Video capsule endoscopy (VCE) has become a clinically accepted diagnostic modality in the last 20 years and has established a technological roadmap for other capsule endoscopy (CE) devices, incorporating microscale technology, a local power supply and wireless communication. However, VCE does not provide a therapeutic function and research in therapeutic capsule endoscopy (TCE) has been limited. This paper proposes a new route towards viable TCE based on multiple CE devices including essential nanoscale components. A first device is used for multimodal diagnosis, with quantitative microultrasound as a complement to video imaging. Ultrasound-enhanced fluorescent marking of sites of pathology allows follow-up with a second device for therapy. This is based on fluorescence imaging and ultrasound-mediated targeted drug delivery. Subsequent treatment verification and monitoring with a third device exploits the minimally invasive nature of CE. Clinical implementation of a complete patient pathway remains the subject of research but several key components have been prepared in early prototype form. These are described, along with gaps that remain to be filled

Button, T. W.

Cochran, S.

Cox, B. F.

Cumming, D. R. S.

Gourevich, D.

Lay, H. S.

Mulvana, H.

Nathke, I. S.

Stewart, F.

S. Cochran

T. W. Button

B. F. Cox

D. R. S. Cumming

D. Gourevich

H. S. Lay

H. Mulvana

I. S. Nathke

F. Stewart

Crossref

Nanotechnology in multimodal theranostic capsule endoscopy

Video capsule endoscopy (VCE) has become a clinically accepted diagnostic modality in the last 20 years and has established a technological roadmap for other capsule endoscopy (CE) devices, incorporating microscale technology, a local power supply and wireless communication. However, VCE does not provide a therapeutic function and research in therapeutic capsule endoscopy (TCE) has been limited. This paper proposes a new route towards viable TCE based on multiple CE devices including essential nanoscale components. A first device is used for multimodal diagnosis, with quantitative microultrasound as a complement to video imaging. Ultrasound-enhanced fluorescent marking of sites of pathology allows follow-up with a second device for therapy. This is based on fluorescence imaging and ultrasound-mediated targeted drug delivery. Subsequent treatment verification and monitoring with a third device exploits the minimally invasive nature of CE. Clinical implementation of a complete patient pathway remains the subject of research but several key components have been prepared in early prototype form. These are described, along with gaps that remain to be filled.</p

