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Towards A Graphene Chip System For Blood Clotting Disease Diagnostics / JACOB MITCHELL

Swansea University Author: JACOB MITCHELL

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DOI (Published version): 10.23889/SUthesis.59099

Abstract

Point of care diagnostics (POCD) allows the rapid, accurate measurement of analytes near to a patient. This enables faster clinical decision making and can lead to earlier diagnosis and better patient monitoring and treatment. However, despite many prospective POCD devices being developed for a wide...

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Published: Swansea 2022
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Guy, Owen J.
URI: https://cronfa.swan.ac.uk/Record/cronfa59099
first_indexed 2022-01-06T12:38:59Z
last_indexed 2022-01-07T04:26:50Z
id cronfa59099
recordtype RisThesis
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However, despite many prospective POCD devices being developed for a wide range of diseases this promised technology is yet to be translated to a clinical setting due to the lack of a cost-e&#xFB00;ective biosensing platform.This thesis focuses on the development of a highly sensitive, low cost and scalable biosensor platform that combines graphene with semiconductor fabrication tech-niques to create graphene &#xFB01;eld-e&#xFB00;ect transistors biosensor. The key challenges of designing and fabricating a graphene-based biosensor are addressed. This work fo-cuses on a speci&#xFB01;c platform for blood clotting disease diagnostics, but the platform has the capability of being applied to any disease with a detectable biomarker.Multiple sensor designs were tested during this work that maximised sensor ef-&#xFB01;ciency and costs for di&#xFB00;erent applications. The multiplex design enabled di&#xFB00;erent graphene channels on the same chip to be functionalised with unique chemistry. 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The Post-Transfer pro-cess higher quality (less damage, residue and doping, con&#xFB01;rmed by Raman spec-troscopy).Following sensor fabrication, the next stages of creating a sensor platform involve the passivation and packaging of the sensor chip. Di&#xFB00;erent approaches using dielec-tric deposition approaches are compared for passivation. Molecular Vapour Deposi-tion (MVD) deposited Al2O3 was shown to produce graphene channels with lower damage than unprocessed graphene, and also improves graphene doping bringing the Dirac point of the graphene close to 0 V. The packaging integration of micro&#xFB02;uidics is investigated comparing traditional soft lithography approaches and the new 3D printed micro&#xFB02;uidic approach. Speci&#xFB01;c micro&#xFB02;uidic packaging for blood separation towards a blood sampling point of care sensor is examined to identify the laminar approach for lower blood cell count, as a method of pre-processing the blood sample before sensing.To test the sensitivity of the Post-Transfer MVD passivated graphene sensor de-veloped in this work, real-time IV measurements were performed to identify throm-bin protein binding in real-time on the graphene surface. The sensor was function-alised using a thrombin speci&#xFB01;c aptamer solution and real-time IV measurements were performed on the functionalised graphene sensor with a range of biologically relevant protein concentrations. The resulting sensitivity of the graphene sensor was in the 1-100 pg/ml concentration range, producing a resistance change of 0.2% per pg/ml. Speci&#xFB01;city was con&#xFB01;rmed using a non-thrombin speci&#xFB01;c aptamer as the neg-ative control. 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spelling 2022-01-06T15:30:49.7886922 v2 59099 2022-01-06 Towards A Graphene Chip System For Blood Clotting Disease Diagnostics 9ffa4647d8c9ecbf722eed1dfb840230 JACOB MITCHELL JACOB MITCHELL true false 2022-01-06 Point of care diagnostics (POCD) allows the rapid, accurate measurement of analytes near to a patient. This enables faster clinical decision making and can lead to earlier diagnosis and better patient monitoring and treatment. However, despite many prospective POCD devices being developed for a wide range of diseases this promised technology is yet to be translated to a clinical setting due to the lack of a cost-effective biosensing platform.This thesis focuses on the development of a highly sensitive, low cost and scalable biosensor platform that combines graphene with semiconductor fabrication