Radiopaque thermoplastic polymer

Abstract

To provide a polymer composition comprising a thermoplastic polymer configured to (a) be bonded to iodine, (b) include a vinyl group, and (c) include urethane linkages.SOLUTION: The invention includes a method comprising: providing a triiodobenzene monomer; providing an aliphatic monomer comprising at least one of (a)(i) multiple amine functional groups, (a)(ii) multiple alcohol functional groups, and (a)(iii) multiple carboxylic acid functional groups; providing a diisocyanate; mixing the triiodobenzene monomer, the aliphatic monomer and the diisocyanate into a solution; forming a thermoplastic polymer from the solution.SELECTED DRAWING: Figure 36

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 579,124, filed October 30, 2017, entitled "Thermoplastic Polymer Systems for Medical Devices," the contents of which are incorporated herein by reference. Technical Field

[0002] FIELD OF THE INVENTION Embodiments of the present invention are in the field of shape memory polymer medical devices. [Background technology]

[0002]

[0003] Approximately 3-4% of asymptomatic healthy individuals have unruptured cranial aneurysms. Aneurysm rupture can lead to subarachnoid hemorrhage, stroke, subsequent brain damage, and death. Stroke is the second leading cause of death worldwide, and efficient embolization of cerebral aneurysms is needed to prevent rupture and reduce the morbidity and mortality of hemorrhagic stroke. Current treatments utilize minimally invasive embolic coils to fill the aneurysm and block blood flow, but these devices only partially occlude the aneurysm, limiting recanalization. Thermally activated shape-memory polymer (SMP) embolic foams offer promising options for treating cerebral aneurysms due to their high volumetric expansion capacity and excellent biocompatibility. Summary of the Invention

[0003]

[0004] Features and advantages of embodiments of the present invention will become apparent from the appended claims, the following detailed description of one or more exemplary embodiments, and the corresponding figures. Where appropriate, reference labels are shown in the figures to indicate corresponding or similar elements. [Brief explanation of the drawings]

[0004] [Figure 1]

[0005] The left photograph shows a digital subtraction angiogram of an untreated porcine sidewall aneurysm model, and the middle photograph shows an aneurysm model treated with bare platinum coils. The inflow of injected contrast is masked by the two-dimensional coil projection. The right photograph shows an angiographic image of an aneurysm treated with SMP foam-coated embolic coils. The embolic foam and thrombus prevent the injected contrast from entering the aneurysm. [Figure 2]

[0006] 10 illustrates monomers of a material system including different combinations of system materials in alternative embodiments. [Figure 3]

[0007] Photograph showing a medium density foam made with HDI, 15 / 35 / 50% molar equivalents of ATIPA / BEP / DEG, respectively, and a polyurethane foaming surfactant and catalyst. The x-ray image lacks a tissue analog to simulate imaging through the human skull. [Figure 4]

[0008] 1 shows the glass transition temperature (Tg) of the olefins tuned by varying the ATIPA molar ratio from 20 to 30% and the TEG / DEG ratio from 40 to 50%. All compositions used 100% HDI, with the other polyol equivalent being BEP. [Figure 5]

[0009] 1 is a table showing foam acceptance criteria. [Figure 6]

[0010] Photograph of a 2.5 mm foam device and GDC platinum coil imaged through a pig skull. Iohexol was solvent swollen into the foam with 10-40 wt% ethanol solutions. Physical incorporation of iohexol resulted in undesirable mechanical properties (although in some embodiments it can be used instead of or in addition to chemical incorporation). [Figure 7]

[0011] FIG. 1 is a schematic showing an alternative solvent-based synthesis strategy that alleviates potential monomer miscibility concerns. [Figure 8]

[0012] Photographs showing a phase-separated cloudy foam containing 20 equivalent percent ATIPA synthesized using a tertiary amine blow catalyst (A), and an optically clear foam containing 30 equivalent percent ATIPA synthesized without a conventional blowing catalyst (B). [Figure 9]

[0013] 1 is a table showing embodiments of ATIPA foam compositions, where monomers are listed in mole %. [Figure 10]

[0014] 1 shows an overview of the ATIPA foaming process in one embodiment. [Figure 11]

[0015] 1 is a table showing physical and thermodynamic ATIPA foaming properties for various embodiments. [Figure 12]

[0016] 5A and 5B are photomicrographs at 50x and 100x magnification of ATIPA foams with different volumes of physical blowing agent (Enovate®). [Figure 13]

[0017] 5A and 5B are photomicrographs at 50x and 100x magnification of foams with 20 equivalent percent ATIPA and varying hexanetriol composition. [Figure 14]

[0018] 1 shows microscopic images of foams with different ATIPA contents at 50x and 100x magnification. [Figure 15]

[0019] 50x microscope images of a series of ATIPA foams with different isocyanate compositions. [Figure 16]

[0020] (a) Representative stress-strain curves for X-ray visible foams (ATIPA and tungsten loaded foams and non-visible control foams), and (b) a table showing the calculated mechanical properties from each curve. [Figure 17]

[0021] The imaging frame includes foam samples with different thicknesses and different ATIPA contents, a platinum embolic coil (GDC10) and catheter segment for radiodensity reference, and a prototype 8 mm diameter foam cylinder device in the expanded and crimped states. The samples were imaged with a camera, non-compression angiography, and angiography through a 1 / 2" aluminum human skull analog. [Figure 18]

[0022] An imaging frame containing 20% ​​equivalent ATIPA foam samples of varying density and thickness, a platinum embolic coil (GDC10) for radiodensity reference, and a prototype 2 mm diameter foam cylinder device in an expanded and crimped state. The samples were imaged with a camera, non-compression angiography, and angiography through a 1 / 2" aluminum human skull analog. [Figure 19]

[0023] 1 is a dry DSC thermogram showing minimal change in dry Tg of foams of different densities with varying volumes of physical blowing agent (Enovate®). [Figure 20]

[0024] 10 shows the dry and wet plasticized DSC thermograms of 20 eq. % ATIPA foams with different HT contents. [Figure 21]

[0025] 1 is a thermogram of dry and wet plasticized 20 equivalent weight % ATIPA foams with different isocyanate contents. [Figure 22]

[0026] 1 shows thermograms of dried foams with different ATIPA contents. [Figure 23]

[0027] 10 is a tangent delta plot from compression DMA of dry 20 eq. % ATIPA foams with different HT compositions. [Figure 24]

[0028] 10 is a tangent delta plot of compression DMA of dry foams with varying ATIPA composition. [Figure 25]

[0029] On the left is the unrestrained expansion profile of a 2mm diameter foam compressed with a 0.006" wire and submerged in 37°C water, and on the right is a snapshot of the foam after 25 minutes of immersion. [Figure 26]

[0030] 1 shows ATR FTIR spectra of 20AT foams with increasing HT content. [Figure 27]

[0031] Figure 1 shows ATR FTIR spectra of 20AT foams with increasing TMHDI content, with the spectrum of the non-visible 100TM H60 control foam included for comparison. [Figure 28]

[0032] 1 shows ATR FTIR spectra of foams with increasing ATIPA content at a fixed theoretical crosslink density. [Figure 29]

[0033] 1 is a table of TPU property-tuning monomers used in various embodiments. [Figure 30]

[0034] 1 shows a synthetic scheme for the formation of linear TPUs with pendant vinyl groups. [Figure 31]

[0035] 1 shows various iodobenzenes used in various embodiments. [Figure 32]

[0036] A shows the modification of amine groups on ATIPA for incorporation into TPU, and B shows the functionalization of ATIPA with allyl isocyanate. [Figure 33]

[0037] FIG. 1 is a schematic diagram illustrating an embodiment of a process involving functionalization of a radioactive monomer and subsequent material processing. [Figure 34]

[0038] FIG. 1 illustrates embodiments of monomers that can be used to functionalize radiopaque monomers. [Figure 35]

[0039] 1 shows ATR FTIR spectra showing the difference between ATIPA before and after functionalization with IEMA. The top spectrum is for ATIPA + IEMA in THF, and the bottom spectrum is for ATIPA in THF. [Figure 36]

[0040] FIG. 1 illustrates a process for forming a TPU in one embodiment. [Figure 37]

[0041] FIG. 1 shows a cross-linked TPU in an embodiment. [Figure 38]

[0042] ATR FTIR spectra showing the difference between the control and ATIPA TPU compositions. Significant peaks are labeled and the difference in the amine stretch peak ratio is circled. The top spectrum is for the ATIPA TPU, and the bottom spectrum is for the TPU control. [Figure 39]

[0043] FIG. 2 is a diagram showing electron beam (electron beam) crosslinking in an embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0005]

[0044] The terms "one embodiment," "various embodiments," etc. may include a particular feature, structure, or characteristic, but not all embodiments necessarily include the particular feature, structure, or characteristic. Some embodiments may have some, all, or none of the features described in other embodiments. "First," "second," "third," etc. indicate that different examples of similarity are being referenced, although they share a commonality. Adjectives described in this manner should be presented in a predetermined order, temporally, spatially, ranked, or otherwise.

[0006]

[0045] The inventors have discovered that proper SMP-based device placement can be achieved by visualizing the material using conventional fluoroscopic techniques, as lack of device visualization limits the application of this extremely valuable material system in treating cerebral aneurysms.

[0007]

[0046] Various embodiments are discussed below. Some embodiments are first discussed in an "Overview of Embodiments." Some embodiments are discussed in a "High-Level Embodiments" and a "More Detailed Embodiments."

[0008]

[0047] Overview of the embodiment

[0048] Some embodiments include an X-ray visible SMP foam system for endovascular embolization devices and other implantable tissue scaffolds. One embodiment includes a thermosetting biomemory shape-memory polyurethane foam system incorporating a contrast agent as a monomer. Using fluoroscopic techniques, the foam is implanted into the desired biological structure, where it expands and fills volumetrically within the tissue, promoting embolization and subsequent cellular infiltration and healing. X-ray visualization of the SMP allows physicians to observe true volume filling as the foam expands. This allows for proper device placement, reduces the risk of tissue overfill, and improves procedural safety.

[0009]

[0049] Some embodiments provide a foam-only endovascular embolic device that eliminates the need for metal components, such as platinum backbone coils, for fluoroscopic visualization. This allows for more foam to be incorporated into the device cross-section, potentially resulting in better volumetric filling for delivery through a comparable catheter size. In some embodiments, clinicians can directly visualize the actual device expansion and tissue filling, overcoming the limitations of current embolic foam devices. The porosity of this material results in better healing outcomes and durable emboli.

[0010]

[0050] X-ray visualization is facilitated by including the vascular contrast agent as a monomer in the polymer synthesis and chemically incorporating a radioactive dense triiodobenzene motif into the polymer network, which is visualized by fluoroscopy due to three covalently bound iodine atoms.

[0011]

[0051] Some such embodiments may provide safer treatment of intracranial aneurysms, resulting in improved clinical efficacy, although some embodiments are also suitable for other endovascular embolization applications (e.g., filling of the left atrial appendage, embolization of abdominal aortic aneurysms, peripheral vascular embolization, and more generally, perivascular void filling around tissues and / or medical devices).

[0012]

[0052] Compared to particulate additives, the chemical approach of incorporating triiodobenzene monomers into materials during synthesis does not affect the mechanical integrity of the bulk material and may increase contrast loading ratios. This radioactive SMP material system can be used to create low-density foams for embolization, eliminating the need for metal components such as platinum backbones or marker bands. This material system allows for the creation of fully polymeric, biodurable embolization devices for a variety of applications, including cerebrovascular or peripheral embolization. The incorporation of aromatic diisocyanates provides an extremely rigid polymer system for bone tissue applications requiring X-ray visualization. In some embodiments, degradable conjugates, such as ethers, esters, or tertiary amines, are incorporated to create biodegradable material formulations.

[0013]

[0053] These materials can be made, for example, by combining (a) 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), diethylene glycol (DEG), triethylene glycol (TEG), 2-butyl-2-ethylpropanediol (BEP), 3-methylpentanediol, butanetriol, and hexanetriol with (b) a diisocyanate (e.g., hexamethylene diisocyanate (HDI) or trimethylhexamethylene diisocyanate (TMHDI)). Alternative compositions incorporate other iodine-containing monomers, such as iohexol, triiodophenol, or diatrizoic acid (instead of ATIPA). Alternative compositions also incorporate other polyols, such as glycerol, trimethylolpropane, pentaerythritol, pentanediol, 3-methyl-1,3,5-pentanetriol, and cyanuric acid. Alternative compositions also include multifunctional crosslinkers with terminal hydroxyl, amine, or carboxylic acid end groups, such as 1,3-diamino-2-propanol, aspartic acid, 1,2-diaminopropane, 2,2-dimethyl-1,3-propanediamine, 1,8-diaminooctane, 3-amino-1,2-propanediol, or 2-amino-2-methyl-1,3-propanediol.

[0014]

[0054] In some embodiments, ATIPA functions as a contrast agent and a foaming agent in a foaming reaction. Foams are synthesized with the addition of surfactants, tin gelling catalysts, tertiary amine blowing catalysts, and physical foaming agents such as Enovate®. Nanoparticle or microparticle additives containing platinum, tungsten, or tantalum can be added to the material during synthesis to create other X-ray attenuating composites.

