Point of care nanotechnology for early blood clot detection and characterisation in disease screening, theranostic and self monitoring applications
Lead Research Organisation:
University College London
Department Name: Pharmaceutics
Abstract
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Organisations
- University College London (Lead Research Organisation)
- ETH Zurich (Collaboration)
- Eindhoven University of Technology (Collaboration)
- SWANSEA UNIVERSITY (Collaboration)
- Helmholtz Zentrum München (Collaboration)
- Hemair Systems (Collaboration)
- Walgreens Boots Alliance (United Kingdom) (Project Partner)
- Swansea Bay University Health Board (Project Partner)
Publications
Al-Jamal KT
(2011)
Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing.
in Proceedings of the National Academy of Sciences of the United States of America
A, Servant (Author)
(2013)
Graphene hydrogel hybrids: biomaterials with higher capabilities?
in ACS Nano
Laura Methven (Author)
(2013)
Modified MWNT show reduced hemolytic effect and do not induce anemia in vivo.
in Small
Zhao W
(2010)
Preparation of graphene by exfoliation of graphite using wet ball milling
in Journal of Materials Chemistry
| Description | Electro-responsive polymer matrices were developed as the therapeutic component of the first point of care (POC) device capable of the early detection and characterisation of abnormal clots. Stimuli-responsive hydrogel hybrids were engineered to allow the device to perform a therapeutic function, and to deliver drug in a pulsatile manner, remotely controlled by the ON/OFF application of an electric voltage generated by the device when the detection of a clot occurs. The drug delivery system is composed of multi-walled carbon nanotubes (MWNTs) incorporated in an electro-responsive hydrogel matrix such as poly (methyl methacrylate) (PMAA). The use of MWNTs considerably improved the sensitivity and response of the hydrogel hybrids to the applied electric field compared to the hydrogels without MWNTs. The pulsatile release of a model drug in the blood upon the application of the electric field was also demonstrated in vivo when the hybrid gels were subcutaneously implanted in mice. The MWNT hybrid gels demonstrated higher drug release and sharper responses to the electric field, significantly outperforming the blank gel during the same time period and under the same conditions of stimulation. An optimisation of the system was explored by using graphene sheets as nanofillers of the PMAA hydrogel matrix. These novel graphene gel hybrids demonstrated higher drug release capabilities than the MWNT hybrid gels. A systemic model of thrombosis was selected to enable comparison with clinical blood samples and lay the groundwork for point-of-care device testing. Intravenous injection of thrombin was used to induce a widespread prothrombotic state without causing animal death and reduced occurrence of stroke compared to other methods to induce systemic thrombosis. The thrombin-induced systemic model was characterised and compared to healthy animals using a wide range of techniques. Traditional methods were used in conjunction with our haemorheological technique for the early detection and characterisation of blood clots. The prothrombotic state of the disease model was confirmed by: platelet aggregate formation (full blood profile); a 4-fold increase in the number of activated platelets (flow cytometry); a ten-fold increase in thrombin-antithrombin levels (ELISA); observation of more compact fibrin networks in the clot structure (scanning electron microscopy) and thromboembolisms (histological analysis). Together these data confirm that this in vivo model is prothrombotic. Employing our haemorheological technique, clotting time was reduced by half and the mature clot was 2.5 times more rigid in structure in blood from the disease model. This is the first time that haemorheological measurements have been made in mouse. It is possible to measure blood samples from both healthy and diseased mice. This in vivo model of thrombosis is suitable for validation of the point-of-care device. |
| Exploitation Route | Work under the grant involving samples of blood was conducted principally in collaboration with our partner, ABMU NHS Trust at the NHS Morriston Hospital EPSRC-NHS Clinical Haemorheology Labaoratory (opened in 2005). The routes for exploiting such sensitive and stimuli-responsive delivery systems for industrial applications rely on the capacity of these gels to be easily attached on, and form a part of the device developed for early clot detection. The pulsatile delivery of anticoagulant agents such as heparin or warfarin could be generated subsequently to the early detection of a clot combining diagnosis and therapy in a single device. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| URL | http://www.nanomedicinelab.com/cooperation-and-support/collaborations/ |
