Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity.

Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.

Graphene materials as 2D non-viral gene transfer vector platforms.

Advances in genomics and gene therapy could offer solutions to many diseases that remain incurable today, however, one of the critical reasons halting clinical progress is due to the difficulty in designing efficient and safe delivery vectors for the appropriate genetic cargo. Safety and large-scale production concerns counter-balance the high gene transfer efficiency achieved with viral vectors, while non-viral strategies have yet to become sufficiently efficient. The extraordinary physicochemical, optical and photothermal properties of graphene-based materials (GBMs) could offer two-dimensional components for the design of nucleic acid carrier systems. We discuss here such properties and their implications for the optimization of gene delivery. While the design of such vectors is still in its infancy, we provide here an exhaustive and up-to-date analysis of the studies that have explored GBMs as gene transfer vectors, focusing on the functionalization strategies followed to improve vector performance and on the biological effects attained.

Engineering Cell Fate for Tissue Regeneration by In Vivo Transdifferentiation.

Changes in cell identity occur in adult mammalian organisms but are rare and often linked to disease. Research in the last few decades has thrown light on how to manipulate cell fate, but the conversion of a particular cell type into another within a living organism (also termed in vivo transdifferentiation) has only been recently achieved in a limited number of tissues. Although the therapeutic promise of this strategy for tissue regeneration and repair is exciting, important efficacy and safety concerns will need to be addressed before it becomes a reality in the clinical practice. Here, we review the most relevant in vivo transdifferentiation studies in adult mammalian animal models, offering a critical assessment of this potentially powerful strategy for regenerative medicine.

Graphene for multi-functional synthetic biology: the last 'zeitgeist' in nanomedicine.

The high versatility of graphene has attracted significant attention in many areas of scientific research from electronics to physics and mechanics. One of the most intriguing utilisation of graphene remains however in nanomedicine and synthetic biology. In particular, the last decade has witnessed an exponential growth in the generation of novel candidate therapeutics of multiple biological activities based on graphene constructs with small molecules, such as anti-cancer drugs. In this Digest, we summarise the different synthetic strategies and routes available to fabricate these promising graphene conjugates and the opportunities for the design of multi-functional tools for synthetic biology that they offer.

Chronic ecotoxic effects to Pseudomonas putida and Vibrio fischeri, and cytostatic and genotoxic effects to the hepatoma cell line (HepG2) of ofloxacin photo(cata)lytically treated solutions.

Ofloxacin (OFL), a broad-spectrum and widespread-used photolabile fluoroquinolone, is frequently found in treated wastewaters, aquatic and terrestrial ecosystems leading to increasing concern during the past decades regarding its effects to the environment and human health. The elimination of OFL and other xenobiotics by the application of advanced oxidation processes using photolytic (PL) and photocatalytic (PC) treatments seems promising. However, an integrated assessment scheme is needed, in which, not only the removal of the parent compound, but also the effects of the photo-transformation products (PTPs) are investigated. For this purpose, in the present study, a chronic ecotoxic assessment using representative bacteria of marine and terrestrial ecosystems and a cytostatic and genotoxic evaluation using hepatoma cell line were performed. PL and PC treatments of OFL were applied using UV radiation. The photo-transformation of OFL during the treatments was monitored by DOC measurements and UPLC-MS/MS analysis. The chronic ecotoxicity of OFL and treated samples was evaluated using Pseudomonas putida and Vibrio fischeri; whereas the cytostasis and genotoxicity were estimated by the cytokinesis-block micronucleus assay (CBMN). The main results suggest that photo-transformation of OFL took place during these treatments since the concentration of OFL decreased when the irradiation time increased, as quantified by UPLC-MS/MS analysis, and this was not coupled with an analogous DOC removal. Furthermore, nine compounds were identified as probable PTPs formed through piperazinyl dealkylation and decarboxylation. The ecotoxicity of treated solutions to the bacteria studied decreased while the cytostasis to the hepatoma cell line remained at low levels during both treatments. However, the genotoxicity to the hepatoma cell line demonstrated a different pattern in which treated samples induced a greater number of MNi for the 4-16 min of irradiation (p<0.05) during both treatments. After 64 min of irradiation, the effects decreased to non genotoxic levels (p<0.05). These findings suggest that UV radiation for various treatment processes (catalytic or not), such as disinfection, may create genotoxic by-products. Therefore, in relevant technical applications, the residence time during treatment should receive special attention.

