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Periodontitis is a complex inflammatory disease that occurs in periodontal supporting tissue.1 In a statistical analysis investigating the occurrence of periodontitis in 17 nations over the course of the last decade, it was found that the prevalence of periodontitis was approximately 60%. Furthermore, the proportion of severe periodontitis reached a significant 24%.2
Periodontitis is often referred to as a “silent” disease because it is seldom associated with obvious signs and symptoms unless the disease has progressed to an advanced stage.3,4 Untreated periodontitis may end up in the destruction of the supporting tissue of the teeth, potentially causing tooth loss and diminished quality of life, particularly in severe instances.5 However, periodontitis is not only a local phenomenon, periodontal pathogens and their metabolites and inflammatory mediators can enter the bloodstream, thus causing the development of systemic diseases.6,7 Such as, there is an established link between periodontitis with diabetes, metabolic syndrome, cardiovascular disease, and chronic kidney disease.8–10 In addition, associations to be confirmed exist between periodontitis and several other diseases, such as adverse pregnancy outcomes,11 Alzheimer’s disease,12 and cancer.13
Scaling and root planing (SRP) is the prevailing treatment for periodontitis,14 with the goal of eliminating both supragingival and subgingival plaque and tartar. For the clinician, proper execution of SRP is an effective but challenging process that requires a rigorous, meticulous approach.15,16 Mechanical treatment alone cannot stop progressive periodontitis because of periodontitis is driven by bacteria that cannot be removed thoroughly by mechanical instruments. This requires some complementary treatment to improve, such as mouthwash, antibiotics, probiotics, and so forth.17–19 However, in recent years, periodontal pathogens have also developed antibiotic resistance, which has affected the success of periodontitis treatment. Hence, alternative antibacterial approaches are required to effectively manage and cure periodontal disease.20 In addition, guided tissue regeneration/guided bone regeneration (GTR/GBR) seems to be a favorable alternative for some patients with severe periodontitis who continue to have unsatisfactory results after the completion of basic periodontal treatment.21 However, no GTR/GBR membrane meets all the requirements of good mechanical strength, suitable degradation rate, satisfactory osteogenesis, and clinical operability at the same time.22 Therefore, it is crucial to pursue more efficient therapies to tackle these issues.
Nanomaterials have been widely noticed in many biomedical fields, particularly in the realm of cancer research.23–28 In the past few years, therapeutic nanoparticles (NPs), as a developing engineering solution for treating periodontitis, have received extensive attention.29–32 NPs possess distinct therapeutic qualities, including exceptional antibacterial, anti-inflammatory, and antioxidant properties, immunomodulatory capacities, and the promotion of bone regeneration ability. These attributes are a result of the material’s inherent characteristics and its combination with various medications. Silver NPs have excellent antimicrobial activity against periodontitis pathogens.33 The combination of silver nanoparticles with the anti-inflammatory drug ebselen improves biosafety and provides synergistic anti-inflammatory and antibacterial effects.34 Bai et al delivered minocycline hydrochloride (MH) using polydopamine (PDA)-functionalized mesoporous silica. The remodeling of the periodontitis microenvironment by the synergistic action of PDA and MH resulted in a decrease in ROS levels and the conversion of macrophages to an anti-inflammatory phenotype.35 According to the latest research, we are of the opinion that NPs have the potential to be crucial in the future management of periodontitis.
There are few reviews about nanoparticles in the treatment of periodontitis. Previously, the role of some single classes of nanoparticles in periodontitis treatment has been summarized in the literature, such as metal nanoparticles.36 Several studies have also investigated nanoparticles for use in periodontal delivery systems.37–40 Shawky et al presented the application of periodontal membranes loaded with antibiotics, metal nanoparticles, and metal oxides for topical periodontal drug delivery.41 In conclusion, the current study lacks a systematic introduction of nanoparticles for the treatment of periodontitis. This article examines the NPs currently employed in the treatment of periodontitis. These NPs vary in size from 1 to 1000 nm36,42 and are categorized into three groups: inorganic NPs, organic NPs, and nanocomposites (including nanofibers, hydrogels, and membranes) (Figure 1). The objective of this review is to offer a more thorough analysis of the present research progress on the use of NPs in managing periodontitis. This review summarizes the challenges and future directions of NPs in the treatment of periodontitis.
Nanomaterials, A New Strategy Treating Periodontitis Pathologic Mechanisms and Treatment of PeriodontitisPeriodontal disease is an infectious disease involving multiple pathogenic factors and risk promoters. Conventional wisdom suggests that penetration of periodontal tissues by specific bacteria and/or their metabolites is a key step in the pathogenesis of periodontitis.43 For instance, Porphyromonas gingivalis (P. gingivalis) has been recognized as such a key pathogen.44 However, monocausal ideas lack support from in vivo or situ evidences. Instead, more evidence suggests that periodontitis is associated with ecological disorders.45 Ecological dysbiosis refers to changes in the quantity or influence of specific species within a diverse microbial community, which disrupts the homeostasis of the host microorganisms and leads to immune-related destructive inflammation.46 Periodontal health requires a controlled state of immune inflammation capable of maintaining a state of host-microbe homeostasis within the periodontium.47 Plaque biofilms, believed to be the causative agent of periodontitis, are organized aggregates of microorganisms that exist within a complex intercellular matrix.48 Once the host-microbe homeostasis is disrupted, periodontal inflammation (unattached loss and resorption of alveolar bone) occurs. When ecologically dysfunctional microbiota act on the periodontal tissue of a susceptible host. Plaque microorganisms are pathogenic either directly by damaging periodontal tissues through their metabolites or indirectly by causing an immune response in the host.49
Host susceptibility is also essential in the progression of periodontitis. In individuals who are susceptible, the host response is dysregulated and destructive. Although bacteria are necessary for disease pathogenesis, it is primarily an excessive inflammatory response of the host to this microbial challenge that ultimately leads to periodontal tissue damage. In turn, the tissue breakdown products caused by inflammation can serve as nutrients for bacteria. Thus, inflammation and ecological disorders are mutually reinforcing.49–51 Neutrophils are the first line of defense against pathogens and employ many defense mechanisms such as degranulation, chemotaxis, phagocytosis, neutrophil extracellular traps, and the generation of reactive oxygen species (ROS).52 Normally, ROS are produced primarily to act as antimicrobials, but excessive ROS can lead to an increased oxidative load. When the balance between antioxidants and ROS is disrupted, oxidative stress is generated within the affected tissues, resulting in pathological change that ultimately leads to the destruction of host tissues.
