First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses

Jack P.M. Andrews; Shruti S. Joshi; Evangelos Tzolos; Maaz B. Syed; Hayley Cuthbert; Livia E. Crica; Neus Lozano; Emmanuel Okwelogu; Jennifer B. Raftis; Lorraine Bruce; Craig A. Poland; Rodger Duffin; Paul H.B. Fokkens; A. John F. Boere; Daan L.A.C. Leseman; Ian L. Megson; Phil D. Whitfield; Kerstin Ziegler; Seshu Tammireddy; Marilena Hadjidemetriou; Cyrill Bussy; Flemming R. Cassee; David E. Newby; Kostas Kostarelos; Mark R. Miller

doi:10.1093/annweh/wxac087.128

First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses

Jack P.M. Andrews, Shruti S. Joshi, Evangelos Tzolos, Maaz B. Syed, Hayley Cuthbert, Livia E. Crica, Neus Lozano, Emmanuel Okwelogu, Jennifer B. Raftis, Lorraine Bruce, Craig A. Poland, Rodger Duffin, Paul H.B. Fokkens, A. John F. Boere, Daan L.A.C. Leseman, Ian L. Megson, Phil D. Whitfield, Kerstin Ziegler, Seshu Tammireddy, Marilena HadjidemetriouCyrill Bussy, Flemming R. Cassee, David E. Newby, Kostas Kostarelos, Mark R. Miller

Division of Biomedical Sciences

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Abstract

Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxide nanosheets at a concentration of 200 μg m⁻³ or filtered air were inhaled for 2 h by 14 young healthy volunteers in repeated visits. Overall, graphene oxide nanosheet exposure was well tolerated with no adverse effects. Heart rate, blood pressure, lung function and inflammatory markers were unaffected irrespective of graphene oxide particle size. Highly enriched blood proteomics analysis revealed very few differential plasma proteins and thrombus formation was mildly increased in an ex vivo model of arterial injury. Overall, acute inhalation of highly purified and thin nanometre-sized graphene oxide nanosheets was not associated with overt detrimental effects in healthy humans. These findings demonstrate the feasibility of carefully controlled human exposures at a clinical setting for risk assessment of graphene oxide, and lay the foundations for investigating the effects of other two-dimensional nanomaterials in humans. Clinicaltrials.gov ref: NCT03659864.

Original language	English
Pages (from-to)	i52-i53
Number of pages	1
Journal	Nature Nanotechnology
Volume	67
Issue number	S1
DOIs	https://doi.org/10.1093/annweh/wxac087.128
Publication status	Published - 16 Feb 2024

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Nature nano paper -Inhaled Graphene Oxide
© The Author(s) 2023. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.
Accepted author manuscript, 42.3 MBLicence: CC BY

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Andrews, J. P. M., Joshi, S. S., Tzolos, E., Syed, M. B., Cuthbert, H., Crica, L. E., Lozano, N., Okwelogu, E., Raftis, J. B., Bruce, L., Poland, C. A., Duffin, R., Fokkens, P. H. B., Boere, A. J. F., Leseman, D. L. A. C., Megson, I. L., Whitfield, P. D., Ziegler, K., Tammireddy, S., ... Miller, M. R. (2024). First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses. Nature Nanotechnology, 67(S1), i52-i53. https://doi.org/10.1093/annweh/wxac087.128

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title = "First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses",

abstract = "Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxide nanosheets at a concentration of 200 μg m−3 or filtered air were inhaled for 2 h by 14 young healthy volunteers in repeated visits. Overall, graphene oxide nanosheet exposure was well tolerated with no adverse effects. Heart rate, blood pressure, lung function and inflammatory markers were unaffected irrespective of graphene oxide particle size. Highly enriched blood proteomics analysis revealed very few differential plasma proteins and thrombus formation was mildly increased in an ex vivo model of arterial injury. Overall, acute inhalation of highly purified and thin nanometre-sized graphene oxide nanosheets was not associated with overt detrimental effects in healthy humans. These findings demonstrate the feasibility of carefully controlled human exposures at a clinical setting for risk assessment of graphene oxide, and lay the foundations for investigating the effects of other two-dimensional nanomaterials in humans. Clinicaltrials.gov ref: NCT03659864.",

