A Combined Experimental/Computational Study of Dicationic Ionic Liquids with Bromide and Tungstate Anions.

A panel of dicationic ionic liquids (DILs) with different rigid xylyl (ortho, meta, para) spacers and different anions (bromide and tungstate) has been synthetised and characterised through different experimental and computational techniques. Differences and analogies between the systems are analysed using information derived from their DFT structures, semiempirical dynamics, thermal behaviour, and catalytic properties versus the well-known reaction of CO2 added to epichlorohydrin. A comparison between the proposed systems and some analogues that present non-rigid spacers shows the key effect displayed by structure rigidity on their characteristics. The results show an interesting correlation between structure, flexibility, properties, and catalytic activity.

Radical Mediated Decarboxylation of Amino Acids via Photochemical Carbonyl Sulfide (COS) Elimination.

Herein, we present the first examples of amino acid decarboxylation via photochemically activated carbonyl sulfide (COS) elimination of the corresponding thioacids. This method offers a mild approach for the decarboxylation of amino acids, furnishing N-alkyl amino derivatives. The methodology was compatible with amino acids displaying both polar and hydrophobic sidechains and was tolerant towards widely used amino acid-protecting groups. The compatibility of the reaction with continuous-flow conditions demonstrates the scalability of the process.

Structure-Dependence and Mechanistic Insights into the Piezoelectric Effect in Ionic Liquids.

We reported recently that two imidazolium room-temperature ionic liquids (RTILs) exhibit the direct piezoelectric effect (J. Phys. Chem. Lett., 2023, 14, 2731-2735). We have subsequently investigated several other RTILs with pyrrolidinium and imidazolium cations and tetrafluoroborate and bis(trifluoromethylsulfonyl)imide anions in an effort to gain insight into the generality and mechanism of the effect. All the RTILs studied exhibit the direct piezoelectric effect, with a magnitude (d33) and threshold force that depend on the structures of both the cation and anion. The structure-dependence and existence of a threshold force for the piezoelectric effect are consistent with a pressure-induced liquid-to-crystalline solid phase transition in the RTILs, and this is consistent with experimental X-ray diffraction data.

A thiol-ene mediated approach for peptide bioconjugation using 'green' solvents under continuous flow.

Flow chemistry has emerged as an integral process within the chemical sector permitting energy efficient synthetic scale-up while improving safety and minimising solvent usage. Herein, we report the first applications of the photoactivated, radical-mediated thiol-ene reaction for peptide bioconjugation under continuous flow. Bioconjugation reactions employing deep eutectic solvents, bio-based solvents and fully aqueous systems are reported here for a range of biologically relevant peptide substrates. The use of a water soluble photoinitiator, Irgacure 2959, permitted synthesis of glycosylated peptides in fully aqueous conditions, obviating the need for addition of organic solvents and enhancing the green credentials of these rapid, photoactivated, bioconjugation reactions.

Synthetic Glycans Reveal Determinants of Antibody Functional Efficacy against a Fungal Pathogen.

Antibodies play a vital role in the immune response to infectious diseases and can be administered passively to protect patients. In the case of Cryptococcus neoformans, a WHO critical priority fungal pathogen, infection results in antibodies targeting capsular glucuronoxylomannan (GXM). These antibodies yield protective, non-protective, and disease-enhancing outcomes when administered passively. However, it was unknown how these distinct antibodies recognized their antigens at the molecular level, leading to the hypothesis that they may target different GXM epitopes. To test this hypothesis, we constructed a microarray containing 26 glycans representative of those found in highly virulent cryptococcal strains and utilized it to study 16 well-characterized monoclonal antibodies. Notably, we found that protective and non-protective antibodies shared conserved reactivity to the M2 motif of GXM, irrespective of the strain used in infection or GXM-isolated to produce a conjugate vaccine. Here, only two antibodies, 12A1 and 18B7, exhibited diverse trivalent GXM motif reactivity. IgG antibodies associated with protective responses showed cross-reactivity to at least two GXM motifs. This molecular understanding of antibody binding epitopes was used to map the antigenic diversity of two Cryptococcus neoformans strains, which revealed the exceptional complexity of fungal capsular polysaccharides. A multi-GXM motif vaccine holds the potential to effectively address this antigenic diversity. Collectively, these findings underscore the context-dependent nature of antibody function and challenge the classification of anti-GXM epitopes as either "protective" or "non-protective".

Bacterial Cellulose Electrospun Fiber Mesh Coated with Chitin Nanofibrils for Eardrum Repair.

