Imperial College London

ProfessorAlexandraPorter

Faculty of EngineeringDepartment of Materials

Professor of Bio-imaging and Analysis
 
 
 
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Contact

 

+44 (0)20 7594 9691a.porter

 
 
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Location

 

B341 Royal School of MinesRoyal School of MinesSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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166 results found

Kumar P, Zavala-Reyes JC, Kalaiarasan G, Abubakar-Waziri H, Young G, Mudway I, Dilliway C, Lakhdar R, Mumby S, Kłosowski MM, Pain CC, Adcock IM, Watson JS, Sephton MA, Chung KF, Porter AEet al., 2023, Characteristics of fine and ultrafine aerosols in the London underground., Science of the Total Environment, Vol: 858, ISSN: 0048-9697

Underground railway systems are recognised spaces of increased personal pollution exposure. We studied the number-size distribution and physico-chemical characteristics of ultrafine (PM0.1), fine (PM0.1-2.5) and coarse (PM2.5-10) particles collected on a London underground platform. Particle number concentrations gradually increased throughout the day, with a maximum concentration between 18:00 h and 21:00 h (local time). There was a maximum decrease in mass for the PM2.5, PM2.5-10 and black carbon of 3.9, 4.5 and ~ 21-times, respectively, between operable (OpHrs) and non-operable (N-OpHrs) hours. Average PM10 (52 μg m-3) and PM2.5 (34 μg m-3) concentrations over the full data showed levels above the World Health Organization Air Quality Guidelines. Respiratory deposition doses of particle number and mass concentrations were calculated and found to be two- and four-times higher during OpHrs compared with N-OpHrs, reflecting events such as train arrival/departure during OpHrs. Organic compounds were composed of aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs) which are known to be harmful to health. Specific ratios of PAHs were identified for underground transport that may reflect an interaction between PAHs and fine particles. Scanning transmission electron microscopy (STEM) chemical maps of fine and ultrafine fractions show they are composed of Fe and O in the form of magnetite and nanosized mixtures of metals including Cr, Al, Ni and Mn. These findings, and the low air change rate (0.17 to 0.46 h-1), highlight the need to improve the ventilation conditions.

Journal article

Bernardini A, Trovatelli M, Klosowski M, Pederzani M, Zani D, Brizzola S, Porter A, Rodriguez y Baena F, Dini Det al., 2022, Reconstruction of ovine axonal cytoarchitecture enables more accurate models of brain biomechanics, Communications Biology, Vol: 5, ISSN: 2399-3642

There is an increased need and focus to understand how local brain microstructure affects the transport of drug molecules directly administered to the brain tissue, for example in convection-enhanced delivery procedures. This study reports a systematic attempt to characterize the cytoarchitecture of commissural, long association and projection fibres, namely the corpus callosum, the fornix and the corona radiata, with the specific aim to map different regions of the tissue and provide essential information for the development of accurate models of brain biomechanics. Ovine samples are imaged using scanning electron microscopy combined with focused ion beam milling to generate 3D volume reconstructions of the tissue at subcellular spatial resolution. Focus is placed on the characteristic cytological feature of the white matter: the axons and their alignment in the tissue. For each tract, a 3D reconstruction of relatively large volumes, including a significant number of axons, is performed and outer axonal ellipticity, outer axonal cross-sectional area and their relative perimeter are measured. The study of well-resolved microstructural features provides useful insight into the fibrous organization of the tissue, whose micromechanical behaviour is that of a composite material presenting elliptical tortuous tubular axonal structures embedded in the extra-cellular matrix. Drug flow can be captured through microstructurally-based models using 3D volumes, either reconstructed directly from images or generated in silico using parameters extracted from the database of images, leading to a workflow to enable physically-accurate simulations of drug delivery to the targeted tissue.

Journal article

Morfill C, Pankratova S, Machado P, Fernando NK, Regoutz A, Talamona F, Pinna A, Klosowski M, Wilkinson RJ, Fleck RA, Xie F, Porter AE, Kiryushko Det al., 2022, Nanostars Carrying Multifunctional Neurotrophic Dendrimers Protect Neurons in Preclinical In Vitro Models of Neurodegenerative Disorders, ACS APPLIED MATERIALS & INTERFACES, ISSN: 1944-8244

Journal article

Phillips T, Heaney CE, Benmoufok E, Li Q, Hua L, Porter AE, Chung KF, Pain CCet al., 2022, Multi-Output Regression with Generative Adversarial Networks (MOR-GANs), Applied Sciences, Vol: 12, Pages: 1-24, ISSN: 2076-3417

Regression modelling has always been a key process in unlocking the relationships betweenindependent and dependent variables that are held within data. In recent years, machine learninghas uncovered new insights in many fields, providing predictions to previously unsolved problems.Generative Adversarial Networks (GANs) have been widely applied to image processing producinggood results, however, these methods have not often been applied to non-image data. Seeing thepowerful generative capabilities of the GANs, we explore their use, here, as a regression method. Inparticular, we explore the use of the Wasserstein GAN (WGAN) as a multi-output regression method.The resulting method we call Multi-Output Regression GANs (MOR-GANs) and its performanceis compared to a Gaussian Process Regression method (GPR) - a commonly used non-parametricregression method that has been well tested on small datasets with noisy responses. The WGANregression model performs well for all types of datasets and exhibits substantial improvements overthe performance of the GPR for certain types of datasets, demonstrating the flexibility of the GAN asa model for regression.

