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.

Definition: A rapidly developing area at the interfaces of engineering/physical sciences, life sciences and medicine. Includes:- cell therapies (including stem cells), three dimensional cell/ matrix constructs, bioactive scaffolds, regenerative devices, in vitro tissue models for drug discovery and pre-clinical research.Social and economic needs include:Increased longevity of the ageing population with expectations of an active lifestyle and government requirements for a longer working life.Need to reduce healthcare costs, shorten hospital stays and achieve more rapid rehabilitationAn emergent disruptive industrial sector at the interface between pharmaceutical and medical devicesRequirement for relevant laboratory biological systems for screening and selection of drugs at theearly development stage, coupled with Reduction, Refinement, Replacement of in vivo testing. Translational barriers and industry needs: The tissue engineering/ regenerative medicine industry needs an increase in the number of trained multidisciplinary personnel to translate basic research, deliver new product developments, enhance manufacturing and processing capacity, to develop preclinical test methodologies and to develop standards and work within a dynamic regulatory environment. Evidence from N8 industry workshop on regenerative medicine.Academic needs: A rapidly emerging internationally competitive interdisciplinary area requiring new blood ---------------------

Parkinson's disease (PD) is the second most common neurodegenerative disorder (second only to Alzheimer's disease). It is characterized by a progressive loss of motor ability over time. Partly due to the world's ageing population, PD is now one of the leading causes of disability worldwide. We know that PD is associated with a loss of dopamine cells in the brain. Treatment with dopamine replacement medications is highly effective in the early stages of the disease. Unfortunately however, over time, people become resistant to this medication, and develop new motor symptoms as a result. The symptoms that are particularly resistant to dopamine medications include balance impairment, and changes to the way people walk. As these complications progress, they impair quality of life, and eventually lead to falls and a loss of independence. We know that a small region of the brainstem, called the pedunculopontine nucleus (PPN), is involved in the control of balance and walking. We also know, primarily from work in animals, that the PPN can influence dopamine levels in the brain regions from which dopamine is lost in PD. However, we understand very little about the PPN and how it is connected with the rest of the brain in humans. As a result, therapies that have been developed to target the PPN have so far failed to meet our clinical expectations for improving balance and walking impairments. There are two recent technological advances that will help us to address this problem. First, new advances in how we image the brain have recently made it possible to examine the structure of the brain in more detail. Our study will apply these advances to investigate how the PPN might be targeted for new treatment strategies in PD. Second, we will take advantage of a new development in deep brain stimulation technology. Deep brain stimulation is a treatment for PD that applies electrical stimulation to the regions of brain that become disrupted by the disease. This is a highly effective treatment, but it does not work for everyone, and is extremely costly and invasive. When the deep brain stimulation electrodes are implanted in the brain however, researchers can record from the electrodes to understand more about how PD effects the brain. This approach has lead to the understanding that activity in the brain regions targeted by deep brain stimulation is aberrant in PD, and that this activity can be 'normalised' by dopamine medication. Until very recently these recordings could only be made around the time of the brain surgery, when people are generally immobile and fatigued. Now however, it is possible to record from the electrodes wirelessly, meaning people can fully recover from the surgery before taking part in research. As a result, we can now ask people to carry out some of the motor tasks that we know depend on the PPN, and record brain activity at the same time. By combining the information we can get about the brain from these two technologies when people are on and off their dopamine medications, we have the opportunity to examine how the PPN modifies how the brain uses dopamine to perform motor functions in the human for the first time. We can also examine how the PPN might participate in treatment responses to both dopamine replacement and deep brain stimulation. These findings will guide the development of new therapies that can target the PPN, and will enable us to personalise current treatment approaches to improve their effectiveness