CN114616258A

CN114616258A - Radiopaque polymers for medical devices

Info

Publication number: CN114616258A
Application number: CN202080076097.8A
Authority: CN
Inventors: 史蒂芬·迪安·古德里奇
Original assignee: Endoshape Inc
Current assignee: Endoshape Inc
Priority date: 2019-09-12
Filing date: 2020-09-09
Publication date: 2022-06-10
Also published as: EP4025616A4; EP4025616A1; WO2021050474A1

Abstract

Polymers having a crosslinked network are provided. The crosslinked network comprises a) one or more first repeat units derived from a monomer of formula I, b) one or more second repeat units derived from a monomer of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and c) one or more third repeat units derived from a monomer of formula IVa and/or formula IVb. Also provided are methods of making the polymers, compositions comprising the polymers, and devices comprising the polymers.

Description

Radiopaque polymers for medical devices

Cross Reference to Related Applications

This application claims priority and benefit of U.S. provisional patent application No. 62/899,270 filed on 12.9.2019, which is incorporated herein by reference in its entirety.

Background

Shape Memory Materials are defined by their ability to recover a predetermined Shape after significant mechanical deformation (K.Otsuka and C.M.Wayman, "Shape Memory Materials" New York: Cambridge University Press, 1998). Shape memory effects are typically induced by temperature changes and have been observed in metals, ceramics and polymers. From a macroscopic point of view, the shape memory effect of polymers is different from that of ceramics and metals, because lower stresses and greater recoverable strains are achieved in polymers.

The basic thermomechanical response of a Shape Memory Polymer (SMP) material is defined by four critical temperatures. Glass transition temperature T_gGenerally represented by a transition in the modulus-temperature space, may be used as a reference point for temperature normalization for some SMP systems. SMP provides for varying T over a temperature range of several hundred degrees by controlling the chemistry or structure_gThe ability of the cell to perform. Pre-deformation temperature T_dIs the temperature at which the polymer deforms into its temporary shape. Initial deformation T according to the desired stress and strain level_dCan be higher or lower than T_gBut occurs (Y.Liu, K.Gall, M.L.Dunn, and P.McCluskey, "thermodynamic Recovery Couplings of Shape Memory Polymers in Flexure&Structures, volume 12, pages 947 to 954, 2003). Storage temperature T_sA temperature at or below which shape recovery does not occur and is equal to or lower than T_d. Storage temperature T_sBelow the glass transition temperature Tg. At a recovery temperature T_rIn the following, the shape memory effect is activated, which causes the material to substantially resume its original shape. T is_rHigher than T_sAnd is usually at T_gNearby. Recovery may be by heating the material to a fixed T_rThen held, or by continued heating to T_rAnd exceeds T_rTo be accomplished isothermally. From a macroscopic point of view, the polymer will exhibit a useful shape memory effect, provided that the polymer has a distinct and significant glass transition (b. sitting,"Shape memory polymers," act. chimique, volume 3, pages 182 to 188, 2002), modulus-temperature plateau in the rubbery state (c.d. liu, s.b. chun, p.t. mather, l.zheng, e.h. haley, and e.b. coughlin, "chemical cross-linked polycycle: synthesis, characterization, and shape memory was used, "macromolecules, Vol.35, No. 27, pp.9868 to 9874, 2002), and the maximum achievable strain ε during deformation_maxAnd permanent plastic strain after recovery epsilon_pThe great difference between them (f.li, r.c. larock, "New sobean Oil-Styrene-Divinylbenzene Thermosetting copolymers.v. shape memory effect," j.app. pol.Sci., volume 84, pages 1533 to 1543, 2002). Will epsilon_max-ε_pIs defined as the recoverable strain epsilon_recoverAnd the recovery rate is defined as ε_recover/ε_max。

The microscopic mechanism responsible for Shape Memory in polymers depends on both chemical properties and Structure (T.Takahashi, N.Hayashi and S.Hayashi, "Structure and Properties of Shape Memory block polymers," J.App.pol.Sci., Vol.60, pp.1061 to 1069, 1996; J.R.Lin and L.W.Chen, "Study on Shape-Memory Bei: of polyethylene-treated polymers, II.Influence of the Hard-section content," J.App.Pol.Sci.No. 69, 1563 to 1574, 1998; J.R.Lin.Chen.H.Chen.J.S.W.J.S.J.S.H.J.S.W.Chen., P.S.J.S.P.S.J.S.P.S.J.S.S.J.S.S.S.J.S.S.P.S.J.P.S.J.P.S.S.S.J.S.J.S.J.S.S.S.S.J.S.S.J.J.S.S.J.S.J.S.S.S.J.J.S.J.J.S.S.J.J.S.S.S.S.S.J.S.S.J.J.J.S.J.S.J.J.J.J.M.P.M.M.P.P.S.P.P.J.M.S.S.S.S.M.M.S.S.P.M.S.P.P.M.J.P.M.P.M.S.P.P.P.P.P.P.P.P.P.P.M.P.M.P.P.P.P.P.J.M.P.P.M.S.S.P.P.P.J.S.S.J.M.M.P.P.P.P.P.P.S.M.P.P.P.P.P.P.M.M.P.P.M.M.P.P.P.P.P.P.P.P.P.P.P.M.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.S.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.P.S.P.P., 2000; h.m.jeong, s.y.lee and b.k.kim, "Shape memory polyurethane associating acidic recombinant phase," j.mat.sci., volume 35, pages 1579 to 1583, 2000; lendlein, A.M.Schmidt and R.Langer, "AB-polymer network based on oligo (epsilon-caprolone) segments showg shape-memory properties, "proc.nat.acad.sci., vol 98, No. 3, pages 842 to 847, 2001; zhu, g.liang, q.xu, and q.yu, "Shape-memory effects of radiation cross-linked poly (epsilon-caprolene)," j.app.poly.sci., volume 90, pages 1589 to 1595, 2003). One driving force for shape recovery of polymers is the low conformational entropy state that is created and subsequently stabilized during the thermomechanical cycle. (C.D.Liu, S.B.Chun, P.T.Mather, L.Zheng, E.H.Haley, and E.B.Coughlin, "chemical cross-linked polycycloolefin: Synthesis, chromatography, and shape memory viewer," macromolecules. Vol.35, No. 27, pp.9868 to 9874, 2002). If the polymer is below T_gOr in some of the hard polymer regions below T_gWill deform to its temporary shape, the internal energy recovery force will also contribute to the shape recovery. In any case, in order to achieve shape memory properties, the polymer must have some degree of chemical cross-linking to form a "memorable" network, or must contain a limited portion of hard domains for physical cross-linking.

The SMP is processed in a manner known as design whereby the polymer is deformed and set into a temporary shape. (A.Lendlein, S.Kelch, "Shape Memory Polymer," Advanced Chemie, International Edition, 41, 1973 to page 2208, 2002.) when exposed to an appropriate stimulus, the SMP returns substantially from the temporary Shape to its permanent Shape. Depending on the initial monomer system, the stimulus may be, for example, temperature, magnetic field, water, or light.

For SMPs used in medical devices where temperature is the chosen stimulus, an external heat source may be used by the physician to provide any control of shape recovery, or the core temperature of the body may be used to stimulate shape recovery when entered or placed in the body from an ambient temperature, which may be room temperature. (Small W et al, "biological applications of thermally activated shape memory polymers" Journal of Materials Chemistry, Vol. 20, pp. 3356-3366, 2010.)

For implantable medical devices, the life expectancy of the device may be limited by the duration of time it must maintain its mechanical properties and function in the body. For biodegradable devices, this life expectancy is intentionally shortened, providing a mechanism for materials and devices to degrade over time and be absorbed by the body's metabolic processes. For non-biodegradable devices, referred to as bio-durable devices or devices with bio-durability, they are not intended to degrade and they must retain their material properties and function for a longer period of time, possibly for the lifetime of the patient.

For medical devices used in vivo, whether permanent implants or instruments for diagnostic or therapeutic purposes, the ability to visualize the device using typical clinical imaging modalities such as X-ray, fluoroscopy, CT scanning and MRI is often a requirement for clinical use. Devices intended for imaging by X-ray and fluoroscopy typically contain metals or metal byproducts to cause radiopacity. Radiopacity refers to the relative inability of electromagnetic, and particularly X-rays, to pass through dense materials, which are described as "radiopaque," appearing opaque/white in radiographic images. More radiopaque materials appear brighter and whiter in the image. (Novelline, Robert. squire's Fundamentals of radiology. Harvard University Press, 5 th edition, 1997). Given the complexity of the content in X-ray or fluoroscopic images, clinicians are sensitive to image quality with respect to the brightness or signal intensity of the material in the image. Two major factors that affect the radiopacity brightness or signal strength of a material are density and atomic number. Polymer-based medical devices requiring radiopacity typically use polymer blends containing a small weight percentage of heavy atom, radiopaque fillers such as titanium dioxide (TiO)₂) Or barium sulfate (BaSO)₄). The ability of the device to be visualized fluoroscopically depends on the amount or density of filler mixed into the material, which is usually limited to small amounts, since filler may adversely affect the material properties of the base polymer. On the other hand, medical device imaging companies have developed standardized liquid contrast agents that are used intermittently by physicians to highlight vascular structures and the like when filled with the contrast agent during X-ray or fluoroscopy. The medium typically comprises a heavy atom fluid, such as iodine, to conductResulting in radiopacity.

Mosner et al reported iodine-incorporating monomers and reported 3 different triiodinated aromatic monomers that could be homopolymerized to varying degrees or require copolymerization to be incorporated (MosZner et al, "Synthesis and polymerization of hydrophilic iodine-containing monomers," Die Angewandte Makromolekulare Chemie 224(1995) 115-123). Iodinated monomers have also been studied by Koole et al, the Netherlands, as disclosed in 1994 to 1996, ranging from monoiodinated to triiodinated aromatic monomers (Koole et al, "students on a new radiopaque polymeric biology," Biomaterials 1994 Nov; 15 (14): 1122-8.Koole et al, "A transparent thread-iodine molecular building block leading to new radiopaque polymeric biology," J Biomed matter Res, 1996 Nov; 32 (3): 459-66). This included the biocompatibility results of a 2 year implantation study of monoiodinated aromatic methacrylate copolymer systems in rats. (Koole et al, "Stability of radiopaque iodine-containing Biomaterials," Biomaterials 2002 Feb; 23 (3): 881-6) Koole also discusses them in U.S. Pat. No. 6,040,408, originally filed as a European patent application on 8.1994, which limits its claims to aromatic monomers containing no more than two covalently bonded iodine groups. (U.S. Pat. No. 6,040,408, "Radiopaque Polymers and Methods for Preparation of" Koole, 3.21.2000). In addition, U.S. patent application publication 20060024266 to Brandom et al claims polyiodified aromatic monomers in shape memory polymers, emphasizing the use of crystallizable polymer Side groups (U.S. patent application publication 20060024266, "Side-chain crystalline polymers for medical applications, Brandom et al, 7/5/2005).

The information included in the background section of this specification, including any references cited herein and any descriptions or discussions thereof, is included for technical reference purposes only and is not to be considered subject matter defined by the scope of the present invention.

Disclosure of Invention

Polymers having a crosslinked network are provided. The crosslinked network comprises:

a) one or more first repeat units derived from a monomer of formula I:

b) one or more second repeat units derived from a monomer of formula IIa, formula IIb, formula IIIa, and/or formula IIIb:

and

c) one or more third repeating units derived from a monomer of formula IVa and/or formula IVb:

wherein each instance of m is independently an integer from 8 to 16; n in each instance is independently an integer from 2 to 22; p1 for each occurrence is independently an integer from 2 to 22; p2 for each occurrence is independently an integer from 1 to 50; ar is an iodinated 5-or 6-membered aryl or heteroaryl group; r is hydrogen or has the formula

And S of each case₁、S₂And S₃Independently hydrogen or methyl.

Methods of making the polymers described herein are also provided. The method comprises the following steps:

i) forming a monomer mixture comprising:

a) one or more monomers of formula I:

b) one or more monomers of formula IIa, formula IIb, formula IIIa and/or formula IIIb:

and

c) one or more monomers of formula IVa and/or formula IVb:

wherein each occurrence of m is independently an integer from 8 to 16; n in each instance is independently an integer from 2 to 22; p1 for each occurrence is independently an integer from 2 to 22; p2 for each occurrence is independently an integer from 1 to 50; ar is an iodinated 5-or 6-membered aryl or heteroaryl group; r is hydrogen or has the formula

And S for each case₁、S₂And S₃Independently hydrogen or methyl; and

ii) providing a free radical initiator to polymerize the monomer mixture.

