A Short Review on Radiopaque Polyurethanes in Medicine: Physical Principles, Effect of Nanoparticles, Processing, Properties, and Applications

Abstract

Polyurethanes are used in a wide range of biomedical applications due to their variety of physical–chemical, mechanical, and structural properties, and biotic and abiotic degradation. They are widely used in bio-imaging procedures when metallic-based filler particles are incorporated, making the final product radiopaque. It would be advantageous, however, if polyurethanes with intrinsic radiopacity could be produced in their synthesis, avoiding a series of disadvantages in the processing and final product and also presenting potential antimicrobial activities. This review’s objective was to study the radiopacifying characteristics of nanoparticles, the physical principles of radiopacity, and the variety of medical applications of polyurethanes with nanoparticles. It was found in this study that the synthetization of radiopaque polyurethanes is not only possible but the efficiency of synthetization was improved when using atoms with high electron density as part of the backbone or when grafted, making them great multipurpose materials.

1. Introduction

Polyurethanes (PUs) are versatile materials that can be used in a wide range of applications including building and construction, transportation, furniture and bedding appliances, packaging textiles, fibers and apparel, electronics, and footwear, among other uses. This is due to the variety of physical–chemical, mechanical, and structural properties attributed to different monomer types and ratios, allowing the formulation of soft foam to rigid parts [1,2,3,4,5,6]. PUs are one of the most promising polymers that can be used for biomedical applications, mainly due to their new biobased macromolecular architectures, which allow the control of biotic and abiotic degradation [7,8]. Medical-grade PU-based polymers can be commercially found under various trade names, such as Carbothane^®, Pellethane^®, and Tecoflex^® from Lubrizol (US) [9] or Carbosil^®, Bionate^®, or Tecoflex^® from DSM (Holland) [10]. According to IndustryARC [11], the medical polyurethane market size is forecast to reach USD 5.2 billion by 2026, with a CAGR of 4.3% during 2021–2026.

Some examples of PUs for biomedical applications are visualized in Scheme 1.

Besides mechanical requirements, cytotoxicity, and biocompatibility, another important feature is the visualization of the sample under a medical procedure. The radiopacity is the most important characteristic to visualize the medical device inside the human body; higher radiopacity means a better visualization. The radiopacity level depends on where the device will be inserted. Metals and ceramics are intrinsically radiopaque, while polymers tend to be translucid due to the presence of the 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 a high electron density reagent (contrast agent) [12,13].

This short review’s objective is to explain the properties and materials that induce radiopacity in polyurethanes, the physical principles of radiopacity, and the medical applications, processing, and properties of these materials.

2. Radiopacity Measurement

When an external apparatus is inserted into the human body, the positioning of the apparatus 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 approve, the apparatus by the visual aspect or quantitatively via the grayscale value using a photo-densitometer where the grayscale value is converted to absorbance values [14,15].

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 a radiopacity equal to or greater than pure aluminum of the same thickness [16]. 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, depthless projections [17], the various grayscale tones, ranging from white to black, correspond to the various anatomical features of the teeth [18].

In computed tomography, the 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 [19]. The degree of a material’s attenuation capabilities can only be clearly determined from its X-ray pictures, despite the fact that these imaging modalities allow for quantitative measures of the radiopacity [20,21]. Figure 1 shows the Hounsfield scale of different hard and soft tissues in the human body.

Figure 2 shows the image of an arm in a radiographic image, where the metal rods fixed in the arm are observed. The radiopacity shown by the metal rod helps professionals to monitor the evolution of the surgery after the fixation of the bones.

3. Radiopaque Polyurethanes

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 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. [23] pointed out the 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 3 and Figure 4 compare the radiopacity of UHMWPE and PLLA for medical applications.

Other polymers used for biomedical applications can consulted in

Table 1. Summary of contrast agents incorporated into synthetic polymers for implantable devices. The table was reused under CC-BY 4.0 [23].

Contrast Agent	Blending Method	Polymer	Application	Content	Reported Effects	Polymer Biodegradable	Biological Response	Ref.
BaSO4	Blended in the powder phase	PMMA	Bone cement	9–15 wt%	Hard particles, third body wear, reduced tensile, and flexural strength	NO	Osteoclast formation	[24] [25] [26]
	Blended in the powder phase	PMMA	Vertebroplasty cement	30 wt%	Hard particles, third body wear, lower viscosity	NO	Osteoclast formation	[27] [28] [29]
	Twin-screw micro-compounding	PLLA	Bioresorbable stents	5–20 wt%	Increased tensile modulus and strength, decreased elongation at break and ductility	YES	No adverse effects after 21 days	[30] [31]
	Magnetic stirring in organic solvent	PLGA	Bioresorbable stent	17.9 v/v%	Increased Young’s modulus, reduced elasticity, increased radial strength	YES	Na	[32]
	Solution mixing	PLGA	Bone fixation plate	1:10 and 1:3 w/w PLGA:BaSO4	Radiopaque up to 56 days, BaSO4 leaching < 0.5 mg/day; insufficient to induce cytotoxicity	YES	No adverse effects	[33]
Lipiodol ultra fluid	Immersion in oil at elevated temperature	UHMWPE	TKA insert	25 mL	Physical alteration–swelling, 54% reduction in surface radiopacity after 4 weeks	NO	Na	[34]
Iohexol (IHX)	Stirring	PLA	Bioresorbable implants	40 wt%	Reduced tensile strength, elongation at break and increased tensile modulus, enhanced crystallinity, slower polymer degradation	YES	Thin fiber capsule	[35]
	Blended in the powder phase	PMMA	Bone cement	10 wt%	Better biocompatibility compared to conventional contrast agents	NO	Osteoclast formation	[26]
Iodixanol (IDX)	Blended in the powder phase	PMMA	Bone cement	10 wt%	Higher osteoclast formation than IHX	NO	Osteoclast formation	[26]
Iobitridol	Dissolved in liquid phase	CPC	Bone cement	56 mg mL−1	Rapid release of contrast, no significant change in mechanical properties, no effect on injectability, cohesion, or setting time	YES	No adverse effects	[36]
Iodinated diphenol	Polymerization reaction	PLA diol	Coronary stent	<1% of 1 mL of iodine contrast	Increased ultimate tensile strength and elongation at break, long-term radiopacity	YES	No adverse effects	[37]
Bismuth salicylate (BS)	Dissolved in liquid phase	PMMA	Vertebroplasty cement	10 w/w	Reduced compressive and tensile strength, reduced strain, lower setting temperature, increased radiopacity, longer injection time, Better compatibility than BaSO4	NO	Na	[38] [39]
Triphenyl bismuth (TPB)	Dissolved in liquid phase	PMMA	Bone cement	10 wt%	Increased ultimate tensile strength, Young’s modulus and strain to failure, lower setting temperature, better homogeneity	NO	Na	[40]
Bismuth oxide Bi2O3	Blended into fiber	UHMWPE	Sublaminar cables	20 wt%	Decreased tensile strength, limited leaching below toxic levels	NO	No adverse effects	[41] [42]
Titanium dioxide TiO2	Blending	PE	Orbital implant	6%	Slight decrease in tensile strength and modulus, significant decrease in compressive strength and modulus, reduced hardness	NO	No adverse effects	[43]
Iron oxide Fe3O4	Twin-screw extrusion	PLLA	Bone screws	20 wt%	Reduced flexural strength, increased crystallinity, increased thermal stability	YES	Osteogenic effect, no adverse effects	[44]

