{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:36:00Z","timestamp":1760229360882,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T00:00:00Z","timestamp":1654819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Minister of Foreign Affairs and International Collaboration (MAECI)","award":["US19GR07","2-P41-EB015871-31","DP2GM128198","2017SZ5WZB"],"award-info":[{"award-number":["US19GR07","2-P41-EB015871-31","DP2GM128198","2017SZ5WZB"]}]},{"DOI":"10.13039\/100000070","name":"National Institute of Biomedical Imaging and Bioengineering","doi-asserted-by":"publisher","award":["US19GR07","2-P41-EB015871-31","DP2GM128198","2017SZ5WZB"],"award-info":[{"award-number":["US19GR07","2-P41-EB015871-31","DP2GM128198","2017SZ5WZB"]}],"id":[{"id":"10.13039\/100000070","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["US19GR07","2-P41-EB015871-31","DP2GM128198","2017SZ5WZB"],"award-info":[{"award-number":["US19GR07","2-P41-EB015871-31","DP2GM128198","2017SZ5WZB"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MUR PRIN2017\u2013ACTION","award":["US19GR07","2-P41-EB015871-31","DP2GM128198","2017SZ5WZB"],"award-info":[{"award-number":["US19GR07","2-P41-EB015871-31","DP2GM128198","2017SZ5WZB"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Black phosphorus nanosheets (2D BP) are emerging as very promising, highly selective chemotherapeutic agents due to their fast degradation in the intracellular matrix of cancer cells. Here, optical diffraction tomography (ODT) and Raman spectroscopy were exploited as a powerful label-free approach to achieve integrated insights into the processes accompanying the administration of exfoliated 2D BP flakes in human prostatic adenocarcinoma and normal human prostate epithelial cells. Our ODT experiments provided unambiguous visualization of the 2D BP internalization in cancer cells and the morphological modifications of those cells in the apoptotic phase. The cellular internalization and damaging occurred, respectively, 18 h and 36\u201348 h after the 2D BP administration. Changes in the chemical properties of the internalized 2D BP flakes were monitored by Raman spectroscopy. Interestingly, a fast oxidation process of the 2D BP flakes was activated in the intracellular matrix of the cancer cells after 24 h of incubation. This was in sharp contrast to the low 2D BP uptake and minimal chemical changes observed in the normal cells. Along with the understanding of the 2D BP fate in the cancer cells, the proposed label-free morpho-molecular approach offers a powerful, rapid tool to study the pharmacokinetic properties of engineered nanomaterials in preclinical research.<\/jats:p>","DOI":"10.3390\/nano12121994","type":"journal-article","created":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T22:37:20Z","timestamp":1655073440000},"page":"1994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Label-Free Morpho-Molecular Imaging for Studying the Differential Interaction of Black Phosphorus with Tumor Cells"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1465-1739","authenticated-orcid":false,"given":"Valentina","family":"Mussi","sequence":"first","affiliation":[{"name":"Institute for Microelectronics and Microsystems, National Research Council, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9568-3945","authenticated-orcid":false,"given":"Ines","family":"Fasolino","sequence":"additional","affiliation":[{"name":"Institute of Polymers, Composites and Biomaterials, National Research Council, 80125 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8251-4379","authenticated-orcid":false,"given":"Debadrita","family":"Paria","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1207-2864","authenticated-orcid":false,"given":"Sara","family":"De Simone","sequence":"additional","affiliation":[{"name":"Institute for Microelectronics and Microsystems, National Research Council, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-7313","authenticated-orcid":false,"given":"Maria","family":"Caporali","sequence":"additional","affiliation":[{"name":"Institute for the Chemistry of Organometallic Compounds, National Research Council, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Serrano-Ruiz","sequence":"additional","affiliation":[{"name":"Institute for the Chemistry of Organometallic Compounds, National Research Council, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Institute of Polymers, Composites and Biomaterials, National Research Council, 80125 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ishan","family":"Barman","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA"},{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA"},{"name":"Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0516-4181","authenticated-orcid":false,"given":"Maria Grazia","family":"Raucci","sequence":"additional","affiliation":[{"name":"Institute