not dissolve, instead it swelled, indicating cross-linking.

[0138] Example 6 Preparation of poly(50% I2DTE-co-10% I2DT-O-NHCH2CH2OH-co-40% PTMC carbonate) with pendant ethanolamine functional groups (which can be crosslinked by heat) A 500 mL two-neck flask equipped with an overhead stirrer and nitrogen inlet was charged with 20 g of the polymer (deprotected polymer) obtained in Example 3, 200 mL of tetrahydrofuran (THF), 0.13 g of ethanolamine, and 0.11 g of hydroxybenzatriazole, and cooled in an ice-water bath. Upon addition of the ethanolamine, a light red-brown color was obtained. Then, when the reaction mixture became colorless, EDCI (0.27 g) was added to the flask.

[0139] After stirring for 2 hours, the ice-water bath was removed, the reaction mixture was allowed to warm to room temperature (20° C.), and an additional 0.2 g of EDCI was added and stirred for 1 hour.

[0140] 200 mL of DI water was added to quench the reaction and precipitate the polymer. The precipitate was isolated by filtration and washed with water. The polymer was dried in a vacuum oven at 45° C. for 24 hours. The product was then dissolved in 200 mL of THF and, with stirring at 400 rpm, 200 mL of IPA was added and then allowed to stand for 30 minutes. The supernatant was siphoned off and the fine, soft precipitate was stirred with 100 mL of IPA, allowed to stand, and the supernatant was siphoned off. The last step was repeated with 50 mL of IPA.

[0141] The precipitate was isolated by filtration, washed with IPA, and finally dried in a vacuum oven at 45° C. for 4 days. 1 H NMR (dmsO-d6) showed a new peak at 8.12 ppm corresponding to the amide NH. The other two peaks due to CH2 groups were masked by the H2O peak at 3.4 ppm.

[0142] The film preparation and crosslinking were carried out as in Example 5.

[0143] Examples 7, 8 and 9 collectively provide an example suitable for the preparation of a terpolymer, poly(45%I2DTE-co-10%I2DT / AEMA-co-45%PTMC10K carbonate), similar to the terpolymer from Example 5 having a propanediol-based X linkage and the terpolymer from Example 6 having an ethanolamine-based X linkage, but with 2-aminoethyl methacrylate (AEMA)-based pendant functional groups.

[0144] Example 7 Preparation of poly(45%I2DTE-co-10%I2DTtBu-co-45%PTMC10K carbonate) To a 1 L 3-neck flask equipped with an overhead stirrer, nitrogen outlet, and syringe pump inlet, the following monomers were added: 22.5 g I2DTE, 22.5 g PTMC10K, and 5 g I2DTtBu. The monomers were dissolved by stirring with 270 mL chloroform and 12 mL pyridine. To the stirred solution, 4.2 g triphosgene dissolved in 18 mL chloroform was added using a syringe pump until the reaction mixture became very viscous. It was quenched with a mixture of 5 mL water in 45 mL THF.

[0145] The reaction mixture was added with 450 mL of IPA and the polymer was precipitated while stirring at 300 rpm. Stirring was continued for an additional 60 min and the supernatant was siphoned off. The precipitate was washed with 250 mL of IPA. The polymer was dissolved in 300 mL of DCM and precipitated with 500 mL of IPA. The precipitate was isolated by filtration and dried in a vacuum oven at 30 °C for 1 h, then further dried at 65 °C for 24 h.

[0146] Example 8 Removal of the tert-Bu protecting group to form poly(45%I2DTE-co-10%I2DT-co-45%PTMC10K carbonate) 40 grams of polymer from Example 7 was dissolved in a 1 L round bottom flask with 200 mL of DCM by stirring for 3 hours. Once the polymer was completely in solution, 200 mL of trifluoroacetic acid was added and stirred overnight at room temperature. 100 mL of IPA was added to the reaction mixture with vigorous stirring, and the resulting solution was transferred to a 1 L beaker and precipitated by adding 200 mL of IPA with vigorous stirring. The supernatant was siphoned off and the precipitate was further stirred with 100 mL of IPA. The wash was repeated with another 100 mL of IPA. The precipitate was dried in a vacuum oven at 40 °C.

[0147] Example 9 Coupling of aminoethyl methacrylate (AEMA) to poly(45%I2DTE-co-10%I2DT-co-45%PTMC10K carbonate) 10 g of the terpolymer from Example 8 was dissolved in 125 mL of tetrahydrofuran in a 250 mL round bottom flask and stirred with an overhead stirrer under a nitrogen atmosphere. AEMA·HCl (0.185 g) and triethylamine (0.168 g) were added to the stirred reaction mixture.

[0148] [ka]

[0149] Then, 0.145 g of EDCI was added to the flask and stirring was continued for 3 hours. The polymer was precipitated by adding 100 mL of IPA to the reaction mixture. The polymer was redissolved in 100 mL of THF and precipitated with 100 mL of IPA. The last step was repeated once more. The precipitate was washed successively with 50 mL of IPA and 25 mL of IPA. It was then dried overnight in a vacuum oven at 40 °C. The product 1 The 1 H NMR spectrum showed two singlets at 5.655 and 6.040 ppm corresponding to the two vinyl protons.

[0150] For crosslinked films made from the polymer of Example 9, see also Example 14.

[0151] Examples 10, 11 and 12 collectively provide examples suitable for the preparation of poly(50% I2DTE-co-10% I2DT / AEMA-co-40% PTMC10K carbonate) with 2-aminoethyl methacrylate (AEMA) based pendant functional groups.

