Progress in Niobium Oxide-Containing Coatings for Biomedical Applications: A Critical Review

Abstract

Typically, pure niobium oxide coatings are deposited on metallic substrates, such as commercially pure Ti, Ti6Al4 V alloys, stainless steels, niobium, TiNb alloy, and Mg alloys using techniques such as sputter deposition, sol–gel deposition, anodizing, and wet plasma electrolytic oxidation. The relative advantages and limitations of these coating techniques are considered, with particular emphasis on biomedical applications. The properties of a wide range of pure and modified niobium oxide coatings are illustrated, including their thickness, morphology, microstructure, elemental composition, phase composition, surface roughness and hardness. The corrosion resistance, tribological characteristics and cell viability/proliferation of the coatings are illustrated using data from electrochemical, wear resistance and biological cell culture measurements. Critical R&D needs for the development of improved future niobium oxide coatings, in the laboratory and in practice, are highlighted.

1. Introduction

Aging, illness, and accidents provide threats to human health. It is essential to seek appropriate materials and devices to aid repair or replacement of damaged body parts over extended periods.¹ According to a definition presented by American National Institute of Health, a biomaterial is “a synthetic or natural material or combination of the materials excluding drugs, which is deployed to partially or entirely replace any tissue/organ or maintain or enhance the life quality of the individuals.” This definition excludes gypsum, waxes, finishing materials, etc.^2,3 The biomaterials should encourage favorable biological responses in the host tissue.⁴ Depending on the type of constituent material, biomaterials can be broadly categorized as follows: (i) metallic, e.g., Ti and Ti-based alloys, Mg alloys, Co–Cr, stainless steel, NiTi; (ii) ceramic, e.g., calcium phosphates (CaP); (iii) polymer, e.g., polyurethane (PU); (iv) composite, e.g., CaP-PU; and (v) natural, e.g., skin.⁵⁻¹⁴ It is important to appreciate the contributions made by biomaterials to modern medicine. They are used in a variety of clinical applications, including orthopedic, cardiovascular, facial, and dentistry treatments. The total market for bioimplants in 2020 is about 89 million USD, forecasted to grow with a compound annual growth rate (CAGR) of 6.5% during the time period of 2020–2026. Orthopedic implants hold the largest fraction of the global implant market. Over 22 million orthopedic surgeries take place annually worldwide, which is expected to reach about 28 million in 2022.¹⁵⁻¹⁸

Metallic materials are by far the most commonly employed synthetic bulk implants since they took advantage of high mechano-corrosion properties together with acceptable biological performance. The appropriate strength of these materials offers the opportunity to exploit them as load-bearing implants in dentistry and orthopedics.¹⁹⁻²⁵ The first scientific reports on the use of metals as synthetic implantable material traced back to 1895. For over 100 years, the development progress of metal implants has not been stopped so that the focus on controlling the overall properties of these implants to attain better performance has grown rapidly in recent years,²⁶ but several problems limit the successful long-term in vivo use of metallic implants:

• The presence of a harsh environment in the human body, wear between joints, and stress load cycles that may be repeated millions of times in a lifetime crucially challenge the implantation process. While corrosion of orthopedic implants may be caused by the presence of corrosive species, such as Cl^– ions, the low pH associated with the presence of F^– ions around dental implants can dominate during corrosion.²⁷ Although research in this field has placed a high premium on assessing the influence of the corrosive physiological medium on releasing the toxic ions, tribology plays a central role in realizing the concentration of the released ions especially in the knee, hip, joints, etc.²⁸ For instance, it is reported that 6.7 × 10¹³ to 2.5 × 10¹⁵ Co particles per year can be released from implanted Co–Cr material. When evaluating the Co level in the periprosthetic fluid of patients suffered from failed implants, it has been recognized that the Co level surpassed 22 mg/L, at least 4 times higher than in those without complaints. Furthermore, every step walk leads to the release of 10⁶ debris nanoparticles from metalware.²⁹ NiTi, stainless steel, and Ti6Al4 V implants are the other materials that the ion release from their surface greatly threaten the implantation success and patient’s health, by inducing allergic reactions.³⁰ It is important to adopt effective, empirical strategies to increase the corrosion resistance of biomaterials. This not only prolongs the service lifetime of the implant but also avoids inflammation.

• The mismatch between the elastic modulus of the synthetic implant material and natural bone, which can lead to stress shielding. While the elastic modulus of the natural bone is in the range of 10–40 GPa, Co–Cr alloys and stainless steels show an elastic modulus above 200 GPa. This can substantially decrease the bone density (osteopenia) since the implanted material with higher elastic modulus bears the applied loads.³¹⁻³³

• Insufficient osseointegration, which refers to the inefficiency of the implanted material in enabling an appropriate platform for apatite to nucleate and grow at the implant/host tissue interface. When the material is implanted in vivo, the present proteins adsorb on the surface of the implant. Hence, the surface condition of the biomaterial plays a major role in osseointegration. Under in vivo conditions, different cells, such as osteoblasts, fibroblasts, and endothelials come into contact with the biomaterial for tissue remodeling. As a brief summary, the more the bioactive surface, the higher the integration between the implant and host tissue occurs. Among the common metallic biomaterials, stainless steels can suffer from a lack of bioactivity.³⁴⁻⁴⁰

• Bacterial infection: when the biomaterial is implanted in vivo, in particular for knee joints and dental applications, a competition between the present microorganisms and host cells starts to occupy the largest fraction of the surface of the biomaterial, so-called “race for the surface”. If the microorganisms win this race, bacterial colonies can be formed over the surface, leading to the preprosthetic infection that can damage the local tissues. To avoid the mentioned challenge at an early stage of implantation, and to get higher implantation efficiency, it is necessary to adopt cost-effective, flexible, and feasible strategies.⁴¹⁻⁴⁶

The surface of the implant is the place where the first interactions between implant and host cell/tissue occur. Surface-related features, encompassing topography, energy, and chemical composition, determine the protein adsorption, osseointegration quality, and implant fixation. It is possible to change the final characteristics of the bulk implant by modifying its surface so that the surface, i.e., the initial interaction site, offers quite different functions compared to the bulk implant.⁴⁷⁻⁵³ To date, a variety of surface finishing techniques, including electrochemical deposition,⁵⁴ sol–gel,⁵⁵ sputter deposition,⁵⁶ spray deposition,⁵⁷ biomimetic deposition,⁵⁸ as well as coating materials, such as CaP,⁵⁹ TiO₂,⁶⁰ ZrO₂,⁶¹ ZnO,⁶² Nb₂O₅,⁶³ etc., have been proposed to induce favorable properties to the surface of the biomaterials. For instance, it is possible to induce bioactivity for superior osseointegration by the application of CaP family coatings or prevent bacterial inflammations through deposition of silver or zinc-containing layers. These strategies can open new windows to develop the new generation of implants that bypass the challenges faced by metal implants and can avoid putting an additional burden on the patient.⁶⁴ The nanostructured topography of the surface of the biomaterials brings forth promising perspectives since a vast majority of the biological interactions, such as osteoblast adhesion and biomineralization, occur on the nanoscale, and the nanometric surface roughness can appreciably affect the adhesion process.⁶⁵Figure 1 illustrates a timeline for the development of biomaterials, biomedical application of Nb, and biocompatible Nb₂O₅ coatings.

Figure 1.

Timeline for the development of biomaterials, biomedical application of Nb, and biocompatible Nb₂O₅ coatings.⁶⁶⁻⁷⁴

The present review paper attempts to discuss the properties, application, and market of niobium and its oxides, putting emphasis on their biomedical properties and applications. The overall characteristics of the pure Nb_xO_y and Nb_xO_y-containing coatings deposited by various surface finishing techniques will also be treated in detail, putting stress on the importance of surface finishing with pure Nb_xO_y and Nb_xO_y-containing layers along with a relationship between the operating parameters and final properties of the resultant films.

2. Important Properties of Niobium and Niobium Oxide

Niobium (Nb) is a refractory metal, possessing high thermal stability, erosion-resistant properties, low vapor pressure, good chemical stability in a variety of hostile environments, excellent corrosion resistance, suitable tribomechanical properties, e.g., high wear resistance, excellent ductility at room temperature, favorable biocompatibility, and low thermal expansion. Nb falls under the category of transition metals, crystallizing in a body-centered cubic (BCC) crystal lattice.⁷⁵⁻⁷⁹Table 1 lists some of the physical properties of the Nb.

