Periodic Reporting for period 3 - CResPace (Adaptive Bio-electronics for Chronic Cardiorespiratory Disease) Reporting period: 2020-01-01 to 2021-06-30 Summary of the context and overall objectives of the project 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 networksb. an integrated circuit of the respiratory central pattern generatorc. a central pattern generator designed to reproduce beat-to-beat cardiac resynchronization and an evaluation of its safety enveloped. an intelligent cardiac resynchronization pacemaker that respond to physiological feedback and its clinical benefits Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The third reporting period has delivered a full study of the neuronal pacemaker safety. This study found that the timing of cardiac pulses remains stable with respect to noise and temperature changes thanks to the robustness of dynamic limit cycles underpinning pulse generation. High magnetic fields, emulating magnetic resonance imaging, were further found to minutely alter the timing of pacing pulses on a scale one thousandth of the natural heart rate variability induced by breathing. Fortunately, all those data were acquired prior to the COVID pandemic which allowed several papers to be submitted during the period adding to those published earlier. Elsewhere the intellectual property on computational methods to diagnose channelopathies and physiological sensors (WP7) are being protected and translated with the help of commercial partners. A second generation of physiological sensors has been produced and is being tested. The 17% increase in cardiac output in chronic rodent models of heart failure paced by CPG was a major result validating the importance of our RSA pacing. This study is now published in J.Physiol. 598, 455-4721 (2020). The shutdown of trial facilities and laboratories during the COVID lockdown has put the planned trials on hold and delayed the scaling of the pacemaker on a VLSI chip. As a result, the consortium has opted to produce and test a partially implantable neuronal pacemaker wirelessly integrating sensors, pacing unit and monitoring station. Although significant work remains, the technology is now trial ready, and the consortium has a strong pipeline of translational opportunities being exploited and publications for the next period and beyond. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) 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). picture3.png
