A Phase I Dose-Escalation Clinical Trial to Assess the Safety and Efficacy of Umbilical Cord-Derived Mesenchymal Stromal Cells in Knee Osteoarthritis.

Osteoarthritis (OA) is the most common degenerative joint disease. Mesenchymal stromal cells (MSC) are promising cell-based therapy for OA. However, there is still a need for additional randomized, dose-dependent studies to determine the optimal dose and tissue source of MSC for improved clinical outcomes. Here, we performed a dose-dependant evaluation of umbilical cord (UC)-derived MSC (Celllistem) in a murine model and in knee OA patients. For the preclinical study, a classical dose (200.000 cells) and a lower dose (50.000 cells) of Cellistem were intra-articularly injected into the mice knee joints. The results showed a dose efficacy response effect of Cellistem associated with a decreased inflammatory and degenerative response according to the Pritzker OARSI score. Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2 × 106 cells), medium-dose group (20 × 106), and high-dose group (80 × 106). All the doses were safe, and no serious adverse events were reported. Nonetheless, 100% of the patients injected with the high-dose experienced injection-related swelling in the knee joint. According to WOMAC total outcomes, patients treated with all doses reported significant improvements in pain and function compared with baseline after 3 and 6 months. However, the improvements were higher in patients treated with both medium and low dose as compared to high dose. Therefore, our data demonstrate that the intra-articular injection of different doses of Cellistem is both safe and efficient, making it an interesting therapeutic alternative to treat mild and symptomatic knee OA patients. Trial registration ClinicalTrials.gov NCT03810521.

Correction: Vicencio et al. Transcriptional Signatures and Network-Based Approaches Identified Master Regulators Transcription Factors Involved in Experimental Periodontitis Pathogenesis. Int. J. Mol. Sci. 2023, 24, 14835.

In the original publication [...].

Transcriptional Signatures and Network-Based Approaches Identified Master Regulators Transcription Factors Involved in Experimental Periodontitis Pathogenesis.

Periodontitis is a chronic inflammatory disease characterized by the progressive and irreversible destruction of the periodontium. Its aetiopathogenesis lies in the constant challenge of the dysbiotic biofilm, which triggers a deregulated immune response responsible for the disease phenotype. Although the molecular mechanisms underlying periodontitis have been extensively studied, the regulatory mechanisms at the transcriptional level remain unclear. To generate transcriptomic data, we performed RNA shotgun sequencing of the oral mucosa of periodontitis-affected mice. Since genes are not expressed in isolation during pathological processes, we disclose here the complete repertoire of differentially expressed genes (DEG) and co-expressed modules to build Gene Regulatory Networks (GRNs) and identify the Master Transcriptional Regulators of periodontitis. The transcriptional changes revealed 366 protein-coding genes and 42 non-coding genes differentially expressed and enriched in the immune response. Furthermore, we found 13 co-expression modules with different representation degrees and gene expression levels. Our GRN comprises genes from 12 gene clusters, 166 nodes, of which 33 encode Transcription Factors, and 201 connections. Finally, using these strategies, 26 master regulators of periodontitis were identified. In conclusion, combining the transcriptomic analyses with the regulatory network construction represents a powerful and efficient strategy for identifying potential periodontitis-therapeutic targets.

Characterization of biofilm formation by Exiguobacterium strains in response to arsenic exposure.

IMPORTANCE: In this work, we characterized the composition, structure, and functional potential for biofilm formation of Exiguobacterium strains isolated from the Salar de Huasco in Chile in the presence of arsenic, an abundant metalloid in the Salar that exists in different oxidation states. Our results showed that the Exiguobacterium strains tested exhibit a significant capacity to form biofilms when exposed to arsenic, which would contribute to their resistance to the metalloid. The results highlight the importance of biofilm formation and the presence of specific resistance mechanisms in the ability of microorganisms to survive and thrive under adverse conditions.

Proteomic profile of human gingival crevicular fluid reveals specific biological and molecular processes during clinical progression of periodontitis.

