The second d-LIVER Periodic annual report has been approved the European Commission with a very favourable feedback from the external reviewers, stating “The project ‘d-LIVER’ has made considerable progress in the 2nd year of running and has achieved the targets set in most of the scientific and organisational areas involved.” And “The consortium has used its resources in a near-perfect and well-controlled way, with the few very small deviations easily explained.”
A public summary of the second d-LIVER Periodic annual report is available from here: d-LIVER Periodic Report – Year 2 (public summary)
2nd Period Progress (extract from public summary)
In general, the second period of the project (01/10/2012 to 30/09/2013) was focussed on building upon the excellent groundwork produced during Period 1 which developed the clinical scenarios, elaborated the system specifications, initiated development of both wearable and (bio)chemical sensors and specified initial elements of the ICT security and communication framework.
In Period 1, the project expressed the vision and mission of the d-LIVER concept in terms of a common high level system description with all partners helping to define the design goal specifications (the system requirements specifications) and to develop a vocabulary of d-LIVER technical and clinical terms. During Period 2, key objectives were to review and update the system specifications and project understanding as a result of continual progress in technology development and to outline the applicable regulatory requirements for d-LIVER in order to be able to carry out clinical investigations involving volunteer test subjects later in the project.
Further to the initial development of clinical application scenarios during Period 1, the project has commenced a number of clinical needs studies including: investigation of patient quality of life at home; definition of suitable outcome variables; investigation of economic burden of chronic liver disease; and identification of potential clinical variables for the initiation of the d‑LIVER treatment and BAL support sessions. The clinical centres in the UK and Germany initiated a prospective study to capture individual quality of life assessments of chronic liver failure patients over the course of one year and these studies have shown favourable recruitment rates. Continuation of the Quality of Life and Cost Effectiveness studies, with possible expansion to include other European countries, should lead to more robust data to compare the populations. Based on liver demographic clinical and biochemical function parameters, biological indices and certain test methods, work on defining outcome variables could allow a comprehensive model for the prediction of morbidity and mortality to be elaborated. In addition, work commenced for the planning of evaluation procedures of the d‑LIVER system which involved the preparation of study protocols in line with European directives and ethical guidelines. In the first period, physical and biochemical sensors for the monitoring of patient parameters at home and in the BAL were characterized and their performance compared with the d-LIVER requirements. At the end of the first period, 8 sensors out of 11 were operational and 6 met the project requirements. During the second period, strategies for some sensors were reviewed to make them operational and work on other sensors focused on integrateability and further characterization. The overall objective was to make a decision at the end of the period on which blood biochemistry sensors would be integrated in the d-LIVER cartridge and instrument. The potential impact, in terms of the clinical consistency of the overall system, for sensors which are not being pursued for integration at this time was assessed.
The ideal goal for the blood biochemistry system is to be able to measure all biochemical parameters in a single microfluidic cartridge using a finger-prick blood sample. In Period 1, this commenced with microfluidic cartridge designs for various cases, including so-called ‘best case’ and ‘worst case’ fluidic scenarios. The scenarios outlined the need for new microfluidic functions, which would simplify the cartridge significantly. As a consequence, work in this area in Period 2 concentrated on the top-level concept design of the development of the functional fluidic component modules and their separate testing. The outcomes if this work included: development of the microfluidic scenarios and first designs of the cartridge; successful realization and testing of the serum generation and integrated sample mixing and dilution solutions; and establishment of injection moulding and hot embossing processes for small scale production.
A model bioreactor with a capacity of 8ml was built as a demonstrator in the second period. To operate the bioreactor, commercial sensors and actuators were used in different control loops. They enabled the observation of vital cell parameters. In particular temperature, pH, flow rates of liquids and gases were regulated. To monitor the cell quality and functionality, impedance and ammonium sensors were designed and integrated along with an oxygen sensor into the system. To operate the bioreactor, software was developed which supervised all control loops and monitored operating parameters including oxygen content on a display. Additionally hardware and software to monitor and evaluate the sensor signals was also developed. In initial tests, the functionality of the system could be demonstrated.
During the second period of the project, all tasks in support of the design, development and build of the instrumentation platforms that will service the requirements of d-LIVER were commenced. These included the blood biochemistry instrument and the wearable system for continuous collection of physiological patient parameters.
In Period 2 the first basic LPMS prototype was developed. This supports a set of commercial Continua certified off-the-shelf devices and can partially or initially interact with simulators of d-LIVER devices or with early device prototypes. The system platform further includes a first version of the Care Flow Engine that executes personalised treatment plans of patients and, as part of the basic functionality, modules for initial medication management, patient inquiries as well as one cognitive test were implemented.
In all of the technical development Workpackages particular attention has been paid to establishing procedures for system quality, manufacturability and traceability according to international standards for medical devices even allowing for the fact that, at this stage, there are no regulatory issues which will prevent evaluations taking place within the framework of the project.
Within the work on a potential new source of hepatocytes for the BAL, seeding an experimental pancreatic progenitor cell into bioreactors has been completed and a manuscript describing the work has been accepted for publication. A procedure for the isolation of human progenitor cells from human pancreas has been developed and these cells have been successfully expanded and differentiated to hepatocytes in culture. Because human pancreas tissue has been in short supply, several fall-back options have continued to be investigated, including the use of human pancreatic cell lines, human induced pluripotent stem cells (hiPSCs) and use of a novel polymer matrix to promote a hepatic phenotype.
The project continued to disseminate results of d-LIVER to a broad audience via the website, flyers, factsheets, workshops and conferences. Issues around background and foreground IP were explored with the intention to identify and manage the intellectual property developed and to ensure that suitable initial exploitation plans were produced by each partner with the support of the Exploitation Committee.
An initial element of the d-LIVER project video was produced by TRiBECA Knowledge Ltd. This was designed to cover the aims of the project and to include interviews with patients affected by chronic liver disease. The final version of the first video was shown to the Commission Reviewers at the 2nd Annual Technical Review prior to being included on the project public website.
Expected End Results & Impacts
The liver is a complex organ with various vital functions in synthesis, detoxification and regulation; its failure therefore constitutes a life-threatening condition. 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. 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
The complete public summary is available from here: d-LIVER Periodic Report – Year 2 (public summary).
Other deliverables for download are available from The Project – Public Deliverables