Journal article

Mirón-Barroso S, Correia JS, Frampton AE, Lythgoe MP, Clark J, Tookman L, Ottaviani S, Castellano L, Porter AE, Georgiou TK, Krell Jet al., 2022, Polymeric carriers for delivery of RNA cancer therapeutics, Non-Coding RNA, Vol: 8, Pages: 58-58, ISSN: 2311-553X

As research uncovers the underpinnings of cancer biology, new targeted therapies have been developed. Many of these therapies are small molecules, such as kinase inhibitors, that target specific proteins; however, only 1% of the genome encodes for proteins and only a subset of these proteins has ‘druggable’ active binding sites. In recent decades, RNA therapeutics have gained popularity due to their ability to affect targets that small molecules cannot. Additionally, they can be manufactured more rapidly and cost-effectively than small molecules or recombinant proteins. RNA therapeutics can be synthesised chemically and altered quickly, which can enable a more personalised approach to cancer treatment. Even though a wide range of RNA therapeutics are being developed for various indications in the oncology setting, none has reached the clinic to date. One of the main reasons for this is attributed to the lack of safe and effective delivery systems for this type of therapeutic. This review focuses on current strategies to overcome these challenges and enable the clinical utility of these novel therapeutic agents in the cancer clinic.

Journal article

Yallop M, Wang Y, Masuda S, Daniels J, Ockenden A, Masani H, Scott TB, Xie F, Ryan M, Jones C, Porter AEet al., 2022, Quantifying impacts of titanium dioxide nanoparticles on natural assemblages of riverine phytobenthos and phytoplankton in an outdoor setting, SCIENCE OF THE TOTAL ENVIRONMENT, Vol: 831, ISSN: 0048-9697

Journal article

Lakhdar R, Mumby S, Abubakar-Waziri H, Porter A, Adcock IM, Chung KFet al., 2022, Lung toxicity of particulates and gaseous pollutants using ex-vivo airway epithelial cell culture systems, ENVIRONMENTAL POLLUTION, Vol: 305, ISSN: 0269-7491

Journal article

Gomez-Gonzalez MA, Rehkamper M, Han Z, Ryan MP, Laycock A, Porter AEet al., 2022, ZnO Nanomaterials and Ionic Zn Partition within Wastewater Sludge Investigated by Isotopic Labeling, Global Challenges, Vol: 6, ISSN: 2056-6646

The increasing commercial use of engineered zinc oxide nanomaterials necessitates a thorough understanding of their behavior following their release into wastewater. Herein, the fates of zinc oxide nanoparticles (ZnO NPs) and ionic Zn in a real primary sludge collected from a municipal wastewater system are studied via stable isotope tracing at an environmentally relevant spiking concentration of 15.2 µg g−1. Due to rapid dissolution, nanoparticulate ZnO does not impart particle-specific effects, and the Zn ions from NP dissolution and ionic Zn display indistinguishable behavior as they partition equally between the solid, liquid, and ultrafiltrate phases of the sludge over a 4-h incubation period. This work provides important constraints on the behavior of engineered ZnO nanomaterials in primary sludge—the first barrier in a wastewater treatment plant—at low, realistic concentrations. As the calculated solid–liquid partition coefficients are significantly lower than those reported in prior studies that employ unreasonably high spiking concentrations, this work highlights the importance of using low, environmentally relevant doses of engineered nanomaterials in experiments to obtain accurate risk assessments.

Journal article

Naruphontjirakul P, Li S, Pinna A, Barrak F, Chen S, Redpath AN, Rankin SM, Porter AE, Jones JRet al., 2022, Interaction of monodispersed strontium containing bioactive glass nanoparticles with macrophages, Biomaterials Advances, Vol: 133, Pages: 1-12, ISSN: 2772-9508

The cellular response of murine primary macrophages to monodisperse strontium containing bioactive glass nanoparticles (SrBGNPs), with diameters of 90 ± 10 nm and a composition (mol%) of 88.8 SiO2–1.8CaO-9.4SrO (9.4% Sr-BGNPs) was investigated for the first time. Macrophage response is critical as applications of bioactive nanoparticles will involve the nanoparticles circulating in the blood stream and macrophages will be the first cells to encounter the particles, as part of inflammatory response mechanisms. Macrophage viability and total DNA measurements were not decreased by particle concentrations of up to 250 μg/mL. The Sr-BGNPs were actively internalised by the macrophages via formation of endosome/lysosome-like vesicles bordered by a membrane inside the cells. The Sr-BGNPs degraded inside the cells, with the Ca and Sr maintained inside the silica network. When RAW264.7 cells were incubated with Sr-BGNPs, the cells were polarised towards the pro-regenerative M2 population rather than the pro-inflammatory M1 population. Sr-BGNPs are potential biocompatible vehicles for therapeutic cation delivery for applications in bone regeneration.

