Integrated micro-electrodes and micro-capillaries for the study and control of neuronal activity

Lead Research Organisation: University of Leeds
Department Name: Electronic and Electrical Engineering

Abstract

Hyper-reflexia and hyper-tonicity of the muscles, commonly referred to as spasticity, is a common and debilitating phenomenon in motor disorders like stroke, spinal cord injury, multiple sclerosis or severe brain trauma. This work aims to explore a possible long term and adaptable treatment route via the exploitation of standard silicon and Micro-Electro Mechanical System (MEMS) manufacturing methods to form micron scale electrode arrays formed alongside micro-capillaries with the intention of implanting these electrodes in the brain and spine for localized stimulation and sensing. The materials and sizes will be chosen to have the least possible adverse effects and it is hoped that this can provide a long term means of receiving, stimulating and control of nerve signals after trauma such as spinal cord injury or stroke.This is technically challenging and novel and would also permit for the first time a much more detailed and comprehensive study of neuronal signals with micron precision within the spine. External stimulation both electrical and pharmacological (using directed picolitre quantities of drugs), together with electrical sensing and feedback, is unique, allowing a hitherto impossible level of manipulation, understanding and thereby control, of neurological behaviour, and without the drawbacks of systemic drug treatments. Ultimately the aim of the work will be to control pain and motor responses (and smart prosthetics) using adaptable electronic and pharmacological signals.

Technical Summary

Hyper-reflexia and hyper-tonicity of the muscles - commonly referred to as spasticity, is a common and debilitating phenomenon in motor disorders like stroke, spinal cord injury, multiple sclerosis or severe brain trauma. It is presently treated with systemic infusion of Baclofen - GABA is a potent inhibitory neurotransmitter prevalent throughout the central nervous system. Although its primary action is in the spinal cord, its uptake is weak if administered orally (25 - 100 mg/day), so intrathecal infusion (ITB) in the spinal cord is widely used (50 - 1500 ug/day). Infusion of baclofen is highly effective in reducing hyper-tonicity of the muscles; however, long term use still has ill effects. This work will exploit standard Micro-Electro Mechanical System (MEMS) processing to form micron scale electrode arrays embedded alongside micro-capillaries with the lowest possible cross-section profile for localized stimulation and sensing in nerves. This is technically challenging and novel and would also permit for the first time a much more detailed and comprehensive study of neuronal interactions and their modulation with a precision at the micron-scale within the spine. Highly localised stimulation both electrical and pharmacological (using directed picolitre quantities of neurotransmitters or their agonist and antagonists), together with electrical sensing both near and far, is unique, allowing a hitherto impossible level of manipulation, understanding and thereby control, of neurological behaviour, and without the drawbacks of systemic or even intrathecal drug treatments. Ultimately the work will be aimed at external control of pain and motor responses using adaptable electronic and pharmacological signals.

Planned Impact

Summary of Impact activities:

The milestones and milestone description along with target date and Impact funding requested is given below*

M1 - Engage with public at the University of Leeds and outside (All laboratory members, throughout project, no specific funding requested)

M2 - Bring in summer (high school) and under-graduate students in order to give students the chance to explore the new technologies in use (at 6 months, no specific funding requested)

M3 - Development and maintenance of project website to disseminate and present the progress of the project to both the scientific community and general public (established by month 3, and updated throughout the lifetime of the project, £1000 funding requested)

M4 - Talks at local Café Scientifique to present our findings (Year 1, no specific funding requested)

M5 - Dissemination of project results by publishing and presenting at conferences and in high impact journals, and on the project and university websites (Year 1, no specific funding requested)

M6 - Introduce a new seminar series to discuss miniaturised medical devices for medical purposes to introduce the hypothesis and early findings (Year 1, £6,000 funding requested)

M7 - Present data at SFN 2014 to disseminate project findings (Year 2, no specific funding requested)

Publications

10 25 50
 
Description Microfluidic channel capping
Considerable time has been taken to develop a methodology to encapsulate the fabricated microfluidic channels and the flip chip method was chosen as a possible path. An AML Aligner Wafer Bonder was required to controllably bond the separate pieces with the precision alignment of the wafers being carried out on a Karl Suss MJB 3 mask aligner. The SU-8 - SU-8 wafer bonding process requires very good temperature control to minimise outgassing, which degrades the bonding process (100+/-5°C and 5kN pressure).

ADEX
Time has also been spent on studying a new material based on SU-8, trade name ADEX is a Bisphenol-A (epichlorohydrin) epoxy resin based thick dry film sheet (TDFS) manufactured by DJ DevCorp in the USA. It has very good thickness characteristics and its use eliminates many of the waste and complexities of liquid SU-8, due to edge bead and thickness variations obtained with the liquid SU-8 spinning process.
Exploitation Route Project is just at the half way point and the most challenging phase has been completed. Full success requires durther work and in-situ trials and once completed groups at Leeds, Bristol, and in the US are poised to adopt.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The work has been presented at various patient and interested party workshops on Dementia, Microfluidics and Cerebral palsy to both publicise the on-going efforts in the area, potential and to seek interested collaborators with which to take the work forward.
First Year Of Impact 2016
Sector Healthcare
Impact Types Societal

 
Description EPSRC IAA Impact acceleration funding EP/K503836/1
Amount £4,700 (GBP)
Funding ID EP/K503836/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 09/2015 
End 09/2015
 
