A Review on Radiopaque Polyurethanes: Materials, Processing, and Properties

1. Introduction

Polyurethanes (PUs) are used in a wide range of applications due to their variety of physical-chemical, mechanical, and structural properties [1,2,3,4]. Lately, PU has been used for biomedical applications, mainly due to their new biobased macromolecular architectures, which allow the control of biotic and abiotic degradation [5,6]. Put this, medical-grade PU-based polymers can be commercially found under various trade names, such as Carbothane^®, Pellethane^®, and Tecoflex^® from Lubrizol (US) [7] or Carbosil^®, Bionate^®, or Tecoflex^® from DSM (Holland) [8]. According to IndustryARC [9] the medical polyurethane market size is forecast to reach US$ 5.2 billion by 2026, with a CAGR of 4.3% during 2021-2026.

Some examples of PU for biomedical applications can be seen in Figure 1 [5].

Among the application characteristics, one of the most important is the visualization of the sample under a medical procedure. The radiopacity is one of the most important characteristics to visualize a sample, higher radiopacity means a better visualization inside the human body. Metals and ceramics are intrinsically radiopaque while polymers tend to be translucid due to the presence of low electronic density of atoms. Therefore, the radiopacity in polymers can be obtained in two distinct situations: the incorporation of a ceramic or metallic filler in the polymer or by synthesizing an intrinsic radiopaque polymer with high electron density reagents such as iodinated bisphenol A.

This review’s objective is to explain the properties and materials that induce radiopacity on polymers as well as the physical principles of radiopacity and the medical applications of these materials.

2. Principles and Effects of Radiopacity

2.1. Beer and Beer-Lambert Law

Beer’s and Beer-Lambert’s law states the light attenuation as it passes through some material. That is the reason why some materials are translucid or radiopaque under X-ray emission, for example. Beer’s law states that a material’s concentration and absorbance are directly proportional to each other and can be expressed by Equation (1) [10] where $\mathit{k}$ is $\mathit{a}.\mathit{b}$, $\mathit{b}$ is a constant and $\mathit{a}$ is absorptivity. If put in the form of molar absorptivity.

$$\mathit{k}=\mathit{\epsilon }.\mathit{b}$$

(1)

Hence, Beer’s law can be treated as absorptivity ($a$) or molar absorptivity ($\epsilon$), as Equation (2) shows.

$$\mathrm{A}=\mathrm{kc}$$

(2)

The Beer-Lambert law relates the attenuation of light to the properties of the material through which the light is traveling. The relationship can be expressed by Equation (3): where A is absorbance, ε is the molar extinction coefficient (which depends on the nature of the chemical and the wavelength of the light used), l is the length of the path light must travel in the solution in centimeters, and c is the concentration of a given solution.

$$\mathit{A}=\mathit{\epsilon }\mathit{b}\mathit{c}$$

(3)

It is noteworthy to mention that sometimes and mistakenly the Beer-Lambert law is treated as the Beer’s law [10].

For X-ray measurement, it can be represented by equation 4 where $\mathit{I}$ is the intensity output, ${\mathit{I}}_{\mathbf{0}}$ is the intensity input, $\frac{\mathit{\mu }}{\mathit{\rho }}$ is the linear attenuation coefficient, $\mathit{\rho }$ is the density and $\mathit{x}$ is the thickness of the material.

$$I=I_0.e^{-\frac{\mu }{\rho }.\rho .x}$$

(4)

Physically, the Beer-Lambert law can be represented differently according to Figure 2A. Figure 2B shows the effect of the radiopacity of the chemical characteristics of the sample.

Figure 2A shows the physical representation of the Beer-Lambert law. When a wavelength with a certain energy is emitted and passes a sample, the length of a photon is half of the wavelength, and the radius is proportional to the square root of the wavelength [11]. Therefore, the higher the interaction of the photons and particles with the source, the higher the energy is lost as it passes through the sample and hence higher the radiopacity in the visualized image.

As demonstrated in Figure 2B above, the attenuation (absorption or scattering of the X-rays) of X-rays depends on sample characteristics. The attenuation is mainly dependent on the tissue type and medical device, electron density, and specific gravity of the material. For example, polymers mainly contain elements that have low electron density and low specific gravity, such as C, H, and O, which results in poor radiopacity. This is the reason why the bones present higher contrast compared to muscles.