[0152] Example 10 Preparation of poly(50% I2DTE-co-10% I2DTtBu-co-40% PTMC10K carbonate) To a 1 L 3-neck flask equipped with an overhead stirrer, nitrogen outlet, and syringe pump inlet, 25 g of monomer I2DTE, 20 g of PTMC10K, and 5 g of monomer I2DTtBu were added. The monomers were dissolved by stirring with 270 mL of chloroform and 16 mL of pyridine. To the stirred solution, 5.9 g of triphosgene dissolved in 16 mL of chloroform was added until the reaction mixture became very viscous. It was quenched with a mixture of 5 mL of water in 45 mL of THF. The reaction mixture was added with 450 mL of IPA and the polymer was precipitated with stirring at 300 rpm. It was stirred for an additional 60 min and the supernatant was siphoned off. The precipitate was washed with 250 mL of IPA. The polymer was dissolved in 300 mL of DCM and precipitated with 500 mL of IPA. The precipitated polymer was isolated by filtration. The polymer was dried in a vacuum oven at 30° C. for 1 hour and then further dried at 65° C. for 24 hours.

[0153] Example 11 Removal of the tert-Bu protecting groups to form poly(50%I2DTE-co-10%I2DT-co-40%PTMC10K carbonate) 45 g of the polymer from Example 10 was stirred with 500 mL of DCM for 2 hours and dissolved in a 1 L round bottom flask. Once in complete solution, 370 mL of trifluoroacetic acid was added and stirred overnight at room temperature. 200 mL of IPA was added to the reaction mixture with vigorous stirring, and the resulting solution was transferred to a 1 L beaker and precipitated by adding 250 mL of IPA with vigorous stirring. The supernatant was siphoned off and the precipitate was dissolved in 500 mL of DCM. The polymer was precipitated with 250 mL of IPA. After removing the supernatant, the precipitate was stirred with 250 mL of IPA. The product was isolated by filtration and washed twice with 100 mL of IPA. The product was transferred to a stainless steel pan and dried in a vacuum oven at 40 °C for 2 days.

[0154] Example 12 Coupling of aminoethyl methacrylate (AEMA) to poly(50%I2DTE-co-10%I2DT-co-40%PTMC10K carbonate) 20 g of the polymer from Example 11 was converted to a polymer with aminoethyl methacrylate pendant chains using a procedure similar to that described in Example 9. The resulting polymer was dried in a vacuum oven at 50° C. for 5 days.

[0155] Example 13 shows an example suitable for preparing a terpolymer similar to that from Example 12, containing both COOH and AEMA pendant chains. By maintaining the COOH pendant chains, the biodegradation rate can be accelerated.

[0156] Example 13 Preparation of terpolymers containing both COOH and 2-amidoethyl methacrylate (AEMA) functional groups The terpolymer, poly(40%I2DTE-co-20%I2DTtBu-co-40%PTMC10K carbonate), was prepared using the same procedure as in Example 10. The tert-butyl groups of the terpolymer were converted to COOH groups using trifluoroacetic acid. Only half of the amount of COOH groups was converted to 2-amidoethyl methacrylate groups by reacting with the calculated amount of 2-aminoethyl methacrylate and EDCI.

[0157] Example 14 Crosslinked films made from the polymers of Examples 9, 12 and 13 A 0.2 mm thick film of the polymer prepared in Example 9 was prepared by compression molding at 175°C.

[0158] The film pieces when stirred with DCM dissolved within minutes, indicating that no crosslinking occurred during compression molding.

[0159] A solution containing 100 mg of AIBN in 2 mL of acetone was prepared and diluted with 2 mL of heptane.

[0160] The film strips were immersed in the AIBN solution for 2 minutes.

[0161] The film was dried in a vacuum oven at 40° C. for 5 minutes.

[0162] The film was heated in an oil bath at 100° C. for 10 minutes.

[0163] The film was blotted dry and immersed in DCM, where it did not dissolve even after several days.

[0164] The films from Examples 12 and 13 were compression molded and crosslinked in a similar manner.

[0165] Alternative to Examples 9, 12, and 14 using HEMA: 2-hydroxyethyl methacrylate (HEMA) can be attached to the COOH groups using a similar procedure instead of AEMA. In this case, a catalytic amount of 4-dimethylaminopyridine (DMAP) is added to facilitate the reaction. See the examples above and Figures 4 and 5.

[0166] Example 15 Preparation of oligomeric trimethylene carbonate diols with HEMA-like pendant chains (precursor diols with double bonds in the side branches for free radical polymerization) A 500 mL round bottom flask is charged with glyceryl monomethacrylate (20 g, 0.124 mol), trimethylene carbonate (157 g, 1.24 mol) and heated under nitrogen until all solids are melted. The flask is then heated to 130 °C and Sn(II) octoate (0.24 g, 500 ppm) is added to the flask. The flask is heated at this temperature for 4 hours. The flask is then cooled to room temperature. To remove unreacted monomers and catalyst, the product is dissolved in dichloromethane (DCM) and precipitated twice with heptane. The product is dried in a vacuum oven at 30 °C for 24 hours. The purity of the product is 1 The reaction temperature was measured by H NMR. The product is used without further treatment. Instead of TMC, other compounds such as lactide (L or D / L), caprolactone, glycolide, etc., can be used. For TMC, the reaction temperature is lower than the others.

