All metals in contact with biological systems undergo corrosion.
This electrochemical process leads to the formation of metal ions,
which may activate the immune system by forming complexes with endogenous
proteins.
Implant degradation products have been shown to be associated
with dermatitis, urticaria, and vasculitis. If cutaneous signs of
an allergic response appear after implantation of a metal device,
metal sensitivity should be considered. Currently, there is no generally
accepted test for the clinical determination of metal hypersensitivity
to implanted devices.
The prevalence of dermal sensitivity in patients with a joint
replacement device, particularly those with a failed implant, is
substantially higher than that in the general population.
Until the roles of delayed hypersensitivity and humoral immune
responses to metallic orthopaedic implants are more clearly defined,
the risk to patients may be considered minimal.
It is currently unclear whether metal sensitivity is a contributing
factor to implant failure.
Implant-related metal sensitivity has been well documented in
case and group studies; however, overall it remains a relatively
unpredictable and poorly understood phenomenon in the context of
orthopaedic implant materials1-3.
Dermal hypersensitivity to metal is common, affecting about 10% to
15% of the population1,2,4,5.
Dermal contact with and ingestion of metals have been reported to
cause immune reactions, which most typically manifest as hives,
eczema, redness, and itching1,6,7.
Historically, the ability of implant materials to demonstrate appropriate
host and material responses has resulted in the elimination of candidate
materials based on observation of adverse host responses. However,
some adverse responses are difficult to characterize in preclinical
and clinical settings because of their infrequent or subtle nature. In
vivo metal hypersensitivity or hypersensitivity-like reactivity
to metallic biomaterials is one such response. Although little is
known about the short and long-term pharmacodynamics and bioavailability
of circulating metal degradation products in vivo5,8-10, there have been many reports
of sensitivity responses temporally associated with implantation of
metal components. Degradation products of metallic biomaterials
include particulate wear debris, colloidal organometallic complexes
(specifically or nonspecifically bound), free metallic ions, inorganic
metal salts or oxides, and precipitated organometallic storage forms.
All metals in contact with biological systems corrode11,12, and the released ions, while
not sensitizers on their own, can activate the immune system by
forming complexes with native proteins5,13,14.
These metal-protein complexes are considered to be candidate antigens
(or, more loosely termed, allergens) for eliciting hypersensitivity
responses. Nonbiodegradable polymeric biomaterials used for load-bearing
in total joint arthroplasty are not easily chemically degraded in
vivo and have not been intensely investigated or implicated
in case or group studies as sources of hypersensitivity-type immune
responses. This is presumably due to the relatively large size of
the degradation products associated with the mechanical wear of
polymers in vivo; these products may be large enough
to prevent the formation of polymer-protein haptenic complexes with
human antibodies. The biological response in this situation is a
response to particles. However, immunogenic reactions associated
with polymethylmethacrylate have been reported, albeit less frequently15, and may be due to a still-present
unreacted monomer that serves in a hapten-like manner.
Metals known as sensitizers (haptenic moieties in antigens) are
beryllium16, nickel4,6,7,16, cobalt16,
and chromium16; in addition, occasional
responses to tantalum17, titanium18,19, and vanadium17 have
been reported. Nickel is the most common metal sensitizer in humans,
followed by cobalt and chromium1,4,6,7.
The prevalence of metal sensitivity among the general population
is approximately 10% to 15% (Fig. 1), with nickel
sensitivity having the highest prevalence (approximately 14%)1. Cross-reactivity between nickel
and cobalt is most common1,5.
The amounts of these metals found in medical-grade alloys are shown
in Table I.
Although the specifics associated with metal-protein binding
and the biological mechanisms by which these complexes become immunogenic remain
relatively uncharacterized, much has been learned over the past
thirty years. The following review attempts to help clarify (1)
what is currently known about implant-related metal sensitivity,
(2) what methods are used to test for metal sensitivity, and (3)
the conclusions of case-specific and general metal-sensitivity studies
regarding implant-related metal sensitivity.
Metal hypersensitivity might be merely a clinical curiosity except
for known overaggressive immune responses to haptenic antigens leading
to putative clinical complications. Hypersensitivity can be either
an immediate (within minutes) humoral response (initiated by an
antibody or the formation of antibody-antigen complexes of type-I,
II, and III reactions) or a delayed (within hours to days) cell-mediated
response20,21. Implant-related
hypersensitivity reactions are generally the latter type of response,
in particular type-IV delayed-type hypersensitivity (DTH).
