Controlling the Interaction of Nanoparticles with Cell Membranes by the Polymeric Tether.

The well control over the cell-nanoparticle interaction can be of great importance and necessity for different biomedical applications. In this work, we propose a new and simple way (i.e., polymeric tether) to tuning the interaction between nanoparticles and cell membranes by dissipative particle dynamics simulations. It is found that the linked nanoparticles (via polymeric tether) can show some cooperation during the cellular uptake and thereby have a higher wrapping degree than the single nanoparticle. The effect of the property of the polymer on the wrapping is also investigated, and it is found that the length, rigidity, and hydrophobicity of the polymer play an important role. More interestingly, the uptake of linked nanoparticles could be adjusted to the firm adhesion via two rigid polymeric tethers. The present study may provide some useful guidelines for novel design of functional nanomaterials in the experiments.

Coal-burning endemic fluorosis is associated with reduced activity in antioxidative enzymes and Cu/Zn-SOD gene expression.

To study the effect of fluorine on the oxidative stress in coal-burning fluorosis, we investigated the environmental characteristics of coal-burning endemic fluorosis combined with fluorine content surveillance in air, water, food, briquette, and clay binder samples from Bijie region, Guizhou Province, southwest of China. The activities of antioxidant enzymes including copper/zinc superoxide dismutase (Cu/Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and level of lipid peroxidation such as malondialdehyde (MDA) were measured in serum samples obtained from subjects residing in the Bijie region. Expression of the Cu/Zn-SOD gene was assessed by quantitative reverse transcriptase PCR (qRT-PCR). Our results showed that people suffering from endemic fluorosis (the high and low exposure groups) had much higher MDA level. Their antioxidant enzyme activities and Cu/Zn-SOD gene expression levels were lower when compared to healthy people (the control group). Fluorosis can decrease the activities of antioxidant enzymes, which was associated with exposure level of fluorine. Down-regulation of Cu/Zn-SOD expression may play an important role in the aggravation of oxidative stress in endemic fluorosis.

In Situ Rapid-Formation Sprayable Hydrogels for Challenging Tissue Injury Management.

Rapid-acting, convenient, and broadly applicable medical materials are in high demand for the treatment of extensive and intricate tissue injuries in extremely medical scarcity environment, such as battlefields, wilderness, and traffic accidents. Conventional biomaterials fail to meet all the high criteria simultaneously for emergency management. Here, a multifunctional hydrogel system capable of rapid gelation and in situ spraying, addressing clinical challenges related to hemostasis, barrier establishment, support, and subsequent therapeutic treatment of irregular, complex, and urgent injured tissues, is designed. This hydrogel can be fast formed in less than 0.5 s under ultraviolet initiation. The precursor maintains an impressively low viscosity of 0.018 Pa s, while the hydrogel demonstrates a storage modulus of 0.65 MPa, achieving the delicate balance between sprayable fluidity and the mechanical strength requirements in practice, allowing flexible customization of the hydrogel system for differentiated handling and treatment of various tissues. Notably, the interactions between the component of this hydrogel and the cell surface protein confer upon its inherently bioactive functionalities such as osteogenesis, anti-inflammation, and angiogenesis. This research endeavors to provide new insights and designs into emergency management and complex tissue injuries treatment.

Construction of highly ductile, UV-shielding polylactide/poly(butylene adipate-co-terephthalate) biocomposites with hyperbranched polysiloxane functionalized lignin as a biocompatibilizer.

Biodegradable polylactide/poly(butylene adipate-co-terephthalate) (PLA/PBAT) blends have been widely utilized as packaging materials. However, it is urgent to develop a biocompatibilizer to improve the interfacial interaction of the biodegradable immiscible polymer blends in practice. In this paper, a novel type of hyperbranched polysiloxane (HBPSi) with terminal methoxy groups was synthesized and then utilized to functionalize lignin through a hydrosilation reaction. The HBPSi modified lignin (lignin@HBPSi) was incorporated into immiscible PLA/PBAT blends to serve as a biocompatibilizer. The lignin@HBPSi was uniformly dispersed in the PLA/PBAT matrix with improved interfacial compatibility. Dynamic rheological results revealed that the addition of lignin@HBPSi reduced the complex viscosity, improving the processing ability of the PLA/PBAT composite. The PLA/PBAT composite containing 5 wt% lignin@HBPSi had a superior toughness with an elongation at break of 300.2 % and a slight enhancement in tensile stress (34.47 MPa). In addition, the presence of lignin@HBPSi contributed to blocking ultraviolet rays in the full ultraviolet band. This work provides a feasible way to develop highly ductile PLA/PBAT/lignin composites with good UV-shielding properties for the packaging applications.