, where the respective mechanical characteristics and contrast agent concentrations are shown.

Different from other polymers, polyurethanes are more versatile and the amount of PUs that can be synthetized is almost unlimited. The characteristics of the final product is dependent on the type and concentration of the monomers and synthesis conditions, among others. Therefore, soft products, such as foams, or rigid parts, such as structural rods, can be manufactured depending on the requirements needed. PUs can be synthesized to be intrinsically radiopaque by inserting a contrast agent in the chain backbone or by the incorporation of metallic or ceramic particles in the blend processing. When the contrast agent is inserted in the chain backbone, it obtains some advantages such as avoiding problems in the manufacturing of the product by incorporating particles in the polymer/particle mixture stage, which would speed up the process, avoiding the lixiviation of the material and potentially lowering the cost of production [45,46,47]. 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. When synthesizing polyurethanes with heavy atoms, the major role is to build blocks of polymers with intrinsic radiopacity without a significant loss of mechanical and physical properties. There have been several studies where attempts at synthesizing intrinsically radiopaque polyurethanes were successful. For industrial purposes, lower cost, and higher demand, it seems that the incorporation of a ceramic or metallic contrast agent is more appropriate.

Table 2. Reagents, characterization, and reported effects of some radiopaque polyurethanes reported in the literature.