Figure 3 presents an image with data taken from a didactic website. The website enables the insertion of tissue type, tissue thickness, and energy as input values and obtains the X-ray transmission value, tissue density of blood, and mass attenuation as output parameters.

2.2. Photoelectric, Compton, and Rayleigh Effects

The photoelectric effect (PEE), Compton, and Rayleigh effects (also known as coherent scattering) are the main X-ray interaction processes. Photoelectrons are emitted when electrons are released from a substance upon an incidence of an X-ray, for example. When the energy of the incident radiation approaches the electron binding energy in each of the atom’s many shells. When an electron at a higher energy level fills the hole left by the ejected electron, a characteristic X-ray with an energy equal to the difference between the binding energies of the two electrons is subsequently released (Figure 4) [13,14].

In general, photoelectrons can also be released from shells other than K and L, depending on the atomic number of the atom (occupation of other shells) (i.e., M and N). The low-energy characteristic X-rays are completely absorbed by the bodily tissues. The photoelectric interaction’s (mPE) linear attenuation coefficient is solely dependent on the energy of the input beam, the tissue-effective atomic number, and the tissue density [14,16]. Imaging creates a contrast between high- and low-density materials since the mPE for high atomic number materials will be larger than for less dense and low atomic number materials. For soft tissue with low attenuation capacity and bone with high attenuation, more contrast is obtained [17].

The photon in the Compton Effect (CE) is scattered by low binding energy electrons (outer-layer electrons), which only absorb a portion of the energy from the X-rays and let the photon enter the material at a lower energy and in a different direction. A photon of fixed energy can produce electrons of variable energy, ranging in value from zero to a maximum value because the energy transfer is dependent on the direction of the ejected electron, which is random [18], as demonstrated in Figure 4. In this case, it’s not the atomic number of the component atoms, but rather the electron density of the tissues, which determines the likelihood of Compton scattering. Moreover, it has a minor dependence on the X-ray incident energy. The PEE predominates over the CE at low-energy X-rays, but with high-energy X-rays, increasing the CE reduces the image contrast [16]. At extremely low photon energies, an elastic scattering phenomenon known as the Rayleigh scattering (RE) takes place. Only in mammography, which employs low photon energy, does this scattering become significant because diagnostic radiology uses photons above this range. In this instance, the atom’s electron cloud scatters the incident photons, slightly ionizing the surrounding area [16].

2.3. Radiopacity Measurement

When an external apparatus is inserted into the human body, the positioning is dependent on the radiopacity of the device aiming to easily detect the surrounding anatomical structures. In practical applications, the radiopacity can be determined qualitatively by a medical doctor who can approve or not the apparatus by the visual aspect or quantitatively via grayscale value using a photo-densitometer where the grayscale value is converted to absorbance values [19,20].

Considering dental materials, since pure aluminum’s radiopacity is extremely comparable to dentin’s, the International Standards Organization (ISO) emphasizes that any restorative material must exhibit radiopacity equal to or greater than pure aluminum of the same thickness [19]. Transmission densitometry is the gold standard and traditional typical method for measuring radiopacity. Using this method, the grayscale value of photographic images (films or digital) is calculated and compared to that of a standard aluminum wedge with 10 steps from 1 cm to 10 cm. The grayscale value is proportional to the ratio of the incident to transmitted X-ray radiation. The value is stated in relation to the thickness of aluminum which is equal. Since radiography images are two-dimensional, or depthless, projections [21], the various grayscale tones, ranging from white to black, correspond to the various anatomical features of the teeth [22].

In computed tomography, radiopacity is quantified using quantities known as Hounsfield Units (HU), named after the engineer who invented computed tomography, Godfrey Hounsfield. The linear attenuation coefficient of distilled water is used to standardize the HU of a substance. At standard temperature and pressure, water and air are assigned HU values of 0 and 1000, respectively [23]. The degree of a material’s attenuation capabilities can only be clearly appreciated from its X-ray pictures, despite the fact that these imaging modalities allow for quantitative measures of radiopacity [24,25]. Figure 5 shows the image of an arm in a radiographic image where it is observed the metal rods fixed in the arm.

