PHOENIX aims to revolutionise biomedical research by developing the next generation human-based Organs-on-chips (OoC). OoC is a promising technology potentially able to outperform conventional preclinical models in providing patho-physiologically relevant setting for investigating human diseases, thus tackling the limited translational value of animal testing. OoC wide adoption is currently hampered by poor maturation of cellular models and shortage of non-destructive readout methods. PHOENIX will take current OoC platforms to the next level, overcoming such limitations by integration of core technologies already validated by the Consortium, namely Electric Recording (3dMEA), Force Sensing (3dFORCE) and Mechanical Stimulation (3dMECH). Two platforms will be developed: i) μHeart, to model functional cardiac tissues, and ii) μNMC to model neuro-muscular circuits. PHOENIX ecosystem will be completed by satellite products and qualified against specific contexts of use in clinically and industrially relevant environments. PHOENIX potential will be showcased with two genetic pathologies as demonstrators: LMNA-cardiomyopathies and Freidreich’s Ataxia, conditions in which electrical instability and mechanical impairment play important roles. For each platform, two versions will be released (Base and Pro), addressing the need of identified customer segments (research labs and Pharma/Biotech). In line with the 3Rs, PHOENIX platforms represent the ideal clinically relevant tools to test drugs and gene therapies, leading to faster/safer development processes, reducing the need for animal testing. Robust dissemination, exploitation and communication activities will address both key stakeholders (OoC players, end-users, end-beneficiaries and regulatory bodies) and society at large, fostering acceptance, adoption, economic viability and regulatory compliance. PHOENIX will last 4 years with a Consortium comprising 9 partners (Academic, SMEs and LEs) from 4 EU Countries.

Increased demand for high-quality healthcare for our aging population means that medical device design must satisfy multiple requirements for enhanced biocompatibility, anti-bacterial resistance, manipulation of proteins and improved physical properties. The use of micro/nano structures integral to the surface of a device is a novel way to uniformly tune and control these properties. Polymer materials are ubiquitous in medical devices: in Europe alone, this sector includes 27,000 companies employing 675,000 people with an annual turnover of €110 billion. Precision processing of polymers with micro/nano structures is critical to developing high value-added medical devices. Our ETN focuses on surface integrity issues when micro/nano processing polymers for high performance medical devices. We will develop micro/nano-scale precision manufacturing processes, specifically moulding and forming, and additive and subtractive manufacturing, aimed at 6 classes of medical devices that have particular industry-defined

The launch of a novel drug to the market is preceded by clinical testing and validation both on animal in vitro and in vivo models. Animal models used in drug development have known methodological drawbacks leading to the failure of drugs. Further, animal tests are associated with ethical issues. Moreover, a strong bias in in-human testing still overlooks major population groups e.g. children, women, different ethical groups. It is estimated that 197,000 deaths per year in the EU are caused by Adverse Drug Reactions (ADRs) and the total cost to society of ADRs is €79 billion. The emerging Organ-on-Chip (OOC) field, an alternative to animal test, brings great potential for safe testing and validation: An OOC-systems consists of a 3D-microstructured channel network embedded on a small plastic device that simulates the mechanics and physiological response of an entire organ or organs. Project UNLOOC will develop, optimize, and validate a multitude of ECS-based tools to build OOC-models to replace animal and in-human testing. UNLOOC aims to combine three important characteristics for routine use of OOC models, i.e platforms that combine ECS-based technologies with established biological material, capitalize on AI, parallelized test set-ups allowing efficient high-throughput demands, and standardized procedures enabling reliable results. UNLOOC will develop ECS-based hardware and software tools and validate them in five Use Cases (UCs) performed in 10 European countries. The applications developed and validated will be used by academia and pharma industry to drive drug development, create cosmetics without animal test, personalized medicine and gain new insights into disease. Given the large OOC market, these solutions have great economic value, on average it would result in cost reduction of up to $169M and $706M per new drug reaching the market and will put Europe at the forefront of this booming research field (see impact section for details).

iConsensus will provide innovative analytical, hardware, software and high-throughput (HTP) solutions for the development, monitoring and control of mammalian cell cultivation process producing biopharmaceuticals. iConsensus will develop an analytical platform with on-line/at-line sensors and detection methods measuring multiple factors in the cell culture and the produced biopharmaceutical. Under advanced data management, the analytical platform will be integrated in new micro-bioreactors for HTP screening on one hand and in classical stirred tank vessel bioreactor on the other hand. Based on the analytical information, feedback control will be applied. When deemed suitable, implementation in GMP production of the sensing and control tools will be carried on.

ONE-BLUE will provide an integrated assessment of contaminants of emerging concern (CECs) and their impacts, will develop new monitoring tools, and will provide an advanced understanding of the combined effects of CECs and climate change (CC) on the different marine ecosystems and their biodiversity. The following objectives are defined: • Improve the current knowledge of the concentrations, profiles, fate, behaviour, and effects of CECs, in the different marine compartments and ecosystems through three case studies (Atlantic and Arctic oceans and the Mediterranean Sea) and develop safety guidelines and protocols for future CECs monitoring in marine ecosystems. • Provide an advanced understanding of possible interaction between CC and CECs in marine ecosystems with studies under controlled conditions in marine mesocosms. • Develop a database (DB), the CECsMarineDB, following FAIR principles, with a database management system (DBMS) to collect the data generated in ONE-BLUE and capitalize data from other projects and existing DBs. A graphical user interface (GUI) will be developed and used for data exploration and demonstration of the fate and behaviour of CECs in a changing environment. • Provide new solutions in support of the implementation of relevant EU policies; (i) a series of new approach methodologies (NAMs) to improve the ecotoxicity assessment of CECs in marine ecosystems; (ii) a tiered effect-directed approaches (EDA) combining toxicological assessment and chemical analysis; (iii) an advanced ultrasonic system for sampling and enrichment micro/nanoplastics from seawater; (iv) a remote autonomous sensor to assess CECs in marine waters in quasi-real-time; a decision support system (DSS) based on machine and deep learning strategies to assess and forecast combined effects of CC and CECs in marine ecosystems. • Disseminate the project results and establish the exploitation plan for the developed technologies.