Hierarchical Assembly of Flexible Biopolymer Polyphosphate-Manganese into Nanosheets.

Polyphosphate (polyP) is one of the most compact inorganic polyanionic biopolymers that participates in various physiological processes. However, the development of polyP-based nanomaterials is still in its infancy. Here, biocompatible polyphosphate-manganese nanosheets are designed and synthesized by a hierarchical assembly strategy. The thickness and the lateral size of the resulting polyP-Mn nanosheets (PMNSs) are 5 nm and 120-130 nm, respectively. Molecular dynamics simulations suggested that the polyP-hexadecyl trimethyl ammonium bromide flat structure possesses a strong aggregating capacity and serves as the template for the 2D assembly of polyP-Mn. The PMNSs can activate the inflammatory response of macrophages resulting in the recovery of innate immunological functions to inhibit tumor proliferation. This work has initiated a new direction in constructing layered polyP-based nanomaterials and provides guidance for biocompatible and biodegradable biopolymer-based materials in the regulation of innate responses.

Tumor polyamines as guest cues attract host-functionalized liposomes for targeting and hunting via a bio-orthogonal supramolecular strategy.

Inspired by the attractions of fruit flies to polyamines of rotten food, we developed a facile, bio-orthogonal, supramolecular homing and hunting strategy, relying on the elevated levels of polyamines in tumor as the natural guest cues to attract cucurbit [7] uril (CB[7]) functionalized liposomes to the tumor site, owing to the strong, bio-orthogonal host-guest interactions between CB[7] and polyamines. This supramolecular homing enabled a high targeting efficiency of CB[7] functionalized liposomes, and allowed better tissue penetration and retention in breast tumor. The employment of a receptor functionalized nanomedicine for direct tropism towards endogenous biomarkers as guest cues, reminiscent of natural chemotaxis but in a bio-orthogonal manner, has not been previously reported, offering new sights to the design and development of new nanoformulations that rely on bio-orthogonal interactions for chemotaxis-guided targeting.

Cryo-Shocked Platelet Coupled with ROS-Responsive Nanomedicine for Targeted Treatment of Thromboembolic Disease.

Thrombolysis with tissue plasminogen activator (tPA) provides the most common therapy for ischemic stroke onset within the past 4.5 h. However, enhanced neutrophil infiltration and secondary blood-brain barrier injury caused by tPA administration have limited its therapeutic application, and tPA treatment is often accompanied by hemorrhagic transformation. To overcome the limitations of thrombolysis by tPA, maximize the therapeutic efficacy, and improve the safety, herein, we report a cryo-shocked platelet-based cell-hitchhiking drug delivery system, which consists of cryo-shocked platelet (CsPLT) and reactive oxygen species (ROS)-responsive liposomes loaded with thrombolytic tPA and anti-inflammation drug aspirin (ASA). CsPLT and liposomes were facilely conjugated via host-guest interactions. Under the guidance of CsPLT, it selectively accumulated in the thrombus site and quickly released the therapeutic payloads in response to the high ROS. tPA subsequently exhibited localized thrombolytic activity to suppress the expansion of thrombus, while ASA assisted in the inactivation of reactive astrogliosis, microglial/macrophage, and obstruction of neutrophil infiltration. This cryo-shocked platelet-hitchhiking tPA/ASA delivery system not only improves the thrombus-targeting efficiency of the two drugs for highly localized thrombolytic effects and anti-inflammation actions and platelets inactivation but also provides insights to the development of targeted drug delivery systems for thromboembolic disease treatment.

Research on the electrochemistry synergied cellulase enzymes strengthens the anaerobic fermentation of cow dung.

