Development of an Enzymatic Organic Electrochemical Transistor for Studying Cerebral Cholesterol Metabolism in Alzheimer's Pathology

Alzheimer's disease (AD) affects more than 50 million people worldwide and is expected to affect three times more people by 2050. AD is the most common form of dementia and causes progressive decline of neurons in the brain, which leads to memory impairment, decline in language and problem-solving skills. Recent studies show that dysfunction in cerebral cholesterol metabolism is directly linked to AD pathogenesis. Moreover, there is a significant change in cholesterol metabolism in the cerebral spinal fluid (CSF) of AD's patients. However, the current laboratory methods used for analysis of CSF cholesterol impose limitations to experiments because they are complex, expensive, and time-consuming. Therefore, in this PhD project, a novel method for measuring cerebral cholesterol from CSF is proposed. Organic polymer electrochemical transistors (OECTs) will be used as point-of-care (POC) biosensors, which can outperform current clinical detection methods. This will offer a fast, easily accessible, and reliable in-vitro method to study whether cholesterol in CSF can act as an early biomarker of AD.

The first aim of the project is to design and fabricate an in-vitro biosensor to investigate the role of cholesterol's metabolism in the spread of AD in the brain. This will be achieved through treating cell cultures and samples with different cerebral cholesterol concentrations and using high resolution imaging to investigate the effect of cholesterol metabolism on AD's biomarkers. The second aim of the project is to develop the OECT biosensor into a point-of-care device, which can perform reliable monitoring of the cerebral cholesterol's concentration from CSF sample at the time of the medical consultation to help patients recognise the risk of developing AD at the early stages. For this purpose, the fabricated organic electrochemical transistors will be biofunctionalised with redox enzymes that are specific for cerebral cholesterol and are safe and reliable for long-term use.

In this project, OECTs with a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) channel will be fabricated by processes such as layer deposition, lithography, etching, and spin-coating. PEDOT:PSS is one of the most promising bioelectronics materials due to its combined ionic and electronic charge, leading to huge signal amplification, outperforming most transistors. Moreover, it is very stable in aqueous media, which makes it very suitable for detection of cholesterol in CSF. Techniques for biofunctionalising the gate with different cholesterol oxidases including nanoparticles and artificial mediators will be investigated for achieving optimum response time and high selectivity. Then the accuracy of the OECTs will be tested by using CSF samples. Finally, they will be applied in real-time experiments to investigate the correlation between AD's pathology and cerebral cholesterol. Thus, OECTs hold a great potential for POC, which can address the challenges imposed by the current complex and time-consuming clinical methods for quantifying CSF cholesterol.



Thus, at the end of this project, a novel biosensor for measuring CSF cholesterol will be produced, aligning with the strategies of sensors and instrumentation to incorporate a new advanced device to provide a future with better healthcare and diagnosis. The implementation of the project will be based on knowledge and ideas from microelectronic device technology in healthcare since it incorporates a low-power design of the OECTs microelectronic devices by novel technologies and materials such as the PEDOT:PSS organic polymer and nanoparticles. The vision of this project aligns fully with the ideas from clinical technologies research area since it focuses on developing a novel POC device for diagnosis and monitoring of AD and thus improves health and care by proposing a novel, reliable and fast sensing technology.

The primary outputs from the CDT will be cohorts of highly qualified, interdisciplinary postgraduates who are experts in a wide range of sensing activities. They will benefit from a world leading training experience that recognises sensor research as an academic discipline in its own right. The students will be taught in all aspects of Sensor Technologies, ranging from the physical and chemical principles of sensing, to sensor design, data capture and processing, all the way to applications and opportunities for commercialisation, with a strong focus in entrepreneurship, technology translation and responsible leadership. Students will learn in extensive team and cohort engaging activities, and have access to cutting-edge expertise and infrastructure. 90 academics from 15 different departments participate in the programme and more than 40 industrial partners are actively involved in delivering research and business leadership training, offering perspectives for impact and translation and opportunities for internships and secondments. End users associated with the CDT will benefit from the availability of outstanding, highly qualified and motivated PhD students, access to shared infrastructure, and a huge range of academic and industrial contacts.

Immediate beneficiaries of our CDT will be our core industrial consortium partners (MedImmune, Alphasense, Fluidic Analytics, ioLight, NokiaBell, Cambridge Display Technologies, Teraview, Zimmer and Peacock, Panaxium, Silicon Microgravity, etc., see various LoS) who incorporate our cross-leverage funding model into their corporate research strategies. Small companies and start-ups particularly benefit from the flexibility of the partnerships we can offer. We will engage through weekly industry seminars and monthly Sensor Cafés, where SME employees can interact directly with the CDT students and PIs, provide training in topical areas, and, in turn, gain themselves access to CDT infrastructure and training. Ideas can be rapidly tested through industrially focused miniprojects and promising leads developed into funded PhD programmes, for which leveraged funding is available through the CDT.

Government departments and large research initiatives are formally connected to the CDT, including the Department for the Environment, Food and Rural Affairs (DEFRA); the Cambridge Centre for Smart Infrastructure and Construction (CSIC); the Centre for Global Equality (CGE); the National Physics Laboratory (NPL); the British Antarctic Survey (BAS), who all push our CDT to generate impacts that are in the public interest and relevant for a healthy and sustainable future society. With their input, we will tackle projects on assisted living technologies for the ageing population, diagnostics of environmental toxins in the developing world, and sensor technologies that help replace the use of animals in research. Developing countries will benefit through our emphasis on open technologies / open innovation and our exploration of responsible, ethical, and transparent business models. In the UK, our CDT will engage directly with the public sector and national policy makers and regulators (DEFRA, and the National Health Service - NHS) and, with their input, students are trained on impact and technology translation, ethics, and regulatory frameworks.