Discovery Research Portal

                                                              University of DundeeNanotechnology in multimodal theranostic capsule endoscopyCochran, S.; Button, T. W.; Cox, B. F.; Cumming, D. R. S.; Gourevich, D.; Lay, H. S.;Mulvana, H.; Nathke, I. S.; Stewart, F.Published in:2017 IEEE 17th International Conference on Nanotechnology, NANO 2017DOI:10.1109/NANO.2017.8117439Publication date:2017Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Cochran, S., Button, T. W., Cox, B. F., Cumming, D. R. S., Gourevich, D., Lay, H. S., ... Stewart, F. (2017).Nanotechnology in multimodal theranostic capsule endoscopy. In 2017 IEEE 17th International Conference onNanotechnology, NANO 2017 (pp. 434-435). [8117439] United States: IEEE. DOI:10.1109/NANO.2017.8117439General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 20. Mar. 2018   Abstract— Video capsule endoscopy (VCE) has become a clinically accepted diagnostic modality in the last 20 years and has established a technological roadmap for other capsule endoscopy (CE) devices, incorporating microscale technology, a local power supply and wireless communication. However, VCE does not provide a therapeutic function and research in therapeutic capsule endoscopy (TCE) has been limited. This paper proposes a new route towards viable TCE based on multiple CE devices including essential nanoscale components. A first device is used for multimodal diagnosis, with quantitative microultrasound as a complement to video imaging. Ultrasound-enhanced fluorescent marking of sites of pathology allows follow-up with a second device for therapy. This is based on fluorescence imaging and ultrasound-mediated targeted drug delivery. Subsequent treatment verification and monitoring with a third device exploits the minimally invasive nature of CE. Clinical implementation of a complete patient pathway remains the subject of research but several key components have been prepared in early prototype form. These are described, along with gaps that remain to be filled. I. INTRODUCTION Conventional endoscopy through oral and anal routes, respectively, provides routine access to the upper and lower parts of the gastrointestinal (GI) tract. Whilst these techniques are minimally invasive, subjects must attend hospital, require sedation, and have the procedure administered by highly skilled clinicians. Assessment of the full length of the GI tract with double-balloon enteroscopy is possible, but this is a non-routine procedure performed only in large healthcare centres. Video capsule endoscopy (VCE) [1] has been developed, introduced and accepted as a routine clinical procedure in the past 20 years. It is based on three areas of innovation linked to work in other fields: miniaturization of cameras and related electronic circuitry; minimal power consumption from a local battery; and wireless communication with a data logger. A fourth innovation, automated information extraction and interpretation is still a topic of research. Additionally, localization with accuracy compatible with targeted therapy remains impossible. Conventional optical endoscopy is now allied with multiple additional diagnostic modalities. Of these, ultrasound (US) has been argued to be most important [2] since it permits subsurface imaging of optically-opaque tissue. Its implementation is based on its nature as a safe, inexpensive, real-time technique deployed at the point of care. Resulting  * This research is supported by the UK EPSRC Sonopill Programme, ref. GR/K034537. It previously drew support from the EU Nanoporation project, ref. 230674. S.Cochran, D.Cumming, H.Lay and H.Mulvana are with the School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK (Phone: +44 141 330 3317); e-mail: sandy.cochran@glasgow.ac.uk).  data have been shown to be amenable to quantitative analysis in some situations and it carries therapeutic potential through ultrasound-mediated targeted drug delivery (UmTDD). II. PROPOSED PATIENT PATHWAY Important components in a multimodal diagnostic CE device include sensing and actuation devices, a battery power supply, and wireless communication circuitry and an antenna. A therapeutic device must additionally include a reservoir and release mechanism for the nanotechnological therapeutic agent and a targeting mechanism is likely to be essential for non-systemic therapies. The form of a typical CE device is a cylinder with spherical ends, overall length 30 mm, diameter 10 mm [3]. Hence, a solution comprising two or more separate devices in a theranostic combination may be needed to accommodate the proposed functions. This has the additional advantage that clinical validation may be incorporated in the procedure at the diagnostic stage, prior to therapy. The proposed patient pathway begins with a patient presenting with indications of a condition such as Crohn’s disease. The patient is subject to conventional diagnosis and a diagnostic CE device is administered if the diagnostic outcome is positive. This device generates optical and microultrasound (US) data identifying disease sites within the GI tract through quantitative analysis working at the nanoscale. These sites are marked with fluorescent nanoparticles using an US-mediated process. By reviewing the results manually, a clinician validates the diagnosis then administers a therapeutic CE device. This device can detect fluorescent markers but does not require diagnostic or more than minimal communication capabilities. Instead, available volume is used for a reservoir of a nanotherapeutic agent, a release mechanism, and US components to drive the agent towards the target and permeabilize the tissue to enhance uptake. Subsequently, a further CE device can be administered to verify disease response. The ability of CE devices to penetrate the full length of the gut in a minimally invasive manner thus allows closed loop diagnosis and therapy.  