Tissue Engineered Heart Valves (TEHVs) can restore function in the pulmonary and aortic positions and have shown capacity for tissue regeneration and growth in pre-clinical models. Yet, this concept has not been extended to the Mitral Valve (MV), whose pathologies affect >25% of the valve disease patients in Europe. In this proposal, we introduce a bio-inspired design methodology and bioprocessing technology to engineer BIOMITRAL: a polymeric, stent-less, tissue engineered MV that recapitulates native structure-function. Key to our approach is the engineering of MV leaflets and chordal apparatus. In the native MV, this set of tendon-like appendages mechanically connects the leaflets to the left ventricle (LV) and allows for harmonization of the valve kinematics, coaptation and ventricle contractile dynamics. Commercial MV prostheses used for MV replacement, as well as most existing TEHVs are mounted on synthetic stents that lack of this important structure and consequently neglect this physiological mechanism. In addition, non-degradable stents cannot adapt to patient's growth, de-facto negating a key advantage in TEHVs. Our specific hypothesis is that recapitulating native leaflet structure-function and incorporating engineered chordal apparatus will lead to an engineered MV with enhanced functional and remodeling performances. To verify our hypothesis, we will: Aim 1. Characterize the structure-function of freshly isolated human valve tissue and use the derived properties to fabricate stented (control) and stentless BIOMITRAL prototypes; Aim 2. Assess prototypes mechanics and kinematics in silico via finite element modeling and in vitro in a pulse duplicator; Aim 3. Evaluate BIOMITRAL in vivo functional performance and assess remodeling in a chronic ovine model. Engineering a “living” MV with bioinspired leaflets and chordae that connect engineered leaflets with the LV is a revolutionary concept that can fundamentally transform the design of MV prostheses.

SimInSitu is aiming to develop a sophisticated in-silico method to predict the short- and long-term behavior of in-situ tissue engineered heart valves by combing advanced tissue remodeling algorithms with a personalized virtual heart modelling approach. The method will be specifically developed to predict the complex transformation process of biodegradable heart valves from the initially synthetic scaffold into a fully remodeled & functional valve. This transformation process, named ETR for Endogenous Tissue Restoration, is the core technology for a new generation of very promising biodegradable vascular device currently developed by Xeltis. ETR makes the use of animal derived tissue, which is used in the majority of commercially available bioprosthetic heart valves, obsolete and avoids thereby durability related issues and potentially minimized the need for reoperations. Though, significant progress was made during the past years in developing ERT based devices, it remains very challenging, costly, time-consuming, and rich with obstacles. New knowledge can only be generated through a tedious trial & error process (requiring preclinical and clinical studies), since the restorative process cannot be replicated in an in-vitro environment. Advanced Computer Modelling & Simulation technologies have the potential to overcome this limitation by allowing to test new designs, modified scaffold compositions, or other applications in a virtual patient-specific environment – in-silico. SimInSitu will not only develop such a computer model, but will also verify and validate it thoroughly by making use of the extensive in-vitro and in-vivo data available and where necessary will generate new data to support the credibility of this in-silico method. The availability of this computer model could contribute significantly to an acceleration of especially the ETR-device development and accelerate their translation into the clinic and market.

PROTECT-CHILD is a project that aims to improve the outcomes of rare pediatric transplant patients by integrating multiple sources of high-throughput data from registries, hospital-based and public repositories, complying with ongoing initiatives such as the European Open Science Cloud (EOSC) and the European Health Data Space (EHDS). The project focuses on the co-design of a secure and privacy-preserving infrastructure, harmonization of data standards, and creation of a public/private infrastructure for assembling large datasets to improve clinical outcomes. The project involves top-level expertise from a consortium of technology specialists, data standardization experts, and High-Performance Computing (HPC) centers, as well as clinical experts, legal experts, patients’ representatives, and policy makers. The project is aligned with EHDS and General Data Protection Regulation (GDPR) principles and aims to empower secure and compliant processing, analysis, and sharing of sensitive personal data, including genomics, while preserving data privacy and security.