[0167] Example 16 Preparation of copolymers containing precursor-diols from Example 15 In the second step, the oligomeric precursor (diol) from Example 15 is coupled using triphosgene with one or preferably several monomers and / or oligomeric diols selected to impart the desired properties, such as sufficient strength and degradability, to the final copolymer. The copolymer components can be PRD-diDAT and / or I2DTE (for strength and radiopacity), oligoPLLA-diols (for degradation and crystallinity), oligoPLDL-diols (for degradation), oligoPGA-diols (for degradation), oligoPCL-diols (for additional elasticity), oligoPTMC-diols (for additional elasticity), etc.

[0168] Example 17 Preparation of copolymers containing oligomeric precursor TMC / HEMA from Example 15 with PR-diI2DAT and PLLA7k diol A copolymer with the composition poly(50%PR-diI2DAT-co-30%PLLA7k-co-TMC / HEMA1k carbonate) was prepared. 75 g of PR-diI2DAT, 45 g of PLLA7kDiOl, and 30 g of “oligoTMC / HEMA” from reaction 15 were added to a 1 L three-neck flask equipped with an overhead stirrer, nitrogen outlet, and syringe pump. The components were dissolved by stirring with 1000 ml of chloroform and 40 ml of pyridine. To the stirred solution was added 17.8 g of triphosgene dissolved in 71.2 ml of chloroform until the reaction mixture became viscous. It was quenched with a mixture of 5 ml of water in 100 ml of THF. The polymer was precipitated by adding 3000 ml of IPA to the reaction mixture while stirring at 200 rpm. The supernatant was siphoned off and the precipitate was washed three times with 1000 ml of IPA. The copolymer was redissolved in 500 ml DCM, precipitated with 1500 ml IPA, and washed three times with 500 ml IPA. The precipitated copolymer was isolated by filtration and dried in a vacuum oven at 55° C. for 24 hours.

[0169] Example 18 Preparation of Films Containing the Copolymer of Example 17 A film of the polymer from Example 17 was prepared by compression molding at 175°C. The film is then deformed into a cylindrical shape by wrapping it around a metal cylinder where the two ends of the film should overlap slightly. DCM is applied to one side of the film using a Q-tip or other device, and the other end is pressed onto the wet part of the film. After about 15-20 minutes, the prepared tube was removed and dried in a vacuum oven at 35-40°C for 2 hours.

[0170] Example 19 Introduction of free radical initiator into the polymer tube of Example 18 To introduce the free radical initiator into the cylinder, a suitable solvent or mixture of solvents should be selected. The solvent should dissolve the free radial initiator but not the polymer. The polymer should only swell slightly in the solvent so that some initiator is absorbed into the device. An initiator such as AIBN is dissolved in a solvent (e.g., a 1:1 mixture of acetone and heptane). The polymer cylinder is placed in the AIBN solution for a known time, then removed and dried in air for 20 minutes, then dried in a vacuum oven at 50°C for several hours.

[0171] Example 20 Crosslinking of the polymer cylinder of Example 19 In this example, the cylinder is crosslinked by heating to a higher temperature, for example above 100° C. To test if the device is crosslinked, a portion of the device is added to DCM. If it is crosslinked, it should not dissolve. The film or cylinder before crosslinking can be dissolved in DCM.

[0172] Example 21 Preparation of tubular substrates by spray coating Using a tubular casting technique such as spray coating, the tubular substrate is formed by spraying a solution consisting of a mixture of a polymer containing HEMA or AEMA functional groups on the side branches and the free radical initiator AIBN. The tubular substrate prepared by the spray technique is intended for latent crosslinking by free radical polymerization.

[0173] Example 22 Preparation of tubular substrates by dip coating A tubular casting technique such as dip coating is used to form tubular substrates from a solution of a polymer containing HEMA or AEMA functional groups on the side branches and a free radical initiator, AIBN. Tubular substrates prepared by dip coating are intended for potential crosslinking by free radical polymerization.

[0174] Example 23 Preparation of crosslinked films containing the copolymer of Example 17 by solvent casting technique From the copolymer of Example 17, crosslinked films with crosslinks in the rubber phase were prepared using a solvent casting technique and subsequent heat treatment. 0.5 grams of the copolymer from Example 17 and 20 milligrams of the free radical initiator AIBN were dissolved in 40 ml of DCM. 2-3 hours of stirring were used to ensure complete dissolution. The solution was cast onto a flat surface (glass Petri dish) and left for slow solvent evaporation (at least 10-15 hours at room temperature conditions followed by vacuum drying). The prepared solvent cast films were crosslinked at temperatures between 80-120 °C. The optimal duration and temperature of heat treatment were determined by monitoring the residual heat of curing of the heat treated films. Curing was considered complete when no exothermic peaks related to curing were observed in the DSC thermograms of the heat treated films.

[0175] As in the previous examples, the solvent cast film containing AIBN can be calendered into the form of a tubular substrate prior to heat treatment, for example to obtain a crosslinked tube suitable for stent manufacture.

[0176] [Table 1]

[0177] All references, patents, applications and articles cited above are in the public domain (whether published online or not) and are incorporated by reference as if fully set forth herein.