of Polymers, Composites and Biomaterials, National Research Council, 80125 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9426-8352","authenticated-orcid":false,"given":"Annalisa","family":"Convertino","sequence":"additional","affiliation":[{"name":"Institute for Microelectronics and Microsystems, National Research Council, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1021\/acsnano.9b08133","article-title":"Nanomaterials for nanotheranostics: Tuning their properties according to disease needs","volume":"14","author":"Wong","year":"2020","journal-title":"ACS Nano"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19200","DOI":"10.1007\/s11356-019-06459-2","article-title":"Advances in nanomedical applications: Diagnostic, therapeutic, immunization, and vaccine production","volume":"27","author":"Kamel","year":"2020","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7238","DOI":"10.1021\/jp057170o","article-title":"Calculated absorption and scattering properties of gold nanoparticles of different size, shape, and composition: Applications in biological imaging and biomedicine","volume":"110","author":"Jain","year":"2006","journal-title":"J. Phys. Chem. B"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1021\/ja057254a","article-title":"Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods","volume":"128","author":"Huang","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9494","DOI":"10.1039\/C4NR00708E","article-title":"Nanoparticles for photothermal therapies","volume":"6","author":"Jaque","year":"2014","journal-title":"Nanoscale"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Arvizo, R.R., Miranda, O.R., Moyano, D.F., Walden, C.A., and Giri, K. (2011). Modulating pharmacokinetics, tumor uptake and biodistribution by engineered nanoparticles. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024374"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.addr.2009.11.002","article-title":"Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging","volume":"62","author":"Veiseh","year":"2010","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/nnano.2011.249","article-title":"Vertical nanowire electrode arrays as a scalable platform for intracellular interfacing to neuronal circuits","volume":"7","author":"Robinson","year":"2012","journal-title":"Nat. Nanotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1126\/science.1128640","article-title":"Detection, stimulation, and inhibition of neuronal signals with high-density nanowire transistor arrays","volume":"313","author":"Patolsky","year":"2006","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e1900264","DOI":"10.1002\/adbi.201900264","article-title":"A glial-silicon nanowire electrode junction enabling differentiation and noninvasive recording of slow oscillations from primary astrocytes","volume":"4","author":"Saracino","year":"2020","journal-title":"Adv. Biosyst."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/nnano.2013.273","article-title":"Free-standing kinked nanowire transistor probes for targeted intracellular recording in three dimensions","volume":"9","author":"Qing","year":"2014","journal-title":"Nat. Nanotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"415102","DOI":"10.1088\/1361-6528\/aad6cd","article-title":"Array of disordered silicon nanowires coated by a gold film for combined NIR photothermal treatment of cancer cells and Raman monitoring of the process evolution","volume":"29","author":"Convertino","year":"2018","journal-title":"Nanotechnology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2001110","DOI":"10.1002\/adhm.202001110","article-title":"A Silver-coated disordered silicon nanowires provide highly sensitive label-free glycated albumin detection through molecular trapping and plasmonic hotspot formation","volume":"10","author":"Paria","year":"2021","journal-title":"Adv. Healthc. Mater."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111951","DOI":"10.1016\/j.msec.2021.111951","article-title":"Silver-coated silicon nanowire platform discriminates genomic DNA from normal and malignant human epithelial cells using label-free Raman spectroscopy","volume":"122","author":"Mussi","year":"2021","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1021\/ac061808q","article-title":"Silicon nanowire arrays for label-free detection of DNA","volume":"79","author":"Gao","year":"2007","journal-title":"Anal. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/adhm.201500538","article-title":"Highly disordered array of silicon nanowires: An effective and scalable approach for performing and flexible electrochemical biosensors","volume":"5","author":"Maiolo","year":"2016","journal-title":"Adv. Healthc. Mater."