{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T03:18:19Z","timestamp":1781925499817,"version":"3.54.5"},"reference-count":50,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T00:00:00Z","timestamp":1737331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010757","name":"National Centre for the Replacement Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["NC\/R001642\/1"],"award-info":[{"award-number":["NC\/R001642\/1"]}],"id":[{"id":"10.13039\/501100010757","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Keele University Open Research grant"},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["NC\/R001642\/1"],"award-info":[{"award-number":["NC\/R001642\/1"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>\n                    The study of\n                    <ns3:italic>in vivo<\/ns3:italic>\n                    thrombus formation has principally been performed using intravital microscopy in mice and other species. These have allowed us to visualise the molecular and cellular processes that regulate thrombus formation inside the body. However current\n                    <ns3:italic>in vivo<\/ns3:italic>\n                    arterial thrombosis models are difficult to standardise between labs and frequently produce results that do not reliably translate successfully in human clinical trials. Here we provide a step-by-step description with accompanying video tutorials to demonstrate how to produce a 3D humanised thrombus-on-a-chip model, which uses perfusion of fluorescently-labelled human blood over a mechanically-injured human tissue engineered arterial construct (TEAC) within a 3D printed microfluidic flow chamber to replicate thrombus formation within a healthy artery. We also provide a written methodology on how to use 3D printing to produce a mechanical injury press that can reproducibly damage the TEAC as a stimulus for thrombus formation as part of a mechanical injury model. Perfusion of the uninjured TEAC with whole human blood containing DiOC6-labelled platelets without initiating notable thrombus formation. The mechanical injury press was shown to induce a reproducible puncture wound in the TEAC. Fluorescence microscopy was used to demonstrate that thrombus formation could be observed reproducibly around sites of injury. This humanised thrombosis-on-a-chip model can replace the use of animals in\n                    <ns3:italic>in vivo<\/ns3:italic>\n                    thrombosis models for preclinical assessment of anti-thrombotic therapies. This method also offers multiple scientific advantages: allowing new drugs to be directly tested on human blood from a diverse array of donors, facilitating use of a realistic and reproducible injury modality as well as removing the potential confounding effects of general anaesthetics in animal studies. The use of human thrombus-on-a-chip models combining TEACs offers a new methodology to reduce animal use whilst improving the predictive capabilities of preclinical trials of anti-thrombotic therapies.\n                  <\/ns3:p>","DOI":"10.12688\/f1000research.158910.1","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T10:55:06Z","timestamp":1737370506000},"page":"110","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A humanised thrombus-on-a-chip model utilising tissue-engineered arterial constructs: A method to reduce and replace mice used in thrombosis and haemostasis research."],"prefix":"10.12688","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8518-562X","authenticated-orcid":false,"given":"Jacob","family":"Ranjbar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Gibbins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Roe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4135-9733","authenticated-orcid":false,"given":"Paul","family":"Roach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2413-4823","authenticated-orcid":false,"given":"Alan G.S.","family":"Harper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"a005132","DOI":"10.1101\/cshperspect.a005132","article-title":"Extracellular matrix proteins in hemostasis and thrombosis.","volume":"4","author":"W Bergmeier","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"410-417","DOI":"10.1097\/MOH.0000000000000070","article-title":"Shaping the platelet response to vascular injury.","volume":"21","author":"T Stalker","year":"2014","journal-title":"Curr. Opin. Hematol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"176-183","DOI":"10.1111\/voxs.12331","article-title":"Role of red blood cells in haemostasis and thrombosis.","volume":"12","author":"R Litvinov","year":"2017","journal-title":"ISBT Sci. Ser."