Real-Time Neural Chemical Sensing in the Peripheral Nervous System

Lead Research Organisation: Imperial College London
Department Name: Electrical and Electronic Engineering

Abstract

The nervous system is a large network of communication channels. In the brain approximately one hundred billion neurons, each connected to up to 10,000 other neurons perform operation speeds unmatched by man-made devices. The peripheral nervous system (PNS) alone can achieve speeds of communication of up to 270mph. Every action, conscious or not is driven by this network, enabling all biological functions. Subsequently, neural disorders that affect the function of the peripheral nervous system have a significant impact on many aspects of life, in some cases reducing quality of life and in others, life span itself.
Being able to interface with the nervous system allows us to diagnose, detect and treat neural disorders. Over the last several decades scientists have taken great steps in creating efficient neural interfaces, and as such a wealth of new disorders are treatable nowadays, including Epilepsy (surgery diagnostics recordings) and Parkinson's (deep brain stimulators). Nevertheless, we are still far from developing the science fiction type interpretations of these interfaces, there is still a wealth of information needed and there are many other disorders that need tackling.
Over the last several years our group has developed a strong cross-disciplinary track record that enabled the interfacing of engineering systems to biology using various types of sensors, facilitating a number of biomedical applications. Through grants and spin-out companies we've established technology in the biomedical space that have research and commercial value. This project brings this expertise together to develop the next generation of neural sensing technology , for developing future interfaces.
The project introduces a novel way of measuring the chemical response of nerve activity coupled with the traditional electrical signals it produces. This will allow us to know more about the neural behaviour over time and eventually to diagnose changes related to disorders. To achieve this, this project consists of three key parts: (1) The sensor development, which includes the design of the electrodes for recording the electrical activity and ion sensitive sensors, (2) The electronics to extract the chemical and electrical recordings and (3) Extensive tests and measurements to characterise the capabilities of the platform.
To realise this platform we have outlined work packages relating to each stage, with experienced researchers leading these. Given the scale of this project a management team is essential for guiding and steering the project towards its milestones and deliverables. In addition we have brought on board three partners (IBMT Fraunhoffer, King's College London and GlaxoSmithKline) to advise and guide the project towards realistic clinical and commercial outcomes. The outcome of the project will be a platform interfacing with the neural activity beyond the current state of the art, paving the way for multiple studies and research opportunities where chemical activity plays a vital role.

Planned Impact

Neurodegenerative diseases have been highlighted as a significant research gap in EPSRC funding. The importance of effective treatment and health wellbeing relies on better characterization of diseases, enabling technological platforms for addressing global health challenges and cheap and robust sensors for accurate real-time measurements for critical to know parameters. The UK has a strong neuroscience and engineering base with a significant academic record. However, the merging of the two fields in the UK is still at its first steps. In the US, neurotechnology and biomedical engineering is a multi-billion pound industry with one of the largest academic bases in the world. The type of work proposed here helps in placing the UK on an equal footing with these leaders. Given the already expressed interest from collaborating partners there is potential to expand the impact internationally. The expected outcomes will benefit considerably through close collaborations and commercial opportunities. The team involved in our cross-disciplinary environment complements the key aspects of the project, and strengthens inter-group collaborations.
Commercially, neural interface technology is a multibillion pound market, currently dominated by the
US. Interface technology is used for three areas: early detection, diagnosis and therapy. Therapy is the most widely
commercialised with many neural stimulation for the brain (deep brain stimulators for Parkinson's and Epilepsy) and the peripheral nerves (Cyberonics VNS, Victhom Neurostep). Interfaces for recording have mainly had success for brain recording of electrical activity. However, at present, what we propose here is not available -recording of the chemical activity associated with neural activity. A device of this type has clear commercial aspirations and would place the UK and ICL at the forefront of state of the art neural interfaces. Intellectual property and potential for developing a spin-out by leveraging on our groups experience in translating research technology to a commercial space, only strengthens the commercial aspirations of this technology.
In addition, there are many conditions, including Epilepsy and Neuropathies whose influence can be directly assessed
based on the electrical behaviour of our nervous system. Given that the chemical changes are the driver of this electrical behaviour there is scope to explore chemical changes associated with such disorders. Hence, in the neuroscience domain there is great potential for utilising this technology in several research areas. In addition, chemical recording will not be plagued with the electrical interference notorious for making neural electrical recording difficult to implement for implantation. Again leveraging on our groups expertise on chemical sensors we will employ several techniques for obtaining very accurate chemical recordings and increase longevity. We aim to utilise this technology to expand our research portfolio and establish collaborations with neuroscience clinics around the UK and Europe, thus realising significant clinical and academic impact.
All of this will have significant impact on the UK establishing itself as a contender in the competitive neurotechnology
domain. Bringing in new potential collaborations, commercial outcomes and through effective dissemination of this work we will strengthen the UK's academic and commercial position. Already we have interest from GlaxoSmithKline, who are keen to exploit this technology in the commercial space and King's College London who similarly are interested in pursuing clinical outcomes of this type of technology. Hence both institutions will act as project partners to guide the research towards these high impact outcomes.

