Inhibition of Periodontitis Induction Using a Stimuli-Responsive Hydrogel Carrying Naringin.

BACKGROUND: Developing a drug carrier with favorable handling characteristics that can respond to environmental changes after inflammation, such as pH changes, may be beneficial for treating periodontitis. This study aims to investigate the preclinical feasibility of using naringin, a naturally derived polymethoxylated flavonoid compound with anti-inflammatory properties, to inhibit periodontitis induction via a thermogelling and pH-responsive injectable hydrogel. METHODS: The hydrogel was made of amphipathic carboxymethyl-hexanoyl chitosan (CHC), ß-glycerol phosphate (ß-GP), and glycerol. Thermogelling and pH-responsive characteristics of the hydrogel, as well as cell viability after treatment with the hydrogel containing naringin, were evaluated in vitro. Hydrogel was subgingivally delivered when experimental periodontitis was induced in vivo, and therapeutic effect was evaluated with microcomputed tomography imaging, histology, and expression of inflammation-associated genes, including toll-like receptor (TLR)2, the receptor for advanced glycation end products (RAGE), myeloid differentiation primary response gene-88, and tumor necrosis factor (TNF)-α. RESULTS: The hydrogel was consistently fluidic at 4°C but rapidly gelled at 37°C. Release of naringin was faster at pH 5.5 to 6.5, and viability was significantly promoted by treatment with 0.85% naringin. Naringin-carrying CHC-ß-GP-glycerol hydrogel sites showed significantly reduced periodontal bone loss (P <0.05) and inflammatory infiltration (P <0.01) as well as significantly downregulated TLR2 (P <0.05), RAGE (P <0.01), and TNF-α (P <0.05) relative to the sites with experimental periodontitis alone. CONCLUSION: Naringin-carrying CHC-ß-GP-glycerol colloidal hydrogel can be used to inhibit induction of experimental periodontitis with favorable handling and inflammation-responsive characteristics.

pH-Responsive Hydrogel With an Anti-Glycation Agent for Modulating Experimental Periodontitis.

BACKGROUND: Stimulus-responsive devices have emerged as a novel approach for local drug delivery. This study investigates the feasibility of a novel chitosan-based, pH-responsive hydrogel loaded with N-phenacylthiazolium bromide (PTB), which cleaves the crosslinks of advanced glycation end products on the extracellular matrix. METHODS: A chitosan-based hydrogel loaded with PTB was fabricated, and the in vitro release profile was evaluated within pH 5.5 to 7.4. BALB/cJ mice and Sprague-Dawley rats were used to evaluate the effects during the induction and recovery phases of periodontitis, respectively, and animals in each phase were divided into four groups: 1) no periodontitis induction; 2) ligature-induced experimental periodontitis (group PR); 3) experimental periodontitis plus hydrogel without PTB (group PH); and 4) experimental periodontitis plus hydrogel with PTB (group PP). The therapeutic effects were evaluated by microcomputed tomographic imaging of periodontal bone level (PBL) loss and histomorphometry for inflammatory cell infiltration and collagen density. RESULTS: PTB was released faster at pH 5.5 to 6.5 and consistently slower at pH 7.4. In the induction phase, PBL and inflammatory cell infiltration were significantly reduced in group PP relative to group PR, and the loss of collagen matrix was significantly reduced relative to that observed in group PH. In the recovery phase, PBL and inflammatory cell infiltration were significantly reduced, and significantly greater collagen deposition was noted in group PP relative to groups PR and PH at 4 and 14 days after silk removal. CONCLUSION: Chitosan-based, pH-responsive hydrogels loaded with PTB can retard the initiation of and facilitate the recovery from experimental periodontitis.

Osseous wound repair under inhibition of the axis of advanced glycation end-products and the advanced glycation end-products receptor.

BACKGROUND/PURPOSE: Blockade of advanced glycation end-products (AGE) is able to reduce diabetic complications and control periodontitis. This study aimed to determine whether the application of aminoguanidine (AG), an AGE inhibitor, or N-phenacylthiazolium bromide (PTB), an AGE breaker, facilitates the healing of an osseous wound in non-diabetic animals. METHODS: 2.6 mm diameter full-thickness osseous wounds were created bilaterally in 54 healthy Sprague-Dawley rats. Rats received daily normal saline, AG, or PTB injections respectively and were euthanized after 7 days, 14 days, or 28 days (n = 6). The wound healing pattern was assessed by micro-computed tomography, histology, histochemistry for the fiber arrangement, and the gene expression levels of AGE receptor, tumor necrosis factor-α, type I collagen, and fibronectin. RESULTS: Under the AG and PTB administration, osteogenesis was apparently promoted in the early stages of healing, but the union of the osseous wound and the fibril re-arrangement was apparently retarded. No significant difference was found in any of the micro-computed tomography parameters as compared to the control in the first 14 days, whereas the relative bone volume was significantly higher in the control at Day 28. AGE receptor and tumor necrosis factor-α were depressed in the PTB group, but only temporarily at Day 14 in the AG group. Therefore, at Day 14, type I collagen was significantly upregulated in the PTB group, and fibronectin was significantly increased in the AG group. CONCLUSION: Anti-AGE agents reduced inflammation but did not apparently facilitate osteogenesis during the osseous wound repair.

