d-LIVER Final Progress Report

February 22, 2016 in d-LIVER News, News

The final d-LIVER report has been approved the European Commission with the comment “good progress” from the external reviewers.

Extract from the Final Progress Report – description of the main science and technology (S&T) results:

WP1: Clinical application scenarios and validation

WP1 was the clinical driver for the whole of the d-LIVER project. It is essential that technology development in the medical diagnostics, monitoring and management fields is driven by real clinical need rather than by technology push. WP1 therefore initially defined the clinical needs for patient monitoring and created a mutual understanding of d-LIVER systems between technology developers and clinicians such that the required technical specifications for the different system components could be elucidated.

From the outset WP1 investigated a number of objective and subjective factors which could be affected by successful technology development and implementation into different European healthcare systems. This included an assessment of patient quality of life at home, economic burden of chronic liver failure and the definition of suitable indication and outcome variables. These studies were carried out in 3 clinical centres in the UK, Germany and Italy, and the regional differences were reported in public deliverables available on the project website.

The final clinical evaluation studies to be carried out using the sensor, instrumentation and information technologies developed in technical Workpackages were designed well in advance and local ethics approval obtained for each individual study in good time. These evaluations included:

  • Wearable device (functionality, usability, patient perception)
  • Electronic number connection test for cognitive function (comparison with standard method and patient acceptability)
  • Home monitoring and management of encephalopathy (HoME) study using LPMS from WP7 (cognitive function, changes to drug regimen, patient acceptability of tablet-based App, comparison with standard care)
  • Overall d-LIVER system including Blood Biochemistry Instrument and LPMS (multi-centre, patient acceptability, ease of use)
  • Biochemical sensor measurements of patient samples and comparison with hospital laboratory results (correlation, agreement, method interchangeability, effect on clinical decision making)
  • Bioartificial liver support unit (detoxification of liver patient serum using progenitor cells in clinical grade BAL)

 

WP2: System design and medical device regulatory requirements

The overall goal of WP2 was to address components, functionalities and requirements of the d‑LIVER systems and to provide direction for the detailed implementation and evaluation to be carried out in other technical Workpackages, thus establishing a shared understanding among the different fields of competence within the d-LIVER project and communication and information flow between the partners across the different enabling Workpackages. The Workpackage thus facilitated the description of different terms, components and their interfaces in more detail and provided a definition of the overall d-LIVER system goals and technical requirements, based on the clinical medical device regulatory requirements elucidated in Workpackage 1. The main objective was to translate the vision and mission of the d-LIVER concept into workable formats, by providing detailed information concerning the technical and system level implementation plan and creating a top-level view of the systems to be developed.

 

WP3: Sensor development

The objective of WP3 was to develop physical and biochemical sensors for the monitoring of patient parameters at home. The sensors developed were designed to monitor a defined set of biochemical parameters (electrolytes, biomolecules and blood clotting) and physiological parameters (heart rate, skin temperature and blood pressure) which would be the most effective in remote monitoring and management of patients with chronic liver disease. At the outset of the project there were initially 11 parameters in total: albumin, bilirubin, creatinine, ammonia, bile acids, sodium, potassium, clotting time, heart rate, temperature and blood pressure.

The biochemical and physical sensors were characterized and their performance was compared with the requirements of the d-LIVER project. At the end of the first year, 8 individual sensors out of the 11 were operational and 6 met the project requirements.

Strategies for some sensors were then reviewed to make them operational and work on other sensors focused on integrateability and further characterization. Front-end electronic board and signal processing required for the cartridge readout was also developed. At the end of second year, the decision was made to remove ammonia and bile acids sensors from the d‑LIVER blood biochemistry cartridge (BBC) and to choose an optical configuration for the clotting time sensor. Work then focused on the integration of the 6 sensors that were finally integrated in the BBC and the 3 in wearable device (see WP6). For the 6 biochemical sensors in the cartridge, all are now operational under “in cartridge” conditions and have undergone clinical comparative analysis using 150 patient samples with excellent correlation with hospital laboratory referee methods in most cases.

 

WP4: Microfluidics, packaging and integration

Workpackage 4 was dedicated to the design and manufacture of the integrated sensor microfluidic cartridges required by d-LIVER as well as the fluidic evaluation of these devices. An iterative chip development programme was instigated which allowed initial designs to be tested using milling procedures prior to locking down designs and proceeding to produce larger numbers of cartridges by injection moulding for the analytical and clinical evaluation studies. Within WP4 a microfluidic cartridge for the blood biochemistry instrument was developed and for that purpose, suitable polymer materials as well as potential coatings were identified within the first few months of the project. Important issues such as biocompatibility and haemocompatibility were assessed and care was taken to ensure that these materials were compliant with safety regulations and directives for medical devices on the basis of, the international standard ISO 10993 and the guidelines of Unites States Pharmacopeia Class VI. Suitable polymer materials for the fluidic devices were identified with regard to processability and performance and polycarbonate proved to be the most favourable for use. Specifically, micromilling, injection moulding, solvent bonding and γ-sterilization could be applied to this material and, in addition, certain types of polycarbonate are optically transparent – an important issue for the clotting time sensor developed in WP3.