[0178] The following, the contents of which are incorporated herein by reference in their entirety: JR Laird, EJ Armstrong, Endovascular Today, 2014, 13(Suppl):9-11, Title: "Overview of superficial femoral artery stents"; C. DI Mario, H. Griffiths, O. Goktekin, N. Peeters, J. Verbist, M. Bosiers, K. Deloose, B. Heublein, R. Rohde, V. Kasese, C. Ilsley, R. Erbel. J. Interv. Card, 2004, 17(6):391-395, Title: "Drug-removable bioabsorbable magnesium stents"; M. Peuster, C. Hasse, T. Schloo, C. Fink, P. Beerbaum, C. von Schnakenburg, Biomaterials, 2006, 27(28):4955-4962, Title: "Long-term biocompatibility of corrodible peripheral iron stents in the descending aorta" M. Bosiers, Cardiovasc. Interv. Rad. 2009, 32(3):424-435, Title: "AMS Insights - Absorbable metallic stents for the treatment of below-the-knee critical limb ischemia: A 6-month analysis"; JD Wind, C. Staudt-Bickel, DR Paul, WJ Koros, Macromolecules, 2003, 36, 1882-1888, Title: "Solid covalent crosslinking of polyimide films for reduced carbon dioxide plasticization" M. Werner, A. Micari, A. Cioppa, G. Vadala, A. Schmidt, H. Sievert, P. Rubino, A. Angelini, D. Scheinert, G. Biamino, JACC Cardiovasc. Interv. 2014, 7(3):305-312, Title: "Evaluation of the biodegradable peripheral Igaki-Tamai stent for the treatment of de novo lesions of the superficial femoral artery."

[0179] The scope of the present disclosure is not intended to be limited by the description of specific embodiments, but is instead defined by the claims, which should be interpreted broadly based on the language employed in the claims and not limited to the examples described herein, but should also be interpreted broadly during prosecution, and these examples should be interpreted as non-exclusive.

[0180] Various modifications to the implementations described in this disclosure may be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other implementations without departing from the spirit or scope of the present disclosure. Thus, the present disclosure is not intended to be limited to the implementations shown herein, but should be accorded the widest scope consistent with the principles and features disclosed herein. Particular embodiments of the present disclosure are encompassed by the claims set forth below or presented in the future.

[0181] Certain embodiments of the present disclosure are encompassed in the claims presented at the end of this specification or in other claims presented later. Additional embodiments are encompassed in the following set of numbered embodiments:

[0182] EMBODIMENT 1 A biocompatible polymer pre-cured material configured to assume the form of a polymer comprising elastomeric backbone units (M), non-elastomeric backbone units, and crosslinkable pendant groups; wherein at least a portion of the crosslinkable pendant groups have tert-butyl ester end groups configured for transesterification and are in a latent form configured for conversion by activation treatment to an activated form having acryloyl or (C1-C3 alkyl)acryloyl end groups; At least a portion of the latent forms of the crosslinkable pendant groups are bonded to carbon or nitrogen atoms in the elastomeric or non-elastomeric backbone units; the crosslinkable pendant groups are configured to react during a curing process, thereby curing the biocompatible polymer pre-cured material into a biocompatible polymer post-cured material; Biocompatible polymer pre-cured.

[0183] EMBODIMENT 2 The potential form of the crosslinkable pendant group is represented by the structural formula (Ia):

[0184] [ka]

[0185] It is expressed as The activated form of the crosslinkable pendant group is represented by the structural formula (IIa) or (IIb):

[0186] [ka]

[0187] Represented by where * indicates the point of attachment to a carbon or nitrogen atom in the elastomeric or non-elastomeric backbone unit; L A is a single bond or -(C1-C 10 ) alkylene-; Z 1 and Z 2 are each independently O, S, or NH; L B1 is -(C1-C 10 )Alkylene-, -(C1-C 10 ) alkenylene-, or -(C1-C6) alkylene-phenylene-(C1-C6) alkylene-; L B2 is -(C1-C 10 ) alkylene-O-, -(C1-C 10 ) alkenylene-O-, or -(C1-C6) alkylene-phenylene-(C1-C6) alkylene-O-; L B1 or L B2 wherein the phenylene is optionally substituted with one, two or three substituents independently selected from (C1-C6) alkyl and halogen; and R 0is H or (C1-C6) alkyl; A biocompatible polymer pre-cured product according to embodiment 1.

[0188] EMBODIMENT 3 3. The biocompatible polymer pre-cured product of embodiment 1 or 2, wherein the activated form of the crosslinkable pendant group is represented by structural formula (IIa), and the curing process comprises heating and transesterification.

[0189] EMBODIMENT 4 3. The biocompatible polymer pre-cured product of embodiment 1 or 2, wherein the activated form of the crosslinkable pendant groups is represented by Structural Formula (IIb) and the curing process comprises free radical initiation.

[0190] EMBODIMENT 5 the non-elastomeric backbone units each independently comprise a repeat unit represented by structural formula (IIIa) or (IIIb),

[0191] [ka]

[0192] During the ceremony, X 1 , X 2 , X 3 and X 4 are each independently Br or I; y 1 , y 2 , y 3 and y 4 are each independently 0, 1, 2, 3 or 4; A1, A2 and A 1 are the following expressions, respectively:

[0193] [ka]

[0194] (However, A1, A2 or A 1is selected independently from: A1, A2, and A of formula (IIa) or (IIIb) 1 Groups can be integrated either left to right or right to left, R1, R2, R3, R4, R 4a and R 4b are each independently (C1-C 30 ) alkylene, (C2-C 30 ) alkenylene, (C1-C 30 )heteroalkylene, or (C2-C 30 ) heteroalkenylene, where the heteroalkylene or heteroalkenylene optionally contains 1, 2, or 3 heteroatoms selected from O, S, or N; and R 3 , R X and R y are each independently H or (C1-C6)alkylene; A biocompatible polymer pre-cured product according to any one of the first to fourth embodiments.