Evaluation of the osteogenic potential of growth factor-rich demineralized bone matrix in vivo.

BACKGROUND: The study evaluates the osteogenic properties and biocompatibility of growth factor-rich demineralized bone matrix (GDBM) by comparing with cancellous mineralized bone matrix (CMBM) and anorganic bovine bone matrix (ABBM). METHODS: Thirty-six Sprague-Dawley rats were used (n = 6/group/time point). To assess biocompatibility and osteoinductivity, the respective bone matrices were randomly placed in subcutaneous pouches for 7 and 28 days and evaluated by histology and osteopontin expression. Osteoconductivity was assessed by randomly implanting respective bone matrices in osteotomies on femurs for 14 and 28 days and evaluated by microcomputed tomography and histology. RESULTS: Neither acute inflammation nor mineralized tissue was noted in any of the subcutaneous specimens, whereas expression of osteopontin was more prominent in the GDBM group. Among the femoral specimens, the greatest relative bone volume (bone volume [BV] divided by trabecular volume [TV]) and trabecular thickness was noted in the ABBM group at both time points, whereas less BV/TV was noted in GDBM group at day 14. Residual matrix particles were noted in all examined groups at both time points, without significant differences regarding defect fill between groups. The GDBM group presented similar levels of newly formed bone compartment and marrow space to those of the ABBM group. CONCLUSIONS: GDBM demonstrated acceptable biocompatibility and osteogenic potential comparable to ABBM in vivo. Further investigations in a more clinically relevant model are warranted.

Spillover of cytokines and reactive oxygen species in ventilator-induced lung injury associated with inflammation and apoptosis in distal organs.

BACKGROUND: The mechanism between ventilator-induced lung injury (VILI) and multiple organ injury is unclear. The aim of our study was to investigate the mechanisms of VILI-induced distal organ injury. METHODS: VILI was induced in rat lungs with high tidal volume (V(T)) ventilation of 40 mL/kg for 6 h. Rats with low V(T) ventilation of 6 mL/kg served as controls. Inflammatory and apoptotic indices in lung and distal organs were assessed. RESULTS: VILI increased lung weight, airway pressure, inflammation, and apoptotic pathologic changes without hemodynamic changes. The white blood cell count and the levels of H2O2, interleukin-1ß (IL-1ß), tumor necrosis factor alpha, and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid were higher in the VILI group compared with the control group. H2O2, IL-1ß, and tumor necrosis factor alpha in blood from the left ventricle were up-regulated. H2O2, IL-1ß, tumor necrosis factor alpha, macrophage inflammatory protein-2, c-Jun N-terminal kinase, p38, nuclear factor kappa B, and caspase-3 in lung, heart, liver, and kidney tissues in the VILI group were up-regulated. Furthermore, the apoptotic score for the kidneys was higher than those for other distal organs in the VILI group. CONCLUSIONS: High V(T) ventilation induces VILI and is associated with inflammation and apoptosis in distal organs. Up-regulation of reactive oxygen species and cytokines in VILI is associated with systemic inflammatory responses. Kidney tissue appears to be more vulnerable than heart and liver tissues following VILI.

Effects of guideline-oriented pharmacotherapy in patients with newly diagnosed COPD: a prospective study.

BACKGROUND: Whether guideline-oriented pharmacotherapy prevents the decline in pulmonary function or reduces systemic inflammation associated with chronic obstructive pulmonary disease (COPD) is uncertain. OBJECTIVES: The aim of this study was to assess the outcome of COPD in clinical practice under real-world conditions in Taiwan as measured by pulmonary function and systemic inflammation parameters (C-reactive protein (CRP) or white blood cell (WBC)) after initiation of guideline-oriented pharmacotherapy. METHODS: Newly diagnosed COPD patients were enrolled and prospectively observed in real-world outpatient practice following initiation of pharmacotherapy of COPD. Pulmonary function, WBC and neutrophil counts, and CRP level of COPD patients were assessed annually. This study enrolled 566 patients and 263 returned for follow-up visits. RESULTS: Significantly higher postbronchodilator FVC, FEV1, and FEV1/FVC but lower DLCO were found at 1 year compared to baseline values. During 4-year follow-up period, FVC and FEV1 remained stable. DLCO progressively declined compared to baseline. No significant changes were seen in CRP and neutrophil count over a 3-year period. Values of CRP, WBC, and neutrophil count correlated inversely with FEV1, FVC, FEV1/FVC, and DLCO. CONCLUSIONS: Guideline-oriented pharmacotherapy of COPD improves airflow limitation but does not prevent the alveolar destruction and systemic inflammation under real-world conditions in Taiwan.