Reagents	Characterization	Reported Effects	Ref.
2,3-diiodo-2-butene-1,4-diol (I-BOL) (aliphatic chain extender) 4,4′-methylenebis(phenyl isocyanate) (MDI) Hexamethylene diisocyanate (HDI) Polytetramethylene glycol (PTMG) 2-Butyne-1,4-diol, dibutyltin dilaurate (DBTDL)	FTIR X-ray opacity Surface properties under aqueous conditions In vitro cytotoxicity Blood compatibility	HDI-based polyurethane was partially crystalline with a phase-separated surface morphology. MDI-based polyurethane has phase-mixed surface morphology, which undergoes dynamic surface reorganization in aqueous medium to a phase-separated surface morphology. Studies on in vitro cytotoxicity and blood compatibility with MDI-based polyurethane revealed cytocompatibility, blood compatibility, and radiopacity	[48]
4,4′-isopropylidenebis[2-(2,6-diiodophenoxy)ethanol] (IBPA) (chain extender) 4,4′-methylenebis(phenyl isocyanate)(MDI) Poly(tetramethylene glycol) (PTMG)	FTIR TGA DMTA EDX GPC X-radiography In vitro cytotoxicity Radiopaque properties	Highly radiopaque polyurethane with an iodine content of 23% (better than aluminum). In vitro non-cytotoxicity using L929 mouse fibroblast cells, visible even after 12 weeks of implantation	[49]
N,N′-Bis(3-hydroxypropxyl)-2,3,5,6-tetraiodoterephthalamide (HPTDP) (chain extender) Poly(tetramethylene glycol) (PTMG) 4,40-Diphenylmethane diisocyanate) (MDI)	NMR Mechanical properties In vitro degradation Cytotoxicity Radiopaque properties	Good radiopacity (compared to aluminum). Radiopacity did not decrease after oxidative degradation treatment. Has good thermal stability and mechanical properties, non-toxicity	[50]
1,6-diisocynatohexane (HDI) Poly(hexamethylene carbonate)diol (PHCD) 2,2′-(2,5-diiodobenzene-1,4-diyl)bis(oxy)diethanol (DBD) Barium sulfate (BaSO4)	FTIR EDX Mechanical properties DMTA X-radiography Opacity Fluoroscopy In vitro cytotoxicity	Melt processable, non-cytotoxic, and blood compatible and possesses a high degree of optical transparency	[51]
4,4′-isopropylidinedi-(2,6-diiodophenol) (IBPA) (chain extender) 4,4′-methylenebis(phenyl isocyanate) (MDI) polypropylene glycol polycaprolactone diol poly(hexamethylene carbonate) diol	FTIR Contact angle GPC Thermal properties DMTA EDX XRF XRD Radiopacity Cytotoxicity	Highly radiopacity compared to aluminum, 18–19% iodine in the polymer matrix, radiopacity equivalent to 20%wt barium sulfate, non-cytotoxicity in L929 cells by direct contact and MTT assay	[52]
4,4′-isopropylidinedi-(2,6-diiodophenol) (IBPA) (chain extender) Poly(e-caprolactone) (PCL) Isophorone diisocyanate (IPDI)	FTIR NMR GPC EDX DSC TGA WAXD X-ray opacity Enzyme-accelerated degradation cytocompatibility	Highly radiopacity, controllable biodegradability, and cell cytocompatibility tracked during the in vitro enzymatic degradation test, non-toxic biomaterials	[53]
Polycaprolactone diol polytetramethylene glycol Diphenylmethane 4,4′-diisocyanate (MDI) Dicyclohexyl methane 4,4′-diisocyanate (HMDI) Dibutyl tin dilaurate (DBTDL) Bisphenol-S Biusphenol-AF Bisphenol-A 3,3′,5,5′-Tetrabromo bisphenol-S (TBBPS) 3,3′,5,5′-Tetrabromo bisphenol-A 3,3′,5,5′-Tetrabromo bisphenol-AF	FTIR Hardness Tensile Properties Specific gravity Swelling and sol fraction DMTA DSC TGA XRD LOI Water absorption	The addition of bromine atoms in the polyurethanes markedly decreased their degrees of crystallinity. The brominated polyurethane elastomers have good flame retardancy. All of the unbrominated polyurethanes showed good mechanical properties and high thermal stabilities. Polyurethanes based on bisphenol-S had lower solvent resistance caused by the dipolar nature of sulfonyl groups in the polymer chains	[54]
4,4′-isopropylidinedi-(2,6-diiodophenol) (IBPA) isophorone diisocyanate (IPDI) doxorubicin hydrochloride (DOX) triethylene glycol (TEG) iodinated poly(lactic acid)-polyurethane (I-PLAU)	GPC Thermal properties XRD X-radiography Contact angle Blood compatibility Cell culture Cytotoxicity assay In vivo muscle implantation In vivo drug release Antitumor assay in vitro	Sufficient radiopacity, in vitro non-toxicity, in vivo biocompatibility, release profile controlled by the microstructure, efficient inhibition of tumor cell growth	[55]
4,4′-methylenediphenyl diisocyanate (MDI) polyethylene glycol (PEG) 4-(4-iodophenyl)-1,2,4-triazolidine-3,5-dione (IUr) Graphene oxide (GO)	FTIR NMR XRD CHNO FESEM TGA DMTA	Improved thermal and mechanical properties, heat durability, well dispersed GO in the polymeric matrix, significant contrast.	[56]
4,4′-isopropylidinedi-(2,6-diiodophenol) (IBPA) iodinated polycaprolactone-polyurethanes (I-PCLUs) Doxorubicin (Dox)	Optical microscopy SEM UV-vis spectroscopy In vitro drug release In vitro antitumor assay In vivo experiments (muscle implantation, hepatic embolization, chemoembolization of rabbit hepatic tumor model)	Effective drug-loading, sustained release mode for four weeks, kept well X-ray visibility after drug release, inhibition of the tumor cell proliferation, good histocompatibility, effective chemoembolization, and radiopacity.	[57]
zirconium oxide bismuth oxide tantalum pentoxide polypropylene glycol (PPG) 4,4′-methylene diphenyl diisocyanate (MDI) glycerol	Cytotoxicity Culture cells	Cytocompatible and interconnected pores, promising for further development as bases for bone-substituting materials.	[58]
4,4′-isopropylidinedi(2,6-diiodophenol) (IBPA) Dibutyltin dilaurate (DBTL) Polyvinyl alcohol (PVA) Poly(hexamethylene carbonate)diol (PHCD) 4,4′-methylene-bis(cyclohexyl isocyanate)	NMR FTIR TGA GPC ESEM Elemental analysis Cytocompatibility In vitro degradation studies In vivo imaging	Non-toxicity, visible under fluoroscopic conditions, and excellent X-ray opacity.	[59]
4,4′-isopropylidinedi(2,6-diiodophenol) (IBPA) poly(e-caprolactone) diol (PCL) isophorone diisocyanate (IPDI)	Degradation tests TGA X-ray opacity FESEM DSC XRD Contact angle	Poor hydrophilicity, reduced rate of degradation, and no great attenuation of the X-ray opacity after 3-month degradation.	[60]

summarizes the synthesis and characterization of the radiopaque polyurethanes reported in the literature.

For all the mentioned polymers in Table 2, the synthesis method involves a reactor and specific time/temperature/pressure that is dependent on the monomers and the type of polymer being targeted. A brief explanation of the synthesis and the results obtained in Table 2 are described below. More details can be found in the respective references. Dawlee and Jayabalan [48] developed an aliphatic and aromatic polyurethane with inherent radiopacity and is bifunctionally active for blood-compatible applications. The synthesis methods for both PUs followed the conventional two-step solution polymerization using I-BOL as the chain extender, as schematized in Figure 5.

