Continuous Synthesis of Gold Nanoparticles in Micro- and Milli-fluidic Systems

Gold nanomaterials have diverse applications ranging from healthcare and nanomedicine to analytical sciences and catalysis. Microfluidic and millifluidic reactors offer multiple advantages for their synthesis and manufacturing, including controlled or fast mixing, accurate reaction time control and excellent heat transfer. These advantages are demonstrated by reviewing gold nanoparticle synthesis strategies in flow devices. However, there are still challenges to be resolved, such as reactor fouling, particularly if robust manufacturing processes are to be developed to achieve the desired targets in terms of nanoparticle size, size distribution, surface properties, process throughput and robustness. Solutions to these challenges aremore effective through a coordinated approach from chemists, engineers and physicists, which has at its core a qualitative and quantitative understanding of the synthesis processes and reactor operation. This is important as nanoparticle synthesis is complex, encompassing multiple phenomena interacting with each other, often taking place at short timescales. The proposed methodology for the development of reactors and processes is generic and contains various interconnected considerations. It aims to be a starting point towards rigorous design procedures for the robust and reproducible continuous flow synthesis of gold nanoparticles

Porokeratosis: Two Faces, One Family

Porokeratosis is a disorder of keratinisation whose pathogenesis is yet unclear. It has been postulated that it results from the proliferation of an abnormal clone of keratinocytes, triggered by several factors, such as immunosuppression or prolonged ultraviolet exposure. Various clinical forms are recognized whose common denominator is a keratotic ring surrounding a central zone of atrophy. The histological hallmark is the cornoid lamella, a thin column of hyperproliferative abnormal keratinocytes. We describe two cases of porokeratosis. A 67-year-old woman with an erythematous purplish round plaque surrounded by a keratotic border that had appeared 6 years previously on the left sural region was diagnosed as ‘giant’ porokeratosis. A 49-year-old man presented with small papules coalescent in an erythematous oval plaque on the lateral side of the left foot consistent with linear porokeratosis

Synthetic guidelines for the precision engineering of gold nanoparticles

Gold nanoparticles (AuNPs) are one of the most studied nanomaterials with applications spanning from catalysis to biomedicine. While numerous chemical protocols exist that allow bespoke tailoring of chemical, physical and biological properties, their translation towards industrial-scale production remains a challenge. Batch synthesis often suffers from poor reproducibility and scalability, while emerging approaches, such as continuous flow synthesis, are not widely implemented in research labs. Herein, we provide a critical review of recent developments in the field of AuNP synthesis and identify synthetic guidelines for precision engineering of nanoparticle properties

Modelling the Synthesis of Nanoparticles in Continuous Microreactors: the Role of Diffusion and Residence Time Distribution on Nanoparticle Characteristics

A mathematical model for the liquid-phase synthesis of spherical nanoparticles in continuous flow micro- and milli-reactors was developed, accounting for residence time distributions (RTD). These distributions were derived for the reactants and the particles involved in the synthesis. The kinetic parameters needed to describe the reactions were calculated from experimental data available in the literature from batch reactors, with the aid of population balance modelling. They were subsequently used, without further modification, to simulate the synthesis in flow reactors via population balance modelling, averaging the results at the reactor outlet using the reactor RTDs. The model was employed to describe the synthesis of silica nanoparticles as a case study, and validated against flow reactor results from the literature. The results demonstrate direct RTD effects and indirect diffusion-induced effects on the evolution of the particle size distribution during the flow synthesis. The former are created by the inherent widening of the RTDs, due to the different residence time experienced by each fluid element, leading to a broadening of the particle size distribution. The latter are induced by the difference in diffusivity between nanoparticles and liquid reactants, which leads to different dispersion processes in the reactor for the different components of the reaction mixture. These effects appear as the major cause of particle size distribution difference between (single phase) flow and batch syntheses

A study of the interaction of cationic dyes with gold nanostructures

The interaction of methylene blue and crystal violet dyes with a range of gold nanoparticles (AuNPs), gold nanoclusters and gold/silver nanoclusters is reported

A Modular Millifluidic Platform for the Synthesis of Iron Oxide Nanoparticles with Control over Dissolved Gas and Flow Configuration