Journal article

Garcia-Giner V, Han Z, Giuliani F, Porter AEet al., 2021, Nanoscale imaging and analysis of bone pathologies, Applied Sciences-Basel, Vol: 11, Pages: 1-32, ISSN: 2076-3417

Understanding the properties of bone is of both fundamental and clinical relevance. The basis of bone’s quality and mechanical resilience lies in its nanoscale building blocks (i.e., mineral, collagen, non-collagenous proteins, and water) and their complex interactions across length scales. Although the structure–mechanical property relationship in healthy bone tissue is relatively well characterized, not much is known about the molecular-level origin of impaired mechanics and higher fracture risks in skeletal disorders such as osteoporosis or Paget’s disease. Alterations in the ultrastructure, chemistry, and nano-/micromechanics of bone tissue in such a diverse group of diseased states have only been briefly explored. Recent research is uncovering the effects of several non-collagenous bone matrix proteins, whose deficiencies or mutations are, to some extent, implicated in bone diseases, on bone matrix quality and mechanics. Herein, we review existing studies on ultrastructural imaging—with a focus on electron microscopy—and chemical, mechanical analysis of pathological bone tissues. The nanometric details offered by these reports, from studying knockout mice models to characterizing exact disease phenotypes, can provide key insights into various bone pathologies and facilitate the development of new treatments.

Journal article

Valente P, Kiryushko D, Sacchetti S, Machado P, Cobley CM, Mangini V, Porter AE, Spatz JP, Fleck RA, Benfenati F, Fiammengo Ret al., 2021, Reply to Comment on Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-D-aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro, ACS NANO, Vol: 15, Pages: 15409-15417, ISSN: 1936-0851

Journal article

Gomez-Gonzalez MA, Koronfel MA, Pullin H, Parker JE, Quinn PD, Inverno MD, Scott TB, Xie F, Voulvoulis N, Yallop ML, Ryan MP, Porter AEet al., 2021, Nanoscale chemical imaging of nanoparticles under real-world wastewater treatment conditions, Advanced Sustainable Systems, Vol: 5, ISSN: 2366-7486

Understanding nanomaterial transformations within wastewater treatment plants is an important step to better predict their potential impact on the environment. Here, spatially resolved, in situ nano-X-ray fluorescence microscopy is applied to directly observe nanometer-scale dissolution, morphological, and chemical evolution of individual and aggregated ZnO nanorods in complex “real-world” conditions: influent water and primary sludge collected from a municipal wastewater system. A complete transformation of isolated ZnO nanorods into ZnS occurs after only 1 hour in influent water, but larger aggregates of the ZnO nanorods transform only partially, with small contributions of ZnS and Zn-phosphate (Zn3(PO4)2) species, after 3 hours. Transformation of aggregates of the ZnO nanorods toward mixed ZnS, Zn adsorbed to Fe-oxyhydroxides, and a large contribution of Zn3(PO4)2 phases are observed during their incubation in primary sludge for 3 hours. Discrete, isolated ZnO regions are imaged with unprecedented spatial resolution, revealing their incipient transformation toward Zn3(PO4)2. Passivation by transformation(s) into mixtures of less soluble phases may influence the subsequent bioreactivity of these nanomaterials. This work emphasizes the importance of imaging the nanoscale chemistry of mixtures of nanoparticles in highly complex, heterogeneous semi-solid matrices for improved prediction of their impacts on treatment processes, and potential environmental toxicity following release.

Journal article

Kumar P, Kalaiarasan G, Porter AE, Pinna A, Kłosowski MM, Demokritou P, Chung KF, Pain C, Arvind DK, Arcucci R, Adcock IM, Dilliway Cet al., 2021, An overview of methods of fine and ultrafine particle collection for physicochemical characterisation and toxicity assessments., Science of the Total Environment, Vol: 756, Pages: 1-22, ISSN: 0048-9697

Particulate matter (PM) is a crucial health risk factor for respiratory and cardiovascular diseases. The smaller size fractions, ≤2.5 μm (PM2.5; fine particles) and ≤0.1 μm (PM0.1; ultrafine particles), show the highest bioactivity but acquiring sufficient mass for in vitro and in vivo toxicological studies is challenging. We review the suitability of available instrumentation to collect the PM mass required for these assessments. Five different microenvironments representing the diverse exposure conditions in urban environments are considered in order to establish the typical PM concentrations present. The highest concentrations of PM2.5 and PM0.1 were found near traffic (i.e. roadsides and traffic intersections), followed by indoor environments, parks and behind roadside vegetation. We identify key factors to consider when selecting sampling instrumentation. These include PM concentration on-site (low concentrations increase sampling time), nature of sampling sites (e.g. indoors; noise and space will be an issue), equipment handling and power supply. Physicochemical characterisation requires micro- to milli-gram quantities of PM and it may increase according to the processing methods (e.g. digestion or sonication). Toxicological assessments of PM involve numerous mechanisms (e.g. inflammatory processes and oxidative stress) requiring significant amounts of PM to obtain accurate results. Optimising air sampling techniques are therefore important for the appropriate collection medium/filter which have innate physical properties and the potential to interact with samples. An evaluation of methods and instrumentation used for airborne virus collection concludes that samplers operating cyclone sampling techniques (using centrifugal forces) are effective in collecting airborne viruses. We highlight that predictive modelling can help to identify pollution hotspots in an urban environment for the efficient collection of PM mass. This review provides

Journal article

Pinna A, Baghbaderani MT, Hernandez VV, Naruphontjirakul P, Li S, McFarlane T, Hachim D, Stevens MM, Porter AE, Jones JRet al., 2021, Nanoceria provides antioxidant and osteogenic properties to mesoporous silica nanoparticles for osteoporosis treatment, Acta Biomaterialia, Vol: 122, Pages: 365-376, ISSN: 1742-7061

