72nd Publication- JPBS- 7th Name.pdf

S1345
© 2021 Journal of Pharmacy and Bioallied Sciences | Published by Wolters Kluwer - Medknow
Background: With increase in exposure to titanium in daily life and its use
in medical procedures, there is a greater chance for developing titanium
hypersensitivity. Our aim and objective is to examine whether patient patients
with titanium implants had a greater incidence of titanium hypersensitivity or not.
Titanium is widely considered to have good biocompatibility. A passivating surface
layer of TiO2
is formed when exposed to air which gives it good corrosion resistance.
These properties along with its high strength, lightweight, and improvements
in smelting technologies have led to its widespread use as an intraosseous and
periosteal implant in dentistry and orthopedics. Materials and Methods: Only
case–control studies were used for the meta‑analysis. Studies with a sample size
of <5 were excluded. Cutaneous and epicutaneous tests were used in the study.
Results: Three studies met the inclusion criteria. Titanium hypersensitivity is
more prevalent in patients with titanium implants. Conclusions: It is also used
in a variety of medical devices such as pacemakers and insulin pumps. Moreover,
our external exposure to titanium is increasing. It is used in aerospace, chemical,
and automobile industries. It is also used in jewelry, home furnishings, and in
making sports and marine equipment. Titanium implants increase the possibility of
developing titanium hypersensitivity, and thus, it should be considered as a major
factor in unexplained implant failure where other causes have been excluded.
Keywords: Dental implants, hypersensitivity, metallurgy, titanium
Prevalence of Titanium Hypersensitivity in Patients with Titanium
Implants: A Systematic Review and Meta‑analysis
Rajsandeep Singh1
, Gurvanit Lehl2
, Arshad Bin Hussain3
, Tejal Nivrutti Abhang4
, Manisha Mangesh Kulkarni5
,
Mohamed Fadul A. Elagib6
, Rahul V. C. Tiwari7
Access this article online
Quick Response Code:
Website: www.jpbsonline.org
DOI: 10.4103/jpbs.jpbs_159_21
Address for correspondence:
Dr. Rahul V. C. Tiwari,
Department of OMFS, Narsinbhai Patel Dental College and
Hospital, Sankalchand Patel University, Visnagar ‑ 384 315,
Gujarat, India.
E‑mail: drrahulvctiwari@gmail.com
the degranulation of mast cells and basophils. They
can thus cause Type I and Type IV hypersensitization
reactions.[1]
Titanium ions accumulate in the peri‑implant
Introduction
Titanium is mostly used as titanium dioxide. It is
used as a whitening agent in paints, sunscreens, and
as a filler in pharmaceutical and food industries. This
widespread can cause an increased number of patients
to be sensitized to titanium. Hypersensitivity is an
exaggerated immune response to a known antigen. Metal
ions act as haptens and combine with proteins to trigger
a cell‑mediated immune response. They can also cause
1
Department of Prosthodontics,
Government Medical College
and Hospital, Chandigarh,
India, 2
Department of
Pedodontics, Government
Medical College and
Hospital, Chandigarh, India,
3
Department of Public Health
Dentistry, Regional Dental
College, Guwahati, Assam,
4
Department of Prosthodontics,
Vasantdada Patil Dental
College and Hospital,
Sangli, India, 5
Department of
Prosthodontics, YCMM RDF’s
Dental College, Ahmednagar,
Maharashtra, India,
6
Department of Periodontics
and Community Dental
Sciences, College of Dentistry,
King Khalid University, Abha,
Saudi Arabia, 7
Department
of OMFS, Narsinbhai Patel
Dental College and Hospital,
Sankalchand Patel University,
Visnagar, Gujarat, India
Abstract
This is an open access article distributed under the terms of the Creative Commons
Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak,
and build upon the work non‑commercially, as long as the author is credited and the new
creations are licensed under the identical terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
How to cite this article: Singh R, Lehl G, Hussain AB, Abhang TN,
Kulkarni MM, Elagib MF, et al. Prevalence of titanium hypersensitivity in
patients with titanium implants: A systematic review and meta‑analysis.
J Pharm Bioall Sci 2021;13:S1345-9.
Original Article
Submitted: 11‑Mar‑2021.
Revised: 10-Apr-2021.
Accepted: 09‑May‑2021.
Published: 10-Nov-2021.
[Downloaded free from http://www.jpbsonline.org on Wednesday, November 10, 2021, IP: 49.204.225.73]

