Materials 15 03150 v2
Materials 15 03150 v2
Materials 15 03150 v2
Review
Titanium Dental Implants: An Overview of Applied
Nanobiotechnology to Improve Biocompatibility and
Prevent Infections
Rayane C. S. Silva , Almerinda Agrelli , Audrey N. Andrade, Carina L. Mendes-Marques ,
Isabel R. S. Arruda , Luzia R. L. Santos , Niedja F. Vasconcelos and Giovanna Machado *
Centro de Tecnologias Estratégicas do Nordeste-Cetene, Av. Prof. Luiz Freire, 01, Cidade Universitária,
Recife CEP 50740-545, PE, Brazil; rayane.silva@cetene.gov.br (R.C.S.S.); almerinda.agrelli@cetene.gov.br (A.A.);
audrey.andrade@cetene.gov.br (A.N.A.); carina.marques@cetene.gov.br (C.L.M.-M.);
isabel.arruda@cetene.gov.br (I.R.S.A.); luzia.santos@cetene.gov.br (L.R.L.S.);
niedja.vasconcelos@cetene.gov.br (N.F.V.)
* Correspondence: giovanna.machado@cetene.gov.br; Tel.: +55-81-3334-7200
Abstract: This review addresses the different aspects of the use of titanium and its alloys in the
production of dental implants, the most common causes of implant failures and the development of
improved surfaces capable of stimulating osseointegration and guaranteeing the long-term success of
dental implants. Titanium is the main material for the development of dental implants; despite this,
different surface modifications are studied aiming to improve the osseointegration process. Nanoscale
Citation: Silva, R.C.S.; Agrelli, A.; modifications and the bioactivation of surfaces with biological molecules can promote faster healing
Andrade, A.N.; Mendes-Marques, C.L.; when compared to smooth surfaces. Recent studies have also pointed out that gradual changes in the
Arruda, I.R.S.; Santos, L.R.L.; implant, based on the microenvironment of insertion, are factors that may improve the integration
Vasconcelos, N.F.; Machado, G. of the implant with soft and bone tissues, preventing infections and osseointegration failures. In
Titanium Dental Implants: An
this context, the understanding that nanobiotechnological surface modifications in titanium dental
Overview of Applied
implants improve the osseointegration process arouses interest in the development of new strategies,
Nanobiotechnology to Improve
which is a highly relevant factor in the production of improved dental materials.
Biocompatibility and Prevent
Infections. Materials 2022, 15, 3150.
Keywords: osseointegration; biofilms; bone–implant interface; prostheses and implants; coating;
https://doi.org/10.3390/
ma15093150
surface modifications; nanotechnology
Academic Editors:
Anişoara Cîmpean
and Florin Miculescu
1. Introduction
Received: 29 March 2022 Oral health problems affect about 3.5 billion people worldwide, with an estimated
Accepted: 21 April 2022 267 million people suffering from tooth loss [1]. Tooth loss is often associated with trauma,
Published: 27 April 2022 periodontal disease and caries, which may affect the individual’s health not only in aes-
Publisher’s Note: MDPI stays neutral thetic and social issues, but also by impairing chewing, speech, and increasing the risk of
with regard to jurisdictional claims in developing diseases [2,3]. One of the worst oral health conditions is the complete loss of
published maps and institutional affil- dentition, known as edentulism, which although preventable, is still a common problem
iations. worldwide [4]. In this context, dental implants emerged as the main form of treatment for
total or partial tooth loss, replacing mobile dentures that were anchored in remaining teeth
or soft tissue, and which, as a consequence, caused their alteration over time [5].
The success of dental implants brought the possibility of restoring the dental functions
Copyright: © 2022 by the authors. and the health of the patient, being a market capable of moving around USD 4.6 billion
Licensee MDPI, Basel, Switzerland. globally [6]. Among the different materials found on the market, titanium implants are the
This article is an open access article most used due to their biocompatibility and low cost.
distributed under the terms and
Titanium is a bioinert material, inducing little or no deleterious effect on the surround-
conditions of the Creative Commons
ing tissue. However, despite the description of several inherent advantages of the material,
Attribution (CC BY) license (https://
without adequate surface treatment, it ends up having a low integration with the bone
creativecommons.org/licenses/by/
and gingival tissue, which may lead to dental implant failures. These failures occur due to
4.0/).
poor osseointegration, affecting the stability of the implant in the bone, which can lead to
the establishment of infections and inflammatory processes in the peri-implant space [7].