A Patient-Ready Wearable Transcutaneous CO2 Sensor.

Continuously monitoring transcutaneous CO2 partial pressure is of crucial importance in the diagnosis and treatment of respiratory and cardiac diseases. Despite significant progress in the development of CO2 sensors, their implementation as portable or wearable devices for real-time monitoring remains under-explored. Here, we report on the creation of a wearable prototype device for transcutaneous CO2 monitoring based on quantifying the fluorescence of a highly breathable CO2-sensing film. The developed materials are based on a fluorescent pH indicator (8-hydroxy-1,3,6-pyrenetrisulfonic acid trisodium salt or HPTS) embedded into hydrophobic polymer matrices. The film's fluorescence is highly sensitive to changes in CO2 partial pressure in the physiological range, as well as photostable and insensitive to humidity. The device and medical-grade films are based on our prior work on transcutaneous oxygen-sensing technology, which has been extensively validated clinically.

Copper Doped Carbon Dots for Addressing Bacterial Biofilm Formation, Wound Infection, and Tooth Staining.

Oral infectious diseases and tooth staining, the main challenges of dental healthcare, are inextricably linked to microbial colonization and the formation of pathogenic biofilms. However, dentistry has so far still lacked simple, safe, and universal prophylactic options and therapy. Here, we report copper-doped carbon dots (Cu-CDs) that display enhanced catalytic (catalase-like, peroxidase-like) activity in the oral environment for inhibiting initial bacteria (Streptococcus mutans) adhesion and for subsequent biofilm eradication without impacting the surrounding oral tissues via oxygen (O2) and reactive oxygen species (ROS) generation. Especially, Cu-CDs exhibit strong affinity for lipopolysaccharides (LPS) and peptidoglycans (PGN), thus conferring them with excellent antibacterial ability against Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli), such that they can prevent wound purulent infection and promoting rapid wound healing. Additionally, the Cu-CDs/H2O2 system shows a better performance in tooth whitening, compared with results obtained with other alternatives, e.g., CDs and clinically used H2O2, particularly its negligible enamel and dentin destruction. It is anticipated that the biocompatible Cu-CDs presented in this work are a promising nano-mouthwash for eliminating oral pathogenic biofilms, prompting wound healing as well as tooth whitening, highlighting their significance in oral health management.

Au@Ag Nanorods-PDMS Wearable Mouthguard as a Visualized Detection Platform for Screening Dental Caries and Periodontal Diseases.

The development of easy-to-use, low-cost, and visualized detection platforms for screening human dental caries and periodontal diseases is in urgent demand. In this work, a Au@Ag nanorods-poly(dimethylsiloxane) (Au@Ag NRs-PDMS) wearable mouthguard, which can visualize the tooth lesion sites through the color change of it at the corresponding locations, is presented. The Au@Ag NRs-PDMS composite exhibits a distinct color response to hydrogen sulfide (H2 S) gas generated by bacterial decay at the lesion sites. Moreover, the Au@Ag NRs-PDMS mouthguard is demonstrated to own desired mechanical properties, excellent chemical stability, as well as good biocompatibility, and can accurately locate the lesion sites in human oral cavity. These findings suggest that the mouthguard has the potential to be utilized on a large scale to help people self-monitor their oral health in daily life, and treat oral diseases locally.

Antitumoral efficacy by systemic delivery of heparin conjugated polyethylenimine-plasmid interleukin-15 complexes in murine models of lung metastasis.