3. Biomedical Applications of NPs

Inorganic NPs have unique physical, electrical, magnetic, and optical properties due to the intrinsic properties of the material [26]. Also, the detection through layers of skin and muscle in bioimaging diagnostics is possible, for example, Au NPs possess free electrons at their surface that continually oscillate at a frequency dependent on their size and shape, giving them specific photothermal properties [27]. Beyond imaging applications, it is noteworthy to mention that most metallic-based nanoparticles present antimicrobial properties that may be beneficial for several biomedical applications, be it in drug delivery methods, antimicrobial activities, or prevention of infections through contact with hospital devices.

3.1. Antimicrobial Activity of Metallic and Ceramic Nanoparticles and the Influence of Their Particle Characteristics

It’s been a growing concern that many microbes are developing resistance against many antibiotics. This, coupled with the abuse of drugs, as well as the release of antibiotics to the environment has impeded the progress expected from that treatment option [28,29]. Microbes with high mutative capacity and rapid morphological changes may lead to microbial resistance to antibiotics. To overcome the resistance developed by microbes, nanoparticle-based treatments are starting to present a very promising approach.

Nanoparticles (NPs) are substances with a diameter ranging from 1-100 nm (nm) [30,31,32]. According to the World Health Organization, in addition to their reduced size and selectivity for bacteria, metal-based nanoparticles have proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult but also broadens the spectrum of antibacterial activity [33]. Inorganic materials have been used to synthesize nanostructured particles for various drug delivery and imaging applications [26]. Figure 6 and Figure 7 scheme how metallic and ceramic nanoparticles act on the inactivation and/or destruction of different types of microbes.

Inorganic NPs can be engineered to have a wide variety of sizes, structures, and geometries [26]. For biomedical applications when modifying the size, shape, concentration, capping method, and/or surface chemistry of NPs, the properties of metal NPs are affected to the extent that it influences their behavior on microbial life forms, conditioning them to become better drug delivery agents or present better bactericidal or bacteriostatic behavior for example [34,35]. Table 1 shows the effect of the inorganic particles in microbial strains according to concentration and size.

The size of the nanoparticle has a direct influence on the antimicrobial activity of the substance. A vast variety of analyses on NPs suggests that a large surface area is imperative for microbial attachment and rapid penetration into the cell [59,60]. Furthermore, studies disclosed that nanoparticles with high surface area present the ability to deliver a large number of antibiotics or other substances, their variation in size and shape makes them ideal antimicrobial weapons [60,61,62]. As reported by Philip, D. [63], the NP shape is also directly important in determining the types and extent of interaction with the membrane or enzymes of microorganisms. For instance, ZnO nanoparticles of different shapes (plate, sphere, and pyramid) showed shape-dependent activity on a typical enzyme β-galactosidase (GAL) [64].

It has been observed, that NPs containing magnetic iron oxide, composed of magnetite (Fe3O4) or maghemite (Fe2O3), possess superparamagnetic properties at certain sizes and may be used as contrast agents, drug delivery vehicles, and thermal-based therapeutics [65].

3.2. Metallic Nanomaterials Characteristics on Bio-Imaging and Its Effects

As demonstrated by Beer-Lambert’s law, the radiopacity of a material depends on the atomic number of its elements, the material thickness, the intensity of the energy input, and its particle aspect (round, irregular, triangular, etc.). These conditions for radiopacity synergize with most metallic and ceramic intrinsic properties, making them uniquely qualified for applications such as diagnostics and imaging.

Marghalani et al. [66] investigated the effect of the filler characteristics on the radiopacity levels of nanocomposites for radiographic diagnosis using different particle size formulations (from 100–1500 nm). In general, the irregular-shape series showed more radiopacity than the spherical-shape ones. Another interesting feature is the decrease in the radiopacity values with increasing filler particle size for both formats. Finally, a higher filler amount promotes higher radiopacity. These characteristics have also been studied by Marghalani [66], where spherical nanofiller particles, mainly silica-based and irregular particles of ground glass melts (Ba–Al-B-silicate glass) had their radiopacity tested. The irregular filler-based series formulations were more radiopaque than the spherical series, this was attributed to the incorporation of a higher atomic number element; in this case, barium [67,68,69]. The barium element is found mainly in irregular shape series allowing this higher opacity in comparison to the spherical series.