To reduce such problems, different surface treatments are investigated to promote better
osseointegration and prevent the formation of harmful bacterial biofilms. Nanotechnology
has generated positive impacts in dentistry, being able to produce surfaces with a spe-
cific topography and chemical composition to improve the biocompatible characteristics
of materials [8]. Commercial implants are already found with nanostructured surface
modifications, such as SLActive® (Straumann, Basel, Switzerland), which is reported to
induce a faster response to osseointegration, and HAnane Surface® (Promimic, Gothenburg,
Sweden), which brings the titanium coating with nanohydroxyapatite and can stimulate
the performance of osteoblasts and promote bone growth [9].
Surface bioactivation with biomolecules is also the subject of major investigations
to ensure the long-term success of implants. When implanted, biomolecules from the
blood or produced by the cells of the host tissue are initially adhered to the metal to
later initiate the cellular anchoring itself [10]. Therefore, the bioactivation of materials
with molecules that have biological properties can not only help cell adhesion, but also
regulate their activity on the implant surface, inducing cell proliferation, migration and
differentiation. In this context, this review discusses the different aspects involved in the
successful osseointegration of titanium implants and the main surface treatments applied
for the development of biomimetic surfaces used in these implants.
are titanium alloys (Ti-6Al-4V and Ti-6Al-4V—Extra Low Interstitial alloys). These grades
differ in resistance to corrosion, strength, and ductility [17].
An ideal material for the fabrication of dental implants should be biocompatible and
have adequate strength, toughness, and corrosion and fracture resistance. These properties
are usually related to the oxygen residuals in the metal. Grade IV CpTi presents the highest
oxygen content (0.4%) and consequently, excellent mechanical strength, which is why it is
the most widely used type of titanium for dental implants [11].
Titanium alloys emerged with the interest of reducing device manufacturing costs
and were considered a potential metallic material in the biomedical industry. The alloying
elements added to titanium are largely divided into alphas (α) stabilizers, such as alu-
minum, oxygen, nitrogen, and carbon, and betas (β) stabilizers, such as vanadium, iron,
nickel, and cobalt. Therefore, dental titanium alloys exist in three structural forms: α, β,
or a combination of the two (α-β) [18]. The α-β combination alloy (Ti-6Al-4V) is the most
used in dental applications [11]. It consists of 6% aluminum and 4% vanadium, and is
highly strong and resistant to corrosion. Aluminum is an α-phase stabilizer. It increases the
strength of the alloy and decreases its density. On the other hand, vanadium is a β-phase
stabilizer [19]. Beta stabilizing elements are expensive when compared to α stabilizers [20].
Thus, replacing the common β stabilizers for cheaper substitutes is the current industry
demand. On this matter, Fe is the most common element used to replace the β-stabilizing
element because of its low cost and strongness. However, it has been reported that high
temperatures promote the formation of intermetallic compounds, such as TiFe or Ti2 Fe,
which have a negative influence on the ductility and mechanical properties of alloys [21,22].
The surface of titanium implants is important because of their influence on inter-
action with the bone. The surface of the main materials used as dental implants (CpTi
and Ti-6Al-4V) is composed of the oxide TiO2 , which allows high resistance to corrosion
with a clinical success rate of up to 99% [23,24]. Although aluminum remains the most
important and commonly used α stabilizer, it was reported that it makes working and
machining titanium alloys difficult [25]. The use of Ti-6Al-4V has been reported to have
good biological acceptance [26,27]. However, small quantities of aluminum and vanadium
are eventually released, which may induce an inflammatory process. Aluminum inhibits
bone mineralization, leading to bone malformation and vanadium is cytotoxic and may
induce allergic reactions [28,29]. This is why dental implants are more often made from
CPTi. To prevent these biological problems, vanadium-free alloys, such as Ti-6Al-7Nb
and Ti-5Al-2.5Fe, have been developed [17]. Furthermore, alloys composed of non-toxic
elements, such as Nb, Ta, Zr, and Pd, are under development.
