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Adaptive Bio-electronics for Chronic Cardiorespiratory Disease

Periodic Reporting for period 2 - CResPace (Adaptive Bio-electronics for Chronic Cardiorespiratory Disease)

Reporting period: 2018-07-01 to 2019-12-31

Worldwide increase in life expectancy is accelerating the shift from prescription drugs to implantable medical devices for the treatment of medical conditions and age related diseases. Biomedical implants, without the long-term side effects of many drugs, have become essential to administer therapies for chronic diseases like Parkinson, cardiac arrhythmias, tremors and chronic pain.Moreover many diseases i.e congestive heart failure, spinal cord lesions, dystonia, epilepsy, chronic migraine have no or adequate therapy at present.Addressing these challenges is becoming urgent to ease the burden on patients,medical practitioners and National Health resources.

The CResPace consortium answers this challenge by bringing together multidisciplinary academic and industrial research teams from across Europe to develop fit-and-forget medical devices.These devices will be able to adapt to the physiological signals that regulate bodily functions and in this way restore functions that are lost through disease(s).We devise sophisticated mathematical tools and computational techniques that enable bioelectronic implants to read nervous activity in real time and help diseased organs save energy and restore normal function.This vision is embodied in a novel prototype of cardiac resynchronization pacemaker that provides beat-to-beat adaptation of heart rate and heart chamber timings to arterial gas pressure, hemodynamics and respiration.

The main objectives of the project are to develop:
a. large scale data assimilation tools to build quantitative models of medullary neurons and small networks
b. an integrated circuit of the respiratory central pattern generator
c. a central pattern generator designed to reproduce beat-to-beat cardiac resynchronization and an evaluation of its safety envelope
d. an intelligent cardiac resynchronization pacemaker that respond to physiological feedback and its clinical benefits
The work done at the end of the second period has focussed on the following:
(i) the construction of optimal models of adaptive bioelectronics,
(ii) the demonstration of a novel therapy for congestive heart failure in rodent animal models,
(iii) the construction of neuronal hardware inspired from medullary central pattern generators accompanied by the extensive probing of their dynamics and safety envelope,
(iv) the design and construction of implant telemetry and sensor platform for the acquisition of physiological data and their integration in the adaptive pacemaker demonstrator.

We have now created a complete database of membrane voltage recordings of medullary neurons and hippocampal neurons under stimulation by complex current protocols. These recordings have allowed us to transfer the electrical properties of actual cells into miniature silicon neurons. This demonstration of optimal and implantable silicon neurons that respond identically to biological neurons paves the way to repairing neurons lost to disease. The outcome of this published work has been widely disseminated to an estimated 1.6bn audience.

We have successfully built a 3 neuron respiratory central pattern generator and a 4 neuron cardiac central pattern generator on printed circuit board and a 3 neuron cardiac central pattern generator on a VLSI device. The respiratory central pattern generator has been trialled on rat models of heart failure to resynchronize cardiac and respiratory rhythms. This work compared the outcomes of tonically paced heart failure rats, unpaced heart failure rats and heart failure rats paced by the respiratory CPG. This, now published, study shows that CPG pacing increased cardiac output and stroke volume by restoring respiratory sinus arrhythmia compared to monotonic pacing via an improvement in systolic function that persists beyond the pacing treatment period. This result is highly encouraging as a potential cure for patients with congestive heart failure and is currently being evaluated for improving existing pacemakers.

We have conducted successful large animal trials of miniature O2, CO2 arterial gas sensors, blood pressure sensors, and lung inflation sensors as well as the telemetry linking these implants together with a base station.

We have built an adaptive VLSI model of the medullary central pattern generators at the base of the brain that describe the adaptation of heart rate, atrio-ventricular delay, inter-atria delay and respiratory sinus arrhythmia to changes in blood pressure and respiration patterns. Adaptation to O2 and CO2 is currently being evaluated. However the model is now sufficiently advanced to be transferred in silico to replicate the adaptation of cardiac function to key physiological feedback.

The last phase of the project will see the pacemaker being integrated and tested in animal trials. Existing findings are in the process of being evaluated for translation, IP protection and further publications.
a. The significant improvements of cardiac function induced by reinstating respiratory sinus arrhythmia In animal models of heart failure is likely to relieve the burden of heart failure in human patients. Additional studies in large animal models are being conducted by a private company. The finding are also being evaluated by a large medical device manufacturer for improving existing pacemakers.
b. The technology for miniaturizing arterial gas sensors and blood pressure sensors has matured to the point where these sensors may be translated to a wider range of bioelectronic devices which will increase the quality of life of patients by monitoring and adapting to physiological feedback in-vivo.
c. The methods and knowhow we have developed while building adaptive bioelectronics in the context of cardiac resynchronization therapy form a body of knowledge that may now be transposed to other fields, for example training neural networks to provide therapies to other chronic diseases (e.g. spinal cord injury) and to provide biocircuits that can be used to repair biological circuits lost to disease (Alzheimer, channelopathies).
d. Key recent findings have been published in Nature Communications (Dec 2019) and the Journal of Physiology (Dec 2019).