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materials

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/).

Materials 2022, 15, 3150. https://doi.org/10.3390/ma15093150 https://www.mdpi.com/journal/materials


Materials 2022, 15, 3150 2 of 17

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.

2. Titanium and Its Alloys


Titanium is the ninth most abundant metal and it was discovered by William Gregory
in 1791. It presents itself in its pure form as a silver metal with unique physical-chemical
characteristics, such as low density (4506 g/cm3 ) and high strength (590 MPa) [11]. Ti-
tanium can quickly react with oxygen and this provides resistance to corrosion on the
metal’s surface because of the formation of an oxide layer on the metal’s surface. Studies
with this metal are developed for the most diverse themes, such as applications in sports,
pigments, jewelry, marine equipment, aerospace, and medical industries [12]. Concerning
the dental industry, titanium and its alloys are known to be non-toxic and even more bio-
compatible than chromium-cobalt and stainless steel [13]. In addition, they are compatible
with computed tomography (CT) and magnetic resonance imaging (MRI). These titanium
biomaterials are the basis for the manufacture of prostheses and dental implants.
Due to the different properties observed in titanium forms, it has been verified that
titanium oxide (TiO2 ) is the most reported in studies related to dental implants. TiO2 is
formed by the high capacity of titanium metal to react with air forming hydroxyl and
hydroxide groups, which gives it a high capacity for resisting corrosion. This oxide layer
confers titanium, and its biocompatibility. TiO2 can be found in three different crystalline
forms in ambient conditions: anatase, brookite, and rutile. The phase transitions are
possible by performing heat treatment at the end of the synthesis. While brookite (that is
arranged in orthorhombic geometry) is the most difficult to obtain, rutile and anatase (both
presenting octahedral geometry) are easily formed [14]. The difference found between the
rutile and anatase phases is due to distortions between the octahedral formed by TiO6 . To
obtain these structures, several methods can be used, from hydrothermal to electrochemical.
Therefore, changes in the physicochemical parameters within the synthesis will lead to
the preferential formation of one of the intended phases [15]. Thus, the phase directly
affects the success of its use for applications in dentistry. Anatase is often associated with
applications requiring osseointegration and, therefore, is the most used in dental implants.
Although other materials are found in the manufacture of dental implants according
to their chemical composition, such as ceramics or polymers, at present, titanium is the
material most commonly used [16]. Currently, six different types of titanium are available
as implant biomaterials. Of these, four are grades of commercially pure titanium (CPTi)
(Grade I, Grade II, Grade III, and Grade IV), which is 98–99.6% pure titanium, and two
Materials 2022, 15, 3150 3 of 17

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].

