Piezoelectric hydrogel for treatment of periodontitis through bioenergetic activation.

The impaired differentiation ability of resident cells and disordered immune microenvironment in periodontitis pose a huge challenge for bone regeneration. Herein, we construct a piezoelectric hydrogel to rescue the impaired osteogenic capability and rebuild the regenerative immune microenvironment through bioenergetic activation. Under local mechanical stress, the piezoelectric hydrogel generated piezopotential that initiates osteogenic differentiation of inflammatory periodontal ligament stem cells (PDLSCs) via modulating energy metabolism and promoting adenosine triphosphate (ATP) synthesis. Moreover, it also reshapes an anti-inflammatory and pro-regenerative niche through switching M1 macrophages to the M2 phenotype. The synergy of tilapia gelatin and piezoelectric stimulation enhances in situ regeneration in periodontal inflammatory defects of rats. These findings pave a new pathway for treating periodontitis and other immune-related bone defects through piezoelectric stimulation-enabled energy metabolism modulation and immunomodulation.

Efficient clearance of periodontitis pathogens by S. gordonii membrane-coated H2O2 self-supplied nanocomposites in a "Jenga" style.

As a key pathogen of periodontitis, P. gingivalis requires support of the initial colonizing bacterium (S. gordonii preferably) to form symbiotic biofilms on gingival tissues with enhanced antibiotic resistance. Here, we report a new strategy to treat periodontitis biofilms with S. gordonii membrane-coated H2O2 self-supplied nanocomposites (ZnO2/Fe3O4@MV NPs) in a "Jenga" style. Integration of our special MV coatings enables selectively enhanced internalization of the cargos in S. gordonii, thus inducing severe damage to the foundational bacterial layer and collapse/clearance of symbiotic biofilms consequently. This strategy allows us to clear the symbiotic biofilms of S. gordonii and P. gingivalis with active hydroxyl radicals (˙OH) derived from ZnO2-Fe3O4@MV NPs in a H2O2 self-supplied, nanocatalyst-assisted manner. This "Jenga-style" treatment provides a cutting-edge proof of concept for the removal of otherwise robust symbiotic biofilms of periodontitis where the critical pathogens are difficult to target and have antibiotic resistance.

Mussel-Inspired Polydopamine Composite Mesoporous Bioactive Glass Nanoparticles: An Exploration of Potential Metal-Ion Loading Platform and In Vitro Bioactivity.

Exploring new approaches to realize the possibility of incorporating biologically active elements into mesoporous silicate bioactive glass nanoparticles (MBG NPs) and guaranteeing their meso- structural integrity and dimensional stability has become an attractive and interesting challenge in biomaterials science. We present a postgrafting strategy for introducing different metal elements into MBG NPs. This strategy is mediated by polydopamine (PDA) coating, achieving uniform loading of copper or copper-cobalt on the particles efficiently and ensuring the stability of MBG NPs in terms of particle size, mesoporous structure, and chemical structure. However, the PDA coating reduced the ion-binding free energy of the MBG NPs for calcium and phosphate ions, resulting in the deposition of minimal CaP clusters on the PDA@MBG NP surface when immersed for 7 days in simulated body fluid, indicating the absence of hydroxyapatite mineralization.

A bioinspired and high-strengthed hydrogel for regeneration of perforated temporomandibular joint disc: Construction and pleiotropic immunomodulatory effects.

Due to the lack of an ideal material for TMJ (temporomandibular joint) disc perforation and local inflammation interfering with tissue regeneration, a functional TGI/HA-CS (tilapia type I gelatin/hyaluronic acid-chondroitin sulfate) double network hydrogel was constructed in this paper. It was not only multiply bionic in its composition, structure and mechanical strength, but also endowed with the ability to immunomodulate microenvironment and simultaneously induce in situ repair of defected TMJ discs. On the one hand, it inhibited inflammatory effects of inflammasome in macrophages, reduced the extracellular matrix (ECM)-degrading enzymes secreted by chondrocytes, reversed the local inflammatory state, promoted the proliferation of TMJ disc cells and induced fibrochondrogenic differentiation of synovium-derived mesenchymal stem cells (SMSCs). On the other hand, it gave an impetus to repairing a relatively-large (6 mm-sized) defect in mini pigs' TMJ discs in a rapid and high-quality manner, which suggested a promising clinical application.