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"3868","DOI":"10.3390\/ijms23073868","article-title":"Beyond Hemostasis: Platelet Innate Immune Interactions and Thromboinflammation.","volume":"23","author":"J Mandel","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2361-2371","DOI":"10.1016\/j.jacc.2022.11.005","article-title":"The Global Burden of Cardiovascular Diseases and Risk: A Compass for Future Health.","volume":"80","author":"M Vaduganathan","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1641-1644","DOI":"10.1111\/j.1538-7836.2011.04350.x","article-title":"Towards standardization of in vivo thrombosis studies in mice.","volume":"9","author":"C Denis","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3390\/gels9060477","article-title":"Developing Biomimetic Hydrogels of the Arterial Wall as a Prothrombotic Substrate for in vitro Human Thrombosis Models.","volume":"9","author":"J Ranjbar","year":"2023","journal-title":"Gels."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2079-2093","DOI":"10.1161\/ATVBAHA.107.142810","article-title":"Murine models of vascular thrombosis (Eitzman series).","volume":"27","author":"R Westrick","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"S64-S69","DOI":"10.1016\/S0049-3848(08)70022-7","article-title":"Overview of murine thrombosis models.","volume":"122","author":"H Whinna","year":"2008","journal-title":"Thromb. Res."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"432-438","DOI":"10.1080\/09537104.2019.1678119","article-title":"How useful are ferric chloride models of arterial thrombosis?","volume":"31","author":"S Grover","year":"2020","journal-title":"Platelets."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"423-431","DOI":"10.1080\/09537104.2020.1748589","article-title":"Mouse laser injury models: variations on a theme.","volume":"31","author":"T Stalker","year":"2020","journal-title":"Platelets."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"486-494","DOI":"10.1055\/s-0037-1613739","article-title":"Murine thrombosis models.","volume":"92","author":"S Day","year":"2004","journal-title":"Thromb. Haemost."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"S3-S12","DOI":"10.1160\/THS10-11-0730","article-title":"Comparison of two murine models of thrombosis induced by atherosclerotic plaque injury.","volume":"105","author":"B Hechler","year":"2011","journal-title":"Thromb. Haemost."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"215-221","DOI":"10.1016\/0021-9150(87)90249-8","article-title":"Comparison of atherosclerotic lesions and HDL-lipid levels in male, female, and testosterone-treated female mice from strains C57BL\/6, BALB\/c, and C3H.","volume":"64","author":"B Paigen","year":"1987","journal-title":"Atherosclerosis."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"173-184","DOI":"10.1111\/j.1538-7836.2009.03666.x","article-title":"Arterial thrombosis: relevance of a model with two levels of severity assessed by histologic, ultrastructural and functional characterization.","volume":"8","author":"B Hechler","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2652-2653","DOI":"10.1182\/blood-2015-09-668384","article-title":"Ferric chloride thrombosis model: unraveling the vascular effects of a highly corrosive oxidant.","volume":"126","author":"S Schoenwaelder","year":"2015","journal-title":"Blood."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"197-206","DOI":"10.1002\/rth2.12184","article-title":"The mode of anesthesia influences outcome in mouse models of arterial thrombosis.","volume":"3","author":"M Sashindranath","year":"2019","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1363-1379","DOI":"10.1161\/CIRCRESAHA.115.306823","article-title":"Animal Models of Thrombosis From Zebrafish to Nonhuman Primates: Use in the Elucidation of New Pathologic Pathways and the Development of Antithrombotic Drugs.","volume":"118","author":"P Jagadeeswaran","year":"2016","journal-title":"Circ. Res."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.amjcard.2020.10.027","article-title":"Translation of Cardiovascular Animal Models to Human Randomized Trials.","volume":"137","author":"M Vyas","year":"2020","journal-title":"Am. J. Cardiol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"467-477","DOI":"10.1002\/ana.20741","article-title":"1,026 experimental treatments in acute stroke.","volume":"59","author":"V O\u2019Collins","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"16-23","DOI":"10.1097\/MOH.0000000000000789","article-title":"Modelling arterial thrombus formation in vitro.","volume":"31","author":"A Drysdale","year":"2024","journal-title":"Curr. Opin. Hematol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"748-752","DOI":"10.1111\/jth.14717","article-title":"Subcommittee on Biorheology. in vitro flow based systems to study platelet function and thrombus formation: Recommendations for standardization: Communication from the SSC on Biorheology of the ISTH.","volume":"18","author":"P Mangin","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"29-34","DOI":"10.1016\/j.cobme.2017.12.001","article-title":"Thrombosis-on-a-chip: Prospective impact of microphysiological models of vascular thrombosis.","volume":"5","author":"N Pandian","year":"2018","journal-title":"Curr. Opin. Biomed. Eng."