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).

Every year chronic diseases, including neurodegenerative and cardiac diseases, cause 40 million deaths worldwide. This toll is predicted to double in the next twenty years, based on an ageing population, population growth and unhealthy lifestyles. In the UK, chronic conditions are the leading cause of deaths and disability, affecting approximately one in three of adults. GLUTRONICS seeks to enhance the quality of life of the millions worldwide affected by chronic conditions, and reduce the incidence of the associated premature deaths, by advancing the progress on implantable bioelectronics for personalised therapy though long-lasting, lightweight and miniature implantable power sources. The use of bioelectronics in healthcare is fast-growing; the UK government has recognised as critical the development of innovative technologies, such as neuromodulators and electroceuticals, that can support preventative, personalised and digitalised care by enabling real-time monitoring, informing on disease progression, and providing tailored intervention. Nonetheless, current implantable medical devices are invasive, primarily due to the need for a power source, typically lithium-ion batteries, which can represent over 80% of the total volume and weight of a device. Lithium batteries hinder long-term use and comfortable deployment of medical devices because are difficult to miniaturise and require high-risk routine surgeries for replacement. As an example, the neurostimulation of the cervical vagus nerve for the treatment of patients affected by epilepsy, requires the implantation of the bulky pacemaker battery in the chest (approximately the size of a tea bag of 20-50 gr), which is connected to electrodes located in the neck via extension wires. In the UK, there are approximately 60,000 children who suffer from epilepsy and may need to have such an invasive device implanted in their body. Moreover, although the neuromodulation of the vagus nerve has shown potential therapeutic benefits for several conditions, including depression, attention disorder and Parkinson's, the invasiveness of current bioelectronic devices, and the consequent major intervention their installation would require, makes their use for these conditions unpractical. GLUTRONICS will lead to a new generation of bioelectronics that are powered by the sugars naturally present in physiological fluids with cutting-edge glucose fuel cells. With a team's experience spanning research on fundamental science (electrocatalysis, glucose fuel cells, mathematical modelling), proof-of-concept trials in animals, in-human studies, regulatory approvals, and commercial translation, and with a cohort of industrial collaborators, GLUTRONICS will globally lead innovation on implantable glucose fuel cells. This success will be possible by: i) generating stable and biocompatible, fully-integrated abiotic glucose fuel cell designs, optimised for maximum power extraction; ii) creating a safe implantation design and an artificial subcutaneous pocket that enables long-term operations thanks to a continuous replenishment of glucose and minimum biofouling risks; iii) creating an implantable monitoring system to measure daily rhythms for tailored in vivo energy management. Load cell tests, both in vitro and in vivo, will simulate the powering of a neuromodulator (power demand >1µW). Chronic tests in large animal models (i.e., pigs), in surgical sites that align with potential areas of application, will demonstrate the clinical potential of the proposed technology. Technical, legal and ethical challenges in the research will be considered via dedicated co-creation activities and several other engagement initiatives, which will provide inputs from a diverse range of stakeholders (patients, carers, clinicians, Med Tech experts, health economists, policymakers) and enable responsible innovation.

