RADIOPAQUE POLYMERS FOR MEDICAL DEVICES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62/899,270 filed September 12, 2019, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Shape memory materials are defined by their capacity to recover a predetermined shape after significant mechanical deformation (K. Otsuka and C. M. Wayman, “Shape Memory Materials” New York: Cambridge University Press, 1998). The shape memory effect is typically initiated by a change in temperature and has been observed in metals, ceramics, and polymers. From a macroscopic point of view, the shape memory effect in polymers differs from ceramics and metals due to the lower stresses and larger recoverable strains achieved in polymers.

[0003] The basic thermomechanical response of shape memory polymer (SMP) materials is defined by four critical temperatures. The glass transition temperature, T , is typically represented by a transition in modulus-temperature space and can be used as a reference point to normalize temperature for some SMP systems. SMPs offer the ability to vary T _g over a temperature range of several hundred degrees by control of chemistry or structure. The predeformation temperature, Td, is the temperature at which the polymer is deformed into its temporary shape. Depending on the required stress and strain level, the initial deformation Td can occur above or below T (Y. Liu, K. Gall, M. L. Dunn, and P. McCluskey, “Thermomechanical Recovery Couplings of Shape Memory Polymers in Flexure.” Smart Materials & Structures, vol. 12, pp. 947-954, 2003). The storage temperature, T _s , represents the temperature in which no shape recovery occurs and is equal to or is below Td. The storage temperature T _s is less than the glass transition temperature T _g. At the recovery temperature, T _r , the shape memory effect is activated, which causes the material to substantially recover its original shape. T _r is above T _s and is typically in the vicinity of T _g. Recovery can be accomplished isothermally by heating the material to a fixed T _r and then holding, or by continued heating up to and past T _r. From a macroscopic viewpoint, a polymer will demonstrate a useful shape memory effect if it possesses a distinct and significant glass transition (B. Sillion, “Shape memory polymers,” Act. Chimique., vol. 3, pp. 182-188, 2002), a 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, “Chemically cross-linked polycyclooctene: Synthesis, characterization, and shape memory behavior.” Macromolecules vol. 35, no. 27, pp. 9868-9874, 2002), and a large difference between the maximum achievable strain, emax, during deformation and permanent plastic strain after recovery, e _R (F. Li, R. C. Larock, “New Soybean Oil-Styrene-Divinylbenzene Thermosetting Copolymers. V. Shape memory effect.” J. App. Pol. Sci., vol. 84, pp. 1533-1543,

2002). The difference emax - e _R is defined as the recoverable strain, erecover, while the recovery ratio is defined as erecover/ emax.

[0004] The microscopic mechanism responsible for shape memory in polymers depends on both chemistry and structure (T. Takahashi, N. Hayashi, and S. Hayashi, “Structure and properties of shape memory polyurethane block copolymers.” J. App. Pol. Sci., vol. 60, pp. 1061- 1069, 1996; J. R. Lin and L. W. Chen, “Study on Shape-Memory Behavior of Polyether-Based Polyurethanes. II. Influence of the Hard-Segment Content.” J. App. Pol. Sci., vol. 69, pp. 1563- 1574, 1998; J. R. Lin and L. W. Chen, “Study on Shape-Memory Behavior of Polyether-Based Polyurethanes. I. Influence of soft-segment molecular weight.” J. App. Pol. Sci., vol 69, pp. 1575-1586, 1998; F. Li, W. Zhu, X. Zhang, C. Zhao, and M. Xu, “Shape memory effect of ethylene-vinyl acetate copolymers.” J. App. Poly. Sci., vol. 71, pp. 1063-1070, 1999; H. G. Jeon, P. T. Mather, and T. S. Haddad, “Shape memory and nanostructure in poly(norbornyl-POSS) copolymers.” Polym. Int., vol. 49, pp. 453-457, 2000; H. M. Jeong, S. Y. Lee, and B. K. Kim, “Shape memory polyurethane containing amorphous reversible phase.” J. Mat. Sci., vol. 35, pp. 1579-1583, 2000; A. Lendlein, A. M. Schmidt, and R. Langer, “AB-polymer networks based on oligo(epsilon-caprolactone) segments showing shape-memory properties.” Proc. Nat. Acad. Sci., vol. 98, no. 3, pp. 842-847, 2001; G. Zhu, G. Liang, Q. Xu, and Q. Yu, “Shape-memory effects of radiation cross-linked poly(epsilon- caprolactone) ” J. App. Poly. Sci., vol. 90, pp. 1589-1595,

2003). One driving force for shape recovery in polymers is the low conformational entropy state created and subsequently frozen during the thermomechanical cycle (C. D. Liu, S. B. Chun, P. T. Mather, L. Zheng, E. H. Haley, and E. B. Coughlin, “Chemically cross-linked polycyclooctene: Synthesis, characterization, and shape memory behavior.” Macromolecules. Vol. 35, no. 27, pp. 9868-9874, 2002). If the polymer is deformed into its temporary shape at a temperature below T , or at a temperature where some of the hard polymer regions are below T , then internal energy restoring forces will also contribute to shape recovery. In either case, to achieve shape memory properties, the polymer must have some degree of chemical crosslinking to form a “memorable” network or must contain a finite fraction of hard regions serving as physical crosslinks.

[0005] SMPs are processed in a manner that is termed programming, whereby the polymer is deformed and set into a temporary shape. ( A. Lendlein, S. Kelch, “Shape Memory Polymer,” Advanced Chemie, International Edition, 41, pp. 1973-2208, 2002.) When exposed to an appropriate stimulus, the SMP substantially reverts back to its permanent shape from the temporary shape. The stimulus may be, for example, temperature, magnetic field, water, or light, depending on the initial monomer systems.

[0006] For SMPs used in medical devices, wherein temperature is the chosen stimulus, an external heat source may be used to provide discretionary control of the shape recovery by the physician, or the body’s core temperature may be utilized to stimulate the shape recovery upon entry or placement within the body from the environmental temperature, which may be room temperature. (Small W, et al “Biomedical applications of thermally activated shape memory polymers” Journal of Materials Chemistry, Vol 20, pp 3356-3366, 2010.)

[0007] For implantable medical devices, the life expectancy of the device can be defined by the duration that it must maintain its mechanical properties and functionality in the body. For biodegradable devices, this life expectancy is intentionally short, providing a mechanism for the material and device to degrade over time and be absorbed by the body’s metabolic processes.

For non-biodegradable devices, referred to as biodurable devices, or devices exhibiting biodurability, they are not intended to degrade and they must maintain their material properties and functionality for longer periods, possibly for the life the patient.

[0008] For medical devices used within the body, either permanent implants or instrumentation used for diagnostic or therapeutic purposes, the ability to visualize the device using typical clinical imaging modalities, e.g. X-ray, Fluoroscopy, CT Scan, and MRI is typically a requirement for clinical use. Devices intended to be imaged by X-ray and Fluoroscopy, typically contain either metals or metal byproducts to induce radiopacity. Radiopacity refers to the relative inability of electromagnetism, particularly X-rays, to pass through dense materials, which are described as 'radiopaque' appearing opaque/white in a radiographic image. A more radiopaque material appears brighter, whiter, on the image. (Novelline, Robert. Squire's Fundamentals of Radiology. Harvard University Press. 5th edition. 1997). Given the complexity of the content within an X-ray or Fluoroscopic image, clinicians are sensitive to the quality of the image regarding the brightness or signal strength of the material in the image. The two main factors that contribute to radiopacity brightness, or signal strength of a material are density and atomic number. Polymer based medical devices requiring radiopacity typically utilize a polymer blend that incorporates a small amount, by weight percent, of a heavy atom, radiopaque filler such as Titanium Dioxide (TiCk), or Barium Sulfate (BaSCri). The device’s ability to be visualized on fluoroscopy is dependent upon the amount, or density, of the filler mixed into the material, which is typically limited to a small quantity as the filler can detrimentally affect the base polymer’s material properties. Meanwhile, medical device imaging companies have developed standardized liquid contrast media to be intermittently used by physicians to highlight vascular structures, etc. during X-ray or Fluoroscopy when filled with this contrast media. This media commonly contains a heavy atom fluid, such as iodine, to induce radiopacity.

[0009] Iodine-incorporating monomers were reported by Mosner et al., who reported 3 different triiodinated aromatic monomers, which differed in the degree to which they could be homopolymerized or required copolymerization in order to be incorporated. (Moszner et al “Synthesis and polymerization of hydrophobic iodine-containing methacrylates” Die Angewandte Makromolekulare Chemie 224 (1995) 115-123) Iodinating monomers were also pursued by Koole et al in the Netherlands, as published from 1994-1996 with a range of monoiodinated to triiodinated aromatic monomers (Koole et al “Studies on a new radiopaque polymeric biomaterial,” Biomaterials 1994 Nov; 15(14): 1122-8. Koole et al “A versatile three- iodine molecular building block leading to new radiopaque polymeric biomaterials,” J Biomed Mater Res, 1996 Nov; 32(3):459-66). This included biocompatibility results of a 2-year implantation study in rats of monoiodinated aromatic methacrylate copolymer systems. (Koole et al “Stability of radiopaque iodine-containing biomaterials,” Biomaterials 2002 Feb; 23(3):881- 6) They are also discussed by Koole in US Patent 6,040,408, filed initially as a European patent application in August, 1994, which limits its claims to aromatic monomers containing no more than two covalently bonded iodine groups. (US Patent 6,040,408, “Radiopaque Polymers and Methods for Preparation Thereof,” Koole, 21 Mar 2000). Also, US Patent Application Publication 20060024266 by Brandom et al. claimed polyiodinated aromatic monomers in shape memory polymers, emphasizing the use of crystallizable polymer side-groups (US Patent Application Publication 20060024266, “Side-chain crystallizable polymers for medical applications, Brandom et al, 05 Jul 2005).

[0010] The information included in this Background section of the specification, including any references cited herein and any description or discussion thereof, is included for technical reference purposes only and is not to be regarded subject matter by which the scope of the invention is to be bound. BRIEF SUMMARY OF THE INVENTION

[0011] A polymer with a cross-linked network is provided. The cross-linked network comprises: a) one or more first repeating units derived from a monomer of Formula I:

Formula I b) one or more second repeating units derived from a monomer of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb:

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

Formula IVb wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5- membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula each instance of Si, S2, and S3 independently is hydrogen or methyl.

[0012] A method of making a polymer described herein is also provided The method comprises: i) forming a monomer mixture comprising: a) one or more monomers of Formula I:

Formula I b) one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula

Illb:

Formula Ila Formula lib

Formula Ilia and/or Formula lllb and c) one or more monomers of Formula IVa and/or Formula IVb:

Formula IVb wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5- membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula and each instance of Si, S2, and S3 independently is hydrogen or methyl; and ii) providing a free radical initiator to polymerize the monomer mixture.

[0013] A cross-linked polymer network is also provided. The cross-linked polymer network is formed from a monomer mixture comprising: a) one or more monomers of Formula F

Formula I b) one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula

Illb:

Formula Ilia and/or Formula Illb

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

Formula IVb

? wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5- membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula each instance of Si, S2, and S3 independently is hydrogen or methyl, wherein the monomer mixture comprises about 60 wt.% to about 95 wt.% of the one or more monomers of Formula I, about 1 wt.% to about 40 wt.% of the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb, and about 1 wt.% to about 25 wt.% of the one or more monomers of Formula IVa and/or Formula IVb.

