Exogenous monocyte myeloid-derived suppressor cells ameliorate immune imbalance, neuroinflammation and cognitive impairment in 5xFAD mice infected with Porphyromonas gingivalis.

BACKGROUND: Periodontitis is closely associated with the pathogenesis of Alzheimer's disease (AD). Porphyromonas gingivalis (Pg), the keystone periodontal pathogen, has been reported in our recent study to cause immune-overreaction and induce cognitive impairment. Monocytic myeloid-derived suppressor cells (mMDSCs) possess potent immunosuppressive function. It is unclear whether mMDSCs-mediated immune homeostasis is impaired in AD patients with periodontitis, and whether exogenous mMDSCs could ameliorate immune-overreaction and cognitive impairment induced by Pg. METHODS: To explore the influence of Pg on cognitive function, neuropathology and immune balance in vivo, 5xFAD mice were treated with live Pg by oral gavage, three times a week for 1 month. The cells of peripheral blood, spleen and bone marrow from 5xFAD mice were treated with Pg to detect the proportional and functional alterations of mMDSCs in vitro. Next, exogenous mMDSCs were sorted from wild-type healthy mice and intravenously injected into 5xFAD mice that were infected with Pg. We used behavioral tests, flow cytometry and immunofluorescent staining to evaluate whether exogenous mMDSCs could ameliorate the cognitive function, immune homeostasis and reduce neuropathology exacerbated by Pg infection. RESULTS: Pg exacerbated cognitive impairment in 5xFAD mice, with the deposition of amyloid plaque and increased number of microglia in the hippocampus and cortex region. The proportion of mMDSCs decreased in Pg-treated mice. In addition, Pg reduced the proportion and the immunosuppressive function of mMDSCs in vitro. Supplement of exogenous mMDSCs improved the cognitive function, and enhanced the proportions of mMDSCs and IL-10+ T cells of 5xFAD mice infected with Pg. At the same time, supplement of exogenous mMDSCs increased the immunosuppressive function of endogenous mMDSCs while decreased the proportions of IL-6+ T cells and IFN-γ+ CD4+ T cells. In addition, the deposition of amyloid plaque decreased while the number of neurons increased in the hippocampus and cortex region after the supplement of exogenous mMDSCs. Furthermore, the number of microglia increased with an increase in the proportion of M2 phenotype. CONCLUSIONS: Pg can reduce the proportion of mMDSCs, induce immune-overreaction, and exacerbate the neuroinflammation and cognitive impairment in 5xFAD mice. Supplement of exogenous mMDSCs can reduce the neuroinflammation, immune imbalance and cognitive impairment in 5xFAD mice infected with Pg. These findings indicate the mechanism of AD pathogenesis and Pg-mediated promotion of AD, and provide a potential therapeutic strategy for AD patients.

pH-responsive cinnamaldehyde-TiO2 nanotube coating: fabrication and functions in a simulated diabetes condition.

Current evidence has suggested that diabetes increases the risk of implanting failure, and therefore, appropriate surface modification of dental implants in patients with diabetes is crucial. TiO2 nanotube (TNT) has an osteogenic nanotopography, and its osteogenic properties can be further improved by loading appropriate drugs. Cinnamaldehyde (CIN) has been proven to have osteogenic, anti-inflammatory, and anti-bacterial effects. We fabricated a pH-responsive cinnamaldehyde-TiO2 nanotube coating (TNT-CIN) and hypothesized that this coating will exert osteogenic, anti-inflammatory, and anti-bacterial functions in a simulated diabetes condition. TNT-CIN was constructed by anodic oxidation, hydroxylation, silylation, and Schiff base reaction to bind CIN, and its surface characteristics were determined. Conditions of diabetes and diabetes with a concurrent infection were simulated using 22-mM glucose without and with 1-µg/mL lipopolysaccharide, respectively. The viability and osteogenic differentiation of bone marrow mesenchymal stem cells, polarization and secretion of macrophages, and resistance to Porphyromonas gingivalis and Streptococcus mutans were evaluated. CIN was bound to the TNT surface successfully and released better in low pH condition. TNT-CIN showed better osteogenic and anti-inflammatory effects and superior bacterial resistance than TNT in a simulated diabetes condition. These findings indicated that TNT-CIN is a promising, multifunctional surface coating for patients with diabetes needing dental implants. Graphical abstract.

