Periodic Reporting for period 1 - FLAMIN-GO (From pathobioLogy to synoviA on chip: driving rheuMatoId arthritis to the precisioN medicine GOal) Reporting period: 2021-01-01 to 2022-06-30 Summary of the context and overall objectives of the project Rheumatoid Arthritis (RA) is an autoimmune disease where cells of the immune system wrongfully attack the joints, leading to their damage. Of note, if not adequately treated, RA can lead to the development of physical disabilities. Up to date, no definitive cure exists for RA. Available treatments present two main problems: 1) RA drugs are expensive, which negatively impacts the global economy; cuts in healthcare spending and the budgets obsessively oriented towards short-term savings make it difficult to implement the right measures to strengthen the rheumatological care network, which would allow, in the medium-long term, a drastic containment of costs linked to the establishment of complications of an inadequately treated disease; 2) not all RA patients respond to the therapies. This interindividual variability underlines the unmet need of a specific therapy designed ad hoc for each patient, the so-called “personalized medicine”, aimed at finding the drug that works in each single patient, reducing any side effects due the drug’s toxicity. Although conventional clinical trials might address those issues related to response/non-response of powerful expensive drugs, this approach is time consuming and ethically doubtful as part of the patients still fail to achieve disease benefit. RA patients and their families also often face financial burdens due to high drug costs. Thus, it is crucial to find an alternative strategy that can deliver innovative trials, which will reduce the costs for R&D as well as for patient’s families and the health care system in general.Based on the above premises, FLAMIN-GO project aims at providing solutions to the following questions: 1) How can we improve the screening for new RA drugs by reducing the time and costs? 2) How can we abrogate any occurrence of side effects in RA patients? 3) Can we identify new biomarkers or therapeutic targets for RA?FLAMIN-GO’s main objective is thus to develop a personalized next-generation joint-on-chip that, by effectively mimicking the complexity of RA joint, will allow performing personalized clinical trials-on-chip. Organ-on-chip (OoC) represents an emergent technology that might play a transformative part in pharmaceutical R&D. OoC is a microfluidic platform creating controlled microenvironments with vasculature-like perfusion, in which human multicellular structures mimicking the physiological architecture and function of human tissues and organs are integrated. This technology has been developed to substitute in vitro and animal models, which often inaccurately model human physiology.Specifically, in FLAMIN-GO project the joint-on-chip will be built using the cells isolated from the patients who usually undergo biopsy, required for the follow-up of their RA. The chip will be composed of three units: synovial, inflamed blood vessels and osteochondral. On this 3D model, the current drugs available in the portfolio of FDA-approved medicines and potentially new drugs will be tested. Once the most effective drug is chosen, it could be administrated to the patient in 1-2 months.The FLAMIN-GO project will explore these questions by drawing together 14 partners from 6 EU countries plus UK, Switzerland and Turkey, including experts from hospital, academia, and industry partners that cover the whole value chain with complementary expertise. The consortium gathers specialists in the fields of rheumatology, material science, tissue engineering, nanotechnology, cell biology and 3D modelling in a cohesive, transdisciplinary, multi-sectorial approach taking on the challenge to drive RA personalized care. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far In the first reporting period (M1-18) FLAMIN-GO aimed at conceiving, fabricating and testing the RA Synovial Unit (RA Syn-U), the Inflamed Blood Vessel Unit (Vas-U) and the Osteochondral Unit (OC-U), which will be assembled in the next project phases to create a functional 3D chip. To detect the cell activity within the chip, nanosensors were also developed. For Syn-U, we started the screening of different materials that serve to create a scaffold for each cell type, once integrated in the chip. These materials must be biocompatible, i.e. without evoking a toxic effect for the cells. Then, we assessed the behavior of fibroblast-like synoviocytes in terms of morphology and viability in each tested material. Among them, we chose the most effective one. For Vas-U, we developed and validated a human perfusable vascular tissue-on-chip, followed by the optimization of the bio-ink formulation to obtain the capillary-like structure supporting the endothelial cells organization and maturation. For OC-U, we developed and validated a human perfusable osteochondral tissue-on-chip, where the mechanical and biochemical environments of both physiological and inflammatory joint conditions were mimicked in a microfluidic platform, simulating RA cartilage and bone tissues. Lastly, to monitor the physiological stress state distribution occurring in vivo and culture environment within the chip, we developed the prototype of a lab sensor chip and 2 nanoparticles sensing forces and PH/Oxygen. RA patients’ enrollment also started, and biopsies have been collected and stored for the isolation of cells that will be integrated in the chip. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Starting from individual patient biopsies, the OoC will replicate each patient’s joint, thus making it possible to test and allocate the best on-market drug for that patient, reducing unnecessary exposure to the risk of side effects, avoiding wastage of health care resources, and most importantly improving patients’ quality of life. Thanks to the development of personalized treatment in RA, it seems feasible to reduce both healthcare costs and socioeconomic impacts. In fact, allocating the right drug to the right patient and achieving early remission could avoid long-term treatment, disability, low quality-of-life, and as a consequence reduce the health-care burden. At the present, more than 2.9 million people are diagnosed with RA in Europe. Total costs to society are estimated at € 45.3 billion in Europe and at € 41.6 billion in the United States. In EU, total costs increase from around € 5,000 for patients with minimal functional disability to € 20,000 for patients with severe disease. In the latter group, up to 40% of RA patients leave work completely, within 5 years of diagnosis. Finally, it is estimated the OoC will reduce the costs about of 10–26% per new drug reaching the market. The joint-on-chip developed by FLAMIN-GO will provide the solution regarding the drug allocation in RA. FLAMIN-GO Consortium at the Project Review Meeting - Santa Maria di Leuca (5th July 2022)
