Key points

Introduction

The regeneration of periodontal tissues is the ultimate goal of periodontal therapy. Despite impressive progress over the last 30 years, especially in terms of nonsurgical and surgical therapies (antibiotics, photodynamic therapy, probiotics, minimally invasive surgical approaches, biomaterials development, etc), tissue regeneration remains difficult to achieve in some specific clinical scenario, such as complex lesions with a lack of bone walls or those that are difficult to reach, such as a furcation area. Pharmacologic approaches have been proposed to optimize treatment outcomes, targeting either infection, inflammation, or tissue growth. However, systemic administration is complex because it induces an unnecessary systemic loading of the drug as well as a decreased bioavailability at the periodontal pocket site. ^, To overcome such limitations and improve treatment outcomes, innovative nanotechnologies have been developed and tested over the last years with promising results. Nanomedicine has been defined as “the monitoring, repair, construction, and control of human biological systems at the molecular level, using engineered nanodevices and nano-structures.” It uses the properties of materials at a nanometric scale to improve diagnosis and imaging, as well as to promote tissue regeneration through the delivery of bioactive compounds or drugs.

The application of nanomedicine and nanotechnologies has been suggested to be a part of the therapeutic arsenal for several diseases such as cancers and inflammatory diseases such as rheumatoid arthritis, aiming to deliver most efficiently the drug or active compounds to a specific site. Therefore, the use of such nanotechnologies for the treatment of periodontal diseases, mainly periodontitis, has been proposed with the goal to deliver a sufficient concentration of active molecules at the targeted site and to avoid its distribution in nonspecific tissues, consequently decreasing the risk of side effects. The onset and development of the periodontal lesion involve several cell types, including epithelial cells from the junctional epithelium, fibroblasts from the connective tissue, bone cells, and all immune cells, especially polymorphonuclear neutrophils and macrophages. The targeting of such cells to arrest the proinflammatory host response and/or to promote the proresolution of the inflammation is then required and several nanocarriers have been developed. Nanocarriers are polymers of biological or synthetic origin that are used to deliver drugs such as antibiotics, antibodies, or other macromolecules adsorbed on their surfaces or within their core and are for most of them biodegradable. Indeed, chitosan, polylactic-co-glycolic acid (PLGA), carbon quantum dots, and mesoporous silica/bioactive glass have been developed and tested in several applications including periodontitis ^, ( Fig. 1 ). The aim of this review is to describe the advantages of such nanoparticles and the feasibility of their use in the specific context of periodontitis treatment.

Nanomedicine strategies designed for periodontal treatment. Nanoparticles/nanoreservoirs could be implemented in different scaffolds to display their antibacterial, anti-inflammatory, and proregenerative properties with a low risk of systemic side effects.

Chitosan-based nanomaterials

Chitosan is a natural polysaccharide that can be easily produced via the alkaline N -deacetylation process of a natural biopolymer commonly found in the shells of marine crustaceans and in fungi cells walls, the chitin. It is widely used to synthesize biomedical scaffolds or implants owing to its biocompatibility, antibacterial properties, positive host response, and sufficient mechanical strength. It is already used as a wound dressing due to its interesting hemostatic and antimicrobial properties contributing to the formation of the blood clot and to a decrease in the risk of infection at the treated site. ^, The inherent antimicrobial properties of chitosan, mainly associated with its cationic nature, have been demonstrated against different microorganisms in several cellular and animal models. In the context of periodontitis, the antibacterial properties of chitosan nanoparticles have been tested against major periodontal pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans . Indeed, it was shown that exposure of these bacteria to chitosan nanoparticles inhibits bacterial growth in vitro. Chitosan-based nanoparticles could also be loaded with antimicrobial peptide to interact with pathogens in a planktonic state, as well as when organized in biofilms as observed for P.gingivalis , Fusobacterium nucleatum , and Streptococcus gordonii . It can also be loaded with drugs such as antibiotics, that is, minocycline and antiseptics such as chlorhexidine to enhance their properties. ^, Chitosan nanoparticles or nanoreservoirs have also been used to deliver on site immune-modulatory molecules and proregenerative factors. Several studies have been conducted in this regard with significant effects ^, ( Table 1 ). For instance, the delivery of statins using chitosan carriers was evaluated and showed promising results in terms of periodontal regeneration. In a model of experimental periodontitis in dogs or in a mouse calvarial defect. Chitosan has also been used to synthesize nanoreservoirs that could be constructed on the fibers of scaffolds such as membrane. Such technology demonstrated efficiency toward the delivery of growth factors such as BMP-2 enhancing bone regeneration with improved biocalcification of the scaffold and especially in the context of maxillary bone regeneration ( Fig. 2 ).

Chitosan nanoreservoirs containing BMP-2 in polycaprolactone fibers.

Polylactic-co-glycolic acid

PLGA is a synthetic biodegradable copolymer widely used in medical applications owing to its minimal cytotoxicity. Its degradation by hydrolysis results in biocompatible byproducts, lactic acid and glycolic acid, that are physiologically metabolized. PLGA has been used as a nanocarrier to deliver active drugs to treat several diseases or to promote tissue regeneration. It has been used extensively to design scaffolds, including barrier membranes, bone scaffolds, sponges, and gels ( Fig. 3 ). PLGA displays interesting physical properties because its viscosity is modulable; however, it is also associated with an initial burst release of the active molecule, and therefore is often use in combination with chitosan in a core shell technique. The modulation of the thickness of the shell could be interesting to increase the time needed to deliver the active molecule. In the context of periodontal treatment, PLGA nanoparticles (or PLGA–chitosan nanoparticles) have already been tested in several model (in vitro and in vivo) and in clinical settings ( Table 2 ). Indeed, antibiotics, compounds of natural origin with anti-inflammatory properties such as curcumin, metals such as silver, and immunomodulatory drugs such as statins have been loaded. Most of the studies exhibited positive outcomes resulting in a decrease in a decrease of periodontal pathogens growth and inflammatory cytokine secretion. Interestingly, PLGA nanoparticles have also been tested as methylene blue carrier in the context of treatment of periodontal pockets with photodynamic therapy. ^, The use of nanocarriers, such as PLGA, allows to deliver locally a high concentration of photosensitizer at the site, decreasing the risk of multidrug resistance.

