1. Introduction

Dental biomaterials form the backbone, which helps prevent, restore, and rehabilitate oral form and function. Designing and testing these materials produces various mechanical and biological properties, leading to their harmonious presence inside the oral cavity. The last few decades have seen notable developments in dental materials, and properties such as adhesion to the tooth surface and biomimetics have been extensively explored^[1]. All the approved materials meet the biocompatibility standards, but they do not account for the interfacial interaction with oral microcosms^[2][3].

Methacrylate-based resin composites and polymers are the main components of dental restorative materials used to address the restoration of carious and missing teeth^[4]. These materials meet most of the standard requirements but continue to be afflicted by issues concerning premature mechanical and esthetic failures^[5]. These failures are multifactorial, but interaction with the host-factors is considered as a key factor^[6][7]. In the host-factors, the critical factor of microbiological interaction at the surface leads to biofilm formation ^[8]. The etiologic role of oral biofilms in dental caries and periodontal diseases has been previously documented ^[9]. The improved scientific evidence also indicates an active interaction at the dental materials and oral biofilm interface. Majority of the studies, including clinical trials concerning biofilm research, are related to stomatognathic diseases and address a wide range of issues such as caries, periodontitis, and demineralization^[10]. Nevertheless, it is essential to note that the interfacial interaction between the dental material and biofilm is multifactorial. Subsequently, research on a variety of methods are focused on improving this interaction.

Dental biomaterials differ from the hard tissues in the oral cavity in terms of both their physical and chemical properties. Advancements in biomimetic restorative materials are rapidly occurring, but they exhibit a different surface interaction. The key surface properties of topography, roughness, surface energy, and the inherent chemical composition alter the biofilm interaction at the surface of the restorative materials^[11][12][13]. Materials with low surface energies are associated with a higher affinity for bacterial adhesion, and many dental materials present higher surface energies than natural enamel ^[14][15]. Dental plaque is an ecologically dominant form of oral biofilm associated with cariogenic and periodontal infections. The increase in surface microroughness and topography is correlated to the surface energy and plays a defining role in microbial adhesion. A rough surface leads to an increase in the difficulty of removing dental plaque like biofilms with conventional methods (e.g., mechanical brushing) alone. Microroughness, expressed as the arithmetic mean (Ra) value, has been suggested for comparing the surface roughness of the materials, and a maximum threshold of 0.2 μm has been proposed to limit microbial adhesion^[14]. Biofilm formation showed considerable variation, independent of the bacterial adhesion correlation to the prescribed threshold ^[16]. Hence, regardless of the surface finish, dental materials lack any inherent biofilm resistance and are prone to secondary infections.

Broadly, two approaches have been reported for the management of oral biofilm formation, comprised physical and chemical methods. While physical methods involve mechanical removal of the biofilm by actions such as tooth brushing, conventional chemical methods include dentifrices ^[17] and dental mouth rinses^[18]. These approaches have focused on substituting or adding chemicals and have displayed good efficacy in an in vitro environment. However, these approaches have inherent limitations, such as dependence on user compliance, and a tendency to damage restorations (e.g., by esthetic and strength deterioration) and oral tissue (e.g., due to hypersensitivity, desiccation, and discoloration) ^[19].

Apart from adhesive resins, the methacrylate-based resins used in the fabrication of prosthodontic, removable appliances are also limited by issues of plaque biofilm formation ^[20]. Plaque biofilm formation on acrylic-based appliances is the cause of secondary fungal and bacterial infections, leads to a degradation of the polymer constituents, and reduces the appliances' longevity^[21]. The challenges mentioned above have laid the foundation for the development of novel approaches to counter biofilms. Many of these new methodologies, currently under research, involve modification of the dental materials by using antibiotics, incorporation of metal oxides ^[22], nanoparticles ^[23], and anti-adhesion coatings using hydrophilic polymers^[24].

Amidst a large number of methods, the approach utilizing the resistance to biofilm formation due to anti-adhesion properties has attracted attention. This property is characteristically reported for zwitterionic polymers (ZPs). The innovation and application of ZPs is a close form of biomimicry against fouling, inspired by the mammalian cell phosphatidylcholine membrane, which is characteristically present on the outer surface ^[25][26]. These polymers are formed by an equal amount of anionic and cationic groups on their chains with a high dipole moment. With a net charge of zero, these polymers present superior surface lubrication, antifouling, and biocompatibility. This leads to a wide range of multi-disciplinary adaptations of these polymers, including dental biopolymers^[27].