Promises, facts and challenges for carbon nanotubes in imaging and therapeutics.

The use of carbon nanotubes in medicine is now at the crossroads between a proof-of-principle concept and an established preclinical candidate for a variety of therapeutic and diagnostic applications. Progress towards clinical trials will depend on the outcomes of efficacy and toxicology studies, which will provide the necessary risk-to-benefit assessments for carbon-nanotube-based materials. Here we focus on carbon nanotubes that have been studied in preclinical animal models, and draw attention to the promises, facts and challenges of these materials as they transition from research to the clinical phase. We address common questions regarding the use of carbon nanotubes in disease imaging and therapy, and highlight the opportunities and challenges ahead.

Subcellular S-factors for low-energy electrons: a comparison of Monte Carlo simulations and continuous-slowing-down calculations.

PURPOSE: To study the energy deposition by low-energy electrons in submicron tissue-equivalent targets by comparing two widely used methodologies, namely, the continuous-slowing-down-approximation (CSDA) convolution integral and the Monte Carlo (MC) simulation. METHODS: An MC track-structure code that simulates collision-by-collision the complete slowing down process is used to calculate the energy deposition in spherical volumes of unit density water medium. Comparisons are made with calculations based on the CSDA convolution integral using both empirical and MC-based range-energy analytic formulae. RESULTS: We present self-irradiation absorbed fractions and S-factors for monoenergetic electrons of initial energies from 0.1-10 keV distributed uniformly in spheres of 5, 10, 50, 100, 500, and 1000 nm radius. The MC and CSDA results were found, in some cases, to differ by a factor of 2 or more; differences generally increase with decreasing sphere size. Contrary to high energies, the uncertainties associated with the straight-ahead approximation implicit in the CSDA calculations are of the same order as those related to straggling and delta-ray effects. CONCLUSION: The use of the CSDA methodology may be unsuitable for the sub-micron scale where a more realistic description of electron transport becomes important.

A Monte-Carlo code for the detailed simulation of electron and light-ion tracks in condensed matter.

In an effort to understand the basic mechanism of the action of charged particles in solid radiation dosimeters, we extend our Monte-Carlo code (MC4) to condensed media (liquids/solids) and present new track-structure calculations for electrons and protons. Modeling the energy dissipation process is based on a model dielectric function, which accounts in a semi-empirical and self-consistent way for condensed-phase effects which are computationally intractable. Importantly, these effects mostly influence track-structure characteristics at the nanometer scale, which is the focus of radiation action models. Since the event-by-event scheme for electron transport is impractical above several kilo-electron volts, a condensed-history random-walk scheme has been implemented to transport the energetic delta rays produced by energetic ions. Based on the above developments, new track-structure calculations are presented for two representative dosimetric materials, namely, liquid water and silicon. Results include radial dose distributions in cylindrical and spherical geometries, as well as, clustering distributions, which, among other things, are important in predicting irreparable damage in biological systems and prompt electric-fields in microelectronics.

An analytic dosimetry study for the use of radionuclide-liposome conjugates in internal radiotherapy.

UNLABELLED: A dosimetric analysis has been performed to evaluate the potential of liposome systems as carriers of radionuclides in internal radiotherapy. METHODS: Pharmacokinetic data for a variety of liposome constructs (multilamellar vesicles [MLV]; small unilamellar vesicles [SUV]; and sterically stabilized liposomes, monosialoganglioside [G(M1)]-coated) were used to obtain tumor and normal-organ absorbed dose estimates for (67)Cu, (188)Re, (90)Y, and (131)I. Dosimetry was performed for two tumor models: subcutaneous Ehrlich ascites tumor, growing intramuscularly, and C26 colon carcinoma, growing intrahepatically. Dose estimates were obtained using the MIRD schema. Tumor doses were obtained assuming local deposition of electron energy; photon contributions were incorporated assuming spheric tumor geometry. With the conservative assumption that intravenously administered liposomes achieve rapid equilibration with the red marrow extracellular fluid volume, red marrow absorbed dose estimates were obtained from blood kinetics. RESULTS: For intramuscular tumors, absorbed dose ratios for tumor to red marrow ranged from 0.93 ((131)I-MLV) to 13.9 ((90)Y-SUV). Tumor-to-liver ratios ranged from 0.08 ((188)Re-MLV) to 0.92 ((188)Re-SUV); corresponding values for tumor to spleen were 0.13 ((90)Y-MLV) and 0.54 ((188)Re-G(M1)). The optimal combination of radionuclide and liposome system was obtained with (90)Y-SUV. Tumor-to-liver ratios for the G(M1)-coated construct were greatest when the tumor was intrahepatic (1.13 for (90)Y). For a given liposome system, absorbed dose ratios for tumor to normal tissue exhibited up to a twofold variation depending on the radionuclide selected. CONCLUSION: This study provides a dosimetric evaluation for the use of some liposome systems as carriers in targeted radionuclide therapy. Although much further work must be undertaken before any clinical application is considered, these results suggest that radionuclide targeting using liposomes is feasible and may have the advantage of reduced red marrow absorbed dose.