Lignocellulose degradation (LCD) was the key factor limiting the development of anaerobic fermentation (AF) by the cow dung (CD). In the research, the effects of cellulase pretreatment (CP) and microvoltage (MV) alone and combination on the gas production and LCD during the AF were investigated. The results showed that both CP and MV had an significant effect on the AF, though the synergistic reaction was more pronounced. The total biogas yield (TBY) could reach 11521 mL, and the highest methane production rate was 73% in the synergistic reactions, which was increased by 18.7% and 10.0% compared to CP and MV alone respectively. Meanwhile, the degradation rates of cellulose and lignin could be increased by 33.44% and 22.23%, respectively. The results of SEM, FT-IR and excitation emission matrix demonstrated that CP and MV played an important role in improving the fermentation efficiency. The microbial biomass change results indicated that the synergistic effect of CP and 0.8 V MV on the LCD was achieved by promoting the growth of lignocellulose-degrading bacteria. Moreover, the electricity could not only accelerate the movement of microorganisms and enzymes, but also promoted and enhanced the activity of enzymes, which provided an important reference for further development of the AF technology and the biogas industry.

Supramolecular erythrocytes-hitchhiking drug delivery system for specific therapy of acute pneumonia.

Acute pneumonia is an inflammatory syndrome often associated with severe multi-organ dysfunction and high mortality. The therapeutic efficacy of current anti-inflammatory medicines is greatly limited due to the short systemic circulation and poor specificity in the lungs. New drug delivery systems (DDS) are urgently needed to efficiently transport anti-inflammatory drugs to the lungs. Here, we report an inflammation-responsive supramolecular erythrocytes-hitchhiking DDS to extend systemic circulation of the nanomedicine via hitchhiking red blood cells (RBCs) and specifically "drop off" the payloads in the inflammatory lungs. ß-cyclodextrin (ß-CD) modified RBCs and ferrocene (Fc) modified liposomes (NP) were prepared and co-incubated to attach NP to RBCs via ß-CD/Fc host-guest interactions. RBCs extended the systemic circulation of the attached NP, meanwhile, the NP may get detached from RBCs due to the high ROS level in the inflammatory lungs. In acute pneumonia mice, this strategy delivered curcumin specifically to the lungs and effectively alleviated the inflammatory syndrome.

Hydrophilic graphene oxide-dopamine-cationic cellulose composites and their applications in N-Glycopeptides enrichment.

Glycosylation is one of the most important post-translational modifications of proteins, and plays an important role in the structure and function of proteins. However, due to the diversity of glycopeptide forms and their low abundance, it is extraordinarily challenging to capture and separate glycopeptides with high selectivity from complex biological samples with mass spectrometric analysis. Here, we synthesized a new type of hydrophilic composite based on electrostatic interactions, which has been proven to be effective in immobilizing cationic cellulose on graphene oxide-dopamine carriers (expressed as GO-DA-JR), for highly specific enrichment of N-glycopeptides. The introduction of cationic cellulose provides not only a perfect surface charge for the composite but also a greater ability to enrich glycosylated peptides. Thirty-two glycopeptides from human serum immunoglobulin G (IgG) tryptic digests were observed with a greatly improved signal-to-noise ratio (S/N) and also presented high performance in anti-interfering enrichment of glycopeptides from complex samples containing 100-fold bovine serum albumin tryptic digests. In addition, GO-DA-JR has higher sensitivity (1 fmol/µL IgG) and better enrichment capacity (up to 150 mg/g). Moreover, the results of glycopeptide enrichment and glycosylation analysis from human serum also show egood enrichment selectivity from real biological samples. This work exhibits high selectivity, high sensitivity, good stability and operability, indicating its potential for applications of glycopeptides enrichment in post-translational modification proteomics.

Relationship between the morphological, mechanical and permeability properties of porous bone scaffolds and the underlying microstructure.

