Targeted drug delivery into glial scar using CAQK peptide in a mouse model of multiple sclerosis.

In multiple sclerosis, lesions are formed in various areas of the CNS, which are characterized by reactive gliosis, immune cell infiltration, extracellular matrix changes and demyelination. CAQK peptide (peptide sequence: cysteine-alanine-glutamine-lysine) was previously introduced as a targeting peptide for the injured site of the brain. In the present study, we aimed to develop a multifunctional system using nanoparticles coated by CAQK peptide, to target the demyelinated lesions in animal model of multiple sclerosis. We investigated the binding of fluorescein amidite-labelled CAQK and fluorescein amidite-labelled CGGK (as control) on mouse brain sections. Then, the porous silicon nanoparticles were synthesized and coupled with fluorescein amidite-labelled CAQK. Five days after lysolecithin-induced demyelination, male mice were intravenously injected with methylprednisolone-loaded porous silicon nanoparticles conjugated to CAQK or the same amount of free methylprednisolone. Our results showed that fluorescein amidite-labelled CAQK recognizes demyelinated lesions in brain sections of animal brains injected with lysolecithin. In addition, intravenous application of methylprednisolone-loaded nanoparticle porous silicon conjugated to CAQK at a single dose of 0.24 mg reduced the levels of microglial activation and astrocyte reactivation in the lesions of mouse corpus callosum after 24 and 48 h. No significant effect was observed following the injection of the same dose of free methylprednisolone. CAQK seems a potential targeting peptide for delivering drugs or other biologically active chemicals/reagents to the CNS of patients with multiple sclerosis. Low-dose methylprednisolone in this targeted drug delivery system showed significant beneficial effect.

Mir-122 upregulation and let-7f downregulation combination: The effects on hepatic differentiation of hiPSCs on the PCL-Gel-HA nanofibrous scaffold.

Cell therapy and tissue engineering as promising candidates for the liver transplantation dilemma are of special interest. Induced pluripotent stem cells (iPSCs) are one of the best sources in this field, but their differentiation methods to hepatocytes have remained challenging. We transduced human iPSCs (hiPSCs) with miR-122 and off-let-7f (hiPSCsmiR-122 + off-let-7f ) to evaluate how they can differentiate hiPSCs to hepatocyte-like cells (HLCs) without any extrinsic growth factor. Additionally, we studied the effect of Poly ɛ-caprolactone-gelatin-hyaluronic acid (PCL-Gel-HA) nanofibrous scaffold as an extracellular matrix (ECM) simulator on differentiation improvement. Definitive endoderm markers (FOXA2 and SOX17), as well as hepatic markers (AFP, Albumin, CK18, HNF4α) expression, were significantly higher in hiPSCsmiR-122 + off-let-7f derived HLCs (hiPSCs-HLCs) compared to the control group (miR-scramble transduced hiPSCs: hiPSCsscramble ). hiPSCs-HLCs indicated hepatocyte morphological characteristics and positive immunostaining for AFP, Albumin and HNF4α. Albumin and urea secretion were significantly higher in hiPSCs-HLCs than hiPSCsscramble . Comparing these markers in the PCL-Gel-HA group with the tissue culture plate (TCP) group revealed that PCL-Gel-HA could improve differentiation towards HLCs significantly. Regarding our results, these microRNAs can be used to differentiate hiPSCs to the functional hepatocytes for disease modelling, drug screening and cell-based therapy in future studies.

Decellularized human amniotic membrane reinforced by MoS2-Polycaprolactone nanofibers, a novel conductive scaffold for cardiac tissue engineering.

