Search Results (135)

Background: Sequential distalization of the upper arch with clear aligners is widely used to correct Class II malocclusion, but its predictability across molars, canines, and incisors is unclear. This study compared virtual planning with intraoral outcomes and identified the associated side effects. Methods: A retrospective study analyzed 80 maxillary quadrants from 40 patients with dental Class II malocclusion treated with Invisalign^® (Smart Track^® material) using a sequential V-pattern distalization protocol with Class II elastics and vertical rectangular/optimized attachments. Predicted movements were extracted from ClinCheck Pro^®. Scans at baseline and after the first approved aligner stage were superimposed on the palatal rugae using Geomagic Control X^®. Extrusion/intrusion, buccolingual movement, mesiodistal translation, rotation, angulation, and torque were measured for molars, canines, and incisors. Results: Molar distalization reached 1.80 of the 2.60 mm planned (69.2%), and canines 1.12 of 2.45 mm (45.7%) and incisor intrusion reached only 0.03 of the 1.45 mm planned (2.1%). Buccolingual molar movement was most predictable (97.4%), and molar rotation showed moderate-to-good predictability (88.4%); incisor rotation, angulation and torque accuracy were 62.2%, 53.8% and 23.2%, respectively. Molar angulation and torque were markedly overexpressed, with unplanned intrusion of 0.80 mm; canine angulation/torque were similarly overexpressed. Incisor intrusion/torque movements were least predictable. Conclusions: Predictability of sequential upper-arch distalization varied widely across tooth groups and movement types. Linear distalization was moderately to poorly predictable and rotational movements were well reproduced, but angulation/torque control were the least predictable, especially for molars and canines, with unintended molar intrusion and buccal torque. Incisor torque, intrusion, and retrusion were most underexpressed. Vertical rectangular attachments improved molar tipping control, while absent attachments and Power Ridges worsened incisor torque/translation. Clinicians should anticipate overcorrection and refinement stages to avoid false expectations based on the initial ClinCheck outcome. Full article

Background/Objectives: Oral appliance (OA) therapy is an established treatment option for patients with mild-to-moderate obstructive sleep apnea (OSA). Although OAs of various designs have been developed, clinical evidence regarding the effectiveness of separated-type OAs in OSA remains limited. We evaluated the clinical outcomes of patients with OSA treated using a custom-made separated-type OA. Methods: This retrospective study included 47 Japanese patients with OSA who were diagnosed using polysomnography and referred for OA therapy between March 2015 and March 2025. Baseline demographic and clinical characteristics were obtained from medical records for all patients. Treatment effectiveness was analyzed in the 27 patients who underwent both baseline and follow-up polysomnography. The normality of within-patient Apnea–Hypopnea Index (AHI) differences was assessed using the Shapiro–Wilk test, and paired comparisons were performed using the paired t-test. Results: Follow-up polysomnography after OA therapy was performed in 27 patients (57.4%). In these patients, AHI significantly decreased from 17.4 ± 8.6 events/h at baseline to 8.2 ± 5.1 events/h after OA therapy (mean reduction, 9.23 events/h; 95% CI, 6.33–12.12; paired t-test, p < 0.001). OSA severity classification improved after treatment, and no patients were classified as having severe OSA at follow-up. Conclusions: Treatment with a custom-made separated-type OA was associated with a significant reduction in AHI among patients who underwent follow-up polysomnography, suggesting that separated-type OAs may be a useful option for selected patients with mild-to-moderate OSA. These findings should be interpreted with caution because of the retrospective design and incomplete follow-up data. Full article