III. RELEVANT RESULTS Preliminary results have been obtained for some of the stages in the outline procedure and the prototype CE devices from which these results were obtained have demonstrated key components though the need for a local power supply and wireless communication was avoided with multimodal tethers. T.W.Button is with the School of Metallurgy and Materials, University of Birmingham, Birmingham, B15 2TT, UK. B.F.Cox, I.S.Näthke and F.Stewart are with the School of Life Sciences, University of Dundee, Dundee, DD1 4HN, UK. D.Gourevich was with the Institute for Medical Science and Technology, University of Dundee, Dundee, DD2 1FD, UK when she participated in the work described here. Nanotechnology in Multimodal Theranostic Capsule Endoscopy S.Cochran*, T.W.Button, B.F.Cox, D.R.S.Cumming, D.Gourevich,  H.S.Lay, H.Mulvana, I.S.Näthke and F.Stewart   Nevertheless, the prototype CE devices themselves conform to the maximum dimensions set by current clinical practice. A. Microultrasound Diagnosis and Quantitative Analysis US uses frequencies above the conventional diagnostic upper limit of 20 MHz. Through its reduced wavelength, it has been demonstrated that such high frequencies provide direct access to ultrasonic effects resulting from scattering from nanoscale acoustically-contrasting features. Following early results [4], an exploratory program based on US scanning of porcine tissue ex vivo with a typical frequency of 47 MHz is under way and has shown that the distinct layers within the GI tract can be imaged. The highly specialized single-element transducers for this work used 1-3 connectivity piezoceramic - polymer composite material made with micromoulding and casting processes. To avoid US artefacts whilst maintaining the sensitivity inherent in piezocomposites, these materials were designed with pseudo-random ceramic phase patterns [5]. These allow higher than usual frequencies to be achieved with viable ceramic dimensions. Additionally, successful in vivo testing has begun, with simpler piezopolymer transducers. To progress towards automated diagnosis, quantitative analysis of the scan data has been explored [6], focusing on measurement of acoustic impedance, attenuation and backscattering, with promising results presented in this paper. B. Fluorescence Marking and Imaging  To explore the marking process [7], experiments were performed on ex vivo murine and porcine tissue using fluorescent CdSeS/ZnS quantum dots (QDs) (Sigma-Aldrich, USA). These were directed towards the focal zone of a miniature high intensity focused US (HIFU) transducer operating at 4 MHz. The results presented in this paper show preferential concentration where the US was applied.  In the work outlined here, fluorescence imaging was based on the configuration of single-photon avalanche diode (SPAD) arrays with bespoke application-specific integrated circuits (ASICs) in miniaturized configurations for capsule deployment [8]. Successful demonstrations of both imaging and miniaturization are demonstrated. C. Therapeutic CE Device Feasibility To determine if the HIFU components for UmTDD can be incorporated in CE, and the extent of their capabilities, a prototype device was constructed. This included a confocal arrangement of: a HIFU source (Meggitt Sensing Systems, Kvistgaard, Denmark), diameter 4 mm, focal distance 6 mm, frequency 4 MHz; a miniature white light camera (Micro ScoutCam 1.2, Medigus, Omer, Israel), length 5 mm, diameter 1.2 mm; and a delivery channel for agents mimicking drugs and drug-delivery vehicles [9]. The prototype demonstrated that a stream of microbubbles could be directed towards a target based on US radiation force from the HIFU transducer, with an excitation level of 8 Vpp, compatible with the voltage amplitude that may be available in a CE device. Measuring transepithelial resistance in a model of the wall of the GI tract using Caco-2 cell monolayers showed that the same transducer with similar excitation levels could influence uptake in vitro [9]. D. Ultrasound-mediated Targeted Drug Delivery A typical use for the clinical procedure outlined above is to deliver drugs to treat localized disease within the GI tract in a targeted manner. With UmTDD, this involves three mechanisms [10]: packaging of the drug to passivate it so that systemic effects will be reduced; physical direction of the packaged drug towards the treatment site; and reduction in the permeability of the target to enhance uptake. Additionally, it may be necessary to disrupt the drug - package complex so that the drug may be released and taken up by cells. An approach explored by the authors is to combine a drug with a nanoscale, chemically-engineered package. This is demonstrated through work on the creation of a chemical complex comprising the chemotherapeutic drug doxorubicin (Dox) and γ-cyclodextrin. With Dox on its own as a control, it is shown that the chemical complex has a reduced effect on cells in vitro whereas mildly hyperthermic and cavitational effects of US compatible with use in the GI tract enhanced the effect of the drug when applied as a nanoscale complex [11].  IV. CONCLUSIONS A potential theranostic strategy for treatment of diseases of the GI tract based on the use of nanotechnology combined with CE has been outlined. This relies on US analysis of targets at the nanoscale, marking with nanoscale agents and delivery of nanoscale drug complexes for treatment. The clinical procedure involves multiple steps with development relying on multidisciplinary research. Progress in several directions is presented in this paper and further work is under way to demonstrate the viability of the procedure. REFERENCES [1] G.Iddan et al, “Wireless capsule endoscopy” Nature (Brief Comm) vol. 405, 2000, p. 417 [2] M.V.Sivak, “Gastrointestinal endoscopy: past and future” Gut vol. 55,  2006, pp. 1061 – 4 [3] Medtronic, ous.pillcamcolon.com, accessed 19th March, 2017 [4] A.Fatehullah et al, “Increased variability in ApcMin/+ intestinal tissue can be measured with microultrasound” Sci. Rep. vol. 6, 2016, article 29570 [5] Y. Jiang et al, “Micro-moulded randomised piezocomposites for high frequency ultrasound imaging” IEEE Int. Ultrasonics. Symp. Proc., 2012, DOI: 10.1109/ULTSYM.2012.0045 [6] H.S.Lay et al, “Microultrasound characterisation of ex vivo porcine tissue for ultrasound capsule endoscopy” J. Phys.: Conf. Series vol. 797, 2017, article 012003 [7] B.F.Cox et al, “Ultrasound facilitated marking of gastrointestinal tissue with fluorescent material” IEEE Int. Ultrasonics. Symp. Proc., 2016, DOI: 10.1109/ULTSYM.2016.7728782 [8] M.A.Al-Rawhani et al, “Wireless fluorescence capsule for endoscopy using single photon-based detection” Sci. Rep. vol. 5, 2015, article 18591 [9] F.W.Stewart et al, “SonoCAIT: Proof-of-Concept Ultrasound-enabled Therapeutic Capsule Endoscope” submitted to J. Med. Robotics Res., 2017 [10] F.W.Stewart et al, “Theranostics in the gut”, to appear in M.Thanou (ed.) Theranostics and Image Guided Drug Delivery, Royal Society of Chemistry, 2017, in press [11] D.Gourevich et al, “Ultrasound-mediated targeted drug delivery with a novel cyclodextrin-based drug carrier by mechanical and thermal mechanisms” J. Controlled Release vol. 170, 2013, pp. 316 - 24 

