A Soft Total Artificial Heart-First Concept Evaluation on a Hybrid Mock Circulation.

The technology of 3D-printing has allowed the production of entirely soft pumps with complex chamber geometries. We used this technique to develop a completely soft pneumatically driven total artificial heart from silicone elastomers and evaluated its performance on a hybrid mock circulation. The goal of this study is to present an innovative concept of a soft total artificial heart (sTAH). Using the form of a human heart, we designed a sTAH, which consists of only two ventricles and produced it using a 3D-printing, lost-wax casting technique. The diastolic properties of the sTAH were defined and the performance of the sTAH was evaluated on a hybrid mock circulation under various physiological conditions. The sTAH achieved a blood flow of 2.2 L/min against a systemic vascular resistance of 1.11 mm Hg s/mL (afterload), when operated at 80 bpm. At the same time, the mean pulmonary venous pressure (preload) was fixed at 10 mm Hg. Furthermore, an aortic pulse pressure of 35 mm Hg was measured, with a mean aortic pressure of 48 mm Hg. The sTAH generated physiologically shaped signals of blood flow and pressures by mimicking the movement of a real heart. The preliminary results of this study show a promising potential of the soft pumps in heart replacements. Further work, focused on increasing blood flow and in turn aortic pressure is required.

Rapid surface-biostructure interaction analysis using strong metal-based nanomagnets.

Nanomaterials are increasingly suggested for the selective adsorption and extraction of complex compounds in biomedicine. Binding of the latter requires specific surface modifications of the nanostructures. However, even complicated macromolecules such as proteins can afford affinities toward basic surface characteristics such as hydrophobicity, topology, and electrostatic charge. In this study, we address these more basic physical interactions. In a model system, the interaction of bovine serum albumin and amyloid ß 42 fibrillar aggregates with carbon-coated cobalt nanoparticles, functionalized with various polymers differing in character, was studied. The possibility of rapid magnetic separation upon binding to the surface represents a valuable tool for studying surface interactions and selectivities. We find that the surface interaction of Aß 42 fibrillar aggregates is mostly hydrophobic in nature. Because bovine serum albumin (BSA) is conformationally adaptive, it is known to bind surfaces with widely differing properties (charge, topology, and hydrophobicity). However, the rate of tight binding (no desorption upon washing) can vary largely depending on the extent of necessary conformational changes for a specific surface. We found that BSA can only bind slowly to polyethylenimine-coated nanomagnets. Under competitive conditions (high excess BSA compared to that for ß 42 fibrillar aggregates), this effect is beneficial for targeting the fibrillar species. These findings highlight the possibility of selective extractions from complex media when advantageous basic physical surface properties are chosen.

Physical defect formation in few layer graphene-like carbon on metals: influence of temperature, acidity, and chemical functionalization.

A systematical examination of the chemical stability of cobalt metal nanomagnets with a graphene-like carbon coating is used to study the otherwise rather elusive formation of nanometer-sized physical defects in few layer graphene as a result of acid treatments. We therefore first exposed the core-shell nanomaterial to well-controlled solutions of altering acidity and temperature. The release of cobalt into these solutions over time offered a simple tool to monitor the progress of particle degradation. The results suggested that the oxidative damage of the graphene-like coatings was the rate-limiting step during particle degradation since only fully intact or entirely emptied carbon shells were found after the experiments. If ionic noble metal species were additionally present in the acidic solutions, the noble metal was found to reduce on the surface of specific, defective particles. The altered electrochemical gradients across the carbon shells were however not found to lead to a faster release of cobalt from the particles. The suggested mechanistic insight was further confirmed by the covalent chemical functionalization of the particle surface with chemically inert aryl species, which leads to an additional thickening of the shells. This leads to reduced cobalt release rates as well as slower noble metal reduction rates depending on the augmentation of the shell thickness.

Effects of flame made zinc oxide particles in human lung cells - a comparison of aerosol and suspension exposures.