Both PUs were dissolved in dimethyl formamide (DMF) and cast to form films prior to characterizations. The FTIR analyses showed the presence of hydrogen-bonded N-H groups, which is essential for the microphase separation in PUs between the hard segments. Other important absorption bands were also described as the presence of C=O stretching (bonded) and N-H stretching (bonded), which is indicative of H bonding interactions between ether groups of the soft segments and the urethane amide in the hard segments. The GPC analysis indicated that the aromatic polyurethane showed higher molecular weight and polydispersity compared to the aliphatic one with a lower isocyanate index. By analyzing XRD, the authors claimed that crystalline regions were found only for the aliphatic PU. The absence of crystallinity for aromatic PU was attributed to the poor phase separation and steric hindrance of the hard segment. The presence of iodine atoms was confirmed by EDX for both polyurethanes but with a higher concentration for the aliphatic PU (attributed to its lower molecular weight), while the concentration was determined by elemental analyses (3% and 10%, for the aromatic and aliphatic, respectively). Both concentrations are sufficiently high for clinical monitoring. TGA showed a mass loss of almost 22% for the aliphatic polyurethane while only 5% mass loss was presented for the aromatic polyurethane at 260 °C due to the higher intermolecular bond strength for the latter. According to the DMTA results, the T_g difference was 8 °C. The lower temperature for the aliphatic polyurethane was attributed to the phase separation of the hard and soft segments. The aromatic polyurethane has more rigid domains but with mixed morphology, which led to a decrease in the chain flexibility of soft segments and hence a higher glass transition temperature. The tensile mechanical properties showed a higher tensile strength (35.75 MPa against 4.37 MPa), ultimate elongation (752.23% versus 482.78%), modulus (12.10 MPa versus 10.08 MPa), and toughness (106.87 MPa against 11.57 MPa) for the aromatic polyurethane. It is noteworthy to mention that the modulus values can be considered equal due to the standard error deviation. The higher values found for the aromatic polyurethane were attributed to an improvement of the cohesiveness and function as constituents of the urethane and phenyl groups for the secondary inter chain hydrogen bonding. Both polyurethanes were shown to be adequate for various biomedical applications. Regarding the radiopacity, both polyurethanes exhibited similar radiopacity to that of an aluminum wedge. The dynamic contact angle, which is important for biocompatibility, showed a surface reorganization in an aqueous medium that is more favored for the reorganization for aliphatic polyurethane. It was demonstrated to be non-cytotoxic for both polyurethanes for L929 mouse fibroblast cells around PU films, even after 24 h of contact, with cell viability of 83.9% and 111% metabolic activity for the aromatic and aliphatic polyurethanes, respectively. Finally, the blood compatibility showed no significant difference in the counts of RBC and WBC even after 30 min of exposure to human blood for the aromatic polyurethane. The blood compatibility for the aliphatic polyurethane was not tested due to the previous results presented. In general, the physical and mechanical properties of the neat polyurethanes decrease following the incorporation of a contrast agent, while the physical–mechanical, biological, and radiocontrast properties were not compromised.

Kiran et al. [49] synthesized and characterized iodinated polyurethanes with inherent radiopacity. The authors synthesized 4,40-isopropylidinedi(2,6-diiodophenol) (IBPA) and used it as a chain extender with MDI and PTMG through a two-step process polymerization at a molar ratio of 1:2.2:1.2, respectively. It produced two distinct polyurethanes named MTIB and MTB; the former was produced with IBPA as a chain extender and the latter was produced using Bisphenol-A (4,40-isopropylidenediphenol) (BPA) as a chain extender for comparative studies using the same aforementioned molar ratio. The chain extender was incorporated in the pre-polymer in the second stage of the synthesis using dibutyltin dilaurate as a catalyst. EDX and elemental analysis showed the presence of 23% iodine from IBPA. The X-radiograph of the MTIB was shown to be sharper compared to the MTB and aluminum standard, with a darker image than that of an aluminum wedge, while MTB was not all visible. The FTIR presented characteristic absorption bands of the formation of polyurethanes. The molecular weight of MTIB was lower compared to MTB due to the presence of bulky iodine atoms in IBPA, as demonstrated in GPC analysis. The TGA analysis showed two decomposition stages for both polyurethanes; for MTB, the decomposition temperature started at 260 °C, while for MTIB, the temperature was 220 °C. The glass transition temperature measured by DMTA showed similar results (around −33 °C) for both polymers. The non-cytotoxicity of MTIB was confirmed using L929 mouse fibroblast cells with 91% metabolically active cells compared to cells exposed to the extract of UHMWPE control. Figure 6 shows a schematic representation of the synthesis procedure performed by the authors.

Qu et al. [50] synthesized and characterized radiopaque poly(ether urethane) with iodine-containing diol as a chain extender, named IPEU following a two-step condensation polymerization process (Figure 7).

The IPEU contained poly(tetramethylene glycol) (PTMG) as the soft segment and MDI/N,N′-Bis(3-hydroxypropxyl)-2,3,5,6-tetraiodoterephthalamide (HPTDP) as the hard segment. HPTDP was synthesized by the authors. The authors compared the IPEU polyurethane with PEU (using the same reactants in the molar ratio of MDI:PTMG = 1:1, without a chain extender. The FTIR showed the expected functional groups for the polyurethanes, as the absorption peak at 1632 cm⁻¹ related to the NH-C=O stretching of HPTDP. Four different IPEU samples with different molar ratios of MDI/chain extended/ PTMG were incorporated in the study to verify the influence of the iodine-containing diol in the polyurethane. The molecular weight of the IPEU decreases following the incorporation of HPTDP due to the higher rigidity of this component in the polymer structure. The TGA analysis of IPEU showed two distinct decomposition stages (between 200 and 305 °C and between 305 and 450 °C). All IPEUs showed a similarity in the first decomposition stage, while for the second decomposition stage, a higher mass remained at higher temperatures by increasing the hard segment content. For PEU, the stability was maintained up to 343 °C with a mass loss of 50% at 386 °C. The authors claimed that all IPEUs have better thermal stability because only 5% mass loss occurred at 300 °C. DSC showed only one glass transition temperature for all polyurethanes studied, with higher values for IPEUs compared to PEU due to the hard segments of the MDI reagent. The presence of only one peak and not two, as commonly demonstrated in the literature, was attributed to the compatibility of the hard and soft segments in the amorphous phase. Breaking tensile strength and breaking tensile elongation were evaluated for all IPEU and were shown to be slightly higher by increasing the hard segment and the feed chain extender content. If one considers the standard deviation, the values of the breaking strength can be considered very close to each other. Higher values were directly associated with the higher molecular weight of the polyurethanes. The non-cytotoxicity of IPEU was confirmed using L929 mouse fibroblast cells. No morphological changes were observed by the authors. Figure 8 shows the morphology of the cells growing on the surface (scored as zero).

