The oral cavity is a unique complex ecosystem colonized with huge numbers of microorganism species. Oral cavities are closely associated with oral health and sequentially with systemic health. Many factors might cause the shift of composition of oral microbiota, thus leading to the dysbiosis of oral micro-environment and oral infectious diseases. Local therapies and dental hygiene procedures are the main kinds of treatment. Currently, oral drug delivery systems (DDS) have drawn great attention, and are considered as important adjuvant therapy for oral infectious diseases. DDS are devices that could transport and release the therapeutic drugs or bioactive agents to a certain site and a certain rate in vivo. They could significantly increase the therapeutic effect and reduce the side effect compared with traditional medicine. In the review, emerging recent applications of DDS in the treatment for oral infectious diseases have been summarized, including dental caries, periodontitis, peri-implantitis and oral candidiasis. Furthermore, oral stimuli-responsive DDS, also known as "smart" DDS, have been reported recently, which could react to oral environment and provide more accurate drug delivery or release. In this article, oral smart DDS have also been reviewed. The limits have been discussed, and the research potential demonstrates good prospects.Molecules 2020, 25, 516 2 of 29 problems. For example, systemic antibiotics such as tetracycline, beta-lactam antibiotics, nitroimidazoles have been used, especially in cases of periodontal diseases and peri-implantitis [12]. However, systemic antibiotics could cause problems like drug resistance, dysbacteriosis, and systemic side effects [13,14]. The antibacterial effect is also limited as very little could arrive at the oral lesion area after systemic circulation [15][16][17]. Fluoride in drinking water has been used for the prevention of dental caries but might cause excessive intake, leading to fluorosis [18]. Therefore, local drug therapy is now more considered for oral infectious diseases [19,20]. However, the conventional forms of local therapy, like drug suspension or rinse of anti-infection agents, could be easily washed off and thus could not last long in the oral cavity. Complex local lesions like deep periodontal pockets and teeth fissure are also difficult to reach. In order to improve the effect of prophylaxis and treatment, more precise targeting therapy is quite essential [21,22]. Therefore, drug delivery systems have drawn great attention in recent decades in oral infectious diseases. Drug delivery systems (DDS) are devices that can transport and release the therapeutic agents or bioactive substances to certain sites at certain rates in vivo [23,24], usually composed of the carriers and associated therapeutics [25]. They have been widely explored in biomedical research. With local drug administration and controlled drug release, DDS could provide higher curative efficiency and fewer side effects [23,26,27]. With all these advantages, DDS has been reported w...

Secondary caries caused by dental plaque is one of the major reasons for the high failure rate of resin composite restoration. Although antimicrobial agent–modified dental restoration systems have been researched for years, few reported intelligent anticaries materials could respond to the change of the oral environment and help keep oral eubiosis. Herein, we report tertiary amine (TA)–modified resin adhesives (TA@RAs) with pH-responsive antibacterial effect to reduce the occurrence of secondary caries. Two kinds of newly designed TA monomers were synthesized: DMAEM (dodecylmethylaminoethyl methacrylate) and HMAEM (hexadecylmethylaminoethyl methacrylate). In the minimum inhibitory concentration and minimum bactericidal concentration test against Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii, they exhibited antibacterial effect only in acidic medium, which preliminarily verified the acid-activated effect of TAs. Then DMAEM and HMAEM were incorporated into adhesive resin at the mass fraction of 5%, yielding TA@RAs. In vivo and in vitro tests showed that the mechanical properties and biocompatibility of the adhesive were not affected. A S. mutans biofilm model in acidic and neutral medium was used and confirmed that TA@RAs could respond to the critical pH value of de-/remineralization and acquire reversible antibiofilm effect via the protonation and deprotonation of TAs. Meanwhile, the stability of antibacterial effect was confirmed via a 5-d pH-cycling experiment and a saliva-derived biofilm aging model. Furthermore, 16S rRNA gene sequencing showed that TA@RAs could increase the diversity of the saliva-derived biofilms, which implied that the novel materials could help regulate the microbial community to a healthy one. Finally, an in vitro demineralization model and in vivo secondary caries model were applied and demonstrated that TA@RAs could prevent secondary dental caries effectively. In summary, the reversible pH-responsive and non–drug release antibacterial resin adhesives ingeniously overcome the defect of the present materials and hold great promise for clinical application.