Gene therapy shows promising application in cancer therapy, but the lack of an ideal gene delivery system is still a tough challenge for cancer gene therapy. Previously, we prepared a novel cationic nanogel, heparin-polyethylenimine (HPEI), which had potential application in gene delivery. In the present study, we constructed a plasmid with high expression efficiency of interleukin-15 (IL15) and investigated the effects HPEI-plasmid IL15 (HPEI-pIL15) complexes on the distribution level of the lung. We then evaluated the anticancer effect of HPEI-pIL15 complexes on lung metastases of B16-F10 melanoma and CT26 colon carcinoma. These results demonstrated that intravenous injection of the HPEI-pIL15 complex exhibited the highest plasmid distribution level in the lung compared with that of PEI2K-pIL15 and PEI25K-pIL15, and mice treated with HPEI-pIL15 had a lower tumor metastasis index compared with other treatment groups. Moreover, the number of natural killer cells, which were intermingled among the tumor cells, and the level of tumor necrosis factor-α and interferon-γ in the serum also increased in the pIL15-treated mice. Furthermore, the cytotoxic activity of spleen cells also increased significantly in the HPEI-pIL15 group. In addition, induction of apoptosis and inhibition of cell proliferation in lung tumor foci in the HPEI-pIL15 group was observed. Taken together, treating lung metastasis cancer with the HPEI nanogels delivered by plasmid IL15 might be a new and interesting cancer gene therapy protocol.

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.

Humidity-Insensitive Tissue Oxygen Tension Sensing for Wearable Devices†.

Quantification of tissue oxygen partial pressure (pO2 ) at the skin surface is crucial for diagnostic applications in burns, reconstructive surgeries, diabetic ulcers, etc. Further, current advances in wearable and communications technologies have widened the use of transcutaneous oxygen monitors (TCOM) for home care or even enhance athletic performance. For TCOM technology to find widespread use, devices must function reliably yet independently of changes in environmental conditions, humidity in particular. To this end, we have explored the incorporation of an oxygen-sensing metalloporphyrin within different host matrix materials of different compositions with the goal of overcoming the humidity sensitivity of previously explored oxygen-sensing materials. We developed a tetraethyl orthosilicate (TEOS)-based, highly breathable, oxygen-sensing metalloporphyrin polymer film which responds to changes in oxygenation independent of humidity.

Superelastic and superhydrophobic bacterial cellulose/silica aerogels with hierarchical cellular structure for oil absorption and recovery.

Bacterial cellulose aerogels/silica aerogels (BCAs/SAs) are prepared using three-dimensional self-assembled BC skeleton as reinforcement and methyltriethoxysilane derived silica aerogels as filler through vacuum infiltration and freeze drying. The BCAs/SAs possess a hierarchical cellular structure giving them superelasticity and recyclable compressibility. The BCAs/SAs can bear a compressive strain up to 80% and recover their original shapes after the release of the stress. The BCAs/SAs exhibit super-hydrophobicity with a contact angle of 152° and super-oleophilicity resulting from the methyl groups on the surface of silica aerogel filler. This endows the BCAs/SAs outstanding oil absorbing capability with the quality factor Q from 8 to 14 for organic solvents and oils. Moreover, the absorbed oil can be retrieved by mechanically squeezed with a recovery of 88% related to the superelastic ability of the composites. In addition, the oil absorbing of BS/SAs could be well maintained with the quality factor Q about 11 for gasoline after harsh conditional treatment down to -200 °C and up to 300 °C. Such outstanding elastic and oleophilic properties make the BC/SAs tremendous potential for applications of oil absorbing, recovery and oil-water separation.

Calcium and phosphate ions as simple signaling molecules with versatile osteoinductivity.

Due to the continually increasing clinical need to heal large bone defects, synthetic bone graft substitutes have become ever more necessary with calcium phosphates (CaP) widely used due to their similarity to the mineral component of bone. In this research, different concentrations of calcium ions (Ca2+), phosphate ions (Pi), or their combination were provided to mesenchymal stem cells (MSCs) to evaluate their influence on proliferation and differentiation. The results suggest that 1-16 mM Ca2+ and 1-8 mM Pi is osteoinductive, but not cytotoxic. Furthermore, three distinct calcium phosphates (i.e. monobasic, dibasic, and hydroxyapatite) with different dissolution rates were investigated for their Ca2+ and Pi release. These biomaterials were then adjusted to release ion concentrations within the established therapeutics window for which MSC bioactivity was assessed. These findings suggest that CaP-based biomaterials can be leveraged to achieve Ca2+ and Pi dose-dependent osteoinduction for bone regenerative engineering applications.