BACKGROUND AND OBJECTIVE: There is no clear understanding of molecular events occurring in the periodontal microenvironment during clinical disease progression. Our aim was to explore qualitative and quantitative differences in gingival crevicular fluid (GCF) protein profiles from patients diagnosed with periodontitis between non-progressive and progressive periodontal sites. METHODS: Five systemically healthy patients diagnosed with periodontitis were monitored weekly in their progression of the disease and GCF samples from 10 candidate sites were obtained. Two groups of five sites, matched from an equal number of teeth, were selected from the five patients: Progression (PG) and Non-Progression (NP). Global protein identification was performed with high-throughput proteomic approaches and label-free analysis determined their relative abundances. Proteins were identified by Proteome Discoverer v2.4 and searched against human SwissProt protein databases. Enrichment bioinformatic analyses were performed in STRING-DB and ShinyGO environment. RESULTS: 1504 and 1500 proteins were identified in NP and PG respectively. Forty-eight proteins were exclusively identified in PG, while 52 were identified in NP. Moreover, 35 proteins were more abundant in PG and 29 proteins in NP (twofold change, p < .05). The NP group was mainly represented by proteins from "response to biotic stimuli and other organisms," "processes of cell death regulation," "peptidase regulation," "protein ubiquitination," and "ribosomal activity" GO categories. The most represented GO categories of the PG group were "assembly of multiprotein complexes," "catabolic processes," "lipid metabolism," and "binding to hemoglobin and haptoglobin." CONCLUSIONS: There are quantitative and qualitative differences in the proteome of GCF from periodontal sites according to the status of clinical progression of periodontitis. Progressive periodontitis sites are characterized by a protein profile associated with catabolic processes, immune response, and response to cellular stress, while stable periodontitis sites show a protein profile mainly related to wound repair and healing processes, cell death regulation, and chaperone-mediated autophagy. Understanding the etiopathogenic role of these profiles in progressive periodontitis may help to develop new diagnostic and therapeutic approaches.

Levels of Pro-Inflammatory and Bone-Resorptive Mediators in Periodontally Compromised Patients under Orthodontic Treatment Involving Intermittent Forces of Low Intensities.

During orthodontic treatment, diverse cytokines, enzymes, and osteolytic mediators produced within the teeth surrounding periodontal tissues determine the rate of alveolar bone remodeling and consequent teeth movement. In patients with teeth presenting reduced periodontal support, periodontal stability should be ensured during orthodontic treatment. Thus, therapies based on the application of low-intensity intermittent orthodontic forces are recommended. To determine if this kind of treatment is periodontally well tolerated, this study aimed to analyze the production of receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), interleukin (IL)-6, IL-17A, and matrix metalloproteinase (MMP)-8 in periodontal tissues of protruded anterior teeth with reduced periodontal support and undergoing orthodontic treatment. Patients with periodontitis-associated anterior teeth migration received non-surgical periodontal therapy and a specific orthodontic treatment involving controlled low-intensity intermittent orthodontic forces. Samples were collected before periodontitis treatment, after periodontitis treatment, and at 1 week to 24 months of the orthodontic treatment. During the 2 years of orthodontic treatment, no significant differences were detected in the probing depth, clinical attachment level, supragingival bacterial plaque, and bleeding on probing. In line with this, the gingival crevicular levels of RANKL, OPG, IL-6, IL-17A, and MMP-8 did not vary between the different evaluation time-points of the orthodontic treatment. When compared with the levels detected during the periodontitis, the RANKL/OPG ratio was significantly lower at all the analyzed time-points of the orthodontic treatment. In conclusion, the patient-specific orthodontic treatment based on intermittent orthodontic forces of low intensities was well tolerated by periodontally compromised teeth with pathological migration.

Electrolyzed water for the microbiologic control in the pandemic dental setting: a systematic review.

