Periodontal disease in patients with WHIM syndrome.

AIM: WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome is a rare combined primary immunodeficiency disease caused by gain-of-function (GOF) mutations in the chemokine receptor CXCR4 and includes severe neutropenia as a common feature. Neutropenia is a known risk factor for periodontitis; however, a detailed periodontal evaluation of a WHIM syndrome cohort is lacking. This study aimed to establish the evidence base for the periodontal status of patients with WHIM syndrome. MATERIALS AND METHODS: Twenty-two adult WHIM syndrome patients and 22 age- and gender-matched healthy volunteers (HVs) were evaluated through a comprehensive medical and periodontal examination. A mouse model of WHIM syndrome was assessed for susceptibility to naturally progressing or inducible periodontitis. RESULTS: Fourteen patients with WHIM syndrome (63.6%) and one HV (4.5%) were diagnosed with Stage III/IV periodontitis. No WHIM patient presented with the early onset, dramatic clinical phenotypes typically associated with genetic forms of neutropenia. Age, but not the specific CXCR4 mutation or absolute neutrophil count, was associated with periodontitis severity in the WHIM cohort. Mice with a Cxcr4 GOF mutation did not exhibit increased alveolar bone loss in spontaneous or ligature-induced periodontitis. CONCLUSIONS: Overall, WHIM syndrome patients presented with an increased severity of periodontitis despite past and ongoing neutrophil mobilization treatments. GOF mutations in CXCR4 may be a risk factor for periodontitis in humans.

Ligand conjugate SAR and enhanced delivery in NHP.

N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a leading RNA interference (RNAi) platform allowing targeted inhibition of disease-causing genes in hepatocytes. More than a decade of development has recently resulted in the first approvals for this class of drugs. While substantial effort has been made to improve nucleic acid modification patterns for better payload stability and efficacy, relatively little attention has been given to the GalNAc targeting ligand. In addition, the lack of an intrinsic endosomal release mechanism has limited potency. Here, we report a stepwise analysis of the structure activity relationships (SAR) of the components comprising these targeting ligands. We show that there is relatively little difference in biological performance between bi-, tri-, and tetravalent ligand structures while identifying other features that affect their biological activity more significantly. Further, we demonstrate that subcutaneous co-administration of a GalNAc-functionalized, pH responsive endosomal release agent markedly improved the activity and duration of effect for siRNA conjugates, without compromising tolerability, in non-human primates. These findings could address a significant bottleneck for future siRNA ligand conjugate development.

Biomechanical analysis of the osseointegration of porous tantalum implants.

STATEMENT OF PROBLEM: Although implants containing porous tantalum undergo osseointegration, whether this material significantly alters new bone formation and improves implant stability during healing in comparison to titanium is unclear. PURPOSE: The purpose of this in vivo study was to determine the influence of the inclusion of porous tantalum into a dental implant on the biomechanical properties of the bone-implant interface and peri-implant bone which may contribute to secondary implant stability. MATERIAL AND METHODS: Threaded titanium implants with a porous tantalum midsection (Trabecular Metal Dental Implant; Zimmer Biomet) or without (Tapered Screw-Vent; Zimmer Biomet) were placed in rabbit tibiae and allowed to heal for 4, 8, or 12 weeks. The implants were evaluated by resonance frequency analysis and removed with surrounding bone for nanoindentation testing. Two-way ANOVA was used to determine the impact of implant type, bone region, and time on the outcomes implant stability quotient (ISQ), hardness, and elastic modulus (α=.05). RESULTS: Resonance frequency analysis found no significant difference in ISQ values between implant types at 4, 8, or 12 weeks, and ISQ values did not increase for either implant over time. Nanoindentation showed no significant differences in hardness or elastic modulus in newly formed bone adjacent to either implant type at any time point. CONCLUSIONS: The stiffness of the bone-implant interface was similar for threaded titanium implants with or without porous tantalum when placed in the rabbit tibia and allowed to heal for at least 4 weeks. The new peri-implant bone adjacent to dental implants containing porous tantalum showed no difference in nanomechanical properties to the new bone around implants comprised completely of threaded titanium at all healing time points.

