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.

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.

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.

A microfluidic reactor was developed to enhance the speed (reaction time <4 min) and control of the synthesis of gold nanoparticles (3–25 nm) with or without capping agents using carbon monoxide as gaseous reductant, which is easy to remove from the reaction mixture by venting. Gas–liquid segmented flow was formed inside a 1 mm inner diameter coiled flow inverter with aqueous gold precursor and the reducing gas to produce gold nanoparticles with polydispersity as low as 5%. The uncapped gold nanoparticles make the product attractive for surface-enhanced Raman scattering, and showed an average enhancement factor of 1.94 × 10⁵. Various capping agents (tri-sodium citrate, polysorbate 80, oleylamine and poly(ethyleneglycol) 2-mercaptoethyl ether acetic acid) and different operational parameters were also tested, demonstrating that the proposed synthesis is flexible and can continuously produce a variety of gold nanoparticles, with potential for other applications.