Review

Metal is not inert: Role of metal ions released by biocorrosion in aseptic

loosening—Current concepts
Dieter Cadosch,1,2 Erwin Chan,1 Oliver P. Gautschi,1,2 Luis Filgueira1
1
School of Anatomy and Human Biology, University of Western Australia, Crawley, Australia
2
Department of Orthopaedic and Trauma Surgery, Royal Perth Hospital, Perth, Australia

Received 27 January 2009; revised 21 May 2009; accepted 5 August 2009

Published online 16 October 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.32625

Abstract: Metal implants are essential therapeutic tools
for the treatment of bone fractures and joint replacements.
The metals and metal alloys used in contemporary ortho-
pedic and trauma surgery are well tolerated by the major-
ity of patients. However, complications resulting from
inflammatory and immune reactions to metal implants
have been well documented. This review briefly discusses
the different mechanisms of metal implant corrosion in the
human body, which lead to the release of significant levels
of metal ions into the peri-implant tissues and the systemic
blood circulation. Additionally, this article reviews the
effects of the released ions on bone metabolism and the
immune system and discusses their involvement in the
pathophysiological mechanisms of aseptic loosening
and metal hypersensitivity in patients with metal implants.
Ó 2009 Wiley Periodicals, Inc. J Biomed Mater Res 91A:
1252–1262, 2009
Key words: metal implants; biocorrosion; metal ions; asep-
tic loosening; immunoreactivity

