Connecting the dots towards precision orthodontics.

Precision orthodontics entails the use of personalized clinical, biological, social and environmental knowledge of each patient for deep individualized clinical phenotyping and diagnosis combined with the delivery of care using advanced customized devices, technologies and biologics. From its historical origins as a mechanotherapy and materials driven profession, the most recent advances in orthodontics in the past three decades have been propelled by technological innovations including volumetric and surface 3D imaging and printing, advances in software that facilitate the derivation of diagnostic details, enhanced personalization of treatment plans and fabrication of custom appliances. Still, the use of these diagnostic and therapeutic technologies is largely phenotype driven, focusing mainly on facial/skeletal morphology and tooth positions. Future advances in orthodontics will involve comprehensive understanding of an individual's biology through omics, a field of biology that involves large-scale rapid analyses of DNA, mRNA, proteins and other biological regulators from a cell, tissue or organism. Such understanding will define individual biological attributes that will impact diagnosis, treatment decisions, risk assessment and prognostics of therapy. Equally important are the advances in artificial intelligence (AI) and machine learning, and its applications in orthodontics. AI is already being used to perform validation of approaches for diagnostic purposes such as landmark identification, cephalometric tracings, diagnosis of pathologies and facial phenotyping from radiographs and/or photographs. Other areas for future discoveries and utilization of AI will include clinical decision support, precision orthodontics, payer decisions and risk prediction. The synergies between deep 3D phenotyping and advances in materials, omics and AI will propel the technological and omics era towards achieving the goal of delivering optimized and predictable precision orthodontics.

Calcium Phosphate Delivery Systems for Regeneration and Biomineralization of Mineralized Tissues of the Craniofacial Complex.

Calcium phosphate (CaP)-based materials have been extensively used for mineralized tissues in the craniofacial complex. Owing to their excellent biocompatibility, biodegradability, and inherent osteoconductive nature, their use as delivery systems for drugs and bioactive factors has several advantages. Of the three mineralized tissues in the craniofacial complex (bone, dentin, and enamel), only bone and dentin have some regenerative properties that can diminish due to disease and severe injuries. Therefore, targeting these regenerative tissues with CaP delivery systems carrying relevant drugs, morphogenic factors, and ions is imperative to improve tissue health in the mineralized tissue engineering field. In this review, the use of CaP-based microparticles, nanoparticles, and polymer-induced liquid precursor (PILPs) amorphous CaP nanodroplets for delivery to craniofacial bone and dentin are discussed. The use of these various form factors to obtain either a high local concentration of cargo at the macroscale and/or to deliver cargos precisely to nanoscale structures is also described. Finally, perspectives on the field using these CaP materials and next steps for the future delivery to the craniofacial complex are presented.

Unilateral Loss of Maxillary Molars in Young Mice Leads to Bilateral Condylar Adaptation and Degenerative Disease.

The adaptive response of the mandible and temporomandibular joint (TMJ) to altered occlusion in juvenile patients is presently unclear. To address this question, we established a mouse model in which all molars were extracted from the maxillary right quadrant in prepubertal, 3-week-old mice and analyzed morphological, tissue, cellular, and molecular changes in the mandible and condyle 3 weeks later. Unilateral loss of maxillary molars led to significant, robust, bilateral changes, primarily in condylar morphology, including anteroposterior narrowing of the condylar head and neck and increased convexity at the condylar surface, as determined by geometric morphometric analysis. Furthermore, both condyles in experimental mice exhibited a degenerative phenotype, which included decreased bone volume and increased mineral density near the condylar head surface compared to control mice. Changes in condylar morphology and mineralized tissue composition were associated with alterations in the cellular architecture of the mandibular condylar cartilage, including increased expression of markers for mature (Col2a1) and hypertrophic (Col10a1) chondrocytes, suggesting a shift toward differentiating chondrocytes. Our results show significant bilateral condylar morphological changes, alterations in tissue composition, cellular organization, and molecular expression, as well as degenerative disease, in response to the unilateral loss of teeth. Our study provides a relatively simple, tractable mouse tooth extraction system that will be of utility in uncovering the cellular and molecular mechanisms of condylar and mandibular adaptation in response to altered occlusion. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Morphologic and histologic characterization of sheep and porcine TMJ as large animal models for tissue engineering applications.

