Self-seeded coprecipitation flow synthesis of iron oxide nanoparticles via triphasic reactor platform: Optimising heating performance under alternating magnetic fields

Liquid-liquid segmentation is a common method to prevent reactor fouling when synthesising nanoparticles in flow, despite limiting synthetic protocols to single reagent addition steps before segmentation. This work demonstrates how a modular triphasic (gas–liquid–liquid) flow reactor platform overcomes this limitation, facilitating a continuous and fouling-free four-step co-precipitation flow synthesis of iron oxide nanoparticles (IONPs) for magnetically induced hyperthermia cancer treatment (MHCT). For this and other biomedical applications water-based IONP syntheses such as co-precipitation are favoured, but producing IONPs > 10 nm as needed for MHCT remains challenging. To overcome this size barrier for co-precipitation syntheses, a seeded growth co-precipitation strategy was employed here for the first time. After demonstrating the synthesis in batch, a triphasic flow reactor was developed to translate the multistep batch protocol into flow. Nitrogen gas was used to space the liquid–liquid segmented slugs evenly, enabling self-synchronised solution addition into the aqueous slugs dispersed in heptane. Three additions of the iron precursor solution followed by citric acid solution addition formed the seeds, grew them to larger IONPs and stabilised them. The flow platform was used for screening of the synthetic parameters to optimise the IONP heating performance in an alternating magnetic field, hence investigating their potential as MHCT heating agents. The optimal reactor settings identified made it possible to continuously synthesise 0.46 gIONPs/h colloidally stable IONPs in the aqueous phase of size ∼15 nm. The fouling-free flow reactor operated at short overall residence times (<5 min) using just ferric and ferrous salts, sodium carbonate and citric acid. The IONPs exhibited high heating performance, with an intrinsic loss power up to 3.76 nH m2 kgFe-1

Some Structural and Chemical Changes in Endocardial Endothelium of Rats in Emotional and Pain Stress Complicated by Hypercholesterolemia

The objective of the research was to study the content of some neutral lipids of endocardial endothelium in rats in relation to structural changes occurring in it, in the co-existence of emotional and pain stress, as well as alimentary hypercholesterolemia. Materials and methods. The electric-impulse model was used for stress modeling. Alimentary hypercholesterolemia was modeled feeding animals an atherogenic diet. The concentration of triacylglycerols, free and esterified cholesterol were examined using the method of thin-layer chromatography performed on silica gel. The concentration of free fatty acids was determined using the radiochemical method. The state of endocardial endothelium was studied with the help of light microscopy; the impression smears obtained from macro preparations of ventricle were analyzed.Results. In co-existence of stress and hypercholesterolemia, significant increase in free cholesterol as well as free fatty acid concentration was noticed. This essentially exceeded the analogical indices under the action of stress only. Structural changes in the endocardium followed by desquamation of separate endotheliocytes were the result of stress reaction. In the action of both pathogenic factors, this process was intensified; layer-by-layer exfoliation of endotheliocytes was observed. Conclusions. In acute emotional and pain stress, changes in lipid spectrum of membrane structures of endocardial endotheliocytes the main manifestation of which is the accumulation of free cholesterol in cells and increase in the levels of free fatty acids take place. The increase in the number of desquamated endothelial cells is the result of stress action as well. Alimentary hypercholesterolemia significantly increases such pathological changes. 

Stable Iron Oxide Nanoflowers with Exceptional Magnetic Heating Efficiency: Simple and Fast Polyol Synthesis

Magnetically induced hyperthermia has reached a milestone in medical nanoscience and in phase III clinical trials for cancer treatment. As it relies on the heat generated by magnetic nanoparticles (NPs) when exposed to an external alternating magnetic field, the heating ability of these NPs is of paramount importance, so is their synthesis. We present a simple and fast method to produce iron oxide nanostructures with excellent heating ability that are colloidally stable in water. A polyol process yielded biocompatible single core nanoparticles and nanoflowers. The effect of parameters such as the precursor concentration, polyol molecular weight as well as reaction time was studied, aiming to produce NPs with the highest possible heating rates. Polyacrylic acid facilitated the formation of excellent nanoheating agents iron oxide nanoflowers (IONFs) within 30 min. The progressive increase of the size of the NFs through applying a seeded growth approach resulted in outstanding enhancement of their heating efficiency with intrinsic loss parameter up to 8.49 nH m2 kgFe-1. The colloidal stability of the NFs was maintained when transferring to an aqueous solution via a simple ligand exchange protocol, replacing polyol ligands with biocompatible sodium tripolyphosphate to secure the IONPs long-term colloidal stabilization