[0015]

[0055] After synthesis, the material is cut, cleaned, processed and incorporated into a medical device.

[0016]

[0056] High Level Implementation

[0057] A-Specific Objectives:

[0058] Some embodiments include an X-ray visible SMP embolic foam material system for the treatment of cerebral aneurysms. In one embodiment, X-ray imaging can be achieved through the incorporation of radioactive iodine atoms into the polymer network. This chemical approach can broaden the application of SMP embolic foams by addressing the limitations of non-visible formulations. The incorporation of a triiodobenzene-based contrast agent as a monomer into a shape-memory polyurethane backbone can result in a radioactive polyurea amide. This contrast agent monomer provides X-ray visibility and functions as both a foaming agent during foaming and a chemical crosslinker that creates shape memory.

[0017]

[0059] In one embodiment, the amount of radiographic contrast, thermodynamic properties, and foam morphology can be controlled. The degree of radiographic contrast is controlled by the amount of contrast agent monomer present during synthesis. Different ratios of diisocyanate to polyol during polyurethane synthesis alter thermomechanical properties. Foam morphology, such as pore size and density, can be tailored by varying the viscosity of the foam premix and by varying the amount of physical blowing agent, surfactant, or catalyst during synthesis. This ability to independently control material properties enhances the utility of radiographically visible embolization foams by enabling device optimization to meet specific application needs.

[0018]

[0060] The following relates to the usefulness of material systems.

[0061] Item 1: X-ray visible SMP formulations with different contrast agents, polyols, and diisocyanate monomer formulations are chemically and thermomechanically characterized.

[0062] Item 2: Adjust foaming parameters to achieve foam density, mechanical properties, and volumetric recovery suitable for neurovascular embolization.

[0063] Objective 3: Validate the fluoroscopic visibility of the embolic foam device prototype delivered to a living aneurysm model.

[0019]

[0064] B-Significance

[0065] The traditional gold standard for preventing hemorrhagic stroke is the treatment of cranial aneurysms with bare platinum coils (BPCs). Although BPCs have reduced the number of hemorrhagic strokes in the United States by approximately 103,000 per year, this treatment still has clinical limitations. For example, even at packing densities (30–35%) that are considered very high by clinical standards, embolization is incomplete. Increasing packing density by increasing the number of coils can lead to overfilling and aneurysm rupture. Furthermore, even with initially effective embolization, recanalization rates are as high as 35% and 50% for large and giant aneurysms, respectively. The number of coils required, the procedure time, and complexity of BPCs make them cost-prohibitive for filling aortic aneurysms. Therefore, the effectiveness and cost limitations of BPCs are desirable as a solution for more efficient volumetric filling.

[0020]

[0066] Hydrocoils have been developed to increase volumetric aneurysm filling for comparable coil lengths. After implantation, the hydrophilic coating on the coil swells with water, effectively increasing the coil diameter. The packing density of Hydrocoils is consistently greater than 50% and can be three times that of BPCs. Despite the increased packing density, studies have not shown a clear advantage of Hydrocoils in preventing aneurysm recurrence, and the costs associated with the hydrophilic coating are not justified.

[0021]

[0067] Low-density SMP embolic foams have been proposed as a solution to alleviate many of the drawbacks associated with conventional embolic therapy. Low-density SMP foams can be compressed to a fraction of their expanded volume, enabling delivery via a microcatheter. After implantation, the compressed foam can be restored to its original expanded shape by application of heat or other stimuli. The volumetric expansion capacity and biocompatibility of SMP foams make them excellent for filling aneurysmal lesions and a promising solution for improving healing. Therefore, we demonstrated the biocompatibility of SMP foams implanted in a porcine carotid aneurysm model. Pathological examination showed that polyurethane SMP foams exhibited superior healing potential compared with BPC implants. However, conventional SMP formulations are not visualized by X-ray, potentially limiting their effective delivery in clinical settings.

[0022]

[0068] Many medical applications of SMP involve intravascular delivery under fluoroscopic imaging. Fluoroscopic visualization is essential for proper and safe placement of the device within the aneurysmal tissue. The lack of radiographic contrast of SMP during cerebral aneurysm embolization can be partially addressed by using SMP coated on radial BPC. Figure 1 highlights the limitations of this approach. The left frame shows typical anatomy of a porcine sidewall aneurysm model. The middle frame shows a digital subtraction angiogram of an aneurysm treated with conventional BPC, demonstrating a dense 2D projection of the coil mass, which clinicians use as a primary indicator of coil adequacy. Although the aneurysm appears densely coiled, the average packing density of the embolic coils ranges from 30 to 35%. The right frame shows an aneurysm treated with SMP foam-coated embolic coils. While the aneurysm appears loosely packed on radiographs, the interstitial spaces between the coils are filled with embolic foam and thrombus mass, which are not visible on radiographs due to the limited injected contrast. The use of injected contrast as a primary indicator of aneurysm embolization deviates from standard two-dimensional x-ray imaging projections, creating a barrier to clinical application of the device. This procedural modification could result in the foam-coated coil being overfilled by the aneurysm. However, some embodiments may reduce the risk of this complication by allowing the clinician to more clearly observe the true volume embolization.

[0023]

[0069] C-Innovation:

[0070] In some embodiments, a mass density of 0.015 gcm -3 These include ultra-low-density SMP foams with a high crosslinking density that can achieve 97% shape recovery. These properties allow for a 70-fold volume expansion of the foam. When used in conjunction with conventional coiling techniques, these low-density SMP foams can significantly reduce the number of coils required to fill an aneurysm, potentially reducing procedure time and costs. Furthermore, the expansion force of SMP foams is significantly less than the applied force of BPCs, potentially reducing the risk of aneurysm detachment during implantation. Similar to other coil-based embolization devices, embolization foams disrupt blood flow and induce thrombus formation within the foam, resulting in occlusion of the aneurysm.

[0024]

[0071] Traditionally, the radiographic visualization of SMP foams has been enhanced by incorporating tungsten microparticles into the foam matrix. However, this approach reduces the toughness of the composite, raising concerns about in vivo microparticle generation and subsequent embolization in the bloodstream. Furthermore, the degree of opacification achieved by microparticle incorporation is insufficient for small-diameter, low-density devices for neurovascular embolization. To address the reduced toughness of the material by improving dispersion within the matrix, radiopaque nanoparticle additives were tested. While low concentrations of nanoparticles improved mechanical strength and toughness, increasing the filler to the loading level required for adequate radiographic visualization resulted in a decrease in mechanical properties. Therefore, there is a need to improve the radiographic contrast of SMPs without compromising their mechanical integrity.

[0025]

[0072] In some embodiments, as an alternative to opaque SMP micro- or nanocomposites, iodine motifs are incorporated into the polymer matrix to enhance X-ray visualization without affecting the bulk foam properties. Compared to particulate additives, this chemical approach of incorporating triiodobenzene monomers into the material during synthesis does not affect the mechanical integrity of the bulk material and may enhance contrast loading. This radioactive SMP material system provides an embolic material system comprising a low-density foam that does not require metal components such as a platinum backbone or marker bands. This material system may enable fully (or nearly fully) polymeric, degradable embolic devices for a variety of applications, including cerebrovascular or peripheral embolization. While this invention focuses on the incorporation of iodine into a specific SMP foam system, some embodiments are applicable to a variety of polymeric biomaterials, allowing for their imaging upon implantation.

[0026]

[0073] D - Approach:

[0074] In one embodiment, the imaging agent identified for SMP polymerization is 5-amino-2,4,6-triiodoisophthalic acid (ATIPA). As shown in Figures 2(a) and 2(b), the X-ray imaging of the ATIPA molecule is derived from a triiodobenzene motif containing three high-z iodine atoms. The ATIPA molecule's X-ray imaging is based on a triiodobenzene motif with three high-z iodine atoms, terminated with a primary aromatic amine and two carboxylic acids, providing three functional groups for crosslinking reactions with isocyanates. Furthermore, the reaction of the isocyanate with the carboxylic acid yields an amide bond and carbon dioxide, making ATIPA a chemical blowing agent for foam polymerization.

[0027]

[0075] Figure 2(a) also lists various diisocyanates and polyols selected for their favorable solubility and ability to control the Tg and crosslink density of the resulting SMP foam. Diisocyanates include hexamethylene diisocyanate (HDI) and trimethylhexamethylene diisocyanate (TMHDI). Polyols include N,N,N,N',N'-tetrakishydroxypropylethylenediamine (HPED), triethylene glycol (TEG), diethylene glycol (DEG), and 2-butyl-2-ethyl-1,3-propanediol (BEP). Several polymer foams were synthesized by varying the molar equivalent ratio of these components, and the effects on morphological and thermodynamic properties were quantified.

[0028]

[0076] D.0 - Data

[0077] A major barrier to polymerizing ATIPA is its limited solubility with other monomers, especially diisocyanates. We have successfully polymerized various compositions using ATIPA, DEG, BEP, and HDI to obtain polymeric foams, as shown in Figure 3. The foams were blown by reacting ATIPA (15% molar equivalent), dicarboxylic acid, and diisocyanate, and then X-ray imaged at 133 mgI / ml. Foam density and pore size were controlled by varying the hydroxyl equivalent ratio of the prepolymer and changing the premix viscosity.

[0029]

[0078] D.1 -Item 1: Chemically and thermomechanically characterize X-ray visible SMP formulations made with varying contrast agent, polyol, and diisocyanate monomer formulations.

[0079] In some embodiments, polymer samples are prepared by modifying ATIPA with 20-30 mol% of the non-isocyanate component. The goal is to characterize the bulk material, and the sample is tested in its natural state, regardless of density. When using ATIPA as the monomer, 20-30 mol% yields approximately 175-275 mgI / ml of iodine. This iodine loading density is comparable to conventional angiography injection concentrations, allowing for sufficient material visualization with minimal path length.

[0030]

[0080] Figure 4 shows differential scanning calorimetry (DSC) thermograms of two high-density SMP foam systems incorporating varying concentrations of ATIPA using different hydroxyl monomer compositions (40-50 mol% TEG or DEG) to tune the Tg between 30 and 55°C. This data set demonstrates that some embodiment monomer combinations can be used to synthesize materials with transitions relevant to body temperature actuation. Additional monomer combinations can provide tighter control over the bulk thermodynamic properties as determined by DSC. In some embodiments, compounds are synthesized to bracket a range of miscible molar equivalent ratios. Other compositions include ATIPA and crosslinkers to provide greater control over material properties, including gel fraction and shape memory strain recovery.

[0031]

[0081] FTIR spectra provide a chemical signature for each composition and authenticate the covalent incorporation of iodine into the polymer network. Gel fraction analysis in tetrahydrofuran confirmed sufficient cross-linking.

[0032]

[0082] D.2 - Item 2: Adjust foaming parameters to achieve foam density, mechanical properties, and volumetric recovery suitable for neurovascular embolization.

[0083] Foam morphology is controlled by varying surfactant concentration, catalyst concentration (amine and tin), prepolymer hydroxyl ratio (viscosity), and physical blowing agent concentration (Enovate® 245fa). All catalysts and surfactants are available from Air Products®. Temperature-dependent premix viscosity profiles can be obtained using a cone and plate viscometer. Scanning electron microscopy can quantify the pore size and morphology of the finished foam. Density is determined by the uniform (1 cm) 3 ) can be measured by gravimetric analysis of the material block. Success criteria for density and pore size may be based on the specifications of the prototype neuroembolization device.

[0033]

[0084] Foam specimens can be cut with a dogbone carbon dioxide laser for uniaxial tensile testing. Ultimate tensile strength, strain to failure, and toughness can be used to determine the functional relationship between foam morphology, composition, and mechanical integrity. The minimum tensile strength threshold of 80 kPa (in some embodiments) is based on the strength of an SMP composition opacified with 7% by volume of nanoparticulate tungsten.

[0034]

[0085] Cyclic free strain recovery and cyclic constrained recovery experiments may be performed under compression on a TA Instruments Q800 Dynamic Mechanical Analyzer® to determine the shape memory capacity of each formulation. These experiments may quantify bulk thermomechanical properties such as glassy modulus, rubbery modulus, and glass transition temperature. They may also quantify the shape fixity, recovery force, and strain recovery of each SMP foam composition. Compositions with higher ATIPA and HPED concentrations exhibit higher shape memory recovery due to their higher crosslink density. Figure 5 summarizes all material characterization techniques for Objectives 1-2 and the acceptance criteria used to select formulations for device prototyping.

[0035]

[0086] D.3-Item 3: Validate fluoroscopic visualization of an embolic foam device prototype delivered to a living aneurysm model.

[0036]

[0087] In some embodiments, delivery is possible through a 0.021" ID microcatheter (thus, in some embodiments, the crimped outer diameter is smaller than the ID of the microcatheter). The device may be delivered under fluoroscopic visualization into an aneurysm phantom with simulated physiological flow at body temperature. For comparison, a competitive 360° GDC-10® bare platinum embolic coil may be delivered into the phantom. The entire delivery procedure may be imaged through a ½" aluminum plate to simulate the opacity of the human skull. The device may also be placed in a planar fixture and imaged through hard and soft porcine tissue. Figure 6 shows an example of a 2.5 mm foam fixture with iohexol physically incorporated into the material via solvent swelling.