[0014] A radiopaque polymer device for medical applications is further provided. The device comprises a polymer described herein. In certain embodiments, the device is non- metallic.

[0015] A composition comprising the polymer with a cross-linked network is also provided.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 : DMA curve for an SMP formulation with examples of T _r , Tg, To and Tan Delta Peak.

[0017] Figures 2A-2B: Embolic coils exiting from very thin, single lumen catheters to form an occlusive mass much larger than the diameter of the coil.

[0018] Figure 3 : Plot of the iso-37 °C tan delta vs. weight fraction of C2-DMA monomer of the polymer of Example 4.

[0019] Figure 4: Plot of the glass transition temperature (Tg) vs. weight fraction of C2-DMA monomer of the polymer of Example 4.

[0020] Figure 5: Plot of the iso-37 °C modulus vs. weight fraction of C2-DMA monomer of the polymer of Example 4.

DETAILED DESCRIPTION OF THE INVENTION

[0021] In one aspect, a polymer with a cross-linked network is provided. Typically, the cross-linked polymer network comprises a first repeating unit derived from a monofunctional radiopaque monomer, a second repeating unit derived from a short crosslinking monomer, and a third repeating unit derived from a long crosslinking monomer. In certain aspects, neither the first, second, nor third repeating unit is fluorinated. The cross-linked network can be characterized by covalent bonding between said first repeating unit and said second repeating unit such that the second repeating unit forms the crosslinking of the cross-linked network. The crosslinking can be further enhanced by the third repeating unit. Alternatively, or additionally, the cross-linked network can be characterized by covalent bonding between said first repeating unit and said third repeating unit such that the third repeating unit forms the crosslinking of the cross-linked network. The crosslinking can be further enhanced by the second repeating unit. In some embodiments, the second and/or third repeating unit imparts enhanced biodurability and/or radiopacity properties. For example, the second repeating unit and/or the third repeating unit can causes the cross-linked network to have the characteristics of an elastomer or a reinforced plastic. [0022] Without wishing to be bound by any particular theory, it is believed that a polymer comprising a combination of the second and third repeating units may result in better mechanical properties and better shape recovery than a polymer comprising the second repeating unit but not the third repeating unit or the third repeating unit but not the second repeating unit. For example, a polymer comprising the second repeating unit but not the third repeating unit may have good mechanical durability but bad shape recovery. Alternatively, a polymer comprising the third repeating unit but not the second repeating unit may have good shape recovery but may be too brittle.

[0023] Generally, the polymers and polymer compositions described herein comprise a radiopaque functionality. In an embodiment, the polymers and polymer compositions of the invention include covalently bound heavy atoms such as iodine. In this embodiment, the distribution of iodine or other radiopaque functionality within the polymer is sufficiently homogeneous so as to be efficacious for imaging applications.

[0024] Use of monomers with different chemical structures and amounts thereof can be used to suppress formation of crystalline regions in the polymer. In an embodiment, the monomers are selected for phase compatibility in the liquid and solid state. Phase compatibility of the monomers can facilitate random incorporation of the monomer units during free radical polymerization and homogeneity in the resulting polymer.

[0025] As used herein, a cross-linked network is a plurality of polymer units wherein a large portion (e.g., > 80%) and optionally all the polymer units are interconnected, for example via covalent crosslinking, to form a single polymer. In an embodiment, the invention provides a radiopaque polymer in the form of a cross-linked network in which at least some of the crosslinks of the network structure are formed by covalent bonds. Radiopacity refers to the relative inability of electromagnetism, particularly X-rays, to pass through dense materials. The two main factors contributing to a material's radiopacity are density and atomic number of the radiopaque element. In an embodiment, this invention utilizes incorporated (trapped) iodine molecules within the cross-linked network (i.e., polymer matrix) to induce radiopaque functionality. In an embodiment, the radiopaque polymer is an iodinated polymer. As referred to herein, iodinated polymers are produced by incorporating (trapping) iodine molecules on a select monomer prior to formulation of the monomer into a polymer. In different embodiments, the concentration of iodine in the radiopaque polymer is at least 200 or at least 300 mg/mL.

[0026] In an embodiment, the iodinated cross-linked polymers of the invention are formed by the polymerization of 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 containing only one polymerizable group, while “short crosslinking monomer” refers to a monomer of Formula II or Formula III containing more than one polymerizable group, and “long crosslinking monomer” refers to a monomer of Formula IV containing more than one polymerizable group. Upon polymerization, the monomers in the monomer mixture contribute constitutional units to the network, with each constitutional unit being an atom or group of atoms (with pendant atoms or groups, if any) comprising a part of the essential structure of a macromolecule, an oligomer molecule, a block or a chain. Since the constitutional units typically appear multiple times in the network, they may also be termed repeating units. Repeating units derived from a given type of monomer need not be located adjacent to one another in the network or in a given sequence in the network.

[0027] In some embodiments, the polymer comprises a cross-linked network comprising: a) one or more first repeating units derived from a monomer of Formula I:

Formula I b) one or more second repeating units derived from a monomer of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb:

Formula Ila Formula lib

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

Formula IVb wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5- membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula ; and each instance of Si, S2, and S3 independently is hydrogen or methyl.

[0028] In some embodiments, the one or more second repeating units are derived from a monomer of Formula Ila and/or Formula lib (e.g., Formula Ila or Formula lib). In certain embodiments, the second repeating unit is derived from a monomer of Formula Ila. In other embodiments, the second repeating unit is derived from a monomer of Formula lib.

[0029] In some embodiments, the one or more second repeating units are derived from a monomer of Formula Ilia and/or Formula lllb (e.g., Formula Ilia or Formula lllb). In certain embodiments, the second repeating unit is derived from a monomer of Formula Ilia. In other embodiments, the second repeating unit is derived from a monomer of Formula Illb.

[0030] In some embodiments, the one or more second repeating units are derived from a monomer of Formula Ila and/or Formula Ilia (e.g., Formula Ila and Formula Ilia).

[0031] In some embodiments, the 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 repeating unit is derived from a monomer of Formula IVa. In other embodiments, the second repeating unit is derived from a monomer of Formula IVb.

[0032] Each m independently is an integer from 8 to 16 (i.e., 8, 9, 10, 11, 12, 13, 14, 15, or 16). Accordingly, the one or more first repeating units derived from a monomer of Formula I can have an alkylene chain from 8 to 16 -CFh- units in length. In some embodiments, each m independently is 8, 9, 10, 11, or 12. In preferred embodiments, each m is 10.

[0033] Each n independently is 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). Accordingly, the one or more second repeating units derived from a monomer of Formula Ila or Formula lib can have an alkylene chain from 2 to 22 (e.g., from 2 to 16, from 2 to 10, from 6 to 22, from 10 to 22, or from 10 to 14) -CFh- units in length. In some embodiments, each n independently is 10, 11, 12, 13, or 14. In preferred embodiments, each n is 12.

[0034] Each pi independently is 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). Accordingly, the one or more third repeating units derived from a monomer of Formula IVa or Formula IVb can have an alkylene chain from 2 to 22 (e.g., from 2 to 16, from 2 to 10, from 2 to 6, from 2 to 4, from 6 to 22, from 10 to 22, or from 10 to 14) -CFb- units in length. In some embodiments, each pi independently is 2, 3, 4, 5, or 6. In preferred embodiments, each n is 4 or 6.

[0035] Each p2 independently is an integer from 1 to 50 (e.g., from 1 to 40, from 1 to 30, from 1 to 20, from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 4, from 2 to 50, from 2 to 40, from 2 to 30, from 2 to 20, from 2 to 10, from 2 to 8, from 2 to 6, from 2 to 4, from 4 to 50, from 4 to 40, from 4 to 30, from 4 to 20, or from 4 to 10). In some embodiments, each p2 is an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6).

[0036] Each instance of Si, S2, and S3 independently is hydrogen or methyl. In some embodiments each instance of Si, S2, and S3 is hydrogen. In some embodiments each instance of Si, S2, and S3 is methyl.

[0037] In some embodiments, the monomer of Formula Ila or Formula lib is:

[0038] In some embodiments, the monomer of Formula Ilia or Formula Illb is:

QQ

[0040] In some embodiments, the monomer of Formula IVb is a polyethylene glycol dimethacrylate or a polyethylene glycol diacrylate. The polyethylene glycol dimethacrylate or a polyethylene glycol diacrylate can have any suitable weight average molecular weight. For example, the polyethylene glycol dimethacrylate or a polyethylene glycol diacrylate can have a weight average molecular weight of from 200 g/mol to 2,000 g/mol, e.g., 200 g/mol to 1,500 g/mol, 200 g/mol to 1,000 g/mol, 500 g/mol to 2,000 g/mol, 500 g/mol to 1,500 g/mol, or from 500 g/mol to 1,000 g/mol. In some embodiments, the monomer of Formula IVb is polyethylene glycol diacrylate (weight average molecular weight of approximately 575 g/mol) or polyethylene glycol dimethacrylate (weight average molecular weight of approximately 1,000 g/mol).

[0041] Ar is an iodinated 5-membered or 6-membered aryl or heteroaryl. In some embodiments, the iodinated 5-membered or 6-membered aryl or heteroaryl comprises at least two iodine atoms. In certain embodiments, the iodinated 5-membered or 6-membered aryl or heteroaryl comprises at least three iodine atoms. Accordingly, the iodinated 5-membered or 6- membered aryl or heteroaryl can contain an average of between 1 to 5, 1 to 4, 2 to 4, 3 to 4, or 3 to 5 iodine atoms per 5-membered or 6-membered aryl or heteroaryl. In certain embodiments, the iodinated 5-membered or 6-membered aryl or heteroaryl contains an average of between 2 to 4 or 3 to 4 iodine atoms per 5-membered or 6-membered aryl or heteroaryl. In preferred embodiments, the iodinated 5-membered or 6-membered aryl or heteroaryl contains an average of about 3 iodine atoms per 5-membered or 6-membered aryl or heteroaryl. [0042] The 5-membered or 6-membered aryl or heteroaryl can be any suitable aromatic substituent. As used herein, “5-membered or 6-membered aryl” refers to a substituted or unsubstituted monocyclic aromatic substrate (e.g., phenyl) comprising 5 or 6 atoms about the aromatic core or ring. As used herein, “5-membered or 6-membered heteroaryl” substituted or unsubstituted monocyclic aromatic substrate which contains at least 1 heteroatom (e.g., O, S, N, and/or P) in the core of the molecule (i.e., any atom about the aromatic core or ring). Typically, the iodinated 5-membered or 6-membered aryl or heteroaryl is an iodinated 6-membered aryl. For example, the iodinated 5-membered or 6-membered aryl or heteroaryl can be selected from:

In preferred embodiments, the iodinated 6-membered aryl is of the formula:

[0043] Each R independently is hydrogen or of the formula Accordingly, the one or more third repeating units derived from a monomer of Formu Ilia and/or Formula Illb can have five or six acrylate groups. In some embodiments, R is hydrogen. In other embodiments, R is of the formula , wherein each instance of S2 independently is hydrogen or methyl.