Recently, a new dentistry alloy based on the binary formulation of 83–87% titanium
and 13–17% zirconium (Roxolid® , Straumann, Basel, Switzerland) has been developed. It
has been related that it exhibits better tensile and fatigue strength characteristics compared
to CpTi and Ti-6Al-4V. In vivo studies in animal models have shown bone integration
of threaded zirconia implants comparable to that of titanium after insertion in different
animal models [30–32].
As titanium is unaesthetic in the frontal area, ceramic implants have been constructed
as dental implants [33]. Ceramics are known to present an inert behavior and good physical
properties [16]. Firstly, it was used as a coating material for metal implants aiming to
improve osseointegration. Over recent years, various forms of ceramic coatings have been
used on dental implants. Bioactive ceramics, such as calcium phosphates and bioglasses,
and inert ceramics, such as aluminum oxide and zirconium oxide are widely used in many
medical, orthopedic, and dental applications [34].
Polymers have also been used as dental implant materials. Polymethylmethacry-
late, polytetrafluoroethylene, polyethylene, polysulfone, and polyurethane are the most
reported to be utilized in this matter [35]. Acting as a coating layer, polymeric materials
are more easily manipulated and do not generate an electrolytic current as metals do.
Although they are aesthetically pleasing, a lack of adhesion and immunologic reactions
have been reported [16,36–38].
are more easily manipulated and do not generate an electrolytic current as metals do.
Although they are aesthetically pleasing, a lack of adhesion and immunologic reactions
have been reported [16,36–38].
Figure 1. Representation of oral osseointegration events over time in a dental implant. The figure
shows the sequence of cellular-level responses that occur after implant insertion for 24 h to
approximately 8 weeks. Non-infectious and infectious complications are reported as factors
that hinder osseointegration. Factors that improve this process are bioactivation and surface
modification techniques.
the variables that make oral rehabilitation treatment susceptible to failure can be divided
by the patients and implant profiles [45,48–50].
from the patient’s immune response that leads to an inflammatory process in the mucosa
and bone near the implant, both in association with the organized microorganisms in
biofilm [65]. A frequency of around 30% of peri-implant diseases is estimated, with this
rate being higher in smokers [66].
The oral microbiome is the second largest in the human body, with approximately
700 species of microorganisms such as bacteria, fungi, viruses, and protozoa that interact
with each other synergistically, antagonistically, or even as signaling. These oral microor-
ganisms adhere to each other and also to the biotic or abiotic matrix, grouping a finely
organized community called biofilm [67].
Microorganisms in their different habitats can present in their free form, called plank-
tonic microorganisms, or grouped in communities, the latter being their preferred form.
The community of microorganisms attached to a surface is called biofilm. Microorganisms
in a biofilm are protected by an exopolysaccharide (EPS) matrix formed by proteins, lipids,
and extracellular DNA released from lysed cells. Up to 90% of the biofilm mass is made up
of EPS [68].
Bacteria in biofilms can exchange genetic material via horizontal gene transfer, in-
cluding mechanisms of conjugation, transformation, transduction, and membrane vesicles,
acquiring new genes, including antibiotic resistance genes, which makes the treatment of
infections more difficult [68]. In addition, due to the physical protection provided by EPS,
microorganisms in a biofilm are more resistant to the action of antimicrobials and the host’s
immune response, making them more difficult to eliminate and, therefore, facilitating the
emergence of infectious processes [69].
Failure in dental implants is associated with periodontitis where there is a change in
the microbial flora from a predominately Gram-positive non-motile, aerobic, and facultative
anaerobic composition to a Gram-negative motile, anaerobic microbe. Staphylococcus aureus
and coagulase-negative staphylococci are associated with peri-implant infections. As
these microorganisms can adhere to titanium surfaces, they may be significant in the
colonization of dental implants and subsequent infections [70]. It is concerning that biofilms
are responsible for about 65% of diseases including peri-implantitis and periodontitis.
Hence, the microbial attacks may cause dental implant failure [71].
Biofilms formed on the tooth surface are called dental plaque. Biofilm formation on
teeth begins with bacterial adhesion to a film attached to the enamel. This film is constituted
by salivary proteins which bacteria adhere to through surface molecules present on bacteria,
especially lectins, that act as adhesins [71]. Once adhered, the biofilm formation process
begins (as shown in Figure 2).