BACKGROUND: Electrolyzed water has brought recent attention due to its antimicrobial properties. Indeed, electrolyzed water has been proposed to sterilize dental materials and instruments without compromising their structural integrity. In addition, electrolyzed water has been proposed as a mouthwash to control bacterial and viral oral infections without detrimental effects on the oral mucosa. However, no current consensus or evidence synthesis could indicate its potentially favorable use in the dental setting, particularly during the COVID-19 context. Therefore, this systematic review aimed to elucidate whether electrolyzed water could improve microbiologic control in the COVID-19 pandemic dental setting. METHODS: MEDLINE via Pubmed, EMBASE, Cochrane's CENTRAL, Scopus, LILACS, and Web of Science databases were searched up to September 2021 to identify experimental studies utilizing electrolyzed water for eliminating microorganisms in a dental setting. Besides, a manual and a grey literature search were performed. The data selection and extraction were performed individually and in duplicate. The Risk of Bias (RoB) was assessed with the Nature Publication Quality Improvement Project (NPQIP) score sheet. The study protocol was registered at PROSPERO CRD42020206986. RESULTS: From a total of 299 articles, 63 studies met the inclusion criteria. The included studies assessed several types of electrolyzed waters, which showed a high disinfection potential when used to deal with different oral conditions. Electrolyzed water demonstrated a broad antimicrobial spectrum and was highly efficient in the dental office disinfection against viruses, fungi, and bacteria, being compatible with most dental materials. In addition, electrolyzed water could protect against SARS-CoV-2 infection and contamination in the dental office. Regarding the RoB, only 35.18% of entries were answered as 'Yes', thus achieving less than half of the reporting sheet. CONCLUSION: Electrolyzed water effectively disinfects contaminated surfaces, dental materials, and equipment. Therefore, their use is recommendable in the SARS-CoV-2 pandemic dental setting.

Biomarkers of Periodontitis and Its Differential DNA Methylation and Gene Expression in Immune Cells: A Systematic Review.

The characteristic epigenetic profile of periodontitis found in peripheral leukocytes denotes its impact on systemic immunity. In fact, this profile not only stands for periodontitis as a low-grade inflammatory disease with systemic effects but also as an important source of potentially valuable clinical biomarkers of its systemic effects and susceptibility to other inflammatory conditions. Thus, we aimed to identify relevant genes tested as epigenetic systemic biomarkers in patients with periodontitis, based on the DNA methylation patterns and RNA expression profiles in peripheral immune cells. A detailed protocol was designed following the Preferred Reporting Items for Systematic Review and Meta-analysis -PRISMA guideline. Only cross-sectional and case-control studies that reported potential systemic biomarkers of periodontitis in peripheral immune cell types were included. DNA methylation was analyzed in leukocytes, and gene expression was in polymorphonuclear and mononuclear cells. Hypermethylation was found in TLR regulators genes: MAP3K7, MYD88, IL6R, RIPK2, FADD, IRAK1BP1, and PPARA in early stages of periodontitis, while advanced stages presented hypomethylation of these genes. TGFB1I1, VNN1, HLADRB4, and CXCL8 genes were differentially expressed in lymphocytes and monocytes of subjects with poorly controlled diabetes mellitus, dyslipidemia, and periodontitis in comparison with controls. The DAB2 gene was differentially overexpressed in periodontitis and dyslipidemia. Peripheral blood neutrophils in periodontitis showed differential expression in 163 genes. Periodontitis showed an increase in ceruloplasmin gene expression in polymorphonuclears in comparison with controls. Several genes highlight the role of the epigenetics of peripheral inflammatory cells in periodontitis that could be explored in blood as a source of biomarkers for routine testing.

Neutrophil N1 and N2 Subsets and Their Possible Association with Periodontitis: A Scoping Review.

Periodontitis is a chronic non-communicable disease caused by dysbiotic changes that affect the subgingival microbiota. During periodontitis, neutrophils play a central role in the initial recognition of bacteria, and their number increases with the appearance of the first signs of periodontal inflammation. Recent evidence has led to the proposition that neutrophils can also functionally polarize, determining selective activity patterns related to different diseases. Two well-defined neutrophil phenotypes have been described, the pro-inflammatory N1 subset and the suppressor N2 subset. To date, it has not been established whether these different neutrophil subtypes play a role in the pathogenesis of periodontitis. Thus, this scoping review aimed to determine whether there was evidence to suggest that the neutrophils present in periodontal tissues can be associated with certain phenotypes. The research question, population, concept, and context sought to identify original articles, in humans, that detected the presence of neutrophils in the periodontal tissues of people affected by periodontitis. Based on the search strategy, we found 3658 studies. After removing the papers with abstracts not related to the outcome measures and eligibility criteria, 16 articles were included for qualitative analysis. Several studies identified the presence of different neutrophil subsets, specifically, the naive, pro- and para-inflammatory, hyper-reactive and hyper-active, and high- and low-responder phenotypes. The existing evidence demonstrates the presence of pro-inflammatory, hyper-reactive and high-responder neutrophils in periodontal tissues affected with periodontitis. There is no evidence demonstrating the presence of the N1 or N2 phenotypes in periodontal tissues during periodontitis. However, the existence of pro-inflammatory phenotypes, which increase NETosis and degranulation, and increase the production of pro-inflammatory cytokines, could be suggestive of the N1 phenotypes.