                                                                    University of DundeeNanotechnology in multimodal theranostic capsule endoscopyCochran, S.; Button, T. W.; Cox, B. F.; Cumming, D. R. S.; Gourevich, D.; Lay, H. S.Published in:2017 IEEE 17th International Conference on Nanotechnology, NANO 2017DOI:10.1109/NANO.2017.8117439Publication date:2017Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Cochran, S., Button, T. W., Cox, B. F., Cumming, D. R. S., Gourevich, D., Lay, H. S., Mulvana, H., Nathke, I. S.,& Stewart, F. (2017). Nanotechnology in multimodal theranostic capsule endoscopy. In 2017 IEEE 17thInternational Conference on Nanotechnology, NANO 2017 (pp. 434-435). [8117439] IEEE.https://doi.org/10.1109/NANO.2017.8117439General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 19. Apr. 2023   Abstract— Video capsule endoscopy (VCE) has become a clinically accepted diagnostic modality in the last 20 years and has established a technological roadmap for other capsule endoscopy (CE) devices, incorporating microscale technology, a local power supply and wireless communication. However, VCE does not provide a therapeutic function and research in therapeutic capsule endoscopy (TCE) has been limited. This paper proposes a new route towards viable TCE based on multiple CE devices including essential nanoscale components. A first device is used for multimodal diagnosis, with quantitative microultrasound as a complement to video imaging. Ultrasound-enhanced fluorescent marking of sites of pathology allows follow-up with a second device for therapy. This is based on fluorescence imaging and ultrasound-mediated targeted drug delivery. Subsequent treatment verification and monitoring with a third device exploits the minimally invasive nature of CE. Clinical implementation of a complete patient pathway remains the subject of research but several key components have been prepared in early prototype form. These are described, along with gaps that remain to be filled. I. INTRODUCTION Conventional endoscopy through oral and anal routes, respectively, provides routine access to the upper and lower parts of the gastrointestinal (GI) tract. Whilst these techniques are minimally invasive, subjects must attend hospital, require sedation, and have the procedure administered by highly skilled clinicians. Assessment of the full length of the GI tract with double-balloon enteroscopy is possible, but this is a non-routine procedure performed only in large healthcare centres. Video capsule endoscopy (VCE) [1] has been developed, introduced and accepted as a routine clinical procedure in the past 20 years. It is based on three areas of innovation linked to work in other fields: miniaturization of cameras and related electronic circuitry; minimal power consumption from a local battery; and wireless communication with a data logger. A fourth innovation, automated information extraction and interpretation is still a topic of research. Additionally, localization with accuracy compatible with targeted therapy remains impossible. Conventional optical endoscopy is now allied with multiple additional diagnostic modalities. Of these, ultrasound (US) has been argued to be most important [2] since it permits subsurface imaging of optically-opaque tissue. Its implementation is based on its nature as a safe, inexpensive, real-time technique deployed at the point of care. Resulting  * This research is supported by the UK EPSRC Sonopill Programme, ref. GR/K034537. It previously drew support from the EU Nanoporation project, ref. 230674. S.Cochran, D.Cumming, H.Lay and H.Mulvana are with the School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK (Phone: +44 141 330 3317); e-mail: sandy.cochran@glasgow.ac.uk).  data have been shown to be amenable to quantitative analysis in some situations and it carries therapeutic potential through ultrasound-mediated targeted drug delivery (UmTDD). II. PROPOSED PATIENT PATHWAY Important components in a multimodal diagnostic CE device include sensing and actuation devices, a battery power supply, and wireless communication circuitry and an antenna. A therapeutic device must additionally include a reservoir and release mechanism for the nanotechnological therapeutic agent and a targeting mechanism is likely to be essential for non-systemic therapies. The form of a typical CE device is a cylinder with spherical ends, overall length 30 mm, diameter 10 mm [3]. Hence, a solution comprising two or more separate devices in a theranostic combination may be needed to accommodate the proposed functions. This has the additional advantage that clinical validation may be incorporated in the procedure at the diagnostic stage, prior to therapy. The proposed patient pathway begins with a patient presenting with indications of a condition such as Crohn’s disease. The patient is subject to conventional diagnosis and a diagnostic CE device is administered if the diagnostic outcome is positive. This device generates optical and microultrasound (US) data identifying disease sites within the GI tract through quantitative analysis working at the nanoscale. These sites are marked with fluorescent nanoparticles using an US-mediated process. By reviewing the results manually, a clinician validates the diagnosis then administers a therapeutic CE device. This device can detect fluorescent markers but does not require diagnostic or more than minimal communication capabilities. Instead, available volume is used for a reservoir of a nanotherapeutic agent, a release mechanism, and US components to drive the agent towards the target and permeabilize the tissue to enhance uptake. Subsequently, a further CE device can be administered to verify disease response. The ability of CE devices to penetrate the full length of the gut in a minimally invasive manner thus allows closed loop diagnosis and therapy.  III. RELEVANT RESULTS Preliminary results have been obtained for some of the stages in the outline procedure and the prototype CE devices from which these results were obtained have demonstrated key components though the need for a local power supply and wireless communication was avoided with multimodal tethers. T.W.Button is with the School of Metallurgy and Materials, University of Birmingham, Birmingham, B15 2TT, UK. B.F.Cox, I.S.Näthke and F.Stewart are with the School of Life Sciences, University of Dundee, Dundee, DD1 4HN, UK. D.Gourevich was with the Institute for Medical Science and Technology, University of Dundee, Dundee, DD2 1FD, UK when she participated in the work described here. Nanotechnology in Multimodal Theranostic Capsule Endoscopy S.Cochran*, T.W.Button, B.F.Cox, D.R.S.Cumming, D.Gourevich,  H.S.Lay, H.Mulvana, I.S.Näthke and F.Stewart   Nevertheless, the prototype CE devices themselves conform to the maximum dimensions set by current clinical practice. A. Microultrasound Diagnosis and Quantitative Analysis US uses frequencies above the conventional diagnostic upper limit of 20 MHz. Through its reduced wavelength, it has been demonstrated that such high frequencies provide direct access to ultrasonic effects resulting from scattering from nanoscale acoustically-contrasting features. Following early results [4], an exploratory program based on US scanning of porcine tissue ex vivo with a typical frequency of 47 MHz is under way and has shown that the distinct layers within the GI tract can be imaged. The highly specialized single-element transducers for this work used 1-3 connectivity piezoceramic - polymer composite material made with micromoulding and casting processes. To avoid US artefacts whilst maintaining the sensitivity inherent in piezocomposites, these materials were designed with pseudo-random ceramic phase patterns [5]. These allow higher than usual frequencies to be achieved with viable ceramic dimensions. Additionally, successful in vivo testing has begun, with simpler piezopolymer transducers. To progress towards automated diagnosis, quantitative analysis of the scan data has been explored [6], focusing on measurement of acoustic impedance, attenuation and backscattering, with promising results presented in this paper. B. Fluorescence Marking and Imaging  To explore the marking process [7], experiments were performed on ex vivo murine and porcine tissue using fluorescent CdSeS/ZnS quantum dots (QDs) (Sigma-Aldrich, USA). These were directed towards the focal zone of a miniature high intensity focused US (HIFU) transducer operating at 4 MHz. The results presented in this paper show preferential concentration where the US was applied.  In the work outlined here, fluorescence imaging was based on the configuration of single-photon avalanche diode (SPAD) arrays with bespoke application-specific integrated circuits (ASICs) in miniaturized configurations for capsule deployment [8]. Successful demonstrations of both imaging and miniaturization are demonstrated. C. Therapeutic CE Device Feasibility To determine if the HIFU components for UmTDD can be incorporated in CE, and the extent of their capabilities, a prototype device was constructed. This included a confocal arrangement of: a HIFU source (Meggitt Sensing Systems, Kvistgaard, Denmark), diameter 4 mm, focal distance 6 mm, frequency 4 MHz; a miniature white light camera (Micro ScoutCam 1.2, Medigus, Omer, Israel), length 5 mm, diameter 1.2 mm; and a delivery channel for agents mimicking drugs and drug-delivery vehicles [9]. The prototype demonstrated that a stream of microbubbles could be directed towards a target based on US radiation force from the HIFU transducer, with an excitation level of 8 Vpp, compatible with the voltage amplitude that may be available in a CE device. Measuring transepithelial resistance in a model of the wall of the GI tract using Caco-2 cell monolayers showed that the same transducer with similar excitation levels could influence uptake in vitro [9]. D. Ultrasound-mediated Targeted Drug Delivery A typical use for the clinical procedure outlined above is to deliver drugs to treat localized disease within the GI tract in a targeted manner. With UmTDD, this involves three mechanisms [10]: packaging of the drug to passivate it so that systemic effects will be reduced; physical direction of the packaged drug towards the treatment site; and reduction in the permeability of the target to enhance uptake. Additionally, it may be necessary to disrupt the drug - package complex so that the drug may be released and taken up by cells. An approach explored by the authors is to combine a drug with a nanoscale, chemically-engineered package. This is demonstrated through work on the creation of a chemical complex comprising the chemotherapeutic drug doxorubicin (Dox) and γ-cyclodextrin. With Dox on its own as a control, it is shown that the chemical complex has a reduced effect on cells in vitro whereas mildly hyperthermic and cavitational effects of US compatible with use in the GI tract enhanced the effect of the drug when applied as a nanoscale complex [11].  IV. CONCLUSIONS A potential theranostic strategy for treatment of diseases of the GI tract based on the use of nanotechnology combined with CE has been outlined. This relies on US analysis of targets at the nanoscale, marking with nanoscale agents and delivery of nanoscale drug complexes for treatment. The clinical procedure involves multiple steps with development relying on multidisciplinary research. Progress in several directions is presented in this paper and further work is under way to demonstrate the viability of the procedure. REFERENCES [1] G.Iddan et al, “Wireless capsule endoscopy” Nature (Brief Comm) vol. 405, 2000, p. 417 [2] M.V.Sivak, “Gastrointestinal endoscopy: past and future” Gut vol. 55,  2006, pp. 1061 – 4 [3] Medtronic, ous.pillcamcolon.com, accessed 19th March, 2017 [4] A.Fatehullah et al, “Increased variability in ApcMin/+ intestinal tissue can be measured with microultrasound” Sci. Rep. vol. 6, 2016, article 29570 [5] Y. Jiang et al, “Micro-moulded randomised piezocomposites for high frequency ultrasound imaging” IEEE Int. Ultrasonics. Symp. Proc., 2012, DOI: 10.1109/ULTSYM.2012.0045 [6] H.S.Lay et al, “Microultrasound characterisation of ex vivo porcine tissue for ultrasound capsule endoscopy” J. Phys.: Conf. Series vol. 797, 2017, article 012003 [7] B.F.Cox et al, “Ultrasound facilitated marking of gastrointestinal tissue with fluorescent material” IEEE Int. Ultrasonics. Symp. Proc., 2016, DOI: 10.1109/ULTSYM.2016.7728782 [8] M.A.Al-Rawhani et al, “Wireless fluorescence capsule for endoscopy using single photon-based detection” Sci. Rep. vol. 5, 2015, article 18591 [9] F.W.Stewart et al, “SonoCAIT: Proof-of-Concept Ultrasound-enabled Therapeutic Capsule Endoscope” submitted to J. Med. Robotics Res., 2017 [10] F.W.Stewart et al, “Theranostics in the gut”, to appear in M.Thanou (ed.) Theranostics and Image Guided Drug Delivery, Royal Society of Chemistry, 2017, in press [11] D.Gourevich et al, “Ultrasound-mediated targeted drug delivery with a novel cyclodextrin-based drug carrier by mechanical and thermal mechanisms” J. Controlled Release vol. 170, 2013, pp. 316 - 24 

