Detecting bladder volume and pressure from sacral nerve signals: the key to future artificial control

Lead Research Organisation: Royal Veterinary College
Department Name: Comparative Biomedical Sciences CBS

Abstract

This project is about the treatment of urinary incontinence, consequent of damage to the spinal cord.

Managing the urinary bladder is of the first importance to clinicians and patients following trauma to the spinal cord. Historically, kidney damage due to high bladder pressures and/or infection was the usual cause of death resulting from such an injury. Infections still raise mortality and morbidity, exacerbated by the risk of antibiotic resistance. In order to achieve urination-i.e. complete voluntary micturition (CVM) and as an alternative to the expensive process of intermittent sterile catheterisation, a neuroprosthesis for controlling the bladder after spinal cord injury (SCI) was developed by GS Brindley at the MRC Neurological Prostheses Unit in London 30 years ago. The Brindley method employs sacral anterior root stimulation (SARS) but is not popular in Europe, in terms of the fraction of the SCI population treated, because implantation of the device is accompanied by cutting the sacral posterior (sensory) nerve roots (rhizotomy) to prevent reflex incontinence during bladder filling and improve stimulated voiding. Clearly there is a need for a new neuroprosthesis that is more widely acceptable (primarily because no rhizotomy is necessary) and which, in addition, reduces the lifetime cost of care. The aim of this project is to design and demonstrate such a device.

Since its introduction, the Brindley method has been improved in several ways in attempts to address the problems mentioned. However, in spite of these developments, at present (a) no satisfactory, practical method exists for detecting the onset of bladder contractions in a chronic implant and, (b) no method is available to inform the patient of the level of bladder fullness to indicate when the bladder should be emptied. These are critical obstacles to the design of a complete prosthesis and our proposed solution is to use the bladder neural signals themselves since surgically implanted electrodes are essential anyway (i.e. for stimulation). A suitable site for the electrodes is the extradural roots; this is surgically attractive and electrodes are routinely implanted here in the Brindley procedure. In order that the nerves are similar to those in man, it is essential to use a large experimental animal as a preclinical model and we propose to use sheep for these experiments.

Publications

10 25 50
 
Description In the first part of the grant, we have designed a new nerve implant (called 'neuroprosthesis') created to be placed around sacral nerves; these nerves naturally control the urinary bladder. Our aim is to create an intelligent implant to control incontinence problems in people after severe spinal cord injury. This implant was designed based on the sheep anatomy and the size of their nerves and it is hoped that an identical implant could be used in human. The design of the neuroprosthesis was done so that it could ensheath the nerve and record nerve signals with adequate impedance, i.e. to avoid the background noise of the environment. The electrode design is a cuff containing an array of electrodes (multi-electrode cuff). Once satisfied with the design, we have then tested it's ability to record nerve signal when experimentally triggered along the nerve. We could successfully prove that the new implant was able to detect electrically induced nerve signals. In particular, the implant could record speed of nerve signals as they travelled through the implant. But importantly, we could also detect signal from skin stimulation (i.e. sensory skin signals); we also recorded signals signals from the bladder but these are not discernable yet from background noise and further analysis is required. The processing of the recordings is our next step.

In the second part of our grant, we have continued to refine the method of implanting our new cuff electrode and we have designed a surgical tool to ease wrapping the cuff around the sacral nerve and allow close contact between nerve and electrode. This device also facilitates gluing the lead of the cuff. This method now seems effective.
We have then designed a connector placed on the sheep's head that is connected to the sacral cuff electrode via silicone embedded cables. The head connector is made of titanium and covered with a structure that allows the skin to heal around it. This system allows us to connect recording devices at the head of the animals that can interrogate the cuff electrode placed around the sacral nerve innervating the bladder. The system is placed in surgery and the animal recovered and we know that this is safe. The animals live normally with the system in place (so far we have followed them up for 2 months) and this will allow us to study bladder physiology and nerve signals originating from the bladder while the animal is awake.
During surgery, we have studied bladder electrical signals recorded through our cuff electrode. This has required a vast amount of engineering of amplifiers which has proved rewarding: we have now been able to reliably record bladder electrical signals while the bladder is being distended by sterile water in surgery. We observe a good correlation between increase in bladder pressure and nerve signals ascending from the bladder to the brain. We have tested the effect of different anaesthetic drugs on bladder pressure in sheep as well. We are in a phase of analysing the electoral signals from the recordings we have done. We have acquired a vast amount of recordings and the analysis is on going but preliminary findings are promising.
We now need to move onto awake recordings during bladder distension with sterile water, which will generate further data. We know that it is possible to inflate the bladder with a catheter placed in the bladder of the sheep awake. We are also planning to conduct recordings while the sheep is walking on a treadmill.
We have faced problems with external interferences (radio-frequency signals) around our recording rooms and are working on fixing this. But the background noise measures within the sheep are very good so far in awake implanted animals.
We are also in the process of describing the anatomy of the sheep sacral system, which is not clearly known.
Exploitation Route We have presented the design of our implant at a conference and we will make this available through publication. This implant can be exploited by others for further testing in view of recording sensory signals from nerves. In the particular expample of incontinence, we engage with sacral nerves and hope to record bladder sensory signals such as bladder fullness. Having now progressed the design of our implants, other might be able to use it in this indication. However, it is possible that other researchers will use it to record sensory signals from other nerves, such as the laryngeal nerve involved in breathing. Our findings are of interest to the neuroscience communitee, engineers working with implantable materials, and doctors in particular.