OBJECTIVE: The aim of this study was to compare and characterize the structural and ultrastructural organization of the temporomandibular joint (TMJ) between two large animal models for use in the development of tissue engineering strategies. MATERIALS AND METHODS: Whole TMJs from sheep and pigs were evaluated with micro-computed tomography (µCT) for morphology and quantitative analyses of bone parameters. Histological examination was performed on the TMJ disc and its attachments to investigate regional distribution of collagen, elastin, and glycosaminoglycans (GAGs). RESULTS: µCT analyses demonstrate higher bone mineral density (BMD) in the temporal fossa compared to the mandibular condyle in both species, with this variable being significantly higher in sheep than pig. Quantitative morphometry of the trabecular condyle reveals no statistical differences between the species. Histology demonstrates similar structural organization of collagen and elastin between species. Elastin staining was nearly twofold greater in sheep than in the pig disc. Finally, Safranin-O staining for GAGs in the TMJ disc was localized to the intermediate zone in the sheep but was absent from the porcine disc. CONCLUSIONS: Our findings show some important differences in the pig and sheep TMJ µCT variables and histology and composition of the disc and discal attachment. These disparities likely reflect differences in masticatory and TMJ functional loading patterns between the two species and provide insights into large animal models towards human applications. CLINICAL RELEVANCE: As with the established pig model, the sheep is a suitable large animal model for TMJ research such as regenerative strategies, with specific considerations for design parameters appropriate for human-analog applications.

Standardization of mineral density maps of physiologic and pathologic biominerals in humans using cone-beam CT and micro-CT scanners.

OBJECTIVES: The lack of standardized X-ray imaging remains a challenge for comparative studies on spatial scans acquired from different clinic-specific X-ray scanners. The central objectives of this study are: 1) to delineate mineral density (MD) values, and 2) generate spatial MD maps of various physiologic and pathologic biominerals, and 3) propose a standardization protocol within the safe-operating zone of a CT scanner that underpins normalization of absorbed dose to shape and density of tissues. METHODS: A systematic approach to propose a standardization protocol for CT imaging in vivo included: 1) estimation of pathologic MD ranges by performing a comparative meta-analysis on 2009-2019 data from the PubMed database; 2) calibration of cone-beam CT (CBCT) and micro-CT scanners with phantoms of known mineral densities (0, 250, 500, 750 and 3000 mg/cc) and shapes (cylinders and polyhedrons); 3) scanning craniofacial bones (N = 5) and dental tissues (N = 5), and ectopic minerals from humans (N = 3 each, pulp, salivary gland, kidney and prostrate stones, and penile and vascular plaques); 4) underscoring the effect of shape-factor (surface area-to-volume ratio) on MD of biominerals. RESULTS: Higher MDs of physiologic and pathologic cortical bones (504-1009 mg/cc) compared to trabecular bone (82-212 mg/cc) were observed. An increase in shape-factor increased the CBCT error in MD measurement and revealed that the scanner resolution is dependent on the absorbed dose and shape-factor of detectable features. SIGNIFICANCE: CT scanners should be calibrated with phantoms containing segments of known shape-factors and mineral densities to identify safe-operating zones. The calibrated approach will narrow the gap between length-scale dependent measurements, and will permit spatiotemporal quantitative and reliable detection of pathologies.

Using Twitter to promote #orthodontic research and clinical innovations: Practice and challenges.