Peri-Implant Diseases and Biologic Complications at Implant-Supported Fixed Dental Prostheses in Partially Edentulous Patients.

PURPOSE: This is a single center, retrospective study to assess the prevalence of peri-implant disease and biologic complications in a cohort of partially edentulous subjects in relation to selected prosthetic factors. MATERIALS AND METHODS: Subjects previously treated with one or more implant-supported fixed dental prosthesis (ISFDPs) were recalled for a comprehensive examination. Clinical and radiographic records were taken and questionnaires were administered. The prevalence of implant failure, peri-implant disease and other biologic complications were correlated with selected prosthetic, clinical and patient-related factors using chi-square and multiple regression analyses. RESULTS: A convenience sample of 71 subjects with 100 prostheses supported by 222 dental implants were enrolled in the study. The mean follow-up time after prosthesis delivery was 3.3 ± 1.5 years (range of 1-9 years). The cumulative implant survival rate was 99.1%. Peri-implantitis was the most frequent major biologic complication (5% of implants), while the most frequent minor biologic complication was peri-implant mucositis (84.10% of implants). A diagnosis of peri-implant mucositis was more likely associated with cement-retained prostheses compared to screw-retained prostheses (OR 6.8, 95% CI 1.1-78.6, p = 0.045) and for short-span prostheses (≤3 prosthetic units) (OR 2.3, 95% CI 1.1-5.0, p = 0.034). Subject-reported quality of life measures were high regardless of the existence of major and/or minor complications, but decreased with increasing number of minor and total biologic complications. CONCLUSIONS: Peri-implant mucositis and other minor biologic complications were highly prevalent. The distribution of the observed complications differed based on the method of prosthesis retention and the number of prosthetic units replaced.

Prosthesis Survival Rates and Prosthetic Complications of Implant-Supported Fixed Dental Prostheses in Partially Edentulous Patients.

PURPOSE: To determine the prevalence and distribution of prosthetic complications affecting implant-supported fixed dental prostheses (ISFDPs). MATERIALS AND METHODS: Subjects previously treated with one or more ISFDP(s) were identified from an electronic health record search and recalled for comprehensive clinical examination. Past prosthesis failures and complications were identified from the patient records while any existing complications, not previously recorded, were assessed during examination. ISFDP survival and failure rates were calculated with Kaplan-Meier curves and life table analysis, while regression Poisson analysis was used to identify associations between outcomes and possible patient- and prosthesis-based risk factors. RESULTS: Seventy-four subjects with 107 ISFDPs were enrolled in the study with a mean time between prosthesis delivery and exam of 3.14 years (range: 1.00-9.00 years). Four prostheses failed, resulting in a cumulative prosthesis survival rate of 96.26%. Prosthetic complications affected 48.59% of ISFDPs, the majority (94.87%) of them minor complications. Only the use of a nightguard was associated with a lower prevalence of prosthetic screw loosening (HR 0.11, 95% CI 0.02-0.59, p = 0.007) while no outcome differences were noted for other variables. Patient satisfaction was high regardless of presence or number of complications. CONCLUSIONS: ISFDPs demonstrated a high survival rate and overall high, patient-reported satisfaction. Minor prosthetic complications were common but were only significantly associated with nightguard use.

Bone response to porous tantalum implants in a gap-healing model.

OBJECTIVES: The objective of this study was to determine the relative osteogenic behavior of titanium implants with or without a porous tantalum modification when placed with a gap between the implant and existing bone. MATERIALS AND METHODS: A gap-healing model in the rabbit tibia was used for placement of titanium implants. Forty-eight rabbits received 96 implants, with 48 of the implants containing a porous tantalum middle section and the remaining 48 implants were composed of solid titanium. After 4, 8, and 12 weeks of healing, biomechanical stability was measured with removal torque testing, implant-adherent cells were isolated for analysis of osteogenic gene expression, and histomorphometric analysis was performed on sections of the implants and surrounding bone. RESULTS: Increased osteogenic activity at 4 weeks was demonstrated by upregulation of key osteogenic genes at implants containing porous tantalum which was accompanied by greater bone-implant contact at 4, 8, and 12 weeks and significantly greater removal torque at 8 and 12 weeks. CONCLUSIONS: Implants containing porous tantalum demonstrated increased peri-implant bone formation within this gap-healing model as shown by significant differences in biomechanical and histomorphometric outcomes. Such implants may represent an alternative to influence bone healing in surgical sites with an existing gap.