[0044] As used herein, the term “group” may refer to a functional group of a chemical compound. Groups of the present compounds refer to an atom or a collection of atoms that are a part of the compound. Groups of the present invention may be attached to other atoms of the compound via one or more covalent bonds. Groups may also be characterized with respect to their valence state. The present invention includes groups characterized as monovalent, divalent, trivalent, etc. valence states.

[0045] As used throughout the present description, the expression “a group corresponding to” an indicated species expressly includes a moiety derived from the group including a monovalent, divalent or trivalent group.

[0046] As is customary and well known in the art, hydrogen atoms in the Formulas included are not always explicitly shown, for example, hydrogen atoms bonded to the carbon atoms of the polymer backbone, crosslinking groups, aromatic group, etc. The structures provided herein, for example in the context of the description of the Formulas, are intended to convey to one of reasonable skill in the art the chemical composition of compounds of the methods and compositions of the invention, and as will be understood by one of skill in the art, the structures provided do not indicate the specific positions of atoms and bond angles between atoms of these compounds.

[0047] As used herein, the terms “alkylene” and “alkylene group” are used synonymously and refer to a divalent group derived from an alkyl group as defined herein. The invention includes compounds having one or more alkylene groups.

[0048] As used herein, “derived” when referring to a monomer unit, means that the monomer unit has substantially the same structure of a monomer from which it was made, wherein the terminal olefin has been transformed during the process of polymerization.

[0049] The polymer with a cross-linked network can comprise any suitable amount of the one or more first repeating units, the one or more second repeating units, and the one or more third repeating units. For example, the polymer can comprise about 25 wt.% to about 99 wt.% of the one or more first repeating units, about 0.1 wt.% to about 74.9 wt.% of the one or more second repeating units, and about 0.1 wt.% to about 74.9 wt.% of the one or more third repeating units. In some embodiments, the polymer comprises about 60 wt.% to about 95 wt.% of the one or more first repeating units, about 1 wt.% to about 40 wt.% of the one or more second repeating units, and about 1 wt.% to about 25 wt.% of the one or more third repeating units. In certain embodiments, the polymer comprises about 75 wt.% to about 90 wt.% (e.g., about 80 wt.% to about 90 wt.%) of the one or more first repeating units (e.g., about 80 wt.% to about 90 wt.%), about 5 wt.% to about 15 wt.% (e.g., about 5 wt.% to about 10 wt.%) of the one or more second repeating units, and about 1 wt.% to about 10 wt.% (e.g., about 1 wt.% to about 8 wt.% or about 1 wt.% to about 6 wt.%) of the one or more third repeating units.

[0050] In some embodiments, the cross-linked network further comprises one or more fourth repeating units derived from a monomer of Formula V and/or Formula VI:

Formula VI wherein each instance of p3 independently is an integer from 2 to 36; each instance of p4 independently is an integer from 2 to 22; each instance of p5 independently is an integer from 1 to 50; each R1 is methyl or hydroxyl; and each instance of Sr independently is hydrogen or methyl.

[0051] Each p3 independently is 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). Accordingly, the one or more fourth repeating units derived from a monomer of Formula V and/or Formula VI can have an alkylene chain from 2 to 36 (e.g., from 2 to 36, from 2 to 24, from 2 to 18, from 2 to 12, from 6 to 36, from 6 to 24, from 6 to 12, from 10 to 32, from 10 to 24, or from 10 to 16) -CFh- units in length. In some embodiments, each p3 independently is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In preferred embodiments, each n is 9, 10, 11, 12, 13, 14, or

15.

[0052] Each p4 independently is 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). Accordingly, the one or more fourth repeating units derived from a monomer of Formula V and/or Formula VI can have an alkylene chain from 2 to 22 (e.g., from 2 to 16, from 2 to 10, from 2 to 6, from 2 to 4, from 6 to 22, from 10 to 22, or from 10 to 14) -CFb- units in length. In some embodiments, each p4 independently is 2, 3, 4, 5, or 6. In preferred embodiments, each n is 2, 4, or 6.

[0053] Each p5 independently is an integer from 1 to 50 (e.g., from 1 to 40, from 1 to 30, from 1 to 20, from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 4, from 2 to 50, from 2 to 40, from 2 to 30, from 2 to 20, from 2 to 10, from 2 to 8, from 2 to 6, from 2 to 4, from 4 to 50, from 4 to 40, from 4 to 30, from 4 to 20, or from 4 to 10). In some embodiments, each p5 is an integer from 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6).

[0054] Each instance of S4 independently is hydrogen or methyl. In some embodiments each instance of S4 is hydrogen. In some embodiments each instance of S4 is methyl.

[0055] The number of repeating units described or shown herein is not specifically limited, but is rather any number that is functionally feasible, that is, can be synthesized and has the desired use in the desired polymer compositions, polymers, methods and devices.

[0056] Generally, the polymer with a cross-linked 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 useful for 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 “space-triggered”, as the phrase is conventionally used. In a space triggered material the materials return to their original shape upon removal of a spatial constraint, as is the case when a coil-shaped specimen emerges from its temporary elongated configuration within a deployment catheter and regains its coil shape, for example. It should be made clear that certain polymers and polymer compositions described herein may technically have shape memory properties, but those properties may or may not be used in the devices and methods of the 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 particular embodiment is described using a shape memory polymer, it is recognized that other polymers and polymer compositions that are not specifically defined as having shape memory properties may be interchangeable and used in that embodiment.

[0057] In some embodiments, the polymer, polymer compositions, or devices of the invention do not contain any metal materials or metal components or elements but still exhibit suitable radiopacity for clinical viewing using conventional imaging systems. Clinicians are commonly challenged by obscuring artifacts from metal and metal based implanted devices when attempting to image using either CT scan (Computed Tomography) or MRI (Magnetic Resonance Imaging). The significance of the artifact is typically based upon the amount of metal content and can be so excessive as to inhibit the ability to clinically image the device. This situation can require an alternative means to clinically evaluate the patient or device (e.g. angiogram, etc.) which may not only be more costly, but more invasive and risky to the patient. As such, a non-metallic, radiopaque polymer reflects a significant advantage and differentiation from other approaches for radiopaque devices.

[0058] In some embodiments, the polymers of the present invention are sufficiently amorphous that some conventional analysis methods do not indicate the presence of residual amounts of crystallinity. In other words, in some embodiments, the polymer is substantially amorphous and/or the structure is chosen so as to discourage crystallinity. The degree of crystallinity can be measured by any suitable method such as, for example, by using differential scanning calorimetry (DSC). In certain embodiments, the polymers described herein are not sufficiently crystalline as to cause devices incorporating the polymers to be inoperative in the desired uses. Such morphology is unlike the disclosure of US Patent 7939611 by Brandom et ah, which discloses side-chain crystallizable units in their molten liquid embolic agent in order to encourage semi-crystallinity. In general, if shape memory polymers are semicrystalline, shape change can be hindered and slowed, and device performance can become clinically undesirable. The crystallinity of the shape memory polymer and non-shape memory polymers described here can be affected by the selection of the components used to form the polymer, as further described herein.

[0059] The glass transition temperature and rubbery modulus of the polymers of the present invention can be adjusted independently, as further described herein.

[0060] The polymer with a cross-linked network can have any suitable glass transition temperature. In some embodiments, the glass transition temperature of the polymer is from 0 °C to 75 °C, though any other polymer glass transition temperature that produces a useful final product is intended to be included as well. In some embodiments, the glass transition temperature may be suppressed below body temperature. When a polymer formed from such a device is delivered in a catheter or other delivery device, the material may already transition to its rubbery state in the delivery device. This can allow achievement of a more rapid response (elastic response) from the device after delivery (e.g. in the vessel). The polymer may be a shape memory polymer having a glass transition temperature (Tg) between 15 °C to 75 °C and a rubbery modulus between O.IMPa and 500 MPa at 37 °C. The polymer may be such that Tg is at or below body temperature. Typically, the polymer exhibits a glass transition temperature (Tg) and a Tan Delta (Loss Modulus/ Storage Modulus ratio) curve related to temperature; the polymer's maximum rate of shape change occurs at an environmental operating temperature (To) that is coincident with a temperature at or above a rubbery plateau Tan Delta value. In certain embodiments, the polymer with a cross-linked network has a glass transition temperature of from 0 °C to 50 °C, for example, from 15 °C to 50 °C, from 15 °C to 35 °C, from 25 °C to 50 °C, from 25 °C to 45 °C, from 25 °C to 40 °C, from 25 °C to 35 °C, from 25 °C to 30 °C, from 30 °C to 50 °C, from 30 °C to 45 °C, from 30 °C to 40 °C, from 30 °C to 35 °C, from 40 °C to 50 °C, or from 40 °C to 45 °C. In preferred embodiments, the polymer has a glass transition temperature of from 15 °C to 35 °C or from 25 °C to 35 °C.

[0061] In some embodiments, the polymers or polymer compositions have sufficient resistance to water absorption that it can be used to fabricate medical devices or device components for use in a physiological environment with exposure to body fluid(s). In an embodiment, the medical devices or device components show little change in their mechanical properties or degradation of their mechanical integrity during the useful lifetime of the device. In an embodiment, the devices and compositions described here are useful for permanent (or long term) implantation or use in a biological system. In an embodiment, devices or device components formed using the polymers or polymer compositions of the invention exhibit a water uptake of less than 0.5% by weight over a 24 hour period. In an embodiment, devices or device components formed using the polymers or polymer compositions of the invention exhibit a water uptake of less than 0.1% by weight over a 24 hour period.

[0062] In some embodiments, the polymers or polymer compositions further comprise a metal marker band. In an embodiment of this aspect, the metal marker band comprises platinum- iridium or gold.

[0063] In some embodiments, the polymers or polymer compositions as described herein are substantially amorphous. In certain embodiments, the polymers or polymer compositions as described herein are shape memory polymers or polymer compositions.

[0064] As used herein, a crystalline material displays long range order. The crystallinity of polymers is characterized by their degree of crystallinity, or weight or volume fraction of crystalline material in the sample ranging from zero for a completely non-crystalline polymer to one for a theoretical completely crystalline polymer.

[0065] If a polymer is semicrystalline, shape change can be hindered and slowed, and performance of devices incorporating the polymer can become clinically unacceptable. In some embodiments, the polymer compositions of the invention are considered substantially amorphous. As used herein, substantially amorphous is defined as the absence of crystalline features as detected by differential scanning calorimetry (DSC), or by inconsistency and lack of reproducibility in mechanical tensile test results, e.g., stress-strain curve at a fixed temperature. In certain embodiments, lack of reproducibility may be indicated by reproducibility of less than 95% at 95% confidence interval. A substantially amorphous polymer may incorporate relatively small amounts of crystallinity. As is typical of amorphous polymers, the substantially amorphous polymer compositions of the invention show a transition from a glassy state to a rubbery state over a glass transition temperature range. Crystallinity can be reduced or eliminated by reducing the concentration of specific monomers that enhance this condition, and/or by introducing dissimilar structures to ensure that the polymer’s molecular structure doesn’t align during polymerization to result in crystallinity.