Therefore, it is imperative to provide an overview of current progress on the developing role of ZPs in dental biomaterial science. In this scoping review, ZPs are briefly introduced, followed by oral biofilm characterization, present trends in the research, and the development of zwitterionic dental materials reported in recent years. In the last section, the existing challenges and road to the future development of oral biofilm-resistant materials are highlighted. We hope that this review will stimulate more innovative ideas to advance research and point toward the persistent question of “what next?”.

2. Theoretical aspects of zwitterionic polymers

The use of hydrophilic polymers such as poly(vinyl alcohol) and poly(ethylene glycol) (PEG) has been suggested to address the problem of surface fouling. PEG has been used as the gold standard of nonfouling polymers as a biocompatible polymer but has poor stability due to autoxidation ^[28]. The degradation of the PEG chains further increases with an increase in temperature above 35 °C and an ionic environment, such as hemodynamics^[29]. ZPs form the closest alternative to PEG when considering amphiphilicity. ZPs containing an equal number of cations and anions have been classified based on their chemical structure.

ZPs with anion and cation groups existing on the same monomeric units form polybetaines (also known as polyzwitterions), such as poly(sulfobetaine methacrylate) (SBMA), poly(carboxybetaine methacrylate) (CBMA), and poly(2-methacryloyloxyethyl phosphorylcholine) (MPC). When both ion groups are present on different monomers, the ZPs are of the polyampholyte type, such as 2-(dimethylamino)ethyl methacrylate and methylmethacrylate block copolymer (DMAEMA-MAA). All ZPs can exist in different architectures, among which the membrane and brush type are the most commonly grafted types.

The distinctive feature of ZPs occurs due to its antipolyelectrolyte effect (APE) ^[30],^[31]and super-hydration ability ^[24]. The salt-responsive state of ZPs, which also affects their viscosity in a solution with low-molecular salt (LMS), is regarded as the opposite of the poly-electrolyte effect, hence it is termed as the APE. This property, detailed by Georgiev et al. ^[30], has been extensively explored. Accordingly, the introduction of LMS is believed to reduce the interchain dipole interaction within the polymer. The change in the polymer's charge interaction promotes the extension of the chains, and subsequent swelling of the globalized polymer occurs. The reduction in the interchain interaction encourages the polymer-water interaction to achieve an entropy balance, resulting in the formation of a tightly-bound water layer^[32]. This characteristic, bound, water layer formation is the second unique feature of ZPs, referred to as their super-hydration ability.

Figure 1. Schematic representation of the (A) zwitterionic polymers (ZPs) and (B) the salt-responsive antipolyelectrolyte effect (APE) of the ZP brushes. PSBMA—poly (sulfobetaine methacrylate), PCBMA—poly (carboxybetaine methacrylate), and PMPC—poly (2-methacryloyloxyethyl phosphorylcholine).

The super-hydration ability, characterized by the formation of the hydration shell via electrostatic interaction, is also influenced by the arrangement of water molecules within the shell. The arrangement mimicking free water causes an increase in the affinity to water^[33]. Therefore, the formation of a compactly-bound, thick, energetic layer occurs on the ZP brush. This layer enforces a strong steric effect, facilitating a strong resistance to protein adsorption and subsequently to fouling ^[26]. In other words, the development of biofilm resistance takes place as a combination of surface hydration and steric repulsion ^[34].

3. Human oral biofilm: composition and properties

The microbiome has been described as the presence of pathogenic, symbiotic, and commensal microorganisms together in a community, and thus an oral biofilm can be considered a sub-microbiome^[35]. Moreover, the biofilm is a microbially-derived, sessile community wherein cells that are irreversibly attached to the substrate or each other are embedded in an extracellular polymer substance (EPS) matrix^[36]. Advancements in genomic studies have helped decode the oral microbiome, evidencing a broad heterogeneous nature of the oral microbiota with more than 600 different species coexisting ^[37][38].

The development of oral biofilms is a spatiotemporal phenomenon that is composed of initial, physicochemical interactions. This initial contact establishes the foundation for the biofilm's growth and maturation, incorporating a nutrient, pH, and oxygen level gradient ^[39]. The multi-stage biofilm life cycle is described in detail in the review by Stoodley et al. ^[40], and the biofilm has also been recently discussed as an "emergent form of bacterial life" by Flemming et al.^[41]. Therefore, to better understand the mechanisms that help combat biofilm formation in the oral cavity, it is important to understand the development of this emergent life form.