d-LIVER applies scenario-driven development methodologies to address an unmet need for bio-artificial liver support via continuous detoxification as remote transient therapy at the Point-of-Need. The liver is a complex organ with various vital functions in synthesis, detoxification and regulation; its failure is life-threatening and the only curative treatment is transplantation. Whilst awaiting transplantation, or after liver resection, patients need to be supported with detoxification systems which, currently mainly based on filtration, do not support metabolic liver function. This can only be provided by living cells. Thus, development of ICT-enabled bio-artificial liver support systems with associated remote monitoring to assist in the treatment and management of liver patients in care settings extending from the hospital to the home is essential.

d-LIVER targets sensor-based monitoring of patient health status at home, concentrating on continuous monitoring of physiological parameters and discrete measurement of a defined set of biochemical species. d‑LIVER also targets remote monitoring and control of the bio-artificial liver and communication with patient sensor networks and hospital information systems. Systems will be capable of remote, secure communication of the status of both the patient and the bio-artificial liver to central clinical services such that they can schedule swift and beneficial treatment and remedial actions. In this way d-LIVER will provide fundamental advances in liver support by reducing hospitalisation costs while enhancing quality of care and, at the same time, reinforcing European leadership in Personal Health systems.

In a parallel, high-risk, activity the production of human hepatocytes from pancreatic progenitor cells will be investigated. These would be ideal for use in d-LIVER systems since they may provide an unlimited supply of hepatocytes, which would overcome drawbacks associated with both primary hepatocytes and stem cells.

Policy Context

The d-LIVER project responds to European Commission FP7 ICT Objective 5.1 – Personal Health Systems which emphasises the target outcome of "Minimally invasive systems and ICT-enabled artificial organs" and in particular the requirement to address the need for artificial liver support through continuous detoxification as remote transient therapy at point of need, as stated in Target Outcome a3) Liver Failure.

As of today, liver transplantation is still the only curative treatment for liver failure due to end-stage liver diseases. Donor organ shortage, high cost and the need for immunosuppressive medications are still the major limitations in the field of liver transplantation. Many patients, especially those who are not listed for high urgency transplantation, may not survive until a suitable donor organ is available.

Description of target users and groups

European mortality due to diseases related to the liver account for some 250 000 people per annum, and this is increasing every year and increasing worldwide. The liver disease application scenarios identified for project execution will address these mortality figures as to the following estimation, if applied and provided comprehensively in point-of-need clinical settings worldwide:

1. Chronic liver failure – prevent chronic liver failure in 20 % of cases of a total of 1 000 000 annually.
2. Chronic cholestatic itch – improve quality-of-life and the ability to work in 50 % of cases of a total of 10 000 annually.
3. Bridging therapy before liver transplantation – prevent mortality of patients on the transplant waiting list on which 80 % (some 10 % of all listed patients) die waiting for a liver. A total of 10 000 annually.
4. Acute liver failure – treat acute liver failure in 40 % of cases of a total of 100 000 annually.

In summary, this means that, provided d-LIVER achieves successful results and these can be commercialised as expected, the resulting LPMS could theoretically save up to 250 000 lives annually, if applied comprehensively worldwide, including about 40 000 in Europe alone.

It should also be recognised that the impact of the successful development of the ICT-enabled bio-artificial liver systems within the d-LIVER project, designed for periodic use in the living environment, may be much more wide-ranging. It could be envisaged, for instance, that the system would have exploitable opportunities in drug discovery, screening and toxicity studies in the pharmaceutical industry and in acute care in remote clinical settings. Clinicians and surgeons involved in the d-LIVER project have also identified a clear and urgent clinical demand for such systems within a hospital environment, in support of patients who have undergone liver transplant surgery such that the metabolic burden on the new organ is offset until it has had an opportunity to recover.

Given the significant potential clinical and societal benefits of d-LIVER and the size of target market, this project is very timely. The convergence of biotechnology, medical sciences and ICT technologies in d-LIVER is extremely promising. d-LIVER will deliver the required substantial innovation in novel and beneficial products and services and will give impetus and profitability to a wide range of European industrial activities.

Description of the way to implement the initiative

d-LIVER targets sensor-based monitoring of patient health status at home, concentrating on continuous monitoring of physiological parameters and discrete measurement of a defined set of biochemical species. The project will implement remote monitoring and control of the bio-artificial liver and communication with patient sensor networks and hospital information systems. ICT-enabled systems will be capable of remote, secure communication of the status of both the patient, via a Liver Patient Management System (LPMS), and the bio-artificial liver (BAL) to central clinical services such that they can schedule swift and beneficial treatment and remedial actions.

