Allergy and Hypersensitivity to Implant Materials

Implant alloys

Metal

Approximate (%)

316 L stainless steel

Nickel

8.3–35

Chromium

Manganese

Molybdenum

2–3

Nitrogen

0.1

Carbon

0.03

Sulfur

0.03

Silicon

0.75

Phosphorus

0.045

Iron

Balance

Cobalt-chromium-molybdenum steel (ASTM F75)

Chromium

27–30

Molybdenum

5–7

Nickel

<0.5

Iron

<0.75

Carbon

<0.35

Silicon

Manganese

Tungsten

<0.2

Phosphorus

<0.02

Sulfur

<0.01

Nitrogen

<0.25

Aluminum

<0.1

Titanium

<0.1

Boron

<0.01

Cobalt

Balance

Vitallium

Cobalt

Chromium

Silicon

0.5

Manganese

0.5

Carbon

0.02

Boron

0.1

Molybdenum

5.6

Iron

None

Titanium

89.9

Aluminum

5.5–6.5

Vanadium

3.5–4.5

Nickel

Trace

Nitinol

Titanium

Nickel

Oxinium

Zirconium (oxidized)

97.5

Niobium

2.5

Nickel

None

From Basko-Plluska et al. [18]

ASTM American Society for Testing and Materials

Several alloy compositions are currently on the market, depending on the type of implant, the joint, and whether implantation is permanent or nonpermanent (Tables 20.1 and 20.2). Details can usually be obtained from the manufacturer of the implanted material.

Table 20.2

Composition of titanium alloys

Basic material	Analysis values in wt.-%
Basic material	Al	Cu	Fe	Mo	Ni	Si	V	Ti
Titanium iodide
Debit	–	–	–	–	–	–	–	>99.99
Actual	0.01	<0.002	0.01	0.004	0.002	0.004	0.01	>99.9
Pure titanium-2
Debit	–	–	<0.30	–	–	–	–	Balance*
Actual
Pure titanium-2 d6	0.32	0.006	0.11	<0.01	0.017	0.007	0.04	Balance*
Pure titanium-2 d42	0.09	0.012	0.06	<0.01	0.017	0.047	0.1	Balance*
TiAl6V4
Debit	5.5–6.5	–	<0.3	–	–	–	3.5–4.5	Balance*
Actual
TiAl6V4 d10	5.21	<0.005	0.18	0.01	0.029	0.01	4.0	Balance*
TiAl6V4 d16	5.18	<0.005	0.23	0.01	0.034	0.03	4.1	Balance*
TiAl6V4 d22	5.59	<0.005	0.17	0.02	0.016	0.01	3.8	Balance*
TiAl6V4 d35	5.88	<0.005	0.19	0.01	0.026	0.01	4.1	Balance*
TiAl6V4 d60	5.48	<0.005	0.07	0,01	0.023	0.01	3.9	Balance*
TiAl6Nb7
Debit	5.5–6.5	–	<0.3	–	–	–	(Nb 6.5–7.5)	Balance*
Actual
TiAl6Nb7 d14,5	5.59	0.016	0.24	0.01	0.016	0.05	0.02	Balance*
TiAl6Nb7 d22	5.97	0.017	0.23	<0.01	0.021	0.01	0.02	Balance*
TiAl6Nb7 d28	6.1	0.018	0.18	<0.01	0.012	0.01	0.02	Balance*

According to Schuh et al. [12]

Balance* undefined Nb content due to the analysis focus, which was on allergenic elements

For TKR, the currently used metal alloys are most often either stainless steel (nickel and iron), cobalt-chromium alloys (Vitallium®) [18] (Table 20.1), or titanium alloys [12, 13, 19] (Tables 20.1 and 20.2).

So far, palladium has been a relevant contact allergen mainly in dental alloys [20]. In some orthopedic alloys, it is apparently also present, according to information from producers (personal communication, Thomas Rustemeyer, Amsterdam). This information should be confirmed because of the frequency of palladium sensitization and its practical consequences.

Some rare reports have implicated bone components: the methyl-methacrylate monomer; benzoyl peroxide used as initiator of polymerization [8]; dimethyl para-toluidine as an activator of polymerization; hydroquinone as a stabilizing and inhibiting agent; additives such as the antibiotics gentamycin, clindamycin, and erythromycin; contrast agents such as barium sulfate and zirconium dioxide; and dyes such as chlorophyll-copper complexes [21].

The most commonly used metals include iron (Fe), chromium (Cr), cobalt (Co), nickel (Ni), titanium (Ti), vanadium (V), aluminum (Al), niobium (Nb), molybdenum (Mo), and zirconium (Z). In addition, there are traces of other metals such as manganese (Mn) and zinc (Zn), and nonmetallic elements.