INTRODUCTION predominately used in contemporary surgery are

The first metal hip prosthesis was implanted in
1956 under great engineering and medical efforts. In
the meantime, total joint arthroplasty has been per-
formed routinely in over a million patients world-
wide every year. The constant aging of our popula-
tion will contribute to an increasing number of
patients with implanted metal devices.1 As long as
tissue engineering and biodegradable bone substi-
tutes do not lead to products that will be applicable
in clinical routine, prosthetic and osteosynthetic
devices, made of metal and metal alloys, will remain
indispensable in orthopedic and trauma surgery.
Most patients tolerate metal implants well; however,
complications resulting from inflammatory and
immune reactions to metals have been well docu-
mented in up to 10% of patients, with the incidence
continuing to increase.2–8
Many different metals and metal alloys have been
used for joint replacement, internal fixation of bone
fractures, and after osteotomy. The metal implants
Correspondence to: D. Cadosch; e-mail: dcadosch@gmx.net
Ó 2009 Wiley Periodicals, Inc.
made of commercially pure titanium, titanium alloys
(e.g., Ti6Al7Nb, TiAl6V4), and medical grade stain-
less steel (SS316L). The employed metallic biomateri-
als are composed of a variety of metals including
aluminum (Al), chromium (Cr), cobalt (Co), nickel
(Ni), molybdenum (Mo), vanadium (V), titanium
(Ti), and iron (Fe). Stainless steel SS316L, for exam-
ple, contains Cr (16–18%), Ni (10–14%), and various
trace metals (5%) balanced with Fe.9,10 Over recent
decades, significant developments have taken place
to provide suitable metallic biomaterials with opti-
mal biofunctionality, such as stability and a surface
texture allowing cellular adhesion, combined with
excellent biocompatibility of low intrinsic toxicity,
inflammatory activation, and immunogenicity.11
However, their permanent tendency to corrode
when implanted into a physiological environment
remains a serious concern.12–14 Several case reports
and studies have indicated that metal implants
undergo corrosion inside the human body by vari-
ous mechanisms including mechanical wear, biolog-
ical activity, and mechanically accelerated electro-
chemical processes.15–17 Thus, significant amounts of
metallic particles are released into the tissues sur-
rounding metal implants and elevated concentra-
tions of metal ions have been measured in clinically
ROLE OF METAL IONS RELEASED BY BIOCORROSION IN ASEPTIC LOOSENING
retrieved capsular and periprosthetic tissues, as well
as in distant organs (liver, spleen, and lymph nodes)
and body fluids (serum and urine) in total hip
arthroplasty patients.18–21 Implants used for osteo-
synthesis have to withstand completely different
forces than implants used for joint replacements.
Thus, large implant-derived particles (in the nano-
meter range) are produced exclusively by the
mechanical wear process in articular coupling of
prostheses and are not present in patients with
osteosynthesis implants. However, both osteosynthe-
sis and joint replacement implants are exposed to
biological activity and electrochemical processes.
A wide range of molecular and cellular interplays
have been demonstrated between the released biocor-
rosion products and the human organism, involving
the immune and skeletal system. There is increasing
clinical and research-based evidence that a relevant
percentage of patients with metal implants may de-
velop metal hypersensitivity and severe inflamma-
tory side effects, leading to aseptic loosening of the
implant and even systemic reactions.22–25 The phago-
cytosis of metal wear particles by tissue macrophages
induces production of proinflammatory cytokines
that enhance osteolytic activity at the implant-bone
interface.23,26–28 This mechanism has been thoroughly
investigated and is beyond the scope of this review.
Although many studies have investigated the role of
metal wear particles in osteoclastogenesis and aseptic
loosening, little is known about the direct effects of
metal ions released by biocorrosion. At the bone-
metal interface, metal ions may directly interact with
bone cells contributing to aseptic loosening by accel-
erating osteoclastic bone resorption and/or inhibiting
the function of osteoblasts. Various studies have
demonstrated that nontoxic concentrations of metal
ions affect the differentiation and function of osteo-
blastic cells in vitro.29,30 We have previously demon-
strated that metal ions (such as titanium) directly
induce the differentiation of osteoclast precursors to-
ward mature osteoclasts capable of effective bone
resorption.31 Furthermore, once released into the sys-
temic blood circulation, the metal ions bind to serum
proteins and form haptens or hapten-like complexes,
which are considered to be relevant antigens recog-
nized by T-lymphocytes and candidates for eliciting
hypersensitivity reactions.19,32 Exposed to metal–pro-
tein complexes, T-lymphocytes proliferate and differ-
entiate to produce soluble factors such as interleukin
(IL)-6, IL-1a/b, and tumor necrosis factor-alpha
(TNF-a) that trigger a particular immune response
and activate osteoclastogenesis.33–35 The extent of this
immune response upon implantation of metallic
devices depends predominantly on the individual
immune reactivity and on material characteristics.36
This article reviews the close relationship between
bone cell metabolism, the immune system, and the
1253
metal ions released by biocorrosion from the most
commonly used metallic biomaterials in contempo-
rary bone surgery.
BIOCORROSION
To date, it is well recognized that corrosion of me-
tallic materials implanted in the human body is an
inevitable deteriorating reaction leading to the
release of undesirable metal ions/corrosion prod-
ucts, which are not biocompatible. In the chemist’s
view, corrosion is the visible destruction of a metal
caused by interactions with its environment, which
may cause rupture of a structure or loss of function,
for example, breakage of an orthopedic implant. This
aspect is no longer important for modern metals/
alloys in surgery as material loss due to any corro-
sive attack is minimal and does not usually compro-
mise the stability of the implant.17,37 However, de-
spite the great progress in providing corrosion resist-
ant metallic biomaterials, in a physiological
environment corrosion remains a slow and continu-
ous process, which leads to the release of significant
amounts of metal ions and other corrosion products.
For instance, the corrosion of a stainless steel
implant releases Fe, Cr, and Ni ions; corrosion of ti-
tanium and titanium alloys release titanium (mostly
at the Ti(IV) oxidation state), vanadium and alumi-
num ions.38–50 Dissolved metal ions can accumulate
in the tissue, surrounding metal implants or can be
released into the systemic blood circulation and
transported to distal organs.18–21 Indeed, significantly
higher concentrations of metal ions have been
observed in the body fluids of patients with stainless
steel implants 10–13 years after primary hip arthro-
plasty when compared with individuals without
implants. This included concentrations of Ni in
blood of
0.51 lg/L, in plasma of
0.26 lg/L, and
in urine of
2.26 lg/L, and plasma Cr levels of

0.19 lg/L.14 Similarly, Ti concentrations of
135.57
lg/L were measured in patients with Ti-6Al-4V total
knee replacements after 57 months.51 The amount of
metal ions released depends on the quality of the
surgical procedure and on the function of the
implant. Leopold et al. measured a threefold increase
in Ti levels in patients with well-functioning Ti-alloy
joint replacements, while patients with failed
implants showed as much as a 50-fold increase in se-
rum concentrations when compared with individuals
without implants.52 A further study reported
1 lg/
L of Ti in serum of patients with stable prosthesis;
however, the concentrations increased up to
4 lg/L
in the case of failed implants.53 In a physiological
environment, metallic biomaterials undergo corro-
sion through a variety of mechanisms. Extensive
research has been carried out to understand the
Journal of Biomedical Materials Research Part A
1254 CADOSCH ET AL.