Dissociation of murine oral mucosal tissues for single cell applications.

Single-cell RNA sequencing and flow cytometry approaches have been instrumental in understanding cellular states within various tissues and organs. However, tissue dissociation methods can potentially alter results and create bias due to preferential recovery of particular cell types. Here we present efforts to optimize methods for dissociation of murine oral mucosal tissues and provide three different protocols that can be utilized to isolate major cell populations in the oral mucosa. These methods can be used both in health and in states of inflammation, such as periodontitis. The optimized protocols use different enzymatic approaches (collagenase II, collagenase IV and the Miltenyi whole skin dissociation kit) and yield preferential recovery of immune, stromal and epithelial cells, respectively. We suggest choosing the dissociation method based on the cell population of interest to study, while understanding the limitations of each approach.

The effect of electronic cigarette use on peri-implant conditions in men: a systematic review and meta-analysis.

OBJECTIVE: To systematically review the effect of electronic cigarette (e-cigarette) use on clinical, radiographic, and immunologic peri-implant parameters in males. STUDY DESIGN: A comprehensive search of indexed databases was conducted to identify studies reporting data on both e-cigarette users and nonsmokers with implant-supported prosthesis with ≥1-year in function, up to May 2022. Marginal bone loss (MBL), probing depth (PD), plaque index (PI), and bleeding on probing (BOP) were recorded. Peri-implant sulcular fluid volume (PISF), tumor necrosis factor alpha (TNF-α) and interleukin 1ß (IL-ß) levels were also assessed. A meta-analysis was performed using random-effect models to determine the effect of e-cigarette use in primary and secondary outcomes. RESULTS: Four cross-sectional studies were included with a total of 327 participants (165 e-cigarette users and 162 nonsmokers). All studies showed greater MBL, PI, PD, and lower BOP in e-cigarette users compared with never smokers. The meta-analysis indicated significant heterogeneity for all outcomes except MBL for distal implant surfaces, with the mean difference between e-cigarette users and nonsmokers of 0.89 mm (95% CI: 0.67-1.11, P < .01). The PISF volume, TNF-α, and IL-1ß levels were increased in e-cigarette users (P < .01) with no heterogeneity present between studies. CONCLUSIONS: E-cigarette use shows a negative effect on clinical, radiographic, and immunologic parameters of dental implants.

Dual peptide-functionalized hydrogels differentially control periodontal cell function and promote tissue regeneration.

Restoring the tooth-supporting tissues lost during periodontitis is a significant clinical challenge, despite advances in both biomaterial and cell-based approaches. This study investigated poly(ethylene glycol) (PEG) hydrogels functionalized with integrin-binding peptides RGD and GFOGER for controlling periodontal ligament cell (PDLC) activity and promoting periodontal tissue regeneration. Dual presentation of RGD and GFOGER within PEG hydrogels potentiated two key PDLC functions, alkaline phosphatase (ALP) activity and matrix mineralization, over either peptide alone and could be tuned to differentially promote each function. Hydrogel matrix mineralization, fostered by high concentrations of GFOGER together with RGD, identified a PDLC phenotype with accelerated matrix adhesion formation and expression of cementoblast and osteoblast genes. In contrast, maximizing ALP activity through high RGD and low GFOGER levels resulted in minimal hydrogel mineralization, in part, through altered PDLC pyrophosphate regulation. Transplantation of PDLCs in hydrogels optimized for either outcome promoted cementum formation in rat periodontal defects; however, only hydrogels optimized for in vitro mineralization improved new bone formation. Overall, these results highlight the utility of engineered hydrogel systems for controlling PDLC functions and their promise for promoting periodontal tissue regeneration.

Hydrogel Swelling-Mediated Strain Induces Cell Alignment at Dentin Interfaces.