In this study, we develop a bio-based and bioactive nanofibrous patch based on bacterial cellulose (BC) and chitin nanofibrils (CNs) using an ionic liquid as a solvent for BC, aimed at tympanic membrane (TM) repair. Electrospun BC nanofiber meshes were produced via electrospinning, and surface-modified with CNs using electrospray. The rheology of the BC/ionic liquid system was investigated. The obtained CN/BC meshes underwent comprehensive morphological, physicochemical, and mechanical characterization. Cytotoxicity tests were conducted using L929 mouse fibroblasts, revealing a cell viability of 97.8%. In vivo tests on rabbit skin demonstrated that the patches were nonirritating. Furthermore, the CN/BC fiber meshes were tested in vitro using human dermal keratinocytes (HaCaT cells) and human umbilical vein endothelial cells as model cells for TM perforation healing. Both cell types demonstrated successful growth on these scaffolds. The presence of CNs resulted in improved indirect antimicrobial activity of the electrospun fiber meshes. HaCaT cells exhibited an upregulated mRNA expression at 6 and 24 h of key proinflammatory cytokines crucial for the wound healing process, indicating the potential benefits of CNs in the healing response. Overall, this study presents a natural and eco-sustainable fiber mesh with great promise for applications in TM repair, leveraging the synergistic effects of BC and CNs to possibly enhance tissue regeneration and healing. Impact statement Repair of tympanic membrane perforations following chronic otitis media is a main clinical issue in otologic surgery, where the underlying infection obstacles self-healing. To address this challenge, our study proposes a bio-based patch made of nanoscale carbohydrate materials (i.e., bacterial cellulose electrospun fibers and chitin nanofibrils) processed via green solvents. The scaffold is nonirritating in vivo, and cytocompatible with fibroblasts, endothelial cells, and keratinocytes. In epithelial cells, it stimulates the expression of the antimicrobial peptide human beta defensin 2, with a pathway of cytokine expression compatible with the wound healing process. Therefore, it could be applied with unsolved infective pathology.

Challenging DESs and ILs in the valorization of food waste: a case study.

In this study, the efficacy of two of the best performing green solvents for the fractionation of lignocellulosic biomass, cholinium arginate (ChArg) as biobased ionic liquid (Bio-IL) and ChCl:lactic acid (ChCl:LA, 1:10) as natural deep eutectic solvent (NADES), was investigated and compared in the pretreatment of an agri-food industry waste, apple fibers (90°C for 1 h). For the sake of comparison, 1-butyl-3-methylimidazolium acetate (BMIM OAc) as one of the best IL able to dissolve cellulose was also used. After the pretreatment, two fractions were obtained in each case. The results gathered through FTIR and TG analyses of the two materials and the subsequent DNS assay performed after enzymatic treatment led to identify ChArg as the best medium to delignify and remove waxes, present on the starting apple fibers, thus producing a material substantially enriched in cellulose (CRM). Conversely, ChCl:LA did not provide satisfactorily results using these mild conditions, while BMIM OAc showed intermediate performance probably on account of the reduced crystallinity of cellulose after the dissolution-regeneration process. To corroborate the obtained data, FTIR and TG analyses were also performed on the residues collected after the enzymatic hydrolysis. At the end of the pretreatment, ChArg was also quantitatively recovered without significant alterations.

Betaine mediated enhancement of thermal stability and acidity tolerance of vanadium(V) solutions.

A panel of novel vanadium(IV)-betaine complexes has been synthesized according to new and efficient methodologies and characterized through both spectroscopic techniques and thermal analyses. Vanadium(IV)-betaine solutions have been electrochemically oxidized and the effect of betaine ligands on the thermal and pH stability of vanadium(V) solutions has been evaluated under different temperature and acidity conditions. The obtained results displayed a remarkable effect for both of the examined parameters, achieving the preparation of aqueous vanadium(V) solutions displaying long term stability at more than 55 °C under mild acidic conditions. The species formed in the betaine rich vanadium(V) solutions have been sprectroscopically identified in relationship with the acidity of the solution, and the obtained results were confirmed through computational techniques. Vanadium-betaine based solutions have been finally tested in a lab-scale redox flow battery setup, providing preliminary insight into the possible use of this type of electrolyte in VRFBs.

In vitro screening of imidazolium and pyrrolidinium based ionic liquids toxicity on subcellular fractions of the Mediterranean mussel Mytilus galloprovincialis.