We have established a sheep model that posses a cuff electrode placed around sacral nerves connected through a cable to an interface at the head. This allows to connect a cable onto a connector at the head and interrogate sacral nerve with the animal awake. This 'preparation' is completely new, feasible in our hands and appears safe and painless in animals who can leave with the cuff electrode and the connector at the head. Therefore, this model could be used by other researchers to study various questions related to bladder physiology, or potentially study pathological conditions that can be created in this model. If is also conceivable that the model can be used for other nerves (i.e. vagal nerve), by using the same interfaces (cuff and connector fixed on the head).

We have also gathered electrophysiological recordings from the bladder during filling and the result of this needs to be further analysed. But this will constitute extremely valuable data describing bladder physiology, thus far unknown. We also possess urodynamic and anatomical data as well in the sheep now, which were not known before and we are planing to describe these. As the project has progressed, we have collected post-mortem sacral nerve samples that we are currently analysing with histopathology and axonal markers to look at the distribution of axons along the sacral nerves in sheep and the reactions caused by our cuff implant.
Sectors Electronics,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The essence of this project is to investigate if bladder pressure and volume can be estimated using electrodes implanted at an extradural site - sacral nerves - acutely and chronically in a large animal experimental model. The conduction velocities of the sensory (myelinated) afferent fibres from mechanoreceptors of the genital region in sheep are similar to those of fibres conveying bladder pressure and volume information in man (approximately 38 and 41 m/s respectively). In order to discriminate between these signals, we propose to use a method that we have been developing called velocity selective recording (VSR) that may make this possible without using nerve interfaces that are difficult to implant or that endanger these important nerves. The principle of VSR is based on the fact that action potentials (APs) propagate at specific velocities and that these velocities are closely related to the nerve fibre diameter (for myelinated nerves). If, therefore, a recording of neural traffic can be characterised in terms of its velocity spectrum, it will provide a signature relating the recorded signals to their function (VSR can also discriminate between afferent and efferent traffic on a mixed nerve, such as extradural bladder nerves). The method requires multi-electrode cuffs (MECs) and we have used such devices with as many as 11 electrodes along the length of a nerve cuff. Since the signals appearing at the electrodes of an MEC in response to naturally-occurring (physiological) ENG are very small (order of 1 µV) a very low noise environment is required. This requires not only specially-designed recording instrumentation but also an electrically quiet environment with well-characterised and understood background interference sources. This latter requirement is particularly hard to achieve in a modern operating room (OR), which tends to contain many electrically-based devices. Most of our effort to date has therefore been directed towards preparing and characterising the experimental set-up in a designated OR at the Royal Veterinary College (RVC) so that successful neural recordings can be made that make maximum use of our various resources and that do not require expensive additional interference reduction equipment. Initially, we have designed a new nerve interface, multi-electrode cuff (from silicone with steel electrodes), connected to a Cooper cable for signal extraction (photograph 1). The cuff design is based on the anatomy of sheep sacral nerves. Using this implant, we have conducted impedance measurements following stimulation of explanted pig vagal nerves and then live recordings in sheep. This showed impedance values of ~5kO for frequencies ranging 100-1,000Hz, which fulfils theoretical requirements for afferent bladder sacral nerve recording. Then, four acute implantations have been carried out on sheep (15 June 2018, 30 October 2018, 13 December 2018 and 1 March 2019 - photograph 2). The first three experiments were significantly compromised by the presence of electrical interference and only compound action potentials (CAPs) trafficking through sacral nerves, evoked by sacral nerve electrical stimulation were recordable. In response to this, two extra days were spent in the OR (3 January and 1 February 2019) with the instrumentation alone, in an attempt to understand these interfering sources. These efforts were successful and in the most recent critical experiment (1 March 2019) we were able to record physiological ENG in response to touch stimulation of the skin in the region of the animal's tail, innervated by sacral nerves. These recordings were clear above the noise and repeatable. Recording CAPs from both sacral nerve electrical stimulation and skin stimulation validates our new cuff electrode design and brings confidence that the interface nerve / cuff electrode is exploitable. Sacral nerves were sampled in two animals for morphometry to serve as controls against future chronic experiments. During in vivo experiments in sheep, we have acquired new data on sheep's physiological bladder function (during anaesthesia) and found: (i) peak bladder pressures ranging from 23 to 31cmH2O during S2 and S3 electrical stimulation - image 1; (ii) maximal bladder pressure during filling cystometry ranging from 6 to 59cmH2O for infused volumes of 187 to 727mL - image 2; and (iii) a drop in bladder compliance after 4 hours of anaesthesia. So far, we have used two methods for detecting bladder afferent signals: (i) monitoring the running RMS amplitude of the wide-band amplifier output, and (ii) listening to this raw recording during the experiment. Despite filling the bladder to very large volume (1 litre) and the consequent high pressure (up to 59cmH2O), there was no apparent neural signal. This might be due to the long period of anaesthesia and the observed reduction in bladder compliance, but it shows that signal processing is essential. The challenge now is, therefore, to see whether the bladder afferent signals can be extracted using VSR. In summary, our findings to date have been; 1. A custom 5-channel integrated amplifier system (CMOS asic) has been constructed (configurable for 10 channels as needed) and its performance verified; 2. A new multi-electrode cuff (MEC) has been designed and built (4 electrodes initially but with a capability to increase to 10 or more); 3. A special tool has been designed to aid the implantation of the MECs on extradural roots of sheep; 4. The OR has been characterised for electrical interference and counter measures taken so that the recording instrumentation is not compromised by the environment; 5. The cuff impedances (2-and 4-wire configurations) have been extensively characterised in vitro and in vivo; 6. Repeatable 4-electrode (configured as 3 dipole channels) in vivo measurements have been made of naturally-occurring (physiological) ENG evoked by (a) stroking and (b) pricking with needles the tissue close to the animal's tail; 7. New data on sheep's physiological bladder function (during anaesthesia) have been acquired for future reference; in parallel nerve morphometry has been done on two controls. *******
First Year Of Impact 2018
 