The radiopacity of the samples was evaluated by X-ray images. The IPEU images were sharper than PEU. The contrast increased with iodine content incorporation, and comparing with aluminum, good radiopaque properties for the higher iodine contents were found. The in vitro oxidative treatment was evaluated for 6 weeks while in vivo and reproduced the effect of one year within 24 days. For the IPEU samples, GPC analyses demonstrated a decrease in the molecular weight and increased polydispersity after oxidative treatment. After 6 weeks, the surface of IPEU showed degradation signals represented as large pits, which was attributed to the extraction of low molecular weight products resulting from chain scission.

Kiran and Joseph [51] produced radiopaque polyurethane for biomedical applications. The polyurethane (named XPU) was synthesized by reacting 1,6-diisocyanatohexane with poly(hexamethylene carbonate)diol and 2,2′-(2,5-diiodobenzene-1,4-diyl)bis(oxy)diethanol (DBD). DBD was synthesized using the iodinate hydroquinone bis(2-hydroxyethyl) ether as a chain extender. XPU was compared with barium sulfate-filled polyurethane as the control material containing 10–30 wt%) of the contrast agent (Figure 9).

FTIR spectra showed all the characteristic bands of polyurethane. EDX and ultraviolet-visible spectroscopy indicated the presence of 14.53% iodine. GPC of the polyurethane indicated that Mw, Mn, and polydispersity were 54,470, 30,900, and 1.76, respectively. The tensile strength was 5.2 MPa, fracture tensile strain was 66%, and toughness was 3.2 MPa, while the DMTA showed a glass transition of −21.1 °C. As claimed by the authors, the molecular weight showed higher values than reported cases, but the mechanical properties showed lower values due to the lower concentration of aromatic content in the polymer matrix. TGA showed a thermal stability up to 230 °C. The X-ray opacity of XPU was compared to polyurethanes containing barium sulfate (demonstrated in Figure 10). It is noted that XPU has an X-ray opacity equivalent to 15% barium sulfate polyurethane.

The cytotoxicity was tested on L929 mouse fibroblast cells using PVC as the positive control and HDPE as the negative control. The morphology of the cells growing on XPU was similar to the negative control, showing its non-cytotoxicity (demonstrated in Figure 11). It was demonstrated that 93% of the cells were metabolically active after 24 h of contact with UHMWPE. The in vitro hemocompatibility showed no significant difference in RBC counts before and after exposure, while a slight increase in WBC consumption was observed compared to the control. Finally, any leachable activator for the coagulation pathways was observed, indicating that the hemocompatible nature of polyurethanes was not affected.

Kiran et al. [52] developed polyurethane thermoplastic elastomers with inherent radiopacity using MDI, PPG/PCL/PHCD with IBPA as the chain extender. The polymerization was carried out by a two-step reaction process at a molar ratio of 2.2:1.2:1.0, respectively. The authors synthesized three different polyurethanes: MDI/PPG/IBPA (RPU1), MDI/PCL/IBPA (RPU2), and MDI/PHCD/IBPA (RPU3) (Figure 12).

The presence of iodine for all samples was confirmed by EDX and the content was confirmed by XRF (19.08%, 18.04%, and 18.80%, respectively). FTIR analysis showed the characteristics absorption bands for PU, indicating that the polymer synthetized is indeed polyurethane while the molecular weights varied for each synthesized PU due to the differences in the reactivity and chain stiffness of the polyols used. The contact angle results indicated lower results for RPU2 and RPU3 compared to RPU1 attributed to the greater number of polar functionalities presented in ester and carbonate linkages. TGA showed two main decomposition stages for all PUs, with RPU2 and RPU3 being thermically stable up to 220 °C, a temperature 120 °C higher compared to RPU1. Regarding the mechanical properties, toughness (77.74 MPa) was obtained for RPU2, higher elongation at break (803%) for RPU1, and higher tensile strength (41.2 MPa) and modulus (33.2 MPa) for RPU3. These results are indicative that the property is highly dependent on the type of polyol used. RPU1 results are due to the flexibility of the PPG segment, compared to stiffer groups (PCL and PHCD) that promote a close packing and increase the intermolecular forces, increasing the other properties analyzed. DMTA showed higher storage modulus for RPU3 (31.2 MPa) and T_g (7.4 °C) while it showed lower values for the storage modulus (1.95 MPa) for RPU1 and lower T_g (−21.3 °C) for RPU2. The storage modulus value was higher for RPU3 due to the higher stiffness of the chain backbone. The crystallization of RPU was prevented by the hard segment’s presence in RPUs, as demonstrated in XRD analysis. The X-ray opacity presented darker images for all RPUs compared to aluminum control, showing the availability for use in biomedical applications. Fluoroscopy image of RPU2 compared with that of polyurethane containing 20% barium sulfate showed identical radiopacity for both samples. In vitro, cell culture cytotoxicity performed on L929 mouse fibroblast cells indicated that the cells retained the original morphology even after 72 h of contact with RPUs. The quantitative cell viability presented approximately 81% metabolic activity for all RPUs.

Sang et al. [53] synthesized biodegradable radiopaque iodinated poly(ester urethane)s containing poly(ε-carpolactone) blocks, named I-PUs. I-PUs were synthesized from PCL diol, IPDI, and IBPA. The authors synthesized and incorporated IBPA containing four iodine atoms per molecule as a chain extender. The synthesis was performed by a two-step polymerization process (Figure 13). Three different molar ratios of PCL/IPDI/IBPA (1:2:1, 1:3:2, and 1:4:3), named as PU-121, PU-132, and PU-143, were studied.

The thermal behavior and crystallization of the polyurethanes were characterized by DSC, TGA, and XRD. PU-121 was the only sample to exhibit a crystallization peak in the cooling process at 1.3 °C and melting peaks at 43.1/47.9 °C. XRD demonstrated less sharp and undetectable peak intensities for PU-132 and PU-143, while two small intensity peaks were observed for PU-121. TGA curves showed a maximum decomposition temperature of 337, 323, and 313 °C for PU-121, PU-132, and PU-143, respectively. X-ray radiopacity showed that I-PUs were easily detected and clearly visible; by increasing the iodine content, a better contrast is observed. The in vitro enzymatic degradation test showed that all I-PUs presented a similar degradation profile: a constant mass loss over time followed by a rapid mass loss in the third month. The surface morphology (Figure 14) indicated a smooth and neat texture in the first two weeks, followed by small cracks and pits after five weeks, and observed surface erosions more and more manifest up to the ninth week, and finally, after three months, the surface texture was rough and highly porous with some caves and channels. The cytocompatibility was conducted using RaDSC to examine the cell viability and morphology. The I-PUs showed non-cytotoxicity and retained their original morphology.

