Transcript Web_designx - people.bath.ac.uk

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
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
Respiratory Feedback,
Diaphragm EMG or
Phrenic Nerve
Robust
SA
Responds to
changes in
dynamics
Objective
To improve cardiac output & coronary blood flow in heart failure by restoring
variability of heart rate in patients with heart failure
Aims

Proof of principle:
Customer feedback

Proposed work


Slowing the heart rate in phase with respiration
CPG slows heart rate during
late expiratory phase - 3
Silicon CPG mutually interconnected to a rat
Neuron 2
Resources
rat
Heart
Rate
Hz
PHRENIC
Inspire
PHRENIC
Inspiration
Neuron 2
Neuron 1
Nogaret et al. (2013). J.NeuroSci. Meth. 212, 124-132; J. Physiol. 593, 763 (2015)
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.
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
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
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 10-20 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
Aims

Workflow:
Proposed work
Customer feedback

Resources


Design, test and validation of CPG implants
CPG fabbed
CPG on PCB
Test & validation
Stage1
VLSI CAD
Stages
2&3
Implant assembly
Feedback
to
stage 3
Wireless link
Sheep trials
electrophysiological
data to program
implants
Proof ofAssimilation
principle: dataof
assimilation
from electrophysiological
recordings of
songbird HVC neurons
We adapt heart stimulation to
the breathing rate and timing
by programming the CPG with
data assimilation:
1.
Assimilate cardiac
electrophysiological data
to obtain synaptic
conductances
2.
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, 217-237 (2011)
Meliza et al., PLoS Comp. Biol. 9, 3223 (2013)
Proofcapability:
of principle: data
assimilation
from electrophysiological
Running
of songbird
neurons
Processing
Micro
and nano-devices
madetitle
by the recordings
Nogaret over
the lastHVC
20 years
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, 226802 (2009)
50µm
New.J.Phys. 10, 083010 (2008)
Appl.Phys.Lett. 71, 2937 (1997)
PRB 74, 6443 (1993)
10µm
2µm
GaAs neuron
Free standing GaMnAs nerve fibre
Single electron tunnel device
RT diode interconnect
50nm
2.5µm
100nm
Silicon MEMs
Appl. Phys. Lett. 99, 242107 (2013)
EPR microwave source and coplanar waveguide
Appl. Phys. Lett. 99, 242107 (2012)
GaAs/AlAs RT loop InAs/GaSb tunnel diodes
PRB 50, 8074 (1994)
PRB 51, 13198 (1995)
Processing
CAD ofDevice
printed
circuits
boards
andat
lithographic
plates
Proofcapability:
of principle: data assimilation
from
processing
electrophysiological
expertise
recordings
Bath
ofmask
songbird
HVC neurons
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.
So called
of the
art:”
neural
hardware
Proof“State
of principle:
data
assimilation
State
from
of electrophysiological
the art“CPG”
in CPG hardware
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.