Gas–liquid reactions are poorly explored in the context of nanomaterials synthesis, despite evidence of significant effects of dissolved gas on nanoparticle properties. This applies to the aqueous synthesis of iron oxide nanoparticles, where gaseous reactants can influence reaction rate, particle size and crystal structure. Conventional batch reactors offer poor control of gas–liquid mass transfer due to lack of control on the gas–liquid interface and are often unsafe when used at high pressure. This work describes the design of a modular flow platform for the water-based synthesis of iron oxide nanoparticles through the oxidative hydrolysis of Fe2+ salts, targeting magnetic hyperthermia applications. Four different reactor systems were designed through the assembly of two modular units, allowing control over the type of gas dissolved in the solution, as well as the flow pattern within the reactor (single-phase and liquid–liquid two-phase flow). The two modular units consisted of a coiled millireactor and a tube-in-tube gas–liquid contactor. The straightforward pressurization of the system allows control over the concentration of gas dissolved in the reactive solution and the ability to operate the reactor at a temperature above the solvent boiling point. The variables controlled in the flow system (temperature, flow pattern and dissolved gaseous reactants) allowed full conversion of the iron precursor to magnetite/maghemite nanocrystals in just 3 min, as compared to several hours normally employed in batch. The single-phase configuration of the flow platform allowed the synthesis of particles with sizes between 26.5 nm (in the presence of carbon monoxide) and 34 nm. On the other hand, the liquid–liquid two-phase flow reactor showed possible evidence of interfacial absorption, leading to particles with different morphology compared to their batch counterpart. When exposed to an alternating magnetic field, the particles produced by the four flow systems showed ILP (intrinsic loss parameter) values between 1.2 and 2.7 nHm2/kg. Scale up by a factor of 5 of one of the configurations was also demonstrated. The scaled-up system led to the synthesis of nanoparticles of equivalent quality to those produced with the small-scale reactor system. The equivalence between the two systems is supported by a simple analysis of the transport phenomena in the small and large-scale setup

How Does SARS-CoV-2 Affect the Central Nervous System? A Working Hypothesis

Interstitial pneumonia was the first manifestation to be recognized as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, in just a few weeks, it became clear that the coronavirus disease-2019 (COVID-19) overrun tissues and more body organs than just the lungs, so much so that it could be considered a systemic pathology. Several studies reported the involvement of the conjunctiva, the gut, the heart and its pace, and vascular injuries such as thromboembolic complications and Kawasaki disease in children and toddlers were also described. More recently, it was reported that in a sample of 214 SARS-CoV-2 positive patients, 36.4% complained of neurological symptoms ranging from non-specific manifestations (dizziness, headache, and seizures), to more specific symptoms such hyposmia or hypogeusia, and stroke. Older individuals, especially males with comorbidities, appear to be at the highest risk of developing such severe complications related to the Central Nervous System (CNS) involvement. Neuropsychiatric manifestations in COVID-19 appear to develop in patients with and without pre-existing neurological disorders. Growing evidence suggests that SARS-CoV-2 binds to the human Angiotensin-Converting Enzyme 2 (ACE2) for the attachment and entrance inside host cells. By describing ACE2 and the whole Renin Angiotensin Aldosterone System (RAAS) we may better understand whether specific cell types may be affected by SARS-CoV-2 and whether their functioning can be disrupted in case of an infection. Since clear evidences of neurological interest have already been shown, by clarifying the topographical distribution and density of ACE2, we will be able to speculate how SARS-CoV-2 may affect the CNS and what is the pathogenetic mechanism by which it contributes to the specific clinical manifestations of the disease. Based on such evidences, we finally hypothesize the process of SARS-CoV-2 invasion of the CNS and provide a possible explanation for the onset or the exacerbation of some common neuropsychiatric disorders in the elderly including cognitive impairment and Alzheimer disease

A model for the formation of gold nanoparticles in the citrate synthesis method

This paper presents a new model for predicting the evolution of the particle size of gold nanoparticles (GNPs) in the citrate synthesis method. In this method, the precursor is an acid solution of tetrachloroauric acid, while the reducing agent is a base solution of sodium citrate. The acid-base properties of the solutions influence how the size of the particles evolves during the synthesis. In the literature, various mechanistic theories have been proposed to explain this evolution. Turkevich et al. (1951), who pioneered this synthesis method, suggested the “organizer theory”. This mechanistic description of the synthesis was modelled by Kumar et al. (2007), but recently Agunloye et al. (2017) showed that in several cases this model performed poorly, since it does not account for the acid-base properties of the reactants. In this work, we present a kinetic model based on the synthesis seed-mediated mechanistic description proposed by Wuithschick et al. (2015). In this description, the precursor concurrently reduces into gold atoms and hydroxylates into a passive form. The gold atoms then aggregate into seed particles, which finally react with the passive form of the precursor in a growth step. We validated the model using experimental data from the literature obtained for conditions in which the seed-mediated mechanism is valid. The predicted GNP final sizes closely agree with those obtained experimentally