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e54680","DOI":"10.1371\/journal.pone.0054680","article-title":"Sources of variability in platelet accumulation on type 1 fibrillar collagen in microfluidic flow assays.","volume":"8","author":"K Neeves","year":"2013","journal-title":"PLoS One."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"042203","DOI":"10.1063\/1.5024901","article-title":"Endothelial cell culture in microfluidic devices for investigating microvascular processes.","volume":"12","author":"R Mannino","year":"2018","journal-title":"Biomicrofluidics."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"4104-4117","DOI":"10.1039\/D1LC00347J","article-title":"An \u201cocclusive thrombosis-on-a-chip\u201d microfluidic device for investigating the effect of anti-thrombotic drugs.","volume":"21","author":"J Berry","year":"2021","journal-title":"Lab Chip."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"353-358","DOI":"10.1557\/PROC-436-353","article-title":"Viscoelastic properties of healthy human artery measured in saline solution by AFM-based indentation technique.","volume":"436","author":"A Lundkvist","year":"1996","journal-title":"MRS Online Proc. Libr."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"645-655","DOI":"10.1016\/j.bpj.2017.06.033","article-title":"Stiff Substrates Increase Inflammation-Induced Endothelial Monolayer Tension and Permeability.","volume":"113","author":"R Urbano","year":"2017","journal-title":"Biophys. J."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2788","DOI":"10.3390\/ijms20112788","article-title":"Role of Platelet Glycoprotein VI and Tyrosine Kinase Syk in Thrombus Formation on Collagen-Like Surfaces.","volume":"20","author":"N Jooss","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"856-858","DOI":"10.1111\/j.1538-7836.2011.04230.x","article-title":"Biorheology Subcommittee of the SSC of the ISTH. Collagen surfaces to measure thrombus formation under flow: possibilities for standardization.","volume":"9","author":"J Heemskerk","year":"2011","journal-title":"J. Thromb. Haemost."},{"key":"ref31","first-page":"127-135","article-title":"Collagen binding assay for von Willebrand factor (VWF:CBA): detection of von Willebrands Disease (VWD), and discrimination of VWD subtypes, depends on collagen source.","volume":"83","author":"E Favaloro","year":"2000","journal-title":"Thromb. Haemost."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"3371-3382","DOI":"10.1074\/jbc.M109.055178","article-title":"Carbohydrates and activity of natural and recombinant tissue factor.","volume":"285","author":"J Krudysz-Amblo","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"691-699","DOI":"10.1089\/ten.tec.2015.0582","article-title":"A Real-Time Monitoring System to Assess the Platelet Aggregatory Capacity of Components of a Tissue-Engineered Blood Vessel Wall.","volume":"22","author":"F Musa","year":"2016","journal-title":"Tissue Eng. Part C Methods."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"340","DOI":"10.3390\/pharmaceutics13030340","article-title":"The Combination of Tissue-Engineered Blood Vessel Constructs and Parallel Flow Chamber Provides a Potential Alternative to in vivo Drug Testing Models.","volume":"13","author":"W Njoroge","year":"2021","journal-title":"Pharmaceutics."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1408-1417","DOI":"10.1021\/acsbiomaterials.9b01873","article-title":"Integrated Biophysical Characterization of Fibrillar Collagen-Based Hydrogels.","volume":"6","author":"A Avendano","year":"2020","journal-title":"ACS Biomater Sci. Eng."},{"key":"ref36","doi-asserted-by":"publisher","DOI":"10.21252\/ac05-bg65","author":"A Harper","year":"2024","journal-title":"NC3R gateway resources. A humanised thrombus-on-a-chip model utilising tissue-engineered arterial constructs: A method to reduce and replace mice used in thrombosis and haemostasis research."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"2153823","DOI":"10.1080\/09537104.2022.2153823","article-title":"Developing human tissue engineered arterial constructs to simulate human in vivo thrombus formation.","volume":"34","author":"J Ranjbar","year":"2023","journal-title":"Platelets."},{"key":"ref38","article-title":"Mechanical Injury of a tissue-engineered human arterial construct replicates the thrombotic and pharmacological properties of the native artery. [abstract].","author":"J Ranjbar","year":"2022"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2820-2822","DOI":"10.1111\/j.1538-7836.2010.04084.x","article-title":"Towards a standardization of the murine tail bleeding model.","volume":"8","author":"T Greene","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"30-36","DOI":"10.5493\/wjem.v2.i2.30","article-title":"Standardizing a simpler, more sensitive and accurate tail bleeding assay in mice.","volume":"2","author":"Y Liu","year":"2012","journal-title":"World J. Exp. Med."