Polypyrrole-Doped Conductive Self-Healing Composite Hydrogels with High Toughness and Stretchability.

In recent years, hydrogels with self-healing capability and conductivity have become ideal materials for the design of electrodes, soft robotics, electronic skin, and flexible wearable devices. However, it is still a critical challenge to achieve the synergistic characteristics of high conductivity, excellent self-healing efficiency without any stimulations, and decent mechanical properties. Herein, we developed a ferric-ion (Fe3+) crosslinked acrylic acid and chitosan polymer hydrogel using embedded polypyrrole particles with features of high conductivity (2.61S·m-1) and good mechanical performances (a tensile strength of 628%, a stress of 0.33 MPa, an elastic modulus of 0.146 MPa, and a toughness of 1.14 MJ·m-3). In addition, the self-healing efficiency achieved 93% in tensile strength after healing in the air for 9 h without any external stimuli. Therefore, with these outstanding mechanical, self-healing, and conductive abilities all in one, it is possible to fabricate a new kind of soft material with wide applications.

Polypyrrole-doped conductive self-healing multifunctional composite hydrogels with a dual crosslinked network.

Soft hydrogel materials can be applied for use in biosensors, wearable electronics, artificial skin, soft robots, and so on. Practical applications require the materials to have various properties such as high conductivity, toughness, self-healing, stretchability, and so on. However, achieving all these features in a single material remains challenging at present. Herein, the fabrication of novel composite carboxymethylcellulose/poly(acrylic acid)/polypyrrole/Al(III) (CMC/PAA/PPy/Al(III)) multifunctional hydrogels using a simple method is described. The mechanical and electrical self-healing properties are attained by multiple dynamic coordinations between Al3+ ions and carboxyl groups from CMC and PAA together with the hydrogen bonding between PPy and the -OH of CMC and/or the -COOH of PAA. The electrical conductivity is achieved by the conductive polymer PPy, free ions, and the synergistic effect between the PPy particles and the free ions. Moreover, desirable mechanical properties, such as stretchability (1344%), toughness, and mouldability are realized by establishing a balance between the chemical and physical crosslinking networks, and the nanostructure of PPy. Thus, the resultant hydrogels have potential applications in electronic skin, biomedical implants, and wearable electronic devices in the future.

Electrospun nitrocellulose membrane for immunochromatographic test strip with high sensitivity.

The main goal of this work is to develop an economical, portable, disposable, and reliable point of care paper biosensor based on visualization, which can be used to detect viruses, bacteria, and proteins. However, the sensitivity of immunochromatography test (ICT) strips based on nitrocellulose to target detection has always been a problem. Here, we use an electrospun nitrocellulose (ENC) fiber membrane instead of traditional nitrocellulose fiber membrane to construct ICT strips for early pregnancy detection. By proper selection of the diameter of the ENC fiber to adjust the pore size, porosity, and morphology of the membrane, ICT strips with low flow rate and high protein loading were obtained. Based on these properties, a convenient and sensitive method for the colorimetric determination of human chorionic gonadotropin was developed. Under the optimal conditions, the detection limit of ICT based on ENC membrane is 10 mIU mL-1 (S/N = 3), the linear detection range is 5-1000 mIU mL-1, and the linear relationship is Y = 0.0434 X - 0.0136 (R2 = 0.9802). In addition, the test strip has good specificity and stability, and will not produce false-positive results. Graphical abstract.

[Synthesis and experimental study of a novel polymer/gene compound drug controlled release system for the treatment of erectile dysfunction].