English

                                                                    University of DundeeNanotechnology in multimodal theranostic capsule endoscopyCochran, S.; Button, T. W.; Cox, B. F.; Cumming, D. R. S.; Gourevich, D.; Lay, H. S.Published in:2017 IEEE 17th International Conference on Nanotechnology, NANO 2017DOI:10.1109/NANO.2017.8117439Publication date:2017Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Cochran, S., Button, T. W., Cox, B. F., Cumming, D. R. S., Gourevich, D., Lay, H. S., Mulvana, H., Nathke, I. S.,& Stewart, F. (2017). Nanotechnology in multimodal theranostic capsule endoscopy. In 2017 IEEE 17thInternational Conference on Nanotechnology, NANO 2017 (pp. 434-435). Article 8117439 IEEE.https://doi.org/10.1109/NANO.2017.8117439General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 24. Sep. 2025   Abstract— Video capsule endoscopy (VCE) has become a clinically accepted diagnostic modality in the last 20 years and has established a technological roadmap for other capsule endoscopy (CE) devices, incorporating microscale technology, a local power supply and wireless communication. However, VCE does not provide a therapeutic function and research in therapeutic capsule endoscopy (TCE) has been limited. This paper proposes a new route towards viable TCE based on multiple CE devices including essential nanoscale components. A first device is used for multimodal diagnosis, with quantitative microultrasound as a complement to video imaging. Ultrasound-enhanced fluorescent marking of sites of pathology allows follow-up with a second device for therapy. This is based on fluorescence imaging and ultrasound-mediated targeted drug delivery. Subsequent treatment verification and monitoring with a third device exploits the minimally invasive nature of CE. Clinical implementation of a complete patient pathway remains the subject of research but several key components have been prepared in early prototype form. These are described, along with gaps that remain to be filled. I. INTRODUCTION Conventional endoscopy through oral and anal routes, respectively, provides routine access to the upper and lower parts of the gastrointestinal (GI) tract. Whilst these techniques are minimally invasive, subjects must attend hospital, require sedation, and have the procedure administered by highly skilled clinicians. Assessment of the full length of the GI tract with double-balloon enteroscopy is possible, but this is a non-routine procedure performed only in large healthcare centres. Video capsule endoscopy (VCE) [1] has been developed, introduced and accepted as a routine clinical procedure in the past 20 years. It is based on three areas of innovation linked to work in other fields: miniaturization of cameras and related electronic circuitry; minimal power consumption from a local battery; and wireless communication with a data logger. A fourth innovation, automated information extraction and interpretation is still a topic of research. Additionally, localization with accuracy compatible with targeted therapy remains impossible. Conventional optical endoscopy is now allied with multiple additional diagnostic modalities. Of these, ultrasound (US) has been argued to be most important [2] since it permits subsurface imaging of optically-opaque tissue. Its implementation is based on its nature as a safe, inexpensive, real-time technique deployed at the point of care. Resulting  * This research is supported by the UK EPSRC Sonopill Programme, ref. GR/K034537. It previously drew support from the EU Nanoporation project, ref. 230674. S.Cochran, D.Cumming, H.Lay and H.Mulvana are with the School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK (Phone: +44 141 330 3317); e-mail: sandy.cochran@glasgow.ac.uk).  data have been shown to be amenable to quantitative analysis in some situations and it carries therapeutic potential through ultrasound-mediated targeted drug delivery (UmTDD). II. PROPOSED PATIENT PATHWAY Important components in a multimodal diagnostic CE device include sensing and actuation devices, a battery power supply, and wireless communication circuitry and an antenna. A therapeutic device must additionally include a reservoir and release mechanism for the nanotechnological therapeutic agent and a targeting mechanism is likely to be essential for non-systemic therapies. The form of a typical CE device is a cylinder with spherical ends, overall length 30 mm, diameter 10 mm [3]. Hence, a solution comprising two or more separate devices in a theranostic combination may be needed to accommodate the proposed functions. This has the additional advantage that clinical validation may be incorporated in the procedure at the diagnostic stage, prior to therapy. The proposed patient pathway begins with a patient presenting with indications of a condition such as Crohn’s disease. The patient is subject to conventional diagnosis and a diagnostic CE device is administered if the diagnostic outcome is positive. This device generates optical and microultrasound (US) data identifying disease sites within the GI tract through quantitative analysis working at the nanoscale. These sites are marked with fluorescent nanoparticles using an US-mediated process. By reviewing the results manually, a clinician validates the diagnosis then administers a therapeutic CE device. This device can detect fluorescent markers but does not require diagnostic or more than minimal communication capabilities. Instead, available volume is used for a reservoir of a nanotherapeutic agent, a release mechanism, and US components to drive the agent towards the target and permeabilize the tissue to enhance uptake. Subsequently, a further CE device can be administered to verify disease response. The ability of CE devices to penetrate the full length of the gut in a minimally invasive manner thus allows closed loop diagnosis and therapy.  