This finding agrees with a study that showed a direct effect that occurs between the filler type and the radiopacity of the filling material [68]. The sharp edges of the irregularly shaped nanofillers of these nanocomposites may absorb the light resulting in a radiopaque characteristic [70,71]. Additionally, irregular edges and surfaces of these nanofiller series can yield a mismatch of the refractive indices between fillers and resin interface leading to high radiopacity of the nanocomposite. Besides radiopacity, the nanoparticles can be used for imaging as demonstrated in Figure 8, where an example of the use of nanoparticles for identification in the human body is presented.

Similar to “radiopaque particles”, bioimaging particles are used as contrast agents for in vitro and in vivo biological imaging in real-time, monitoring biological functions without affecting normal life processes such as respiration and movement.

It is noteworthy to mention that materials of high biocompatibility and low cytotoxicity are of great value when determining the uses of metallic-based nanoparticles. It has been noted that NP’s unique size-related characteristics and potential toxicity, show a display of biological effects in animal models and in cultured cells that differ from those observed with bulk material [73].

Since only a few of the NPs have decent biocompatibility and low cytotoxicity when utilizing them in unique niche applications that require properties unattainable by organic materials, metallic nanoparticles must be used carefully, especially in the case of heavy metals [65,74]. Beyond that, for some applications like endoscopy, materials must preferably have good synergy with the polymer they are incorporated with to avoid adverse results such as heterogeneous dispersions (which affect the physical and mechanical properties of polymers), loss of radiopacifying atoms, leaching of toxic radiopacifying additives, and systemic absorption by the host. For these reasons, biocompatible and low-toxicity polymers with intrinsic radiopacity would charm with the potential to attend these applications with lower drawbacks. Table 2 shows some examples of nanomaterials used for bioimaging applications.

4. Polymers with Intrinsic Radiopacity

Many polymers can be used in medical implants for permanent or temporary use. These polymers must attend specific functions, such as drug delivery, provide physical and structural support to vascular systems, or restore the normal function of joints in arthroplasty. Besides desirable characteristics such as ease of production, various mechanical properties, and biocompatibility, they also present a high potential for controlling properties to satisfy a wide range of requirements, which is a positive aspect. Common polymers include polyethylene, polytetrafluorethylene, poly(lactic acid), polypropylene, and polyurethane. Emonde et al. [20] pointed out radiopacity and polymers/fillers for different applications such as bone cement, joint replacements, bioresorbable stents, craniofacial implants, spinal implants, implant dentistry, and internal fixation systems. Figure 9 and Figure 10 compare the radiopacity of synthetic polymers in medical applications.

Polyurethanes particularly can be synthesized to be intrinsically radiopaque. This avoids problems in the manufacturing of the product by incorporation of particles in the polymer/particle mixture stage which would speed up the process, avoiding the lixiviation of the material and potentially lower the cost of production [109,110,111]. Since one of the main characteristics of radiopaque materials is the high electron density, one of the main alternatives (and more appropriate) is incorporating heavy atoms (such as barium or iodine) through physical blends or polymer salt complexes. Table 3 shows some studies of different polymers with their respective mechanical characteristics and contrast agent concentrations.

When synthesizing polyurethanes with heavy atoms the major role is to build blocks of polymers with intrinsic radiopacity without significant loss of mechanical and physical properties. There have been several studies where attempts at synthesizing intrinsically radiopaque polyurethanes were successful.

Dawlee and Jayabalan [110] synthesized intrinsically radiopaque polyurethanes with chain extender 4,4′-isopropylidenebis [2-(2,6-diiodophenoxy)ethanol] and claimed that the final product is cytocompatible with L929 mouse fibroblast cells. Furthermore, the toxicological studies and subcutaneous implantation of PTMGMDIBPA (polyurethane prepared with poly(tetramethylene ether) glycol polyol) indicated nontoxic and reasonable tissue compatibility of the iodinated polyurethane. Also, the sample was visible even after 12 weeks of implantation.

James et al. [111] produced an aliphatic polyurethane (Tecoflex 80A) with 5-iodine-containing molecule, N-(2,6-diiodocarboxyphenyl)-3,4,5-triiodo benzamide (DCPTB). The optimal reaction mechanism was obtained by incorporating 8% iodine (wt/wt) in the polymer. The radiopacity was equivalent to that of a 2 mm thick aluminum wedge but a reduced thermal stability compared to the starting polymer.