Corrigendum: RvE1 Impacts the Gingival Inflammatory Infiltrate by Inhibiting the T Cell Response in Experimental Periodontitis.

[This corrects the article DOI: 10.3389/fimmu.2021.664756.].

Survival and Mechanical Complications of Posterior Single Implant-Supported Restorations Using Prefabricated Titanium Abutments: A Medium- and Long-Term Retrospective Analysis with up to 10 Years Follow-up.

PURPOSE: To evaluate the survival of implants and abutments and the incidence of mechanical complications of single posterior implant-supported restorations using prefabricated titanium abutments. MATERIALS AND METHODS: This retrospective clinical study analyzed 172 Astra Tech OsseoSpeed internal hexagon implants (Dentsply Sirona) placed in 85 patients with a follow-up between January 2009 and January 2019. All implants were restored with prefabricated titanium abutments and cement-retained metal-ceramic crowns. The clinical outcomes recorded were implant and abutment survival rates and mechanical complications (abutment/implant fractures, screw loosening/fracture, decementation of the superstructure, veneer chipping/fractures) and were analyzed according to age, sex, implant length/diameter, bone graft, arch, implant position, parafunctional habit or dental status, and opposite arch. Kaplan-Meier survival analysis was used to determine whether the distribution of time to event/failure differed based on implant position (premolar or molar), implant diameter, or abutment angulation. RESULTS: During the observation period (mean: 108 months), implant and abutment cumulative survival rates were 97.7% and 98.3%, respectively, with no statistically significant differences between implant positions (molar/premolar), implant diameters (3.5 vs 4 mm), or abutment angles (straight vs 15 degrees). Of the 172 single posterior implant-supported restorations, 14 mechanical complications (8.2%) were recorded. In particular, 3 abutment fractures (1.7%), 2 screw loosenings (1.2%), 2 screw fractures (1.2%), 1 implant fracture (0.6%), 2 chipping/fractures of veneering materials (1.2%), and 4 decementations of the superstructure (2.3%) occurred. CONCLUSION: The single posterior implant-supported restorations using prefabricated titanium abutments remain a clinically acceptable treatment in terms of prosthetic procedure and cost-effectiveness.

Senescent CD4+CD28- T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis.

Senescent cells express a senescence-associated secretory phenotype (SASP) with a pro-inflammatory bias, which contributes to the chronicity of inflammation. During chronic inflammatory diseases, infiltrating CD4+ T lymphocytes can undergo cellular senescence and arrest the surface expression of CD28, have a response biased towards T-helper type-17 (Th17) of immunity, and show a remarkable ability to induce osteoclastogenesis. As a cellular counterpart, T regulatory lymphocytes (Tregs) can also undergo cellular senescence, and CD28- Tregs are able to express an SASP secretome, thus severely altering their immunosuppressive capacities. During periodontitis, the persistent microbial challenge and chronic inflammation favor the induction of cellular senescence. Therefore, senescence of Th17 and Treg lymphocytes could contribute to Th17/Treg imbalance and favor the tooth-supporting alveolar bone loss characteristic of the disease. In the present review, we describe the concept of cellular senescence; particularly, the one produced during chronic inflammation and persistent microbial antigen challenge. In addition, we detail the different markers used to identify senescent cells, proposing those specific to senescent T lymphocytes that can be used for periodontal research purposes. Finally, we discuss the existing literature that allows us to suggest the potential pathogenic role of senescent CD4+CD28- T lymphocytes in periodontitis.

A micro-CT analysis of radicular dentine thickness in mandibular first premolars presenting C-shaped root canals: Identification of potential danger zones.

