Implantable Biosensors for Monitoring of Neuroinflammation

Neuroinflammation plays an important role in the onset and progression of many neurodegenerative diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's diseases. Recent research has uncovered a link between the presence of certain metabolites in cerebrospinal fluid (CSF) and neuroinflammation. Pro-inflammatory macrophages were shown to cause breaks in the tricarboxylic acid cycle leading to altered levels of succinate, itaconate and fumarate. Point-of-care testing for these biomarkers offers an opportunity to screen and diagnose such neurological diseases and monitor their progression.

Currently, the state-of-the-art biosensors for metabolite detection include microarray technologies, mass spectroscopy and Forster Resonance Energy Transfer microscopy. These are able to measure multiple biomarkers but lack the ability to perform real-time monitoring of animal models in-vivo and can have problems with sensitivity for low concentration biomarkers. This creates a need for new technologies which are able to perform point-of-care testing with low limits of detection and high sensitivity.

Electrochemical biosensors are a simple, low cost technology providing fast and highly sensitive analysis for specific target analytes. Implantable biosensor technologies enable the in-vivo electrochemical monitoring of biomarkers in real-time. This project proposes to develop a novel implantable biosensor which can monitor levels of these key metabolites in real-time and output recordable data.

The overall aim of the project is to develop and validate new ways and electrochemical technologies to monitor biomarkers of neuroinflammation in-situ. This would develop the potential for real-time point-of-care screening, early diagnosis, and monitoring of neurological diseases. In order to achieve this aim we devise two key objectives: (1) Development of biosensors capable of detecting neuroinflammation biomarkers in CSF. (2) Validation of the usability of the developed sensors through in-vivo implantation in a murine animal models for continuous monitoring.

This approach is broken down into three main stages. Firstly, we will design the biosensor: identifying suitable molecular mechanisms of the metabolite for measurement, and designing, developing and characterising a novel electrochemical biosensor with suitable capabilities and specifications. In-vitro testing in solution and cell culture media, and ex-vivo testing of cerebrospinal fluid will validate the performance of our developed biosensor technologies and inform optimisations of the devices. Finally, the developed sensors will be demonstrated through implantation in murine models for real-time continuous monitoring with results being validated through comparison with ex-vivo and microdialysis experiments.

Research will primarily be carried out in Dr Occhipinti's group, for all design, device development and characterisation experimental tasks, with access to advanced fabrication and characterisation facilities available in the Cambridge Graphene Centre and the Nanoscience Centre. The preclinical work will be developed in Dr Pluchino's lab in the Department of Clinical Neurosciences, who carry out translational research specialised in regenerative neuroimmunology.

This project is multidisciplinary and covers a number of EPSRC's research themes including engineering, physical sciences and healthcare technologies with research areas such as clinical technologies, sensors and instrumentations, and microelectronic device technology being explored.

The development and demonstration of a suitable biosensor will provide a step forward in the understanding and monitoring of neurodegenerative diseases.

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.