Publications
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A method for the measurement of mass and number of graphene oxide sheets in suspension based on non-spherical approximations
Crica L.E., Dennison T.J., Guerini E.A., Kostarelos K. 2D Materials; 8 (3, 035044) 2021. 10.1088/2053-1583/abfe01. IF: 7.103
Currently, particle analysis of 2D materials in suspension is commonly restricted to microscopic techniques in the dry state, and thus does not permit an accurate investigation of colloidal suspensions. Colloids in bulk can be assessed by light scattering and diffraction to investigate features such as their hydrodynamic size, charge and concentration. However, the main drawback of such techniques lies in the application of analytical and computational methods based on models assuming particle sphericity which are not representative for 2D materials. Resonance mass measurement (RMM) is a technique which can enable the analysis of 2D materials in suspension without the assumptions of spherical models. Here, we report the application of RMM to measure particle mass and concentration for three types of graphene oxide (GO) aqueous dispersions. Using micro- and nano-suspended resonating sensors, we were able to decipher gravimetric differences between GO and graphitic materials. Our results support the urge for proper definitions and standardisations of graphene based materials, and offer a new method of characterisation for 2D material colloids in liquid suspension. © 2021 The Author(s). Published by IOP Publishing Ltd.
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Adenoviral Mediated Delivery of OSKM Factors Induces Partial Reprogramming of Mouse Cardiac Cells In Vivo
Kisby T., de Lázaro I., Fisch S., Cartwright E.J., Cossu G., Kostarelos K. Advanced Therapeutics; 4 (2, 2000141) 2021. 10.1002/adtp.202000141. IF: 0.000
The induction of in vivo reprogramming toward pluripotency has been demonstrated in several tissues utilizing either transgenic inducible mice or gene delivery approaches. However, the effects of exogenous reprogramming factor expression in the mammalian heart have not been previously reported. The present study aims to investigate the response of cardiac cells to ectopic Oct3/4, Sox2, Klf4, and cMyc (OSKM) expression in vivo using a non-integrating adenoviral vector. Direct intramyocardial injection of this vector achieves effective and transient OSKM overexpression in the healthy heart and after myocardial infarction. The expression of these factors induces transient upregulation of a number of endogenous pluripotency (endo-Oct3/4, Gdf3) and reprogramming related (Cdh1, Fut4) genes, confirming the induction of cell reprogramming. Despite the initiation of reprogramming, markers of fully de-differentiated cells including Nanog remain silenced, consistent with a partially reprogrammed state. Furthermore, no indications of tumorigenesis or teratoma formation are observed. Overall, these data suggest that adenoviral mediated OSKM delivery can be utilized to induce partial in vivo reprogramming. However, the absence of any clear regenerative effects after myocardial infarction indicates that further optimization of vector mediated reprogramming strategies is essential to overcome barriers to therapeutic efficacy. © 2020 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH
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Deep Tissue Translocation of Graphene Oxide Sheets in Human Glioblastoma 3D Spheroids and an Orthotopic Xenograft Model
de Lázaro I., Sharp P., Gurcan C., Ceylan A., Stylianou M., Kisby T., Chen Y., Vranic S., Barr K., Taheri H., Ozen A., Bussy C., Yilmazer A., Kostarelos K. Advanced Therapeutics; 4 (1, 2000109) 2021. 10.1002/adtp.202000109. IF: 0.000
Its anatomical localization, a highly heterogeneous and drug-resistant tumor cell population and a “cold” immune microenvironment, all challenge the treatment of glioblastoma. Nanoscale drug delivery systems, including graphene oxide (GO) flakes, may circumvent some of these issues bypassing biological barriers, delivering multiple cargoes to impact several pathways simultaneously, or targeting the immune compartment. Here, the interactions of GO flakes with in vitro (U-87 MG three-dimensional spheroids, without stromal or immune compartments) and in vivo (U-87 MG orthotopic xenograft) models of glioblastoma are investigated. In vitro, GO flakes translocated deeply into the spheroids with little internalization in tumor cells. In vivo, intracranially administered GO also show extensive distribution throughout the tumor and demonstrate no impact on tumor growth and progression for the duration of the study. Internalization within tumor cells is also scarce, with the majority of flakes preferentially taken up by microglia/macrophages. The results indicate that GO flakes could offer deep and homogenous distribution throughout glioblastoma tumors and a means to target their myeloid compartment. Further studies are warranted to investigate the mechanisms of GO flakes transport within the tumor mass and their capacity to deliver bioactive cargoes but, ultimately, this information could inform the development of immunotherapies against glioblastoma. © 2020 The Authors. Published by Wiley-VCH GmbH
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Graphene active sensor arrays for long-term and wireless mapping of wide frequency band epicortical brain activity
Garcia-Cortadella R., Schwesig G., Jeschke C., Illa X., Gray A.L., Savage S., Stamatidou E., Schiessl I., Masvidal-Codina E., Kostarelos K., Guimerà-Brunet A., Sirota A., Garrido J.A. Nature Communications; 12 (1, 211) 2021. 10.1038/s41467-020-20546-w. IF: 14.919
Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces. © 2021, The Author(s).