While Twitter has substantial benefits in real-time sharing and dissemination of information and facilitating discussions, currently there is a noticeable absence of its use in the orthodontic profession and peer-reviewed journals. This review aims to introduce the basics of using social media; provide a perspective and prospective vision on effective practices on the use of Twitter in sharing orthodontic discoveries and clinical innovations; and discuss the limitations and caveats of using such approaches in sharing and assimilating information. There has been increasing debate on the potential role of social media, specifically Twitter, in shaping the way scholars and clinicians access, discuss, and disseminate research and clinical innovations. Despite various caveats, such as misinformation, privacy concerns, and unprofessionalism, Twitter can be used to efficiently share discoveries and innovations and facilitate networking. Thus, the use of Twitter during professional orthodontic meetings can enhance their impact by enabling nonattendees to participate in the meeting virtually and in real time. Moreover, utilization of Twitter by peer-reviewed journals can aid in enhancing the dissemination of information. That, with the optimization of algorithms and strategies, can also maximize reach and impact. Future efforts are essential to develop standardized guidelines for the use of Twitter among orthodontic healthcare professionals and scholars to better manage scientific integrity, privacy, and ethical concerns. Professional orthodontic organizations, journals, and researchers should be aware of the potential benefits of Twitter strategies that could be applied to maximize the impact and dissemination of orthodontic discoveries to reach the largest possible audience that will facilitate collaboration and discussion, and advance the delivery of cutting-edge treatments.

IGF-1 TMJ injections enhance mandibular growth and bone quality in juvenile rats.

OBJECTIVES: Dentofacial orthopaedic treatment of mandibular hypoplasia has unpredictable skeletal outcomes. Although several biomodulators including insulin-like growth factor 1 (IGF-1) are known to contribute to chondrocyte proliferation, their efficacy in modulating mandibular growth has not been validated. The aim of this study was to determine the effect of locally delivered IGF-1 on mandibular growth and condylar bone quality/quantity in juvenile rats. SETTING AND SAMPLE POPULATION: Institutional vivarium using twenty-four 35-day-old male Sprague-Dawley rats. METHODS: PBS or 40 µg/kg (low-dose) IGF-1 or 80 µg/kg (high-dose) IGF-1 was injected bilaterally into the temporomandibular joints of the rats at weekly intervals for four weeks. Cephalometric and micro-computed tomography measurements were used to determine mandibular dimensions. Bone and tissue mineral density, volume fraction and mineral content were determined, and serum IGF-1 concentrations assayed. RESULTS: Intra-articular administration of high-dose IGF-1 contributed to a significant 6%-12% increase in mandibular body and condylar length compared to control and low-dose IGF-1-treated animals. Additionally, IGF-1 treatment resulted in a significant decrease in the angulation of the lower incisors to mandibular plane. Condylar bone volume, bone volume fraction, mineral content and mineral density were significantly increased with high-dose IGF-1 relative to control and low-dose IGF-1 groups. Serum IGF-1 levels were similar between all groups confirming limited systemic exposure to the locally administered IGF-1. CONCLUSION: Local administration of high-dose 80 µg/kg IGF-1 enhances mandibular growth and condylar bone quality and quantity in growing rats. The findings have implications for modulating mandibular growth and potentially enhancing condylar bone health and integrity.

The Significance of Utilizing A Corticotomy on Periodontal and Orthodontic Outcomes: A Systematic Review and Meta-Analysis.

PURPOSE: This systematic review compares the clinical and radiographic outcomes for patients who received only a corticotomy or periodontal accelerated osteogenic orthodontics (PAOO) with those who received a conventional orthodontic treatment. METHODS: An electronic search of four databases and a hand search of peer-reviewed journals for relevant articles published in English between January 1980 and June 2021 were performed. Human clinical trials of ≥10 patients treated with a corticotomy or PAOO with radiographic and/or clinical outcomes were included. Meta-analyses were performed to analyze the weighted mean difference (WMD) and confidence interval (CI) for the recorded variables. RESULTS: Twelve articles were included in the quantitative analysis. The meta-analysis revealed a localized corticotomy distal to the canine can significantly increase canine distalization (WMD = 1.15 mm, 95% CI = 0.18-2.12 mm, p = 0.02) compared to a conventional orthodontic treatment. In addition, PAOO also showed a significant gain of buccal bone thickness (WMD = 0.43 mm, 95% CI = 0.09-0.78 mm, p = 0.01) and an improvement of bone density (WMD = 32.86, 95% CI = 11.83-53.89, p = 0.002) compared to the corticotomy group. CONCLUSION: Based on the findings of the meta-analyses, the localized use of a corticotomy can significantly increase the amount of canine distalization during orthodontic treatment. Additionally, the use of a corticotomy as a part of a PAOO procedure significantly increases the rate of orthodontic tooth movement and it is accompanied by an increased buccal bone thickness and bone density compared to patients undergoing a conventional orthodontic treatment.