In order to regenerate myocardial tissues with functional characteristics, we need to copy some properties of the myocardium, such as its extracellular matrix and electrical conductivity. In this study, we synthesized nanosheets of Molybdenum disulfide (MoS2), and integrated them into polycaprolactone (PCL) and electrospun on the surface of decellularized human amniotic membrane (DHAM) with the purpose of improving the scaffolds mechanical properties and electrical conductivity. For in vitro studies, we seeded the mouse embryonic cardiac cells, mouse Embryonic Cardiac Cells (mECCs), on the scaffolds and then studied the MoS2 nanocomposites by scanning electron microscopy and Raman spectroscopy. In addition, we characterized the DHAM/PCL and DHAM/PCL-MoS2 by SEM, transmission electron microscopy, water contact angle measurement, electrical conductivity, and tensile test. Besides, we confirmed the scaffolds are biocompatible by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT assay. Furthermore, by means of SEM images, it was shown that mECCs attached to the DHAM/PCL-MoS2 scaffold have more cell aggregations and elongated morphology. Furthermore, through the Real-Time PCR and immunostaining studies, we found out cardiac genes were maturated and upregulated, and they also included GATA-4, c-TnT, NKX 2.5, and alpha-myosin heavy chain in cells cultured on DHAM/PCL-MoS2 scaffold in comparison to DHAM/PCL and DHAM. Therefore, in terms of cardiac tissue engineering, DHAM nanofibrous scaffolds reinforced by PCL-MoS2 can be suggested as a proper candidate.

Mechanochemical Synthesis of Rosin-Modified Montmorillonite: A Breakthrough Approach to the Next Generation of OMMT/Rubber Nanocomposites.

The current investigation presents a green mechanochemical procedure for the synthesis of a special kind of rubber-compatible organo-montmorillonite (OMMT) for use in the inner liner compound of tires. The compatibility character of the OMMT arises from the mechanochemical reaction of the raw bentonite mineral and gum rosin as some of the organic constituents of the inner liner composition. The monitoring of OMMT synthesis by various characterization techniques reveals that gum rosin gradually intercalates into the montmorillonite (MMT) galleries during milling and increases the interlayer spacing to 41.1 ± 0.5 Å. The findings confirm the simultaneous formation of single- or few-layered OMMT platelets with average sizes from the sub-micron range up to several micrometers during the milling process. The mechanical properties of the OMMT/rubber nanocomposite, such as tensile strength, tear resistance and elongation, present a good enhancement in comparison to the un-modified material. Moreover, the organo-modification of the inner liner composition also leads to a property improvement of about 50%.

Polyethylene glycol triggers the anti-cancer impact of curcumin nanoparticles in sw-1736 thyroid cancer cells.

Curcumin has been recognized as an effective anticancer agent. However, due to its hydrophobic property, the cell absorption is not satisfied. Herein, the curcumin nanoparticles were prepared in the presence of polyethylene glycol 6000 (PEG6000) to reduce its elimination by immune system. For first time, not only the curcumin was encapsulated within the niosome nanoparticles modified by PEG, there are no reports related to the anticancer property of curcumin against thyroid cancers. The nanoparticles was developed and its anticancer was studied on sw-1736 cancer cell line. The nanoparticles were examined by scanning electron microscopy (SEM) and dynamic light scattering (DLS). Also, the release profile of curcumin, the IC50 concentration, the radical amount and the gene expression were evaluated. The optimized nanoparticles showed a diameter of 212 ± 31 nm by SEM and the encapsulation efficiency and loading capacity of 76% and 16.8% respectively. DLS confirmed the polydispersity index (PDI) of 0.596 and the release model was shown a sustained release with the delivery of 68% curcumin after 6 days. Also, the nanoparticles indicated the higher storage stability at 4 °C. After the cell treatment, the apoptotic bodies were appeared and IC50 was obtained as 0.159 mM. Moreover, the generated radicals by the treated cells was 86% after 72 h and the gene pattern indicated the bax/bcl2 ratio of 6.83 confirming the apoptosis effect of the nanoparticles. The results approved the nanoparticles could be suggested as an anticancer drug candidate for thyroid cancers. The encapsulated curcumin within the niosome nanoparticles modified with PEG, could be released and up-taken by the thyroid cancer cell line due to the same hydrophobic property of cell membrane and the niosome particles. The reaction between curcumin and cellular components generates radicals and activates the apoptotic pathway. The corresponding reaction finally makes cell death.

Optimization of Nanoclay/Polyacrylonitrile Scaffold Using Response Surface Method for Bone Differentiation of Human Mesenchymal Stem Cells.