Crosslinked polymer networks are also provided. The crosslinked polymer network is formed from a monomer mixture comprising:

a) one or more monomers of formula I:

and

c) one or more monomers of formula IVa and/or formula IVb:

wherein each instance of m is independently an integer from 8 to 16Counting; n in each instance is independently an integer from 2 to 22; p1 for each occurrence is independently an integer from 2 to 22; p2 for each occurrence is independently an integer from 1 to 50; ar is an iodinated 5-or 6-membered aryl or heteroaryl group; r is hydrogen or has the formula

And S of each case₁、S₂And S₃Independently hydrogen or methyl, wherein the monomer mixture comprises from about 60 to about 95 weight percent of the one or more monomers of formula I, from about 1 to about 40 weight percent of the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and from about 1 to about 25 weight percent of the one or more monomers of formula IVa and/or formula IVb.

Radiopaque polymeric devices for medical applications are further provided. The device comprises a polymer as described herein. In certain embodiments, the device is non-metallic.

Also provided are compositions comprising polymers having a crosslinked network.

Drawings

FIG. 1: having a T_r、T_g、T_oAnd DMA curves for SMP formulations of the examples with Tan delta peaks.

Fig. 2A to 2B: the embolic coil is withdrawn from a very thin single lumen catheter to form an occlusive mass much larger than the diameter of the coil.

FIG. 3: graph of iso-37 ℃ tan delta versus weight fraction of C2-DMA monomer for the polymer of example 4.

FIG. 4 is a schematic view of: glass transition temperature (T) of the Polymer of example 4_g) Graph against weight fraction of C2-DMA monomer.

FIG. 5: plot of iso-37 ℃ modulus versus weight fraction of C2-DMA monomer for the polymer of example 4.

Detailed Description

In one aspect, a polymer having a crosslinked network is provided. Typically, the crosslinked polymer network comprises a first repeat unit derived from a monofunctional radiopaque monomer, a second repeat unit derived from a short crosslinking monomer, and a third repeat unit derived from a long crosslinking monomer. In certain aspects, none of the first repeat unit, the second repeat unit, or the third repeat unit is fluorinated. The crosslinked network may be characterized by covalent bonding between the first repeat unit and the second repeat unit such that the second repeat unit forms crosslinks of the crosslinked network. The crosslinking may be further enhanced by the third repeat unit. Alternatively or additionally, the crosslinked network may be characterized by covalent bonding between the first repeat unit and the third repeat unit such that the third repeat unit forms crosslinks of the crosslinked network. The crosslinking may be further enhanced by the second repeat unit. In some embodiments, the second repeat unit and/or the third repeat unit imparts enhanced biodurability and/or radiopaque properties. For example, the second repeat unit and/or the third repeat unit may impart elastomeric or reinforced plastic properties to the crosslinked network.

Without wishing to be bound by any particular theory, it is believed that a polymer comprising a combination of a second repeat unit and a third repeat unit may yield better mechanical properties and better shape recovery than a polymer comprising the second repeat unit but no third repeat unit or comprising the third repeat unit but no second repeat unit. For example, a polymer comprising a second repeat unit but no third repeat unit may have good mechanical durability but poor shape recovery. Alternatively, a polymer comprising a third repeat unit but no second repeat unit may have good shape recovery but may be too brittle.

Typically, the polymers and polymer compositions described herein comprise radiopaque functionality. In one embodiment, the polymers and polymer compositions of the present invention comprise covalently bound heavy atoms, such as iodine. In this embodiment, the distribution of iodine or other radiopaque functionality within the polymer is sufficiently uniform to be effective for imaging applications.

The use of monomers having different chemical structures and amounts thereof can be used to inhibit the formation of crystalline regions in the polymer. In one embodiment, the monomers are selected for phase compatibility in the liquid and solid states. The phase compatibility of the monomers can promote random incorporation of the monomer units during free radical polymerization and homogeneity of the resulting polymer.

As used herein, a crosslinked network is a plurality of polymer units, wherein a majority (e.g., ≧ 80%) and optionally all of the polymer units are interconnected, e.g., by covalent crosslinking, to form a single polymer. In one embodiment, the present invention provides radiopaque polymers in the form of a crosslinked network, wherein at least some of the crosslinks of the network structure are formed by covalent bonds. Radiopacity refers to the relative inability of electromagnetic, and particularly X-rays, to pass through a dense material. Two major factors that affect the radiopacity of a material are the density and the atomic number of the radiopaque element. In one embodiment, the present invention utilizes iodine molecules incorporated (trapped) within a crosslinked network (i.e., a polymer matrix) to induce radiopaque functionality. In one embodiment, the radiopaque polymer is an iodinated polymer. As mentioned herein, iodinated polymers are produced by incorporating (capturing) iodine molecules on selected monomers prior to formulating the monomers into a polymer. In various embodiments, the concentration of iodine in the radiopaque polymer is at least 200mg/mL or at least 300 mg/mL.

In one embodiment, the iodinated, crosslinked polymers of the present invention are formed by polymerizing a monomer mixture comprising an iodinated monofunctional monomer, a short crosslinking monomer, a long crosslinking monomer, and an initiator. The monomer mixture may also comprise one or more additional iodinated monofunctional monomers, one or more additional short crosslinking monomers, and/or one or more long crosslinking monomers. As used herein, "monofunctional" refers to a monomer comprising only one polymerizable group, while "short crosslinking monomer" refers to a monomer of formula II or formula III comprising more than one polymerizable group, and "long crosslinking monomer" refers to a monomer of formula IV comprising more than one polymerizable group. Upon polymerization, the monomers in the monomer mixture provide the network with constitutional units, where each constitutional unit is an atom or group of atoms (with pendant atoms or groups, if any) that comprise part of the necessary structure of a macromolecule, oligomer molecule, block, or chain. Since the constituent units are usually present multiple times in the network, they may also be referred to as repeating units. The repeating units derived from a given type of monomer need not be located adjacent to each other in the network or in a given order in the network.

In some embodiments, the polymer comprises a crosslinked network comprising:

a) one or more first repeat units derived from a monomer of formula I:

and

And S of each case₁、S₂And S₃Independently hydrogen or methyl.

In some embodiments, one or more second repeat units are derived from a monomer of formula IIa and/or formula IIb (e.g., formula IIa or formula IIb). In certain embodiments, the second repeat unit is derived from a monomer of formula IIa. In other embodiments, the second repeat unit is derived from a monomer of formula IIb.

In some embodiments, one or more second repeat units are derived from a monomer of formula IIIa and/or IIIb (e.g., formula IIIa or IIIb). In certain embodiments, the second repeat unit is derived from a monomer of formula IIIa. In other embodiments, the second repeat unit is derived from a monomer of formula IIIb.

In some embodiments, one or more second repeat units are derived from a monomer of formula IIa and/or formula IIIa (e.g., formula IIa and formula IIIa).

In some embodiments, one or more third repeating units are derived from a monomer of formula IVa and/or formula IVb (e.g., formula IVa or formula IVb). In certain embodiments, the second repeat unit is derived from a monomer of formula IVa. In other embodiments, the second repeat unit is derived from a monomer of formula IVb.

Each m is independently an integer from 8 to 16 (i.e., 8, 9, 10, 11, 12, 13, 14, 15, or 16). Thus, one or more first repeat units derived from a monomer of formula I may have a length of 8 to 16-CH₂-alkylene chain of units. In some embodiments, each m is independently 8, 9, 10, 11, or 12. In some preferred embodiments, each m is 10.

Each n is independently an integer from 2 to 22 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22). Thus, one or more second repeat units derived from a monomer of formula IIa or formula IIb can have a length of 2 to 22 (e.g., 2 to 16, 2 to 10, 6 to 22, 10 to 22, or 10 to 14) -CH₂-alkylene chain of units. In some embodiments, each n is independently 10, 11, 12, 13, or 14. In some preferred embodiments, each n is 12.

Each p1 is independently an integer from 2 to 22 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22). Thus, one or more third repeating units derived from a monomer of formula IVa or formula IVb may have a length of 2 to 22 (e.g., 2 to 16, 2 to 10, 2 to 6, 2 to 4, 6 to 22, 10 to 22, or 10 to 14) -CH₂Alkylene of the unitsAnd (3) a chain. In some embodiments, each p1 is independently 2, 3, 4, 5, or 6. In some preferred embodiments, each n is 4 or 6.

Each p2 is independently an integer from 1 to 50 (e.g., 1 to 40, 1 to 30, 1 to 20, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 2 to 50, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 50, 4 to 40,4 to 30, 4 to 20, or 4 to 10). In some embodiments, each p2 is an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6).

S in each case₁、S₂And S₃Independently hydrogen or methyl. In some embodiments, S for each occurrence₁、S₂And S₃Is hydrogen. In some embodiments, S for each occurrence₁、S₂And S₃Is methyl.

In some embodiments, the monomer of formula IIa or formula IIb is:

in some embodiments, the monomer of formula IIIa or formula IIIb is:

in some embodiments, the monomer of formula IVa or formula IVb is:

in some embodiments, the monomer of formula IVb is polyethylene glycol dimethacrylate or polyethylene glycol diacrylate. The polyethylene glycol dimethacrylate or polyethylene glycol diacrylate may have any suitable weight average molecular weight. For example, the polyethylene glycol dimethacrylate or polyethylene glycol diacrylate may have a weight average molecular weight of 200g/mol to 2,000g/mol, such as 200g/mol to 1,500g/mol, 200g/mol to 1,000g/mol, 500g/mol to 2,000g/mol, 500g/mol to 1,500g/mol, or 500g/mol to 1,000 g/mol. In some embodiments, the monomer of formula IVb is polyethylene glycol diacrylate (weight average molecular weight of about 575g/mol) or polyethylene glycol dimethacrylate (weight average molecular weight of about 1,000 g/mol).

Ar is an iodinated 5-or 6-membered aryl or heteroaryl group. In some embodiments, the iodinated 5-or 6-membered aryl or heteroaryl groups contain at least two iodine atoms. In certain embodiments, the iodinated 5-or 6-membered aryl or heteroaryl groups contain at least three iodine atoms. Thus, an iodinated 5-or 6-membered aryl or heteroaryl group can contain an average of 1 to 5, 1 to 4, 2 to 4, 3 to 4, or 3 to 5 iodine atoms per 5-or 6-membered aryl or heteroaryl group. In certain embodiments, an iodinated 5-or 6-membered aryl or heteroaryl group comprises an average of 2 to 4 or 3 to 4 iodine atoms per 5-or 6-membered aryl or heteroaryl group. In some preferred embodiments, the iodinated 5-or 6-membered aryl or heteroaryl groups contain an average of about 3 iodine atoms per 5-or 6-membered aryl or heteroaryl group.

The 5-or 6-membered aryl or heteroaryl group can be any suitable aromatic substituent. As used herein, "5-or 6-membered aryl" refers to a substituted or unsubstituted, monocyclic aromatic substrate (e.g., phenyl) comprising 5 or 6 atoms around an aromatic core or ring. As used herein, a "5-or 6-membered heteroaryl" substituted or unsubstituted monocyclic aromatic substrate comprises at least 1 heteroatom (e.g., O, S, N, and or P) in the core of the molecule (i.e., the aromatic core or any atom surrounding the aromatic ring). Typically, the iodinated 5-or 6-membered aryl or heteroaryl is an iodinated 6-membered aryl. For example, the iodinated 5-or 6-membered aryl or heteroaryl group may be selected from:

in some preferred embodiments, the iodinated 6-membered aryl groups have the formula:

each R is independently hydrogen or has the formula

Thus, one or more third repeating units derived from a monomer of formula IIIa and/or formula IIIb may have five or six acrylate groups. In some embodiments, R is hydrogen. In other embodiments, R has the formula

Wherein S in each case₂Independently hydrogen or methyl.

As used herein, the term "group" may refer to a functional group of a compound. A group of a compound of the present invention refers to an atom or collection of atoms that are part of the compound. The groups of the present invention may be attached to other atoms of the compound by one or more covalent bonds. A group may also be characterized with respect to its valence state. The present invention includes groups characterized by monovalent, divalent, trivalent, etc. valency.

As used throughout this specification, the expression "a group corresponding to a specified substance" explicitly includes a moiety derived from a group including a monovalent group, a divalent group, or a trivalent group.

As is conventional and well known in the art, the hydrogen atoms contained in the chemical formula are not always clearly shown, for example, hydrogen atoms bonded to carbon atoms of the polymer backbone, crosslinking groups, aromatic groups, and the like. The structures provided herein, for example in the context of describing chemical formulas, are intended to convey the chemical makeup of the compounds of the methods and compositions of the present invention to those of ordinary skill in the art, and as will be understood by those of skill in the art, the structures provided do not indicate the particular positions of the atoms of these compounds and the bond angles between the atoms.

