Radiopaque nano and polymeric materials for atherosclerosis imaging, embolization and other catheterization procedures.

A review of radiopaque nano and polymeric materials for atherosclerosis imaging and catheterization procedures is presented in this paper. Cardiovascular diseases (CVDs) are the leading cause of death in the US with atherosclerosis as a significant contributor for mortality and morbidity. In this review paper, we discussed the physics of radiopacity and X-ray/CT, clinically used contrast agents, and the recent progress in the development of radiopaque imaging agents and devices for the diagnosis and treatment of CVDs. We focused on radiopaque imaging agents for atherosclerosis, radiopaque embolic agents and drug eluting beads, and other radiopaque medical devices related to catheterization procedures to treat CVDs. Common strategies of introducing radiopacity in the polymers, together with examples of their applications in imaging and medical devices, are also presented.

Introduction

Cardiovascular disease (CVD) is responsible for a significant percentage of morbidity, mortality, and financial burden on individuals and families, particularly in developed countries like the United States. Common manifestations of these diseases include vascular stenosis such as atherosclerosis, hypertension, chronic obstructive pulmonary disease, and blood-clotting disorders such as embolisms and thromboses. Though cardiovascular and blood diseases can be attributed to a variety of factors, the aging of the general population has been correlated with an increasingly prevalent diagnosis in medical practice. The 2017 Heart Disease and Stroke Statistics Update compiled by the American Heart Association revealed that nearly 801,000 deaths were attributed to CVD, making it the leading cause of death in the United States and claiming more lives than all forms of cancer and lower respiratory diseases combined. Four hundred ninety six thousand, or 61.5% of these deaths were attributed to vascular stenosis-related diseases or complications. In 2010, an estimated 7,588,000 inpatient cardiovascular operations and procedures were performed in the United States and CVD also ranked highest in the number of hospital patient discharges. It should be noted that these figures only represent clinical data. It is estimated that 92.1 million US adults live with some degree of CVD. Of these, 46.7 million are estimated to be 60 years of age or older and a total of 11.5% of American adults (27.6 million) have been diagnosed with heart disease. By 2030, 43.9% of the US adult population is projected to have some form of CVD.

Radiopacity and the application in CVD imaging

Embolization procedures are often guided by ultrasound and X-ray imaging. Ultrasound is a non-invasive imaging modality which uses sound waves that have frequencies higher than what human can hear. A sound wave is generated by a transducer and partially reflected when there is a change in the acoustic impedance. The ultrasound collects the reflected waves, or echoes, and transforms them into digital images. Intravascular ultrasound has been used extensively for cardiovascular imaging and catheterization procedures5, 6. Compared to ultrasound, X-rays have even higher frequencies, and can provide more detailed and clear images. X-ray fluoroscopy shows real-time images, facilitating interventional procedures like the guidance of catheters for embolization, and an X-ray angiogram can be used to map the vasculature along with any abnormalities like stenosis or thrombosis7, 8. More recently, computed tomography (CT) has also been used as a noninvasive alternative to traditional X-ray techniques to produce three-dimensional images and show size, shape, and composition10, 11. However, X-ray is limited in the contrast it can provide toward differentiating between different soft tissue and healthy and pathological tissue. Therefore, a contrast agent with a different radiopacity than the surrounding tissues is often used to enhance the images. We will introduce the basics of radiopacity in the following paragraphs.

Physics of X-ray and radiopacity

Although there are many different applications of X-rays, the physics behind the phenomena is largely the same. X-rays are produced by the collision and deflection of accelerated electrons with the target. The two types of resultant radiation are called Bremsstrahlung and characteristic radiation. The deflected incident electrons continue producing Bremsstrahlung and characteristic radiation until its energy is depleted.

In the diagnostic energy ranges, the photoelectric effect, the main form of interaction between X-ray photons and the subjects, and the Compton effect are the two processes through which photons can interact with the absorbing subject. Fig. 1 shows the relative amount of interactions by the photoelectric effect and the Compton effect. The photoelectric effect occurs when a X-ray photon of higher energy than the k-/l-edge energy of the target transfers all of its energy to an inter-shell electron, causing the photon to cease to exist while a photoelectron is emitted11, 13. The atom will then emit characteristic X-rays when a higher energy electron fills in the void left by the photoelectron.

