Reaction engineering approach to the flow synthesis of nanomaterials for sensing and biomedical applications

Nanomaterials promise to revolutionize technologies belonging to many different fields thanks to their peculiar properties arising from their small size, at the interface between that of molecules and that of particles, high surface area and distinctive optical and electronic properties. Some nanomaterials-based products started appearing on the market over the last two decades. However, a striking difference still exists between the number of nanomaterials-focused scientific contributions being published and the number of nanomaterials-based products currently sold, with full exploitation of the benefits coming from the use of nanomaterials in everyday life still far from happening. This distance between science and the market appears even more evident in the field of biomedicine. Different reasons hide behind the very low ratio between available nanomaterials-based medical products and scientific effort in the field. One of these reasons is the difficulty in manufacturing these materials in a reproducible manner and on a sufficiently large scale. Scale-up of these productions often leads to irreproducible results and a lack of the desired materials properties, especially when facing the strict regulations for medical application. Conventional manufacturing strategies based on the use of batch systems suffer from batch-to-batch variability, caused by slow and irreproducible mixing and inhomogeneous temperature profile. Flow reactors represent a solution to these issues, thanks to their high surface area, product volumes higher than reactor volume, and reduced human intervention during operation. Over the last decade, the number of works regarding flow synthesis of nanomaterials exponentially increased. Nonetheless, a formal design protocol for such reactors is still not available, with researchers relying on a pure black-box approach. This approach is experimentally intensive and case dependent, complicating the scale-up of the reactors. Difficulties arise also in implementing model-based control systems, essential in industrial settings. The aim of this thesis is to develop a design approach for flow reactors synthesizing nanomaterials based on the combination of kinetics studies and classic reactor design principles. A theoretical background was first established using the well-studied synthesis of silica nanoparticles. A model was developed demonstrating the possibility of describing the reactor behaviour through the combination of residence time distribution theory and kinetic data obtained in batch. Supported by this theoretical background, the thesis shows the successful attempt at designing two flow reactors for the synthesis and growth of gold nanoparticles, eventually enabling control over the particle size between 10 and 150 nm, as well as granting high synthesis reproducibility (with deviation in the average size between runs in the order of ). The reactor design used to develop these reactors started from kinetic data acquired in batch via in situ time- 4 resolved UV-Vis spectroscopy, which are used to determine the process operating conditions of the flow reactor. The first reactor designed for the synthesis of gold nanoparticles produced 11 nm gold seeds through a modified Turkevich method developed in this thesis, named passivated Turkevich method, where the precursor coordination sphere is engineered to maximize the synthesis reproducibility. The second reactor developed in this thesis uses the seeds produced by the first reactor and grows them to a controllable final size (up to 150 nm) in a single growth step. The growth was performed through a different synthetic protocol, and again, the design of the reactor followed the same principles, starting with the study of the synthesis kinetics in batch via in situ time-resolved UV-Vis spectroscopy, showing the flexibility of the proposed reactor design approach. To obtain a detailed description of the particle evolution during their synthesis, this thesis also focused on the development of a model for the interpretation of the time-resolved UV-Vis data obtained during the synthesis of Au nanoparticles. The developed model renders the evolution of the particle size and number density during the synthesis. This model also explains the distinctive evolution of the Au nanoparticles optical properties observed during the Turkevich synthesis, with the peak absorbance moving from low to high energies. This phenomenon is explained through the adsorption of Au precursor species on the surface of the growing nanoparticles, which induces a change in the particle free electron density. The model reconciles in this way the latest mechanistic studies of the Turkevich synthesis (where no particle aggregates are observed) with the Mie theory. The design approach proposed in the thesis is useful for the translation of nanomaterials synthesis from batch to flow. However, flow reactors can access operating conditions hardly achievable in batch, possibly enabling new nanomaterials syntheses or further optimization of existing ones. This was demonstrated in this thesis for the synthesis of iron oxide nanoparticles, where flow reactors allowed the straightforward introduction in the aqueous system of gaseous reactants at high pressures and temperatures. Four reactor systems were designed by a combination of two modules, namely a membrane gas-liquid contactor and a reaction coil. These reactor systems allowed control over the flow profile, use of gaseous reactants as well as access to temperatures above the solvent boiling point through straightforward system pressurization. Control over these variables led to a significant decrease in the reaction time (from several hours down to 3 min) and control over particle crystal structure, size, and morphology. Finally, one of these reactor systems was scaled up by a factor of 5 without loss in product quality. The advantages of flow reactors to perform synthesis aided by low penetration depth radiations was then explored. Microwave heating is currently attracting attention as an alternative heating 5 technology which could allow faster heating rates and more homogeneous temperature profiles in large scale flow systems as a result of the bulk microwave heating mechanism, against surface-mediated conventional heating. This thesis investigated the use of microwave heating to perform the synthesis of iron oxide nanoparticles via the aqueous coprecipitation of iron chlorides in basic media, followed by stabilization through the addition of citric acid and dextran. The microwave synthesis led to the generation of multicore assemblies of iron oxide nanoparticles with a similar single-core size of conventionally produced ones, but with significantly larger hydrodynamic diameters. This suggests changes possibly induced by either the different heating profiles or the microwave radiation itself in the nucleation and aggregation rates, which determine the final assembly size. The scale-up of the microwave reactor was then investigated, with a successful increase in the production rate by a factor of 8. Eventually, the development of a new synthetic protocol for the synthesis of thermoresponsive magnetic nanogels and its translation from batch to flow are presented. This nanomaterial is developed through a bottom-up approach studying the synthesis of each unit composing the final product. The core of this material comprises iron oxide nanoparticles, produced via flow chemistry: different particles were screened with varying size and surface chemistry. Colloidal stability and hydrophobicity of the coating determined the successful encapsulation of the particles in the nanogel. In parallel, the nanogel formulation was optimized to achieve the desired size and transition temperature for the eventual temperature-triggered drug release application. The coating kinetics were studied, demonstrating that the synthesis finishes after ~5-10 min, a much shorter reaction time than those normally employed in the literature. The kinetics information is then used to guide the design of a single-phase flow reactor producing said nanomaterial, leading to a g/day production scale in a lab setting