Liaw [54] synthesized polyurethane elastomers based on polycaprolactone diol, polytetramethylene glycol, diphenyl methane 4,4 diisocyanate, dicyclohexyl methane 4,4 diisocyanate, and three different chain extenders: bisphenol-A, bisphenol-S, bisphenol-AF, and the respective brominated derivatives. The polymerization of the polyurethanes was carried out in a two-step procedure (Figure 15). Higher hardness and tensile strength were found for the polyester polyurethanes derived from bisphenols, while polyester urethanes presented smaller density values due to the higher flexibility and lower cohesive energy from ether linkages than ester linkages. The presence of the sulfone group increases the tensile strength of PU, which was corroborated by a decrease in the crystalline region, as visualized on XRD. The solvent absorption and swelling in water or benzene of polyether polyurethanes were higher compared to polyester polyurethanes. Bisphenol-AF-based PUs presented lower water absorption compared to other bisphenol-based polyurethanes. The thermal stability studied by TGA showed that the brominated bisphenol incorporation increases the thermal stability compared to the other polyurethanes due to the presence of aromatic rings. DMTA indicated that HMDI-based PUs have a higher temperature at the onset of the storage modulus and a lower modulus temperature and tanδ due to the formation of tight crystalline structures formed by long soft segments of HMDI combined with low molar mass diol. The incorporation of bromine atoms decreases the thermal stability due to the phase separation phenomena, which increases the free volume of the polymeric chain.

Sang et al. [55] produced iodinated poly(lactic acid)-polyurethane (I-PLAU) for chemoembolization therapy using IBPA as a chain extender. The polymerization process was carried out using a two-step process in two distinct molar ratios PLLA:IPDI:IBPA of 1:2:1 and 1:3:2, named I-PLAU-121 and I-PLAU-132, respectively (Figure 16).

GPC indicated a higher molecular weight for I-PLAU-121, while the iodine content was 13.1 wt%, and the iodine content for I-PLAU-132 was 7.5 wt%. The ¹H NMR confirmed the I-PLAU copolymer synthesis. DSC demonstrated a glass transition temperature of 48 °C and 54.3 °C for I-PLAU-121 and I-PLAU-132, respectively. Also, a lower crystallinity and higher cold crystallization were obtained for the latter when compared to the former, as seen in XRD. The lower crystallinity was attributed to the higher amount of bulky iodine (which also promotes a higher steric hindrance) that affects the molecular symmetry of the polymeric chain reducing the chain packing. The in vitro radiopacity for both samples showed sufficient radiopacity when compared to the aluminum control. The hemocompatibility of both film samples was tested via platelet adhesion using SEM images. For I-PLAU-121, a discoid shape was observed, while for I-PLAU-132, flattened and irregular shapes are noted, which can be indicative of thrombus formation (Figure 17a,b). The static contact angle was measured and showed a contact angle of θ = 78.9° and θ = 84.6° for the aforementioned samples, indicating that both polyurethanes can act as coagulation agents and induce blood coagulation (Figure 17c,d).

The in vitro cytotoxicity indicated no difference in the iodine content on human adipose stem cells with a relative growth rate of 92.33% for I-PLAU-121 and 93.12% for I-PLAU-132. After 72 h, the values decrease by 85.75% and 83.33% for the samples, respectively. The histological analysis of the in vivo intramuscular implantation was performed using I-PLAU-132 for up to 4 weeks. Even after 4 weeks of implantation, the tissue around the PU sample showed no evidence of any macroscopic abnormalities, indicating acceptable biocompatibility and biodegradability. The authors also prepared and characterized I-PLAU/DOX beads by the emulsion/solvent evaporation method, obtaining a spherical reddish color. By SEM, it was observed that a tightened surface and nonporous internal structure for I-PLAU-121/DOX beads were observed, while some pores with irregular size and shape were noted for I-PLAU-132/DOX beads. This difference was attributed to the increase in the iodinated chain extender. The drug encapsulation efficiency (DEE) was 68% for I-PLAU-121/DOX beads and of 43% for I-PLAU-132/DOX beads due to the porosity of the bead. The cumulative release of DOX-loaded beads was similar for both polyurethanes in the first 5 days. After, I-PLAU-132/DOX beads showed higher cumulative release (almost 80%) compared to 40% for I-PLAU-121/DOX beads after 30 days. The anti-cancer cell viability Hela cells showed that the porous structure of I-PLAU-132/DOX beads had a slightly stronger effect than the nonporous structure of I-PLAU-121/DOX beads. In both cases, the proliferation of Hela cells is suppressed by a continuous release of the beads.

Shiralizadeh et al. [56] synthetized a radiopaque polyurethane-urea (PUU) with graphene oxide using 4-(4-iodophenyl)-1,2,4-triazolidine-3,5-dione (IUr) as a chain extender. The synthesis was carried out using MDI, PEG, and IUr. The MDI/PEG prepolymer was prepared and IUr was added to the solution followed by the incorporation of graphene oxide (GO) (two-step polyaddition reaction). Six different samples were analyzed by the author, named PUU-IUr using 4-(4-iodophenyl)-1,2,4 triazolidine-3,5-dione as the chain extender; PUU–PhUr using 4-phenyl-1,2,4 triazolidine-3,5-dione as the chain extender; and PUU-IUr-0.1, PUU-IUr-0.2, PUU-IUr-0.5, and PUU-IUr-1, incorporating GO with the respective chain extender and Go (wt%). For example, PUU-IUr-0.5 contains 0.5wt% GO and IUr as the chain extender (Figure 18).