Table 1. Some of the Physical Properties of the Nb^80,81.

physical properties	amount
melting point	2447 °C
boiling point	4741 °C
density	8.57 g cm–3
electrical resistivity	15.2 μΩ cm at 273 K
relative atomic mass	92.906

Regarding biological characteristics of Nb, it is a nontoxic and allergy-free metal, indicting acceptable biocompatibility and osteoconductivity.⁸²⁻⁸⁴ As in the case of titanium (Ti), Nb is known as an “essential metal” since it enables significant chemical stability in the physiological medium. Therefore, Nb is considered as a potential metallic element in fabrication of synthetic implantable materials and devices for soft and hard tissues.⁸⁵ Thanks to its promising properties, the main focus of research has been to realize the in vitro and in vivo performance of Nb and in particular Nb-containing alloys. Results of a comparative work on the biological performance of Nb, Ti, and stainless steel, as three important and useful synthetic implant materials, showed that there are much more mitochondrial activity and cell proliferation on Nb compared to the others. The highest rate of the in vivo osseointegration of tested implants is also registered for Nb.^86,87 To fabricate bulk synthetic implants, it is encouraged to alloy the Nb with other biocompatible materials, such as Ti, rather than using it in its pure form. When alloyed with Ti, Nb can stabilize the β phase, which contributes to decreasing the elastic modulus of Ti, thereby diminishing the risk of the “stress shielding”. Moreover, the positive role of this element in improving corrosion and biological features of the composite implants should not be neglected.^72,88,89

Besides technical aspects, cost and availability during materials selection for the fabrication of a synthetic implant can be critical.⁹⁰ Brazil has the largest Nb reserves, equivalent to approximately 98.53% of total Nb in the world. Nb ore reserves exceed 212 billion tonnes in Brazil, which makes this country the biggest producer of Nb, about 96% of world production. Brazil is followed by Canada and Australia, which contain 1.01% and 0.46% of world’s Nb ores reserves, respectively.⁹¹⁻⁹³ Interestingly, Europe is the main consumer of Nb, where 30% of total Nb is consumed. Worldwide, Nb is supplied in various forms, including niobium pentoxide (Nb₂O₅), niobium carbide (NbC), metal niobium, ferroniobium alloy (FeNb), and lithium niobate (LiNbO₃). Furthermore, it is possible to purchase niobium pentachloride (NbCl₅) only from Russia. FeNb dominates the global production of Nb-containing materials. FeNb is used for fabrication of high strength steels, occupying about 89% of Nb world production. It is to be noted that the largest application of Nb is corresponded to structure steels, more than 34% of total Nb market. Overall, the total Nb market value is about 1389 USD in 2019, which is anticipated to stand at 1748 USD by the end of 2027.⁹⁴

The tremendous osteoconductivity, biocompatibility, and corrosion performance of Nb are dominated by the oxide layer formed over its surface. The corrosion properties of the formed oxide layer determine the overall corrosion resistance of the Nb in acidic or neutral environments. Among various oxides, Nb₂O₅ is the most common type of niobium oxide and can be spontaneously generated over the surface when Nb is exposed to an oxygen-containing environment. It is tightly adherent to the Nb and can fully cover its surface.^86,95−99 Nb₂O₅ illustrates high resistance against both corrosion and wear, excellent thermodynamic, thermal, and chemical stabilities, high reflective index, low density, outstanding mechanical strength, and fracture toughness, nontoxicity, hypoallergenic, great biological characteristics, enabling cellular attachment, growth, spreading, proliferation, metabolic activity, collagen synthesis, seriously influencing endothelial cell responses, alkaline phosphatase activity (ALP), and supporting HAp formation in the various physiological media due to the small lattice mismatch (1.1%) between the oxide and mineral HAp phase.^73,100−110 Due to the above properties, Nb₂O₅ coatings show significant potential for applications in a variety of industrial applications, such as electrochromic devices, optical windows, solar cells, sensing devices, catalysts, supercapacitors, and biomedical.^111,112 Although the initial interests in Nb₂O₅ and its polymorphs, e.g., NbO₆, are traced back to the 1940s, the potential benefits and applications of Nb₂O₅ have not been fully exploited so far. In the early years, the main industrial applications of this transition metal were as sensors and catalysts, in which Nb₂O₅ was used in the bulk or film form.^113,114 Recently, the biomedical applications of Nb₂O₅ in bulk and coating form have drastically increased owing to their exceptional biological features. Synthetic orthopedic implants, biosensors, and radiopacifying agent coupled with Portland cement in dentistry and filler for dental adhesive resin are important medical applications of Nb₂O₅.^{72,112,115,116}

3. Pure Nb_xO_y Coatings

Background

Typically, pure niobium oxide coatings are deposited over a variety of metallic substrates, including commercially pure Ti, Ti6Al4 V alloys, stainless steels (particularly AISI 316L grade), Nb, TiNb alloy, and Mg alloys using techniques such as sputter deposition, sol–gel deposition, anodizing, and wet plasma electrolytic oxidation (PEO).^117−121

Magnetron-sputtered pure Nb₂O₅ coatings can be obtained using a Nb metallic target in either pure oxygen^117,122 or mixed oxygen + argon atmospheres.^123,124 To deposit sol–gel derived Nb₂O₅ coatings, three types of sols can be prepared using various precursors with specific molar ratios as below: (i) butanol, acetylacetone, and niobium alkoxide;^121,125 (ii) niobium ethoxide, iso-propanol, acetylacetone, and polyethylene glycol (PEG);¹²⁶ and (iii) niobium butoxide, triethanolamine, ethanol, and PEG.¹²⁷

The anodizing of Nb-containing substrates can be carried out from three types of electrolyte: (i) NaF or Na₂HPO₄-containing HF(aq);¹¹⁸ (ii) a mixture of Ca(H₂PO₄)₂, Ca(OOCCH₃)₂, and C₁₀H₁₄N₂Na₂O₈;⁸⁸ and (iii) a mixture of C₂H₆O₂ and NH₄F.¹²⁸

PEO coating of Nb anode material can be carried out from phosphoric acid and hydrogen peroxide-containing and calcium acetate monohydrate electrolytes. It is also possible to employ a bath composed of a mixture of phosphoric acid and calcium acetate monohydrate.¹²⁰Table 2 provides the advantages, limitations, and schematic illustration of common techniques employed for achieving pure niobium oxide coatings.

Table 2. Advantages, Limitations, and Schematic Illustration of the Common Techniques Used to Apply Pure Niobium Oxide Coatings^129−137.

The published literature on the evaluation of final characteristics of pure Nb_xO_y coatings has emphasized the influence of the coatings on the overall performance of the underlying implants, drawing relationships between the role of operating parameters and properties of the resultant coating and providing an insight into the biological performance of metal oxide coatings, such as Nb₂O₅, Ta₂O₅, and TiO₂.^105,124,138 The following text will provide a systematic overview of the properties of pure Nb_xO_y coatings.

Morphology and Topography

The surface morphology and topography of the Nb_xO_y deposits are highly dependent on the type of the employed coating technique, applied operating factors, and post-treatments. Among the various niobium oxides, Nb₂O₅ coatings have attracted increasing attention. Regardless of the coating method, four different types of surface morphologies: conelike,¹¹⁸ nodular,¹³⁸ granular,⁹¹ and spheroidal¹²⁰ have been observed for Nb₂O₅ coatings.

Overall, the surface of the pure coatings produced via the radio frequency (RF) magnetron sputtering and reactive sputtering methods are homogeneous, tightly adherent to the substrate, and without visible defects, such as cracks and discontinuities. The constituent particles are uniformly arranged over the surface of the coating.^{91,117,139,140} The surface topography of the films confirmed the formation of a densely packed surface without surface-related defects.^{91,117,139,140} It has been claimed that the application of magnetron sputtering can ensure formation of a dense and uniform coating.¹²⁴ The insertion of nitrogen gas during RF magnetron sputtering can lead to the formation of niobium-oxynitride coating, in which a higher degree of the crystallinity is seen in deposits from a high gas flow rate. This can also give rise to surface roughness. While amorphous coatings are grown in an equiaxial fashion, crystalline deposits tend to be columnar.¹³⁸

Published literature on the surface morphology of the sol–gel derived films is very contradictory. While some reports demonstrated the formation of the coatings containing a network of pores with different diameters from nanometer to micrometers by sol–gel dip coating,^105,127 one study confirmed the formation of a crack-free surface with a low porosity content through sol–gel spin coating even after calcination at 500 °C.¹²⁶ The aim behind the application of the calcination is to eliminate solvent and residual organics, convert oxides, and achieve a crystalline deposit.¹²⁶ However, the evaporated solvent can lead to pore generation in the so-called “evaporation induced self-assembly process”, which can significantly decrease the density of the obtained film. It should be noted that the pores remain at the top surface of the film and may have little effect on the mechano-corrosion properties of the coatings.^105,127,141 Moreover, the sol–gel derived Nb_xO_y films are susceptible to blistering originated from the difference between the coefficient of thermal expansion (CTE) of the underlying metallic implant and ceramic top layer.^126,142 The constituent particles of the sol–gel derived films include both spherical¹²⁵ and wavy¹²⁶ morphologies. The formation of some aggregated particles over the surface of the films have also been reported.¹²⁶ Although the deposited oxide coating increases the surface roughness of the underlying substrate, the degree of increment greatly depends on the calcination temperature. Eisenbrath et al.¹²¹ have indicated that the surface roughness of the Nb₂O₅ coatings increased from 7 to 40 nm when the calcination temperature was raised from 450 to 700 °C. The nanoporous nature of the sol–gel derived coatings is the reason why the deposited film enhances the surface roughness of the substrate. The higher the surface roughness, the superior bioactivity and biocompatibility are obtained,^105,143 which will be comprehensively discussed in the following text.