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2101638","DOI":"10.1002\/adfm.202101638","article-title":"Nanowire Assisted Mechanotyping of Cellular Metastatic Potential","volume":"31","author":"Paria","year":"2021","journal-title":"Adv. Funct. Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8642","DOI":"10.1039\/c1sm05838j","article-title":"Culture of mammalian cells on patterned superhydrophilic\/superhydrophobic silicon nanowire arrays","volume":"7","author":"Piret","year":"2011","journal-title":"Soft Matter"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1802061","DOI":"10.1002\/adma.201802061","article-title":"Two-Dimensional Antimonene-Based Photonic Nanomedicine for Cancer Theranostics","volume":"30","author":"Tao","year":"2018","journal-title":"Adv. Mater."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.addr.2016.05.013","article-title":"Graphene-Based Nanomaterials for Bioimaging","volume":"105","author":"Lin","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_21","first-page":"31136","article-title":"A novel top-down synthesis of ultrathin 2d boron nanosheets for multimodal imaging-guided cancer therapy","volume":"10","author":"Ji","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8579","DOI":"10.1039\/C8CC04653K","article-title":"Two-dimensional tellurium nanosheets for photoacoustic imaging-guided photodynamic therapy","volume":"54","author":"Lin","year":"2018","journal-title":"Chem. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1021\/nl100996u","article-title":"Graphene in mice: Ultrahigh in vivo tumor uptake and efficient photothermal therapy","volume":"10","author":"Yang","year":"2010","journal-title":"Nano Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12967","DOI":"10.1038\/ncomms12967","article-title":"Biodegradable black phosphorus-based nanospheres for in vivo photothermal cancer therapy","volume":"7","author":"Shao","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13991","DOI":"10.1002\/chem.201502006","article-title":"The cytotoxicity of layered black phosphorus","volume":"21","author":"Latiff","year":"2015","journal-title":"Chem. Eur. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1002\/anie.201810878","article-title":"Black phosphorus: Bioactive nanomaterials with inherent and selective chemotherapeutic effects","volume":"58","author":"Zhou","year":"2019","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1021\/acs.nanolett.0c01098","article-title":"ROS-mediated selective killing effect of black phosphorus: Mechanistic understanding and its guidance for safe biomedical applications","volume":"20","author":"Kong","year":"2020","journal-title":"Nano Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5856","DOI":"10.1038\/s41598-021-85310-6","article-title":"2D exfoliated black phosphorus influences healthy and cancer prostate cell behaviors","volume":"11","author":"Fasolino","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9333","DOI":"10.1021\/acsami.8b21592","article-title":"Exfoliated black phosphorus promotes in vitro bone regeneration and suppresses osteosarcoma progression through cancer-related inflammation inhibition","volume":"11","author":"Raucci","year":"2019","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8330","DOI":"10.1021\/acs.chemmater.6b03592","article-title":"Interaction of Black Phosphorus with Oxygen and Water","volume":"28","author":"Huang","year":"2016","journal-title":"Chem. Mater."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2001538","DOI":"10.1002\/admi.202001538","article-title":"Black Phosphorus: Degradation Mechanism, Passivation Method, and Application for In Situ Tissue Regeneration","volume":"7","author":"Peng","year":"2020","journal-title":"Adv. Mater. Interfaces"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7561","DOI":"10.1021\/jacs.8b02156","article-title":"Degradation Chemistry and Stabilization of Exfoliated Few-Layer Black Phosphorus in Water","volume":"140","author":"Zhang","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nmeth1078","article-title":"Tomographic phase microscopy","volume":"4","author":"Choi","year":"2007","journal-title":"Nat. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4170","DOI":"10.3390\/s130404170","article-title":"Quantitative Phase Imaging Techniques for the Study of Cell Pathophysiology: From Principles to Applications","volume":"13","author":"Lee","year":"2013","journal-title":"Sensors"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112863","DOI":"10.1016\/j.bios.2020.112863","article-title":"Coarse Raman and optical diffraction tomographic imaging enable label-free phenotyping of isogenic breast cancer cells of varying metastatic potential","volume":"175","author":"Paidi","year":"2021","journal-title":"Biosens. Bioelectron."