Publications

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Perra E (2018) The Crucial Role of Nerve Depolarisation in High Frequency Conduction Block in Mammalian Nerves: Simulation Study. in Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference

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Rapeaux A (2015) Fiber size-selective stimulation using action potential filtering for a peripheral nerve interface: A simulation study. in Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference

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Sohbati M (2015) Personalized Microchips for Health Care in IEEE Potentials

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Sohbati M (2015) Dimension and Shape Effects on the ISFET Performance in IEEE Sensors Journal

 
Description 1. Designed and fabricated (in house) of a 3mm x 4mm array of individually addressable pH sensitive microneedles (nine in total), which were subject to gold patterning and then sensitized by electro-deposition of iridium oxide. The sensitivity is 0.07 units of pH change.
2. The array was integrated into a portable device for real-time wireless recording of pH distributions in biological samples. We also developed miniaturised electronics suitable for the sensors readout, analog-to-digital conversion and wireless transmission of the potentiometric data, all embodied within the device.
3. We have demonstrated real-time recording of the cardiac pH distribution during cycles of global ischemia and reperfusion in cardiac muscles.
4. The device may be used for carrying out direct pH measurements of soft and heterogeneous samples such as neural tissue, as well as muscles, organs and food.
5. Developed Iridium Oxide on Iridium microwire pH sensors and captured pH changes (in collaboration with another project). In this setting, we have been able to capture Vagus nerve signalling in correlation to physiological stimuli. The first method of its kind able to achieve this.
6. We also investigated modifying the surface properties of the electrodes to be Sodium and Potassium sensitive.
7. Developed new types of Ion Sensitive Field Effect Transistors (ISFETS), ion-selective membranes and circuits and systems for their deployment in chemical sensing in peripheral nervous system.
8. Investigated optimum ISFET geometry (shape and dimension) design for non-modified CMOS manufacturing of ion-sensitive transistors. The result was the optimum ratio of the sensing plate to the electronic channel of the transistor in order to get the most coupling efficiency of the signal while not consuming too much area of the semiconductor chip.
9. Developed a new type of interface circuits for ISFETs that eliminate the effect of temperature on ionic concentration change measurement and allows a linear conversion of the signal to digital representation without any limit on dynamic range (both analogue and digital approaches).
Exploitation Route It will allow the community to have a combined method of monitoring electrical and chemical activity, suitable for chronic models. Currently the only options for chemical activity are via imaging techniques not suitable for anything other than acute experiments. In addition, peripheral
Sectors Electronics,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The area of Biomedical Electronics has been gathering momentum recently. The use of electroceuticals (targeted electrical stimulation of the nervous system) as a therapy for many health conditions, instead of or in conjunction with pharmacological agents has been initiated by our group together with colleagues from GSK. The general public has been gradually becoming aware of this approach. Furthermore, the PI and Dr Nikolic prepared the Sensors Transformation Map for the World Economic Forum. We show how sensors can transform our existence and how they fit into the Fourth Industrial Revolution. The WEF in Davos is well know forum which is a main gathering of world leaders, policy makers, but also help the general public to learn more about our every-day pressing issues.
First Year Of Impact 2017
Sector Education,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Policy & public services