BACKGROUND: Predominantly, studies of nanoparticle (NPs) toxicology in vitro are based upon the exposure of submerged cell cultures to particle suspensions. Such an approach however, does not reflect particle inhalation. As a more realistic simulation of such a scenario, efforts were made towards direct delivery of aerosols to air-liquid-interface cultivated cell cultures by the use of aerosol exposure systems.This study aims to provide a direct comparison of the effects of zinc oxide (ZnO) NPs when delivered as either an aerosol, or in suspension to a triple cell co-culture model of the epithelial airway barrier. To ensure dose-equivalence, ZnO-deposition was determined in each exposure scenario by atomic absorption spectroscopy. Biological endpoints being investigated after 4 or 24h incubation include cytotoxicity, total reduced glutathione, induction of antioxidative genes such as heme-oxygenase 1 (HO-1) as well as the release of the (pro)-inflammatory cytokine TNFα. RESULTS: Off-gases released as by-product of flame ZnO synthesis caused a significant decrease of total reduced GSH and induced further the release of the cytokine TNFα, demonstrating the influence of the gas phase on aerosol toxicology. No direct effects could be attributed to ZnO particles. By performing suspension exposure to avoid the factor "flame-gases", particle specific effects become apparent. Other parameters such as LDH and HO-1 were not influenced by gaseous compounds: Following aerosol exposure, LDH levels appeared elevated at both timepoints and the HO-1 transcript correlated positively with deposited ZnO-dose. Under submerged conditions, the HO-1 induction scheme deviated for 4 and 24h and increased extracellular LDH was found following 24h exposure. CONCLUSION: In the current study, aerosol and suspension-exposure has been compared by exposing cell cultures to equivalent amounts of ZnO. Both exposure strategies differ fundamentally in their dose-response pattern. Additional differences can be found for the factor time: In the aerosol scenario, parameters tend to their maximum already after 4h of exposure, whereas under submerged conditions, effects appear most pronounced mainly after 24h. Aerosol exposure provides information about the synergistic interplay of gaseous and particulate phase of an aerosol in the context of inhalation toxicology. Exposure to suspensions represents a valuable complementary method and allows investigations on particle-associated toxicity by excluding all gas-derived effects.

In vivo risk evaluation of carbon-coated iron carbide nanoparticles based on short- and long-term exposure scenarios.

BACKGROUND: While carbon-encapsulated iron carbide nanoparticles exhibit strong magnetic properties appealing for biomedical applications, potential side effects of such materials remain comparatively poorly understood. Here, we assess the effects of iron-based nanoparticles in an in vivo long-term study in mice with observation windows between 1 week and 1 year. MATERIALS & METHODS: Functionalized (PEG or IgG) carbon-encapsulated platinum-spiked iron carbide nanoparticles were injected intravenously in mice (single or repeated dose administration). RESULTS: One week after administration, magnetic nanoparticles were predominantly localized in organs of the reticuloendothelial system, particularly the lung and liver. After 1 year, particles were still present in these organs, however, without any evident tissue alterations, such as inflammation, fibrosis, necrosis or carcinogenesis. Importantly, reticuloendothelial system organs presented with normal function. CONCLUSION: This long-term exposure study shows high in vivo compatibility of intravenously applied carbon-encapsulated iron nanoparticles suggesting continuing investigations on such materials for biomedical applications.

Template-particle stabilized bicontinuous emulsion yielding controlled assembly of hierarchical high-flux filtration membranes.

A novel solvent-evaporation-based process that exploits template-particle stabilized bicontinuous emulsions for the formation of previously unreached membrane morphologies is reported in this article. Porous membranes have a wide range of applications spanning from water filtration, pharmaceutical purification, and battery separators to scaffolds for tissue engineering. Different situations require different membrane morphologies including various pore sizes and pore gradients. However, most of the previously reported membrane preparation procedures are restricted to specific morphologies and morphology alterations require an extensive optimization process. The tertiary system presented in this article, which consists of a poly(ether sulfone)/dimethylacetamide (PES/DMAc) solution, glycerol, and ZnO-nanoparticles, allows simple and exact tuning of pore diameters ranging from sub-20 nm, up to 100 nm. At the same time, the pore size gradient is controlled from 0 up to 840%/µm yielding extreme asymmetry. In addition to structural analysis, water flux rates of over 5600 L m(-2) h(-1) are measured for membranes retaining 45 nm silica beads.