tech-niques to create graphene field-effect transistors biosensor. The key challenges of designing and fabricating a graphene-based biosensor are addressed. This work fo-cuses on a specific platform for blood clotting disease diagnostics, but the platform has the capability of being applied to any disease with a detectable biomarker.Multiple sensor designs were tested during this work that maximised sensor ef-ficiency and costs for different applications. The multiplex design enabled different graphene channels on the same chip to be functionalised with unique chemistry. The Inverted MOSFET design was created, which allows for back gated measurements to be performed whilst keeping the graphene channel open for functionalisation. The Shared Source and Matrix design maximises the total number of sensing channels per chip, resulting in the most cost-effective fabrication approach for a graphene-based sensor (decreasing cost per channel from £9.72 to £4.11).The challenge of integrating graphene into a semiconductor fabrication process is also addressed through the development of a novel vacuum transfer method-ology that allows photoresist free transfer. The two main fabrication processes; graphene supplied on the wafer “Pre-Transfer” and graphene transferred after met-allisation “Post-Transfer” were compared in terms of graphene channel resistance and graphene end quality (defect density and photoresist). The Post-Transfer pro-cess higher quality (less damage, residue and doping, confirmed by Raman spec-troscopy).Following sensor fabrication, the next stages of creating a sensor platform involve the passivation and packaging of the sensor chip. Different approaches using dielec-tric deposition approaches are compared for passivation. Molecular Vapour Deposi-tion (MVD) deposited Al2O3 was shown to produce graphene channels with lower damage than unprocessed graphene, and also improves graphene doping bringing the Dirac point of the graphene close to 0 V. The packaging integration of microfluidics is investigated comparing traditional soft lithography approaches and the new 3D printed microfluidic approach. Specific microfluidic packaging for blood separation towards a blood sampling point of care sensor is examined to identify the laminar approach for lower blood cell count, as a method of pre-processing the blood sample before sensing.To test the sensitivity of the Post-Transfer MVD passivated graphene sensor de-veloped in this work, real-time IV measurements were performed to identify throm-bin protein binding in real-time on the graphene surface. The sensor was function-alised using a thrombin specific aptamer solution and real-time IV measurements were performed on the functionalised graphene sensor with a range of biologically relevant protein concentrations. The resulting sensitivity of the graphene sensor was in the 1-100 pg/ml concentration range, producing a resistance change of 0.2% per pg/ml. Specificity was confirmed using a non-thrombin specific aptamer as the neg-ative control. These results indicate that the graphene sensor platform developed in this thesis has the potential as a highly sensitive POCD. The processes developed here can be used to develop graphene sensors for multiple biomarkers in the future. E-Thesis Swansea Graphene, gFET, Biosensor, Packaging 6 1 2022 2022-01-06 10.23889/SUthesis.59099 ORCiD identifier: https://orcid.org/0000-0003-1377-725X COLLEGE NANME COLLEGE CODE Swansea University Guy, Owen J. Doctoral Ph.D EPSRC doctoral training grant 2022-01-06T15:30:49.7886922 2022-01-06T12:25:00.5908303 Faculty of Science and Engineering School of Engineering and Applied Sciences - Uncategorised JACOB MITCHELL 1 59099__22059__d03c1920e97d40c0b6c3d63b6e8580e9.pdf Mitchell_Jacob_J_PhD_Thesis_Final_Redacted_Signature.pdf 2022-01-06T15:26:06.0917780 Output 6270168 application/pdf E-Thesis – open access true Towards A Graphene Chip System For Blood Clotting Disease Diagnostics © 2020 by Jacob J. Mitchell is licensed under a Creative Commons Attribution (CC BY) License. true eng https://creativecommons.org/licenses/by/4.0/
title Towards A Graphene Chip System For Blood Clotting Disease Diagnostics
spellingShingle Towards A Graphene Chip System For Blood Clotting Disease Diagnostics
JACOB MITCHELL
title_short Towards A Graphene Chip System For Blood Clotting Disease Diagnostics
title_full Towards A Graphene Chip System For Blood Clotting Disease Diagnostics
title_fullStr Towards A Graphene Chip System For Blood Clotting Disease Diagnostics