Bone scaffolds are widely used as one of the main bone substitute materials. However, many bone scaffold microstructure topologies exist and it is still unclear which topology to use when designing scaffold for a specific application. The aim of the present study was to reveal the mechanism of the microstructure-driven performance of bone scaffold and thus to provide guideline on scaffold design. Finite element (FE) models of five TPMS (Diamond, Gyroid, Schwarz P, Fischer-Koch S and F-RD) and three traditional (Cube, FD-Cube and Octa) scaffolds were generated. The effective compressive and shear moduli of scaffolds were calculated from the mechanical analysis using the FE unit cell models with the periodic boundary condition. The scaffold permeability was calculated from the computational fluid dynamics (CFD) analysis using the 4×4×4 FE models. It is revealed that the surface-to-volume ratio of the Fischer-Koch S-based scaffold is the highest among the scaffolds investigated. The mechanical analysis revealed that the bending deformation dominated structures (e.g., the Diamond, the Gyroid, the Schwarz P) have higher effective shear moduli. The stretching deformation dominated structures (e.g., the Schwarz P, the Cube) have higher effective compressive moduli. For all the scaffolds, when the same amount of change in scaffold porosity is made, the corresponding change in the scaffold relative shear modulus is larger than that in the relative compressive modulus. The CFD analysis revealed that the structures with the simple and straight pores (e.g., Cube) have higher permeability than the structures with the complex pores (e.g., Fischer-Koch S). The main contribution of the present study is that the relationship between scaffold properties and the underlying microstructure is systematically investigated and thus some guidelines on the design of bone scaffolds are provided, for example, in the scenario where a high surface-to-volume ratio is required, it is suggested to use the Fischer-Koch S based scaffold.

The contact mechanics and occurrence of edge loading in modular metal-on-polyethylene total hip replacement during daily activities.

The occurrence of edge loading in hip joint replacement has been associated with many factors such as prosthetic design, component malposition and activities of daily living. The present study aimed to quantify the occurrence of edge loading/contact at the articulating surface and to evaluate the effect of cup angles and edge loading on the contact mechanics of a modular metal-on-polyethylene (MoP) total hip replacement (THR) during different daily activities. A three-dimensional finite element model was developed based on a modular MoP bearing system. Different cup inclination and anteversion angles were modelled and six daily activities were considered. The results showed that edge loading was predicted during normal walking, ascending and descending stairs activities under steep cup inclination conditions (≥55°) while no edge loading was observed during standing up, sitting down and knee bending activities. The duration of edge loading increased with increased cup inclination angles and was affected by the cup anteversion angles. Edge loading caused elevated contact pressure at the articulating surface and substantially increased equivalent plastic strain of the polyethylene liner. The present study suggested that correct positioning the component to avoid edge loading that may occur during daily activities is important for MoP THR in clinical practice.

Efficacy of a combination of high and low dosage of PEGylated FGF-21 in treatment of diabetes in db/db mice.

The aim of this study is to explore a new method-high dose starting and low dose maintaining for PEGylated Fibroblast growth factor 21 (pFGF-21) treatment. Db/db mice were initially treated with pFGF-21 of high dose, then treated with pFGF-21 of low doses. The mice were treated with pFGF-21 at initial dose of 1.0mg/kg for 14days, then treated with pFGF-21 at maintenance doses of 0.125/0.250/0.375/0.500mg/kg for 30days. The hypoglycemic and hypolipidemic effects of pFGF-21 of different maintenance doses were compared. The pharmacological efficacy of the maintenance doses of pFGF-21 was evaluated by blood glucose levels, oral glucose tolerance test, glycosylated hemoglobin levels, insulin levels, body weight, lipid profile parameters, the mRNA expressions of glycolysis-related genes, the mRNA expressions of gluconeogenesis-related genes and the mRNA expressions of lipid metabolism-related genes. Results showed that in comparison to the mice treated only with initial dose, the treatment with pFGF-21 at maintenance doses of 0.125/0.250/0.375/0.500mg/kg exhibited favorable efficacy in lowering blood glucose levels and glycosylated hemoglobin levels, thus alleviating insulin resistance and improving dyslipidemia. However, among all of the maintenance doses, the dose of 0.125mg/kg was less effective than the other maintenance doses. These results suggest that using the treatment method of high dose of PEGylated FGF-21 in the start and low dose maintaining results in favorable control of the glycolipid metabolic balance. This study provides a new method for PEGylated FGF-21 treatment which is beneficial to promote the clinical application of PEGylated FGF-21.