Osteoporosis, a chronic metabolic bone disease, is the most common cause of fractures. Drugs for treating osteoporosis generally inhibit osteoclast (OC) activity, but are rarely aimed at encouraging new bone growth and often cause severe systemic side effects. Reactive oxygen species (ROS) are one of the key triggers of osteoporosis, by inducing osteoblast (OB) and osteocyte apoptosis and promoting osteoclastogenesis. Here we tested the capability of the ROS-scavenger nanoceria encapsulated within mesoporous silica nanoparticles (Ce@MSNs) to treat osteoporosis using a pre-osteoblast MC3T3-E1 cell monoculture in stressed and normal conditions. Ce@MSNs (diameter of 80 ± 10 nm) were synthesised following a scalable two-step process involving sol-gel and wet impregnation methods. The Ce@MSNs at concentration of 100 μg mL−1 induced a significant reduction in oxidative stress produced by t-butyl hydroperoxide and did not alter cell viability significantly. Confocal microscopy showed that MSNs and Ce@MsNs were internalised into the cytoplasm of the pre-osteoblasts after 24 h but were not in the nucleus, avoiding any DNA and RNA modifications. Ce@MSNs provoked mineralisation of the pre-osteoablasts without osteogenic supplements, which did not occur when the cells were exposed to MSN without nanoceria. In a co-culture system of MC3T3-E1 and RAW264.7 macrophages, the Ce@MSNs exhibited antioxidant capability and stimulated cell proliferation and osteogenic responses without adding osteogenic supplements to the culture. The work brings forward an effective platform based for facile synthesis of Ce@MSNs to interact with both OBs and OCs for treatment of osteoporosis.

Journal article

Aldegaither N, Sernicola G, Mesgarnejad A, Karma A, Balint D, Wang J, Saiz E, Shefelbine SJ, Porter AE, Giuliani Fet al., 2021, Fracture toughness of bone at the microscale, Acta Biomaterialia, Vol: 121, Pages: 475-483, ISSN: 1742-7061

Bone's hierarchical arrangement of collagen and mineral generates a confluence of toughening mechanisms acting at every length scale from the molecular to the macroscopic level. Molecular defects, disease, and age alter bone structure at different levels and diminish its fracture resistance. However, the inability to isolate and quantify the influence of specific features hampers our understanding and the development of new therapies. Here, we combine in situ micromechanical testing, transmission electron microscopy and phase-field modelling to quantify intrinsic deformation and toughening at the fibrillar level and unveil the critical role of fibril orientation on crack deflection. At this level dry bone is highly anisotropic, with fracture energies ranging between 5 and 30 J/m2 depending on the direction of crack propagation. These values are lower than previously calculated for dehydrated samples from large-scale tests. However, they still suggest a significant amount of energy dissipation. This approach provides a new tool to uncouple and quantify, from the bottom up, the roles played by the structural features and constituents of bone on fracture and how can they be affected by different pathologies. The methodology can be extended to support the rational development of new structural composites.

Journal article

Depalle B, McGilvery CM, Nobakhti S, Aldegaither N, Shefelbine SJ, Porter AEet al., 2021, Osteopontin regulates type I collagen fibril formation in bone tissue, Acta Biomaterialia, Vol: 120, Pages: 194-202, ISSN: 1742-7061

Osteopontin (OPN) is a non-collagenous protein involved in biomineralization of bone tissue. Beyond its role in biomineralization, we show that osteopontin is essential to the quality of collagen fibrils in bone. Transmission electron microscopy revealed that, in Opn−/− tissue, the organization of the collagen fibrils was highly heterogeneous, more disorganized than WT bone and comprised of regions of both organized and disorganized matrix with a reduced density. The Opn−/− bone tissue also exhibited regions in which the collagen had lost its characteristic fibrillar structure, and the crystals were disorganized. Using nanobeam electron diffraction, we show that damage to structural integrity of collagen fibrils in Opn−/- bone tissue and their organization causes mineral disorganization, which could ultimately affect its mechanical integrity.

Journal article

Han Z, Porter AE, 2020, In situ electron microscopy of complex biological and nanoscale systems: challenges and opportunities, Frontiers in Nanotechnology, Vol: 2, Pages: 1-14, ISSN: 2673-3013

In situ imaging for direct visualization is important for physical and biological sciences. Research endeavors into elucidating dynamic biological and nanoscale phenomena frequently necessitate in situ and time-resolved imaging. In situ liquid cell electron microscopy (LC-EM) can overcome certain limitations of conventional electron microscopies and offer great promise. This review aims to examine the status-quo and practical challenges of in situ LC-EM and its applications, and to offer insights into a novel correlative technique termed microfluidic liquid cell electron microscopy. We conclude by suggesting a few research ideas adopting microfluidic LC-EM for in situ imaging of biological and nanoscale systems.

