Tendinopathies and osteoarthritis (OA) are extremely common and these injuries associate with high health and socioeconomic costs, long-term postoperative rehabilitation, and loss of productivity. To date, none of the existing surgical or non-surgical alternatives have provided a successful long-term effect, and often the treated tissues do not restore their complete strength and functionality. To fill the critical gap of proper treatments TRiAnkle proposes to develop 3D bioprinted scaffolds based on collagen and gelatine, functionalised with stem cells and/or nanoencapsulated regenerative factors. The surgical implantation of these new functionalised biomaterials will enable the targeted delivery of the mentioned biologically active agents to promote cell growth and differentiation to enable better and faster regeneration of injured collagen-rich tissues like articular cartilage, ligament and tendon of the ankle. Two case-studies will be implemented: the partial rupture (>50%) of Achilles tendon and osteochondral cartilage injuries, which will serve as a technological platform to deliver new regenerative therapies for any other articular, tendinous or ligament diseases of weight-bearing joints. By achieving this goal, TRiAnkle will enable, in comparison with current surgical treatments: - To increase by 10-15% of the ankle joints functionality recovery ratios due to the presence of pro-regenerative components that promote the healing process decreasing also the risk of re-rupture or recidivation. - To reduce the recovery time and the associated healthcare costs up to 50% due to the use of scaffolds that mimic the natural structure and mechanical properties of joint tissues. TRiAnkle will be implemented by a multidisciplinary team made up of biomaterial production companies, manufacturing technologies experts, material engineers, preclinical validation centers, healthcare professionals, patients associations and experts in ethical, regulatory and exploitation.

Major current hurdles for wide clinical use of AAV vectors are attributable primarily to: (i) host elimination by both immune and non-immune sequestering mechanisms – such neutralization by host antibody responses critically limits the possibility of repeated AAV delivery; (ii) AAVs are prevalent in the environment and hence a large proportion of the population carry AAV antibodies (up to 80%)– this pre-existing immunity renders AAV unable to infect target cells forcing substantial patient cohorts to be excluded from clinical trials. The current proposal is founded on compelling track record in the field and brings together a ‘best-with-best’ multidisciplinary team of international leading academic and EFPIA partners with complimentary expertise in gene therapy, immunology, chemistry, engineering, biotechnology, drug safety, viral vector production, regulatory and clinical trials. The overall goal is to analyse the currently available clinical data and then design preclinical and clinical studies to fill the knowledge gaps in advanced therapies development. Our main aims are to: 1) Develop improved model systems for predicting product immunogenicity in humans. This will be achieved by generating human and NHP 3D hepatic models; 2) Enhance our understanding of gene/cell therapy drug metabolism inside a host of cell types. The plan is to define metabolism of the therapeutic vector genome in different cell types to understand whether rates of degradation, episomal maintenance, or integration, and metabolic stress induced by AAV vector transgene expression vary from cell to cell. We will then adopt strategies to mitigate the loss of vector genomes and improve persistence; 3) Use diverse clinical expertise to establish the clinical factors around pre-existing immunity limiting patient access to advanced therapies therapy; 4) Engage regulators to ensure that the concepts and the data generated through this IMI programme will fill the gaps and support furture trials.

Ischemic heart disease is the main cause of death in the EU, straining patients and economies. Regenerative Medicine has failed at delivering a definitive solution, and even the breakthrough of cell reprogramming, biomaterials or 3D printing, have not been able to find a curative solution. Generating a muscle with efficient pumping requires a careful recapitulation of the myocardial architecture. BRAV∃ is born with the ambition of shaping this quantum leap in the field. The overall concept is to provide a lasting functional support to injured hearts through the fabrication of regenerative personalized advanced tissue engineering-based biological ventricular assist devices (BioVADs). To do so, we will apply multimodal deep cardiac phenotyping, coupled to advanced Computational Modelling and biomechanical analysis in a large animal model of disease, to create a personalised 3D printable design. We will for the first time create a fibre-reinforced human heart-sized cardiac tissue able to recapitulate the low Young´s Modulus of the myocardium while withstanding pressures generated during the cardiac circle. Using the latest human induced pluripotent stem cell (hiPSC) technology and industrial-scale growth and differentiation, we will cellularize this novel human heart-sized constructs, creating a highly efficiently aligned cardiac tissue (including vasculature). BioVADs will be matured in in-Consortium built electromechanical stimulation bioreactors before transplantation in a porcine model of disease. We anticipate our BioVADs will constitute a one-shot regenerative treatment of IHD, decreasing the burden on healthcare providers and improving the quality of life of patients. Crucially, we will for the first time generate a wealth of information on heart development at a human scale. Delivering this novel application whilst developing the technological environment (bioreactor, chamber, pacemaker) will boost the capacity of the EU to grow economically and lead the field.