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1 Introduction

Titanium (Ti, atomic number 22) is a silver-white transitional (reactive) metal first discovered in Cornwall in 1791. This extremely strong metal was aptly named after the Titans of Greek mythology who were considered the embodiment of strength. Despite its early discovery and its being the ninth most abundant element on earth, titanium was not isolated until 1910, and a viable commercial extraction process was not developed until 1938. Titanium is relatively difficult and hence expensive to extract, but its properties—high resistance to corrosion, high biocompatibility, low specific gravity, high specific strength, and nonmagnetic—have made it highly desirable for a number of specialized applications, first in aerospace and military applications followed by food, pharmaceuticals, and cosmetics.

These same properties, coupled with its inherent capacity for osseointegration, have made titanium a favorite choice for medical and dental implants, and related publications from dentistry and medicine have increased exponentially since the 1970s [1]. The reputation of titanium as biologically inert and therefore nonallergenic has been and remains strong. Indeed, titanium was not even among the 35 metals covered in a 1999 text devoted to the topical effects of metals and their systemic absorption by the skin [2]. Titanium has been touted as the ideal material for dental and surgical implants, especially for patients who are hypersensitive to other conventional metals, for whom it may indeed be the safest choice [3,4,5,6,7].

Yet even while the statement that titanium was “fully inert” was being made in the mid-1990s [4], titanium had already been implicated in hypersensitivity reactions since the 1980s, and its role in implant failure had been questioned since the early 1990s. Admittedly, allergic reactions to titanium are rare. Their occurrence in relation to medical and dental implants, however, raises concerns. Despite titanium’s resistance to corrosion, ample evidence has shown that, like any metal, it is not completely inert. In the human body, titanium implants are subjected to mechanical and chemical stresses that can lead to physicochemical corrosion that could be involved with implant loosening or failure. Corrosion also leads to the release of ions and oxides that may combine with proteins to become haptens. This process may increase an individual’s risk of becoming hypersensitive to titanium. Furthermore, the proportion of the population exposed to medical and dental implants, many of which will incorporate titanium because of its exceptionally beneficial profile, will increase as the population ages.

To further understanding of this unquestionably increasingly important metal, this chapter (1) reviews the sources and properties of titanium and its alloys, (2) evaluates the efficacy of methods used to diagnose titanium allergies, and (3) discusses the implications of the evidence for titanium allergies related specifically to dental and medical devices. The mechanisms underlying metal hypersensitivity are discussed elsewhere in this text.

2 Titanium and Its Alloys and Their Uses

Most titanium ore (95%) is refined into titanium dioxide (TiO2). Globally, each year 4 million tons of TiO2 are used as a whitener in products ranging from paint, ink, food, cosmetics, pharmaceuticals, plastics, paper, candy, and toothpaste [8]. The remaining 5% of titanium ore is refined to metal [9].

Because of its immediate reactivity with oxygen, metallic titanium does not exist in nature; rather, it exists in three mineral forms of titanium dioxide: rutile, anatase, and brookite. Anatase has the greatest chemical reactivity, which is thought to result from the large facet size of its crystals and which is potentially associated with increased toxicity [10]. In addition to distinct crystalline structures, TiO2 particles are divided into two size distributions: TiO2FP (fine particles, 100–2500 nanometers) and TiO2NP (nanoparticles, 1–100 nanometers). The smaller the particle size is, the larger is the surface area, which increases catalytic activity and likely also influences bioreactivity.

From the perspective of materials science, titanium and its alloys are classified into types based on their metal content and crystalline structures. Hexagonal close-packed crystalline-structured alloys are termed alpha types, while body-centered cubic crystalline-structured alloys are termed beta types. Different stabilizing elements increase or decrease the temperature at which alpha structures phase shift to beta structures (Table 34.1). Alpha stabilizing elements, which include aluminum (Al), tin (Sn), gallium (Ga), zirconium (Zr), carbon (C), oxygen (O), and nitrogen (N), contribute to increased high-temperature performance of alloys in combustion engine applications and to other properties such as weldability and machinability. Beta stabilizing elements include vanadium (V), molybdenum (Mo), niobium (Nb), tantalum (Ta), and chromium (Cr), which improve the room temperature strength of alloys. There are also hybrid alloys, which contain both alpha and beta stabilizing elements. Hybrid alloys are further subdivided into near alpha, alpha + beta, and near beta. Both alpha and beta types also may contain iron (Fe), copper (Cu), nickel (Ni), silicon (Si), and boron (B), which are added to modify physical and chemical properties.