Ionic liquids (ILs) have been considered eco-friendly alternatives to conventional organic solvents. However, several studies have reported that ILs exert toxicity towards aquatic invertebrates. Applying in vitro methodology, the aim of the present study was to evaluate the potential effect of three ILs on the biochemical performance of exposed Mytilus galloprovincialis digestive gland and gills cellular fractions. Carboxylesterase might be involved in the derived toxicity mechanism of ILs as activity levels increased significantly in digestive gland exposed fractions. This group of ILs did not seem to induce genotoxicity, except in gills cellular fractions exposed to 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide. In the literature, in vitro methodology has been suggested as an important complement to animal testing and in silico studies. The present research underlines its efficacy as a quick pre-screening before in vivo testing, particularly with heterogenic groups of substances with high variability in composition, such as ILs and deep eutectic solvents.

Fibrinogen-Based Bioink for Application in Skin Equivalent 3D Bioprinting.

Three-dimensional bioprinting has emerged as an attractive technology due to its ability to mimic native tissue architecture using different cell types and biomaterials. Nowadays, cell-laden bioink development or skin tissue equivalents are still at an early stage. The aim of the study is to propose a bioink to be used in skin bioprinting based on a blend of fibrinogen and alginate to form a hydrogel by enzymatic polymerization with thrombin and by ionic crosslinking with divalent calcium ions. The biomaterial ink formulation, composed of 30 mg/mL of fibrinogen, 6% of alginate, and 25 mM of CaCl2, was characterized in terms of homogeneity, rheological properties, printability, mechanical properties, degradation rate, water uptake, and biocompatibility by the indirect method using L929 mouse fibroblasts. The proposed bioink is a homogeneous blend with a shear thinning behavior, excellent printability, adequate mechanical stiffness, porosity, biodegradability, and water uptake, and it is in vitro biocompatible. The fibrinogen-based bioink was used for the 3D bioprinting of the dermal layer of the skin equivalent. Three different normal human dermal fibroblast (NHDF) densities were tested, and better results in terms of viability, spreading, and proliferation were obtained with 4 × 106 cell/mL. The skin equivalent was bioprinted, adding human keratinocytes (HaCaT) through bioprinting on the top surface of the dermal layer. A skin equivalent stained by live/dead and histological analysis immediately after printing and at days 7 and 14 of culture showed a tissuelike structure with two distinct layers characterized by the presence of viable and proliferating cells. This bioprinted skin equivalent showed a similar native skin architecture, paving the way for its use as a skin substitute for wound healing applications.

Lignin-Derivative Ionic Liquids as Corrosion Inhibitors.

Corrosion is a significant problem that negatively affects a wide range of structures and buildings, resulting in their premature failure, which causes safety hazards and significant economic loss. For this reason, various approaches have been developed to prevent or minimize the effects of corrosion, including corrosion inhibitors. Recently, biobased inhibitors have gained a certain interest thanks to their unique properties, eco-friendliness, and availability. Among all the green precursors, lignin is of particular interest, being a natural polymer that can be obtained from different sources including agricultural residues. Corrosion inhibitors based on ionic liquids (ILs) also present interesting advantages, such as low volatility and high tunability. If combined, it may be possible to obtain new lignin-based ILs that present interesting corrosion inhibitor properties. In this work, the inhibition properties of new biobased lignin ILs and the influence of anions and cations on the corrosion of mild steel in an aqueous solution of 0.01 M NaCl were investigated by Potentiostatic Electrochemical Impedance Spectroscopy (PEIS) and Cyclic Potentiodynamic Polarization (CPP). Moreover, the surface was characterized using SEM, EDS, and optical profilometry. The IL choline syringate showed promising performance, reducing the corrosion current after 24 h immersion in 0.01 M sodium chloride, from 1.66 µA/cm2 for the control to 0.066 µA/cm2 with 10 mM of the IL present. In addition to its performance as a corrosion inhibitor, both components of this IL also meet or exceed the current additional desired properties of such compounds, being readily available, and well tolerated in organisms and the environment.

Marine Collagen-Based Bioink for 3D Bioprinting of a Bilayered Skin Model.

