Gels as adjuvant to non-surgical periodontal therapy: A systematic review and meta-analysis.

Objective: This systematic review and meta-analysis evaluated the effect of the use of available drugs loaded gels used as adjunct to non-surgical periodontal therapy. Methods: Systematic research on PubMed/MEDLINE, Cochrane Central register of Controlled Trials, and Embase databases up to December 2021 was performed. Randomized clinical trials (RCT) which compared the outcomes of scaling and root planing (SRP) + local adjuvant administration (gel) versus SRP + placebo or SRP alone in Humans were included. The primary outcome measures were PPD and CAL changes at 3 months. Results: After articles screening, 77 articles were included and assessed for quality. Then, a meta-analysis was conducted in studies with at least 3 months of follow-up. Clinical improvements were found to be significant for tetracyclines (-0.51 [-0.71;-0.31] p < 0.001), macrolides (-0.71 [-1.04;-0.38] p < 0.001), statins (-0.84 [-0.98;-0.70] p < 0.001), metformin (-1.47 [-1.66;-1.29] p < 0.001) and hyaluronan (-1.61 [-2.28;-0.94] p < 0.001) loaded gels, but non-significant for chlorhexidine (-0.48 [-1.10; 0.14] p = 0.13), metronidazole (-0.50 [-1.20; 0.20] p = 0.16) and bisphosphonates (-0.42 [-1.39; 0.54] p = 0.539) gels. Conclusion: Adjunctive use of drugs loaded gels to non-surgical periodondal treatment could improve PPD reduction at 3 months. However, huge disparities remain when comparing the outcomes of the differents drugs used. Future comparative studies should be considered to determine precisely short and long term benefits of such treatments.

Primary failure of eruption and tooth resorption / Défaut primaire d'éruption et résorption radiculaire externe

Introduction: The number of adult patients who seek an orthodontic treatment is increasing. These Primary failure of eruption (PFE) is defined as the partial or complete failure of eruption of at least one posterior tooth, without any mechanical obstacle. A better understanding of the biological mechanisms involved in PFE would enable to refine the diagnostic and prognostic criteria. This rare disease is currently related to PTHR1 gene variants. This gene codes for a transmembrane receptor involved in bone metabolism. However, there is few evidence associating PFE and bone remodeling abnormalities such as external root resorption. External root resorption is the loss of cementum and dentin tissues, resulting from the activation of clastic cells. Materials and Methods: Human teeth affected by PFE were extracted and histological sections were made after fixation of the tissues in 4% PFA. The observations were correlated with three-dimensional imaging by cone beam computed tomography (CBCT) carried out in the preoperative phase. Results: Histological and radiographic analysis confirm the presence of ankylosis area in patients with no history of orthodontic treatment. Large areas of resorption of external root replacement were detected. Discussion: The results call the causal link between the appearance of ankylosis areas and the establishment of orthodontic traction in patients with PFE into question. The installation of an orthodontic force in this context could be only an aggravating factor, accelerating the processes of ankylosis or triggering them more prematurely. Conclusion: With or without orthodontic treatment, teeth with PFE are likely to progress to ankylosis and resorption of replacement external root.