[0037]

[0088] D.4 - Some alternative embodiments

[0089] In some embodiments, a solvent-based synthetic approach can be used to improve upon the bulk curing approach (instead of, or in addition to, the covalently bonded iodine-based monomers described above). The contrast agent is designed to be soluble in highly polar solvents, such as water and alcohol, which are unsuitable for polyurethane synthesis. However, ATIPA is soluble in tetrahydrofuran (THF), dimethylformamide (DMF), and dimethyl sulfoxide (DMSO). Figure 7 outlines an alternative synthetic strategy for incorporating solid ATIPA monomer into polyurethane SMP foams. First, the contrast agent is prepolymerized with excess HDI in anhydrous THF solution. This first prepolymerization overcomes solubility issues and allows for the use of multiple polyols to manipulate the Tg and crosslink density of the final material. Furthermore, this process effectively eliminates carbon dioxide generation from the foaming process, allowing for foaming to be controlled depending on the ATIPA content. After prepolymerization, THF is removed from the oligomer solution using rotary evaporation. In some embodiments, the prepolymer solution is mixed with a stoichiometrically equivalent amount of polyol and cured into a neat film. In some embodiments, polymer foams may be synthesized by combining the prepolymer solution with a polyol crosslinker, a surfactant, a polyurethane catalyst, and a physical blowing agent. In some embodiments, an amide catalyst for the carboxylic acid reaction may be used to further optimize the foam.

[0038]

[0090] Iohexol, an alternative to ATIPA, is an FDA-approved vascular contrast agent. The molecule is water-soluble, generally biocompatible, and cleared by the kidney. Iohexol is terminally modified with six hydroxyl functional groups, which promote water solubility and serve as reactive sites for polymerization. Iohexol is soluble in dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

[0039]

[0091] These were chosen as alternative synthesis strategies due to concerns about additional fabrication complexity and residual solvents. Neat polymer films may be chemically characterized using Fourier transform infrared spectroscopy (FTIR) and gel fraction analysis. Each material composition may also be thermomechanically tested using tensile testing, dynamic mechanical analysis (DMA), and differential scanning calorimetry (DSC). Compositions may be down-selected for foaming based on physical glass transition temperature (DSC), ultimate toughness (tensile testing), and rubbery modulus (DMA), similar to the specific proposed objectives.

[0040]

[0092] Thus, some embodiments provide an X-ray visible SMP material system with a flexible structure-property relationship that can be tailored for characterization of neuroembolic devices. Controlling the key material parameters allows several embodiments to be implemented.

[0041]

[0093] More detailed embodiments

[0094] The inventors have found that the mass density is 0.015 gcm -3 We have fabricated an ultra-low-density SMP foam with a high crosslinking density that achieves a low tensile strength and 97% shape recovery. All of these properties allow for a 70-fold volumetric expansion of the foam. When used in conjunction with conventional coiling techniques, this low-density SMP foam can significantly reduce the number of coils required to fill an aneurysm, potentially reducing procedure time and costs. Furthermore, the expansion force of the SMP foam is significantly lower than that of BPC, which reduces the risk of aneurysm dissection during implantation. Similar to other coil-based embolization devices, the embolization foam embolizes aneurysms by obstructing blood flow and inducing thrombus formation within the foam.

[0042]

[0095] Many medical applications of SMP involve intravascular delivery under fluoroscopic imaging. To properly and safely place the device within the aneurysmal tissue, visualization of the device is essential. When SMPs are not radiographically visible in cerebral aneurysm embolization, coating them onto a radial BPC can partially address this issue. Figure 1 highlights the limitations of this approach. The left panel shows the typical anatomy of a porcine sidewall aneurysm model. The center panel shows a digital subtraction angiogram of an aneurysm treated with a conventional BPC, demonstrating a dense 2D projection of the coil mass, which clinicians use as a primary indicator of adequate coiling. Although the aneurysm appears densely coiled, the average sealing density of embolic coils is 30–35%. The right panel shows an aneurysm treated with SMP foam-coated embolic coils. Although aneurysms appear loosely filled on radiographic projections, the limited penetration of injected contrast material demonstrates that the interstitial spaces between the coils are filled with non-radiographically visible embolic foam and thrombus mass. Using injected contrast as a primary indicator of aneurysm embolization deviates from standard two-dimensional radiographic projections, hindering the device's clinical application. This procedural modification could potentially result in overfilling of the aneurysm with foam-coated coils. The proposed radiographically visible SMP formulation aims to reduce the risk of this complication by enabling clinicians to better visualize true volumetric embolization.

[0043]

[0096] Traditionally, the radiographic visualization of SMP foams has been enhanced by incorporating tungsten microparticles into the foam matrix. However, this approach reduces the toughness of the composite, raising concerns about in vivo microparticle generation and subsequent embolization in the bloodstream. Furthermore, the degree of opacification achieved by microparticle incorporation is not sufficient for the small-diameter, low-density devices used in neurovascular embolization. To address the reduced toughness of the material, radiopaque nanoparticle additives were investigated to enhance dispersion within the matrix. While low-concentration nanoparticles improved mechanical strength and toughness, increasing the filler concentration required for adequate radiographic visualization resulted in a decrease in mechanical properties. Therefore, there is a need to improve the radiographic contrast of SMPs without compromising their mechanical integrity.

[0044]

[0097] In particular, bulk loading of tungsten microparticles into SMP embolic foams does not induce sufficient radiographic contrast for neurovascular applications. Furthermore, increasing the microparticle loading rate to improve material contrast compromises mechanical performance, such as reducing fracture toughness and increasing microparticle generation.

[0045]

[0098] In one embodiment, instead of micro- or nano-composition of opaque SMPs, iodine motifs are incorporated into the polymer matrix to enhance X-ray visibility without affecting the bulk foaming properties.

[0046]

[0099] The chemical approach of incorporating triiodobenzene monomers into materials during synthesis may enhance contrast loading ratios without affecting the mechanical integrity of the bulk material compared to particulate additives. This radioactive SMP material system provides an embolic material system that includes a low-density foam without the need for metal components such as platinum backbones or marker bands. The material system provides a fully (or nearly fully) polymeric, degradable embolic device for a variety of applications, including cerebrovascular or peripheral embolization. While this work relates to the incorporation of iodine into specific SMP foam systems, in some embodiments, it may be applied to polymeric biomaterials to achieve imaging during implantation.

[0047]

[0100] Figure 6 shows the X-ray visualization results of combining an X-ray contrast agent with a shape-memory polymer foam. The 2.5 mm diameter foam cylinder was solvent swollen with a solution of iohexol in ethanol and vacuum-dried. The expanded foam was imaged through a pig skull using conventional fluoroscopy. The visibility of the composite was comparable to that of a commercially available GDC10 embolic coil. Physical incorporation of iohexol (although still included instead of or in addition to some chemically incorporated systems) resulted in visible but compromised mechanical properties comparable to ceramic materials, further motivating chemical incorporation.

[0048]

[0101] Figure 2(a) shows the monomers selected for the X-ray visualization SMP system. Aliphatic isocyanates were selected for the polyurethane composition based on their biocompatibility in embolization applications. Additionally, the molar ratio of HDI to TMHDI could be varied to control the hydrophobicity of the material and adjust the expansion rate of the material.

[0049]

[0102] In one embodiment, the contrast agent monomer is 5-amino-2,4,6-triiodoisophthalic acid (ATIPA). The X-ray imaging of the ATIPA molecule comes from a triiodobenzene motif incorporating three high-z iodine atoms. It terminates with a primary aromatic amine and two carboxylic acids, which provide three functional groups upon crosslinking with isocyanates. Furthermore, the reaction of the isocyanates with the carboxylic acids generates an amide bond and carbon dioxide, allowing ATIPA to function as a chemical blowing agent during foam polymerization.

[0050]

[0103] Solubility has been a significant barrier to the development of this system. ATIPA is a hydrophilic solid monomer with zero solubility in isocyanates. While ATIPA is soluble in tetrahydrofuran and dimethyl sulfoxide, a solvent-free synthesis procedure is preferred (at least in some embodiments) to mitigate organic contaminants in end-use medical products. Here, we propose the following solvents, which offer excellent ATIPA solubility and Tg control in the final material: 2-butyl-2-ethyl-propanediol (BEP), 3-methyl-1,5-pentanediol (MPD), diethylene glycol (DEG), triethylene glycol (TEG), 1,2,4-butanetriol (BT), and 1,2,6-hexanetriol (HT).

[0051]

[0104] Figure 8 shows other solubility barriers using this material. While the solubility of the premix resin was good, the final material exhibited significant phase separation. Precipitation of ATIPA was observed, primarily during the addition of the tertiary amine blow catalyst. This precipitation was also observed in the early stages of material development using the polyol crosslinking monomers HPED and TEA. We concluded that tertiary amines cause ATIPA to precipitate from solution and should be avoided in some embodiments, but may be used in others. Even without the catalyst, the reactivity of ATIPA is not significantly adversely affected during foaming of the material.

[0052]

[0105] The following discussion concerns the optimization of systems using HDI, TMHDI, ATIPA, BEP, MPD, and HT. Instead of TEG or DEG, MPD was proposed to mitigate the risk of biocompatibility of degradation products by not incorporating ether linkages that are susceptible to oxidative degradation, creating an aliphatic system that is theoretically more biodurable.

[0053]

[0106] Materials and Methods

[0107] Foam synthesis

[0108] Figure 9 summarizes the foam compositions synthesized in some embodiments. The equivalent weight percentages for Side A of the polyurethane synthesis are calculated based on reactive hydroxyl, amine, and carboxylic acid functional groups. A 2% molar excess of isocyanate was added to each foam synthesis to account for ambient water contamination during foam mixing. HDI, TMHDI, BEP, MPD, ATIPA, and HT were obtained from VWR Scientific and Sigma-Aldrich.

[0054]

[0109] Figure 10 outlines the ATIPA foaming protocol. Briefly, one day prior to foaming, a hydroxyl (OH) premix was prepared by combining non-isocyanate monomers (ATIPA, BEP, MPD, HT) in a 0.6 equivalent ratio in a 15 ml polypropylene FlacTek mixing cup. The contents were mixed in a FlacTek® high-speed shear mixer at 3400 rpm for 30 seconds, heated to 50°C for 1 hour, mixed again at 3400 rpm for 30 seconds, and heated at 50°C overnight. The 30 and 40 eq.% ATIPA compositions were prepared by adding 5 and 8 wt.% anhydrous THF to the OH premix until fully dissolved.

[0055]

[0110] A viscous isocyanate (NCO) premix was prepared in a dry glove box by adding a 0.4 mole ratio of reactive polyol equivalents to total diisocyanate equivalents to a 150 ml polypropylene FlacTek® mixing cup. The contents were mixed at 3400 rpm for 10 minutes until a single phase was formed. The premix was shaken at 1 rpm at room temperature for 2-5 hours until the mixture reached a room temperature viscosity comparable to honey. The OAT composition was supplemented with 0.04 g of AirProducts® T131 gelling catalyst and 0.08 g of AirProducts® BL22 blowing catalyst to increase the cure time during foaming.

[0056]

[0111] To stabilize the foaming, 4% by weight of surfactant DCI990 was added to the NCO premix and mixed for 30 seconds. The OH premix was added to the NCO premix and mixed for 30 seconds. 1-2 ml of Enovate® was immediately added to the reactive resin and mixed for 30 seconds. The reactants were immediately transferred to a 90°C oven and cured for 20 minutes. After curing, the foam skin was removed with a razor blade, and the foam was post-cured at 50°C for 12 hours. The cured foam was cubed and stored in dry polypropylene bags.

[0057]

[0112] Physical characterization

[0113] Pore ​​size was determined from light microscope images acquired at 50x and 100x magnification using a Keyence® VHX-5000 measurement system (with a variable illumination adapter). Foam samples were cut into 2-4 mm thin sections in the longitudinal and transverse planes. Ten pore size measurements were made on each foam image.

[0058]

[0114] Approximately 1 cm from each composition 3 Six cubes were collected from the measured specimens and subjected to density measurements. The density was calculated by dividing the mass of the specimen by the product of its length, width, and height.

[0059]

[0115] Fluoroscopy

[0116] Foam samples were prepared for X-ray imaging by cutting 1 cm x 1 cm specimens into 8, 4, 2, and 1 mm thick slices and attaching them to polypropylene sheets. Platinum embolic coils were attached to each foam array as X-ray fiducials. Peripheral embolic prototypes were prepared by cutting the foam into 8 mm diameter cylinders and threading them longitudinally onto 0.006 inch stainless steel wires. One prototype was imaged in the expanded state, while the other was longitudinally crimped using a MachineSolutions SC250 heated stent crimper. The specimens were equilibrated at 100 °C for 15 minutes at the crimping inner diameter, radially compressed, and retrieved while cooling to ambient temperature. A 2 mm diameter neurovascular prototype without a backbone wire was also prepared and longitudinally crimped. Angiographic and fluoroscopic images were acquired using a Philips® AlluraXperFD20 X-ray system.