Cleft lip and palate (CL/P) are among the most common congenital craniofacial anomalies, arising from disruptions in facial development during early embryogenesis. These conditions show significant clinical and genetic heterogeneity and are broadly classified into syndromic and nonsyndromic forms. The objective of this review is to summarize current knowledge on the embryological, genetic, and molecular mechanisms underlying CL/P and to highlight their clinical implications. A comprehensive review of the literature was conducted, focusing on studies in developmental biology, human genetics, and genomics related to CL/P. Emphasis was placed on both syndromic and nonsyndromic forms, including findings from genome-wide association studies, gene mutation analyses, and investigations of gene–environment interactions. Syndromic clefting is frequently associated with pathogenic variants in genes such as IRF6, TP63, and TBX22, which play key roles in epithelial differentiation, transcriptional regulation, and palatal development. In contrast, nonsyndromic CL/P results from complex interactions between multiple genetic variants and environmental factors. Genome-wide association studies have identified numerous susceptibility loci, many located in noncoding regulatory regions active during craniofacial development. Environmental influences, including maternal nutrition, smoking, alcohol exposure, and folate metabolism, have been shown to significantly modify risk. CL/P is a multifactorial condition involving intricate interactions between genetic and environmental factors. Advances in genomics and developmental biology have enhanced understanding of its etiology and are contributing to improved risk assessment, diagnosis, and the development of future precision medicine approaches. Full article

Craniosynostosis (CS) is a congenital birth defect defined by the premature closure of one or more cranial sutures. Approximately 70% of CS cases are nonsyndromic, with underlying causes frequently remaining unidentified. This study seeks to identify short noncoding RNAs, specifically microRNAs (miRNAs), associated with syndromic, nonsyndromic, and all forms of CS to advance understanding of its etiology. Through a systematic review, a total of 165 genes were identified as associated with human CS (112 syndromic, 37 nonsyndromic, and 13 overlapping). Bioinformatic analyses identified several miRNAs capable of regulating these CS-related genes. We found that miR-377 and miR-335-3p were specifically involved in the regulation of genes associated with syndromic CS, while miR-371-5p, miR-329, and miR-204-5p were specifically involved in gene regulation related to nonsyndromic CS. In contrast, miR-651-3p, miR-362-3p, and miR-425 play a role in both syndromic and nonsyndromic CS. Subsequent enrichment analysis using ShinyGO revealed that the predicted targets of these nine candidate miRNAs were preferentially enriched in the TGF-beta signaling pathway. Notably, functional modulation of these miRNAs altered the undifferentiated state, cell proliferation, and osteogenic differentiation of suture progenitor cells. Taken together, our study indicates that these miRNAs play a role in CS by changing the cell characteristics of suture progenitor cells. Full article