different forms of corrosion occurring in the human

body14; the most commonly observed include (1) me-
chanical wear processes [e.g., in the articular cou-
pling of prostheses leading to the formation of wear
particles (excellent reviews articles are available on
the production of wear debris and their effects and
will not be discussed21,26,54)], (2) physiochemical cor-
rosion, and (3) cellular-gated mechanisms.11,23,37

Physiochemical corrosion

As tissue fluids enter into contact with the metal

surface, corrosion occurs via an electrochemical re-
dox reaction, in which oxidation (electron loss of the
metal) is coupled with reduction (electron gain of
electrolyte components).37 In terms of how a biologi-
cal environment can affect corrosion, it is believed
that proteins can influence the electrochemical
behavior of implant metals/alloys. However, overall
results are not conclusive and the exact effect of pro-
teins on corrosion is still the topic of much debate.55
Some authors demonstrate that proteins can enhance
the propagation of charges between implant and sur-
rounding fluids while others suggest a reduced
charge transfer by proteins.56–59
Cellular mechanism
Besides the electrochemical aspect of corrosion, it
has been debated whether mature osteoclasts are
able to corrode the metal surface. Previous results
from our group demonstrate that osteoclast precur-
sors are able to grow and differentiate on stainless
steel, aluminum and chromium, and to directly cor-
rode the metal surface as demonstrated by resorp-
tion pits on the metal surface and the release of
corresponding metal ions into culture media
(Fig. 1).15,60 We proposed that this process may take
place at the bone-implant interface, representing an
additional mechanism of metal corrosion in vivo and
contributing to the levels of metal ions measured in
the periprosthetic tissues and serum from total
arthroplasty patients.
EFFECTS OF RELEASED METAL IONS ON
BONE METABOLISM
Total joint replacement has been a great success
with improvements in the surgical techniques, skele-
tal fixation, prophylaxis against infections, and fa-
tigue strength of the component. However, the for-
mation of periprosthetic osteolytic lesions, impairing
the maintenance of a stable interface between the
implant and the bone (aseptic loosening) develops in
Figure 1. Scanning electron microscopy images showing
human osteoclasts growing on glass coverslips (A) and on
stainless steel disks (B).

15–20% of all patients within 20 years of a primary
hip arthroplasty with reported failure rates of 13%
for the femoral component and 34% for the acetabu-
lar component.61–64 Recently, great effort has been
directed toward understanding the pathophysiologi-
cal cascade of events initiated by biocorrosion prod-
ucts, resulting in periprosthetic bone loss and ulti-
mately aseptic loosening. Normal bone maintenance
relies on the balance between bone formation and
bone resorption. The net bone loss at the metal-tissue
interface occurs because of an increased bone resorp-
tion or reduced bone formation. Increased bone
resorption can be due to an increase of one or more
of the following events: recruitment of osteoclast
precursors from the blood circulation at the bone-
implant interface, their differentiation into mature
multinucleated cells, their functional activation, and
finally their survival.
Increased recruitment of osteoclast precursors and
their subsequent differentiation into mature osteo-
clasts may be involved in the pathomechanisms of
aseptic implant loosening. It is reasonable to assume
that some of the osteoclast precursors recruited to
the peri-implant tissues are able to differentiate into
mature osteoclasts. In line with this possibility, sev-
eral animal studies have demonstrated that osteo-
clast precursors in tissues surrounding subcutane-
ously implanted wear particle cells differentiate into