OBJECTIVE: To overcome the deficiency in the current therapies for erectile dysfunction (ED), we designed and synthesized a novel high-efficiency polymer/gene compound drug controlled release system and discussed the feasibility of pH and temperature dually sensitive injectable hydrogel in ED gene therapy. METHODS: We synthesized optimal siRNA gene nanoparticles by characterizing the zeta potential of polylysine (PLL)/siRNA gene compounds, and established a pH and temperature dually sensitive injectable gene compound drug controlled release system via Schiffs reaction between glycol chitosan (GC) and benzaldehyde capped OHC-PEO-PPO-PEO-CHO. Then we demonstrated the sustained release of the system at different temperatures. RESULTS: When the mass ratio of PLL to siRNA was 20:1, the zeta potential of the PLL/siRNA gene compound reached the peak (+23.5 mV) and the siRNA was encapsulated by PLL in the maximal degree. GC and OHC-PEO-PPO-PEO-CHO was crosslinked via benzoicimine reaction when environmental pH was changed from 5.5 to 7.4. The reslease of the siRNA encapsulated in this system kept at a low rate at 37 degrees C, significantly enhanced with the increase of the temperature to 60 degrees C, rising to (122.5 +/- 5.3) microg at 1 000 minutes as compared with (23.8 +/- 6.0) microg at 37 degrees C (P < 0.05). CONCLUSION: The polymer/gene compound drug controlled release system was successfully synthesized, which improved the stability and capacity of gene carriers and achieved siRNA release at different temperatures, promising to be a new approach to the gene therapy of ED.

pH/Temperature Dual-Responsive Protein-Polymer Conjugates for Potential Therapeutic Hypothermia in Ischemic Stroke.

Thrombolytic therapy for ischemic stroke still has several limitations, such as a narrow therapeutic time window and adverse effects. Therapeutic hypothermia is a neuroprotective strategy for stroke. In this study, we developed pH/temperature dual-responsive protein-polymer conjugates (PEG-uPA-PEG-PPG-PEG) by modifying a urokinase-type plasminogen activator (uPA) with polyethylene glycol (PEG) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG, a thermosensitive polymer) via pH-sensitive imine bonds and disulfide bonds, respectively. At 37 °C and pH 7.4 (normothermia and physiological pH), PEG-uPA-PEG-PPG-PEG exhibits antiprotease hydrolysis and masked bioactivity of uPA due to the protective effect of the polymer segments wrapped around the protein surface. However, at 33 °C and pH 6.0 (hypothermia and pH at the thrombotic site), uPA loses the protective effect and recovers its bioactivity due to PEG dissociation and PEG-PPG-PEG stretching. The masked bioactivity of uPA at normothermia and physiological pH could reduce the risk of acute hemorrhage complication, and the recovery of protein activity at acidic pH and 33 °C is of great significance for thrombolytic therapy at mild hypothermia. Thus, PEG-uPA-PEG-PPG-PEG provides promising potential for therapeutic hypothermia in ischemic stroke.

pH-sensitive polymeric vesicles from coassembly of amphiphilic cholate grafted poly(L-lysine) and acid-cleavable polymer-drug conjugate.

Herein we report a coassembly method toward the preparation of pH-sensitive polymeric vesicular aggregates, using comb-shaped amphiphilic polymers, i.e., cholate grafted poly(L-lysine) (PLL-CA), with an amphiphilic poly(ethylene glycol)-doxorubicin conjugate (PEG-DOX). Because the drug conjugate includes a low-pH labile bond, i.e., benzoic imine, the permeability of the coassembled polymeric vesicles can be tuned by changing either the PLL-CA/PEG-DOX weight ratio or the environmental pH from 7.4 to 6.5. Furthermore, at lower pH values such as 5.0, the vesicles destabilize. The pH sensitivity leads to enhanced uptake of the vesicles by cancer cells (MCF-7) under a condition close to the extracellular environment of solid tumor (pH = 6.5) and subsequent efficient endosome escape after the endocytosis.

Superhydrophilic nanocomposite adsorbents modified via nitrogen-rich phosphonate-functionalized ionic liquid linkers: enhanced phosphopeptide enrichment and phosphoproteome analysis of tau phosphorylation in the hippocampal lysate of Alzheimer's transgenic mice.