Identification of tumor antigens and immune subtypes in head and neck squamous cell carcinoma for mRNA vaccine development.

The mRNA vaccines have been considered effective for combating cancer. However, the core components of the mRNA vaccines against head and neck squamous cell carcinoma (HNSCC) and the effects remain unclear. Our study aims to identify effective antigens in HNSCC to develop mRNA vaccines for corresponding potential patients. Here, we analyzed alternative splicing and mutation of genes in TCGA-HNSCC samples and identified seven potential tumor antigens, including SREBF1, LUC7L3, LAMA5, PCGF3, HNRNPH1, KLC4, and OFD1, which were associated with nonsense-mediated mRNA decay factor expression, overall survival prognosis and the infiltration of antigen-presenting cells. Furthermore, to select suitable patients for vaccination, immune subtypes related to HNSCC were identified by consensus clustering analysis, and visualization of the HNSCC immune landscape was performed by graph-learning-based dimensionality reduction. To address the heterogeneity of the population that is suitable for vaccination, plot cell trajectory and WGCNA were also utilized. HNSCC patients were classified into three prognostically relevant immune subtypes (Cluster 1, Cluster 2, and Cluster 3) possessing different molecular and cellular characteristics, immune modulators, and mutation statuses. Cluster 1 had an immune-activated phenotype and was associated with better survival, while Cluster 2 and Cluster 3 were immunologically cold and linked to increased tumor mutation burden. Therefore, HNSCC patients with immune subtypes Cluster 2 and Cluster 3 are potentially suitable for mRNA vaccination. Moreover, the prognostic module hub genes screened seven genes, including IGKC, IGHV3-15, IGLV1-40, IGLV1-51, IGLC3, IGLC2, and CD79A, which could be potential biomarkers to predict prognosis and identify suitable patients for mRNA vaccines. Our findings provide a theoretical basis for further research and the development of anti-HNSCC mRNA vaccines and the selection of suitable patients for vaccination.

3D-printed mesoporous bioactive glass/GelMA biomimetic scaffolds for osteogenic/cementogenic differentiation of periodontal ligament cells.

Integrated regeneration of periodontal tissues remains a challenge in current clinical applications. Due to the tunable physical characteristics and the precise control of the scaffold microarchitecture, three-dimensionally (3D) printed gelatin methacryloyl (GelMA)-based scaffold has emerged as a promising strategy for periodontal tissue regeneration. However, the optimization of the printing biomaterial links the formulation and the relationship between the composition and structures of the printed scaffolds and their comprehensive properties (e.g. mechanical strength, degradation, and biological behaviors) remains unclear. Here, in this work, a novel mesoporous bioactive glass (BG)/GelMA biomimetic scaffold with a large pore size (∼300 µm) was developed by extrusion-based 3D printing. Our results showed that the incorporation of mesoporous bioactive glass nanoparticles (BG NPs) significantly improved shape fidelity, surface roughness, and bioactivity of 3D-printed macroporous GelMA scaffolds, resulting in the enhanced effects on cell attachment and promoting osteogenic/cementogenic differentiation in human periodontal ligament cells. The excellent maintenance of the macropore structure, the visibly improved cells spreading, the release of bioactive ions (Si4+, Ca2+), the upregulation of gene expressions of osteogenesis and cementogensis, and the increase in alkaline phosphatase (ALP) activity and calcium nodules suggested that BG NPs could endow GelMA-based scaffolds with excellent structural stability and the ability to promote osteogenic/cementogenic differentiation. Our findings demonstrated the great potential of the newly formulated biomaterial inks and biomimetic BG/GelMA scaffolds for being used in periodontal tissue regeneration and provide important insights into the understanding of cell-scaffold interaction in promoting the regeneration of functional periodontal tissues.

A novel dental infiltration resin based on isosorbide-derived dimethacrylate with high biocompatibility, hydrolysis resistance, and antibacterial effect.

