Unraveling
the Applicability of LbL Coatings for Drug
Delivery in Dental Implant-Related Infection Treatment
Introduction Periodontal disease has
been reported to affect millions of patients
worldwide according to the World Health Organization (WHO), impacting
up to 1 billion of the global adult population ( www.who.int/news-room/fact-sheets/detail/oral-health ). Periodontitis
(PD), characterized by chronic inflammation of the supporting tissues
around the teeth, develops due to a complex interaction between the
host and parasites, progressively compromising the integrity of the
periodontal tissues. , It is characterized by bacterial-induced
inflammatory responses and the destruction of periodontal tissues,
including the periodontal ligament, cement, and alveolar bone. The
more severe stages of periodontitis (stage III and IV) affect over
700 million people, representing approximately 11% of the global population. Indeed, PD ranks as the sixth most prevalent
chronic condition globally and is considered the leading cause of
tooth loss in adults. , Consequently, PD presents a significant
public health challenge due to its high prevalence and the substantial
burden caused by tooth loss and impaired chewing function, negatively
impacting the quality of life. Importantly, a history of PD
poses a significant risk factor for
peri-implantitis, which refers to the irreversible pathological condition
occurring in tissues around dental implants. Historically, there has been a lack of consensus regarding the true
prevalence of peri-implantitis, with heterogeneity in results attributed
to variations in disease definitions and a lack of standard diagnosis. − However, contrary to previous assumptions, peri-implantitis as a
biological complication has been significantly underestimated for
many years. It was only after the 2017 World Workshop on the Classification
of Periodontal and Peri-Implant Diseases and Conditions that clinical
parameters became better defined, revealing a prevalence of this condition
much higher than expected. As such, recent
studies have reported a troubling prevalence of peri-implantitis,
ranging from 34% to 56% at the patient level within an average time
frame of 2–7.8 years after prosthesis loading. These numbers underline not only the concerns for public
health but also the significant economic burden caused by peri-implantitis.
In view of this, the global peri-implantitis treatment market has
been projected to reach a value of US$ 4.5 billion by 2032. Evidently,
these projections are based on the increasing number of dental implants
that have been and will be used for oral rehabilitation. The alarming
peri-implantitis prevalence percentage further indicates that current
clinical procedures aimed at preventing and treating peri-implantitis
are insufficiently effective. The
primary disease-causing factor for peri-implantitis is the
biofilm accumulated on dental implant components at the tissue–oral
cavity interface. Therefore, nonsurgical supportive therapy involving
biofilm removal is a mandatory step at the initial stage of the peri-implantitis
treatment. The treatment of peri-implantitis ranges from nonsurgical
to surgical procedures, depending on the outcomes of the initial steps. Regardless of the chosen approach, the main
objective of the treatment is to achieve complete resolution of the
inflammation by biofilm removal and microbial agent elimination. In
view of this, several methods have been described to achieve surface
decontamination, such as the use of antiseptics, − local and systemic
antibiotic administration, , and lasers and antimicrobial
photodynamic therapy. , However, the limited number of
studies to support the benefits of adjunctive therapy compromise the
reliability of the evidence and make the valuation of conventional
treatments difficult. , Biomaterials offer a range
of possibilities for developing therapeutic
interventions, from the use of polymeric films with antimicrobial
effects on dental implant surfaces to the use of drug delivery systems
or even using titanium modifications on implant/abutment surfaces
to prevent and/or treat peri-implantitis. − However, despite
the large number of antimicrobial coating approaches discussed by
literature, to date, all proposed surfaces have not reached the commercial
stage. A well-designed review clearly revealed a growing number of published
articles under the antimicrobial coatings field, with potential highlights
on the preclinical studies. This result confirms that the stagnation
in clinical application might be attributed to the complexity of the
factors involved in the antimicrobial coating development, from product
construction to product application. Indeed, problems in translating
preclinical findings to clinical applications can be attributed in
part to cytotoxicity, material behavior, drug release control, and
duration of product antimicrobial activity to make it clinically viable. However, the lack of knowledge about the clinical
purpose of the desired material might directly affect the success
of the antimicrobial coating. In fact, understanding the rationale
behind developing a surface
modification is the initial step toward successfully acquiring new
materials. It is imperative, however, to consider the distinctions
between preventive and treatment approaches in guiding the complexity
of biomaterials. As peri-implantitis is an inflammatory condition
initiated by a dysbiotic biofilm adherent to a substrate, preventive
strategies are related to material development with direct antimicrobial
action, through either contact killing or antifouling surfaces. In this case, the material should be resistant
to pH differences caused by food consumption and withstand the mechanical
action of brushing to maintain its function in the long term. From
a treatment perspective, biomaterial-based coatings should be easily
degraded to directly combat the infection and/or the inflammatory
response, through the release of antimicrobial agents and/or substances
implicated in the inhibition of osteoclastogenesis, and restore the
health of peri-implant tissues in patients diagnosed with peri-implantitis. − To this purpose, drug delivery technologies have enabled the delivery
of a therapeutic to its target site, minimizing off-target accumulation
and facilitating patient compliance. Drug release technology
provides a higher local drug concentration
to specific sites on and around the implant, thereby offering immediate
action against implant-associated infections. The basic idea behind
drug release systems is to create a responsive structure, called a
smart coating, on the surface capable of loading drugs and releasing
them in a regulated manner over time. To this end, chemical cross-linking
processes and layer-by-layer (LbL) systems − constructed using natural and/or synthetic polymers might act as intelligent strategies for releasing
the loaded drugs. Among the techniques for building smart coatings,
here we will focus on LbL assembly as an appealing strategy to immediately
fight against the already installed disease. LbL assembly has many advantages such as the high reproducibility
of film formation in an easy, versatile, flexible and inexpensive
process, nanometer control over film thickness, and a wide variety
of natural and/or synthetic polymeric materials to be used as multivalent
species to build up the film. − Basically, the LbL method involves
the alternating adsorption of complementary multivalent species on
a substrate through electrostatic interactions, hydrogen bonding,
or other secondary interactions, which will work as a structure for
drug incorporation. , While research on LbL technology
has expanded in recent years,
the challenge of translating it into commercial products may stem
from a lack of understanding related to the system limitations, coating
purpose, and the meaning of disease stage for its application. To
the best of our knowledge, this is the first study that breaks down
the barriers of the LbL system description and provides detailed chemical
and biological information to clarify its strict application in terms
of physical site and purpose as antimicrobial coatings. Likewise,
we give a deeper overview of the onset and progression concepts of
the disease to clarify the indications for the LbL system as a coating
for implant abutments aimed at the treatment of peri-implantitis.
Finally, we relate the chemical nature of the LbL system to its functionality
and discuss the oral cavity as an uncontrolled environment that limits
its clinical applicability. 

