1. Ashok Chauhan PhD (ECR) Graham Fisher (Mentor) Alain Nogaret PhD (PI)
Central Pattern Generator Bioelectronic implants that adapt to physiological feedback to provide the chronic therapies needed to treat cardiorespiratory disease
Ashok Chauhan PhD (ECR)
Graham Fisher (Mentor)
Alain Nogaret PhD (PI)
Julian Paton PhD
Partners:
ICURe3 roundabout, 21 August 2015

2. Fulfilling unmet needs in cardiology
Aims
Customer feedback
Proposed work
Resources
   
Fulfilling unmet needs in cardiology
UK Heart failure Audit:
900,000 Patients
5% of hospital admissions
Increasing incidence
Existing Heart Failure devices:
CRT target LBBB (15% patients )
Pacing + Respiration uncoupled
Vagus + Respiration uncoupled
CPG/Device
Vagus
Robust
Responds to changes in dynamics
Respiratory Feedback,
Diaphragm EMG or
Phrenic Nerve SA
Objective
To improve cardiac output & coronary blood flow in heart failure by restoring variability of heart rate in patients with heart failure

3. CPG slows heart rate during late expiratory phase - 3
Aims
Customer feedback
Proposed work
Resources
   
Proof of principle: Slowing the heart rate in phase with respiration
Silicon CPG mutually interconnected to a rat
PHRENIC
Inspiration
rat
Neuron 2
Nogaret et al. (2013). J.NeuroSci. Meth. 212, ; J. Physiol. 593, 763 (2015)
CPG slows heart rate during
late expiratory phase - 3
Neuron 1
Heart
Rate Hz
Inspire
The CPG slows down the heat rate in synchrony with respiration to restore natural respiratory sinus arrhythmia (RSA).
VN stimulation remains synchronized with respiration as the respiration rate varies.

4. (Acute, anaesthetised rat)
Aims
Customer feedback
Proposed work
Resources
   
Demonstration of increased cardiac output
Transverse heart
sections
15% increase
(Acute, anaesthetised rat)
Infarct
bradycardia
Infarct
Increased cardiac output with RSA presumably synchronises venous return with
increased heart rate , as no such effect is observed during bradycardia alone

5. Feedback from medical device corporations and cardiologists
Aims
Customer feedback
Proposed work
Resources
   
Feedback from medical device corporations and cardiologists
“This technology is bridging a big gap in the market by overcoming many limitations of existing devices. This technology could be brought to market a lot quicker due to the quality of the device and the proof-of-principle in animal trials.”
Mr James Fouhy, Boston Scientific
“Human clinical trials could be setup very rapidly for this device”
Prof Vivek Reddy, Cardiologist, Mount Sinai Hospital, New York
“I am impressed with the design of the silicon central pattern generator as well as the vision for subsequent development. The devices go beyond the intelligence of those on the market, use the fundamentals of biology and hence are elegant and potentially powerful. Critically, the devices are not simply evolutions of prior concepts, they stand to be unique.
This is truly exciting and inspirational for the medical field. I believe the devices you have made are already imminently translatable and should attract immediate industrial interest. I am aware of at least one large strategic medical device manufacturer.”
Prof Paul A Sobotka, Cardiologist, Ohio State Univ.
Entrepreneur in Residence, OSTP, White House
Chief Medical Officer Cibiem Inc

6. Feedback from cardiologists and prosthetics corporations
Aims
Customer feedback
Proposed work
Resources
   
Feedback from cardiologists and prosthetics corporations
“It will be essential to obtain data on chronic stimulation of conscious animal models prior to human trials”
Dr Wilfried Mullens, Cardiologist, Cleveland Ohio
Dr Jagmeet Singh, Director Holter Lab, Massachusets General Hospital
Dr Benjamin Steinberg, Cardiologist, Durham, North Carolina
“The device you describe is cutting edge and or great importance clinically as there are caveats with all devices we currently use. For example multiple leads are not ideal, coupling between heart rate with changes in body demands such as during exercise for example, is limited and un-physiological.”
Dr Edward Duncan, Cardiac electrophysiologist, NHS Hospital Bristol
“Chronic trials on large animals and successful human trials conducted in agreement with CE mark regulations would see the device sold to large medical device company within 3-4 years.”
Dr Pete Wall, Isca Healthcare, Consultant on regulatory procedures for medical implants
“Huge opportunities for collaboration in interfacing electronics with biology…”
Mr Martin Wehrle, Ottobock, Prosthetic device manufacturer