FTIR spectroscopy showed the expected absorption bands, showing that the final material is indeed PU, which was also corroborated by NMR spectroscopy. The elemental analysis estimated the C, H, N, and O amounts in PUU-IUr and PUU-PhUr. The results showed that the experimental values were close to the calculated ones—C (54.85 and 59.58), H (6.12 and 6.23), O (27.05 and 28.34), N (5.54 and 6.58), and I (6.93 and 0) for PUU-IUr and PUU-PhUr, respectively. The incorporation of GO proved to be well dispersed, not altering the arrangement of the polymeric chains, as demonstrated by XRD. The authors attribute the dispersion to the bulky iodine atoms on the pendant group of the polymer, which apart the polymeric chains and allow GO to be penetrated into the polymer gallery. TGA curves showed two decomposition stages for all samples at 270 and 520 °C, attributed to urethane and urea linkages and the polyol, respectively. The storage modulus and the tan δ curves from DMTA showed that GO increased the storage modulus (desirable compatibility and strong hydrogen bonding interactions) and T_g from tan δ, indicating a restriction in the molecular chain mobility by adding GO. FE-SEM analysis showed that GO was well dispersed into the polymeric matrix, corroborating the XRD results, but at higher GO concentrations, agglomerations could be observed. X-radiography showed an excellent radiopacity for the iodine samples, being unaffected by GO. Finally, the cytotoxicity showed an inverse effect on the fibroblast cells’ viability.

Wang et al. [57] synthesized polycaprolactone-polyurethane (I-PCLUs) via the chain extender method, using PCL, IPDI, and IBPA at two molar ratios (1:2:1 and 1:3:2), named as I-PCLU-121 and I-PCLU-132, respectively. After, the polymers and free dox in water were prepared using a W₁/O/W₂ double-emulsion method in a PVA solution, forming polymeric beads (Figure 19).

The drug release and in vitro anti-tumor effect were evaluated for the I-PCLU beads. It was observed that the spherical format of the beads was maintained with a relatively high drug-loading in the shell layer of beads promoted by the diffusion of DOX into the water phase during preparation. A higher fluorescent intensity and drug-loading were observed for I-PCLU-132/DOX due to the smaller pores and thicker shell structure. The X-ray visibility was maintained after drug release with a sustained release mode for four weeks for both ratios of I-PCLU/Dox. The bioactivity was retained, as observed in the in vitro cancer cell viability, which inhibits the tumor cell proliferation. The proposed formulation proposed by the authors showed to be effective in muscle implantation (as demonstrated in Figure 20), being easily injected as an aqueous solution and promoting an effective chemoembolization effect by restricting tumor growth.

Egorikhina et al. [58] studied the biological characteristics of four different polyurethane-based bone-replacement materials, described as Composition 1 (PPG, MDI, glycerol), Composition 2 (PPG, MDI, glycerol, bismuth oxide (15 wt%), Composition 3 (PPG, MDI, glycerol, tantalum pentoxide (15 wt%)), and Composition 4 (PPG, MDI, glycerol, zirconium oxide (15 wt%)). The polymers were synthesized in two stages: first, MDI and PPG prepolymer were prepared, followed by the addition of glycerol and a contrast agent (Figure 21).

The samples Composition 1 and Composition 4 showed non-toxicity after 1- and 7-day extract while Composition 2 showed mild toxicity levels after both periods. The toxicity level of Composition 3 was shown to be variable. The interaction between cells and the polymers was also monitored. After 24 h, Composition 1 presented cell adhesion to the specimen surface and a fairly uniform distribution of the cells. After 72 h, the number of stained cell nuclei increased but only 50% of the cells were spindle-shaped (which indicates good adhesion to the specimen surface). The incorporation of bismuth (Composition 2) increases the cytotoxicity with less evenly distributed cells on the surface of the polymer. Composition 3 (containing tantalum) showed a zero to mild degree after 1 day and a medium degree after 7 days of incubation with cells distributed unevenly as small colonies. Finally, Composition 4 (containing zirconium) was non-toxic after 1- and 7-day extraction but no adherent morphology was observed on the polymeric surface within 3 days. The authors claimed that different contrast agents act differently in the distribution and sizes of the pores in their structure.

Kiran et al. [59] synthesized radiopaque polyurethanes (XPU) using H12MDI, PHCD, and a synthesized IBPA in the molar ratio 2.2:1.2:1.0. After, XPU was converted into microspheres (XPM) with different sizes (obtained at a stirring speed of 500, 750, and 1000 rpm) (Figure 22).

XPU was characterized by FTIR, GPC, and TGA. The characteristic absorption bands of polyurethane were observed in FTIR, confirming that the material formed is indeed PU. GPC showed a mass average molecular mass of 39,600 and a number average molar mass of 21,000. A thermal stability of 230 °C was observed by TGA. The microspheres (XPM) obtained at 500, 750, and 1000 rpm showed an average diameter of 500, 360, and 230 μm, respectively. The iodine content was 23.6% (confirmed by elemental analysis and elucidated by EDX). The cytocompatibility of microspheres was evaluated using L929 mouse fibroblast cells. After 24 h, the cells retained their original morphology, indicating the non-toxicity of the XPM. The metabolic activity showed to be 92, 91, and 94% for the diameters of 230, 360, and 500 μm, also confirming the non-toxicity of the microspheres. In vitro degradation (PBS solution of pH 7.4 at 37 °C) with the percentage mass loss remained at several points. Also, degradation studies showed no mass loss after 30 days. Finally, The X-ray image was performed by inserting the microspheres into the leg of the rabbit cadaver. An easier visualization of the radiopaque material was noted, validating the radiopacity effect of the synthesized material.