As used herein, the terms "alkylene" and "alkylene group" are used synonymously to refer to a divalent group derived from an alkyl group as defined herein. The present invention includes compounds having one or more alkylene groups.

As used herein, when referring to a monomer unit, "derivatised" means that the monomer unit has substantially the same structure as the monomer from which it was prepared, wherein the terminal olefin has been converted during the polymerisation process.

The polymer having a crosslinked network can comprise any suitable amount of one or more first repeat units, one or more second repeat units, and one or more third repeat units. For example, the polymer may comprise from about 25% to about 99% by weight of one or more first repeat units, from about 0.1% to about 74.9% by weight of one or more second repeat units, and from about 0.1% to about 74.9% by weight of one or more third repeat units. In some embodiments, the polymer comprises from about 60% to about 95% by weight of the one or more first repeat units, from about 1% to about 40% by weight of the one or more second repeat units, and from about 1% to about 25% by weight of the one or more third repeat units. In certain embodiments, the polymer comprises from about 75% to about 90% (e.g., from about 80% to about 90%) by weight of one or more first repeat units (e.g., from about 80% to about 90%), from about 5% to about 15% (e.g., from about 5% to about 10%) by weight of one or more second repeat units, and from about 1% to about 10% (e.g., from about 1% to about 8% or from about 1% to about 6%) by weight of one or more third repeat units.

In some embodiments, the crosslinked network further comprises one or more fourth repeat units derived from a monomer of formula V and/or formula VI:

wherein p3 for each occurrence is independently an integer from 2 to 36; p4 for each occurrence is independently an integer from 2 to 22; p5 for each occurrence is independently an integer from 1 to 50; each R1 is methyl or hydroxy; and S of each case₄Independently hydrogen or methyl.

Each p3 is independently an integer from 2 to 36 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36). Thus, one or more fourth repeat units derived from a monomer of formula V and/or formula VI may have a length of 2 to 36 (e.g., 2 to 36, 2 to 24, 2 to 18, 2 to 12, 6 to 36, 6 to 24, 6 to 12, 10 to 32, 10 to 24, or 10 to 16) — CH₂-alkylene chain of units. In some embodiments, each p3 is independently 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In some preferred embodiments, each n is 9, 10, 11, 12, 13, 14, or 15.

Each p4 is independently an integer from 2 to 22 (i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22). Thus, one or more fourth repeat units derived from a monomer of formula V and/or formula VI may have a length of 2 to 22 (e.g., 2 to 16, 2 to 10, 2 to 6, 2 to 4, 6 to 22, 10 to 22, or 10 to 14) -CH₂-alkylene chain of units. In some embodiments, each p4 is independently 2, 3, 4, 5, or 6. In some preferred embodiments, each n is 2, 4 or 6.

Each p5 is independently an integer from 1 to 50 (e.g., 1 to 40, 1 to 30, 1 to 20, 1 to 10, 1 to 8, 1 to 6, 1 to 4, 2 to 50, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 8, 2 to 6, 2 to 4, 4 to 50, 4 to 40,4 to 30, 4 to 20, or 4 to 10). In some embodiments, each p5 is an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6).

All things being equalS of condition₄Independently hydrogen or methyl. In some embodiments, S for each occurrence₄Is hydrogen. In some embodiments, S for each occurrence₄Is methyl.

The number of repeating units described or illustrated herein is not particularly limited, but is any number that is functionally feasible, i.e., that can be synthesized and has a desired use in a desired polymer composition, polymer, method, and device.

Typically, the polymer having a crosslinked network is a radiopaque polymer. In some embodiments, the radiopaque polymer is a Shape Memory Polymer (SMP). In some aspects, the polymers and polymer compositions disclosed herein can be used in medical devices. In some aspects, the polymers and polymer compositions disclosed herein may be shape memory polymers as defined herein and known in the art, but are not used in a manner in which they are externally triggered. For example, the polymers and polymer compositions disclosed herein can be "sterically-triggered," as the phrase is conventionally used. For example, in a space-triggered material, the material returns to its original shape after the space constraint is removed, such as when a disc-shaped sample emerges from its temporary elongated configuration within the deployment catheter and returns to its disc shape. It should be clear that certain polymers and polymer compositions described herein may technically possess shape memory properties, but these properties may or may not be used in the devices and methods of the present invention. As used herein, the polymers and polymer compositions disclosed herein are intended to include shape memory aspects and non-shape memory aspects as applicable. If a shape memory polymer is used to describe a particular embodiment, it should be recognized that other polymers and polymer compositions not specifically defined as having shape memory properties may be interchangeable and used in this embodiment.

In some embodiments, the polymers, polymer compositions, or devices of the present invention do not comprise any metallic material or metallic component or metallic element, but still exhibit suitable radiopacity for clinical observation using conventional imaging systems. Clinicians are often challenged by blurring artifacts (artifacts) from metallic and metal-based implanted devices when attempting to image using CT scans (computed tomography) or MRI (magnetic resonance imaging). The significance of the artifact is typically based on the amount of metal content and may be so excessive as to inhibit the ability to clinically image the device. Such a situation may require an alternative method to clinically evaluate the patient or device (e.g., angiography, etc.), which may not only be more costly, but also be more invasive and risky for the patient. Thus, non-metallic radiopaque polymers exhibit significant advantages and differences over other approaches used for radiopaque devices.

In some embodiments, the polymers of the present invention are sufficiently amorphous that some conventional analytical methods do not indicate the presence of a residual amount of crystallinity. In other words, in some embodiments, the polymer is substantially amorphous and/or the structure is selected to hinder crystallinity. The degree of crystallinity may be measured by any suitable method, for example by using Differential Scanning Calorimetry (DSC). In certain embodiments, the crystallization of the polymers described herein is insufficient to render a device incorporating the polymers inoperative in a desired use. Such morphology differs from the disclosure of U.S. patent 7939611 to Brandom et al, which discloses side chain crystallizable units in its molten liquid embolic agent to promote semi-crystallinity. Generally, if the shape memory polymer is semi-crystalline, the shape change may be hindered and slowed, and device performance may become clinically undesirable. The crystallinity of the shape memory polymers and non-shape memory polymers described herein can be influenced by the selection of components used to form the polymers, as further described herein.

The glass transition temperature and the rubbery modulus of the polymers of the present invention can be independently adjusted as further described herein.

The polymer having a crosslinked network can have any suitable glass transition temperature. In some embodiments, the glass transition temperature of the polymer is from 0 ℃ to 75 ℃, although any other polymer glass transition temperature that results in a useful end product is also intended to be included. In some embodiments, the glass transition temperature can be inhibited from falling below body temperature. When a polymer formed from such a design is delivered in a catheter or other delivery device, the material may have transformed into its rubbery state in the delivery device. This may allow for a faster response (elastic response) from the device after delivery (e.g. in the container). The polymer can be a shape memory polymer having a glass transition temperature (Tg) of 15 ℃ to 75 ℃ and a rubbery modulus at 37 ℃ of 0.1MPa to 500 MPa. The polymer may have a Tg at or below body temperature. In general, polymers exhibit a temperature-dependent Tan δ (loss modulus/storage modulus ratio) curve and a glass transition temperature (Tg); the maximum rate of shape change of the polymer occurs at an ambient operating temperature (To) that is consistent with a temperature at or above the Tan delta value of the rubbery plateau region. In certain embodiments, the glass transition temperature of the polymer having a crosslinked network is from 0 ℃ to 50 ℃, e.g., from 15 ℃ to 50 ℃, from 15 ℃ to 35 ℃, from 25 ℃ to 50 ℃, from 25 ℃ to 45 ℃, from 25 ℃ to 40 ℃, from 25 ℃ to 35 ℃, from 25 ℃ to 30 ℃, from 30 ℃ to 50 ℃, from 30 ℃ to 45 ℃, from 30 ℃ to 40 ℃, from 30 ℃ to 35 ℃, from 40 ℃ to 50 ℃, or from 40 ℃ to 45 ℃. In some preferred embodiments, the polymer has a glass transition temperature of 15 ℃ to 35 ℃ or 25 ℃ to 35 ℃.

In some embodiments, the polymer or polymer composition has sufficient water resistance to absorb, which can be used to manufacture a medical device or device component for use in a physiological environment exposed to bodily fluids. In one embodiment, the medical device or device component exhibits little change in its mechanical properties or degradation of its mechanical integrity over the useful life of the device. In one embodiment, the devices and compositions described herein can be used for permanent (or long-term) implantation or use in biological systems. In one embodiment, a device or device component formed using the polymer or polymer composition of the present invention exhibits less than 0.5 weight percent water uptake over a 24 hour period. In one embodiment, a device or device component formed using the polymer or polymer composition of the present invention exhibits less than 0.1 weight percent water absorption over a 24 hour period.

In some embodiments, the polymer or polymer composition further comprises a metallic marker band. In one embodiment of this aspect, the metallic marker band comprises platinum-iridium or gold.

In some embodiments, a polymer or polymer composition as described herein is substantially amorphous. In certain embodiments, a polymer or polymer composition as described herein is a shape memory polymer or shape memory polymer composition.

As used herein, a crystalline material exhibits long range order. The crystallinity of polymers is characterized by the degree of their crystallinity or the weight fraction or volume fraction of crystalline material in the sample, ranging from zero (for fully amorphous polymers) to one (for theoretically fully crystalline polymers).

If the polymer is semi-crystalline, shape changes may be hindered and slowed, and the performance of devices incorporating the polymer may become clinically unacceptable. In some embodiments, the polymer compositions of the present invention are considered to be substantially amorphous. As used herein, substantially amorphous is defined as the absence of crystalline features as detected by Differential Scanning Calorimetry (DSC), or by the inconsistency and lack of reproducibility in mechanical tensile test results, such as stress-strain curves at a fixed temperature. In certain embodiments, the lack of reproducibility may be indicated by a reproducibility of less than 95% at a 95% confidence interval. Substantially amorphous polymers may incorporate a relatively small amount of crystallinity. As typical amorphous polymers, the substantially amorphous polymer compositions of the present invention exhibit a transition from a glassy state to a rubbery state over the glass transition temperature range. Crystallinity can be reduced or eliminated by reducing the concentration of particular monomers that enhance this, and/or by introducing a different structure to ensure that the molecular structure of the polymer does not undergo orientation during polymerization that leads to crystallinity.

In one embodiment, the monomers used to form the radiopaque polymer (including the crosslinking monomers) are selected to ensure compatibility (e.g., uniformity after polymerization). In one embodiment, the radiopaque polymer is sufficiently uniform in terms of solid phase compatibility of the polymerized units and sufficiently random incorporation of the units throughout the polymerization process to achieve the desired performance characteristics. Phase incompatibility can lead to voids in the polymer morphology. Voids in the polymer matrix impair mechanical properties and may lead to absorption of water and other fluids, which displaces the void volume produced, even when the incompatible phases are hydrophobic or even "water repellent". As polymerization proceeds from low to high conversion, excessive non-random incorporation of comonomers, particularly di (meth) acrylate or other poly (meth) acrylate crosslinkers, can result in non-uniform crosslink density, such that regions have higher (brittle) and lower (rubbery) crosslink densities.

In one embodiment, the radiopaque polymer is sufficiently uniform that reproducible results (95% reproducible data at 95% confidence intervals) can be obtained in a simple ultimate tensile test at a fixed temperature. In one embodiment, the homogeneity of the polymer may be improved by selecting the components of the monomer solution to reduce phase separation in the liquid or solid state. In addition, the monomer components and polymerization techniques may be selected to facilitate random incorporation of monomer and crosslinker groups by free radical polymerization during curing. In one embodiment, the same type of polymerizable group is present in each monomer. For example, for monomers (and crosslinking monomers) having an acrylate polymerizable group and an aliphatic hydrocarbon linker, it is expected that the induction exerted on the acrylate group by typical aliphatic linker attachment is similar.

In another aspect, a method of making a polymer having a crosslinked network as described herein is provided. The method comprises the following steps:

i) forming a monomer mixture comprising:

a) one or more monomers of formula I:

and

c) one or more monomers of formula IVa and/or formula IVb:

And S of each case₁、S₂And S₃Independently hydrogen or methyl; and

ii) providing a free radical initiator to polymerize the monomer mixture. m, n, p1, p2, Ar, R, S₁、S₂And S₃Each as described herein. In some embodiments, the monomer mixture is substantially homogeneous.