A Monte Carlo track structure code for electrons (approximately 10 eV-10 keV) and protons (approximately 0.3-10 MeV) in water: partitioning of energy and collision events.

An event-by-event Monte Carlo simulation code for track structure studies is described. In the present form the code transports protons (approximately 0.3-10 MeV) and electrons (approximately 10 eV-10 keV) in a water medium in the gas phase approximation. For the type of particles and energy range considered, ionization, electronic excitation and electron elastic scattering are the most important collision events accounted for in the transport simulation. Efforts were made to ensure that the analytic representation of the various interaction cross sections rests on well established experimental data and theory. For example, the secondary-electron spectrum as well as partial and total ionization cross sections are represented by a semitheoretical formulation combining Bethe's asymptotic expansion and binary-encounter theory. Binding effects for five levels of ionization and eight levels of electronic excitation of the water molecule are explicitly considered. The validity of the model cross sections is examined against available experimental data and theoretical predictions from other similar studies. Results pertaining to the partitioning of energy loss and interaction events for the first-collision probability and nanometre-size track segments are presented.

Tissue dosimetry of liposome-radionuclide complexes for internal radiotherapy: toward liposome-targeted therapeutic radiopharmaceuticals.

BACKGROUND: Quantitative examination of the important physical parameters, such as the tumor absorbed dose and the tumor-to-normal-tissue (T-NT) absorbed dose ratios, for effective use of radionuclide-liposome conjugates m internal radiotherapy was carried out. METHODS: The Medical Internal Radiation Dose (MIRD) formalism was used to develop a set of dosimetric equations. Pharmacokinetic functions used as input information to the dosimetric model were derived from experimental time-biodistribution data. Multilamellar (MLV), small unilamellar (SUV) and sterically stabilized (GM1- and PEG-coated) liposomes were examined in combination with the very promising particle emitting radionuclides: 67Cu, 188Re and 211At. For comparative purposes, the widely used: 90Y and 131I were also included in the study. For all radionuclide-liposome combinations, the mean absorbed dose per amount of radioactivity administered was obtained: (i) for two different types of human xenografts located in the muscle and liver tissue, and (ii) for normal liver, spleen, kidneys, and total body. RESULTS: Regardless of radionuclide, the poorest values were obtained for the MLV liposomes. Due to more rapid uptake of sterically stabilized (GM,-coated) liposomes to the muscle tumor tissue as compared to SUVs, 211At and 188Re deliver higher tumor doses when combined with the former, while 67Cu, 90Y and 131I are more effective with SUVs. The most promising results were obtained for the [211At-GM1] complex in the liver tumor. CONCLUSION: The importance of liposome size and steric barrier when designing effective radionuclide-carrier systems was revealed, but most importantly the optimal matching between the radionuclide half-life and the time of maximum liposome accumulation ratio between the tumor and normal tissue.

Free cholesterol enhances adenoviral vector gene transfer and expression in CAR-deficient cells.