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Graphene Oxide Nanosheets Interact and Interfere with SARS-CoV-2 Surface Proteins and Cell Receptors to Inhibit Infectivity
Unal M.A., Bayrakdar F., Nazir H., Besbinar O., Gurcan C., Lozano N., Arellano L.M., Yalcin S., Panatli O., Celik D., Alkaya D., Agan A., Fusco L., Suzuk Yildiz S., Delogu L.G., Akcali K.C., Kostarelos K., Yilmazer A. Small; 17 (25, 2101483) 2021. 10.1002/smll.202101483. IF: 13.281
Nanotechnology can offer a number of options against coronavirus disease 2019 (COVID-19) acting both extracellularly and intracellularly to the host cells. Here, the aim is to explore graphene oxide (GO), the most studied 2D nanomaterial in biomedical applications, as a nanoscale platform for interaction with SARS-CoV-2. Molecular docking analyses of GO sheets on interaction with three different structures: SARS-CoV-2 viral spike (open state – 6VYB or closed state – 6VXX), ACE2 (1R42), and the ACE2-bound spike complex (6M0J) are performed. GO shows high affinity for the surface of all three structures (6M0J, 6VYB and 6VXX). When binding affinities and involved bonding types are compared, GO interacts more strongly with the spike or ACE2, compared to 6M0J. Infection experiments using infectious viral particles from four different clades as classified by Global Initiative on Sharing all Influenza Data (GISAID), are performed for validation purposes. Thin, biological-grade GO nanoscale (few hundred nanometers in lateral dimension) sheets are able to significantly reduce copies for three different viral clades. This data has demonstrated that GO sheets have the capacity to interact with SARS-CoV-2 surface components and disrupt infectivity even in the presence of any mutations on the viral spike. GO nanosheets are proposed to be further explored as a nanoscale platform for development of antiviral strategies against COVID-19. © 2021 The Authors. Small published by Wiley-VCH GmbH
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Graphene oxide prevents lateral amygdala dysfunctional synaptic plasticity and reverts long lasting anxiety behavior in rats
Franceschi Biagioni A., Cellot G., Pati E., Lozano N., Ballesteros B., Casani R., Coimbra N.C., Kostarelos K., Ballerini L. Biomaterials; 271 (120749) 2021. 10.1016/j.biomaterials.2021.120749. IF: 12.479
Engineered small graphene oxide (s-GO) sheets were previously shown to reversibly down-regulate glutamatergic synapses in the hippocampus of juvenile rats, disclosing an unexpected translational potential of these nanomaterials to target selective synapses in vivo. Synapses are anatomical specializations acting in the Central Nervous System (CNS) as functional interfaces among neurons. Dynamic changes in synaptic function, named synaptic plasticity, are crucial to learning and memory. More recently, pathological mechanisms involving dysfunctional synaptic plasticity were implicated in several brain diseases, from dementia to anxiety disorders. Hyper-excitability of glutamatergic neurons in the lateral nucleus of the amygdala complex (LA) is substantially involved in the storage of aversive memory induced by stressful events enabling post-traumatic stress disorder (PTSD). Here we translated in PTSD animal model the ability of s-GO, when stereotaxically administered to hamper LA glutamatergic transmission and to prevent the behavioral response featured in long-term aversive memory. We propose that s-GO, by interference with glutamatergic plasticity, impair LA-dependent memory retrieval related to PTSD. © 2021 The Authors
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Nanotools for Sepsis Diagnosis and Treatment
Papafilippou L., Claxton A., Dark P., Kostarelos K., Hadjidemetriou M. Advanced Healthcare Materials; 10 (1, 2001378) 2021. 10.1002/adhm.202001378. IF: 9.933
Sepsis is one of the leading causes of death worldwide with high mortality rates and a pathological complexity hindering early and accurate diagnosis. Today, laboratory culture tests are the epitome of pathogen recognition in sepsis. However, their consistency remains an issue of controversy with false negative results often observed. Clinically used blood markers, C reactive protein (CRP) and procalcitonin (PCT) are indicators of an acute-phase response and thus lack specificity, offering limited diagnostic efficacy. In addition to poor diagnosis, inefficient drug delivery and the increasing prevalence of antibiotic-resistant microorganisms constitute significant barriers in antibiotic stewardship and impede effective therapy. These challenges have prompted the exploration for alternative