Response surface methodology (RSM) based on the D-optimal algorithm was employed here for the electrospinning of nanoclay/polyacrylonitrile (PAN) composite scaffold by the aim of obtaining the lower fiber diameter and better mechanical properties for bone regeneration. The input parameters included the electrospinning voltage, flow rate and the ratio of nanoclay/PAN and the obtained values for the optimum point were 17 kV for the applied voltage, 0.41 ml/hr for flow rate, and 19.06% for the nanoclay/PAN ratio. The composite scaffold was fabricated in accordance with these optimum values and then studied by scanning electron microscopy and tensile apparatus. The fiber diameter and Young's modulus of the prepared scaffold were respectively 145 ± 12 nm and 267 ± 8.7 MPa that the values were between predicted by RSM. Moreover, the biocompatibility and osteogenic differentiation of the composite scaffold were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and alkaline phosphatase assays. The bare scaffold and tissue culture polystyrene were used as control groups. The results approved stronger bioactivity and bone regeneration with the composite scaffold as a presence of clay nanoparticles.

The biomedical potential of cellulose acetate/polyurethane nanofibrous mats containing reduced graphene oxide/silver nanocomposites and curcumin: Antimicrobial performance and cutaneous wound healing.

In this study, nanofibrous scaffolds were prepared from polyurethane and cellulose acetate using electrospinning. Reduced graphene oxide/silver nanocomposites, rGO/Ag, were also used into the mats due to the strong antibacterial activity of rGO/Ag nanocomposites. In order to prevent the agglomeration of silver nanoparticles, AgNPs, the nanoparticles were decorated onto the reduced graphene oxide (rGO) sheets. Initially, Graphene oxide, briefly GO, was synthesized by the improved Hummer method. Then, nanocomposites of reduced graphene oxide were decorated with Ag and were fabricated via a green and facile hydrothermal method. Thereafter, the scaffold containing rGO/Ag nanocomposites, curcumin or both of them were prepared using the electrospinning method. The obtained scaffolds were characterized by scanning electron microscopy (SEM), contact angle, tensile analysis, porosity, and water vapor transmission rate (WVTR). 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay, MTT, confirmed the biocompatibility of the composite nanofibers. The scaffolds were able to hinder both of the Gram-negative and Gram-positive bacteria through direct contact with them. In vivo histopathological studies indicated that the scaffold incorporated rGO/Ag nanocomposites and curcumin has the most effect on wound healing and can promote the healing rate of artificial wounds, which indicates the good biomedical potential of nanomaterial in wound healing.

Mechanochemical reaction of Al and melamine: a potential approach towards the in situ synthesis of aluminum nitride-carbon nanotube nanocomposites.

In the current study, an inexpensive solid-state mechanochemical technique is proposed for the in situ synthesis of nanostructured aluminum nitride (AlN) and carbon nanotubes (CNTs). The CNTs and nitrogen-doped CNTs are synthesized through a novel bottom-up milling approach in which melamine as the solid source of both carbon and nitrogen is milled with aluminum. However, the efficiency of CNT formation remarkably enhances when the milled powder is exposed to a subsequent heat treatment. The effect of various parameters such as milling media, aluminum-to-melamine molar ratio (Al/M), milling time and subsequent heating temperature on the yield and formation mechanism of the produced CNTs are assessed. A detailed characterization of the final products reveals that small amorphous carbon nitride domains resulting from polymerization of melamine molecules at the intermediate stages of milling are responsible for the synthesis of CNTs either during the milling or subsequent heat treatment processes.

Electrospun triple-layered PLLA/gelatin. PRGF/PLLA scaffold induces fibroblast migration.