The primary objective of periodontal therapy is to remove inflammation while promoting the restoration and regeneration of periodontal tissues, thereby restoring the physiology and function of periodontal tissues. Current clinical treatments focus on eliminating bacteria, but regeneration of periodontal tissues remains a challenge. Periodontal tissues have limited regenerative capacity and do not restore their function on their own after disease.53,54 Scholars have been trying to explore more effective therapeutic strategies to restore periodontal tissue function to address the shortcomings and deficiencies of existing treatments. The progress in nanotechnology has enabled the creation of nanomaterials with diverse functional characteristics for the supplementary treatment of periodontitis and the regeneration of periodontal tissues.35,53,55,56 Nevertheless, these endeavors are currently in the exploratory phase. It will be a great breakthrough in periodontitis treatment if solving the problems of tissue regeneration after periodontitis.
Adjunctive pharmacotherapy aims to inhibit “periodontal pathogens” and the pathological process of periodontitis, including inhibition of reactive oxygen species production, excessive inflammatory reaction, and apoptotic cell death. Improvement of the microenvironment in periodontitis protects both the undamaged tissues from damage and some of the already damaged tissues from further deterioration. In addition, the combination of nanoparticles and scaffolds has the characteristics of both. The integration of nanoparticles’ functional properties with the scaffold material’s exceptional mechanical characteristics and biocompatibility holds promise for addressing the limitations in bioactivities and physicochemical functions observed in current tissue-engineered membranes, which will offer a fresh approach to therapy for periodontal tissue regeneration.
Nanoparticles Improve the Periodontal MicroenvironmentBased on the above characteristics, functional nanomaterials ameliorate these pathological processes of periodontitis. More precisely, these methods can be classified into the subsequent three domains. The first method is directly impeding the formation and maturation of periodontally relevant pathogenic bacteria and plaque biofilms. For instance, silver NPs57 and iron oxide NPs58 with magnetic fields can kill bacteria, platinum NPs are both antibacterial and biofilm-eliminating,59 and carbon quantum dots can penetrate biofilms.60,61 Due to its different antibacterial mechanism in comparison to antibiotics, the main advantage of NPs is their ability to slow down the emergence of antimicrobial resistance.
The second approach involves mitigating tissue damage by improving the periodontitis microenvironment and utilizing the tissue’s own reparative and regenerative capacity. For example, cerium oxide NPs62 and polydopamine NPs63 have antioxidant and ROS scavenging effects. In addition, some nanomaterials are used for drug transportation. Including inorganic NPs such as hydroxyapatite NPs (deliver tetracycline and ibuprofen),64 silver NPs (deliver chlorhexidine or metronidazole),65 and mesoporous silica NPs (deliver chlorhexidine and silver ions);66 organic NPs such as chitosan (deliver minocycline),67 poly lactic-co-glycolic acid NPs (deliver metformin).68
In addition, a third approach is to promote periodontal tissue regeneration, using NPs by themselves or in combination with other active ingredients as scaffolds to treat periodontitis and achieve substantial functional recovery. For example, AuNPs can promote osteogenic differentiation by activating autophagy and other pathways.69 Incorporation of MgONPs into scaffold materials enhances membrane tensile strength and modulates degradation rate, while small-dose release of magnesium ions promotes osteogenic differentiation.70
Inorganic NPsInorganic nanoparticles can be readily constructed, engineered, and fabricated into a variety of sizes, structures, and geometries, such as nanospheres, nanorods, and nanostars.71–74 The nanomaterials synthesized typically exhibit consistent dimensions, primarily in the range of tens of nanometers, and possess excellent dispersibility. The inherent characteristics of certain inorganic elements, such as the osteogenic differentiation-promoting effect of Au, may help to treat periodontitis.75,76 Appropriate modifications can make them easier to internalize and improve bioavailability.77,78 It is widely acknowledged, therefore, that studies are necessary to ensure the safety of inorganic nanoparticles for in vivo applications.