Small iron oxide nanoparticles as MRI T1 contrast agent: scalable inexpensive water-based synthesis using a flow reactor

Small iron oxide nanoparticles (IONPs) were synthesised in water via co-precipitation by quenching particle growth after the desired magnetic iron oxide phase formed. This was achieved in a millifluidic multistage flow reactor by precisely timed addition of an acidic solution. IONPs (≤5 nm), a suitable size for positive T1 magnetic resonance imaging (MRI) contrast agents, were obtained and stabilised continuously. This novel flow chemistry approach facilitates a reproducible and scalable production, which is a crucial paradigm shift to utilise IONPs as contrast agents and replace currently used Gd complexes. Acid addition had to be timed carefully, as the inverse spinel structure formed within seconds after initiating the co-precipitation. Late quenching allowed IONPs to grow larger than 5 nm, whereas premature acid addition yielded undesired oxide phases. Use of a flow reactor was not only essential for scalability, but also to synthesise monodisperse and non-agglomerated small IONPs as (i) co-precipitation and acid addition occurred at homogenous environment due to accurate temperature control and rapid mixing and (ii) quenching of particle growth was possible at the optimum time, i.e., a few seconds after initiating co-precipitation. In addition to the timing of growth quenching, the effect of temperature and dextran present during co-precipitation on the final particle size was investigated. This approach differs from small IONP syntheses in batch utilising either growth inhibitors (which likely leads to impurities) or high temperature methods in organic solvents. Furthermore, this continuous synthesis enables the low-cost (<£10 per g) and large-scale production of highly stable small IONPs without the use of toxic reagents. The flow-synthesised small IONPs showed high T1 contrast enhancement, with transversal relaxivity (r2) reduced to 20.5 mM−1 s−1 and longitudinal relaxivity (r1) higher than 10 mM−1 s−1, which is among the highest values reported for water-based IONP synthesis

A versatile non-fouling multi-step flow reactor platform: demonstration for partial oxidation synthesis of iron oxide nanoparticles

In the last decade flow reactors for material synthesis were firmly established, demonstrating advantageous operating conditions, reproducible and scalable production via continuous operation, as well as high-throughput screening of synthetic conditions. Reactor fouling, however, often restricts flow chemistry and the common fouling prevention via segmented flow comes at the cost of inflexibility. Often, the difficulty of feeding reagents into liquid segments (droplets or slugs) constrains flow syntheses using segmented flow to simple synthetic protocols with a single reagent addition step prior or during segmentation. Hence, the translation of fouling prone syntheses requiring multiple reagent addition steps into flow remains challenging. This work presents a modular flow reactor platform overcoming this bottleneck by fully exploiting the potential of three-phase (gas–liquid–liquid) segmented flow to supply reagents after segmentation, hence facilitating fouling free multi-step flow syntheses. The reactor design and materials selection address the operation challenges inherent to gas–liquid–liquid flow and reagent addition into segments allowing for a wide range of flow rates, flow ratios, temperatures, and use of continuous phases (no perfluorinated solvents needed). This “Lego®-like” reactor platform comprises elements for three-phase segmentation and sequential reagent addition into fluid segments, as well as temperature-controlled residence time modules that offer the flexibility required to translate even complex nanomaterial synthesis protocols to flow. To demonstrate the platform's versatility, we chose a fouling prone multi-step synthesis, i.e., a water-based partial oxidation synthesis of iron oxide nanoparticles. This synthesis required I) the precipitation of ferrous hydroxides, II) the addition of an oxidation agent, III) a temperature treatment to initiate magnetite/maghemite formation, and IV) the addition of citric acid to increase the colloidal stability. The platform facilitated the synthesis of colloidally stable magnetic nanoparticles reproducibly at well-controlled synthetic conditions and prevented fouling using heptane as continuous phase. The biocompatible particles showed excellent heating abilities in alternating magnetic fields (ILP values >3 nH m2 kgFe−1), hence, their potential for magnetic hyperthermia cancer treatment. The platform allowed for long term operation, as well as screening of synthetic conditions to tune particle properties. This was demonstrated via the addition of tetraethylenepentamine, confirming its potential to control particle morphology. Such a versatile reactor platform makes it possible to translate even complex syntheses into flow, opening up new opportunities for material synthesis

Development of an in-line magnetometer for flow chemistry and its demonstration for magnetic nanoparticle synthesis