The operating parameters involved in the anodizing process, e.g., time, cell voltage applied, and acid concentration, noticeably affect the surface morphology of the deposited films. The prolonged anodization time from 20 to 90 min results in a change in the morphology of the coating from amorphous to the self-assembled crystalline one, consisting of microcones. Such a microstructure can be emerged when the oxygen ions diffuse through the newly formed oxide layer and interact with the present Nb ions that are present over the underlying substrate. The presence of salts in the acidic electrolyte determines the morphology and porosity content of the formed microstructure.^118,144,145 Furthermore, at longer anodizing times, a higher rate of oxide growth is seen.¹⁴⁶ It is reported that the deposition of Nb₂O₅ layer over the Nb foil changes its morphology through formation of some small pores. The content, distribution, and size of the pores crucially depends on the applied potential. While the surface of oxide films fabricated at the potential of 200 V contains 2 μm-sized pores with quite uniform dispersion, those deposited under 250 V show heterogeneous surfaces with three-time larger pores. The applied potential not only varies the surface characteristics but also changes the thickness and surface roughness, where a thicker layer with higher surface roughness can be obtained when a higher potential is applied.⁸⁸ The type and concentration of acidic electrolyte have significant influence on the surface properties. The lower the HF(aq) concentration leads to the higher oxide layer growth. The as-reached F^– ions to the surface of Nb metal interact with the interstitial Nb ions to form Nb₂O₅.¹⁴⁶

Contradictory results have been reported on the surface morphology of Nb₂O₅ coatings obtained by PEO deposition. While Pereira et al.¹²⁰ showed the formation of the compact surface with spheroidal particles after PEO in phosphoric acid solution, Lokeshkumar et al.¹⁴⁷ demonstrated that the deposited layer was porous, consisting of interconnected open pores. It is stated that the chemical composition of the used solution and operating parameters determine the homogeneity of the Nb₂O₅ deposit. For instance, the film produced from Na₃SiO₄·12H₂O + KOH electrolyte under a final cell voltage of 80 V had a heterogeneous surface containing microcracks, while that deposited from Na₃PO₄·9H₂O + KOH at a final cell voltage of 75 V produced a uniform surface morphology. In general, the use of a silicate bath leads to thicker deposits.¹⁴⁷ It is also possible to couple the PEO route with other electrochemical deposition technique, such as electrophoretic deposition (EPD), to incorporate desired second phase to the growing oxide layer¹⁴⁷ and apply two-step PEO with various electrolyte composition.¹²⁰ For example, biocompatible hydroxyapatite (HAp) particles can be incorporated to the PEO-fabricated Nb₂O₅ film via EPD. The included particles markedly affect the surface properties of the oxide layer with closing the pores and diminishing their size.¹⁴⁷Table 3 summarizes the thickness and surface roughness of the Nb_xO_y coatings deposited via different methods on a variety of substrates.

Table 3. Thickness and Surface Roughness of the Nb_xO_y Coatings Deposited via Different Methods on Various Substrates^a.

coating method	substrate type	thickness/nm	surface roughness (Ra)/nm	refs
magnetron sputtering	Ti6Al4 V	210	2.4 ± 0.5	(117)
RF magnetron sputtering	cp Ti	121.63		(148)
magnetron sputtering	Ti6Al4 V	210	2.4 ± 0.5	(139)
magnetron sputtering	Ti6Al4 V	180	16.5	(122)
magnetron sputtering	Ti6Al4 V	210		(140)
RF magnetron sputtering	316L stainless steel	688.5–825.9	2.05–3.41	(138)
reactive magnetron sputtering	Ti6Al4 V	300–450		(91)
reactive and nonreactive magnetron sputtering	AISI 316LVM steel		18.5	(124)
DC magnetron sputtering	316L stainless steel	300	2.94	(123)
sol–gel	cp Ti	100	7–40	(121)
sol–gel	316L stainless steel	2–3 × 103	18.6	(126)
sol–gel	β-type Ti alloy	160	4–50	(125)
sol–gel	AZ31 Mg alloy	2 × 103	26.75	(105)
anodizing	Nb	2–13 × 103	130–900	(88)

^aA change in the deposition technique or processing parameters can significantly alter the surface characteristics.

Microstructure

The published results regarding the atomic arrangement of the sputter deposited Nb₂O₅ coatings show differences. While an enormous majority of the reports indicated that the magnetron sputtered films are amorphous,^{117,122,139,149} there is a study confirming the generation of a crystalline Nb₂O₅ coating via magnetron sputtering at 60 °C.¹⁴⁸ Deposition at low temperature and a lack of substrate heating during the deposition process are the main reasons explaining the generation of an amorphous Nb₂O₅ layer.^117,122,139 The postheat treatment of the crystalline Nb₂O₅ coatings at 700 °C for 60 min leads to the emergence of new Nb₂O₅ and βNb₂O₅ peaks as well as changing the height and width of existing peaks.¹⁴⁸ The oxygen/nitrogen gas flow ratio realizes the atomic arrangement of the sputtered niobium oxynitride film. The amorphous coating changes to the polycrystalline one when the oxygen content exceeds beyond a threshold. In such a condition, film growth is dependent on the oxygen and niobium reaction even if nitrogen flows into the vacuum chamber. The presence of nitrogen led to a niobium oxynitride coating without changing the crystal lattice.^138,150

Sol–gel derived coatings can be either amorphous or crystalline depending on the temperature of the must be carefully established. While Pradhan et al.¹¹⁹ showed that the films calcined at 450 °C are amorphous and crystalline transformation occurred above 500 °C, Amaravathy et al.¹⁰⁵ approved the deposition of the sol–gel derived crystalline Nb₂O₅ layer through calcination at 380 °C. The films calcined at about 500 °C are composed of a hybrid amorphous + crystalline lattice. A rise in calcination temperature not only leads to the appearance of some new Nb₂O₅ peaks but also changes the unit cell geometry of the lattice. For instance, a change in unit cell geometry from hexagonal to orthorhombic is obtained at the calcination temperature above 575 °C.¹¹⁹Table 4 outlines the crystallite size of the sol–gel derived Nb₂O₅ films as a function of calcination temperature. The crystallite size of the coatings is measured using the Scherrer equation as follows:^151−153

1

where k, λ, β, and θ are the Scherrer constant, wavelength of X-ray, fwhm, and Bragg angle, respectively. The Scherrer constant depends on the crystallite shape. For instance, it is taken to be 0.89 for spherical crystallites.¹⁵⁴

Table 4. Crystallite Size of the Sol–Gel Derived Nb₂O₅ Films as a Function of Calcination Temperature.

type of sol–gel film deposition	calcination temperature/°C	atomic arrangement/unit cell	crystallite size/nm	refs
not mentioned	500	mixture of amorphous + crystalline	23 ± 4	(119)
	550	crystalline/hexagonal	37 ± 6
	575	crystalline/hexagonal	43 ± 3
	650	crystalline/orthorhombic	74 ± 3
dip-coating	500	crystalline/hexagonal	30–40	(127)
dip-coating	380	crystalline/monoclinic	48	(105)
spin-coating	500	crystalline/hexagonal	41.49	(126)
spin-coating	550	not mentioned	24	(155)
	600		38
	650		39
	700		58

As seen, all of the sol–gel derived coatings are nanostructured, which provide a larger surface area to interact with the cells improving the cell adhesion and adsorption of proteins.¹⁰⁵

The phase structure of the Nb₂O₅ produced via anodization of Nb substrate is only composed of peaks assigned to the orthorhombic Nb₂O₅.¹¹⁸

PEO-coated Nb₂O₅ are crystalline and can be present in both hexagonal and orthorhombic unit cell geometry.^120,147 Although the composition of the acidic electrolyte used in the PEO process has no influence on the emerged phases, it can only alter the height and width of the emerged peaks.¹⁴⁷

Tribomechanical Behavior

The implanted material should benefit from appropriate tribomechanical properties since it endures normal and shear forces as well as undergoing friction during the service time. This issue is particularly highlighted for dental and orthopedic implants. Thus, the method and composition of the coating should be controlled in such a way that meet the required tribomechanical properties. Also, the bonding strength and durability of the coating should be taken into consideration since the film may detach as a result of the forces endured.^156−158 Meanwhile, there should be a balance between the elastic modulus of the implant material and natural bone, especially for orthopedic implants. A big mismatch can result in “stress-shielding”, which eventually causes a failure in implantation. For instance, the elastic modulus values of the stainless steel and cortical bone are 180 and 17 GPa, respectively. Such a mismatch can lead to stress-shielding. Surface modification of the implants is needed to satisfy mechanical and chemical requirements.^159,160 Nanoindentation, nanoscratching, pull-off tensile testing, wear testing, and corrosion studies can be employed to analyze the tribomechanical characteristics of biocoatings.^161−164

The application of the Nb₂O₅ coating by the sputter deposition route can greatly raise the nanohardness and elastic modulus of the metallic implants, in particular the Ti-based ones. It is reported that the nanohardness and elastic modulus of the Ti6Al4 V implant increases from ≈5.5 to ≈8.6 GPa and from 112 to 142 GPa, respectively.^{117,122,139,140} The sputter deposited Nb₂O₅ films possess desirable tribological performance as there are no scratches detected on the surface of the coatings after a steel wool test under a load of 0.5 N.^117,122,139 Kalisz et al.¹⁴⁰ have demonstrated that the nanohardness of the coatings negligibly decreases, about 5%, after a corrosion test in a corrosive medium containing NaCl and KF. The surface morphology of the Nb₂O₅ coating after a tribocorrosion test, which provides a perspective on the synergistic action of corrosion and wear, in Ringer’s solution under the normal load of 5 N at rotating speed of 5 rpm that applies to a bone pin indicating the formation of some pits together with a sign of an adhesive wear track. In general, it is claimed that the Nb₂O₅ layer offers tremendous wear resistance; however, it could be degraded when it underwent wear in a corrosive, in vivo environment.¹²⁴ An SEM micrograph of a Nb₂O₅ coating after tribocorrosion testing is shown in Figure 2. The sign of adhesive wear is observable for Nb₂O₅ coating after the tribocorrosion assay.