Metallic NPs Silver NPsSilver NPs (AgNPs) with a size of less than 100 nm and a uniform spherical shape have high and broad-spectrum antimicrobial activity.57 Antibacterial mechanisms of AgNPs include but are not limited to, the released silver ions can disrupt the cell walls and cell membranes, denature ribosomes, interrupt adenosine triphosphate production, and interfere with DNA replication.79 Beyond the common roles of antibacterial, antifungal, and drug carriers, AgNPs have been observed to enhance human periodontal ligament fibroblasts (HPDLFs) osteogenic differentiation in a dose-responsive way at the concentration range of 25–100 μM.80
The biosynthetic approach offers significant advantages over physical and chemical synthesis methods as it represents a non-toxic and more sustainable approach to the synthesis of NPs. The green chemistry approach focuses on environmental concerns, efficiency, and economy.81 Prapaipittayakhun et al biosynthesized AgNPs using the stem bark extract of Oroxylum indicum (L.) Kurz (OI) as a reducer. They then investigated the biological properties of OI/Ag NPs on human periodontal ligament stem cells (hPDLSCs). Acquired materials enhanced the proliferation of H2O2-treated hPDLSCs and reduced the production of interleukin 1 beta (IL-1β) in lipopolysaccharide (LPS)-treated hPDLSCs. LPS, also known as endotoxin, which is a crucial constituent of the outermost membrane of gram-negative bacteria, might activate the immune system and cause severe infectious diseases.82 OI/Ag NPs improved the alkaline phosphatase (ALP) activity and calcium concentration of hPDLSCs, which was beneficial for osteoblast differentiation.83
In another study, Steckiewicz et al created AgNPs that were combined with chlorhexidine (AgNPs-CHL) or metronidazole (AgNPs-PEG-MET). Compared to AgNPs-PEG-MET, AgNPs-CHL had greater antibacterial efficacy despite having higher cytotoxicity. Anyway, both NPs showed beneficial properties at non-toxic concentrations. They both decreased the levels of the pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α and the metalloproteinases MMP3 and MMP8 which suggests that they hinder tissue breakdown.65
AuNPsThe first biomedical applications of AuNPs occurred in the 1970s.84 Since then, different modified AuNPs have been employed to make progress in the management of periodontitis. It reported that 45 nm AuNPs could induce human periodontal ligament cells (hPDLCs) differentiation and regulate the periodontitis microenvironment by modulating the phenotype of macrophages. In vivo, treatment with 45 nm AuNPs showed a significant increase in newly developed periodontal tissues.85 Their capacity to stimulate differentiation may rely on the initiation of the autophagic pathway by upregulating the expression of microtubule-associated protein light chain 3 (LC3) and downregulating the expression of sequestosome 1/p62.69 In another study, Zhang et al effectively synthesized L/D-cysteine-anchored AuNPs (L/D-Cys-AuNPs). In vitro experiments showed that more L-type NPs tended to be internalized in hPDLCs than D-type NPs and had a more noticeable effect on the osteogenesis of hPDLCs. Moreover, animal experiments indicated that L-type NPs could activate the autophagy of cells, leading to the greatest effect on cell differentiation and periodontal regeneration.75
The researchers found that treatment with AuNPs repaired the autophagic lysosomal system damaged by inflammation. As a result, the ability of bone formation in periodontal ligament stem cells (PDLSCs) nurtured under inflammatory circumstances was restored.86 Transcriptional factor EB (TFEB), a key controller of autophagy and the creation of lysosomes, is commonly recognized as a component that promotes cell survival.87 The collapse of TFEB in PDLSC rendered AuNPs ineffective. Meanwhile, human β-defensin 3 (hBD3), a peptide with wide-ranging antibacterial properties, has been demonstrated to possess diverse biological activities in periodontitis.88 The combination of hBD3 and AuNPs has a notable effect on enhancing the process of osteogenic differentiation in hPDLCs inside inflammatory microenvironments by stimulating the Wnt/β-catenin signaling pathway.76 Additionally, AuNPs can enhance the process of bone-forming differentiation in hBD3 gene-modified hPDLCs and contribute to periodontal regeneration through the activation of the p38 MAPK pathway.89
In addition to the above-mentioned applications of AuNPs in promoting osteogenic differentiation, AuNPs have also been employed as photothermal therapeutic agents in the treatment of periodontitis. Using near-infrared (NIR) light as an excitation source is preferred because red light can penetrate deeper compared to other lasers.90 AuNPs have favorable photothermal and antibacterial characteristics when exposed to NIR radiation.91 Among AuNPs, metal-phenolic networks (MPNs) are versatile hybrid nanomaterials created through the binding of metal ions with polyphenols. These nanoplatforms have a diverse array of potential uses in the field of pharmaceuticals.92 Wang et al prepared a novel photothermal nanocomposite by encapsulating MPNs onto the surface of branched AuAg NPs. The photothermal characteristics of AuAg NPs (AuAg@PC-Fe) were enhanced by this method, along with a decrease in oxidative stress and inflammation. AuAg@PC-Fe demonstrated the ability to efficiently eradicate periodontal bacteria when exposed to 808 nm near-infrared light. In addition, AuAg@PC-Fe inhibited the nuclear factor kappa-B signaling pathway to treat periodontitis.93 Dong et al incorporated epigallocatechin gallate (EGCG) into a hydrogel modified with gold nanoparticles (E-Au@H) to enable NIR photosensitization, antibacterial activity, and regeneration of periodontal tissue (Figure 2A). The E-Au@H was quickly heated to a temperature of 50.7°C in under 5 minutes when exposed to NIR light, demonstrating a remarkable photothermal effect (Figure 2B and C). Moreover, the release of EGCG was effectively controlled by NIR irradiation, and the released EGCG could enhance the antibacterial impact, stimulate angiogenesis, and improve the process of osseous regeneration. In a rat periodontitis model, after a 4-week treatment, the E-Au@H+NIR group inhibited 87% of plaque biofilms and reduced the distance between the cementoenamel junction and the alveolar bone crest (CEJ-ABC distance) by approximately 38% compared to the periodontitis group (Figure 2D and E). Based on the experimental findings, this hydrogel including a NIR responsive composite nano platform presents novel prospects for the management of periodontal disease.94
Figure 1 Classification and structural description of nanoparticles for the treatment of periodontitis. Created with BioRender.com.
Figure 2 (A) Schematic of near-infrared-triggered tea polyphenol-modified gold nanoparticle-loaded hydrogel for the treatment of periodontitis. The E-Au@H was rapidly heated under NIR irradiation to release EGCG, which sterilizes the bacteria, enhances vascular development, and accelerates the regeneration of periodontal bone tissue. (B) Thermal image of the sample captured after 5 minutes of exposure to infrared radiation. (C) The temperature variation profiles of various materials following 5 minutes of 808 nm NIR irradiation. (D) Quantification of CEJ-ABC distance in maxillary molars. (E) Quantitative results of the bacterial standard plate counting method. **P < 0.01, and ***P < 0.001. Reprinted from Materials & Design, 225, Dong Z, Lin Y, Xu S, et al. NIR-triggered tea polyphenol-modified gold nanoparticles-loaded hydrogel treats periodontitis by inhibiting bacteria and inducing bone regeneration, 111487. Copyright 2023 with permission from Elsevier.94
Abbreviations: NaBH4, sodium borohydride; EGCG, epigallocatechin gallate; Alg, sodium alginate; PVA, polyvinyl alcohol; NIR, near-infrared; E-Au@H, EGCG was loaded into gold nanoparticle-modified hydrogels; PTT, photothermal therapy; BMP2, bone morphogenetic protein2; Runx2, runt-related transcription factor 2; OCN, osteocalcin; OPN, osteopontin; ALP, alkaline phosphatase; CEJ-ABC, from the cementoenamel junction to the alveolar bone crest; CFU, colony-forming unit; HL (Red), healthy group; Control (Yellow), periodontitis untreated group; E-Au@H (Blue), periodontitis treated with E-Au@H; E-Au@H+NIR (Green), periodontitis treated with E-Au@H+NIR.
