Drug delivery systems for oral disease applications

Abstract There are many restrictions on topical medications for the oral cavity. Various factors affect the topical application of drugs in the oral cavity, an open and complex environment. The complex physical and chemical environment of the oral cavity, such as saliva and food, will influence the effect of free drugs. Therefore, drug delivery systems have served as supporting structures or as carriers loading active ingredients, such as antimicrobial agents and growth factors (GFs), to promote antibacterial properties, tissue regeneration, and engineering for drug diffusion. These drug delivery systems are considered in the prevention and treatment of dental caries, periodontal disease, periapical disease, the delivery of anesthetic drugs, etc. These carrier materials are designed in different ways for clinical application, including nanoparticles, hydrogels, nanofibers, films, and scaffolds. This review aimed to summarize the advantages and disadvantages of different carrier materials. We discuss synthesis methods and their application scope to provide new perspectives for the development and preparation of more favorable and effective local oral drug delivery systems.


Introduction
The oral cavity is a complex environment which communicates with the external environment, the upper respiratory tract, and the digestive system. 1,2 A wide variety of microorganisms is present in the oral cavity, including bacteria and fungi, such as Streptococcus mutans (S. mutans), Lactobacillus spp.
Porphyromonas gingivalis (P. gingivalis), and Candida albicans. [3][4][5] These microorganisms colonize different parts of the oral cavity, including tooth surfaces and the periodontium, and form biofilms which invade oral cavity tissues. Periodontitis is a consequence of alterations in the ecology of resident microbial communities. The intimate interaction of bacteria with the host leads to an inflammatory reaction. 6 Dental caries is a consequence of dietary, sugardriven biofilm accumulation and localized acidification.
Due to frequent sugar consumption, the development of a predominantly acidic environment will favor the growth of aciduric bacteria in the biofilm. Aciduric bacteria include Streptococcus spp., Lactobacillus spp., etc. As a result, the dynamic balance between commensals and opportunistic pathogens is disrupted, causing deleterious microbial community shifts and disrupting tooth-enamel mineral homeostasis. [7][8][9][10] According to the global burden of disease (GBD) study, permanent tooth caries is among the ten diseases with the highest incidence for years lived with disability. 11 Periodontal diseases comprise a wide range of inflammatory conditions affecting tooth-supporting structures (the gingiva, bone, and periodontal ligaments), which starts with the localized inflammation of the gingiva, initiated by a microbial biofilm that forms on the teeth and gingiva. [12][13][14] Periodontal diseases lead to teeth loss and contribute to systemic inflammation, which is highly prevalent worldwide. 15 Thus, periodontal diseases represent a significant public health problem. 16 Regarding the topical application of drugs to the oral cavity, the influence of the oral environment on the drugs should be considered. Its complex physical and chemical environment and the complexity of bacterial biofilm affect drug application via the oral cavity. 17 For example, salivary flow rates in the mouth might affect the efficacy of topical anesthesia to some extent, whereas side effects and drug resistance are inevitable in systemic administration. 18 Salivary clearance might dilute and weaken the active ingredients in the oral environment. Therefore, carrier systems had to be designed to consistently release active ingredients so their estimated concentrations can be effective.
Recently, emerging advanced biomaterials, including hydrogels, films, nanofibers, and particles hold great potential as cell/drug carriers for local drug delivery and biomimetic scaffolds. 19 Biofilms decrease the effects of drugs on microorganisms, and antibacterial substances are easily metabolized. Moreover, there is no perfect way of delivering drugs to sites such as the periodontal pocket and the periapical area. In the reviewing process, "oral/oral cavity/mouth/ mouth cavity" and "drug delivery systems/carrier materials/drug targeting" were used as research items in the Pubmed, MEDLINE, and Web of Science databases. Relevant articles with an impact factor greater than five and published after 2015 were included. Moreover, we added some articles about the progress of experiments based on previous classic reviews. All drug delivery systems were classified as nanoparticles, hydrogels, nanofibers, and films according to their material properties. The carrier materials used as oral drug delivery systems in recent years are summarized in Table 1, and their different forms are described in Figure 1. This review discusses drug delivery systems in the oral cavity, which are prepared by various methods to adapt to complex situations. For example, they can be used as support structures to promote regeneration in defective tissues or as drug carriers to release active ingredients which

Nanoparticles
Nanoparticles have widely served as drug delivery systems in the oral cavity. 23,24 Nanoparticles include ZHANG Y, JIANG R, LEI L, YANG Y, HU T

Inorganic nanoparticles
In general, mesoporous materials are used as inorganic nanoparticle carrier systems. Mesoporous materials include mesoporous silica nanoparticles (MSNs) and mesoporous calcium silicate nanoparticles (MCSNs). [28][29][30] MSNs have been modified by amination to make them more suitable for use in the oral environment.
In recent studies, the amine-functionalized expanded pore mesoporous silica (aMSN) was synthesized to incorporated silver ions into MSNs, synthesizing silverdecorated mesoporous silica nanoparticles (Ag-MSNs) and using them to load chlorhexidine (CHX). They showed redox/pH-responsive release properties due to CHX and silver ions which could inhibit S. mutans biofilm growth. Ag-MSNs @ CHX were more effective than an equivalent amount of free CHX in limiting S. mutans biofilm formation since they induced bacterial cell death, particularly in the long term. Though S. mutans was only used as a model to evaluate the effect of Ag-MSNs @ CHX, the material may be considered for treating diseases caused by bacterial biofilms, such as periodontal diseases.
To promote tissue regeneration, biocompatible GFs. The PL-loaded hydrogels showed preferential supportive properties for encapsulated human dental pulp cells (hDPCs) in in vitro culture conditions. These hydrogels could serve as scaffold for GF delivery and cell recruitment, with great potential in future developments for regenerative dentistry. 86 Moreover, antibiotics and nitric oxide (NO), releasing biomimetic nanomatrix gel, were synthesized by the selfassembly of peptide amphiphiles, which could promote tooth revascularization with the maturation of root canals. 87 Hydrogels can also be used to treat fungal infections and deliver anesthetics. Hydroxypropyl methylcellulose (HPMC) was used to load Histatin-5 (Hst-5), an antimicrobial peptide, which could treat oral candidiasis. 88 A nanostructured lipid-biopolymer hydrogel was developed to continuously deliver lidocaine-prilocaine for trans-buccal preanesthesia, which showed stability (for 6 months in critical conditions) and suitable mechanical properties for oral administration. 89 Natural products can also be used to make thermosensitive hydrogels for oral applications.

Other Drug-delivery Systems
In dental tissue engineering, growth factors and scaffolds are widely used to provide a 3D-scaffold structure with a highly porous, interconnected network that enables the transport of cellular nutrients. [109][110][111] Polycaprolactone (PCL)/polylactic-co-glycolic acid was combined with amorphous polycaprolactone (PCL) to synthesize scaffolds which were immobilized with adenoviruses onto the scaffold surface to locally deliver gene vectors encoding platelet-derived growth factor-BB or bone morphogenetic protein-7.  1997;14:33-53. doi: 10.1111/j.1600-0757.1997 Translation of a solution-based biomineralization concept into a carrier-