Introduction: Les défauts primaires d'éruption (DPE) se caractérisent par l'échec total ou partiel de l'éruption d'une ou plusieurs dents postérieures, sans obstacle mécanique. Une meilleure compréhension des mécanismes biologiques impliqués dans les DPE permettrait d'affiner les critères diagnostiques et pronostiques. Cette pathologie rare est actuellement imputée à des variants du gène PTHR1. Ce gène code pour un récepteur transmembranaire impliqué dans le métabolisme osseux. Cependant, on trouve peu de données associant DPE et anomalies du remodelage osseux de type résorption radiculaire externe. La résorption radiculaire externe correspond à la perte de tissus cémentaire et dentinaire résultant de l'activation de cellules clastiques. Matériels et méthodes: Des dents d'origine humaine atteintes de DPE ont été avulsées et des coupes histologiques réalisées après fixation des tissus. Les observations ont été corrélées avec l'imagerie tridimensionnelle par tomographie volumique à faisceau conique (TVFC ou encore CBCT). Résultats: Les analyses histologiques et radiographiques montrent la présence de plage d'ankylose chez des patients sans antécédent de prise en charge orthodontique. De larges zones de résorptions radiculaires externes de remplacement ont été détectées. Discussion: Les résultats remettent en cause le lien de causalité entre l'apparition d'ankylose et la mise en place de traction orthodontique chez les patients atteints de DPE. La mise en place d'une force orthodontique dans ce contexte pourrait n'être qu'un facteur aggravant, accélérant les processus d'ankylose ou les déclenchant plus prématurément. Conclusion: Avec ou sans traitement orthodontique, les dents atteintes de DPE sont susceptibles d'évoluer vers l'ankylose et la résorption radiculaire externe de remplacement.

M101, a therapeutic oxygen carrier derived from Arenicola marina, decreased Porphyromonas gingivalis-induced hypoxia and improved periodontal healing.

BACKGROUND: Porphyromonas gingivalis exacerbates tissue hypoxia and worsens periodontal inflammation. This study investigated the effect of a therapeutic oxygen carrier (M101), derived from Arenicola marina, on hypoxia and associated inflammation in the context of periodontitis. METHODS: The effect of M101 on GLUT-1, GLUT-3, HIF-1α, and MMP-9 expression, hypoxia, and antioxidant status in oral epithelial cells (EC) exposed to CoCl2 (1000 µM), P. gingivalis (MOI 100), and CoCl2 + P. gingivalis was evaluated through hypoxia detection fluorescence assay, antioxidant concentration colorimetric assay, and RTqPCR. Evaluation of M101 on EC proliferation was evaluated in an in vitro wound assay. In experimental periodontitis, periodontal wound healing and osteoclastic activity were compared among natural wound healing, placebo, and gels containing M101 (1  and 2 g/L) groups through histomorphometry and TRAP (tartrate-resistant acid phosphatase activity assay) assay respectively. The expression of HIF-1α, MMP-9, and NFκB in periodontal tissues was also evaluated through immunofluorescence studies. RESULTS: M101 downregulated GLUT-1, GLUT-3, HIF-1α, and MMP-9 levels in EC exposed to CoCl2 , P. gingivalis, and CoCl2 + P. gingivalis (p < 0.05). Fluorescence and colorimetric analyses confirmed hypoxia reduction and antioxidant capacity improvement in such EC upon M101 treatment. Moreover, M101 improved significantly the in vitro wound closure. In vivo, the attachment level was significantly improved, and osteoclastic activity was reduced in mice treated with M101 gels compared to placebo and natural wound healing groups (p < 0.05). HIF-1α, MMP-9, and NFκB expression in periodontal tissues was reduced in M101 gels treated mice compared to the controls. CONCLUSION: M101 showed promise in resolving hypoxia and associated inflammation-mediated tissue degradation. Its potential in the clinical management of periodontitis must be further investigated.

Isolation of Splenic Microvesicles in a Murine Model of Intraperitoneal Bacterial Infection.