3. Osseointegration Process and Complications Associated with Dental Implants


Materials 2022, 15, 3150 4 of 17
Since the discovery of the phenomenon of osseointegration by P.I Branemark in
1952 based on some observations of experiments on rabbit fibia, titanium prostheses
have been the object of study by several research groups in the world [39]. The osseoin-
3. Osseointegration
tegration phenomenon Process
can be andbroadly
Complications
defined Associated
as a functional with contact
Dental Implants
with sufficient
stability between the prosthesis and the bone [40]. Especially
Since the discovery of the phenomenon of osseointegration by P.I Branemark for dental implants, the
in 1952
American Academy of Dental Implants, defined osseointegration
based on some observations of experiments on rabbit fibia, titanium prostheses have in 1986 as “Contact es-
tablished
been thewithout
object ofthe interposition
study by several of non-bone
research tissue
groups between normal[39].
in the world remodeled bone and an im-
The osseointegration
plant entailingcan
phenomenon a sustained
be broadly transfer
definedandasdistribution
a functional of contact
load from thesufficient
with implant to within between
stability the bone
tissue” [41].
the prosthesis and the bone [40]. Especially for dental implants, the American Academy
In thisImplants,
of Dental way, a sequence of biological events
defined osseointegration is involved
in 1986 as “Contactin osseointegration.
established without After
the
the insertionofofnon-bone
interposition the endosseous implant,
tissue between normalimmune
remodeledandbone
inflammatory
and an implant responses
entailingoccur, fol-
a sustained
transferby
lowed and distribution of
angiogenesis andload from the implant
osteogenesis. to within
In this process,the physicochemical
bone tissue” [41]. characteristics
of theIn implant,
this way, such
a sequence of biological
as topography andevents is involved will
hydrophilicity, in osseointegration.
allow the anchorage After the of
insertion
blood of the endosseous
proteins, implant, sites
forming interaction immune and inflammatory
for cells responsescalled
through cell receptors occur,integrins.
followed
by angiogenesis
Then, cells, such as and osteogenesis.
neutrophils, In this
occupy theprocess,
implantphysicochemical
surface, and after characteristics
2 to 4 days, mono- of the
implant,
cytes andsuch as topography
macrophages arriveand hydrophilicity,
[42]. Such steps are will allow the
essential foranchorage
homeostasis of blood
thanks proteins,
to the
formingofinteraction
release cytokinessitesandfor cells through
growth factors cell
whichreceptors called integrins.
will induce collagen Then,
matrixcells, such as
deposition
neutrophils, occupy the implant surface, and after 2 to 4 days, monocytes
and initial bone tissue formation [43] (Figure 1). In addition, for osseointegration to be and macrophages
arrive [42].
effective, theSuch steps
implant are have
must essentialotherforspecific
homeostasis thanks to
characteristics the as
such release
adequateof cytokines
geome-
and maximum
try, growth factors which
contact will induce
between collagenand
the implant matrix
the deposition and initial
tooth, roughness, bonein
usually tissue
the
formation
range of 1.5[43]
µ m,(Figure 1). In health
the physical addition, for host,
of the osseointegration
and, more recently,to be effective,
changesthe implant
in the sur-
mustofhave
face other specific
the implants characteristics
[44]. These modifications suchcan as adequate
range from geometry,
structuralmaximum
modifications contact
on
between the implant and the tooth, roughness, usually in the range
the implant surface to bioactivation with molecules capable of accelerating the osseoin- of 1.5 µm, the physical
health of the
tegration host, and
process and, preventing
more recently, changes in the
complications surface
related to ofthethe implants [44].
development of These
peri-
modifications can range from
implant mucositis and peri-implantitis. structural modifications on the implant surface to bioactiva-
tion with molecules capable of accelerating the osseointegration process and preventing
complications related to the development of peri-implant mucositis and peri-implantitis.

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.

3.1. Non-Infectious Complications


Even with technological advances in rehabilitation with oral implants, there are still
failures that represent an increase in therapeutic time, causing additional costs and dis-
comfort for the patient [45,46]. Several factors may lead to treatment failures, such as the
occurrence of an inflammatory process in the peri-implant tissues and mechanical failures
(fractures and loosening by non-infectious pathways) [47,48]. The main factors related to
Materials 2022, 15, 3150 5 of 17

the variables that make oral rehabilitation treatment susceptible to failure can be divided
by the patients and implant profiles [45,48–50].

3.1.1. Patient’s Profile


It is important to clarify that not every patient can receive a prosthesis over implants for
oral rehabilitation. Cases of pre-existing diseases, where patients had osteoporosis, diabetes,
and hypertension, had a higher rate of treatment failure, and errors in the delay in healing
that lead to a loose implant condition require a longer period of adaptation [45,51]. The
continuous use of some drugs, such as those used by patients with autoimmune diseases,
rheumatoid arthritis, and cancer treatment, can lead to failure in the dental implant, causing
the body to recover at a slower pace [52].
Cases in the literature where carriers of genetic syndromes such as Down commonly
present macroglossia and crossbite (reverse joint), unstable mechanical factors, and unfavor-
able occlusion, affect the osseointegration process and the success of implant therapy [52,53].
Smokers and those with a history of periodontal disease have significantly increased failure
statistics in implant treatment [50,54].
Behavioral factors such as parafunctional habits associated with the anatomy itself,
such as bone quality and quantity of the maxillary bones, are considered risk factors for
failure as they generate occlusal overload and complications such as fractures in the implant.
The correct positioning of the implant in these cases is essential to minimize stress and
pressure on the site [47,55]. This is the case, for example, of people who suffer from bruxism,
causing a strong pressure on the implant, which may yield and fracture [52].
Moreover, some systemic conditions influence implant osseointegration, such as cancer
treatment, inflammatory bowel disease and osteoporosis. Chemotherapeutic agents used
to treat cancer can induce vascular changes that culminate in bone poor nutrition as well
as reduce the formation of the collagen matrix of bone tissue, both resulting in a weaker
bone and leading to a possible reduction in the survival rates of dental implants [56,57].
High levels of pro-inflammatory cytokines are present in immune-mediated inflammatory
bowel diseases, such as arthritis and ulcerative colitis, through the combination of the
Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway, a crucial
role in the regulation of inflammation. The TLR4/NF-κB receptor is a regulator of the
processes of autophagy, oxidative stress and osteoclastogenesis [58–60]. In the case of
osteoporosis, there is a loss of bone density due to both the aging process and the decrease
in estrogen levels, leading to an increase in bone porosity and, consequently, increasing the
risk of fractures [61].

