[Thoughts on the Biological Evaluation of Biodegradable Cardiovascular Implants].

In recent years, new degradable materials have been applied to cardiovascular implants. Cardiovascular implants with different physicochemical properties and degradation properties have special endpoints for their biological evaluation. In this study, the end points of biological evaluation of degradable cardiovascular implants were reviewed by taking vascular stents and occluders as examples.

When Dynamic Diselenide Bonds Meet Dynamic Imine Bonds in Polymeric Materials.

In both natural and artificial functional systems, the cooperation between different dynamic interactions is of vital importance for realizing complicated functions. Dynamic covalent bonds are one kind of relatively stable dynamic interactions and have shown synergistic effect in natural systems such as functional proteins. However, synergistic interactions between different dynamic covalent bonds in polymeric materials are still unclear. Herein, polymeric materials containing diselenide and imine bonds are prepared, and then the synergistic effect between the two dynamic covalent bonds is quantitatively evaluated in typical processes of dynamic materials. The results reveal that dynamic covalent bonds show weak synergistic effect in the degradation process and have strong synergistic effect in stress relaxation process. Therefore, introducing multiple dynamic covalent bonds in polymeric materials can extensively enhance their dynamic properties.

Cationic Conjugated Polyelectrolytes with Aggregation-Induced Ratiometric Fluorescence.

The molecular diversity of aggregation-induced emission remains a challenge due to the limitation of conventional synthesis methods. Here, a series of novel neutral and cationic conjugated polymers composed of various ratios of tetraarylethylene (TAE) containing a bridged oxygen (O) and fluorene (F) units is designed and synthesized via the geminal cross-coupling (GCC) of 1,1-dibromoolefins. The incorporation of TAE segments into the conjugated backbone of polyfluorene produces pronounced aggregation-induced ratiometric fluorescence, i.e., aggregation-induced emission (AIE) at 520-600 nm and grows synergistically with aggregations-caused quenching (ACQ) at 400-450 nm. The content of fluorene unit in the polymer backbones determines the intensity of the initial fluorescence in the blue light region. The huge distinction (about 150 nm) in dual emission wavelengths caused by the environment change makes these conjugated polyelectrolytes particularly suitable for ratiometric fluorescence sensing. Based on electrostatic interaction mechanism, the gradual addition of heparin into the cationic conjugated polymers aqueous solutions can induce dual-color fluorescence changes with a detection limit of 9 × 10-9 m. This work exhibits the great facility of using GCC reaction to synthesis the conjugated TAE polymers with superior AIE properties and special functions.

UV-guided isolation of enantiomeric polyacetylenes from Bupleurum scorzonerifolium Willd. with inhibitory effects against LPS-induced NO release in BV-2 microglial cells.

UV-guided fractionation led to the isolation of thirteen new polyacetylenes (1-13) from the roots of Bupleurum scorzonerifolium Willd. All polyacetylenes were analyzed as racemates since the lack of optical activity and Cotton effects in the ECD spectra. The sequent chiral-phase HPLC resolution successfully gave twelve pairs of enantiomers 1a/1b and 3a/3b-13a/13b. Their structures were elucidated based on the HRESIMS and NMR data analyses. The absolute configurations were determined by the combination of Snatzke's method, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Using Griess methods and MTT assays, polyacetylenes 1a, 3a, 4a/4b-12a/12b, and 13a displayed inhibitory activities against LPS-induced NO release in BV-2 microglial cells.

Melatonin attenuates polystyrene microplastics induced motor neurodevelopmental defect in zebrafish (Danio rerio) by activating nrf2 - isl2a Axis.