Figure 1

At most diagnostic CT energy levels, the photoelectric effect is dominant. Image taken from Ref. 12. Available from: 〈https://www.intechopen.com/books/advanced-image-acquisition-processing-techniques-and-applications-i/high-density-devices-applied-to-a-gamma-camera-implementation〉, which is licensed under CC BY 3.0.

For a CT contrast agent to be effective, images need to be taken with peak voltages higher than the k-edge of the agent, providing contrast enhancement between the surroundings and the agent itself. Hounsfield units (HU)=1000×(μ−μwater)/(μwater−μair) quantify X-ray attenuation, where μ are linear attenuation coefficients. The Hounsfield scale is standardized based on HUwater=0 and HUair=—100013, 14.

Clinically used radiopaque contrast agents

For vasculature and tissues to be differentiated by visual inspection, radiopaque contrast agents are administered to the areas of interest, which increases the attenuation of the targeted tissues. CT contrast agents are usually elements with large atomic numbers like iodine, barium, gold, or bismuth that have k-/l-edges of higher energies than tissue to facilitate the absorption of X-ray photons13, 15. For CT, iodinated contrast agents are the most prevalent and FDA approved.

Iodinated contrast agents are commonly used intravenously to visualize organs and vasculature. However, iodinated contrast agents also are rapidly cleared by the kidney, which means that higher doses must be given for longer CT scans13, 16. Side effects of the iodinated agents can include contrast-induced nephropathy, nausea, vomiting, and even anaphylaxis17, 18. Furthermore, CT contrast agents are usually on the molar concentration scale, which has researchers looking for new contrast agents with greater imaging capabilities, smaller dose requirements, and lower toxicity.

Small molecule iodinated contrast agents can be ionic and nonionic. Compared with nonionic contrast agents, ionic contrast agents have greater chances to interact with biological structures and have high osmolality, possibly resulting in issues like osmotic dilution and renal toxicity19, 20, 21. The structure of these contrast agents usually contains single or double aromatic rings. Fig. 2 shows the structure of iohexol (Omnipaque), a single aromatic ring molecule. Some commercially available small molecule iodinated contrast agents are listed in Table 1.

Figure 2

Molecular structure of iohexol (Omnipaque), a small molecule iodinated single aromatic ring contrast agent available for commercial use.

Table 1

Commercially available small-molecule iodinated contrast agents.

Category	Generic name	Brand name	Manufacturer
Ionic	Diatrizoate	Gastrografin	Therapex
	Iothalamate	Conray	Liebel-Flarsheim Company
Nonionic	Iodixanol	Visipaque	GE Healthcare
	Iohexol	Omnipaque	GE Healthcare
	Iopamidol	Isovue	BIPSO GmbH
	Iopromide	Ultravist	Bayer Healthcare
	Ioversol	Optiray	Liebel-Flarsheim Company
	Ioxilan	Oxilan	Guerbet LLC

While lanthanide-based contrast agents, specifically gadolinium chelates, are used in MRI imaging, they can also act as CT contrast agents in cardiovascular and pulmonary angiographies because of high atomic numbers, leading to better attenuation14, 22. Gadoxetate disodium, brand name Eovist, made by Bayer Healthcare, is a contrast agent that can be used for CT imaging the liver14, 23. However, although gadolinium compounds can be used as both MRI and CT contrast agents due to its chemical and physical properties, more research is needed to improve their efficacy as multimodal contrast agents. Multimodal contrast agents based on perfluorooctyl bromide have been used for many years to help image the liver, spleen, and vasculature13, 24. Barium sulfate is a common orally-taken contrast agent used for imaging of the gastrointestinal tract. In some countries, xenon gas is used clinically as an alternative to iodinated media in cerebrovascular imaging. Xenon has a short half-life of around 30 s; side effects related to its anesthetic properties include nausea, headaches, and vomiting.