Sang et al. [60] synthesized biodegradable iodinated polyurethanes (I-PUs) using PCL, IPDI, and IBPA with two molar ratios (1:2:1, 1:3:2) coded as I-PU-121 and I-PU-132. The chain extender (IBPA) was synthesized by the authors (Figure 23).

The results were compared to a noniodinated polyurethane (coded as PU-C) using BPA as a chain extender. The enzymatic degradation was evaluated regarding the mass loss. Within 2 weeks, the mass loss of the three samples was lower than 12%. After 6 weeks, the lipase diffuses into the interior of the samples and accelerates degradation, promoting a sharp increase in mass loss. After 3 months a higher degradation was observed for PU-C (60.8%), followed by I-PU-121 (47.1%) and I-PI-132 (38.2%). These results showed the improvement of the enzymatic resistance by the incorporation of the iodine-containing agent. Optical images showed that all polyurethanes changed from dark to pale yellow after 3-month incubation in lipase media. All samples showed to be brittle in this period. The authors claimed that the color change observed for I-PUs are indicative of better enzymatic degradation compared to PU-C. X-ray opacity showed a dark image with clear profiles for the iodinated polyurethanes compared to the noniodinated control samples (PU-C). SEM images showed that after 3-month degradation, PU-C films showed an eroded surface, while I-PUs showed some pits and dimples, suggesting that the iodine helps to delay degradation. EDX indicated an iodine content of 8.6 and 12.3% for I-PU-121 and I-PU-132, respectively, even after 3-month degradation. DSC analyses were conducted in three different conditions > initial, after 9 weeks, and after 3 months. PU-C and I-PU-121 showed no significant differences regarding the melting temperature and the melting enthalpy; both increased for the former and slightly decreased for the latter with time. For I-PU-132, the melting peaks appeared only after 9 weeks, suggesting that PCL chains can rearrange themselves during degradation. XRD confirmed that bulky iodine incorporation has difficult chain packing and hence crystallization. The static contact angle in water showed values of 76.8° for I-PU-121, 83.6° for I-PU-132, and 68.6° for PU-C, demonstrating changes in the hydrophobicity by incorporating iodine atoms into the polymeric chains. Higher values for the contact angle were obtained by increasing the period of degradation.

4. Limitations and Challenges

Considering that most applications are related to biomedical applications, the limitations can be enumerated mainly as biocompatibility, mechanical properties, radioactivity, cytotoxicity, and cost. All the materials used for radiopacity must be biocompatible to ensure an appropriate response in a specific application, guarantee patient safety and comfort, and minimize side effects in the human body. The medical advice must retain its integrity, whether for hard or flexible parts; hence, the mechanical properties resulting from the incorporation of a radiopacifying agent (as a nanoparticle or as part of the polymeric chain) have to be maintained for a determined application. The studies pointed out that some mechanical properties decrease by incorporating the radiopacifier agent. The radioactivity is related to the atomic number of the radiopacifier agent and concentration, which corresponds to the specific structure in which the material will be inserted into the human body. The cytotoxicity needs to be extensively studied [61], but some studies using barium sulfate have already been successfully applied to prevent biological reactions. In some cases, it is recommended to use cross-linking techniques to maintain the inorganic filler in the medical device to avoid (or reduce) the mitigation of the contrast agent. Finally, the overall cost of the final part is important because it provides commercial viability.

The synthesis challenges arise in achieving industrial-scale production while maintaining the same parameter control in bench synthesis. There is a need to develop novel, cheap, and alternative economic sources, such as biodegradable polyurethanes or polyurethanes from renewable sources, to produce environmentally friendly products. Also, depending on the application, a higher viscosity/lower fluidity is required in the process, which considerably changes the synthesis route/conditions. Regarding medical applications, it is expected that the incorporation of the radiopacifier elements will result in similar mechanical properties compared to the neat polymer, either by optimizing the synthesis parameters or by developing new layouts of the final product. Also, it is expected that, besides biocompatibility, other properties such as bioactivity, biodegradability, and regeneration, depending on the exposure time of the medical device, will be considered in the application. Also, the manufacturing of radiopaque polyurethanes to respond to different environmental stimuli can be of great importance in human body applications.

Radiopaque materials can be optimized by layering techniques or computational modeling. Layering techniques consist of concentrating the radiopacity in specific regions where it is most necessary, while computational modeling allows for the simulation and optimization of the distribution of radiopaque materials within the device, ensuring efficient use of the materials for the maximum radiopacity requirement. It is also worth mentioning materials that require only temporary radiopacity, as in the case of implants such as stents or contrast agents that are eliminated by the renal system, such as iohexol, for example. An important issue is that some contrast agents such as ferric oxide can promote the stimulation of bone growth.

The radiopacity can be ensured either by including high-atomic-number elements such as metals, or by incorporating these elements as part of the polymeric chain, such as iodine. Some examples of metals widely used in implants and catheters are gold and platinum, which ensure excellent radiopacity, biocompatibility, stability, and corrosion resistance, contributing to the long-term reliability of these materials for biomedical applications. When inorganic metallic compounds or organic compounds are incorporated into the polymeric matrix, the physical blending of the contrast agent (the most prevalent and economical method) has some drawbacks such as poor homogeneity, which can lead to the incorporation of a higher amount of the agent. This poor homogeneity can be improved by including soluble radiopacity agents in the polymeric matrix, which also results in a lower amount of the agent for the same level of radiopacity.

Recent advances in science and technology have allowed the fabrication of tailor-made materials at the nanoscale and the use of 3D printing for the fabrication of radiopaque materials. Continued research and innovation will allow more balanced properties among radiopacity, mechanical properties, biocompatibility, and cost, ultimately improving patient outcomes in diagnostic and interventional procedures.

5. Conclusions

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 PUs are more efficiently synthesized with heavy atoms with a high electron density as part of the back chain bone or when grafted. The synthetization of polyurethanes with biocompatible, low-cytotoxicity, and 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 enables multipurpose use in biomedical applications.

It is worth mentioning 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, a 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 the 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 an 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.