Cell and tissue alignment is a defining feature of periodontal tissues. Therefore, the development of scaffolds that can guide alignment of periodontal ligament cells (PDLCs) relative to tooth root (dentin) surfaces is highly relevant for periodontal tissue engineering. To control PDLC alignment adjacent to the dentin surface, poly(ethylene glycol) (PEG)-based hydrogels were explored as a highly tunable matrix for encapsulating cells and directing their activity. Specifically, a composite system consisting of dentin blocks, PEG hydrogels, and PDLCs was created to control PDLC alignment through hydrogel swelling. PDLCs in composites with minimal hydrogel swelling showed random alignment adjacent to dentin blocks. In direct contrast, the presence of hydrogel swelling resulted in PDLC alignment perpendicular to the dentin surface, with the degree and extension of alignment increasing as a function of swelling. Replicating this phenomenon with different molds, block materials, and cells, together with predictive modeling, indicated that PDLC alignment was primarily a biomechanical response to swelling-mediated strain. Altogether, this study describes a novel method for inducing cell alignment adjacent to stiff surfaces through applied strain and provides a model for the study and engineering of periodontal and other aligned tissues.

Tissue Engineered Neurovascularization Strategies for Craniofacial Tissue Regeneration.

Craniofacial tissue injuries, diseases, and defects, including those within bone, dental, and periodontal tissues and salivary glands, impact an estimated 1 billion patients globally. Craniofacial tissue dysfunction significantly reduces quality of life, and successful repair of damaged tissues remains a significant challenge. Blood vessels and nerves are colocalized within craniofacial tissues and act synergistically during tissue regeneration. Therefore, the success of craniofacial regenerative approaches is predicated on successful recruitment, regeneration, or integration of both vascularization and innervation. Tissue engineering strategies have been widely used to encourage vascularization and, more recently, to improve innervation through host tissue recruitment or prevascularization/innervation of engineered tissues. However, current scaffold designs and cell or growth factor delivery approaches often fail to synergistically coordinate both vascularization and innervation to orchestrate successful tissue regeneration. Additionally, tissue engineering approaches are typically investigated separately for vascularization and innervation. Since both tissues act in concert to improve craniofacial tissue regeneration outcomes, a revised approach for development of engineered materials is required. This review aims to provide an overview of neurovascularization in craniofacial tissues and strategies to target either process thus far. Finally, key design principles are described for engineering approaches that will support both vascularization and innervation for successful craniofacial tissue regeneration.

Matrix Control of Periodontal Ligament Cell Activity Via Synthetic Hydrogel Scaffolds.

Rebuilding the tooth-supporting tissues (periodontium) destroyed by periodontitis remains a clinical challenge. Periodontal ligament cells (PDLCs), multipotent cells within the periodontal ligament (PDL), differentiate and form new PDL and mineralized tissues (cementum and bone) during native tissue repair in response to specific extracellular matrix (ECM) cues. Thus, harnessing ECM cues to control PDLC activity ex vivo, and ultimately, to design a PDLC delivery vehicle for tissue regeneration is an important goal. In this study, poly(ethylene glycol) hydrogels were used as a synthetic PDL ECM to interrogate the roles of cell-matrix interactions and cell-mediated matrix remodeling in controlling PDLC activity. Results showed that PDLCs within matrix metalloproteinase (MMP)-degradable hydrogels expressed key PDL matrix genes and showed a six to eightfold increase in alkaline phosphatase (ALP) activity compared with PDLCs in nondegradable hydrogel controls. The increase in ALP activity, commonly considered an early marker of cementogenic/osteogenic differentiation, occurred independent of the presentation of the cell-binding ligand RGD or soluble media cues and remained elevated when inhibiting PDLC-matrix binding and intracellular tension. ALP activity was further increased in softer hydrogels regardless of degradability and was accompanied by an increase in PDLC volume. However, scaffolds that fostered PDLC ALP activity did not necessarily promote hydrogel ECM mineralization. Rather, matrix mineralization was greatest in stiffer, MMP-degradable hydrogels and required the presence of soluble media cues. These divergent outcomes illustrate the complexity of the PDLC response to ECM cues and the limitations of current scaffold materials. Nevertheless, key biomaterial design principles for controlling PDLC activity were identified for incorporation into scaffolds for periodontal tissue regeneration. Impact statement Engineered scaffolds are an attractive approach for delivering periodontal ligament cells (PDLCs) to rebuild the tooth-supporting tissues. Replicating key extracellular matrix (ECM) cues within tissue engineered scaffolds may maximize PDLC potential. However, the identity of important ECM cues and how they can be harnessed to control PDLC activity is still unknown. In this study, matrix degradability, cell-matrix binding, and stiffness were varied using synthetic poly(ethylene glycol) hydrogels for three-dimensional PDLC culture. PDLCs exhibited dramatic and divergent responses to these cues, supporting further investigation of ECM-replicating scaffolds for control of PDLC behavior and periodontal tissue regeneration.