Microplastics, a new type of ecological pollutant, have now become a major environmental concern worldwide. Polystyrene microplastics (PS), one of the most abundant form of microplastics, cause deleterious effects across species. Melatonin (MT), which is secreted by pineal gland, exhibits protective role against pollutant-induced damage. However, whether MT could ameliorate PS-induced neurodevelopmental toxicity remain unclear. In our study, zebrafish embryos were treated with PS (0.5, 25 mg/L) in the presence or absence of MT (1 µM) from 4 h post-fertilization (hpf) to 144 hpf. Locomotion behavior, oxidative stress, apoptosis, proliferation and development of caudal primary (Cap) motoneuron axon were analyzed. Gene expression was determined by qRT-PCR or whole-mount in situ hybridization. Results showed that PS exposure significantly reduced swimming speed of zebrafish larvae and induced excessive reactive oxygen species (ROS), apoptosis and aberrant proliferation. In addition, PS treatment markedly shortened the length of Cap motoneuron axons and decreased expression of neurodevelopment related genes. While, MT administration considerably rescued the neurodevelopmental toxicity of PS. Mechanistically, MT activated nrf2 (nuclear factor-E2-related factor 2) - isl2a (ISL LIM homeobox 2a) axis to antagonize the side effects of PS. In all, our findings suggest that PS exposure during early life lead to aberrant neurodevelopment of zebrafish, and MT might be a therapeutic option for protecting such disorder.

Evaluation of the genotoxicity and teratogenicity of xylan using different model approaches.

Xylan is the second most abundant polysaccharide group in plants and has a wide variety of food and pharmaceutical applications. However, little information on the safety assessment of extracted xylan as dietary supplement is available. As part of a comprehensive toxicological assessment, this study examined the potential toxicity of xylan extracted from sugarcane bagasse by three genotoxicity studies (Ames test, in vivo mice bone marrow micronucleus test, and mice sperm abnormality test) and a teratogenicity study in rats. In the Ames test, xylan showed no mutagenic activity on histidine dependent strains of Salmonella typhimurium at concentrations up to 5000 µg/plate; results of the in vivo mice bone marrow micronucleus test and mice sperm abnormality test indicated no significant effect on sperm morphology and micronucleus rate of polychromatic erythrocytes in mice at doses up to 5 g/kg body weight. In the teratogenicity study, a total of 60 pregnant rats were exposed to 10, 5, and 2.5% xylan in diet, from gestation days 7 to 16, and the no-observed-adverse-effect levels (NOAEL) of xylan was determined to be 9.8 g/kg body weight. The safe dose of xylan for human was estimated to be 98 mg/kg/day (i.e., 6.86 g/day for a 70-kg person), using a 100-fold safety factor. Taken together, results of this study indicated that xylan is practically nontoxic in terms of potential dietary consumption by humans in food or as a dietary supplement.

Multienzyme-Mimic Ultrafine Alloyed Nanoparticles in Metal Organic Frameworks for Enhanced Chemodynamic Therapy.

Nanozyme-based chemodynamic therapy (CDT) has emerged as an effective cancer treatment because of its low side effects and without the requirement of exogenous energy. The therapeutic effect of CDT highlights the pivotal importance of active sites, H2 O2 supplement and the glutathione (GSH) depletion of a nanozyme. The construction of a single kind of catalyst with multiple functions for the enhanced CDT is still a big challenge. In this work, seven types of bimetallic nanoparticles are synthesized using a metal-organic framework (MOF) as a stable host instead of a Fenton or Fenton-like ions supplier. Among them, Cu-Pd@MIL-101 with an alloy loading of 9.5 wt% modified by PEG (9.5% CPMP) is found to exhibit the highest peroxidase (POD) like activity combined with a superoxide dismutase (SOD) mimic activity and the function of GSH depletion. The in vivo results suggest that the stable and ultrafine nanoparticles possess favorable CDT effect for tumor and good biosafety as well as biocompatibility. This work has provided a credible strategy to construct nanozymes with an excellent activity and may pave a new way for the design of enhanced tumor CDT treatment.

Network meta-analysis of the treatment efficacy of different lasers for peri-implantitis.

The aim of this study was comparing different lasers with conventional non-surgical treatment (CNT) for the management of peri-implantitis, regarding probing depth (PD), plaque index (PLI), clinical attachment level (CAL), and sulcus bleeding index (SBI). Randomized controlled trials (RCTs) on different lasers and CNT for peri-implantitis were searched. Pairwise and network meta-analyses were performed to analyze the PD, PLI, CAL, and SBI outcomes. The risk of bias, evidence quality, statistical heterogeneity, and ranking probability were also evaluated. Eleven studies were included in this study, involving three types of lasers. Diode + CNT had significantly superior efficacy to CNT alone, regarding PD reduction, while Er:YAG + CNT had significantly superior efficacy than CNT in terms of the PLI, CAL, and SBI. The highest probability of being most effective for PD was diode + CNT (49%), while Er:YAG + CNT had the highest probability of improving the PLI, CAL, and SBI (66%, 53%, and 79%, respectively). Diode + CNT was significantly superior for PD management in peri-implantitis compared with CNT alone, while Er:YAG + CNT significantly improved the PLI, CAL, and SBI. Therefore, Er:YAG + CNT might be recommended methods considered for management of peri-implantitis.