In this study, new graphene-based IMAC nanocomposites for phosphopeptide enrichment were prepared according to the guideline of our new design strategy. Superhydrophilic polyethyleneimine (PEI) was introduced, to which a phosphonate-functionalized ionic liquid (PFIL) was covalently bound, to form superhydrophilic and cationic surface layers with high densities of nitrogen atoms, phosphonate functional groups, and high-loading metal ions. Due to the combined features of superhydrophilicity, flexibility, highly dense metal binding sites, large surface area and excellent size-exclusion effect, the fabricated nanocomposite G@mSiO2@PEI-PFIL-Ti4+ exhibits superior detection sensitivity to enrich phosphopeptides (tryptic ß-casein digest, 0.1 fmol), and extraordinary enrichment specificity to enrich phosphopeptides from a digest mixture of ß-casein and bovine serum albumin (BSA) (molar ratio, 1 : 12 000). The excellent size-exclusion effect was also observed, and 27 endogenous phosphopeptides were identified in human saliva. All these results could be attributed to the unique superhydrophilic nanocomposite structure with a high density of a cationic linker modified with phosphonate functionality. Moreover, G@mSiO2@PEI-PFIL-Ti4+ adsorbents were used to extract phosphopeptides from the tryptic digests of hippocampal lysates for quantitative phosphoproteome analysis. The preliminary results indicate that 1649 phosphoproteins, 3286 phosphopeptides and 4075 phosphorylation sites were identified. A total of 13 Alzheimer's disease (AD)-related phosphopeptides within tau proteins were detected with a wide coverage from p-Thr111 to p-Ser404, in which the amounts of some phoshopeptides at certain sites in AD transgenic mice were found statistically higher than those in wild type littermates. Besides, phosphorylated neurofilament heavy chains, a potential biomarker for amyotrophic lateral sclerosis and traumatic brain injury, were also identified. Finally, the adsorbent was applied to human cerebrospinal fluid (CSF) and blood samples. 5 unique phosphopeptides of neuroendocrine specific VGF were identified in the CSF, while many phosphopeptides originated from the nervous system were found in the blood sample. All these results suggest that our new IMAC materials exhibit unbiased enrichment ability with superior detection sensitivity and specificity, allowing the global phosphoproteome analysis of complicated biological samples more convincible and indicating the potential use in disease diagnosis.

Bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles as novel tumor targeting carriers.

In this study, we have developed a novel carrier, micelle-type bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles (NPs), for the detection and treatment of pancreatic cancer. These NPs contained 4-arm-PEG as corona, and PLGA as core, the particle surface was conjugated with cyclo(arginine-glycine-aspartate) (cRGD) as ligand for in vivo tumor targeting. The hydrodynamic size of the NPs was determined to be 150-180 nm and the critical micellar concentration (CMC) was estimated to be 10.5 mg l( - 1). Our in vitro study shows that these NPs by themselves had negligible cytotoxicity to human pancreatic cancer (Panc-1) and human glioblastoma (U87) cell lines. Near infrared (NIR) microscopy and flow cytometry demonstrated that the cRGD conjugated PLGA-4-arm-PEG polymeric NPs were taken up more efficiently by U87MG glioma cells, over-expressing the α(v)ß(3) integrin, when compared with the non-targeted NPs. Whole body imaging showed that the cRGD conjugated PLGA-4-arm-PEG branched polymeric NPs had the highest accumulation in the pancreatic tumor site of mice at 48 h post-injection. Physical, hematological, and pathological assays indicated low in vivo toxicity of this NP formulation. These studies on the ability of these bioconjugated PLGA-4-arm-PEG polymeric NPs suggest that the prepared polymeric NPs may serve as a promising platform for detection and targeted drug delivery for pancreatic cancer.

Alendronate-Decorated Nanoparticles as Bone-Targeted Alendronate Carriers for Potential Osteoporosis Treatment.