Table 34.1 Types of titanium and their stabilizing elements [11, 26, 135, 136]
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Titanium and its alloys are also classified by grade, a numbering system used to identify the ASTM (American Society for Testing and Materials) standard that applies to each alloy. In 2015 Wood and Warshaw provided an extensive tabulation of many industrial and medical grades of titanium [11]. The first four grades and grade 7, which are classified as commercially pure titanium (CpTi), are unalloyed. Their purity ranges from 99.0% to 99.5%, and their oxygen content from low to extra high as the grade increases. The remaining grades are alloys in which titanium is combined with various percentages of a variety of other elements such as palladium, ruthenium, nickel, molybdenum, gallium, tantalum, vanadium, aluminum, tin, zirconium, chromium, iron, niobium, and silicon. The formulations are designed for specific purposes, depending on the desired property or combination of properties such as ductility, strength, hardness, electric resistivity, creep resistance, and resistance to corrosion from a specific media.

The first-generation biomedical implants, which were used between 1950 and 1990, were commercially pure alpha or mixed alpha and beta alloys. Since 1990 second-generation biomedical implants have primarily been manufactured from beta alloys [12]. Consequently, clinicians could easily encounter patients with implants of either type. The most common grades used in implantable devices are found in Table 34.2.

Table 34.2 Common titanium alloys used in medical and dental devices
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Grade 2 CpTi (purity, 99.2%; oxygen content, medium) is notable because it is often used for dental and medical implants. Grade 4 CpTi (purity, 99%; oxygen content, extra high) is also used in some dental implants. Grade 5, Ti-6Al-4V (i.e., alloyed with 6% aluminum, 4% vanadium, a maximum of 0.25% iron, and a maximum of 0.2% oxygen), is one of the workhorses of titanium alloys accounting for about half of total titanium alloy usage [13]. Lightweight but strong while highly resistant to corrosion, it has been a favorite of the aerospace, marine, and chemical processing industries.

Although grade 5 is stronger than pure titanium grades, its surface wear properties can be relatively poor in certain loading situations, and the alloy can corrode. Surface treatments such as nitriding and oxidizing improve its surface wear properties [14,15,16]. Yet, vanadium has been shown to accumulate in organs such as the bone, liver, and kidneys in implant patients. Furthermore, vanadium is cytotoxic—so much so that some vanadium compounds are considered promising treatments for cancer [17]. Vanadium also may be a type IV allergen [18, 19]. Consequently, the suitability of grade 5 Ti for permanent implants was questioned. In response to these concerns, Ti-7Nb (6% aluminum and 7% niobium) was developed as a biomedical replacement with niobium used as a substitute for vanadium [20]. This alloy has been used in hip implants since 1986.

Grade 23 Ti, or Ti-6Al-4V ELI, which has a higher purity than Ti-6AL-4V, is another option for dental and medical implants. It is suitable in applications that call for high strength, light weight, good resistance to corrosion, and durability. Its ability to tolerate mechanical and chemical damage is superior to that of the other alloys. It has been used in orthopedic pins, screws, and cables; joint replacement devices; bone fixation devices; ligature clips and surgical staples; springs; and orthodontic appliances.

Ti nitride (TiN), Ti niobium nitride (TiNbN), and Ti carbon nitride (TICN), which are extremely hard ceramic materials, also are used in medical devices, notably in surface coatings of newer hip, knee, and dental prostheses; stents; and pacemaker leads [21,22,23,24,25]. They are used as a top-layer coating that helps resist corrosion of articulating surfaces and retain sharp edges, for example, in scalpel or orthopedic bone saw blades. Because the color of TiN is gold, it is also used in costume jewelry.

Nitinol is an alloy composed of about 55% nickel and 45% titanium (with traces of chromium). It was developed by the US Navy, from which its name is derived (Nickel-Titanium Naval Ordnance Laboratory). Its unique property of shape memory or reversible deformation (i.e., recovers its original shape after load is removed) made it desirable for applications in a variety of industries such as dental, medical, optical (eyeglass frames), sporting goods, and aerospace. The addition of copper to a nickel titanium alloy increases resistance to permanent deformation compared to NiTi alone [26]. This combination increases the utility of the alloy when more consistent force is required, for example, to move maloccluded teeth with orthodontic treatment [27].

When electropolished, nitinol forms a stable protective TiO2 layer that acts as an effective and self-healing barrier against ion exchange. That nitinol releases nickel at a slower pace than stainless steel also made it attractive for use in medical devices, the first of which was introduced in the late 1970s. These early devices were made without electropolishing, and corrosion was observed. Es-Souni and coworkers comprehensively reviewed the corrosion, cytotoxicity, biocompatibility, and nickel release but without discussing the simultaneous potential for concomitant Ti release [28].

The use of nitinol is now widespread. It can be found in endovascular devices such as stents, endografts, septal occluders, filters (luminal shields), cardiac pacemakers, and implantable cardioverter/defibrillators (ICD); dental implants and appliances such as orthodontic archwires; bone suture wires and staples; cochlear implant electrodes; temporary implantable nitinol devices (TIND) to relieve lower urinary tract symptoms (LUTS) related to benign prostatic hypertrophy; Filshie® clips for tubal ligation; superelastic springs for the treatment of craniosynostosis; biopsy site markers; and radiation seed capsules for treatment of prostate and other cancers [29].