Temporomandibular Joint Bioengineering Conference: Working Together Toward Improving Clinical Outcomes.

The sixth temporomandibular joint (TMJ) Bioengineering Conference (TMJBC) was held on June 14-15 2018, in Redondo Beach, California, 12 years after the first TMJBC. Speakers gave 30 presentations and came from the United States, Europe, Asia, and Australia. The goal of the conference has remained to foster a continuing forum for bioengineers, scientists, and surgeons and veterinarians to advance technology related to TMJ disorders. These collective multidisciplinary interactions over the past decade have made large strides in moving the field of TMJ research forward. Over the past 12 years, in vivo approaches for tissue engineering have emerged, along with a wide variety of degeneration models, as well as with models occurring in nature. Furthermore, biomechanical tools have become more sensitive and new biologic interventions for disease are being developed. Clinical directives have evolved for specific diagnoses, along with patient-specific biological and immunological responses to TMJ replacement devices alloplastic and/or bioengineered devices. The sixth TMJBC heralded many opportunities for funding agencies to advance the field: (1) initiatives on TMJ that go beyond pain research, (2) more training grants focused on graduate students and fellows, (3) partnership funding with government agencies to translate TMJ solutions, and (4) the recruitment of a critical mass of TMJ experts to participate on grant review panels. The TMJ research community continues to grow and has become a pillar of dental and craniofacial research, and together we share the unified vision to ultimately improve diagnoses and treatment outcomes in patients affected by TMJ disorders.

Effect of orthodontic forces on levels of enzymes in gingival crevicular fluid (GCF): A systematic review.

OBJECTIVE: Orthodontic force application releases multiple enzymes in gingival crevicular fluid (GCF) for activation, resorption, reversal, deposition of osseous elements and extracellular matrix degradation. The current systematic review critically evaluated all existing evidence on enzymes in orthodontic tooth movement. METHODS: Literature was searched with predetermined search strategy on electronic databases (PubMed, Scopus, Embase), along with hand search. RESULTS: Initial search identified 652 studies, shortlisted to 52 studies based on PRISMA. Quality assessment further led to final inclusion of 48 studies (13 moderately and 35 highly sensitive studies). Primary outcomes are significant upregulation in GCF levels of enzymes-aspartate aminotransferase (AST), alkaline phosphatase (ALP), matrix metalloproteinases (MMPs), lactate dehydrogenase (LDH), ß-glucuronidase (ßG), tartrate resistant acid phosphatase (TRAP), acid phosphatase (ACP) and down regulation in cathepsin B (Cb). Site specificity is shown by ALP, TRAP, AST, LDH, MMP9 with levels at compression site increasing earlier and in higher quantities compared with tension site. ALP levels are higher at tension site only in retention. A positive correlation of LDH, ALP and AST is also observed with increasing orthodontic force magnitude. CONCLUSIONS: A strong evidence of variation in enzymes (ALP, AST, ACP TRAP, LDH, MMPs, Cb) in GCF is found in association with different magnitude, stages and sites of orthodontic force application.

Effect of orthodontic forces on levels of enzymes in gingival crevicular fluid (GCF): A systematic review

Abstract Objective: Orthodontic force application releases multiple enzymes in gingival crevicular fluid (GCF) for activation, resorption, reversal, deposition of osseous elements and extracellular matrix degradation. The current systematic review critically evaluated all existing evidence on enzymes in orthodontic tooth movement. Methods: Literature was searched with predetermined search strategy on electronic databases (PubMed, Scopus, Embase), along with hand search. Results: Initial search identified 652 studies, shortlisted to 52 studies based on PRISMA. Quality assessment further led to final inclusion of 48 studies (13 moderately and 35 highly sensitive studies). Primary outcomes are significant upregulation in GCF levels of enzymes-aspartate aminotransferase (AST), alkaline phosphatase (ALP), matrix metalloproteinases (MMPs), lactate dehydrogenase (LDH), β-glucuronidase (βG), tartrate resistant acid phosphatase (TRAP), acid phosphatase (ACP) and down regulation in cathepsin B (Cb). Site specificity is shown by ALP, TRAP, AST, LDH, MMP9 with levels at compression site increasing earlier and in higher quantities compared with tension site. ALP levels are higher at tension site only in retention. A positive correlation of LDH, ALP and AST is also observed with increasing orthodontic force magnitude. Conclusions: A strong evidence of variation in enzymes (ALP, AST, ACP TRAP, LDH, MMPs, Cb) in GCF is found in association with different magnitude, stages and sites of orthodontic force application.