Background/Objectives: Contemporary patient-specific subperiosteal implants have re-emerged as graftless solutions for oral and maxillofacial rehabilitation, driven by advances in digital planning, CAD/CAM workflows, additive manufacturing, and biomaterial engineering. Their indications have progressively expanded from severely atrophic edentulous jaws to segmental defects, single-tooth replacement, congenital craniofacial anomalies, salvage situations, and oncologic reconstruction. This scoping review aimed to map the current evidence on modern patient-specific subperiosteal implants, focusing on indications, workflow, design principles, materials, outcomes, complications, and maintenance. Methods: A scoping review was conducted according to PRISMA-ScR principles to identify clinical studies, case series, case reports, systematic and scoping reviews, technical notes, finite element analyses, in vitro studies, and relevant translational investigations dealing with contemporary custom-made or CAD/CAM subperiosteal implants. The evidence was narratively synthesized according to clinical indication and thematic domains, including full-arch rehabilitation, sectional and single-tooth applications, congenital and post-oncologic defects, rescue indications, biomechanics, material selection, surface response, prosthetic protocols, and complication management. No quantitative meta-analysis was performed because of the scoping design and the substantial heterogeneity of study types, indications, implant systems, outcome definitions, and follow-up durations. Results: The final evidence map included 116 records, of which 56 were unique human clinical records with extractable denominators and 60 were biomechanical, in vitro, surface-biology, review, consensus, historical, or conceptual records. Of the 56 unique clinical records, 49 were mapped within the six indication-level clinical sections, while seven were retained as cross-cutting clinical evidence addressing patient-reported outcomes, design-related complications, bone apposition, anchorage strategy, comparative graftless rehabilitation, or reconstructive/prosthetic principles. The six indication-level sections included 52 clinical-record assignments: 15 for full-arch rehabilitation, 13 for segmental or sectional rehabilitation, one for single-tooth rehabilitation, four for congenital or craniofacial indications, 13 for post-oncologic or post-ablative reconstruction, and six for rescue or salvage indications. Because three records addressed more than one indication, these counts represent indication-level assignments rather than mutually exclusive clinical records. Reported survival in most short- to mid-term clinical series was generally high, commonly ranging from 90% to 100%, although lower values of 70–80% were reported in selected longer-term cohorts and survival clearly overestimated clinical success in some studies. Expanding applications include posterior mandibular and maxillary defects, lateral incisor agenesis, cleft-related or syndromic deformities, maxillectomy reconstruction, obturator support, and hybrid rehabilitation with endosseous implants; however, evidence for the indications at the extremes of this spectrum—single-tooth replacement and primary oncologic reconstruction—remains limited to small, largely single-group case series and reports. Soft-tissue events, including dehiscence, mucositis, recession, and framework exposure, were the dominant complications and showed wide variability, with reported recession/exposure rates ranging from approximately 10% in some sectional and full-arch series to as high as 65% in bilateral maxillary cohorts; their clinical significance varied from asymptomatic stable findings to progressive inflammatory complications requiring revision. Conclusions: Patient-specific subperiosteal implants represent a promising and increasingly versatile reconstructive option; however, the present findings should be interpreted as evidence mapping rather than as definitive comparative evidence. Their clinical use should remain highly selective, prosthetically driven, and supported by meticulous planning, rigid fixation, soft-tissue management, and structured maintenance. Standardized success criteria, longer follow-up, and comparative prospective studies are required. Full article

Orthodontic pain, a fundamental biological response to mechanically induced tooth movement, is primarily associated with sterile inflammation and neurogenic processes within the periodontal ligament (PDL). Although photobiomodulation therapy (PBMT) has been widely investigated as a nonpharmacological approach for pain attenuation, its mechanisms of action remain incompletely understood, and current interpretations are often limited to peripheral anti-inflammatory effects. This review re-examines the biological basis of orthodontic pain by integrating evidence derived predominantly from in vitro and in vivo experimental studies. Particular emphasis is placed on neurogenic inflammation, neuropeptide regulation, and neuron–glia interactions along the trigeminal nociceptive pathway. PBMT can reduce periodontal inflammatory/neuropeptide-related markers and pain-related behaviors in selected models; however, evidence for direct central neuron–glia modulation remains largely marker-based and parameter-dependent. Direct functional validation of trigeminal circuit modulation (e.g., electrophysiological recordings or calcium imaging) remains limited in orthodontic pain models; thus, the proposed neuroimmune mechanisms should be interpreted as testable hypotheses for future work. By synthesizing mechanistic insights across multiple biological levels, this review proposes a broader framework for understanding PBMT-mediated pain modulation extending beyond conventional peripheral models. These perspectives may help clarify inconsistencies in the reported outcomes and provide a rationale for future hypothesis-driven experimental and translational research. Full article

Aim: This study aimed to compare two-piece zirconia and two-piece titanium implants inserted into the anterior mandible for removable overdentures in a 3-year randomized split-mouth clinical trial. Methods: Twenty fully edentulous mandibular patients received two zirconia and two titanium implants allocated by computer-generated randomization. The primary endpoint was bleeding-on-probing (BOP) at 12 months. Secondary outcomes included implant survival and success (Albrektsson criteria), marginal bone level changes, peri-implant cytokines (IL-1β, IL-6, and TNFα), prosthetic complications, and patient-reported outcomes (PROMs). Results: After 3 years, overall survival was 98.61% and overall success was 84.72%. Titanium implants showed higher success compared with zirconia implants (91.70% vs. 77.78%), while survival was 100% and 97.22%, respectively. Marginal bone loss was significantly greater around zirconia implants at 36 months (p < 0.01). No significant differences were observed in IL-1β, IL-6, or TNFα levels up to 12 months. PROMs revealed a trade-off, with zirconia favored for esthetics and cleaning perception, while titanium was rated superior for stability. Conclusions: Within the limitations of this split-mouth RCT, zirconia implants demonstrated reduced success and inferior marginal bone stability compared with titanium implants in overdenture therapy. Careful case selection and close follow-up appear essential when zirconia implants are used in this indication. Full article