The function of fibroblast cells in wounded areas results in reconstruction of the extra cellular matrix and consequently resolution of granulation tissue. It is suggested that the use of platelet-rich plasma can accelerate the healing process in nonhealing or slow-healing wounds. In this study, a simple and novel method has been used to fabricate an electrospun three-layered scaffold containing plasma rich in growth factor with the aim of increasing the proliferation and migration of fibroblast cells in vitro. First, plasma rich in growth factor was derived from platelet rich plasma, and then a three-layered scaffold was fabricated using PLLA nanofibers as the outer layers and plasma rich in growth factor-containing gelatin fibers as the internal layer. The growth morphology of cells seeded on this scaffold was compared to those seeded on one layered PLLA scaffold. The study of the cell growth rate on different substrates and the migration of cells in response to the drug release of multilayered scaffold was investigated by the cell quantification assay and a modified under agarose assay. Scanning electron microscopy and fluorescence images showed that cells seeded on multilayered scaffold were completely oriented 72 hours after seeding compared to those seeded on PLLA scaffold. The cell quantification assay also indicated significant increase in proliferation rate of cells seeded on three-layered scaffold compared to those seeded on PLLA scaffold and finally, monitoring cell migration proved that cells migrate significantly toward the three-layered scaffold up to 48 to 72 hours and afterwards start to show a diminished migration rate toward this scaffold.

Magnetoelectric nanocomposite scaffold for high yield differentiation of mesenchymal stem cells to neural-like cells.

While the differentiation factors have been widely used to differentiate mesenchymal stem cells (MSCs) into various cell types, they can cause harm at the same time. Therefore, it is beneficial to propose methods to differentiate MSCs without factors. Herein, magnetoelectric (ME) nanofibers were synthesized as the scaffold for the growth of MSCs and their differentiation into neural cells without factors. This nanocomposite takes the advantage of the synergies of the magnetostrictive filler, CoFe2 O 4 nanoparticles (CFO), and piezoelectric polymer, polyvinylidene difluoride (PVDF). Graphene oxide nanosheets were decorated with CFO nanoparticles for a proper dispersion in the polymer through a hydrothermal process. After that, the piezoelectric PVDF polymer, which contained the magnetic nanoparticles, underwent the electrospun process to form ME nanofibers, the ME property of which has the potential to be used in areas such as tissue engineering, biosensors, and actuators.

Induced pluripotent stem cell-derived extracellular vesicles: A novel approach for cell-free regenerative medicine.

In recent years, induced pluripotent stem cells (iPSCs) have been considered as a promising approach in the field of regenerative medicine. iPSCs can be generated from patients' somatic cells and possess the potential to differentiate, under proper conditions, into any cell type. However, the clinical application of iPS cells is restricted because of their tumorigenic potential. Recent studies have indicated that stem cells exert their therapeutic benefit via a paracrine mechanism, and extracellular vesicles have been demonstrated that play a critical role in this paracrine mechanism. Due to lower immunogenicity, easier management, and presenting no risk of tumor formation, in recent years, researchers turned attention to exosomes as potential alternatives to whole-cell therapy. Application of exosomes derived from iPSCs and their derived precursor provides a promising approach for personalized regenerative medicine. This study reviews the physiological functions of extracellular vesicles and discusses their potential therapeutic benefit in regenerative medicine.

Dendrimer functionalized magnetic nanoparticles as a promising platform for localized hyperthermia and magnetic resonance imaging diagnosis.

Magnetic iron oxide nanoparticles are a well-explored class of nanomaterials known for their high magnetization and biocompatibility. They have been used in various biomedical applications such as drug delivery, biosensors, hyperthermia, and magnetic resonance imaging (MRI) contrast agent. It is necessary to surface modify the nanoparticles with a biocompatible moiety to prevent their agglomeration and enable them to target to the defined area. Dendrimers have attracted considerable attention due to their small size, monodispersed, well-defined globular shape, and a relative ease incorporation of targeting ligands. In this study, superparamagnetic iron oxide nanoparticles were synthesized via a coprecipitation method. The magnetic nanoparticles (MNPs) had been modified with (3-aminopropyl) triethoxysilane, and then polyamidoamine functionalized MNPs had been synthesized cycling. Various characterization techniques had been used to reveal the morphology, size, and structure of the nanoparticles such as scanning electron microscopy, transmission electron microscope, X-ray diffraction analysis, and vibrating sample magnetometer, Fourier-transform infrared spectroscopy and zeta potential measurements. In addition, the cytotoxicity property of G3-dendrimer functionalized MNPs were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide assay which confirmed the biocompatibility of the nanocomposites. Dendrimer functionalized MNPs are able to act as contrast agents for MRI and magnetic fluid hyperthermia mediators. A superior heat generation was achieved for the given concentration according to the hyperthermia results. MRI results show that the synthesized nanocomposites are a favorable option for MRI contrast agent. We believe that these dendrimer functionalized MNPs have the potential of integrating therapeutic and diagnostic functions in a single carrier.