Resumo Objetivo: a aplicação da força ortodôntica libera múltiplas enzimas no fluído crevicular gengival (FCG), desencadeando a ativação, reabsorção, reversão, deposição de elementos ósseos e degradação da matriz extracelular. A presente revisão sistemática avaliou criticamente toda a evidência disponível sobre os níveis de enzimas durante a movimentação ortodôntica. Métodos: utilizando-se estratégias predeterminadas, foram realizadas buscas em bases de dados eletrônicas (PubMed, Scopus, Embase), sendo também feitas buscas manuais. Resultados: a busca inicial identificou 652 estudos e, com base nas diretrizes do PRISMA, foram selecionados 52 estudos. A avaliação qualitativa resultou na inclusão final de 48 estudos (13 estudos com moderada sensibilidade e 35 com alto nível de sensibilidade). Os desfechos primários foram o aumento significativo dos níveis no FCG das enzimas aspartato aminotransferase (AST), fosfatase alcalina (FA), metaloproteinases de matriz (MMPs), lactato desidrogenase (LDH), β-glucuronidase (βG), fosfatase ácido-resistente ao tartarato (TRAP), fosfatase ácida (FAC) e baixa regulação de catepsina B (Cb). Especificidade quanto ao local foi mostrada para FA, TRAP, AST, LDH e MMP9 com os níveis no lado de compressão aumentando mais rápido e em maiores quantidades, quando comparado ao lado de tensão. Os níveis de FA foram maiores no lado de tensão somente no período de contenção. Uma correlação positiva de LDH, FA e AST também foi observada à medida que a magnitude de força ortodôntica aumentou. Conclusões: há fortes evidências indicando que as variações nas enzimas (FA, AST, FAC, TRAP, LDH, MMPs, Cb) presentes no FCG estão associadas a diferentes magnitudes, estágios e locais de aplicação da força ortodôntica.

Preface to COAST 2018 Innovators' Workshop: Bridging the biology and technology gap in orthodontics and craniofacial care.

OBJECTIVE: A third focused workshop explored how to transfer novel findings into clinical orthodontic practice. SETTING AND SAMPLE POPULATION: Participants met at the Scottsdale Plaza Resort, 12-16 September 2018 for the Consortium for Orthodontic Advances in Science and Technology 2018 Innovators' Workshop. Thirty speakers and four lunch-hour focus group leaders shared and exchanged information with approximately 45 registered attendees. MATERIAL AND METHODS: This Innovators' Workshop was organized according to five themed sessions which covered: (a) The relevance of genetics, biology and environment to therapeutic outcomes; (b) Application of bioinformatics in craniofacial research; (c) Regeneration with and for orthodontic treatment; (d) Technology in precision orthodontics; and (e) Muscle, joint, and airway: Growth, function and pain. RESULTS: The papers that comprise this supplemental issue exemplify the important outcomes of the 2018 COAST Workshop. In addition, matters identified as important needs include improved understanding of neural, skeletal and muscle tissue crosstalk in early craniofacial growth; standardized methods for three-dimensional radiographic and surface landmark and reference plane identification, measurements and serial superimpositioning techniques for use in the clinic; sharing and making available existing data sets (eg, cone beam computed tomography images, genotype-phenotype data); evidence of the usefulness and effectiveness of new devices; guidelines of what to measure to characterize the airway; more information about the influences of the soft tissues on craniofacial morphology; and information about effective digital work flows applied to clinical and educational settings. CONCLUSIONS: Progress in bridging the biology-technology gap has identified new needs for improvements in orthodontics and craniofacial care.

