In the UK, approximately 142,000 people are admitted to Intensive Care Units (ICU) each year. A large proportion of these patients have life-threatening pulmonary illness and require mechanical ventilation; the mortality rate in this group is around 35%, and even survival may bring ongoing suffering lasting years after discharge. Critical pulmonary disease thus has enormous financial impact and represents a significant burden of suffering for the general population. Despite years of research, there has been a lack of progress in our understanding of critical illness and in our ability to personalise treatment. Traditional clinical research approaches (using randomised clinical trials) have been costly and often inconclusive, and have provided disappointing improvements in critical care (diagnosis, survival, cost-effectiveness). The development of more effective personalised treatments for this patient population would therefore have significant national and global impact. In this project, we will develop novel methods for personalising and optimising the therapy delivered in the ICU. We will work closely with our business and clinical partners to transfer our high-fidelity modelling technologies from the research lab to the ICU, in order that real-time, personalised, patient simulation can be achieved with the aim of guiding the treatment of critical illness. This approach offers potentially "low-cost" improvements in patient-care, since it is based on smarter strategies and technologies that exploit and optimise multiple interventions, without requiring expensive new pharmaceuticals or devices. Using large-scale integration of incoming data streams from routine patient monitoring, our technology will allow us to establish a matched simulation of an individual patient's physiology. The resulting personalised bedside simulation will allow clinicians to test planned interventions and to estimate vital parameters in the patient that would otherwise be inaccessible. In addition to acting passively, the technology will proactively advise on optimised treatment strategies that are expected to improve patient outcome. The technology will scan the patient's treatment and physiological data continually, seeking potential improvements in management, and testing proposed treatment strategies by applying them to the personalised simulation and assessing outcome. Personalised optimisation of critical care treatment offers the opportunity to improve patient outcomes and reduce days spent receiving mechanical ventilation in the intensive care unit, and has the potential for enormous impact in terms of reducing patient suffering and healthcare expenditure. We will make this potential a reality by working closely with our business partner Medtronic (the world's largest standalone medical technology development company, and a leading ventilator manufacturer) and with our clinical partner Prof. Luigi Camporata, a consultant in intensive care medicine at Guy's and St Thomas' NHS Foundation Trust (one of the UK's leading centres for research on the treatment of critical illness).

TRANSFORMATIVE RESEARCH VISION We aim to create a platform of wirelessly networked therapeutic implants which are powered by harvesting energy from the body's own energy supply: glucose. The use of energy harvesting will allow for much smaller implants with much easier surgical implementation, and thus much wider use. The ability of multiple implants to reliably communicate with each other will allow for new types of personalised medical therapies. In particular, it will allow for tuning of the therapeutic interventions according to sensed information from across the body. CLINICAL APPLICATION SPACE Across the world, societies are rapidly ageing, so a key challenge is to ensure healthy optimal lifespans for as many as possible. Drug therapies have been improving, but it can be difficult to optimally modulate or tune the body's function to the normal daily cycle. So, in recent years there has been a surge of interest in bioelectronic solutions. For example, SetPoint Medical just received FDA approval (Autumn 2020) for a vagal nerve implant to treat arthritis. Here in the UK, Galvani is hoping to achieve similar success with trials already underway. Bioelectronics has many modes of operation - including pacemakers for heart, brain and body, sensory restoration (for the deaf and blind), and short-term healing applications such as supporting opioid withdrawal. The market is therefore very large, and expected to grow rapidly in the coming decades. In the first instance, we will target Cardiac Arrhythmias. WHY OUR TEAM? We have brought together a leading UK team of bioelectronic experts with knowledge in microelectronics, ultrasonic communication, micro-fuel cells, artificial intelligence, and medical device design to push this project forward. Furthermore, three of the team have direct experience in the medical technology industry, and we have separately been involved in multiple large clinical translation projects. We strongly believe we can achieve success in this high-risk, high-reward project as we have already created working pre-requisites for each of the components. WHY NOW? Bioelectronic implants have steadily been reducing in size. The Medtronic Micro cardiac pacemaker now has the diameter of a marker pen. However, further miniaturisation is difficult because implantable batteries need to be armoured. Further decreases in size will make battery capacity negligible given the minimum dimensions of the armour plate. Furthermore, existing implants act as independent entities and can only sense in their immediate vicinity. As such it is difficult, for example, to fully synchronise the left and right ventricle stimulation of the heart. Similarly synchronous stimulus of an internal organ, e.g. the liver or pancreas, according to clinical signs elsewhere in the body is currently very challenging, if not impossible. UNDERPINNING INNOVATIONS: our proposal is based on two breakthrough capabilities that we have been developing in respective labs, and are only now becoming possible: 1. GLUCOSE ENERGY HARVESTING: We are now able to harvest sufficient energy to drive a cardiac pacemaker from glucose in the body's interstitial fluid. At the core of the harvester is a fuel cell that uses metallic-nanostructured catalysts with an architecture scalable to long term operation inside the body. 2. RELIABLE ULTRASONIC INTRABODY COMMUNICATIONS: We have developed a prototype ultrasound communication scheme with in-built error correction, which can, for the first time, allow for reliable communication between disperse implants. When optimised for use in intrabody networks, our system will allow for dispersed sensing and intelligence not currently possible.