Figure 2.

SEM micrograph of Nb₂O₅ coating after tribocorrosion testing.¹²⁴ Reprinted with permission from ref (124). Copyright 2021 by the authors.

The results of an in vivo assay can enable a more realistic view of the mechanical performance of the coatings. The in vivo removal of torque is a suitable characterization method to reveal whether the osseointegration is sufficiently firm. The sputter deposited Nb₂O₅ layer shows an acceptable torque value. The value was enhanced with time, confirming the generation of a favorable implant/bone bonding, which can promote bone growth and facilitate mechanical interlocking between the coating and underlying implant.¹⁴⁸

The application of Nb₂O₅ coating via a sol–gel route gives rise to the hardness of the metallic implant. Moreover, the elastic modulus of the layer is much lower than that of underlying metallic substrate due to its porous microstructure, decreasing the risk of stress-shielding effect. The sol–gel derived ceramic layer possesses high bonding strength, qualifying its use in orthopedic applications.¹²⁶

The adhesion strength between the PEO-fabricated Nb₂O₅ coating and Nb substrate is reported to be sufficient for biomedical applications, irrespective of the composition of the used electrolyte.¹²⁰Table 5 summarizes the reported mechanical properties of Nb_xO_y biocoatings.

Table 5. Reported Mechanical Properties of Nb_xO_y Biocoatings.

coating type	deposition method	characterization method	hardness	elastic modulus/GPa	refs
Nb2O5	sputter deposition	nanoindentation	8.64 GPa	142	(117)
Nb2O5	sputter deposition	nanoindentation	8.64 GPa		(139)
Nb2O5	sputter deposition	nanoindentation	5.58 ± 0.3 GPa		(122)
Nb2O5	sputter deposition	nanoindentation	8.64 GPa (before corrosion)		(140)
			8.16 GPa (after corrosion in NaCl and KF-containing media)
Nb2O5	sol–gel	Vickers microhardness	444 ± 3.2 HV		(126)

Information on tribomechanical properties of the Nb_xO_y biocoatings is scarce in the open literature. For future works, establishing the mechanisms involved in a change in the tribomechanical properties with the application of Nb_xO_y coating, identifying relationships between the processing parameters and tribomechanical performance of the resultant deposit, studying all of the tribomechanical aspects, encompassing hardness, elastic modulus, interfacial strength, and tribocorrosion response of the coatings, should be addressed in detail.

Corrosion Performance

In general, the corrosion resistance of the metallic implants, including Ti6Al4 V and 316L stainless steel, outstandingly promotes when they are protected by sputter deposited Nb₂O₅ coatings. However, the factors governing such an enhancement in the corrosion behavior have not been clearly considered in the literature.^{117,122,139,140} In the case of an uncoated metallic implant, e.g., Ti6Al4 V, a passive layer can be formed over its surface when it is immersed in the corrosive medium. Since the Ti has a negative reversible potential, it is susceptible to oxidation upon exposing to aqueous electrolytes. The passive layer contributes to the corrosion resistance through providing an initial barrier against the present corrosive species. It is to be emphasized that the protective capability of the layer directly depends on the pH of the medium so that the layer cannot resist against aggressive anions.^165,166 There are practical works that provide a comparative insight into the corrosion protection performance of the ceramic coatings, e.g., Nb₂O₅, NbN, and TiO₂, in the biological media. For instance, Ramirez et al.¹⁴⁹ have reported that sputter deposited Nb₂O₅ provided stronger corrosion protection than that of NbN produced by the same technique. On the other hand, Orozco-Hernández et al.¹²⁴ have revealed the better corrosion inhibition of TiO₂ compared to Nb₂O₅ without correlating the results with their morphological and microstructural characteristics. Unlike TiO₂ films, the sputter deposited Nb₂O₅ ones are prone to fall into pitting corrosion.

The sol–gel produced Nb₂O₅ coatings improve the corrosion resistance of the underlying metallic substrates since they can act as a potential barrier against corrosive species.^{105,125−127} Unlike bare substrate, a passive film forms over the coated one when it is immersed into the corrosive electrolyte.¹⁰⁵ Although the breakdown potential obtained from the potentiodynamic polarization assay is dependent on the oxygen evolution at substrate/coating interface, by which the corrosive species reach to the substrate via cracks and/or pores passage, the potential values of bare and coated-substrate reveal that the porous nature of the sol–gel derived films did not adversely affect their corrosion resistance. The simulated body fluid (SBF)-soaked Nb₂O₅ coatings show much higher corrosion resistance than that of as-deposited Nb₂O₅ due to the fact that the immersion in SBF leads to an apatite layer, which provides an extra blocking barrier and prevents the dissolution of the metal ions.^126,127,167 It is well established that the volume of the evolved hydrogen when an implant is immersed in SBF alters the biocompatibility of the surrounding cells. Thus, the corrosion resistant material, which produces lower hydrogen volume in SBF, is more biocompatible. There are much lower hydrogen bubbles emerged over the surface of the Nb₂O₅-coated AZ31 Mg alloy than bare alloy, contributing to its better biological characteristics.¹⁰⁵ The results of a comparative study of the corrosion performance of the several sol–gel derived metal oxide coatings on Ti implants revealed that the Nb₂O₅ coating has the lowest corrosion resistance without addressing the parameters lead to difference in resistance of the coatings.¹²⁵

Anodized Nb substrates show better corrosion behavior compared with the bare Nb.^88,168 The improvement degree deeply depends on the cell voltage during anodizing. Canepa et al.⁸⁸ have reported that the corrosion resistance of the anodized Nb linearly increases with the increase in cell voltage from 0 to 200 V, followed by a slight drop with a further rise up to 250 V. While the increased thickness and better morphological properties of the oxide layer leads to enhanced corrosion resistance, a higher porosity content degrades the resistance of the samples produced at 250 V. Results of a comparative work revealed that the formed oxide layer during the anodization of Ta and Nb possesses superior corrosion protection than that of Ti While Nb₂O₅ coatings deposited by PEO on the Nb substrate promote its corrosion behavior, the enhancement is not marked due to the high porosity of the film. In addition, the thickness and phase composition of the deposit govern the corrosion protection efficiency. The PEO process that performed in silicate-based solution has superior corrosion resistance to that produced from phosphate-based electrolyte may be due to the lower porosity content.^147,169Table 6 lists the corrosion parameters of the Nb_xO_y biocoatings deposited by various methods.

Table 6. Corrosion Parameters of the Nb_xO_y Biocoatings Deposited by Various Methods^a.

coating type	deposition method	test medium	highest Ecorr/mV	lowest jcorr/μA cm–2	highest Rp/kΩ	highest Rct/kΩ	ref
Nb2O5	sputter deposition	0.5 M/L NaCl, 2 g/L KF; pH 2 at room temperature	–401	0.24			(117)
Nb2O5	sputter deposition	0.5 M/L NaCl, 2 g/L KF; pH 2 at room temperature	–401	0.24			(139)
Nb2O5	sputter deposition	0.5 mol/L NaCl, 2 g/L KF; pH 2 at room temperature	–251	0.09			(122)
Nb2O5	sputter deposition	0.5 mol/L NaCl, 2 g/L KF; pH 2 at room temperature	–401	0.24			(140)
Nb2O5	sputter deposition	8.9 g/L NaCl; pH 7.4 at room temperature		0.12	3200		(149)
Nb2O5	sputter deposition	Ringer’s solution, at 37 ± 0.2 °C	–170	22.1		52.8	(124)
Nb2O5	sol–gel	SBF, at room temperature	–202			141.41	(126)
Nb2O5	Sol–gel	0.9% NaCl, pH 7.4 at 37 °C		83	4820		(125)
Nb2O5	sol–gel	SBF, pH 7.4	–1586 ± 49	53.2 ± 4			(105)
Nb2O5	anodizing	Ringer’s solution, at 37 °C	–200		32400	29	(88)
Nb2O5	PEO	SBF, pH 7.4	–472.97	0.0218			(147)

^aE_corr, j_corr, and R_p obtained from potentiodynamic polarization are corrosion potential, corrosion current density, and polarization resistance, respectively. R_ct values are charge transfer resistance obtained from electrochemical impedance spectroscopy (EIS).