Platinum NPsPlatinum NPs (PtNPs) are agglomerations of platinum atoms that measure between 1 to 100 nanometers in size. PtNPs exhibit exceptional biocompatibility, remarkable durability, and possess surface chemistry, and are widely applied in the biomedical domain, particularly in the areas of cancer treatment and photothermal therapy. However, relatively few studies have been conducted on the application of PtNPs in periodontal treatment.
Itohiya et al examined the antimicrobial properties and potential for decomposition of organic matter of PtNPs made by infrared pulsed laser irradiation methods.59 Colony formation of P. gingivalis was completely inhibited at concentrations of PtNPs greater than 5 ppm. Results proved that PtNPs could deactivate LPS by decomposing it. In short, PtNPs are promising for use in periodontal therapy.
Wu et al prepared an injectable ointment using Pt nanoclusters (PtNC) modified graphitic carbon nitride (CN) and PEG400/PEG4000. The ointment (named CN-PtNCs) showed oxidase-like or peroxidase-like abilities and could produce ROS to kill pathogens. Experiments showed that CN-PtNCs exhibited strong biofilm elimination against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). The results showed that CN-PtNC groups reduced the CEJ-ABC distance and probing depth (distance from the gingival margin to the bottom of the periodontal pocket) (P < 0.05), which means that periodontal inflammation was relieved and the results were better than the clinical standard drug. Finally, the CN-PtNCs, characterized by good biocompatibility, high bioavailability, and anti-inflammatory and analgesic properties, demonstrated good therapeutic effects on periodontitis in rats.95
Metal Oxides NPsWith the development of nanomaterials, some nanomaterials, such as metal oxides, have been found to have efficient catalytic activity similar to that of natural enzymes. Nanomaterials with enzyme-like properties are called “nanoenzymes”.96,97 Since the first report of Fe3O4 nanoenzymes in 2007, many kinds of nanoenzymes have been developed and have shown great potential for applications in biochemical testing, environmental management, and disease diagnosis. Metal oxide nanoenzymes, which avoid the instability and low yield of natural enzymes, also demonstrate significant promise for utilization in the field of periodontitis treatment.
Cerium oxide NPs (CeO2NPs) are typical and widely explored nanoenzymes with multiple enzymatic activities, including superoxide dismutase (SOD) and catalase (CAT)-like activities, oxidase mimetic activity, and hydroxyl radicals (·OH) scavenging capacity. Yu et al investigated the impact of CeO2NPs on ameliorating the microenvironment of periodontitis, and the mechanism by which it exerts anti-inflammatory effects. The findings from both in vitro and in vivo provided evidence of the ability of CeO2NPs to scavenge various types of ROS and suppress inflammatory responses induced by ROS in the presence of LPS. Furthermore, CeO2NPs could hinder the MAPK-NF-κB signaling pathway, so effectively suppressing pro-inflammatory factors’ production. CeO2NPs have been found to effectively reduce alveolar bone resorption, osteoclast activity, and inflammation in a rat model of periodontitis.62 Ren et al synthesized a multifunctional nanocomposite (MSN@Ce@PEG NPs) by loading CeO2 onto the surface of mesoporous silica (MSN) and then being modified with PEG (Figure 3A). The authors explored the anti-oxidative stress damage and in vivo therapeutic effects of the obtained NPs in a rat model, as well as potential biotoxicity. The results of the experiment showed that the obtained NPs exhibited good biocompatibility. The materials were able to prevent the inflammatory destruction of periodontal tissues in addition to effectively regulating intracellular ROS and enhancing the differentiation of hPDLSCs. The levels of bone loss and BV/TV ratios indicated that injection of MSN@Ce@PEG inhibited bone resorption (Figure 3B-D).98
Figure 3 (A) Synthesis and application of MSN@Ce@PEG NPs in the treatment of periodontitis. (B-D) Quantitative measurements of alveolar bone loss of both buccal and palatal areas. *P < 0.05, **P < 0.01, ***P < 0.001, and N.S. means P > 0.05. Reprinted from Chemical Engineering Journal, 423, Ren S, Zhou Y, Fan R, et al. Constructing biocompatible MSN@Ce@PEG nanoplatform for enhancing regenerative capability of stem cell via ROS-scavenging in periodontitis, 130207. Copyright 2021 with permission from Elsevier.98
Abbreviations: MSN, mesoporous silica nanoparticles; CeO2, cerium oxide; MSN@Ce, CeO2 onto the surface of MSN; MSN@Ce@PEG, MSN@Ce modified with PEG; ROS, reactive oxygen species; BV/TV, bone volume/tissue volume; Control, no periodontitis group; P+Saline, periodontitis with saline; P+MSN, periodontitis with MSNs; P+MSN@Ce@PEG, periodontitis with MSN@Ce@PEG NPs.