In this way d-LIVER will provide fundamental advances in liver support by reducing hospitalisation costs while enhancing quality of care and, at the same time, reinforcing European leadership in Personal Health systems. In a parallel, high- risk, high reward activity, d-LIVER will identify human pancreatic progenitor cells which can differentiate into human hepatocytes and be cultured into the large numbers of functional cells which can supplement vital liver functions. The project includes benchmarking and validation studies to demonstrate the clinical utility of the d-LIVER system in the remote environment.

d-LIVER is an ambitious programme involving a partnership of 13 organisations who all have a significant role in the project. The scope of the technology under development ranges from bio-artificial liver development, biosensors, microfluidics, ambient health information management, instrumentation and integration. Such a diverse range of activities requires extremely high quality management to enable a sustainable and effective structure both for the project and technical management of the programme. This requires a professional management approach which, besides the day-to-day management, allows for unbiased resolution of partner issues, strategic planning, and independent review.

Effective communication and efficient project structure are the keys to success - they enable seamless integration of the partners to the extent that the consortium can operate as one large organisation with shared objectives and goals and with the drive and motivation to achieve them. A goal-orientated management structure is used to ensure the success of the programme in addressing the pull from the market place. The input from the Exploitation Committee and the independent External Advisory Panel is invaluable in achieving this. The management structure also takes into account the technical risks inherent in this type of research.

Technology solution

The d-LIVER project is application-orientated and is based on four inter-linked scenarios, defined by clinicians, which drive ICT and sensor technology development in order to meet exactly the needs for continuous clinical support, monitoring and therapy of liver patients at the point of need from hospital to home settings. These scenarios are:

1. Chronic liver failure
2. Chronic cholestatic itch
3. Bridging therapy before liver transplantation
4. Acute liver failure

On the basis of these scenarios, a full set of both physical and biochemical parameters have been defined in d‑LIVER which will be required to be measured either at regular intervals (patient status monitoring) or continuously (BAL efficacy monitoring). Each scenario has its own most appropriate sub-set of these essential parameters which will be required to be measured and communicated with the ICT LPMS. Monitoring fundamentally focuses on five main branches:

1. Indication/ decision/ timing/ planning for bio-artificial liver support sessions;
2. Basic remote monitoring during d-LIVER bio-artificial liver support therapy;
3. Evaluation of therapy success after liver support / detoxification;
4. Remote monitoring of patient liver function/ toxin level/ general condition until the indication for the next session;
5. Actual recommendations for patients at home regarding personal life-style and behaviour based on patient data monitored by the LPMS.

The ICT aspects of the d-LIVER project follow three strands. The first strand deals with the remote monitoring of the patient who may be undergoing transient detoxification. To enable this, wearable sensors are being developed to continuously monitor the physical indicators of the health status of the patient at home using a variety of clinically relevant parameters (e.g. heart rate, blood pressure, temperature). A blood biochemistry instrument is also under development which will perform discrete biochemical analyses in blood with emphasis on accuracy of measurements, robustness, and operational stability. The wearable sensors will be enabled, via a data logger, for interactive communication with the LPMS. In addition, the blood biochemistry instrument will collect and store all of the measurements and communicate the results to the LPMS for interpretation.

The second ICT strand deals with monitoring and communication associated with the bioartificial device itself. An existing cell-based BAL system is being further developed and specifically tailored for application at the point‑of‑need. Sensor technologies are being developed to allow the quality and efficacy of the cells within the bio-artificial device to be continuously self-monitored. A closed-loop system is being implemented to allow autonomous monitoring and remote control of both biochemical and biophysical parameters affecting the cell environment and the function of the bio-artificial support system, such that the patient detoxification session can be personalised and optimised.

The third ICT strand covers interoperable communication between the BAL, the patient sensor network/instrument and hospital information and/or emergency (e.g. paramedic or ambulance) systems. The development of the innovative LPMS will lead to a completely new dimension of home-care for the patient. The LPMS, as well as providing general remote feedback on patient status to clinicians and, when necessary, to emergency services for crisis management, will also schedule patient treatment and clinic-based remedial actions on the artificial support system itself using specially adapted triaging software based on analysis and correlation of the multi-parametric data with established biomedical knowledge.

We consider that the d-LIVER project strategy on the communication architecture which includes using standards at both ends of the communication is the key to ensuring that other devices on the user side and other information services at the professional side will be able to connect to the d-LIVER platform in the future. Consortium members have strong experience from Continua Health Alliance activities and this places the consortium in line with the vision of the healthcare industry, which originally created Continua as a non-profit, open industry coalition to ensure interoperability between different types and different vendor’s medical devices. Through the dissemination of the d-LIVER project results, Continua specified solutions will be promoted for European industry.

