Engineering Conferences International

    Nanomedicines for the treatment of autoimmune inflammation: engineering design, mechanisms and diseases

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    The complexity of autoimmune diseases is a barrier to the design of strategies that can blunt autoimmunity without impairing general immunity. We have shown that systemic delivery of nanoparticles (NPs) coated with autoimmune disease-relevant peptide-major-histocompatibility-complex (pMHC) molecules triggers the formation and profound expansion of antigen-specific T-regulatory T-cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of a broad range of established autoimmune phenomena. I will highlight the engineering principles impacting biological activity, will illustrate how these nanomedicines interact with cognate T-cells and will describe the pharmacokinetic behavior and toxicological profile of this novel class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner

    Tolerance induction with quantum dots displaying tunable densities of self-antigen

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    During autoimmune diseases like type 1 diabetes or multiple sclerosis (MS), the immune system mistakenly recognizes and attacks healthy tissues in the body. In MS, myelin, which surrounds and protects the axons of neurons, is attacked by inflammatory cells leading to neurodegeneration. The current standard of care for MS patients is regular injection of immunosuppressive drugs that non-specifically suppress immune function, leaving patients immunocompromised and open to opportunistic infection. New investigations aim to address this problem with immunotherapy-based strategies that promote myelin-specific tolerance. Recent reports reveal that the development of inflammation or tolerance against certain molecules is influenced by the concentration and form of self-antigen presented to immune cells (i.e. free, particle).Strategies that allow tunable delivery of self-antigen are therefore of great interest to further probe these connections. Quantum dots (QDs) were chosen as the nanomaterial to investigate these questions because they can be conjugated with a large and controllable number of biomolecules.Additionally, their size facilitates rapid drainage through lymphatics to lymph nodes (LNs), where they accumulate and can be visualized by deep-tissue imaging due to their intrinsic fluorescence. QDs could be decorated with up to 130 myelin oligodendrocyte glycoprotein (MOG) peptides, a known self-antigen of MS (Fig 1A). Please click Additional Files below to see the full abstract

    Polymer-nanoparticle interactions in supramolecular hydrogels: Enabling long- term antibody delivery

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    Antibody drugs are a rapidly growing set of therapeutics that increasingly prove effective for clinical applications spanning from macular degeneration treatments, to targeted cancer therapies, and to passive immunization. These antibody treatments can be engineered to target almost any cell surface moiety and their production has since been scaled to an industrial level. Despite these advances, parenteral administration of antibodies is severely constrained by high viscosities at desirable doses, poor long-term antibody stability, high required frequency of administration, and therapeutically suboptimal pharmacokinetics. Herein, we demonstrate the development of supramolecular polymer-nanoparticle (PNP) interactions between poly(ethylene glycol)-poly(lactic acid) block copolymer nanoparticles (PEG-PLA) and modified hydroxypropylmethylcellulose (HPMC-x) polymers to engineer shear-thinning, self-healing hydrogels capable of stabilizing and delivering high concentrations of antibodies over prolonged timeframes (Figure 1). The PNP interactions underpinning the behavior of these materials afford injectability and tunable mechanical properties, while also controlling antibody release kinetics. In this work, we investigate how the thermodynamics of the PNP interaction affect in vitro and in vivo antibody release kinetics, pharmacokinetics, and bioavailability. Analysis of PEG-PLA surface density, HPMC-x hydrophobicity and modification extent, and hydrogel formulation reveal explicit design handles relating PNP thermodynamics to in vivo antibody release kinetics via subcutaneous injection. Differences in antibody release kinetics between in vitro and in vivo experiments were examined through mathematical modelling, revealing possible mechanisms of antibody uptake from subcutaneous space to the bloodstream when compared to literature. Overall, this work presents a robust set of design parameters to tune PNP interactions to develop a new nanotechnology-based platform for long-term, controlled antibody delivery. Please click Additional Files below to see the full abstract

    Utilizing ectopic Hsp90 expression to diagnose breast cancer at the point-of-care using fluorescence microscopy

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    Although pathological examination serves as the gold standard for breast cancer diagnosis, it requires labor-intensive sample preparation and time-consuming evaluation, resulting in long turn-around time and extensive infrastructure. We have developed a simple molecular imaging platform that can quickly assess patient’s samples and provide a molecular signal to reflect disease pathology as an alternative to traditional pathology, particularly for applications in low resource settings. We identified Heat shock protein 90 (Hsp90) as a molecular target to diagnose breast cancer as it is overexpressed on the surface of all breast cancer cell subtypes to orchestrate stress response to cancer formation. Based on this feature, we have established a non-invasive and rapid molecular imaging approach to quantify Hsp90 expression on breast tissue biopsies using a FITC tethered Hsp90 inhibitor (HS-27) that binds to surface Hsp90 of breast cancer cells. A wide-field, high resolution, handheld fluorescent microscope referred to as the Pocket Mammoscope has been developed to perform rapid non-contact Hsp90 fluorescent imaging of entire tissue biopsies at point of care. Please click Additional Files below to see the full abstract