3.1.2. Implant Profile


The conical–cylindrical and conical–hexagonal shape designs are the most common
among today’s implants and can vary in structural characteristics, such as 4–10 mm in
length by 1 to 2 mm in diameter. Mini hexagonal implants with a length of 4–6 mm are the
ones with the highest success rate and the shortest osseointegration time [45,62,63]. Some
metallic oral implants can induce a hypersensitivity reaction, descriptions of paresthesias
or dysesthesias in patients allergic to implant compounds, such as nickel and/or titanium,
compound allergy symptoms including swelling, loss of taste, and a tingling sensation [62].
The influence of the anatomical location on the success of implants was evaluated by
authors in implants placed in the maxilla and mandible. One evaluation criterion is the
bone loss around the implant; in the maxilla the marginal bone loss was significantly higher
than in the mandible in most of the patients [45,54,64] so the implant insertion site must be
evaluated and taken into consideration in the treatment planning.

3.2. Infectious Complications


Microbial infections can make the osseointegration process difficult, leading, in ex-
treme cases, to the loss of the implant [7]. The main infectious complications that lead
to implant loss are known as peri-implantitis and peri-implant mucositis, which result
Materials 2022, 15, 3150 6 of 17

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-
in the biofilm, such
ony
as formation;
fimbriae. andsame
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,
fimbriae, and pili, among
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

4. Nanotechnology for Promoting Osseointegration


4.1. Nanostructures on Titanium Surfaces
Surface modifications bearing nanostructures on titanium surfaces may provide prop-
erties to solve the main problems with dental implants’ fixation. Titanium and its alloys
are bio-inert and have poor chemical bonding with bone at the early stage of the implan-
tation [81]. For the optimal behavior of the implant, it expects a positive interaction with
the extracellular matrix, which is on the nanoscale dimension and interacts with phys-
iology cells also at the nanometric level. Artificial nanostructures on titanium surfaces
are relevant for the cell–material interaction and enhance cell adhesion, proliferation, and
differentiation, as well as the total bioactivity of the implant [82].
Titania nanotubes are the most explored nanostructure from titanium and its alloys
due to the possibility of mimicking the bone structure and presenting a positive cellular
response [83]. This approach is defined as a biomimetic surface, due to the reproduction of
the original bone nanostructure with the formation of the artificial nanotubes on the implant
surface [84]. Other structures, such as nanoparticles and nanopores, are still explored on
implant surfaces. Table 1 summarizes the major nanostructures grown on titanium surfaces
through different methods.

Table 1. Nanostructured modifications on titanium and its alloys.

Nanostructure Material Method Application Ref.


TiO2 Anodization Experimental optimization [79]
Nanotubes
Hydrothermal
TiO2 /nano Brushite Implant material/Bone regeneration [80]
treatment/Anodization
Acid etching/
Silicate nanoparticle TiO2 Orthopedic and dental implants [81]
Electrospray deposition
Nanotubes/ 3D printing/
Porous Calcium phosphate-Sr-Si/TiO2 Orthopedic and dental implants [82]
Anodization
Nanoparticles Silver nanoparticles Electrodeposition Antibacterial property/Implant material [83]
Acid etching/ Biocompatibility and antibacterial activity/
Nanowires Zn-Ti [84]
Chemical treatment Implant material
Nanowire/coating Na2 Ti3 O7 /SrTiO3 Chemical treatment Implant material [85]
Nanofibers Keratin/Ti Mechanical treatment Peri-implantitis/ Dental implants [86]

Nanopores TiO2 Chemical and Biological integration/Dental implants [87]


electrochemical treatment
Nanotubes TiO2 /Hydroxyapatite/Chitosan Electrochemical treatment Dental implants [88]

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.