Journal of Biomedical Materials Research Part A

ROLE OF METAL IONS RELEASED BY BIOCORROSION IN ASEPTIC LOOSENING
mature osteoclasts in culture.65–67 It is likely that the
increased recruitment of osteoclast precursors is due
to increased production of chemotactic cytokines
induced by wear particles, and metal ions released
by biocorrosion. In fact, more recently, particulate
wear debris (predominantly polyethylene) has been
shown to induce chemokine expression in macro-
phages, fibroblasts, and osteoblasts, including IL-8,
monocyte chemoattractant protein-1, macrophage
inflammatory protein 1, and eotaxin.68–71 Human
in vitro experiments by our group have shown that
titanium ions enhance the synthesis and secretion of
CCL17/TARC (thymus and activation-regulated
chemokine) and CCL22/MDC (macrophage-derived
chemokine) in mature osteoclasts.72 Most importantly,
recent studies have demonstrated that osteoclasts also
express CCL22 upon activation by RANK-L.73,74
Taken together, these studies lead to the conclusion
that recruitment of osteoclast precursors is an impor-
tant mechanism by which wear particles and possibly
metal ions stimulate osteolysis in patients with ortho-
pedic implants.
Osteoclasts are formed by the fusion of bone mar-
row-derived mononuclear precursors, which circu-
late in the CD14þ monocyte fraction of peripheral
blood.75 Osteoclastic differentiation from hematopoi-
etic and circulating monocytes is a multistep event
that occurs in the presence of macrophage-colony-
stimulating factor (M-CSF) and the receptor activator
of NF-jB ligand (RANK-L) (expressed by osteoblasts
and other bone-related stromal cells). The process
includes precursor proliferation, commitment to the
osteoclast lineage, expression of osteoclast specific
genes such as tartrate-resistant acid phosphatase
(TRAP), and finally fusion into multinucleated giant
cells.76 Several studies have shown, in both animal
and human in vitro models, that periprosthetic oste-
olysis is primarily driven by an increased osteoclas-
tic differentiation and activity.26,77–80 A similar
increased presence of mature osteoclasts has been
reported in patients with aseptic loosening.81 In
addition, synovial fluid of patients with loose
implants contains elevated levels of TRAP, presum-
ably due to secretion of this enzyme by the increased
number of osteoclasts.82,83 It is well recognized that
phagocytosis of metallic wear particles by macro-
phages induces their activation, producing mediators
that enhance osteoclast formation.27 The release of
proinflammatory cytokines, including TNF-a, IL-6,
and IL-1a/b by activated macrophages has been
recognized as one of the primary cellular mecha-
nisms responsible for increased osteoclast differentia-
tion.84–86 These cytokines act synergistically enhanc-
ing differentiation of osteoclast precursors into
mature osteoclasts able to efficiently resorb the peri-
implant bone.87,88 TNF-a acts directly on osteoclast
precursors, whereas IL-6 and IL-1a/b act indirectly
1255
by increasing the expression of RANK-L and M-CSF
by osteoblasts, which in turn, directly drives osteo-
clastogenesis through a mechanism involving cell-to-
cell contact.88 The latter is part of the coupling
between bone resorption and formation, which is
essential not only during bone growth but also dur-
ing bone remodeling and fracture healing. In addi-
tion to activated macrophages exposed to wear par-
ticles, the potential role of metal ions released by
biocorrosion from the implant surface must also be
considered. We have shown that titanium ions
directly induce the differentiation of osteoclast pre-
cursors toward mature osteoclasts in
20% of indi-
viduals.31 These results suggest that Ti(IV) may dis-
connect the osteoclast function from the osteoblastic
control mechanisms, while still exhibiting relevant
bone resorbing capacity. In summary, the studies
discussed in the previous sections demonstrate that
metal wear and ions induce increased differentiation
and activation of osteoclast precursors leading to a
large number of mature osteoclasts able to effectively
resorb the bone surrounding metal implants, but
also potentially enhance biocorrosion of the implant,
resulting in more ion release and the development
of a vicious cycle.
In addition to an enhanced recruitment and func-
tional maturation of osteoclast precursors, it is also
reasonable to assume that cytokines released in
response to biocorrosion products increase osteoclast
survival. This hypothesis is supported by studies
showing that several bone resorptive cytokines
increase osteoclast survival.89,90 For example, IL-1
increases osteoclast survival by activating RANK
and thereby inhibiting apoptosis.91 Greenfield et al.
found that conditioned media from marrow cells
incubated with titanium particles slightly increased
osteoclast survival.77 Results from our group exhib-
ited an increased expression of IL-1 in the superna-
tant of osteoclast cultured on surgical stainless steel
and titanium foils.15 The previous studies along