[0066] In an embodiment, the monomers (including crosslinking monomers) used to form the radiopaque polymer are selected to assure compatibility (e.g. homogeneity after polymerization). In an embodiment, the radiopaque polymer is sufficiently homogenous in terms of solid-phase compatibility of the polymerized units and in the sufficiently random incorporation of units throughout polymerization to obtain the desired performance characteristics. Phase incompatibility can lead to voids in the polymer morphology. Voids in the polymer matrix compromise mechanical performance and can lead to uptake of water and other fluids that displace the generated void volume, even when the incompatible phases are hydrophobic or even “water-repellant.” Excessively non-random incorporation of comonomers, especially di(meth)acrylate or other poly(meth)acrylate crosslinkers, as polymerization proceeds from low conversion to high conversion can lead to a non-uniform crosslink density, with regions of higher (brittle) and lower (rubbery) crosslink density.

[0067] In an embodiment, the radiopaque polymer is homogenous enough that repeatable results (95% reproducible data at 95% confidence interval) can be obtained in a simple ultimate tensile test at a fixed temperature. In an embodiment, homogeneity of the polymer may be improved by selection of the components of the monomer solution to reduce phase separation in the liquid or solid state. In addition, the monomer components and polymerization technique may be selected to facilitate random incorporation of monomer and crosslinker groups by free radical polymerization during the cure. In an embodiment, the same type of polymerizable groups is present in each of the monomers. For example, for monomers (and crosslinking monomers) having acrylate polymerizable groups and aliphatic hydrocarbon linkers, the inductive effect exerted upon the acrylate group by the typically aliphatic linker attachments is expected to be similar.

[0068] In another aspect, a method of making a polymer with a cross-linked network described herein is provided. The method comprises: i) forming a monomer mixture comprising: a) one or more monomers of Formula I:

Formula I b) one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb: and wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5- membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula each instance of Si, S2, and S3 independently is hydrogen or methyl; and ii) providing a free radical initiator to polymerize the monomer mixture. Each of m, n, pi, p2, Ar, R, Si, S2, and S3 is as described herein. In some embodiments, the monomer mixture is substantially homogeneous.

[0069] Generally, the amount of the one or more monomers of Formula I (i.e., radiopaque monomers) in the monomer mixture is at least about 25 wt.%. As used herein, the wt.% of radiopaque monomer in the mixture may be the 100 * (the weight of the radiopaque monomer/ the weight of the sum total of monomers). In some embodiments, the amount of the one or more monomers of Formula I (i.e., radiopaque monomers) is from about 25 wt.% to about 99 wt.% of the monomer mixture. For example, the amount of the radiopaque monomer is from about 25 wt.% to about 98 wt.%, from about 25 wt.% to about 95 wt.%, from about 25 wt.% to about 90 wt.%, from about 25 wt.% to about 85 wt.%, from about 25 wt.% to about 80 wt.%, from about 25 wt.% to about 75 wt.%, from about 25 wt.% to about 98 wt.%, from about 50 wt.% to about 95 wt.%, from about 50 wt.% to about 90 wt.%, from about 50 wt.% to about 85 wt.%, from about 50 wt.% to about 80 wt.%, from about 50 wt.% to about 75 wt.%, from about 60 wt.% to about 98 wt.%, from about 60 wt.% to about 95 wt.%, from about 60 wt.% to about 90 wt.%, from about 60 wt.% to about 85 wt.%, from about 60 wt.% to about 80 wt.%, from about 60 wt.% to about 75 wt.%, from about 70 wt.% to about 98 wt.%, from about 70 wt.% to about 95 wt.%, from about 70 wt.% to about 90 wt.%, from about 70 wt.% to about 85 wt.%, from about 70 wt.% to about 80 wt.%, from about 70 wt.% to about 75 wt.%, from about 80 wt.% to about 99 wt.%, from about 80 wt.% to about 95 wt.%, from about 80 wt.% to about 90 wt.%, from about 85 wt.% to about 99 wt.%, from about 85 wt.% to about 95 wt.%, from about 86 wt.% to about 95 wt.%, from about 87 wt.% to about 95 wt.%, from about 88 wt.% to about 95 wt.%, from about 89 wt.% to about 95 wt.%, or from about 90 wt.% to about 95 wt.% of the monomer mixture. In certain embodiments, the amount of the radiopaque monomer is from about 60 wt.% to about 95 wt.% of the monomer mixture. In preferred embodiments, the amount of the radiopaque monomer is from about 75 wt.% to about 90 wt.% (e.g., about 80 wt.% to about 90 wt.%) of the monomer mixture. [0070] Generally, the amount of the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb (i.e., short crosslinking monomers) in the monomer mixture is less than about 75 wt.%. As used herein, the wt.% of short crosslinking monomers in the mixture may be the 100 * (the weight of the short crosslinking monomers / the weight of the sum total of monomers). In some embodiments, the amount of the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb (i.e., short crosslinking monomers) is from about 0.1 wt.% to about 74.9 wt.% of the monomer mixture. For example, the amount of the short crosslinking monomers is from about 0.1 wt.% to about 50 wt.%, 0.1 wt.% to about 40 wt.%, from about 0.1 wt.% to about 25 wt.%, from about 0.1 wt.% to about 15 wt.%, from about 0.1 wt.% to about 10 wt.%, from about 0.1 wt.% to about 9 wt.%, from about 0.1 wt.% to about 8 wt.%, from about 0.1 wt.% to about 7 wt.%, from about 0.1 wt.% to about 6 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.5 wt.% to about 50 wt.%, from about 0.5 wt.% to about 40 wt.%, from about 0.5 wt.% to about 25 wt.%, from about 0.5 wt.% to about 15 wt.%, from about 0.5 wt.% to about 10 wt.%, from about 0.5 wt.% to about 9 wt.%, from about 0.5 wt.% to about 8 wt.%, from about 0.5 wt.% to about 7 wt.%, from about 0.5 wt.% to about 6 wt.%, from about 0.5 wt.% to about 5 wt.%, from about 1 wt.% to about 50 wt.%, from about 1 wt.% to about 40 wt.%, from about 1 wt.% to about 25 wt.%, from about 1 wt.% to about 15 wt.%, from about 1 wt.% to about 10 wt.%, from about 1 wt.% to about 9 wt.%, from about 1 wt.% to about 8 wt.%, from about 1 wt.% to about 7 wt.%, from about 1 wt.% to about 6 wt.%, from about 1 wt.% to about 5 wt.% of the monomer mixture, from about 5 wt.% to about 50 wt.%, from about 5 wt.% to about 40 wt.%, from about 5 wt.% to about 25 wt.%, from about 5 wt.% to about 15 wt.%, or from about 5 wt.% to about 10 wt. In certain embodiments, the amount of the short crosslinking monomer is from about 1 wt.% to about 40 wt.% of the monomer mixture. In preferred embodiments, the amount of the short crosslinking monomer is from about 5 wt.% to about 15 wt.% (e.g., about 5 wt.% to about 10 wt.%) of the monomer mixture.

[0071] Generally, the amount of the one or more monomers of one or more monomers of Formula IVa and/or Formula IVb (i.e., long crosslinking monomers) in the monomer mixture is less than about 75 wt.%. As used herein, the wt.% of long crosslinking monomers in the mixture may be the 100 * (the weight of the long crosslinking monomers / the weight of the sum total of monomers). In some embodiments, the amount of the one or more monomers of Formula IVa and/or Formula IVb (i.e., long crosslinking monomers) is from about 0.1 wt.% to about 74.9 wt.% of the monomer mixture. For example, the amount of the long crosslinking monomers is from about 0.1 wt.% to about 50 wt.%, from about 0.1 wt.% to about 25 wt.%, from about 0.1 wt.% to about 15 wt.%, from about 0.1 wt.% to about 10 wt.%, from about 0.1 wt.% to about 9 wt.%, from about 0.1 wt.% to about 8 wt.%, from about 0.1 wt.% to about 7 wt.%, from about 0.1 wt.% to about 6 wt.%, from about 0.1 wt.% to about 5 wt.%, from about 0.5 wt.% to about 50 wt.%, from about 0.5 wt.% to about 25 wt.%, from about 0.5 wt.% to about 15 wt.%, from about 0.5 wt.% to about 10 wt.%, from about 0.5 wt.% to about 9 wt.%, from about 0.5 wt.% to about 8 wt.%, from about 0.5 wt.% to about 7 wt.%, from about 0.5 wt.% to about 6 wt.%, from about 0.5 wt.% to about 5 wt.%, from about 1 wt.% to about 50 wt.%, from about 1 wt.% to about 25 wt.%, from about 1 wt.% to about 15 wt.%, from about 1 wt.% to about 10 wt.%, from about 1 wt.% to about 9 wt.%, from about 1 wt.% to about 8 wt.%, from about 1 wt.% to about 7 wt.%, from about 1 wt.% to about 6 wt.%, from about 1 wt.% to about 5 wt.% of the monomer mixture, from about 5 wt.% to about 50 wt.%, from about 5 wt.% to about 25 wt.%, from about 5 wt.% to about 15 wt.%, or from about 5 wt.% to about 10 wt. In certain embodiments, the amount of the long crosslinking monomer is from about 1 wt.% to about 25 wt.% of the monomer mixture. In preferred embodiments, the amount of the long crosslinking monomer is from about 1 wt.% to about 10 wt.% (e.g., about 1 wt.% to about 8 wt.% or about 1 wt.% to about 6 wt.%) of the monomer mixture.

[0072] In some embodiments, the monomer mixture further comprises one or more additional monomers of Formula V and/or Formula VI:

Formula VI wherein each instance of p3 independently is an integer from 2 to 36; each instance of p4 independently is an integer from 2 to 22; each instance of p5 independently is an integer from 1 to 50; each R1 is methyl or hydroxyl; and each instance of S4 independently is hydrogen or methyl. The additional monomer can be present in the monomer mixture in any suitable amount. For example, the additional monomer can be present in an amount 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 to about 50 wt.%, from about 20 wt.% to about 50 wt.%, or from about 10 to about 70 wt.% and all lower, intermediate, and higher values and ranges therein.

[0073] 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 can be present in an amount from about 0.1 wt.% to about 10 wt.% based on the weight of the sum total of monomers. In certain embodiments, the free radical initiator is present in an amount from about 0.1 wt.% to about 5 wt.% (e.g., about 0.5 wt.% or about 1 wt.%).

[0074] A wide range of free radical initiating systems may be used for polymerization. In different embodiments, the initiator may be a photoinitiator, a thermal initiator or a redox (reduction oxidation) initiator. Photoinitiating systems are particularly useful, provided that a photoinitiator is chosen that does not require wavelengths of light that are absorbed excessively by the base monomer ingredients of the formulation. Irgacure 819 (Ciba (BASF), Bis(2,4,6- trimethylbenzoyl)-phenylphosphineoxide) is one example of a photoinitiator that has been found to be particularly useful for the curing system.