Biological Characteristics

The biological characteristics of the pure Nb_xO_y coatings, including cell viability, adhesion, proliferation, differentiation, and growth along with the ability of the oxide coatings to provide a favorable substrate for nucleation and growth of stoichiometric HAp upon immersion in the SBF, and antibacterial activity, are of the important aspects that have been addressed in the literature.^{119,120,149,155}

Overall, the published results on the influence of sputter deposited Nb_xO_y coatings on the biological characteristics of underlying implants show pronounced differences. While a vast majority of the results confirmed the improvement of the coating characteristics is related to the type of the underlying substrate. Unlike Nb₂O₅-coated 316L SS,¹²³ the application of Nb₂O₅ layer over the Ti6Al4 V degrades the cell adhesion and proliferation. The reason addressing such a different behavior is assigned to the higher hydrophobicity of the Nb₂O₅ layer than that of Ti6Al4 V.¹⁴⁹

The enhanced performance of the coated-implants is attributed to the synergistic role of higher hydrophilic nature, surface roughness, and more polarized structure of the Nb_xO_y. The level of improvement in the biological properties is a function of surface topography, wettability, and atomic order, which can be controlled by operating parameters involved in the sputtering technique. For example, the Nb₂O₅ coatings sputter deposited under a higher N₂/O₂ gas ratio offer superior human fibroblast cell adhesion due to their amorphous atomic order.¹³⁸

As an important factor realizing the biocompatibility of a synthetic implanted material, besides cell compatibility, the material should not lead to a harmful inflammation when it comes in contact with living cells and tissues. Corrosion and abrasion occurrence in the physiological medium can result in the inflammatory due to the released toxic ions from the surface of the material, thereby failing the implantation.^170−172 IL-10 and IL-17 are of anti-inflammatory cytokines, which play a key role in impeding inflammatory, e.g., chronic inflammatory and autoimmune pathologies. Moreover, TNF-α deals with inflammation prevention and osteoblast activation.^173,174 The Nb₂O₅-coated metallic substrates induce higher anti-inflammatory cytokines, revealing their excellent capability in diminishing the toxicity.^91,123

The antibacterial activity of the metallic implant is highly improved with protecting its surface by sputter deposited NbO_xN_y coating. The antibacterial activity of the coatings against S. aureus is promoted when the atomic order is changed from amorphous to crystalline with tuning the N₂/O₂ gas ratio.¹³⁸

The sol–gel derived Nb₂O₅ deposits benefit from the appropriate biological properties; however, the processing parameters in particular calcination time and temperature markedly alter the properties. Besides, the immersion time can also govern the features of the formed apatite layer.^{74,119,126,127} The in vitro bioactivity assay by immersing the sample into the SBF solution containing an analogous ionic composition to human blood plasma is a preliminary route to realize whether the sample is bioactive. If the incubated material supports the formation of apatite, it is bioactive. The more compact the apatite layer is formed and chemical composition is closer to that of stoichiometric HAp, i.e., Ca/P = 1.67, the better bioactivity is obtained. The results of SBF soaking assay give a reliable view of in vivo bone bonding, where the sample that cannot stimulate the apatite formation is not qualified for further in vivo assays.^175−178 Pradhan et al.¹¹⁹ have observed that the platelike apatite crystals are generated over the surface of the sol–gel derived Nb₂O₅ coating calcined at 525 °C after immersion in SBF for 30 days, while the calcination at lower and higher temperatures, e.g., 450 and 650 °C, as well as immersion for 1–7 days do not stimulate apatite formation. The difference in the bioactivity of the coatings has been ascribed to their various atomic arrangement and unit cell geometry, where the hexagonal-Nb₂O₅ coating possesses bioactivity but amorphous and orthorhombic-Nb₂O₅ ones do not. Oxygen depletion and oxide vacancies may seriously affect the bioactivity of oxide-containing coatings. It is essential to perform in-depth studies to address their role in the bioactivity of Nb_xO_y coatings.

The implant/cell interaction is greatly affected by the surface characteristics of the implant, such as chemical composition, surface roughness, surface energy, and surface wettability.^179−181 During the initial stage of implantation, when the surrounding cells are connected to the implant, the material adsorbs the existing proteins in the body fluid, such as vitronectin and fibronectin, to provide a desirable platform for cell adhesion and osseointegration. At higher values of hydrophilicity, i.e., at lower contact angles, the number of adsorbed proteins over the surface of the implant is increased, leading to superior cell adhesion and improved implant/cell interaction. The higher surface roughness results in a higher surface wettability.^182−184 The sol–gel Nb₂O₅-coated implants have more hydrophilic surface than bare ones irrespective of the chemical composition of the implant and the medium used for contact angle measurement.^105,126

Depending on the operating factors involved in the sol–gel technique, which alter the surface roughness and phase structure of the Nb₂O₅ deposit, the deposit can variously affect the cell viability.^119,121,155 For instance, while hexagonal-Nb₂O₅ coating showed a slight decrease in cell viability after 30 days of incubation, orthorhombic-Nb₂O₅ did not influence the number of living cells. The various unit cell geometry is obtained due to the difference in the calcination temperature. Although Nb₂O₅ coatings show no toxicity to the cells, in-depth studies are required to address how the crystalline structure changes the biological behavior of the coatings.¹¹⁹ The different surface roughness originating from various calcination times and temperatures determines the cell viability, where the highest cell number is attained for the Nb₂O₅ film with the smoothest surface. It is emphasized that the influence of surface roughness on the cell adherence rate can be neglected at longer incubation times. Whether the surface roughness alters the osteoblast adhesion greatly depends on the atomic arrangement of the coating. While the surface roughness has no influence on the cell spreading in the crystalline coating, the amorphous deposit with low surface roughness facilitates the spreading. Moreover, the increased surface roughness of the Nb₂O₅ film, e.g., at a surface roughness of 15 and 40 nm, promotes the collagen-I synthesis, where there is no dense collagen-I layer formed over the film with a roughness of 7 nm.^121,155

Vascular stent grafts are largely employed in aortic aneurysms and coronary bypasses. Development of synthetic vascular grafts, which possess both high performance and durability are of prime significance as there is still a serious fail in stenting, about 10–25% out of total cases. To address this issue and develop a hybrid ceramic coated-metallic stent, Chai et al.¹⁸⁵ have made a comparative insight into the performance of cp Ti that coated by various biocompatible ceramic coatings. They have reported both TiO₂ and Nb₂O₅, coatings deposited by the sol–gel technique show favorable homocompatibility, while SiO₂ is less homocompatibile. They have also inferred that the Nb₂O₅-coated Ti exhibits the highest endothelial cell proliferation after various days of incubation.

As mentioned earlier, the bioactivity of the implant can be examined via immersion in some standard media, containing various salts and proteins that simulate in vivo conditions, including SBF, simulated salvia, phosphate buffer saline (PBS), Dulbecco’s Modified Eagle’s Medium (DMEM), etc.^118,186,187 The results of in vitro bioactivity assay carried out in human saliva medium, which is different with simulated saliva due to encompassing more than 43 proteins and enzymes, such as statherin and mucins, etc., indicated that the microcone shaped Nb₂O₅ formed during the anodization of Nb foil in the electrolyte composed of 2.5 wt % HF(aq) and 100 mg of NaF can support mineral formation. The phase structure of the minerals is consisted of Hap.^118,188,189 Elemental analysis showed a higher phosphorus content than calcium in the structure of the film.¹¹⁸ This indicates the presence of an intermediate amorphous phase, covering the underlying HAp crystals.¹⁹⁰

In general, the PEO fabricated Nb₂O₅ coatings are more hydrophilic than the underlying Nb substrate. However, the chemical composition of the electrolyte bath can slightly alter the wettability.^120,147 For instance, the coatings produced from silicate-based solutions are more hydrophilic than those deposited from phosphate-based electrolytes. Evaluating the biocompatibility of the PEO produced Nb₂O₅ coatings with a variety of assays, such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), apoptosis test, direct contact assay, confirms that they are nontoxic and the cultured cells over their surface can stay alive and grow.¹⁴⁷Table 7 outlines the biological properties of pure Nb_xO_y coatings.

Table 7. Biological Properties of Pure Nb_xO_y Coatings^a.

coating type	deposition method	type of cultured cell	assay type	% highest cell viability/%	highest reported absorbance	apatite generation ability	refs
NbOxNy	sputter deposition	healthy human lung fibroblast cell line (MRC5)	MTT	125 ± 5			(138)
Nb2O5	sputter deposition	cells derived from a human cementoblastoma	MTT		0.49		(149)
Nb2O5	sol–gel	mouse fibroblast cell line L-929	MTT	105 ± 45			(119)
Nb2O5	sol–gel	MC3T3-E1 osteoblast cell	direct contact	102 ± 10			(121)
Nb2O5	sol–gel	HPMEC* endothelialcells	triplicate assay		1.2 ± 0.1		(185)
Nb2O5	PEO	fibroblast cell line L-929	MTT	83			(147)

^aHPMEC: Primary human pulmonary microvascular endothelial cells.