Adsorption and separation of amyloid beta aggregates using ferromagnetic nanoparticles coated with charged polymer brushes.

Amyloid beta (Aß) protein aggregates, which include fibrils and oligomers, are neurotoxic and are considered to cause Alzheimer's disease. Thus, separation of these Aß aggregates from biological samples is important. Herein, we report the use of strongly ferromagnetic few-layer graphene-coated magnetic nanoparticles (C/Co), which were functionalized with a cationic polymer, poly[3-(methacryloyl amino)propyl]trimethylammonium chloride (polyMAPTAC), C/Co@polyMAPTAC, for the adsorption and magnetic separation of Aß aggregates. Fast adsorption (∼1 min) of Aß fibrils and oligomers onto the particles was observed. Interestingly, the Aß monomer was not captured by the particles, suggesting that binding to Aß molecules is toxic species-selective. Selective adsorption was also observed in the presence of serum albumin protein. We also showed that C/Co@polyMAPTAC could reduce the cytotoxicity of the Aß aggregate solutions. This study should be useful for further elucidation of the application of nanoparticle adsorption in mediating Aß toxicity.

Uptake of ferromagnetic carbon-encapsulated metal nanoparticles in endothelial cells: influence of shear stress and endothelial activation.

AIM: Magnetic field guided drug targeting holds promise for more effective cancer treatment. Intravascular application of magnetic nanoparticles, however, bears the risk of potentially important, yet poorly understood side effects, such as off-target accumulation in endothelial cells. MATERIALS & METHODS: Here, we investigated the influence of shear stress (0-3.22 dyn/cm(2)), exposure time (5-30 min) and endothelial activation on the uptake of ferromagnetic carbon-encapsulated iron carbide nanomagnets into endothelial cells in an in vitro flow cell model. RESULTS: We found that even moderate shear stresses typically encountered in the venous system strongly reduce particle uptake compared with static conditions. Interestingly, a pronounced particle uptake was observed in inflamed endothelial cells. CONCLUSION: This study highlights the importance of relevant exposure scenarios accounting for physiological conditions when studying particle-cell interactions as, for example, shear stress and endothelial activation are major determinants of particle uptake. Such considerations are of particular importance with regard to successful translation of in vitro findings into (pre-)clinical end points.

Characterization of carbon-coated magnetic nanoparticles using clinical blood coagulation assays: effect of PEG-functionalization and comparison to silica nanoparticles.

Intravascular application of magnetic nanocarriers is a critical step in the development of new therapeutic strategies, including magnetic drug targeting or hyperthermia. However, injection of particulate matter bears the intrinsic risk of contact activation of the blood coagulation cascade. In this work, we use point-of-care assays to study coagulation dynamics and clotting parameters in blood samples exposed to relevant concentrations of surface-functionalized carbon-coated iron carbide nanomagnets using unmodified nanomagnets and poly(ethylene)glycol-functionalized nanomagnets with different end-groups, including -OCH3, -NH2, -COOH, -IgG, and -ProteinA-protected-IgG (-IgG-ProtA). Silica nanoparticles with a comparable surface area are used as a reference material. For magnetic nanoparticles, we observe a decrease in clotting time by 25% compared to native blood at concentrations of 1 mg mL-1, independent of the surface functionalization, and only minor differences in receptor expression on platelets (GP-IIb-IIIa, CD62, and CD63) relative to control samples were observed. Interestingly, the inter-subject variance of the clotting time is similar to the nanoparticle-induced effect in a single subject with average clotting time. Whilst the present study is based on in vitro assays and a small group of healthy blood donors, the comparison to broadly used silica nanoparticles, and the fact that experimental intergroup variability is comparable to the observed effects from the carbon-coated nanomagnets suggests continuing investigations on their potential clinical use.

Endotoxin removal by magnetic separation-based blood purification.