EPS allows microorganisms to remain attached to surfaces, protect them, and in
addition, play a structural role that holds the microbiota together and gives the biofilm
the characteristic mushroom shape [72]. EPS matrix components vary according to the
microorganisms that are present in the biofilm and their formation is a key point for biofilm
growth. In addition to this structural function, the EPS matrix protects the microorganisms
from the biofilm. Biofilm formation is, therefore, a response of microorganisms to some
inhospitable conditions [73], such as a lack of nutrients, changes in the environment’s
pH, the presence of antimicrobial agents, and the action of the host’s immune system,
among others [74].
The biofilm life stages are: 1. adhesion; 2. production of the EPS matrix; 3. microcolony
formation; and 4. detachment and dispersal. Briefly, microorganisms in their planktonic
form adhere to the biotic or abiotic surface through appendages such as flagellum, fimbriae,
and pili, among others [75]. Initially, this adhesion is reversible, however, as other microor-
ganisms attach, adhesion becomes irreversible. Microorganisms begin to produce the EPS
matrix, and then maturation and three-dimensional growth of the biofilm occurs due to the
multiplication of microorganisms within the matrix [69], reaching, usually, a mushroom
shape [76]. The last stage is characterized by the detachment and dispersion of microorgan-
isms from the biofilm, allowing these microbes to reach other sites far from the primary site
of infection, where they will attach and initiate a new cycle of biofilm formation [77].
Materials 2022, 15,
Materials 2022, 15, 3150
x FOR PEER REVIEW 77 of
of 17
18
Figure 2. Schematic representation of oral biofilm formation on dental implants. The figure shows
Figure 2. Schematic representation of oral biofilm formation on dental implants. The figure shows
the different stages of bacterial biofilm formation ranging from adhesion to the establishment of
the different stages of bacterial biofilm formation ranging from adhesion to the establishment of the
the mature colony.
mature colony.
EPS mechanism
The allows microorganisms to remain attached
by which microorganisms change to from
surfaces, protect
sessile them, and
to scattering in
cells
addition, play a structural role that holds the microbiota together
involves a complex network of molecular changes based on the expression of genes that and gives the biofilm
the characteristic
completely alter themushroom
phenotypeshapeof these[72]. EPS matrix components
microorganisms: vary EPS
genes expressing according to the
and fimbriae
microorganisms that are present in the biofilm and their formation
are downregulated, while genes expressing the microbe’s phenotypic characteristics that is a key point for bio-
film growth. In addition to this structural function, the EPS matrix protects
are essential for its planktonic life, such as flagellum and chemotaxis, are upregulated [78]. the microor-
ganisms
The from the biofilm.
dispersion process Biofilm formation
is related is, conditions
to stress therefore, awithinresponse
the of microorganisms
microcolony, such
to some inhospitable conditions [73], such as a lack of
as nutrient limitation, toxic waste accumulation, and O2 depletion, among nutrients, changes in others.
the environ-
Such
ment’s pH,favor
conditions the presence of antimicrobial
some microorganisms’ agents,
death, formingand theemptyaction of the
spaces host’s
in the immune
microcolony
system, among others [74].
center. Surviving microbes induce EPS dissolution and, through gene regulation processes,
Thethe
repress biofilm life stages
expression are:whose
of genes 1. adhesion;
products2. production
favor their of the EPS matrix;
anchorage 3. microcol-
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ony
as formation;
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At the 4. detachment and dispersal.
time, they begin to expressBriefly,
factors microorganisms in their plank-
that allow their locomotion and
tonic form
escape fromadhere to the biotic
the microcolony, asor abiotic
shown bysurface
flagellum, through appendages
for example [78]. such as flagellum,
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The organization others [75]. Initially,
and coordination this adhesion
of microorganisms is biofilm
in the reversible, however, by
are regulated as
other microorganisms attach, adhesion becomes irreversible.
quorum sensing which is defined as an intra- and inter-species bacterial communication Microorganisms begin to
producebased
system the EPSon matrix, and thenand
the production maturation
secretionand of three-dimensional
chemical signalinggrowth molecules of the bio-
called
film occurs due
autoinducers to the
which multiplication
are responsible for of microorganisms
the expression ofwithin certainthe matrix
genes. [69],molecules
These reaching,
usually,
are a mushroom
only perceived shape [76].