 
Description The Royal Society Neural Interface Perspective
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description EPSRC - Platform Grant
Amount £692,737 (GBP)
Funding ID EP/N002474/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 08/2015 
End 07/2020
 
Description Global Challanges Research Fund
Amount £209,169 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 03/2017
 
Description Wellcome-Imperial Institutional Strategic Support Award
Amount £73,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2017
 
Description Network of Excellence with Prof Maria Belvisi, Imperial College London 
Organisation Imperial College London
Department Imperial College Business School
Country United Kingdom 
Sector Academic/University 
PI Contribution This is an Wellcome Trus Institutional Strategic Support Fund Network of Excellence award for 12 months for our joint proposal with Prof Belvisi, entitled "Monitoring and Modulating Respiratory Symptoms". This project focuses on creating the technology that will allow us to not only record the vagal afferent signalling between the lung and brain, but also regulate it. We propose an innovative collaboration between the Faculties of Medicine and Engineering in developing novel implantable devices to monitor and regulate vagal nerve activity that we will validate in human and animal in vitro systems and a unique in vivo animal model. We develop the electrode technology for interfacing with the peripheral nervous system, electronics (analog/digital) for implantable systems to interface with the electrodes and advanced signal processing for extraction and quantifying the dynamic behaviour of the bio-signals.
Collaborator Contribution Prof M. Belvisi and Dr Mark Birrell are recognized experts in the respiratory field with both academic and industrial experience. They are providing experimental in vivo and in vitro models for developing and testing our technology.
Impact The project is highly multi-disciplinary and the diverse nature of the team enables a distinctive multi-faceted approach to this challenging project, providing a unique insight into the development of a novel functional mapping of electrical and chemical patterns in the vagal nerve and in testing electrical stimulation as a novel paradigm for treating cough and other symptoms of respiratory disease.
Start Year 2016
 
Description Potassium Sensor for neural recording in peripheral nerves 
Organisation University of Toronto
Department Department of Chemical and Physical Sciences
Country Canada 
Sector Academic/University 
PI Contribution We initiated the collaboration and send the Ir wire samples to Toronto, on which they deposit their anti bio-fouling membrane which is selective to potassium. After returning the samples to us, we create 3-electrode sensors and characterise them using our propitiatory fluidic chamber set-up and impedance spectroscopy instrumentation.
Collaborator Contribution Professor Mike Thompson's group at Department of Chemistry has developed a special material, which has both anti-bio-fouling and potassium capturing properties. They also have developed the procedure how to deposit this material on thin (~100um diameter) wires of Ir and to perform chemical characterisation of the substrate.
Impact publications expected soon
Start Year 2017
 
Title Method and apparatus for measuring activity in the peripheral nervous system 
Description A method and apparatus for measuring activity in the peripheral nervous system comprises a nerve cuff having an array of chemical detectors such as chemFETS or ISFETS. Activity within the nerve causes chemical responses which can be detected. The use of chemical rather than electrical detection minimizes interference problems and allows the cuffs to be made smaller. 
IP Reference US9055875 
Protection Patent granted
Year Protection Granted 2015
Licensed No
Impact The main advantage of using K+ and Na+ sensors in close proximity to the active nerve is that this provides a way of discriminating between neural activity and muscular interference, which degrades conventional neural recordings. Recording is important in order to achieve a closed-loop stimulation. Existing Neural Stimulation schemes do suffer from a number of serious drawbacks. In particular, periodic stimulation is irrelevant to the possible occurrence of a seizure and power drain is high since the stimulator is operated continually. The device therefore requires battery change-and therefore surgery-every few years. Using an intelligent closed-loop stimulation these issues can be mitigated.
 