Description Restoration of urinary function in spinal injury using olfactory ensheathing cell transplant combined with bladder nerve electrical stimulation
Amount £136,658 (GBP)
Organisation International Spinal Research Trust (Spinal Research) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2020 
End 03/2024
 
Title Sacral cuff electrode implantation device and head connector for live bladder ascending signal recording 
Description We have created a sheep model including implantation of a sacral cuff electrode (implanted with a new surgical tool) and a connector fixed on the skull and breaching the skin via a hydroxyapatite interface (therefore that can be interrogated from the animal awake). The cuff can then be interrogated with the animal awake during movement and bladder filling. This 'preparation' is new and has never been done. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2020 
Provided To Others? No  
Impact We have not published on this yet and therefore not had any impact yet but intend to do so in the near future. 
 
Description Mr Justin Perkins Clinical Science and Services Large Animal surgeon / Dr Ludovic Pelligant Comparative Biomedical Sciences Large Animal anaesthetist 
Organisation Royal Veterinary College (RVC)
Country United Kingdom 
Sector Academic/University 
PI Contribution None to date.
Collaborator Contribution Helped to develop a research protocol for using sheep as a large animal model.
Impact None yet.
Start Year 2017
 
Description Professor Richard Piercy MA VetMB MS PhD Dip ACVIM MRCVS Professor of Comparative Neuromuscular Disease 
Organisation Royal Veterinary College (RVC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Prof. Piercy is Professor of Comparative Neuromuscular Disease at the Royal Veterinary College. He is an RCVS recognised specialist in Equine Internal Medicine and a Diplomate of the American College of Veterinary Internal Medicine. He directs the Comparative Neuromuscular Disease Laboratory at the RVC. His clinical work mainly involves horses with neurological and neuromuscular problems. Within our project, he is hosting the histopathology work we do on sheep sacral nerves. Our collaboration brings a new species in his lab and allows to validate methods used for other species to sheep.
Collaborator Contribution Prof. Piercy's lab allows us to run histopathology techniques he uses for large animal peripheral nerves (mainly in horses) that perfectly fits what we are trying to achieve with our sheep specimens.
Impact No output yet
Start Year 2019
 