Radiopaque nanoparticles and biomaterials for atherosclerosis imaging and catheterization procedures

Vascular stenosis is the most prevalent and leading cause of death in those affected by CVD. Healthy arteries are flexible and have smooth inner walls free from occlusion and pressure. However, vascular stenosis occurs when a progressive narrowing of the lumen obstructs local blood flow and inhibits the perfusion of tissue and organs. Vascular stenosis can manifest from extrinsic or intrinsic conditions. Extrinsic stenosis is caused by external compression on arteries usually as the result of tumors, aneurysms or foreign objects, which obstructs optimal blood flow. Intrinsic stenosis, or atherosclerosis, is a condition of intramural buildup and interaction of high concentrations of apolipoprotein B-containing lipoproteins, cells such as macrophages, dendritic cells, T cells, and other cellular material inside medium to large thick-walled arteries. This volatile interaction leads to an inflammatory response and eventually the development of complex lesions, or plaques, that extend into and narrow the arterial lumen. These plaque lesions can rupture and thrombosis can migrate, preventing the flow of oxygen rich blood to vital tissue and organs including the heart (coronary artery disease), brain (ischemic stroke) or the lower extremities (peripheral vascular disease). An increased blood concentration of apolipoprotein B–containing lipoproteins, can be enough to cause atherosclerosis, such as in familial hypercholesterolemia. In most cases, however, atherosclerosis is able to develop at lower concentrations in combination with other potential risk factors including hypertension, smoking, obesity, male sex, and genetic susceptibility to the disease32, 33, which suggests the multifactorial nature of the disease. The most serious vascular stenosis disease is congenital heart disease (CHD), which often leads to the clinical complications of myocardial infarction and angina pectoris, and cerebrovascular disease, which often leads to stroke. Myocardial infarction and stroke were the two highest causes of death in those affected by cardiovascular disease in 2016, accounting for 45.1% and 16.5% of death respectively. Due to the prevalence of vascular stenosis morbidity and mortality, a consistently successful treatment of atherosclerosis has been a highly desirable clinical achievement.

Current standard treatment varies by severity and risk of the disease but includes diet and lifestyle changes, lipid reduction medications such as MG-CoA reductase inhibitors, and therapeutic agents targeting various factors, such as chemokine38, 39, 40 and corresponding receptors41, 42, macrophage migration inhibitory factor43, 44, platelets45, 46, 47, 48, and so on. In severe cases, surgical treatments include highly invasive interventions such as coronary artery bypass grafting that uses autologous vessels to bypass diseased coronary arteries, carotid endarterectomy that removes plaque buildup, and percutaneous coronary intervention that opens up blocked or narrowed coronary arteries. In a percutaneous coronary intervention procedure, under the image guidance of X-ray fluoroscopy, an interventional radiologist or a cardiologist inserts a catheter into the diseased coronary artery from the femoral artery and uses a balloon from the catheter tip to open narrowed arteries. Sometimes, a stent is also deployed during the procedure to ensure blood flow through the diseased vessels.

Aside from opening up occluded blood vessels via balloon catheter and stent, the catheterization technique can also be used to deliver medication or artificial embolic agents to block blood flow to an area of the body, termed embolization. An embolization procedure is usually image guided by ultrasound or X-ray. When X-ray fluoroscopy is used, the embolic agents are usually mixed with a contrast agent, and the mixture is injected via the catheter. The X-ray fluoroscopy monitors the injection and the flow of the mixture in real time, and the catheter guides the delivery of the embolic agents to the vessels of interest. X-ray fluoroscopy has many applications that are extraordinarily diverse. As a pathological procedure, it is used extensively in occluding internal hemorrhages such as gastrointestinal bleeding, cerebral aneurysms, postpartum bleeding and surgical/traumatic bleeding. A significant emerging application of embolization is its potential as a treatment for certain types of cancer. In tumor therapy, embolization is used to reduce tumors by slowing or stopping blood supply to cancerous cells54, 55. Embolic agents in the form of liquid and small particles are manipulated to create capillary occlusion, though it should be noted that this can lead to higher risk of necrosis and ischemia. The occlusion is commonly built through an endovascular procedure but the result can also be achieved by other means such as by percutaneous injection of embolic agents into the tumor. In cancer treatment applications, the embolic agents, in addition to blocking blood supply to the tumor, can also be used as a mechanism for delivering drugs to attack the tumor chemically. However, most commercially available embolic agents are radiolucent. To make them radiopaque, embolic agents are mixed with iodine-based contrast agents. However, once the contrast agent has circulated off, it is difficult to determine the location and integrity of these embolic agents. Thus, researches have been focused on the development of radiopaque embolic agents that could be easily monitored by X-ray without the help of external mixing of contrast agents.