This work describes a magnetic separation-based approach using polymyxin B-functionalized metal alloy nanomagnets for the rapid elimination of endotoxins from human blood in vitro and functional assays to evaluate the biological relevance of the blood purification process. Playing a central role in gram-negative sepsis, bacteria-derived endotoxins are attractive therapeutic targets. However, both direct endotoxin detection in and removal from protein-rich fluids remains challenging. We present the synthesis and functionalization of ultra-magnetic cobalt/iron alloy nanoparticles and a magnetic separation-based approach using polymyxin B-functionalized nanomagnets to remove endotoxin from human blood in vitro. Conventional chromogenic Limulus Amebocyte Lysate assays confirm decreased endotoxin activity in purified compared to untreated samples. Functional assays assessing key steps in host defense against bacteria show an attenuated inflammatory mediator expression from human primary endothelial cells in response to purified blood samples compared to untreated blood and less chemotactic activity. Exposing Escherichia coli-positive blood samples to polymyxin B-functionalized nanomagnets even impairs the ability of gram-negative bacteria to form colony forming units, thus making magnetic separation based blood purification a promising new approach for future sepsis treatment.

Nanomagnet-based removal of lead and digoxin from living rats.

In a number of clinical conditions such as intoxication, bacteraemia or autoimmune diseases the removal of the disease-causing factor from blood would be the most direct cure. However, physicochemical characteristics of the target compounds limit the applicability of classical filtration and diffusion-based processes. In this work, we present a first in vivo magnetic blood purification rodent animal model and demonstrate its ability to rapidly clear toxins from blood circulation using two model toxins with stable plasma levels (lead (Pb(2+)) and digoxin). Ultra-strong functionalized metal nanomagnets are employed to eliminate the toxin from whole blood in an extracorporeal circuit. In the present experimental demonstration over 40% of the toxin (i.e. lead or digoxin) was removed within the first 10 minutes and over 75% within 40 minutes. After capturing the target substance, a magnetic trap prevents the toxin-loaded nanoparticles from entering the blood circulation. Elemental analysis and magnetic hysteresis measurements confirm full particle recovery by simple magnetic separation (residual particle concentration below 1 µg mL(-1) (detection limit)). We demonstrate that magnetic separation-based blood purification offers rapid blood cleaning from noxious agents, germs or other deleterious materials with relevance to a number of clinical conditions. Based on this new approach, current blood purification technologies can be extended to efficiently remove disease-causing factors, e.g. overdosed drugs, bacteria or cancer cells without being limited by filter cut-offs or column surface saturation.

Electrical resistivity of assembled transparent inorganic oxide nanoparticle thin layers: influence of silica, insulating impurities, and surfactant layer thickness.

The electrical properties of transparent, conductive layers prepared from nanoparticle dispersions of doped oxides are highly sensitive to impurities. Production of cost-effective thin conducting films for consumer electronics often employs wet processing such as spin and/or dip coating of surfactant-stabilized nanoparticle dispersions. This inherently results in entrainment of organic and inorganic impurities into the conducting layer leading to largely varying electrical conductivity. Therefore, this study provides a systematic investigation on the effect of insulating surfactants, small organic molecules and silica in terms of pressure dependent electrical resistivity as a result of different core/shell structures (layer thickness). Application of high temperature flame synthesis gives access to antimony-doped tin oxide (ATO) nanoparticles with high purity. This well-defined starting material was then subjected to representative film preparation processes using organic additives. In addition ATO nanoparticles were prepared with a homogeneous inorganic silica layer (silica layer thickness from 0.7 to 2 nm). Testing both organic and inorganic shell materials for the electronic transport through the nanoparticle composite allowed a systematic study on the influence of surface adsorbates (e.g., organic, insulating materials on the conducting nanoparticle's surface) in comparison to well-known insulators such as silica. Insulating impurities or shells revealed a dominant influence of a tunneling effect on the overall layer resistance. Mechanical relaxation phenomena were found for 2 nm insulating shells for both large polymer surfactants and (inorganic) SiO(2) shells.