Preparazione di nanocompositi elastomerici a base di nanotubi di carbonio come sensori di deformazione

La tesi si occuperà della preparazione di dispersioni stabili costituite da nanotubi di carbonio a parete multipla (MWCNTs) e materiali polimerici elastomerici di natura stirenica per l’ottenimento di dispositivi innovativi e efficienti per la misura della deformazione meccanica. Operativamente si prevedono due differenti strategie: la prima interesserà la dispersione dei nanotubi di carbonio, MWCNTs, mediante ultrasonicazione a tempi variabili in una soluzione di xilene contenente disciolto un polimero stirenico quali il copolimero a blocchi Poli(stirene-b-(etilene-co-propilene)-b-stirene-b-(etilene-co-propilene)) (SEPSEP), il Poli(stirene-b-(etilene-co-butadiene)-b-stirene) (SEBS) e il Poli(stirene-co-butadiene) reticolato (SBR). La seconda seguirà un processo di dispersione covalente dei MWCNTs funzionalizzati con gruppi amminici all’interno delle stesse matrici polimeriche funzionalizzate con anidride maleica in miscelatore di tipo termo-meccanico. Le dispersioni così ottenute saranno analizzate in termini di prove spettroscopiche (FTIR e Raman) e microscopiche (TEM) mentre il contenuto di MWCNT disperso sarà determinato mediante prove di termogravimetria (TGA). In seguito si procederà alla realizzazione del sensore determinando inizialmente la soglia di percolazione del dispositivo realizzato. I sensori di deformazione saranno realizzati a partire dai film di materiale nanocomposito ottenuto mediante pressofusione delle dispersioni. Un circuito elettrico sarà appositamente realizzato in laboratorio allo scopo di misurare la variazione di resistenza del dispositivo in funzione dello stiro meccanico

The Role of Leptin in Antipsychotic-Induced Weight Gain: Genetic and Non-Genetic Factors

Schizophrenia is a chronic and disabling mental illness affecting millions of people worldwide. A greater proportion of people with schizophrenia tends to be overweight. Antipsychotic medications have been considered the primary risk factor for obesity in schizophrenia, although the mechanisms by which they increase weight and produce metabolic disturbances are unclear. Several lines of research indicate that leptin could be a good candidate involved in pathways linking antipsychotic treatment and weight gain. Leptin is a circulating hormone released by adipocytes in response to increased fat deposition to regulate body weight, acting through receptors in the hypothalamus. In this work, we reviewed preclinical, clinical, and genetic data in order to infer the potential role played by leptin in antipsychotic-induced weight gain considering two main hypotheses: (1) leptin is an epiphenomenon of weight gain; (2) leptin is a consequence of antipsychotic-induced “leptin-resistance status,” causing weight gain

Influence of Functional Bio-Based Coatings Including Chitin Nanofibrils or Polyphenols on Mechanical Properties of Paper Tissues

The paper tissue industry is a constantly evolving sector that supplies markets that require products with different specific properties. In order to meet the demand of functional properties, ensuring a green approach at the same time, research on bio-coatings has been very active in recent decades. The attention dedicated to research on functional properties has not been given to the study of the morphological and mechanical properties of the final products. This paper studied the effect of two representative bio-based coatings on paper tissue. Coatings based on chitin nanofibrils or polyphenols were sprayed on paper tissues to provide them, respectively, with antibacterial and antioxidant activity. The chemical structure of the obtained samples was preliminarily compared by ATR-FTIR before and after their application. Coatings were applied on paper tissues and, after drying, their homogeneity was investigated by ATR-FTIR on different surface areas. Antimicrobial and antioxidant properties were found for chitin nanofibrils- and polyphenols-treated paper tissues, respectively. The mechanical properties of treated and untreated paper tissues were studied, considering as a reference the same tissue paper sample treated only with water. Different mechanical tests were performed on tissues, including penetration, tensile, and tearing tests in two perpendicular directions, to consider the anisotropy of the produced tissues for industrial applications. The morphology of uncoated and coated paper tissues was analysed by field emission scanning electron microscopy. Results from mechanical properties evidenced a correlation between morphological and mechanical changes. The addition of polyphenols resulted in a reduction in mechanical resistance, while the addition of chitin enhanced this property. This study evidenced the different effects produced by two novel coatings on paper tissues for personal care in terms of properties and structure.This research was funded by the Bio-Based Industries Joint Undertaking under the European Union Horizon 2020 research program (BBI-H2020), ECOFUNCO project, grant number G.A 837863