Engineered magnetic nanoparticles (MNP) have a unique design and precision for a range of medical uses in the environmental and biomedical fields.99,100 Sun et al co-loaded Ce6 and Coumarin 6 (C6) into Fe3O4-silane core-shell structures to form multifunctional NPs (Fe3O4-silane@Ce6/C6 MNPs). The multifunctional NPs are non-cytotoxic and have a range of characteristics, such as chemical stability, water solubility, and superparamagnetic qualities. Compared to the control, Fe3O4-silane@Ce6/C6-mediated antimicrobial PDT demonstrated a significantly higher reduction in biofilm. The reduction of biofilm colony-forming units by Fe3O4-silane@Ce6/C6-mediated antimicrobial PDT was about 4–5 orders of magnitude. The co-loading of Ce6 and C6 allowed real-time monitoring of antimicrobial PDT by ratiometric emission at the same wavelength. Fe3O4 with the magnetic field was able to kill bacteria by the magnetic field and thus target the site of infection. All things considered, Fe3O4-silane@Ce6/C6 MNPs showed strong anti-biofilm action against pathogens linked to periodontitis while maintaining good biocompatibility, time-monitoring, and magnetic localization capability. The use of multifunctional nanoparticles in antimicrobial applications to stop the progression of periodontitis shows considerable promise.58
Research on magnesium oxide nanomaterials in periodontitis treatment has focused on periodontal tissue regeneration. The findings demonstrated that adding magnesium oxide NPs (MgONPs) to poly (L-lactic acid) (PLA)/gelatin considerably enhanced the membranes’ overall performance. This included boosting the membranes’ tensile strength to preserve structural stability and modifying their rate of degradation to account for periodontal tissue. In vitro, studies have shown that the multifunctional membranes have considerable antimicrobial and osteogenic properties and are of great value for the regeneration of tissues. In a model of periodontal defects in rats, the MgO-embedded membranes effectively guided the regeneration of periodontal tissues.70 Peng et al prepared polycaprolactone (PCL)/gelatin core-shell nanocellulose membranes doped with MgONPs, called Coaxial-MgO, using the coaxial electrostatic spinning technique.101 The obtained films have better hydrophilicity and can consistently release Mg2+ at a concentration of about 5 mM. It has been indicated that 5–10 mM Mg2+ has a mild toxic effect on cells and can enhance the development of bone cells.102 Coaxial-MgO membranes showed an improved proliferation rate of hPDLSCs in comparison to Blending-MgO and Blending-Blank and significantly enhanced the adhesion of hPDLCs. In vitro, Coaxial-MgO membranes enhanced ALP activity, mineralized nodule formation, osteogenesis-related genes [runt-related transcription factor 2(Runx2), type I collagen (Col I), ALP], and high antimicrobial effects against E. coli and S. aureus in comparison to controls.
Hydroxyapatite NPsHydroxyapatite, calcium-deficient hydroxyapatite (CDHA), and β-tricalcium phosphate (β-TCP) are often utilized in calcium phosphate cements (CPCs) in the field of biological applications.103 HA is highly regarded as a ceramic biomaterial for the replacement and regeneration of bone and hard tissues. This is because it possesses exceptional biocompatibility, osteoconductivity, and a composition that closely resembles that of bone.104 Madhumathi et al developed a dual topical drug delivery system consisting using calcium phosphate bioceramic nanocarriers. CDHA and β-TCP were synthesized using a microwave-accelerated wet chemical method. The drug transporter CDHA was selected for tetracycline, meanwhile, TCP was chosen as the carrier for ibuprofen. The CDHA/TCP (CTP) system exhibited a better regulated drug release profile in comparison to the HA/TCP (BCP) biphasic system. The in vitro biological investigations demonstrated that the CTP system exhibits biocompatibility and possesses notable antimicrobial and anti-inflammatory properties. In a rat model of cranial defects, the drug-loaded CTP system demonstrated superior bone repair and fresh bone production when compared with the control group (without carrier) after 12 weeks.64
Xiang et al exploited a bioactive dual-functionalized apatite nanocrystal. In short, a biomimetic nanohydroxyapatite material was created by employing a polydopamine structure as a template, which was termed tHA. This material was then changed on its surface with bone-forming peptide-1 (BFP-1) and vascular endothelial growth factor-mimicking peptide (QK) using a single step of catechol chemistry. In vitro experiments showed that the synthesized apatite nanocomposites, particularly tHA-BFP/QK, enhanced the cytocompatibility of the original apatite. The nanocomposites have unaffected BFP-1 and QK activities, which can accelerate the biological activity proliferation and development of PDLSCs. The tHA-BFP/QK NPs group significantly enhanced periodontal bone formation in animal experiments.105
Excessive activation of toll-like receptor 9 (TLR9), a component of the immune system, plays a key role in the progress of numerous inflammatory disorders.106 Elevated levels of TLR9 are also linked to the destruction of the tissues of periodontal disease. Studies on animals have demonstrated that immunological responses mediated by TLR9 result in the development of inflammatory periodontal bone loss. Additionally, mice lacking TLR9 have been found to be resistant to periodontitis.107,108 Cell-free DNA (cfDNA), a ligand for TLR9, refers to the release of nuclear and mitochondrial DNA from injured host cells, and it also includes the presence of bacterial or viral DNA.109 Previous studies have demonstrated that positively charged nanomaterials can effectively treat several inflammatory illnesses in animal models by removing negatively charged cfDNA.110 Huang et al explored the correlation between cfDNA levels and the intensity of periodontitis. They utilized selenium-doped hydroxyapatite NPs (SeHAN) with the cationic polyamidoamine dendrimers (PAMAM-G3) to create cationic NPs cfDNA scavengers (G3@SeHANs). Figure 4A illustrates the process by which cfDNA contributes to bone loss. Figure 4B-D show the size, SEM and Zeta potential changes of SeHANs before and after coating with PAMAM-G3. The researchers then explored the therapeutic potential of this nanoparticle in periodontitis treatment. The results indicated that both G3@SeHANs and PAMAM-G3 effectively suppressed the proinflammatory response associated with periodontitis in laboratory experiments by eliminating cfDNA. Additionally, both substances were able to reduce the extent of bone loss caused by inflammation in a mouse model of periodontitis generated by ligation. G3@SeHANs also modulated macrophage polarization and promoted M2 over M1 macrophage phenotype. Furthermore, G3@SeHANs exhibited superior therapeutic efficacy compared to PAMAM-G3 in vivo, specifically in terms of decreasing pro-inflammatory responses and alveolar bone loss. The expression of TLR9 in periodontal tissues epithelium, as well as the levels of pro-inflammatory factors, were reduced after treatment with nanoscavengers (Figure 4E-G).111
Figure 4 (A) The diagram illustrates the process by which cfDNA contributes to bone loss. The cfDNA-scavenging nanoparticles can prevent bone loss and reduce the symptoms of periodontitis. (B) Size measurement of nanoparticles. (C) Scanning electron microscopy imaging of SeHANs before and after coating with PAMAM-G3. (D) Zeta potential of nanoparticles. PBS, PAMAM-G3, or G3@SeHANs were injected on both sides of mice into six sites around the ligature on days 0, 3, 6, 9, and 12; samples were collected on day 15. (E) Expression of TLR9 in periodontal tissues epithelium. (F) TNF-α and (G) IL-6 levels in periodontal tissues. *P < 0.05, **P < 0.01, and ****P < 0.0001. Reproduced from Huang H, Pan W, Wang Y, et al. Nanoparticulate cell-free DNA scavenger for treating inflammatory bone loss in periodontitis. Nat Commun. 2022;13(1):5925. Published 2022 Springer Nature. Available under a CC-BY license.111
Abbreviations: TLR9, toll-like receptor 9; cfDNA, Cell-free DNA; SeHANs, selenium-doped hydroxyapatite nanoparticles; G3@SeHANs, SeHANs with the cationic dendrimer PAMAM-G3.; Normal, healthy group; Untreated, periodontitis treated with phosphate-buffered saline; PAMAM-G3, periodontitis treated with PAMAM-G3; G3@SeHANs, periodontitis treated with G3@SeHANs.