Measurement of Cable Force through a Fiber Bragg Grating-Type Thin Rod Vibration Sensor and Its Application.

The key to evaluating the health status of cable-stayed bridges lies in the accuracy of cable force measurement. When measuring the cable force using the conventional frequency method, the clearance between the bracing cable and the protective tube is typically disregarded. Moreover, due to their large size, existing vibration sensors are difficult to install into protective tubes for steel strand-type bracing cables to measure the cable force. To address the above difficulties, a type of thin rod vibration sensor only 5 mm in diameter was designed based on the high sensitivity of Fiber Bragg grating (FBG), and high-throughput data processing software for engineering calculation (EC) was self-developed. Then, the recognition principle of the thin rod vibration sensor was theoretically analyzed and a step-by-step tension test was carried out. The results demonstrated that the relative error of the cable force measured by the thin rod vibration sensor within 12.865 Hz was less than 5% and the sensitivity reached 28.7 pm/Hz, indicating its high measurement precision. Upon subsequent application of the thin rod vibration sensor to a monitoring test in the field, the relative error of the fundamental frequency between artificial and natural excitations was less than 4%. In addition, the error relative to both the theoretical frequency and the third-party sampling frequency was less than 5%, further verifying the accuracy and applicability for monitoring the cable force of bridges under natural excitation. Compared with the traditional cantilever FBG sensor, the improved sensor with supporting data processing software has the advantages of small cross-section, high reliability, and good sensitivity. The research results can provide a reference for the subsequent accurate measurement of cable force and the development of a supporting sensor data processing system.

Timely eradication of HCV viremia by PegIFN/RBV is crucial in prevention of post RFA recurrence in CHC-HCC patients.

BACKGROUND: Secondary prevention of hepatocellular carcinoma (HCC) among patients with chronic hepatitis C (CHC) who achieve sustained virologic response (SVR) with interferon-based therapy has been proved effective. However, tertiary prevention with PegIFN/RBV therapy of HCC recurrence seems limited effect in CHC-HCC patients post curative therapies. This study aims to investigate the timing and impact of PegIFN/RBV treatment on prevention of HCC recurrence in patients after RFA treatment. METHODS: From 2013 to 2016, a total of 137 CHC-HCC patients from a 508 patient based cohort receiving complete RFA treatment in Chang Gung Memorial Hospital, Linkou Medical Center were retrospectively recruited. Pre-RFA patient demographics were analyzed by cox regression analysis for prediction on tumor recurrence. Statistics analysis was performed with SPSS V.20 (IBM, USA). RESULTS: The mean age of the 137 patients were 69.6 year-old and 71.5% of patients were cirrhotic. After propensity score matching, one hundred and two patients were enrolled into the analysis. Fifty-one patients (50%) received PegIFN/RBV therapy and twenty-seven patients (52.9%) achieved SVR. Patients who could achieve SVR had lower tumor recurrence rate than non-SVR and untreated groups (29.6% vs. 66.7% vs. 49.0%, P = 0.030). The effect is more prominent in those achieve SVR prior to compared with after RFA despite not reach statistically significant (26.1% vs. 50.0%, P = 0.334). CONCLUSION: Timely treatment with SVR achievement has the lowest tumor recurrence rate in CHC-HCC patients. Secondary prevention might be even more important than tertiary prevention in CHC patients, especially regarding prevention of post RFA HCC recurrence.

Novel mandibular advancement bite block with supplemental oxygen to both nasal and oral cavity improves oxygenation during esophagogastroduodenoscopy: a bench comparison.