The development of radiopaque nanomaterials is aimed at improving the shortcomings of the above-mentioned small molecular weight contrast agents, such as oxicity and short imaging window. The general goal of its development is to enhance the contrast of either the diseased area or the nanomaterials themselves for easy deployment and long-term monitoring. In this review, we surveyed from published literature the various nanoparticles and biomaterials used for imaging atherosclerosis and catheterization procedures.

Research and development of nanoparticle contrast agents for atherosclerosis imaging

From the abovementioned discussion, the toxicity mainly comes from the contact between iodine and the blood or tissue components, and the short imaging window is from the fast clearance of small molecular weight iodine. Thus, research and development of radiopaque nanomaterials is focused on masking iodine in the nanomaterials by physical entrapment, chemical conjugation or polymerization, thus preventing the contact of bare iodine molecule, confining the radiopacity to the polymeric chain and prolonging the half-life of the polymerized iodine. Alternatively, noble elements with higher Z numbers are also synthesized into nanoparticles as contrast agents. These noble elements are toxic in their ionic forms, but as nanoparticles are either inert or made biocompatible by surface modification. The nanoparticle structures include nanoemulsion, micelle, dendrimer, and liposome. Nanoemulsion, for instance, has also been used in small molecular weight contrast agent, such as Lipiodol, an iodinated contrast agent made from poppy-seed oil58, 59. Compared with small molecular weight contrast agents, these nanoparticles usually have less toxicity and longer circulation in the body. More importantly, the nanoparticles can undergo surface modification to target specific lesions for more accurate imaging.

While the calcification of atherosclerotic plaque provides a good CT imaging of the target, the progression of atherosclerosis also offers other targets including macrophages and fibrin.Macrophages can uptake large amounts of nanomaterials and contribute to the poor delivery efficiency. However, macrophages also accumulate in the plaque and offer a good target for CT imaging. For example, Hyafil et al. developed a suspension containing crystalline iodinated particles, N1177, for noninvasive macrophage imaging (Fig. 3). N1177 did not affect the viability of J774 macrophages or their phagocytic capacity or cytokine production. Two hours after injection, N1177 accumulated in the macrophages in the atherosclerotic plagues on a rabbit model (Fig. 4). Another study done by Cormode et al. used gold high-density lipoprotein nanoparticle contrast agent (Au-HDL) and a multicolor CT to characterize the macrophage burden, calcification, and stenosis of atherosclerotic plaques. Au-HDL mainly localized in the macrophages, and the multicolor CT was able to differentiate Au-HDL, iodine based contrast agent, and calcified material in the atherosclerosis.

Figure 3

Properties of the contrast agent N1177. (a) Schematic representation of the iodinated compound of the contrast agent N1177 with the three iodine atoms in red. (b) Electron microscopic view of N1177 showing electron-dense iodinated granules coated by polymers appearing as negative prints after staining with a solution of uranyl acetate. Note the various sizes and shapes of nanoparticles found in the suspension. Scale bar, 100 nm. (c and d) Optical microscopy in a phase-contrast mode of macrophages after 1 h incubation in vitro with N1177 (c) or with the conventional CT contrast agent (d). Numerous dark granules were visualized only in the cytoplasm of macrophages incubated with N1177. Scale bar, 100 μm. (Reprinted from Fig. 1 in Ref. 61 with permission).

Figure 4

N1177-enhanced CT and corresponding 18F-FDG PET of aorta from atherosclerotic rabbit. Fused PET/CT coronal view of aorta obtained at 3 h after injection of 18F-FDG (A) and corresponding axial aortic sections acquired before (B and D) and at 2 h after injection of N1177 (C and E). In same rabbit, aortic regions with high (A; red cross) and low (A; blue cross) activities identified with PET at 3 h after injection of 18F-FDG were associated with strong (E; red cross) and weak (C; blue cross) intensities of enhancement detected with CT at 2 h after injection of N1177 on corresponding axial views, respectively. (Reprinted from Fig. 2 in Ref. 63 with permission).