Microvesicles (MVs) are submicron fragments released from the plasma membrane of activated cells that act as proinflammatory and procoagulant cellular effectors. In rats, spleen MVs (SMVs) are surrogate markers of pathophysiological conditions. Previous in vitro studies demonstrated that Porphyromonas gingivalis (P. gingivalis), a major periodontal pathogen, enables the endothelial shedding and apoptosis while lipopolysaccharide (LPS) favors the shedding of splenocyte-derived microvesicles (SMVs). In vivo studies showed the feasibility of pharmacological control of SMV shedding. The present protocol establishes a standardized procedure for isolating splenic SMVs from the P. gingivalis acute murine infection model. P. gingivalis infection was induced in young C57BL/6 mice by intraperitoneal injection (three injections of 5 x 107 bacteria/week). After two weeks, the spleens were collected, weighed, and the splenocytes were counted. SMVs were isolated and quantified by protein, RNA, and prothrombinase assays. Cell viability was assessed by either propidium iodide or trypan blue exclusion dyes. Following splenocyte extraction, neutrophil counts were obtained by flow cytometry after 24 h of splenocyte culture. In P. gingivalis-injected mice, a 2.5-fold increase in spleen weight and a 2.3-fold rise in the splenocyte count were observed, while the neutrophils count was enhanced by 40-folds. The cell viability of splenocytes from P. gingivalis-injected mice ranged from 75%-96% and was decreased by 50% after 24 h of culture without any significant difference compared to unexposed controls. However, splenocytes from injected mice shed higher amounts of MVs by prothrombinase assay or protein measurements. The data demonstrate that the procoagulant SMVs are reliable tools to assess an early spleen response to intraperitoneal P. gingivalis infection.

Lenabasum Reduces Porphyromonas gingivalis-Driven Inflammation.

The aim of this study was to evaluate the potential anti-inflammatory and anti-resorptive effects of lenabasum in the context of Porphyromonas gingivalis (Pg)-induced inflammation. Lenabasum or ajulemic acid (1',1'-dimethylheptyl-THC-11-oic-acid), a synthetic analog of THC-11-oic acid, has already demonstrated anti-inflammatory properties for the treatment of several inflammatory diseases. In vitro, the cytocompatibility of lenabasum was evaluated in human oral epithelial cells (EC), oral fibroblasts and osteoblasts by metabolic activity assay. The effect of lenabasum (5 µM) treatment of Pg-LPS- and P. gingivalis-infected EC on the pro- and anti-inflammatory markers was studied through RTqPCR. In vivo, lenabasum was injected subcutaneously in a P. gingivalis-induced calvarial abscess mouse model to assess its pro-healing effect. Concentrations of lenabasum up to 5 µM were cytocompatible in all cell types. Treatment of Pg-LPS and Pg-infected EC with lenabasum (5 µM; 6 h) reduced the gene expression of TNF-α, COX-2, NF-κB, and RANKL, whereas it increased the expression of IL-10 and resolvin E1 receptor respectively (p < 0.05). In vivo, the Pg-elicited inflammatory lesions' clinical size was significantly reduced by lenabasum injection (30 µM) vs untreated controls (45%) (p < 0.05). Histomorphometric analysis exhibited improved quantity and quality of bone (with reduced lacunae) and significantly reduced calvarial soft tissue inflammatory score in mice treated with lenabasum (p < 0.05). Tartrate-resistant acid phosphatase activity assay (TRAP) also demonstrated decreased osteoclastic activity in the treatment group compared to that in the controls. Lenabasum showed promising anti-inflammatory and pro-resolutive properties in the management of Pg-elicited inflammation, and thus, its potential as adjuvant periodontal treatment should be further investigated.

Nanomedicine and Periodontal Regenerative Treatment.

Current periodontal treatments aim to control bacterial infection and decrease inflammation. To optimize contemporary conventional treatments that present limitations owing to an inability to reach the lesion site, new methods are based on nanomedicine. Nanomedecine allows delivery of host-modulatory drugs or antibacterial molecules at the lesion site in an optimal concentration with decreased toxicity and risk of systemic side effects. Chitosan and polylactic-co-glycolic acid-loaded nanoparticles, carbon quantum dots, and mesoporous silicates open new perspectives in periodontitis management. The potential therapeutic impact of the main nanocarriers is discussed.

Modulation of immune-inflammatory responses through surface modifications of biomaterials to promote bone healing and regeneration.

