Acute liver failure (ALF) is a medical emergency that carries mortality of 80-90% in patients who fulfill liver transplant criteria. Liver transplantation depends on the timely availability of a suitable donor organ and requires life-long immunosuppression with life-threatening complications. Alternatively, the liver has a tremendous regenerative potential: if the failing liver could be supported until regeneration occurs, organ replacement and its associated complications can be avoided. Currently there is no proven liver support device available that can bridge the patient to native liver recovery or to transplant. It has been demonstrated that partial replacement of a patient's liver with a healthy donor liver (called an auxiliary transplantation) can allow clinical stability during native liver regeneration, eventually making the transplanted liver redundant, in up to 70% of the patients. For this, only a small mass of liver tissue is necessary to support the patient. Auxiliary transplant still requires availability of a suitably sized organ, major surgery, and immunosuppression, however. Transplantation of hepatocytes (cells rather than an organ) has been shown to improve synthetic and detoxification function in small animal models with subsequent human application in patients with ALF. The advantages of hepatocyte transplantation in this context are considerable. For example, (i) hepatocytes may be derived from livers which are unsuitable for transplantation; (ii) isolated cells can be frozen for years and used off-the-shelf, something that is impossible with entire organs, thereby eliminating the wait for an appropriate organ; (iii) cells isolated from one liver could treat more than one patient, thereby reducing the need for donor organs; and (iv) this provides options to infants and small children for whom the wait for an appropriately sized organ may be extremely prolonged. Earlier clinical experiences with human hepatocytes in ALF have been only partly successful when cells were injected either in the liver, or the peritoneal cavity, mainly because of rejection and use of immunosuppression in extremely sick patients, which increases the risk of infections. We have developed a technique using liver cells encapsulated in a bio-compatible gel (hepatocyte microbeads - HMB001) that can be infused temporarily in the peritoneal cavity of the patient, to replace the failing liver until regeneration. Importantly, the gel protects the cells from the immune system. The patients therefore do not require immunosuppression. We have previously treated 8 children and infants with HMB001 on a named patient basis (compassionate use). The technique proved to be safe and, importantly, displayed some efficacy: though all children met eligibility for organ transplantation, 4 children recovered with the treatment while awaiting transplant thus entirely avoiding the need for liver transplantation and are still well, up to 8 years after the procedure. We have refined our prototype of hepatocyte microbeads, which now involves multiple cell types and an improved gel that better supports the cell function (HMB002). The new microbeads have shown superior function and longevity in vitro as well as in vivo, in preclinical studies. The aim of this project is to run a clinical trial to test these new microbeads.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

What is the link between blood clotting and liver disease? Liver disease is common and is now the largest cause of death in adults aged 30 to 59 years of age. Two serious complications of liver disease are bleeding and blood clots (thrombosis). Bleeding affects up to 1 in 10 adults with liver disease per year and blood clots up to 1 in 20 adults with liver disease per year. Most bleeding is due to pressure changes in the blood vessels in the abdomen leading to swelling of veins around the oesophagus (called varices). What is known about blood clotting in liver disease? The liver produces many of the substances involved in blood clotting, and patients with liver disease often have marked abnormalities in blood clotting measured with routinely available tests. This is because routinely available tests only measure the effect of proteins which increase blood clotting (pro-coagulants). In liver disease, the proteins which reduce blood clotting (anti-coagulants) are also reduced and overall, clotting is thought to be 'rebalanced'. Specialist tests (thrombin generation and thromboelastography) which are able to measure either the effect of the body's anti-coagulants or blood cells demonstrate that clotting is actually normal or increased in most patients with liver disease. Why are blood tests to measure blood clotting in liver disease important? Current routine tests are poor at predicting bleeding and clotting complications in patients with liver disease. Because the blood clotting tests in patients with liver disease look abnormal, treatments like transfusion of plasma (blood clotting proteins), platelets (small cells important for blood clotting) or fibrinogen (the final protein needed for blood clot formation) may be given to try and improve the blood test results, even though this might not reduce the risk of bleeding. In patients who are bleeding, the treatment approach is based on studies in different patient groups such as trauma where plasma transfusion has been shown to improve outcomes. In liver disease, studies show treatment with plasma can worsen bleeding from varices by increasing the pressure in the veins. Patients with liver disease are also at increased risk of thrombosis; most patients in hospital are given medications to reduce the risk of thrombosis ('blood thinners' or anticoagulants) but due to the changes seen on routine laboratory tests, doctors sometimes worry these medications might increase the risk of bleeding. Balancing the risks of bleeding and thrombosis and deciding which blood test results should be treated can be very difficult. This is particularly important in seriously ill patients as they are at higher risk of bleeding and thrombosis, and often need multiple procedures. What will I do? I will look at specialist blood tests (thrombin generation, thromboelastography, neutrophil extracellular traps) in patients with liver disease admitted to intensive care to see whether these tests could be used routinely to guide the need for transfusion and predict the risk of bleeding or thrombosis. I will also look at whether these tests remain the same over time and how transfusion changes the results. Why is this research important? As current tests are not helpful, many patients get transfusions when they probably don't need to. This is wasteful, costly and puts patients at risk of side effects. This is important both for patients with liver disease and bleeding (4000/year) and those having procedures/operations. Better tests will reassure doctors when transfusion is not needed and will improve management of bleeding complications and prevention of thrombosis in hospital.