[A study of using dexmedetomidine in ventilator bundle treatment in an ICU].

OBJECTIVE: To compare the sedative effect and safety of dexmedetomidine and midazolam in the intensive care unit (ICU) patients undergoing ventilator bundle treatment. METHODS: A prospective single-blind randomized controlled trial (RCT) was conducted. Ninety patients receiving ICU ventilator-assisted therapy and ventilator bundle treatments for more than 3 days in the First Department of Critical Care Medicine of the Second Hospital of Lanzhou University from January 2013 to December 2014 were enrolled. The patients were randomly divided into two groups for sedative treatment. The patients in dexmedetomidine group (n = 42) were given dexmedetomidine 0.2-0.7 µg x kg(-1) x h(-1) to achieve a goal of satisfactory sedation [Richmond agitation-sedation scale (RASS) score 0 to - 2 during the day, and -1 to -3 at night). The patients in midazolam group (n = 48) were given midazolam 2-3 mg intravenously first, and then 0.05 mg x kg(-1) x h(-1) for maintenance. The drug dose was adjusted according to RASS every 4 hours to maintain the appropriate sedation depth. The patients in both groups received continuous intravenous infusion of fentanyl for analgesia. Ventilator bundle treatments included the head of a bed up 30 degrees to 45 degrees, awaken and extubation appraisal, daily use of proton pump inhibitors for peptic ulcer prevention, prevention of deep vein thrombosis (DVT), chlorhexidine mouth nursing, and removal of sputum by suction from subglottic area. When the patients in both groups obtained satisfactory target sedation, daily awakening was conducted, and spontaneous breathing test (SBT) was carried out to determine optional weaning time. When the condition was optimal, weaning was conducted, otherwise ventilator bundle treatments were continued. The systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), respiratory frequency (RR) were monitored before and 15, 30, 60, 120, 180 minutes after the treatment, and at the moment of extubation and 30 minutes after extubation. The duration of mechanical ventilation, extubation time, length of ICU stay, and the incidence of adverse events were also recorded. RESULTS: Both dexmedetomidine and midazolam could give rise to sedation with same score of analgesia in patients in both groups, and similar effect of sedation and analgesia could be achieved. Compared with midazolam, dexmedetomidine could significantly reduce the duration of mechanical ventilation (hours: 108.33 ± 21.96 vs. 119.85 ± 20.29, t = -2.586, P = 0.011), earlier extubation time (hours: 112.95 ± 22.20 vs. 128.58 ± 26.18, = -3.031, P = 0.003), length of ICU stay (hours: 149.21 ± 20.47 vs. 163.88 ± 33.59, = -2.457, P = 0.016), the incidence of delirium [9.5% (4/42) vs. 31.2% (15/48 ), χ2 = 6.349, P = 0.012], but it would elevate the incidence of severe hypotension [28.6% (12/42) vs. 8.3% (4/48), χ2 = 6.277, P = 0.012] and severe bradycardia [19.0% (8/42) vs. 8.3% (4/48), χ2 = 2.225, P = 0.136]. Both drugs could lower SBP, DBP, MAP, and HR, and the effect in dexmedetomidine group was more significant from 60 minutes after treatment [SBP (mmHg, 1 mmHg = 0.133 kPa): 113.12 ± 14.42 vs. 124.40 ± 15.79, DBP (mmHg): 69.02 ± 9.62 vs. 76.94 ± 10.41, MAP (mmHg): 83.76 ± 10.50 vs. 92.77 ± 11.87, HR (bpm): 79.19 ± 12.28 vs. 87.42 ± 17.77, P < 0.05 or P < 0.01]. Both sedatives could significantly lower the rate of spontaneous breathing, and the effect of midazolam group was more significant from 60 minutes after treatment compared with dexmedetomidine group (times/min: 18.27 ± 4.29 vs. 20.07 ± 4.11, P < 0.05). CONCLUSIONS: The sedative effects of dexmedetomidine in the ICU patients treated with ventilator bundle treatment are satisfactory, and it can shorten the duration of mechanical ventilation, extubation time and length of ICU stay, reduce the incidence of delirium. However, monitoring should be strengthened in order to prevented and control the adverse effects such as severe hypotension and severe bradycardia.