7. Workflow: Design, test and validation of CPG implants
Aims
Customer feedback
Proposed work
Resources
   
Workflow: Design, test and validation of CPG implants
CPG fabbed
CPG on PCB
Test & validation
Stage1
VLSI CAD
Stages
2 & 3
Implant assembly
Sheep trials
Feedback to
stage 3
Wireless link

8. Assimilation of electrophysiological data to program implants
Proof of principle: data assimilation from electrophysiological recordings of songbird HVC neurons
Assimilation of electrophysiological data to program implants
We adapt heart stimulation to the breathing rate and timing by programming the CPG with data assimilation:
Assimilate cardiac electrophysiological data to obtain synaptic conductances
Set the conductance values in the hardware
This method has successfully obtained quantitative models of real neurons (songbird HVC)
PI/UCSD work
Toth et al., Biol Cybern. 105, (2011)
Meliza et al., PLoS Comp. Biol. 9, 3223 (2013)

9. Processing capability:
Processing capability: Micro and nano-devices made by the Nogaret over the last 20 years
Proof of principle: data assimilation from electrophysiological recordings of songbird HVC neurons
Running title
PI’s expertise in micro/nanofabrication: >20 years of experience in processing GaAs/AlGaAs, InAs/AlSb/GaSb, Si etc. with optical / electron beam lithography and designing advanced devices for Physics research (87 papers, 957 citations). One of the most experienced device physicists in the UK.
NRC GaTech (91-93) / Nottingham (94-98) / Glasgow nanofab (94-98) / Bath Univ. nanofab (98-now).
Phys.Rev.Lett. 22, (2009)
New.J.Phys. 10, (2008)
Appl.Phys.Lett. 71, 2937 (1997)
PRB 74, 6443 (1993)
50µm
10µm
2µm
GaAs neuron
Free standing GaMnAs nerve fibre
Single electron tunnel device
RT diode interconnect
50nm
2.5µm
100nm
Silicon MEMs
EPR microwave source and coplanar waveguide
GaAs/AlAs RT loop
InAs/GaSb tunnel diodes
Appl. Phys. Lett. 99, (2013)
Appl. Phys. Lett. 99, (2012)
PRB 50, 8074 (1994)
PRB 51, (1995)

10. in the miniaturized form suitable for medical implants.
Processing capability: CAD of printed circuits boards and lithographic mask plates
Proof of principle: data assimilation from electrophysiological recordings of songbird HVC neurons
Device processing expertise at Bath
Design of CPG circuit on Printed Circuit Board
(ALREADY BUILT and TESTED )
Design of lithographic process
for implant chips
scaling
Software: PCB design (Techsoft UK)
Software: Wavemaker (Bernard Microsystems)
The PI and the University of Bath have unique expertise for making CPG circuits
in the miniaturized form suitable for medical implants.

11. State of the art in CPG hardware
So called “State of the art:” “CPG” neural hardware
State of the art in CPG hardware
Proof of principle: data assimilation from electrophysiological recordings of songbird HVC neurons
CalTech
Coordination of robotic legs.
(binary pulses, feed-forward neural network,
BUT: no adaptation)
Tenore et al., ISCA 2005
NorthEastern Univ. & ETH Zurich
Swimming motion in fish and lampreys.
(Neuron approximation, small parameter space, external control electronics,
BUT: no adaptation)
Ijspeert et al, Science 315, 1416 (2007)
Lee et al., Neurocomp. 71, 284 (2007)
CPG electronics implemented elsewhere is: rudimentary, far from biological reality unsuited for medical applications and ”stiff” as no adaptation programmed in.