AIM: To describe the radicular dentine thickness in mandibular first premolars presenting C-shaped root canals, to identify the canal walls with less thickness as potential danger zones. In addition, to describe the internal and external anatomical characteristics of these teeth and associate them with the dentine thickness. METHODOLOGY: A total of 70 mandibular first premolars presenting C-shaped root canals were examined. Their internal morphology was analysed using Vertucci's and Fan's criteria, and their external morphology was analysed using the ASUDAS score. Besides, the dentine thickness around the root canals was two/three-dimensionally determined at five root planes and quantified in the distal and the mesial aspects. RESULTS: According to Fan's, ASUDAS, and Vertucci's classifications, the most common canal configurations were category C3, grade 3, and type V, respectively. In Vertucci's type III anatomy, the mesial root wall of the lingual canal showed significantly less dentine thickness than the distal wall in the middle plane (p = .031). Similarly, in Vertucci's type V anatomy, significantly less dentine thickness was observed in the mesial root wall of the buccal and lingual canals in the middle plane (p < .001) and the buccal canal in the middle-apical plane (p = .014) than the distal root wall of these canals. In teeth with ASUDAS grade 3 and 4 scores, significantly less dentine thickness was observed in the mesial in comparison with the distal root wall of these canals. These differences were demonstrated in the middle and middle-apical planes (p < .001) of grade 3 teeth and the middle-apical plane (p < .001) of grade 4 teeth. In these root planes, the Ver1-AS3 and VerV-AS3 combinations presented a 4-times greater risk of presenting walls with a critical dentine thickness of 0.6 mm (odds ratio [OR] = 4, p = .025) than the combinations Ver1-AS2, VerV-AS2, VerV-AS4, and VerIII-AS3. CONCLUSIONS: The root canal system configuration of mandibular first premolars with C-shaped canals showed a wide range of anatomical variations. The lowest dentine thickness was located in the mesial wall of the canals in the middle and apical root thirds of Vertucci's type III and V anatomies and in teeth with deep radicular grooves scored as ASUDAS grades 3 and 4. In the middle and middle-apical planes, the presence of the combinations Ver1-AS3 and VerV-AS3 showed a high risk of presenting a critical dentine thickness of 0.6 mm. Therefore, these root canal walls with less dentine thickness represent potential instrumentation danger zones in mandibular first premolars with C-shaped canals.

Treatment of a single gingival recession with a subepithelial connective tissue graft with a double papilla flap: A case report.

Gingival recessions are widely prevalent deformities that affect the normal position of the gingiva and cause exposure of the tooth root, and are often associated with unsatisfactory aesthetics and dentin hypersensitivity. The double papilla technique for root covering is a periodontal plastic surgery technique recommended for the treatment of gingival recessions. In this case report, we show the clinical results after a 12-month follow-up of a root-covering procedure in an upper canine affected by a gingival recession. A 56-year-old patient presenting a Cairo type I gingival recession on the vestibular surface of tooth 23 was treated with a one-stage surgical procedure, carried out using the double papilla technique in combination with a partially epithelialized connective tissue graft, reaching 100% root coverage. After a 12-month follow-up, this technique showed highly successful results both in 100% coverage of the defect and in long-term stability and aesthetics.

Contribution of -Omics Technologies in the Study of Porphyromonas gingivalis during Periodontitis Pathogenesis: A Minireview.

Periodontitis is a non-communicable chronic inflammatory disease characterized by the progressive and irreversible breakdown of the soft periodontal tissues and resorption of teeth-supporting alveolar bone. The etiology of periodontitis involves dysbiotic shifts in the diversity of microbial communities inhabiting the subgingival crevice, which is dominated by anaerobic Gram-negative bacteria, including Porphyromonas gingivalis. Indeed, P. gingivalis is a keystone pathogen with a repertoire of attributes that allow it to colonize periodontal tissues and influence the metabolism, growth rate, and virulence of other periodontal bacteria. The pathogenic potential of P. gingivalis has been traditionally analyzed using classical biochemical and molecular approaches. However, the arrival of new techniques, such as whole-genome sequencing, metagenomics, metatranscriptomics, proteomics, and metabolomics, allowed the generation of high-throughput data, offering a suitable option for bacterial analysis, allowing a deeper understanding of the pathogenic properties of P. gingivalis and its interaction with the host. In the present review, we revise the use of the different -omics technologies and techniques used to analyze bacteria and discuss their potential in studying the pathogenic potential of P. gingivalis.