Preparation of water suspensions of nanocalcite for cultural heritage applications

The consolidation of degraded carbonate stone used in ancient monuments is an important topic for European cultural heritage conservation. The products most frequently used as consolidants are based on tetraalkoxy- or alkylalkoxy-silanes (in particular tetraethyl-orthosilicate, TEOS), resulting in the formation of relatively stable amorphous silica or alkylated (hydrophobic) silica inside the stone pores. However, silica is not chemically compatible with carbonate stones; in this respect, nanocalcite may be a suitable alternative. The present work concerns the preparation of water suspensions of calcite nanoparticles (CCNPs) by controlled carbonation of slaked lime using a pilot-scale reactor. A simplified design of experiment was adopted for product optimization. Calcite nanoparticles of narrow size distribution averaging about 30 nm were successfully obtained, the concentration of the interfacial agent and the size of CaO being the most critical parameters. Primary nanoparticle aggregation causing flocculation could be substantially prevented by the addition of polymeric dispersants. Copolymer-based dispersants were produced in situ by controlled heterophase polymerisation mediated by an amphiphilic macro-RAFT (reversible addition-fragmentation transfer) agent. The stabilized CCNP aqueous dispersions were then applied on carbonate and silicate substrates; Scanning Electron Microscopy (SEM)analysis of cross-sections allowed the evaluation of pore penetration, interfacial binding, and bridging (gap-filling) properties of these novel consolidants

High temperature flow synthesis of iron oxide nanoparticles : size tuning via reactor engineering

Batch thermal decomposition syntheses of iron oxide nanoparticles (IONPs) provide precise control of particle properties, but their scalability and reproducibility is challenging. This is addressed in this work via a versatile high temperature flow reactor with adjustable temperature profiles through three individual stages operated between 180 °C and 280 °C. The tuneable temperature profiles in combination with self-seeded growth methods made it possible to synthesise IONPs between 2 and 17 nm (a size increase that corresponds to a >600 fold particle volume increase) at production rates of several gIONP per day. The precursor solutions contained only iron(III) acetylacetonate in a polyol solvent and no nucleation or growth inhibitors, oxidation or reducing agents, ligands or any other additives . This broad size range covers most biomedical applications and is of special interest for T1 MRI contrast agents (2–5 nm), as well as for magnetic hyperthermia cancer therapy (>10 nm). The potential of the IONPs produced was demonstrated by their high longitudinal relaxivity >16 mM−1 s−1 at a transversal/longitudinal relaxivity ratio <2.5 (small IONPs) and specific absorption rates increasing with the IONP size up to180 W/gFe. In addition, the polyol method employed allowed for simple ligand exchange with biocompatible sodium tripolyphosphate to make the IONPs stable in water, thus rendering them suitable for biomedical applications. The continuous high temperature process presented shows how to control the particle size not via the chemistry (e.g., chemical additives affecting the particle size through the surface chemistry), but engineering parameters, i.e., reactor temperature profiles, reagent addition sequences and seeded growth strategies

Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles

Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles

Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles

We describe the outcome of a large international interlaboratory study of the measurement of particle number concentration of colloidal nanoparticles, project 10 of the technical working area 34, "Nanoparticle Populations" of the Versailles Project on Advanced Materials and Standards (VAMAS). A total of 50 laboratories delivered results for the number concentration of 30 nm gold colloidal nanoparticles measured using particle tracking analysis (PTA), single particle inductively coupled plasma mass spectrometry (spICP-MS), ultraviolet-visible (UV-Vis) light spectroscopy, centrifugal liquid sedimentation (CLS) and small angle X-ray scattering (SAXS). The study provides quantitative data to evaluate the repeatability of these methods and their reproducibility in the measurement of number concentration of model nanoparticle systems following a common measurement protocol. We find that the population-averaging methods of SAXS, CLS and UV-Vis have high measurement repeatability and reproducibility, with between-labs variability of 2.6%, 11% and 1.4% respectively. However, results may be significantly biased for reasons including inaccurate material properties whose values are used to compute the number concentration. Particle-counting method results are less reproducibile than population-averaging methods, with measured between-labs variability of 68% and 46% for PTA and spICP-MS respectively. This study provides the stakeholder community with important comparative data to underpin measurement reproducibility and method validation for number concentration of nanoparticles