Two Genotypes of Coxsackievirus A2 Associated with Hand, Foot, and Mouth Disease Circulating in China since 2008.

Coxsackievirus A2 (CV-A2) has been frequently detected and commonly associated with hand, foot, and mouth disease (HFMD) in China since 2008. However, limited sequences of CV-A2 are currently available. As a result, we have been focusing on the genetic characteristics of CV-A2 in the mainland of China during 2008-2015 based on national HFMD surveillance. In this study, 20 CV-A2 strains were isolated and phylogenetic analyses of the VP1 sequences were performed. Full-length genome sequences of two representative CV-A2 isolates were acquired and similarity plot and bootscanning analyses were performed. The phylogenetic dendrogram indicated that all CV-A2 strains could be divided into four genotypes (Genotypes A-D). The CV-A2 prototype strain (Fleetwood) was the sole member of genotype A. From 2008 to 2015, the CV-A2 strains isolated in China dispersed into two different genotypes (B and D). And the genotype D became the dominant circulating strains in China. Strains isolated in Russia and India from 2005 to 2011 converged into genotype C. Intertypic recombination occurred between the Chinese CV-A2 strains and other enterovirus-A donor sequences. This result reconfirmed that recombination is a common phenomenon among enteroviruses. This study helps expand the numbers of whole virus genome sequence and entire VP1 sequence of CV-A2 in the GenBank database for further researcher.

[Epidemiological features and pathogenic characteristics of hand, foot and mouth disease in Gansu Province, China during 2008-2012].

This study aims to analyze the epidemiological features and pathogenic characteristics of hand, foot and mouth disease (HFMD) in Gansu Province, China and to provide a basis for the development of effective prevention and control measures. The descriptive epidemiological analysis was used to analyse the data of HFMD cases in Gansu. The specimens collected from hospitals were subjected to RT-PCR or real-time PCR to detect human enterovirus (HEV) nucleic acid, and HEV strains were isolated using human rhabdomyosarcoma cells and human laryngeal carcinoma cells. The complete VP1-encoding region of several identified enterovirus A71 (EV71) and coxsackievirus A16 (CVA16) was subjected to full-length amplification by RT-PCR and then to sequencing and analysis. A total of 52 550 HFMD cases were reported in Gansu from 2008 to 2012, including 205 severe cases and 27 deaths. The incidence rates in the whole province from 2008 to 2012 were 22.42/10(5), 49.29/10(5), 47.20/10(5), 27.27/10(5), and 55.84/10(5), respectively. There were cases in all the 14 cities or prefectures in Gansu, and Lanzhou had the largest number of cases (16 001 cases), accounting for 30.45% of all cases in the province. HFMD cases were mostly reported during May to July, accounting for 51.69% of all cases throughout the year. The male-to-female ratio was 1.69:1. Of all the cases, 87.59% were under the age of five. Of the 5 416 cases for laboratory tests, 3 322 (61.34%) were positive for HEV nucleic acid, including EV71 (46.96%), CVA16 (41.57%), and other HEVs (11.47%). Among the 186 severe cases, 114 (61.29%) were positive for HEV nucleic acid, and 82.46% of the positive cases for EV71. All the 25 dead cases were infected with EV71. A total of 402 strains were isolated from 3 111 specimens collected from hospitals (2 123 throat swab specimens, 705 stool specimens, and 705 herpes specimens), including EV71 (70.15%), CVA16 (27.11), other coxsackievirus A (3.98%), coxsackievirus B (2.49%), echovirus (1.74%), and adenovirus (1.99%). The genotyping of VP1- encoding region showed that all the 194 EV71 strains isolated during 2008-2012 belonged to the C4a evolutionary branch of C4 subtype; among the 45 CVA16 strains, 12 belonged to the Bla evolutionary branch of B1 subtype and 33 to the B1b evolutionary branch, and B1b became the predominant subtype in 2012. In conclusion, in Gansu Province, HFMD occurs mostly in children under the age of five; EV71 and CVA16 are the main pathogens of this disease, and the two are predominant alternately from 2008 to 2012; the severe and dead cases of HFMD are closely related to infection with EV71; the types of pathogens varied across different regions in the same year during 2008-2012.