4. Nb_xO_y-Containing Coatings

Background

Irrespective of the applied surface finish technique, the deposited pure Nb_xO_y coatings may face several drawbacks. One practical way to address these drawbacks and induce new beneficial properties to the pure Nb_xO_y coatings is incorporating elements or compounds into the pure coating. The concept of “composite coating” is a potential approach that leads to fruitful results in this case. The included reinforcing agent can be either organic or inorganic chemicals. PEG,¹⁴⁸ CuO,¹²² graphene,¹²² cerium (Ce),¹⁹¹ zinc (Zn),¹⁹² copper (Cu),¹⁴⁰ and erythromycin⁴³ are examples of reinforcing phases that have been successfully included to enhance the final properties of the pure Nb_xO_y coatings. There are also some studies that have exploited Nb₂O₅ as a secondary phase to develop more efficient biocoatings, which are encompassed in this section.^73,110 Apart from the well-established deposition techniques, e.g., sputter deposition and sol–gel, Nb_xO_y-containing layers can also be obtained through annealing the CaP-coated Nb-containing substrates¹⁹³ and/or air plasma spraying of Nb coatings.¹⁹⁴ The following text presents the characteristics of the Nb_xO_y-containing coatings based on the type of the added material(s).

Metallic Additives

Cu, Ce, and Zn are the metallic elements that have been incorporated into the Nb₂O₅ coatings to provide special properties and functions to them. The metallic element-reinforced Nb₂O₅ coatings can be deposited through sputter deposition and sol–gel routes.^{117,140,191,192} In the former case, an extra target composed of the desired element is coupled with the Nb target, leading to the metallic element-reinforced Nb₂O₅ coating. The amount of the reinforcing phase in the resultant film can be controlled either via changing the operating parameters or the amount of element in the target.¹¹⁷ To obtain sol–gel derived metallic element-reinforced Nb₂O₅ deposits, a sol corresponding to the additive composition is prepared, followed by adding the as-prepared sol to the Nb₂O₅ sol. The content of additives in the deposited film can be tailored by varying the concentration of the precursors in the sol.^191,192 For instance, the concentration of zinc nitrate hexahydrate in the sol governs the content of Zn in the sol–gel Zn–Nb₂O₅ composite deposits.¹⁹²

Cu is an essential trace element, known as the most active biological active metal, playing a central role in catalyzing metabolic processes. It also contributes to the angiogenesis and bone formation. Excellent activity of the Cu, in particular Cu²⁺ cation as the most active form of Cu, against microorganisms along with negligible cytotoxicity makes it a propitious candidate for antibacterial applications.^195−197 Cu–Nb₂O₅ composite coatings are obtained using the magnetron sputtering technique. The addition of Cu to the Nb₂O₅ deposit markedly affects the surface-related characteristics, where a more smooth and homogeneous surface is obtained. The rounded particles formed in microstructure of the pure coatings disappear with the inclusion of Cu.^117,140 The surface roughness of the Nb₂O₅ decreases with incorporation of the Cu, followed by a slight increase in roughness with further increase in the content of Cu in the coating. However, the surface roughness of the composite layers is still much less than that of pure film.¹¹⁷ Tribomechanical properties, including nanohardness, elastic modulus, and scratch resistance of the Nb₂O₅ films, degrade when the Cu is included in the film. A 10% and 26% decrease in nanohardness and elastic modulus is reported for Nb₂O₅-25 at % Cu composite coatings compared to Nb₂O₅ coating, respectively. The introduction of a noble metal to the ceramic coating promotes its corrosion resistance.¹¹⁷ The more Cu that is included, the higher the corrosion protection obtained.^117,140 The postcorrosion surface morphology reveals that, unlike the pure Nb₂O₅ layer, there is no change in morphology of the composite films due to the slow generation of the passive layer over the composite film.¹⁴⁰ Unlike the Nb₂O₅ layer, the nanohardness of the composite coating did not change after corrosion assay. The diminished nanohardness of the pure film is attributed to the formation of the passive layer during the assay.^140,198,199 The contact angle of composite coating is slightly higher than that of pure layer, irrespective of the type of employed droplet.¹¹⁷

Recently, tremendous attention has been paid to Ce in biomedical applications due to its exponential corrosion resistance. In its oxide form, Ce gives rise to the biological responses of the cultured cells, such as proliferation and differentiation.^200,201 Katta et al.¹⁹¹ have merely studied the influence of Ce content in the structure of sol–gel derived Ce-included Nb₂O₅ coating on final characteristics of the produced layer without addressing how embedded metallic additives can affect the properties of pure Nb₂O₅ coating. They have reported that an increase in Ce content from 1 to 2 wt % has no noticeable effect on the morphology and phase structure of the films. However, the higher Ce amount in the film leads to the enhanced thickness and surface roughness. On the other hand, the hydrophilicity and corrosion protection efficiency of the sol–gel layers enhance with a higher included Ce phase. The Ce-reinforced Nb₂O₅ coatings exhibit self-healing behavior within the anodic region of the potentiodynamic polarization curve. The formed cerium oxides and/or hydroxides can prevent corrosion progress through healing the present defects over the surface of the sol–gel film. The following reactions may occur within the anodic region:^202,203

2

3

Regardless of the content of included Ce, Ce-included Nb₂O₅ films illustrate appropriate biocompatibility where osteoblast cells can attach and spread over the surface of the films due to the presence of porous and rough surfaces. Moreover, an increase in Ce content has constructive influence on the biocompatibility.¹⁹¹

Similar to Cu, Zn is an essential element, playing a major role in mineralization, metabolic functions, cell signaling, and immune system performance. High antibacterial performance of the Zn offers the prospect of using Zn as a strong antibacterial agent.^192,204 The present microcracks all over the microstructure of the sol–gel derived Nb₂O₅ films that are generated due to difference between the CTE of the top layer and biomaterial can be eliminated by addition of Zn to the pure coating. This can contribute to a higher hardness and corrosion resistance.^67,192 Furthermore, the increased Zn content not only changes the surface morphology but also raises the surface roughness. Unlike morphological characteristics, the phase composition of the films do not change with Zn inclusion. Compared to pure Nb₂O₅, Zn-reinforced ones illustrate higher in vitro bioactivity through facilitating the precipitation of higher amounts of mineral stoichiometric HAp. There is an inverse relation between the content of Zn in the Zn-incorporated Nb₂O₅ layer and the measured contact angle value. It is reported that there is an optimum content for Zn at the highest corrosion performance. In such an optimum condition, the highest compactness, crystallinity, and sufficient thickness are obtained. Simply put, increasing the Zn amount for any percent may degrade this property. The included Zn considerably improves the antibacterial activity of the pure Nb₂O₅ layer owing to the formation of ZnO in the structure of the layer.¹⁹² The formed ZnO can inhibit bacteria adhesion and suppress their growth via enabling a desirable platform for generation of reactive oxygen species (ROS), e.g., O^2–, OH^–, H₂O₂, that severely harms bacteria.²⁰⁵ The higher surface roughness and presence of functional active groups over the surface of Zn-reinforced Nb₂O₅ films facilitate the osteoblast cell adhesion and proliferation.¹⁹²

Ceramic Additives

Recently, a rising interest has been seen in using CuO for biomedical applications owing to its excellent physicochemical properties and high antibacterial and antimicrobial performance against a broad spectrum of bacteria, such as S. aureus, E. coli, P. aeruginosa, S. typhimurium, K. pneumoniae, Enterococcus faecalis, etc. In general, it can be stated that the oxide form of the metals that possess antibacterial activity, e.g., Zn, Cu, and Zn, can exhibit similar performance.^206−208 However, a controlled dosage of CuO should be employed for biomedical applications since a higher concentration of this metal oxide can cause toxicity to mammalians and vertebrates. This is due to fabrication of ROS, which can highly damage mitochondria and deoxyribonucleic acid (DNA).^209−211 CuO-containing Nb₂O₅ films are deposited via magnetron sputtering method, where the CuO reinforcing phase can be included in the microstructure of growing Nb₂O₅ though a cosputtering route. The composite coating deposition process accomplished by sputtering Nb and Cu targets under a pure oxygen atmosphere. A smoother surface can be obtained when the CuO reinforcement is incorporated into the microstructure of pure Nb₂O₅ film. The included CuO phase can also improve the nanohardness of the pure layer from 4.78 to 7.19 GPa. Moreover, a slight increase in maximum scratch depth of coatings with CuO addition is observed. Interestingly, both J_corr and E_corr values are escalated with inclusion of CuO to a pure Nb₂O₅ layer. This means while the embedded reinforcing agent has a beneficial influence on the thermodynamic aspect of corrosion, it degrades the kinetic aspect. The mechanism(s) governing such a corrosion behavior remains to be elucidated in the published literature.¹²²