In 2002 a nitinol contraceptive device for implantation in the fallopian tubes was introduced. As a result of postmarketing reports of adverse events, including systemic allergic contact dermatitis (ACD), the US Food and Drug Administration (FDA) issued a black box warning in 2016. The warning includes the risk of metal sensitization following placement that could result in the need for removal of the device. Clinical trials for a nitinol intrauterine device (IUD) are currently underway and are thought to be promising.

The number of titanium alloys with dental and medical applications continues to increase steadily as inventors and manufacturers seek proprietary physicochemical attributes. A majority are beta or near beta formulations (Tables 34.1 and 34.2). Titanium is also used in dental and medical instruments, which can withstand repeated sterilization without compromise of cutting edges, and in vascular guidewires, heart valves, wheelchairs, crutches, and external prosthetic devices.

3 Properties of Titanium

Titanium is considered a highly biocompatible metal for several reasons: its resistance to corrosion from bodily fluids, bio-inertness, capacity for osseointegration, and high fatigue limit. Titanium’s ability to withstand the harsh bodily environment is a result of the nonporous protective film that naturally forms on the surface of the metal in the presence of oxygen. This process, known as passivation, begins within milliseconds of the metal being exposed to the atmosphere. Within 1 s, a surface oxide film 2- to 7-nm thick is formed. The layer is strongly adhered, insoluble, and chemically impermeable. The film effectively prevents further oxidation between the metal and the surrounding environment. Furthermore, if the layer is disrupted, the exposed metallic substrate rapidly self-heals or repassivates. This capability underlies titanium’s resistance to corrosion [30]. The integrity of the oxide layer, however, can be affected by wear. In an in vitro study, for example, corrosion reduced the hardness of the surface oxides in several titanium alloys, including Ti-6Al-4V, especially in the presence of proteins [31].

Titanium’s capacity for osseointegration is another feature that has made it highly attractive for orthopedic and dental implants. Its inherent ability to fuse to bone, which has been recognized since 1940, confers a distinct advantage compared to the less durable fixation associated with adhesives (which can also be allergens) [32, 33]. Titanium’s capacity for osseointegration reflects an interaction between the surface characteristics of the material and living tissue. Critical to the process of osseointegration is angiogenesis, which is necessary for vascularization at the interface between an implant and adjacent tissue. Without vascularization, a fibrous capsule forms around an implant that can result in loosening and eventual failure of an implant. Although the mechanism is poorly understood, both the surface microstructure and surface energy of titanium appear to enhance angiogenesis by modulating secretion of angiogenic growth factors by osteoblasts, at least partially through signaling of the α2β1 integrin [34].

Besides relatively low wear resistance and resultant dissolution of metal ions from local corrosion reactions, the first-generation titanium implants (CpTi, alpha type and Ti-6Al-V4, alpha + beta type) were also relatively stiff (high Young’s modulus) compared to bone tissue. In comparison, the mechanical (reduced Young’s modulus) and chemical properties (passive film properties) of second-generation beta alloys such as Ti-(40–45)Nb were considerably improved. Although severe surface treatments have been found to affect the passive film properties, resistance to corrosion does not deteriorate. These features make Ti-(40–45)Nb a promising material for the development of new implants [35]. Ongoing progress in materials science related to medical and dental implants highlights the need for careful reporting of device constituents.

Finally, titanium is nonferromagnetic. This feature is important from a medical perspective because it safely allows individuals with implants to undergo magnetic resonance imaging.

Despite these favorable theoretical properties, which have led to the widespread use of titanium alloys in medical and dental products, evidence of wear, corrosion, and ion release in vitro and in vivo is a harbinger of the possible risks of immunologic complications. Corrosion of implant metals primarily manifests with pitting and crevices, fretting, cracking, delamination, and galvanism [36, 37]. Wear and corrosion may result in the buildup of titanium ions and oxide metallic particulates in adjacent tissue [38,39,40]. In vitro studies have shown that titanium ions are released from Ti grade 2, Ti-6Al-4V, Ti-6Al-7Nb, and Ti-15Zr-4Nb-4Ta when immersed individually in eight different media and incubated for 7 days. The highest Ti release was in solutions of L-cysteine and lactic acid [41], and release increased as pH decreased [42]. Similarly, Ti release has been reported in other in vitro studies [43,44,45,46,47,48,49]. The release of Ti ions from implants has also been identified in animal models [50, 51]. Perhaps more importantly from an immunological perspective is the finding of elevated concentrations of titanium in serum after the implantation of many kinds of devices, including hip, knee, spinal fusion, external and internal fixation, and dental prostheses [52,53,54,55,56,57,58,59,60]. In contrast, however, other studies of titanium concentrations after the placement of spinal fusion instrumentation and maxillofacial miniplates have failed to find a statistically significant increase in ion release [58, 61]. Fage and coworkers recently summarized extensive evidence from in vivo and in vitro reports of corrosion and release of titanium [62]. Decreased pH, exposure to fluoride and increased temperature also may contribute to corrosion [41, 63, 64].