Microsphere controlled drug delivery for local control of tooth movement.

Background: Because orthodontic tooth movement is dependent upon osteoclast-mediated resorption of alveolar bone adjacent to the pressure side of tooth roots, biologic mediators that regulate osteoclasts can be utilized to control tooth movement. Objectives: To develop a novel method to locally enhance orthodontic anchorage. Methods: We encapsulated osteoprotegerin (OPG) in polymer microspheres and tested the effectiveness of microsphere encapsulated versus non-encapsulated OPG for enhancing orthodontic anchorage in a rodent model of tooth movement. A single injection of 1 mg/kg non-encapsulated or microsphere encapsulated OPG was delivered into the palatal mucosa mesial to the first maxillary molar 1 day prior to tooth movement. A positive control group received injections of 5 mg/kg non-encapsulated OPG every 3 days during tooth movement. After 28 days of tooth movement, hemi-maxillae and femurs were dissected. Molar mesial and incisor distal tooth movement was measured using stone casts that were scanned and magnified. Local alveolar, distant femur bone, and tooth root volumes were analyzed by micro computed tomography. Serum OPG levels were measured by ELISA. Osteoclast numbers were quantified by histomorphometry. Results: The single injection of microsphere encapsulated OPG significantly enhanced orthodontic anchorage, while the single injection of non-encapsulated OPG did not. Injection of encapsulated OPG inhibited molar mesial movement but did not inhibit incisor tooth movement, and did not alter alveolar or femur bone volume fraction, density, or mineral content. Multiple injections of 5 mg/kg non-encapsulated OPG enhanced orthodontic anchorage, but also inhibited incisor retraction and altered alveolar and femur bone quality parameters. Increased OPG levels were found only in animals receiving multiple injections of non-encapsulated 5 mg/kg OPG. Osteoclast numbers were higher upon tooth movement in animals that did not receive OPG. Osteoclast numbers in OPG injected animals were variable within groups. Conclusions: Microsphere encapsulation of OPG allows for controlled drug release, and enhances site-specific orthodontic anchorage without systemic side effects. With additional refinements, this drug delivery system could be applicable to a broad array of potential biologic orthodontic therapeutics.

Three-Dimensional Force Measurements During Rapid Palatal Expansion in Sus scrofa.

Rapid palatal expansion is an orthodontic procedure widely used to correct the maxillary arch. However, its outcome is significantly influenced by factors that show a high degree of variability amongst patients. The traditional treatment methodology is based on an intuitive and heuristic treatment approach because the forces applied in the three dimensions are indeterminate. To enable optimal and individualized treatment, it is essential to measure the three-dimensional (3D) forces and displacements created by the expander. This paper proposes a method for performing these 3D measurements using a single embedded strain sensor, combining experimental measurements of strain in the palatal expander with 3D finite element analysis (FEA). The method is demonstrated using the maxillary jaw from a freshly euthanized pig (Sus scrofa) and a hyrax-design rapid palatal expander (RPE) appliance with integrated strain gage. The strain gage measurements are recorded using a computer interface, following which the expansion forces and extent of expansion are estimated by FEA. A total activation of 2.0 mm results in peak total force of about 100 N-almost entirely along the direction of expansion. The results also indicate that more than 85% of the input activation is immediately transferred to the palate and/or teeth. These studies demonstrate a method for assessing and individualizing expansion magnitudes and forces during orthopedic expansion of the maxilla. This provides the basis for further development of smart orthodontic appliances that provide real-time readouts of forces and movements, which will allow personalized, optimal treatment.

Nisin ZP, a Bacteriocin and Food Preservative, Inhibits Head and Neck Cancer Tumorigenesis and Prolongs Survival.