author = "Andrews, {Jack P.M.} and Joshi, {Shruti S.} and Evangelos Tzolos and Syed, {Maaz B.} and Hayley Cuthbert and Crica, {Livia E.} and Neus Lozano and Emmanuel Okwelogu and Raftis, {Jennifer B.} and Lorraine Bruce and Poland, {Craig A.} and Rodger Duffin and Fokkens, {Paul H.B.} and Boere, {A. John F.} and Leseman, {Daan L.A.C.} and Megson, {Ian L.} and Whitfield, {Phil D.} and Kerstin Ziegler and Seshu Tammireddy and Marilena Hadjidemetriou and Cyrill Bussy and Cassee, {Flemming R.} and Newby, {David E.} and Kostas Kostarelos and Miller, {Mark R.}",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the British Occupational Hygiene Society. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. Funding Information: We thank all the staff at the Edinburgh Wellcome Trust Clinical Research Facility and M. Doris for their assistance with the participant study days. We also thank J. MacLeod for performing the screening visit exercise tests and the NHS Royal Infirmary of Edinburgh staff for the clinical biochemistry measurements. We also thank F. Howie and K. Wilson for their assistance in measuring TNF-α and IL-6, and the members of the University of Edinburgh SuRF histology laboratories for the processing and imaging of Badimon strips. We gratefully acknowledge the assistance of the SSC2b medical students (J. Garcia Fernandez, L. Buijs, S. Henry and N. Cameron) who participated in the initial data processing. We thank the staff at the Manchester Mass Spectrometry Facility, FTIR Facility, EM Facility and Bio-AFM Facility for assistance and advice regarding instrumentation. The University of Manchester Bioimaging Facility microscopes (EM, AFM) used in the present study were purchased with grants from the UK Research and Innovation (UKRI) Biotechnology and Biological Sciences Research Council, the Wellcome Trust and the University of Manchester Strategic Fund. We also acknowledge the UK Research and Innovation (UKRI) Engineering and Physical Sciences Research Council (EPSRC) Harwell XPS facility based at Cardiff University for the provision of X-ray photoelectron spectrometric data. Finally, we thank all the volunteers taking part in the study, which would not have been possible without them. This work was funded by the British Heart Foundation (grant numberSP/15/8/31575, M.R.M.), a UKRI and Engineering and Physical Sciences Research Council EPSRC 2D-Health Programme Grant (UKRI-EPSRC EP/P00119X/1) and the University of Manchester Strategic Fund studentship (both K.K.). The ICN2 is funded by the CERCA programme/Generalitat de Catalunya and has been supported by the Severo Ochoa Centres of Excellence programme (grant number SEV-2017-0706) and is currently supported by the Severo Ochoa Centres of Excellence programme, grant number CEX2021-001214-S, both funded by MCIN/AEI/10.13039.501100011033. S.S.J. and D.E.N. are supported by the British Heart Foundation (grant numbers FS/CRTF/20/24087, CH/09/002, RG/05/003, RG/10/9/28286, PG/03/017/15071, RG/16/10/32375 and RE/18/5/34216, all D.E.N.). D.E.N. is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). ",

year = "2024",

month = feb,

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doi = "10.1093/annweh/wxac087.128",

language = "English",

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Andrews, JPM, Joshi, SS, Tzolos, E, Syed, MB, Cuthbert, H, Crica, LE, Lozano, N, Okwelogu, E, Raftis, JB, Bruce, L, Poland, CA, Duffin, R, Fokkens, PHB, Boere, AJF, Leseman, DLAC, Megson, IL, Whitfield, PD, Ziegler, K, Tammireddy, S, Hadjidemetriou, M, Bussy, C, Cassee, FR, Newby, DE, Kostarelos, K & Miller, MR 2024, 'First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses', Nature Nanotechnology, vol. 67, no. S1, pp. i52-i53. https://doi.org/10.1093/annweh/wxac087.128

TY - JOUR

T1 - First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses

AU - Andrews, Jack P.M.

AU - Joshi, Shruti S.

AU - Tzolos, Evangelos

AU - Syed, Maaz B.

AU - Cuthbert, Hayley

AU - Crica, Livia E.

AU - Lozano, Neus

AU - Okwelogu, Emmanuel

AU - Raftis, Jennifer B.

AU - Bruce, Lorraine

AU - Poland, Craig A.

AU - Duffin, Rodger

AU - Fokkens, Paul H.B.

AU - Boere, A. John F.

AU - Leseman, Daan L.A.C.

AU - Megson, Ian L.

AU - Whitfield, Phil D.

AU - Ziegler, Kerstin

AU - Tammireddy, Seshu

AU - Hadjidemetriou, Marilena

AU - Bussy, Cyrill

AU - Cassee, Flemming R.

AU - Newby, David E.

AU - Kostarelos, Kostas

AU - Miller, Mark R.