[Epidemiology of hand, foot, and mouth disease and genetic characterization of enterovirus A71: a survey from 2007 to 2012 in Linyi of Shandong Province, China].

To investigate the epidemiology of hand, foot, and mouth disease (HFMD) and the genetic characteristics of enterovirus A71 (EV-A71) in Linyi of Shandong Province, China during 2007-2012. The number of reported HFMD cases were obtained from the National Notifiable Disease Reporting System (NNDRS) were analyzed by descriptive epidemiology method; the VP1 region of EV-A71 isolated from HFMD patients in Linyi was amplified and sequenced. Finally, the genetic variability and phylogenecity of VP1 sequences of EV-A71 were analyzed by MEGA 5.0. The results showed that HFMD incidence was reported in each year from 2007 to 2012 in Linyi, and the highest incidence and mortality were reported in 2009, when there were total 14697 cases and 9 of death. The reported incidence was 140.28/100000, and the mortality was 0.086/100000. The peak incidence usually occurred between April and July, and the summit occurred in May. Scattered children accounted for 77.37%-92.00% of all cases. The peak age was 2.5 years during 2007-2009 and 1.5 years during 2010-2012. A total of 1365 laboratory-confirmed HFMD cases were reported in the 6 consecutive years, accounting for 2.98% of the gross number. Among these reports, the ratio of EV-A71 was 44.18%, and the ratio of coxsackievirus A16 (CVA16) was 46.59%. All EV-A71 strains isolated in Linyi during 2007-2012 belonged to the C4a evolutionary branch of C4 genotype. In conclusion, HFMD outbreaks occurred every year in Linyi during 2007-2012. Incidence varied significantly among different counties. The peak incidence in each year lasted from April to July. Most of the patients were children under 3 years of age, and scattered children took the highest proportion. Co-circulation of EV-A71 and CVA16 was the major cause of HFMD in each year. Since the first report of HFMD prevalence caused by EV-A71 (C4a) in 2007, the virus has been prevalent continuously in Linyi for 6 years.

[Rash and fever illness caused by herpes simplex virus type 1 needs to be distinguished from hand, foot and mouth disease].

An epidemic of rash and fever illnesses suspected of hand, foot and mouth disease (HFMD) occurred in Gansu Province of China in 2008, laboratory tests were performed in order to identify the pathogen that caused this epidemic. Eight clinical specimens collected from the 4 patients (each patient has throat swab and herpes fluid specimens) with rash and febrile illness, were inoculated onto RD and HEp-2 cells for virus isolation, and the viral nucleic acid was then extracted with the positive virus isolates, the dual-channel real-time reverse transcript-polymerase chain reaction (RT-PCR) was performed to detect the nucleic acid of human enterovirus (HEV) in the viral isolates at the same time. For the viral isolates with the negative results of HEV, a sequence independent single primer amplification technique (SISPA) was used for "unknown pathogen" identification. Totally, 6 viral isolates were identified as herpes simplex virus type 1 (HSV-1). Comprehensive analyses results of the clinical manifestations of the patients, epidemiological findings and laboratory test indicated that this epidemic of rash and febrile illness was caused by HSV-1. The differences among the gG region of 6 HSV-1 isolates at nucleotide level and amino acid level were all small, and the identities were up to 98. 8% and 97.9%, respectively, showing that this outbreak was caused by only one viral transmission chain of HSV-1. HSV-1 and other viruses that cause rash and febrile illnesses need differential diagnosis with HFMD. The etiology of rash and febrile illness is sometimes difficult to distinguish from the clinical symptoms and epidemiological data, the laboratory diagnosis is therefore critical.