Objectives: The available infiltration resin has raised biosafety and treatment stability concerns because of the cytotoxicity of the main component, TEGDMA, and its susceptibility to hydrolysis in the oral environment. This study aimed to develop a TEGDMA-free infiltration resin to overcome these drawbacks. Methods: Using the synthetic bioderived monomer bis(methacrylate) isosorbide (IBM) and the zwitterionic compound 2-methacryloyloxyethyl phosphorylcholine (MPC), a novel infiltrant IBMA was developed and preferentially selected. We investigated the performance of the IBMA resin regarding cytotoxicity, antibiofilm adhesion, and hydrolysis resistance and further verified its ability to restore the demineralized enamel and stability of the infiltrated area under artificial aging conditions. Results: Compared with the commercial TEGDMA-based infiltration resin ICON, IBMA not only demonstrated similar enamel morphologic and esthetic restorative effects in chalky lesions but also exhibited favorable cell viability, durable Streptococcus mutans UA159 biofilm-repellent performance, and higher enamel microhardness (204.0 ± 5.12 HV) of the infiltrated enamel. Specifically, because of the high crosslink density [(47.77 ± 5.76) ×103 mol/mm3] and low water sorption [12.79 ± 2.56 µg/mm3] of the polymer network, the IBMA resin was more resistant to hydrolysis than ICON, which prevents the disruption of the infiltrant's micropore-blocking effect after aging. Enamel lesions treated with IBMA demonstrated good color stability after the tea-staining challenge, which was significantly better than that in the ICON group. Conclusion: Based on these findings, the IBMA resin exhibits favorable cell viability, hydrolysis resistance, and biofilm-repellent properties, which alleviates the defects of traditional TEGDMA systems. Therefore, it is a better alternative for microinvasive treatment involving early caries and enamel whitish discoloration.

Superior low-immunogenicity of tilapia type I collagen based on unique secondary structure with single calcium binding motif over terrestrial mammals by inhibiting activation of DC intracellular Ca2+-mediated STIM1-Orai1/NF-кB pathway.

The reason for low- or non-immunogenicity of fish collagens is still in doubt, which, to some extent, bottlenecks their production and clinical application as biomaterials. Employing bovine or porcine type I collagens (BCI or PCI) as controls in this paper, we intensively investigate the influence of tilapia type I collagens (TCI) on the function of dendritic cells (DCs) and T cells. From bio-informatic analyses, as well as data obtained in vitro and in vivo, we find the variations in amino acid sequences lead to only one calcium binding motif in the secondary structure of TCI, compared with three in BCI or PCI. So when TCI (together with the minor amount of Ca2+ they take) are uptaken, intracellular [Ca2+] remains stable and DCs maintain immature. On the contrary, those that have uptaken PCI or BCI experience not only increased [Ca2+] in the plasma but also phosphorylation of p65, resulting in activation of STIM1-Orai1/NF-кB signaling pathway and DC maturation. We fully prove our results on mice models, with no obvious cellular and humoral immune reactions. Our study primarily reveal the underlying mechanisms why TCI, different from BCI or PCI, show almost non-immunogenicity. Our findings are of great importance for the promotion and wide application of TCI in biomedicine.

The reversal of drug resistance by two-dimensional titanium carbide Ti2 C (2D Ti2C) in non-small-cell lung cancer via the depletion of intracellular antioxidant reserves.

BACKGROUND: Chemoresistance is a major barrier limiting the therapeutic efficacy of late stage non-small cell lung cancer (NSCLC). In this study, we sought to use two-dimensional titanium carbide (2D Ti2 C) to reverse cisplatin resistance in NSCLC. METHODS: We first achieved favorable properties as a potential anti-tumor agent. We then compared cell viability and cisplatin uptake in chemoresistant NSCLC cells before and after the use of 2D Ti2 C. Afterwards, we explored the effects of 2D Ti2 C on intracellular antioxidant reserves, followed by evaluating the subsequent changes in the expression of core drug resistance genes. Finally, we confirmed the tumor inhibitory effect and bio-safety of 2D Ti2 C in a drug-resistant lung cancer model in nude mice. RESULTS: Due to the properties of thin layer, large specific surface area, and abundant reactive groups on the surface, 2D Ti2 C can deplete the antioxidant reserve systems such as the glutathione redox buffer system, γ-glutamylcysteine synthetase (γ-GCS), glutathione peroxidase (GPx), glutathione-S-transferase-Pi (GST-π), and metallothionein (MT), thereby increasing the intracellular accumulation of cisplatin and decreasing the expression of drug resistance genes. CONCLUSIONS: 2D Ti2 C can reverse NSCLC chemoresistance both in vitro and in vivo, suggesting that it may potentially become a novel and effective means to treat chemoresistant NSCLC in the clinic.