Natural Killer T (NKT) Cells and Periodontitis: Potential Regulatory Role of NKT10 Cells.

Natural killer T (NKT) cells constitute a unique subset of T lymphocytes characterized by specifically interacting with antigenic glycolipids conjugated to the CD1d receptor on antigen-presenting cells. Functionally, NKT cells are capable of performing either effector or suppressor immune responses, depending on their production of proinflammatory or anti-inflammatory cytokines, respectively. Effector NKT cells are subdivided into three subsets, termed NKT1, NKT2, and NKT17, based on the cytokines they produce and their similarity to the cytokine profile produced by Th1, Th2, and Th17 lymphocytes, respectively. Recently, a new subgroup of NKT cells termed NKT10 has been described, which cooperates and interacts with other immune cells to promote immunoregulatory responses. Although the tissue-specific functions of NKT cells have not been fully elucidated, their activity has been associated with the pathogenesis of different inflammatory diseases with immunopathogenic similarities to periodontitis, including osteolytic pathologies such as rheumatoid arthritis and osteoporosis. In the present review, we revise and discuss the pathogenic characteristics of NKT cells in these diseases and their role in the pathogenesis of periodontitis; particularly, we analyze the potential regulatory role of the IL-10-producing NKT10 cells.

Premature Senescence of T-cells Favors Bone Loss During Osteolytic Diseases. A New Concern in the Osteoimmunology Arena.

Cellular senescence is a biological process triggered in response to time-accumulated DNA damage, which prioritizes cell survival over cell function. Particularly, senescent T lymphocytes can be generated prematurely during chronic inflammatory diseases regardless of chronological aging. These senescent T lymphocytes are characterized by the loss of CD28 expression, a co-stimulatory receptor that mediates antigen presentation and effective T-cell activation. An increased number of premature senescent CD4+CD28- T lymphocytes has been frequently observed in osteolytic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, osteopenia, osteoporosis, and osteomyelitis. Indeed, CD4+CD28- T lymphocytes produce higher levels of osteoclastogenic molecular mediators directly related to pathologic bone loss, such as tumor necrosis factor (TNF)-α, interleukin (IL)-17A, and receptor-activator of nuclear factor κB ligand (RANKL), as compared with regular CD4+CD28+ T lymphocytes. In addition, premature senescent CD8+CD28- T lymphocytes have been negatively associated with bone healing and regeneration by inhibiting osteoblast differentiation and mesenchymal stromal cell survival. Therefore, accumulated evidence supports the role of senescent T lymphocytes in osteoimmunology. Moreover, premature senescence of T-cells seems to be associated with the functional imbalance between the osteolytic T-helper type-17 (Th17) and bone protective T regulatory (Treg) lymphocytes, as well as the phenotypic instability of Treg lymphocytes responsible for its trans-differentiation into RANKL-producing exFoxp3Th17 cells, a key cellular phenomenon directly related to bone loss. Herein, we present a framework for the understanding of the pathogenic characteristics of T lymphocytes with a premature senescent phenotype; and particularly, we revise and discuss their role in the osteoimmunology of osteolytic diseases.

Humanized Mouse Models for the Study of Periodontitis: An Opportunity to Elucidate Unresolved Aspects of Its Immunopathogenesis and Analyze New Immunotherapeutic Strategies.