Drug-induced respiratory depression is a major cause of serious adverse events. Adequate oxygenation is very important during sedated esophagogastroduodenoscopy (EGD). Nasal breathing often shifts to oral breathing during open mouth EGD. A mandibular advancement bite block was developed for EGD using computer-assisted design and three-dimensional printing techniques. The mandible is advanced when using this bite block to facilitate airway opening. The device is composed of an oxygen inlet with one opening directed towards the nostril and another opening directed towards the oral cavity. The aim of this bench study was to compare the inspired oxygen concentration (FiO2) provided by the different nasal cannulas, masks, and bite blocks commonly used in sedated EGD. A manikin head was connected to one side of a two-compartment lung model by a 7.0 mm endotracheal tube with its opening in the nasopharyngeal position. The other compartment was driven by a ventilator to mimic "patient" inspiratory effort. Using this spontaneously breathing lung model, we evaluated five nasal cannulas, two face masks, and four new oral bite blocks at different oxygen flow rates and different mouth opening sizes. The respiratory rate was set at 12/min with a tidal volume of 500 mL and 8/min with a tidal volume of 300 mL. Several Pneuflo resistors of different sizes were used in the mouth of the manikin head to generate different degrees of mouth opening. FiO2 was evaluated continuously via the endotracheal tube. All parameters were evaluated using a Datex anesthesia monitoring system. The mandibular advancement bite block provided the highest FiO2 under the same supplemental oxygen flow. The FiO2 was higher for devices with oxygen flow provided via an oral bite block than that provided via the nasal route. Under the same supplemental oxygen flow, the tidal volume and respiratory rate also played an important role in the FiO2. A low respiratory rate with a smaller tidal volume has a relative high FiO2. The ratio of nasal to oral breathing played an important role in the FiO2 under hypoventilation but less role under normal ventilation. Bite blocks deliver a higher FiO2 during EGD. The ratio of nasal to oral breathing, supplemental oxygen flow, tidal volume, and respiratory rate influenced the FiO2 in most of the supplemental oxygen devices tested, which are often used for conscious sedation in patients undergoing EGD and colonoscopy.

Oral capnography is more effective than nasal capnography during sedative upper gastrointestinal endoscopy.

The role of capnography in esophagogastroduodenoscopy (EGD) is controversial. Simultaneous supplemental oxygen, position of patient, open mouth breathing pattern, and anatomy of the oral and nasal cavity can influence capnography accuracy. This study first measured capnographic data via the nasal or oral cavity during sedated EGD. Secondly, we investigated the influence of supplementary oxygen through the oral cavity on the capnographic reading. Patients with ASA class I or II status admitted for routine EGD exams were enrolled. End-tidal carbon dioxide measurements were performed simultaneously via nasal catheter and oral catheter with standard oral bite and nasal cannula supplementary oxygen when the patient is awake, during sedation and during sedation with endoscopy. The influence of oral supplementary oxygen, oral capnography were recorded using a mandibular advancement bite block. One hundred and four patients were enrolled. Breathing in the conscious patient is conducted primarily via the nostrils (95%). When sedated with endoscope placement, the percentage of nasal breathing decreased significantly to 47% and oral capnography sufficiently captured data in 100% of patients. Supplementary oral oxygen decreased oral capnographic measurement significantly (38.89 ± 7.148 vs. 30.73 ± 7.84, p < 0.001). However, the measurements using the MA bite block did not differ from oral cavity catheter (28.86 ± 8.51 vs. 30.73 ± 7.839, p = 0.321). The conscious patient breathes mostly nasally while the sedated patient breathes mostly orally during EGD when an oral bite is in place. Capnography measurement via oral cannula increases the measurement accuracy and efficacy. Oral supplementary oxygen may decrease capnographic measurement but still provide sufficient reading for interpretation.

CCL4 is the only predictor for non-responder in GT-1 CHC patients with favorable IL28B genotype when treated with PegIFN/RBV.

BACKGROUND: Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1). METHODS: 60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-γ, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response. RESULTS: Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p = 0.001; CXCL11: p < 0.001; CCL3: p = 0.006; CCL4: p = 0.005). However, only rs12979860 CC genotype was the independent factors for NR in GT-1 CHC infection (OR, 8.985; p = 0.008). In addition, baseline serum level of CCL4 was found to be the only independent factor for NR in GT-1 CHC patients with favorable IL28B genotype (OR, 1.134; p = 0.039). CONCLUSIONS: IL28B genotype is the predictor for NR in GT-1 CHC patients treated with PegIFN/RBV, while baseline serum level of CCL4 is the only predictor for NR in GT-1 CHC patients with favorable IL28B genotype.

pVEGF-loaded lipopolysaccharide-amine nanopolymersomes for therapeutic angiogenesis.