Porous bioactive glass micro- and nanospheres with controlled morphology: developments, properties and emerging biomedical applications.

In recent years, porous bioactive glass micro/nanospheres (PBGSs) have emerged as attractive biomaterials in various biomedical applications where such engineered particles provide suitable functions, from tissue engineering to drug delivery. The design and synthesis of PBGSs with controllable particle size and pore structure are critical for such applications. PBGSs have been successfully synthesized using melt-quenching and sol-gel based methods. The morphology of PBGSs is controllable by tuning the processing parameters and precursor characteristics during the synthesis. In this comprehensive review on PBGSs, we first overview the synthesis approaches for PBGSs, including both melt-quenching and sol-gel based strategies. Sol-gel processing is the primary technology used to produce PBGSs, allowing for control over the chemical compositions and pore structure of particles. Particularly, the influence of pore-forming templates on the morphology of PBGSs is highlighted. Recent progress in the sol-gel synthesis of PBGSs with sophisticated pore structures (e.g., hollow mesoporous, dendritic fibrous mesoporous) is also covered. The challenges regarding the control of particle morphology, including the influence of metal ion precursors and pore expansion, are discussed in detail. We also highlight the recent achievements of PBGSs in a number of biomedical applications, including bone tissue regeneration, wound healing, therapeutic agent delivery, bioimaging, and cancer therapy. Finally, we conclude with our perspectives on the directions of future research based on identified challenges and potential new developments and applications of PBGSs.

Biodistribution, inter-/intra-cellular localization and respiratory dysfunction induced by Ti3C2 nanosheets: Involvement of surfactant protein down-regulation in alveolar epithelial cells.

Two-dimensional Ti3C2 nanosheets have been extensively used in biomedical fields and are mostly designed to enter the circulatory system. However, few studies have focused on the in vivo anatomical location and physiological function of major organs on exposure to Ti3C2 nanosheets. This study attempts to determine whether and how Ti3C2 nanosheets disrupt the physiological function of the involved organs. Our studies demonstrated that Ti3C2 nanosheets were mainly distributed in the lungs and liver after entering circulation. In the lungs, they were retained in the cytoplasm of alveolar epithelial cells and endothelial cells, and inhibited pulmonary surfactant protein B (SP-B) expression on alveolar epithelial cell, causing increased airway resistance-induced respiratory disorder following a 28-day Ti3C2 nanosheet exposure. Furthermore, our data showed that Ti3C2 nanosheets did not cause abnormal proinflammatory cytokines and histopathological changes. These findings demonstrated that Ti3C2 nanosheets might disturb respiration without inflammatory responses and pathological lesions, suggesting that these effects may occur by decreasing SP-B-mediated airway resistance. This indicates that organ function maintenance differs from biological safety for Ti3C2 nanosheets, an important consideration during potential clinical application and human exposure.

In vitro evaluation of poly (vinyl alcohol)/collagen blended hydrogels for regulating human periodontal ligament fibroblasts and gingival fibroblasts.

Periodontitis is a chronic inflammatory disease that can destroy periodontal tissue. Guided tissue regeneration (GTR) is widely applied to treat periodontitis. However, the challenge is to develop a GTR membrane capable of simultaneously regenerating periodontal tissue and preventing epithelial downgrowth into the defect. Herein, blended hydrogels composed of polyvinyl alcohol (PVA) and fish collagen (Col) were prepared as GTR membranes. The morphology, Col release, and cellular behavior of the blended hydrogels were evaluated. The results showed that the surface porosity and Col release of the PVA/Col blended hydrogels were enhanced by increasing the Col concentration. The adhesion and proliferation of human periodontal ligament fibroblasts (HPDLFs) and human gingival fibroblasts (HGFs) on the PVA/Col blended hydrogels can be regulated by tuning the PVA/Col ratio. The PVA/Col (50:50) blended hydrogel exhibited the highest cell proliferation rate for HPDLFs with spread cell morphology; the lowest viability for HGFs was found on the PVA/Col (100:0) hydrogel. Thus, by controlling the ratio of PVA to Col, multifunctional PVA/Col blended hydrogels able to regulate the cellular behavior of HPDLFs and HGFs can be developed, demonstrating their potential as GTR membrances for guiding periodontal tissue regeneration.