[0060]

[0117] DSC

[0118] The dry Tg of 5-10 mg foam samples placed in a vented aluminum pan was measured using a TA Q200® differential scanning calorimeter. The foam samples were equilibrated at -40°C for 5 minutes, then heated to 120°C, cooled to -40°C, and reheated to 120°C at a 10°C / min ramp rate. The Tg was calculated from the inflection point of the second heating curve.

[0061]

[0119] Example 24a recites a Tg calculated using the process in the paragraph above (i.e., the Tg specified in the claims is calculated using the above test for time, temperature, process, and inflection point of the second heating curve).

[0062]

[0120] Wet Tg foam samples were immersed in 50°C water for 30 minutes to achieve wet plasticization. The foam was compressed between 2-ton tissue paper sheets using a Carver® laboratory press for 30 seconds to remove moisture. 5–10 mg of foam sample was added to an aluminum pan and sealed. The foam sample was cooled to -40°C, equilibrated for 5 minutes, and then heated to 100°C at 10°C / min. The wet Tg was calculated from the inflection point of the heating curve.

[0063]

[0121] DMA

[0122] Dynamic mechanical analysis was performed using a TA Q800®. Foam cylinders were prepared using an 8 mm biopsy punch and cut to approximately 5 mm in length with a razor blade. Samples were equilibrated at 0 °C for 5 min and heated to 120 °C at 3 °C / min while deforming at 1 Hz to 40 μm.

[0064]

[0123] No Force Expansion

[0124] The foam was cut into 2 mm diameter cylinders and threaded longitudinally with 0.006 inch stainless steel wire. Samples were radially compressed using a MachineSolutions® SC250 heated stent crimper. Crimped samples were allowed to relax for 24 hours before being inflated in a 37°C water bath. Samples were imaged at 5 minute intervals for a total of 45 minutes. Five diameter measurements were taken along the length of the foam using ImageJ® software.

[0065]

[0125] ATR FTIR

[0126] ATR FTIR spectra were obtained using a Bruker ALPHA Infrared Spectrometer® with a diamond ATR® crystal, and data analysis was performed using Bruker OPUS Spectroscopy software®.

[0066]

[0127] Tensile test

[0128] Dry foam specimens were prepared using an ASTM Type IV dogbone punch. Uniaxial tensile tests were performed at room temperature using an Insight30 Material Tester® (MTS Systems Corporation, Eden Prairie, MN) at a constant strain rate of 50 mm / min. The ultimate tensile strength (kPa), break strain (%), and modulus of elasticity (kPa) were calculated from the stress-strain curves of each specimen.

[0067]

[0129] Gel fractionation

[0130] Foam samples measuring approximately 1 cubic centimeter were washed and ultrasonicated three times for 30 minutes in a 20:1 dilution ratio in isopropyl alcohol to remove residual surfactant. The samples were dried under vacuum at 100°C for 12 hours. The dried foam samples were subjected to mass analysis and added to a 20 mL vial filled to the shoulder with THF and heated at 50°C with 1 Hz oscillation for 48 hours. The THF was removed, and the samples were dried under vacuum at 60°C for 24 hours. Gel fractions are reported as the final sample mass divided by the original sample mass.

[0068]

[0131] Results and Discussion

[0132] For compositions 1-5 in Figure 11, which contain different volumes of Enovate®, there is a clear trend for material density to decrease with increasing volume of physical blowing agent. While there are statistically significant differences in dry Tg values ​​(1-way ANOVA, α=0.05), this variation is not expected to significantly impact device design criteria. The relationship between material density and pore morphology is better illustrated in the light microscope images described below.

[0069]

[0133] Compositions 6–9, varying in HT content, had comparable densities and consistently average pore sizes between 300–400 μm, and the differences in dry Tg between each composition were statistically significant (1-way ANOVA, α=0.01). Increasing the HT content increased the crosslink density of the material. Reducing the molecular weight between crosslinks increased the network stiffness and the glass transition temperature. For a given composition, with a fixed contrast agent loading (20% ATIPA) and foam density, HT composition demonstrated an effective method for controlling Tg.

[0070]

[0134] Compositions 10 to 13 differ in the ATIPA content. The HT content was also varied to maintain a constant theoretical crosslink density. The bulk density of the foams decreased with increasing ATIPA content. This result is believed to be due to the blowing reaction of the two carboxylic acid groups present in the ATIPA monomer. The dry Tg also increased with increasing ATIPA content. Although the theoretical crosslink density of the compositions was constant, the aromatic structure of ATIPA was more rigid than the aliphatic HT monomer, resulting in higher network stiffness and glass transition temperatures.

[0071]

[0135] Compositions 15-17 all contained 20 equivalent percent ATIPA and varied in isocyanate content. Varying the isocyanate composition had significantly less effect on Tg than varying the HT content. Foams with increased TMHDI content could be produced, but were qualitatively more brittle than HDI foams and were not selected for device optimization, although they may be suitable for some embodiments.

[0072]

[0136] The average gel fraction for selected compositions was 94.5-99.0%. These values ​​are comparable to those reported for conventional non-visible SMP foam formulations. A high gel fraction reduces the risk of complications associated with leachable chemicals from permanently implanted biomaterials. This risk can be further mitigated by using more rigorous foam cleaning protocols, if necessary, to remove unreacted leachable material prior to device implantation.

[0073]

[0137] After characterization of foams 1-17, compositions 18 and 19 were fabricated at a 4x scale for tensile testing and for fabricating neurovascular prototypes. The compositions were chemically modified to achieve desirable morphological and thermomechanical properties.

[0074]

[0138] optical microscope

[0139] Figure 12 shows the effect of increasing the blowing agent on foam morphology. The "0ml" composition, which uses no physical blowing agent, retains pores due to the ATIPA foaming reaction. While the pore size is comparable to the 1.0ml foam at 0.5ml, the strut morphology accounts for the significant difference in bulk material density. Similarly, the 1.5ml and 2.0ml small pore foams have the lowest material density due to the thin strut structure.

[0075]

[0140] Figure 13 shows foams with comparable pore size, density, and strut morphology but different HT compositions. It is important to note that the composition, and subsequent thermodynamic properties, of the material can be varied independently of foam morphology to optimize the material for a given medical device. Additionally, both chemical ATIPA blowing and physical blowing can be used to control morphology independently of composition.

[0076]

[0141] The differences in pore morphology are significant because the foams in Figure 14 were corrected for viscosity changes in premixes with different ATIPA contents without changing foaming parameters. However, this species showed miscibility up to 30 eq.% ATIPA. It is important to note that the 30 eq.% ATIPA composition required 5 wt.% anhydrous THF during synthesis to prevent precipitation of the ATIPA.

[0077]

[0142] Figure 15 details the foams with different isocyanate contents. All foams are qualitatively optically clear. This promising monomer miscibility allows for varying the isocyanate composition to control bulk thermodynamic properties and hydrophobicity to tailor material performance.

[0078]

[0143] Tensile test

[0144] FIG. 16 shows representative stress-strain curves and associated calculations for a conventional SMP foam, a tungsten-loaded SMP composition, a 25 eq. % ATIPA foam, and a 30 eq. % ATIPA foam (Compositions 18 and 19).

[0079]

[0145] The novel ATIPA foam composition achieves unprecedented material properties for low-density SMP foams. The enhanced material strength (peak stress) is attributed to the aromatic structure of the ATIPA monomer. The inventors previously avoided aromatic polyurethane monomers, such as toluene diisocyanate, due to concerns about the biocompatibility of the aromatic diamines in their degradation products. However, aromatic compounds have traditionally been stronger than aliphatic compounds. This polymer system was designed for biodegradability with minimal sites for oxidative or hydrolytic degradation, and in some embodiments, the biocompatibility of the aromatic degradation products was sufficient.

[0080]

[0146] The higher ductility (strain at break) compared to the non-visible control SMP foam is attributed to a lower crosslink density. The inventors noted that conventional foams use polyols with a functionality of 3 (TEA) or 4 (HPED). These crosslink sites are crosslinked with short diisocyanate segments (TMHDI or HDI) to create a highly crosslinked material. This crosslink density imparts excellent shape memory but at the expense of relatively poor overall toughness. The inventors determined that while this is not an issue for neat foams, it becomes problematic for tungsten-loaded composites, introducing stress concentrations at the strut cross-section. Alternatively, the ATIPA composition of the present invention employs aliphatic diols MPD and BEP to increase the molecular weight between crosslinks, thereby increasing ductility. The stiffness of ATIPA allows for chain extension while maintaining the overall material transition temperature within the functional biomedical range (40-60°C).

[0081]

[0147] The combined increase in ductility and strength results in a significant increase in tensile toughness. Compared to the non-visible foam, the 25AT and 30AT compositions are over 11 times and over 14 times tougher, respectively. Compared to the 6% vol tungsten nanoparticle foam, the 25AT and 30AT compositions are 46 and 57 times tougher, respectively. This dramatic increase in toughness significantly reduces the risk of unwanted embolic particles detaching from the foam and drifting downstream from the target treatment area. Alternatively, foam parameters could be optimized to incorporate cell openers to create open voids in the original foam.

[0082]

[0148] X-ray imaging

[0149] Figure 17 summarizes the X-ray visualization of low-density foams with different ATIPA contents. Foams with ATIPA contents between 10 and 30 equivalent percent showed comparable X-ray visualization, as the material density decreased at higher contrast agent loadings due to the ATIPA blowing reaction. This reciprocal trend was comparable for iodine content within the same expanded sample path length.

[0083]

[0150] An 8 mm cylindrical peripheral embolization prototype demonstrated visualization in the expanded state, even when imaged through a skull analog. When the material was radially compressed, its visualization was comparable to commercially available platinum embolization coils. Radial compression also corrected for differences in bulk material density, revealing differences in X-ray visualization of samples with different ATIPA content. For testing, the radially compressed 30AT sample was more significantly visualized than the 20AT sample when imaged through an aluminum skull analog.

[0084]

[0151] Figure 18 shows details of foams with a fixed 20% ATIPA composition at varying densities. Increasing material density allows for increased material visibility, with the highest density foams visible through skull analogs at only 1 mm thickness. Even with longitudinal compression, 2 mm neurovascular prototypes provided limited visibility.

[0085]

[0152] In some embodiments, limited material visualization at the neurovascular device scale has been addressed by incorporating foams with a high proportion of ATIPA. Alternatively, in some embodiments, a combined approach of chemical opacification and tungsten nanoparticle loading has been employed to achieve unprecedented levels of SMP foam visualization at the neurovascular device scale. Based on tensile test data, the fracture toughness of ATIPA composites with tungsten nanoparticle stress concentrators was higher than that of conventional non-visualized SMP foams. This provides excellent radiographic visualization during device implantation while maintaining a traditionally acceptable risk level for undesirable embolic particulates.

[0086]

[0153] DSC

[0154] Differential scanning calorimetry was used to determine the effect of composition on the Tg and width of the thermal transitions. This data is an important resource for developing materials tailored to specific device design criteria, including foam expansion ratios. Figure 19 shows the consistent thermal properties of foams with varying densities using physical blowing agents, further facilitating foam morphology control independent of transition temperatures. Reducing foam density allows more material to be compressed into a cross-section that can be delivered through a catheter. This allows for greater volume expansion in vivo and more effective packing for easier embolization.

[0087]

[0155] Figure 20 shows incremental control over both the dry and wet plasticized Tg for HT compositions. Increasing the molar ratio of trifunctional HT monomers increases crosslink density, leading to a stronger polymer structure and an increased glass transition. The wet and dry transitions for each composition were set near body temperature (37°C), allowing the material to passively expand after implantation. Based on these thermograms, 20HT, 30HT, and 40HT compositions were selected for further analysis for device development. The 10HT composition was determined to have too low a dry transition to allow sufficient working time for prototype-scale neurovascular devices, but it may be applicable in some embodiments.

[0088]

[0156] Increasing the HT content increases the value of the transition temperature and the width of the transition. As can be seen in the lower left corner of the figure, the fully plasticized 10HT composition still contained enough moisture for water freezing to be recorded on the thermogram.

[0089]

[0157] Varying the isocyanate content also allowed for control of Tg, albeit to a lesser extent (Figure 21). Instead of varying the crosslink density, increasing the molar ratio of TMHDI also increased the stiffness of the polymer chains between crosslinks. Increasing Tg and increasing TMHDI content increases the bulk hydrophobicity of the material, which is expected to decrease the wet plasticization rate and overall foam expansion time of the material.

[0090]

[0158] Thermograms for increasing ATIPA composition are shown in Figure 22. The Tg increase and the width of the transition increased significantly. The transition is much less well defined. With the exception of the 40AT composition, which was too fragile for full analysis and prototyping, the changes in the thermogram profile motivated further DMA analysis of selected compositions.

[0091]

[0159] DMA

[0160] Referring to Figures 23 and 19, the peak Tan δ values ​​are approximately 20°C higher than the DSC dry Tg values. However, the incremental difference for each composition is comparable. This DMA data further contributes to the increase in Tg with increasing HT content.