Despite the wide usage of magnetic nanoparticles, it remains challenging to synthesise particles with properties that exploit each application's full potential. Time consuming experimental procedures and particle analysis hinder process development, which is commonly constrained to a handful of experiments without considering particle formation kinetics, reproducibility and scalability. Flow reactors are known for their potential of large-scale production and high-throughput screening of process parameters. These advantages, however, have not been utilised for magnetic nanoparticle synthesis where particle characterisation is performed, with a few exceptions, post-synthesis. To overcome this bottleneck, we developed a highly sensitive magnetometer for flow reactors to characterise magnetic nanoparticles in solution in-line and in real-time using alternating current susceptometry. This flow magnetometer enriches the flow-chemistry toolbox by facilitating continuous quality control and high-throughput screening of magnetic nanoparticle syntheses. The sensitivity required to monitor magnetic nanoparticle syntheses at the typically low concentrations (<100 mM of Fe) was achieved by comparing the signals induced in the sample and reference cell, each of which contained near-identical pairs of induction and pick-up coils. The reference cell was filled only with air, whereas the sample cell was a flow cell allowing sample solution to pass through. Balancing the flow and reference cell impedance with a newly developed electronic circuit was pivotal for the magnetometer's sensitivity. To showcase its potential, the flow magnetometer was used to monitor two iron oxide nanoparticle syntheses with well-known particle formation kinetics, i.e., co-precipitation syntheses with sodium carbonate and sodium hydroxide as base, which have been previously studied via synchrotron X-ray diffraction. The flow magnetometer facilitated batch (on-line) and flow (in-line) synthesis monitoring, providing new insights into the particle formation kinetics as well as, effect of temperature and pH. The compact lab-scale flow device presented here, opens up new possibilities for magnetic nanoparticle synthesis and manufacturing, including 1) early stage reaction characterisation 2) process monitoring and control and 3) high-throughput screening in combination with flow reactors

Heat-Up Colloidal Synthesis of Shape-Controlled Cu-Se-S Nanostructures—Role of Precursor and Surfactant Reactivity and Performance in N2 Electroreduction

Copper selenide-sulfide nanostructures were synthesized using metal-organic chemical routes in the presence of Cu- and Se-precursors as well as S-containing compounds. Our goal was first to examine if the initial Cu/Se 1:1 molar proportion in the starting reagents would always lead to equiatomic composition in the final product, depending on other synthesis parameters which affect the reagents reactivity. Such reaction conditions were the types of precursors, surfactants and other reagents, as well as the synthesis temperature. The use of ‘hot-injection’ processes was avoided, focusing on ‘non-injection’ ones; that is, only heat-up protocols were employed, which have the advantage of simple operation and scalability. All reagents were mixed at room temperature followed by further heating to a selected high temperature. It was found that for samples with particles of bigger size and anisotropic shape the CuSe composition was favored, whereas particles with smaller size and spherical shape possessed a Cu2−xSe phase, especially when no sulfur was present. Apart from elemental Se, Al2Se3 was used as an efficient selenium source for the first time for the acquisition of copper selenide nanostructures. The use of dodecanethiol in the presence of trioctylphosphine and elemental Se promoted the incorporation of sulfur in the materials crystal lattice, leading to Cu-Se-S compositions. A variety of techniques were used to characterize the formed nanomaterials such as XRD, TEM, HRTEM, STEM-EDX, AFM and UV-Vis-NIR. Promising results, especially for thin anisotropic nanoplates for use as electrocatalysts in nitrogen reduction reaction (NRR), were obtained

Генетическая оценка производителей кулундинской тонкорунной породы овец по качеству потомства