A well defect-suitable and high-strength biomimetic squid type II gelatin hydrogel promoted in situ costal cartilage regeneration via dynamic immunomodulation and direct induction manners.

Reconstructing segmental costal cartilage defects resulting from autologous cartilage grafts in plastic surgery remains a challenge. The present study focused on a biomimetic strategy for in situ costal cartilage regeneration that did not rely on an autogenous/xenogenous tissue graft. A multifunctional biomimetic SGII/HA-DN hydrogel based on a "chemical-curing, shaping, and light-curing" gelation system was developed and evaluated for its mechanical properties, clinical applications and biological functions. This hydrogel showed good suitability to repair defects and a high mechanical support strength (11 MPa, which is close to the natural strength of costal cartilage). Biologically, the hydrogel exhibited dual-immunomodulatory effects on the pro-inflammatory/anti-inflammatory phenotypes of neutrophils and M1/M2 macrophage polarization and subsequently promoted the chondrogenesis of cartilage stem/progenitor cells through both direct induction and indirect stimulation by the M2 macrophage-mediated TGF-ß/Smad pathway. Furthermore, this SGII/HA-DN hydrogel could regulate the local microenvironment, inducing new costal cartilage regeneration in vivo. Our findings demonstrate that the newly developed multifunctional SGII/HA-DN hydrogel provides a strategy with high prospect for the biomimetic repair of segmental costal cartilage defects in clinical practice.

Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes.

Cartilage lesions in degenerative osteoarthritis (OA) are involved with pathological microenvironmental alterations induced by inflammatory macrophages, and apoptotic and/or hypertrophic chondrocytes. However, current non-operative therapies for cartilage repair in OA can rarely achieve long-term and satisfactory outcomes. This study aims to evaluate a newly developed squid type II collagen (SCII) for repairing OA-induced cartilage lesions. Our in vitro data show that SCII induces M2 polarization of macrophages, and activates macrophages to express pro-chondrogenic genes (TGF-ß and IGF), which greatly improves the microenvironment around chondrocytes to produce type II collagen and glycosaminoglycan. In addition, glycine in SCII activates glycine receptors on inflammatory chondrocytes to decrease intracellular calcium concentration, leading to effective inhibition of chondrocyte apoptosis and hypertrophy. The in vitro effects of SCII are further confirmed in vivo. In a rat model of OA, SCII increases the ratio of M2 macrophages, elevates the levels of pro-chondrogenic cytokines (TGF-ß1 and TGF-ß3) in synovial fluid, and inhibits chondrocyte apoptosis and MMP13 production. Our findings show that SCII immunomodulates M2 activation of macrophages to skew the local OA microenvironment towards a pro-chondrogenic atmosphere, and promotes cartilage repair under inflammatory condition. It shows great potential for SCII to be a novel biomaterial for cartilage repair in OA.

Dual-Functional Dendritic Mesoporous Bioactive Glass Nanospheres for Calcium Influx-Mediated Specific Tumor Suppression and Controlled Drug Delivery in Vivo.

The development of nanomaterials for stable, controlled delivery of drugs and efficient suppression of tumor growth with desirable biosafety remains challenging in the nano-biomedical field. In this study, we prepared and optimized mesoporous bioactive glass (MBG) nanospheres to establish a functional drug delivery system and analyzed the effect of the dendritic mesoporous structure on drug loading and release. We then utilized an in vitro model to examine the biological effects of dendritic MBG nanospheres on normal and tumor cells and studied the molecular mechanism underlying specific tumor suppression by MBG nanospheres. Finally, we investigated the combinational effect of MBG nanospheres and a cancer therapeutic drug with an in vivo tumor xenograft model. Our results show that the dendritic MBG nanospheres have been successfully synthesized by optimizing calcium: silicon ratio. MBG nanospheres exhibit a dendritic mesoporous structure with a large specific surface area, demonstrate high drug loading efficiency, and release drugs in a controlled fashion to effectively prolong drug half-life. Ca2+ in nanospheres activates transient receptor potential channels and calcium-sensing receptor on tumor cells, mediates calcium influx, and directly regulates the calpain-1-Bcl-2-caspase-3 signaling pathway to specifically suppress tumor growth without affecting normal cells. In addition, dendritic MBG nanospheres synergize with cancer drugs to improve antitumor efficacy and reduce systemic toxicity. Dendritic MBG nanospheres with antitumor activity and controlled drug release have been successfully achieved and the underlying molecular mechanism was elucidated, paving the way for translational application.