Therapeutic angiogenesis via gene delivery is promising for tissue survival and regeneration after injury or ischemia. A stable, safe and efficient gene vector is essential for successful angiogenesis. We have demonstrated that our newly developed lipopolysaccharide-amine nanopolymersomes (LNPs) have higher than 95% transfection efficiency when delivering pEGFP into mesenchymal stem cells (MSCs). To explore their clinical potential in therapeutic angiogenesis, in this study, we studied their toxicity, storage stability, protection ability to genes and efficacy to deliver therapeutic genes of pVEGF in MSCs and zebrafish. The results show that LNPs can condense pVEGF to form pVEGF-loaded nanopolymersomes (VNPs), and protect pVEGF against DNase digestion in 6 h. Both LNPs and VNPs have low toxicity to MSCs, erythrocytes and zebrafish embryos. LNPs are stable at 4 °C for at least two years with unchanged size and transfection efficiency. MSCs transfected by VNPs continuously synthesize VEGF for at least four days under control, with a peak (21.25 ng ml(-1)) ∼35-fold greater than that for the untreated group. VNPs induce significant and dose-dependent angiogenesis in zebrafish without causing death, deformity or delay in growth and development, and the induced maximal vessel area of subintestinal vessel plexus is 2.5-fold higher than that for the untreated group. Our study suggests that VNP has high potential in therapeutic angiogenesis.

Efficient cytosolic delivery mediated by polymersomes facilely prepared from a degradable, amphiphilic, and amphoteric copolymer.

To solve problems in polymersome preparation caused by liposolubility of copolymers and to improve the cytosolic delivery efficiency of polymersomes to drugs, a lipopolysaccharide-amine (LPSA) copolymer with amphotericity and amphiphilicity is developed. LPSA contains two hydrophilic oppositely charged blocks (anionic oxidized alginate (OA), cationic polyethyleneimine (PEI 1.8 k)) and one hydrophobic block (cholesteryl), where OA is the backbone and cholesteryl-grafted PEI is the side chain. The two hydrophilic blocks first guarantee that LPSA will dissolve in water, and then help polymersome formation via electrostatic interactions to generate water insoluble interpolyelectrolyte complexes, which supplement the hydrophobic part to reach the right hydrophilicity/hydrophobicity ratio, and thus realize a one-step self-assembly of polymersomes in water. Our results show LPSA nanopolymersomes (LNPs) have low cytotoxicity and degradability, and an excellent ability to enter cells. TEM observation demonstrates that LNPs are entrapped in endosomes after endocytosis, and are then released to cytosols because of their strong endosomal escape capacity. As an example of cytosolic delivery to bioactive molecules, pDNA is delivered in mesenchymal stem cells, and more than 95% of cells express a large target protein, indicating that LNPs have high cytosolic delivery efficiency. Our study provides a novel, easy, and universal method to design copolymers for the preparation of polymersomes as efficient cytosolic delivery nanocarriers.

Enhanced removal of heavy metals by α-FeOOH incorporated carboxylated cellulose nanocrystal: synergistic effect and removal mechanism.

Simultaneous and highly efficient removal of heavy metal cations and oxyanions is significant for both water and soil remediation, but it remains a major challenge due to the complexity. In this work, a novel hybrid of α-FeOOH incorporated carboxylated cellulose nanocrystal (Fe/CNC) is synthesized via a hydrothermal process, which shows improved α-FeOOH dispersion and heavy metal removal capacity. In single adsorbate system, maximum adsorption capacities toward Pb(II), Cd(II), and As(V) by Fe/CNC reach 126.06, 53.07, and 15.80 mg g-1, respectively, and the Fe leaching is much lower than that of α-FeOOH. In binary and ternary adsorption systems, simultaneous removal of Pb(II), Cd(II), and As(V) is proved, and the competition and synergy coexist among heavy metals. FTIR and XPS spectra have revealed the synergistic removal mechanism: Pb(II) and Cd(II) are mainly removed by surface complexation with oxygen-containing functional groups on C-CNC and α-FeOOH, and precipitation on the surface of α-FeOOH, while ligand exchange with Fe-OH is responsible for As(V) removal. The soil incubation experiments show that exchangeable and carbonate-bound Pb, Cd, and As are transformed into more stable forms in contaminated soil containing Fe/CNC composites. This work provides a novel composite material for remediation of heavy metal-contaminated environments.

Dopamine-assisted co-deposition of hydroxyapatite-functionalised nanoparticles of polydopamine on implant surfaces to promote osteogenesis in environments with high ROS levels.

Environments with high reactive oxygen species (ROS) levels, which are common in patients with diseases such as diabetes, periodontitis, and osteoporosis, impair the osseointegration of implants. To address this issue, by using a one-pot dopamine-assisted co-deposition method, we constructed a three-dimensional coating of hydroxyapatite-functionalised nanoparticles of polydopamine (HA/nPDAs) on implant surfaces, where polydopamine is designed to protect cells via scavenging excessive ROS and HA facilitates osteogenesis. First, nanoparticles of polydopamine (nPDAs) were prepared by self-polymerization and assembly of dopamine under alkaline conditions, and HA/nPDAs were obtained by incubating nPDAs in simulated body fluid (SBF) due to metal chelation and ionic interactions triggered by the catechol moieties of PDA. Thereafter, HA/nPDAs with thickness of ~4 µm were constructed on titanium surfaces by immersing titanium discs in a weak alkaline solution of HA/nPDAs and dopamine through interface interactions driven by catechol chemistry. The properties of coatings (e.g., thickness, composition, hydrophilia and morphology) can be controlled by preparation conditions such as mineralization time and reactant concentration. The coatings display efficient ROS-scavenging ability, promote cell proliferation, and upregulate the activity of alkaline phosphatase and the expression of osteogenesis-related genes in environments with high or normal ROS levels, demonstrating the great promise of such coatings for osseointegration promotion, especially in the state of high ROS in diseases. This study provides a facile, efficient, mild, and universal strategy in engineering functional surfaces on any substrates for diversified applications by simple variation of co-deposited components, through taking advantages of versatile catechol chemistry and nanoparticles with stereo structure and great specific surface area.

Anti-Acid Biomimetic Dentine Remineralization Using Inorganic Silica Stabilized Nanoparticles Distributed Electronspun Nanofibrous Mats.

BACKGROUND: To manage the sharp pain of dentine hypersensitivity, various materials are utilized to conduct dentine remineralization. However, many prior materials are limited with their single function and complicated operations. In this study, silica and calcium (strontium) carbonates mineralized nano cellulose fibrous (Si/Ca(Sr)-NCF) mat with the ability to release acid resistant and biomimetic mineralizational silica/calcium (strontium) carbonate co-precipitation nanoparticles (Si/Ca(Sr) NPs) were fabricated. The dentine occluding effects, antibacterial activity and cytocompatibility of the Si/Ca(Sr)-NCF mats were evaluated. METHODS: The Si/Ca(Sr)-NCF mats were fabricated by dipping the electrospun nano cellulose fiber (NCF) into silica and calcium (strontium) carbonate liquid. Physicochemical characterizations and ion release were confirmed by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), ion release assays and transmission electron microscopy (TEM). Sixty dentine discs were randomly divided into five groups: 1, blank NCF; 2, Si/Ca(Sr 0)-NCF; 3, Si/Ca(Sr 0.01)-NCF; 4, Si/Ca(Sr 0.05)-NCF; 5, Si/Ca(Sr 0.1)-NCF. Dentine discs were mineralized by the mats and observed with SEM immediately, after acid challenge and remineralized in artificial saliva. The releasing liquid was investigated by TEM and type I collagen model. Then, antibacterial property and cytocompatibility were evaluated. RESULTS: SEM and TEM results confirmed that the experiment mats continuously released amorphous Si/Ca(Sr) NPs and consequently realized anti-acid dentine biomimetic remineralization. Homogeneous surface coverage and collagen intrafibrillar mineralization in strontium adding groups illustrated the mineralization effect was not only by in site precipitation, but also collagen heterogeneous nucleation. Additionally, acceptable antibacterial and cytocompatibility properties were illustrated in low and middle Sr2+ containing mats. CONCLUSION: In vitro studies on human dentine discs and type I collagen demonstrated that Si/Ca(Sr)-NCF system was a multifunction system inducing anti-acid, biomimetic, antibacterial and cytocompatible dentine remineralization. This multifunction mat would be a promising DH treatment candidate for complicated exposed dentine surfaces.

Mandibular advancement devices shorten desaturation duration in patients at high risk for obstructive sleep apnea syndrome during intravenous propofol sedation in the decubitus position.

BACKGROUND: The purpose of this study was to determine the efficacy of a mandibular advancement device (MAD) for increasing patient safety during sedated total knee arthroplasty (TKA) and total hip replacement (THR). METHODS: Forty patients undergoing TKA or THR surgery in the supine or lateral recumbent positions under spinal anesthesia were enrolled. Sedation and oxygenation were administered. The MAD (Sweet Sleep Anti-Snoring Device) was then placed after 15 minutes of observation. SpO2, PetCO2, blood pressure, and respiratory rate were recorded. RESULTS: Sedated patients in the decubitus position had higher saturation nadirs, shorter desaturation durations, shorter airway obstruction durations, and fewer rescue events than those in the supine position. In patients at a high risk of obstructive sleep apnea syndrome (OSAS), desaturation duration, obstruction duration, apnea duration, desaturation duration, and rescue events were significantly lower after MAD placement. However, the saturation nadir did not improve after MAD placement. CONCLUSION: The MAD may shorten the duration of desaturation events during spontaneous breathing sedative procedures in the lateral recumbent position but not in the supine position. Breathing patterns did not change from nasal breathing to oral breathing or vice versa between pre- and postplacement of the MAD. Sedation score evaluation affects breathing pattern changes from oral breathing to nasal breathing and vice versa.

Porphyromonas gingivalis-Induced Cognitive Impairment Is Associated With Gut Dysbiosis, Neuroinflammation, and Glymphatic Dysfunction.

Background: Periodontal pathogen and gut microbiota are closely associated with the pathogenesis of Alzheimer's disease (AD). Porphyromonas gingivalis (Pg), the keystone periodontal pathogen, can induce cognitive impairment. The gut has a connection and communication with the brain, which is an important aspect of the gut-brain axis (GBA). In the present study, we investigate whether Pg induces cognitive impairment through disturbing the GBA. Methods: In this study, Pg was orally administered to mice, three times a week for 1 month. The effects of Pg administration on the gut and brain were evaluated through behaviors, gut microbiota, immune cells, glymphatic pathway clearance, and neuroinflammation. Results: Pg induced cognitive impairment and dysbiosis of gut microbiota. The α-diversity parameters did not show significant change after Pg administration. The ß-diversity demonstrated that the gut microbiota compositions were different between the Pg-administered and control groups. At the species level, the Pg group displayed a lower abundance of Parabacteroides gordonii and Ruminococcus callidus than the control group, but a higher abundance of Mucispirillum schaedleri. The proportions of lymphocytes in the periphery and myeloid cells infiltrating the brain were increased in Pg-treated animals. In addition, the solute clearance efficiency of the glymphatic system decreased. Neurons in the hippocampus and cortex regions were reduced in mice treated with Pg. Microglia, astrocytes, and apoptotic cells were increased. Furthermore, amyloid plaque appeared in the hippocampus and cortex regions in Pg-treated mice. Conclusions: These findings indicate that Pg may play an important role in gut dysbiosis, neuroinflammation, and glymphatic system impairment, which may in turn lead to cognitive impairment.

Porphyromonas gingivalis induces periodontitis, causes immune imbalance, and promotes rheumatoid arthritis.