Typically, the amount of one or more monomers of formula I (i.e., radiopaque monomers) in the monomer mixture is at least about 25 weight percent. As used herein, the wt% of radiopaque monomer in the mixture may be 100 (weight of radiopaque monomer/weight of the sum of all monomers). In some embodiments, the amount of the one or more monomers of formula I (i.e., radiopaque monomers) is from about 25% to about 99% by weight of the monomer mixture. For example, the amount of radiopaque monomer is from about 25% to about 98%, from about 25% to about 95%, from about 25% to about 90%, from about 25% to about 85%, from about 25% to about 80%, from about 25% to about 75%, from about 25% to about 98%, from about 50% to about 95%, from about 50% to about 90%, from about 50% to about 85%, from about 50% to about 80%, from about 50% to about 75%, from about 60% to about 98%, from about 60% to about 95%, from about 60% to about 90%, from about 60% to about 85%, from about 60% to about 80%, from about 60% to about 75%, from about 70% to about 98%, from about 95% to about 95%, from about 95% by weight of the monomer mixture, About 70 wt% to about 90 wt%, about 70 wt% to about 85 wt%, about 70 wt% to about 80 wt%, about 70 wt% to about 75 wt%, about 80 wt% to about 99 wt%, about 80 wt% to about 95 wt%, about 80 wt% to about 90 wt%, about 85 wt% to about 99 wt%, about 85 wt% to about 95 wt%, about 86 wt% to about 95 wt%, about 87 wt% to about 95 wt%, about 88 wt% to about 95 wt%, about 89 wt% to about 95 wt%, or about 90 wt% to about 95 wt%. In certain embodiments, the amount of radiopaque monomer is from about 60% to about 95% by weight of the monomer mixture. In some preferred embodiments, the amount of radiopaque monomer is from about 75% to about 90% (e.g., from about 80% to about 90%) by weight of the monomer mixture.

Typically, the amount of one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb (i.e., short crosslinking monomers) in the monomer mixture is less than about 75 weight percent. As used herein, the weight% of short crosslinking monomers in the mixture may be 100 (weight of short crosslinking monomer/weight of sum of monomers). In some embodiments, the amount of one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb (i.e., short crosslinking monomers) is from about 0.1% to about 74.9% by weight of the monomer mixture. For example, the amount of short-crosslinking monomer is about 0.1 wt.% to about 50 wt.%, 0.1 wt.% to about 40 wt.%, about 0.1 wt.% to about 25 wt.%, about 0.1 wt.% to about 15 wt.%, about 0.1 wt.% to about 10 wt.%, about 0.1 wt.% to about 9 wt.%, about 0.1 wt.% to about 8 wt.%, about 0.1 wt.% to about 7 wt.%, about 0.1 wt.% to about 6 wt.%, about 0.1 wt.% to about 5 wt.%, about 0.5 wt.% to about 50 wt.%, about 0.5 wt.% to about 40 wt.%, about 0.5 wt.% to about 25 wt.%, about 0.5 wt.% to about 15 wt.%, about 0.5 wt.% to about 10 wt.%, about 0.5 wt.% to about 9 wt.%, about 0.5 wt.% to about 8 wt.%, about 0.5 wt.% to about 5 wt.%, about 5 wt.% to about 5 wt.%, about 6 wt.% to about 5 wt.%, about 5 wt.% to about 6 wt.% of the monomer mixture, About 1 wt% to about 40 wt%, about 1 wt% to about 25 wt%, about 1 wt% to about 15 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 9 wt%, about 1 wt% to about 8 wt%, about 1 wt% to about 7 wt%, about 1 wt% to about 6 wt%, about 1 wt% to about 5 wt%, about 5 wt% to about 50 wt%, about 5 wt% to about 40 wt%, about 5 wt% to about 25 wt%, about 5 wt% to about 15 wt%, or about 5 wt% to about 10 wt%. In certain embodiments, the amount of short crosslinking monomer is from about 1% to about 40% by weight of the monomer mixture. In some preferred embodiments, the amount of short crosslinking monomer is from about 5% to about 15% by weight (e.g., from about 5% to about 10% by weight) of the monomer mixture.

Typically, the amount of one or more monomers of formula IVa and/or formula IVb (i.e., long crosslinking monomer) in the monomer mixture is less than about 75% by weight. As used herein, the wt% of long crosslinking monomers in the mixture may be 100 (weight of long crosslinking monomers/weight of sum of monomers). In some embodiments, the amount of one or more monomers of formula IVa and/or formula IVb (i.e., long crosslinking monomers) is from about 0.1% to about 74.9% by weight of the monomer mixture. For example, the amount of long-crosslinking monomer is about 0.1% to about 50%, about 0.1% to about 25%, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 9%, about 0.1% to about 8%, about 0.1% to about 7%, about 0.1% to about 6%, about 0.1% to about 5%, about 0.5% to about 50%, about 0.5% to about 25%, about 0.5% to about 15%, about 0.5% to about 10%, about 0.5% to about 9%, about 0.5% to about 8%, about 0.5% to about 7%, about 0.5% to about 6%, about 0.5% to about 1%, about 1% to about 25%, about 0.5% to about 5%, about 1% to about 1%, about 5% to about 25%, about 0.5% to about 7%, about 0.5% to about 10%, about 0.5% to about 1%, about 1% by weight of the monomer mixture, About 1 wt% to about 15 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 9 wt%, about 1 wt% to about 8 wt%, about 1 wt% to about 7 wt%, about 1 wt% to about 6 wt%, about 1 wt% to about 5 wt%, about 5 wt% to about 50 wt%, about 5 wt% to about 25 wt%, about 5 wt% to about 15 wt%, or about 5 wt% to about 10 wt%. In certain embodiments, the amount of long crosslinking monomer is from about 1% to about 25% by weight of the monomer mixture. In some preferred embodiments, the amount of long crosslinking monomer is from about 1% to about 10% by weight (e.g., from about 1% to about 8% or from about 1% to about 6% by weight) of the monomer mixture.

In some embodiments, the monomer mixture further comprises one or more additional monomers of formula V and/or formula VI:

wherein p3 for each occurrence is independently an integer from 2 to 36; p4 for each occurrence is independently an integer from 2 to 22; p5 for each occurrence is independently an integer from 1 to 50; each R1 is methyl or hydroxy; s for each case₄Independently hydrogen or methyl. The additional monomer can be present in the monomer mixture in any suitable amount. For example, the additional monomer may be present in an amount such that: from about 0 wt% to about 10 wt%, from about 2.5 wt% to about 90 wt%, from about 5 wt% to about 80 wt%, from about 10 wt% to about 80 wt%, from about 20 wt% to about 90 wt%, from about 2.5% to about 10 wt%, from about 5 wt% to about 50 wt%, from about 5% to about 25 wt%, from about 25 wt% to about 50 wt%, from about 50 wt% to about 80 wt%, from about 10 wt% to about 50 wt%, from about 20 wt% to about 50 wt%, or from about 10 wt% to about 70 wt%, and all lower, intermediate, and higher values and ranges therein.

The free radical initiator can be present in any suitable amount such that the desired level of polymerization is achieved. For example, the free radical initiator may be present in an amount of about 0.1 wt% to about 10 wt%, based on the weight of the sum of the monomers. In certain embodiments, the free radical initiator is present in an amount of about 0.1% to about 5% by weight (e.g., about 0.5% or about 1% by weight).

A wide range of free radical initiating systems can be used for the polymerization. In various embodiments, the initiator may be a photoinitiator, a thermal initiator, or a redox (redox) initiator. Photoinitiating systems are particularly useful, the precursor being a photoinitiator selected for wavelengths of light that do not require excessive absorption by the base monomeric components of the formulation. Irgacure819(ciba (basf), bis (2, 4, 6-trimethylbenzoyl) -phenylphosphine oxide) is an example of a photoinitiator that has been found to be particularly useful for curing systems.

Photopolymerization occurs when the monomer solution is exposed to light of sufficient power and wavelength to initiate polymerization. The wavelength and power of the light that can be used to initiate polymerization depends on the initiator used. Light used in the present invention includes any wavelength and power capable of initiating polymerization. Preferred wavelengths of light include ultraviolet light. In various embodiments, the light source provides primarily light having a wavelength of 200nm to 500nm or 200nm to 400 nm. In one embodiment, 1mW/cm is applied²To 100mW/cm²For a period of 10 seconds to 60 minutes at 200nm to 500 nm. Any suitable source may be used, including laser sources. The source may be filtered to a desired wavelength band. The source may be broadband or narrowband, or a combination. During the process, the light source may provide continuous or pulsed light.

Thermal initiation systems are also useful in the case of the preparation of particularly large or irregularly shaped objects which are difficult to irradiate uniformly, having low-temperature initiators or high-temperature initiators, some common examples being benzoyl peroxide and Azobisisobutyronitrile (AIBN). Free-radical initiating systems which generate free radicals by any type of redox reaction, e.g. in the case of irregularly shaped objects, are also usefulFenton systems involving ferrous salts with t-butyl hydroperoxide or other metal-organic (organic such as triethylamine + hydroperoxide), or photo-organic redox systems, an example of the latter being eosin-Y + triethanolamine visible light initiated systems. In certain embodiments, the free radical initiator is

P (commercially available from Arkema; Alsip, IL).

Many pseudo living radical polymerization systems, some of which are capable of producing polymers with narrower molecular weight distributions than conventional radical polymerization, are also described in the art and can be used to produce crosslinker segments for use in SMP, or for SMP curing. For example, styrene monomer polymerized to low conversion in conventional systems may be driven to high conversion in pseudo-reactive systems. These pseudo-reactive systems typically involve a variable combination of reversible chain growth termination and/or chain transfer steps. "living" free radical polymerization known in the art includes, but is not limited to, NMP, RAFT, and ATRP.

Additionally; any other type of non-conventional free radical polymerization process (whether pseudo-living or not) that generates free radicals capable of initiating polymerization of the radiopaque and non-radiopaque monomers and crosslinkers (including SMPs) of the present invention falls within the scope of the potential method of initiating polymerization. These and other free radical initiating systems are conceivable and known to those skilled in the art.

In some embodiments, some examples of useful initiating systems include inactive, pseudo-active, or active anionic polymerization, cationic polymerization, free radical polymerization, and Ziegler-Natta (Ziegler-Natta) and olefin metathesis. The use of these systems is known in the art. In one embodiment, these systems are useful if the prepolymerization stage is at least difunctional and has hydroxyl groups or other groups known in the art that can be used to attach polymerizable groups, including acrylate groups in one embodiment.

In one embodiment, some or all of the components of the monomer mixture are combined at a temperature above ambient temperature. In various embodiments, the initiator may be added simultaneously with the monomer components or just prior to or during shaping. In another embodiment using a thermal initiator, the monomer mixture components may be divided into two parts; wherein the high storage temperature component is in part a and the lower storage temperature component is in part B. The thermal initiator may be added to the lower storage temperature component in part B at a storage temperature below the polymerization temperature of the initiator. In one embodiment, forming the monomer mixture (or a portion of the monomer mixture) at above ambient temperature may help maintain the solubility of the monomer mixture components, thereby enabling the formation of a homogeneous mixture.

In one embodiment, the monomer mixture is maintained at a temperature above ambient temperature during the free radical polymerization. In one embodiment, the monomer mixture is maintained at a temperature of from 65 ℃ to 150 ℃ or from 65 ℃ to 100 ℃ during the polymerization step. In one embodiment, the pre-curing step is performed in a vacuum environment. In separate embodiments, the curing step is carried out using a free radical mechanism, an anionic mechanism, a cationic mechanism, a Diels-alder mechanism, a thiol-ene mechanism, a polycondensation mechanism, or other mechanisms known in the art. During molding, pressure may be applied during polymerization to ensure mold filling.

In one embodiment, an additional curing or heat treatment step is employed after the polymerization step (e.g., after photopolymerization). In one embodiment, the cured part is removed from the mold and then subjected to an additional curing operation by exposure to elevated temperatures. In one embodiment, during this further step, the curing temperature is from 50 ℃ to 150 ℃ and the curing time is from 5 seconds to 60 minutes. In various embodiments, the amount of functional group conversion is at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more. In one embodiment, the amount of extractables is less than or equal to 5%. In one embodiment, the amount of extractables is less than or equal to 3%. In one embodiment, the amount of extractables is less than or equal to 2%. In one embodiment, the amount of extractables is less than or equal to 1% or less than or equal to 0.5%. In one embodiment, the amount of extractables is determined by isopropanol extraction.

In another aspect, a crosslinked polymer network is provided. The crosslinked polymer network is formed from a monomer mixture comprising:

a) one or more monomers of formula I:

and

c) one or more monomers of formula IVa and/or formula IVb:

And S for each case₁、S₂And S₃Independently hydrogen or methyl, wherein the monomer mixture comprises from about 60 to about 95 weight percent of one or more monomers of formula I, from about 1 to about 40 weight percent of one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and from about 1 to about 25 weight percent% of one or more monomers of formula IVa and/or formula IVb. m, n, p1, p2, Ar, R, S₁、S₂And S₃Each as described herein.