Periodontitis is an oral inflammatory disease in which the polymicrobial synergy and dysbiosis of the subgingival microbiota trigger a deregulated host immune response, that leads to the breakdown of tooth-supporting tissues and finally tooth loss. Periodontitis is characterized by the increased pathogenic activity of T helper type 17 (Th17) lymphocytes and defective immunoregulation mediated by phenotypically unstable T regulatory (Treg), lymphocytes, incapable of resolving the bone-resorbing inflammatory milieu. In this context, the complexity of the immune response orchestrated against the microbial challenge during periodontitis has made the study of its pathogenesis and therapy difficult and limited. Indeed, the ethical limitations that accompany human studies can lead to an insufficient etiopathogenic understanding of the disease and consequently, biased treatment decision-making. Alternatively, animal models allow us to manage these difficulties and give us the opportunity to partially emulate the etiopathogenesis of periodontitis by inoculating periodontopathogenic bacteria or by placing bacteria-accumulating ligatures around the teeth; however, these models still have limited translational application in humans. Accordingly, humanized animal models are able to emulate human-like complex networks of immune responses by engrafting human cells or tissues into specific strains of immunodeficient mice. Their characteristics enable a viable time window for the study of the establishment of a specific human immune response pattern in an in vivo setting and could be exploited for a wider study of the etiopathogenesis and/or treatment of periodontitis. For instance, the antigen-specific response of human dendritic cells against the periodontopathogen Porphyromonas gingivalis favoring the Th17/Treg response has already been tested in humanized mice models. Hypothetically, the proper emulation of periodontal dysbiosis in a humanized animal could give insights into the subtle molecular characteristics of a human-like local and systemic immune response during periodontitis and support the design of novel immunotherapeutic strategies. Therefore, the aims of this review are: To elucidate how the microbiota-elicited immunopathogenesis of periodontitis can be potentially emulated in humanized mouse models, to highlight their advantages and limitations in comparison with the already available experimental periodontitis non-humanized animal models, and to discuss the potential translational application of using these models for periodontitis immunotherapeutics.

The influence of flap design on patients' experiencing pain, swelling, and trismus after mandibular third molar surgery: a scoping systematic review.

Third molar removal surgery usually comes accompanied by postoperative discomfort, which could be influenced by the surgical approach chosen. This scoping systematic review aimed at compiling the available evidence focused on the influence of flap design, including envelope flap (EF), triangular flap (TF), and modified triangular flap (MTF), on postoperative pain, swelling, and trismus, as primary outcome measures, and any result mentioning healing promotion or delay, as secondary outcome measure, after mandibular third molar extraction surgery. An electronic search, complemented by a manual search, of articles published from 1999 to 2020 was conducted in the Medline (PubMed), EMBASE and Web of Science databases including human randomized controlled trials, prospective, and retrospective studies with at least 15 patients. The risk of bias of the included studies was assessed either with the Cochrane's Risk of Bias tool or with the Newcastle-Ottawa scale. Every step of the review was performed independently and in duplicate. The initial electronic search recovered 2102 articles. After applying the inclusion criteria, 12 articles were included. For patient's perceived postoperative pain, TF and MTF frequently reported better results than EF. For swelling, the literature is divided, despite a trend favoring EF. For trismus, data showed that its occurrence is mostly associated with the duration of the surgery rather than with the chosen flap. For healing, the limited data is inconclusive. Finally, randomized studies showed a high risk of bias, whereas nonrandomized studies were mostly of good quality and low risk of bias. Although there was no clear consensus regarding the influence of different flap designs for third mandibular molar extraction on postoperative clinical morbidities; the surgeon's experience, estimated surgical difficulty, molar position and orientation, and surg ery duration should be considered when choosing among the different flap designs.

RvE1 Impacts the Gingival Inflammatory Infiltrate by Inhibiting the T Cell Response in Experimental Periodontitis.

Periodontitis is a chronic inflammatory disease associated with the formation of dysbiotic plaque biofilms and characterized by the progressive destruction of the alveolar bone. The transition from health to disease is characterized by a shift in periodontal immune cell composition, from mostly innate (neutrophils) to adaptive (T lymphocytes) immune responses. Resolvin E1 (RvE1) is a specialized pro-resolution mediator (SPMs), produced in response to inflammation, to enhance its resolution. Previous studies have indicated the therapeutic potential of RvE1 in periodontal disease; however, the impact of RvE1 in the microbial-elicited osteoclastogenic immune response remains uncharacterized in vivo. In the present study, we studied the impact of RvE1 on the gingival inflammatory infiltrate formation during periodontitis in a mouse model. First, we characterized the temporal-dependent changes of the main immune cells infiltrating the gingiva by flow cytometry. Then, we evaluated the impact of early or delayed RvE1 administration on the gingival immune infiltration and cervical lymph nodes composition. We observed a consistent inhibitory outcome on T cells -particularly effector T cells- and a protective effect on regulatory T cells (Tregs). Our data further demonstrated the wide range of actions of RvE1, its preventive role in the establishment of the adaptive immune response during inflammation, and bone protective capacity.