Understanding Peri-implantitis According
to the 2017 World Workshop on the Classification of Periodontal
and Peri-Implant Diseases and Conditions, peri-implantitis is a pathological
condition characterized by inflammation around dental implants with
subsequent loss of supporting bone. , In the clinical
setting, peri-implant mucositis is assumed to precede peri-implantitis,
signaling the initial state of the inflammatory process. The onset
of peri-implant mucositis exhibits clinical signs of red aspects around
the implant with swollen soft tissues and the presence of bleeding
and/or suppuration on probing, yet without bone loss. As a more severe inflammatory condition, peri-implantitis
is influenced and regulated by the immune response. While the inflammatory
reaction contributes to bone resorption around the implant, the dysbiotic
biofilm adherent to the surface consistently triggers the innate response , − . Once the biofilm is well established onto the dental
implant components,
the immune system responds to it leading to immunoinflammatory mediators. , The immune system mobilizes macrophages, neutrophils, and T- and
B-cells, promoting the release of pro-inflammatory cytokines interleukin-1
(IL-1) and tumor necrosis factor-alpha (TNF-α), anti-inflammatory
cytokines, e.g., interleukin-10 (IL-10), and chemokines, e.g., interleukin-8
(IL-8), that lead to osteolysis and inflammatory tissue damage. , , The lesions at peri-implantitis
sites harbor larger proportions of polymorphonuclear leukocytes (PMN)
and M1 macrophages phenotypes when compared to periodontitis. , Macrophage polarization to M1 indicates a strong pro-inflammatory
response with high expression of pro-inflammatory products, such as
IL-1β, IL-6, IL-12, and TNF. The secretion of such cytokines
activates osteoclast precursors and contributes to the bone resorption.
The higher expression of M1 macrophages may be associated with the
faster progression of peri-implantitis compared to periodontitis. − In fact, some individuals exhibit an exacerbated response
to the
inflammatory process, making them more susceptible to developing peri-implant
diseases. , , , Some conditions such as uncontrolled diabetes mellitus,
autoimmune disorders, genetic factors, smoking and alcohol consumption,
and some treatments such as bisphosphonate therapy, head and neck
radiotherapy, chemotherapy, antibiotics use, and anti-inflammatory
medications are known to alter the microbiome and hence the inflammatory
response, which makes these individuals more susceptible to inflammatory
conditions. , , Peri-implantitis is a relatively recent condition, presenting
numerous
challenges in comprehending its risk factors that influence disease
progression and its impact on systemic diseases. For instance, existing literature confirms poor oral hygiene
and a history of periodontitis as significant risk factors for peri-implantitis. , , , Despite longitudinal studies affirming the influence of metabolic
conditions like diabetes and habitual tobacco smoking on periodontitis,
conclusive evidence regarding their effects on peri-implantitis remains
elusive. , However, examining the biological pathways
implicated in smokers, it is apparent that similarities exist in the
inflammatory responses between periodontitis and peri-implantitis,
suggesting potential consequences of inflammatory products. Nicotine, in particular, not only enhances the
production of pro-inflammatory cytokines by osteoblasts, such as IL-6
and TNF-α, known to contribute to bone resorption, but also
plays an important role in decreasing PMN chemotaxis and in the hyperactivation
of macrophages (which secrete considerable pro-inflammatory mediators),
in addition to decreasing vascularization. , , If left untreated, this may lead to peri-implant
diseases and eventual implant loss. However, it is crucial to note
that the absence of evidence may stem from a lack of longitudinal
studies establishing such associations and causality. Evidently,
dental implants are more prone to pathogen invasion
compared to natural teeth due to several factors. Basically, in a
natural tooth, cementum is a sheathlike structure covering the surface
of root dentin and providing anchorage for collagen fibers in a pattern
of perpendicular orientation. Furthermore,
epithelial cells attach to the enamel and cementum via hemismosomes
to achieve epithelial sealing around the teeth. Hemidesmosomes are
a set of highly specialized epithelial attachment apparatus components
responsible for providing stable and firm attachment to the extracellular
matrix, intracellularly filament, and cytoskeleton. , The tight seal at the soft tissue on the alveolar bone and the teeth
surface plays a crucial role in serving as the first protective barrier
to prevent bacterial infiltration. , Unlike a tooth,
the implant lacks structures such as root cementum and periodontal
ligament responsible for connecting the soft tissues to the tooth
through dentoalveolar and dentogingival fibers. , , Even after proper healing, the tissue around
dental implants experiences reduced blood flow due to poor vascularity
and a deeper sulcus, allowing bacteria to penetrate deeper due to
the absence of collagen fibers (known as Sharpey’s fibers)
inserted into the implant structure. The absence of such structures
affects the direction of the collagen fibers. Histologically, collagen
fibers are oriented parallel or circumferentially to the region of
the abutment surfaces, resulting in a weaker connective interface, , lack of soft tissue resistance against the inflammatory response,
and hence rapid disease progression. In view of the differences
in pathology and histological organization
around percutaneous natural teeth and dental implants, it is straightforward
to state that peri-implantitis treatment poses a significant challenge
to clinicians. In this sense, an important question can be raised
to conceptualize the outcome of treating peri-implantitis. From a
clinical standpoint, the diagnosis of peri-implantitis requires clinical
signs such as presence of bleeding and/or suppuration on gentle probing,
increased probing depth compared to previous examinations, and presence
of bone loss beyond crestal bone level changes resulting from initial
bone remodeling. During the treatment
of peri-implantitis, it is not expected to recover the lost bone.
According to the European Federation of Periodontology (EFP) S3 level
clinical practice guideline, 2023, reconstructive
procedures can be used in the management of osseous defects, as a
sequential stage of surgical treatment of peri-implantitis. Surgical
approaches can be employed in the sites with persisting signs of pathology
after nonsurgical therapy, to provide access to the implant surface
and achieve the resolution of the inflammatory lesion. Clinically,
the end points of successful surgical therapy of peri-implantitis
can be translated by ≤1 point of bleeding on probing, absence
of suppuration on probing, probing depth ≤5 mm, and absence
of progressive bone loss compared to pretreatment bone levels to verify
disease resolution. Although the EPF recommends the surgical management
of osseous defects in peri-implantitis patients, through the access
flap with or without reconstructive procedures, no evidence demonstrating
superiority of any specific surgical technique has been identified. In short, researchers in the fields of dentistry,
(material) engineering, and tissue regeneration are confronted with
a substantial clinical problem to address with innovative treatment
approaches. Therefore, understanding and delineating the initiation
and progression of the disease are pivotal initial steps toward devising
effective treatment strategies to be discussed below for this biological
complication. 