Polymeric Additives

The polymeric additives, e.g., PEG and erythromycin, can be added to the pure Nb₂O₅ layers to tackle specific deficiencies or evolve new functions. The polymer-reinforced Nb₂O₅ composite layers can be deposited via magnetron sputtering and sol–gel techniques. While sputter deposition of composite coatings is carried out using composite targets,⁴⁵ to obtain sol–gel derived polymer-added Nb₂O₅ composite films it is necessary to prepare a polymer-containing sol, followed by adding the sol to the as-prepared Nb₂O₅ sol with desired ratios.⁴³

PEG is a class of antifouling polymers, adopting its high antifouling performance from surface hydration and steric hindrance effects. The hydrophilic nature, low toxicity, solubility in water, and bioactivity of PEG appreciably extend its clinical applications, such as drug delivery and wound healing.²¹² In drug delivery applications, PEG serves as a carrier for hydrophobic drug molecules. This can highly promote the dissolution properties and aqueous stability of the loaded drugs.^45,148 Besides, PEG can serve as a linker, which covalently binds peptides to antibacterial agents, such as gold nanoparticles.²¹³ While the included PEG has no noticeable effect on the phase structure of the pure Nb₂O₅ layers, an increase in surface roughness with the PEG embedment has been reported.⁴⁵ The composite coating illustrates higher bonding strength to the underlying implant than that of the pure film. It is attributed to the higher content of formed apatite throughout the coated-implant. Moreover, the composite layer that implanted in vivo for 2 weeks has higher adhesion strength than that of the pure layer implanted for 6 weeks, indicating the faster healing period for dental implants coated by composite film. Such an achievement brings forth promising outcomes for both patients and dentists.¹⁴⁸ For antibacterial applications, the Nb₂O₅-PEG composite deposit can be immersed in an antimicrobial peptide-containing medium, e.g. glycopeptide, so that the PEG acts as the linker for loading the antimicrobial peptide on the coating. The included PEG gives rise to drug delivery efficiency, thereby promoting the antibacterial activity of the coated implant against both Gram-negative and Gram-positive bacteria. However, the concentration of the incorporated antimicrobial peptide that induced acceptable antibacterial performance is different for various types of the bacteria.⁴⁵

Erythromycin is usually employed to treat bacterial infection and can be synthesized using a strain of Streptomyces erythreus, which is present in soil. It shows high antibacterial efficiency against some of the Gram-positive bacteria, including listeria, streptococci, etc. Antibacterial activity of erythromycin is related to its ability to prevent protein synthesis of bacteria through binding to the 50S ribosomal element.^214−216 The antibacterial performance of sol–gel derived erythromycin-loaded Nb₂O₅ films directly depends on the dosage of the loaded antibiotic and immersion time. It may be correlated with the higher concentration of the released erythromycin at higher antibiotic dosage and/or prolonged immersion time.⁴³

Summary of Properties

As it is perceived, section 4 of this review encompasses descriptions about general aspects of Nb₂O₅ coatings reinforced by various additives and attempts to provide a meaningful relationship between the processing variables, such as content of included reinforcements and parameters involved in the deposition method, and overall characteristics of the resultant composite layers. To give a better view of the influence of studied variables on the mechano-corrosion properties and wettability of the composite films, comparative tables are presented. This section not only contributes to scholars in selection of the most appropriate fabrication method, material type, and operating factors depending on necessities of the targeted application but also reveals the untreated points in this field that remain to be addressed. Table 8 and Table 9 summarize the mechanical and corrosion properties of the particle-strengthened Nb₂O₅ composite layers.

Table 8. Mechanical Properties of the Particle-Strengthened Nb₂O₅ Composite Layers.

type of reinforcing phase	studied variable (amount)	deposition technique	characterization method	highest reported hardness	highest reported elastic modulus/GPa	refs
Cu	content of reinforcing phase; 17–25 at %	magnetron sputtering	nanoindentation	7.79 GPa	105	(117)
Cu	composite film containing constant content of 25 at %	magnetron sputtering	nanoindentation	7.79 GPa		(140)
Zn	molar ratios of Nb to Zn: ranging from 0.5:0 to 0.5:0.75	sol–gel	Vickers	363 HV		(192)
CuO	composite film containing constant content of CuO	magnetron sputtering	nanoindentation	7.19 GPa		(122)

Table 9. Mechanical Properties of the Particle-Strengthened Nb₂O₅ Composite Layers.

type of reinforcing phase	studied variable (amount)	deposition technique	corrosive mediuma	lowest reported jcorr/μA cm–2	highest reported Ecorr/mV	highest reported Rp/kΩ cm2	refs
Cu	content of reinforcing phase; 17–25 at %	magnetron sputtering	0.5 M NaCl, 2 g/L KF; pH 2 at room temperature	0.07	9		(117)
Cu	composite film containing constant content of 25 at %	magnetron sputtering	0.5 M NaCl, 2 g/L KF; pH 2 at room temperature	0.07	10		(140)
Ce	weight percent of Ce in the prepared sols; 1–2 wt %	sol–gel	SBF	0.012	–234	297930	(191)
Zn	molar ratios of Nb to Zn: ranging from 0.5:0 to 0.5:0.75	sol–gel	SBF	0.07	–172	548.30	(192)
CuO	composite film containing constant content of CuO	magnetron sputtering	0.5 M NaCl, 2 g/L KF; pH 2 at room temperature	9.93	262		(122)

^aThe test temperature is a key factor affecting the results of corrosion assay. The majority of the published papers can be criticized for not reporting the accurate temperature recorded during the corrosion test since room temperature may be varied in a considerable range depending on the place and time at which the test was performed.

Reported results suggested that the highest value of nanohardness of the composite films is in the range of 7–8 GPa. To obtain different nanohardness and elastic modulus values, the content of included reinforcement and/or processing parameters can be changed.

The results reveal that the particle-reinforced Nb₂O₅ composite layers are generally corrosion resistant and show high corrosion performance in a variety of corrosive media. However, the importance of the test medium cannot be neglected. The contact angle values of the particle-reinforced Nb₂O₅ composite coatings are outlined in Table 10.

Table 10. Contact Angle Values of the Particle-Reinforced Nb₂O₅ Composite Coatings^a.

type of reinforcing phase	studied variable (amount)	deposition technique	used droplet type in wettability assay	the lowest reported contact angle/deg	refs
Cu	17–25 at %	magnetron sputtering	water, ethanol, ethylene glycol	7.2 ± 2.3	(117)
Ce	1–2 wt %	sol–gel	water	26	(191)
Zn	molar ratios of Nb:Zn from 0.5:0 to 0.5:0.75	sol–gel	water	26	(192)

^aIn accordance with reported data, the particle-reinforced Nb₂O₅ composite coatings are hydrophilic, irrespective of the fabrication method.

Nb₂O₅ as Reinforcing Phase

Nb₂O₅ carries the promise of improved morphological characteristics, hardness, corrosion resistance, bioactivity, and biocompatibility if it is added as a reinforcing phase to a matrix at the proper concentration. Usually, Nb₂O₅ is employed to strengthen the polymer layers, such as polypyrrole (PPY) and polydimethylsiloxane (PDMS).^73,110

The surface uniformity of the electrochemically deposited PPY coatings is enhanced with the introduction of Nb₂O₅ particles. Furthermore, the size and number of present microcracks, surface roughness, and grain size decrease when Nb₂O₅ is codeposited.¹¹⁰ The microstructure of sol–gel derived PDMS-Nb₂O₅ film becomes more polymorphic with an increase in the concentration of Nb₂O₅ dopant. The content of the included dopant has no positive contribution to elimination of the present microcracks.⁷³ The composite PPY-Nb₂O₅ layer shows higher hardness than that of pure PPY film due to the densification of the polymer matrix. Moreover, the corrosion protection efficiency of the PPY films rises with codeposition of the Nb₂O₅ phase due to increasing the localization of charge in the PPY chain and improving the surface homogeneity. The higher the included reinforcing phase, the superior the corrosion resistance. The hydrophilicity of PPY coating enhances when Nb₂O₅ is included in the deposit. This is ascribed to the hydrophilic nature of Nb₂O₅ in the polymer matrix.¹¹⁰ On the other hand, there is an interesting relationship between the wettability of the PDMS-Nb₂O₅ composite layer and Nb₂O₅ concentration. The hydrophobicity of the PDMS coating is enhanced with the codeposition of Nb₂O₅ up to a certain concentration, i.e., 80%, followed by a slight decrease in contact angle value with a further rise in the concentration of Nb₂O₅ in the range of 90–100%. The enhanced hydrophobicity in the mentioned range is attributed to the formation of hybrid spheres in the structure of the deposit that enhances the surface roughness. The interesting point is that the pure Nb₂O₅ coating (100% Nb₂O₅) exhibits a hydrophilic nature. The contact angle value of pure Nb₂O₅ is less than a half and a third of pure PDMS and PDMS-80% Nb₂O₅, respectively.⁷³ The reported results on the effect of Nb₂O₅ concentration on the biocompatibility of polymer matrix composite deposits are different. While Kumar et al.¹¹⁰ have reported a direct correlation between the amounts of loaded Nb₂O₅ and biocompatibility of the electrochemically deposited PPY-Nb₂O₅ coatings, Young et al.⁷³ have illustrated that the biocompatibility of PDMS-Nb₂O₅ increases with a certain amount of codeposited Nb₂O₅, i.e., 40%, followed by a decrease in the property by a further rise in Nb₂O₅ concentration up to 70%. Again, an increase in biocompatibility has been observed when Nb₂O₅ concentration is increased in the range of 70–100%. The dependence of final characteristics of a ceramic-reinforced polymer matrix composite coating to the content of the included ceramic reinforcing phase, herein Nb₂O₅, hold the promise to meet the various expectations in fabrication and applications of implants. The composite films containing low ceramic phase are suitable for soft tissue applications, while for hard tissue applications it is recommended to increase the content of Nb₂O₅ in the coating. Table 11 outlines the reported results for contact angle and cell proliferation of Nb₂O₅-reinforced polymer matrix composite layers.