[0195] EMBODIMENT 6 The non-elastomeric backbone unit is

[0196] [ka]

[0197] (In the formula, R is H or (C1-C6)alkyl; Z is O or NH; L B1 HA-(C1-C 10 )Alkylene-, -(C1-C 10 ) alkenylene- or -(C1-C3) alkylene-phenylene-(C1-C3) alkenylene-, where the phenylene is optionally substituted with 1, 2 or 3 substituents independently selected from (C1-C6) alkyl and halogen. 6. The biocompatible polymer pre-cured product according to any one of embodiments 1 to 5, comprising a repeating group selected from the group consisting of:

[0198] EMBODIMENT 7 Structural formula (IVa):

[0199] [ka]

[0200] The biocompatible polymer pre-cured product according to any one of embodiments 1 to 6, wherein the elastomer backbone unit (M) represented by the formula (I) comprises a repeating group selected from the group consisting of -(C1-C6)alkylene-O-, -C(=O)-(C1-C6)alkylene-O-, -(C1-C6)alkylene-C(=O)O-, and -C(=O)O-(C1-C6)alkylene-O-, and any combination thereof.

[0201] EMBODIMENT 8 The elastomer backbone unit (M) is

[0202] [ka]

[0203] 8. The biocompatible polymer pre-cured product according to any one of the preceding embodiments, comprising a repeating group selected from the group consisting of:

[0204] EMBODIMENT 9 The biocompatible polymer pre-cured product according to any one of the preceding claims, wherein the elastomeric backbone unit (M) is derived from a monomer selected from the group consisting of caprolactone, tetramethylene oxide, trimethylene carbonate, ethylene glycol, dioxanone, glycolide, and lactide; and M forms a selected form of monomer, oligomer, homomacromer, and any random or block comacromer.

[0205] EMBODIMENT 10 Structural formula (IVa)

[0206] [ka]

[0207] c% by weight of an elastomer backbone unit (M) represented by the formula: Structural formula (IIIa),

[0208] [ka]

[0209] The first repeating group represented by the formula: Structural formula (IIIb)

[0210] [ka]

[0211] and b % by weight of a second repeating group represented by (In the formula, a+b+c=100%) wherein at least a portion of the crosslinkable pendant groups are attached to carbon atoms of a second repeat group in the non-elastomeric backbone unit in a latent or activated form of Structural Formula (Ia), (IIa) or (IIb): 10. A biocompatible polymer pre-cured product according to any one of the first to ninth embodiments.

[0212] EMBODIMENT 11 A biocompatible polymer pre-cured product according to embodiment 10: A 1 is -C(=O)O-, The elastomer backbone unit (M) is represented by the formula

[0213] [ka]

[0214] and derived from monomers selected from the group consisting of caprolactone, tetramethylene oxide, trimethylene carbonate, ethylene glycol, dioxanone, glycolide, and lactide; 11. A biocompatible polymer pre-cured product according to embodiment 10.

[0215] EMBODIMENT 12 The first repeat group in the non-elastomeric backbone unit is

[0216] [ka]

[0217] and any combination thereof; The second repeat group to which the crosslinkable pendant group is attached is

[0218] [ka]

[0219] and any combination thereof; where R is H or (C1-C6) alkyl, such as methyl, ethyl, propyl, and butyl; Z 1 and Z 2 are each independently O or NH; L B1 HA-(C1-C 10 )Alkylene-, -(C1-C 10 ) alkenylene-, or -(C1-C 10 )Alkylene-phenylene-(C1-C 10 ) alkylene-, where the phenylene is optionally substituted with 1, 2, or 3 substituents independently selected from (C1-C6) alkyl and halogen. 12. A biocompatible polymer pre-cured product according to embodiment 11.

[0220] EMBODIMENT 13 The curing process includes heating and transesterification, The first repeat group in the non-elastomeric backbone unit is

[0221] [ka]

[0222] and the second repeat group to which the crosslinkable pendant group is attached is

[0223] [ka]

[0224] or any combination thereof, 13. A biocompatible polymer pre-cured product according to embodiment 12.

[0225] EMBODIMENT 14 14. The biocompatible polymer pre-cured product of embodiment 13, having a weight average molecular weight of about 50,000 to about 100,000, about 50,000 to about 300,000, about 50,000 to about 500,000, about 50,000 to about 700,000, or about 50,000 to about 1,000,000 g / mol.

[0226] EMBODIMENT 15 The curing process involves heating and transesterification, and is in the non-elastomeric backbone units. The first repeat group is

[0227] [ka]

[0228] and the second repeat group to which the crosslinkable pendant group is attached is

[0229] [ka]

[0230] or any combination thereof, 13. A biocompatible polymer pre-cured product according to embodiment 12.

[0231] EMBODIMENT 16 16. The biocompatible polymer pre-cured product of embodiment 15, having a weight average molecular weight of about 50,000 to about 100,000, about 50,000 to about 300,000, about 50,000 to about 500,000, about 50,000 to about 700,000, or about 50,000 to about 1,000,000 g / mol. EMBODIMENT 17 the curing process involves free radical initiation and is in the non-elastomeric backbone units; The first repeat group is

[0232] [ka]

[0233] and the second repeat group to which the crosslinkable pendant group is attached is

[0234] [ka]

[0235] or any combination thereof.