Some of these metals are well-known contact allergens, e.g., contact sensitization to nickel as demonstrated by a positive patch test is present in up to 30 % of young females, and the approximate sensitization rate in the general population is 10 % [5]. Chromium, which is present, e.g., in leather, due to the tanning process, and in some cements, due to the production process, is also a well-known contact sensitizer, particularly in occupational settings. Cobalt is among the 20 most common contact allergens, according to recent surveys [5]. In Table 20.3, metals with a high potential for contact sensitization and others with lower sensitization capacity are listed. For other metals used in metal alloys devised for implantation, contact sensitization, as demonstrated by positive patch tests, or clinical contact allergy, as demonstrated by allergic contact dermatitis upon skin exposure, is rare. Contact sensitization to titanium [12] or vanadium appears to be extremely rare, and, if at all, has been attributed to traces of nickel or other alloy metals. Contact sensitization to aluminum has been rarely reported, mainly in patients receiving specific immune therapy enhanced with aluminum hydroxide as adjuvant or in children receiving vaccinations, although there are controversial results in the literature [22]. Despite some case reports, contact allergy to iron or molybdenum has not been formally proven yet [23]. For a few metals such as gallium, magnesium, niobium, ruthenium, tungsten, and zirconium, no cases of contact allergic reactions have been reported [23].

Table 20.3

Sensitizing potential of metals

A. Metals with sensitizing capacity (formation of metal ions)

Aluminum

Beryllium

Chromium

Cobalt

Copper

Gold

Mercury

Nickel

Palladium

Platinum

Rhodium

Tin

B. Metals with low or no sensitizing capacity

Antimonium

Cadmium

Iron

Molybdenum

Niobium

Lead

Silver

Titanium

Tungsten

Vanadium

Zinc

Zirconium

C. Metals for which granulomatous reactions have been reported (particularly to solid metals and metal oxides)

Aluminum

Beryllium

Chromium

Gold

Mercury

Nickel

Titanium

Zirconium

Modified from Flint [14]

20.2 Potential Pathomechanisms

Some metals are essential trace elements and have vital functions in the organism, such as iron in hemoglobin, cobalt in vitamin B12, and chromium and manganese in some enzyme systems [24]. Still, they may lead to contact allergy upon skin exposure. The often-misused term “allergy” requires a specific immunological mechanism, i.e., a T cell-mediated response of the adaptive immune system. The typical sensitization process requires at least 5–10 days, based upon experimental animal models. After the metal hapten has bound to a carrier and has become a full antigen, antigen processing by antigen-presenting cells (such as tissue macrophages in the dermis or in peri-joint tissue or Langerhans cells in the epidermis) takes place. After presentation of the allergen to T cells (particularly CD8 T cell subsets), formation of specific T cell clones to the antigen in question is established [25].

Apart from delayed-type hypersensitivity reactions mediated by T cells, which can be diagnosed by patch tests or possibly lymphocyte stimulation tests, other pathogenetic mechanisms have also been implicated. Also, nonspecific local inflammatory stimulation by metal ions has been implicated [9]. It has been recently shown for nickel that nickel ions may also induce an innate immune response by binding to toll-like receptors [26, 27] and may then secondarily induce a specific T cell-mediated immune response. For other metals, however, this particular pathomechanism has not been demonstrated so far.

A considerable number of individuals in the general population are sensitized to nickel, chromium, or cobalt, usually by skin contact. This results in a large group of individuals who may be at risk if the receive implants with metal alloys in the future. When mechanical wear leads to the release of metal particles, these can be found in the surrounding tissues of arthroplasties. Increased levels have been found in the periprosthetic tissues, in the circulating blood, and in distant organs such as hair, liver, and lymph nodes [28–30]. Metal particles themselves may still remain inert. However, for titanium, for example, granulomatous reactions have been reported, but sensitization could not be demonstrated [31].

As mentioned above, the process of physical chemical corrosion requires contact with tissue fluids, which may result in oxidation of the metal surface [32]. The extent to which the tissue fluids, particularly proteins, influence the electrochemical reactivity on the metal surface remains a matter of debate [33–36].

High metal concentrations may result in direct toxicity. Toxicity may result in sterile inflammatory responses, particularly mediated by the innate and, possibly, the adaptive immune system.

Very rarely, some cases of systemic toxicity from metal implants, particularly metal-on-metal implants with higher corrosion rates [37, 38], and molybdenum [7] have been reported.

20.3 Clinical Manifestations

A number of patients develop symptoms such as reduced mobility, overheating, swelling, recurrent joint effusions, or loosening of the implant. When all other causes have been excluded, an allergic hypersensitivity reaction to an implant component is suspected; often, however, no such etiologies may be identified.

Rarely, patients develop localized eczematous reactions in the skin overlying the implant or disseminated exanthematous reactions. In a series of cases, allergic contact dermatitis or other eczematous manifestations have been reported [18]. Most often, eczematous lesions localized to the area of implantation with possible later dissemination have been observed. Also, urticarial reactions, itching, and pain have been seen. In most cases, patch tests have been performed, some with negative results and, others with positive results to nickel, cobalt, or chromium. These were most often observed with osteosynthesis materials, e.g., plates, screws nails, or wires. Disseminated or systemically induced cutaneous reactions have been more rarely reported. Local swelling and erysipelas-like reactions have also been associated with hypersensitivity. Rarely, vasculitis and fistulas have been observed. Finally, local pain and impairment of flexibility and, particularly, loosening of articulations as well as of osteosynthesis plates and screws have been implicated. In many of the reported cases, however, further interventions and outcomes have not been described.

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