with our results suggest that increased osteoclast
survival may further enhance the complex pathome-
chanism of increased osteolysis in the cases of asep-
tic loosening.
While the aforementioned studies have mostly
examined the bone-resorption limb of the patho-
physiological mechanisms of aseptic loosening, more
recent investigations have focused on the effects of
biocorrosion products on bone formation. Investiga-
tions have demonstrated that titanium wear particles
inhibit the expression of the osteoblastic genes that
code for collagen type-I and type-III.92 Other studies
have revealed that nontoxic concentrations of metal
ions affect the differentiation and function of osteo-
blastic cells in vitro.29,30 Consequently, enhanced bio-
corrosion and metal ion release may well have a
negative effect on osteoblastic functions, resulting in
Journal of Biomedical Materials Research Part A
1256
reduced peri-implant bone formation and eventually
increasing implant loosening.
OSTEOIMMUNOLOGY—LINKS BETWEEN
IMMUNITY AND BONE SYSTEM
Recently, published evidence has shown that the
immune system is closely connected to the develop-
ment of bone cells. This might not be surprising,
considering that the production of immune cells of
hematopoietic origin comes from the bone marrow
and that improper bone development leads to a defi-
cient bone marrow size and function.93 In addition,
osteoclasts, the only and essential bone resorbing
cells, derive from the same precursor cells as macro-
phages and dendritic cells, professional antigen-pre-
senting cells.75 This linkage plays also a major role
in rheumatoid arthritis, cancerous bone metastasis,
and other destructive bone disorders as indicated by
an increasing amount of published studies.74,94–96
There is increasing evidence indicating that
inflammatory immune responses influence bone me-
tabolism. A variety of T-lymphocyte derived factors
and cytokines, including RANK-L and TNF-a, have
been shown to directly and indirectly promote osteo-
clast activity and inhibit osteoblast function.77,97–102
Other T-lymphocyte-derived cytokines, including
interferon-gamma (IFN-g) and IL-4, have been
shown to decrease osteoclast activity and thereby
decrease bone remodeling and probably delay bone
fracture healing.103,104 Increased levels of IL-10, a
cytokine produced by regulatory T-lymphocytes,
have been measured in patients with orthopedic
implants.105 However, despite increasing evidence
supporting the linkage between the immune system
and bone cells, the role of the immune system in the
systemic and peri-implant tissue responses, charac-
terized by increased osteolysis and implant failure
(aseptic loosening), remains poorly understood with
several studies reporting conflicting results regard-
ing their actual involvement.54,106
EFFECTS OF RELEASED IONS ON THE
IMMUNE SYSTEM
Dermal hypersensitivity to metal is common, with
up to 20% of Caucasians being sensitive to nickel.107
Immune reactions to dermal contact and ingestion of
metals, manifested as skin conditions such as ec-
zema, urticaria, erythema, and pruritis are believed
to be of a type IV cell mediated hypersensitivity.12
The earliest case of an allergic manifestation towards
an orthopedic implant was reported by Foussereau
et al., when a patient presented with an eczematous
Journal of Biomedical Materials Research Part A
CADOSCH ET AL.
rash over a stainless steel fracture plate.108 Besides
the clinical observations of metal hypersensitivity
observed in some patients with orthopedic implants,
strengthened by the alleviation of symptoms after
the removal of the causative metal implant, evidence
for the involvement of the immune system comes
from several histological studies of retrieved peri-
implant tissues.109 These studies have shown the
infiltration of lymphocytes, monocytes, dendritic
cells, macrophages, and mast cells into the peri-
implant tissues at various time points after metal
implantation. Immunohistochemical analysis of peri-
implant tissues revealed high levels of immune spe-
cific markers correlating with an inflammatory
response, including CD3þ T-lymphocytes, CD4þ
cells, CD11cþ macrophages/dendritic cells, and cells
with abundant MHC class II (HLA-DR) expression
(dendritic cells).109–111 Infiltration with B-lympho-
cytes has bee seen only occasionally under certain
circumstances.112 The observation of accumulation of
inflammatory cells led to the description of the peri-
implant area as an ‘‘immuno-incompetent, fibro-
inflammatory, integration-deficient zone.’’113 Another
indicator of immune activity is the finding of
increased cytokine levels in the serum of patients
with orthopedic implants. In that respect, cytokines
able to induce bone resorption [such as IL-1b, TNF-
a, IL-6, and macrophage-granulocyte colony-stimu-
lating factor (GM-CSF)] have been of particular inter-
est, and elevated serum cytokine levels have been
reported in patients with total hip prosthesis.114
Currently, immune reactivity to metal ions includ-
ing titanium is considered to be a type IV hypersensi-