Marine organisms (i.e., fish, jellyfish, sponges or seaweeds) represent an abundant and eco-friendly source of collagen. Marine collagen, compared to mammalian collagen, can be easily extracted, is water-soluble, avoids transmissible diseases and owns anti-microbial activities. Recent studies have reported marine collagen as a suitable biomaterial for skin tissue regeneration. The aim of this work was to investigate, for the first time, marine collagen from basa fish skin for the development of a bioink for extrusion 3D bioprinting of a bilayered skin model. The bioinks were obtained by mixing semi-crosslinked alginate with 10 and 20 mg/mL of collagen. The bioinks were characterised by evaluating the printability in terms of homogeneity, spreading ratio, shape fidelity and rheological properties. Morphology, degradation rate, swelling properties and antibacterial activity were also evaluated. The alginate-based bioink containing 20 mg/mL of marine collagen was selected for 3D bioprinting of skin-like constructs with human fibroblasts and keratinocytes. The bioprinted constructs showed a homogeneous distribution of viable and proliferating cells at days 1, 7 and 14 of culture evaluated by qualitative (live/dead) and qualitative (XTT) assays, and histological (H&E) and gene expression analysis. In conclusion, marine collagen can be successfully used to formulate a bioink for 3D bioprinting. In particular, the obtained bioink can be printed in 3D structures and is able to support fibroblasts and keratinocytes viability and proliferation.

Toxicity of ionic liquids in marine and freshwater microorganisms and invertebrates: state of the art.

The variety of applications and expected growth in ionic liquid production are raising concerns about the release of these compounds into aquatic systems. Up to date, 103 studies have provided ecotoxicological data regarding the exposure effects of Ionic Liquids towards aquatic microorganisms and invertebrate species: 61 were devoted to freshwater species (n = 28), while marine species (n = 12) were mentioned in 42. The aim of this review, by gathering published studies on ionic liquids and model aquatic organisms, was to present the toxic effects described in distinct species and to understand which are the main factors influencing the toxicity of some ionic liquids. In accordance with the most recognized pattern, freshwater species were featured in a higher number of publications than marine ones. After literature analysis, algal species were the most represented organisms in aquatic toxicity assessments. Among tested compounds, the imidazolium cations in combination with long alkyl-chain anions, showed to be the most toxic one. In analytical terms, it is not straightforward to find the undissociated compound in a natural compartment, as ionic liquids are composed of ionic components, easily subjected to dissociation. Given the aforementioned, the present review paper points out the need of increasing the number of organisms being assessed in ionic liquids toxicity assays, in order to start defining monitoring procedures. Moreover, such would allow a better understanding of ionic liquids contamination status and, also, the opportunity to remark the effectiveness of new in silico methods for the ecotoxicity assessment of this kind of substances.

Betaine- and L-Carnitine-Based Ionic Liquids as Solubilising and Stabilising Agents for the Formulation of Antimicrobial Eye Drops Containing Diacerein.

The therapeutic efficacy of topically administered drugs, however powerful, is largely affected by their bioavailability and, thus, ultimately, on their aqueous solubility and stability. The aim of this study was to evaluate the use of ionic liquids (ILs) as functional excipients to solubilise, stabilise, and prolong the ocular residence time of diacerein (DIA) in eye drop formulations. DIA is a poorly soluble and unstable anthraquinone prodrug, rapidly hydrolysed to rhein (Rhe), for the treatment of osteoarthritis. DIA has recently been evaluated as an antimicrobial agent for bacterial keratitis. Two ILs based on natural zwitterionic compounds were investigated: L-carnitine C6 alkyl ester bromide (Carn6), and betaine C6 alkyl ester bromide (Bet6). The stabilising, solubilising, and mucoadhesive properties of ILs were investigated, as well as their cytotoxicity to the murine fibroblast BALB/3T3 clone A31 cell line. Two IL-DIA-based eye drop formulations were prepared, and their efficacy against both Staphylococcus aureus and Pseudomonas aeruginosa was determined. Finally, the eye drops were administered in vivo on New Zealand albino rabbits, testing their tolerability as well as their elimination and degradation kinetics. Both Bet6 and Carn6 have good potential as functional excipients, showing solubilising, stabilising, mucoadhesive, and antimicrobial properties; their in vitro cytotoxicity and in vivo ocular tolerability pave the way for their future use in ophthalmic applications.

Are natural deep eutectic solvents always a sustainable option? A bioassay-based study.

The traditional use of organic solvents in various branches of industry is being rethought as these compounds very often display high volatility, toxicity and lipophilicity (related to the ability to interact with biological membranes). More recently, developments in the field of Green Chemistry are focusing on the design of more sustainable and cost-effective solvent alternatives like Ionic Liquids (ILs), bio-based solvents and natural deep eutectic solvents (NADESs). The present study aimed at performing an ecotoxicological screening of 15 NADESs using an extensive set of marine and freshwater bioassays, based on different endpoints as the following: immobilization of the crustacean Daphnia magna, growth inhibition of Raphidocelis subcapitata and of Phaeodactylum tricornutum, larval development alterations on the serpulid Ficopomatus enigmaticus and bioluminescence inhibition of Aliivibrio fischeri. What emerged was a general absence of toxicity of all samples. However, both algal assays showed a certain degree of biostimulation, up to over 100% growth increase in respect to controls with 8 out of 15 compounds tested with Raphidocelis subcapitata. Despite NADESs-induced negligible toxicity effects to invertebrates, encouraging their labelling as "sustainable" solvents, the liability of their intentional or accidental release into aquatic systems may represent a serious risk in terms of ecosystem functioning impairments.

