Low cost nanowire diagnostic platform

Lead Research Organisation: University of Southampton
Department Name: Electronics and Computer Science

Abstract

Laboratory tests are a vital and growing part of the accurate diagnosis of a patient's condition, with around 1 billion tests performed in the UK each year. With the expansion of interest in evidence-based medicine, laboratory tests are increasingly used to tailor individual treatment plans according to need, to monitor disease progression, to stratify risk, and for population screening programs. To enable the routine application of predictive, preventative and personalized healthcare, these biochemical tests need to be performed at a large scale, at low cost, and preferably also at point-of-need locations rather than exclusively in clinical laboratories. The realization of this socio-economically highly desirable situation
necessitates the development of new, more cost-effective, technologies for the quantification of molecules that are biomarkers for the diagnosis and management of specific diseases.

The project aim is to develop a point-of-care (PoC) nanowire diagnostic system to measure inflammatory biomarkers found in a small droplet of blood, and builds on results from EPSRC Nanotechnology for Healthcare project EP/6061696/1. The project will develop a low-cost nanowire platform technology with integrated sample processing. Nanowire fabrication will use a novel top down process and temperatures low enough for large scale manufacture on inexpensive glass or polymer substrates.

Our target application is the diagnosis and management of respiratory diseases, including COPD (chronic obstructive pulmonary disease) and asthma, that are often exacerbated by viral infections. Using a translational approach, we will focus on the detection of a number of clinically relevant protein biomarkers of viral infection and treatment. Viral infections
trigger an immune response characterized by expression of the antiviral interferons and their down stream response genes (e.g. interferon-inducible protein 10 and beta2-microglobulin) or activation markers such as neopterin. These can be used as early biomarkers of infection, or to evaluate or predict the clinical response to antiviral therapy with interferon-alpha or beta, which are often measured in conjunction with detection of neutralizing antibodies. Tumor necrosis factor alpha (TNFa) and the acute phase protein, C-reactive protein (CRP), are also used as biomarkers of inflammation linked to infective exacerbations. The nanowire arrays will be used to quantify levels of CRP, TNFa, neopterin, IP-10 and beta2-microglobulin (nanowire functionalization with specific antibodies) and levels of antibodies to interferon-beta (functionalization with interferon-beta itself). The project will also explore the potential of DNA aptamers as synthetic antibodies, a more costeffective and nanowire-compatible approach than classical protein antibodies. Many diseases do not have a single biomarker that correlates with disease state, hence the need to use a panel of biomarkers for more accurate diagnosis and management of disease.

The project will have unique access to clinical samples -serum and induced sputum- obtained from patients admitted to the Acute Medical Unit at Southampton General Hospital suffering from acute asthma exacerbations, 60-80% of which are triggered by a respiratory virus, and following their recovery. We will also have access to serum samples from asthmatic
volunteers undergoing Phase I clinical trials using inhaled interferon-beta which is being developed for treatment of virusinduced asthma exacerbations. Results will be directly compared against data obtained using traditional methods (ELISA) and to clinical outcomes (e.g. respiratory virus detection, exacerbation severity, response to treatment).

Planned Impact

Laboratory tests are a vital part of the accurate diagnosis of a patient's condition, with around 1 billion tests performed in the UK each year. Laboratory tests can also be used to tailor individual treatment plans according to need, to monitor disease progression, to stratify risk, and for population screening programs. This project seeks to enable the routine application of predictive, preventive and personalized healthcare by performing biochemical tests at a much larger scale, at
much lower cost, and at point-of-care locations. The project will realize this socio-economically highly desirable situation by developing a new, more cost-effective, technology for the quantification of macromolecular biomarkers.

The project builds on state-of-the-art research carried out in EPSRC project EP/6061696/1, which demonstrated titration curves for two inflammatory biomarkers, IL-8 and TNF-a on polysilicon nanowires. The proposed TSB project aims to demonstrate multiplexed biosensing of up to ten inflammatory biomarkers in real blood. The achievement of this goal will be a world first and will represent a major advance on the state-of-the-art. This achievement will not only generate a high
academic impact, but will also be a major step on the path to the commercial exploitation of nanowire biosensing technologies.