Efficient adenovirus vector-mediated gene transfer depends on the presence of sufficient amounts of the high-affinity coxsackie-adenovirus (Ad) receptor (CAR) on the surface of the target cell leading to receptor-mediated endocytosis of the vector. The present study evaluates the effect of free cholesterol, a lipid component of endocytic vesicles, on Ad uptake into CAR-deficient cells. Infection in the presence of free cholesterol at its maximum solubility in water led to increased binding, uptake, and expression of Ad in human skin fibroblasts and alveolar macrophages, two primary human cells known to be deficient in CAR. The effect of free cholesterol was maximal at its solubility maximum in aqueous solution. Increase of Ad vector-mediated gene transfer with cholesterol was dependent on the lack of CAR receptor expression on the surface and was diminished by overexpression of CAR in CAR-deficient cells. Cholesterol-mediated increase of Ad-mediated gene expression was dependent on coincubation of both cholesterol and Ad and was not dependent on the cholesterol content of the cell. Increased Ad vector-mediated gene expression in the presence of free cholesterol was also observed in murine skin in vivo. Structural analysis of the Ad-cholesterol mixture showed complexation between Ad particles leading to formation of multivirus aggregates due to hydrophobic interaction. The addition of free cholesterol with Ad vectors may be a simple way to increase Ad-mediated gene transfer to cells that are poor targets due to their lack of a sufficient number of Ad receptors.

Double-blind clinical study reveals synergistic action between alpha-hydroxy acid and betamethasone lotions towards topical treatment of scalp psoriasis.

OBJECTIVE: A double-blind, single-site, split-face clinical study was organized and carried out in order to evaluate the efficacy, tolerability, and safety of a glycolic acid containing scalp lotion in conjunction with a betamethasone (as the 17-valerate) scalp application against conditions of psoriasis. BACKGROUND: Alpha-hydroxy acids (AHA) have been proposed as therapeutic modalities against skin exfoliative conditions such as ichthyosis, xeroderma, and psoriasis. AHAs are hereby clinically investigated as therapeutic modalities adjuvant to corticosteroids in order to diminish systemic and topical adverse side-effects most frequently associated with use of the latter. METHODS: Twenty patients suffering from scalp psoriasis and other psoriatic conditions were included in a double-blind, split-face clinical study, using combinations of a 10% (w/w) glycolic acid scalp lotion, placebo lotion (excipients only), and a 0.1% (w/w) betamethasone scalp application, applied twice daily without any bandage for a period of 8 weeks. Clinical assessments were carried out by highly experienced physician evaluations based on a four-grade scale, prior to treatment and after 2, 4, 6 and 8 weeks. RESULTS: Improvement was observed in all cases included in the study following treatment with the 10% glycolic acid lotion. However, when equal parts of the 0.1% betamethasone lotion were combined, most of the treated sites were healed. Moreover, the duration of treatment required for healing was in this case reduced to approximately half of that needed when the glycolic acid or the betamethasone lotions were used separately for treatment. CONCLUSIONS: The present clinical study demonstrates for the first time that the effective and well tolerated therapeutic efficacy of glycolic acid scalp lotions is enhanced when used in conjunction with a 0.1% betamethasone scalp application against scalp psoriasis. This potential offers the practising dermatologist with novel treatment modes against severe skin conditions by combining topical corticosteroid with exfoliative agent therapy.

Addition of (Tri-)Block Copolymers to Phospholipid Vesicles: A Study of the Molecular Morphology and Structure by Using Hydrophobic Dye Molecules as Bilayer Probes

A dispersion of soybean lecithin in water leads to the formation of multilamellar vesicles (MLVs), which on sonication break down into small unilamellar vesicles of approximately 50 nm in diameter. The addition of polymeric molecules in the liposomal system is thought to provide the liposomes with a steric barrier. The molecules used were (tri-) block copolymers (Synperonics) containing a central hydrophobic part (polypropylene oxide) and two hydrophilic chains (polyethylene oxide). The aim of this work was to study whether it was possible to anchor deep inside the lipid bilayer the copolymer hydrophobic block. The exact localization of the copolymer molecules was investigated using a multiprobe technique. The full spectra of two hydrophobic dyes, namely Nile red (NIL) and Pinacyanol chloride (PCYN), were compared while solubilized inside the liposome bilayer. The sensitivity of their spectral characteristics to polarity and self-aggregation produced a monitor of the bilayer microenvironment. The more hydrophobic NIL proved an accurate polarity sensor of the bilayer microenvironment and the formation of PCYN dimers and nonabsorbing aggregates can be directly related to the local (bilayer) concentration of the dye and the volume available to the solubilized dye molecules. Shifts of the maximum absorbance (lambdamax) for both dyes showed that the bilayer environment was becoming more apolar with increasing copolymer concentration. The absorbance peak of PCYN due to dimer/aggregate formation increased at moderate copolymer concentrations, indicating that the polymer is incorporated inside the lipid bilayer.