Similar to macrophages, fibrin is also accumulated in atherosclerotic plaque and a good target for atherosclerosis imaging. The fibrin monomers are generated by cleavage of fibrinogen, which then polymerize and crosslink to form a stable clot. Fibrin deposition can initiate and contribute to plaque growth, and thrombus formation on ruptured atherosclerotic plaques is a precursor of myocardial infarction and stroke. Thus, fibrin targeted imaging could reveal information not only on the plaque but also identify “vulnerable” plaques that may lead to myocardial infarction and stroke. Winter et al. conjugated anti-fibrin F(ab)' fragments to iodinated oil nanoparticle and imaged such “vulnerable” human fibrin clots in vitro.

Recent progress on the development of radiopaque polymeric materials for medical devices or agents for embolization and other catheterization procedures

The application of nanoparticle contrast agents and the development of radiopaque polymeric materials are to improve existing treatment or devices. Current existing vascular implants or medical devices are usually made of various metals with an inert surface. They are highly radiopaque, but other properties are suboptimal, such as the inability of inert surfaces to seal aneurysms or the non-degradability that requires surgical removal after the intended use. Radiopaque polymeric materials are versatile and aimed at improving these shortcomings when forged into these medical devices. In this section, we will briefly introduce the disease and procedure if they have not been discussed, the inadequacy of current devices and how radiopaque polymeric materials could improve these shortcomings.

One of the most used strategies in developing radiopaque polymer is to incorporate radiopaque materials in the polymer. Radiopaque materials include small molecular weight salts or compounds or nanoparticles containing iodine, barium, tantalum, bismuth, or gold. These radiopaque materials can be either blended into the polymer during the manufacturing at a specific ratio or infused into the manufactured polymer by organic solvent treatment.

Embolic and chemoembolic materials

Chemoembolization is an effective intervention for liver tumor treatment. In a typical procedure, a viscous drug carrier (the embolic agent) is mixed with contrast agent and injected through the portal vein under X-ray guidance for optimal embolization result. A variety of radiopacifiers, such as barium sulphate and silver iodide complexes, were also used to introduce radiopacity. Barium sulfate-containing alginate microspheres, tantalum-containing polyurethane microspheres and various zinc-silicate bioglasses71, 72 were also tested. Among all these studies, the most common and incorporated radiopaque agent is still organoiodine compound.

Reports of the research and development of radiopaque embolization beads using organoiodine compounds appeared as early as the 1980s73, 74, 75, 76, 77, 78. Poly(2-hydroxyethymethacrylate) was among the first hydrogels used in the research. Iodine based contrast agent was covalently linked with the hydrogel via acylation with 3-acetylamino-2,4,6-triiodobenzoyl chloride to introduce radiopacity. Alternatively, radiopacity could also be introduced via radical polymerization using 2-[4-iodobenzoyloxy]-ethyl methacrylate. Surface functionalization could also be achieved by binding new monomer. For example, acrylic microspheres were synthesized from methyl methacrylate, methacrylic acid and 2-[4-iodobenzoyloxy]-ethyl methacrylate. Methacrylic acid served as a carboxylic acid group source on the microsphere surface for thrombin immobilization. The microspheres were visible under X-ray when inserted into a rabbit cadaver, and the radiopacity was dependent on iodine concentration. The conjugated thrombin on the surface captured fibrin, accelerated sphere aggregation, and induced additional thrombin generation in vitro.

Another commonly used material is polyvinyl alcohol. Radiopacity can be introduced by covalent linkage of organoiodine compounds81, 82, insertion of Lipiodol into the microsphere, coacervation of Lipiodol with polyvinyl alcohol at the cloud point of the polyvinyl alcohol solution followed by cross-linking reaction, or multiple emulsions followed by cross-linking reaction. Biocompatibles Inc. produced polyvinyl alcohol based beads, and they have been studied in the development of radiopaque drug eluting beads86, 87, 88. Radiopacity was introduced by loading Lipiodol into the polyvinyl alcohol hydrogel microspheres (100–300 µm). The iodine content by weight in the radiopaque microspheres reached 35.7%, and the loading was high enough to produce visible CT attenuation in vivo. Then doxorubicin was loaded into the radiopaque beads to create radiopaque drug eluding beads (Fig. 5). The impact of bead size to local drug distribution following transcatheter arterial chemoembolization was also studied. Small beads (70–150 µm) and large beads (100–300 µm) were prepared from loading DC/LC Beads with doxorubicin and Lipiodol and injected into normal swine liver and kidney. It was observed that small beads penetrated farther into the distal regions and created a higher spatial frequency and a more homogeneous distribution than large beads (Fig. 6). The distance of drug penetration from the bead surface into the tissue was similar between small and large beads. Thus, small beads resulted in a higher and more uniform drug coverage in the targeted tissues. When evaluated on a rabbit liver VX2 tumor model, the mean tumoral doxorubicin concentration in the group treated by the small beads almost tripled the group treated by the large beads, which was statistically significant. However, the plasma doxorubicin and doxorubicinol pharmacokinetics profiles were similar between the two groups.

