Keywords
biofilm - caries - hydroxyapatite - periodontitis
Introduction
Bacterial biofilms are complex structures and mostly consist of several species that
are embedded in a matrix of extracellular polymeric substances.[1]
[2]
[3]
[4]
[5] The presence, growth, and metabolism of oral biofilms are the main causes for dental
caries and periodontitis.[4]
[5]
[6] These two diseases affect more than 2.44 billion people (active caries with permanent
dentition)[7] and 743 million people (severe periodontitis) worldwide.[8]
Therefore, a main preventive measure in oral care is to control oral bacterial biofilms.[4] This can be mainly achieved by mechanical plaque removal, for example, tooth brushing
(manual or electric toothbrush), flossing, and others, as well as by the toothpaste
formulation (i.e., abrasives).[9]
[10]
[11]
[12]
[13] The mechanical biofilm removal can be supported by antibacterial agents in toothpastes
or mouthwashes.[14] Frequently used antibacterial agents are, for example, chlorhexidine, metal salts,
quaternary ammonium salts, and others.[4]
[15]
[16]
[17]
[18] However, daily use of products with some of these antimicrobials might lead to unwanted
side effects; for example, chlorhexidine and stannous salts lead to extrinsic stain
of teeth.[15]
[19]
[20] Consequently, dental research is focused on new approaches in oral biofilm management.[21]
[22]
[23]
[24]
[25] Hence, biomimetic approaches are promising, because they mimic structures or processes
that have been evolutionarily optimized by nature over a long period of time.[26]
[27]
[28] In the field of enamel-inspired materials, hydroxyapatite, Ca5 (PO4)3 (OH), as a biomimetic oral care ingredient, has gained increasing attention in the
last decades.[24]
[26]
[27]
[29]
[30]
[31]
[32]
[33]
[34]
[35] Hydroxyapatite shows a good biocompatibility and has been widely used for biomedical
applications such as bone cements and implant coatings for many years.[36]
[37]
[38] Regarding preventive dentistry, products with hydroxyapatite offer a broad range
of applications, that is, prevention of dental caries, prevention of gingivitis/periodontitis,
and dentin hypersensitivity.[29]
[33]
[34]
[39]
[40]
[41]
[42]
[43]
[44]
[45] Interestingly, in situ studies show remarkable effects of hydroxyapatite particles,
reducing initial bacterial colonization to enamel and oral surfaces.[24]
[35]
[46],
This review summarizes published studies on hydroxyapatite with respect to biofilm
management and presents possibilities for further research avenues.
Study Selection
In vivo, in situ, and in vitro studies on hydroxyapatite in oral care, recently reviewed by Enax and Epple[26] and Meyer et al,[27] were included into this review. In addition, two databases (PubMed and SciFinder)
were used for literature search with following search terms: “Hydroxyapatite” AND
(“in vitro study” OR “in situ study” OR “in vivo study” OR “clinical study” AND “remineralization” OR “caries” OR “bacteria” OR “plaque”
OR “biofilm” OR “periodontitis”) OR “oral care.” The references were screened for
relevance and included in this review, respectively.
Concepts in Modern Biofilm Management
Classical Antibacterial Agents
Antibacterial agents, frequently used in oral care products such as toothpastes and
mouthwashes, are summarized in [Table 1]. Regarding biofilm control/plaque reduction, the well-known gold standard is chlorhexidine.
Chlorhexidine shows a wide effect of spectrum against Gram-positive and Gram-negative
bacteria and is known to show a high substantivity. However, long-term use of chlorhexidine
increases the risk of side effects such as taste alteration (dysgeusia)[47] or staining of the tooth surface.[48] The antibacterial potential of other substances, for example, metal salts, quaternary
ammonium salts, and natural extracts, is lower compared with chlorhexidine,[21] but can be used on a daily basis and is commonly introduced in oral care products.
It is important to know that the antibacterial effect of metal salts (e.g., zinc chloride
and stannous fluoride) is mainly attributed to the metal ion (i.e., Zn2+ and Sn2+) and not to its counterion.[15] This is also true for amine fluorides where the cationic surfactant (ammonium salt)
shows the antibacterial effect, and not the fluoride ion itself.[10]
[11]
[49] Furthermore, zinc ions are not only known for their antibacterial effect but also
to prevent oral malodor by inhibiting volatile sulfur compounds.[50]
[51]
[52] Regarding antimicrobial effects, zinc ions show a high substantivity in the oral
cavity.[53] Zinc ions can inhibit bacterial metabolism (i.e., glycolysis and trypsin-like protease),
leading to a reduced biofilm formation.[15] Compared with other antibacterial metal salts (i.e., Sn ), zinc does not stain the
enamel surface.[15]
Table 1
Examples of biofilm controlling agents used in oral care products such as toothpastes
and mouthwashes (in alphabetic order)
|
Substance classes
|
Examples
|
|
Abbreviation: PCA, pyrrolidone carboxylic acid.