strategies that pursue accurate diagnosis and effective treatment. Nanomaterials are examined for both diagnostic and therapeutic purposes in sepsis. The nanoparticle (NP)-enabled capture of sepsis causative agents and/or sepsis biomarkers in biofluids can revolutionize sepsis diagnosis. From the therapeutic point of view, currently existing nanoscale drug delivery systems have proven to be excellent allies in targeted therapy, while many other nanotherapeutic applications are envisioned. Herein, the most relevant applications of nanomedicine for the diagnosis, prognosis, and treatment of sepsis is reviewed, providing a critical assessment of their potentiality for clinical translation. © 2020 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
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Reasons for success and lessons learnt from nanoscale vaccines against COVID-19
Kisby T., Yilmazer A., Kostarelos K. Nature Nanotechnology; 16 (8): 843 - 850. 2021. 10.1038/s41565-021-00946-9. IF: 39.213
[No abstract available]
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Shedding plasma membrane vesicles induced by graphene oxide nanoflakes in brain cultured astrocytes
Musto M., Parisse P., Pachetti M., Memo C., Di Mauro G., Ballesteros B., Lozano N., Kostarelos K., Casalis L., Ballerini L. Carbon; 176: 458 - 469. 2021. 10.1016/j.carbon.2021.01.142. IF: 9.594
Microvesicles (MVs) generated and released by astrocytes, the brain prevalent cells, crucially contribute to intercellular communication, representing key vectorized systems able to spread and actively transfer signaling molecules from astrocytes to neurons, ultimately modulating target cell functions. The increasing clinical relevance of these signaling systems requires a deeper understanding of MV features, currently limited by both their nanoscale dimensions and the low rate of their constituent release. Hence, to investigate the features of such glial signals, nanotechnology-based approaches and the applications of unconventional, cost-effective tools in generating MVs are needed. Here, small graphene oxide (s-GO) nanoflakes are used to boost MVs shedding from astrocytes in cultures and s-GO generated MVs are compared with those generated by a natural stimulant, namely ATP, by atomic force microscopy, light scattering, attenuated total reflection–fourier transform infra-red and ultraviolet resonance Raman spectroscopy. We also report the ability of both types of MVs, upon acute and transient exposure of patch clamped cultured neurons, to modulate basal synaptic transmission, inducing a stable increase in synaptic activity accompanied by changes in neuronal plasma membrane elastic features. © 2021 The Author(s)
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The impact of graphene oxide sheet lateral dimensions on their pharmacokinetic and tissue distribution profiles in mice
Jasim D.A., Newman L., Rodrigues A.F., Vacchi I.A., Lucherelli M.A., Lozano N., Ménard-Moyon C., Bianco A., Kostarelos K. Journal of Controlled Release; 338: 330 - 340. 2021. 10.1016/j.jconrel.2021.08.028. IF: 9.776
Although the use of graphene and 2-dimensional (2D) materials in biomedicine has been explored for over a decade now, there are still significant knowledge gaps regarding the fate of these materials upon interaction with living systems. Here, the pharmacokinetic profile of graphene oxide (GO) sheets of three different lateral dimensions was studied. The GO materials were functionalized with a PEGylated DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), a radiometal chelating agent for radioisotope attachment for single photon emission computed tomography (SPECT/CT) imaging. Our results revealed that GO materials with three distinct size distributions, large (l-GO-DOTA), small (s-GO-DOTA) and ultra-small (us-GO-DOTA), were sequestered by the spleen and liver. Significant accumulation of the large material (l-GO-DOTA) in the lungs was also observed, unlike the other two materials. Interestingly, there was extensive urinary excretion of all three GO nanomaterials indicating that urinary excretion of these structures was not affected by lateral dimensions. Comparing with previous studies, we believe that the thickness of layered nanomaterials is the predominant factor that governs their excretion rather than lateral size. However, the rate of urinary excretion was affected by lateral size, with large GO excreting at slower rates. This study provides better understanding of 2D materials in vivo behaviour with varying structural features. © 2021