The authors have studied the genetic value of producers of the aboriginal Kulunda finewool sheep breed based on various analysis methods of the productivity of their progeny. The data on 574 offspring (daughters) received from 16 rams-producers of the “Steptoe” breeding farm of Altai Krai were used in the research. The genotypes of ram progeny were evaluated by the productivity of the rams at one year of age. In assessing the fathers, the number of effective daughters needed to confirm a sufficient number of offspring was calculated. Water, soil, and feed were tested for heavy metals content in the sheep breeding area, which did not exceed the MPC (Maximum Permissible Concentration). The breeding indices of the progeny ranged from 114 to 1562. The live weight of the rams was 120 kg. The live weight of the daughters was 50.0 kg. The sheep (daughters) had a wool gain of 5.7 kilograms per ewe. The authors established a high homogeneity of the genotypes of rams producers in terms of the live weight of daughters. The genetic variability of the fathers was 3.2%. According to productivity indices, the rams-producers (#4452, 26133, 3611, 0125 and 44244) occupied the first five ranks. The effect of the genotypes of ram producers on the daughters’ live weight and wool hair gain was established. The ranking data showed the advantage of daughters in several traits obtained from prepotent producers. The authors suggest that ram sires no. 3611, 0125, 26133 and 44244 should be used extensively to improve breeding efficiency. The authors also applied the Hozo method in the absence of normal distribution of traits. In other cases, data processing by methods of variation statistics was used.Изучена генетическая ценность производителей аборигенной кулундинской тонкорунной породы овец на основе различных методов анализа продуктивности их потомков. В исследованиях использовали данные по 574 дочерям, полученным от 16 баранов-производителей из племзавода ОАО «Степное» Алтайского края. Оценка генотипов баранов-производителей была проведена по продуктивности ярок в годичном возрасте. Рассчитано количество эффективных дочерей, необходимое для подтверждения достаточного количества потомков при оценке отцов. В зоне разведения овец исследованы вода, почва и корма на содержание тяжелых металлов, которые не превышали ПДК. Селекционные индексы производителей изменялись от 114 до 1562. Живая масса баранов равнялась 120 кг, а их дочерей – 50,0 кг. Настриг шерсти дочерей составил 5,7 кг. Установлена высокая однородность генотипов производителей по живой массе дочерей. Генетическая изменчивость отцов была равна 3,2%. Производители № 4452, 26133, 3611, 0125 и 44244 занимали первые пять рангов по показателям продуктивности. Установлено влияние генотипов баранов-производителей на живую массу и настриг шерсти дочерей. Данные ранжирования показали преимущество дочерей по ряду признаков, полученных отпрепотентныхпроизводителей. Дляповышенияэффективностиселекциипредложено широкоиспользоватьбаранов-производителей№ 3611, 0125, 26133 и 44244. Приотсутствии нормальности распределения признаков был применен метод Hozo. В остальных случаях использована обработка данных методами вариационной статистики

Adverse Fetal and Neonatal Outcomes Associated with a Life-Long High Fat Diet: Role of Altered Development of the Placental Vasculature

Maternal obesity results in a number of obstetrical and fetal complications with both immediate and long-term consequences. The increased prevalence of obesity has resulted in increasing numbers of women of reproductive age in this high-risk group. Since many of these obese women have been subjected to hypercaloric diets from early childhood we have developed a rodent model of life-long maternal obesity to more clearly understand the mechanisms that contribute to adverse pregnancy outcomes in obese women. Female Sprague Dawley rats were fed a control diet (CON - 16% of calories from fat) or high fat diet (HF - 45% of calories from fat) from 3 to 19 weeks of age. Prior to pregnancy HF-fed dams exhibited significant increases in body fat, serum leptin and triglycerides. A subset of dams was sacrificed at gestational day 15 to evaluate fetal and placental development. The remaining animals were allowed to deliver normally. HF-fed dams exhibited a more than 3-fold increase in fetal death and decreased neonatal survival. These outcomes were associated with altered vascular development in the placenta, as well as increased hypoxia in the labyrinth. We propose that the altered placental vasculature may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival

Efficacy of Microelements, Antioxidants and Nitric Oxide Donators Use for the Correction of NO-Synthase System in the Myocardium of Rats with Hypothyroid Dysfunction on the Background of Combined Iodine and Selenium Deficiency

The performance of NO-synthase system in the myocardium of rats with iodine deprivation, on the background of combined iodine and selenium deficiency and under conditions of iodine correction (potassium iodide); iodine and selenium (potassium iodide, selenium active); iodine, selenium, antioxidants, donators of NO (potassium iodide, selenium active, a-tocopherol acetate, L-arginine hydrochloride) was analyzed in the article. The development of hypothyroid dysfunction was detected to be accompanied by inhibition of NO-synthase system in the myocardium, mainly through inducible NOS. Potassium iodide and selenium active had positive influence on the metabolism of nitric oxide in the myocardium. This could be the result of restoration of thyroid gland functional capacity. The introduction of a-tocopherol acetate and L-arginine hydrochloride was accompanied by increase in constitutive NOS activity. Comparative analysis of experimental research on the capabilities of hypothyroid dysfunction correction on the background of microelements imbalance using potassium iodide, simultaneous administration of selenium and potassium iodide, involving a-tocopherol acetate and L-arginine hydrochloride to the scheme of correction confirms the importance of individual approach to the prevention and correction of thyroid disease manifestations