|
|
Amine fluorides
|
Olaflur, dectaflur (antibacterial effect is based on the cationic amine)
|
|
Bisbiguanides
|
Chlorhexidine
|
|
Calcium phosphates
|
Hydroxyapatite (biomimetic approach; reduction of bacterial colonization without antibacterial
effects)
|
|
Phenols
|
Triclosan
|
|
Quaternary ammonium salts
|
Cetylpyridinium chloride (antibacterial effect is based on the cationic amine)
|
|
Stannous salts
|
Stannous chloride, stannous fluoride (antibacterial effect based on Sn2+-ions)
|
|
Surfactants
|
Sodium lauryl sulfate, sodium cocoamphoacetate
|
|
Zinc salts
|
Zinc chloride, zinc citrate, zinc PCA (antibacterial effect is based on Zn2+-ions)
|
Nevertheless, all the above-mentioned agents have common property that they can kill
both harmful and beneficial bacteria. However, the overall goal in biofilm management
is to keep the oral microbiome in a homeostatic state.[5]
[54] This means antimicrobials might lead to a selection of potentially pathogenic bacteria
and consequently to a dysbiosis of the microbiome.[5]
[54]
Therefore, research also focuses on alternative concepts, that is, on biomimetic approaches
keeping the microbiome in balance.[4]
[10]
[11]
[23]
[24]
Particulate Hydroxyapatite in Biofilm Management
Different types of hydroxyapatite are used in oral care formulations worldwide (e.g.,
hydroxyapatite and zinc hydroxyapatite).[26] Numerous studies on hydroxyapatite in dental care have been published in the last
years.[26]
[27]
[30] For example, a (fluoride-free) zinc hydroxyapatite-containing toothpaste showed
a comparable clinical performance in periodontitis patients compared with an antibacterial
fluoridated toothpaste with amine fluoride (Olaflur) and stannous fluoride, for example,
in reduction of bleeding on probing.[33] In addition, a zinc hydroxyapatite mouthwash showed a reduction in plaque accumulation
and gingivitis in children in vivo.[42]
Details on biofilm management using hydroxyapatite have been thoroughly analyzed in
several in situ[24]
[35] and in vivo studies.[46]
These studies analyzed the influence of a hydroxyapatite mouthwash as well as hydroxyapatite
particles and the liquid phase of the mouthwash. Antibacterial effects could be mainly
assigned to the liquid phase, whereas hydroxyapatite particles show antiadherent properties,
that is, reduction in initial bacterial colonization to the enamel surface.[35] Interestingly, pure hydroxyapatite particles dispersed in water (i.e., without any
apatite substituents such as zinc or other additives commonly used in oral care products)
reduced the bacterial attachment to enamel surfaces comparable to the gold standard
chlorhexidine in situ, without any antibacterial effect.[24] Studying the raw material is very important to analyze its efficiency and efficacy,
because other ingredients such as ethanol (usually used in combination with essential
oils),[55] surfactants, preservatives, and others as well as an acidic pH value (e.g., formulations
with amine fluoride) in oral care formulations may have an influence on the results
of biofilm management.[4] Besides in situ studies, in vitro studies using subminimal inhibitory concentration
show inhibitory effects of zinc hydroxyapatite products against cariogenic biofilms.[56]
[57] This means biofilm formation is inhibited, but bacteria are not killed. In addition,
it has been reported that the use of a mouthwash, containing zinc hydroxyapatite and
zinc L-pyrrolidone carboxylate, leads to a reduced bacterial attachment to suture
threads.[46] In summary, these findings make hydroxyapatite a potent biomimetic alternative to
classical antibacterial agents for oral care use. In addition to the existing studies,
future research needs to focus on the incorporation of hydroxyapatite particles into
oral biofilms and thus a clarification of the mode of action.[58] Synergistic effects in biomimetic oral biofilm management may be achieved by combining
hydroxyapatite particles with saliva proteins, such as lactoferrin or other enzymes.[23]
[59]
Conclusions
Due to its high biocompatibility as well as its structural and chemical similarity
to human enamel, hydroxyapatite is a promising oral care ingredient. Studies show
that it reduces the bacterial attachment to enamel surfaces similar to chlorhexidine
in situ, but without killing the bacteria. In addition, hydroxyapatite particles offer
other beneficial effects in the oral cavity, for instance, remineralization of enamel
and dentin as well as prevention of dentin hypersensitivity. Although more research
is needed to understand hydroxyapatite’s mode of action in reducing the bacterial
attachment to the enamel surface and to compare its efficiency toward other antibacterial
substances in vivo, hydroxyapatite may be a promising biomimetic alternative or supplement
for oral biofilm management.