The effect of cup outer sizes on the contact mechanics and cement fixation of cemented total hip replacements.

One important loosening mechanism of the cemented total hip arthroplasty is the mechanical overload at the bone-cement interface and consequent failure of the cement fixation. Clinical studies have revealed that the outer diameter of the acetabular component is a key factor in influencing aseptic loosening of the hip arthroplasty. The aim of the present study was to investigate the influence of the cup outer diameter on the contact mechanics and cement fixation of a cemented total hip replacement (THR) with different wear penetration depths and under different cup inclination angles using finite element (FE) method. A three-dimensional FE model was developed based on a typical Charnley hip prosthesis. Two acetabular cup designs with outer diameters of 40 and 43 mm were modelled and the effect of cup outer diameter, penetration depth and cup inclination angle on the contact mechanics and cement fixation stresses in the cemented THR were studied. The results showed that for all penetration depths and cup inclination angles considered, the contact mechanics in terms of peak von Mises stress in the acetabular cup and peak contact pressure at the bearing surface for the two cup designs were similar (within 5%). However, the peak von Mises stress, the peak maximum principal stress and peak shear stress in the cement mantle at the bone-cement interface for the 43 mm diameter cup design were predicted to be lower compared to those for the 40 mm diameter cup design. The differences were predicted to be 15-19%, 15-22% and 18-20% respectively for different cup penetration depths and inclination angles, which compares to the clinical difference of aseptic loosening incidence of about 20% between the two cup designs.

Contact mechanics of modular metal-on-polyethylene total hip replacement under adverse edge loading conditions.

Edge loading can negatively impact the biomechanics and long-term performance of hip replacements. Although edge loading has been widely investigated for hard-on-hard articulations, limited work has been conducted for hard-on-soft combinations. The aim of the present study was to investigate edge loading and its effect on the contact mechanics of a modular metal-on-polyethylene (MoP) total hip replacement (THR). A three-dimensional finite element model was developed based on a modular MoP bearing. Different cup inclination angles and head lateral microseparation were modelled and their effect on the contact mechanics of the modular MoP hip replacement were examined. The results showed that lateral microseparation caused loading of the head on the rim of the cup, which produced substantial increases in the maximum von Mises stress in the polyethylene liner and the maximum contact pressure on both the articulating surface and backside surface of the liner. Plastic deformation of the liner was observed under both standard conditions and microseparation conditions, however, the maximum equivalent plastic strain in the liner under microseparation conditions of 2000 µm was predicted to be approximately six times that under standard conditions. The study has indicated that correct positioning the components to avoid edge loading is likely to be important clinically even for hard-on-soft bearings for THR.

Synthesis of tethered poly(N-isopropylacrylamide) for detection of breast cancer recurrence DNA.

We have grafted temperature-responsive tethered poly(N-isopropylacrylamide) (PNIPAAm) onto silicon surfaces through atom transfer radical polymerization (ATRP) as a medium to extract human genomic DNA molecules from a biological specimen, namely human blood incorporating target DNA (hgDNA584) and control DNA (hgDNA528) at concentrations of 0.5, 1, and 50 ng µL(-1). The variable adhesion forces of the tethered PNIPAAm brushes on the surfaces were used to capture and release DNA molecules through changes in temperature. After amplifying the signal of the hgDNA584 and hgDNA528 strands released from the tethered PNIPAAm on the substrate using the polymerase chain reaction (PCR), we identified these DNA macromolecules using agarose gel electrophoresis. The accuracy of the detection of hgDNA584 and hgDNA528 was controlled through the design of specific primers in the PCR process. The quantities of these two DNA molecules obtained through the capture and release from tethered PNIPAAm brushes under temperature tuning conditions were sufficient for them to be amplified recognizably, suggesting that this approach could be used in miniaturized lab-on-a-chip cartridges for rapid disease diagnosis.