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"817-824","DOI":"10.1182\/blood-2015-02-628594","article-title":"Resolving the multifaceted mechanisms of the ferric chloride thrombosis model using an interdisciplinary microfluidic approach.","volume":"126","author":"J Ciciliano","year":"2015","journal-title":"Blood."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"3078-3085","DOI":"10.1111\/jth.15059","article-title":"Injury measurements improve interpretation of thrombus formation data in the cremaster arteriole laser-induced injury model of thrombosis.","volume":"18","author":"S Grover","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"102256","DOI":"10.1016\/j.rpth.2023.102256","article-title":"Sex Matters: Policy on Reporting Sex as a Biological Variable at Research and Practice in Thrombosis and Hemostasis.","volume":"7","author":"B Samuelson Bannow","year":"2023","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1147-1152","DOI":"10.1097\/00000542-200205000-00018","article-title":"Ketamine suppresses platelet aggregation possibly by suppressed inositol triphosphate formation and subsequent suppression of cytosolic calcium increase.","volume":"96","author":"T Nakagawa","year":"2002","journal-title":"Anesthesiology."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"764-772","DOI":"10.1007\/BF02254361","article-title":"Mechanisms involved in the antiplatelet activity of ketamine in human platelets.","volume":"11","author":"Y Chang","year":"2004","journal-title":"J. Biomed. Sci."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"197-206","DOI":"10.1002\/rth2.12184","article-title":"The mode of anesthesia influences outcome in mouse models of arterial thrombosis.","volume":"3","author":"M Sashindranath","year":"2019","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"615-632","DOI":"10.1172\/JCI117014","article-title":"Increased platelet deposition on atherosclerotic coronary arteries.","volume":"93","author":"G Zanten","year":"1994","journal-title":"J. Clin. Invest."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"898-909","DOI":"10.1096\/fj.04-2748com","article-title":"Human atheromatous plaques stimulate thrombus formation by activating platelet glycoprotein VI.","volume":"19","author":"S Penz","year":"2005","journal-title":"FASEB J."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"372","DOI":"10.3390\/biomimetics9060372","article-title":"Developing a Biomimetic 3D Neointimal Layer as a Prothrombotic Substrate for a Humanized in vitro Model of Atherothrombosis.","volume":"9","author":"J Echrish","year":"2024","journal-title":"Biomimetics (Basel)."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"675-679","DOI":"10.1042\/ETLS20190061","article-title":"Animal experimentation: implementation and application of the 3Rs.","volume":"3","author":"D Lewis","year":"2019","journal-title":"Emerg. Top Life Sci."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/14-110\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-110\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/14-110\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T03:12:03Z","timestamp":1743736323000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/14-110\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,20]]},"references-count":50,"URL":"https:\/\/doi.org\/10.12688\/f1000research.158910.1","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.174562.r369848","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.174562.r369847","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.174562.r369852","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.174562.r369850","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.174562.r369852","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.174562.r369847","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.174562.r369848","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,20]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/14-110\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.174562.r369847, Michael Emerson, Imperial College London, London, 21 Mar 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-110\/v1#referee-response-369847","order":0,"name":"referee-response-369847","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.174562.r369852, Navaneeth Krishna Rajeeva Pandian, Harvard Medical School, Wyss Institute at Harvard, Boston, 31 Mar 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-110\/v1#referee-response-369852","order":1,"name":"referee-response-369852","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.174562.r369848, Kaushik N. Shankar, University of Pennsylvania, Philadelphia, Pennsylvania, 04 Apr 2025, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/14-110\/v1#referee-response-369848","order":2,"name":"referee-response-369848","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by an NC3R- and British Heart Foundation co-funded PhD studentship (NC\/R001642\/1). The production of the video resources was supported by the Keele University Open research funds.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}