Osteoporosis is a skeletal disorder characterized by a low bone mass and density. Alendronate (Alen), a second-generation bisphosphonate drug, was indicated as the first-line regimen for the treatment of osteoporosis. However, the use of Alen has been limited due to its low bioavailability and gastrointestinal side effects. Herein, Alen-decorated nanoparticles were prepared through ionic cross-linking between poly (lactic-co-glycolic acid), ß-cyclodextrin-modified chitosan (PLGA-CS-CD), and Alen-modified alginate (ALG-Alen) for Alen loading and bone-targeted delivery. Alen was selected as a therapeutic drug and a bone-targeting ligand. The nanoparticles have negatively charged surfaces, and sustained release of Alen from the nanoparticles can be observed. Cytotoxicity detected using cell counting kit-8 (CCK-8) assay and lactate dehydrogenase release test on MC3T3 cells showed that the nanoparticles had good cytocompatibility. A hemolysis test showed that the hemolysis ratios of nanoparticles were <5%, indicating that the nanoparticles had no significant hemolysis effect. Moreover, the Alen-decorated nanoparticles exhibited enhanced binding affinity to the hydroxyapatite (HAp) disks compared with that of nanoparticles without Alen modification. Thus, the Alen-decorated nanoparticles might be developed as promising bone-targeted carriers for the treatment of osteoporosis.

PLGA-PEG Nanoparticles Facilitate In Vivo Anti-Alzheimer's Effects of Fucoxanthin, a Marine Carotenoid Derived from Edible Brown Algae.

The marine natural product fucoxanthin has been reported previously to produce anti-Alzheimer's disease (AD) neuroprotective effects in vitro and in vivo. Fucoxanthin was also demonstrated to be safe in preclinical and small population clinical studies, but the low bioavailability of fucoxanthin in the central nervous system (CNS) has limited its clinical applications. To overcome this, poly lactic-co-glycolic acid-block-polyethylene glycol loaded fucoxanthin (PLGA-PEG-Fuc) nanoparticles with diameter at around 200 nm and negative charge were synthesized and suggested to penetrate into the CNS. Loaded fucoxanthin could be liberated from PLGA-PEG nanoparticles by sustained released in the physiological environment. PLGA-PEG-Fuc nanoparticles were shown to significantly inhibit the formation of Aß fibrils and oligomers. Moreover, these nanoparticles were taken up by both neurons and microglia, leading to the reduction of Aß oligomers-induced neurotoxicity in vitro. Most importantly, intravenous injection of PLGA-PEG-Fuc nanoparticles prevented cognitive impairments in Aß oligomers-induced AD mice with greater efficacy than free fucoxanthin, possibly via acting on Nrf2 and NF-κB signaling pathways. These results altogether suggest that PLGA-PEG nanoparticles can enhance the bioavailability of fucoxanthin and potentiate its efficacy for the treatment of AD, thus potentially enabling its future use for AD therapy.

Dually responsive injectable hydrogel prepared by in situ cross-linking of glycol chitosan and benzaldehyde-capped PEO-PPO-PEO.

Injectable hydrogels with pH and temperature triggered drug release capability were synthesized based on biocompatible glycol chitosan and benzaldehyde-capped poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEO-PPO-PEO). Aqueous solutions of the above polymers formed hydrogel under physiological conditions, allowing a desirable injectability, through the formation covalent benzoic-imine bond with pH and temperature changes. Rheological characterization demonstrated that the gelation rate and the moduli of the hydrogels were able to be tuned with chemical composition as well as pH and temperature of the polymer solution. Both hydrophobic and hydrophilic drugs could be incorporated inside the hydrogel through the in situ gel forming process and undergo a controlled release by altering pH or temperature. In vivo tests proved the formation and biocompatibility of the hydrogel in rat model.

Determination of cadmium(II), cobalt(II), nickel(II), lead(II), zinc(II), and copper(II) in water samples using dual-cloud point extraction and inductively coupled plasma emission spectrometry.