The final BBC developed and manufactured is shown in Figure 2. This was designed to measure six blood parameters (clotting time, Na+, K+, bilirubin, albumin, and creatinine) at home on a daily basis. From the viewpoint of the patient, the use of the BBC should be as easy as possible within the home environment and with no accidental harm to the patient. For these reasons, the fundamental design rule was the minimization of the volume of blood to be provided to the BBC by the patient, such that a standard finger prick technique could be used. The developed cartridge consisted of two components; the microfluidic cartridge which housed all of the sensors and a reservoir chip which contained any reagents or solutions which were required to realise the sensor-based measurements in blood. Whole blood (20µl) was drawn into the cartridge by capillary forces and was then separated to release the serum component. Serum was then diluted 1:5 on-chip and flowed sequentially over the sensors. One patent application on the BBC was submitted a second one is under preparation by patent attorneys.

 

WP5: Development and monitoring of Bioartificial Liver Support Unit

WP5 focused on development of a bioreactor technology that addresses the cellular needs of 3D tissue density conditions in a highly physiological environment. An approach was taken which was designed to cultivate human or porcine liver cells within a four-compartment hollow fibre‑based bioreactor which exhibited a controlled 3D perfusion environment – the d-LIVER “Bioartificial Liver Support Unit” (BAL). This complex four-compartment bioreactor technology would allow enhanced mass-exchange by counter-current flow perfusion, as well as integral, decentralized oxygenation through gas-permeable capillary membranes (that facilitate long-term culture and storage, in contrast to whole organs which cannot be stored for long periods in a viable state). Thus, this construction would enable close-to-physiological nutrient and oxygen supply to the cells cultured in the extra-capillary space. An important aspect of the technology development was automation of culture and cell viability monitoring using closed-loop control.

WP5 defined the requirements of the multi-parametric sensor system which would be employed for continuous monitoring of cell viability within the BAL. Concepts for the integration of the different sensors were developed and initially realized in 8ml bioreactors. This included sensors for control of perfusion conditions in the BAL (temperature, system pressures, pH and oxygen), mass flow meters for control of gas flow rates, and sensors for assessment of cell viability and functionality (impedance, ammonia). Sensors were successfully integrated and tested in culture experiments. The results showed that changes in cell behaviour could be graded into different states dependent on the toxin concentration. Measures and procedures for cell recovery or culture termination could then be undertaken dependent on the actual state of the bioreactor culture.

These sensor systems were up-scaled in the final year of the project to provide a clinical grade BAL which was then tested successfully using the hepatocyte-like progenitor cells developed in WP8.

 

WP6: Instrumentation platforms

The objectives of this Workpackage were to develop and build the instrumentation platforms that would serve the requirements of d-LIVER as optimized prototypes for clinical evaluation. One of the key requirements in WP6 was to develop an instrument for the home-care setting that could perform a panel of biochemical analyses from a single finger-prick sample of blood – the so-called Blood Biochemistry Instrument (BBI). Due to the requirement that the BBI be ultimately used by liver patients at home, it had to be simple and easy to use. The only interfaces with the user are a power plug, an on/off button, an Ethernet socket, a Wi-Fi link and a touchscreen. The BBI instrument design included housing, power management, control unit with dedicated software and user interface, electronics allowing controlling all the interfaces with dedicated firmware, and communication aspects. The instrument  was able to host and assemble the BBC (see WP4) which, in turn, housed the sensors developed by WP3. The BBI was designed to control actuators interfacing with the microfluidic cartridge, to perform the driving of the blood sample in the cartridge, to process the signal outputs from the sensors and to then transmit the results wirelessly to the Liver Patient Management System (LPMS) developed in WP7.

A second element of instrumentation development in WP6 was the development of wearable physiological sensors which are intended to worn on the body to continually measure parameters such as temperature, activity, heart rate and blood pressure where the different sensor functionalities are integrated into one single unit which can transmit data via a Bluetooth Health Device Profile (HDP) to the d-LIVER Personal Health Manager (PHM) which was developed in WP7. As shown in Figure 5, the wearable device consists of an electronic compartment which has an on/off button on the front and two LEDs on upper edge to indicate the status, and a connector slot for the on-body electrodes. On the back side are two push buttons to attach the belt the compartment was designed to be splash protective and could be gently swiped with a soft cloth with water or disinfection agent.