| Description | The significant clinical (screening and monitoring) potential of the new haemorheological biomarkers exploited in the work under report led to the award of £1.5M in 2011 to establish a new Haemostasis Biomarker Research Unit at Morriston NHS Hospital. Within this new Unit the prototype/proof of concept point of care rheometrical devices developed during the work under report are being assessed and validated alongside conventional haemorheological and clot assay techniques, with 9 new staff appointments (Clinical Fellows, Clinical Haemorheologists and Research Nurses) taking the technology from the laboratory to use at the point of care in (i) operating theatres; (ii) treatment rooms and (iii) on patient wards, in collaboration with partner NHS Consultants in seven carefully chosen Care Pathways (including stroke, sepsis, diabetes, cancer and trauma). In addition, these point of care assessment/validation studies include the effects of fluid dilution, temperature change and aniplatelt therapy including aspirin). |
| Sector | Cultural,Policy & Public Services |
| Impact Types | Cultural |
| Description | Engineering Responsive Nanomaterials for Pulsatile Neural Regeneration |
| Amount | £117,753 (GBP) |
| Funding ID | EP/K001558/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2012 |
| End | 12/2013 |
| Title | Subcutaneous gel release model |
| Description | Subcutaneous implantation of hybrid gel, stimulation of drug release by electrical stimulation and subsequent blood sampling and analysis. |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Provided To Others? | No |
| Impact | Subsequent studies from other laboratories have repeated the experimental method described with success |
| Title | Systemic thrombosis mouse model |
| Description | Intravenous injection of 5U/ml thrombin into mouse tail vein to induce a procoagulant state. |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Provided To Others? | No |
| Impact | N/A |
| Description | Development of new device. |
| Organisation | Hemair Systems |
| Country | India |
| Sector | Private |
| PI Contribution | 1 day visit to Swansea University for discussions with Biotech company, Hemair, and Rhodri Williams regarding the development of a new device. |
| Start Year | 2010 |
| Description | Development of wireless drug delivery system with magnetic field actuation Description * |
| Organisation | ETH Zurich |
| Department | Institute of Robotics and Intelligent Systems |
| Country | Switzerland |
| Sector | Academic/University |
| PI Contribution | A navigatable and wirelessly actuated by a magnetic field polymer matrix was engineered and developed for controlled and targeted drug delivery. |
| Start Year | 2011 |
| Description | Functionalisation of carbon based nanomaterials with contrast agents for diagnosis using the MRI technique |
| Organisation | Eindhoven University of Technology |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | Collaboration with Department of Biomedical Engineering in Eindhoven University of Technology for the functionalisation of carbon based nanomaterials with contrast agents for diagnosis using the MRI technique. |
| Start Year | 2010 |
| Description | The effect of carbon nanotubes on rheological properties |
| Organisation | Swansea University |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | 2 day visit to Swansea University to perform haemorheological experimentation in human blood with Karl Hawkins. The effect of carbon nanotubes on rheological properties was examined. |
| Start Year | 2011 |
| Description | Track nanoparticles in vivo |
| Organisation | Helmholtz Zentrum München |
| Department | Institute for Biological and Medical Imaging |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | 5 day visit to the Institute for Biological and Medical Imaging (IBMI), Helmholtz Centre, Munich to track nanoparticles in vivo using multi-spectral optoacoustic technology. |
| Start Year | 2012 |
| Title | Development of wireless drug delivery system with magnetic field actuation |
| Description | A navigatable and wirelessly actuated by a magnetic field polymer matrix was engineered and developed for controlled and targeted drug delivery. |
| Type Of Technology | New/Improved Technique/Technology |
| Year Produced | 2012 |