Dawlee and Jayabalan [112] developed segmented polyurethane elastomers with low iodine content exhibiting radiopacity and blood compatibility. The polyurethane was prepared aliphatic using chain extender 2,3-diiodo-2-butene-1,4-diol, polyol polytetramethylene glycol, and 4,4′-methylenebis(phenyl isocyanate) (MDI). The radiopacity was considered good at 3% iodine in aromatic PU and 10% in aliphatic PU. The PUs showed cytocompatibility with L929 fibroblast cells, non-hemolytic, and possessed good blood compatibility.

Kiran et al. [113] used an IBPA (Bisphenol-A with 4,4′-isopropylidinedi-(2,6-diiodophenol) as a chain extender for the preparation of a radiopaque PU. The authors obtained a highly radiopaque PU, in-vitro non-cytotoxic test using L929 mouse fibroblast cells and a desirable range of physical properties.

Qu et al. [114] synthesized radiopaque poly(ether urethane) with 15 wt% iodine-containing diol as a chain extender. The radiopacity did not alter after 6 weeks of exposition of an oxidative degradation treatment. The authors claimed that the thermal, mechanical, and cytotoxicity properties were satisfactory.

Kiran et al. [115] synthesized PU with an iodinated chain extender (IBPA) and three different diols (polypropylene glycol, polycaprolactone diol, and poly(hexamethylene carbonate) diol. The authors claimed that radiopacity was equivalent to the one containing 20 wt % barium sulfate, nontoxicity when exposed to L929 cells by direct contact and MTT assay (a colorimetric assay for assessing cell metabolic activity).

Kiran and Joseph [116] synthesized opaque polyurethane containing iodinated hydroquinone 2,2′-(2,5-diiodobenzene-1,4-diyl)bis(oxy)diethanol (DBD) ether as chain extender and obtained equivalent opacity to 15 wt % barium sulfate with polyurethane, optical transparency, hemocompatible and noncytotoxic to L929 fibroblast cell lines.

Sang et al. [117] synthesized radiopaque iodinated poly(ester urethane)s containing poly(ε-caprolactone) blocks and claimed a high radiopacity compared with an aluminum wedge of equivalent thickness. A prolonged enzymatic degradation test was also superior compared to the reference sample. Also, distinct mass loss and degradation occurred in the third month. [118].

Sang et al. [119] synthesized poly(lactic acid)-polyurethane for chemoembolization therapy and constated an X-ray visibility and drug-loaded beads as multifunctional embolic agents and noninvasive intraoperative location and postoperative examination.

It is feasible, as presented, to synthesize intrinsically radiopaque polyurethanes by different methods without compromising significantly their physical and mechanical properties.

5. Conclusion

This mini-review demonstrates the effect of the concentration, type, and format of different nanoparticles on the radiopacity of polyurethane. It was found that barium sulfate and iodinated compounds are the most clinically administered radiopaque agents.

One of the main characteristics is the cost-effectiveness and tailor-made properties that can be achieved compared to conventional materials. The synthetization of radiopaque polyurethanes is not only possible, as referenced here, but it has been observed that radiopaque PU’s are more efficiently synthesized with heavy atoms with a high electron density as part of the back chain bone or grafted. The synthetization of polyurethanes with biocompatible and low cytotoxicity high electron density composites or atoms produces a radiopaque and antimicrobial material without the downsides of incorporating nanoparticles in the processing steps of the product and enabling a multipurpose use on biomedical applications.

It is noteworthy to mention that physical blending is the most prevalent and economical method to induce radiopacity in polymers. However, the resultant mixture often lacks homogeneity and nanoparticle agglomeration which compromises the radiopacity. To minimize this drawback a higher concentration of the nanoparticle is required. Of course, surface-modifying agents can be used to improve dispersion. Also, higher radiopacity can be used if the contrast agent is soluble, which provides a homogeneous distribution between the phases and allows the use of a lower concentration of contrast agent than surface modification for the same level of radiopacity. The recommendation is that the amount of contrast agent must be as low as possible to provide acceptable radioactivity and mechanical properties. It is important to keep in mind that the radiopacity has to be coherent (visible enough) with the respective anatomical structures of different tissues.