Microfluidic synthesis of protein-loaded nanogels in a coaxial flow reactor using a design of experiments approach

Ionic gelation is commonly used to generate nanogels but often results in poor control over size and polydispersity. In this work we present a novel approach to the continuous manufacture of protein-loaded chitosan nanogels using microfluidics whereby we demonstrate high control and uniformity of the product characteristics. Specifically, a coaxial flow reactor (CFR) was employed to control the synthesis of the nanogels, comprising an inner microcapillary of internal diameter (ID) 0.595 mm and a larger outer glass tube of ID 1.6 mm. The CFR successfully facilitated the ionic gelation process via chitosan and lysozyme flowing through the inner microcapillary, while cross-linkers sodium tripolyphosphate (TPP) and 1-ethyl-2-(3-dimethylaminopropyl)-carbodiimide (EDC) flowed through the larger outer tube. In conjunction with the CFR, a four-factor three-level face-centered central composite design (CCD) was used to ascertain the relationship between various factors involved in nanogel production and their responses. Specifically, four factors including chitosan concentration, TPP concentration, flow ratio and lysozyme concentration were investigated for their effects on three responses (size, polydispersity index (PDI) and encapsulation efficiency (% EE)). A desirability function was applied to identify the optimum parameters to formulate nanogels in the CFR with ideal characteristics. Nanogels prepared using the optimal parameters were successfully produced in the nanoparticle range at 84 ± 4 nm, showing a high encapsulation efficiency of 94.6 ± 2.9% and a high monodispersity of 0.26 ± 0.01. The lysis activity of the protein lysozyme was significantly enhanced in the nanogels at 157.6% in comparison to lysozyme alone. Overall, the study has demonstrated that the CFR is a viable method for the synthesis of functional nanogels containing bioactive molecules

Highly reproducible, high-yield flow synthesis of gold nanoparticles based on a rational reactor design exploiting the reduction of passivated Au(III)

Reproducibility in the synthesis of nanomaterials is a crucial aspect for their real-life applications. It is particularly pertinent in the context of gold nanoparticles, where a plethora of seeded-growth methods are being developed to control particle morphology and size. The translation of such methods to manufacturing can be hindered by poor reproducibility of the seed production step. This study focuses on the development of a highly reproducible platform for the synthesis of gold nanoparticles, as potential substrates for glucose sensing. A flow reactor was designed, starting from a detailed study of the synthesis in batch. The well-established Turkevich synthesis was investigated via in situ time-resolved UV-vis spectroscopy. In order to enhance the reproducibility of the synthesis the effect of passivating the gold precursor stock before its use in the synthesis was investigated. It is shown that starting from a pre-passivated precursor provided improved control over the initial reaction stage, at the expense of a small increase in the reaction time. At the optimal reaction conditions, the proposed modified Turkevich method allowed for the synthesis in batch of ∼12 nm monodisperse (RSD ∼10%) particles, with a variability from batch to batch of only ∼5%. The information gathered from the batch study, in particular the reaction time, was used to translate the synthesis from batch to flow. The system utilized for the flow synthesis consisted of a segmented flow reactor, where an organic stream was employed to segment the reactive aqueous stream to avoid reactor fouling and improve monodispersity. The use of segmented flow enables treating each droplet as a “travelling batch”, hence allowing the direct use of the kinetic data obtained in batch to design the flow reactor, leading to the rapid identification of the minimum residence time to allow for reaction completion. The flow reactor enabled the synthesis of ∼11 nm monodisperse (RSD ∼10%) particles, with full precursor conversion and reproducibility between reactor runs higher than that obtained in batch (variability of ∼2%). The flow-produced gold nanoparticles were tested for glucose sensing, exploiting their glucose oxidase-mimicking behaviour and demonstrated satisfactory glucose detection in the range of 1–10 mM