    Directed self-assembly of block copolymers for sub-10nm fabrication

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    Directed self-assembly of block copolymers, based on microphase separation, is a promising strategy for high-volume and cost-effective nanofabrication. Over the past decades, manufacturing techniques have been made huge progress that it is now possible to engineer complex systems of heterogeneous materials around a few tens of nanometers (Such as 193i lithography). Further evolution of these techniques, however, is faced with difficult challenges not only because of diffraction limit, but also in prohibitively high capital equipment costs. Materials that self-assemble, on the other hand, spontaneously form nanostructures down to length scales at the molecular scale, but the micrometer areas or volumes over which the materials self-assemble with adequate perfection in structure is incommensurate with the macroscopic dimensions of devices and systems of devices of industrial relevance. Directed Self-Assembly (DSA) refers to the integration of self-assembling materials with traditional manufacturing processes. The key concept of DSA is to take advantage of the self-assembling properties of materials and at the same time meet the constraints of manufacturing. Technically DSA is similar to the double patterning in terms of resolution enhancement. In this report we will discuss the use of lithographically-defined chemically patterned surfaces to direct the assembly of block copolymer films for semiconductor manufacturing

    Dielectric behavior of FLASH sintered KNN

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    The market for lead-based piezoceramics, mainly (Pb1-x ZrxTiO3, PZT) - based materials, is higher than $100 billion per year. Due to lead-toxicity, the demand for lead-free piezoceramics is increasing. Potassium Sodium Niobate solid solutions, namely K0.5Na0.5NbO3, KNN, is currently one of the most promising materials for electromechanical applications. However, monophasic conventionally sintered KNN is hard to obtain, due to alkali evaporation during sintering (T\u3e 1100 ºC, t \u3e 2h). Within this context, there is an increasing interest in sustainable sintering techniques, as FLASH, to decrease both sintering time and temperature, avoiding alkali vaporization. However, FLASH applied to bulk ceramics, frequently produces inhomogeneous specimens. Figure 1 – Variation of length with temperature of FLASH sintered KNN, after a 2 h isothermal step. SEM micrograph showing the uniformly dense microstructure. In this work, we propose an experimental approach that allows the production of homogeneous, highly dense, KNN. In this method, the use of FLASH sintering contributed to reduce KNN sintering temperature for more than 200 ºC and the cycle time in ~3h. Uniform densification was achieved by using an isothermal step before the application of the electric field. Scanning Electron Microscopy (SEM) and Specific Surface Area (SSA) measurements were performed to characterize the pre-FLASH sintering microstructure. Please click Additional Files below to see the full abstract

    Much-efficient and cost-effective manufacturing of antibody biotherapeutics employing integrated negative chromatography technology

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    New approaches for fully connected and integrated downstream processes to reduce costs and improve efficiency are being assessed with the implementation of the NCAP Project (negative chromatography antibody purification). This project aims to resolve the manufacturing bottleneck facing modern antibody bio-therapeutics through exploring the great potential of the negative chromatography technology, i.e. purifying antibodies by binding all the surrounding impurities instead of binding target antibodies. High-throughput, miniaturised technologies have been implemented to enable the screening of multiple novel ligands based on a custom agarose backbone. The objectives are: (1) replace the conventional expensive and fragile protein-A affinity chromatography medium with inexpensive and more robust small-ligand-based media; (2) investigate novel downstream processes incorporating as many negative chromatography steps as possible to achieve much-efficient and capacity-unlimited manufacturing of biopharmaceuticals; (3) upstream and downstream process integration, and intensification by pushing the boundaries of the negative chromatography technology. This process is independent of the expression level in the upstream and should bring enormous potential cost benefits; providing a platform for truly continuous and integrated manufacturing processes, reducing hold times, enabling faster throughput and reducing the cost of raw materials