Journal article

Alzahabi KH, Usmani O, Georgiou TK, Ryan MP, Robertson BD, Tetley TD, Porter AEet al., 2020, Approaches to treating tuberculosis by encapsulating metal ions and anti-mycobacterial drugs utilizing nano- and microparticle technologies, Emerging Topics in Life Sciences, Vol: 4, Pages: 581-600, ISSN: 2397-8554

Tuberculosis (TB) is caused by a bacterial infection that affects a number of human organs, primarily the lungs, but also the liver, spleen, and spine, causing key symptoms of fever, fatigue, and persistent cough, and if not treated properly, can be fatal. Every year, 10 million individuals become ill with active TB resulting with a mortality approximating 1.5 million. Current treatment guidelines recommend oral administration of a combination of first-line anti-TB drugs for at least 6 months. While efficacious under optimum conditions, ‘Directly Observed Therapy Short-course’ (DOTS) is not without problems. The long treatment time and poor pharmacokinetics, alongside drug side effects lead to poor patient compliance and has accelerated the emergence of multi-drug resistant (MDR) organisms. All this, combined with the limited number of newly discovered TB drugs to treat MDR-TB and shorten standard therapy time, has highlighted the need for new targeted drug delivery systems. In this respect, there has been recent focus on micro- and nano-particle technologies to prepare organic or/and metal particles loaded with TB drugs to enhance their efficacy by targeted delivery via the inhaled route. In this review, we provide a brief overview of the current epidemiology of TB, and risk factors for progression of latent stage tuberculosis (LTBI) to the active TB. We identify current TB treatment regimens, newly discovered TB drugs, and identify studies that have used micro- or nano-particles technologies to design a reliable inhalation drug delivery system to treat TB more effectively.

Journal article

Ruggero F, Porter AE, Voulvoulis N, Carretti E, Lotti T, Lubello C, Gori Ret al., 2020, A highly efficient multi-step methodology for the quantification of micro-(bio)plastics in sludge., Waste Management and Research, Vol: 39, Pages: 956-965, ISSN: 0734-242X

The present study develops a multi-step methodology for identification and quantification of microplastics and micro-bioplastics (together called in the current work micro-(bio)plastics) in sludge. In previous studies, different methods for the extraction of microplastics were devised for traditional plastics, while the current research tested the methodology on starch-based micro-bioplastics of 0.1-2 mm size. Compostable bioplastics are expected to enter the anaerobic or aerobic biological treatments that lead to end-products applicable in agriculture; some critical conditions of treatments (e.g. low temperature and moisture) can slow down the degradation process and be responsible for the presence of microplastics in the end-product. The methodology consists of an initial oxidation step, with hydrogen peroxide 35% concentrated to clear the sludge and remove the organic fraction, followed by a combination of flotation with sodium chloride and observation of the residues under a fluorescence microscope using a green filter. The workflow revealed an efficacy of removal from 94% to 100% and from 92% to 96% for plastic fragments, 0.5-2 mm and 0.1-0.5 mm size, respectively. The methodology was then applied to samples of food waste pulp harvested after a shredding pre-treatment in an anaerobic digestion (AD) plant in Italy, where polyethylene, starch-based Mater-Bi® and cellophane microplastics were recovered in amounts of 9 ± 1.3/10 g <2 mm and 4.8 ± 1.2/10 g ⩾2 mm. The study highlights the need to lower the threshold size for the quantification of plastics in organic fertilizers, which is currently set by legislations at 2 mm, by improving the background knowledge about the fate of the micro-(bio)plastics in biological treatments for the organic waste.

Journal article

Michaeloudes C, Seiffert J, Chen S, Ruenraroengsak P, Bey L, Theodorou IG, Ryan M, Cui X, Zhang J, Shaffer M, Tetley T, Porter AE, Chung KFet al., 2020, Effect of silver nanospheres and nanowires on human airway smooth muscle cells: role of sulfidation, Nanoscale Advances, Vol: 2, Pages: 5635-5647, ISSN: 2516-0230

Background: The toxicity of inhaled silver nanoparticles on contractile and pro-inflammatory airway smooth muscle cells (ASMCs) that control airway calibre is unknown. We explored the oxidative activities and sulfidation processes of the toxic-inflammatory response. Method: Silver nanospheres (AgNSs) of 20 nm and 50 nm diameter and silver nanowires (AgNWs), short S-AgNWs, 1.5 μm and long L-AgNWs, 10 μm, both 72 nm in diameter were manufactured. We measured their effects on cell proliferation, mitochondrial reactive oxygen species (ROS) release and membrane potential, and also performed electron microscopic studies. Main results and findings: The greatest effects were observed for the smallest particles with the highest specific surface area and greatest solubility that were avidly internalised. ASMCs exposed to 20 nm AgNSs (25 μg mL−1) for 72 hours exhibited a significant decrease in DNA incorporation (−72.4%; p < 0.05), whereas neither the 50 nm AgNSs nor the s-AgNWs altered DNA synthesis or viability. There was a small reduction in ASMC proliferation for the smaller AgNS, although Ag+ at 25 μL mL−1 reduced DNA synthesis by 93.3% (p < 0.001). Mitochondrial potential was reduced by both Ag+ (25 μg mL−1) by 47.1% and 20 nm Ag NSs (25 μg mL−1) by 40.1% (*both at p < 0.05), but was not affected by 50 nm AgNSs and the AgNWs. None of the samples showed a change in ROS toxicity. However, malondialdehyde release, associated with greater total ROS, was observed for all AgNPs, to an extent following the geometric size (20 nm AgNS: 213%, p < 0.01; 50 nm AgNS: 179.5%, p < 0.01 and L-AgNWs by 156.2%, p < 0.05). The antioxidant, N-acetylcysteine, prevented the reduction in mitochondrial potential caused by 20 nm AgNSs. The smaller nanostructures were internalised and dissolved within the ASMCs with the formation of non-reactive silver sulphide (Ag2S) on their surface, but with very little uptake of L-AgNWs. When A