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"srep44540","DOI":"10.1038\/srep44540","article-title":"Raman sensitive degradation and etching dynamics of exfoliated black phosphorus","volume":"7","author":"Alsaffar","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"245404","DOI":"10.1103\/PhysRevB.94.245404","article-title":"Dephasing in strongly anisotropic black phosphorus","volume":"94","author":"Hemsworth","year":"2016","journal-title":"Phys. Rev. B"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/j.jssc.2008.03.008","article-title":"A fast low-pressure transport route to large black phosphorus single crystals","volume":"181","author":"Nilges","year":"2008","journal-title":"J. Solid State Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1500441","DOI":"10.1002\/admi.201500441","article-title":"The role of water in the preparation and stabilization of high-quality phosphorene flakes","volume":"3","author":"Caporali","year":"2016","journal-title":"Adv. Mater. Interfaces"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5407","DOI":"10.1364\/OL.40.005407","article-title":"Active illumination using a digital micromirror device for quantitative phase imaging","volume":"40","author":"Shin","year":"2015","journal-title":"Opt. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"011005","DOI":"10.1117\/1.JBO.19.1.011005","article-title":"High-resolution three-dimensional imaging of red blood cells parasitized by Plasmodium falciparum and in situ hemozoin crystals using optical diffraction tomography","volume":"19","author":"Kim","year":"2013","journal-title":"J. Biomed. Opt."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18437","DOI":"10.1038\/srep18437","article-title":"Evolution of cellular morpho-phenotypes in cancer metastasis","volume":"5","author":"Wu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1097-0320(19980101)31:1<1::AID-CYTO1>3.0.CO;2-R","article-title":"Annexin V-affinity assay: A review on an apoptosis detection system based on phosphatidylserine exposure","volume":"31","author":"Nieland","year":"1998","journal-title":"Cytometry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nature12138","article-title":"Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells","volume":"497","author":"Commisso","year":"2013","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/S0962-8924(00)89101-1","article-title":"Macropinocytosis","volume":"5","author":"Swanson","year":"1995","journal-title":"Trends Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s40824-018-0142-x","article-title":"Application of black phosphorus nanodots to live cell imaging","volume":"22","author":"Shin","year":"2018","journal-title":"Biomater. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"271ra7","DOI":"10.1126\/scitranslmed.3010633","article-title":"Surface-Enhanced Resonance Raman Scattering Nanostars for High-Precision Cancer Imaging","volume":"7","author":"Harmsen","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1743-8977-10-2","article-title":"Deciphering the mechanisms of cellular uptake of engineered nanoparticles by accurate evaluation of internalization using imaging flow cytometry","volume":"10","author":"Vranic","year":"2013","journal-title":"Part. Fibre Toxicol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s004410000193","article-title":"The morphology of apoptosis","volume":"301","year":"2000","journal-title":"Cell Tissue Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/jrs.5238","article-title":"Raman spectroscopy in black phosphorus","volume":"49","author":"Ribeiro","year":"2018","journal-title":"J. Raman Spectrosc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1080\/05704920701551530","article-title":"Raman spectroscopy of biological tissues","volume":"42","author":"Movasaghi","year":"2007","journal-title":"J. Appl. Spectros. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"126104","DOI":"10.1063\/1.4937468","article-title":"Thermal effects on the Raman phonon of few-layer phosphorene","volume":"3","author":"Ling","year":"2015","journal-title":"APL Mater."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"13113","DOI":"10.1016\/j.ceramint.2016.05.099","article-title":"Dopants induced structural and optical anomalies of anisotropic edges of black phosphorous thin films and crystals","volume":"42","author":"Sarswat","year":"2016","journal-title":"Ceram. Int."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/12\/12\/1994\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:27:28Z","timestamp":1760138848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/12\/12\/1994"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,10]]},"references-count":53,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["nano12121994"],"URL":"https:\/\/doi.org\/10.3390\/nano12121994","relation":{},"ISSN":["2079-4991"],"issn-type":[{"type":"electronic","value":"2079-4991"}],"subject":[],"published":{"date-parts":[[2022,6,10]]}}}