Titanium transport studies have shown that 99.8% of Ti is bound to transferrin [57]. Titanium preferentially binds to the N-lobe of transferrin, which may provide entry of Ti into cells via transferrin receptors [65]. Water-soluble Ti(IV) citrate and Ti(IV) nitrilotriacetate are stable in physiological conditions; yet, only the Ti(IV) citrate binds with transferrin. This is likely due to the greater stability of the Ti(IV) nitrilotriacetate compared with Ti(IV) citrate [66]. Physiologic ligands, including citrate and lactate, form water-soluble Ti(IV) complexes that may be an intermediate step between ion release from an implant and subsequent binding with transferrin. Transport of these Ti complexes may explain the presence of Ti in widespread tissues and organs, including the lymph nodes in some implant patients [39, 40, 67, 68]. Nanoparticles of titanium dioxide also combine with albumin and may contribute to the dissemination of implant corrosion debris [69]. Increased DNA damage by TiO2 nanoparticles appears to be mediated by toll-like receptor 4 (TLR 4) with overexpression increasing the uptake through cell surfaces into the cytoplasm [70]. Whether serum albumin and transferrin-bound Ti or serum-soluble ionic Ti ligand complexes have a role in bioavailability of Ti for haptenization and antigen-presenting cell sensitization and elicitation mechanisms is unknown.

4 Diagnostic Options for Determining Titanium Sensitization

The efficacy of patch testing for titanium is controversial—a situation that may primarily reflect the properties of the patch testing substances and variable techniques that have been used. In terms of patients with medical or dental implants, the timing of patch testing, before or after the implant, has also been questioned. Guidelines have been proposed and may be meaningful for the detection of relevant allergies to Ni, Co, and Cr; without standardized efficacious patch test preparations for titanium, however, patch testing to determine sensitization to titanium will likely continue to be largely unhelpful [71]. In vivo diagnostic test preparations can be obtained from manufacturers and compounding pharmacies in the United States, Europe, and Japan. In vitro diagnostic tests are offered by several specialized laboratories in the United States and Europe, but concerns about their sensitivity and specificity also exist.

4.1 The Elusive Optimal Patch Test Formulation

Although titanium is not included in major series such as the European Baseline Series, the Core Series of the American Contact Dermatitis Society, or the standard series of the North American Contact Dermatitis Group, various formulations of the metal have been tested in special metal or prosthetic series or in cases suspected of having a titanium allergy. For example, in a large patch test series of metal allergens, the Mayo Clinic patch tested with 1% titanium dioxide and 10% titanium in petrolatum as well as with an unspecified titanium alloy disc [72]. In an earlier study from Mayo of patients referred for patch testing related to a medical device, patients were patch tested with a disc of the exact alloy provided by the manufacturer of the device [73]. The concentration of Ti ions or TiO2 released from the surface of manufacturer-supplied Ti discs when placed on the skin for 48 h is unknown. Not surprisingly, testing with disparate titanium compounds and metallic discs worldwide has usually been associated with negative or equivocal results. Undoubtedly, irritant, doubtful, or negative patch test reactions to titanium in case reports and prospective studies have contributed to the controversy about the sensitizing potential of titanium and reinforced the common bias that it is not an allergen.

Wood and Warshaw as well as Fage and colleagues have summarized the clinical results of patch testing reported in the literature (Table 34.3) [11, 62]. By far, titanium dioxide (whether compounded using the more reactive anatase or less reactive rutile is often unknown or not reported) in petrolatum has been the most commonly reported patch test preparation (Fig. 34.1). However, very few positive patch reactions to TiO2 have been reported [74]. Overwhelmingly the use of TiO2 for patch testing has been associated with negative reactions, which would be predicted by its physicochemical properties as discussed below. The few reported positive reactions could have been irritant reactions related to a high or low pH of the patch test preparations depending on how it was manufactured or a true-positive reaction due to another metal contaminant.

Table 34.3 Summary of titanium compounds used in patch testing
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Fig. 34.1
figure 1

Photographs showing the crystalline structure of titanium dioxide (EOS Rebel T2i; Bresser Microscope MPO 401; magnification, PL4/0.1 160). (a) Both large and small particle sizes can be seen. Patch testing with titanium in older studies would have used similar powder with particles sizes up to 100 nm, which will not penetrate the stratum corneum. (b) The particle sizes of nanopowders are more uniformly small (about 25 nm) but still too large to penetrate the skin; they can, however, penetrate the oral mucosa [134]

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Fage et al. reviewed titanium penetration in animal and human studies that were primarily performed to demonstrate the remarkable safety profile of topically applied medicaments, cosmetics, and sunscreens containing TiO2 [62]. In one study, for example, sunscreen with titanium dioxide was applied to the volar arm, which was then tape stripped. The distribution of titanium dioxide particles was analyzed spectroscopically. Even after repeated applications of the sunscreen, no microparticles were found in the deep layers of the stratum corneum. Based on histological investigation of the tape-stripped areas, less than 1% of the applied TiO2 was found in a given follicle, and no penetration of titanium dioxide into viable skin tissue could be detected [75]. How a water-insoluble oxide of titanium that does not penetrate the skin and is safely used in millions of tons of topically applied products each year became the leading choice for patch testing to detect titanium sensitization from an implanted metallic prosthesis is unclear.