Cell-mediated delayed-type hypersensitivity is characterized
by antigen activation of sensitized TDTH lymphocytes releasing various
cytokines that result in the recruitment and activation of macrophages.
TDTH lymphocytes are subset populations of T helper (TH) lymphocytes
purported to be of the CD4+ TH-1 subtype (and, in rare
instances, of the CD8+ cytotoxic T-cell [Tc] subtype).
This TH-1 subpopulation of T-cells is characterized by its cytokine
release profile—for example, interferon-g (IFN-g), tumor
necrosis factor-a (TNF-a), interleukin-1 (IL-1), and interleukin-2
(IL-2). TH-1 cells are generally associated with responses to intracellular
pathogens and autoimmune diseases. Although TDTH cells
mediate a delayed-type hypersensitivity reaction, only 5% of
the participating cells are antigen-specific TDTH cells within a fully
developed delayed-type hypersensitivity response. The majority of
delayed-type-hypersensitivity participating cells are macrophages.
The effector phase of a delayed-type hypersensitivity response
is initiated by contact of sensitized T-cells with an antigen. In
this phase, T-cells, which are antigen-activated, are characterized
as TDTH cells and, in conjunction with activated antigen presenting
cells (APCs), can secrete a variety of cytokines that recruit and
activate macrophages, monocytes, neutrophils, and other inflammatory cells.
These released cytokines include IL-3 and granulocyte-macrophage
colony-stimulating factor (GM-CSF), which promote production of
granulocytes; monocyte chemotactic activating factor (MCAF), which
promotes chemotaxis of monocytes toward areas of delayed-type hypersensitivity activation;
IFN-g and TNF-b, which produce a number of effects on local endothelial
cells facilitating infiltration; and migration inhibitory factor (MIF),
which inhibits the migration of macrophages away from the site of
a delayed-type hypersensitivity reaction. Therefore activation,
infiltration, and eventual migration inhibition of macrophages is
the final phase of a delayed-type hypersensitivity response. Activated
macrophages, because of their increased ability to present class-II
major histocompatibility complexes (MHCs) and IL-1, can trigger the
activation of more TDTH cells, which in turn activate more macrophages,
which activate more TDTH cells, and so on. This delayed-type-hypersensitivity
self-perpetuation response can create extensive tissue damage.
The specific T-cell subpopulations, the cellular mechanism of
recognition and activation, and the antigenic metal-protein determinants
elicited by these metals remain incompletely characterized. The
subsets of participating lymphocytes of nickel-sensitive individuals
were found to be primarily CD4+ and CD45RO+ cells,
whereas CD8+ and CD8+CD11b+ lymphocytes
were shown to be underrepresented22.
Sensitive T-cells have been shown to recognize metals such as nickel
in the context of major histocompatibility complex class-II molecules22,23. The Langerhans cells of the
dermis are well characterized as the primary antigen presenting
cells associated with dermal hypersensitivity. The dominant antigen
presenting cell (if any) responsible for mediating an implant-related
hypersensitivity response remains unknown. Candidate antigen presenting
cells in the periprosthetic region include macrophages, endothelial
cells, lymphocytes, Langerhans cells, dendritic cells, and, to a
lesser extent, parenchymal tissue cells. While there is general
consensus implicating the T-cell receptor in metal-induced activation,
there are conflicting reports regarding which region or receptor
specificity is responsible for dominating metal reactivity22-26. Some investigators have reported
no preferential receptor selection22,
while others have shown the CDR3B region of the VB17+ T-cell
receptor to be critical in the sense that, without this region,
metal reactivity is abrogated25,26.
Metals have also been shown to act as facilitating agents in the
cross-linking of receptors (for example, VB17 of CDR1 T-cell receptor)
to create superantigen-like enhancement of T-cell receptor-protein contact25,26, whereby metalloproteins or metal-peptide
complexes that would not otherwise be antigenic are able to provoke
a response. Furthermore, other investigators have shown that, entirely
independent of a metal-altered endogenous protein antigen, metal
has been reported to cross-link thiols of cell-surface proteins
of murine thymocytes (that is, CD3, CD4, and CD45), which
have been reported to result in the activation of a tyrosine kinase (p56lck),
involved with the activation of T-cells through the T-cell receptor27-30. However, despite reports of
non-hapten-related mechanisms of metal-induced lymphocyte activation,
clonal lymphocyte specificity associated with type-IV delayed-type
hypersensitivity remains the dominant mechanism associated with
implant-related hypersensitivity responses27-29.