Title Nerve stimulating and monitoring device 
Description A device for detecting impulses within a nerve, the device comprising a support for securing to the epineurium of the nerve, at least one spike extending from said support, arranged to penetrate the perineurium and at least one chemical sensor arranged on a surface of the at least one spike. 
IP Reference WO2016005400 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact N/A
 
Description Grand Round - lecture at St Mary's Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Title of the talk: 'Neural engineering for appetite control and other technology developments at Centre for Bio-Inspired Technology'. Lecture at the Cockburn Lecture Theatre, 2nd floor QEQM Building, St Mary's Hospital, atteded by clinical and non-clinical personel from the Section of Hepatology and Gastroenterology.
Year(s) Of Engagement Activity 2017
 
Description Imperial-Westminster Science Talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact An outreach programme organised with the Westminster School London. Dr Nikolic is helping the school to organise these talks - three science talks every year. It is very much a series of talks that aims to appeal to A level science students across London, but particularly those at schools with which Westminster School has established a summer school link (mainly in Lambeth and Southwark area). The topic of the talk from any type of scientific research and technology applications.
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
 
Description Interviewed by New Scientist about news related to human clinical trials related to optogenetics 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviewed over the phone by Clair Wilson, from New Scientist, regarding the announcement by GenSight Biologics of their clinical trials that involve 12 people in the UK who are about to have an optogenetic treatment for retinitis pigmentosa: "Blindness treatment will insert algae gene into people's eyes".
Year(s) Of Engagement Activity 2018
URL https://www.newscientist.com/article/2158645-blindness-treatment-will-insert-algae-gene-into-peoples...
 
Description New Scientist Live - festival of ideas 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact DIY DNA: GENE SEQUENCING AT HOME, Chris Toumazou & Maria Karvela, Sat 23 September 2016. New Scientist Live is a festival of ideas, discovery and 'What Ifs', taking place at ExCeL London. Rooted in the biggest, best and most provocative science, New Scientist Live will touch on all areas of human life. The show will feature four immersive zones covering Brain & Body, Technology, Earth and Cosmos. For four days this September, New Scientist Live will be like no other place on earth. 22-25 SEPTEMBER 2016 AT EXCEL LONDON
Year(s) Of Engagement Activity 2016
URL https://live.newscientist.com/chris-toumazou/
 
Description World Economic Forum - Sensor Transformation Map presented on Imperial College web site 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Many of the World Economic Forum maps such as Biotechnology, Blockchain, Banking and Capital markets, and Sensors were co-curated by leading Imperial academics.
The maps are intended to be used to inform work across the Forum's System Initiatives as well as strategic decision-making by governments and businesses around the world.
Year(s) Of Engagement Activity 2017
URL http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_9-1-2018-13-43-25
 
Description World Economic Forum - Sensors Transformation Map, Co-editor 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The World Economic Forum launched its Transformation Maps in 2017. Global transformation maps help explain Fourth Industrial Revolution and they also cover themes including Economies, Global Issues, Industries, System initiatives. The Sensors map was curated by Dr Konstantin Nikolic, from the Institute of Biomedical Engineering and Professor Christofer Toumazou, from the Department of Electrical and Electronic Engineering. They explain that new developments in sensor materials and uses have the potential to improve our lives in revolutionary ways."Smart sensors can sift through deluges of data in order to intelligently extract information. For example, a new generation of blood glucose sensors, used by diabetics, utilize data processing to connect with insulin pumps in a closed loop system, which in effect forms an artificial pancreas."
Year(s) Of Engagement Activity 2017
URL https://toplink.weforum.org/knowledge/insight/a1Gb0000001jJXlEAM/explore/summary