Control of inflammation is indispensable for optimal oral wound healing and tissue regeneration. Several biomaterials have been used to enhance the regenerative outcomes; however, the biomaterial implantation can ensure an immune-inflammatory response. The interface between the cells and the biomaterial surface plays a critical role in determining the success of soft and hard tissue regeneration. The initial inflammatory response upon biomaterial implantation helps in tissue repair and regeneration, however, persistant inflammation impairs the wound healing response. The cells interact with the biomaterials through extracellular matrix proteins leading to protein adsorption followed by recruitment, attachment, migration, and proliferation of several immune-inflammatory cells. Physical nanotopography of biomaterials, such as surface proteins, roughness, and porosity, is crucial for driving cellular attachment and migration. Similarly, modification of scaffold surface chemistry by adapting hydrophilicity, surface charge, surface coatings, can down-regulate the initiation of pro-inflammatory cascades. Besides, functionalization of scaffold surfaces with active biological molecules can down-regulate pro-inflammatory and pro-resorptive mediators' release as well as actively up-regulate anti-inflammatory markers. This review encompasses various strategies for the optimization of physical, chemical, and biological properties of biomaterial and the underlying mechanisms to modulate the immune-inflammatory response, thereby, promoting the tissue integration and subsequent soft and hard tissue regeneration potential of the administered biomaterial.

Eruption of Bioengineered Teeth: A New Approach Based on a Polycaprolactone Biomembrane.

Obtaining a functional tooth is the ultimate goal of tooth engineering. However, the implantation of bioengineered teeth in the jawbone of adult animals never allows for spontaneous eruption due mainly to ankylosis within the bone crypt. The objective of this study was to develop an innovative approach allowing eruption of implanted bioengineered teeth through the isolation of the germ from the bone crypt using a polycaprolactone membrane (PCL). The germs of the first lower molars were harvested on the 14th day of embryonic development, cultured in vitro, and then implanted in the recipient site drilled in the maxillary bone of adult mice. To prevent the ankylosis of the dental germ, a PCL membrane synthesized by electrospinning was placed between the germ and the bone. After 10 weeks of follow-up, microtomography, and histology of the implantation site were performed. In control mice where germs were directly placed in contact with the bone, a spontaneous eruption of bioengineered teeth was only observed in 3.3% of the cases versus 19.2% in the test group where PCL biomembrane was used as a barrier (p < 0.1). This preliminary study is the first to describe an innovative method allowing the eruption of bioengineered tooth implanted directly in the jawbone of mice. This new approach is a hope for the field of tooth regeneration, especially in children with oligodontia in whom titanium implants are not an optimal solution.

Characterization of a hyaluronic acid-based hydrogel containing an extracellular oxygen carrier (M101) for periodontitis treatment: An in vitro study.

Periodontitis is an inflammatory disease associated with anaerobic bacteria leading to the destruction of tooth-supporting tissues. Porphyromonas gingivalis is a keystone anaerobic pathogen involved in the development of severe lesions. Periodontal treatment aims to suppress subgingival biofilms and to restore tissue homeostasis. However, hypoxia impairs wound healing and promotes bacterial growth within periodontal pocket. This study aimed to evaluate the potential of local oxygen delivery through the local application of a hydrogel containing Arenicola marina's hemoglobin (M101). To this end, a hydrogel (xanthan (2%), hyaluronic acid (1%)) containing M101 (1-2 g/L) (Xn(2%)-HA(1%)-M101) was prepared and characterized. Rheological tests revealed the occurrence of high deformation without the loss of elastic properties. Dialysis experiment revealed that incorporation of M101 within the gel did not modify its oxygen transportation properties. Samples of release media of the gels (1 g/L (10%) and 2 g/L (10%) M101) decreased significantly the growth of P. gingivalis after 24 h validating its antibacterial effect. Metabolic activity measurement confirmed the cytocompatibility of Xn(2%)-HA(1%)-M101. This study suggests the therapeutic interest of Xn(2%)-HA(1%)-M101 gel to optimize treatment of periodontitis with a non-invasive approach.