title_full_unstemmed Towards A Graphene Chip System For Blood Clotting Disease Diagnostics
title_sort Towards A Graphene Chip System For Blood Clotting Disease Diagnostics
author_id_str_mv 9ffa4647d8c9ecbf722eed1dfb840230
author_id_fullname_str_mv 9ffa4647d8c9ecbf722eed1dfb840230_***_JACOB MITCHELL
author JACOB MITCHELL
author2 JACOB MITCHELL
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hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Uncategorised{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Uncategorised
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description Point of care diagnostics (POCD) allows the rapid, accurate measurement of analytes near to a patient. This enables faster clinical decision making and can lead to earlier diagnosis and better patient monitoring and treatment. However, despite many prospective POCD devices being developed for a wide range of diseases this promised technology is yet to be translated to a clinical setting due to the lack of a cost-effective biosensing platform.This thesis focuses on the development of a highly sensitive, low cost and scalable biosensor platform that combines graphene with semiconductor fabrication tech-niques to create graphene field-effect transistors biosensor. The key challenges of designing and fabricating a graphene-based biosensor are addressed. This work fo-cuses on a specific platform for blood clotting disease diagnostics, but the platform has the capability of being applied to any disease with a detectable biomarker.Multiple sensor designs were tested during this work that maximised sensor ef-ficiency and costs for different applications. The multiplex design enabled different graphene channels on the same chip to be functionalised with unique chemistry. The Inverted MOSFET design was created, which allows for back gated measurements to be performed whilst keeping the graphene channel open for functionalisation. The Shared Source and Matrix design maximises the total number of sensing channels per chip, resulting in the most cost-effective fabrication approach for a graphene-based sensor (decreasing cost per channel from £9.72 to £4.11).The challenge of integrating graphene into a semiconductor fabrication process is also addressed through the development of a novel vacuum transfer method-ology that allows photoresist free transfer. The two main fabrication processes; graphene supplied on the wafer “Pre-Transfer” and graphene transferred after met-allisation “Post-Transfer” were compared in terms of graphene channel resistance and graphene end quality (defect density and photoresist). The Post-Transfer pro-cess higher quality (less damage, residue and doping, confirmed by Raman spec-troscopy).Following sensor fabrication, the next stages of creating a sensor platform involve the passivation and packaging of the sensor chip. Different approaches using dielec-tric deposition approaches are compared for passivation. Molecular Vapour Deposi-tion (MVD) deposited Al2O3 was shown to produce graphene channels with lower damage than unprocessed graphene, and also improves graphene doping bringing the Dirac point of the graphene close to 0 V. The packaging integration of microfluidics is investigated comparing traditional soft lithography approaches and the new 3D printed microfluidic approach. Specific microfluidic packaging for blood separation towards a blood sampling point of care sensor is examined to identify the laminar approach for lower blood cell count, as a method of pre-processing the blood sample before sensing.To test the sensitivity of the Post-Transfer MVD passivated graphene sensor de-veloped in this work, real-time IV measurements were performed to identify throm-bin protein binding in real-time on the graphene surface. The sensor was function-alised using a thrombin specific aptamer solution and real-time IV measurements were performed on the functionalised graphene sensor with a range of biologically relevant protein concentrations. The resulting sensitivity of the graphene sensor was in the 1-100 pg/ml concentration range, producing a resistance change of 0.2% per pg/ml. Specificity was confirmed using a non-thrombin specific aptamer as the neg-ative control. These results indicate that the graphene sensor platform developed in this thesis has the potential as a highly sensitive POCD. The processes developed here can be used to develop graphene sensors for multiple biomarkers in the future.
published_date 2022-01-06T04:57:37Z
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