[0075] Photopolymerization occurs when monomer solution is exposed to light of sufficient power and of a wavelength capable of initiating polymerization. The wavelengths and power of light useful to initiate polymerization depends on the initiator used. Light used in the invention includes any wavelength and power capable of initiating polymerization. Preferred wavelengths of light include ultraviolet. In different embodiments, the light source primarily provides light having a wavelength from 200 to 500 nm or from 200 to 400 nm. In an embodiment, 1-100 mW/cm ² of 200-500nm light is applied for a time from 10 sec to 60 mins. Any suitable source may be used, including laser sources. The source may be filtered to the desired wavelength band. The source may be broadband or narrowband, or a combination. The light source may provide continuous or pulsed light during the process.

[0076] Thermal initiating systems, with low-temperature or high-temperature initiators, common examples being benzoyl peroxide and azobisisobutyronitrile (AIBN), are also useful in situations where a particularly large or irregularly-shaped object that is difficult to illuminate uniformly is to be prepared. Also of use in the latter scenario are free radical initiating systems that produce free radicals by any type of redox reaction, such as the Fenton system involving ferrous salts with tert-butyl hydroperoxide, or other metal -organic, organic such as triethylamine + hydroperoxides, or photo-organic redox systems, an example of the latter being the Eosin-Y + triethanolamine visible light initiating system. In certain embodiments, the radical initiator is Luperox® P (commercially available from Arkema; Alsip, IL).

[0077] A number of pseudo-living free radical polymerization systems, some of which are capable of producing polymers with narrower molecular weight distributions than conventional free radical polymerizations, are also described in the art and can be amenable to production of crosslinker segments for SMPs or for SMP curing. For example, styrene monomers that polymerize to low conversion in a conventional system may be driven to high conversion in a pseudo-living system. These pseudo-living systems typically involve variable combinations of reversible chain propagation-termination and/or chain transfer steps. “Living” free radical polymerizations known to the art include, but are not limited to, NMP, RAFT, and ATRP.

[0078] Additionally; any other type of non-conventional free radical polymerization process, whether pseudo-living or not, that produces free radicals capable of initiating polymerization of the radiopaque and non-radiopaque monomers and crosslinkers comprising the SMPs of this invention, fall within the scope of potential initiating-polymerization methods. These and other free radical initiating systems are conceivable and known to those skilled in the art.

[0079] In embodiments, examples of the useful initiating systems include anionic, cationic, free radical polymerizations that are non-living, pseudo-living or living as well as Ziegler-Natta and olefin metathesis. The use of these systems is known in the art. In an embodiment, these systems are useful if a prepolymerized segment is at least difunctional and has hydroxyl or other groups known in the art which can be used to attach polymerizable groups, including acrylate groups in an embodiment.

[0080] In an embodiment, some or all of the components of the monomer mixture are combined at a temperature greater than ambient temperature. In different embodiments, the initiator may be added at the same time as the monomer components or added just prior to or at the time of molding. In another embodiment where a thermal initiator is used, the monomer mixture ingredients may be divided into two parts; wherein the high storage temperature ingredients are in Part A, and the lower storage temperature ingredients are in Part B. The thermal initiator may be added to the lower storage temperature ingredients in Part B at a storage temperature that is below the initiator’s polymerization temperature. In an embodiment, forming the monomer mixture (or a portion of the monomer mixture) at greater than ambient temperature can assist in maintaining solubility of the monomer mixture components, thereby enabling formation of a homogenous mixture. [0081] In an embodiment, the monomer mixture is held at a temperature greater than ambient temperature during free radical polymerization. In an embodiment, the monomer mixture is held a temperature between 65 °C and 150 °C or from 65 °C and 100 °C during the polymerization step. In an embodiment, a pre-cure step is performed in a vacuum environment. In separate embodiments, the curing step is performed using free radical, anionic, cationic, Diels-alder, thiol- ene, polycondensation, or other mechanisms known in the art. During molding, pressure may be applied during polymerization to ensure mold filling.

In an embodiment, an additional curing or heat treatment step is employed after the polymerization step (e.g. after photopolymerization). In an embodiment, the cured parts are removed from the mold and then undergo additional curing operations through exposure to elevated temperatures. In an embodiment, the curing temperature is from 50 °C and 150 °C and the curing time from 5 seconds to 60 minutes during this additional step. In different embodiments, the amount of functional group conversion is at least 30%, 40%, 50%, 60%, 70% , 80% or 90% or higher. In an embodiment, the amount of extractables is less than or equal to 5%. In an embodiment, the amount of extractables is less than or equal to 3%. In an embodiment, the amount of extractables is less than or equal to 2%. In an embodiment, the amount of extractables is less than or equal to 1% or less than or equal to 0.5%. In an embodiment, the amount of extractables is determined by isopropanol extraction.

[0082] In another aspect, a cross-linked polymer network is provided. The cross-linked polymer network is formed from a monomer mixture comprising: a) one or more monomers of Formula I:

Formula I b) one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula

Illb:

Formula Ilia and/or Formula lllb

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

Formula IVb

? wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5- membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula and each instance of Si, S2, and S3 independently is hydrogen or methyl, wherein the monomer mixture comprises about 60 wt.% to about 95 wt.% of the one or more monomers of Formula I, about 1 wt.% to about 40 wt.% of the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula lllb, and about 1 wt.% to about 25 wt.% of the one or more monomers of Formula IVa and/or Formula IVb. Each of m, n, p1, p2, Ar, R, S1, S2, and S3 is as described herein.

[0083] Additional features of the cross-linked polymer network will be readily apparent from the description provided herein. [0084] In another aspect, the invention provides radiopaque medical devices. The original molded shape of radiopaque medical devices of the present invention can be deformed into a temporary shape typically having a reduced profile to facilitate insertion into a vessel, lumen, or other aperture or cavity. After insertion, the device can self-expand to assume a deployed configuration. In an embodiment, the medical device may assume its deployed configuration due to changes in temperature or other stimuli. In an 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 an embodiment, the medical device’s deployed configuration may have one or more useful purposes including lumen occlusion, lumen opening or stenting, device anchoring or retention, patching or sealing a surface, structural restoration or localized drug delivery. The devices may use a SMP property of the compound or composition or may not use this property, if found in the compound or composition. In some embodiments, the device’s propensity for water uptake is less than 1.0% by weight over a 24 hour period.

[0085] The device can be useful for purposes of an indwelling, permanent implant to provide the function of: opening, or maintaining an open anatomical lumen; closing an anatomical lumen, either partially as a valve, or complete lumen occlusion for any physiological fluid or gas flow or for a applied therapeutic fluid or gas flow; support of an anatomical structure to assist in therapeutic restoration of an organ, vascular, digestive, excrement, or airway function; support of an anatomical structure to assist in therapeutic restoration of an orthopaedic, maxillofacial, spinal, joint or other skeletal or function; or to support hemostasis by covering an area after tissue dissection or resection, a patch, such as for hemostasis of the liver, or other organ. In an embodiment, the device is useful for diagnostic or therapeutic instrument or device to provide the function of: a) a catheter for the purposes of accessing an anatomical location; delivering another device and/or therapeutic agent; or controlling the access or delivery of another device and/or therapeutic agent; or b) a temporarily indwelling device to provide a limited time therapeutic benefit, such as a vena cava filter that is placed in a vessel, left indwelling for a period of time, for example to capture blood clots, and subsequently removed when the therapeutic period is completed.

[0086] In some embodiments, the device is non-metallic. In other embodiments, the device contains metal. For example, the device can contain metal in the form of marker bands, as conventionally used for visualization. In one aspect, the device comprises platinum-iridium or gold marker bands, as known in the art. As known in the art, “marker bands” may be used to achieve a specific product requirement, such as demarcation of an edge of the device or alignment of two devices for proper use, for example. The use of marker bands is optional with the devices described herein.

[0087] In many applications, biodurability can be defined as durability for the period of time necessary to assure that the body has overcome the need of the device’s function, e.g. a fallopian tube occlusion device that relies upon scar tissue formation to close the lumen no longer needs the device to generate scar tissue once the lumen is fully closed. If that period of time is 90 days, for example, then the biodurable life of the device can be this value plus a suitable safety factor used in the design. Biodurability then is the ability of the device, and its material, to withstand the environmental challenges at its location of placement in the body, e.g. if in the bloodstream, it must withstand a bloody environment. In an embodiment, the radiopaque polymer is not biodegradable within the desired lifetime of the medical device. In another embodiment, the radiopaque polymer is not biodegradable within three years. In an embodiment, the non- biodegradable polymer does not include aromatic groups other than those present in naturally occurring amino acid. In an embodiment, the non-biodegradable polymer does not contain esters that are readily hydrolyzed at physiological pH and temperature.

[0088] For almost all locations within the body, one of the several primary mechanisms of degradation can be caused by absorption of water or moisture. Whether the environment contains interstitial fluids, blood, saliva, urine, bile, intracranial fluid, etc., these environments are aqueous based. If the device or its material absorbs water, the material properties and device dimensions can change due to swelling, or the device function can be affected, such as the autogenesis of an errant electrical path, or the material properties can degrade causing the device to weaken or break apart. Therefore a primary consideration for biodurability of an implanted device is the device and all of its material’s ability to not absorb water.

[0089] In an embodiment, water uptake, or water absorption, can change the device’s characteristics or detrimentally affect the device’s performance over its intended life. In an embodiment, medical devices fabricated from the polymers of the invention will exhibit minimal water uptake. The water uptake can be measured over a test period equivalent to the lifetime or the device or can be measured over a shorter screening period. In an embodiment, the extent of water uptake is <1% by weight over 24 hours. For devices which exhibit water uptake of greater than 1% by weight over 24 hours, typically continuous exposure results in material changes such as brittleness and eventual mechanical failure in standard testing.

[0090] The minimal level of iodine concentration needed to achieve sufficient radiopacity to provide clinically acceptable imaging may be determined empirically. In an embodiment, evaluation of identically sized devices formulated from polymers using different weight percentages of iodinated monomer can be compared under simulated clinical use conditions. Using physicians’ subjective review and correlating their opinion with the results from an image analysis program, such as Image J, to quantify signal levels, clinically imaging quality is correlated with iodine concentration. The result is a determination of the minimum iodine concentration to assure acceptable image quality. Generally, 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 between about 350 mg/mL and about 1,000 mg/mL (e.g., between about 400 mg/mL and about 1,000 mg/mL, between about 450 mg/mL and about 1,000 mg/mL, between about 500 mg/mL and about 1,000 mg/mL, between about 550 mg/mL and about 1,000 mg/mL, between about 600 mg/mL and about 1,000 mg/mL, between about 350 mg/mL and about 900 mg/mL, between about 400 mg/mL and about 900 mg/mL, between about 450 mg/mL and about 900 mg/mL, between about 500 mg/mL and about 900 mg/mL, between about 550 mg/mL and about 900 mg/mL, between about 600 mg/mL and about 900 mg/mL, or between about 500 mg/mL and about 800 mg/mL). [0091] In another embodiment, the signal obtained from a radiopaque polymer device may be compared with that of a platinum device of similar dimensions. In an embodiment where signal level is obtained by x-ray under a 6 inch water phantom, the signal from the radiopaque polymer device may be up to 30% of that of the platinum device, for example, by virtue of the platinum device being a double-wound device with a central hollow region (theoretical AutoZeff calculator result with estimated influence of the central hollow region of a platinum metal embolic coil device).