Some diseases affecting the oral mucosa can be life-threatening and/or associated with life-threatening complications. Conventional diagnostic methods for most oral mucosal diseases are usually employed at a fully established disease state. All these peculiarities usually result in late diagnosis, poor prognosis, poor treatment outcomes, and reduced overall survival rates, hence the need for novel methods for the early detection of these disease conditions. Small extracellular vesicle (sEV)-based diagnosis carries great potential for early diagnosis of oral mucosal diseases, as sEVs reflect the physiological status of their parent cells. sEVs are also widely distributed in body fluids, which helps overcome the problem of inaccessibility in sample or specimen collection in some cases. Furthermore, the composition of sEVs can be used as diagnostic biomarkers for several disease conditions, including oral mucosal diseases. This review critically examines the emerging role of sEVs-derived biomarkers from saliva and blood in the diagnosis of some oral mucosal diseases, such as hand, foot, and mouth disease (HFMD), oral lichen planus (OLP), oral leukoplakia (OL), and oral squamous cell carcinoma (OSCC). It also discusses the need for the validation and standardization of the potential sEV-derived diagnostic biomarkers of these oral mucosal diseases for clinical application. Full article

Satellite glial cells (SGCs) in sensory ganglia are increasingly recognized as active regulators of neuronal excitability and inflammatory signaling involved in pain conditions. In craniofacial and orofacial pain, trigeminal SGCs exhibit stimulus-dependent responses that develop over time and contribute to disease-related plasticity. Additionally, advances in experimental modeling, computational analysis, and data integration have fueled interest in “digital twins” as tools for hypothesis generation and decision support in biomedicine. However, most current biomedical applications are loosely defined and rarely explicitly address glial biology. Here, we propose a digital twin-inspired framework focused on trigeminal satellite glial cells to combine stimulus-response experiments with computational state modeling. Instead of claiming a fully developed digital twin, we describe a hybrid experimental–computational approach where glial activation states are inferred from measurable outputs, iteratively refined, and used to explore what-if scenarios related to pain mechanisms and treatments. These scenarios are intended to guide experimental design and hypothesis prioritization rather than to generate clinical predictions. We detail how this framework could enhance understanding of underlying mechanisms, prioritize potential interventions, and align with New Approach Methodologies (NAMs) and the 3Rs by reducing exploratory animal use. We also discuss key limitations, including biological simplification, uncertainty, and translational challenges. By viewing glial systems as dynamic, updateable entities rather than static readouts, this approach offers a practical and ethically grounded pathway toward more integrated research on craniofacial pain. Full article

Cleft palate only (CPO) is a multifactorial craniofacial malformation with significant genetic and epigenetic contributions. Among these, microRNAs (miRNAs) have emerged as key regulators of palate development, although their alterations in CPO remain incompletely characterized. In this study, we performed a comprehensive miRNA expression analysis on palatal tissues from an Italian cohort of non-syndromic CPO patients, compared with a human embryonic palatal mesenchymal (HEPM) cell line. Using the NanoString^® nCounter^® platform for miRNA profiling, we identified significant deregulation of several miRNAs, notably the upregulation of miR-205-5p and miR-200c-3p and the downregulation of miR-125a-5p in CPO tissues. Based on these expression changes, a functional analysis was carried out to identify potential target genes. Validation in primary cell cultures derived from patient tissues confirmed these expression patterns. Functional analyses and target predictions implicated PAX9, a key transcription factor essential for palatogenesis, as a probable target of miR-205-5p, while miR-125a-5p was associated with the regulation of PRTG and PRSS35—genes involved in neural crest cell biology and extracellular matrix remodeling, respectively. Although modulation of certain predicted targets of miR-200c-3p was observed, in vitro inhibition experiments did not show significant changes in gene expression, highlighting the complexity of miRNA regulatory networks and the need for further studies to unravel these interactions. These findings identify miRNA alterations associated with CPO tissue and fibroblasts, highlighting novel candidate pathways for further mechanistic and therapeutic investigation. Full article