Nanoparticle-Stabilized Oxygen Microcapsules Prepared by Interfacial Polymerization for Enhanced Oxygen Delivery.

Most tumors have more severe hypoxia levels than normal tissue; tumor hypoxia is thus a useful target for cancer treatment. Here, we develop an effective oxygen delivery vehicle of polydopamine-nanoparticle-stabilized oxygen microcapsules by interfacial polymerization. The oxygen microcapsules have excellent biocompatibility. Oxygen could easily diffuse out from the microcapsules, thus increasing and maintaining the microenvironment at an oxygen-rich state. In vitro cell cultures confirm that oxygen microcapsules could effectively improve the hypoxia microenvironment, showing the lowest fluorescent intensity of hypoxia-green-labeled cells. When injected subcutaneously in vivo, oxygen microcapsules could also improve the tumor's hypoxia microenvironment, thus suppressing the growth of tumor. Synergetic therapy using oxygen microcapsules and gemcitabine drugs is an effective way for tumor treatment, showing the best performance in suppressing the tumor's growth.

Axial-Circular Magnetic Levitation: A Three-Dimensional Density Measurement and Manipulation Approach.

Magnetic levitation (MagLev) is a promising technology for density-based analysis and manipulation of diamagnetic objects of various physical forms. However, one major drawback is that MagLev can be performed only along the central axis (one-dimensional MagLev), thereby leading to (i) no knowledge about the magnetic field in regions other than the axial region, (ii) inability to handle objects of similar densities, because they are aggregated in the axial region, and (iii) objects that can be manipulated (e.g., separated or assembled) in only one single direction, that is, the axial direction. This work explores a novel approach called "axial-circular MagLev" to expand the operational space from one dimension to three dimensions, enabling substances to be stably levitated in both the axial and circular regions. Without noticeably sacrificing the total density measurement range, the highest sensitivity of the axial-circular MagLev device can be adjusted up to 1.5 × 104 mm/(g/cm3), approximately 115× better than that of the standard MagLev of two square magnets. Being able to fully utilize the operational space gives this approach greater maneuverability, as the three-dimensional self-assembly of controllable ring-shaped structures is demonstrated. Full space utilization extends the applicability of MagLev to bioengineering, pharmaceuticals, and advanced manufacturing.

Bioreducible crosslinked cationic nanopolyplexes from clickable polyethylenimines enabling robust cancer gene therapy.

Bioreducible crosslinked polyplexes from branched polyethylenimine (BPEI, 10 kDa) were successfully constructed through DNA neutralization by disulfide-linked azidated BPEI (PAZ) and subsequent DNA condensation by azadibenzocyclooctyne-modified BPEI (PDB), following their self-crosslinking via azide-azadibenzocyclooctyne click chemistry. Click-crosslinked cationic polyplexes (c-polyplexes) revealed high extracellular colloidal stability against negative heparin and ions while intracellular bioreducible degradability for efficient gene unpacking. In vitro gene transfection in cancer cells indicated that the c-polyplexes produced markedly higher transfection efficiency than non-crosslinked counterparts in the serum. The c-polyplexes also had prolonged circulation kinetics, elevated gene accumulation level in SKOV-3 tumor xenografted in a mouse model and in turn superior transgene expression in the tumor. By small hairpin RNA for VEGF silencing, the c-polyplexes exerted significant tumor growth inhibition following with low systemic toxicity in the mouse. This study highlights the design of clickable polycations to construct crosslinked cationic nanopolyplexes for intravenous gene delivery against cancer.

Harnessing the versatility of PLGA nanoparticles for targeted Cre-mediated recombination.