Why Do We Still Need New Strategies to Treat
Peri-implantitis? While the progressive tissue destruction
caused by peri-implantitis
stems from the host’s inflammatory response, it is the flora
of pathogenic microorganisms within the dysbiotic biofilm that evokes
the initiation of this inflammation. According
to the EFP clinical practice guideline, the initial treatment approach
for peri-implantitis should prioritize nonsurgical methods that focus
on biofilm removal and implant surface decontamination to control
peri-implant biofilms and inflammation. Ideally, decontaminating the implant surface should be performed
through supramarginal and submarginal instrumentation. For the latter,
EFP guidelines recommend performing nonsurgical supra- and submarginal
instrumentation with curets and/or (ultra)sonic devices as the basic
control intervention methods. − However, there is a risk of damaging
the implant surface while attempting to remove the biofilm. , In vitro studies have demonstrated that released
titanium particles following implant surface damage have the potential
to trigger severe inflammatory responses via macrophages and osteoclasts and to modulate the peri-implant biofilm to
a dysbiotic state. To minimize this risk,
curets are now being crafted from softer materials like plastic or
carbon fiber instead of stainless steel. Nevertheless, regardless of material type, curets may not completely
eliminate adhered biofilm since they cannot reach the areas between
the threads of the implants. Moreover,
given the complexity of an already established peri-implant dysbiotic
biofilm, ensuring its successful disorganization in areas with limited
access further complicates treatment. Surgical strategies may be considered when nonsurgical treatments
fail or in cases of moderate or severe peri-implantitis, offering
greater access to peri-implant regions. , According
to evidence-based recommendation, surgical intervention is indicated
for patients diagnosed with peri-implantitis, for whom end points
of nonsurgical therapy (i.e., probing depth ≤5 mm and ≤1
point of bleeding on probing) have not been achieved. The goal of surgical therapy is to provide direct access,
through flap elevation, to facilitate procedures required for implant
surface decontamination and achieve resolution of the inflammatory
process. Although the literature has
presented the use of air-polishing, Er:YAG laser, chlorhexidine or
photodynamic therapy, or even adjunctive local antibiotics, for implant
surface decontamination, the EFP does not recommend these treatments
due to lack of evidence on efficacy. , Despite literature
suggesting that chemical agents can enhance disinfection by reaching
mechanically inaccessible niches, in clinical practice, local antibiotics
are typically administered via irrigation, leading to easy dissolution
of the applied antibiotic and thus limited therapeutic effect. Furthermore, the resident microbiota and its
matrix can impede the access of local antimicrobials, preventing their
penetration into deeper layers of the biofilm. The prescription of antibiotics for systemic treatment
along with
(non)surgical therapies is still a concern and has not been recommended
by the EFP. , , In comparison to planktonic bacteria, those bacteria within biofilms
exhibit greater tolerance to antimicrobial agents, rendering systemic
antibiotics less effective as adjuncts. A recent scoping review further concluded that, although there is
insufficient data to support evidence-based antibiotic protocols for
peri-implantitis, systemic metronidazole adjunct to mechanical debridement
improved the clinical outcomes of nonsurgical treatment. Overall, research on systemic antibiotics for
peri-implantitis treatment is scarce and inconclusive, and due to
the heterogeneous administration protocols reported in the literature,
there is no consensus on any effective antibiotic protocol for treating
peri-implantitis. When indicated, a careful
risk/benefit assessment should be conducted to evaluate the potential
for adverse events (e.g., allergic reactions) and antibiotic resistance. While it can be argued that all available means
should be incorporated into the treatment plan given the difficulty
of achieving successful peri-implantitis treatment, overall antimicrobial
agents should not be used empirically due to the overgrowth of difficult-to-eradicate
opportunistic pathogens. In fact,
the high prevalence of peri-implantitis highlights that
no clinical procedure can yet be considered effective in treating
this pathological condition. Moreover, peri-implantitis might not
only lead to implant loss but also poses a risk of pathogenic bacteria
from the infected oral site reaching the bloodstream, causing significant
morbidity and generating considerable healthcare costs. Recent work
has highlighted the potential links between peri-implant health and
systemic inflammation, including uncontrolled diabetes mellitus, psychological
stress, cardiovascular disease, obesity, and even recent infectious
diseases that caused severe acute respiratory syndrome caused by SARS-CoV-2. Similar to periodontitis, chronic inflammation
around dental implants
harbors pathogenic bacteria and potential pro-inflammatory cytokines
that can influence other systemic inflammatory conditions, such as
cardiovascular diseases. Multiple studies have shown that peri-implantitis
and cardiovascular diseases share common inflammatory pathways, potentially
leading to an increased risk of cardiovascular events in individuals
with untreated peri-implantitis. , − Diabetes is another possible disease that could be influenced by
peri-implantitis due to the fact that this oral disease could bring
a hyperinflammatory state, which could exacerbate insulin resistance,
thus impairing glycemic control and the reparative capacity of the
body. , Although there is insufficient evidence
to confirm such relationships mentioned above, the consequences of
peri-implantitis progression may extend beyond implant loss, underscoring
the need for strategies to stabilize the disease in the short term. 

Developing a Drug Delivery System Using Layer-by-Layer
(LbL) Technology to Treat Peri-implantitis LbL assembly is
a promising avenue in the field of peri-implantitis
management due to its applicability with a variety of substances,
in addition to being an easy, versatile, and flexible process for
multilayer formation to act directly in the affected site. , Given that peri-implantitis is already established and requires
prompt treatment, it is crucial to consider therapeutic interventions
that address the inflammatory and infectious nature of the disease.
Controlled and local administration of antimicrobial agents could
help to reduce the local infection and subsequent inflammation, while
substances targeting cells involved in bone resorption could help
halt the progression of tissue loss resulting from peri-implantitis.
In both cases, a drug delivery system capable of releasing therapeutic
agents directly at the target site, such as via abutments, is appealing.