Journal article

Valente P, Kiryushko D, Sacchetti S, Machado P, Cobley CM, Mangini V, Porter AE, Spatz JP, Fleck RA, Benfenati F, Fiammengo Ret al., 2020, Conopeptide-Functionalized Nanoparticles Selectively Antagonize Extrasynaptic N-Methyl-D-aspartate Receptors and Protect Hippocampal Neurons from Excitotoxicity In Vitro, ACS NANO, Vol: 14, Pages: 6866-6877, ISSN: 1936-0851

Journal article

Chen S, Greasley SL, Ong ZY, Naruphontjirakul P, Page SJ, Hanna J, Redpath AN, Tsigkou O, Rankin S, Ryan MP, Porter AE, Jones JRet al., 2020, Biodegradable zinc-containing mesoporous silica nanoparticles for cancer therapy, Materials Today, Vol: 6, Pages: 1-11, ISSN: 1369-7021

Triple-negative breast cancers are extremely aggressive with limited treatment options because of the reduced response of the cancerous cells to hormonal therapy. Here, monodispersed zinc-containing mesoporous silica nanoparticles (MSNPs-Zn) were produced as a tuneable biodegradable platform for delivery of therapeutic zinc ions into cells. We demonstrate that the nanoparticles were internalized by cells, and a therapeutic dose window was identified in which the MSNPs-Zn were toxic to breast cancer cells but not to healthy epithelial (MCF-10a) cells or to murine macrophages. A significant reduction in the viability of triple negative MDA-MB-231 and MCF-7 (ER+) breast cancer cells was seen following 24 h exposure to MSNPs-Zn. The more aggressive MDA-MB-231 cells, with higher metastatic potential, were more sensitive to MSNPs-Zn than the MCF-7 cells. MSNPs-Zn underwent biodegradation inside the cells, becoming hollow structures, as imaged by high-resolution transmission electron microscopy. The mesoporous silica nanoparticles provide a biodegradable vehicle for therapeutic ion release inside cells.

Journal article

McGilvery CM, Abellan P, Klosowski MM, Livingston AG, Cabral JT, Ramasse QM, Porter AEet al., 2020, Nanoscale chemical heterogeneity in aromatic polyamide membranes for reverse osmosis applications, ACS Applied Materials & Interfaces, Vol: 12, Pages: 19890-19902, ISSN: 1944-8244

Reverse osmosis membranes are used within the oil and gas industry for seawater desalination on off-shore oilrigs. The membranes consist of three layers of material: a polyester backing layer, a polysulfone support and a polyamide (PA) thin film separating layer. It is generally thought that the PA layer controls ion selectivity within the membrane but little is understood about its structure or chemistry at the molecular scale. This active polyamide layer is synthesized by interfacial polymerization at an organic/aqueous interface between m-phenylenediamine and trimesoyl chloride, producing a highly cross-linked PA polymer. It has been speculated that the distribution of functional chemistry within this layer could play a role in solute filtration. The only technique potentially capable of probing the distribution of functional chemistry within the active PA layer with sufficient spatial and energy resolution is scanning transmission electron microscopy combined with electron energy-loss spectroscopy (STEM-EELS). Its use is a challenge because organic materials suffer beam-induced damage at relatively modest electron doses. Here we show that it is possible to use the N K-edge to map the active layer of a PA film using monochromated EELS spectrum imaging. The active PA layer is 12 nm thick, which supports previous neutron reflectivity data. Clear changes in the fine structure of the C K-edge across the PA films are measured and we use machine learning to assign fine structure at this edge. Using this method, we map highly heterogeneous intensity variations in functional chemistry attributed to N—C═C bonds within the PA. Similarities are found with previous molecular dynamics simulations of PA showing regions with a higher density of amide bonding as a result of the aggregation process at similar length scales. The chemical pathways that can be deduced may offer a clearer understanding of the transport mechanisms through the membrane.

Journal article

Rodrigues RL, Xie F, Porter AE, Ryan MPet al., 2020, Geometry-induced protein reorientation on the spikes of plasmonic gold nanostars, NANOSCALE ADVANCES, Vol: 2, Pages: 1144-1151, ISSN: 2516-0230

Journal article

Gonzalez Carter D, Goode A, Kiryushko D, Masuda S, Hu S, Lopes Rodrigues R, Dexter D, Shaffer MSP, Porter AEet al., 2019, Quantification of blood-brain barrier transport and neuronal toxicity of unlabelled multiwalled carbon nanotubes as a function of surface charge, Nanoscale, Vol: 11, Pages: 22054-22069, ISSN: 2040-3364