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the British Occupational Hygiene Society. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. Funding Information: We thank all the staff at the Edinburgh Wellcome Trust Clinical Research Facility and M. Doris for their assistance with the participant study days. We also thank J. MacLeod for performing the screening visit exercise tests and the NHS Royal Infirmary of Edinburgh staff for the clinical biochemistry measurements. We also thank F. Howie and K. Wilson for their assistance in measuring TNF-α and IL-6, and the members of the University of Edinburgh SuRF histology laboratories for the processing and imaging of Badimon strips. We gratefully acknowledge the assistance of the SSC2b medical students (J. Garcia Fernandez, L. Buijs, S. Henry and N. Cameron) who participated in the initial data processing. We thank the staff at the Manchester Mass Spectrometry Facility, FTIR Facility, EM Facility and Bio-AFM Facility for assistance and advice regarding instrumentation. The University of Manchester Bioimaging Facility microscopes (EM, AFM) used in the present study were purchased with grants from the UK Research and Innovation (UKRI) Biotechnology and Biological Sciences Research Council, the Wellcome Trust and the University of Manchester Strategic Fund. We also acknowledge the UK Research and Innovation (UKRI) Engineering and Physical Sciences Research Council (EPSRC) Harwell XPS facility based at Cardiff University for the provision of X-ray photoelectron spectrometric data. Finally, we thank all the volunteers taking part in the study, which would not have been possible without them. This work was funded by the British Heart Foundation (grant numberSP/15/8/31575, M.R.M.), a UKRI and Engineering and Physical Sciences Research Council EPSRC 2D-Health Programme Grant (UKRI-EPSRC EP/P00119X/1) and the University of Manchester Strategic Fund studentship (both K.K.). The ICN2 is funded by the CERCA programme/Generalitat de Catalunya and has been supported by the Severo Ochoa Centres of Excellence programme (grant number SEV-2017-0706) and is currently supported by the Severo Ochoa Centres of Excellence programme, grant number CEX2021-001214-S, both funded by MCIN/AEI/10.13039.501100011033. S.S.J. and D.E.N. are supported by the British Heart Foundation (grant numbers FS/CRTF/20/24087, CH/09/002, RG/05/003, RG/10/9/28286, PG/03/017/15071, RG/16/10/32375 and RE/18/5/34216, all D.E.N.). D.E.N. is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA).

PY - 2024/2/16

Y1 - 2024/2/16

N2 - Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxide nanosheets at a concentration of 200 μg m−3 or filtered air were inhaled for 2 h by 14 young healthy volunteers in repeated visits. Overall, graphene oxide nanosheet exposure was well tolerated with no adverse effects. Heart rate, blood pressure, lung function and inflammatory markers were unaffected irrespective of graphene oxide particle size. Highly enriched blood proteomics analysis revealed very few differential plasma proteins and thrombus formation was mildly increased in an ex vivo model of arterial injury. Overall, acute inhalation of highly purified and thin nanometre-sized graphene oxide nanosheets was not associated with overt detrimental effects in healthy humans. These findings demonstrate the feasibility of carefully controlled human exposures at a clinical setting for risk assessment of graphene oxide, and lay the foundations for investigating the effects of other two-dimensional nanomaterials in humans. Clinicaltrials.gov ref: NCT03659864.

AB - Graphene oxide nanomaterials are being developed for wide-ranging applications but are associated with potential safety concerns for human health. We conducted a double-blind randomized controlled study to determine how the inhalation of graphene oxide nanosheets affects acute pulmonary and cardiovascular function. Small and ultrasmall graphene oxide nanosheets at a concentration of 200 μg m−3 or filtered air were inhaled for 2 h by 14 young healthy volunteers in repeated visits. Overall, graphene oxide nanosheet exposure was well tolerated with no adverse effects. Heart rate, blood pressure, lung function and inflammatory markers were unaffected irrespective of graphene oxide particle size. Highly enriched blood proteomics analysis revealed very few differential plasma proteins and thrombus formation was mildly increased in an ex vivo model of arterial injury. Overall, acute inhalation of highly purified and thin nanometre-sized graphene oxide nanosheets was not associated with overt detrimental effects in healthy humans. These findings demonstrate the feasibility of carefully controlled human exposures at a clinical setting for risk assessment of graphene oxide, and lay the foundations for investigating the effects of other two-dimensional nanomaterials in humans. Clinicaltrials.gov ref: NCT03659864.

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SP - i52-i53

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JF - Nature Nanotechnology

IS - S1

ER -

First-in-human controlled inhalation of thin graphene oxide nanosheets to study acute cardiorespiratory responses

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