4.2. Surface Modification Techniques (Methods)


The surface modifications on dental implants are made through some techniques, in
which mechanical, chemical, electrochemical and layer addition methods stand out [6]. The
surface modifications change the physicochemical properties, from morphology, wettability,
and roughness, as well as confer new properties, such as antibacterial action and interaction
with the cell environment [87].
Materials 2022, 15, 3150 9 of 17

4.2.1. Mechanical Method


Mechanical treatments mainly modify the morphology of the implant surface and thus
alter the roughness. Rougher surfaces provide greater adaptability of the implant to the
environment. The most common mechanical methods are blasting and polishing, which use
external forces to modify the metallic surface [88]. Granato et al., (2019) evaluated the effect
of the chemical, blasting, and polishing treatment on the surface of the commercially pure
Ti (grade II) and Ti-6Al-4V alloy (grade V), two titanium alloys used on dental implants,
compared to the machined surface without treatment. The treatments presented similar
results in the topography of both alloys, with improvement in the osseointegration during
the first period of evaluation time [89].

4.2.2. Chemical Methods


Among the chemical methods, which also change the morphology, there is the surface
treatment with acid, which removes impurities and lamination marks from the metallic
surface. Chemicals attack the substrate, increasing the roughness and contact area [90]. The
conventional method uses a mixture of hydrochloric acid (HCl) and sulfuric acid (H2 SO4 )
solutions, with a temperature around 50–70 ◦ C in successive immersions and subsequent
surface cleaning [91].

4.2.3. Electrochemical Methods


Electrochemical modifications are based on oxidation and reduction reactions and
work with electron transfers between electrodes. Usually, this procedure is performed in
an electrochemical cell, with three electrodes composed of two inert materials (counter
and reference electrodes) and the surface that will be modified (working electrode) [92]. In
oxidation, a loss of matter that is deposited on an electrode that is being reduced occurs in
one mass transfer. This kind of treatment includes anodization and electrodeposition [93,94].
Both are similar processes and consist of applying a potential or current difference to oxidize
the material that will be deposited on the surface, not inducing corrosion or dissolution. To
prevent the formation of biofilms, silver nanoparticles (AgNPs) can be immobilized on the
implant’s surface by electrodeposition [95], which have shown active antibacterial activity
and have a wide application in the medical field. AgNPs adhere to the bacterial wall,
penetrate the bacteria and interact with cellular structures, such as peptides, biomolecules,
and DNA, leading to bacterial dysfunction and death [86].
A specific electrochemical method with recent application in the biomedical field is
plasma electrolytic oxidation (PEO), an anodic anodization at high voltage. Among the
distinct features of the PEO method are the control of the thickness of the coating deposited
on the titanium substrate, porosity, roughness, and the composition of the molecules
inserted on the coating, i.e., ensuring the control of the properties desired with the surface
modifications [96]. The PEO method has demonstrated that it is effective for the insertion
of inorganic compounds in the porous layer of TiO2 , elements such as Molybdenum [97]
and e Niobium [98], that improve corrosion protection on the titanium surface. The method
also improves the hydroxyapatite formation, which is usually aimed with PEO treatment,
with mainly an electrolyte composition of a Ca and P precursor, in addition to the other
molecules of interest. Santos-Coquillat et al., (2018) [99] utilized the PEO treatment to
obtain a biocompatible surface to improve osseointegration, evaluating by in vitro and
in vivo essays. The coating was composed for Ca/P in the ratio of the 2.0 and 4.0, and
both presented good cell adhesion and proliferation of murine osteoblasts, with better
bone-matrix mineralization for the ratio of ~1.8 of Ca/P.

4.2.4. Layer-by-Layer Technique (LbL)


The modification of the implant surface by adding layers involves the intermolecular
interaction between materials with opposite charges, making an electrostatic interaction
occur or even making the layers interact by hydrogen bonding [100]. Monolayers can
be added, but are not limited to these methods by Spray-drying, Dig-coating, or Spin-
Materials 2022, 15, 3150 10 of 17

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.