Ligand-dependent Cre recombinases are pivotal tools for the generation of inducible somatic mutants. This method enables spatial and temporal control of gene activity through tamoxifen administration, providing new avenues for studying gene function and establishing animal models of human diseases. While this paved the way for developmental studies previously deemed impractical, the generation of tissue-specific transgenic mouse lines can be time-consuming and costly. Herein, we design a 'smart', biocompatible, and biodegradable nanoparticle system encapsulated with tamoxifen that is actively targeted to specific cell types in vivo through surface conjugation of antibodies. We demonstrate that these nanoparticles bind to cells of interest and activate Cre recombinase, resulting in tissue-specific Cre activation. This system provides a versatile, yet powerful approach to induce recombination in a ubiquitious Cre system for various biomedical applications and sets the stage for a time- and cost-effective strategy of generating new transgenic mouse lines.

Ladder chain Cd-based polymer as a highly effective adsorbent for removal of Congo red.

Developing of high effective and fast-rate adsorbent materials has been recently attracted intensive attentions all over the world due to organic dye polluted water treatment. However, few studies have been reported on the ultrahigh-capacity and fast-rate removal of Congo red. In this work, a new stable Cd-based coordination polymer exhibits excellent adsorption performance towards Congo Red. This ladder chain [Cd4(H2L)4(H2O)8(NDS)]n·3n(NDS) (I) (H2L = N1,N2-bis(pyridin-3-ylmethyl) ethane-1,2-diamine, 1,5-H2NDS = 1,5-naphthalene disulfonic acid) has been successfully synthesized by the hydrothermal reaction. At room temperature, the experimental adsorption capacity of coordination polymer (I) towards Congo red can reach up to 16,880 mg g-1 in 20 min (pH = 2.0-3.2), and its higher capacity and faster rate are all better than those in reported inorganic and metal-organic frameworks absorbents. The adsorption process is spontaneous and endothermic reaction, and fits well with the second-order kinetics, Langmuir and Scatchard isotherm adsorption models. The excellent adsorption performance of (I) towards Congo red is related to the strong electrostatic, various hydrogen bonding and π-π stacking interactions under acidic conditions.

Safety assessment of xylan by a 90-day feeding study in rats.

Xylans are present naturally in various plants and have important uses in nutrition, food, novel material and biotechnology; however, to date, data regarding their systemic toxicity and safety evaluation is still limited. This study investigated the potential toxicity of xylan from sugarcane bagasse by a subchronic toxicity study in rats. A total of 80 male and female rats were fed with diets containing 10%, 5%, 2.5% and 0% (control) xylan for 90 days. A toxicological assessment was performed including mortality, body and organ weights, food consumption, blood biochemistry, hematology, urinalysis, gross necropsy and histopathological examinations. There were no signs of toxicity and treatment-related changes in rats treated with xylan. The no-observed-adverse-effect levels (NOAEL) of xylan were 9.0 g kg-1 bw for males and 10.6 g kg-1 bw for females of rats under this experimental condition, respectively.

Layer-by-layer self-assembled multilayers on PEEK implants improve osseointegration in an osteoporosis rabbit model.

This study aims to fabricate and deposit nanoscale multilayers on polyetheretherketone (PEEK) to improve cell adhesion and osseointegration. Bio-activated PEEK constructs were designed with prepared surface of different layers of polystyrene sulfonate (PSS) and polyallylamine hydrochloride (PAH) multilayers. Irregular morphology was found on the 5 and 10-layer PEEK surfaces, while "island-like" clusters were observed for 20-layer (20 L) multilayers. Besides, the 20 L PEEK showed more hydrophilic feature than native PEEK, and the surface contact angle reduced from 39.7° to 21.7° as layers increased from 5 to 20. In vitro, modified PEEK allowed excellent adhesion and proliferation of bone marrow stromal cells, and induced higher cell growth rate and alkaline phosphatase level. In vivo, this bio-active PEEK exhibited significantly enhanced integration with bone tissue in an osteoporosis rabbit model. This work highlights layer-by-layer self-assembly as a practical method to construct bio-active PEEK implants for enhanced osseointegration.

Nuclear-targeting TAT-PEG-Asp8-doxorubicin polymeric nanoassembly to overcome drug-resistant colon cancer.