Nanoparticles capable of penetrating the blood-brain barrier (BBB) will greatly advance the delivery of therapies against brain disorders. Carbon nanotubes hold great potential as delivery vehicles due to their high aspect-ratio and cell-penetrating ability. Studies have shown multiwalled carbon nanotubes (MWCNT) cross the BBB, however they have largely relied on labelling methods to track and quantify transport, or on individual electron microscopy images to qualitatively assess transcytosis. Therefore, new direct and quantitative methods, using well-defined and unlabelled MWCNT, are needed to compare BBB translocation of different MWCNT types. Using highly controlled anionic (-), cationic (+) and non-ionic (0) functionalized MWCNT (fMWCNT), we correlate UV-visible spectroscopy with quantitative transmission electron microscopy, quantified from c. 270 endothelial cells, to examine cellular uptake, BBB transport and neurotoxicity of unlabelled fMWCNT. Our results demonstrate that: i) a large fraction of cationic and non-ionic, but not anionic fMWCNT become trapped at the luminal brain endothelial cell membrane; ii) despite high cell association, fMWCNT uptake by brain endothelial cells is low (< 1.5% ID) and does not correlate with BBB translocation, iii) anionic fMWCNT have highest transport levels across an in vitro model of the human BBB compared to non-ionic or cationic nanotubes; and iv) fMWCNT are not toxic to hippocampal neurons at relevant abluminal concentrations; however, fMWCNT charge has an effect on carbon nanotube neurotoxicity at higher fMWCNT concentrations. This quantitative combination of microscopy and spectroscopy, with cellular assays, provides a crucial strategy to predict brain penetration efficiency and neurotoxicity of unlabelled MWCNT and other nanoparticle technologies relevant to human health.

Journal article

Gomez-Gonzalez MA, Koronfel MA, Goode AE, Al-Ejji M, Voulvoulis N, Parker JE, Quinn PD, Scott TB, Xie F, Yallop ML, Porter AE, Ryan MPet al., 2019, Spatially resolved dissolution and speciation changes of ZnO nanorods during short-term in situ incubation in a simulated wastewater environment, ACS Nano, Vol: 13, Pages: 11049-11061, ISSN: 1936-0851

Zinc oxide engineered nanomaterials (ZnO ENMs) are used in a variety of applications worldwide due to their optoelectronic and antibacterial properties with potential contaminant risk to the environment following their disposal. One of the main potential pathways for ZnO nanomaterials to reach the environment is via urban wastewater treatment plants. So far there is no technique that can provide spatiotemporal nanoscale information about the rates and mechanisms by which the individual nanoparticles transform. Fundamental knowledge of how the surface chemistry of individual particles change, and the heterogeneity of transformations within the system, will reveal the critical physicochemical properties determining environmental damage and deactivation. We applied a methodology based on spatially resolved in situ X-ray fluorescence microscopy (XFM), allowing observation of real-time dissolution and morphological and chemical evolution of synthetic template-grown ZnO nanorods (∼725 nm length, ∼140 nm diameter). Core-shell ZnO-ZnS nanostructures were formed rapidly within 1 h, and significant amounts of ZnS species were generated, with a corresponding depletion of ZnO after 3 h. Diffuse nanoparticles of ZnS, Zn3(PO4)2, and Zn adsorbed to Fe-oxyhydroxides were also imaged in some nonsterically impeded regions after 3 h. The formation of diffuse nanoparticles was affected by ongoing ZnO dissolution (quantified by inductively coupled plasma mass spectrometry) and the humic acid content in the simulated sludge. Complementary ex situ X-ray absorption spectroscopy and scanning electron microscopy confirmed a significant decrease in the ZnO contribution over time. Application of time-resolved XFM enables predictions about the rates at which ZnO nanomaterials transform during their first stages of the wastewater treatment process.

Journal article

O'Connell RA, Porter AE, Higgins JS, Cabral JTet al., 2019, Phase behaviour of poly(2, 6-diphenyl-p-phenylene oxide) (PPPO) in mixed solvents, Polymer, Vol: 180, ISSN: 0032-3861

The solution phase behaviour of poly(2, 6-diphenyl-p-phenylene oxide) (PPPO) is investigated by a combination of turbidimetry, infrared spectroscopy, dynamic light scattering and densitometry, combined with calorimetry and X-ray scattering. We select dichloromethane (DCM) and heptane as, respectively, representative good and poor solvents for the polymer. This ternary system results in a miscibility gap which can be utilised for the design and fabrication of PPPO porous materials, membranes and scaffolds via phase inversion. We establish the phase diagram and resolve the kinetic solidification condition arising from the intersection between the coexistence and glass transition curves. PPPO exhibits a high 230 ∘C and is found to crystallise at 336 ∘C, and melt at 423, 445 ∘C with a double endotherm. The kinetics of demixing and (buoyancy-driven) stratification are quantified by optical imaging and the PPPO-rich phase analysed by SAXS/WAXS to resolve both amorphous and crystalline phases. Equipped with this knowledge, we demonstrate the controlled formation of nodular, bicontinuous and cellular morphologies by non-solvent induced demixing.