5. Biomimetic and Bioactive Surfaces


Titanium-based implant devices are commonly used clinically and have been exten-
sively examined through in vivo studies over the past 35 years to scientifically understand
the workings of the implant–tissue interface. Thus, for the long-term success of these
implants, osseointegration with the surrounding environment is one of the most desired
factors when devices are implanted [102–107]. In this way, biomimetic surfaces have been
developed aiming to achieve structural and biochemical characteristics that accelerate the
integration process between the implant and the surrounding tissues, thus reducing the
risk of inflammatory reactions and bacterial infections.
The coating with biocompatible molecules can stimulate cell adhesion, bone miner-
alization, and the formation of the extracellular matrix (ECM), accelerating the osseoin-
tegration process [104]. Molecules such as proteins, peptides, and mineral components
(such as hydroxyapatite, growth factors, and antibiotics), are among the different molecules
used to perform the functionalization of implants, with very satisfactory results having
been achieved despite the challenges related to the immobilization and stability of these
structures [108,109].
Collagen is the main component of ECM, and type I collagen is the most found in bone,
constituting about 85% of the organic components, along with other ECM proteins such
as laminas, fibronectin and vitronectin. These molecules form an adhesive layer through
their sites of interaction with osteoblastic cell membrane integrins, which favors initial
anchorage, as well as cell proliferation and differentiation [110,111]. In this context, the
attempt to mimic an ECM-like microenvironment on the surface of implants has been a
widely investigated strategy to recreate specific cellular anchorage sites. Chang (2016) [112]
demonstrated in his study that coating the titanium surface with fibronectin increased
the bone volume and stability of the dental implant, thus decreasing the treatment time.
Likewise, studies have shown that type I collagen is efficient in promoting osseointegration
by stimulating bone formation at cellular and molecular levels, positively regulating genes
for osteocalcin (OC) and bone sialoprotein (BSP), which are related to differentiation os-
teoblasts and the matrix mineralization phase [113]. In addition, type I collagen induces
fibroblast cell proliferation and positively regulates the gene expression of matrix metallo-
proteinases that are involved in ECM remodeling, which allows for better biological sealing
of peri-implant tissues [114].
In general, the RGD motif, formed by a tripeptide sequence of arginine-glycine-
aspartate (Arg-Gly-Asp), is responsible for the connection between ECM proteins and
osteoblasts, and thanks to this function, the peptide sequence RGD has been investigated
for its role in the functionalization of implant surfaces [111]. As they are found in cyclic
and linear conformations, c-RGD and l-RGD, respectively, Heller (2017) [115] evaluated
whether these structural differences between peptides would be able to generate different
biological responses in the osseointegration process. According to their study, both forms
are effective in stimulating the adhesion, proliferation, and differentiation of osteoblasts
in experiments in vitro, but in the in vivo analysis, it was possible to observe a significant
increase in vertical bone apposition with implants coated with the c-peptide RGD, showing
that not only the specific sequence of peptides, but also their cyclic structure are important
for the response to osseointegration. The literature includes a vast approach to the use
of proteins and peptides for the functionalization of implants, with different combina-
tions of molecules being evaluated. Vines (2012) [116] pointed out the importance of the
biphasic constitution of ECM by organic and inorganic components, demonstrating that
the formation of composites containing amphiphilic peptides and hydroxyapatite (HA)
Materials 2022, 15, 3150 11 of 17

in a proportion of 66% was responsible for highlighting the osteogenic differentiation of