Mechanochemical synthesis of nanostructured metal nitrides, carbonitrides and carbon nitride: a combined theoretical and experimental study.

Nowadays, the development of highly efficient routes for the low cost synthesis of nitrides is greatly growing. Mechanochemical synthesis is one of those promising techniques which is conventionally employed for the synthesis of nitrides by long term milling of metallic elements under a pressurized N2 or NH3 atmosphere (A. Calka and J. I. Nikolov, Nanostruct. Mater., 1995, 6, 409-412). In the present study, we describe a versatile, room-temperature and low-cost mechanochemical process for the synthesis of nanostructured metal nitrides (MNs), carbonitrides (MCNs) and carbon nitride (CNx). Based on this technique, melamine as a solid nitrogen-containing organic compound (SNCOC) is ball milled with four different metal powders (Al, Ti, Cr and V) to produce nanostructured AlN, TiCxN1-x, CrCxN1-x, and VCxN1-x (x ∼ 0.05). Both theoretical and experimental techniques are implemented to determine the reaction intermediates, products, by-products and finally, the mechanism underling this synthetic route. According to the results, melamine is polymerized in the presence of metallic elements at intermediate stages of the milling process, leading to the formation of a carbon nitride network. The CNx phase subsequently reacts with the metallic precursors to form MN, MCN or even MCN-CNx nano-composites depending on the defect formation energy and thermodynamic stability of the corresponding metal nitride, carbide and C/N co-doped structures.

Hybrid Magnetic-DNA Directed Immobilisation Approach for Efficient Protein Capture and Detection on Microfluidic Platforms.

In this study, a hybrid magnetic-DNA directed immobilisation approach is presented to enhance protein capture and detection on a microfluidic platform. DNA-modified magnetic nanoparticles are added in a solution to capture fluorescently labelled immunocomplexes to be detected optically. A magnetic set-up composed of cubic permanent magnets and a microchannel was designed and implemented based on finite element analysis results to efficiently concentrate the nanoparticles only over a defined area of the microchannel as the sensing zone. This in turn, led to the fluorescence emission localisation and the searching area reduction. Also, compared to processes in which the immunocomplex is formed directly on the surface, the proposed approach provides a lower steric hindrance, higher mass transfer, lower equilibrium time, and more surface concentration of the captured targets leading to a faster and more sensitive detection. As a proof-of-concept, the set-up is capable of detecting prostate-specific membrane antigen with concentrations down to 0.7 nM. Our findings suggest that the approach holds a great promise for applications in clinical assays and disease diagnosis.

Efficient protein immobilization on polyethersolfone electrospun nanofibrous membrane via covalent binding for biosensing applications.

In this paper we introduce novel strategy for antibody immobilization using high surface area electrospun nanofibrous membrane based on ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling chemistry. To present the high performance of proposed biosensors, anti-staphylococcus enterotoxin B (anti-SEB) was used as a model to demonstrate the utility of our proposed system. Polymer solution of polyethersolfone was used to fabricate fine nanofibrous membrane. Moreover, industrial polyvinylidene fluoride membrane and conventional microtiter plate were also used to compare the efficiency of antibody immobilization. Scanning electron microscopy images were taken to study the morphology of the membranes. The surface activation of nanofibrous membrane was done with the help of O2 plasma. PES nanofibrous membrane with carboxyl functional groups for covalent attachment of antibodies were treated by EDC/NHS coupling agent. The quantity of antibody immobilization was measured by enzyme-linked immuno sorbent assay (ELISA) method. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) spectroscopy was performed to confirm the covalent immobilization of antibody on membrane. Atomic force microscopy, scanning electron microscopy and invert fluorescence microscopy were used to analyze the antibody distribution pattern on solid surfaces. Results show that oxygen plasma treatment effectively increased the amount of antibody immobilization through EDC/NHS coupling chemistry. It was found that the use of nanofibrous membrane causes the improved detection signal of ELISA based biosensors in comparison to the standard assay carried out in the 96-well microtiter plate. This method has the potential to improve the ELISA-based biosensor and we believe that this technique can be used in various biosensing methods.