Yet the proliferation of reports of negative patch test reactions to TiO2 in patients with a failed surgical or dental implant, combined with prospective studies that support those negative results, has reinforced the consensus view that an allergy to titanium cannot be the underlying cause. Not surprisingly, no other water-insoluble metallic oxide that cannot penetrate the stratum corneum is routinely used as the preferred patch test substance to diagnose patients with other suspected metal allergies. On the contrary, the selection of a water-soluble salt for the common metals that penetrate the skin benefited from extensive dose-response studies conducted with different salts, concentrations, and excipients in sensitized patients before a consensus began to emerge. When the ability of a substance to penetrate the skin was unclear, intracutaneous injections were used to determine and optimize correlations with the results of patch test dose-response series [76]. Perhaps the absence of sufficient patients with a suspected titanium allergy in a single patch testing center of excellence has limited the application of these disciplines in parallel with the great work done on nickel, cobalt, chromium, and gold. Titanium(III) nitride, titanium(IV) carbide, and calcium titanate(IV) are also all water insoluble. We do not have the benefit of skin penetration, guinea pig maximization test (GPMT), or local lymph node assay (LLNA) studies; yet, these patch test allergens are available commercially, likely simply because they are used as coatings on various implants. A titanium disc fully protected by the spontaneously occurring TiO2 coating is equally unhelpful in assessing suspected type IV sensitivity. The situation is further complicated by the possibility of alloying metals or trace metals being preferentially released, thereby leading to a false-positive interpretation of a patch test reaction. Wood and Warshaw summarized cases of suspected titanium allergy ultimately found to be caused by another relevant allergen [11]. This scenario is particularly apt to develop when nickel-allergic patients are exposed to the ubiquitous NiTi alloys.

Titanium chloride III and IV have also been used as patch test preparations. Although both are initially water soluble, they decompose to TiO2. Ikarashi and coworkers evaluated the sensitization of guinea pigs to TiCl4 using the GPMT and LLNA [77]. Of ten guinea pigs undergoing induction of intradermal TiO2, five were positive on patch test challenge. They also showed mild increases in lymph node weight with TiCl4, but the sensitive LLNA was negative according to the criteria. For patch testing TiCl4 has the added disadvantage of having a low pH, which is likely a contributing factor to reports of irritant reactions (IR) or even false positives. Several doses at log intervals would likely be preferable in order to differentiate between an IR and true contact allergy.

Titanium sulfate is also soluble in water but hydrolyzes to form titanium dioxide. It is not known how quickly hydrolysis occurs on the skin. It is used in the industrial production of rutile TiO2 and in printing inks. Although commercially available as a catalyst for epoxide synthesis, titanium isopropoxide decomposes rapidly in water or moist air to produce TiO2. It is unclear how a stable petrolatum preparation can be prepared with this compound.

Titanium(III) oxalate is sparingly soluble in water (insufficient for an adequate patch test dose) and oxidizes in air to TiO2. Titanium(IV) oxalate is only slightly soluble in water and stable. Its pH, however, is low because of residual oxalic acid content, and a low pH creates concerns about irritant reactions. Recently, a patient was found to be patch test positive to “titanium oxalate” without reference to the exact compound [78]. Reporting patch test results to titanium oxalate without details of oxidation state or the degree of hydration of the patch test substance, which is necessary to determine titanium content and to understand pH, precludes comparisons across studies.

Lalor and colleagues reported negative patch test results using titanium salicylate, titanium tannate, titanium peroxide, and titanium dioxide, four ingredients found in Metanium, an over-the-counter ointment used for decades to treat diaper rash [79]. The specific molecular formulae of these titanium compounds were not reported, making it impossible to replicate their precise use. Suspended, water-insoluble titanium tannate nanoparticles have utility in their ability to adsorb dyes from industrial wastewater due to their porous surface structure and water insolubility—unlikely physicochemical properties for an ideal patch test preparation [80]. Titanium salicylate is an anionic surfactant that is only slightly soluble in water. It is used as a preservative and patented for use in the treatment of rosacea, acne, scars, and skin infections [81, 82]. Its utility as a patch test preparation has not been studied.

Titanium peroxide nanoparticles are of the anatase crystalline structure and able to increase cytotoxic effects of x-ray irradiation against pancreatic cancer because of the increased production of reactive oxygen species [83]. The suspended Ti peroxide nanoparticles also adsorb dyes similar to titanium tannate [84]. Not surprisingly, these three titanium compounds produced negative patch test results in all five patients tested by Lalor et al. [79]. Unexpectedly, two positive reactions were observed when patch testing with the combination in the Metanium ointment. These two positive patch test reactions, however, could have been the result of other ingredients in the formulation known to be contact allergens, including tincture of benzoin [85].

