Periodic Reporting for period 3 - TAVI4Life (A lifelong transcatheter aortic valve prosthesis)
Période du rapport: 2023-10-01 au 2025-03-31
Aortic valve disease represents a major cause of death worldwide. Transcatheter aortic valve implantation (TAVI) has become a valid treatment option and is currently being extended to younger patients. However, available bioprostheses used for TAVI are prone to degeneration, and patients therefore often require multiple re-interventions.The EU-funded TAVI4Life project aims to develop an innovative bioengineered aortic valve prosthesis that combines a regenerative stent and a valve capable of undergoing guided in situ remodelling which is particularly beneficial for young patients. An unconventional bioengineering approach using in vitro, in silico, and in vivo methods will be taken for this novel prosthesis that transforms into a native-like aortic valve and lasts for life.
TAVI techniques have revolutionized the therapy options for valvular heart disease. Initially developed for elderly high-risk patients, TAVI is being extended to younger patients and may become a first-line treatment in the near future.
However, the available bioprostheses for TAVI are prone to degeneration, and patients may thus require multiple re-interventions, significantly affecting their life quality. To date, a native-analogous TAVI prosthesis with in-situ remodeling capacity does not exist. Tissue engineered (TE) heart valves represent a potential solution, but are not yet suitable for high-pressure applications and lack clinical translation because of uncontrolled in-vivo remodeling, impairing their long-term functionality.
In the TAVI4Life project, we aim to develop and validate a novel TAVI prosthesis for young patients with the unique ability to transform into a fully autologous valve within the body and last for life. This project will go far beyond previous TE concepts by engineering a novel decellularized human ECM and a regenerative stent and applying an unconventional bioengineering approach combining in-vitro, in-silico, and in-vivo TE methods. First, we will engineer and characterize a clinical-grade ECM for high-pressure conditions and test patient-specific immuno- and hemocompatibility profile (in-vitro). Next, using computational modeling, we will design and develop a novel stent and implement an analytical valve design to develop the transcatheter prosthesis (in-silico). Finally, we will evaluate valve performance and remodeling in a preclinical large animal model (in-vivo). This highly multidisciplinary approach will lead to a valve prosthesis that lasts for life, as guided in-situ tissue remodeling will enable their long-term performance. The clinical impact will be enormous as, particularly for young patients, the TAVI4Life will significantly enhance their life expectancy and quality of life.
TAVI techniques have revolutionized the therapy options for valvular heart disease. Initially developed for elderly high-risk patients, TAVI is being extended to younger patients and may become a first-line treatment in the near future.
However, the available bioprostheses for TAVI are prone to degeneration, and patients may thus require multiple re-interventions, significantly affecting their life quality. To date, a native-analogous TAVI prosthesis with in-situ remodeling capacity does not exist. Tissue engineered (TE) heart valves represent a potential solution, but are not yet suitable for high-pressure applications and lack clinical translation because of uncontrolled in-vivo remodeling, impairing their long-term functionality.
In the TAVI4Life project, we aim to develop and validate a novel TAVI prosthesis for young patients with the unique ability to transform into a fully autologous valve within the body and last for life. This project will go far beyond previous TE concepts by engineering a novel decellularized human ECM and a regenerative stent and applying an unconventional bioengineering approach combining in-vitro, in-silico, and in-vivo TE methods. First, we will engineer and characterize a clinical-grade ECM for high-pressure conditions and test patient-specific immuno- and hemocompatibility profile (in-vitro). Next, using computational modeling, we will design and develop a novel stent and implement an analytical valve design to develop the transcatheter prosthesis (in-silico). Finally, we will evaluate valve performance and remodeling in a preclinical large animal model (in-vivo). This highly multidisciplinary approach will lead to a valve prosthesis that lasts for life, as guided in-situ tissue remodeling will enable their long-term performance. The clinical impact will be enormous as, particularly for young patients, the TAVI4Life will significantly enhance their life expectancy and quality of life.
The TAVI4Life project is divided into 4 main projects:
a) Produce xenogeneic serum-free human cell-derived tissue engineered matrices (hTEMs) to advance their clinical relevance. Major achievements for this project consist in the successful characterization and multiscale analysis (i.e. proteomics) of hTEMs, which show comparable ECM composition to standard-cultured hTEMs (i.e. with FBS) in terms of protein content. The prevalence of xenogeneic proteins expression into the ECM of hTEMs was determined, which however does not impact a pro-inflammatory response of macrophages in-vitro. These results may anticipate a potential adaptive remodeling response after the initial monocyte recruitment after hTEM implantation. A systematic development of xenogeneic serum-free hTEMs has been successfully achieved, showing overall promising tissue formation, composition, hemo- and biocompatibility in comparison to standard tissue engineering protocols using FBS. Pre-endothelialization of our matrices with endothelial progenitor cells demonstrate principal feasibility to form a confluent and functional endothelium on hTEMs with the expression of specific markers and migration as well as repair capacities. Induced calcifications studies have demonstrated comparable calcification potential of xenogeneic serum-free hTEMs in comparison to control (cultured with FBS supplements) hTEMs.