The association between gingival recession and buccal bone at maxillary anterior teeth.

BACKGROUND: Gingival recession and a thin or absent buccal plate occur frequently at maxillary anterior teeth and necessitate careful treatment planning to prevent future complications. However, the association between these two conditions is unclear and the ability of gingival recession to predict underlying buccal bone deficiencies is unknown. Therefore, the aim of this study is to use clinical and radiographic data to test this association and determine the influence of demographic and clinical parameters on both conditions. METHODS: This investigation comprised a single-center, retrospective study. Data were derived from periodontal examinations performed on 66 adult subjects. Corresponding cone-beam computed tomography images were used to measure the width of buccal bone at two points along the root surface and the distance between the bone crest and cemento-enamel junction (CEJ). Results were then analyzed to determine the association between the presence of gingival recession and the condition of radiographic buccal bone, as well as the relative contribution of demographic parameters and other clinical findings to gingival recession and buccal bone conditions. RESULTS: Gingival recession was present at 32.9% of maxillary anterior teeth and was most common at canines, followed by lateral incisors and central incisors. Mean buccal bone widths were significantly less, and the distance between the CEJ and bone crest was significantly greater for teeth with recession. Accordingly, gingival recession was a significant predictor for buccal bone thickness <1 mm at the level of 4 mm apical to the CEJ (odds ratio 2.733, 95% confidence interval 1.644 to 4.543, P < 0.0001). Probing depths were related to the presence or absence of gingival recession, while patient sex, age, and the apico-coronal height of the gingiva were related to buccal bone thickness. CONCLUSION: Within the limitations of this study, maxillary anterior teeth with pre-existing gingival recession were more likely to have thin (<1 mm) buccal bone.

Nanoparticles for Oral Biofilm Treatments.

Pathogenic oral biofilms are universal, chronic, and costly. Despite advances in understanding the mechanisms of biofilm formation and persistence, novel and effective treatment options remain scarce. Nanoparticle-mediated eradication of the biofilm matrix and resident bacteria holds great potential. In particular, nanoparticles that target specific microbial and biofilm features utilizing nontoxic materials are well-suited for clinical translation. However, much work remains to characterize the local and systemic effects of therapeutic agents that are topically applied to chronic biofilms, such as those that cause dental caries. In this Perspective, we summarize the pathogenesis of oral biofilms, describe current and future nanoparticle-mediated treatment approaches, and highlight outstanding questions that are paramount to answer for effectively targeting and treating oral biofilms.

Polymorphisms in an interferon-gamma receptor-1 gene marker and susceptibility to periodontitis.

Chronic marginal periodontitis is an inflammatory condition in which the supporting tissues of the teeth are destroyed. Interferon (IFN)-gamma is a cytokine that plays a pivotal role in the defense against infection, and mutations in the gene coding for the ligand binding chain (alpha, R1) of the IFN-gamma receptor (IFNGR1) confer suseptibility on infections caused by poorly virulent mycobacteria. Using an intronic (CA)n polymorphic microsatellite marker within the IFNGR1 gene we investigated whether genetic polymorphisms are associated with periodontitis. In 62 periodontitis patients and 56 healthy controls we found a total of 13 polymorphisms, 11 of which were found in the periodontitis patients and 9 in the controls. Although we observed a trend towards an association with disease for allele 192, there were no significant differences in allele frequency between patients and controls. We therefore cannot find any evidence to suggest that IFNGR1, as a single dominant gene, contributes to susceptibility to periodontitis. However, in combination with the environmental risk factor, smoking, the same allelic marker was significantly associated [OR = 5.56 (1.16