[0092]

[0161] The tangent delta plot in Figure 24 shows that the Tg values ​​are 20–30°C higher than the dry DSC values ​​in Figure 21. The DMA curves also show a similar trend, with increasing Tg and transition width with increasing ATIPA content. Most interesting is the shape of the 30AT composition curve. While the signal peak is clear, the Tan delta signal does not return to the baseline after the thermal transition. This indicates the presence of a damping material with a low rubbery modulus, which may be suitable in some embodiments but not others, resulting in weak shape-memory properties. Based on these results, foam compositions for device prototyping were selected based on the maximum intrinsic solubility of ATIPA in the other polyol components. This maximum ranges from 20–25 equivalent percent of ATIPA, depending on the composition.

[0093]

[0162] Spontaneous expansion

[0163] Foams with different HT contents exhibited volume recovery behavior in body temperature water consistent with the trend of Tg. Compositions with higher HT content and Tg took longer to expand, as shown in Figure 25. The 30 and 40 eq.% HT compositions also had higher average volume recovery (99%) compared to the 20 eq.% HT foam with lower crosslink density (91%).

[0094]

[0164] This data indicates that, in some embodiments, it is suitable for the design of neurovascular embolization devices. With an average crimp diameter of 0.0196" ± 0.001", the prototype nearly fits within a 0.021" microcatheter lumen, with a targeted minimum tolerance of 0.002". Altering the foaming agent and surfactant composition and using smaller diameter device backbone filaments may allow for shorter crimp dimensions and reduced bulk foam density.

[0095]

[0165] These expansion profiles show an estimated minimum working time of 10 minutes for the 30HT formulation and 15 minutes for the 40HT formulation. These default expansion times are already within clinically acceptable limits even without the use of a wet-plasticizing surface coating.

[0096]

[0166] FTIR ATR

[0167] The infrared spectrum in Figure 26 does not show significant changes with increasing HT content. However, the spectrum does show peaks characteristic of polyurethane foams. -1 The broad peak at 2852 cm emphasizes the NH vibration. -1 and 2923cm -1 The peak at 2260 cm is due to the symmetric and asymmetric stretching of CH from the methyl group of MPD. -1 No unreacted NCO peak was observed at 1685 cm -1 In the case of segmented polyurethanes, the C=O urethane peak is significantly shifted to the right due to hydrogen bonding. This is consistent with the hydrogen-bonded urethane peaks of other polyurethane SMP foams, which have relatively low molecular weights between crosslinks compared to segmented polyurethanes. A strong hydrogen-bonded amide II peak appears at 1515 cm. -1 can be seen in.

[0097]

[0168] The increasing TMHDI content of the 20 equivalent % ATIPA foam spectra is shown in Figure 27. A non-visible 100TMH60 foam is also included for comparison. The increase in methylation with increasing TMHDI content is evident from the 2800-3000 cm -1 Compared to the non-visible foam, the ATIPA foam does not have the H2O chemical blowing used in conventional polyurethane foaming, and the peak between 1650 cm -1 The urea shoulder is not prominent.

[0098]

[0169] It can be seen that the composition with higher ATIPA content (Figure 28) had an increased NH2 reactive group during synthesis, resulting in a broadened urea shoulder. This is different from the urea content present in conventional polyurethaneurea foams, which use chemically generated water as the blowing agent. The higher ATIPA content also indicates a broader urea shoulder at 1360 cm -1 There is a peak at 770 cm -1 This is also evident from the presence of shoulders.

[0099]

[0170] In this study, we successfully fabricated chemically modified shape-memory polymer foams incorporating triiodobenzene-containing monomers, and demonstrated that by varying the molar ratio of other constituent monomers, the polymer scaffolds could be functionally modified to function as embolic medical devices.

[0100]

[0171] Some examples are described below.

[0172] Example 1 includes a medical device comprising a thermosetting shape memory polymer foam that can be programmed to a transitionable secondary state and stimulated to restore the shape memory polymer foam to a primary state comprising triiodobenzene monomer for direct x-ray visualization.

[0101]

[0173] Example 2 relates to the device of Example 1, wherein the triiodobenzene monomer is selected from 5-amino-2,4,6-triiodoisophthalic acid, diatrizoic acid, iohexol, and triiodophenol.

[0102]

[0174] Example 3 relates to the device of Example 1, in which the monomer 5-amino-2,4,6-triiodoisophthalic acid is used as a crosslinking agent, a foaming agent, and an X-ray contrast agent for the shape memory polymer.

[0103]

[0175] Example 4 relates to the device of Example 1, wherein the shape memory polymer foam composition includes at least one of the following aliphatic polyols: 1,2,6-hexanetriol, 2-butyl-2-ethyl-propanediol, 3-methyl-1,5-pentanediol, diethylene glycol, triethylene glycol, triethanolamine, tetrakis-hydroxypropylethylenediamine, glycerol, trimethylolpropane, trimethylolmethane, and 1,2,4-butanetriol.

[0104]

[0176] Example 5 relates to the device of example 1, wherein the shape memory polymer foam composition includes at least one of the following aliphatic diisocyanates: hexamethylene diisocyanate, trimethylhexamethylene diisocyanate, isophorone diisocyanate.

[0105]

[0177] Example 6 relates to the device of example 1, wherein the shape memory polymer foam composition includes at least one of the following aromatic diisocyanates: 1,3,4-triisocyanate 2,4,6-trimethylbenzene, toluene diisocyanate, diphenylmethane diisocyanate.

[0106]

[0178] Example 6 is another example of the device of Example 1, wherein the shape memory polymer comprises 1,2-diaminopropane, 2,2-dimethyl-1,3-propanediamine, 1,8-diaminooctane, 3-amino-1,2-propanediol, 2-amino-2-methyl-1,3-propanediol, or other fatty acid monomers containing multiple amine or alcohol functional groups.

[0107]

[0179] Example 7 relates to the device of Example 1, wherein the shape memory polymer foam is poly(urethane-urea-amide).

[0108]

[0180] Example 8 relates to the device of Example 1, wherein the compressed shape memory foam contains 50-500 mg / ml of iodine.

[0109]

[0181] However, other embodiments may contain 100, 200, 300, 400 mg / ml or more of iodine.

[0110]

[0182] Example 9 relates to the device of Example 1, wherein the dry glass transition temperature of the shape memory polymer foam is 40 to 80°C.

[0111]

[0183] However, in some other embodiments, the temperature may be 40 to 100, 40 to 90, 40 to 70, or 40 to 60°C.

[0112]

[0185] In other embodiments, the wet plasticized glass transition temperature onset is less than 40, 39, 38, 37, 36, 35, 34°C.

[0113]

[0186] Example 11 relates to the device of Example 1, wherein the secondary state of the device is a radially compressed shape that allows for minimally invasive delivery via a catheter.

[0114]

[0187] Example 12 relates to a method for producing a thermosetting thermoset in which shape memory polymer foams contain triiodobenzene monomers for direct x-ray visualization and can be programmed to a metastable secondary state and revert to the primary state upon stimulation.

[0115]

[0188] Example 13 relates to the method of Example 12, wherein the thermoset shape memory polymer foam is made from a combination of 5-amino-2,4,6-triiodoisophthalic acid, 1,2,6-hexanetriol, 2-butyl-2-ethyl-propanediol, 3-methyl-1,5-pentanediol, an aliphatic diisocyanate, a physical blowing agent, and a surfactant.

[0116]

[0189] Example 14 relates to the method of Example 13, wherein the thermoset shape memory polymer foam is made from a combination of 5-amino-2,4,6-triiodoisophthalic acid, 1,2,6-hexanetriol, 2-butyl-2-ethyl-propanediol, 3-methyl-1,5-pentanediol, an aliphatic diisocyanate, a physical blowing agent, and a surfactant.

[0117]

[0190] Example 15 relates to the device of Example 1, wherein the shape memory polymer foam composition comprises polycaprolactone (PCL).

[0118]

[0191] Example 1a relates to a system comprising a thermosetting shape memory polymer (SMP) foam covalently bonded to iodine; wherein the SMP foam (a) expands from a compressed secondary state to an expanded primary state in response to a thermal stimulus, and (b) is a poly(urethane-urea-amide).

[0119]

[0192] Example 2a relates to the system of Example 1a in which the SMP foam is radiopaque.

[0120]

[0193] Example 3a relates to the system of Example 2a in which the iodine is contained in the triiodobenzene monomer.

[0121]

[0194] Example 4a relates to the system of Example 3a, wherein the triiodobenzene monomer comprises at least one of (a) 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), (b) diatrizoic acid, (c) iohexol, and (d) triiodophenol.

[0122]

[0195] Example 5a relates to the system of Example 4a in which the triiodobenzene monomer comprises ATIPA.

[0123]

[0196] Example 6a relates to the system of Example 5a in which ATIPA crosslinks the polymer chains of the SMP foam.

[0124]

[0197] Another version of Example 6a relates to the system of Example 5a, where (a) ATIPA crosslinks the polymer chains of the SMP foam, and (b) another crosslinker crosslinks the polymer chains of the SMP foam.

[0125]

[0198] Example 7a relates to the system of Example 3a, wherein the SMP foam includes at least one of platinum, tungsten, and tantalum physically bonded within the SMP foam.

[0126]

[0199] Example 8a relates to the system of Example 7a, where at least one of platinum, tungsten, and tantalum is not chemically bonded to the SMP foam.

[0127]

[0200] Example 9a relates to the system of Example 3a, including a backbone that traverses the SMP foam, the backbone comprising at least one of a polymer filament and a metal.

[0128]

[0201] Example 10a relates to the system of Example 9a, where the backbone comprises polymer filaments and is metal-free.

[0129]

[0202] In another version of Example 10a, the backbone comprises a polymer but no metal. In another version of Example 10a, the backbone comprises a majority percentage of polymer and a minority percentage of metal.

[0130]

[0203] Example 11a relates to a method including providing a triiodobenzene monomer; providing a fatty acid monomer comprising at least one of: (a)(i) a plurality of amine functional groups, (a)(ii) a plurality of alcohol functional groups, and (a)(iii) a plurality of carboxylic acid functional groups; providing a diisocyanate; combining the triiodobenzene monomer, the fatty acid monomer, and the diisocyanate into a solution; and forming a thermoset shape memory polymer (SMP) foam from the solution.

[0131]

[0204] Example 12a includes a first component in which the triiodobenzene monomer is selected from the group consisting of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), diatrizoic acid, iohexol, and triiodophenol; and the fatty acid monomer is selected from the group consisting of 1,2,6-hexanetriol (HT); 2-butyl-2-ethyl-propanediol (BEP); 3-methyl-1,5-pentanediol (MPD); diethylene glycol (DEG); triethylene glycol (TEG); triethanolamine (TEA); tetrakis-hydroxypropylethylenediamine (HPED); glycerol; trimethylolpropane; trimethylolmethane; 1,2,4-butanetriol; 1,2,4-butanetriol; 1,3-diamino-2-propanol; and aspartic acid; and the diisocyanate comprises a third member selected from the group consisting of hexamethylene diisocyanate (HDI); trimethylhexamethylene diisocyanate (TMHDI); isophorone diisocyanate; 1,3,4-triisocyanate 2,4,6-trimethylbenzene; toluene diisocyanate; and diphenylmethane diisocyanate.

[0132]

[0205] Example 13a relates to the method of Example 12a, wherein the second component is selected from the group consisting of HT; BEP; MPD; DEG; TEG; TEA; HPED; glycerol; trimethylolpropane; trimethylolmethane; and 1,2,4-butanetriol.

[0133]

[0206] Example 14a relates to the method of Example 12a, wherein the third component is selected from the group consisting of HDI; TMHDI; and isophorone diisocyanate.

[0134]

[0207] Another version of Example 14a relates to the process of Example 12a, wherein the second component is selected from the group consisting of 1,2-diaminopropane; 2,2-dimethyl-1,3-propanediamine; 1,8-diaminooctane; 3-amino-1,2-propanediol; and 2-amino-2-methyl-1,3-propanediol.

[0135]

[0208] Example 15a relates to the method of Example 12a, wherein the third component is selected from the group consisting of 1,3,4-triisocyanate 2,4,6-trimethylbenzene; toluene diisocyanate; and diphenylmethane diisocyanate.

[0136]

[0209] Example 16a relates to the method of Example 12a, wherein the first component is ATIPA.

[0137]

[0210] Another type of Example 16a relates to the method of Example 12a, in which the first component is ATIPA, and the ATIPA is contained in 20 to 30% MW of the first component and the second component.

[0138]

[0211] Example 17a relates to the method of Example 12a, where the second and third components are crosslinked to the first component.

[0139]

[0212] Example 18a relates to the method of Example 17a, wherein the step of forming an SMP foam from a solution uses the first component as a chemical blowing agent.

[0140]

[0213] Example 19a relates to the process of Example 12a, including a fourth member selected from the group consisting of HT; BEP; MPD; DEG; TEG; TEA; HPED; glycerol; trimethylolpropane; trimethylolmethane; 1,2,4-butanetriol; 1,2-diaminopropane; 2,2-dimethyl-1,3-propanediamine; 1,8-diaminooctane; 3-amino-1,2-propanediol; 2-amino-2-methyl-1,3-propanediol; 1,3-diamino-2-propanol; and aspartic acid.