LbL assembly offers a potential solution by serving as a biomaterial-based
surface modification technology that can create a matrix for drug
delivery ( A–C). In the 20th century, Langmuir–Blodgett (LB)
balances were
frequently employed to deposit amphiphilic molecules at the liquid/vapor
interfaces in order to manufacture films. , Although it was initially used only on flat surfaces, this technology
made it possible to create self-assembled films with low mechanical
and thermal stability. In 1960, Iler introduced LbL assembly as an
alternative to overcome the drawbacks of LB films, self-assembling
multilayers into charged colloidal particles. Since then, LbL assembly has been applied in various fields of science
and technology, including the healthcare sector, such as implants, , − wound healing dressings, and tissue engineering. Basically, the deposition method for LbL assembly via electrostatic
interactions involves an alternating sequence of immersing a substrate
in anionic and cationic polyelectrolyte solutions, followed by a washing
step between each solution exchange to ensure the complete removal
of weakly adsorbed polyelectrolytes. Any deviation from this sequence
may lead to nonuniform adsorption of polyelectrolytes, which can compromise
the quality of the manufactured LbL ( B). LbL coatings
can be assembled using a range of chemical interactions, including
hydrogen bonds, charge transfer interactions, molecular recognition,
host–guest, π–π, and biospecific interactions. − From a chemical perspective, understanding the process of structuring
a multilayered coating is complex and involves several factors, including
charge, pH, and ionic strength of the medium. In this sense,
chemical interactions within LbL assemblies, including
covalent and noncovalent interactions, are crucial for determining
the stability, functionality, and drug-release behavior of these films. − Covalent bonds, formed through the sharing of electron pairs, provide
robustness and long-term stability, essential for sustained drug delivery,
often enhanced through cross-linking methods like click chemistry
or disulfide bond formation. − Conversely, noncovalent interactions, such
as electrostatic forces, hydrogen bonding, and van der Waals forces,
drive the dynamic assembly and disassembly of LbL structures, enabling
responsive and controlled drug delivery by facilitating the sequential
buildup of layers with precise control over film thickness and composition. − These interactions might be introduced during the assembly process
by using reactive functional groups on the polymers or molecules that
form the layers. For instance, covalent
cross-linking can be employed to enhance the mechanical strength and
stability of the LbL films, making them more resistant to environmental
conditions such as changes in pH or ionic strength. Cross-linking can be achieved through various chemical
reactions, such as click chemistry, “Schiff” base formation,
or disulfide bond formation. − These covalent bonds provide long-term stability,
which is crucial for applications in which the film must remain intact
for extended periods, such as in sustained drug delivery systems. On the other hand, noncovalent interactions are the primary driving
forces in the formation of LbL films. − These interactions are generally
weaker than covalent bonds but are essential for the dynamic assembly
and disassembly of LbL structures. − For example, electrostatic interactions
are the most commonly utilized forces in LbL assembly, where alternating
layers of positively and negatively charged polyelectrolytes are deposited. The electrostatic attraction between oppositely
charged layers enables the sequential buildup of the film, allowing
for precise control over the film thickness and composition. A LbL coating discloses two possible
configurations: (i) adsorption
in which the charge balance results in electroneutrality, called intrinsic
compensation, and (ii) adsorption that results in an excess net positive
or negative charge, arising from the adsorption of polycations and
polyanions, respectively, called extrinsic compensation , ( A). The
multilayer system becomes unstable due to the excess charges, since
the balance will be altered in favor of stabilizing these loads. Zeta
potential behavior often analyzes these measurements. , , The ionic strength of
polyelectrolyte solutions plays a crucial
role in forming homogeneous layers during LbL coating buildup, and
it is imperative to consider the characteristics and concentration
of the ion(s). The presence of small ions, also known as kosmotropic
ions, results in thin films with low hydration and roughness due to
their low polarization and weak binding with the multilayer systems.
On the other hand, chaotropic ions, which have a higher degree of
polarization, interact more with the multilayers, leading to changes
in the conformation of the polyelectrolytes and affecting the thickness
of the multilayers. , The pH of the medium also has
a significant impact on the formation of multilayers, and it can alter
the degree of ionization of the polyelectrolytes. Consequently, the pH modifies the organization of the multilayers. In short, LbL assembly reveals overriding advantages related to
the low cost, versatility, and simplicity of obtaining well-defined
thickness, composition, and functionality materials. The low cost
is related mainly to the simplicity of the technique. LbL coatings
can be assembled at room temperature without pressure, which means
that this technique will not compromise the integrity of reagents,
such as proteins or drugs. The versatility of LbL assembly as a coating
is due to its ability to vary in composition and its possibility to
create defined sequences of layers. With
regard to the functionality, LbL assembly has found applications within
the biomedical field. In this sense, the multilayers can be purposely
prepared to admit antimicrobial action or can be constructed to receive
the target drug. In this perspective, the literature brings antimicrobial
polyelectrolytes to be applied as a target layer during the LbL system
construction. , The explanation of the antimicrobial
properties of specific polyelectrolytes is related to their hydrophobicity. The antimicrobial capacity of hydrophobic polyelectrolytes has
long been exploited as a replacement for conventional antibiotics. , The antimicrobial effects of the polyelectrolytes are related to
the nature of hydrophobic groups, polyelectrolyte composition, and
length for a series of antimicrobial block polyelectrolytes. Interestingly, although cationic groups also
contribute to the antimicrobial activity of the material, the hydrophobicity
within the polyelectrolytes is the driving component for lipid membrane
binding and pore formation which in turn causes cell death through
a membrane-disruption mechanism. , For instance,
the use of poly(ethylenimine) (PEI) as a strong cationic polyelectrolyte
provides inherent bactericidal activity via its cationic groups. , These bind to phospholipids in cell membranes through electrostatic
interactions, leading to membrane ruptures. The bactericidal
activity of modified PEIs was further enhanced
by the addition of hydrophobic alkyl groups and a more positive charge
density. It was found that linear N , N -dodecyl-ethyl poly(ethylenimine) and poly(acrylic acid) LbL coatings
demonstrate strong antiviral activity against influenza A/WSN (H1N1)
and bactericidal activity against Staphylococcus aureus and Escherichia coli . The balance between cationic groups and hydrophobic
side chains on different sides of overall polyelectrolytes has been
recognized for disrupting bacterial cell membranes and causing membrane
leakage and eventually cell death. , From this
knowledge, the literature suggests a correct balance between hydrophobicity
and hydrophilicity properties within biomaterial polyelectrolytes
to achieve an antimicrobial interaction with bacterial membranes without
causing cytotoxicity or cell repeal. In order to enhance the
interaction between film and substrate
and optimize the antibacterial properties of titanium surfaces, another
study combined ε-polylysine (ε-PL), a typical cationic
antimicrobial peptide, with arabic gum, a polysaccharide, for LbL
construction. They used polydopamine to covalently graft ε-polylysine
onto anodized titanium. The antimicrobial capacity of this system
was attributed to the strong electrostatic interaction between the
negatively charged acidic phospholipid of bacterial cell membranes
and the positive charge from ε-PL. The wizened and ruptured
morphology of S. aureus and E. coli on coated Ti surfaces suggested that ε-PL
effectively killed bacteria by destroying their cell membranes. However,
the limited amount of ε-PL covalently conjugated on the surface
affected the antibacterial efficiency. Interestingly, decreased bacterial
adhesion was found on the surface along with increased layers of ε-PL
and GA, suggesting that these reagents, bound by electrostatic adsorption,
might dissolve into the solution during the bacterial incubation process ( A–B). Despite the apparent advantages provided by the
LbL assembly, it
is important to highlight the inherent limitations of LbL assembly.
The most common method for LbL assembly is the sequential dipping
method, which does not allow for substantial control over the orientation
of the adsorbed components in the multilayers. Basically, different polyelectrolyte solutions are used
to fill individual containers, and a specimen is immersed sequentially/repetitively
in these solutions, with intermediate washing steps, until the desired
number of layers is achieved. Although
the LbL process is time-consuming due to the time required to reach
equilibrium adsorption for each coating step, this system allows a
sustained drug release overtime. Another way to buildup the LbL system
is by using sequential spraying of the specimens instead of dipping.