Orofacial manifestations and dental management of systemic lupus erythematosus: A review.

Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease with numerous clinical manifestations. There is no consensus about the ideal oral management for this group of patients to date. This review aimed to describe the broad spectrum of orofacial and clinical manifestations and their therapeutic approaches. Studies concerning orofacial manifestations of SLE and dental treatment modalities were selected by a literature search (1978-2019) using Google Scholar, PubMed/MEDLINE electronic databases. The initial search strategy provided a total of 129 articles, and of these, 30 were included for qualitative synthesis. The reviewed studies revealed that SLE patients are more at risk of compromised oral and dental health exhibiting increased risk of periodontal diseases and temporomandibular joint disorders. The use of systemic drugs especially immunosuppressive and anticoagulants in SLE patients may also influence their oral management. Results emphasize the need to carry out, at an early stage of the disease, an appropriate oral management of these patients to improve oral health-related quality of life and to prevent the need of more invasive therapeutics. A multidisciplinary approach is needed for dental and medical management of such patients.

Interests of Exosomes in Bone and Periodontal Regeneration: A Systematic Review.

Periodontitis is an infectious inflammatory disease characterized by clinical attachment loss and tooth supporting tissue destruction. As exosomes demonstrated pro-regenerative ability, their use in periodontal treatment has been suggested. The aim of this systematic review is to gather and summarize the most recent data regarding exosomes to determine their potential impact in bone and periodontal regeneration. Electronic databases (Pubmed, Web of Science) were searched up to February 2020. Studies assessing the impact of exosomes administration in experimental bone and periodontal defects have been identified according to PRISMA guidelines. Among the 183 identified articles, 16 met the inclusion criteria and were included in this systematic review. Experimental bone defects were mainly surgically induced with a dental bur or distraction tools. All studies considered bone healing after exosomes administration as the primary outcome. Results showed that mesenchymal stem cells derived exosomes administration promoted bone healing and neovascularization. Nevertheless, a dose-effect relationship was observed. Exosomes administration appears to promote significantly the bone healing and periodontal regeneration. However, only a limited number of studies have been carried out so far and the optimized protocols in this context need to be evaluated.

Influence of parathyroid hormone on periodontal healing in animal models: A systematic review.

OBJECTIVES: The purpose of this systematic review was to determine the potential interest of parathyroid hormone (PTH) as an adjunct to periodontal treatment based on studies performed in rodents. MATERIALS & METHODS: Electronic databases (MEDLINE, Web of Science) were searched up to December 2019. Studies assessing the impact of PTH administration in experimental periodontitis in rodents have been identified. RESULTS: Amongst the 247 identified articles, 10 met the inclusion criteria and were included in this systematic review. Experimental periodontitis was mainly induced by ligature placement or surgically with a dental bur. All studies considered bone healing after PTH administration at different frequencies as primary outcome. Results showed that an intermittent administration of PTH promoted bone healing and neovascularization. Nevertheless, a decrease of soft tissue inflammation was also observed. CONCLUSION: Intermittent administration of PTH appears to enhance significantly periodontal healing and to promote alveolar bone regeneration. However, due to the risk of side effects, the development of scaffolds allowing its local and time-controlled delivery is of importance.

A therapeutic oxygen carrier isolated from Arenicola marina decreased P. gingivalis induced inflammation and tissue destruction.