[0141]

[0214] Example 20a relates to a system comprising an iodine-containing thermosetting open-cell shape memory polymer (SMP) foam that is X-ray visible; wherein the SMP foam (a) expands from a compressed secondary state to an expanded primary state in response to a thermal stimulus; and (b) is a poly(urethane-urea-amide).

[0142]

[0215] The determination of "x-ray visible" or "radiopaque" is made by one of ordinary skill in the art, e.g., a neurosurgeon or interventional neuroradiologist who routinely treats aneurysms using imaging such as fluoroscopy or angiography. While x-ray power varies depending on the imaging equipment used, one of ordinary skill in the art will understand how the foam will appear under normal clinical conditions in which it can be distinguished from surrounding tissue.

[0143]

[0216] Example 20a relates to the system of Example 19a, in which iodine is contained in the triiodobenzene monomer and covalently bound within the polymer network of the SMP foam.

[0144]

[0217] Another version of Example 20a relates to the system of Example 19a, in which iodine is contained in the triiodobenzene monomer and physically incorporated within the SMP foam.

[0145]

[0218] Another version of Example 20a relates to the system of Example 19a, in which iodine is contained in at least one triiodobenzene monomer and is a) covalently bound within the polymer network of the SMP foam, and (b) physically incorporated within the SMP foam, but not chemically bonded.

[0146]

[0219] Example 21a relates to the system of Example 20a, where the SMP foam in the secondary state contains 50-500 mg / ml of iodine.

[0147]

[0220] However, in some other embodiments, the secondary state SMP foam may contain 50-100, 100-200, 200-300, 300-400 mg / ml or more of iodine.

[0148]

[0221] Example 22a relates to the system of Example 21a, where the density of the SMP foam in the primary state is less than 0.1 g / cc and the dry glass transition temperature (Tg) is between 30 and 100°C.

[0149]

[0222] Another type of Example 22a is an SMP foam in a primary state, whose density is less than 0.1 g / cc and whose dry glass transition temperature (Tg) is 30 to 100°C and 1650 cm -1 Fourier transform infrared spectroscopy (FTIR) of Example 21a shows no urea peak.

[0150]

[0223] Other versions of Example 22a have densities less than 0.09, 0.08, 0.07, 0.06, or 0.05 g / cc.

[0151]

[0224] Example 23a relates to the system of Example 22a, where the SMP foam comprises polycaprolactone (PCL).

[0152]

[0225] Example 24a relates to the system of Example 23a, including at least one of a stent and a flow diverter bonded to the SMP foam.

[0153]

[0226] Example 25a relates to the system of Example 23a, including a fully encapsulated kit; a flexible conduit; and a pusher rod; wherein the flexible conduit includes an SMP foam within the flexible conduit, the SMP foam is coupled to the pusher rod, and at least a portion of the pusher rod is contained within the flexible conduit.

[0154]

[0227] For example, the kit may be a sealed, sterile kit that is shipped to a medical facility.The conduit may include some form of catheter.

[0155]

[0228] Radiopaque radiation crosslinked thermoplastic polymer

[0229] Much of the above discussion relates to radiopaque thermosetting polymers. However, some other embodiments relate to thermoplastic polymers equipped with iodine-containing chemical motifs. The motifs can be functionalized prior to incorporation. The result is a polymer composition that is X-ray visible, can be processed using various polymer processing techniques, and can subsequently be crosslinked using electron beam irradiation.

[0156]

[0230] More generally, as described to some extent above, SMPs are materials that have the ability to undergo geometric changes in response to stimuli, known as the shape memory effect. This shape memory effect allows for minimally invasive delivery of medical devices, making SMPs of great interest among biomedical researchers. Polyurethanes (PUs) are commonly used in biomedical applications due to their material performance, biocompatibility, and modifying capabilities. Gas-blown low-density foams offer high volume recovery and rapid hemostasis, making them particularly desirable for embolization.

[0157]

[0231] However, the inventors have determined that this thermoset material platform has limitations in device geometry, ease of manufacturing, feature precision, and process repeatability. Thermoplastic materials are widely used in industry and are compatible with a variety of processing techniques (e.g., extrusion, injection molding, additive manufacturing, etc.) that allow for precise and complex shapes. SMP thermoplastic polyurethane (TPU) materials were previously developed by Hearon et al. (See U.S. Patent No. 8,883,871, assigned to Lawrence Livermore National Security, LLC (LLLC)). The SMP system is highly tunable and processable, allowing for control of polymer properties and architecture. However, the inventors have discovered that the polymeric material inherently lacks radiographic visibility, which can hinder device delivery. The inventors have further determined that the TPU system requires modification to achieve adequate radiographic visibility.

[0158]

[0232] Both thermoplastic and thermosetting polymers are employed here. Thermosetting resins are covalently crosslinked networks that maintain their three-dimensional shape without melting, whereas thermoplastic resins are linear chains that can be formed into complex shapes by solvent or melt processing. Each system has advantages, and the choice of material depends on the application and processing conditions. For example, thermosetting materials cannot be melted, making them useful for high-temperature applications, while thermoplastic materials are useful for applications requiring complex shapes and high-throughput manufacturing.

[0159]

[0233] TPU's elastomeric behavior is tunable, making it widely used in industry. TPU resins can achieve a wide range of material performance characteristics between rigid thermoplastics and flexible elastomers. TPUs are melt-processable and can be used with traditional processing techniques, such as extrusion, dip coating, electrospinning, supercritical foaming, and injection molding, as well as newer methods, such as additive manufacturing. TPU's versatility stems from the ability to produce TPUs with a variety of mechanical properties, controlled primarily by the ratio of hard and soft segments. Other polymer properties, such as molecular weight, crystallinity, and hydrophobicity, can also affect thermoplastic processability. U.S. Patent No. 8,883,871 describes a highly tunable and processable TPU material platform. Its unique architecture allows the material to possess advanced processing capabilities as a thermoplastic and can be post-crosslinked with a thermoset SMP. Thermoset materials offer excellent shape retention and shape memory recovery. Post-polymerization crosslinking allows for systems that combine the advantages of both thermoplastic and thermoset polymers.

[0160]

[0234] Crosslinking of thermoplastic polymers by electron beam irradiation has been performed in many thermoplastic systems. Electron beam irradiation generates radicals on unsaturated carbon vinyl groups. Radicals in close proximity react to form covalent bonds, crosslinking adjacent polymer chains. Depending on the irradiation dose, electron beam treatment can result in either bond formation or chain scission. It has been found that excessive irradiation can cause undesirable changes in the polymer microstructure and crystallinity, making it important to optimize the crosslinking parameters.

[0161]

[0235] The inventors have discovered that to add further value to thermoplastic SMP systems, X-ray visualization is desirable, allowing visualization and monitoring of intravascular medical devices. Because polymer densities are insufficient for radiotransparency, extensive research has been conducted into achieving X-ray visualization through various methods. Previous studies have explored both nanoparticle and microparticle fillers to improve the opacity of thermoset SMP foams, but these methods can alter the bulk thermal and mechanical properties. Barium sulfate is a common additive to medical-grade TPU for X-ray visualization, which can also improve mechanical properties such as toughness and tensile strength.

[0162]

[0236] Some embodiments build on the radiopaque thermosetting polymers described above to address chemical modification of the TPU material, incorporating iodine-containing motifs to improve visualization of the thermosetting SMP. This approach favors the incorporation of physical additives because it does not compromise the bulk properties of the material. However, in some embodiments, this technique is modified to render the TPU material system.

[0163]

[0237] Therefore, given the need for adequate X-ray visualization of medical devices for safe and accurate delivery, materials can be modified to enable medical devices made solely or primarily from polymeric materials without (or with reduced use of) metallic components, such as marker bands that provide radiopacity. As noted above, some embodiments relate to chemically modified, radiopaque thermoset SMP foams. The chemical modification was achieved by incorporating ATIPA, a triiodobenzene monomer with two carboxylic acids and a primary amine, to form thermoset foams via chemical blowing and crosslinking reactions with diisocyanates. However, other embodiments described herein incorporate ATIPA and other triiodobenzene monomers into thermoplastic polymer systems with functionalized side chains and / or pendant groups. More specifically, two ATIPA carboxylic acids are incorporated into a TPU backbone, and the amine groups are functionalized to add value to the material system. This approach has potential applications for many novel medical devices, broadening its applicability in the biomedical field (and industries such as insulation). However, in some embodiments for radiopaque TPUs, the radiopaque TPUs are not limited to medical devices and may be used more generally in areas where radiopaque polymers (thermoset or thermoplastic) are desired.

[0164]

[0238] In one embodiment, radiation-crosslinkable linear TPUs were chemically modified and visualized by X-ray. In some embodiments, pre-functionalization is performed first to incorporate iodine motifs and ensure two available functional groups to maintain the structure of the linear TPU. For example, the ATIPA pre-functionalization step utilizes reaction kinetics to selectively functionalize primary amine groups (primary amines are approximately five times more reactive with isocyanates than carboxylic acids), leaving two carboxylic acid groups to react with the TPU backbone. Furthermore, this pre-functionalization can be used to further improve the material. For example, functionalization with vinyl groups can increase the available cross-linking sites.

[0165]

[0239] This TPU offers several advantages over standard materials. First, the linear TPU chains with pendant vinyl groups can be crosslinked in a post-process via electron beam irradiation. Second, X-ray visualization is achieved through chemical modification. Furthermore, chemical modifications that allow X-ray visualization can impart additional functionality to the material system.

[0166]

[0240] Below is a more detailed discussion of radiopaque TPU.

[0241] approach

[0242] The inventors synthesized linear thermoplastic chains of varying molecular weights with pendant vinyl groups. Next, the inventors tuned the PU chemistry to achieve scaffolds with controlled hydrophobicity and Tg dependence through the selection of diols and diisocyanates (Figure 29). Essentially, the reaction in Figure 30 is based on the reaction of an aliphatic diisocyanate monomer with a diol to grow a linear chain. The diisocyanate selection is a way to tailor the hydrophobicity of the polymer. Two example diisocyanate monomers selected for the formulation are TMHD and HDI (Figure 29). Diols with pendant vinyl groups (e.g., TMPAE and HDD in Figure 29) control the crosslink density. Adding a monofunctional alcohol, such as allyl alcohol (AA), to the reaction terminates the chains and, when added in various molar amounts, can control the molecular weight (MW). Allyl alcohol provides additional vinyl groups for crosslinking, while the addition of an alkyl alcohol, such as ethyl alcohol, can control the e-beam crosslink density-dependent thermoplastic molecular weight.

[0167]

[0243] Improved thermoplastic synthesis

[0244] In one embodiment, the synthesis protocol described in U.S. Patent No. 8,883,871 was modified to improve safety and control the resulting polymer properties. The reaction temperature was lowered below the boiling point of the solvent, and a nitrogen purge was added during the reaction. This open atmosphere condition allowed for carbon dioxide off-gassing during the reaction of the ATIPA carboxylic acid with the isocyanate groups. After synthesis, the polymer in THF was placed in a dish and gradually heated to 75°C over three days, followed by a vacuum pump and a final temperature increase to 90°C over the final two days to prevent TPU bubbling and more thoroughly remove the THF.

[0168]

[0245] ATIPA functionalization

[0246] In one embodiment, an iodobenzene monomer (e.g., a triiodobenzene monomer) is functionalized. Various suitable triiodobenzene monomers are shown in Figure 31. In one embodiment, ATIPA is functionalized with one molar equivalent of a functionalized isocyanate in solution. Due to reaction kinetics, isocyanate groups are approximately five times more reactive with aromatic amines than carboxylic acid (COOH) groups. This process therefore functionalizes the amine groups on ATIPA, allowing thermoplastic polymerization via the remaining two COOH groups. Figure 32A shows the modification of the amine groups on ATIPA for incorporation into TPU.

[0169]

[0247] Figure 32B shows the functionalization of ATIPA with allyl isocyanate. In addition to the benefit of preserving two carboxylic acid groups for incorporation into the TPU structure, functionalization of the primary amine with allyl isocyanate can create additional unsaturated carbon-carbon double bonds that can be used for crosslinking via electron beam irradiation in the final stages of polymer processing. This allows the polymer to be X-ray visible and also improves material properties.

[0170]

[0248] Generally, the isocyanate is selected to tailor the structure of the system (eg, allyl isocyanate increases crosslink density, pentafluoroyl isocyanate allows for plasticization in perfluorocarbons).

[0171]

[0249] Other modifications of ATIPA or similar iodine-containing chemical motifs are also possible. For example, ATIPA or other radiopaque monomers can be functionalized with the monomers of Figure 34 before incorporation into a polymer. For example, acryloyl chloride can react with the amine group on ATIPA to form an amide linkage with a pendant vinyl group.

[0172]

[0250] FIG. 33 illustrates, in one embodiment, one embodiment of a process that includes functionalization of a radiopaque monomer and subsequent material processing.