This method encompasses the advantage of nanometer control over film
thickness without the disadvantages mentioned above. Moreover, spray-based
LbL assembly is faster and smoother than dipping and can even be performed
without a rinsing step. However, spray-based LbL assembly can lead
to vastly rapid release of an incorporated drug ( B). 4.1 LbL Self-Assembly System as a Feasibility
Tool for Drug Release The LbL system as a thin film can also
be designed in the field of biomedical science to work on drug delivery
processes. Importantly, there are specific factors related to the
effective incorporation of the drug and subsequent drug release by
the LbL system: First, the nontoxicity property of the target drugs
and the film material should be confirmed before preparing the LbL
system. , Second, the thin film-carrying drugs should
disclose both chemical and physical stability to favor drug incorporation
and its release. , Third, drug release should occur
in the target site. Fourth, the system should ensure a sustained release
instead of a burst release and ensure a safe dose concentration at
the target site. This control can be achieved by managing the
degradation rate of the LbL system, depending on the drug property
to be incorporated, and considering the material and the assembled
method selected for LbL preparation. In this sense, a variety of interactions
and cross-linking chemistry can be employed for loading drugs onto
prefabricated multilayers: overall drugs can be directly loaded onto
prefabricated LbL; the layers can be built using drugs as building
blocks; and finally, overall drugs can be also modified with cargoes,
for protecting the drug by a shell of a stable chemical structure
and preventing undesirable decomposition. , Contrary to the concepts discussed in the present Review, a recent
study developed a quaternary ammonium carboxymethyl chitosan, collagen,
and hydroxyapatite multilayer coating via the LbL technique by polymerizing
dopamine to prevent infections on implant surfaces. Importantly, although
the objective of this study was to use a naturally fragile and degradable
LbL system focusing on prevention for implants, the authors also considered
the likelihood of disease after implantation, different from peri-implantitis.
To achieve antimicrobial properties, the authors used 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide
hydrochloride (EDC) in the presence of N -hydroxysulfosuccinimide
(sulfo-NHS) to convert carboxyl groups to amine-reactive sulfo-NHS
esters during the construction of the multilayers. EDC/sulfo-NHS were
used as cross-linkers to extend the contact-killing properties and
the release-killing over time ( C–D). With the possibility of using LbL coatings as a carrier matrix
for target biomolecules such as antimicrobial substances or those
that act directly on inflammatory cells, it offers enormous potential
as a drug delivery system. For instance, in a recent study, silver
nanoparticles (AgNPs) were incorporated into LbL coatings based on
oppositely charged amino cellulose (AM) and acylase. The resulting
hybrid system showed an improved antibacterial and antibiofilm effect,
while decreasing cytotoxicity. The beauty
of the LbL assembly lies in the possibility of using it to produce
a hybrid system that can enhance the efficacy of existing drugs. The
capacity of the LbL system to release incorporated drugs occurs because
the multilayered structures are naturally multiresponsive as a consequence
of interactions among the layers, which means that they answer to
different stimuli, such as temperature, pH, and humidity. It is precisely
due to the capacity of the system to respond to multiple stimuli that
LbL assembly displays the ability to incorporate drugs in high concentrations
within a multilayer thin film and release them in a controlled or
uncontrolled manner , ( C). In our previous work, , we demonstrated that
our LbL system changed molecular conformation upon immersion in ultrapure
water and displayed a swelling behavior of the polyelectrolyte matrix.
Our outcomes were also categorical in showing that when samples were
kept in wet conditions, the LbL system with drug incorporated onto
titanium discs displayed the highest roughness, which indicates that
LbL-coating conformational changes contributed to the drug diffusion
process through the multilayered coating. From a clinical perspective,
the physiological environment of the oral cavity would act to disturb
the stimuli-responsive polyelectrolyte of the system and allow the
release of the incorporated drug for local and immediate action. To
understand how the release process occurs and how to control the concentration
of drugs released at the site, it is necessary to understand the chemical
characteristics of both the system and the released agent. To
reach the biological performance of the controlled drug release,
it is required that the system protects the drug, loads the drug,
and releases the drug in a controlled manner for the needed time,
which are all directly influenced by a drug’s molecular structure. Since the electrostatic interactions between
oppositely charged ions from different layers are the most applied
driving force in the LbL assembly, the same principle must be applied
between polyelectrolyte layers and the target drug. An example includes
antibiotics disclosing hydrophilic properties as target drugs, which
are released more quickly upon exposure to the aqueous environment.
This can be explained by the weak interaction between hydrophobic
and hydrophilic molecules from polymers and antibiotics, respectively, which means that there is no driving force
between the molecules from layers and loaders. , To overcome this issue, researchers have studied amphiphilic
inclusion
complexes with overall drugs to enhance the drug capability to entrap
into hydrophobic layers, increase the
interaction between drug and LbL system, and ensure the controlled
drug release overtime. In a recent study, the authors used amphiphilic
molecule anionic beta-cyclodextrin (β-CD) to retain tetracycline,
as a hydrophilic antibiotic, within the LbL-coating titanium substrate
and control TC release from the multilayers up to 30 days ( E–G). The strong interaction between TC and anionic
β-CD and effective loading of the complex within the LbL system
enabled TC retention within the LbL coatings for a prolonged time,
regardless of medium pH. Importantly, the strong antibacterial effect
was observed after 48 h of incubation with more than 5 log reduction
of bacterial growth in comparison to the uncoated titanium surfaces.