Calcium titanate is a synonym of calcium titanium oxide, another water-insoluble nanoparticle used for the immobilization of radioactive waste and as a fire retardant. Application to the surface of an implant as a bioactive coating has likely led to its use as a patch test allergen [86].

The efficacy of an in vivo titanium allergy test depends on antigen penetration through the stratum corneum. Such penetration is unlikely in sufficient concentration with TiO2, titanium nitride, titanium tannate, titanium carbide, calcium titanate, or titanium propoxide nanoparticles. Some investigators have had success with prick testing with TiO2 although they interpret the positive reactions as Type 1 sensitization [87]. If convincing data emerge that TiO2 nanoparticles do indeed function as relevant type IV antigens, pretreatment of the skin with microneedle patches or intracutaneous injection may be worth exploring to overcome the penetration obstacle [88].

A stable, solvent-soluble, protein-reactive titanium salt that penetrates the skin is needed for patch testing. The water-soluble metal salt approach has been successful with other metals; consequently, ligands that render Ti(IV) stable in solution need to be explored. Stable, water-soluble candidates include titanium ascorbate, sodium titanium dimalate, titanium digluconate, sodium titanium citrate, ammonium titanium glycolate, ammonium titanium(IV) oxide oxalate, ammonium titanium(IV) peroxo citrate, titanium(IV) lactate ammonium hydroxide, and titanium(IV) lactate tetramethylammonium hydroxide [89,90,91,92]. Additional candidates soluble in ethanol are titanium octanoate, octylene glycol titanate, and tetrakisethylsiloxy titanate or titanium decanoate miscible in cyclomethicone [89].

Ammonium titanium lactate, sodium titanium citrate, ammonium titanium glycolate, titanium octanoate, octylene glycol titanate, tetrakisethylsiloxy titanate, and titanium decanoate are known to induce superficial blockage of pores. This property led to their consideration as alternatives to aluminum chlorohydrate for use in antiperspirants [89]. Despite the tendency of these multivalent metals to form polymeric gels able to block pores, some ion penetration occurs and is measurable in serum following axillary absorption from an antiperspirant preparation. This finding contributed to concern about aluminum carcinogenicity and estrogen action [93].

In another study, subjects participating in a trial evaluating a novel antiperspirant based on ammonium titanium lactate developed axillary rashes. Twelve of these subjects were patch tested with ammonium titanium lactate and also with 10% titanium dioxide and other common metal allergens. Their findings were compared to other participants who had not developed the skin rash as well as to a group who had never knowingly been exposed to ammonium titanium lactate. In each group there were a few positive reactions to a common metal allergen, but none of the naïve subjects and none of the subjects who had not developed a reaction during the original trial had a positive reaction to either the titanium dioxide or titanium lactate. Of the 12 patients who had had a reaction during the trial, 3 had a positive reaction to the titanium lactate but not to the titanium dioxide. The specific molecular formula with degree of hydration was not reported [94].

Currently, the diagnostic efficacy of a series of metals is being evaluated for patch testing in the T.R.U.E. TEST hydrogels. Five different stable, water-soluble titanium salts in three different concentrations each (Table 34.4), including an ammonium titanium lactate (titanium(IV) lactate ammonium hydroxide), are among the compounds being tested. At the time of this writing, quantitative analytical methods have been developed, stability of the patches has been established, and blinded prospective clinical trials are underway (Fig. 34.2). While it is hoped that this trial will identify the most effective hydrogel and petrolatum formulations for titanium patch testing, complying with all regulatory requirements means that it will still be years before a licensed product might become available. In the interim in the United States, availability from a compounding pharmacy allergen bank on a patient-specific prescription basis is an alternative.

Table 34.4 Titanium salts under investigation by SmartPractice
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Fig. 34.2
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Photographs showing the crystalline structure of (a) potassium titanium oxide oxalate dihydrate and (b) titanium(III) oxalate (EOS Rebel T2i; Bresser Microscope MPO 401; magnification, PL4/0.1 160)

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4.2 Timing of Patch Testing: Before or After Implants?

Opinions vary about the need for patch testing in candidates for medical or dental implants. When patch testing is to be conducted, its timing—before or after placement of the implant—has also been questioned. Although general guidelines for patch testing for metal allergies in this situation have been proposed [71], it must be remembered that the timing of patch testing is irrelevant unless it is conducted with an efficacious substance. Consequently, even though Honari and coworkers, for example, suggested patch testing with titanium dioxide and titanium powder as part of a broad series of metal allergens in conjunction with a baseline series prior to patients receiving an endovascular implant [95], these substances, as discussed, are unlikely to be effective diagnostics.