III. RELEVANT RESULTS Preliminary results have been obtained for some of the stages in the outline procedure and the prototype CE devices from which these results were obtained have demonstrated key components though the need for a local power supply and wireless communication was avoided with multimodal tethers. T.W.Button is with the School of Metallurgy and Materials, University of Birmingham, Birmingham, B15 2TT, UK. B.F.Cox, I.S.Näthke and F.Stewart are with the School of Life Sciences, University of Dundee, Dundee, DD1 4HN, UK. D.Gourevich was with the Institute for Medical Science and Technology, University of Dundee, Dundee, DD2 1FD, UK when she participated in the work described here. Nanotechnology in Multimodal Theranostic Capsule Endoscopy S.Cochran*, T.W.Button, B.F.Cox, D.R.S.Cumming, D.Gourevich,  H.S.Lay, H.Mulvana, I.S.Näthke and F.Stewart   Nevertheless, the prototype CE devices themselves conform to the maximum dimensions set by current clinical practice. A. Microultrasound Diagnosis and Quantitative Analysis US uses frequencies above the conventional diagnostic upper limit of 20 MHz. Through its reduced wavelength, it has been demonstrated that such high frequencies provide direct access to ultrasonic effects resulting from scattering from nanoscale acoustically-contrasting features. Following early results [4], an exploratory program based on US scanning of porcine tissue ex vivo with a typical frequency of 47 MHz is under way and has shown that the distinct layers within the GI tract can be imaged. The highly specialized single-element transducers for this work used 1-3 connectivity piezoceramic - polymer composite material made with micromoulding and casting processes. To avoid US artefacts whilst maintaining the sensitivity inherent in piezocomposites, these materials were designed with pseudo-random ceramic phase patterns [5]. These allow higher than usual frequencies to be achieved with viable ceramic dimensions. Additionally, successful in vivo testing has begun, with simpler piezopolymer transducers. To progress towards automated diagnosis, quantitative analysis of the scan data has been explored [6], focusing on measurement of acoustic impedance, attenuation and backscattering, with promising results presented in this paper. B. Fluorescence Marking and Imaging  To explore the marking process [7], experiments were performed on ex vivo murine and porcine tissue using fluorescent CdSeS/ZnS quantum dots (QDs) (Sigma-Aldrich, USA). These were directed towards the focal zone of a miniature high intensity focused US (HIFU) transducer operating at 4 MHz. The results presented in this paper show preferential concentration where the US was applied.  In the work outlined here, fluorescence imaging was based on the configuration of single-photon avalanche diode (SPAD) arrays with bespoke application-specific integrated circuits (ASICs) in miniaturized configurations for capsule deployment [8]. Successful demonstrations of both imaging and miniaturization are demonstrated. C. Therapeutic CE Device Feasibility To determine if the HIFU components for UmTDD can be incorporated in CE, and the extent of their capabilities, a prototype device was constructed. This included a confocal arrangement of: a HIFU source (Meggitt Sensing Systems, Kvistgaard, Denmark), diameter 4 mm, focal distance 6 mm, frequency 4 MHz; a miniature white light camera (Micro ScoutCam 1.2, Medigus, Omer, Israel), length 5 mm, diameter 1.2 mm; and a delivery channel for agents mimicking drugs and drug-delivery vehicles [9]. The prototype demonstrated that a stream of microbubbles could be directed towards a target based on US radiation force from the HIFU transducer, with an excitation level of 8 Vpp, compatible with the voltage amplitude that may be available in a CE device. Measuring transepithelial resistance in a model of the wall of the GI tract using Caco-2 cell monolayers showed that the same transducer with similar excitation levels could influence uptake in vitro [9]. D. Ultrasound-mediated Targeted Drug Delivery A typical use for the clinical procedure outlined above is to deliver drugs to treat localized disease within the GI tract in a targeted manner. With UmTDD, this involves three mechanisms [10]: packaging of the drug to passivate it so that systemic effects will be reduced; physical direction of the packaged drug towards the treatment site; and reduction in the permeability of the target to enhance uptake. Additionally, it may be necessary to disrupt the drug - package complex so that the drug may be released and taken up by cells. An approach explored by the authors is to combine a drug with a nanoscale, chemically-engineered package. This is demonstrated through work on the creation of a chemical complex comprising the chemotherapeutic drug doxorubicin (Dox) and γ-cyclodextrin. With Dox on its own as a control, it is shown that the chemical complex has a reduced effect on cells in vitro whereas mildly hyperthermic and cavitational effects of US compatible with use in the GI tract enhanced the effect of the drug when applied as a nanoscale complex [11].  IV. CONCLUSIONS A potential theranostic strategy for treatment of diseases of the GI tract based on the use of nanotechnology combined with CE has been outlined. This relies on US analysis of targets at the nanoscale, marking with nanoscale agents and delivery of nanoscale drug complexes for treatment. The clinical procedure involves multiple steps with development relying on multidisciplinary research. Progress in several directions is presented in this paper and further work is under way to demonstrate the viability of the procedure. REFERENCES [1] G.Iddan et al, “Wireless capsule endoscopy” Nature (Brief Comm) vol. 405, 2000, p. 417 [2] M.V.Sivak, “Gastrointestinal endoscopy: past and future” Gut vol. 55,  2006, pp. 1061 – 4 [3] Medtronic, ous.pillcamcolon.com, accessed 19th March, 2017 [4] A.Fatehullah et al, “Increased variability in ApcMin/+ intestinal tissue can be measured with microultrasound” Sci. Rep. vol. 6, 2016, article 29570 [5] Y. Jiang et al, “Micro-moulded randomised piezocomposites for high frequency ultrasound imaging” IEEE Int. Ultrasonics. Symp. Proc., 2012, DOI: 10.1109/ULTSYM.2012.0045 [6] H.S.Lay et al, “Microultrasound characterisation of ex vivo porcine tissue for ultrasound capsule endoscopy” J. Phys.: Conf. Series vol. 797, 2017, article 012003 [7] B.F.Cox et al, “Ultrasound facilitated marking of gastrointestinal tissue with fluorescent material” IEEE Int. Ultrasonics. Symp. Proc., 2016, DOI: 10.1109/ULTSYM.2016.7728782 [8] M.A.Al-Rawhani et al, “Wireless fluorescence capsule for endoscopy using single photon-based detection” Sci. Rep. vol. 5, 2015, article 18591 [9] F.W.Stewart et al, “SonoCAIT: Proof-of-Concept Ultrasound-enabled Therapeutic Capsule Endoscope” submitted to J. Med. Robotics Res., 2017 [10] F.W.Stewart et al, “Theranostics in the gut”, to appear in M.Thanou (ed.) Theranostics and Image Guided Drug Delivery, Royal Society of Chemistry, 2017, in press [11] D.Gourevich et al, “Ultrasound-mediated targeted drug delivery with a novel cyclodextrin-based drug carrier by mechanical and thermal mechanisms” J. Controlled Release vol. 170, 2013, pp. 316 - 24 

Button, T.W.

