Title: Development of a Cryopreservable Bio-artificial Liver (BAL) for the Treatment of Patients with Liver Failure using CE Mark-ready Disposables.
Funder: Department of Health and Social Care

Abstract: To bring our novel BioArtificial Liver machine (UCLBAL) to a first-in-man clinical trial we need to translate the &ldquo;hardware-components&rdquo; of our clinical-scale UCLBAL" - already proven in pre-clinical trials - from reusable to single-use disposables. This requires regulatory compliant materials delivered from drawings-to-tools to sterile-packaged disposables suitable for use in patients. Whilst we have existing Solidworks engineering drawings of our reusable chamber, design changes are required to accommodate disposable materials, and limitations of tool design. This applies to chamber, giving-set providing the interface, and cryocassette, i.e. each aspect of the necessary disposable components. A work-station to hold the BAL will be designed with PPI and stakeholder involvement. Plan of investigation, deliverables and milestones WP1: Tools for manufacture of Biocartridge. (Europlaz, with UCL design and testing). Tool design and production will start with a prototype tool-set in soft-steel, with the first chamber prototype produced from those tools, enabling the &ldquo;finishing&rdquo; process (addition of connectors/tubing etc.) to be designed and tested, and temperature compatibilities of the different materials assessed. After any necessary modifications the final tool set will be produced out of hardened-steel, to provide fully testable disposable chambers for use in the laboratory, and subsequently clinical trials and mass production. WP2: Design and prototype CE-mark ready &ldquo;giving-set&rdquo;. (Allmed, UCL). Use re-usable circuitry to model disposable for clinical use. WP3: BAL workstation design. (RGi). Clinician/Patient-centred design, Usability design to BS.EN.62366. Engineering/prototype design. Formative usability study. Prototype (P1&P2) production. WP4: Design semi-rigid/flexible cryopreservation container (UCL with Origen). The cryocasette design is based on our accumulated data for cooling and warming that leads to acceptable BAL biomass recovery. Work involves engineering solidworks drawings from our functional design, tools and prototype production, and biological testing. Milestone 1: design and implementation of tool manufacture leading to disposable biomass chamber, cryocassette and giving-set. WP5: Purify hydrogel powder needed to enable biomass production (University of Miskolc, Hungary: subcontractor; UCL). Hydrogel dry powder will be purified using our existing SOP in a clean-room environment (MHRA/EMA guidelines), suitable for production of material that will be terminally-sterilised prior to incorporation into the UCLBAL. Biomass prepared from this material will be compared, from the perspective of supporting cellular organoid production and appropriate metabolic viability, with current batches prepared according to same SOP outside a cleanroom environment, Milestone 2: Purified packaged hydrogel powder meeting regulatory requirements WP6: Demonstration of biomass production and effective interface with apheresis machine (UCL). With these tasks completed, demonstrate the disposable &ldquo;package&rdquo; supports biomass production (n=3), interfaces with apheresis machine, and functions for ~ 8h using human blood/plasma in-vitro, to rigorously test the robustness of the system. Milestone 3: disposable hardware that is fit for purpose meeting regulatory requirements and delivered as a sterile product for clinical use. WP7: Cost analyses, and commercialisation, R. Fagan-UCLB (IP) and commercial co-applicants). The cost-of-goods for disposables for the clinical UCLBAL will be established by commercial co-applicants. Our health economics modelling has provided confidence that the UCLBAL will meet NICE guidelines for a commercially viable new therapy; our existing commercialisation plan will be extended, and IP generation completed. WP8: Regulatory Development: D.F,TRO, and Kinesys Regulatory Consulting Following completion of WPs 1-6, the technical file will be produced for disposable components making up the medical device. Produce Investigator brochure and Investigational Medicinal Product dossier parts that incorporate device disposables, our existing in-vitro and in-vivo pre-clinical data, GMP production and testing of master- and working-cell-banks. WP9: Patient, public involvement: (PPI CoAs: AE;EW; RW; CS and UCL). PPI tasks as described above will ensure the BAL remains patient-centred WP10: Project management (UCL with ECM); see Management and Governance section below."

Lay abstract: Why? Liver disease kills over 15,000 people yearly in the UK alone. Liver failure can develop rapidly leading to death within days. The current treatment is a liver-transplant. The lucky few who reach critical-care in time, for whom a suitable donor is found, need immuno-suppressant drugs thereafter. Liver-transplant care costs are &pound;130,000 immediately, and ~&pound;20,000 yearly, lifelong, for medicines. Yet, patients' livers often have the ability to repair themselves, but not the time to do so. Where are we now? A device temporarily replacing liver function would save lives, reducing necessity for liver transplants. We developed a Bio-Artificial Liver (UCLBAL) to &ldquo;buy time&rdquo; for patients' livers to improve, so they can leave hospital without a transplant, or, if damage is irreversible, be sustained until a liver is found. This will be a major British Breakthrough as important as kidney-dialysis and life-support machines, revolutionising liver failure treatment. How? The BAL contains liver cells embedded in a gel (biomass) within a chamber. Patient s blood passes through the chamber, where cells perform functions a sick liver cannot, returning Improved" blood to the patient. We showed good improvement in a liver failure model using our re-usable BAL. Costs? A BAL treatment costs about &pound;25,000 with reducing costs at scale, significantly lower than liver-transplantation and lifelong immuno-suppressants. UK/europe market potential &pound;575m. What now? Produce the parts which contact patient blood as disposable items and technical information for regulators. Here we will produce, develop and validate these disposables for further clinical trials. They are:- Chambers to hold biomass for production and patient use Tube-set connecting all the parts Support-matrix for cells Containers to preserve the BAL until a patient needs it A workstation ensuring best patient/doctor interface for BAL We will involve patients with machine-design, and with telling other patients and families about the BAL."

Research activity codes: 5.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL