Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss.

Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic target for alveolar bone regeneration, because SHN3 expression is elevated in human and mouse mandible tissues with osteoporosis while deletion of SHN3 in mice greatly increases alveolar bone and tooth dentin mass. We used a bone-targeted recombinant adeno-associated virus (rAAV) carrying an artificial microRNA (miRNA) that silences SHN3 expression to restore alveolar bone loss in mouse models of both postmenopausal and senile osteoporosis by enhancing WNT signaling and osteoblast function. Additionally, rAAV-mediated silencing of SHN3 enhanced bone formation and collagen production of human skeletal organoids in xenograft mice. Finally, rAAV expression in the mandible was tightly controlled via liver- and heart-specific miRNA-mediated repression or via a vibration-inducible mechanism. Collectively, our results demonstrate that AAV-based bone anabolic gene therapy is a promising strategy to treat alveolar bone loss in osteoporosis.

Prevalence of chronic periodontitis in patients undergoing peritoneal dialysis and its correlation with peritoneal dialysis-related complications.

OBJECTIVE: The microinflammatory state can influence the occurrence of dialysis-related complications in dialysis patients. Chronic periodontitis (CP), in which plaque biofilm is considered to be the initiating factor, is a chronic infectious disease in the oral cavity. It is still uncertain whether CP affects the microinflammatory state in peritoneal dialysis (PD) and the occurrence of dialysis-related complications. The purpose of this study was to investigate the correlation between the periodontal index and clinical parameters in peritoneal dialysis patients with CP and dialysis-related complications, including peritoneal dialysis-associated peritonitis (PDAP) and cardiovascular and cerebrovascular events (CCEs). METHODS: This was a retrospective cohort study, and 76 patients undergoing PD were enrolled. Clinical parameters, the occurrence of PD-related complications and periodontitis-related indicators, including the gingival index (GI), plaque index (PLI), probing depth (PPD) and clinical attachment loss (CAL), were collected. Correlation analysis was used to explore the correlation between periodontal or clinical parameters and the occurrence of PD-related complications. RESULTS: All the patients had different degrees of periodontitis (mild 9.2%, moderate 72.4%, severe 18.4%); PPD was inversely related to serum albumin (r = - 0.235, p = 0.041); CAL has a positive correlation with serum C-reactive protein (rs = 0.242, p = 0.035); PLI was positively correlated with serum calcium (r = 0.314, p = 0.006). ANOVA, multivariate logistic regression analysis and Kaplan-Meier Survival curve suggested that CAL was a risk factor for the occurrence of PDAP. There was no correlation between periodontal parameters and CCEs or poor prognosis. CONCLUSION: CP is universally present in PD patients, and the presentation of periodontitis influences the systemic inflammatory state in PD patients. CP is a risk factor for PDAP.

Polyvinyl acetate-based soil stabilization for rock slope ecological restoration.

External-soil spray seeding (ESSS) is a method often used for the ecological restoration of bare rock slopes. However, the direct use of ESSS is normally less satisfactory due to the erosion of sprayed soil and low survival rate of the plants on rock slopes. This study proposes a novel approach to addressing this issue through the combined use of ESSS with polyvinyl acetate (PVA) based soil stabilization. The PVA solutions are added to the soil to stabilize soil and improve soil strength while possessing high water and nutrient retention favorable for plant growth. A series of experimental tests on the mechanical properties, water stability, erosion resistance, water retention, and plant growth of the PVA-stabilized soil were conducted to assess the efficacy of the proposed method. The results showed that the proposed method could be promising for rock slope ecological restoration. A proper curing time (e.g., >3 days) was required to achieve beneficial effects of PVA on the soil properties. A shorter curing time would otherwise result in the decrease in the strength with the increased PVA content. It was found that the optimum PVA content was 3% for achieving the maximum water stability, erosion resistance, water retention, and plant growth. The cohesion increased by up to 50% and the internal friction angle increased by 3.5° compared to the natural soil. The disintegration rate of the stabilized soil was generally < 3e-3%/min. The maximum reduction in erosion was up to 83% when the PVA content ≥3%. The mechanisms behind the findings are also discussed.

Construction of Surface-Modified Polydopamine Nanoparticles for Sequential Drug Release and Combined Chemo-Photothermal Cancer Therapy.

Single chemotherapy often causes severe adverse effects and drug resistance to limit therapeutic efficacy. As a noninvasive approach, photothermal therapy (PTT) represents an attractive option for cancer therapy due to the benefits of remote control and precise treatment methods. Nanomedicines constructed with combined chemo-photothermal properties may exert synergistic effects and improved antitumor efficacy. In this study, we developed polydopamine (PDA)-coated nanoparticles grafted with folic acid (FA) and polyethylene glycol to transport doxorubicin (DOX) for targeted cancer therapy. The results showed that this delivery vehicle has a nanoscale particle size and narrow size distribution. No particle aggregation or significant drug leakage was observed during the stability test. This system presented excellent photothermal conversion capability under near-infrared light (NIR) laser irradiation due to the PDA layer covering. In vitro dissolution profiles demonstrated that sequential and triggered DOX release from nanoparticles was pH-, NIR irradiation-, and redox level-dependent and could be best fitted with the Ritger-Peppas equation. FA modification effectively promoted the intracellular uptake of nanoparticles by HepG2 cells and therefore significantly inhibited cell recovery and induced tumor cell apoptosis. Compared to the free DOX group, nanoparticles reduced the DOX concentration in the heart to avoid drug-related cardiotoxicity. More importantly, the in vivo antitumor efficacy results showed that compared with the single chemotherapy strategy, the nanoparticle group exerted combined and satisfactory tumor growth inhibition effects with good biocompatibility. In summary, this nanocarrier delivery system can organically combine chemotherapy and PTT to achieve effective and precise cancer treatment.

Chloride Ions-Responsive Intelligent Coatings for the Active Protection of Degradable Biomedical Mg Alloys.

In this work, the hydroxyapatite (HA) microspheres are utilized as carriers for 8-hydroxyquinoline (8-HQ) inhibitors with a sodium alginate-silver nitrate layer (Ag-SA) added to confer chloride-responsive properties. These 8-HQ@Ag-SA-HA microspheres are subsequently integrated into poly(lactic acid) (PLA) coatings to produce biocompatible coatings. The resulting 8-HQ@Ag-SA-HA microsphere exhibits a spherical structure with a diameter of 3.16 µm. Thermogravimetric analysis indicates that the encapsulated 8-HQ inhibitors are approximately 11.83 wt %. Furthermore, the incorporation of these microspheres fills the micropores within the PLA coating, leading to a denser coating surface, enhanced wettability (contact angle value = 88°), and improved adhesion strength, thereby reinforcing the physical barrier effect. Corrosion tests reveal that the coatings exhibit increased resistance to corrosion in simulated body fluid (SBF) solutions. The released 8-HQ inhibitors in response to chloride ions form a protective layer of Mg(HQ)2, providing the coatings with self-healing properties and ensuring their durability in the SBF environment. Additionally, the cell test demonstrates a significant presence of MG-63 cells, accompanied by a low hemolysis rate of 3.81%, confirming the exceptional biocompatibility of the coatings. These findings offer valuable insights into the development of stimuli-responsive biocompatible coatings for effectively protecting Mg alloys.

Leaching of organic matters and formation of disinfection by-product as a result of presence of microplastics in natural freshwaters.

Microplastics (MPs) are ubiquitous in the environment that may cause negative impacts on the aquatic organisms and human health. They exist in water and wastewater, which are from several sources, such as inappropriate disposal and littering. Therefore, it is important to evaluate the characteristics of MPs in different water types and oxidation processes and study dissolved organic carbon (DOC) leaching and chloroform formation. A commonly existing plastic matter, polyethylene (PE) was placed in different waters and gone through the Fenton-like reaction and the chlorination. The result showed that the PE leached nearly a similar amount of DOC (<1 mg L-1), which was regardless of the water types and under low-dosed irradiation/dark environment. The leached DOC caused the chloroform formation after the chlorination in the waters. During the Fenton-like reaction with the PE, a higher amount of leached DOC (∼3 mg L-1) was detected compared with that in the chlorination (∼0.8 mg L-1). The degree of DOC leaching from the PE caused by the oxidation processes was reflected by the degree of surface structural damage on the PE. However, the chlorination resulted in a higher chloroform formation from the PE (∼20 µg L-1) as the Fenton-like reaction degraded the chloroform. The higher the sodium hypochlorite concentration, the higher the chloroform concentration. When the chloroform existed in the water with the PE, adsorption of chloroform onto the PE was initially observed; however the rate of volatilization would be higher than the rate of adsorption eventually. This study offers useful information for the risk assessment of MPs in our fresh water and drinking water and possible mitigation strategies.

Development of ligand modified erythrocyte coated polydopamine nanomedicine to codeliver chemotherapeutic agent and oxygen for chemo-photothermal synergistic cancer therapy.

The use of conventional chemotherapy often faces limitations such as severe side effects, weak tumor tissue specificity, and the development of multidrug resistance. To conquer these challenges, numerous novel drug carriers have been designed in recent years. However, due to the complex processes of tumor development, metastasis and recurrence, single chemotherapy cannot fulfill the goals of clinical diverse treatment. In this work, by utilizing the inherent characteristics of surface-modified erythrocyte and the outstanding photothermal conversion capability of polydopamine (PDA), we designed and constructed a biomimetic multifunctional nanomedicine DPPR NPs to codeliver chemotherapeutic agent doxorubicin (DOX) and oxygen. The results showed that DPPR NPs exhibited inspiring features including nanoscale droplet size, good physicochemical stability, and sustained, pH-, and NIR triggered drug release behavior. It can dramatically prolong the systematic circulation time and elevated the drug accumulated level in the tumor site. Moreover, DPPR NPs could be effectively internalized into tumor cells and destroyed the intracellular redox balance to mediate cell apoptosis. It exerted excellent in vivo tumor targeting effect, photothermal conversion efficiency, ultrasound imaging responses, antitumor efficacy, and good compatibility. In summary, DPPR NPs provide a biomimetic drug delivery platform to organically combine chemotherapy and photothermal therapy for precise cancer treatment.

Co-pyrolysis kinetics of sewage sludge and bagasse using multiple normal distributed activation energy model (M-DAEM).

In this study, the kinetic models of bagasse, sewage sludge and their mixture were established by the multiple normal distributed activation energy model. Blending with sewage sludge, the initial temperature declined from 437 K to 418 K. The pyrolytic species could be divided into five categories, including analogous hemicelluloses I, hemicelluloses II, cellulose, lignin and bio-char. In these species, the average activation energies and the deviations situated at reasonable ranges of 166.4673-323.7261 kJ/mol and 0.1063-35.2973 kJ/mol, respectively, which were conformed to the references. The kinetic models were well matched to experimental data, and the R2 were greater than 99.999%y. In the local sensitivity analysis, the distributed average activation energy had stronger effect on the robustness than other kinetic parameters. And the content of pyrolytic species determined which series of kinetic parameters were more important.

Tumor cell-targeted delivery of CRISPR/Cas9 by aptamer-functionalized lipopolymer for therapeutic genome editing of VEGFA in osteosarcoma.

Osteosarcoma (OS) is a highly aggressive pediatric cancer, characterized by frequent lung metastasis and pathologic bone destruction. Vascular endothelial growth factor A (VEGFA), highly expressed in OS, not only contributes to angiogenesis within the tumor microenvironment via paracrine stimulation of vascular endothelial cells, but also acts as an autocrine survival factor for tumor cell themselves, thus making it a promising therapeutic target for OS. CRISPR/Cas9 is a versatile genome editing technology and holds tremendous promise for cancer treatment. However, a major bottleneck to achieve the therapeutic potential of the CRISPR/Cas9 is the lack of in vivo tumor-targeted delivery systems. Here, we screened an OS cell-specific aptamer (LC09) and developed a LC09-functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9. Our results demonstrated that LC09 facilitated selective distribution of CRISPR/Cas9 in both orthotopic OS and lung metastasis, leading to effective VEGFA genome editing in tumor, decreased VEGFA expression and secretion, inhibited orthotopic OS malignancy and lung metastasis, as well as reduced angiogenesis and bone lesion with no detectable toxicity. The delivery system simultaneously restrained autocrine and paracrine VEGFA signaling in tumor cells and could facilitate translating CRISPR-Cas9 into clinical cancer treatment.