4.3 In Vitro Tests

In vitro tests such as leucocyte transformation, migration inhibition, and cytokine production have also been explored as diagnostic alternatives for determining titanium sensitization. Lymphocytes from the peripheral blood of suspected allergic patients and controls are incubated with titanium, and evidence of sensitization is measured. The methods with and without radioactive hydrogen labeling used to assess leucocyte proliferation, the modified and Boyden chamber technique to measure leucocyte migratory capacity, and the enzyme-linked immunosorbent assays for specific cytokines are described elsewhere [96,97,98,99,100].

The lack of standardized, validated, and regulated methods and the difficulty transporting viable patient-specific monocytes in sufficient quantity to reproducibly perform the tests make comparisons of results across laboratories and studies difficult. The selection of the titanium compound used to incubate with the lymphocytes may be one of the significant variables contributing to some of the differences across laboratories and between published studies. Most laboratories have used insoluble TiO2 of various nanoparticle sizes and with different or unknown ratios of rutile and anatase forms. When these same in vitro tests have been performed with other metals, soluble salts have been used.

Pellowe and coworkers appear to have developed an ionic titanium antigen by complexing titanium with human serum albumin (HSA), which was subsequently used for LTT and cytokine profiling [101]. The investigators incubated titanium citrate with HSA to produce stable ionic Ti antigens. When peripheral blood mononuclear cells were evaluated, proliferation was elevated in the serum of all six patients tested. Expression of interleukin (IL)-12 and tumor necrosis factor (TNF)-α increased in the Ti implant patients compared to the patients without implants when incubated with the ionic Ti antigen, while IL-10 decreased in implant patients when incubated with TiO2 nanoparticles [101]. Hallab et al. showed similar results following the incubation of Ti-6Al-4V beads in human serum [102]. The concentrations of Ti in the serum fraction correlated with the LTT response. They found two molecular weight ranges of serum proteins (<30 kDa and 180–250 kDa) binding the Ti. The higher molecular weight fraction showed higher LTT reactivity. It is not known if the protein binding is with Ti ions or with TiO2 forming spontaneously following release from the metallic beads.

Vamanu and colleagues had previously described a method to form stable HSA-TiO2 antigens in physiologic solutions, which they proposed for use with LTT [69]. Their transmission electron microscopic images of TiO2 aggregates and their decreasing number in the presence of HSA were interpreted as supporting evidence of the dose-dependent concentration of TiO2 in suspension due to antigen formation. Their use of inductively coupled plasma mass spectrometry accurately measures the concentration of Ti in the physiologic solutions but does not differentiate Ti content between Ti ions and TiO2. It is unclear why more work has not been done exploring the use of stable water-soluble titanium salts rather than insoluble TiO2 for in vitro test research.

In general, the low specificity and sensitivity of the LTT for metals other than nickel have limited its adoption as a clinical tool. Positive LTTs in patients suspected of implant hypersensitivity due to titanium have ranged from 0% to 42%. Recently, Wood and Warshaw summarized the LTT for titanium hypersensitivity in clinical series [11]. In an effort to improve diagnostic sensitivity, Hallab et al. suggested using the results of LTT, lymphocyte migration inhibition, and specific cytokine production in conjunction with each other [103]. Using this approach Vermes and coworkers prospectively followed controls and implant patients for 36 months [104]. They found that titanium reactivity increased significantly after the placement of well-functioning titanium implants.

These evolving in vitro approaches with increased standardization and regulatory oversight will be meaningful for the further elucidation of immune mechanisms catalyzed by Ti exposure but are unlikely to offer a pragmatic logistical and economically viable diagnostic solution any time soon. Not surprisingly, the results of nonstandardized in vitro tests correlate poorly with the results of nonstandardized titanium patch tests.

5 Clinical Implications

Currently, the reported prevalence of contact allergy to titanium is low. Some researchers, however, have suggested that it may be grossly underreported, especially in terms of dental implant titanium hypersensitivity [87, 105]. A recent Delphi consensus study of expert orthopedic surgeons responding to questions about metal allergy suggests a similar situation. The majority agreed that patients undergoing metal arthroplasty surgery need not be routinely questioned about metal allergy before surgery. The predictive value of Delphi studies can be high, but based on the participants’ reported comments, awareness of metal-related allergies, let alone those related to titanium, would appear to be limited [106]. If the finding is generalizable to the orthopedic community at large, most reactions related to titanium implants likely go unrecognized even while the frequency of implant surgeries continues to rise. It is also worth noting that patients are now being reported whose choice of implant is being dictated by their personal claims of preoperative positive patch test reactions to titanium. In one such case a patient with severe symptomatic sick sinus syndrome received a gold-coated pacemaker apparently on the basis of a self-report of a “proven type IV allergy to titanium” determined by patch testing months before his cardiac condition became symptomatic [107].