Cherubism is a rare fibro-osseous disorder of the jaws that typically presents in early childhood and is recognised as genetically heterogeneous. While the condition is well described in non-African populations, African data and molecular confirmation remain limited. Background/Objectives: This structured narrative review aimed to synthesize published African cases of cherubism by describing patterns of presentation, diagnosis, management, and genetic investigation. Methods: A structured narrative literature review was conducted using PubMed, Scopus, Google Scholar, and African Journals Online. Peer-reviewed case reports and case series describing cherubism in African patients were included. Data extraction followed predefined criteria, capturing demographic features, age at onset and presentation, clinical, radiological and histological findings, management strategies, and the use of molecular genetic testing. Findings were synthesised descriptively. Results: Fourteen studies reporting 20 individual cases from eight African countries were identified, with the majority originating from North Africa. Although symptom onset most commonly occurred in early childhood, the median age at presentation for management was 13.75 years, suggesting delayed access to care. Molecular genetic testing was reported in only two cases, while most diagnoses relied on clinical, radiological, and histopathological features. Surgical intervention was commonly described, with fewer cases managed conservatively. Conclusions: Within the limitations of a structured narrative review based predominantly on published case reports and case series, and constrained by the scarcity of molecularly confirmed cases, the available African literature on cherubism remains limited in scope, geographically skewed, and characterised by incomplete genetic reporting. Recurring features include delayed presentation, reliance on clinical diagnosis, and limited use of molecular testing. These observations reflect gaps in reporting and genetic characterisation rather than population-level patterns, underscoring the need for improved molecular diagnostics, multidisciplinary care, and African registries. Full article

Following surgical interventions or acquired trauma, fibrosis often inhibits muscle and skin regeneration. Nintedanib, an antifibrotic drug for lung fibrosis, may help prevent orofacial fibrosis. This study evaluates Nintedanib’s potential for inhibiting myofibroblast differentiation and affecting the fusion of orofacial myoblasts into myotubes. Rat gingival fibroblasts and satellite cells (SCs) were isolated and cultured with TGF-β1 to induce myofibroblast differentiation and prevent myotube formation. Adding 1 and 10 ng/mL TGF-β1 significantly increased the percentage of myofibroblasts. Although Nintedanib did not affect the percentage of myofibroblasts, it strongly decreased the total number of fibroblasts and myofibroblasts. Additionally, Nintedanib at a concentration of 2 μM markedly reduced the expression of Ki-67 in fibroblasts and myofibroblasts. In the SC cultures, 0.2 ng/mL TGF-β1 reduced the fusion index of SCs. Treatment with 2 μM Nintedanib significantly increased the fusion index of SCs. Furthermore, MyoD and MyoG gene expression in SCs was also significantly enhanced by Nintedanib at a concentration of 2 μM. Nintedanib promotes myotube formation while inhibiting (myo)fibroblast proliferation. This dual action stresses its potential as an anti-fibrotic therapy after orofacial surgery or traumatic injury affecting muscle tissue. Full article