The use of small antimicrobial peptides or bacteriocins, like nisin, to treat cancer is a new approach that holds great promise. Nisin exemplifies this new approach because it has been used safely in humans for many years as a food preservative, and recent laboratory studies support its anti-tumor potential in head and neck cancer. Previously, we showed that nisin (2.5%, low content) has antitumor potential in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. The current studies explored a naturally occurring variant of nisin (nisin ZP; 95%, high content) for its antitumor effects in vitro and in vivo. Nisin ZP induced the greatest level of apoptosis in HNSCC cells compared to low content nisin. HNSCC cells treated with increasing concentrations of nisin ZP exhibited increasing levels of apoptosis and decreasing levels of cell proliferation, clonogenic capacity, and sphere formation. Nisin ZP induced apoptosis through a calpain-dependent pathway in HNSCC cells but not in human oral keratinocytes. Nisin ZP also induced apoptosis dose-dependently in human umbilical vein endothelial cells (HUVEC) with concomitant decreases in vascular sprout formation in vitro and reduced intratumoral microvessel density in vivo. Nisin ZP reduced tumorigenesis in vivo and long-term treatment with nisin ZP extended survival. In addition, nisin treated mice exhibited normal organ histology with no evidence of inflammation, fibrosis or necrosis. In summary, nisin ZP exhibits greater antitumor effects than low content nisin, and thus has the potential to serve as a novel therapeutic for HNSCC.

Effect of orthodontic forces on cytokine and receptor levels in gingival crevicular fluid: a systematic review.

This systematic review aimed to generate evidence on role of potent markers of inflammation [cytokines, chemokines, their associated receptors and antagonists] following the application of orthodontic forces. Subsequent to registration with PROSPERO, literature search followed a predetermined search strategy to key databases along with hand search (HS). Seventy-seven articles from PubMed (P), 637 from Scopus (S), 51 from Embase (E), and 3 from hand search (HS) were identified. A total of 39 articles were shortlisted that met strict inclusion and exclusion criteria and quality assessment. Each study was evaluated for participant characteristics, study design, oral hygiene regimen, and gingival crevicular fluid (GCF) handling. Among these studies, biomarkers in the order of frequency were interleukin (IL)-1ß (N=21), tumor necrosis factor (TNF)-α (N=10), IL-8,IL-6(N=8), receptor activator of nuclear factor kappa-B ligand (RANKL) (N=7), monocyte chemoattractant protein (MCP)-1 (N=3), IL-2 (N=4), IL-4, IL-10, RANTES (N=2), IL-1, IL-5, IL-1α, IP-10, osteopontin (OPN) (N=1) and receptors and their antagonists in the order of osteoprotegerin (OPG) (N=8), IL-1RA (N=5), and RANK (N=1). Results revealed an immediate release of inflammatory bone-resorptive mediators, IL-1ß and TNF-α, where IL-1ß increased as early as 1 min to 1 h reaching peak at 24 h while TNF-α increased at 1 h or 1 day. This was accompanied by a fall in bone-protective mediator (OPG) levels at 1 h and 24 h after orthodontic force application. Continuous forces were accompanied by a decrease in mediator levels after attaining peak levels (most commonly at 24 h) while repeated activations in interrupted force upregulated their secretion. Significant correlations of IL-1ß levels with pain intensity, rate of orthodontic tooth movement (OTM) and of activity index (AI) (IL-1ß/IL-1RA) with velocity of tooth movement and growth status of individuals have also been deduced. A greater AI and RANKL/OPG ratio was seen in juveniles as compared to adults or non-growers that were associated with faster rate of OTM in juveniles. None of the studies addressed the effect of estrous cycle in female subjects. Lack of homogeneity in several parameters calls for a better controlled research on the biology of OTM.

Quantification of external root resorption by low- vs high-resolution cone-beam computed tomography and periapical radiography: A volumetric and linear analysis.