Mesoporous Silica NPsMesoporous silica NPs (MSNs) are commonly used as nanocarriers. It has unique physicochemical properties such as high porosity, large surface area, and pore volume, functionalization, tunable pore, and particle size, biocompatibility, and high-loading cavity.112
Silver ion has been used in antibacterial experimental studies to address the problem of bacterial resistance arising from the application of conventional antibiotics. However, it has also been reported that silver ions can induce resistance in bacteria.113 Meanwhile, the development of nanoparticles containing antimicrobial compounds with mutually enhancing properties can prevent this resistance.114 Lu et al utilized mesoporous silica nanoparticles as carriers of chlorhexidine (CHX) and silver ions to exert synergistic antimicrobial activity while preventing the development of drug resistance. The effective antimicrobial concentration of Ag-MSNs@CHX was less cytotoxic to normal cells. Due to their synergistic bactericidal properties and favorable biocompatibility, these nanoparticles have the potential for widespread and effective use in treating bacterial infections in clinical settings. In another research, the authors synthesized redox/pH dual-responsive MSNs (Ag-MSNs@CHX) to inhibit microbial film formation by controlling the release of CHX and Ag+.115 The results indicated that the Ag-MSNs@CHX remarkably inhibited the growth of Streptococcus pyogenes and their biofilms. Importantly, Ag-MSNs@CHX was more effective than equivalent amounts of free CHX in limiting Streptococcus pyogenes biofilm formation via causing the demise of bacterial cells, especially in the long run. In addition, Ag-MSNs significantly reduced the toxicity of CHX to mouse oral epithelial cells. The authors have developed a safe and highly effective method of combating biofilms, which shows promise for use as an oral biofilm therapy.66
Apart from the application of MSNs for the delivery of antimicrobial materials and drugs, a series of studies have been carried out by authors using them as delivery systems in the promotion of osteogenic differentiation. Li et al successfully synthesized quaternary ammonium salts-modified core-shell mesoporous silica containing AgNPs (Ag@QHMS). Ag@QHMS demonstrated more effective and consistent concentration-dependent antimicrobial effects compared to QHMS’s single-contact antimicrobial activity. The lowest inhibitory concentration was within 100 μg/mL. In addition, AG@QHMS could promote the production of osteogenic-related factors such ALP, bone sialoprotein (BSP), Col I, osteocalcin (OCN), Runx2, and osteopontin (OPN), apoptosis does not occur. Within safe concentrations of Ag@QHMS stimulate the deposition of cellular alkaline phosphatase and stromal calcium salts.116 In another study, Casarrubios et al demonstrated that hollow mesoporous nanospheres in SiO2-CaO (nanoMBGs) systems loaded with isoflavones (IPs) enter preosteoblasts mainly through clathrin-dependent mechanisms. The present study demonstrates the positive binding of MC3T3-E1 osteoprogenitor cells to nanoMBG-IPs, stimulating their differentiation into a mature osteoblast phenotype and increasing alkaline phosphatase activity.117
Mitochondrial dysfunction in mesenchymal stem cells (MSCs) of chronic inflammatory bone disease origin is due to excessive intra-mitochondrial calcium and accumulation of damaged mitochondria due to inhibition of mitosis.118,119 Mitochondrial dysfunction is involved in the pathogenesis and progression of periodontitis by influencing oxidative stress and modulating inflammatory responses.120,121 Based on this finding, Zhai et al designed novel precision-engineered NPs. Figure 5 illustrates the composition of the NPs. They consist of a core made of mesoporous silica NPs (TMAMSN) with a positive charge. These nanoparticles act as carriers for loading siRNA and releasing it in a targeted manner in MSCs. The NPs also have a shell made of a composite of ethylene glycol tetraacetic acid (EGTA), which is a calcium chelator, and triphenylphosphine (TPP), which targets mitochondria. This shell is responsible for trapping calcium ions associated with mitochondria. Additionally, the NPs have a PEG corona, which is attached to EGTA fragments through ester bonds. The METP NPs are composed of core-shell structured corona NPs, specifically TMA-MSN-EGTA/TPP-PEG. The obtained METP NPs possess mitochondrial targeting and intracellular microenvironment (esterase and low pH) responsiveness to regulate mitochondrial calcium flux in MSCs by trapping calcium ions around mitochondria in MSCs with mitochondrial dysfunction and transporting small interfering RNA to tissue-specific MSCs to inhibit the Wnt/β-catenin pathway, regulate mitosis and remove damaged mitochondria. These bifunctional METP NPs are anticipated to serve as effective treatments for various chronic inflammation-related bone disorders, such as periodontitis and osteoarthritis.122 In a separate study, calcium, magnesium, and strontium co-doped MSNs were prepared using the sol-gel method by Pouroutzidou et al Upon immersion in simulated body fluids, all co-doped MSNs exhibited the development of hydroxycarbonate apatite on their surface. This, in turn, enhanced the activity of mitochondria and the proliferation of cells.123
Figure 5 Diagram illustrates the structure and function of METP NPs, along with the process by which siβ-catenin loaded METP NPs (METP/siβ-catenin) remove malfunctioning mitochondria and restore the functionality of both mitochondria and MSCs. Reprinted from Zhai Q, Chen X, Fei D, et al. Nanorepairers Rescue Inflammation‐Induced Mitochondrial Dysfunction in Mesenchymal Stem Cells. Adv Sci (Weinh). 2021;9(4):e2103839. Published 2021 Wiley-VCH GmbH. Available under http://creativecommons.org/licenses/by/4.0/.122
Abbreviations: MSCs, mesenchymal stem cells; ER, endoplasmic reticulum; EGTA, Ethylenebis(oxyethylenenitrilo)tetraacetic acid; METP/siβ-catenin, siβ-catenin loaded METP NPs; siRNA, siβ-catenin.