Technology choice: Proprietary technology, Standards-based technology, Open source software

Main results, benefits and impacts

The d-LIVER project is based on four inter-linked scenarios, defined by clinicians, which will drive ICT and sensor technology development, namely: Chronic liver failure, Chronic cholestatic itch, Bridging therapy before liver transplantation, and acute liver failure.

The resulting d-LIVER patient monitoring system is expected to provide:

• Indication/ decision/ timing/ planning for bio-artificial liver support sessions.
• Basic remote monitoring during d-LIVER bio-artificial liver support therapy.
• Evaluation of therapy success after liver support / detoxification.
• Remote monitoring of patient liver function/ toxin level/ general condition until the indication for the next session.
• Actual recommendations for patients at home regarding personal life-style and behaviour based on patient data monitored by the LPMS.

The expected impacts of d-LIVER will therefore be to:

• Use technology to move management of end-stage liver disease (ESLD) patients out of the clinic and into the home or near-home setting;
• Improve quality and length of life by dynamic management of complications (daily not monthly);
• Improve quality of life for patients and carers through avoiding burdensome clinic visits;
• Reduce costs of hospitalisation and improve disease management and treatment at the point of need, through more precise assessment of health status and quicker transfer of knowledge to clinical practice;
• Improve links and interaction between patients and doctors facilitating more active participation of patients in care processes;
• Accelerate the establishment of interoperability standards and of secure, seamless communication of health data between all involved stakeholders, including patients.

Return on investment

Return on investment: €5,000,000-10,000,000

Track record of sharing

Within d-LIVER, one Workpackage is dedicated entirely to dissemination, training, exploitation and management of Intellectual Property. This WP is led by EnablingMNT GmbH, who have extensive experience of managing dissemination of (scientific) research projects towards industrial and end-user exploitation. The consortium firmly intends to disseminate the results from this project to a very wide audience. With technology provider, manufacturers, end users and clinical teams all involved in the project, the diversity regarding where the project information can be publicised is extensive. It must also be noted that for the majority of possible dissemination activities the audiences are either clinical teams across the EU or end users for the proposed integrated d-LIVER system. Thus it is essential that the general public are made aware of the new medical technologies being developed in a broader “publicity type” approach, while the clinical teams and possible commercial exploiters of the technology will both need a more technical workshop and training type approach. To that end, accompanying the scientific and technological outputs planned for d-LIVER, there needs to be a forum to facilitate informed public, industry and government debate about issues raised by the impact of new technology. This involves anticipating societal concerns so as to be able to provide safeguards built into the technological developments (into its regulation, or into its implementation) ensuring smooth and safe market uptake.

Essentially, the aims of the d-LIVER programmes of sharing and engagement are to:

• Understand the societal implications of the d-LIVER technology;
• Understand potential public attitudes towards the d-LIVER technology;
• Identify how societal implications will impact upon policy issues in relation to the d-LIVER technology.

As a result, the expected outcomes of this process will include:

• Survey analysis of public attitudes towards d-LIVER technology;
• Informed debate concerning issues raised by d-LIVER technology;
• Communication with designers and policymakers.

To achieve this, it is planned that a number of one-day d-LIVER Workshops/Roadshows shall be held over the 4-year period of the project. These Roadshows will be held in different European countries to reach the widest audience across Europe. The Roadshows will mainly target the general population and liver patient support groups where information on the various conditions and their treatment will be presented. In addition, the public shall have the opportunity to interact with major experts in the various fields that are directly related to liver disease and dysfunction. An additional set of workshops aimed at healthcare professionals will be organised and held at different locations in collaboration with local stakeholder groups so as to achieve maximum dialogue with the ‘actual’ end-users of the technology.

Lessons learnt

It is too early in the lifetime of the d-LIVER project to describe effectively overall lessons learned from the case. However, it should be stressed that, in a large, multi-disciplinary project such as d-LIVER it is extremely important at the outset to describe different terms, components and their interfaces with a level of detail which provides a definition of the overall system goals and technical requirements, based very clearly on the user needs and clinical requirements of the project. This practice provides the definition of functional units, components, functionalities and requirements of the d-LIVER systems as a basis for a shared understanding among the different fields of competence within the project and which therefore provides direction for the detailed implementation and evaluation to be carried out in the various Workpackages. One interesting point we have found is that, if you offer clinicians new tools, they will find innovative ways of using them and as a result, will often revise their opinions regarding the clinical utility of these tools.

Scope: Pan-European