[0173]

[0251] Figure 35 shows the ATR FTIR spectra showing the difference between ATIPA before and after functionalization with IEMA. The notable differences in peaks are marked with green circles. 1080-1360 cm -1 The C-N amine stretching of ATIPA is less pronounced than after functionalization with IEMA, indicating that the amine positions on ATIPA reacted successfully with the functionalized monomer. This indicates that the NH groups were preferentially functionalized, and the COOH groups (C=O stretching 1700-1725 cm) were preferentially functionalized. -1 Importantly, this demonstrates that the amide NH bending behavior is preserved upon incorporation of functionalized ATIPA into the TPU backbone. Furthermore, a decrease in the amide NH bending behavior was observed with functionalized ATIPA (orange box).

[0174]

[0252] Figure 36 shows a more complete process for the formation of the TPU described above. Figure 36 shows the pendant vinyl groups of the vinyl diol component, or possibly the functionalized ATIPA. These groups allow for linear crosslinking by post-treatment with electron beam irradiation. Figure 37 shows the crosslinked TPU.

[0175]

[0253] Figure 38 shows the ATR FTIR spectra showing the difference between the control and ATIPA TPU compositions. Significant peaks are labeled, and the difference in peak ratios for amine stretches is circled. The presence of alkenes in the IR spectra indicates the presence of vinyl groups available for crosslinking via electron beam irradiation in both compositions.

[0176]

[0254] Figure 39 illustrates electron beam radiation crosslinking, which provides a relatively environmentally friendly process that can be used in industrial scale operations. Figure 39 illustrates the general electron beam radiation crosslinking mechanism.

[0177]

[0255] Thus, as described above, in some embodiments, thermoplastic shape memory polymer compositions are provided that incorporate X-ray visible groups. The compositions may include radiopaque monomers that are chemically incorporated into the polymer backbone via direct reaction between the carboxylic acid, hydroxyl, and amine of the functionalized radiopaque monomer. However, in other embodiments, the monomers or macromers are functionalized by reaction with the radiopaque monomer prior to polymerization. In one embodiment, the monomer is selected from the group consisting of aliphatic diisocyanates (e.g., hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), isophorone diisocyanate (IPDI), aliphatic diols (e.g., butanediols, pentanediols, hexanediols, butynediols), diols containing pendant vinyl (e.g., unsaturated carbon-carbon double bonds), and radiopaque monomers (e.g., 5-amino-2,4,6-triiodoisophthalic acid, diatrizoic acid, iothalmic acid, triiodophenol, etc.). In one embodiment, for example, a monofunctional isocyanate is reacted with a radiopaque monomer containing an amine group to produce a functionalized radiopaque monomer. The functionalized radiopaque monomer is incorporated into the polyurethane network, creating a polyurethane with x-ray visible groups throughout the bulk material.

[0178]

[0256] In one embodiment, methods for producing polymeric foams from the TPUs described herein include freeze-drying, phase separation, emulsion foaming / templated, supercritical gas foaming, or physical blowing.

[0179]

[0257] In some embodiments, the material may be suitable for manufacturing medical devices, including, but not limited to, subcutaneous implants, aneurysm filling devices, peripheral filling devices, bone grafts, etc. However, in some embodiments, the material may also be used in applications other than medical devices, such as aerospace radiation shielding devices, industrial foams for cushions and mattresses, thermal insulation, etc.

[0180]

[0258] Various examples are given below.

[0259] Example 1b. A polymer composition comprising a thermoplastic polymer (a) covalently bonded to iodine, (b) containing vinyl groups, and (c) containing urethane linkages.

[0260] This does not necessarily mean a direct covalent bond with the iodine.

[0181]

[0261] Other types of Example 1b. A polymer composition comprising a thermoplastic polymer (a) covalently bonded to iodine, (b) containing vinyl, acrylate, or methacrylate groups, and (c) containing urethane linkages.

[0182]

[0262] Other types of Example 1b. A polymer composition comprising a thermoplastic polymer (a) covalently bonded to iodine, (b) containing acrylate groups, and (c) containing urethane linkages.

[0183]

[0263] Other types of Example 1b. A polymer composition comprising a thermoplastic polymer (a) covalently bonded to iodine, (b) containing methacrylate groups, and (c) containing urethane linkages.

[0184] [0264 Other types of Example 1b. A polymer composition comprising a thermoplastic polymer (a) covalently bonded to iodine or boron, (b) containing vinyl groups, and (c) containing urethane linkages.

[0185]

[0265] Other types of Example 1b. A polymer composition comprising a thermoplastic polymer (a) covalently bonded to boron, (b) containing vinyl groups, and (c) containing urethane linkages.

[0186]

[0266] Other types of Example 1b. A polymer composition comprising a thermoplastic polymer containing iodine-containing motifs, vinyl groups, and urethane linkages.

[0187]

[0267] Other types of Example 1b. A polymer composition comprising a thermoplastic polymer (a) covalently bonded to iodine, (b) containing vinyl groups, and (c) containing urethane linkages.

[0188]

[0268] The radiopaque TPUs described herein may be formed into a variety of shapes and geometries, which may be porous or non-porous.

[0189]

[0269] Example 2b. The polymer composition of Example 1b, wherein the thermoplastic polymer is radiopaque.

[0190]

[0270] Example 3b. The polymer composition of Example 1b or 2b, where the iodine is contained in the triiodobenzene monomer.

[0191]

[0271] Other types of Example 3b. The polymer composition of Example 1b or 2b, where iodine is included in the diiodobenzene monomer.

[0192]

[0272] Example 4b. The polymer composition of Example 3b, wherein the triiodobenzene monomer comprises at least one of (a) 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), (b) diatrizoic acid, (c) triiodophenol, or (d) iothamine acid.

[0193]

[0273] Other types of Example 4b. The polymer composition of Example 3b, wherein the triiodobenzene monomer comprises at least one of iohexol; 2-{3-[acetyl(propyl)amino]-2,4,6-triiodophenoxy}hexanoic acid; 2,3,5-triiodobenzoic acid; and / or 3-(3-amino-2,4,6-triiodophenyl)propanoic acid.

[0194]

[0274] Example 5b. The polymer composition of Example 4b, wherein the triiodobenzene monomer comprises ATIPA.

[0195]

[0275] Example 6b. The polymer composition of any of Examples 3b-5b, wherein the triiodobenzene monomer contains a functional group containing either a vinyl group or another vinyl group.

[0196]

[0276] Other types of Example 6b. The polymer composition of any of Examples 3b-5b, wherein the functionalized triiodobenzene monomer comprises a functional group that includes a vinyl group.

[0197]

[0277] For example, in Figure 36, the TPU has two potential sites for vinyl groups, but in some other embodiments, the triiodobenzene may lack vinyl groups.

[0198]

[0278] For example, in one embodiment, ATIPA and / or other triiodobenzene monomers are included in the thermoplastic polymer system with functionalized side chains and / or pendant groups.

[0199]

[0279] Example 7b. The polymer composition of any of Examples 3b-6b, wherein the polymer comprises a backbone comprising triiodobenzene monomers.

[0200]

[0280] Example 8b. The polymer composition of Example 7b, in which the triiodobenzene monomer is attached to the backbone by an amide bond.

[0281] Such amide linkage may be possible due to the preservation of the COOH group, as discussed above, with respect to reaction kinetics, which favors functionalization of the amine of ATIPA.

[0201]

[0282] Other types of Example 8b. The polymer composition of Example 7b, wherein the triiodobenzene monomer is attached to the backbone by at least one of an amide linkage, a urethane linkage, or a urea linkage.

[0283] In the case of triiodophenol or other hydroxyl-containing triiodobenzene monomers, the linking group may comprise a urethane.

[0202]

[0284] Example 9b. The composition of any of Examples 1b-8b, wherein the thermoplastic polymer comprises at least one of platinum, tungsten, and tantalum that is physically bonded within the thermoplastic polymer and not chemically bonded to the thermoplastic polymer.

[0285] For example, a "chemical bond" may include a covalent bond, and a physical bond may not rely on a formal chemical bond (e.g., ionic or covalent bonds of van der Waals attraction), but may rely on resistance, etc.

[0203]

[0286] Example 10b. A polymer composition comprising a thermosetting shape memory polymer (SMP) that (a) is covalently bonded to iodine, (b) contains urethane linkages, and (c) has a gel fraction of at least 0.8 and transitions from a secondary state to a primary state in response to a thermal stimulus.

[0287] A gel fraction of at least 0.8 would indicate a thermosetting polymer rather than a thermoplastic polymer. Other embodiments may include a gel fraction of at least 0.5.

[0204]

[0288] Other types of Example 10b. A polymer composition comprising a thermosetting shape memory polymer (SMP) that (a) is covalently bonded to iodine, (b) contains urethane linkages, and (c) has a gel fraction of at least 0.8 and transitions from a secondary state to a primary state in response to a thermal stimulus.

[0205]

[0289] Example 11b. The polymer composition of Example 10b, wherein the SMP is radiopaque.

[0206]

[0290] Example 12b. The polymer composition of any of Examples 10b-11b, wherein the triiodobenzene monomer comprises iodine.

[0207]

[0291] Example 13b. The polymer composition of Example 12b, wherein the triiodobenzene monomer comprises at least one of (a) 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), (b) diatriiodoisophthalic acid, (c) triiodophenol, or (d) iothamine acid.

[0208]

[0292] Example 14b. The polymer composition of Example 13b, wherein the triiodobenzene monomer comprises ATIPA.

[0209]

[0293] Example 15b. The polymer composition of any of Examples 12b-14b, wherein the SMP comprises a backbone comprising triiodobenzene monomers.

[0210]

[0294] Example 16b. The polymer composition of Example 15b, in which the triiodobenzene monomer is attached to the backbone by an amide bond.

[0211]

[0295] Other types of Example 16b. The polymer composition of Example 15b, wherein the triiodobenzene monomer is attached to the backbone by at least one of an amide linkage, a urethane linkage, or a urea linkage.

[0296] For example, in various thermosets described in Figures 1-28, the primary NH groups are not functionalized and can react to form networks, so that attachment to the backbone may be via amides and / or ureas. In some embodiments of the TPUs described in Figures 29-39, the linkages may be via urethanes or other, depending on the functionality of the triiodobenzene monomers used.

[0212]

[0297] Example 17b. The polymer composition of Example 16b, in which the SMP is crosslinked via an alkyl group.

[0213]

[0298] Other types of Example 17b. The polymer composition of Example 16b, in which the SMP is crosslinked via thiol-ene groups that react with vinyl click chemistry, Michael addition, or Diels-Alder reaction.

[0214]

[0299] Example 18b. The polymer composition of any of Examples 10b-17b, wherein the SMP comprises at least one of platinum, tungsten, and tantalum that is physically but not chemically bonded within the SMP.

[0215]

[0300] Example 19b. The polymer composition according to any one of Examples 10b to 18b includes a foam, the foam comprising SMP and 50 to 500 mg / ml of iodine, and having a dry glass transition temperature of 40 to 80°C.

[0216]

[0301] Example 20b. The polymer composition of Example 19b, which includes a physical backbone comprising at least one of polymer filaments or metal that traverses the foam.

[0302] For example, the backbone can include a shape memory nickel-titanium alloy that forms a helical structure on a foam that is deployed within a tissue void (eg, an aneurysm, left atrial appendage).

[0217]

[0303] Example 21b. 1. A method comprising: providing a triiodobenzene monomer; providing a fatty acid monomer comprising at least one of: (a)(i) a plurality of amine functional groups, (a)(ii) a plurality of alcohol functional groups, and (a)(iii) a plurality of carboxylic acid functional groups; combining the triiodobenzene monomer, the fatty acid monomer, and the diisocyanate in a solution; and forming a thermoplastic polymer from the solution.

[0218]

[0304] Example 22b. The method of Example 21b, including functionalizing an amine group prior to combining the triiodobenzene monomer, the fatty acid monomer, and the diisocyanate in solution, wherein the triiodobenzene monomer includes an amine pendant group.

[0219]

[0305] Example 23b. The method of Example 21b, including functionalizing an amine group with a vinyl group prior to combining the triiodobenzene monomer, the fatty acid monomer, and the diisocyanate in solution, wherein the triiodobenzene monomer includes an amine pendant group.

[0220]

[0306] Example 24b. The method of Example 21b including functionalizing the triiodobenzene monomer with an isocyanate prior to combining the triiodobenzene monomer, fatty acid monomer, and diisocyanate into a solution.

[0221]

[0307] Other types of Example 24b. The method of Example 21b including the step of monofunctionalizing the triiodobenzene monomer prior to combining the triiodobenzene monomer, fatty acid monomer, and diisocyanate monomer into a solution.

[0222]

[0308] Example 25b. The method of Example 24b, wherein the isocyanate comprises at least one of allyl isocyanate, ethyl isocyanate, isocyanoethyl methacrylate (IEMA), or acryloyl chloride.

[0223]

[0309] Example 26b. The method of Example 24b, comprising crosslinking the thermoplastic polymer to form a thermoset polymer via electron beam crosslinking of vinyl groups.

[0224]

[0310] Example 27b. The method of any of Examples 22b-26b, wherein the triiodobenzene monomer has a functionality greater than 2 before amine group functionalization and has a functionality of 2 after amine group functionalization.