The Structure-Property Relationship of Pyrrolidinium and Piperidinium-Based Bromide Organic Materials.

Two couples of dicationic ionic liquids, featuring pyrrolidinium and piperidinium cations and different linker chains, were prepared and characterized. 1,1'-(propane-1,3-diyl)bis(1-methylpyrrolidinium) bromide, 1,1'-(octane-1,8-diyl)bis(1-methylpyrrolidinium) bromide, 1,1'-(propane-1,3-diyl)bis(1-methylpiperidinium) bromide, and 1,1'-(octane-1,8-diyl)bis(1-methylpiperidinium) bromide were synthesized in quantitative yields and high purity and thermally characterized through TGA and DSC analysis. In this study, we propose a preliminary comparative evaluation of the effect of the linker chain length and of the size of the aliphatic ammonium ring on the thermal and solubility properties of bromide dicationic ionic liquids.

A Specific Interaction between Ionic Liquids' Cations and Reichardt's Dye.

Solvatochromic probes are often used to understand solvation environments at the molecular scale. In the case of ionic liquids constituted by an anion and a cation, which are designed and paired in order to obtain a low melting point and other desirable physicochemical properties, these two indivisible components can interact in a very different way with the probe. This is the case with one of the most common probes: Reichardt's Dye. In the cases where the positive charge of the cation is delocalized on an aromatic ring such as imidazolium, the antibonding orbitals of the positively charged aromatic system are very similar in nature and energy to the LUMO of Reichardt's Dye. This leads to an interesting, specific cation-probe interaction that can be used to elucidate the nature of the ionic liquids' cations. Parallel computational and experimental investigations have been conducted to elucidate the nature of this interaction with respect to the molecular structure of the cation.

Dielectric Study of Tetraalkylammonium and Tetraalkylphosphonium Levulinate Ionic Liquids.

Broadband dielectric spectroscopy in a broad temperature range was employed to study ionic conductivity and dynamics in tetraalkylammonium- and tetraalkylphosphonium-based ionic liquids (ILs) having levulinate as a common anion. Combining data for ionic conductivity with data obtained for viscosity in a Walden plot, we show that ionic conductivity is controlled by viscosity while a strong association of ions takes place. Higher values for ionic conductivities in a broad temperature range were found for the tetraalkylphosphonium-based IL compared to its ammonium homolog in accordance with its lower viscosity. Levulinate used in the present study as anion was found to interact and associate stronger with the cations forming ion-pairs or other complexes compared to the NTf2 anion studied in literature. In order to analyze dielectric data, different fitting approaches were employed. The original random barrier model cannot well describe the conductivity especially at the higher frequencies region. In electric modulus representation, two overlapping mechanisms contribute to the broad low frequencies peak. The slower process is related to the conduction mechanism and the faster to the main polarization process of the complex dielectric permittivity representation. The correlation of the characteristic time scales of the previous relaxation processes was discussed in terms of ionic interactions.

The ability of deep eutectic solvent systems to extract bioactive compounds from apple pomace.

The objective of this study was to examine the bioactivity of extracts from apple pomace obtained by non-conventional green extraction methods (DES systems). Bioactivity was antioxidant capacity and ability to stimulate insulin secretion from pancreatic beta-cells. The antioxidant capacity of extracts was examined using the DPPH and the FRAP assay. Impact of the extracts on cell viability and insulin secretion were examined using the BRIN-BD11 cell line. ChCl:EG(1:4) extracts resulted in high antioxidant capacity in the DPPH assay (80.1% inhibition versus 11.3%). Extracts obtained from the classical systems demonstrated an ability to promote insulin secretion significantly higher than the positive control, p < 0.05. ChCl:EG(1:4) extracts stimulated insulin secretion to a lesser extent. Overall, the data provides evidence for the potential of DES systems to extract bioactive compounds from apple pomace that have relevance for metabolic health. Further optimisation of the extraction procedures should be tailored to the desired bioactive properties.