Functional reconstruction of critical-sized load-bearing bone defects using a Sclerostin-targeting miR-210-3p-based construct to enhance osteogenic activity.

A considerable amount of research has focused on improving regenerative therapy strategies for repairing defects in load-bearing bones. The enhancement of tissue regeneration with microRNAs (miRNAs) is being developed because miRNAs can simultaneously regulate multiple signaling pathways in an endogenous manner. In this study, we developed a miR-210-based bone repair strategy. We identified a miRNA (miR-210-3p) that can simultaneously up-regulate the expression of multiple key osteogenic genes in vitro. This process resulted in enhanced bone formation in a subcutaneous mouse model with a miR-210-3p/poly-l-lactic acid (PLLA)/bone marrow-derived stem cell (BMSC) construct. Furthermore, we constructed a model of critical-sized load-bearing bone defects and implanted a miR-210-3p/ß-tricalcium phosphate (ß-TCP)/bone mesenchymal stem cell (BMSC) construct into the defect. We found that the load-bearing defect was almost fully repaired using the miR-210-3p construct. We also identified a new mechanism by which miR-210-3p regulates Sclerostin protein levels. This miRNA-based strategy may yield novel therapeutic methods for the treatment of regenerative defects in vital load-bearing bones by utilizing miRNA therapy for tissue engineering. STATEMENT OF SIGNIFICANCE: The destroyed maxillofacial bone reconstruction is still a real challenge for maxillofacial surgeon, due to that functional bone reconstruction involved load-bearing. Base on the above problem, this paper developed a novel miR-210-3p/ß-tricalcium phosphate (TCP)/bone marrow-derived stem cell (BMSC) construct (miR-210-3p/ß-TCP/BMSCs), which lead to functional reconstruction of critical-size mandible bone defect. We found that the load-bearing defect was almost fully repaired using the miR-210-3p construct. In addition, we also found the mechanism of how the delivered microRNA activated the signaling pathways of endogenous stem cells, leading to the defect regeneration. This miRNA-based strategy can be used to regenerate defects in vital load-bearing bones, thus addressing a critical challenge in regenerative medicine by utilizing miRNA therapy for tissue engineering.

Development of fish collagen/bioactive glass/chitosan composite nanofibers as a GTR/GBR membrane for inducing periodontal tissue regeneration.

The development of a guided tissue or bone regeneration (GTR/GBR) membrane with excellent performance has been a major challenge in the biomedical field. The present study was designed to prepare a biomimetic electrospun fish collagen/bioactive glass/chitosan (Col/BG/CS) composite nanofiber membrane and determine its structure, mechanical property, antibacterial activity, and biological effects on human periodontal ligament cells (HPDLCs). The effects of this composite membrane on inducing periodontal tissue regeneration were evaluated using a dog class II furcation defect model. It was found that the composite membrane had a biomimetic structure with good hydrophilicity (the contact angle was 12.83 ± 3°) and a tensile strength of 13.1 ± 0.43 Mpa. Compared to the pure fish collagen membrane, the composite membrane showed some degree of antibacterial activity on Streptococcus mutans. The composite membrane not only enhanced the cell viability and osteogenic gene expression of the HPDLCs, but also promoted the expression of RUNX-2 and OPN protein. Further animal experiments confirmed that the composite membrane was able to promote bone regeneration in the furcation defect of dogs. In conclusion, a biomimetic fish Col/BG/CS composite membrane has been developed in the present study, which can induce tissue regeneration with a certain degree antibacterial activity, providing a basis for potential application as a GTR/GBR membrane.