 

WP7: Communications, Patient Management and Decision Support

At the outset of the project it was the aim that WP7 would deliver an advanced web-based information system – the d-LIVER “Liver Patient Management System” (LPMS) – for the monitoring and management of patients with chronic liver conditions in ambulatory and home settings. In addition, it set out to provide the overall communication and security framework for the d‑LIVER platforms with a particular focus on interoperable and open solutions as well as on patient safety and privacy. WP7 analysed the main use case scenarios (see WP1) and specified, developed and delivered the communication and security framework via continuous validation cycles. Furthermore WP7 was designed to develop, in collaboration with the d-LIVER clinical centres, models for decision support and therapy outcome prediction for chronic liver disease patients.

As a major outcome, the LPMS was iteratively developed in response to formal standards to meet patient safety requirements of the planned clinical evaluation studies, resulting in the production of LPMS 3.0. LPMS 3.0 is a laboratory prototype at Technology Readiness Level 4 to 5, which can be utilized to remotely monitor patients and to support the management of complications in patients with chronic liver failure at home; in particular patients with encephalopathy, ascites and cholestatic itch through a telemonitoring solution adapted for liver diseases in combination with a decision support system that guides patients and doctors through the treatment of these complications. As such, this system controls and adapts the dosage of specific drugs with or without confirmation by the physician according to up-to-date health data obtained from the patient. Of relevance is the fact that LPMS communicates with devices according to Continua Health Alliance standards by using the Device Manager. This facilitates the deployment of the system and general purpose monitoring devices, bought by the patients, will be able to interoperate with the LPMS. The Device Manager does not only integrate Continua Health Alliance devices but also is able to integrate non-Continua devices, such as the BBI.

 

WP8: Progenitor cells for bioartificial liver

The inclusion of WP8 in d-LIVER was important as a programme of “high-risk, high reward” research designed to characterize trans-differentiation of human pancreatic hepatocyte progenitors and to assess hepatic function in vitro in the experimental and clinical grade bioartificial liver support units (BALs) developed by WP5.

There is currently considerable effort directed towards generating human hepatocytes from stem cells since these would have both basic science (e.g. drug metabolism and toxicity screening) and clinical (e.g. incorporation into bio-artificial liver devices) applications. However, embryonic stem cells and induced pluripotent stem cells have so far failed in their ability to generate cells with comparable function to human hepatocytes in vitro or, at the very least, require efficient (i.e. viral-mediated) forced over-expression of liver transcription factors. One alternative to using stem cells as a source for hepatocytes, is to use progenitor cells. Prior to d‑LIVER commencing it had been shown that a rat pancreatic progenitor “B-13” cells appear to be the only cells capable of differentiation into hepatocytes in a highly cost-effective manner, requiring the addition of a simple glucocorticoid hormone treatment. In WP8 the target was to investigate the possibility of generating a cost-effective human equivalent cell line capable of being readily expanded in a simple culture system and converted into functional hepatocytes using a simple regulatory switch. In a major development in the area this goal was achieved and the human equivalent cells shown to be metabolically functional in a clinical grade bioreactor (WP5). A patent application was submitted regarding these cells and their use. The successful outcome of this “high-risk, high reward” Workpackage could therefore have enormous societal benefit by the production of a viable, effective, economical, high quality source of human hepatocytes derived from progenitor cells in sufficient quantity for exploitation in bio-artificial liver devices.

 

Potential impact and the main dissemination activities and exploitation of results

Potential Impact

The specific project impacts are discussed in detail below. However, in general, these can be summarised as follows:

  • Reduced hospitalisation and improved disease management and treatment at the point of need, through more precise assessment of health status.
  • Improved quality of life for liver patients.
  • Economic benefits for health systems without compromising quality of care.
  • Reinforced leadership and innovation of the industry in the area of Personal Health Systems and medical devices.
  • Improved links and interaction between patients and doctors facilitating more active participation of patients in care processes.
  • More effective bioartificial liver support as a result of having a viable, effective, economical, high quality source of human hepatocytes.
  • Demonstrated potential for spin-offs with protected IP through several patent applications.

The liver is a complex organ with various vital functions in synthesis, detoxification and regulation; its failure therefore constitutes a life-threatening condition. Liver failure can either occur without preceding liver disease (acute liver failure), or as decompensation of a chronic liver-related illness.