Upconversion NPsUpconversion NPs (UCNPs) are inorganic crystalline nanomaterials that possess several notable benefits. These include a prolonged fluorescence lifetime, minimal potential for toxicity to living organisms, the ability to penetrate deeply into biological tissues, and the absence of background light interference. Recently, they have been widely used in the fields of PDT, bioimaging, and bio-detection. They are capable of producing visible or NIR emissions when continuously stimulated by NIR.124,125 The large depth of light penetration of UCNPs can be used to address the problem of depth of tissue penetration that exists in conventional photodynamic therapy. Zhang et al used the hydrophobic chains of silane to attach to the hydrophobic groups of UCNPs via hydrophobic-hydrophobic interactions, then loaded Ce6 molecules within this hydrophobic layer. Given that the Ce6 molecule is excited in the red area, the addition of Mn ions (doping content was 30%) was implemented to amplify the red light, hence enhancing the function of PDT. The final composite (NaYF4@Ce6@silane NPs) with extremely effective red upconversion luminescence, demonstrated notable therapeutic properties against P. gingivalis, Prevotella intermedia, and Fusobacterium nucleatum (F. nucleatum) and their respective biofilms when exposed to 980 nm irradiation, with superior biocompatibility and low cytotoxicity (90% cell viability at the concentration of 200 μg/mL). Moreover, NaYF4-Mn@Ce6@silane NPs showed more than 2 log reduction in the number of colony-forming units (CFU) for all three bacterial 4-day biofilms and significantly decreased the production of polysaccharides generated by live bacteria.126
Qi et al obtained a NIR-triggered core-shell nanostructure (UCNPs@TiO2) of which the β-NaYF4:Yb3+, Tm3+ core was synthesized by thermal decomposition and the TiO2 shell further modified by hydrothermal method. UCNPs@TiO2 was hexagonal with an average diameter of 39.7 nm and had a positive surface charge (+12.4 mV). The UCNPs@TiO2 were biocompatible and non-cytotoxic. NIR light (980 nm) can excite the core NaYF4:Yb3+, Tm3+ UCNPs to emit intense ultraviolet (UV) light, which further triggers aPDT function of the shell TiO2 through energy transfer, thus achieving significant antibacterial effects. NIR-triggered aPDT exhibited strong inhibition of Streptococcus sanguinis, P. gingivalis, and F. nucleatum, resulting in 3–4 orders of magnitude reduction in biofilm CFU that was remarkably greater than that of control groups.127
In another study, Hu et al developed a NIR light-responsive nanodelivery system based on carvacrol (CA). The system consists of UCNPs that upconvert 808 nm NIR light to blue light (BL), mesoporous silica (mSiO2, carrier channel), and hydrophobic CA (BL responsive properties). Under NIR light (808 nm), UCNPs@mSiO2-CA (UCMCs) exhibited antimicrobial, anti-inflammatory, and immunomodulatory properties due to the synergistic effect of CA and upconverted BL. Significantly, the results of high-throughput sequencing showed that several well-known signaling pathways associated with inflammation and the immune response, such as the MAPK signaling pathway, TNF signaling pathway, and IL-17 signaling pathway, were found to be more prevalent in the altered immunological microenvironment. In a rat periodontitis model induced by ligation, the group of UCMCs irradiated by NIR 808 nm exhibited significant antibacterial and reduced inflammatory factor production. In addition, The 3D reconstructed images show that the UCMCs group irradiated by NIR exhibited better periodontal restorations, which was also demonstrated by the quantitative results of CEJ-ABC distance and BV/TV.128
Although studies have shown that surface-modified UCNPs are biocompatible and not biotoxic within a certain dosage range, the potential toxicity of UCNPs over a long period has not been monitored. A lot of systematic investigations need to be done before they can be applied to the clinic.
Organic NPsOrganic NPs can be constructed with diverse shapes to maximize drug loading, reduce adverse effects, or slow down the pace of drug release. They are mostly made of polymers with a variety of components and functionalities. Organic NPs can also be equipped with active and targeted delivery capabilities by connecting particular functional groups. The biosafety is significantly higher, the raw ingredients are less expensive, and the physicochemical properties are easier to manage when compared to inorganic NPs. Certain organic polymers, such as ZIF-8 for its antibacterial and osteogenic properties129 and polydopamine for its antioxidant properties,63 can also be therapeutically effective against periodontitis in and of themselves.