A dual-cloud point extraction (d-CPE) procedure has been developed for simultaneous pre-concentration and separation of heavy metal ions (Cd2+, Co2+, Ni2+, Pb2+, Zn2+, and Cu2+ ion) in water samples by inductively coupled plasma optical emission spectrometry (ICP-OES). The procedure is based on forming complexes of metal ion with 8-hydroxyquinoline (8-HQ) into the as-formed Triton X-114 surfactant rich phase. Instead of direct injection or analysis, the surfactant rich phase containing the complexes was treated by nitric acid, and the detected ions were back extracted again into aqueous phase at the second cloud point extraction stage, and finally determined by ICP-OES. Under the optimum conditions (pH=7.0, Triton X-114=0.05% (w/v), 8-HQ=2.0×10(-4) mol L(-1), HNO3=0.8 mol L(-1)), the detection limits for Cd2+, Co2+, Ni2+, Pb2+, Zn2+, and Cu2+ ions were 0.01, 0.04, 0.01, 0.34, 0.05, and 0.04 µg L(-1), respectively. Relative standard deviation (RSD) values for 10 replicates at 100 µg L(-1) were lower than 6.0%. The proposed method could be successfully applied to the determination of Cd2+, Co2+, Ni2+, Pb2+, Zn2+, and Cu2+ ion in water samples.

The integration of 3-D cell printing and mesoscopic fluorescence molecular tomography of vascular constructs within thick hydrogel scaffolds.

Developing methods that provide adequate vascular perfusion is an important step toward engineering large functional tissues. Meanwhile, an imaging modality to assess the three-dimensional (3-D) structures and functions of the vascular channels is lacking for thick matrices (>2 ≈ 3 mm). Herein, we report on an original approach to construct and image 3-D dynamically perfused vascular structures in thick hydrogel scaffolds. In this work, we integrated a robotic 3-D cell printing technology with a mesoscopic fluorescence molecular tomography imaging system, and demonstrated the capability of the platform to construct perfused collagen scaffolds with endothelial lining and to image both the fluid flow and fluorescent-labeled living endothelial cells at high-frame rates, with high sensitivity and accuracy. These results establish the potential of integrating both 3-D cell printing and fluorescence mesoscopic imaging for functional and molecular studies in complex tissue-engineered tissues.

Ultrasound-triggered thrombolysis using urokinase-loaded nanogels.

To find a way to modulate the effect of thrombolytic proteins by increasing their specificity, minimizing their adverse effect as well as lengthening their circulation time for the treatment of ischemic vascular disease holds great promise. In this work, urokinase-type plasminogen activator (uPA) was encapsulated into hollow nanogels which are generated by the reaction of glycol chitosan and aldehyde capped poly(ethylene glycol) (OHC-PEG-CHO) through a one-step approach of ultrasonic spray. The uPA-loaded nanogels, with size of 200-300 nm, have longer circulation time than that of the nude urokinase in vivo, besides the protein can be triggered to release in faster rate under diagnostic ultrasonic condition of 2 MHz, which significantly enhanced the thrombolysis of clots. The results are promising for increasing the specificity and positive effects of thrombolytic agents like recombinant tissue plasminogen activator (rt-PA) for the current treatment of ischemic vascular disease.

pH triggered injectable amphiphilic hydrogel containing doxorubicin and paclitaxel.

Injectable hydrogel with hydrophobic microdomains for incorporating both hydrophilic and hydrophobic drugs, herein doxorubicin hydrochloride (DOX) and paclitaxel (PTX), was synthesized through dynamic bonding of glycol chitosan and benzaldehyde capped poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) via Schiff's reaction triggered by environmental pH. Rheology tests show that the inclusion of hydrophilic drug decreases the gelation time and gains more robust gel, while the addition of hydrophobic drug has opposite influences. Dual-drug release from the DOX+PTX loaded gels was observed and the release rate can be accelerated by decreasing the environmental pH from physiological (7.4) to weak acidic pH (6.8). In vivo investigation proved that the gels were able to diminish the amount of DOX in blood circulation and limit the DOX-induced cardiotoxicity. By intratumoral administration, the hydrogel-drug formulations resulted in efficient growth inhibition of subcutaneous tumor (B16F10) on C57LB/6 mouse model. The advantage of the current system for DOX+PTX combination therapy was demonstrated by a prolongation of survival time in comparison with the single drug therapy.