Statistics related to the frequency of implant procedures further support the contention that titanium-related reactions may be underreported. Based on a 2013 study from the Organization for Economic Cooperation and Development (OECD), which includes 34 member countries, Switzerland, Germany, and Austria performed the most hip replacements (292, 283, and 276 per 100,000 population, respectively), while the United States performed the most knee replacement surgeries followed by Austria (226 and 215 per 100,000 population, respectively) [108]. The same study reported that the average rate of hip replacement procedures across the OECD members increased about 35% between 2000 and 2013 while that of knee replacements doubled. Other researchers applied 2010 prevalence data to 2030 population estimates and predicted that in the United States alone, 11 million individuals will undergo a total knee or hip replacement in 2030 [109]. The rate of dental implants is also expected to continue increasing. In 2013 in the United States, 1,260,000 dental implants procedures were performed, a figure predicted to double in just 7 years [110]. Whether the number of reports of clinical allergy related to these burgeoning numbers of procedures will also increase remains to be seen, but it would not be surprising based on their volume alone.

To date more than 30 different signs and symptoms have been associated with exposure to titanium, most, but not all, related to medical or dental implants (Table 34.5). Dermatitis, pruritus, and pain have been the most common. Based on a search of the FDA’s Medical Device Adverse Event Database (MAUDE) using the keywords, “titanium allergy,” 49 cases of adverse events related to titanium medical devices were reported by consumers between 2001 and 2016 (Table 34.6) [111]. Numerous cases of patients with medical or dental titanium implants needing revision surgery have also been reported (Table 34.7, Figs. 34.3 and 34.4). European data indicate that the number of implant revision procedures is increasing. In Sweden alone, for example, the rate of revision of surgery for total hip replacements due to aseptic loosening, adverse soft tissue reactions, and pain—all of which have been reported to be associated with cases with titanium implants thought to be associated with titanium hypersensitivity—is more than 50% (Table 34.8). In some implant cases, multiple revision procedures have been performed; in some cases, implants have been replaced with devices made from other materials; and in some cases, devices have simply been removed when feasible, often with improvement or resolution of symptoms (Table 34.7) [78, 112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131]. Most of these cases have been reviewed by Wood and Warshaw and by Fage and coworkers [11, 62]. Although titanium allergy is rare and may continue to be so overall, it is difficult to avoid concluding that cases of titanium allergy are likely to increase.

Table 34.5 Summary of clinical presentations in cases associated with exposure to titaniuma
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Table 34.6 Types of titanium devices related to complaints reported to the US Food and Drug Administration between 2001 and 2016
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Table 34.7 Cases whose symptoms improved or resolved after removal of titanium implants or devices (with or without adjuvant treatment)
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Fig. 34.3
figure 3

(a) Photograph of a patient who developed facial eczema that had persisted for 2 years after she received titanium dental implants. (b) One week after her implants were removed, her symptoms worsened, which was attributed to the rechallenge represented by titanium debris resulting from the procedure. (c) However, 10 months after removal of the implants, the patient’s symptoms had resolved. Appearance of the maxillary arch (d) with implants and (e) 10 months after their removal. (Reproduced with permission from [116])

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Fig. 34.4
figure 4

Intraoral views of the (a) maxillary and (b) mandibular arches of a woman with titanium crowns. Nine months after the prosthetic treatment, she developed worsening eczema on her neck, seen in (c) frontal and (d) lateral views. The implants (e, maxillary, and f, mandibular views) were removed, and within 3 months the patient’s eczema resolved (g, frontal, and h, lateral views). (Reproduced with permission from [119])

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Table 34.8 Characteristicsa of first recorded revision of total hip replacement procedures conducted in Sweden and parts of the United Kingdom from 1979 to 2014
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Even while the evidence in support of titanium as a metal allergen mounts, the existing literature must be interpreted with caution. As discussed, the clear lack of a reliable titanium formulation for patch testing casts doubt on negative patch test reactions, especially in symptomatic patients with titanium implants or in those whose symptoms have improved after implant removal. Although improvement in symptoms after removal of a titanium implant does not prove the existence of a titanium allergy, the association is certainly noteworthy. The identity of implants and their component alloys are not always reported; often, the information may be unavailable. When available, however, as much identifying information as possible should be included in publications because hypersensitivity can also be mistakenly attributed to titanium. This situation is highlighted by the case of a patient in need of an orthopedic implant who was suspected of having a titanium allergy because she had developed a facial contact allergy related to her “titanium” glass frames. She had positive patch test reactions to nickel, cobalt, and palladium, all of which were identified in her frames, which included only a trace amount of titanium [132]. The number of metals that can be present in titanium alloys makes it mandatory to rule out other potential allergens as the underlying cause of a patient’s type IV hypersensitivity [133].

The paucity of reliable data concerning almost every aspect of titanium hypersensitivity offers many conundrums whose resolution will await more carefully conducted research and increased clinical awareness. Answers, however, will not be forthcoming if clinicians continue to patch test with allergen preparations, including TiN, TiO2, Ti tannate, Ti carbide, Ti peroxide, Ti isopropoxide, calcium titanate, discs, and powders, whose known physicochemical characteristics contribute to false-negative reactions.