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:10.1038/s41565-023-01572-3

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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)	705-714
Number of pages	10
Journal	Nature Nanotechnology
Volume	19
Issue number	5
Early online date	16 Feb 2024
DOIs	https://doi.org/10.1038/s41565-023-01572-3
Publication status	Published - May 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

Funders	Funder number
Severo Ochoa Centres of Excellence	CH/09/002, RG/16/10/32375, MCIN/AEI/10.13039.501100011033, WT103782AIA, RG/10/9/28286, PG/03/017/15071, RE/18/5/34216, CEX2021-001214-S, FS/CRTF/20/24087, RG/05/003
Severo Ochoa Centres of Excellence programme	SEV-2017-0706
UKRI-EPSRC	EP/P00119X/1
University of Manchester Bioimaging Facility microscopes
University of Manchester Strategic Fund
Wellcome Trust
UK Research and Innovation
British Heart Foundation	numberSP/15/8/31575
British Heart Foundation
University of Manchester

Keywords

Humans
Graphite/chemistry
Male
Adult
Female
Nanostructures/chemistry
Young Adult
Double-Blind Method
Heart Rate/drug effects
Administration, Inhalation
Inhalation Exposure/adverse effects
Blood Pressure/drug effects
Particle Size

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, 19(5), 705-714. https://doi.org/10.1038/s41565-023-01572-3

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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.",

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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.}",

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month = may,

doi = "10.1038/s41565-023-01572-3",

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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. 19, no. 5, pp. 705-714. https://doi.org/10.1038/s41565-023-01572-3

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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.

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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.

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

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