PLGA nanoparticle synthesized with a core-shell technique allowing the loading of an active drug in the core of the particle.

Table 2

Representative studies evaluating potential use of PLGA nanoparticles in the context of periodontal treatment

Study	Type of Study	Active Drug	Size of Particles	Effects
Beg et al, 2020	In vivo: experimental periodontitis in rats. Effect of in situ gel containing nanoparticle of moxifloxacin hydrochloride	Moxifloxacin hydrochloride	204.63–292.81 nm	Histopathologic studies demonstrated almost complete recovery after 3 wk of treatment Results were better in moxifloxacin nanoparticles treated group vs commercially available gel (0.5% chlorhexidine and 1.5% metronidazole)
Ghavimi et al, 2020	In vitro: Staphylococcus aureus, Escherichia coli , and Enterococcus faecalis cultures; Dental pulp stem cells In vivo: alveolar bone defect in mongrel dogs Antibacterial, cytocompatibility and proregenerative properties were evaluated	Membrane functionalized with curcumin and aspirin-loaded PLGA nanoparticles	50–85 nm	An antimicrobial effect of the functionalized membrane against S aureus , E coli , and E faecalis was observed Enhancement of the osteogenic potential at both transcriptional and translational levels After 28 d, the lesion was completely filled with new bone, whereas the area covered by the commercial membrane remained empty
Pérez-Pacheco et al, 2019	Clinical (6 mo): periodontitis patients received SRP + PLGA/PLA nanoparticles loaded with 50 μg of curcumin or SRP + empty nanoparticles	Curcumin	Not specified	PPD, CAL, and BOP were improved in both groups A decrease in red complex bacteria was observed in both groups No difference in terms of GCF cytokine levels were observed between groups No additive benefits of a single local application of curcumin
Lecio et al, 2019	Clinical (6 mo): Effect of PLGA nanospheres containing 20% doxycycline on patients with diabetes type II with chronic periodontitis vs PLGA + placebo	Doxycycline	1 μm	Both groups showed clinical improvement in all parameters after treatment Doxycycline improved deep pockets, BOP, PPD, and CAL (vs placebo) The percentage of sites presenting PPD reduction and CAL gain of ≥2 mm was higher in doxycycline at 3 mo Doxycycline induced an increased level of anti-inflammatory IL-10, and a decrease in of IL-8, IFN-y, IL-6, and IL-17 A decrease in periodontal pathogen counts
Mahmoud et al, 2019	In vitro: telomerase immortalized gingival keratinocytes In vivo: Measure of alveolar bone destruction in mouse experimental periodontitis Effect of peptide (BAR) derived from S gordonii – modified PLGA nanoparticles	BAR (peptide)	333 nm and 312 nm (hydrated)	Less bone loss and IL-17 after treatment No significant lysis or apoptosis of telomerase immortalized gingival keratinocytes after treatment relative to untreated cells
Xue et al, 2019	In vitro: primary human periodontal ligament cells; E coli culture In vivo: Measure of the bone regeneration in the mandible of New Zealand white rabbits Effect of PLGA nanoparticles, CS nanoparticles, silver nanoparticles and a combination of the 3 were evaluated.		112.4 ± 8.33 nm (PLGA nanoparticles) 180.3 ± 11.2 nm (CS nanoparticles)	Nanoparticles were found to have no significant cytotoxicity and were able to promote human periodontal ligament cells mineralization CS nanoparticles and silver nanoparticles in low concentrations showed antibacterial activity The PLGA nanoparticles and CS nanoparticles complex contributed to cell mineralization and had no cytotoxicity The bone recovery rate of PLGA nanoparticles/CS nanoparticles group was greater than that of PLGA nanoparticles/CS nanoparticles/silver nanoparticles group. Results in both test groups were better than control group
Pereira et al, 2018	In vivo: Evaluation of the effect of metformin hydrochloride-loaded PLGA in a ligature-induced periodontitis model in diabetic rats	Metformin hydrochloride	457.1 ± 48.9 nm	Metformin-loaded PLGA decreased inflammation (IL-1β and tumor necrosis factor -α), and bone loss
Rizzi et al, 2016	In vitro: Human keratinovytes Evaluation of proliferative effects of epiregulin- PLGA nanoparticles on human keratinocytes	Epiregulin	190–370 nm	50:50 PLGA- nanoparticles exhibited the best dental adhesive ability Epiregulin-loaded nanoparticles increased cell proliferation
Lee et al, 2016	In vitro: human bone marrow-derived osteoblasts; A actinomycetemcomitans and Prevotella nigrescens culture In vivo: maxillary intrabony defect in dog Evaluation of cytotoxic effect and alkaline phosphatase activity, as well as antibacterial activity and bone regenerative potential of PLGA–lovastatin–chitosan–tetracycline nanoparticles	Lovastatin-chitosan-tetracycline	105–111 nm	PLGA–lovastatin-chitosan–tetracycline nanoparticles showed good biocompatibility, antibacterial activity, and increased alkaline phosphatase activity Increased of new bone formation in defects filled with nanoparticles

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