[0236] EMBODIMENT 18 18. The biocompatible polymer pre-cured product of embodiment 17, having a weight average molecular weight of about 50,000 to about 100,000, about 50,000 to about 300,000, about 50,000 to about 500,000, about 50,000 to about 700,000, or about 50,000 to about 1,000,000 g / mol.

[0237] EMBODIMENT 19 the curing process involves free radical initiation and is in the non-elastomeric backbone units; The first repeat group is

[0238] [ka]

[0239] and the second repeat group to which the crosslinkable pendant group is attached is

[0240] [ka]

[0241] or any combination thereof.

[0242] EMBODIMENT 20 20. The biocompatible polymer pre-cured product of embodiment 19, having a weight average molecular weight of about 50,000 to about 100,000, about 50,000 to about 300,000, about 50,000 to about 500,000, about 50,000 to about 700,000, or about 50,000 to about 1,000,000 g / mol.

[0243] EMBODIMENT 21 21. The biocompatible polymer pre-cured product according to any one of embodiments 1 to 20, wherein at least a portion of the latent forms of the crosslinkable pendant groups represented by structural formula (I) are bonded to elastomer backbone units.

[0244] EMBODIMENT 22 21. The biocompatible polymer pre-cured product of any one of the preceding embodiments, wherein at least a portion of the activated forms of the crosslinkable pendant groups represented by structural formula (IIa) or (IIb) are bonded to the elastomeric backbone units.

[0245] EMBODIMENT 23 The elastomer backbone unit (M) is

[0246] [ka]

[0247] 23. The biocompatible polymer pre-cured product of embodiment 22, comprising one or more of:

[0248] EMBODIMENT 24 24. The biocompatible polymer pre-cured product of embodiment 23, wherein the elastomeric backbone unit (M) comprises a co-macromer derived from glycerol monomethacrylate and trimethyl carbonate.

[0249] EMBODIMENT 25 Comacromer represented by the formula

[0250] [ka]

[0251] (In the formula, p and q each independently represent an integer of 0 to 50.) c% by weight of elastomeric main chain units (M) containing The first repeating group in the non-elastomeric main chain unit

[0252] [ka]

[0253] % by weight: and The second repeating group to which the crosslinkable pendant group is bonded in the non-elastomeric backbone unit is represented by b % by weight: wherein the second repeat group is

[0254] [ka]

[0255] or any combination thereof, Each of a%, b%, and c%, when each of the repeating units is present, is independently in the range of about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 25%, about 1% to about 30%, about 1% to about 35%, about 1% to about 40%, about 1% to about 45%, about 1% to about 50%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 45%, or about 5% to about 50% (based on the weight of the biocompatible polymer pre-cured product), and a+b+c=100%. 24. A biocompatible polymer pre-cured product according to embodiment 22 or 23.

[0256] EMBODIMENT 26 26. The biocompatible polymer pre-cured product according to embodiment 25, having a weight average molecular weight of about 50,000 to about 100,000, about 50,000 to about 300,000, about 50,000 to about 500,000, about 50,000 to about 700,000, or about 50,000 to about 1,000,000 g / mol.

[0257] EMBODIMENT 27 27. The biocompatible polymer pre-cured material according to any one of the preceding embodiments, wherein said form is a medical device, a medical implant, or a part thereof.

[0258] EMBODIMENT 28 28. The biocompatible polymer pre-cured material according to embodiment 27, wherein said form is a vascular scaffold.

[0259] EMBODIMENT 29 29. The biocompatible polymer pre-cured material according to embodiment 27 or 28, wherein said form is tubular.

[0260] EMBODIMENT 30 30. The biocompatible polymer pre-cured material according to any one of embodiments 27 to 29, wherein said configuration is a stent or a stent graft.

[0261] EMBODIMENT 31 The biocompatible polymer pre-cured product of any one of the first to thirty embodiments is configured to be laser cut in its configuration.

[0262] EMBODIMENT 32 32. The biocompatible polymer post-cured product of any one of the preceding embodiments, wherein the curing treatment comprises heating, transesterification, free radical initiation, or a combination thereof.

[0263] EMBODIMENT 33 33. The biocompatible polymer post-cured product of embodiment 32, comprising a crosslink density of about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%.

[0264] EMBODIMENT 34 The post-cured biocompatible polymer of embodiment 32 or 33 is inherently radiopaque.

[0265] EMBODIMENT 35 The post-cured biocompatible polymer of any one of Embodiments 32 to 34 is bioabsorbable.

[0266] EMBODIMENT 36 The post-cured biocompatible polymer of any one of embodiments 32-35 is configured to be laser cut.

[0267] EMBODIMENT 37 A polymer material comprising a pre-cured biocompatible polymer according to any one of embodiments 1 to 31, or a post-cured biocompatible polymer according to any one of embodiments 32 to 36.

[0268] EMBODIMENT 38 A medical device comprising a pre-cured biocompatible polymer according to any one of embodiments 1 to 31, or a post-cured biocompatible polymer according to any one of embodiments 32 to 36.