    Fast pyrolysis bio-oil production in an entrained flow reactor pilot

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    Bio-oil produced from biomass fast pyrolysis could constitute an alternative to fossil liquid fuels, especially to be combusted for local district heating. So far, only few studies have dealt with bio-oil production by biomass fast pyrolysis in an entrained flow reactor [1], yet it could constitute an alternative to the better-known fluidised bed pyrolysis process. In the context of the BOIL project with the CCIAG Company (Grenoble district heating), a new pilot based on an entrained flow reactor concept has been designed [2]. The pilot design has been carried out on the basis of woody biomass fast pyrolysis experiments and modeling performed in a drop tube reactor as a first step laboratory-scale study, and also CFD modeling [2-3]. The facility is composed of a biomass injection system with a hopper and a feeding screw, an electrically heated pyrolysis reactor, a cyclone to separate gas and char, 3 heat exchangers to cool the gas (at 30°C, 0°C and 0°C respectively) and condense bio-oil, and a post-combustion unit to burn the incondensable species. Gas temperature is maintained at 350°C from the reactor outlet to the entrance of the first heat exchanger in order to avoid bio-oil condensation. Several conditions were tested in 14 runs: 3 different biomass feedstocks, varying biomass feeding rates from 2 to 9 kg/h and two reactor temperatures 500°C and 550°C. 85 kg of bio-oil has been produced for combustion tests. Recovered bio-oil mass yield is on average 50%, its LHV is about 15 MJ/kg, its water content 26%w and its pH 2.15. We identified three main difficulties during the runs: about 15% of the bio-oil go through the heat exchanger, some char particles go through the cyclone which causes regular plugging of the first heat exchanger. Detailed analyses of the bio-oil produced have been done and the chemical and physical bio-oil characteristics have been compared to the European Standard recommendations [4]. With a regularly cleaning of the first heat exchanger, we successfully produce bio-oil with physical and chemical properties in agreement with the European Standard recommendations. Combustion tests of the bio-oil produced have been carried on by the CIRAD. They succeeded in obtaining a stable flame (without the use of a pilot flame) in a 50 kW burner and a 250 kW combustion chamber. However the physical and chemical characteristics of the bio-oil involve the use of specific pump and pulverization system adapted. In perspective for future projects, it would be interesting to perform pilot modifications in order to increase bio-oil yield and to minimize heat exchanger cleaning, and to test other resources like agricultural biomass or solid recovered fuels. Bibliography 1. J.A. Knight, C.W. Gorton, R.J. Kovac, Biomass 6, pp. 69-76, 1984. 2. Fast pyrolysis reactor for organic biomass materials with against flow injection of hot gases - US 20170166818 A1 3. Guizani, S.Valin, J.Billlaud, M.Peyrot, S.Salvador, Fuel, 2017, 207, pp.71-84. 4. C.Guizani, S.Valin, M.Peyrot, G.Ratel S.Salvador, Woody biomass fast pyrolysis in a drop tube reactor - Pyro2016 conference 5. Fast pyrolysis bio-oils for industrial boilers – Requirements and test methods – EN 1690

    Challenges and progresses made on the microkinetic description of lignin liquefaction: Application of group contribution methods

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    In this presentation a comprehensive microkinetic modelling framework and experimental tools are used to describe product yield and composition of direct lignin liquefaction processes with and without solvents (See Figure 1). With the framework proposed we aim to develop a unified theory and models capable of describing both dry (pyrolysis) and wet (hydrothermal and solvolysis) lignin liquefaction processes. An important phenomenon that has been shown to occur during lignin pyrolysis (as well as cellulose) is the formation of a liquid intermediate phase, and subsequent ejection of heavy products (\u3e~250 Da) as aerosols from this intermediate. In our presentation we will focus on the nature of lignin pyrolysis liquid intermediate through analysis of phase change equilibria temperatures for relevant lignin fragments, using group contribution methods. Specifically, estimation of boiling (Tb) and melting (Tm) points of lignin fragments was done using ARTIST software (Dortmund Data Bank Software & Separation Technology, GmbH). In total, 50 different lignin fragments were drawn, and their boiling and melting temperatures were calculated. The 50 fragments include monomers, dimers, trimers and tetrameters, with a variety of H, G and S units and inter-unit linkages. Figure 2 shows the calculated phase-change equilibria temperatures plotted against the number of aromatic units in a given lignin fragment. The dotted line at 400 °C is included as the approximate temperature at which both rupture of aliphatic linkages and conversion of short aromatic ring substituents occurs, but is less than the temperature for rearrangement of polycyclic structures. The collection of lignin fragments, such that Tm \u3c 400 \u3c Tb, make up the set of molecules that can exist as a liquid intermediate during pyrolysis, and are therefore the ones that have potential to be ejected as aerosols. The average lignin fragment in this range has 2.50 (± 0.11, standard error) aromatic units, molecular weight of 414 (± 20) Da, melting point of 292 (± 13) °C, and boiling point of 573 (± 19) °C. Relying solely on this analysis, one would expect these to be characteristics of an average molecule ejected as a liquid-phase aerosol during pyrolysis of lignin. Based on the quantification of phase equilibria temperatures, this liquid state can contain dimers and trimers, but typically not tetrameters or larger (they will preferentially depolymerize), or monomers (they will vaporize). It is these dimer and trimer products that should make up the majority of the heavy liquid products collected as aerosols. In order to validate this model, comparison was made with previously published work from Pecha, et al. (Ind. Eng. Chem. Res., 56, 2017, 9079-9089) and Bai, et al. (Fuel, 128, 2014, 170-179), who analyzed lignin pyrolysis oil with FT-ICR-MS. There is good agreement between the weights of species detected experimentally in these studies and those determined in this work based on group contribution calculations. Please click Additional Files below to see the full abstract
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