Additional features of the crosslinked polymer network will be apparent from the description provided herein.

In another aspect, the present invention provides a radiopaque medical device. The original molded shape of the radiopaque medical device of the present invention may be deformed into a temporary shape, typically having a reduced profile, to aid in insertion into a blood vessel, cavity, or other aperture or cavity (cavity). After insertion, the device may self-expand to assume the deployed configuration. In one embodiment, the medical device may assume its deployed configuration due to a change in temperature or other stimulus. In one embodiment, these SMP devices are capable of exhibiting shape memory behavior at physiological temperatures and may be used in surgical and catheter-based procedures. In one embodiment, the deployed configuration of the medical device may have one or more useful purposes, including lumen occlusion, lumen opening or stent implantation, device anchoring or retention, repair or sealing of surfaces, structural repair, or local drug delivery. If SMP properties are found in the compound or composition, the device may or may not utilize the SMP properties of the compound or composition. In some embodiments, the device has a water absorption propensity of less than 1.0 wt% over a 24 hour period.

The device may be used for the purpose of an indwelling permanent implant to provide the following functions: opening or maintaining an open anatomical cavity; partially closing the anatomical cavity as a valve, or completely closing the anatomical cavity occluded for any physiological fluid or gas flow or for an administered therapeutic fluid or gas flow; supporting anatomical structures to aid in the therapeutic restoration of function of organs, vessels, digestion, drainage, or airways; supporting anatomical structures to aid in the therapeutic restoration of orthopedic, maxillofacial, spinal, articular, or other bones or functions; or by covering the area after tissue dissection or resection, patches (patches) to support haemostasis, for example for haemostasis of the liver or other organs. In one embodiment, the device may be used in a diagnostic or therapeutic apparatus or device to provide the following functions: a) a catheter for the purpose of accessing an anatomical site; delivering an additional device and/or therapeutic agent; or controlling the entry or delivery of additional devices and/or therapeutic agents; or b) temporary indwelling devices that provide therapeutic benefit for a limited period of time, such as a vena cava filter that is placed in a blood vessel, left for a period of time, for example to capture blood clots, and then removed at the completion of the treatment session.

In some embodiments, the device is non-metallic. In other embodiments, the device comprises a metal. For example, the device may comprise metal in the form of marker bands as is conventional for visualization. In one aspect, the device comprises a platinum-iridium or gold marker band as known in the art. As is known in the art, a "marker band" may be used to achieve specific product requirements, such as demarcation of device edges or alignment of two devices for proper use, for example. For the devices described herein, the use of marker bands is optional.

In many applications, biodurability may be defined as the durability over a period of time required to ensure that the body has overcome the need for device function (e.g., a tubal occlusion device that relies on scar tissue formation to close a lumen no longer requires the device to create scar tissue once the lumen is completely closed). For example, if the time period is 90 days, the biodurable life of the device may be this value plus a suitable safety factor used in the design. Thus, bio-durability is the ability of the device and its materials to withstand environmental challenges at the location where it is placed in the body, for example if in the bloodstream it must withstand the blood environment. In one embodiment, the radiopaque polymer is non-biodegradable over the expected lifetime of the medical device. In another embodiment, the radiopaque polymer is non-biodegradable within three years. In one embodiment, the non-biodegradable polymer does not contain aromatic groups other than those present in naturally occurring amino acids. In one embodiment, the non-biodegradable polymer does not comprise an ester that is readily hydrolyzed at physiological pH and physiological temperature.

For almost all sites within the body, one of several major degradation mechanisms can be caused by water or moisture absorption. These environments are water-based, whether or not they contain interstitial fluid, blood, saliva, urine, bile, intracranial fluid, etc. If the device or its material absorbs water, the material properties and device dimensions may change due to swelling, or the device function may be affected, such as self-generation of erroneous electrical paths, or the material properties may decrease resulting in weakening or disassembly of the device. Thus, for the biological durability of an implanted device, a major consideration is the ability of the device and all of its materials to not absorb water.

In one embodiment, water absorption or water absorption may alter the characteristics of the device or adversely affect the performance of the device over its expected lifetime. In one embodiment, medical devices made from the polymers of the present invention will exhibit minimal water absorption. Water absorption can be measured during a test period equivalent to the lifetime of the device, or can be measured during a shorter screening period. In one embodiment, the degree of water absorption is < 1% by weight over 24 hours. In standard tests, for devices that exhibit greater than 1 wt.% water uptake in 24 hours, continuous exposure typically results in material changes such as brittleness and eventual mechanical damage.

The minimum iodine concentration level required to achieve sufficient radiopacity to provide clinically acceptable imaging can be determined empirically. In one embodiment, evaluations of the same size devices formulated from polymers using different weight percentages of iodinated monomers can be compared under simulated clinical use conditions. Clinical imaging quality correlates with iodine concentration using subjective comments of physicians and correlating their opinions with results from Image analysis programs (e.g., Image J) to quantify signal levels. The result is that a minimum iodine concentration is determined to ensure acceptable image quality. Typically, the iodine concentration value is at least about 200 mg/mL. In certain embodiments, the minimum iodine concentration value is about 500 mg/mL. In some embodiments, the iodine concentration value is about 350mg/mL to about 1,000mg/mL (e.g., about 400mg/mL to about 1,000mg/mL, about 450mg/mL to about 1,000mg/mL, about 500mg/mL to about 1,000mg/mL, about 550mg/mL to about 1,000mg/mL, about 600mg/mL to about 1,000mg/mL, about 350mg/mL to about 900mg/mL, about 400mg/mL to about 900mg/mL, about 450mg/mL to about 900mg/mL, about 500mg/mL to about 900mg/mL, about 550mg/mL to about 900mg/mL, about 600mg/mL to about 900mg/mL, or about 500mg/mL to about 800 mg/mL).

In another embodiment, the signal obtained from a radiopaque polymer device can be compared to the signal of a platinum device of similar size. In one embodiment, where the signal level is obtained by x-ray under a 6 inch water phantom (water phantom), the signal from the radiopaque polymeric device may be as high as 30% of the signal of the platinum device, for example, since the platinum device is a two-winding device with a central hollow region (the theoretical AutoZeff calculator result is an estimated effect of the central hollow region of the platinum metal embolic coil device).

Any polymer that can be brought back to an original shape from a temporary shape by application of a stimulus such as temperature is considered a Shape Memory Polymer (SMP). The original shape is set by machining and the temporary shape is set by thermomechanical deformation. SMPs have the ability to recover large deformations upon heating. The shape memory function can be used to develop medical devices that can be introduced into the body in a less invasive form, where the pre-deployed or temporary shape is intentionally smaller or thinner, resulting in a smaller profile and smaller opening (smaller catheter or incision) to introduce the device into the patient than would otherwise be required without the shape changing function. The device then undergoes shape recovery to return to its larger form of permanent λ when stimulated by a temperature (typically body temperature but may also be above body temperature).

A polymer is SMP if its original shape is restored by heating it above a shape recovery or deformation temperature (Td), even if its original molded shape is mechanically destroyed at a temperature below Td, or if the memorized shape can be recovered by applying another stimulus. Any polymer that can be brought back to an original shape from a temporary shape by application of a stimulus such as temperature can be considered an SMP.

From biomedicineFrom a device point of view, there are characteristics in the device design that are considered advantageous. They are quantified in terms of stimulus (e.g., temperature) driven response, well defined response temperature, modulus, and elongation. In one embodiment, the thermomechanical properties of the shape memory polymer used to form the device are optimized for one or more of: modulus of rubber state (E)_rub) Glass transition temperature (T)_g) And a recovery speed (S).

The preferred range of the rubbery modulus may be different for different applications. The modulus of biological tissue can range from 20GPa (bone) to 1kPa (eye). In one embodiment, the rubbery modulus is from 0.1MPa to 15MPa at 37 ℃. In one embodiment, the rubbery modulus is from 0.1MPa to 50MPa for the flexible state and from 0.1MPa to 500MPa for the rigid state at 37 ℃. Any rubbery modulus value that produces a functional product can be used. The modulus, e.g., stiffness, of the SMP can be determined to be very soft, about 0.1MPa, by polymer formulation adjustment. In one embodiment, for use as a device such as an embolic coil, such soft material enhances compaction of the coil assembly (coil pack), shortens the resulting assembly for easier placement and ultimately increases the occlusion speed. With other formulations, the modulus of the SMP can be brought to higher values, such as 15MPa, to enhance stiffness. In another embodiment, a stiffer SMP can be used to form a tubular stent, where local stiffness is used to create an outward radial force against the vessel wall upon deployment, which is desirable for retention.

In one embodiment, the polymer is selected based on the desired glass transition temperature (if at least one segment is amorphous) in view of the use environment. In one approach, the polymer transition temperature is adjusted to allow for adjustment at body temperature, T_r～T_gRecovery was about 37 ℃ (a. random and r. langer, "biodegradable. elastic shape-memory polymers for potential biological applications," Science, volume 296, pages 1673 to 1676, 2002). The obvious advantage of this approach is to naturally activate the material using the body's thermal energy. For some applications, such a methodThe disadvantage of formula (I) is that the mechanical properties of the material, such as stiffness, are strongly dependent on T_gAnd may be difficult to change during device design. In particular, when the polymer T is_gNear body temperature, it is difficult to design a very rigid device due to the compliant nature of the polymer. Another possible disadvantage is T_gA desired storage temperature T of the shape memory polymer of about 37 DEG C_sWill generally be below room temperature and require "cold" storage prior to deployment. In various embodiments, the SMPs of the invention have a glass transition temperature, as determined by the peak of tan δ, of 10 ℃ to 75 ℃, 20 ℃ to 50 ℃, 25 ℃ to 50 ℃, or 30 ℃ to 45 ℃. In certain embodiments, the SMPs of the invention have a glass transition temperature, as determined by the peak of tan δ, of from 0 ℃ to 50 ℃. In some preferred embodiments, the SMPs of the invention have a glass transition temperature, as determined by the peak of tan δ, of from 25 ℃ to 35 ℃. In various embodiments, the glass transition temperature can be below body temperature (e.g., 25 ℃ to 35 ℃), near body temperature (32 ℃ to 42 ℃) or above body temperature (40 ℃ to 50 ℃). Any Tg value that results in a functional product can be used.

The storage modulus of the at least partially amorphous polymer decreases in the glass transition region. The DMA results highlight when the material is from its storage temperature (T)_s) Heating to its response temperature (T)_r) And higher. Fig. 1 shows plots of storage modulus (E ') and Tan δ (the ratio of loss modulus (E ") to storage modulus (E') of the material) obtained from Dynamic Mechanical Analysis (DMA) curves of SMP formulations. The curve shows the recovery temperature (T)_r) Glass transition temperature (T)_g) Operating temperature (T)_o) And Tan delta peak. Several methods can be used to determine the glass transition temperature; these include the peak or start of the tan delta curve and the start of the drop in storage modulus. the width of the tan delta peak indicates the width of the glass transition region. In one embodiment, the glass transition temperature is within the specified range and the full width at half maximum of the tan delta peak is from 10 ℃ to 30 ℃ or from 10 ℃ to 20 ℃. The glass transition temperature determined by DMA is frequency dependent and generally increases with increasing frequency. In one embodiment, the measurement frequency is1 Hz. The glass transition temperature may also depend on the heating rate and the applied stress or strain. Other methods of measuring glass transition temperature include thermomechanical analysis (TMA) and Differential Scanning Calorimetry (DSC); TMA and DSC are heating rate dependent.

In general, clinicians expect relatively fast and repeatable shape recovery for each medical device application that involves shape recovery. In one embodiment, the shape memory polymer device of the present invention produces such shape recovery: it is fast enough to be detected, done in a reasonable (intra-operative) time, and repeatable from one device to another. In one embodiment, the shape recovery time may be measured in-service or from a screening step. The shape recovery time from release to 100% recovery or from release to a predetermined amount of recovery can be measured.