AIM: Drug efflux-associated multidrug resistance (MDR) is a main obstacle to effective cancer chemotherapy. Large molecule drugs are not the substrates of P-glycoprotein, and can circumvent drug efflux and be retained inside cells. In this article we report a polymer-drug conjugate nanoparticulate system that can overcome MDR based on size-related exclusion effect. METHODS: Doxorubicin was coupled with the triblock polymeric material cell-penetrating TAT-PEG-poly(aspartic acid). The amphiphilic macromolecules (termed TAT-PEG-Asp8-Dox) could self-assemble into nanoparticles (NPs) in water. The antitumor activity was evaluated in drug-resistant human colon cancer HCT8/ADR cells in vitro and in nude mice bearing HCT8/ADR tumor. RESULTS: The self-assembling TAT-PEG-Asp8-Dox NPs were approximately 150 nm with a narrow particle size distribution, which not only increased the cellular uptake efficiency, but also bypassed P-glycoprotein-mediated drug efflux and improved the intracellular drug retention, thus yielding an enhanced efficacy for killing drug-resistant HCT8/ADR colon cancer cells in vitro. Importantly, the TAT-PEG-Asp8-Dox NPs enhanced the intranuclear disposition of drugs for grater inhibition of DNA/RNA biosynthesis. In nude mice bearing xenografted HCT8/ADR colon cancers, intravenous or peritumoral injection of TAT-PEG-Asp8-Dox NPs for 22 d effectively inhibited tumor growth. CONCLUSION: TAT-PEG-Asp8-Dox NPs can increase cellular drug uptake and intranuclear drug delivery and retain effective drug accumulation inside the cells, thus exhibiting enhanced anticancer activity toward the drug-resistant human colon cancer HCT8/ADR cells.

Multifunctional disulfide-based cationic dextran conjugates for intravenous gene delivery targeting ovarian cancer cells.

A folate-decorated, disulfide-based cationic dextran conjugate having dextran as the main chain and disulfide-linked 1,4-bis(3-aminopropyl)piperazine (BAP) residues as the grafts was designed and successfully prepared as a multifunctional gene delivery vector for targeted gene delivery to ovarian cancer SKOV-3 cells in vitro and in vivo. Initially, a new bioreducible cationic polyamide (denoted as pSSBAP) was prepared by polycondensation reaction of bis(p-nitrophenyl)-3,3'-dithiodipropanoate, a disulfide-containing monomer, and BAP. It was found that the pSSBAP was highly efficient for in vitro gene delivery against MCF-7 and SKOV-3 cell lines. Subsequently, two cationic dextran conjugates with different amounts of BAP residues (denoted as Dex-SSBAP6 and Dex-SSBAP30, respectively) were synthesized by coupling BAP to disulfide-linked carboxylated dextran or coupling pSSBAP-oligomer to p-nitrophenyl carbonated dextran. Both two conjugates were able to bind DNA to form nanosized polyplexes with an improved colloidal stability in physiological conditions. The polyplexes, however, were rapidly dissociated to liberate DNA in a reducing environment. In vitro transfection experiments revealed that the polyplexes of Dex-SSBAP30 efficiently transfected SKOV-3 cells, yielding transfection efficiency that is comparable to that of linear polyethylenimine or lipofectamine 2000. AlamarBlue assay showed that the conjugates had low cytotoxicity in vitro at a high concentration of 100 mg/L. Further, Dex-SSBAP30 has primary amine side groups and thus allows for folate (FA) conjugation, yielding FA-coupled Dex-SSBAP30 (Dex-SSBAP30-FA). It was found that Dex-SSBAP30-FA was efficient for targeted gene delivery to SKOV-3 tumor xenografted in a nude mouse model by intravenous injection, inducing a higher level of gene expression in the tumor as compared to Dex-SSBAP30 lacking FA and comparable gene expression to linear polyethylenimine as one of the most efficient polymeric vectors for intravenous gene delivery in vivo. Disulfide-based cationic dextran system thus has a high potential for intravenous gene delivery toward cancer gene therapy.

A pH and redox dual responsive 4-arm poly(ethylene glycol)-block-poly(disulfide histamine) copolymer for non-viral gene transfection in vitro and in vivo.