Head and neck cancer (HNC) is among the most common malignancy that has a profound impact on human health and life quality. The treatment for HNC, especially for the advanced cancer is stagedependent and in need of combined therapies. Various forms of adjuvant treatments such as chemotherapy, phototherapy, hyperthermia, gene therapy have been included in the HNC therapy. However, there are still restrictions with traditional administration such as limited in situ therapeutic effect, systemic toxicity, drug resistance, etc. In recent years, stimuli-responsive drug delivery systems (DDSs) have attracted the great attention in HNC therapy. These intelligent DDSs could respond to unique tumor microenvironment, external triggers or dual/multi stimulus with more specific drug delivery and release, leading to enhanced treatment efficiency and less reduced side effects. In this article, recent studies on stimuli-responsive DDSs for HNC therapy were summarized, which could respond to endogenous and exogenous triggers including pH, matrix metalloproteinases (MMPs), reactive oxygen species (ROS), redox condition, light, magnetic field and multi stimuli. Their therapeutic remarks, current limits and future prospect for these intelligent DDSs were discussed. Furthermore, multifunctional stimuli-responsive DDSs have also been reviewed. With the modification of drug carriers or co-loading with therapeutic agents. Those intelligent DDSs showed more biofunctions such as combined therapeutic effects or integration of diagnosis and treatment for HNC. It is believed that stimuli-responsive drug delivery systems showed great potential for future clinic translation and application for the treatment of HNC.

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The objective of this study was to develop novel modified giomers by incorporating the antibacterial quaternary ammonium monomers (QAMs), dimethylaminododecyl methacrylate (DMADDM) or dimethylaminohexadecyl methacrylate (DMAHDM) into a commercial giomer. The material performances including mechanical properties, surface characteristics, color data, cytotoxicity and fluoride release of the novel giomers were evaluated. Antibacterial activity against severe early childhood caries (S-ECC) saliva-derived biofilms was assessed by lactic acid production measurement, MTT assay, biofilm staining and 16S rRNA sequencing. A rat model was developed and the anti-caries effect was investigated by micro-CT scanning and modified Keyes’ scoring. The results showed that the material properties of the QAMs groups were comparable to those of the control group. The novel giomers significantly inhibited lactic acid production and biofilm viability of S-ECC saliva-derived biofilms. Furthermore, caries-related genera such as Streptococcus and Lactobacillus reduced in QAMs groups, which showed their potential to change the microbial compositions. In the rat model, lesion depth, mineral loss and scoring of the QAMs groups were significantly reduced, without side effects on oral tissues. In conclusion, the novel giomers incorporated with antibacterial QAMs could inhibit the cariogenic biofilms and help prevent secondary caries, with great potential for future application in restorative treatment.

Background: Secondary caries often result in a high failure rate of resin composite restoration. Herein, we studied the dodecylmethylaminoethyl methacrylate–modified resin adhesive (DMAEM@RA) to investigate its pH-responsive antimicrobial effect on Streptococcus mutans and Candida albicans dual-species biofilms and on secondary caries. Methods: Firstly, the pH-responsive antimicrobial experiments including colony-forming units, scanning electron microscopy and exopoly-saccharide staining were measured. Secondly, lactic acid measurement and transverse microradiography analysis were performed to determine the preventive effect of DMAEM@RA on secondary caries. Lastly, quantitative real-time PCR was applied to investigate the antimicrobial effect of DMAEM@RA on cariogenic virulence genes. Results: DMAEM@RA significantly inhibited the growth, EPS, and acid production of Streptococcus mutans and Candida albicans dual-species biofilms under acidic environments (p < 0.05). Moreover, at pH 5 and 5.5, DMAEM@RA remarkably decreased the mineral loss and lesion depth of tooth hard tissue (p < 0.05) and down-regulated the expression of cariogenic genes, virulence-associated genes, and pH-regulated genes of dual-species biofilms (p < 0.05). Conclusions: DMAEM@RA played an antibiofilm role on Streptococcus mutans and Candida albicans dual-species biofilms, prevented the demineralization process, and attenuated cariogenic virulence in a pH-dependent manner.