Figure 5

Summary of procedural steps for generating radiopaque drug eluting beads. (Reprinted from Ref. 89 with permission).

Figure 6

MicroCT of swine kidney tissue embolized with radiopaque drug eluting beads. Small (70–150 µm) and large (100–300 µm) beads are displayed with consistent size scaling. Small beads penetrate to more distal regions and yield a greater spatial density. (Reprinted from Fig. 2 in Ref. 90 with permission).

Depending on the physical properties of the embolic agent, there are permanent and temporary embolizations. For liver chemoembolization, temporary embolization is desired due to the requirement of repetitive treatment. While permanent embolization has many choices of the embolic agent, temporary embolization essentially has only one commonly used agent, gelatin sponge. Gelatin is degraded by enzymes in vivo to achieve the temporary embolization. However, this degradation is unpredictable and unwanted early recanalization or permanent occlusion may occur. To better monitor not only the in vivo degradation but also the injection of the plugs, Venkatraman's group developed a radiopaque embolic plug based on synthetic polymers The core of the plug consisted of poly(d,l-lactide-co-glycolide) (PLGA, molar ratio 50/50, MW=90,000 g/mol). Different amounts of barium sulfate, tantalum, and bismuth (III) oxychloride were used as radiopaque fillers and co-extruded with PLGA. Bismuth and tantalum yielded brighter and sharper images, and the addition of all fillers lowered the glass transition temperature (Tg) of PLGA. To introduce the shape memory effect of the plug, Tg was further adjusted to slightly below the body temperature by mixing PEG (MW=2000 g/mol) into the PLGA matrix. In the last step, crosslinked poly (ethylene glycol) diacrylate hydrogel was coated on the PLGA core to introduce water-responsive shape memory effect. In vitro degradation data suggested a 90% decrease in PLGA MW by day 25 but less than 50% mass loss by day 30. Then at day 70, the mass loss was 75%. In vivo evaluation on a rabbit model suggested the embolic plug was visible under fluoroscopy without the assistant of additional contrast agent. Embolic plug shape change and complete vascular occlusion was achieved within 2 min.

Stent filler

A strategy similar to the previous section is used on the research and development of radiopaque biodegradable polymeric stents. Radiopaque materials are usually blended with the polymer to introduce radiopacity, such as barium sulfate blended in PLA93, 94, 95. The resulting polymers have been applied to biliary and ureteral stents. For example, a biliary stent can be inserted into the bile duct in the treatment of bile leaks. The biodegradable and radiopaque fiber was manufactured by first blending 96 L/4D PLA with 23% (w/w) BaSO4 using melt spinning then solid-state drawing. Then the fiber was braided into a tubular mesh to create the stent. These biodegradable and radiopaque stents were observed to be intact at 3 months and degraded in 6 months, and they were as effective in the treatment of bile leaks as compared to the control polyethylene stents.