Rate of shape change and operating temperature and T on DMA curve_rThe rate of change of storage modulus therebetween. For SMP, the rate of shape change may be primarily by T_o(working temperature (external heating temperature or body core temperature if self-driven)) and T of the polymer_gTemperature difference influence between (from the formulation). T is_oIs usually set higher than T_r. Generally, a larger difference between these temperatures will produce a faster rate of change up to the intrinsic rate limits of the materials and devices, or the asymptotes of the rate of change of the materials and devices. The limit may be determined by monitoring the shape change response time at different temperatures and plotting this relationship. Typically, the amount of response time decreases until it reaches an asymptote. Corresponding T_oThe lowest, optimal temperature reflecting the fastest rate of shape change of the material. Increasing the temperature above this point does not result in a further reduction in the shape change recovery time, e.g., does not further increase the shape change rate. In one embodiment, when T_oSet to a temperature at which the Tan delta curve is about 60% of its maximum, the intrinsic limit or asymptote begins (see fig. 1, when T is_oSet higher than T of material_gTime). In one embodiment, the maximum rate of shape change of the polymer occurs atHigher than T_gTemperature of (a) is the ambient operating temperature (T)_o) At this temperature, the Tan delta value of the material is equal to 60% of its peak value. The device may be designed such that the optimum temperature is the available operating temperature of the device (e.g., at body temperature or another preselected temperature).

In one embodiment, the device is operated at the lowest temperature at which no further increase in the rate of shape change is seen. In another embodiment, the apparatus operates at a temperature within +/-5 ℃ of the optimal temperature.

In various embodiments, the recovery of the SMPs used in the biomedical devices of the invention is greater than 75%, 80%, 90%, 95%, 80% to 100%, 90% to 100%, or 95% to 100%. In various embodiments, the radiopaque SMP has a maximum achievable strain of 10% to 800%, 10% to 200%, 10% to 500%, 10% to 100%, 20% to 800%, 20% to 500%, 20% to 800%, as measured at a temperature above the glass transition temperature. In various embodiments, the radiopaque SMP has a maximum achievable strain or failure strain of at least 30%, at least 40%, at least 50%, at least 60%, or at least 70%, from 40% to 100%, from 40% to 60%, from 50% to 100%, from 60% to 100%, as measured below the glass transition temperature. In various embodiments, the maximum achievable strain or strain-to-failure of the SMP is at least 30%, at least 40%, at least 50%, at least 60%, or at least 70%, from 40% to 100%, from 40% to 60%, from 50% to 100%, from 60% to 100%, as measured at ambient temperature (20 ℃ to 25 ℃).

In general, the ability of a device (whether technically shape-memory or not) to change configuration or arrangement (e.g., extend) is made possible by: a device is manufactured having a first configuration or configuration (initial configuration) and then configured to a second configuration or configuration (temporary or storage configuration), wherein the configuration is at least partially reversible upon the occurrence of a triggering event. After the triggering event, the device assumes the third configuration. In one embodiment, the third configuration (deployed configuration) is substantially similar to the first configuration. However, for implanted medical devices, the device may be constrained from assuming its original shape (first configuration). In one embodiment, the device is capable of self-expanding to a desired size under physiological conditions.

The present invention can provide a variety of radiopaque polymeric devices for medical applications that incorporate the polymeric compositions of the present invention. The device of the present invention may be non-metallic. In various embodiments, these devices may be used for the purpose of indwelling permanent implants to provide the following functions: opening or maintaining an open anatomical cavity; partially closing the anatomical cavity as a valve, or completely closing the anatomical cavity occluded for any physiological fluid or gas flow or for an administered therapeutic fluid or gas flow; supporting anatomical structures to aid in the therapeutic restoration of function of organs, vessels, digestion, drainage, or airways; supporting anatomical structures to aid in the therapeutic restoration of orthopedic, maxillofacial, spinal, articular, or other bones or functions; or by covering the area in the body after tissue dissection or resection, patches to support hemostasis, for example for hemostasis of the liver or other organs. In other embodiments, these devices may be used for the purpose of a diagnostic or therapeutic apparatus or device to provide the following functions: a catheter for the purpose of accessing an anatomical site; delivering an additional device and/or therapeutic agent; or controlling the entry or delivery of additional devices and/or therapeutic agents; temporary indwelling devices that provide therapeutic benefit for a limited period of time, such as vena cava filters that are placed in a blood vessel, left in place for a period of time, for example to capture blood clots, and then removed at the completion of the treatment session.

In one embodiment of neurovascular cases in which intracranial aneurysms are repaired, the current state of care may be delivered into the aneurysm pocket using very thin metal (platinum) based embolic coils to fill the space and effect separation of the weakened vessel wall from the parent vessel (parent vessel) to reduce the risk of rupture and stroke. However, due to the metallic nature of these devices, two drawbacks typically occur: 1. as the aneurysm continues to grow, about 25% of these patients must return to retreatment, and 2. to diagnose the need for retreatment, many of these patients must undergo invasive angiography (contrast agent injection) under fluoroscopy to the area of the aneurysm to enable visualization of the condition, given the incompatibility of the metal coil material with the MRI or CT scan imaging modalities. Non-metallic radiopaque SMP embolization devices for aneurysm repair are not so limited in imaging capabilities. Although the description herein contains many specificities, these should not be construed as limiting the scope of the invention but as merely providing illustrations of some of the presently preferred embodiments of this invention. For example, the scope of the invention should, therefore, be determined not with reference to the embodiments illustrated, but instead should be determined with reference to the appended claims and their equivalents.

The invention is further illustrated by the following embodiments.

(1) A polymer having a crosslinked network comprising:

a) one or more first repeat units derived from a monomer of formula I:

and

wherein each instance of m is independently an integer from 8 to 16; n for each case independentlyGround is an integer from 2 to 22; p1 for each occurrence is independently an integer from 2 to 22; p2 for each occurrence is independently an integer from 1 to 50; ar is an iodinated 5-or 6-membered aryl or heteroaryl group; r is hydrogen or has the formula

And S of each case₁、S₂And S₃Independently hydrogen or methyl.

(2) The polymer of embodiment (1), wherein the polymer comprises from about 60% to about 95% by weight of the one or more first repeat units, from about 1% to about 40% by weight of the one or more second repeat units, and from about 1% to about 25% by weight of the one or more third repeat units.

(3) The polymer of embodiment (1), wherein the polymer comprises from about 75% to about 90% (e.g., from about 80% to about 90%) by weight of the one or more first repeat units, from about 5% to about 15% (e.g., from about 5% to about 10%) by weight of the one or more second repeat units, and from about 1% to about 10% (e.g., from about 1% to about 8% or from about 1% to about 6%) by weight of the one or more third repeat units.

(4) The polymer of any of embodiments (1) to (3), wherein the iodinated 5-or 6-membered aryl or heteroaryl group comprises at least two iodine atoms.

(5) The polymer of any of embodiments (1) to (4), wherein the iodinated 5-or 6-membered aryl or heteroaryl groups comprise at least three iodine atoms.

(6) The polymer of any of embodiments (1) to (5), wherein the iodinated 5-or 6-membered aryl or heteroaryl is iodinated C₆And (4) an aryl group.

(7) The polymer of embodiment (6), wherein the iodinated C₆Aryl has the formula:

(8) the polymer of any of embodiments (1) to (7), wherein the polymer has a glass transition temperature of from 0 ℃ to 50 ℃.

(9) The polymer of any of embodiments (1) to (8), wherein the polymer has a glass transition temperature of 15 ℃ to 35 ℃.

(10) The polymer of any of embodiments (1) to (9), wherein m is 8, 9, 10, 11, or 12.

(11) The polymer of embodiment (10), wherein m is 10.

(12) The polymer of any of embodiments (1) through (11), wherein the one or more second repeat units are derived from the monomer of formula IIa or formula IIb.

(13) The polymer of any of embodiments (1) through (11), wherein the one or more second repeat units are derived from the monomer of formula IIIa or formula IIIb.

(14) The polymer of any of embodiments (1) through (11), wherein the one or more second repeat units are derived from the monomers of formula IIa and formula IIIa.

(15) The polymer of any of embodiments (1) to (14), wherein the one or more third repeat units are derived from the monomer of formula IVa.

(16) The polymer of any of embodiments (1) to (14), wherein the one or more third repeat units are derived from the monomer of formula IVb.

(17) The polymer of any of embodiments (13) to (16), wherein R has the formula

(18) The polymer of any of embodiments (13) to (16), wherein R is hydrogen.

(19) A method of making a polymer having a crosslinked network, the method comprising:

i) forming a monomer mixture comprising:

a) one or more monomers of formula I:

and

c) one or more monomers of formula IVa and/or formula IVb:

And S of each case₁、S₂And S₃Independently hydrogen or methyl; and

ii) providing a free radical initiator to polymerize the monomer mixture.

(20) The method of embodiment (19), wherein the monomer mixture comprises from about 60% to about 95% by weight of the one or more monomers of formula I, from about 1% to about 40% by weight of the one or more monomers of formula IIa, formula IIb, formula IIIa and/or formula IIIb, and from about 1% to about 25% by weight of the one or more monomers of formula IVa and/or formula IVb.

(21) The method of embodiment (19), wherein the monomer mixture comprises from about 75% to about 90% (e.g., from about 80% to about 90%) by weight of the one or more monomers of formula I, from about 5% to about 15% (e.g., from about 5% to about 10%) by weight of the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and from about 1% to about 10% (e.g., from about 1% to about 8% or from about 1% to about 6%) by weight of the one or more monomers of formula IVa and/or formula IVb.

(22) The process of any one of embodiments (19) to (21), wherein the iodinated 5-or 6-membered aryl or heteroaryl comprises at least two iodine atoms.

(23) The process of any one of embodiments (19) to (22), wherein the iodinated 5-or 6-membered aryl or heteroaryl groups comprise at least three iodine atoms.

(24) The process of any one of embodiments (19) to (23), wherein the iodinated 5-or 6-membered aryl or heteroaryl is iodinated C₆And (3) an aryl group.

(25) The process of embodiment (24), wherein the iodinated C₆Aryl has the formula:

(26) the method of any one of embodiments (19) to (25), wherein the polymer has a glass transition temperature of 0 ℃ to 50 ℃.

(27) The method of any of embodiments (19) to (26), wherein the polymer has a glass transition temperature of 15 ℃ to 35 ℃.

(28) The process of any of embodiments (19) to (27), wherein the process further comprises a curing step after step ii), wherein the curing temperature is from 50 ℃ to 150 ℃ and the curing time is from 5 seconds to 5 hours.

(29) The method of any one of embodiments (19) to (28), wherein the initiator is a photoinitiator.

(30) The method of any one of embodiments (19) to (28), wherein the initiator is a thermal initiator.

(31) The method of any one of embodiments (19) to (30), wherein m is 8, 9, 10, 11 or 12.

(32) The method of embodiment (31), wherein m is 10.

(33) The method of any one of embodiments (19) to (32), wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb is a monomer of formula IIa or formula IIb.

(34) The method of any one of embodiments (19) to (32), wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb is a monomer of formula IIIa or formula IIIb.

(35) The method of any one of embodiments (19) to (32), wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb are monomers of formula IIa and formula IIIa.

(36) The method of any one of embodiments (19) to (35), wherein the one or more monomers of formula IVa and/or formula IVb is a monomer of formula IVa.

(37) The method of any one of embodiments (19) to (35), wherein the one or more monomers of formula IVa and/or formula IVb is a monomer of formula IVb.

(38) The method of any one of embodiments (34) to (37), wherein R has the formula

(39) The method of any one of embodiments (34) to (37), wherein R is hydrogen.

(40) A radiopaque polymer device for medical applications, the device comprising the polymer of any of embodiments (1) to (18).

(41) The radiopaque polymeric device of embodiment (40), wherein the device is non-metallic.

(42) The device of embodiment (40) or embodiment (41), wherein the concentration of iodine in the radiopaque polymer is at least 500 mg/mL.

(43) The device of any of embodiments (40) through (42) for use in medical applications involving exposure to aqueous body fluids, wherein the device has a tendency to absorb water of less than 1.0% by weight over a 24 hour period.

(44) The device of any of embodiments (40) to (43), wherein the polymer is a shape memory polymer having a deployment modulus at 37 ℃ of 10MPa to 200 MPa.

(45) The device of any of embodiments (40) through (44), wherein the polymer exhibits a temperature-dependent Tan δ (loss modulus/storage modulus ratio) curve and a glass transition temperature (Tg); the maximum rate of shape change of the polymer occurs at an ambient operating temperature (To) that coincides with a temperature at or above the Tan delta value of the rubbery plateau region.

(46) The device of any of embodiments (40) to (45), which is used for the purpose of an indwelling permanent implant to provide the following functions:

a. opening or maintaining an open anatomical cavity;

b. partially closing the anatomical cavity as a valve, or completely closing the anatomical cavity occluded for any physiological fluid or gas flow or for an administered therapeutic fluid or gas flow;

c. supporting anatomical structures to aid in the therapeutic restoration of function of organs, vessels, digestion, drainage, or airways;

d. supporting anatomical structures to aid in the therapeutic restoration of orthopedic, maxillofacial, spinal, articular, or other bones or functions; or

e. Hemostasis is supported by covering the area after tissue dissection or resection, patches, for example, for hemostasis of the liver or other organs.