The remaining antibacterial activity of the LbL system was confirmed
even up to 30 days, with 2.8 log reduction of S. aureus compared with the same uncoated surfaces. Summarizing, illustrates how LbL
technology can be tailored for specific dental implant applications
by leveraging different stimuli-responsive features. This table and
summary provide a clear overview of how LbL technology is advancing
the field of dental implants by improving their functionality and
clinical outcomes. It is essential to note that the factors that are
involved in the
structuring of the LbL system are also responsible for the responsive
nature of the bioactive compounds. The most prevalent self-defensive
antibacterial LbL films are pH-responsive because they take advantage
of the release of lactic and acetic acid by different bacteria, which
lowers the pH of the infection’s microenvironment. Thus, pH shifts can alter the conformational
state of the layers in LbL coatings, changing the dimension of the
polyelectrolyte mesh and facilitating the release of drugs. A similar effect occurs when the multilayer
system meets the biological environment. The presence of salts results
in the rearrangement of water molecules within the polyelectrolyte
layers, whose driving force is guided by an entropic effect, modifying
the conformation of the polyelectrolyte present. From this perspective, the release rate does not occur
exclusively through drug diffusion and platform degradation, but the
phenomena involved in extrinsic compensation are also responsible
for changes in the physicochemical properties of the LbL system. 4.2 Physical Properties of LbL Coatings for Implant
Abutment Surfaces Implant abutments are essential components
that serve as bridges or extensions attached to implants to secure
artificial teeth. Unlike the implant itself, which is not subject
to mechanical friction during installation, the significance of abutments
lies in their direct contact with surrounding soft tissue. Hence,
any polyelectrolyte coating applied to abutment surfaces should exhibit
sufficient strength to withstand the forces exerted during placement
without being easily being removed. Furthermore, from a clinical point
of view, screw-retained abutments could be easily replaced by coated
ones during disease treatment. It is widely acknowledged that
surface topography significantly influences the biological response
of surrounding tissues to abutments. Numerous studies have demonstrated that rough surfaces tend to accumulate
more plaque, , increasing the risk of plaque-induced
inflammatory reactions in surrounding tissues compared to smoother
surfaces. Therefore, abutments should ideally feature smooth surfaces,
typically less than or around 0.2 μm, , , to facilitate mechanical cleaning
and ensure peri-implant health, especially in patients at risk of
peri-implantitis. Another critical surface property affecting surface
protein adsorption and cell adhesion quality is wettability, with
cells showing a greater propensity to adhere to hydrophilic surfaces. , In essence, any coating-based approach to combat peri-implantitis
should preserve or enhance the inherent properties of the components. For abutments, the primary challenge lies in developing a coating
that maintains the original topography—ensuring it does not
interfere with smoothness and wettability—while adding antimicrobial
properties without adverse effects on human cells. From a dental implant perspective, LbL technology holds
promise for coating implant abutment surfaces. The multilayers assembled onto abutment surfaces allow
precise control of polyelectrolytes’ vertical dispersion at
the nanoscale, thereby achieving the desired roughness based on the
chosen multilayer creation process. , In other
words, LbL-coating properties such as thickness, homogeneity, and
internal structure can be controlled and determined by various LbL
methods. With regards to the wettability,
hydrophilic/hydrophibic potential
of the LbL system is a key factor that influences protein adsorption,
cell adhesion, and the overall interaction between coating and biological
environment. Hydrophilic surfaces may
promote protein adsorption and enhance cellular attachment, which
can be beneficial in the tissue engineering field. Studies have shown that LbL assembly can be used to finely
tune these properties by selecting appropriate materials for the layers. , − For instance, incorporating hydrophilic
polymers such as poly(ethylene glycol) (PEG) can decrease the contact
angle, thus enhancing material hydrophilicity. Owing to the versatility and flexibility of LbL assembly,
coating
surface properties can be easily modified to enhance their biological
response before they come into contact with cells and tissues . However, caution is warranted when considering this technology
for implants themselves due to the risk of displacement or physical
damage to LbL coatings during implant installation. Clearly, LbL assembly
is a system based on a polyelectrolyte responsive to various conditions,
suggesting its susceptibility to mechanical forces. 

LbL Self-Assembly System as a Feasibility
Tool for Drug Release The LbL system as a thin film can also
be designed in the field of biomedical science to work on drug delivery
processes. Importantly, there are specific factors related to the
effective incorporation of the drug and subsequent drug release by
the LbL system: First, the nontoxicity property of the target drugs
and the film material should be confirmed before preparing the LbL
system. , Second, the thin film-carrying drugs should
disclose both chemical and physical stability to favor drug incorporation
and its release. , Third, drug release should occur
in the target site. Fourth, the system should ensure a sustained release
instead of a burst release and ensure a safe dose concentration at
the target site. This control can be achieved by managing the
degradation rate of the LbL system, depending on the drug property
to be incorporated, and considering the material and the assembled
method selected for LbL preparation. In this sense, a variety of interactions
and cross-linking chemistry can be employed for loading drugs onto
prefabricated multilayers: overall drugs can be directly loaded onto
prefabricated LbL; the layers can be built using drugs as building
blocks; and finally, overall drugs can be also modified with cargoes,
for protecting the drug by a shell of a stable chemical structure
and preventing undesirable decomposition. , Contrary to the concepts discussed in the present Review, a recent
study developed a quaternary ammonium carboxymethyl chitosan, collagen,
and hydroxyapatite multilayer coating via the LbL technique by polymerizing
dopamine to prevent infections on implant surfaces. Importantly, although
the objective of this study was to use a naturally fragile and degradable
LbL system focusing on prevention for implants, the authors also considered
the likelihood of disease after implantation, different from peri-implantitis.
To achieve antimicrobial properties, the authors used 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide
hydrochloride (EDC) in the presence of N -hydroxysulfosuccinimide
(sulfo-NHS) to convert carboxyl groups to amine-reactive sulfo-NHS
esters during the construction of the multilayers. EDC/sulfo-NHS were
used as cross-linkers to extend the contact-killing properties and
the release-killing over time ( C–D). With the possibility of using LbL coatings as a carrier matrix
for target biomolecules such as antimicrobial substances or those
that act directly on inflammatory cells, it offers enormous potential
as a drug delivery system. For instance, in a recent study, silver
nanoparticles (AgNPs) were incorporated into LbL coatings based on
oppositely charged amino cellulose (AM) and acylase. The resulting
hybrid system showed an improved antibacterial and antibiofilm effect,
while decreasing cytotoxicity. The beauty
of the LbL assembly lies in the possibility of using it to produce
a hybrid system that can enhance the efficacy of existing drugs. The
capacity of the LbL system to release incorporated drugs occurs because
the multilayered structures are naturally multiresponsive as a consequence
of interactions among the layers, which means that they answer to
different stimuli, such as temperature, pH, and humidity. It is precisely
due to the capacity of the system to respond to multiple stimuli that
LbL assembly displays the ability to incorporate drugs in high concentrations
within a multilayer thin film and release them in a controlled or
uncontrolled manner , ( C). In our previous work, , we demonstrated that
our LbL system changed molecular conformation upon immersion in ultrapure
water and displayed a swelling behavior of the polyelectrolyte matrix.
Our outcomes were also categorical in showing that when samples were
kept in wet conditions, the LbL system with drug incorporated onto
titanium discs displayed the highest roughness, which indicates that
LbL-coating conformational changes contributed to the drug diffusion
process through the multilayered coating. From a clinical perspective,
the physiological environment of the oral cavity would act to disturb
the stimuli-responsive polyelectrolyte of the system and allow the
release of the incorporated drug for local and immediate action. To
understand how the release process occurs and how to control the concentration
of drugs released at the site, it is necessary to understand the chemical
characteristics of both the system and the released agent. To
reach the biological performance of the controlled drug release,
it is required that the system protects the drug, loads the drug,
and releases the drug in a controlled manner for the needed time,
which are all directly influenced by a drug’s molecular structure. Since the electrostatic interactions between
oppositely charged ions from different layers are the most applied
driving force in the LbL assembly, the same principle must be applied
between polyelectrolyte layers and the target drug. An example includes
antibiotics disclosing hydrophilic properties as target drugs, which
are released more quickly upon exposure to the aqueous environment.
This can be explained by the weak interaction between hydrophobic
and hydrophilic molecules from polymers and antibiotics, respectively, which means that there is no driving force
between the molecules from layers and loaders. , To overcome this issue, researchers have studied amphiphilic
inclusion
complexes with overall drugs to enhance the drug capability to entrap
into hydrophobic layers, increase the
interaction between drug and LbL system, and ensure the controlled
drug release overtime. In a recent study, the authors used amphiphilic
molecule anionic beta-cyclodextrin (β-CD) to retain tetracycline,
as a hydrophilic antibiotic, within the LbL-coating titanium substrate
and control TC release from the multilayers up to 30 days ( E–G). The strong interaction between TC and anionic
β-CD and effective loading of the complex within the LbL system
enabled TC retention within the LbL coatings for a prolonged time,
regardless of medium pH. Importantly, the strong antibacterial effect
was observed after 48 h of incubation with more than 5 log reduction
of bacterial growth in comparison to the uncoated titanium surfaces.