Table 11. Reported Results for Contact Angle and Cell Proliferation of Nb₂O₅-Reinforced Polymer Matrix Composite Layers.

coating type	deposition method	concentration of Nb2O5	droplet liquid used in wettability assay	lowest reported contact angle/deg	type of cultured cells	highest reported absorbance	refs
PPY-Nb2O5	electrochemical deposition	1–20 mg L–1 in the electrolyte	SBF	12.9	MG-63 osteoblast cell	≈1.1	(110)
PDMS-Nb2O5	sol–gel	20–100% in the coating	distilled water	43.4 ± 6.7	fibroblast	2.5	(73)

5. Conclusions and Future Horizons

Surface finishing techniques and the type of materials used to modify the surface of the biomaterial have undergone unprecedented development over the past 3 decades. Niobium oxide-containing coatings are promising candidates to tackle the challenges that threaten the successful long-term use of the metallic implants. The present review paper attempts to discuss the properties, application, and market of niobium and its oxides, putting emphasis on their biomedical properties and applications. The overall characteristics of the pure Nb_xO_y and Nb_xO_y-containing coatings deposited by various surface finishing techniques will also be treated in detail, putting stress on the importance of surface finishing with pure Nb_xO_y and Nb_xO_y-containing layers along with drawing the relationship between the operating parameters and final properties of the resultant films.

In summary, pure Nb_xO_y and Nb_xO_y-containing coatings can be deposited using a variety of dry and wet techniques. The coatings greatly affect the overall characteristics of the underlying biomaterials, where the deposited layers not only address the deficiencies of the biomaterials, such as corrosion resistance but also induce some new properties, e.g., antibacterial activity. The Nb_xO_y-containing composite coatings in which the Nb_xO_y matrix is reinforced by metallic, ceramic, and polymeric additives, are developed to provide much more beneficial properties. The selection of the included reinforcing phase is highly dependent on the targeted application. However, the potential of Nb_xO_y-containing coatings is still not really being put to work for developing high-quality biomaterials used in a variety of clinical applications. Therefore, there is still much to be investigated and understood in this field. In the following text, a list of challenges and upcoming development prospects is presented in light of the status quo of Nb_xO_y-coated biomaterials and the roles that Nb_xO_y-containing coatings can play in biomedical implants.

Having reviewed the benefits and limitations of surface finishing methods, it can be readily appreciated that several approaches that can be employed to fabricate efficient Nb_xO_y-containing coatings for clinical applications. Electrodeposition, EPD, and spraying are potential techniques that may lead to uniform layers with fruitful properties. Regarding pure Nb_xO_y films, in-depth studies are needed to fully understand the effects of operating parameters for each coating technique on the final properties of the resultant layer to explicitly state how a given parameter can change the final properties. The published literature fails to address this important challenge. Moreover, studying the role of pre/post-treatments may lead to some profitable outcomes. Detailed assessments are needed to correlate the changes in mechano-corrosion and biological performance of the Nb_xO_y coated-implants with the physicochemical characteristics of the coatings caused by alteration of the reaction environment during coating deposition.

With respect to a variety of reinforcing phases, biocompatible and bioactive additives, e.g., graphene oxide, carbon nanotubes, and metal oxides, come to mind, which can potentially promote the final performance of the pure Nb_xO_y layers and/or induce new functions to them. The concept of duplex particles-reinforced Nb_xO_y coatings should attract considerable future R&D attention. Having a glance at the number of the published papers in the field of Nb_xO_y-containing composite coatings, it can be inferred that much work remains to establish reliable relationships between the type of reinforcing phases and functions of the resultant composite films. The authors believe that a more concerted focus on Nb_xO_y-containing composite coatings produced by different wet and dry techniques, in which Nb_xO_y acts as the matrix or reinforcing phase, can offer the prospect of using these coatings as the next generation of biocompatible layers in biomedical applications. The role of processing parameters in obtaining efficient Nb_xO_y-containing composite coatings should not be overlooked. The deposition of duplex particles-reinforced Nb_xO_y-containing composite coatings in which the Nb_xO_y matrix is strengthened by two reinforcing agents, and the application of interlayer(s) are two other feasible suggestions which are believed to open numerous possibilities to realize high quality Nb_xO_y-containing composite coatings.

Biographies

Mir Saman Safavi received a B.Sc. (2015) and M.Sc. (2018) from the Department of Materials Science and Engineering at University of Tabriz. During his B.Sc. and M.Sc. studies, he worked on “studying on mechanical properties of Cu-based composites” and “electrodeposition of Ni-based nanocomposite coatings”, respectively. He is a Ph.D. candidate at Sahand University of Technology, working on the surface modification of biomaterials using the electrochemical deposition technique. Mir Saman Safavi has been the author and coauthor of over 40 ISI and conference papers, which have been cited more than 440 times, giving him an H-index of 14.

F. C. Walsh is an Emeritus Professor in Electrochemical Engineering in the Department of Mechanical Engineering at the University of Southampton, U.K., where he founded the Electrochemical Engineering Laboratory He is a member of the National Centre for Advanced Tribology at Southampton and the Materials Engineering Research Group. Previous positions have included Director of the Research Institute for Industry at Southampton, Head of Chemical Engineering at the University of Bath, Head of Chemistry, Physics & Radiography then Pharmacy & Biomedical Sciences at the University of Portsmouth. He has been a Visiting Professor at the University of Wollongong and the University of Strathclyde. Frank has spent his life crossing the boundaries of chemistry, biology, materials science, and chemical engineering. He holds the qualifications of B.Sc. (Applied Chemistry), M.Sc. (Materials Protection), and Ph.D. (Electrodeposition and Electrochemical Engineering) following studies at Portsmouth, Manchester, and Loughborough Universities. He is a Chartered-Chemist, Environmentalist, Scientist, and Engineer and a Fellow of the Royal Society of Chemistry, the Institute of Mining, Materials and Metallurgy, the Institute of Materials Finishing, and the Institute of Corrosion. His R&D output, which spans the areas of energy conversion, electroactive nanomaterials, coating technology, electrochemical monitoring and sensors, corrosion, surface finishing, and electrochemical process engineering, includes 4 text books, 200 conference presentations, and over 500 research papers. Frank was awarded the Westinghouse Prize in 1999 and 2009 (best paper on metallic coatings) and the Johnson Matthey Silver Medal of the Institute of Metal Finishing in 2007 (precious metal nanoparticles inside nanotube arrays), the Breyer Medal of the Royal Australian Chemical Institute in 2000 (international contributions to electrochemical engineering and energy), the NACE Fellow honour in 2011, the Inman Medal of the UK Centre for CO₂ reduction, London (international contributions to environment and energy) in 2012, the 2017 Castner Medal of the (achievements in industrial electrochemistry), and the Gold Medal, the highest award of the Institute of Materials Finishing (lifelong contributions to electrochemical surface finishing) in 2018. In collaboration with industry, Frank has supervised over 50 Ph.D. degrees and developed/improved over 60 industrial processes.

Livia Visai is an Associate Professor in Biochemistry at the Department of Molecular Medicine (DMM), Faculty of Medicine, University of Pavia, Pavia, Italy. She is Referent of the Academic Strategic project of University of Pavia titled “Center for Health Technologies” (CHT) and Coordinator of the Nanomedicine Pillar, Pavia, Italy. She is also operating as an Associate Professor within the National Health Service of the Scientific Clinical Institutes (ICS) Maugeri, Società Benefit Spa, IRCCS, Pavia, Italy. She is coordinating a laboratory interested in studying the effect exerted by the application of nanotechnology in tissue regeneration and in bone remodeling (in particular in microgravity), in the reduction of bacterial infection, and in the diagnosis and therapy of cancer. She has more than 184 papers published in PubMed with a WoS H-index of 46.

Jafar Khalil-Allafi received a B.Sc. (1988; Isfahan University of Technology-Iran), M.Sc. (1992; Iran University of Science and Technology-Iran), and Ph.D. (2002; Ruhr University Bochum-Germany) with the highest rank. Prof. Jafar Khalil-Allafi has received international and national awards and fellowships such as the Thyssen-Krupp innovation price 2002 in Germany. He has been also the supervisor and advisor of more than 100 postgraduate theses. Prof. Jafar Khalil-Allafi has been the author and coauthor of 3 patents, 3 books, and over 100 papers which have been cited more than 3500 times, giving him an H-index of 29.

The authors declare no competing financial interest.