(47) The device of any one of embodiments (40) to (46), for the purpose of a diagnostic or therapeutic apparatus or device to provide the following functions: a. a catheter for the purpose of accessing an anatomical site; delivering an additional device and/or therapeutic agent; or controlling the entry or delivery of additional devices and/or therapeutic agents; temporary indwelling devices that provide a therapeutic benefit for a limited period of time, such as vena cava filters that are placed in a blood vessel, left for a period of time, for example to capture blood clots, and then removed at the completion of the treatment session.

(48) A crosslinked polymer network formed from a monomer mixture comprising:

a) one or more monomers of formula I:

and

c) one or more monomers of formula IVa and/or formula IVb:

(49) The crosslinked polymer network of embodiment (44), wherein the monomer mixture comprises from about 75% to about 90% (e.g., from about 80% to about 90%) by weight of the one or more monomers of formula I, from about 5% to about 15% (e.g., from about 5% to about 10%) by weight of the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and from about 1% to about 10% (e.g., from about 1% to about 8% or from about 1% to about 6%) by weight of the one or more monomers of formula IVa and/or formula IVb.

(50) The crosslinked polymer network of embodiment (48) or embodiment (49) wherein the iodinated 5-or 6-membered aryl or heteroaryl groups contain at least two iodine atoms.

(51) The crosslinked polymer network of any one of embodiments (48) to (50) wherein the iodinated 5-or 6-membered aryl or heteroaryl groups comprise at least three iodine atoms.

(52) The crosslinked polymer network of any one of embodiments (48) to (51), wherein the iodinated 5-or 6-membered aryl or heteroaryl is iodinated C₆And (3) an aryl group.

(53) The crosslinked polymer network of embodiment (52), wherein the iodinated C₆Aryl has the formula:

(54) the crosslinked polymer network of any one of embodiments (48) to (53), wherein the polymer has a glass transition temperature of from 0 ℃ to 50 ℃.

(55) The crosslinked polymer network of any one of embodiments (48) to (54), wherein the polymer has a glass transition temperature of from 15 ℃ to 35 ℃.

(56) The crosslinked polymer network of any one of embodiments (48) to (55), wherein the monomer mixture further comprises a photoinitiator.

(57) The crosslinked polymer network of any one of embodiments (48) to (56) wherein m is 8, 9, 10, 11 or 12.

(58) The crosslinked polymer network of embodiment (57), wherein m is 10.

(59) The crosslinked polymer network of any one of embodiments (48) to (58), wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb is a monomer of formula IIa or formula IIb.

(60) The crosslinked polymer network of any one of embodiments (48) to (58), wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb is a monomer of formula IIIa or formula IIIb.

(61) The crosslinked polymer network of any one of embodiments (48) to (58), wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb are monomers of formula IIa and formula IIIa.

(62) The crosslinked polymer network of any one of embodiments (48) to (61), wherein the one or more monomers of formula IVa and/or formula IVb is a monomer of formula IVa.

(63) The crosslinked polymer network of any one of embodiments (48) to (61), wherein the one or more monomers of formula IVa and/or formula IVb is a monomer of formula IVb.

(64) The crosslinked polymer network of any one of embodiments (60) to (63) wherein R has the formula

(65) The crosslinked polymer network of any one of embodiments (60) to (63) wherein R is hydrogen.

(66) A composition comprising the polymer of any one of embodiments (1) to (18).

The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

Example 1

This example describes an exemplary radiopaque polymer device. Shape memory polymer devices and other non-shape memory polymer devices of the present invention may comprise material formulations that utilize a suitable glass transition temperature in about the body core temperature range. To achieve different property requirements, the T of the polymer_gHypothermia can be intentionally suppressed so that the shape change occurs immediately after release from any physical contraction.

In one embodiment, T_gSMP at 32 ℃ has been used to accelerate the rate of shape change of embolic coils after being expelled from a small lumen catheter. One form of embolization device forms a large crimp of 10mm in diameter, but consists of an SMP wire of only 0.032 "in diameter. The wire may be formed into a pre-deployed coiled shape that is straightened to allow delivery of these devices into small diameter catheters (< 5 fr). When deployed into the bloodstream, these devices recover their crimped shape to effectively occlude a 9mm vessel, which exceeds the 1mm dimension, ensuring sufficient radial force from the material modulus and deflection to provide effective anchoring so that the embolic device does not migrate under the influence of the blood flow in the vessel. Figures 2A to 2B show the exit of an embolic coil from a very thin single lumen catheter to form an image of an occlusion mass much larger than the coil diameter. Fig. 2A shows the coil after initial entry. Fig. 2B shows the coil after deployment.

Likewise, T of the polymer_gCan be set above body temperature, wherein an external heating device is used to provide the physician with any shape change functionality. In another embodiment, T_gSMP at 50 ℃ has been used to place and accurately position tubular stents within anatomical cavities. Maintaining its low profile, pre-deployed temporary shape facilitates the ability of the physician to move and accurately position the device prior to deployment. While held in the desired position, the device is heated to its T by flushing with warm saline water_rThis results in a shape return to the permanent shape of the stent.

Yet another embodiment is to use an elevated T with 42 deg.C (slightly above body core temperature)_gIs used as a clasp (clasps) for holding the deployed device. In its permanent shape, the clasp is open, and in its temporary shape, the clasp is closed. The clasp connects a device such as a vena cava filter (the filter itself may be made of a different SMP) to a delivery wire that contains electrical conductors that connect to a heating element adjacent to the clasp. In SMP buckled in its temporary shape (below T)_g) In the closed condition, the device is advanced into the bloodstream. After reaching its desired position, through the outside of the conductorLow voltage and heating the button by the heating element. When the temperature reaches T_rThe clasp then opens to its restored permanent shape, releasing the vena cava filter.

In yet another embodiment, an elevated T with 42 ℃ (slightly above body core temperature) is used within a section (section) of a unidirectional catheter_gThe SMP of (1). The catheter section is formed into a permanent curved shape to allow for a specific orientation of the catheter tip. The temporary shape is straight, but not necessarily stiff, since a straight catheter is easier to maneuver into position. After entering the body, below T_gA straight catheter is easily maneuvered to the target site where it is heated by an externally heated internally delivered wire or by flushing warm saline solution through the catheter. At material temperature T_rThereafter, the catheter section is crimped, thereby returning to its recovered permanent shape, providing a specific orientation for the catheter tip during use. At the same time, the curvature is not so stiff as to prevent simple removal of the catheter after use.

Example 2

This example provides an exemplary synthesis of the monomer of formula I, 10- (acryloyloxy)

decyl

2, 3, 5-triiodobenzoate (referred to as C10-TIA).

A5L 4-necked flask equipped with a mechanical stirrer, addition funnel, nitrogen inlet, and thermocouple was charged with 10-bromo-1-decanol (300 g; 1.26 moles) and THF (1.4L; 19.4 moles). The mixture was stirred under nitrogen. The flask was cooled in an ice bath to an internal temperature of about 5 ℃. Triethylamine (220 mL; 1.58 moles) was then added slowly to the stirred solution via an addition funnel. A solution of acryloyl chloride (128 mL; 1.58 moles) in THF (200 mL; 2.8 moles) was then charged to the addition funnel. The acryloyl chloride/THF solution was added dropwise to the flask over 2 hours. The resulting white slurry was then warmed to room temperature (about 20 ℃) and stirred for 2 hours at which time TLC analysis indicated that the reaction was complete. The reaction mixture was then diluted with water and extracted with methyl tert-butyl ether. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was adsorbed on silica gel and purified by vacuum chromatography. Analysis by GC-FID of 10-bromo-decyl acrylate-containing groupsColumn fractions of the ester, and all fractions not containing 1, 10-dibromodecane were combined and concentrated. A5L 4-necked flask equipped with a mechanical stirrer, condenser, nitrogen inlet, and thermocouple was then charged moderately with 10-bromo-decyl acrylate followed by DMF (1.2L; 14.2 moles). 2, 3, 5-triiodobenzoic acid (311.9 g; 0.62 mol) and K were then added₂CO₃(143.7 g; 1.04 mol) and the reaction mixture is heated to 85 ℃ under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered, diluted with water, and extracted three times into MTBE. The combined organics were washed with water, brine, and Na₂SO₄Dried, filtered and concentrated. The crude product was adsorbed on silica gel and purified by vacuum chromatography. The combined fractions were concentrated to a solid and then thoroughly dried at 63 ℃ under high vacuum by bubbling nitrogen through the molten C10-TIA. The molten C10-TIA was then poured into a glass tray and allowed to solidify, and then crushed into a consistent solid in a glass mortar and pestle.

Example 3

This example provides an exemplary synthesis of the monomer of formula IIa, dodecane-1, 12-diyl dimethacrylate (referred to as C12-DMA).

Dodecanediol (26.85g) and toluene (300mL) were added to a three-necked flask. The flask was stirred under heating under nitrogen atmosphere to start the azeotropic distillation until about 100mL of distillate was collected and cooled to 60 ℃. A three-neck flask was charged with triethylamine (14.6mL), followed by methacryloyl chloride (8.1 mL). The system was stirred for 60 minutes. The system was extracted with 150mL of 1N HCl, 150mL of 1N sodium bicarbonate and 150mL of distilled water. The organic layer was dried over anhydrous magnesium sulfate and filtered. While under nitrogen, 0.3g of 1% hydroquinone in acetone was added, then all the solvent was removed with a rotary evaporator, and the viscous solution was stirred.

Example 4

This example provides an exemplary synthesis of a polymer having a crosslinked network as described herein.

A20 mL scintillation vial was charged with C10-TIA and varying amounts of ethane-1, 2-diylbis (2-methacrylate) (C2-DMA)) And 8, 17, 26-trioxo-7, 9, 16, 18, 25, 27-hexaoxaritriacontane-1, 33-diyl diacrylate so that the total weight of the monomers is 10 g. The bottle was covered and placed in a 125 ℃ oven for 15 minutes to melt the composition, then the bottle contents were mixed on a vortex and allowed to cool for 5 minutes. Then mixing Luperox

Initiator (50 μ L) was added to the molten mixture and the mixture was vortexed to completely dissolve the composition. The molten composition was purged with argon at 50 ℃ for 15 minutes, then injected into a suitable mold and cured at 125 ℃ for 2 to 3 hours. The resulting polymers with different fractions of C2-DMA and 8, 17, 26-trioxo-7, 9, 16, 18, 25, 27-hexaoxaritriacontane-1, 33-diyl diacrylate were tested for iso-37 ℃ Tan. delta., Tg temperature and iso-37 ℃ modulus, the results are depicted in FIGS. 3 to 5.

As is evident from FIGS. 4 and 5, the Tg temperature and iso-37 ℃ modulus increase with increasing weight percent C2-DMA.

Example 5

This example provides an exemplary list of polymer compositions described herein. Using the general procedure described in embodiment 4, polymers a to I were prepared from polymer compositions a to I as described in table 1.

TABLE 1 Polymer compositions A to I

Table 2 shown below provides the Tg (. degree. C.), Iso-37 ℃ modulus (MPa), and Iso-37 ℃ Tan. delta. for polymers A through I. The modulus value facilitates the deployment of devices that must traverse the length of the catheter without bending, maintaining Tg at or below in vivo temperature to minimize stiffness and remain flexible when implanted, making it possible to recover the shape after deployment. In the polymers shown in table 2, these mechanical property features can be achieved in a sufficiently radiopaque configuration at a device thickness of 0.016 "or less. For example, these mechanical property features may be achieved in a sufficiently radiopaque configuration when the device thickness is as small as 0.010 "or less.

TABLE 2 Properties of polymers A to I

Polymer and process for producing the same	Tg(℃)	Iso-37 ℃ modulus (MPa)	Iso-37℃Tanδ
				A	19	38	0.284
B	36	144	0.371
				C	33	129	0.470
D	26	16	0.485
				E	27	18	0.500
F	31	60	0.587
				G	23	11	0.284
H	19	8	0.380
				I	31	101	0.484

In addition, polymers E and I were converted to coils having a coil size diameter of 0.016 inches and their mechanical durability was analyzed using a 0.034 inch tube diameter. The polymer wire was repeatedly bent to 180 ° until the wire broke. The average number of folds required to reach this limit was 39.5 for polymer E and 33 for polymer I, indicating good mechanical durability.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the extent that they do not: as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

The use of nouns without quantitative modification and "at least one" and similar referents in the context of describing the invention (especially in the context of the following claims) is to be construed to cover one and/or more unless otherwise indicated herein or clearly contradicted by context. The use of the term "at least one" preceded by a list of one or more items (e.g., "at least one of a and B") is to be construed to mean one item (a or B) selected from the listed items or any combination of two or more of the listed items (a and B), unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

When a compound or composition is claimed, it is to be understood that compounds or compositions known in the art, including the compounds or compositions disclosed in the references disclosed herein, are not intended to be included. When Markush (Markush) groups or other groupings are used herein, all individual members of the group, as well as all combinations and possible subcombinations of the group, are intended to be included individually in the disclosure.