The global market for biosensors in home care and home diagnostics was around $4.5bn in 2009 and is predicted to double by 2016. The existing Point of Care market is dominated by self monitoring blood glucose and coagulation and there is considerable scope to develop this market by extending the Point of Care capability to include common chronic diseases such as respiratory diseases. Approximately 10% of the population of the industrial world suffers from asthma and
this percentage has been increasing in recent years. This project directly addressing the design of biosensors for the diagnosis and management of respiratory disease and hence the economic impact of the project is clear. Furthermore, the approach used in the project has wider application than just respiratory disease and hence could be rolled out to address the diagnosis and management of a wide range of other diseases.

This project will have a direct economic impact on the companies involved in the project. Sharp is a multinational company with a strong capability in thin film technology for displays. Sharp Lab Europe is tasked with the development of new technologies for the healthcare market and hence this project directly impacts this mission. OIPT is a leading UK manufacturer of plasma tools for the worldwide R&D market and is interested in selling tools and processes into the rapidly expanding healthcare sensor market. This project aims to develop a biosensor process using a suite of OIPT tools and will therefore enable OIPT to address this new market. Aptamer Solutions is an SME that develops aptamers for application in biosensing. Their involvement in this project will allow them to develop synthetic antibodies for use in the diagnosis and management of respiratory diseases.

Publication and dissemination pathways will include publication in leading peer reviewed journals. Engagement with the wider public will be through the University and company marketing departments. EPSRC project EP/6061696/1 has already received extensive media coverage, including an item on BBC South Today and an article in the Daily Telegraph. High quality media training of researchers will be provided to the researchers involved in this project. Dissemination to end users and industry will be through KTN events and similar networking meetings. The Southampton Nanofabrication Centre also holds an annual Industry Day for the dissemination of research results to a broad range of industry. Dissemination to OIPT customers will be achieved through Workshops, which are held annually and organized by the OIPT marketing team.
 
Description The research discovered new methods to manufacture electronic sensors using low temperature and low cost processes as used by the consumer electronics industry to make Thin Film Transistors. This means that we can make high specification transistors at low cost, so that they can be used for disposable systems. These devices are used to measure the binding of molecules to the transistor surface. We have shown that the transistors can quickly and accurately measure the binding of proteins in human serum and also to monitor enzyme behaviour. Recently we demonstrated that the transistor can be used to detect the amplification of DNA in a very rapid manner using chemistry that works at room temperature. We were able to detect the presence of genes that confer antibiotic resistance to bacteria at the level of a single molecule. The project is in collaboration with three companies: Sharp Labs Europe, Oxford Instruments Plasma Technology and Aptamer Diagnostics.
Exploitation Route The findings will to be taken up by a large electronics company such as Sharp Labs to develop new health care and diagnostic products based on solid-state electronics biosensors. Eventually these devices should see their way into the NHS and into home diagnostics and monitoring kits.
Sectors Agriculture, Food and Drink,Environment,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description OIPT 
Organisation Oxford Instruments Plasma Technology
Country United Kingdom 
Sector Private 
PI Contribution Provision of tools and methods for plasma deposition of dielectrics. Test and characterisation of wafers.
Collaborator Contribution Supply of wafers; knowledge and recipes for in-situ doped p-Si deposition
Impact Commercial outputs are confidential
Start Year 2012
 
Description Public Health England (PHE) 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution We have worked with PHE to develop new low-cost technologies capable of highly sensitive analysis of the response of bacteria to antibiotics. The tests (called phenotypic) measure whether a surrogate antibiotic affects a particular organism. It is anticiapted that these tests could be used to screen patients for resistance to third generation antibiotics.
Collaborator Contribution PHE have provided new chemistry and access to rare antibiotic resistant organisms. They have also developed a suit of probes and primers for our genetic test platform
Impact Multi-disciplinary collaboration which has lead to the development of a new type of diagnostic test for antimicrobial resistance in urinary tract infections. The test targets b-lactam antibiotic resistance, particularly ESBL and Carbapenem resistant organisms.
Start Year 2013
 
Description SLE 
Organisation Sharp Laboratories of Europe Ltd
Country United Kingdom 
Sector Private 
PI Contribution The development of microfluidics systems and processes. Methods and know-how in analytical chemistry for detection of proteins and amplification of DNA
Collaborator Contribution Design, fabrication and development of thin film transistor (TFT) devices made in factories in Japan
Impact Company confidential
Start Year 2013
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 50 members of the public attended a science dissemination event organised in local pubs. The presentations sparked a great deal of interest in diagnostic technologies and significantly changed the public's view on science research
Year(s) Of Engagement Activity 2016
URL https://pintofscience.co.uk/event/honey-i-shrunk-the-lab-