S1346 Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 2 ¦ August 2021
Singh, et al.: Titanium hypersensitivity in dental implants
area, regional lymph nodes, and the lungs.[2‑4]
Titanium
particles can be found in macrophage lysosomes[5,6]
and
can cause Type IV hypersensitivity reactions. Cases of
titanium allergy where the main signs and symptoms
are urticaria, edema, eczema, and pruritus which may
be localized or generalized[7‑9]
have been reported in
the literature. In some cases, more serious problems
such as eczema,[9] slow healing of fractures,[10]
pain, necrosis, and weakening of orthopedic implants
also happens.[11]
Clinical findings and the results from
epicutaneous tests[12‑14]
are used to diagnose metal
allergy. Susceptibility to metal allergy has been shown
to have a genetic link,[10]
and many patients can have
multiple allergies. A history of reaction to metals or
jewelry is a risk factor for developing hypersensitization
to metal implants.[15]
TTherefore, even if the incidence
of titanium allergy in the general population is low,
patients with a previous history of allergic reactions
to metals/jewelry or other significant allergies (e.g.,
penicillin allergy), a metal allergy assessment and
specific allergy tests before placing implants[16]
must
be done in regular practice.. Epicutaneous tests are the
standard procedure to assess Type IV hypersensitivity
reactions.[16‑22]
The relation between failure of titanium
implants and allergy to titanium is complex. Jacobs
et al., 1991,[23]
and Witt and Swann 1991[24]
found
that the levels of titanium in the blood of patients
having loose titanium hip implants were increased.
Subsequently, Frisken et al., 2002,[25]
demonstrated a
higher concentration of titanium ions in the regional
lymph nodes and lungs of animal subjects with failed
titanium implants. Elves et al., 1975,[26]
found that
orthopedic implants which failed without any plausible
explanation had a greater incidence of sensitization
to metals than the control group which consisted of
implants which failed due to known causes. Most of
these studies have been done on orthopedic implants.
To what extent can these be extrapolated to dental
implants is debatable. Dental implants have a limited
area of contact between bone and implant. Furthermore,
the oral mucosa has less number of antigen‑presenting
cells (Langerhans cells) than skin. In addition, dental
implants in the oral cavity are covered by a pellicle
of glycoproteins which decreases their immunologic
potential.[16]
The prevalence of titanium allergy, though
low, has been largely overlooked by profession. Due to
its excellent biocompatibility and mechanical properties,
the use of titanium, or a material of choice for numerous
medical devices, dental and orthopedic rehabilitation is
increasing.[27]
Therefore, it is important to evaluate the
prevalence of titanium hypersensitivity in these patients
and to look for alternatives in patients susceptible to
titanium allergy. Various materials have been suggested
as alternatives. These include zirconia, hydroxyapatite,
tantalum, and polyetheretherketone (PEEK).
Materials and Methods
The research question for this study was to assess
whether titanium implants increase the risk for
developing titanium hypersensitivity as compared to
the general population or not. The electronic search
was conducted using the PubMed library of United
States National Library of Medicine, Cochrane
Central Register of Controlled Trials (CENTRAL)
of the Cochrane Collaboration, Ovid, ResearchGate,
ScienceDirect, EBSCO, Web of Science, and Google
Scholar as online search engines. The keywords used
in the search were “Titanium” AND “IMPLANT”
AND “HYPERSENSITIVITY” or “ALLERGY.” The
references given by the selected articles were also
used to find relevant publications. The Contemporary
Clinical Dentistry (1997–2015), Journal of Maxillofacial
Surgery (1997–2015), and Journal of the American
Dental Association (2000–2020) were hand searched
for relevant articles. For conducting the meta‑analysis,
the Review Manager (RevMan) [Computer program].
Version 5.4, The Cochrane Collaboration, 2020. was
used.
Criteria for selection of studies
The abstracts of all the publications in our search were
screened independently by two reviewers. The articles
Figure 1: Boolean diagram showing the process of selection of the
included studies