Description British Veterinary Neurology Society Annual meeting 3.04.2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Gave a 40 minutes talk in front of ~100 audience of veterinary surgeons, post-graduate student, PhD students, veterinary neurosurgeons and human neurosurgeons. This was a formal lecture with questions in the end. Title was: 'Spinal cord injury: can we repair or bypass'.
Year(s) Of Engagement Activity 2019
 
Description EMBC 2020 Montreal conference papers - 3 papers submitted 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Three papers submitted for EMBC 2020 conference 42nd Annual International Conferences of the IEEE Engineering in Medicine and Biology Society in conjunction with the 43rd Annual Conference of the Canadian Medical and Biological Engineering Society July 20-24, 2020, Montréal, Québec, Canada;
(1) B. Metcalfe, N. Granger, J. Prager, S. Sadrafshari, J. Taylor and N. Donaldson; Selective Recording of Urinary Bladder Fullness from the Extradural Sacral Roots
(2) J Taylor, S. Sadrafshari, N. Donaldson, N Granger, J Prager and B Metcalfe; The Effects of the Presence of Multiple Conduction Velocities in the Analysis of Electrically-Evoked Compound Action Potentials (eCAPs)
(3) S. Sadrafshari, N. Donaldson, N Granger, B. Metcalfe, J Prager and J. Taylor; The Design of a Low Noise, Multi-Channel Interface System for use in Noisy Recording Environments
Year(s) Of Engagement Activity 2020
 
Description NSpine 1.07.2019 - Innovative Spine Education - conference; gave a talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The activity was a couple of 15-20' talk that I gave in front of an audience of~25 people in one of the satellite meeting room of NSpine; one talk was a short lecture and one talk was a case example; the topic was 'Chronic complications of spinal cord injury'; the end of the session was a round table around complications of spinal cord injury; the primary focus of my talk was urinary incontinence, which was discussed during the round table.The round table involved human and vet neurosurgeons.
Year(s) Of Engagement Activity 2019
 
Description Podcast on urinary incontinence 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I presented a podcast as part of 'The Veterinary Rehabilitation Podcast' presented by Dr Megan Kelly; this was entitled 'incontinence' and is a 30 minutes recording.
Year(s) Of Engagement Activity 2019
 
Description Research seminar RVC 23rd May 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact This was a research seminar across two sites, relayed via conference call. This involved ~30 people, composed of scientists, veterinarians, researchers, post-docs or PhD students.
This triggered questions and discussion and was a local school event at the Royal Veterinary College, as part of their research seminar series.
Year(s) Of Engagement Activity 2018
 
Description Research seminar in a research university Texas A&M 1.02.2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Around 50 academics, researchers and post-graduate students affiliated with Texas A&M University (in particular those in the College of Veterinary Medicine) attended a monthly research seminar of ~45 minutes. This allowed presentation of the EPSRC project and the sheep model used as part of this research as well as the method of 'velocity selective recording'. The talk was well received with a session after it for questions and discussions.
Year(s) Of Engagement Activity 2018
 
Description Talk at international congress and poster presentation 31st Annual Symposium of the ESVN-ECVN - September 2018 Copenhagen 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact International conference; talk associated with poster presentation; audience was composed of specialists neurologists and neuroscientists.

DETECTING SACRAL NERVE SIGNALS FOR ARTIFICIAL BLADDER CONTROL IN SPINAL CORD INJURY: A NEW CUFF ELECTRODE DESIGN

N. Granger1, B.W. Metcalfe2, T. Grego3, S. Sadrafshari2, N. Donaldson4, J. Taylor2.

1 The Royal Veterinary College, University of London, Hatfield, UK and CVS Referrals, Bristol Veterinary Specialists at Highcroft, Bristol, UK
2 Department of Electronic & Electrical Engineering, University of Bath, Bath, UK
3 Department of Medical Physics & Biomedical Engineering and Department of Mechanical Engineering, University College London, London, UK
4 Department of Medical Physics and Biomedical Engineering, University College London, London, UK
Year(s) Of Engagement Activity 2018