tivity reaction.115 This is a delayed type of hypersen-
sitivity, which is mediated by sensitized lymphocytes
and has a strong memory component. Cells necessary
for the development of type IV hypersensitivity were
found to be present in perivascular tissue adjacent to
metal implants (stainless steel or titanium).116
Role of innate immunity toward metal implants
The innate immunity is likely to be the most re-
sponsive mechanism toward the presence of wear
particles. The formation of Foreign Body Giant Cells
(FBGC) is a common outcome in the presence of for-
eign material inside the human body. The main cells
responsible for this reaction are macrophages, also
known as ‘‘scavengers’’ as they are able to phagocy-
tose different types of foreign particles. The effective
phagocytosis of metallic wear particles by macro-
phages induces their activation and the release of
proinflammatory cytokines, including TNF-a, IL-6,
and IL-1a/b.27,84–86 Granulocytes have also been the
focus of investigations. In neutrophils, both titanium
and vanadium ions induce an increase in the
ROLE OF METAL IONS RELEASED BY BIOCORROSION IN ASEPTIC LOOSENING
Figure 2. Histogram showing the mean proliferation rates
(6SD) of titanium-specific T-lymphocytes after challenge
with dendritic cells preloaded with 100 lM Ti(IV) (A, B,
C), Ti(III) (D), Ni (E), or V(IV) (F). The cultures A, D, E,
and F had a ratio T-lymphocytes to dendritic cells of 20:1,
B of 40:1, and C of 80:1. The different ratios were achieved
by diluting the dendritic cells. All T-lymphocytes were
generated in vitro using autologous dendritic cells loaded
with 100 lM Ti(IV), cultured over 4 weeks and restimu-
lated once a week. In the experiments, 105 T-lymphocytes
were used for the BrdU proliferation assay. The prolifera-
tion rates were calculated as the percentage of the maximal
proliferation of PHA-activated cells (25 lg/mL) and aver-
aged. a,bsignificantly higher mean proliferations when
compared with the mean proliferation of T-lymphocytes
challenged with Ni (a) or V (b). p < 0.05.
production of superoxide anions that indicate neu-
trophil stimulation.117,118 Nickel ions are detrimental
to neutrophils by destroying their cell membranes,
indicating a toxic component of high concentrations
of metal ions.117 However, little is known about the
role of granulocytes in the pathophysiological mech-
anisms of aseptic loosening.
Role of adaptive immunity toward metal implants
and immunogenicity of metals
The adaptive immunity is the key in the develop-
ment of an antigen specific, delayed, and persistent
reactivity in the body and is the main mechanism by
which type IV hypersensitivity can develop. The
major components of the adaptive immune system
are dendritic cells, B-, and T-lymphocytes.
Metal ions are known to exist in a free soluble state
in water. However, when released into the systemic
blood circulation, metal ions tend to bind to serum
proteins and form haptens or hapten-like com-
plexes.19 Circulating protein–metal complexes may
subsequently be recognized by the immune system as
antigens and elicit hypersensitivity reactions.32 To
date, nickel has been the most investigated metal and
is considered to be a relevant antigen.107,119 However,
the question remains to what extent other metals used
in metal implants are forming immunogenic com-
plexes. Titanium has recently been the focus of our in-
terest in this respect. Single titanium ions alone cannot
be antigenic due to their small size; however, they are
1257
able to complex with serum proteins.32 The trafficking
of titanium (IV) by human serum transferrin has been
implicated in the physiology of this hydrolysis-prone
metal.120–122 More recently, titanium (IV) ions have
also been shown to bind to serum albumin.123 The
strong binding property of titanium for phosphoryl-
ated cellular molecules, such as phospholipids, RNA,
DNA, and phosphorylated proteins has been discov-
ered and described previously.124–127 As many phos-
phorylated proteins play a major role in cell signaling,
through binding to such messenger proteins, titanium
may well interfere with signaling pathways of cellular
and immune functions. Moreover, when complexing
with phosphorylated oligopeptides, it may alter forms
of self-antigens and thereby cause autoimmune-like
reactivity. Our studies have resulted in generating
titanium-specific T-lymphocytes using a human
in vitro model (Fig. 2). Additionally, our research on
titanium biocorrosion and immune reactions against
titanium ions has resulted in a better understanding
and new concepts of implant-related inflammatory
reactions and aseptic loosening. A postulated path-
way involving Ti(IV) ions in the pathomechanism of
aseptic loosening is depicted in Figure 3. However,
the detailed mechanisms of how titanium becomes an-
tigenic and is presented to T-lymphocytes, as well as
how the local inflammatory response is driven,
remains to be further investigated.
TESTING FOR METAL SENSITIVITY
Often, the diagnosis of metal hypersensitivity