Synthesis and characterization of cadmium sulfide nanostructures by novel precursor via hydrothermal method.

A thioglycolic acid (TGA)-assisted hydrothermal process has been developed to synthesize cadmium sulfide nanostructures via reaction between a new precursor cadmium (II) phthalate and TGA. X-ray diffraction, transmission electron microscopy, photoluminescence spectroscopy and Fourier transform infrared were employed to characterize the obtained product. The effects of the reactant concentration, mole ratio of TGA to the Cd2+, temperature and reaction time on the morphology, size of particles, and phase of nanocrystalline CdS products were investigated.

Behavioral/Emotional Problems of Preschoolers: Caregiver/Teacher Reports From 15 Societies.

This study tested societal effects on caregiver/teacher ratings of behavioral/emotional problems for 10,521 preschoolers from 15 societies. Many societies had problem scale scores within a relatively narrow range, despite differences in language, culture, and other characteristics. The small age and gender effects were quite similar across societies. The rank orders of mean item ratings were similar across diverse societies. For 7,380 children from 13 societies, ratings were also obtained from a parent. In all 13 societies, mean Total Problems scores derived from parent ratings were significantly higher than mean Total Problems scores derived from caregiver/teacher ratings, although the size of the difference varied somewhat across societies. Mean cross-informant agreement for problem scale scores varied across societies. Societies were very similar with respect to which problem items, on average, received high versus low ratings from parents and caregivers/teachers. Within every society, cross-informant agreement for item ratings varied widely across children. In most respects, results were quite similar across 15 very diverse societies.

International comparisons of behavioral and emotional problems in preschool children: parents' reports from 24 societies.

International comparisons were conducted of preschool children's behavioral and emotional problems as reported on the Child Behavior Checklist for Ages 1½-5 by parents in 24 societies (N = 19,850). Item ratings were aggregated into scores on syndromes; Diagnostic and Statistical Manual of Mental Disorders-oriented scales; a Stress Problems scale; and Internalizing, Externalizing, and Total Problems scales. Effect sizes for scale score differences among the 24 societies ranged from small to medium (3-12%). Although societies differed greatly in language, culture, and other characteristics, Total Problems scores for 18 of the 24 societies were within 7.1 points of the omnicultural mean of 33.3 (on a scale of 0-198). Gender and age differences, as well as gender and age interactions with society, were all very small (effect sizes < 1%). Across all pairs of societies, correlations between mean item ratings averaged .78, and correlations between internal consistency alphas for the scales averaged .92, indicating that the rank orders of mean item ratings and internal consistencies of scales were very similar across diverse societies.

Preschool psychopathology reported by parents in 23 societies: testing the seven-syndrome model of the child behavior checklist for ages 1.5-5.

OBJECTIVE: To test the fit of a seven-syndrome model to ratings of preschoolers' problems by parents in very diverse societies. METHOD: Parents of 19,106 children 18 to 71 months of age from 23 societies in Asia, Australasia, Europe, the Middle East, and South America completed the Child Behavior Checklist for Ages 1.5-5 (CBCL/1.5-5). Confirmatory factor analyses were used to test the seven-syndrome model separately for each society. RESULTS: The primary model fit index, the root mean square error of approximation (RMSEA), indicated acceptable to good fit for each society. Although a six-syndrome model combining the Emotionally Reactive and Anxious/Depressed syndromes also fit the data for nine societies, it fit less well than the seven-syndrome model for seven of the nine societies. Other fit indices yielded less consistent results than the RMSEA. CONCLUSIONS: The seven-syndrome model provides one way to capture patterns of children's problems that are manifested in ratings by parents from many societies. Clinicians working with preschoolers from these societies can thus assess and describe parents' ratings of behavioral, emotional, and social problems in terms of the seven syndromes. The results illustrate possibilities for culture-general taxonomic constructs of preschool psychopathology. Problems not captured by the CBCL/1.5-5 may form additional syndromes, and other syndrome models may also fit the data.