Journal article

Leo BF, Fearn S, Gonzalez-Carter D, Theodorou I, Ruenraroengsak P, Goode A, Mcphail D, Dexter DT, Shaffer MSP, Chung KF, Porter AE, Ryan MPet al., 2019, Label-free TOF-SIMS imaging of sulfur producing enzymes inside microglia cells following exposure to silver nanowires, Analytical Chemistry, Vol: 91, Pages: 11098-11107, ISSN: 0003-2700

There are no methods sensitive enough to detect enzymes within cells, without the use of analyte labelling. Here we show that it is possible to detect protein ion signals of three different H2S-synthesizing enzymes inside microglia after pre-treatment with silver nanowires (AgNW) using time of flight-secondary ion mass spectrometry (TOF-SIMS). Protein fragment ions, including the fragment of amino acid (C4H8N+ - 70 amu), fragments of the sulfur producing cystathionine-containing enzymes and the Ag+ ion signal could be detected without the use of any labels; the cells were mapped using the C4H8N+ amino acid fragment. Scanning electron microscopy imaging and energy dispersive x-ray chemical analysis showed that the AgNWs were inside the same cells imaged by TOF-SIMS and transformed chemically into crystalline Ag2S within cells in which the sulfur producing proteins were detected. The presence of these sulfur producing cystathionine-containing enzymes within the cells was confirmed by Western Blots and confocal microscopy images of fluorescently labelled antibodies against the sulfur producing enzymes. Label-free ToF-SIMS is very promising for the label-free identification of H2S-contributing enzymes and their cellular localization in biological systems. The technique could in future be used to identify which of these enzymes are most contributory.

Journal article

Ruenraroengsak P, Kiryushko D, Theodorou IG, Klosowski MM, Taylor ER, Niriella T, Palmieri C, Yagüe E, Ryan MP, Coombes RC, Xie F, Porter AEet al., 2019, Frizzled-7-targeted delivery of zinc oxide nanoparticles to drug-resistant breast cancer cells, Nanoscale, Vol: 11, Pages: 12858-12870, ISSN: 2040-3364

There is a need for novel strategies to treat aggressive breast cancer subtypes and overcome drug resistance. ZnO nanoparticles (NPs) have potential in cancer therapy due to their ability to potently and selectively induce cancer cell apoptosis. Here, we tested the in vitro chemotherapeutic efficacy of ZnONPs loaded via a mesoporous silica nanolayer (MSN) towards drug-sensitive breast cancer cells (MCF-7: estrogen receptor-positive, CAL51: triple-negative) and their drug-resistant counterparts (MCF-7TX, CALDOX). ZnO-MSNs were coated on to gold nanostars (AuNSs) for future imaging capabilities in the NIR-II range. Electron and confocal microscopy showed that MSN-ZnO-AuNSs accumulated close to the plasma membrane and were internalized by cells. High-resolution electron microscopy showed that MSN coating degraded outside the cells, releasing ZnONPs that interacted with cell membranes. MSN-ZnO-AuNSs efficiently reduced the viability of all cell lines, and CAL51/CALDOX cells were more susceptible than MCF7/MCF-7-TX cells. MSN-ZnO-AuNSs were then conjugated with the antibody to Frizzled-7 (FZD-7), the receptor upregulated by several breast cancer cells. We used the disulphide (S-S) linker that could be cleaved with a high concentration of glutathione normally observed within cancer cells, releasing Zn2+ into the cytoplasm. FZD-7 targeting resulted in approximately three-fold amplified toxicity of MSN-ZnO-AuNSs towards the MCF-7TX drug-resistant cell line with the highest FZD-7 expression. This study shows that ZnO-MSs are promising tools to treat triple-negative and drug-resistant breast cancers and highlights the potential clinical utility of FZD-7 for delivery of nanomedicines and imaging probes specifically to these cancer types.

Journal article

Parichart N, Tsigkou O, Li S, Porter A, Jones Jet al., 2019, Human mesenchymal stem cells differentiate into an osteogenic lineage in presence of strontium containing bioactive glass nanoparticles, Acta Biomaterialia, Vol: 90, Pages: 373-392, ISSN: 1742-7061

While bioactive glass and ions released during its dissolution are known to stimulate osteoblast cells, the effect bioactive glass has on human stem cells is not clear. Here, we show that spherical monodispersed strontium containing bioactive nanoparticles (Sr-BGNPs) of composition 90.6 mol% SiO2, 5.0 mol% CaO, 4.4% mol% SrO (4.4%Sr-BGNPs) and 88.8 mol% SiO2, 1.8 mol% CaO, and 9.4 mol% SrO (9.4%Sr-BGNPs) stimulate bone marrow derived human stem cell (hMSC) differentiation down an osteogenic pathway without osteogenic supplements. The particles were synthesised using a modified Stӧber process and had diameters of 90 ± 10 nm. Previous work on similar particles that did not contain Sr (80 mol% SiO2, 20 mol% CaO) showed stem cells did not differentiate when exposed to the particles. Here, both compositions of the Sr-BGNPs (up to concentration of 250 μg/mL) stimulated the early-, mid-, and late-stage markers of osteogenic differentiation and accelerated mineralisation in the absence of osteogenic supplements. Sr ions play a key role in osteogenic stem cell differentiation. Sr-BGNP dissolution products did not adversely affect hMSC viability and no significant differences in viability were measured between each particle composition. Confocal and transmission electron microscopy (TEM) demonstrated that monodispersed Sr- BGNPs were internalised and localised within vesicles in the cytoplasm of hMSCs. Degradation of particles inside the cells was observed, whilst maintaining effective cations (Ca and Sr) in their silica network after 24 h in culture. The uptake of Sr-BGNPs by hMSCs was reduced by inhibitors of specific routes of endocytosis, indicating that the Sr-BGNPs uptake by hMSCs was probably via mixed endocytosis mechanisms. Sr-BGNPs have potential as injectable therapeutic devices for bone regeneration or treatment of conditions such as osteoporosis, because of their ability deliver a sustained release of osteogenic inorganic cations, e.g. calcium (Ca) or a

Journal article

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