by bacteria when The lastisstage
there a high is microbial
characterized by the
density anddetachment
this mechanism and
dispersion
plays of microorganisms
an important from the
role in microbial biofilm, allowing
physiological thesesuch
processes, microbes
as the to reach other
expression of
sites far from theand
bioluminescence primary site of
virulence infection,
factors where they
and resistance to will attach and[79].
antimicrobials initiate a new cy-
cle ofInbiofilm
recent formation
years, several[77].studies have been developed to improve osseointegration and
reduceThemicrobial
mechanism infections
by which by modifying the surface
microorganisms change of the
from dental implants,
sessile adding
to scattering to
cells
them antibiotics
involves a complex andnetwork
nanoparticles that bring
of molecular antimicrobial
changes based on andtheantibiofilm
expressioncharacteristics
of genes that
to the implants
completely alter[80].
the This subjectof
phenotype will be better
these addressed in
microorganisms: the next
genes topics. EPS and fim-
expressing
briae are downregulated, while genes expressing the microbe’s phenotypic characteris-
tics that are essential for its planktonic life, such as flagellum and chemotaxis, are up-
regulated [78].
The dispersion process is related to stress conditions within the microcolony, such
as nutrient limitation, toxic waste accumulation, and O2 depletion, among others. Such
Materials 2022, 15, 3150 8 of 17
In recent studies, Park et al., (2021) [85] obtained nanoflowers of the TiO2 on the
titanium surface by the hydrothermal method and explored the structure, composition, and
morphology of the synthesized material. The material was deposited on titanium for 15 min
on microwave radiation exposition, with a rutile phase formation and a super hydrophilic
surface. The increase in surface area and high hydrophilicity improved the adhesion of
the protein albumin on the implant surface. In another study, Wei and coworkers (2020)
produced nanofibers of the poly (lactic-co-glycolic acid) (PLGA) loaded with the anti-
inflammatory aspirin coatings on titanium by electrospinning. The aspirin was released
from nanofibers for up to 60 days, avoiding peri-implant aseptic inflammation and the
coatings promoting the osseointegration ability of the titanium implants, demonstrated
with in vivo tests [86]. To achieve such morphological changes, some techniques were
employed, which are addressed in the next topics.
coating [93]. Chua et al., (2018) [101] functionalized the titanium surface with alternating
layers of hyaluronic acid and chitosan, intercalated forming multilayers with polyelec-
trolytes (PEMs) and immobilizing the RGD peptide (arginine-glycine-aspartic acid) to
increase the interaction with osteoblasts and mesenchymal cells, potentiating interactions
according to the proposed changes.
6. Conclusions
Here, we presented an overview of different surface treatments that are investigated
for the development of high-performance titanium dental implants. We found that factors
such as morphology and chemical composition are promising for the creation of biomimetic
surfaces, resulting in implants that promote faster and more efficient osseointegration
when compared to smooth surfaces. Nanostructured surfaces can generate a topography
of porosity similar to bone and thus assist the bone healing process. The coating with
biomolecules can stimulate cell adhesion, as well as differentiation, proliferation, and
migration, favoring osseointegration. Finally, recent studies indicate that hybrid implants,
with different types of modifications based on the microenvironment of insertion, are future
challenges that may arise as new materials for the production of dental implants.
Author Contributions: Conceptualization: R.C.S.S., A.A., A.N.A., C.L.M.-M., I.R.S.A., L.R.L.S. and
N.F.V.; Writing—original draft preparation: R.C.S.S., A.A., A.N.A., C.L.M.-M., I.R.S.A., L.R.L.S. and
N.F.V.; Writing—review and editing: R.C.S.S., A.A., A.N.A., C.L.M.-M., I.R.S.A., L.R.L.S., N.F.V.
and G.M.; Supervision: G.M.; Funding acquisition: G.M. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by Fundação de Amparo a Ciência e Tecnologia do Estado de
Pernambuco (FACEPE) (grant number APQ-0516-9.25/19), Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) (grant number 442477/2019-8) and the APC was funded by CNPq
(grant number 309910/2021-8).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: This review work was supported by the CETENE/MCTI, CNPq, FACEPE, and
SisNANO/MCTI.
Conflicts of Interest: The authors declare no conflict of interest.
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