The remaining antibacterial activity of the LbL system was confirmed
even up to 30 days, with 2.8 log reduction of S. aureus compared with the same uncoated surfaces. Summarizing, illustrates how LbL
technology can be tailored for specific dental implant applications
by leveraging different stimuli-responsive features. This table and
summary provide a clear overview of how LbL technology is advancing
the field of dental implants by improving their functionality and
clinical outcomes. It is essential to note that the factors that are
involved in the
structuring of the LbL system are also responsible for the responsive
nature of the bioactive compounds. The most prevalent self-defensive
antibacterial LbL films are pH-responsive because they take advantage
of the release of lactic and acetic acid by different bacteria, which
lowers the pH of the infection’s microenvironment. Thus, pH shifts can alter the conformational
state of the layers in LbL coatings, changing the dimension of the
polyelectrolyte mesh and facilitating the release of drugs. A similar effect occurs when the multilayer
system meets the biological environment. The presence of salts results
in the rearrangement of water molecules within the polyelectrolyte
layers, whose driving force is guided by an entropic effect, modifying
the conformation of the polyelectrolyte present. From this perspective, the release rate does not occur
exclusively through drug diffusion and platform degradation, but the
phenomena involved in extrinsic compensation are also responsible
for changes in the physicochemical properties of the LbL system. 

Physical Properties of LbL Coatings for Implant
Abutment Surfaces Implant abutments are essential components
that serve as bridges or extensions attached to implants to secure
artificial teeth. Unlike the implant itself, which is not subject
to mechanical friction during installation, the significance of abutments
lies in their direct contact with surrounding soft tissue. Hence,
any polyelectrolyte coating applied to abutment surfaces should exhibit
sufficient strength to withstand the forces exerted during placement
without being easily being removed. Furthermore, from a clinical point
of view, screw-retained abutments could be easily replaced by coated
ones during disease treatment. It is widely acknowledged that
surface topography significantly influences the biological response
of surrounding tissues to abutments. Numerous studies have demonstrated that rough surfaces tend to accumulate
more plaque, , increasing the risk of plaque-induced
inflammatory reactions in surrounding tissues compared to smoother
surfaces. Therefore, abutments should ideally feature smooth surfaces,
typically less than or around 0.2 μm, , , to facilitate mechanical cleaning
and ensure peri-implant health, especially in patients at risk of
peri-implantitis. Another critical surface property affecting surface
protein adsorption and cell adhesion quality is wettability, with
cells showing a greater propensity to adhere to hydrophilic surfaces. , In essence, any coating-based approach to combat peri-implantitis
should preserve or enhance the inherent properties of the components. For abutments, the primary challenge lies in developing a coating
that maintains the original topography—ensuring it does not
interfere with smoothness and wettability—while adding antimicrobial
properties without adverse effects on human cells. From a dental implant perspective, LbL technology holds
promise for coating implant abutment surfaces. The multilayers assembled onto abutment surfaces allow
precise control of polyelectrolytes’ vertical dispersion at
the nanoscale, thereby achieving the desired roughness based on the
chosen multilayer creation process. , In other
words, LbL-coating properties such as thickness, homogeneity, and
internal structure can be controlled and determined by various LbL
methods. With regards to the wettability,
hydrophilic/hydrophibic potential
of the LbL system is a key factor that influences protein adsorption,
cell adhesion, and the overall interaction between coating and biological
environment. Hydrophilic surfaces may
promote protein adsorption and enhance cellular attachment, which
can be beneficial in the tissue engineering field. Studies have shown that LbL assembly can be used to finely
tune these properties by selecting appropriate materials for the layers. , − For instance, incorporating hydrophilic
polymers such as poly(ethylene glycol) (PEG) can decrease the contact
angle, thus enhancing material hydrophilicity. Owing to the versatility and flexibility of LbL assembly,
coating
surface properties can be easily modified to enhance their biological
response before they come into contact with cells and tissues . However, caution is warranted when considering this technology
for implants themselves due to the risk of displacement or physical
damage to LbL coatings during implant installation. Clearly, LbL assembly
is a system based on a polyelectrolyte responsive to various conditions,
suggesting its susceptibility to mechanical forces. 

Key Challenges for an LbL-Based System to Fight
Peri-implantitis While the LbL system holds significant potential,
it also faces
several key challenges that must be addressed for its successful implementation: Limited Long-Term Efficacy . One of
the primary challenges with the LBL system is ensuring its long-term
efficacy in preventing peri-implantitis recurrence. The durability
of the coatings and their ability to withstand the oral environment,
mechanical stresses, and microbial challenges over time are crucial
factors. , Researchers are actively investigating new
materials and coating techniques that offer enhanced stability and
long-lasting protection against infection and/or inflammatory processes. , Biocompatibility and Tissue
Response . The biocompatibility of the materials used in LbL
coatings is essential
for promoting tissue integration and minimizing adverse reactions. , Ensuring that the coatings do not trigger inflammation or immune
responses is crucial for the success of the implant. Researchers are
exploring novel biomaterials and surface modifications to improve
biocompatibility and enhance soft tissue integration. , Optimal Coating Thickness and
Composition . Achieving the right balance in coating thickness
and composition
is another challenge. Coatings that are too thin may not provide adequate
protection against bacterial infiltration, while overly thick coatings
can interfere with tissue integration and healing. , Finding the optimal combination of materials and layering techniques
is an ongoing area of research. Control over Drug Release . Achieving
controlled release of a drug at the targeted location for the time
necessary to achieve the effect of the treatment is one of the major
challenges to be addressed. The main goal of LbL-targeted drug delivery
systems is to obtain high enough local concentrations of drugs through
spontaneous physiological processes with low systemic exposure. Moreover,
the high drug concentration incorporated into the system should not
be cytotoxic to human cells and tissue surrounding the implant component. Mouth as a Complex and Uncontrolled
Environment . The human mouth is a complex system constantly
exposed to saliva,
bacteria, enzymes, and biochemical processes related to the pH variation.