In the moieties and groups described herein, it is understood that the valency forms of the groups required to achieve the intended purpose in the description or structure are included, even if not specifically set forth. For example, as used herein, groups that are technically "closed shell" groups as listed or described can be used as substituents in the structure. For each closed shell moiety or group, it is understood to include groups corresponding to non-closed moieties, for use in the structures or formulae disclosed herein.

Unless otherwise specified, each formulation or combination of components described or illustrated can be used to practice the invention. The specific names of the compounds are intended to be exemplary, as it is known that one of ordinary skill in the art may name the same compounds differently. For example, in a chemical formula or name, when a compound is described herein such that a particular isomer or enantiomer of the compound is not specified, the description is intended to include each isomer and enantiomer of the compound described alone or in any combination. Those of ordinary skill in the art will understand that methods, apparatus elements, starting materials, and synthetic methods can be used in the practice of the present invention, and in addition to those specifically exemplified, without the aid of undue experimentation. All art-known functional equivalents of any such methods, device elements, starting materials, and synthetic methods are intended to be included herein. Whenever a range is given in the specification, for example, a temperature range, a time range, a composition range, or a mechanical property range, all intermediate ranges and subranges, as well as all individual values included in the given ranges, are intended to be included in the disclosure.

The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. A polymer having a crosslinked network comprising:

a) one or more first repeat units derived from a monomer of formula I:

and

c) one or more third repeat units derived from a monomer of formula IVa and/or formula IVb:

wherein:

m in each instance is independently an integer from 8 to 16;

n in each case is independently an integer from 2 to 22;

p1 for each occurrence is independently an integer from 2 to 22;

p2 for each occurrence is independently an integer from 1 to 50;

ar is an iodinated 5-or 6-membered aryl or heteroaryl group;

r is hydrogen or has the formula

And

s in each case₁、S₂And S₃Independently hydrogen or methyl.

2. The polymer of claim 1, wherein the polymer comprises from about 60% to about 95% by weight of the one or more first repeat units, from about 1% to about 40% by weight of the one or more second repeat units, and from about 1% to about 25% by weight of the one or more third repeat units.

3. The polymer of claim 1, wherein the polymer comprises from about 75% to about 90% by weight of the one or more first repeat units, from about 5% to about 15% by weight of the one or more second repeat units, and from about 1% to about 10% by weight of the one or more third repeat units.

4. The polymer of any one of claims 1 to 3, wherein the iodinated 5-or 6-membered aryl or heteroaryl group comprises at least two iodine atoms.

5. The polymer of any one of claims 1 to 4, wherein the iodinated 5-or 6-membered aryl or heteroaryl group comprises at least three iodine atoms.

6. The polymer of any one of claims 1 to 5, wherein the iodinated 5-or 6-membered aryl or heteroaryl is iodinated C₆And (4) an aryl group.

7. The polymer of claim 6, wherein the iodinated C₆Aryl has the formula:

8. the polymer of any one of claims 1 to 7, wherein the polymer has a glass transition temperature of from O ℃ to 50 ℃.

9. The polymer of any one of claims 1 to 8, wherein the polymer has a glass transition temperature of from 15 ℃ to 35 ℃.

10. The polymer of any one of claims 1 to 9, wherein m is 8, 9, 10, 11 or 12.

11. The polymer of claim 10, wherein m is 10.

12. The polymer of any one of claims 1 to 11, wherein the one or more second repeat units are derived from the monomer of formula IIa or formula IIb.

13. The polymer of any one of claims 1 to 11, wherein the one or more second repeat units are derived from the monomer of formula IIIa or IIIb.

14. The polymer of any one of claims 1 to 11, wherein the one or more second repeat units are derived from the monomers of formula IIa and formula IIIa.

15. The polymer of any one of claims 1 to 14, wherein the one or more third repeat units are derived from the monomer of formula IVa.

16. The polymer of any one of claims 1 to 14, wherein the one or more third repeat units are derived from the monomer of formula IVb.

17. The polymer of any one of claims 13 to 16, wherein R has the formula

18. The polymer of any one of claims 13 to 16, wherein R is hydrogen.

19. A method of making a polymer having a crosslinked network, the method comprising:

i) forming a monomer mixture comprising:

a) one or more monomers of formula I:

and

c) one or more monomers of formula IVa and/or formula IVb:

wherein:

m in each instance is independently an integer from 8 to 16;

n in each instance is independently an integer from 2 to 22;

p1 for each occurrence is independently an integer from 2 to 22;

p2 for each occurrence is independently an integer from 1 to 50;

ar is an iodinated 5-or 6-membered aryl or heteroaryl group;

r is hydrogen or has the formula

And

s in each case₁、S₂And S₃Independently hydrogen or methyl; and

ii) providing a free radical initiator to polymerize the monomer mixture.

20. The method of claim 19, wherein the monomer mixture comprises about 60% to about 95% by weight of the one or more monomers of formula I, about 1% to about 40% by weight of the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and about 1% to about 25% by weight of the one or more monomers of formula IVa and/or formula IVb.

21. The method of claim 19, wherein the monomer mixture comprises about 75% to about 90% by weight of the one or more monomers of formula I, about 5% to about 15% by weight of the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and about 1% to about 10% by weight of the one or more monomers of formula IVa and/or formula IVb.

22. The process of any one of claims 19 to 21, wherein the iodinated 5-or 6-membered aryl or heteroaryl comprises at least two iodine atoms.

23. The process of any one of claims 19 to 22, wherein the iodinated 5-or 6-membered aryl or heteroaryl comprises at least three iodine atoms.

24. The method of any one of claims 19 to 23, wherein the iodinated 5-or 6-membered aryl or heteroaryl groupIs iodinated C₆And (4) an aryl group.

25. The process of claim 24, wherein the iodinated C₆Aryl has the formula:

26. the method of any one of claims 19 to 25, wherein the polymer has a glass transition temperature of from 0 ℃ to 50 ℃.

27. The method of any one of claims 19 to 26, wherein the polymer has a glass transition temperature of 15 ℃ to 35 ℃.

28. The process of any one of claims 19 to 27, wherein the process further comprises a curing step after step ii), wherein the curing temperature is from 50 ℃ to 150 ℃ and the curing time is from 5 seconds to 5 hours.

29. The method of any one of claims 19 to 28, wherein the initiator is a photoinitiator.

30. The method of any one of claims 19 to 28, wherein the initiator is a thermal initiator.

31. The method of any one of claims 19 to 30, wherein m is 8, 9, 10, 11, or 12.

32. The method of claim 31, wherein m is 10.

33. The method of any one of claims 19 to 32, wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb is a monomer of formula IIa or formula IIb.

34. The method of any one of claims 19 to 32, wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb is a monomer of formula IIIa or formula IIIb.

35. The method of any one of claims 19 to 32, wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb are monomers of formula IIa and formula IIIa.

36. The method of any one of claims 19 to 35, wherein the one or more monomers of formula IVa and/or formula IVb is a monomer of formula IVa.

37. The method of any one of claims 19 to 35, wherein the one or more monomers of formula IVa and/or formula IVb is a monomer of formula IVb.

38. The method of any one of claims 34 to 37, wherein R has the formula

39. The method of any one of claims 34 to 37, wherein R is hydrogen.

40. A radiopaque polymer device for medical applications, the device comprising the polymer of any one of claims 1 to 18.

41. The radiopaque polymeric device of claim 40, wherein the device is non-metallic.

42. The device of claim 40 or claim 41, wherein the concentration of iodine in the radiopaque polymer is at least 500 mg/mL.

43. The device of any one of claims 40 to 42 for medical applications involving exposure to aqueous body fluids, wherein the device has a water absorption propensity of less than 1.0 wt% over a 24 hour period.

44. The device of any one of claims 40 to 43, wherein the polymer is a shape memory polymer having a deployment modulus at 37 ℃ of 10MPa to 200 MPa.

45. The device of any one of claims 40 to 44, wherein the polymer exhibits a temperature-dependent Tan δ (loss modulus/storage modulus ratio) curve and a glass transition temperature (Tg); the maximum rate of shape change of the polymer occurs at an ambient operating temperature (To) that is consistent with a temperature at or above the Tan delta value of the rubbery plateau region.

46. The device of any one of claims 40 to 45, for the purpose of an indwelling permanent implant to provide the following functions:

a. opening or maintaining an open anatomical cavity;

47. The device of any one of claims 40 to 46 for the purpose of a diagnostic or therapeutic apparatus or device to provide the following functions: a. a catheter for the purpose of accessing an anatomical site; delivering an additional device and/or therapeutic agent; or controlling the entry or delivery of additional devices and/or therapeutic agents; temporary indwelling devices that provide a therapeutic benefit for a limited period of time, such as vena cava filters that are placed in a blood vessel, left for a period of time, for example to capture blood clots, and then removed at the completion of the treatment session.

48. A crosslinked polymer network formed from a monomer mixture comprising:

a) one or more monomers of formula I:

and

c) one or more monomers of formula IVa and/or formula IVb:

wherein:

m in each instance is independently an integer from 8 to 16;

n in each instance is independently an integer from 2 to 22;

p1 for each occurrence is independently an integer from 2 to 22;

p2 for each occurrence is independently an integer from 1 to 50;

ar is an iodinated 5-or 6-membered aryl or heteroaryl group;

r is hydrogen or has the formula

And

s in each case₁、S₂And S₃Independently of one another is hydrogen or a methyl group,

wherein the monomer mixture comprises from about 60% to about 95% by weight of the one or more monomers of formula I, from about 1% to about 40% by weight of the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and from about 1% to about 25% by weight of the one or more monomers of formula IVa and/or formula IVb.

49. The crosslinked polymer network of claim 44, wherein the monomer mixture comprises from about 75% to about 90% by weight of the one or more monomers of formula I, from about 5% to about 15% by weight of the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb, and from about 1% to about 10% by weight of the one or more monomers of formula IVa and/or formula IVb.

50. The crosslinked polymer network of claim 48 or claim 49, wherein the iodinated 5-or 6-membered aryl or heteroaryl group comprises at least two iodine atoms.

51. The crosslinked polymer network of any one of claims 48 to 50 wherein the iodinated 5-or 6-membered aryl or heteroaryl group comprises at least three iodine atoms.

52. The crosslinked polymer network of any one of claims 48 to 51 wherein the iodinated 5-or 6-membered aryl or heteroaryl is iodinated C₆And (4) an aryl group.

53. The crosslinked polymer network of claim 52, wherein the iodinated C₆Aryl has the formula:

54. the crosslinked polymer network of any one of claims 48 to 53 wherein the glass transition temperature of the polymer is from 0 ℃ to 50 ℃.

55. The crosslinked polymer network of any one of claims 48 to 54 wherein the glass transition temperature of the polymer is from 15 ℃ to 35 ℃.

56. The crosslinked polymer network of any one of claims 48 to 55, wherein the monomer mixture further comprises a photoinitiator.

57. The crosslinked polymer network of any one of claims 48 to 56 wherein m is 8, 9, 10, 11 or 12.

58. The crosslinked polymer network of claim 57 wherein m is 10.

59. The crosslinked polymer network of any one of claims 48 to 58, wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb is a monomer of formula IIa or formula IIb.

60. The crosslinked polymer network of any one of claims 48 to 58, wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb is a monomer of formula IIIa or formula IIIb.

61. The crosslinked polymer network of any one of claims 48 to 58, wherein the one or more monomers of formula IIa, formula IIb, formula IIIa, and/or formula IIIb are monomers of formula IIa and formula IIIa.

62. The crosslinked polymer network of any one of claims 48 to 61, wherein the one or more monomers of formula IVa and/or formula IVb is a monomer of formula IVa.

63. The crosslinked polymer network of any one of claims 48 to 61, wherein the one or more monomers of formula IVa and/or formula IVb is a monomer of formula IVb.

64. The crosslinked polymer network of any one of claims 60 to 63 wherein R has the formula

65. The crosslinked polymer network of any one of claims 60 to 63 wherein R is hydrogen.

66. A composition comprising the polymer of any one of claims 1 to 18.