toward the metal implant is made by exclusion
Figure 3. Postulated model involving the effects of tita-
nium ions released by biocorrosion on the immune system
and the bone metabolism in the pathophysiological mecha-
nisms of aseptic loosening. [Color figure can be viewed in
the online issue, which is available at www.interscience.
wiley.com.]
Journal of Biomedical Materials Research Part A
1258
following a negative clinical, laboratory, and radio-
logical work-up.128 This process is often a frustrat-
ing, expensive, and time-consuming experience for
both the surgeon and the patient. Because of the bio-
logical variation of human immunoreactivity, it is
difficult to predict the possible reactions occurring in
future implant recipients. Several tests have been
developed for detecting immunoreactivity. Delayed-
type hypersensitivity (DTH) reactions against metal
implant components are difficult to diagnose
because of their rare and subtle nature.12 However,
if a metal sensitivity is suspected, a thorough past
medical history including former incompatibility
reactions after metal contact and an appropriate skin
test should be performed.
The gold standard for testing a DTH has been con-
ducted by in vivo skin testing with standardized-
chemical test substances/salts of metals. However,
its validity in detecting a systemic hypersensitivity is
not thoroughly confirmed.129 The likelihood of sensi-
tizing an individual to a metal ion from the patch
test itself is low.130 If there is a prior sensitization to-
ward metal ions, the chance of undesirable allergic
reactions after implantation of metal prostheses is
considerably higher.2,131 The most common reactions
include those of urticaria and a reaction to the adhe-
sive backing from the tape that holds the patch in
place.129 If there is suspicion of a previously existing
nickel sensitization, an epicutaneous test should be
performed for verification and nickel-free implant
prosthesis should be used accordingly.132,133 How-
ever, it has been reported that the general preopera-
tive implementation of an epicutaneous test has only
a moderate predictive value.41 Furthermore, a causal
relationship between implant incompatibility and a
detected contact allergy against a component from
the metal implant by skin testing is being discussed
controversially.36
These issues associated with skin patch testing
have lead to the development of in vitro testing
methods. Currently, there are several in vitro tests
for metal hypersensitivity, most of them based on
leukocyte migration or proliferation.41 Established
tests like the lymphocyte transformation testing
(LTT) can provide a reasonable diagnostic supple-
mentation for the detection of a DTH toward compo-
nents of metal prostheses.134 The LTT involves meas-
uring the proliferative response of lymphocytes fol-
lowing activation. A radioactive or other
proliferation marker is added to lymphocytes to-
gether with the desired challenge agent. The incor-
poration of radioactive [H3]-thymidine marker into
cellular DNA upon division facilities the quantifica-
tion of a proliferation response by measurement of
incorporated radioactivity over a specific time-pe-
riod. After 5 to 7 days, the [3H]-thymidine uptake is
measured.135 Some of the metal allergic patients
Journal of Biomedical Materials Research Part A
CADOSCH ET AL.
demonstrate a specific reactivity of the circulating
blood lymphocytes in the LTT assay.36 Some authors
suggest that the LTT has a better diagnostic value
than skin tests to identify causative agents.136,137 Our
experience using the LTT test has been very positive;
however, we feel additional studies can improve the
feasibility and reliability of the test and we are work-
ing in this direction. Despite this, we would recom-
mend to use the LTT for patients with known skin-
related metal-sensitivity before choosing the material
for a joint replacement or to confirm the clinical di-
agnosis of implant-related metal hypersensitivity
reactions after surgery.
SUMMARY
Metal orthopedic devices remain prone to biocor-
rosion by several mechanisms including the direct
corrosion by osteoclasts, leading to the production of
significant amounts of wear particles and metal ions.
In addition to the increased osteolytic activity caused
by wear particles, current evidence strongly suggests
that the released metal ions contribute to the patho-
physiological mechanism of aseptic loosening by
stimulating both the immune system and bone me-
tabolism through a series of direct and indirect path-
ways. More evidence is linking the immune system
to the bone and to its involvement in the pathophys-
iology of aseptic loosening. To date, revision surgery
remains the only option for the treatment of a failed
orthopedic implant caused by aseptic loosening.
However, by performing a LTT test in patients with
known skin-related metal-sensitivity before choosing
the metal alloy for a joint replacement, the occur-
rence of such complications could be reduced.
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