The pH is influenced by diet, oral hygiene practices, medical conditions,
and medications. Although saliva plays a pivotal role in maintaining
the pH balance in the mouth, a consistent imbalance in oral pH can
affect the molecular structure of the LbL system. Indeed, saliva is
one of the most important fluids to interact with overall biomaterials
in the first instance. The interaction of saliva compounds with biomaterials
may cause chemical–physical–biological alterations in
biomaterials. , In fact, in the present Review,
we have underlied the LbL system to peri-implantitis treatment due
to its ability to release the target drug over time. LbL biodegradation
governs the process of drug release, and the release profile of the
drugs depends upon the nature of the delivery system. However, in
addition to the chemical factors, physical forces related to the chewing,
swallowing, or brushing can directly affect the degradation process
and accelerate the drug release. Definitely,
LbL may be defined as a limited system by the fact that it can release
only one dose at a period of time. However, within the oral cavity,
its particular physiological conditions can be considered confounding
factors, promoting stimuli for the unexpected degradation of the biomaterial,
reducing the shell life of the system and compromising the applicability
of the coating. Clinical Translation
and Standardization . Moving from laboratory research to clinical
application presents
its own set of challenges. , , Ensuring that LbL coatings can be easily applied during implant
rehabilitation, are cost-effective, and have predictable outcomes
in diverse patient populations is crucial. Standardizing coating techniques
and protocols across different dental practices and implant systems
is essential for widespread adoption. Regulatory Approval and Safety . Before
LbL coatings can be used clinically, they must undergo rigorous testing
for safety and efficacy. , Obtaining regulatory
approval from health authorities requires extensive preclinical and
clinical studies to demonstrate the coatings’ benefits and
safety profiles. Meeting these regulatory standards adds to the challenges
of bringing LbL approaches to the market. A major concern is the new
MDR (medical device regulation) for which any adjustment to an existing/approved
product requires rigorous testing and documentation and high costs
for regulatory approval ( https://commit-global.com/how-does-the-eu-mdr-affect-the-translation-process/ ). Despite these challenges, the LbL system offers exciting
possibilities
for improving the success rates of dental implants and reducing the
incidence of peri-implantitis. , , , , Ongoing research and technological advancements are gradually addressing
these obstacles, paving the way for the development of innovative
coating materials that enhance the longevity and performance of dental
implants. Toward the end of this Review, it is essential to
address the current
progress in translating Layer-by-Layer (LbL) antimicrobial coatings
for dental implants from the laboratory to clinical application. This
section covers the stage of development of LbL coatings, the preclinical
testing models used, and the prospects for clinical translation. 

Current Progress in Translating LbL Antimicrobial
Coatings for Implant Abutment Surfaces The development of
LbL to drug delivery has garnered considerable
attention within the dental implant field for the antimicrobial potential
as a coating implant surface. However,
many studies have focused on applying this technology to the implant
itself, which poses challenges due to the mechanical forces and friction
exerted during placement into the bone, potentially compromising the
integrity of the coating, as discussed earlier. − Contrarily to the prevention and treatment concepts, several articles
have described the system as an interesting strategy to prevent infection
. However,
the multilayers built-up on a surface act as a structure to hold the
drug, which means that the LbL needs to be responsive to different
stimuli to enable the release of the drug. The LbL system could be easily prepared on implant
abutment surfaces.
The fact that the system is considered fragile to mechanical action,
which means that it could be easily removed during toothbrushing,
does not invalidate its importance. The main idea of creating a stimulus-responsive
system is to understand that it will be degraded. However, the lifetime
depends on the anionic and cationic reagents used and could be manipulated
to allow the system to remain on the surface for longer, according
to the pharmacological requirement to treat the target disease. Furthermore, implant abutments disclose a different set of challenges
and opportunities for LbL coatings. Developing
antimicrobial coatings for abutments requires specific considerations,
such as to maintain the smoothness and hydrophilicity of the surface,
ensure biocompatibility with soft tissues, prevent bacterial recolonization
at the soft tissue interface, and promote proper tissue integration
without compromising the peri-implant health. − As such, the translation of LbL coatings for implant abutments remains
a distinct and promising avenue of research, with the potential to
significantly improve the clinical outcomes in peri-implantitis treatment.
This is because the LbL coating does not affect the physical properties
and can either maintain the original roughness or make the surface
even more regular. With regard to the wettability, the reagents might
also be selected to reduce the contact angle between surfaces and
water and increase the hydrophilic requested property to abutment
components. Further advancements in this area would likely focus
on optimizing
the durability and efficacy of these coatings under the unique mechanical
and biological conditions encountered by abutments and aligning preclinical
testing models to reflect these specific needs. Several studies have
shown the antimicrobial properties of LbL coatings in vitro , highlighting their ability to inhibit bacterial biofilm formation
and reduce inflammatory responses around dental implants. , However, translating these findings into human clinical practice
requires robust preclinical testing in animal models and further characterization
of the coatings. Preclinical testing is a critical step in understanding
how LbL
coatings perform in biological environments. Most animal studies to
date are targeting the application for implants rather than for abutments,
and they have focused on small-animal models, such as rats and rabbits,
which offer useful insights into biocompatibility and short-term antimicrobial
efficacy. − These studies have demonstrated significant reductions in bacterial
colonization around the coated implants and provided preliminary evidence
of biocompatibility with the surrounding hard tissues. To the best
of our knowledge, with respect to abutment of dental implant applications,
no comprehensive study has yet been conducted on the use of LbL antimicrobial
coatings in animal models. While there is a growing body of research
exploring LbL coatings for various biomedical applications, , , − the translation of this technology is still stuck in the preclinical
phase, mostly because there is a lack of focus on the conceptual issues
involved in the creation process. Specifically for abutments, the
preclinical animal studies remain limited. This gap underscores the
need for further investigation into the efficacy, biocompatibility,
and long-term performance of LbL coatings in vivo , especially in larger and more physiologically relevant animal models. Collaboration between researchers and industry partners is essential
for scaling up production and ensuring cost-effectiveness. Advances in manufacturing processes and materials
are needed to make LbL coatings commercially viable. Ongoing research
aims to refine LbL-coating technologies, optimize drug release mechanisms,
and further validate their clinical efficacy. , − , , Innovations in coating materials and design, along with comprehensive
clinical trials, will be critical for successful translation. 

Conclusion A thorough comprehension
of the working mechanism of Layer-by-Layer
(LbL) assembly is crucial for researchers aiming to implement multilayer
strategies within the dental implant field, particularly in the development
of antimicrobial coatings to combat peri-implantitis. Current knowledge
regarding the LbL system highlights its responsiveness to various
chemical and physical stimuli. However, the responsive and degradable
nature of the materials used in assembling the LbL system imposes
limitations on its biomedical application in terms of the physical
site and purpose. From a dental implant perspective, the fragility
of the coating and its susceptibility to physical force necessitate
the application of the LbL system onto abutment surfaces, which are
in direct contact with soft tissue. Moreover, the versatility
of the LbL system in incorporating a
wide range of drugs and its ability to respond to external stimuli
make it a potential strategy for creating comprehensive antimicrobial
coatings focused on treating peri-implantitis. The mechanism of action
of the LbL system primarily involves the controlled release of drugs,
justifying its use when the disease is already present. In contrast,
for prevention purposes, where the aim is to deter the onset of the
condition, a system with a short shelf life would not suffice. Despite efforts to align clinical conditions with the nature of
the LbL system to better indicate its use as a coating, the complexity
of the oral environment—encompassing saliva, enzymes, varying
pH levels, and brushing—remains a significant challenge to
overcome. 