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Transient reprogramming of postnatal cardiomyocytes to a dedifferentiated state
Kisby T., de Lázaro I., Stylianou M., Cossu G., Kostarelos K. PLoS ONE; 16 (5 May, e0251054) 2021. 10.1371/journal.pone.0251054. IF: 3.240
In contrast to mammals, lower vertebrates are capable of extraordinary myocardial regeneration thanks to the ability of their cardiomyocytes to undergo transient dedifferentiation and proliferation. Somatic cells can be temporarily reprogrammed to a proliferative, dedifferentiated state through forced expression of Oct3/4, Sox2, Klf4 and c-Myc (OSKM). Here, we aimed to induce transient reprogramming of mammalian cardiomyocytes in vitro utilising an OSKM-encoding non-integrating vector. Reprogramming factor expression in postnatal rat and mouse cardiomyocytes triggered rapid but limited cell dedifferentiation. Concomitantly, a significant increase in cell viability, cell cycle related gene expression and Ki67 positive cells was observed consistent with an enhanced cell cycle activation. The transient nature of this partial reprogramming was confirmed as cardiomyocyte-specific cell morphology, gene expression and contractile activity were spontaneously recovered by day 15 after viral transduction. This study provides the first evidence that adenoviral OSKM delivery can induce partial reprogramming of postnatal cardiomyocytes. Therefore, adenoviral mediated transient reprogramming could be a novel and feasible strategy to recapitulate the regenerative mechanisms of lower vertebrates. Copyright: © 2021 Kisby et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Trends in Micro-/Nanorobotics: Materials Development, Actuation, Localization, and System Integration for Biomedical Applications
Wang B., Kostarelos K., Nelson B.J., Zhang L. Advanced Materials; 33 (4, 2002047) 2021. 10.1002/adma.202002047. IF: 30.849
Micro-/nanorobots (m-bots) have attracted significant interest due to their suitability for applications in biomedical engineering and environmental remediation. Particularly, their applications in in vivo diagnosis and intervention have been the focus of extensive research in recent years with various clinical imaging techniques being applied for localization and tracking. The successful integration of well-designed m-bots with surface functionalization, remote actuation systems, and imaging techniques becomes the crucial step toward biomedical applications, especially for the in vivo uses. This review thus addresses four different aspects of biomedical m-bots: design/fabrication, functionalization, actuation, and localization. The biomedical applications of the m-bots in diagnosis, sensing, microsurgery, targeted drug/cell delivery, thrombus ablation, and wound healing are reviewed from these viewpoints. The developed biomedical m-bot systems are comprehensively compared and evaluated based on their characteristics. The current challenges and the directions of future research in this field are summarized. © 2020 Wiley-VCH GmbH
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Viscoelastic surface electrode arrays to interface with viscoelastic tissues
Tringides C.M., Vachicouras N., de Lázaro I., Wang H., Trouillet A., Seo B.R., Elosegui-Artola A., Fallegger F., Shin Y., Casiraghi C., Kostarelos K., Lacour S.P., Mooney D.J. Nature Nanotechnology; 16 (9): 1019 - 1029. 2021. 10.1038/s41565-021-00926-z. IF: 39.213
Living tissues are non-linearly elastic materials that exhibit viscoelasticity and plasticity. Man-made, implantable bioelectronic arrays mainly rely on rigid or elastic encapsulation materials and stiff films of ductile metals that can be manipulated with microscopic precision to offer reliable electrical properties. In this study, we have engineered a surface microelectrode array that replaces the traditional encapsulation and conductive components with viscoelastic materials. Our array overcomes previous limitations in matching the stiffness and relaxation behaviour of soft biological tissues by using hydrogels as the outer layers. We have introduced a hydrogel-based conductor made from an ionically conductive alginate matrix enhanced with carbon nanomaterials, which provide electrical percolation even at low loading fractions. Our combination of conducting and insulating viscoelastic materials, with top-down manufacturing, allows for the fabrication of electrode arrays compatible with standard electrophysiology platforms. Our arrays intimately conform to the convoluted surface of the heart or brain cortex and offer promising bioengineering applications for recording and stimulation. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
