Browsing by Subject "Peri-implantitis"

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    Immunomodulation of oral keratinocytes through titanium surface peptide coatings of cell adhesion oligopeptide motifs and IL-23 Receptor antagonist
    (2021-11) Pizarek, John
    Objectives: Peri-implantitis is the leading cause of implant failure with a prevalence of 8-34%. The dysbiotic bacterial invasion of the peri-implant surface leads to an inflammatory reaction of oral keratinocytes (OK) that attach to the implant surface via the junctional epithelium. During stages of inflammation, the attachment of keratinocytes to bound surfaces decreases. We evaluated OKs’ cytokine response to cell adhesion motif peptides, shown to increase hemidesmosomes (LamLG3 and Net1), bound to plasma activated glass (pGlass), compared to controls pGlass and activated pGlass (DIBO). Next, the innate inflammatory response of OKs through cytokine production, specifically the IL-17/IL-23 inflammatory axis, can induce activation of neutrophils and Th17 cells that are present in higher levels in peri-implantitis. We evaluated an IL-23 receptor antagonist (IL-23Ra) bound to etched titanium for cell proliferation of OKs, production of IL-17 and 23, and cytokine secretome regulation. By inducing cell adhesion or regulating the IL-17/23 pathway may reduce the induction and recruitment of aforementioned inflammatory cells, promoting integrity of the soft tissue interface of implants at sites of bacterial infection.Methods: Plasma disks were covalently functionalized with Net1 and LamLG3 and titanium disks were covalently functionalized with IL-23Ra using silanization. Disks in the cell adhesion studied had activated pGlass (DIBO), uncoated surface, and an antimicrobial peptide serving as controls, and the IL-23Ra study had disks with a randomized sequence peptide and non-coated disks serving as controls. IL-23Ra-coatings were physicochemically analyzed with water contact angle and X-ray photoelectron spectroscopy. Proliferation of OKs was measured. ELISAs were used to analyze levels of IL-23 and IL-17 in presence and absence of pro-inflammatory Porphyromonas gingivalis lipopolysaccharide (LPS). For both studies, supernatant and cell lysates were collected at 5 days and analyzed using a 20 and 36-target cytokine array. The IL-23Ra study assessed the cytokine array with a functional protein association network analysis (STRING). ANOVA and Tukey post-hoc tests assessed statistical significance (p<0.05) Results: Physicochemical analysis demonstrated the successful immobilization of the peptide coatings. The cell adhesion peptides showed a decrease in the production of pro-inflammatory cytokines compared to the three controls. On the other hand, the IL-23Ra-coated titanium significantly increased proliferation of OKs. Further, the IL-23Ra significantly decreased secretion of IL-17 and IL-23, both with and without LPS stimulation, compared to controls. Conclusions: Our results support the use of IL-23Ra-coatings for reduction of the keratinocyte IL17/23 pro-inflammatory pathway and the use of cell adhesion peptides for the reduction of pro-inflammatory cytokine secretion, and may inform immunomodulatory dental implant designs for soft tissue attachment to thereby reduce peri-implantitis rates.
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    Peri-implantitis Prognosis Using Metabolomic Biomarkers in Peri-Implant Crevicular Fluid: A Longitudinal Study
    (2021-05) Alassy, Hatem
    Background: Peri-implant diseases, peri-implantitis (PI) and peri-implant mucositis (PIM), are highly prevalent in subjects with dental implants. Despite this prevalence, diagnosing peri-implant disease (PID) remains challenging because of lack of accuracy and precision of periodontal probing and dental radiographs. Furthermore, these diagnostic tools document history of disease rather than current disease activity. There is no current model to predict the progression of PID. Biomarkers are commonly used in medicine to objectively determine disease state, or responses to a therapeutic intervention. Biomarkers in peri-implant crevicular fluid (PICF) show promise in their diagnostic and prognostic value. Metabolomic analysis of PICF quantifies molecules associated with host and bacterial metabolism may reflect on pathophysiology of peri-implantitis. Un-targeted metabolomics allows the discovery of unknown biomarkers without bias to correlate them with peri-implantitis and its progression. Aim: We hypothesize that the simple metabolites in PICF are predictors of future peri-implantitis progression. We aim to define the unique set of metabolites in the PICF that establish a reliable method for early prediction of bone-loss progression in peri-implantitis. Methods: Clinical and radiographic examinations and PICF samples were collected from 130 implants in 71 subjects at baseline, 6, 12, 18 and 24 months. At baseline, 59 implants were healthy (bone loss < 2mm; PD  4mm), 33 implants had PI (bone loss ≥ 3mm; PD ≥ 6mm) and 38 other implants had bone loss ≥ 2mm and <3mm and PD 5mm. Radiographic bone level changes of 112 implants and relative metabolites in PICF samples were measured at each 6 months interval using proton nuclear magnetic resonance (H-NMR) spectroscopy. MetaboAnalyst 5.0 software correlated metabolite levels with radiographic bone changes of ≥ 1mm within a 6-month interval. Results: In the cross-sectional component at baseline, univariate ROC curve analysis demonstrated that the Cadaverine/Lysine signature was significantly correlated with peri-implantitis (AUC= 0.76; 95% CI 0.658-0.855, p< 0.000) versus healthy implants. While alpha ketoglutarate was significantly correlated with healthy implants (AUC= 0.706; 95% CI 0.593-0.819; p= 0.002). In the longitudinal component, the metabolite levels in PICF of untreated diseased implants that demonstrated progressive radiographic bone loss of ≥ 1mm within a 6-month interval (group A, n=6) were compared to the metabolites of healthy-non-progressing implants (group B, n=26) and to diseased-non-progressing implants (group C, n=8). Proline and 1-3-diaminopropane levels could predict future bone loss of ≥ 1mm (AUC= 0.917 and 0.854 respectively) whereas glucose and arginine levels could predict the absence of bone loss in group C and group B respectively (AUC= 0.896 and 0.801) although statistical significance was not reached for all 4 metabolites. Biotin and propionate levels were higher in group C compared group A and group B (ANOVA p< 0.001; AUC biotin= 0.889; AUC propionate= 0.87). Valine levels were higher in both group A and group C compared to group B (p= 0.002; AUC= 0.841). Conclusions: PICF metabolites identified using H-NMR spectroscopy mapped a specific metabolomic profile able to identify implants with peri-implantitis versus healthy implants with moderate accuracy. Furthermore, specific metabolites discriminated between progressive disease versus non-progressing disease status and health.