[0269] EMBODIMENT 39 Preparing a biocompatible polymer pre-cured product according to any one of embodiments 1 to 31; activating the latent form of the crosslinkable pendant group by an activation treatment; and crosslinking the activated forms of the crosslinkable pendant groups by a curing treatment; A method for preparing a post-cured biocompatible polymer according to any one of embodiments 32 to 36, comprising:

[0270] EMBODIMENT 40 40. The method of embodiment 39, wherein the activation step occurs prior to and substantially simultaneously with the crosslinking step.

[0271] EMBODIMENT 41 41. The method of embodiment 39 or 40, comprising, in any order, one or more activation steps and one or more crosslinking steps.

[0272] EMBODIMENT 42 The method of any one of embodiments 39-41, further comprising pre-curing the biocompatible polymer to form the morphology.

[0273] EMBODIMENT 43 43. The method of embodiment 42, further comprising modifying the morphology, such as by laser cutting, to form a vascular scaffold device or portion thereof.

[0274] EMBODIMENT 44 Preparing a biocompatible polymer pre-cured product according to any one of embodiments 1 to 31; activating the latent form of the crosslinkable pendant groups by an activation treatment; and crosslinking the activated forms of the crosslinkable pendant groups by a curing treatment; A method of making a polymeric material or medical device comprising post-curing a biocompatible polymer of any one of embodiments 32-36, wherein the post-curing biocompatible polymer is bioabsorbable and essentially radiopaque.

[0275] EMBODIMENT 45 45. The method of embodiment 44, wherein the activation step occurs prior to and substantially simultaneously with the crosslinking step.

[0276] EMBODIMENT 46 46. ​​The method of embodiment 44 or 45, comprising, in any order, one or more activation steps and one or more crosslinking steps.

[0277] EMBODIMENT 47 57. The method of any one of embodiments 45-56, further comprising, prior to, and substantially simultaneously with, any one of the activation steps, allowing the biocompatible polymer pre-cured material to assume a form.

[0278] EMBODIMENT 48 48. The method of embodiment 47, further comprising modifying the morphology, such as by laser cutting, to form a vascular scaffold device or portion thereof, prior to, substantially simultaneously with, or subsequent to any one of the crosslinking steps.

[0279] EMBODIMENT 49 The method of any one of embodiments 44 to 48, further comprising determining one or more mechanical properties of the biocompatible polymer before or after curing, wherein the one or more mechanical properties are selected from the group consisting of toughness, elasticity, impact resistance, and crush recovery, and any combination thereof.

[0280] EMBODIMENT 50 A polymeric material made using any combination of all or part of the process steps of any one of embodiments 44-49.

[0281] EMBODIMENT 51 A medical device comprising a polymeric material made using any combination of all or part of the method steps of any one of embodiments 44-49.

[0282] EMBODIMENT 52 The medical device of embodiment 38 or 51 is a vascular scaffold, such as a stent or a stent graft.

[0283] EMBODIMENT 53 The polymeric material of embodiment 37 or 50, or the medical device of any one of embodiments 38 and 51-52, which is tubular in form.

[0284] EMBODIMENT 54 The polymeric material of embodiment 41 or 55, or the medical device of any one of embodiments 38 and 51-52, is tough, resilient, impact resistant, crush recoverable, or a combination thereof.

[0285] EMBODIMENT 55 The polymeric material of embodiment 41 or 55, or the medical device of any one of embodiments 38 and 51-52, further comprising a coating, the coating comprising a pharmaceutical agent, or a drug, or both.

[0286] EMBODIMENT 61 The biocompatible polymer pre-cured according to any one of the preceding embodiments is a homopolymer, a random copolymer, a block copolymer, or any combination thereof.

Claims

1. A polymeric material comprising one or more of a polymer, a homopolymer, a copolymer, a block copolymer, and / or a blend or mixture thereof, the polymeric material is biocompatible and, optionally, inherently radiopaque and / or bioabsorbable; The polymeric material, as initially prepared, comprises at least one polymeric component having a potentially crosslinkable state such that the polymeric component contains functional groups configured to react when subjected to at least one crosslink-initiating treatment to crosslink the polymer; The polymeric material, as initially prepared, comprises at least one polymeric component that has a rubbery or partially rubbery state at a temperature below 37° C.; the polymeric material, prior to being subjected to at least one crosslink initiating treatment, has properties that allow it to be formed into a selected structural shape without initiating crosslinking; and the polymeric material has a crosslinked state such that, after being subjected to at least one crosslink initiating treatment, the polymeric material has a sufficient number and / or density of crosslinks between polymer chains within the material to enhance material properties to produce a tough, resilient material such that a selected shape comprised of the crosslinked polymeric material has crush recoverable properties that allow the selected shape to substantially return to the selected shape after mechanical deformation; At least one of the potentially crosslinkable polymeric components comprises an essentially radiopaque, biocompatible, bioresorbable polymer, the polymer comprising one or more repeat units having the structure: 【Chemistry 1】 wherein each of a, b, and c, if present, is independently present in the range of 1% to 50% by weight of the polymer; X １ , X ２ , X ３ and X ４ are each independently Br or I; Each of y1, y2, y3, and y4 is independently 0, 1, 2, 3, or 4; a, b and c are weight percentages ranging from 0 to 100%, and a+b+c=100%, A １ , A ２ and A １ is as follows 【Chemistry 2】 and wherein A is a linking group independently selected from the group consisting of １ , A ２ Or A １ By the linkage, an O-O or O-N bond is implied, where there is no adjacent oxygen atom, B is at least one polymer component having a rubbery or partially rubbery state when initially prepared; R Ｘ , R ｙ , R ３ are each independently H or C １ -C ６ is an alkyl group of R ４ and R ４ａ are each independently C １ -C １０ is alkylene, R １ , R ２ , R ３ and R ４ are each independently linear or branched, saturated or unsaturated C １ -C １２ alkylene, 2-15 membered heteroalkylene, or 2-15 membered heteroalkenylene, each optionally containing 1-3 heteroatoms independently selected from O, NR, and S; R is H or C １ -C ６ is an alkyl group of R １ , R ２ , R ３ and R ４ at least one of which contains a pendant Z group; The pendant Z groups contain functional groups that can react to crosslink the polymer after it has been fabricated into the desired shape, either by transesterification or by a free radical mechanism; The polymeric material, wherein the polymer is a random or block copolymer.