The only long-term therapy in most cases is orthotopic liver transplantation, unless the liver is able to regenerate. Many patients, especially those who are not listed for high urgency transplantation, may not survive until a suitable donor organ is available, since donor organs are rare. In other cases, contraindications do not permit liver transplantation.

d-LIVER has fundamentally advanced an ICT-enabled system to remotely monitor and manage liver patients in their home, such that patient monitoring is continuous and intervention can be both swift and beneficial, leading to improved patient health and survival along with a significant enhancement of patient quality of life.

The innovative liver patient management system (LPMS) supplied with the sensor and instrumentation systems could lead to a completely new dimension of home care for the patient and a concomitant reduction in morbidity and mortality. The management and therapy of patients with chronic liver disease will thus be taken to a new level. As such, this system can control and adapt the dosage of specific drugs with or without confirmation by the physician according to up-to-date health data obtained from the patient. The LPMS can also alert the patient and the hospital when additional interventions or the next liver support session are required. Complications can be prevented by this strategy and costs conclusively reduced when the patient does not need to be admitted to the hospital.

Potentially, this could also be supplemented by the innovative and functioning bio-artificial liver system based on human progenitor cells which have been developed. This possibility would have an enormous impact on the bio-artificial liver field. Furthermore, it is envisaged that the progenitor cells would have exploitable opportunities in drug discovery, screening and toxicity studies in the pharmaceutical industry.

The success of d-LIVER will enhance the quality of healthcare at a European level and will improve European competitiveness in medical device technology.

Dissemination

Within the first 6 months of the project, a project website www.d-liver.eu was established and this has been maintained throughout the course of the project. The website contains the following public pages:

  • A home page describing the aims of the project and hosting project vision, execution and technology development videos
  • A partner page with specific links to their relevant websites
  • A deliverables page containing any publicly available deliverables and reports
  • Pages with specific information for patients and for healthcare professionals – in English, German and Italian
  • An events page, detailing events where d-LIVER will be, or has been, presented together with copies of any presentations

In addition, a secure Virtual Research Environment and Filestore were created which contain all confidential deliverable reports, the publication clearance procedures and IPR. Finally, a Twitter account was created and maintained which provided immediate announcements on d-LIVER and related activities.

The dissemination activities in d-LIVER achieved their goals in various ways; by collecting, collating and managing the information developed during the project, by disseminating the information as widely as possible via the production and distribution of press releases, newsletters, project flyers and technology updates throughout the course of the project. More specifically, these goals have been achieved through the organisation of Showcase Workshops in conjunction with a strong presence at major Trade Fairs and exhibitions such as AACC, MedTec, Mobile World Congress and Korea Eureka Day as well as a number of presentations and posters at major international conferences e.g. EASL and BASL and publication of articles in high quality scientific journals. As part of these activities an assessment of a Business Development Framework, including a Freedom to Operate analysis, has allowed the production of the Final Exploitation Plan and Technology Roadmap for the future commercialization of d‑LIVER results.

The concepts and ideas behind the d-LIVER project have also been disseminated on a broader level to general audiences through video interviews about d-LIVER which are available on the project website, Futuris and YouTube. Finally, news articles were published on the Futuris and Cordis websites and in national and local newspapers describing the concepts behind the project and its vision for the future of remote monitoring and management of chronic liver disease.

Exploitation

The d-LIVER systems can be viewed as disruptive technologies which could confer new breakthroughs in the world of information-enabled monitoring and management tools. As a consequence it was of particular importance to the project to undertake a coordinated effort to understand the marketplace, the barriers to entry and the competitive position, with the ultimate aim of producing a confidential d-LIVER Final Exploitation Plan and Technology Roadmap. IP protection has been continued for critical components of the systems, including aspects of a Freedom to Operate analysis in line with recommendations at both the systems and component levels. In order to carry this out effectively, d-LIVER needed to:

  • Investigate how d-LIVER could impact the management of chronic liver disease and improve patient quality of life
  • Assess how d-LIVER could address the economic burden of chronic liver disease
  • Determine the most appropriate methods for commercial exploitation from the laboratory, through to remote management and therapy at the point of need
  • Investigate market potential in the targeted clinical application area and for applications outside the area investigated in the project, bearing in mind that the d-LIVER approach might be regarded as a series of platform technologies

The Final Exploitation Plan was prepared which contained an overview of the potential for d‑LIVER monitoring and bioartificial liver support systems, along with details on the category drivers and competitors. Some of the main issues that need to be overcome were discussed and potential business models presented. Final commercialization recommendations were included and these, along with details of exploitation plans, were presented to the European Commission at the final Technical Review.

The complete public summary (including some graphics) is available from here: Final (Periodic) Report (public summary).

Other deliverables for download are available from The Project – Public Deliverables