mesenchymal cells. HA is the main mineral component that constitutes teeth and bones,
presenting itself as an excellent candidate for use in the improvement of biomaterials. In
addition to presenting good biocompatibility, bioactivity, and osteoconductivity, HA has a
direct connection with natural bone, a characteristic defined as biointegration, which ends
up inducing faster healing around the implant, although there are challenges related to the
degradation of this structure with time [117]. Several studies investigate the deposition
of HA on the surface of implants, evaluating not only the efficiency of surface coating
methods, but also its incorporation with organic molecules, such as collagen, peptides,
morphogenetic proteins, antimicrobial agents, and others [118–122].
Another group of biomolecules explored for their therapeutic use in tissue regeneration
are growth factors (GF). GFs are proteins secreted by cells that have, among their properties,
the ability to stimulate cell proliferation, migration, and differentiation, promoting bone
repair after injury. Among the GFs with osteogenic action, we can mention the transforming
growth factor-β (TGF-β), the bone morphogenetic proteins (BMPs), which belong to the
TGF-β superfamily, the insulin-like growth factors (IGFs), and the factor of platelet-derived
growth (PDGF) [123]. Among the more than 20 BMPs described, the literature reports
that BMP-2, 6, and 9 have the best osteogenic potential, being shown that among these,
BMP-9 has a greater capacity to promote cell differentiation and bone mineralization [124].
BMPs act in the differentiation of mesenchymal stem cells (MSCs) into osteoprogenitor
cells, however, the emphasis given to BMP-9 is due to its osteogenic capacity not being
negatively regulated by antagonists such as Noggin, which gives it a greater biological
performance [125]. The study of the use of different types of BMPs in the functionalization
of implants ranges from the use of isolated proteins to their combined use with organic and
inorganic components, and although very promising results have been achieved, studies
continue to advance to ensure a better controlled release and avoid the rapid leaching of
these molecules from the implant’s surface, thus ensuring its long-term performance [126].

Surface Graded Functionalized


In 1984, a group of Japanese researchers invented a new generation of composite
materials, called functionally graded materials (FGMs) [127,128]. These materials consist
of presenting specific characteristics that vary along its dimension, obtaining continuous
gradual properties destined to act distinctly in the exposed regions. In this way, it is possible
to obtain a hybrid material with several functions to be performed. This heterogeneous
profile makes them more advantageous than homogeneous materials as they look like
human structures, such as bones, teeth, and skin, ensuring better clinical performance. In
this context, numerous research has been gaining prominence in various applications of
FGMs, especially in dentistry [105,129].
Dental implants simultaneously form several interfaces with the biological system,
considering the different tissues that the device travels through during and after the
completion of the procedure. From the bottom up along the implant body, three interfaces
are reported: (1) subgingival hard tissue, which is bone tissue, (2) transgingival soft tissue,
and (3) supragingival soft tissue. Technically, the metallic implant attaches directly to the
bone. The neck and implant platform adheres to the sulcular and junctional epithelium.
Finally, there is the implant abutment that is in contact with the oral epithelium, which is
visible in the oral cavity, where you will receive the crown. Each of these interfaces must be
optimized to meet the different demands that the organism itself requires. Thus, hybrid
implants or FGMs assume the profile desired by implant dentistry [130].
At the implant–hard tissue interface, osteogenic properties are extremely important
to promote osseointegration, thus allowing the device to be efficiently and quickly fixed
by the body, ensuring fracture resistance during occlusal loading [131]. In this case, the
biomodification of the terminal end of the implant with collagen and hydroxyapatite may
favor this process, as shown above. Subsequently, at the implant–transgingival soft tissue
interface, the cell adhesion of keratinocytes and fibroblasts is quite desirable to ensure
Materials 2022, 15, 3150 12 of 17

a cohesive and uniform epithelialization, to avoid bacterial infiltration. Therefore, the


intermediate region of the device can be functionalized with collagen, peptides, or other
biomolecules that favor the process of cell adhesion and growth, in addition to presenting
compounds that inhibit bacterial growth. Finally, at the apical end of the implant, it is
mandatory to present broad microbiological bioactivity and anti-adherence to prevent
the growth of bacteria and fungi and, consequently, biofilm formation. This region of the
implant is in contact with the oral mucosa and, therefore, is more likely to develop infectious
processes. For the implant interfaces with the transgingival and supragingival soft tissue,
colonization by bacteria is considered the main risk to trigger serious infections, such as
peri-implantitis. This infectious process is usually accompanied by inflammation, inducing
an immune reaction in the patient and, consequently, “bone loss” and implant “rejection”.
The challenge in obtaining hybrid implants or FGMs is what has motivated research
to obtain concomitant biofunctions in different regions of the implant in the same metallic
device, avoiding colonization by bacteria and promoting the osseointegration process.
However, the studies carried out to date are restricted to homogeneously modifying the
implant surface, just improving its interface with the bone. In the context of studies on the
development of hybrid implants, knowledge is still rudimentary.

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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