2. The polymeric material of claim 1 , wherein said material is in a potentially crosslinkable state, said material not having been subjected to said at least one initiation treatment.

3. The polymeric material of claim 1 , wherein said material is in a crosslinked state and said material has been subjected to said at least one initiation treatment.

4. 4. The polymeric material of any one of claims 1 to 3, wherein at least one polymeric component having a rubbery or partially rubbery state when initially prepared comprises one or more of PCL (polycaprolactone), PTMO (polytetramethylene oxide), PTMC (polytrimethylene carbonate), PEG (polyethylene glycol), polydioxanone, polyglycolide, polylactide, and any comacromers thereof.

5. The polymeric material comprises a polymer comprising one or more repeat units having the structure: 【Chemistry 3】 During the ceremony, M is a macromer having a rubbery or partially rubbery state at a temperature below 37° C. comprising PTMC, PTMO, PCL, PEG, or any co-macromer thereof, optionally further comprising one or more of PLLA, PGA, and polydioxane; Z=O or NH, and X is a single bond or a linear or branched alkylene, alkenylene, or phenylene, each of which may be substituted with one or more substituents selected from alkyl, halogen, -OH, and -C(O)OH; and The polymer is a random or block copolymer, wherein at least one crosslinking initiation treatment comprises heating the potentially crosslinkable polymeric material to induce transesterification; The polymer material according to any one of claims 1 to 4.

6. The polymeric material comprises a polymer including one or more repeat units having the structure: 【Chemistry 4】 During the ceremony, M is a macromer having a rubbery or partially rubbery state at a temperature below 37° C., comprising PTMC, PTMO, PCL, PEG or any co-macromer thereof, optionally further comprising one or more of PLLA, PGA, and polydioxane; and Z=O or NH, and the polymer is a random or block copolymer, At least one crosslink initiation treatment comprises a free radical initiated chain reaction of the polymer in the presence of a free radical initiator; The polymer material according to any one of claims 1 to 5.

7. The polymeric material comprises a polymer including one or more repeat units having the structure: 【Chemistry 5】 During the ceremony, M is a macromer having a rubbery or partially rubbery state at a temperature below 37° C., comprising PTMC, PTMO, PCL, PEG, or any co-macromer thereof, optionally further comprising one or more of PLLA, PGA, and polydioxane; and Z=O or NH, and At least one crosslink initiation treatment comprises a free radical initiated chain reaction of the polymer in the presence of a free radical initiator; The polymeric material of claim 1.

8. The portion in brackets "b" in the formula is represented by the following structural formula: 【Chemistry 6】 8. The polymeric material according to claim 5, wherein the tert-butyl ester of the diphenolic acid of formula (I) is substituted.

9. 7. The polymeric material according to claim 5 or 6, wherein R=H.

10. 7. The polymeric material according to claim 5 or 6, wherein R is a straight or branched chain alkyl group.

11. R is CH ３ Or C ２ H ５ 7. The polymer material according to claim 5 or 6,

12. When the crosslinking functionality is on the side chain of an essentially rubbery PTMC, the polymeric material comprises a polymer that includes one or more repeat units having the following structure: 【Chemistry 7】 wherein each of X and y is independently an integer ranging from 1 to 50. A polymeric material according to any one of claims 1 to 11.

13. the polymeric material comprises a polymer comprising at least two distinct types of repeat units, each such type of repeat unit having a different type of potentially crosslinkable functional group; One such repeat unit is a structural radiopaque component that includes a crosslinkable acryloyl or methacryloyl moiety on the pendant group, Another such repeat unit is an essentially rubbery component containing crosslinkable acryloyl or methacryloyl moieties in pendant groups. A polymeric material according to any one of claims 1 to 12.

14. The polymeric material comprises a polymer including one or more repeat units having the structure: 【Chemistry 8】 where Z is O, S or NH.

13. The polymeric material of claim 12.

15. The polymeric material comprises a polymer including one or more repeat units having the structure: 【Chemistry 16】 wherein M is a macromer having a rubbery or partially rubbery state at a temperature below 37° C. comprising PTMC, PTMO, PCL, PEG, or any co-macromer thereof, optionally further comprising one or more of PLLA, PGA, and polydioxane; Z═O or NH; and X is a single bond or a linear or branched alkylene, alkenylene, or phenylene, each of which may be optionally substituted with one or more substituents selected from alkyl, halogen, —OH, and —C(O)OH; the polymer is a random or block copolymer; wherein at least one crosslinking initiation treatment comprises heating the potentially crosslinkable polymeric material to induce transesterification; The polymeric material of claim 1.

16. A medical device comprising the polymeric material of claim 15.

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