Millions of medical devices are surgically implanted every year, with annual sales approaching US$500 billion worldwide. Failure of implanted devices designed to be permanent can be as high as 20%, impacting patients' quality of life and burdening health services. Glucose sensors are used by most diabetics in the UK, with fine needle electrodes to sense glucose in the outermost tissue - they have recommended lifetimes of only 10-14 days because foreign body encapsulation renders them inaccurate, with each disposable unit costing £50. The foreign body response (FBR) is the hostile immune cell reaction of the body to implants, with chronic inflammation, infection and fibrosis being the major underlying causes of implant failure. With sustained support from Wellcome Trust and EPSRC over the last fifteen years, including a current Large Grant, we are developing novel cell-instructive polymers to reduce and ultimately eliminating medical device failure. To underpin cell-instructive polymer development, we need to be able to monitor the response of the body to novel implants in real-time. Only a snapshot of the complex biological interplay between inflammatory pathways is provided by current histological assessment of inflammatory responses measured on explants. The lack of technology to sense real-time changes of these complex processes hampers our ability to comprehensively understand these intricate inflammatory mechanisms in the hunt for polymers providing the best implant outcomes. We propose the development of a disruptive method to achieve continuous, minimally invasive monitoring of implants in both animal models and humans. Longitudinal real-time measurements of signature inflammatory markers and FBR will be made possible using an innovative wireless bioelectronic approach: conductive nanoantennae will be decorated with antibodies to achieve continuous and minimally invasive electrical monitoring of cytokines and macrophages in a multiplexed fashion. This novel wireless monitoring method will allow us to assess new polymers in situ in real-time, aiding their successful development. When used in humans, sensing will allow the continuous monitoring of the body's response to the new implant and therefore faster and better therapies that will ultimately improve implant success, patient outcomes and savings for healthcare providers. It will have broader application in the clinic for a variety of conditions where (device-unrelated) fibrosis is the source of morbidity and mortality. People with diabetes suffer disproportionately from adverse implant reactions as well as chronic wounds. Through a clinical partnership with a diabetologist, we will develop an impedance sensor that does not require nanoantenna injection for earlier clinical adoption proved on glucose monitors worn by healthy volunteers. This proposal has been co-developed by our interdisciplinary and international team, integrating expertise in cell-instructive materials, immunology, analytic devices engineering, clinical application and medical device commercialisation. The scope spans EPSRC, MRC and BBSRC remits, making it challenging for a single council and review college to fully address the multifaceted expertise and methodological range assembled to tackle this unmet need. Benefits for the biomaterials and medical device fields include mechanistic understanding and acceleration of the novel device development process which will speed impact through MedTech products to improve options for clinicians. Immunologists will better understand the kinetics of the inflammatory response enabling more complete mechanistic descriptions. Reciprocal benefits for the rapidly advancing bioelectronics discipline will be through the clinical and pre-clinical examples it will deliver, along with the methodological experience that will be contained within the journal publications and patent filings.

Networks of Cardiovascular Digital Twins (CVD-Net): Transforming Healthcare through Personalised Predictive Modelling The Networks of Cardiovascular Digital Twins (CVD-Net) Programme Grant aims to revolutionise healthcare by harnessing the power of digital twin (DT) technology. Patient DTs are virtual replicas that continuously assimilate patient data into sophisticated models to provide personalised predictions and inform clinical decisions. Healthcare, despite its national importance (consuming 12% of GDP, generating £70 billion/year and 240,000 jobs), remains unserved by DT technologies. CVD-Net will build a critical mass of research around patient DTs for healthcare, identify the challenges and opportunities in the clinical setting, and provide a roadmap for NHS implementation. We take the view that we must begin by focussing on a specific clinical use case, and that we need to learn by doing, using real-world data, on clinical timescales and making testable predictions. We propose a flexible Programme structure built around developing a minimum viable DT, then testing, optimising, and evaluating the this over iterative design cycles. We focus on pulmonary arterial hypertension (PAH), a life-threatening cardiovascular disease with high mortality and adverse event rates, as a specific use case to develop a demonstrator NHS DT care pathway. The public and patients are receptive to the idea of DTs with 90% (173/196) agreeing with the statement "I would find a digital twin smartphone app that represents my individual cardiovascular health useful". PAH patients suffer high mortality, frequent clinical worsening events and are served by a limited number of national centres. These high event rates and concentration of patients make it possible (and important) to develop and test the forecasting capabilities of a DT in proof-of-concept studies within CVD-Net. Our objective is to create a comprehensive patient DT that can monitor and forecast disease progression, treatment response, and quality of life for individual patients. The DTs will combine data from hospitals, wearable and implantable sensors, and patient-reported outcomes. To realise DTs at the scale and speed of a clinical service, we propose a novel networking approach, where individual "digital threads" (within a DT) will be 'woven' together to form an interconnected 'digital tapestry' to facilitate shared learning and communication. We will utilise innovative techniques including knowledge graphs, transfer learning, federated learning, and meta-learning to address scalability, variability, uncertainty, and data security challenges. We have brought together a unique interdisciplinary team of engineers, clinicians, computational statisticians, and research engineers to deliver CVD-Net. We will access retrospective and collect prospective data to train, test and validate the network of DTs. We will build the IT infrastructure, and analysis workflows to run a demonstrator DT care pathway within the NHS infrastructure. We will work with patients, clinicians, and stakeholders to assess its usability and added value. Via stakeholder engagement, we will evaluate the feasibility, scalability, and wider adoption potential of networked patient DTs in patient care. By generating robust evidence and understanding patient, clinician, and policy considerations, by completion of CVD-Net, we aim to have moved DTs towards prospective evaluation in a clinical trial. Ultimately, CVD-Net has the potential to transform healthcare by providing personalised predictive modelling, enhancing clinical decision-making, and improving patient outcomes. Its applications will benefit patients, clinicians, policymakers, and the research community, making healthcare more precise and efficient while contributing to the transformation of NHS care.

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.