[0092] Any polymer that can recover 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 processing and the temporary shape is set by thermo mechanical deformation. A SMP has the ability to recover large deformation upon heating.

Shape memory functionality can be utilized to develop medical devices that can be introduced into the body in a less invasive form, wherein the pre-deployed, or temporary, shape is intentionally smaller, or thinner, resulting in a lower profile and a smaller opening (smaller catheter or incision) to introduce the device into the patient than would otherwise be required without the shape change functionality. Then, when stimulated by temperature, typically body temperature but can also be greater than body temperature, the device undergoes shape recovery to return to its permanent, larger form. [0093] A polymer is a SMP if the original shape of the polymer is recovered by heating it above a shape recovery temperature, or deformation temperature (Td), even if the original molded shape of the polymer is destroyed mechanically at a lower temperature than Td, or if the memorized shape is recoverable by application of another stimulus. Any polymer that can recover an original shape from a temporary shape by application of a stimulus such as temperature may be considered a SMP.

[0094] From a biomedical device perspective, there are characteristics that are considered favorable in device design. They are quantified in terms of stimuli (such as temperature) driven response, well-defined response temperature, modulus, and elongation. In an embodiment, the thermomechanical properties of the shape memory polymer used to form the device are optimized for one or more of the following: Rubbery modulus (Emb), Glass transition temperature (T _g ), and Speed of recovery (S).

[0095] The preferred ranges of rubbery modulus can be different for different applications. The range of moduli of biological tissue can vary from 20 GPa (bone) to 1 kPa (eye) In an embodiment, the rubbery modulus is between 0. lMPa and 15 MPa at 37°C. In an embodiment, the rubbery modulus is between 0. lMPa and 50 MPa for the flexible state and between 0.1 to 500 MPa for the rigid state at 37°C. Any rubbery modulus value that produces a functional product can be used. By polymer formulation adjustments, the SMP’s modulus, e.g. stiffness, can be established as very soft, on the order of 0.IMPa. In one embodiment, for use as a device such as an embolic coil, this soft material enhances compaction of the coil pack, shortening the resulting pack for easier placement and ultimately increasing the speed of occlusion. Through other formulations, a higher value can be achieved for the SMP’s modulus, such as 15MPa, to enhance stiffness. In another embodiment, stiffer SMPs can be used to form a tube stent wherein localized stiffness is used to generate outward radial force against a vessel wall when deployed which is required for retention.

[0096] In an embodiment, the polymers are selected based on the desired glass transition temperature(s) (if at least one segment is amorphous) taking into consideration the environment of use. In one method, the polymer transition temperature is tailored to allow recovery at the body temperature, T _r ~ T _g ~ 37 °C (A. Lendlein and R. Langer, “Biodegradable, elastic shape- memory polymers for potential biomedical applications.” Science, vol. 296, pp. 1673-1676, 2002). The distinct advantage of this approach is the utilization of the body’s thermal energy to naturally activate the material. The disadvantage of this approach, for some applications, is that the mechanical properties (e.g., stiffness) of the material are strongly dependent on T _g , and can be difficult to alter in the device design process. In particular, it would be difficult to design an extremely stiff device when the polymer T is close to the body temperature due to the compliant nature of the polymer. Another possible disadvantage is that the required storage temperature,

Ts, of a shape memory polymer with T _g ~ 37 °C will typically be below room temperature requiring “cold” storage prior to deployment. In different embodiments, the glass transition temperature of the SMP of the present invention as determined from the peak of tan d is from 10 °C to 75 °C, 20 °C to 50 °C, from 25 °C to 50 °C, or from 30 °C to 45 °C. In certain embodiments, the glass transition temperature of the SMP of the present invention as determined from the peak of tan d is from 0 °C to 50 °C. In preferred embodiments, the glass transition temperature of the SMP of the present invention as determined from the peak of tan d is from 25 °C to 35 °C. In different embodiments, the glass transition temperature may be below body temperature (e.g. 25-35 °C ), near body temperature (32-42 °C) or above body temperature (40- 50°C). Any T value that produces a functional product can be used.

[0097] The storage modulus of at least partially non-crystalline polymers decreases in the glass transition region. DMA results highlight the changes that occur as the material is heated from its storage temperature (T _s ) to its response temperature (Tr) and above. Figure 1 illustrate curves for storage modulus (E’) and Tan Delta (ratio of the materiaTs Loss Modulus (E”) to Storage Modulus (E’)) obtained from dynamic mechanical analysis (DMA) curve of an SMP formulation. This curve illustrates the recovery temperature (T _r ), the glass transition temperature (T ), the operating temperature (T ₀ ) and Tan Delta Peak. Several methods may be used for determining the glass transition temperature; these include the peak or onset of the tan delta curve and the onset of the drop in the storage modulus. The width of the tan D peak is an indication of the breadth of the glass transition region. In an embodiment, the glass transition temperature is in the specified ranges and the full width of the tan D peak at half maximum is from 10-30 °C or from 10-20 °C. The glass transition temperature determined by DMA is frequency dependent and generally increases with increasing frequency. In an embodiment, the measurement frequency is 1 Hz. The glass transition temperature may also depend upon the heating rate and the applied stresses or strains. Other methods of measuring the glass transition temperature include thermal mechanical analysis (TMA) and differential scanning calorimetry (DSC); TMA and DSC are heating rate dependent.

[0098] Typically, for each medical device application that incorporates shape recovery, the clinician is anticipating relatively rapid and repeatable shape recovery. In an embodiment, the shape memory polymer devices of the invention produce shape recovery that is fast enough to be detected, completes in a reasonable (intraoperative) time, and repeatable from one device to another. In an embodiment, the shape recovery time can be measured in use or from a screening procedure. The shape recovery time can be measured either from release to 100% recovery or from release to a predetermined amount of recovery.

[0099] The rate of shape change correlates with the rate of storage modulus change on the DMA curve between the operating temperature and T _r. For SMPs, rate of shape change can be primarily affected by the temperature difference between T ₀ , the operating temperature (external heating or body core temperature if self actuated), and the polymer’s T (derived from the formulation). T ₀ is typically set above T _r. Typically, a larger difference between these temperatures will produce a faster rate of change up to an inherent rate limit, or asymptote of the change rate, of the material and device. This limit can be identified by monitoring shape change response time at different temperatures and plotting this relationship. Typically, the amount of response time decreases until it reaches an asymptote. The corresponding T ₀ reflects the lowest, optimum temperature for the fastest rate of shape change for that material. Increasing the temperature above this point does not induce further reductions in the shape change recover time, e.g. does not further increase the rate of shape change. In an embodiment this inherent limit, or asymptote begins when T ₀ is set at the temperature at which the Tan Delta curve is about 60% of its maximum value (refer to Figure 1, when T ₀ is set above the material’s T _g ). In an embodiment, the polymer’s maximum rate of shape change occurs at an environmental operating temperature (To) that is coincident with the temperature above Tg at which the material’s Tan Delta value is equal to 60% of its peak value. The device may be designed so that this optimum temperature is at a useful operating temperature for the device (e.g. at body temperature or another preselected temperature).

[0100] In an embodiment, the device is operated at a temperature which is the lowest temperature at which no further increase in shape change rate is seen. In another embodiment, the device is operated at a temperature which is within +/- 5 °C of this optimum temperature. [0101] In different embodiments, the recovery ratio of the SMPs employed in the biomedical devices of the invention is greater than 75%, 80%, 90%, 95%, from 80-100%, from 90-100%, or from 95-100%. In various embodiments, the maximum achievable strain is of the radiopaque SMP from 10% to 800%, from 10% to 200%, from 10% to 500%, from 10% to 100%, from 20% to 800%, from 20% to 500%, from 20% to 800%. as measured at a temperature above the glass transition temperature. In different embodiments, the maximum achievable strain or strain to failure of the radiopaque 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 below the glass transition temperature. In different 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 (20-25 °C).

[0102] In general, the ability of the device (whether technically shape memory or not) to change conformation or configuration (e.g. to expand) is made possible by manufacturing a device having a first conformation or configuration (initial configuration) and, thereafter configuring the device into a second conformation or configuration (temporary or storage configuration), wherein this configuration is at least partially reversible upon the occurrence of a triggering event. After the triggering event, the device assumes a third configuration. In an embodiment, the third configuration (deployed configuration) is substantially similar to the first configuration. However, for an implanted medical device, the device may be constrained from assuming its initial shape (first configuration). In an embodiment, the device is capable of self expansion to the desired dimensions under physiological conditions.

[0103] The invention can provide a variety of radiopaque polymer devices for medical applications, these devices incorporating the polymer compositions of the invention. The devices of the invention can be non-metallic. In different embodiments, these devices can be for purposes of an indwelling, permanent implant to provide the function of: opening, or maintaining an open anatomical lumen; closing an anatomical lumen, either partially as a valve, or complete lumen occlusion for any physiological fluid or gas flow or for a applied therapeutic fluid or gas flow; support of an anatomical structure to assist in therapeutic restoration of an organ, vascular, digestive, excrement, or airway function; support of an anatomical structure to assist in therapeutic restoration of an orthopedic, maxillofacial, spinal, joint or other skeletal or function; to support hemostasis by covering an area inside the body after tissue dissection or resection, a patch, such as for hemostasis of the liver, or other organ, In other embodiments, these devices can be used for purposes of a diagnostic or therapeutic instrument or device to provide the function of: a catheter for the purposes of accessing an anatomical location; delivering another device and/or therapeutic agent; or controlling the access or delivery of another device and/or therapeutic agent; a temporarily indwelling device to provide a limited time therapeutic benefit, such as a vena cava filter that is placed in a vessel, left indwelling for a period of time, for example to capture blood clots, and subsequently removed when the therapeutic period is completed. [0104] In one embodiment for neurovascular cases, wherein intracranial aneurysms are repaired, current state of care may use very fine metal (platinum) based embolic coils delivered into the aneurysm sack to fill this space and effect an isolation of the weakened vessel wall from the parent vessel thereby reducing the risk of rupture and stroke. However, because of the metallic nature of these devices, two deficiencies typically occur: 1. Approximately 25% of these patients must return for retreatment as the aneurysm continues to grow, and 2. To diagnose the need for retreatment, many of these patients must have an invasive angiogram (contrast injection) of the aneurysm area under fluoroscopy to be able to visualize the condition given that the metal coil materials are not compatible with MRI or CT Scan imaging modalities. A non- metallic, radiopaque SMP embolic device for aneurysm repair does not suffer this limitation in imaging capability 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 the invention. For example, thus the scope of the invention should be determined by the appended claims and their equivalents, rather than by the examples given.

[0105] The invention is further illustrated by the following embodiments.

[0106] (1) A polymer with a cross-linked network, the cross-linked network comprising: a) one or more first repeating units derived from a monomer of Formula I:

Formula I b) one or more second repeating units derived from a monomer of Formula Ila, Formula lib, Formula Ilia, and/or Formula IHb:

Formula Ila Formula lib

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

Formula IVb wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5- membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula ; and each instance of Si, S2, and S3 independently is hydrogen or methyl.