Background/Objectives: Human papillomavirus (HPV) oncoproteins early (E)6 and E7 cause upregulation of the IL-6 and IL-23 cytokines in HPV16+ cancers, contributing to tumor progression through enhanced tumor cell proliferation and suppression of the tumor specific adaptive CD8 T-cell response. The IL-6 and IL-23 receptors signal through signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment. Methods: To better understand how HPV-induced STAT3 signaling contributes to tumor progression and explore its therapeutic potential, we used the platinum (IV) compound CPA-7, a specific STAT3 inhibitor. CPA-7 was tested in vitro for its ability to inhibit STAT3 signaling, alter proliferation, and cause cell death in HPV16+ C3.43 tumor cells. In vivo, CPA-7 was tested for its ability to affect the HPV specific T-cell response, tumor growth, and survival in C3.43 tumor bearing mice. Results: In vitro, CPA-7 inhibited STAT3 signaling, reduced proliferation, and caused significant cell death to HPV16+ C3.43 cells. In vivo, CPA-7 eradicated early-stage HPV16+ tumors, while therapeutic treatment of late-stage tumors led to a systemically increased presence of tumor-specific CD8 T-cells and halted tumor progression. Conclusions: These results suggest that targeting STAT3 signaling downregulates tumor cell proliferation and induces tumor cell death. In addition, targeting STAT3 increases the HPV-specific anti-tumor adaptive immune response. Combined, this results in significantly reduced late-stage HPV16+ tumor progression. Full article

Multi-target drug design represents a paradigm shift in tackling the complexity and heterogeneity of diseases such as cancer. Conventional single-target therapies frequently face limitations due to network redundancy, pathway compensation, and adaptive resistance mechanisms. In contrast, deep generative models, empowered by advanced artificial intelligence algorithms, provide scalable and versatile platforms for the de novo generation and optimization of small molecules with activity across multiple therapeutic targets. This review provides a comprehensive overview of the recent landscape of AI-driven deep generative modeling for multi-target drug discovery, highlighting breakthroughs in model architectures, molecular representations, and goal-directed optimization strategies. We also examine the emergence of self-improving learning systems, closed-loop frameworks that iteratively refine molecular candidates through integrated feedback, as a transformative approach to adaptive drug design. Finally, key challenges, current limitations, and emerging trends are discussed to guide the evolution of next-generation intelligent and autonomous drug discovery pipelines for multi-target therapeutics. Full article

Dental enamel, the final product of amelogenesis, is a highly mineralized bioceramic that becomes acellular and non-regenerating after tooth eruption. This paper reviews literature that explores inorganic phosphate (Pi) transport during the process of enamel formation or amelogenesis. Evidence from transcriptomics, immunolocalization, and physiology implicates ameloblast-specific sodium-dependent Pi uptake by type III sodium–phosphate cotransporters SLC20A1 (PiT1) and SLC20A2 (PiT2), and by type IIb sodium–phosphate cotransporter SLC34A2 (NaPi-IIb) with stage-specific basal (proximal) or apical (distal) enrichment, and pH-dependent expression. Controlled Pi efflux to the enamel space has been partly attributed to xenotropic and polytropic retrovirus receptor (XPR1) mediated Pi export during maturation-stage amelogenesis. These amelogenesis-specific Pi fluxes operate within a polarized cellular framework in which Ca²⁺ delivery and extrusion, together with bicarbonate-based buffering regulated by cystic fibrosis transmembrane conductance regulator (CFTR), Solute carrier family 26 (SLC26) exchangers, anion exchanger 2 (AE2), and electrogenic sodium bicarbonate cotransporter 1 (NBCe1), at-least partially contribute to cellular Pi activity, and neutralize protons generated as the extracellular hydroxyapatite-based enamel matures. Disruption of phosphate handling reduces crystal growth and final mineral content of enamel, and produces hypomineralized or hypomature enamel with opacities, post-eruptive breakdown, and greater caries susceptibility. This review integrates multi-modal findings to appraise established features of ameloblast Pi handling, define constraints imposed by pH control and Ca²⁺ transport, and identify gaps in ion transporter topology and trafficking dynamics. Full article