Periodontitis induced by bacteria especially Porphyromonas gingivalis (P. gingivalis) is the most prevalent microbial disease worldwide and is a significant risk factor for systemic diseases such as rheumatoid arthritis (RA). RA and periodontitis share similar clinical and pathologic features. Moreover, the prevalence of RA is much higher in patients with periodontitis than in those without periodontitis. To explore the immunologic mechanism of periodontitis involved in RA, we established a mouse model of periodontitis and then induced RA. According to the results of paw thickness, arthritis clinical score, arthritis incidence, microscopic lesion using H&E staining, and micro-CT analysis, periodontitis induced by P. gingivalis promoted the occurrence and development of collagen-induced arthritis (CIA) in mice. Furthermore, periodontitis enhanced the frequency of CD19+ B cells, Th17, Treg, gMDSCs, and mMDSCs, whereas down-regulated IL-10 producing regulatory B cells (B10) in CIA mice preinduced for periodontitis with P. gingivalis. In vitro stimulation with splenic cells revealed that P. gingivalis directly enhanced differentiation of Th17, Treg, and mMDSCs but inhibited the process of B cell differentiation into B10 cells. Considering that adoptive transfer of B10 cells prevent RA development, our study, although preliminary, suggests that down-regulation of B10 cells may be the key mechanism that periodontitis promotes RA as the other main immune suppressive cells such as Treg and MDSCs are up-regulated other than down-regulated in group of P. gingivalis plus CIA.

Constructing self-adhesive and robust functional films on titanium resistant to mechanical damage during dental implanting.

HYPOTHESIS: Osseointegration can be enhanced by introducing bioactive polyelectrolyte-multilayer films on implant surfaces. To guarantee films to function successfully in use, keeping structural integrity during implanting is necessary, which requires films with strong adhesion and cohesion to resist the mechanical damage. Catechol is considered as the origin of amazing adhesion of mussels. We hypothesize that catechol functionalization of polyelectrolytes enables film construction on implants in a non-aggressive way, and helps films resist mechanical damages during implanting. EXPERIMENTS: With lipopolysaccharide-amine nanopolymersomes (NPs), catechol-functionalized hyaluronic acid and NPs (cHA, cNPs) as a polycation, polyanion and primer, respectively, catechol-functionalized polyelectrolyte-multilayer films (cPEMs) were constructed on substrates via Layer-by-layer self-assembly. Effects of catechol functionalization on construction, surface properties, assembly mechanisms, structural integrity, mechanical properties and cytotoxicity of cPEMs were studied. FINDINGS: Self-adhesive cPEMs can be constructed on substrates, which grow exponentially and are driven by coordination, covalent bonding, electrostatic interactions, hydrogen bonding, etc. cPEMs with suitable catechol concentrations can resist mechanical damage to keep structural integrity in simulated clinical implantation, show stronger adhesion and cohesion than non-catechol-functionalized films in nanoscratch and nanoindentation tests, and are non-cytotoxic to MSCs. With excellent drug-loading and cytosolic-delivery capacity of NPs, cPEM is promising in improving osseointegration of implants.

The Construction of Biomimetic Cementum Through a Combination of Bioskiving and Fluorine-Containing Biomineralization.

Despite tremendous attention is given to the construction of biomimetic cementum for regeneration of tooth cementum, the lack of recapitulating the composition and hierarchical structure of cementum often leads to the poor performance of constructed materials. How to highly mimic the sophisticated composition and hierarchy of cementum remains a longstanding challenge in constructing the biomimetic cementum. Inspired by cementum formation process, a novel construction approach via a combination of bioskiving and fluorine-containing biomineralization is developed in this study. The alternative collagen lamellae (ACL) that can highly mimic the rotated plywood structure of cementum collagen matrix is fabricated via bioskiving. Followed by biomineralization in the amorphous calcium phosphate (ACP) solution with different concentration of fluorine, a series of biomimetic cementum is constructed. Screened by physicochemical characterization, the biomimetic cementum with the composition and hierarchical structure highly similar to human cementum is selected. Through in vitro biological assay, this biomimetic cementum is proven to significantly promote the adhesion, proliferation, and cementogenic differentiation of periodontal ligament cells (PDLCs). Furthermore, in vivo study demonstrates that biomimetic cementum could induce cementogenesis. This biomimetic cementum constructed via combinatory application of bioskiving and fluorine-containing biomineralization stands as a promising candidate for achieving cementum regeneration.