[0107] (2) The polymer of embodiment (1), wherein the polymer comprises about 60 wt.% to about 95 wt.% of the one or more first repeating units, about 1 wt.% to about 40 wt.% of the one or more second repeating units, and about 1 wt.% to about 25 wt.% of the one or more third repeating units.

[0108] (3) The polymer of embodiment (1), wherein the polymer comprises about 75 wt.% to about 90 wt.% (e.g., about 80 wt.% to about 90 wt.%) of the one or more first repeating units, about 5 wt.% to about 15 wt.% (e.g., about 5 wt.% to about 10 wt.%) of the one or more second repeating units, and about 1 wt.% to about 10 wt.% (e.g., about 1 wt.% to about 8 wt.% or about 1 wt.% to about 6 wt.%) of the one or more third repeating units.

[0109] (4) The polymer of any one of embodiments (l)-(3), wherein the iodinated 5- membered or 6-membered aryl or heteroaryl comprises at least two iodine atoms.

[0110] (5) The polymer of any one of embodiments (l)-(4), wherein the iodinated 5- membered or 6-membered aryl or heteroaryl comprises at least three iodine atoms.

[0111] (6) The polymer of any one of embodiments (l)-(5), wherein the iodinated 5- membered or 6-membered aryl or heteroaryl is an iodinated G aryl.

[0112] (7) The polymer of embodiment (6), wherein the iodinated G aryl is of formula:

[0113] (8) The polymer of any one of embodiment (l)-(7), wherein the polymer has a glass transition temperature of 0 °C to 50 °C.

[0114] (9) The polymer of any one of embodiment (l)-(8), wherein the polymer has a glass transition temperature of 15 °C to 35 °C.

[0115] (10) The polymer of any one of embodiments (l)-(9), wherein m is 8, 9, 10, 11, or 12.

[0116] (11) The polymer of embodiment (10, wherein m is 10.

[0117] (12) The polymer of any one of embodiments (l)-(l 1), wherein the one or more second repeating units is derived from the monomer of Formula Ila or Formula lib.

[0118] (13) The polymer of any one of embodiments (l)-(l 1), wherein the one or more second repeating units is derived from the monomer of Formula Ilia or Formula Illb.

[0119] (14) The polymer of any one of embodiments (l)-(l 1), wherein the one or more second repeating units are derived from the monomers of Formula Ila and Formula Ilia.

[0120] (15) The polymer of any one of embodiments (1)-(14), wherein the one or more third repeating units is derived from the monomer of Formula IVa.

[0121] (16) The polymer of any one of embodiments (1)-(14), wherein the one or more third repeating units is derived from the monomer of Formula IVb.

[0122] (17) The polymer of any one of embodiments (13)-(l 6), wherein R is of the formula [0123] (18) The polymer of any one of embodiments (13)-(l 6), wherein R is hydrogen.

[0124] (19) A method of making a polymer with a cross-linked network, the method comprising: i) forming a monomer mixture comprising: a) one or more monomers of Formula I:

Formula I b) one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or

Formula lllb:

Formula Ilia and/or Formula lllb and c) one or more monomers of Formula IVa and/or Formula IVb:

Formula IVb wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5-

O. S ₂ membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula ; and each instance of Si, S2, and S3 independently is hydrogen or methyl; and ii) providing a free radical initiator to polymerize the monomer mixture.

[0125] (20) The method of embodiment (19), wherein the monomer mixture comprises about

60 wt.% to about 95 wt.% of the one or more monomers of Formula I, about 1 wt.% to about 40 wt.% of the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb, and about 1 wt.% to about 25 wt.% of the one or more monomers of Formula IVa and/or Formula IVb.

[0126] (21) The method of embodiment (19), wherein the monomer mixture comprises about

75 wt.% to about 90 wt.% (e.g., about 80 wt.% to about 90 wt.%) of the one or more monomers of Formula I, about 5 wt.% to about 15 wt.% (e.g., about 5 wt.% to about 10 wt.%) of the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb, and about 1 wt.% to about 10 wt.% (e.g., about 1 wt.% to about 8 wt.% or about 1 wt.% to about 6 wt.%) of the one or more monomers of Formula IVa and/or Formula IVb.

[0127] (22) The method of any one of embodiments (19)-(21), wherein the iodinated 5- membered or 6-membered aryl or heteroaryl comprises at least two iodine atoms.

[0128] (23) The method of any one of embodiments (19)-(22), wherein the iodinated 5- membered or 6-membered aryl or heteroaryl comprises at least three iodine atoms.

[0129] (24) The method of any one of embodiments (19)-(23), wherein the iodinated 5- membered or 6-membered aryl or heteroaryl is an iodinated G aryl. [0130] (25) The method of embodiment (24), wherein the iodinated Ce aryl is of formula:

[0131] (26) The method of any one of embodiment (19)-(25), wherein the polymer has a glass transition temperature of 0 °C to 50 °C.

[0132] (27) The method of any one of embodiment (19)-(26), wherein the polymer has a glass transition temperature of 15 °C to 35 °C.

[0133] (28) The method of any one of embodiments (19)-(27), wherein the method further comprises a curing step following step ii), wherein the curing temperature is from 50 °C to 150 °C and the curing time is from 5 seconds to 5 hours.

[0134] (29) The method of any one of embodiments (19)-(28), wherein the initiator is a photoinitiator.

[0135] (30) The method of any one of embodiments (19)-(28), wherein the initiator is a thermal initiator.

[0136] (31) The method of any one of embodiments (19)-(30), wherein m is 8, 9, 10, 11, or

12

[0137] (32) The method of embodiment (31, wherein m is 10.

[0138] (33) The method of any one of embodiments (19)-(32), wherein the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb is a monomer of Formula Ila or Formula lib.

[0139] (34) The method of any one of embodiments (19)-(32), wherein the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb is a monomer of Formula Ilia or Formula Illb.

[0140] (35) The method of any one of embodiments (19)-(32), wherein the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb are monomers of Formula Ila and Formula Ilia.

[0141] (36) The method of any one of embodiments (19)-(35), wherein the one or more monomers of Formula IVa and/or Formula IVb is a monomer of Formula IVa.

[0142] (37) The method of any one of embodiments (19)-(35), wherein the one or more monomers of Formula IVa and/or Formula IVb is a monomer of Formula IVb. [0143] (38) The method of any one of embodiments (34)-(37), wherein R is of the formula

[0144] (39) The method of any one of embodiments (34)-(37), wherein R is hydrogen.

[0145] (40) A radiopaque polymer device for medical applications, the device comprising a polymer according to any of embodiments (l)-(l 8).

[0146] (41) The radiopaque polymer device of embodiment (40), wherein the device is non- metallic.

[0147] (42) The device of embodiment (40) or embodiment (41), wherein the concentration of iodine in the radiopaque polymer is at least 500 mg/mL.

[0148] (43) The device of any one of embodiments (40)-(42) for a medical application involving exposure to an aqueous body fluid, wherein the device's propensity for water uptake is less than 1.0% by weight over a 24 hour period.

[0149] (44) The device of any one of embodiments (40)-(43), wherein the polymer is a shape memory polymer having a deployment modulus between 10 MPa and 200 MPa at 37°C.

[0150] (45) The device of any one of embodiments (40)-(44), wherein the polymer exhibits a glass transition temperature (Tg) and a Tan Delta (Loss Modulus/Storage Modulus ratio) curve related to temperature; the polymer's maximum rate of shape change occurs at an environmental operating temperature (To) that is coincident with a temperature at or above a rubbery plateau Tan Delta value.

[0151] (46) The device of any one of embodiments (40)-(45) for purposes of an indwelling, permanent implant to provide the function of: a. opening, or maintaining an open anatomical lumen; b. closing an anatomical lumen, either partially as a valve, or complete lumen occlusion for any physiological fluid or gas flow or for a applied therapeutic fluid or gas flow; c. support of an anatomical structure to assist in therapeutic restoration of an organ, vascular, digestive, excrement, or airway function; d. support of an anatomical structure to assist in therapeutic restoration of an orthopedic, maxiofacial, spinal, joint or other skeletal or function; or e. to support hemostasis by covering an area after tissue dissection or resection, a patch, such as for hemostasis of the liver or other organ.

[0152] (47) The device of any one of embodiments (40)-(46) for purposes of a diagnostic or therapeutic instrument or device to provide the function of: a. a catheter for the purposes of accessing an anatomical location; delivering another device and/or therapeutic agent; or controlling the access or delivery of another device and/or therapeutic agent; or b. a temporarily indwelling device to provide a limited time therapeutic benefit, such as a vena cava filter that is placed in a vessel, left indwelling for a period of time, for example to capture blood clots, and subsequently removed when the therapeutic period is completed.

[0153] (48) A cross-linked polymer network formed from a monomer mixture comprising: a) one or more monomers of Formula I:

Formula I b) one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula

Illb:

Formula Ilia and/or Formula Illb and c) one or more monomers of Formula IVa and/or Formula IVb:

Formula IVb wherein each instance of m independently is an integer from 8 to 16; each instance of n independently is an integer from 2 to 22; each instance of pi independently is an integer from 2 to 22; each instance of p2 independently is an integer from 1 to 50; Ar is an iodinated 5- membered or 6-membered aryl or heteroaryl; R is hydrogen or of the formula ; and each instance of Si, S2, and S3 independently is hydrogen or methyl, wherein the monomer mixture comprises about 60 wt.% to about 95 wt.% of the one or more monomers of Formula I, about 1 wt.% to about 40 wt.% of the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb, and about 1 wt.% to about 25 wt.% of the one or more monomers of Formula IVa and/or Formula IVb.

[0154] (49) The cross-linked polymer network of embodiment (44), wherein the monomer mixture comprises about 75 wt.% to about 90 wt.% (e.g., about 80 wt.% to about 90 wt.%) of the one or more monomers of Formula I, about 5 wt.% to about 15 wt.% (e.g., about 5 wt.% to about 10 wt.%) of the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb, and about 1 wt.% to about 10 wt.% (e.g., about 1 wt.% to about 8 wt.% or about 1 wt.% to about 6 wt.%) of the one or more monomers of Formula IVa and/or Formula IVb.

[0155] (50) The cross-linked polymer network of embodiment (48) or embodiment (49), wherein the iodinated 5-membered or 6-membered aryl or heteroaryl comprises at least two iodine atoms.

[0156] (51) The cross-linked polymer network of any one of embodiments (48)-(50), wherein the iodinated 5-membered or 6-membered aryl or heteroaryl comprises at least three iodine atoms.

[0157] (52) The cross-linked polymer network of any one of embodiments (48)-(51), wherein the iodinated 5-membered or 6-membered aryl or heteroaryl is an iodinated G aryl. [0158] (53) The cross-linked polymer network of embodiment (52), wherein the iodinated Ce aryl is of formula:

[0159] (54) The cross4inked polymer network of any one of embodiment (48)-(53), wherein the polymer has a glass transition temperature of 0 °C to 50 °C.

[0160] (55) The cross-linked polymer network of any one of embodiment (48)-(54), wherein the polymer has a glass transition temperature of 15 °C to 35 °C.