S1347
Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 2 ¦ August 2021
were shortlisted on the basis of the following inclusion
and exclusion criteria. Only case–control studies were
selected. Studies with a heterogeneous sample consisting
of implant materials other than titanium in the same
groups were excluded. Studies with a sample size of <5
were excluded. Studies on both dental and orthopedic
implants were selected. Cutaneous and epicutaneous
tests for titanium hypersensitivity were used. The
relevant data from the selected studies (e.g., study
design, methods, and outcome measures) were extracted
in duplicate independently by two reviewers.
Statistical analysis
The data from the three studies were divided into two
groups. Group I was the test group with patients having
titanium implants and thus suspected of having titanium
allergy. Group II was the control group and included
patients without implants. In each group, the incidence of
titanium allergies was recorded. Since the cutaneous and
epicutaneous tests used in the three studies were slightly
different, the random‑effects model was used in the
study. The individual effect sizes and odds ratios of the
three studies were calculated. The Z‑score for the overall
effect was calculated. For testing the heterogeneity of
the studies, the tau‑squared and I‑squared tests were
conducted. The pooled odds ratios from the studies, with
95% confidence intervals, were obtained through the
meta‑analysis. Begg and Mazumdar test for publication
bias was done. The funnel plot for detecting any
publication bias was made with the standard error as the
y‑axis and the log of the odds ratio as the x‑axis.
Results
Study selection and organization of the data
Through online search engines, 188 titles and abstracts
of studies (both case–control and prospective), case
reports, and literature reviews on titanium allergy
were found [Figure 1]. Out of these, only three case–
control studies were found which exclusively studied
titanium allergy and could be thus clubbed together in a
meta‑analysis [Table 1].
Results of publication bias
Begg and Mazumdar’s rank correlation test showed
a slight publication bias. The funnel plot for the three
studies is shown in Figure 2.
Meta‑analysis
The weighted mean of the odds ratios with 95%
confidence intervals showed a strong tendency for
patients with titanium implants to have a greater
incidence of titanium allergy. However, due to the
limited number of studies and the slight publication
bias, more research needs to be done on titanium
allergy [Figure 3].
Discussion
The massive rise in the use of titanium in various
fields has led to an increase in the chance sensitization
to titanium through percutaneous and permucosal
routes in the general population.[27]
To detect titanium
hypersensitivity, the patch test has not yet been
standardized. A standardized patch test will go a long
way in giving a better idea about the prevalence of
titanium hypersensitivity in the general population.[28,29]
The exact nature of sensitization to titanium is unknown.
Even if titanium is a true sensitizer, it is albeit a weak
one. Thomas P et al.[6]
showed that the tissue retrieved
from a failed titanium hip implant had T‑cells and
macrophages in the absence of B‑cells which suggests
Ti allergy. However, Park et al.[30]
showed that titanium
was not a true dermal sensitizer after local lymph node
assay failed to show the signs of titanium allergy.
Hosoki et al.[31]
described a case of titanium allergy to
dental implants where the symptoms (dermatitis and
pruritus) were resolved on retrieval of the implants. The
prevalence of titanium allergy is probably quite low. It
could, however, be the cause of isolated cases of implant
failure which cannot be ascribed to any other causes.
Figure 2: The funnel plot for the three studies
Figure 3: Forest plot showing the relative effect sizes and the pooled
effect of the studies

S1348 Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 2 ¦ August 2021
Conclusions
It is, therefore, advisable to test for titanium allergy in
patients with a history of multiple and/or severe allergies.
These include allergy to artificial jewelry, nickel, cobalt,
and penicillin. Furthermore, patients with a previous
heavy exposure to titanium (extensive orthopedic, dental
rehabilitation with Ti) and those with unexplained
implant failure should be tested. Once titanium allergy
has been demonstrated in a patient, it is preferable to
use alternative treatment modalities or to use alternative
materials such as tantalum, PEEK, or zirconia.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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22. Suhonen R, Kanerva L. Allergic contact dermatitis caused by
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Table 1: Outcomes and main features of the selected studies
Included
studies
Type of titanium
implant
Group 1* Group 2#
Additional information
Events Total Events Total
de Graaf
et al., 2018[27]
Neurostimulator, insulin
pump, orthopedic,
dental, surgical
22 248 4 210 Patch testing was done with TiO2
, titanium
oxalate hydrate, titanium isopropoxide,
titanium lactate, and titanium citrate
Hosoki et al.,
2018[28]
Dental 4 16 13 254 Patch testing was done for multiple metals, but
the data for titanium were grouped separately
and hence were extracted for use in the study
Sicilia et al.,
2008[29]
Dental 9 35 0 35 Both cutaneous and epicutaneous tests were
done using TiO2
*Patients with titanium implants, #
Patients without titanium implants

S1349
Journal of Pharmacy and Bioallied Sciences ¦ Volume 13 ¦ Supplement 2 ¦ August 2021
Joint Surg Am 1991;73:1475‑86.
24. Witt JD, Swann M. Metal wear and tissue response in failed
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Rustemeyer T. A retrospective study on titanium sensitivity:
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Cross‑sectional observational study exploring clinical risk of
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Analysis for the potential of polystyrene and TiO2 nanoparticles
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In Vitro 2011;25:1863‑9.
31. Hosoki M, Nishigawa K, Miyamoto Y, Ohe G, Matsuka Y.
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