Title Development of both hard shank and soft shank microelectrode arrays together with soft flexible interconnect and insertion tool 
Description The original aim was to realize a range of bespoke passive 1-d,2-d and 3-d microelectrode arrays (MEAs) in both hard (Si) and soft (polymeric) membranes (20-60um thick) which facilitate 16,32 and multiples thereof of channelized recording and / or stimulation sites, with electrode sizes ranging from 10-100um in diameter. For the soft layered MEA an insertion tool and post insertion release mechanism, together with a soft and flexible interconnect needed to be developed. The key development was a bespoke end to end hardware and recording tool for both acute and chronic applications. The large number of addressable contacts is considered to help with the 3R's by helping to generate a richer data set requiring fewer animals for the research into neuro-electronics or electrophysiology. 
Type Of Material Improvements to research infrastructure 
Year Produced 2016 
Provided To Others? Yes  
Impact Still to be reported and related animal studies pending but several related publications are to be expected now that a firm technological base has been established 
 
Title Integrated micro-electrodes and micro-capillaries for the study and control of neuronal activity: update 
Description Year one challenges involved the establishment of the appropriate research infrastructure and microfabrication processes and materials. This primarily centred around re-establishing previous SU-8 processes using a new set of tools and materials and to upskill and train the new research technician in the micromachining of the photo-patternable polymer SU-8. The previous research students that developed these processes had left after finishing their PhD's and a large part of this first year has been for the research technician to establish and refine existing process knowledge together with ncorporating new processing steps, such as wafer-bonding / capping, which was not used in the past. Processes have recently been established to satisfy the manufacturing of low cost microelectrode arrays (MEAs) on silicon, and the focus of the work reported here is on forming microscopic microfluidic channels using SU-8 and similar materials with the ultimate goal of integrating these with MEAs for combined electrical and pharmacological measurement and control. In detail: SU-8 is used as a readily patternable material although the viscosity for the film thicknesses required for the microfluidic channels does present many associated problems. Controlling the curing (outgassing) and the stresses (effects of thermal shocking) in the films as well as substrate adhesion are all non-trivial, at least initially until the process variables have been understood. A change in patterning tool (KS MJB-3 to EVG610) has also complicated matters but offers the significant potential to pattern much larger areas in the long run, thus reducing fabrication costs and processing time. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact In discussions with groups from UCL, Bristol, Newcastle and the US and Ireland re follow on research applications and adoption of techniques. Two follow on grant applications were submitted which would benefit from this work :- A Network for A Biomimetic Neural-interface, EP/N02737X/1, 752,348.73, Collaborators Edinburgh and Newcastle, and Led by Dr Steenson but failed with the "recommendation to resubmit to responsive mode". And also, Stratification, Neuro-regeneration and Neuro-rehabilitation in the Cord Injured Patient, programme grant, led by R. Hall (Leeds) - in review (Hall + 6 partners at Leeds), EP/N029380/1 value £ 6,039,532.00 
 
Description Assistive Technologies for Dimentia Workshop, Leeds 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Study participants or study members
Results and Impact Representation of Leeds Work (Drs Steenson & Russell) re SenseBack and Microfluidics on a number of planned sessions to groups of patients, carers and professionals working in dementia towards education and follow-on funding applications and collaborations.
Year(s) Of Engagement Activity 2016
 
Description Be Curious Festival, Leeds 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Dr Chris Russell (Post Doc on SenseBack) presented a poster to the general public on the work that the Leeds group (DRs Steenson and Russell) are doing in relation to the SenseBack project
Year(s) Of Engagement Activity 2016
 
Description Enabling Technologies for Neuroscience Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact The aims of this workshop, held at the University of Leeds on 22nd September 2015, were to:
• Bring together colleagues, both within the University and external partners, interested in developing tools and technologies for use in preclinical and clinical studies in neuroscience and neurology.
• Initiate interdisciplinary discussions in applied neuroscience research
• Facilitate the formation of interdisciplinary research partnerships, with the intention that these lead, in the future, to the submission of funding bids to external agencies.

The workshop was attended by 35 delegates who collectively had interests which spanned the discipline: 11 Biological Scientists (all UoL); 10 Engineers/Physicists (8 UoL, 3 Ext); 7 Clinically-related (5 UoL, 2 Ext); Research and Innovation Support (4 UoL, 1 Ext).

Delegates were engaged with research goals and needs of different research groupings or fields through short presentations by Chakrabarty (FBS: Basic Neurophysiology), Alix (Univ of Sheffield, Clinical Neurophysiology), Steenson (Eng, Neuroengineering) and Williams (RIS, Medical Innovation). These were followed by the keynote lecture entitled "Monitoring Biochemical Parameters- Diagnostics, wearables and implants" delivered by Prof Dermot Diamond (National Centre for Sensor Research, Dublin City Univ).

Following a panel discussion sessions in which presenters responded to questions from the audience, delegates were allocated to three multi-disciplinary/multi-interest groups, each led by a facilitator, to explore the current and future research questions of neuroscientists and clinicians, the technological barriers they face in undertaking this research, and the tools and technologies that exist or could be developed by engineers or physical scientists to overcome these barriers.

The outcome led to a Network + collaboration bid which was not funded but dialogue continues with some of those involved re a further responsive mode bid.
Year(s) Of Engagement Activity 2015
 
Description Micro-fluidic and microelectrode fabrication & application - controlled localised drug delivery at a Net Market fluidics sectoral (EU) workshop (02/02/2017) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Presentation to a regional EU group of professionals working on similar (mili and microfluidic) fields. Aim was to communicate progress and technology advances with a view to possible collaboration. Other outcome was to hear from professionals in area re commercialisation of Microfluidics.
Year(s) Of Engagement Activity 2017
URL http://www.netmarketfluidics.eu/
 
Description UK-Turkey Researchers Links Workshop 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Dr C Russell on behalf or the Leeds group (Drs Steenson and Russell) and in relation to the Senseback and Microfluidics Work streams at Leeds attended the workshop with a view of forming alliances and follow-on funding applications for joint UK / Turkey collaborations. Status: on going.
Year(s) Of Engagement Activity 2016