[0161] (56) The cross-linked polymer network of any one of embodiments (48)-(55), wherein the monomer mixture further comprises a photoinitiator.

[0162] (57) The cross-linked polymer network of any one of embodiments (48)-(56), wherein m is 8, 9, 10, 11, or 12.

[0163] (58) The cross-linked polymer network of embodiment (57), wherein m is 10.

[0164] (59) The cross-linked polymer network of any one of embodiments (48)-(58), wherein the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb is a monomer of Formula Ila or Formula lib.

[0165] (60) The cross-linked polymer network of any one of embodiments (48)-(58), wherein the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb is a monomer of Formula Ilia or Formula Illb.

[0166] (61) The cross-linked polymer network of any one of embodiments (48)-(58), wherein the one or more monomers of Formula Ila, Formula lib, Formula Ilia, and/or Formula Illb are monomers of Formula Ila and Formula Ilia.

[0167] (62) The cross-linked polymer network of any one of embodiments (48)-(61), wherein the one or more monomers of Formula IVa and/or Formula IVb is a monomer of Formula IVa. [0168] (63) The cross-linked polymer network of any one of embodiments (48)-(61), wherein the one or more monomers of Formula IVa and/or Formula IVb is a monomer of Formula IVb. [0169] (64) The cross-linked polymer network of any one of embodiments (60)-(63), wherein

R is of the formula .

[0170] (65) The cross-linked polymer network of any one of embodiments (60)-(63), wherein

R is hydrogen. [0171] (66) A composition comprising the polymer of any one of embodiments (l)-(l 8).

[0172] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLE 1

[0173] This example describes an exemplary radiopaque polymer device. Shape memory polymer devices and other non-shape memory polymer devices of the invention can incorporate material formulations that utilize a suitable glass transition temperature within a range about body core temperature. To achieve different performance requirements, the polymer’s T may be intentionally suppressed below body temperature resulting in shape change occurrence immediately upon release from any physical constriction.

[0174] In one embodiment, an SMP with a T _g of 32 °C has been utilized to accelerate the rate of shape change of an embolic coil upon expulsion from a small lumen catheter. One form of embolic devices forms a large curl of 10mm in diameter but is constructed of an SMP wire that is only 0.032” in diameter. The wire can be formed into a pre-deployed curled shape that is straightened to allow delivery of these devices in a small diameter catheter (<5fr). When deployed into the blood stream, these devices recovered their curl shape to effectively occlude a 9mm vessel, with the 1mm oversize assuring sufficient radial force from the material modulus and deflection to provide effective anchoring so that the embolic device doesn’t migrate under the influence of blood flow in the vessel. Figures 2A-2B show images embolic coils exit from very thin, single lumen catheters to form an occlusive mass much larger than the diameter of the coil. Figure 2A shows the coil after initial entry. Figure 2B shows the coil after deployment. [0175] Likewise, the polymer’s T may be set above body temperature wherein an external heating device is used to provide the physician with a discretionary shape change function. In another embodiment, an SMP with a T of 50 °C has been used to place and accurately position a tube stent within an anatomical lumen. Maintaining its low profile, predeployed temporary shape benefits the physician’s ability to move and accurately locate the device prior to deployment. When held in the desired position, the device is heated to its T _r by flushing with warmed saline irrigation which causes shape recovery to occur to the stent’s permanent shape.

[0176] Yet, another embodiment is the use of an SMP with an elevated T of 42 °C (just above body core temperature) that is used as a clasp for retaining a deployed device. In its permanent shape, the clasp is open, 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 from a different SMP, to a delivery guidewire that contains electrical conductors joined to a heating element adjacent to the clasp. With the SMP clasp closed in its temporary shape (below T ), the device is advanced into the bloodstream. Upon reaching its desired position, the clasp is heated through an external low voltage passing down the conductors and through the heating element. Upon the temperature reaching T _r , the clasp opens to its recovered, permanent shape, releasing the vena cava filter.

[0177] In yet another embodiment, an SMP with an elevated T _g of 42 °C (just above body core temperature) is used within a section of a mono-directional catheter. The catheter section is formed with a permanent curved shape to allow specific direction of the tip of the catheter. As a straight catheter is easier to manipulate into position, the temporary shape is straight but not necessarily stiff. Upon entry into the body, below T , the straight catheter is easily manipulated to a target location wherein it is warmed by an externally heated, internal delivery wire, or by warmed saline solution flushed through the catheter. Upon the material temperature reaching T _r , the catheter section curls, returning to its recovered, permanent shape, providing specific direction for the catheter tip during use. Meanwhile, the curvature is not so stiff as to preclude simply retrieving the catheter after use.

EXAMPLE 2

[0178] This example provides an exemplary synthesis of a monomer of Formula I, 10-(acryloyloxy)decyl 2,3,5-triiodobenzoate, referred to as C10-TIA.

[0179] A 5-L, 4-neck flask fitted with a mechanical stirrer, addition funnel, nitrogen inlet, and a thermowell was charged with 10-bromo-l-decanol (300 g; 1.26 moles) and THF (1.4 L; 19.4 moles). The mixture was stirred under nitrogen. The flask was cooled in an ice bath to an internal temperature of ~5 °C. Triethylamine (220 mL; 1.58 moles) was then added slowly via the addition funnel into the stirred solution. The addition funnel was then charged with a solution of acryloyl chloride (128 mL; 1.58 moles) in THF (200 mL; 2.8 moles). The acryloyl chloride/THF solution was added dropwise into the flask over 2 hours. The resulting white slurry was then warmed to room temperature (~20 °C) and stirred for 2 hours, when 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 onto silica gel and purified via vacuum chromatography. The column fractions containing acrylic acid 10-bromo-decyl ester were analyzed by GC-FID, and all fractions that did not contain 1,10- dibromodecane were combined and concentrated. Then a 5-L, 4-neck flask fitted with a mechanical stirrer, condenser, nitrogen inlet, and a thermowell was charged with the acrylic acid 10-bromo-decyl ester intermediately followed by DMF (1.2 L; 14.2 moles). Then 2,3,5- triiodobenzoic acid (311.9 g; 0.62 moles) and K ₂ CO ₃ (143.7 g; 1.04 moles) were added, and the reaction mixture was heated to 85 °C 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, dried over Na2S04, filtered, and concentrated. The crude product was adsorbed onto silica gel and purified via vacuum chromatography. The combined fractions were concentrated to a solid and then exhaustively dried by bubbling nitrogen gas through the molten CIO-TIA at 63 °C under high-vacuum. The molten C10-TIA was then poured into a glass dish and allowed to solidify before crushing into a consistent solid in a glass mortar and pestle.

EXAMPLE 3

[0180] This example provides an exemplary synthesis of a monomer of Formula Ila, dodecane- 1,12-diyl dimethacrylate, referred to as C12-DMA.

[0181] Dodecanediol (26.85 g) and toluene (300 mL) to a 3-neck flask. The flask was stirred under heat to initiate azeotropic distillation under a nitrogen atmosphere until about 100 mL of distillate was collected was and cooled to 60 °C. The 3-neck flask was charged with triethylamine (14.6 mL) and followed by methacryloyl chloride (8.1 mL). The system was stirred for 60 minutes. The system was extracted with 150 mL of IN HC1, 150 mL of IN sodium bicarbonate, and 150 mL of distilled water. The organic layer was dried with anhydrous magnesium sulfate and filtered. 0.3 g of 1% hydroquinone in acetone was added, then all solvent removed with a rotary evaporator and then by stirring the viscous solution while sparing with nitrogen.

EXAMPLE 4

[0182] This example provides an exemplary synthesis of a polymer with a cross-linked network described herein.

[0183] A 20 mL scintillation vial was charged with C10-TIA and varying amounts of ethane- 1, 2-diyl bis(2 -methylacrylate) (C2-DMA) and 8,17,26-trioxo-7,9,16,18,25,27- hexaoxatritriacontane-l,33-diyl diacrylate such that the sum total weight of monomers is 10 g. The vial was covered and placed in a 125 °C oven for 15 minutes to melt the composition, after which the vial contents were mixed on a vortexer and allowed to cool for 5 minutes. Then Luperox P® initiator (50 pL) was added to the molten mixture and the mixture was vortexed to dissolve the composition completely. The molten composition was sparged with argon for 15 minutes at 50 °C prior to injection into a suitable mold and cure at 125 °C for 2-3 hours. The resulting polymers with varying fractions of C2-DMA and 8,17,26-trioxo-7,9,16,18,25,27- hexaoxatritriacontane-l,33-diyl diacrylate were tested for their iso-37 °C Tan Delta, Tg temperature, and iso-37 °C modulus, and the results are set forth in Figures 3-5.

[0184] As is apparent from Figures 4 and 5, Tg temperature and iso-37 °C modulus increases as the weight percentage of C2-DMA increases.

EXAMPLE 5

[0185] This example provides an exemplary list of polymer compositions described herein. Polymers A-I were prepared, using the general procedure set forth in Example 4, from Polymer Compositions A-I as set forth in Table 1.

Table 1. Polymer Compositions A-I

[0186] Table 2, shown below, provides the Tg (°C), Iso-37 °C Modulus (MPa), and Iso-37 °C Tan Delta for Polymers A-I. The modulus value assists in deployment of devices that must traverse the length of a catheter without buckling, yet the Tg is kept at or below in-vivo temperature to minimize stiffness and maintain flexibility when implanted, so that post deployment shape recovery is possible. In the polymers shown in Table 2, these mechanical property features can be achieved in configurations that are sufficiently radiopaque at device thicknesses of 0.016” and smaller. For example, these mechanical property features can be achieved in configurations that are sufficiently radiopaque at device thicknesses as small as 0.010” or smaller. Table 2. Polymers A-I Properties

[0187] In addition, Polymers E and I were transformed into coils having a coil size diameter of 0.016 inches, and were analyzed for their mechanical durability using a 0.034 inch tubing diameter. The polymer wires were repeatedly bent to 180° until the wires fractured. The average number of folds necessary to reach this limit was 39.5 for Polymer E and 33 for Polymer I, demonstrating good mechanical durability.

[0188] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. [0189] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) 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.

[0190] When a compound or composition is claimed, it should 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 a Markush group or other grouping is used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure. [0191] In the moieties and groups described herein, it is understood that the valence form of the group that is required to fulfill its purpose in the description or structure is included, even if not specifically listed. For example, a group that is technically a “closed shell” group as listed or described can be used as a substituent in a structure, as used herein. For every closed shell moiety or group, it is understood that a group corresponding to a non-closed structural moiety is included, for use in a structure or formula disclosed herein.

[0192] Every formulation or combination of components described or exemplified can be used to practice the invention, unless otherwise stated. Specific names of compounds are intended to be exemplary, as it is known that one of ordinary skill in the art can name the same compounds differently. When a compound is described herein such that a particular isomer or enantiomer of the compound is not specified, for example, in a formula or in a chemical name, that description is intended to include each isomers and enantiomer of the compound described individual or in any combination. One of ordinary skill in the art will appreciate that methods, device elements, starting materials, and synthetic methods, and other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such methods, device elements, starting materials, and synthetic methods are intended to be included in this invention. 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 ranges given are intended to be included in the disclosure. [0193] 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.

[0194] 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.