Filler on intracranial aneurysm coils

An intracranial aneurysm is a balloon developed on an intracranial vessel. If the aneurysm ruptures, a subarachnoid hemorrhage occurs, which over 25,000 people develop yearly. Treatment of intracranial aneurysms includes surgical clipping and embolization coiling. Embolization coiling achieved slightly better clinical outcomes than surgical clipping on patients with ruptured aneurysms. Embolization coiling is an interventional procedure, where soft platinum coils are deployed through catheters to fill the aneurysm. Then natural clotting occurs around the coils and further blood flow is prevented into the aneurysm. However, the long term clinical outcome of embolization coiling showed an aneurysm recanalization rate up to 15%. One contributing factor to the recanalization is the inert surface of the platinum coils. Such an inert surface discourages endothelial cell adhesion and an organized thrombus structure. When a thrombus is loosened, blood flow can reenter the aneurysm, and recanalization occurs. A stent may be placed at the neck of a wide neck aneurysm to assist the embolization coiling. Alternatively, the coil surface can been modified with bioactive materials, such as collagen or shape memory polymers to improve clotting and scarring, stabilize thrombus and speed up aneurysm occlusion. Total polymeric coils have also been developed for these purposes.

In order to address the aforementioned issues, Hampikian et al. developed a radiopaque total polymeric coil. In this coil, a shape memory polymer Calomer™ was investigated as the coil candidate. Tantalum metal powder (325 mesh) was used as the radiopaque filler at a volume fraction of 3% and weight fraction of 50%. The addition of tantalum powder introduced a small decrease in Tg and shape recovery force but did not affect the shape recovery process or the in vitro deployment. The radiopacity of the coils was confirmed by clinical X-ray imaging.

Radiopaque infera vena cava filters

Our group recently engaged in the development of radiopaque and resorbable infera vena cava filters (IVCFs)100, 101. IVCFs are indicated for at-risk patients who are contraindicated with anticoagulants. The filters are deployed to inferior vena cava to capture thrombi and prevent them from traveling to the organs and cause fatal stoppage of blood flow. There are two types of IVCFs—permanent and temporary. Temporary IVCFs are meant to be removed after 5–6 weeks when the patients are no longer at risk. Failure of removal may cause fatal and costly complications. However, around half of the patients do not return to receive the surgical removal. Thus, a resorbable IVCF based on polydioxanone (PPDO) is developed. However, PPDO is radiolucent and PPDO IVCFs cannot be easily monitored during the deployment or for long term stability. Therefore, our group developed radiopaque PPDO materials for use as ICVF (Fig. 7). PPDO expands but does not dissolve in some organic solvents, such as dichloromethane or chloroform. At the same time, certain organoiodine contrast agents and hydrophobic metal nanoparticles dissolve in dichloromethane or chloroform. Thus, we infused PPDO with organoiodine compounds, and the resulting PPDO had significant enhanced radiopacity on both X-ray and micro-CT and maintained the mechanical strength and biocompatibility compared to untreated PPDO. We further improved the contrast agent by using 2- and 4-nm hydrophobic gold nanoparticles. Due to the higher Z number of gold, the radiopacity was even stronger than iodine infused PPDO, and the gold content and radiopacity remained stable over 6 weeks, which is the expected dwell time of the temporary ICVF (Fig. 8).

Figure 7

Illustration of the generation of radiopaque PPDO IVCF by gold nanoparticle (AuNP) infusion.

Figure 8

Long-term exposure to physiologic conditions did not affect radiopacity or gold content of gold nanoparticle–infused PPDO sutures. AuNP-infused PPDO sutures were suspended in PBS at 37 °C for up to 10 weeks. Three sutures were collected each week and imaged by micro-CT to determine radiopacity. Representative images over weeks 1—6 of the observation period are shown. The gold content was measured by ICP-OES, and the numeric result in ppm is listed under each image. All AuNP-infused PPDO sutures maintained radiopacity, and gold content did not decrease significantly during weeks 0–6 (one-way ANOVA, p=0.778). (Reprinted from Fig. 7 in Ref. 101 with permission).

Conclusions

Many studies have been focused on the improvement of diagnostic imaging and the visualization of catheterization related agents and devices, and aim at decreasing toxicity of current contrast agents, increasing visibility of specific targets in the vascular diseases to achieve a better diagnosis, and more importantly, a better visibility of the agents and devices. The usage of polymer-based agents and devices can achieve decreased toxicity, better biocompatibility, and a more controlled degradability when compared to small molecular contrast agents and metal based devices. However, most polymers are radiolucent and invisible on conventional imaging modalities, such as X-ray and CT. The development of radiopaque nanoparticle- and polymer-based embolic agents and devices could increase specificity of diagnostic imaging and monitoring of catheterization procedures and their outcomes.