INTRODUCTION: The goal of this study was to determine whether cone beam-computed tomography (CBCT) images with resolutions similar to those produced in orthodontic offices have sufficient resolution to accurately quantify root resorption defects. METHODS: Teeth containing simulated root defects were scanned by microcomputed tomography (microCT) and CBCT at 0.2- and 0.4-mm resolutions and were radiographed by the periapical technique. Root length was measured with digital calipers. Comparisons were made to establish significance between imagining modalities and to compare defects of differing severity and position. RESULTS: The mean absolute difference in volumetric measurements of lateral defects from 0.2-mm-resolution CBCT images compared with those from microCT images was significantly smaller than those from 0.4-mm-resolution CBCT images (0.20 ± 0.2 mm(3) vs 0.30 ± 0.3 mm(3); P = 0.002). A Bland-Altman analysis showed that the 95% limits of agreement range between low-resolution CBCT and microCT volumetric measurements was1.44-fold greater than that between high-resolution CBCT and microCT measurements (-0.87-0.68 vs -0.49-0.59 mm(3)). The accuracy of the volumetric measurements was also significantly influenced by defect size (P = 0.004 for high-resolution CBCT, P = 0.005 for low-resolution CBCT) and, on low-resolution scans, by the defect's vertical position (P = 0.012). Linear measurements of apical defects from both the 0.2- and 0.4-mm-resolution CBCT images were significantly more similar to the measurements made with digital calipers than the measurements from the periapical radiographs (P <0.0001 and P <0.0001, respectively). CONCLUSIONS: Our results demonstrated that, compared with measurements from microCT images, high-resolution CBCT scans lead to more accurate volumetric quantifications of lateral resorption defects than do low-resolution scans. Both high- and low-resolution CBCT scans can also be used to more accurately measure external apical root resorption defects than periapical radiographs. Because these results are from CBCT scans of static images, measurements of root resorption defects from scans of patients will most likely be less accurate because of patient movement.

Relaxin induces matrix-metalloproteinases-9 and -13 via RXFP1: induction of MMP-9 involves the PI3K, ERK, Akt and PKC-ζ pathways.

We determined the precise role of relaxin family peptide (RXFP) receptors-1 and -2 in the regulation of MMP-9 and -13 by relaxin, and delineated the signaling cascade that contributes to relaxin's modulation of MMP-9 in fibrocartilaginous cells. Relaxin treatment of cells in which RXFP1 was silenced resulted in diminished induction of MMP-9 and -13 by relaxin, whereas overexpression of RXFP1 potentiated the relaxin-induced expression of these proteinases. Suppression or overexpression of RXFP2 resulted in no changes in the relaxin-induced MMP-9 and -13. Studies using chemical inhibitors and siRNAs to signaling molecules showed that PI3K, Akt, ERK and PKC-ζ and the transcription factors Elk-1, c-fos and, to a lesser extent, NF-κB are involved in relaxin's induction of MMP-9. Our findings provide the first characterization of signaling cascade involved in the regulation of any MMP by relaxin and offer mechanistic insights on how relaxin likely mediates extracellular matrix turnover.

Efficacy of identifying maxillofacial lesions in cone-beam computed tomographs by orthodontists and orthodontic residents with third-party software.

INTRODUCTION: The purpose of this study was to determine the ability of orthodontists and orthodontic residents to identify nonorthodontic incidental findings and false positives in cone-beam computed tomography scans. METHODS: Two groups of 10 cone-beam computed tomography scans containing equal numbers of scans with no, 1, or several abnormal nonorthodontic lesions were selected from a database. Eight orthodontists and 8 orthodontic residents screened the 2 groups of scans before and after a basic cone-beam computed tomography training course. The paired t test was used for statistical analyses. RESULTS: In the initial screening, the orthodontists and residents correctly identified 41.1% of the lesions. This lesion-detection rate improved significantly to a mean of 56.7% after the training course (P <0.0005). In parallel with these findings, the mean percentage of correctly identified extragnathic lesions improved significantly, from 22% to 48% (P <0.0005), and correctly identified temporomandibular joint lesions improved from 20% to 55% (P = 0.01) after the training. In contrast, the rate of correctly identified dentomaxillofacial lesions remained largely unchanged before and after the training. Both groups of evaluators had approximately 5 false positives per 10 scans before training and demonstrated significant decreases in false positives after training. CONCLUSIONS: Relative to known error rates in medical radiology, both groups of evaluators had high error rates for missed lesions and false positives before and after training. Given these findings and since the most frequent cause of medical radiology malpractice litigation is due to missed lesions, it is recommended that an appropriately trained radiologist should be involved in reading and interpreting cone-beam computed tomography scans.