A novel 4-arm poly(ethylene glycol)-b-poly(disulfide histamine) copolymer was synthesized by Michael addition reaction of poly(ethylene glycol) (PEG) vinyl sulfone and amine-capped poly(disulfide histamine) oligomer, being denoted as 4-arm PEG-SSPHIS. This copolymer was able to condense DNA into nanoscale polyplexes (<200 nm in average diameter) with almost neutral surface charge (+(5-10) mV). Besides, these polyplexes were colloidal stable within 4 h in HEPES buffer saline at pH 7.4 (physiological environment), but rapidly dissociated to liberate DNA in the presence of 10 mM glutathione (intracellular reducing environment). The polyplexes also revealed pH-responsive surface charges which markedly increased with reducing pH values from 7.4-6.3 (tumor microenvironment). In vitro transfection experiments showed that polyplexes of 4-arm PEG-SSPHIS were capable of exerting enhanced transfection efficacy in MCF-7 and HepG2 cancer cells under acidic conditions (pH 6.3-7.0). Moreover, intravenous administration of the polyplexes to nude mice bearing HepG2-tumor yielded high transgene expression largely in tumor rather other normal organs. Importantly, this copolymer and its polyplexes had low cytotoxicity against the cells in vitro and caused no death of the mice. The results of this study indicate that 4-arm PEG-SSPHIS has high potential as a dual responsive gene delivery vector for cancer gene therapy.

[Properties and biocompatibility of collagen scaffold modified by genipin cross-linked L-lysine].

Collagen (Coll), as the basic material of matrix scaffolds for cell growth, has been widely used in the field of tissue engineering and regenerative medicine. In this study, collagen protein was modified by L-lysine (Lys), and cross-linked by genipin (GN) to prepare the L-lysine-modified collagen (Lys-Coll-GN) scaffolds. Microstructure, pore size, porosity, stability and biocompatibility of Lys-Coll-GN scaffolds were observed. The results showed that the bond between L-lysine and collagen protein molecule was formed by generating amide linkage, and mouse embryo fibroblasts proliferation was not inhibited in the Lys-Coll-GN scaffolds. In the multiple comparisons of Coll-scaf- folds, Coll-GN scaffolds and Lys-Coll-GN scaffolds, Coll-scaffolds was the worst in mechanical characteristics while the highest in biodegradation rate. Compared to Coll-GN scaffolds, Lys-Coll-GN scaffolds had more fiber structure, higher interval porosity (P<0. 01). Although the tensile stress of Lys-Coll-GN scaffolds reduced significantly, its e- longation length extended when the scaffolds was fractured (P<0. 01). The percentage of Lys-Coll-GN scaffolds residual weight was lower than that of Coll-GN scaffolds after all the scaffolds were treated by collagenase for 5 days (P<0. 01). This study suggested that Lys-Coll-GN scaffold had good biocompatibility, and it improved the mechanical property and degradation velocity for collagen-based scaffold. This study gave a new predominant type of tissue engineering scaffold for the regenerative medicine.

Cu fate driven by colloidal polystyrene microplastics with pipe scale destabilization in drinking water distribution systems.

Microplastics (MPs) and Cu have been detected in drinking water distribution systems (DWDSs). Investigating MP effects on Cu adsorption by pipe scales and concomitant variations of pipe scales was critical for improving the water quality, which remained unclear to date. Therefore, polystyrene microplastics (PSMPs) were adopted for the model MPs to determine their effects on Cu fate and pipe scale stabilization, containing batch adsorption, metal speciation extraction, and Cu release experiments. Findings demonstrated that complexation and electrostatic interactions were involved in Cu adsorption on pipe scales. PSMPs contributed to Cu adsorption via increasing negative charges of pipe scales and providing additional adsorption sites for Cu, which included the carrying and component effects of free and adsorbed PSMPs, respectively. The decreased iron and manganese oxides fraction (45.57 % to 29.91 %) and increased organic fraction (48.51 % to 63.58 %) of Cu in pipe scales when PSMPs were coexisting illustrated that PSMPs had a greater affinity for Cu than pipe scales and thus influenced its mobility. Additionally, the release of Cu could be facilitated by the coexisted PSMPs, with the destabilization of pipe scales. This study was the first to exhibit that Cu fate and pipe scale stabilization were impacted by MPs, providing new insight into MP hazards in DWDSs.