Cox, B.F.

Cumming, D.R.S.

Lay, H.S.

Nathke, I.S.

Enlighten

    Cochran, S. , Button, T.W., Cox, B.F., Cumming, D.R.S., Gourevich, D., Lay, H.S. , Mulvana, H., Nathke, I.S. and Stewart, F. (2017) Nanotechnology in Multimodal Theranostic Capsule Endoscopy. In: IEEE 17th International Conference on Nanotechnology (IEEE-NANO), Pittsburgh, PA, USA, 25-28 July 2017, pp. 434-435. ISBN 9781509030286  (doi:10.1109/NANO.2017.8117439)  This is the author’s final accepted version.  There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it.  http://eprints.gla.ac.uk/157143/                            Deposited on: 12 February 2018        Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk                          Proceedings of the 17th   IEEE International Conference on Nanotechnology               Pittsburgh, USA, July 25-28, 2017          S.Cochran*, T.W.Button, B.F.Cox, D.R.S.Cumming, D.Gourevich,   H.S.Lay, H.Mulvana, I.S.Näthke and F.Stewart   Abstract Video capsule endoscopy (VCE) has become a clinically accepted diagnostic modality in the last 20 years and has established a technological roadmap for other capsule endoscopy (CE) devices, incorporating microscale technology, a local power supply and wireless communication. However, VCE does not provide a therapeutic function and research in therapeutic capsule endoscopy (TCE) has been limited.  This paper proposes a new route towards viable TCE based on multiple CE devices including essential nanoscale components. A first device is used for multimodal diagnosis, with quantitative microultrasound as a complement to video imaging. Ultrasound-enhanced fluorescent marking of sites of pathology allows follow-up with a second device for therapy. This is based on fluorescence imaging and ultrasound-mediated targeted drug delivery. Subsequent treatment verification and monitoring with a third device exploits the minimally invasive nature of CE.  Clinical implementation of a complete patient pathway remains the subject of research but several key components have been prepared in early prototype form. These are described, along with gaps that remain to be filled.  I. INTRODUCTION  Conventional endoscopy through oral and anal routes, respectively, provides routine access to the upper and lower parts of the gastrointestinal (GI) tract. Whilst these techniques are minimally invasive, subjects must attend hospital, require sedation, and have the procedure administered by highly skilled clinicians. Assessment of the full length of the GI tract with double-balloon enteroscopy is possible, but this is a nonroutine procedure performed only in large healthcare centres.  Video capsule endoscopy (VCE) [1] has been developed, introduced and accepted as a routine clinical procedure in the past 20 years. It is based on three areas of innovation linked to work in other fields: miniaturization of cameras and related electronic circuitry; minimal power consumption from a local battery; and wireless communication with a data logger. A fourth innovation, automated information extraction and interpretation is still a topic of research. Additionally, localization with accuracy compatible with targeted therapy remains impossible.  Conventional optical endoscopy is now allied with multiple additional diagnostic modalities. Of these, ultrasound (US) has been argued to be most important [2] since it permits subsurface imaging of optically-opaque tissue. Its implementation is based on its nature as a safe, inexpensive, real-time technique deployed at the point of care. Resulting    * This research is supported by the UK EPSRC Sonopill Programme, ref. GR/K034537. It previously drew support from the EU Nanoporation project, ref. 230674.  S.Cochran, D.Cumming, H.Lay and H.Mulvana are with the School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK (Phone: +44 141 330 3317); e-mail: sandy.cochran@glasgow.ac.uk).   data have been shown to be amenable to quantitative analysis in some situations and it carries therapeutic potential through ultrasound-mediated targeted drug delivery (UmTDD).  II. PROPOSED PATIENT PATHWAY  Important components in a multimodal diagnostic CE device include sensing and actuation devices, a battery power supply, and wireless communication circuitry and an antenna. A therapeutic device must additionally include a reservoir and release mechanism for the nanotechnological therapeutic agent and a targeting mechanism is likely to be essential for non-systemic therapies. The form of a typical CE device is a cylinder with spherical ends, overall length 30 mm, diameter 10 mm [3]. Hence, a solution comprising two or more separate devices in a theranostic combination may be needed to accommodate the proposed functions. This has the additional advantage that clinical validation may be incorporated in the procedure at the diagnostic stage, prior to therapy.  The proposed patient pathway begins with a patient presenting with indications of  &%"*"&% )+! ) (&!%4) disease. The patient is subject to conventional diagnosis and a  diagnostic CE device is administered if the diagnostic outcome is positive. This device generates optical and microultrasound (US) data identifying disease sites within the GI tract through quantitative analysis working at the nanoscale. These sites are marked with fluorescent nanoparticles using an US-mediated process. By reviewing the results manually, a clinician validates the diagnosis then administers a therapeutic CE device. This device can detect fluorescent markers but does not require diagnostic or more than minimal communication capabilities. Instead, available volume is used for a reservoir of a nanotherapeutic agent, a release mechanism, and US components to drive the agent towards the target and permeabilize the tissue to enhance uptake.  Subsequently, a further CE device can be administered to verify disease response. The ability of CE devices to penetrate the full length of the gut in a minimally invasive manner thus allows closed loop diagnosis and therapy.   III. RELEVANT RESULTS  Preliminary results have been obtained for some of the stages in the outline procedure and the prototype CE devices from which these results were obtained have demonstrated key components though the need for a local power supply and wireless communication was avoided with multimodal tethers.  T.W.Button is with the School of Metallurgy and Materials, University of Birmingham, Birmingham, B15 2TT, UK.  B.F.Cox, I.S.Näthke and F.Stewart are with the School of Life Sciences, University of Dundee, Dundee, DD1 4HN, UK.  D.Gourevich was with the Institute for Medical Science and Technology, University of Dundee, Dundee, DD2 1FD, UK when she participated in the work described here.     