Polydopamine NPsPolydopamine (PDA) and its derivatives are extensively utilized in biomedical applications as they possess exceptional NIR absorbance, strong chelating ability for metal ions, and high biocompatibility. These properties make them valuable for uses such as photoacoustic contrast agents, photothermolysis, and chelating agents.130–133 To address the low operational stability and difficult reusability of natural enzymes and antioxidants, this work employed PDA NPs as scavengers of ROS to scavenge multiple ROS and inhibit ROS-induced inflammatory responses.63Figure 6A shows the general synthesis process of PDA NPs and a schematic diagram of its application as an effective scavenger of ROS for periodontitis treatment. Figure 6B presents an SEM image of the PDA NPs. PDA NPs effectively reduced the expression of inflammatory mediators in LPS-treated HGE cells (Figure 6C and D) and led to a significant reduction in ROS levels (Figure 6E). In a mouse periodontitis model, PDA NPs were used as powerful antioxidants to scavenge ROS and reduce periodontitis without causing any adverse effects (Figure 6F). Doping polymeric PolymP-n Active NPs with Ag, and doxycycline (Dox) demonstrated strong antimicrobial effects in in vitro subgingival biofilm model tests.134
Figure 6 (A) Synthesis process of PDA NPs and its application as an effective scavenger of ROS in periodontitis treatment. (B) Scanning electron microscopy image. (C and D) Expression of inflammatory mediators in LPS-treated HGE cells in the absence or presence of PDA NPs (***P < 0.001). (E) Fluorescence images of HGE cells upon various treatments. (Scale bar = 100 μm.) (F) The results of in vivo fluorescence imaging and relative quantification showed that the fluorescence signal gradually diminished when PDA NPs were injected in situ in the LPS-treated group (***P < 0.001). Adapted with permission from Bao X, Zhao J, Sun J, Hu M, Yang X. Polydopamine Nanoparticles as Efficient Scavengers for Reactive Oxygen Species in Periodontal Disease. ACS Nano. 2018;12(9):8882–8892. Copyright 2018 American Chemical Society.63
Abbreviations: LPS, lipopolysaccharides; PDA, polydopamine; ROS reactive oxygen species; NPs, nanoparticles; HGE, human gingival epithelia.
ZIF-8Zinc ions (Zn2+) have a connection by imidazolate (Im) ligands to form the metal-organic framework which is also called zeolitic imidazole framework-8 (ZIF-8). ZIF-8 is promising for use in a variety of biological fields because of its prolonged release of Zn2+, which is essential for osteogenic and antibacterial activities. Antimicrobials encapsulating ZIF-8 exhibit higher biological activity compared to free antimicrobials.129 Li et al doped cerium (Ce) into ZIF-8 to produce a novel nanoparticle (ZIF-8:Ce) with antibacterial and anti-inflammatory properties. The findings showed that the regular and homogenous structure of ZIF-8 was unaffected by the addition of 1% to 10% of Ce. At concentrations lower than 30 μg/mL, ZIF-8:Ce demonstrated strong catalase and superoxide dismutase activity, as well as prolonged release of Zn2+ and Ce3+/Ce4+. When it came to periodontitis pathogens, ZIF-8 had higher anti-biofilm activity. Although the antibacterial effect of ZIF-8 decreased slightly after the incorporation of Ce at 10%, the reduction of CFU remained at about 2 orders of magnitude. More crucially, the anti-inflammatory properties of the novel nanoparticles became stronger with the increase of Ce doping. Furthermore, ZIF-8:Ce10% demonstrated superior anti-inflammatory actions by inhibiting the expression of pro-inflammatory factors by suppressing the translocation of the NF-κB/p65 subunit (p < 0.05). In the meantime, ZIF-8:Ce10% increased macrophage M2 phenotypic polarization and stimulated the release of anti-inflammatory cytokines.135
Gelatin methacrylate (GelMA) is a gelatin derivative, first introduced by Van den Bulcke and colleagues in 2000.136 Liu et al loaded ZIF-8 NPs into GelMA to obtain an injectable photopolymerizable composite hydrogel (GelMA-Z). The gel exhibits a liquid form when exposed to body temperature and can transition into a gel state upon exposure to UV irradiation (Figure 7A). GelMA-Z exhibits sustained release of Zn2+ ions for a duration exceeding 7 days, while also demonstrating favorable compatibility with living cells. In vitro experiments indicated that GelMA-Z up-regulated the expression of osteogenic-related genes and proteins, increased ALP activity, and promoted extracellular matrix mineralization. Moreover, GelMA-Z exhibited notable antibacterial efficacy against P. gingivalis. The hydrogel containing 0.2% w/v ZIF-8 NPs was named GelMA-ZH. The reduction of CEJ-ABC distance in the GelMA-ZH group was seen on both 3D reconstructed images and 2D images of the rat maxilla (Figure 7B and C), which was also demonstrated by the quantification results in CEJ-ABC distance and BV/TV index (Figure 7D and E). Overall, GelMA-Z was shown to promote alveolar bone regeneration in the rat model.137
Figure 7 (A) Synthesis and characterization of composite hydrogels. (B) 3D reconstruction images of maxillary alveolar bone. (M1: the first maxillary molar, M2: the second maxillary molar). (C) 2D images of maxillary alveolar bone. (D and E) Quantification of CEJ-ABC distance and BV/TV index after treatment. *P < 0.05, and **P < 0.01. Reprinted from Acta Biomaterialia, 146, Liu Y, Li T, Sun M, et al. ZIF-8 modified multifunctional injectable photopolymerizable GelMA hydrogel for the treatment of periodontitis, 37-48. Copyright 2022 with permission from Elsevier.137
Abbreviations: ZIF-8, zeolitic imidazolate framework-8; GelMA, gelatin methacryloyl; GelMA-Z, ZIF-8/GelMA composite hydrogel; GelMA-ZH, the hydrogel contains 0.2% w/v ZIF-8 nanoparticles; CEJ-ABC, from the cementoenamel junction to the alveolar bone crest; BV/TV, bone volume/tissue volume.
Chitosan PolysaccharidesChitosan is a polysaccharide biopolymer with diverse functional properties, including biocompatibility, biodegradability, antibacterial and antioxidant effects.
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