The Injectable Woven Bone-Like Hydrogel to Perform Alveolar Ridge Preservation With Adapted Remodeling Performance After Tooth Extraction.

Grafting bone substitute is paramount to prevent the alveolar ridge resorption after tooth extraction and facilitate the subsequent implant treatment. An ideal bone substitute should acquire the excellent osteogenic property, more importantly, possess the suitable remodeling rate in balance with bone formation and desirable clinical manageability. However, none of bone substitute is simultaneously characterized by these features, and currently, the limited remodeling property leads to the excessive waiting time before implantation. Enlightened by woven bone, the transitional tissue that is able to induce osteogenesis during bone healing could be easily remodeled within a short period and depend on the favorable injectability of hydrogel, an injectable woven bone-like hydrogel (IWBLH) was constructed in this study to address the above problems. To mimic the component and hierarchical structure of woven bone, amorphous calcium phosphate (ACP) and mineralized collagen fibril were synthesized and compounded with alginate to form IWBLHs with various ratio. Screened by physiochemical characterization and in vitro biological assays, an optimal IWBLH was selected and further explored in rat model of tooth extraction. Compared with the most widely used bone substitute, we showed that IWBLH could be easily handled to fully fill the tooth socket, perform a comparable function to prevent the alveolar bone resorption, and completely remodeled within 4 weeks. This IWBLH stands as a promising candidate for alveolar ridge preservation (ARP) in future.

Contact analysis of gap formation at dental implant-abutment interface under oblique loading: A numerical-experimental study.

PURPOSE: To develop numerical and experimental methods for investigating the formation of micro-gaps and the change in contact area at the implant-abutment interface of two different connector designs under oblique cyclic loading. MATERIALS AND METHODS: Samples (n = 10 per group) of two-piece implant systems with the conical connection (group A) and the external hexagonal connection (group B) were subjected to cyclic loading with increasing load amplitudes up to 220 N. After loading, the samples were scanned using micro-CT, with silver nitrate as a high-contrast penetrant, and the level of leakage was assessed using a discrete scoring system. Three-dimensional finite element (FE) analyses of the two implant systems were also conducted to reveal the micro-gap formation process, especially bridging of the internal abutment screw space. The experimental and numerical results for the bridging load were then compared. RESULTS: 90% of the samples in group A showed leakage into the internal implant space at a load of around 100 N; while over 80% of those in group B did so at a load of around 40 N. This agreed with the FE analysis, which showed bridging of the internal implant space at loads similar to those measured for the two implant systems. Residual gaps of less than 1.49 µm were predicted for group A only after unloading. CONCLUSIONS: The FE-predicted loads for bridging agreed well with those found experimentally for leakage to occur. The conical connection showed more resistance against formation of micro-gaps at the implant-abutment interface than the external hexagonal connection. Although the minimum load required to bridge the internal implant space was within the range of human biting force, the relation between bacterial invasion and micro-gaps needs further research.

Increased cortical infarction and neuroinflammation in ischemic stroke mice with experimental periodontitis.

Ischemic stroke is a common life-threatening disease. Epidemiological studies have shown that chronic periodontitis is closely related to ischemic stroke. However, it remains unknown whether periodontitis plays a direct role in the injury of cerebral ischemia. To explore the role of chronic periodontitis in the development process of ischemic stroke, we combined two mouse models: experimental periodontitis induced by a periodontal injection of lipopolysaccharide and ischemic stroke induced by the photothrombotic method. Alveolar bone loss and inflammatory infiltration of the periodontal tissue were found in the mice with experimental periodontitis. Periodontitis significantly increased the infarction volume, and numbers of activated microglia and astrocytes. Furthermore, an increased expression of nod-like receptor protein 3 inflammasome and interleukin-1ß was detected in the peri-infarct region. We drew a conclusion that chronic periodontitis exacerbated ischemic stroke by increasing the activation of microglia/astrocytes and the expression of nod-like receptor protein 3 inflammasome and interleukin-1ß. This suggested that chronic periodontitis played a role in ischemic brain injury directly through exacerbating the inflammation of the damaged brain.