Nevertheless, the prototype CE devices themselves conform to the maximum dimensions set by current clinical practice.  A. Microultrasound Diagnosis and Quantitative Analysis  US uses frequencies above the conventional diagnostic upper limit of 20 MHz. Through its reduced wavelength, it has been demonstrated that such high frequencies provide direct access to ultrasonic effects resulting from scattering from nanoscale acoustically-contrasting features. Following early results [4], an exploratory program based on US scanning of porcine tissue ex vivo with a typical frequency of 47 MHz is under way and has shown that the distinct layers within the GI tract can be imaged. The highly specialized single-element transducers for this work used 1-3 connectivity piezoceramic - polymer composite material made with micromoulding and casting processes. To avoid US artefacts whilst maintaining the sensitivity inherent in piezocomposites, these materials were designed with pseudo-random ceramic phase patterns [5]. These allow higher than usual frequencies to be achieved with viable ceramic dimensions. Additionally, successful in vivo testing has begun, with simpler piezopolymer transducers.  To progress towards automated diagnosis, quantitative analysis of the scan data has been explored [6], focusing on measurement of acoustic impedance, attenuation and backscattering, with promising results presented in this paper. B. Fluorescence Marking and Imaging   To explore the marking process [7], experiments were performed on ex vivo murine and porcine tissue using fluorescent CdSeS/ZnS quantum dots (QDs) (Sigma-Aldrich, USA). These were directed towards the focal zone of a miniature high intensity focused US (HIFU) transducer operating at 4 MHz. The results presented in this paper show preferential concentration where the US was applied.   In the work outlined here, fluorescence imaging was based on the configuration of single-photon avalanche diode (SPAD) arrays with bespoke application-specific integrated circuits (ASICs) in miniaturized configurations for capsule deployment [8]. Successful demonstrations of both imaging and miniaturization are demonstrated.  C. Therapeutic CE Device Feasibility  To determine if the HIFU components for UmTDD can be incorporated in CE, and the extent of their capabilities, a prototype device was constructed. This included a confocal arrangement of: a HIFU source (Meggitt Sensing Systems, Kvistgaard, Denmark), diameter 4 mm, focal distance 6 mm, frequency 4 MHz; a miniature white light camera (Micro ScoutCam 1.2, Medigus, Omer, Israel), length 5 mm, diameter 1.2 mm; and a delivery channel for agents mimicking drugs and drug-delivery vehicles [9].  The prototype demonstrated that a stream of microbubbles could be directed towards a target based on US radiation force from the HIFU transducer, with an excitation level of 8 Vpp, compatible with the voltage amplitude that may be available in a CE device. Measuring transepithelial resistance in a model of the wall of the GI tract using Caco-2 cell monolayers showed that the same transducer with similar excitation levels could influence uptake in vitro [9].  D. Ultrasound-mediated Targeted Drug Delivery  A typical use for the clinical procedure outlined above is to deliver drugs to treat localized disease within the GI tract in a targeted manner. With UmTDD, this involves three mechanisms [10]: packaging of the drug to passivate it so that systemic effects will be reduced; physical direction of the packaged drug towards the treatment site; and reduction in the permeability of the target to enhance uptake. Additionally, it may be necessary to disrupt the drug - package complex so that the drug may be released and taken up by cells.  An approach explored by the authors is to combine a drug with a nanoscale, chemically-engineered package. This is demonstrated through work on the creation of a chemical complex comprising the chemotherapeutic drug doxorubicin (Dox) and 5-cyclodextrin. With Dox on its own as a control, it is shown that the chemical complex has a reduced effect on cells in vitro whereas mildly hyperthermic and cavitational effects of US compatible with use in the GI tract enhanced the effect of the drug when applied as a nanoscale complex [11].   IV. CONCLUSIONS  A potential theranostic strategy for treatment of diseases of the GI tract based on the use of nanotechnology combined with CE has been outlined. This relies on US analysis of targets at the nanoscale, marking with nanoscale agents and delivery of nanoscale drug complexes for treatment. The clinical procedure involves multiple steps with development relying on multidisciplinary research. Progress in several directions is presented in this paper and further work is under way to demonstrate the viability of the procedure.  REFERENCES  [1] G.Iddan et al, 1"(#))')+#%&)&'/3*+((" &$$ vol. 405, 2000, p. 417  [2] M.V.Sivak, 1)*(&"%*)*"%#%&)&'/ ')*%+*+(3Gut vol. 55,   2006, pp. 1061 0 4  [3] Medtronic, ous.pillcamcolon.com, accessed 19th March, 2017  [4] *!+##!*#1Increased variability in ApcMin/+ intestinal tissue can be measured with microultrasound3"',&# 6, 2016, article  29570  [5] Y. Jiang et al, 1"(&-moulded randomised piezocomposites for high frequency +#*()&+%"$ "% 3 IEEE Int. Ultrasonics. Symp. Proc., 2012, DOI: 10.1109/ULTSYM.2012.0045  [6] /*#1"(&+#*()&+%!(*(")*"&%&.,",&'&("% *"))+&(+#*()&+%')+#%&)&'/3 J. Phys.: Conf. Series vol. 797, 2017, article 012003  [7] B.F.Cox et al1Ultrasound facilitated marking of gastrointestinal tissue with fluorescent material3 IEEE Int. Ultrasonics. Symp. Proc., 2016, DOI: 10.1109/ULTSYM.2016.7728782  [8] M.A.Al--!%"*#1Wireless fluorescence capsule for endoscopy using single photon-based detection3"',&#  (*"# 18591  [9] *-(**#1SonoCAIT: Proof-of-Concept Ultrasound-enabled  Therapeutic Capsule Endoscope3)+$"***&&&*")) 2017  [10] *-(**#1!(%&)*"s "%*! +*3to appear in M.Thanou  (ed.) Theranostics and Image Guided Drug Delivery, Royal Society of Chemistry, 2017, in press  [11] D.Gourevich et al, 1#*()&+%-mediated targeted drug delivery with a novel cyclodextrin-based drug carrier by mechanical and thermal $!%")$)3 &%*(&###)vol. 170, 2013, pp. 316 - 24   

Nanotechnology in Multimodal Theranostic Capsule Endoscopy

https://discovery.dundee.ac.uk/ws/files/20158425/170514_Nanotechnology_in_Multimodal_Theranostic_Capsule_Endoscopy_Fina..._5b1_5d.pdf

Nanotechnology in multimodal theranostic capsule endoscopy

Abstract

Similar works

Full text

Available Versions

Crossref

Discovery Research Portal

Discovery Research Portal

Discovery Research Portal

Enlighten