The control of inflammation and infection is crucial for periodontal wound healing and regeneration. M101, an oxygen carrier derived from Arenicola marina, was tested for its anti-inflammatory and anti-infectious potential based on its anti-oxidative and tissue oxygenation properties. In vitro, no cytotoxicity was observed in oral epithelial cells (EC) treated with M101. M101 (1 g/L) reduced significantly the gene expression of pro-inflammatory markers such as TNF-α, NF-κΒ and RANKL in P. gingivalis-LPS stimulated and P. gingivalis-infected EC. The proteome array revealed significant down-regulation of pro-inflammatory cytokines (IL-1ß and IL-8) and chemokine ligands (RANTES and IP-10), and upregulation of pro-healing mediators (PDGF-BB, TGF-ß1, IL-10, IL-2, IL-4, IL-11 and IL-15) and, extracellular and immune modulators (TIMP-2, M-CSF and ICAM-1). M101 significantly increased the gene expression of Resolvin-E1 receptor. Furthermore, M101 treatment reduced P. gingivalis biofilm growth over glass surface, observed with live/dead analysis and by decreased P. gingivalis 16 s rRNA expression (51.7%) (p < 0.05). In mice, M101 reduced the clinical abscess size (50.2%) in P. gingivalis-induced calvarial lesion concomitant with a decreased inflammatory score evaluated through histomorphometric analysis, thus, improving soft tissue and bone healing response. Therefore, M101 may be a novel therapeutic agent that could be beneficial in the management of P. gingivalis associated diseases.

A New Polycaprolactone-Based Biomembrane Functionalized with BMP-2 and Stem Cells Improves Maxillary Bone Regeneration.

Oral diseases have an impact on the general condition and quality of life of patients. After a dento-alveolar trauma, a tooth extraction, or, in the case of some genetic skeletal diseases, a maxillary bone defect, can be observed, leading to the impossibility of placing a dental implant for the restoration of masticatory function. Recently, bone neoformation was demonstrated after in vivo implantation of polycaprolactone (PCL) biomembranes functionalized with bone morphogenic protein 2 (BMP-2) and ibuprofen in a mouse maxillary bone lesion. In the present study, human bone marrow derived mesenchymal stem cells (hBM-MSCs) were added on BMP-2 functionalized PCL biomembranes and implanted in a maxillary bone lesion. Viability of hBM-MSCs on the biomembranes has been observed using the "LIVE/DEAD" viability test and scanning electron microscopy (SEM). Maxillary bone regeneration was observed for periods ranging from 90 to 150 days after implantation. Various imaging methods (histology, micro-CT) have demonstrated bone remodeling and filling of the lesion by neoformed bone tissue. The presence of mesenchymal stem cells and BMP-2 allows the acceleration of the bone remodeling process. These results are encouraging for the effectiveness and the clinical use of this new technology combining growth factors and mesenchymal stem cells derived from bone marrow in a bioresorbable membrane.

Development of a thermosensitive statin loaded chitosan-based hydrogel promoting bone healing.

Statins have been proposed as potential adjuvant to periodontal treatment due to their pleiotropic properties. A new thermosensitive chitosan hydrogel loaded with statins (atorvastatin and lovastatin) nanoemulsions was synthesized to allow a spatially controlled local administration of active compounds at lesion site. Spontaneous nano-emulsification method was used to synthesize statins loaded nanoemulsions. In vitro, atorvastatin and lovastatin loaded nanoemulsions were cytocompatible and were able to be uptake by oral epithelial cells. Treatment of Porphyromonas gingivalis infected oral epithelial cells and gingival fibroblasts with atorvastatin and lovastatin loaded nanoemulsions decreased significantly pro-inflammatory markers expression (TNF-α and IL-1ß) and pro-osteoclastic RANKL. Nevertheless, such treatment induced the expression of Bone sialoprotein 2 (BSP2) in osteoblast emphasizing the pro-healing properties of atorvastatin and lovastatin nanoemulsions. In vivo, in a calvarial bone defect model (2 mm), treatment with the hydrogel loaded with atorvastatin and lovastatin nanoemulsions induced a significant increase of the neobone formation in comparison with systemic administration of statins. This study demonstrates the potential of this statins loaded hydrogel to improve bone regeneration and to decrease soft tissue inflammation. Its use in the specific context of periodontitis management could be considered in the future with a reduced risk of side effects.