[0311] Other types of Example 27b. The method of any of Examples 22b-26b, wherein the triiodobenzene monomer has greater than two reactive functionalities prior to amine group functionalization and has two functional groups after amine group functionalization.

[0225]

[0312] Example 28b. The method of any of Examples 22b-27b, wherein the triiodobenzene monomer contains two carboxylic acid functional groups after amine group functionalization.

[0226]

[0313] Example 29b. The triiodobenzene monomers include at least one of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), diatrizoic acid, triiodophenol, or iothamine, and the fatty acid monomers include 2-butene-1,4-diol; 1,4-butanediol; 1,6-hexanediol; 1,8-octanediol; 1,10-decanediol; 1,6-hexanediylbis[oxy(2-hydroxy-3,1-propanediyl)]bisacrylate; bisphenol A glycerolate dimethacrylate; 3,4-dihydroxy-1-butene; 7-octene-1,2-diol; pentaerythritol triacrylate; diethylene glycol (DEG); diethanolamine; hydroquinone bis(2-hydroxyethyl) ether; and triethylene glycol (TEG). The method of any of Examples 21b-28b, wherein the diisocyanate comprises at least one of 1,6-diisocyanatohexane (HDI); trimethylhexamethylene diisocyanate (TMHDI); dicyclohexylmethane 4,4'-diisocyanate (DCHMDI); isophorone diisocyanate (IPDI); trans-1,4-cyclohexylene diisocyanate; 1,3-bis(isocyanatomethyl)cyclohexane; 1,5-diisocyanato-2-methylpentane; 1,7-diisocyanatoheptane; or 1,8-diisocyanatooctane.

[0227]

[0314] Other types of Example 29b. The triiodobenzene monomer comprises at least one of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA); diatrizoic acid; triiodophenol; iothamic acid; iohexol; 2-{3-[acetyl(propyl)amino]-2,4,6-triiodophenoxy}hexanoic acid; 2,3,5-triiodobenzoic acid (monofunctional only incorporating a COOH group); or 3-(3-amino-2,4,6-triiodophenyl)propanoic acid, and the fatty acid monomer comprises at least one of 2-butene-1, 4-Diol;1,4-Butanediol;1,6-Hexanediol;1,8-Octanediol;1,10-Decanediol;1,6-Hexanediylbis[oxy(2-hydroxy-3,1-propanediyl)]bisacrylate;Bisphenol A glycerol acid dimethacrylate;3,4-Dihydroxy-1-butene;7-Octene-1,2-diol;Pentaerythritol triacrylate;Diethylene glycol (DEG);Diethanolamine;Hydroquinone bis(2-hydro) 1-(benzyloxymethyl)triethylene glycol; 2,2'-ethyliminodiethanol; butanediol; pentanediol; hexanediol; butynediol; a diol containing a pendant vinyl group; 1,5-hexadiene-3,4-diol (HDD), or trimethylolpropane allyl ether (TMPAE); and the diisocyanate is 1,6-diisocyanatohexane (HDI). The method of any of Examples 21b-28b, further comprising at least one of: trimethylhexamethylene diisocyanate (TMHDI); dicyclohexylmethane 4,4' diisocyanate (DCHMDI); isophorone diisocyanate (IPDI); trans-1,4-cyclohexylene diisocyanate; 1,3-bis(isocyanatomethyl)cyclohexane; 1,5-diisocyanato-2-methylpentane; 1,7-diisocyanatoheptane; or 1,8-diisocyanatooctane.

[0228]

[0315] Example 30b. The method of any of Examples 21b-25b and 27b-29b, comprising: shaping a thermoplastic polymer using at least one of solution casting, solution spinning, electrospinning, supercritical foaming, dip coating, thermoforming, compression molding, injection molding, extrusion, film blowing, or additive manufacturing; and after shaping the thermoplastic polymer, crosslinking the thermosetting polymer via electron beam crosslinking to form a thermosetting polymer.

[0316] For example, small pore SMP foams may be obtained by supercritical foaming.

[0229]

[0317] Example 31b. The method of any of Examples 21b-25b and 27b-30b, comprising: crosslinking the thermoplastic polymer to make the primary state of the thermoset polymer a permanent shape; applying stress or strain at a temperature above the working transition temperature of the thermoset polymer to stabilize the secondary state of the thermoset polymer; and cooling the thermoset polymer to a temperature below the transition temperature while the thermoset polymer is in the secondary state.

[0230]

[0318] Example 32b. The method of any of Examples 21b-31b, comprising processing the thermoplastic polymer into a foam by at least one of freeze drying, phase separation, emulsion foaming, emulsion templating, chemical blowing, or physical blowing.

[0231]

[0319] Other types of Example 32b. The method of any of Examples 21b-31b, comprising processing the thermosetting polymer into a foam by at least one of freeze drying, phase separation, emulsion foaming, emulsion templating, chemical blowing, or physical blowing.

[0232]

[0320] Example 33b. The method of any of Examples 21b-31b, comprising processing the thermosetting polymer into a foam by blowing based on a blowing agent that is triiodobenzene monomer.

[0233]

[0321] Example 34b. 1. A method comprising: providing a triiodobenzene monomer with two reactive end groups; providing a fatty acid monomer with two reactive functional end groups, the reactive functional end groups including (a)(i) an amine functional group, (a)(ii) an alcohol functional group, and (a)(iii) a carboxylic acid functional group; providing a diisocyanate; combining the triiodobenzene monomer, the fatty acid monomer, and the diisocyanate into a solution; and forming a thermoset shape memory polymer (SMP) foam from the solution.

[0234]

[0322] Example 35b. The triiodobenzene monomer comprises a first member selected from the group consisting of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), diatrizoic acid, iohexol, triiodophenol, 2-{3-[acetyl(propyl)amino]-2,4,6-triiodophenoxy}hexanoic acid, 2,3,5-triiodobenzoic acid, and 3-(3-amino-2,4,6-triiodophenyl)propanoic acid, and the fatty acid monomer comprises 1,2,6-hexanetriol (HT); 2-butyl-2-ethylpropanediol (BEP); 3-methyl-1,5-pentanediol (MPD); diethylene glycol (DEG); triethylene glycol (TEG); triethanolamine (TEA); tetrakis-hydroxypropylethylenediamine (HPED); glycerol 2-amino-2-methyl-1,3-propanediol; 1,3-diamino-2-propanol; and aspartic acid; and the diisocyanate comprises a third component selected from the group consisting of hexamethylene diisocyanate (HDI); trimethylhexamethylene diisocyanate (TMHDI); isophorone diisocyanate; 1,3,4-triisocyanate-2,4,6-trimethylbenzene; toluene diisocyanate; and diphenylmethane diisocyanate.

[0235]

[0323] Example 36b. The method of Example 35, wherein the second component is selected from the group consisting of HT, BEP, MPD, DEG, TEG, TEA, HPED, glycerol, trimethylolpropane, trimethylolmethane, and 1,2,4-butaneburyol.

[0236]

[0324] Example 37b. The method of example 35, wherein the second member is functionalized to reduce the number of reactive end groups to two, and the second member is selected from the group consisting of 1,2-diaminopropane; 2,2-dimethyl-1,3-propanediamine; 1,8-diaminooctane; 3-amino-1,2-propanediol; and 2-amino-2-methyl-1,3-propanediol.

[0237]

[0325] Example 38b. The method of any of Examples 35-37, wherein the third component is selected from the group consisting of HDI, TMHDI, and isophorone diisocyanate.

[0238]

[0326] Example 39b. The method of any of Examples 35-37, wherein the third component is selected from the group consisting of: 1,3,4-triisocyanate 2,4,6-trimethylbenzene; toluene diisocyanate; and diphenylmethane diisocyanate.

[0239]

[0327] Example 40b. The method of any of Examples 35-39, wherein the first component is ATIPA.

[0240]

[0328] Example 41b. The method of any of Examples 35 to 40, comprising cross-linking the second and third components with the first component.

[0241]

[0329] Example 42b. The method of any one of Examples 35 to 41, comprising using the first component as a chemical foaming agent.

[0242]

[0330] Example 43b. The method of any of Examples 35-42, wherein the fatty acid monomer comprises a fourth member selected from the group consisting of HT; BEP; MPD; DEG; TEG; TEA; HPED; glycerol; trimethylolpropane; trimethylolmethane; 1,2,4-butanetriol; 1,2-diaminopropane; 2,2-dimethyl-1,3-propanediamine; 1,8-diaminooctane; 3-amino-1,2-propanediol; 2-amino-2-methyl-1,3-propanediol; 1,3-diamino-2-propanol; and aspartic acid.

[0243]

[0331] Thus, Examples 34b-43b relate to how the methods corresponding to Figures 1-28 can be combined with the methods corresponding to Figures 29-39.

[0244]

[0332] Those skilled in the relevant art will appreciate that many modifications and variations are possible in light of the above teachings. Those skilled in the art will recognize various equivalent combinations and substitutions for the various components shown. Accordingly, it is intended that the scope of the invention be limited by the description in this specification and by the appended claims.

Claims

1. below; providing a triiodobenzene monomer; (a) providing an aliphatic monomer comprising at least one of: (i) a plurality of amine functional groups, (a)(ii) a plurality of alcohol functional groups, and (a)(iii) a plurality of carboxylic acid functional groups; providing a diisocyanate; mixing the triiodobenzene monomer, the aliphatic monomer, and the diisocyanate into a solution; and forming a thermoplastic polymer from said solution; 1. A method comprising: the triiodobenzene monomer comprises at least one of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA); diatrizoic acid; triiodophenol; iohexol; iothalmic acid; 2-{3-[acetyl(propyl)amino]-2,4,6-triiodophenoxy}hexanoic acid; 2,3,5-triiodobenzoic acid (monofunctional only incorporating a COOH group); or 3-(3-amino-2,4,6-triiodophenyl)propanoic acid; The aliphatic monomers include 2-butene-1,4-diol; 1,8-octanediol; 1,10-decanediol; 1,6-hexanediylbis[oxy(2-hydroxy-3,1-propanediyl)]bisacrylate; bisphenol A glycerolate dimethacrylate; 3,4-dihydroxy-1-butene; 7-octene-1,2-diol; pentaerythritol triacrylate; diethylene glycol (DEG); and diethanol. amine; hydroquinone bis(2-hydroxyethyl)ether; triethylene glycol (TEG); 1-(benzyloxymethyl)triethylene glycol; 2,2'-ethyliminodiethanol; butanediol; pentanediol; hexanediol; butynediol; a diol containing a pendant vinyl group; 1,5-hexadiene-3,4-diol (HDD), or trimethylolpropane allyl ether (TMPAE), and the diisocyanate comprises at least one of 1,6-diisocyanatohexane (HDI); trimethylhexamethylene diisocyanate (TMHDI); dicyclohexylmethane 4,4' diisocyanate (DCHMDI); isophorone diisocyanate (IPDI); trans-1,4-cyclohexylene diisocyanate; 1,3-bis(isocyanatomethyl)cyclohexane; 1,5-diisocyanato-2-methylpentane; 1,7-diisocyanatoheptane; or 1,8-diisocyanatooctane; method.

2. the triiodobenzene monomer comprises an amine pendant group, and further comprising the step of functionalizing the amine pendant group with a vinyl group prior to the step of combining the triiodobenzene monomer, the aliphatic monomer, and the diisocyanate into a solution, wherein: the triiodobenzene monomer has greater than two functional groups prior to functionalization with the amine pendant groups; the triiodobenzene monomer has two functional groups after functionalization of the amine pendant groups; The method of claim 1.

3. 10. The method of claim 1, further comprising the step of functionalizing the triiodobenzene monomer with a monofunctional isocyanate prior to the step of combining the triiodobenzene monomer, the aliphatic monomer, and the diisocyanate into solution.

4. 3. The method of claim 2, further comprising crosslinking the thermoplastic polymer via electron beam crosslinking of vinyl groups to form a thermoset polymer.

5. 3. The method of claim 2, wherein after functionalizing the amine pendant groups, the triiodobenzene monomer comprises two carboxylic acid functional groups.

6. Additionally, the following: forming a foam of the thermoplastic polymer using at least one of solution casting, solution spinning, electrospinning, supercritical foaming, dip coating, thermoforming, compression molding, injection molding, extrusion, film blowing, or additive manufacturing; after forming the foam of the thermoplastic polymer, crosslinking the thermoplastic polymer via electron beam crosslinking to form a thermoset polymer; The method according to any one of claims 1 to 3, comprising:

7. Additionally, the following: crosslinking said thermoplastic polymer to render said thermoset polymer morphology permanently primary; applying a stress or strain at a temperature above the actuation transition temperature of the thermosetting polymer to form the thermosetting polymer into a stable secondary state; 7. The method of claim 6, comprising: When the thermosetting polymer is in a secondary state, the method comprises cooling the thermosetting polymer to a temperature below the actuation transition temperature.

8. 5. The method of any one of claims 1 to 4, further comprising processing the thermoplastic polymer into a foam by at least one of freeze drying, phase separation, emulsion foaming, emulsion templating, chemical blowing, or physical blowing.

9. 5. The method of claim 4, wherein the triiodobenzene monomer is a blowing agent, the method further comprising processing the thermosetting polymer into a foam via blowing based on the blowing agent.

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