Multifunctional and biomimetic fish collagen/bioactive glass nanofibers: fabrication, antibacterial activity and inducing skin regeneration in vitro and in vivo.

The development of skin wound dressings with excellent properties has always been an important challenge in the field of biomedicine. In this study, biomimetic electrospun fish collagen/bioactive glass (Col/BG) nanofibers were prepared. Their structure, tensile strength, antibacterial activity and biological effects on human keratinocytes, human dermal fibroblasts and human vascular endothelial cells were investigated. Furthermore, the Sprague Dawley rat skin defect model was used to validate their effect on wound healing. The results showed that compared with pure fish collagen nanofibers, the tensile strength of the Col/BG nanofibers increased to 21.87±0.21 Mpa, with a certain degree of antibacterial activity against Staphylococcus aureus. It was also found that the Col/BG nanofibers promoted the adhesion, proliferation and migration of human keratinocytes. Col/BG nanofibers induced the secretion of type one collagen and vascular endothelial growth factor by human dermal fibroblasts, which further stimulated the proliferation of human vascular endothelial cells. Animal experimentation indicated that the Col/BG nanofibers could accelerate rat skin wound healing. This study developed a type of multifunctional and biomimetic fish Col/BG nanofibers, which had the ability to induce skin regeneration with adequate tensile strength and antibacterial activity. The Col/BG nanofibers are also easily available and inexpensive, providing the possibility for using as a functional skin wound dressing.

Blood-brain barrier dysfunction induced by silica NPs in vitro and in vivo: Involvement of oxidative stress and Rho-kinase/JNK signaling pathways.

Silica nanoparticles (SiO2-NPs) has been extensively exploited in biomedical fields and mostly designed to enter the circulatory system, however, few studies focused on the potential adverse effects of SiO2-NPs exposure on the blood-brain barrier (BBB) that serves as a critical barrier between the central nervous system (CNS) and the peripheral circulation. This study attempts to provide an understanding of whether and how SiO2-NPs disrupts the BBB in vitro and in vivo. Through a human BBB model, we found that SiO2-NPs could induce tight junction loss and cytoskeleton arrangement, and increase inflammatory response and the release of vascular endothelial growth factor (VEGF) of brain microvessel endothelial cells (BMECs), which further activates astrocytes to amplify the generation of VEGF and increase the aquaporin-4 expression, and thus causing BBB disruption through a complex immunoregulatory loop between BMECs and astrocytes under SiO2-NPs exposure. Additionally, our data show that inhibition of reactive oxygen species (ROS) and Rho-kinase (ROCK) could effectively protect the SiO2-NPs-induced BBB dysfunction. In vivo studies further confirmed that SiO2-NPs could cause the BBB paracellular opening, oxidative stress and astrocyte activation in brains of Sprague-Dawley (SD) rats. These findings demonstrate that SiO2-NPs could disturb BBB structure and function and induce BBB inflammation, and suggest that these effects may occur through ROS and ROCK-mediated pathways, which not only improve neurotoxicity evaluation for SiO2-NPs but also provide useful information in development of SiO2-NPs in neuro-therapeutics and nanodiagnostics.

Size- and shape-dependent effects of titanium dioxide nanoparticles on the permeabilization of the blood-brain barrier.

Titanium dioxide nanoparticles (TiO2-NPs) have been found to translocate into the brain by penetrating the blood-brain barrier (BBB), but it remains largely unknown how their physicochemical characteristics may impact BBB permeabilization. By testing TiO2 particles of different shapes and various sizes, we found that: (1) small, spherical TiO2-NPs permeabilized a BBB-like human brain microvasculature endothelial cell monolayer better than rod-like or large particles; (2) TiO2-NPs stimulated F-actin stress fiber formation, and induced paracellular gaps and ROCK II activation. The TiO2-NP-mediated BBB permeabilization was associated with intracellular uptake and cytoskeletal re-organization; and (3) in rats, spherical, small TiO2-NPs significantly increased the BBB permeability and entered the brain. The TiO2-NPs were accumulated in the brain, but no obvious pathological anomaly was observed in the cerebral cortex and hippocampus. Our study investigated the neurotoxicity of TiO2-NPs, thereby providing scientific evaluation for the potential biomedical applications of TiO2-NPs.