OpenBar is a European infrastructure for supporting and assisting Medtech companies, including start-ups and SMEs, in their development of innovative medical devices. OpenBar offers support from the stage of proof of concept at the laboratory scale (TRL4) until the submission of the regulatory dossier to the notified body. This accompaniment includes the design consultancy, the regulatory tests foreseen in the new European regulatory framework MDR and IVDR, the preparation of the scale up manufacturing, the techno-economic studies and the support for industrial development. Medical devices analyzed by OpenBar should be ready for the submission of their regulatory dossier (TRL7) prior to market access. The objective of OpenBar is to reduce the costs and times of development of medical devices and of their regulatory approval. OpenBar is positioned upstream to the CRO (Contract Research Organisations) and the Notified Bodies, with which it collaborates. OpenBar has the ambition to serve any European company of any size, developing innovative medical devices in the field of in vitro diagnostics (IVDM), Active implanted devices (AIMD) and non-active devices (NAMD). It is associated with a large network of partners associated with the 15 European Medtech clusters and 5 professional unions. In parallel with its mission of supporting medtech companies, OpenBar is also developing a programme for the development, validation and even standardization of new tests for the evaluation of the safety of medical devices to meet the new requirements imposed by the two new European directives MDR and IVDR. These include studies of biocompatibility, clinical efficacy, usability (human factor), medical software and the management of personal health data. OpenBar offers a unique European entry point to a range of scientific, technical, economic and regulatory competences in the field of innovative medical devices, served by a consortium composed of the 4 largest Research and Technology Organisations, University Hospitals, universities, private companies, SMEs, investors and consultants. This unique set of partners specializing in the development and the market access of innovative medical devices offers access to its infrastructure of testing and development laboratories, centers of pre-clinical and clinical studies. OpenBar aims to become a sustainable organisation beyond the European funding period. A business plan will be delivered at the end of the project.

As minimally invasive surgery is being adopted in a wide range of surgical specialties, there is a growing trend in precision surgery, focussing on early malignancies with minimally invasive intervention and greater consideration on patient recovery and quality of life. This requires the development of sophisticated micro-instruments integrated with imaging, sensing, and robotic assistance for micro-surgical tasks. This facilitates management of increasingly small lesions in more remote locations with complex anatomical surroundings. The proposed programme grant seeks to harness different strands of engineering and clinical developments in micro-robotics for precision surgery to establish platform technologies in: 1) micro-fabrication and actuation; 2) micro-manipulation and cooperative robotic control; 3) in vivo microscopic imaging and sensing; 4) intra-operative vision and navigation; and 5) endoluminal platform development. By using endoluminal micro-surgical intervention for gastrointestinal, cardiovascular, lung and breast cancer as the exemplars, we aim to establish a strong technological platform with extensive industrial and wider academic collaboration to support seamless translational research and surgical innovation that are unique internationally.