| Impact | Further studies on magnetic actuation of micro- and nano-particles |
| Title | Haemorheological technique in mouse blood |
| Description | Haemorheological measurements have not been performed previously. The technique used for human blood was adapted for use small volumes of mouse blood sample (approx 600ul). This has made it possible to compare haemorheological data from mouse to clinical samples. Dr Methven did the adaptation of human technique and development of protocol for heamorheological technique in mouse blood experiments. Dr Karl Hawkins did the rheological training, development of protocol for heamorheological technique in mouse blood experiments. |
| Type Of Technology | New/Improved Technique/Technology |
| Year Produced | 2012 |
| Impact | Preclinical evidence to educate clinical trial design |
| Title | Injectable hydrogel hybrids for controlled drug delivery |
| Description | An injectable electro-responsive hybrid polymeric implant for the pulsatile and targeted delivery in the brain of Retinoic acid (RA), a growth factor that plays a crucial role in neuron patterning, differentiation and survival in the brain was developed. |
| Type Of Technology | Systems, Materials & Instrumental Engineering |
| Year Produced | 2012 |
| Impact | Prototype for future studies |
| Title | MWNT/Graphene Hydrogel hybrids |
| Description | PMAA-MWNT hydrogel hybrids were fabricated by in-situ radical polymerisation; the concentration of multi walled carbon nanotubes (MWNTs) and of the cross-linker was optimised in order to obtain hydrogels with enhanced responses to the electric field. The incorporation of MWNTs within the polymeric network, confirmed by SEM, improved the physical properties of the hybrids by decreasing significantly the bulk resistivity of the polymeric matrix and improving the thermal properties of the polymeric matrix. |
| Type Of Technology | New Material/Compound |
| Year Produced | 2012 |
| Impact | N/A |
| Title | Mimicking clinical experiments with mouse blood |
| Description | High-specification rheometer was transported to and used at School of Pharmacy for mouse blood samples to mimic the clinical data obtained at Swansea University and CHL Morriston Hospital. |
| Type Of Technology | New/Improved Technique/Technology |
| Year Produced | 2012 |
| Impact | Prototype for clinical trial design |
| Title | Novel MEMS druge delivery device |
| Description | A novel MEMS based drug delivery device has been developed, consisting of an array of metallic contacts on silicon and Pyrex glass wafers. The meander structured device creates a uniform electric field which stimulates drug release. An electro-active hydrogel based polymer matrix has also been developed, which responds to an electrical stimulus and shrinks or de-swells on application of an electric field from the fabricated device. Different drug candidates can be encapsulated within the polymer matrix. The de-swelling of the polymer enables the encapsulated drug to be released from the matrix. |
| Type Of Technology | Physical Model/Kit |
| Year Produced | 2011 |
| Impact | Prototype for further industrial development |
| Description | Nanomedicine Lab website |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Industry/Business |
| Results and Impact | The Nanomedicine Lab describes the in its website the project and the acknowledges its contribution to advance the research conducted. |
| Year(s) Of Engagement Activity | 2009 |
| URL | http://www.nanomedicinelab.com/cooperation-and-support/collaborations/ |
| Description | Nanonews Net on the PNAS article |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | http://www.nanonewsnet.ru/news/2011/dlya-lecheniya-ishemicheskogo-insulta-vpervye-oprobovany-uglerodnye-nanotrubki-dostavlyayu. |
| Year(s) Of Engagement Activity | 2011 |
| URL | http://www.nanonewsnet.ru/news/2011/dlya-lecheniya-ishemicheskogo-insulta-vpervye-oprobovany-uglerod... |
| Description | Nanotubes inject stroke therapy into rats' brains |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | http://www.rsc.org/chemistryworld/News/2011/June/21061102.asp. |
| Year(s) Of Engagement Activity | 2011 |
| URL | http://www.rsc.org/chemistryworld/News/2011/June/21061102.asp |
| Description | Talk softly but carry a tiny stick: Stroke prevention and recovery with nanotube-delivered siRNA |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | http://medicalxpress.com/news/2011-07-softly-tiny-recovery-nanotube-delivered-sirna.html . |
| Year(s) Of Engagement Activity | 2011 |
| URL | http://medicalxpress.com/news/2011-07-softly-tiny-recovery-nanotube-delivered-sirna.html |