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

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

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, 124-132; 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.

(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

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

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 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

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

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, 217-237 (2011) Meliza et al., PLoS Comp. Biol. 9, 3223 (2013)

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, 226802 (2009) New.J.Phys. 10, 083010 (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, 242107 (2013) Appl. Phys. Lett. 99, 242107 (2012) PRB 50, 8074 (1994) PRB 51, 13198 (1995)

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.

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.