The NHS spending is expected to increase from 70 billion a year to more than 90 billion by 2007/8 but this may not be enough for the government to achieve the planned health care delivery targets because it faces new challenges such as the increasing demands of a population that is living longer. Patients will only benefit from this increase in spending if the health care delivery system is more efficient and effective. Discrete event simulation modelling has been touted as an ideal tool in assisting decision makers in bringing about efficiency in health care as it is able to model its inherent complexity and variability and as a result hundreds of simulation models have been built over the last 30 years but only a handful of these have reported implementation or have impacted on policy. Evidence suggests that one factor inhibiting implementation is the limited participation of health care decision makers and stakeholders in the model development. The most important part of model development is conceptual modelling because it is about deciding what and how to model. Currently there are no formal approaches to aid the development of conceptual models in health care. We propose to develop an approach stemming from the problem structuring field of Operational Research that will specifically aim to help health care administrators and clinicians take a more active part in the development of health care conceptual models. We also expect that a more active part will lead them to buy in to the process and findings and to support their implementation. Finally, we expect that this will enable both expert and novice modellers to build more relevant discrete event simulation models in health care by better communicating with stakeholders.

Medical imaging has made major contributions to healthcare, by providing noninvasive diagnostics, guidance, and unparalleled monitoring of treatment and understanding of disease. A suite of multimodal imaging modalities is nowadays available, and scanner hardware technology continues to advance, with high-field, hybrid, real-time and hand-held imaging further pushing on technological boundaries; furthermore, new developments of contrast agents and radioactive tracers open exciting new avenues in designing more targeted molecular imaging probes. Conventionally, the individual imaging components of probes and contrast mechanisms, acquisition and reconstruction, and analysis and interpretation are addressed separately. This however, is creating unnecessary silos between otherwise highly synergistic disciplines, which our current EPSRC CDT in Medical Imaging at King's College London and Imperial College London has already started to successfully challenge. Our new CDT will push this even further by bridging the different imaging disciplines and clinical applications, with the interdisciplinary research based on complementary collaborations and new research directions that would not have been possible five years ago. Through a comprehensive, integrated training programme in Smart Medical Imaging we will train the next generation of medical imaging researchers that is needed to reach the full potential of medical imaging through so-called "smart" imaging technologies. To achieve this ambitious goal we have developed four new Scientific Themes which are synergistically interlinked: AI-enabled Imaging, Smart Imaging Probes, Emerging Imaging and Affordable Imaging. This is complemented by a dedicated 1+3 training programme, with a new MRes in Healthcare Technologies at King's as the foundation year, strong industry links in form of industry placements, careers mentoring and workshops, entrepreneurship training, and opportunities in engaging with international training programmes and academic labs to become part of a wider cohort. Cohort building, Responsible Research & Innovation, Equality, Diversity & Inclusion, and Public Engagement will be firmly embedded in this programme. Students graduating from this CDT will have acquired a broad set of scientific and transferable skills that will enable them to work across the different medical imaging sub-disciplines, gaining a high employability over wider sectors.