Our EPSRC CDT in Advanced Engineering for Personalised Surgery & Intervention will train a new generation of researchers for diverse engineering careers that deliver patient and economic impact through innovation in surgery & intervention. We will achieve this through cohort training that implements the strategy of the EPSRC by working across sectors (academia, industry, and NHS) to stimulate innovations by generating and exchanging knowledge. Surgery is recognised as an "indivisible, indispensable part of health care" but the NHS struggles to meet its rising demand. More than 10m UK patients underwent a surgical procedure in 2021, with a further 5m patients still requiring treatment due to the COVID-19 backlog. This level of activity, encompassing procedures such as tumour resection, reconstructive surgery, orthopaedics, assisted fertilisation, thrombectomy, and cardiovascular interventions, accounts for a staggering 10% of the healthcare budget, yet it is not always curative. Unfortunately, one third of all country-wide deaths occur within 90 days of surgery. The Department of Health and Social Care urges for "innovation and new technology", echoing the NHS Long Term Plan on digital transformation and personalised care. Our proposed CDT will contribute to this mission and deliver mission-inspired training in the EPSRC's Research Priority "Transforming Health and Healthcare". In addition to patient impact, engineering innovation in surgery and intervention has substantial economic potential. The UK is a leader in the development of such technology and the 3rd biggest contributor to Europe's c.150bn euros MedTech market (2021). The market's growth rate is substantial, e.g., an 11.4% (2021 - 2026) compound annual growth rate is predicted just for the submarket of interventional robotics. The engineering scientists required to enhance the UK's societal, scientific, and economic capacity must be expert researchers with the skills to create innovative solutions to surgical challenges, by carrying out research, for example, on micro-surgical robots for tumour resection, AI-assisted surgical training, novel materials and theranostic agents for "surgery without the knife", and predictive computational models to develop patient-specific surgical procedures. Crucially, they should be comfortable and effective in crossing disciplines while being deeply engaged with surgical teams to co-create technology solutions. They should understand the pathway from bench-to-bedside and possess an entrepreneurial mindset to bring their innovations to the market. Such researchers are currently scarce, making their training a key contributor to the success of the UK Government's "Build Back Better - our plan for growth" and UKRI's "five-year strategy". The cross-discipline collaboration of King's School of Biomedical Engineering & Imaging Sciences (BMEIS, host), Department of Engineering, and King's Health Partners (KHP), our Academic Health Science Centre, will create an engineering focused CDT that embeds students within three acute NHS Trusts. Our CDT brings together 50+ world-class supervisors whose grant portfolio (c.£150m) underpins the full spectrum of the CDT's activity, i.e., Smart Instruments & Active Implants, Surgical Data Science, and Patient-specific Modelling & Simulation. We will offer MRes/PhD training pathway (1+3), and direct PhD training pathway (0+4). All students, regardless of pathway, will benefit from continuous education modules which cover aspects of clinical translation and entrepreneurship (with King's Entrepreneurship Institute), as well as core value modules to foster a positive research culture. Our graduates will acquire an entrepreneurial mindset with skills in data science, fundamental AI, computational modelling, and surgical instrumentation and implants. Career paths will range from creating next generation medical innovators within academia and/or industry to MedTech start-up entrepreneurs.

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.

Medical imaging has transformed clinical medicine in the last 40 years. Diagnostic imaging provides the means to probe the structure and function of the human body without having to cut open the body to see disease or injury. Imaging is sensitive to changes associated with the early stages of cancer allowing detection of disease at a sufficient early stage to have a major impact on long-term survival. Combining imaging with therapy delivery and surgery enables 3D imaging to be used for guidance, i.e. minimising harm to surrounding tissue and increasing the likelihood of a successful outcome. The UK has consistently been at the forefront of many of these developments. Despite these advances we still do not know the most basic mechanisms and aetiology of many of the most disabling and dangerous diseases. Cancer survival remains stubbornly low for many of the most common cancers such as lung, head and neck, liver, pancreas. Some of the most distressing neurological disorders such as the dementias, multiple sclerosis, epilepsy and some of the more common brain cancers, still have woefully poor long term cure rates. Imaging is the primary means of diagnosis and for studying disease progression and response to treatment. To fully achieve its potential imaging needs to be coupled with computational modelling of biological function and its relationship to tissue structure at multiple scales. The advent of powerful computing has opened up exciting opportunities to better understand disease initiation and progression and to guide and assess the effectiveness of therapies. Meanwhile novel imaging methods, such as photoacoustics, and combinations of technologies such as simultaneous PET and MRI, have created entirely new ways of looking at healthy function and disturbances to normal function associated with early and late disease progression. It is becoming increasingly clear that a multi-parameter, multi-scale and multi-sensor approach combining advanced sensor design with advanced computational methods in image formation and biological systems modelling is the way forward. The EPSRC Centre for Doctoral Training in Medical Imaging will provide comprehensive and integrative doctoral training in imaging sciences and methods. The programme has a strong focus on new image acquisition technologies, novel data analysis methods and integration with computational modelling. This will be a 4-year PhD programme designed to prepare students for successful careers in academia, industry and the healthcare sector. It comprises an MRes year in which the student will gain core competencies in this rapidly developing field, plus the skills to innovate both with imaging devices and with computational methods. During the PhD (years 2 to 4) the student will undertake an in-depth study of an aspect of medical imaging and its application to healthcare and will seek innovative solutions to challenging problems. Most projects will be strongly multi-disciplinary with a principle supervisor being a computer scientist, physicist, mathematician or engineer, a second supervisor from a clinical or life science background, and an industrial supervisor when required. Each project will lie in the EPSRC's remit. The Centre will comprise 72 students at its peak after 4 years and will be obtaining dedicated space and facilities. The participating departments are strongly supportive of this initiative and will encourage new academic appointees to actively participate in its delivery. The Centre will fill a significant skills gap that has been identified and our graduates will have a major impact in academic research in his area, industrial developments including attracting inward investment and driving forward start-ups, and in advocacy of this important and expanding area of medical engineering.

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.

Digital twins are a fusion of digital technologies considered by many leading advocates to be revolutionary in nature. Digital twins offer exciting new possibilities across a wide range of sectors from health, environment, transport, manufacturing, defence, and infrastructure. By connecting the virtual and physical worlds (e.g. cyber-physcial), digital twins are able to better support decisions, extend operational lives, and introduce multiple other efficiencies and benefits. As a result, digital twins have been identified by government, professional bodies and industry, as a key technology to help address many of the societal challenges we face. To date, digital twin (DT) innovation has been strongly driven by industry practitioners and commercial innovators. As would be expected with any early-adoption approach, projects have been bespoke & often isolated, and so there is a need for research to increase access, lower entry costs and develop interconnectivity. Furthermore, there are several major gaps in underpinning academic research relating to DT. The academic push has been significantly lagging behind the industry pull. As a result, there is an urgent need for a network that will fill gaps in the underpinning research for topics such as; uncertainty, interoperability, scaling, governance & societal effects. In terms of existing networking activities, there are several industry-led user groups and domain-specific consortia. However, there has never been a dedicated academic-led DT network that brings together academic research teams across the entire remit of UKRI with user-led groups. DTNet+ will address this gap with a consortium which has both sufficient breadth and depth to deliver transformative change.