b) Design and development of a polymer-based 3D-printed stent. To fullfil this project, comprehensive in-vitro and in-silico tests have been performed so far. These tests comprised: selection of polymer / combinations, synthesis of the polymer at various concentrations, mechanical tests to check polymer material properties (e.g. viscosity, deformation, elasticity, porosity, etc.), finite element analysis of stent design and CAD modelling, and 3D printed stent prototypes.
c) Design and development of computational modeling-inspired valves. To ensure long-term performance of hTEM-based valves, we are developing a computational modeling pipeline to predict in-vivo deformation and remodeling from initial valve design. Leaflet shortening phenomena on different valve designs have been analyzed to enable us to identify the most promising valve design to support short-term in-vivo remodeling of hTEM. hTEMs mechanical, biochemical and histological data will finally feed a computational feedback loop system, that will allow the precise prediction of adaptive or maladaptive remodeling phenomena (i.e. success vs. failure) for a specific valve design in the long-term.
d) Proof-of-concept of the TAVI4Life in an animal model. We are currently planning the proof-of-concept in vivo studies Additionally, a first TAVI4Life prototype has been successfully tested in-vitro at pulmonary and aortic conditions.
a) Produce xenogeneic serum-free human cell-derived tissue engineered matrices (hTEMs) to advance their clinical relevance. Major achievements for this project consist in the successful characterization and multiscale analysis (i.e. proteomics) of hTEMs, which show comparable ECM composition to standard-cultured hTEMs (i.e. with FBS) in terms of protein content. The prevalence of xenogeneic proteins expression into the ECM of hTEMs was determined, which however does not impact a pro-inflammatory response of macrophages in-vitro. These results may anticipate a potential adaptive remodeling response after the initial monocyte recruitment after hTEM implantation. A systematic development of xenogeneic serum-free hTEMs has been successfully achieved, showing overall promising tissue formation, composition, hemo- and biocompatibility in comparison to standard tissue engineering protocols using FBS. Pre-endothelialization of our matrices with endothelial progenitor cells demonstrate principal feasibility to form a confluent and functional endothelium on hTEMs with the expression of specific markers and migration as well as repair capacities. Induced calcifications studies have demonstrated comparable calcification potential of xenogeneic serum-free hTEMs in comparison to control (cultured with FBS supplements) hTEMs.
b) Design and development of a polymer-based 3D-printed stent. To fullfil this project, comprehensive in-vitro and in-silico tests have been performed so far. These tests comprised: selection of polymer / combinations, synthesis of the polymer at various concentrations, mechanical tests to check polymer material properties (e.g. viscosity, deformation, elasticity, porosity, etc.), finite element analysis of stent design and CAD modelling, and 3D printed stent prototypes.
c) Design and development of computational modeling-inspired valves. To ensure long-term performance of hTEM-based valves, we are developing a computational modeling pipeline to predict in-vivo deformation and remodeling from initial valve design. Leaflet shortening phenomena on different valve designs have been analyzed to enable us to identify the most promising valve design to support short-term in-vivo remodeling of hTEM. hTEMs mechanical, biochemical and histological data will finally feed a computational feedback loop system, that will allow the precise prediction of adaptive or maladaptive remodeling phenomena (i.e. success vs. failure) for a specific valve design in the long-term.
d) Proof-of-concept of the TAVI4Life in an animal model. We are currently planning the proof-of-concept in vivo studies Additionally, a first TAVI4Life prototype has been successfully tested in-vitro at pulmonary and aortic conditions.
Three major achievement will be obtained by the end of TAVI4Life:
1. Xenogeneic serum-free matrices. Their implementation into tissue-engineered cardiovascular devices will fasten and strengthen their clinical tranalsation.
2. First prototype of a regenerative stent.
3. First prototype of a fully regenerative aortic heart valve (TAVI4Life). The implementation of a xenogeneic serum-free hTEM together with a regenerative stent will provide a lifelong prosthesis, which will be particularly beneficial for children.
1. Xenogeneic serum-free matrices. Their implementation into tissue-engineered cardiovascular devices will fasten and strengthen their clinical tranalsation.
2. First prototype of a regenerative stent.
3. First prototype of a fully regenerative aortic heart valve (TAVI4Life). The implementation of a xenogeneic serum-free hTEM together with a regenerative stent will provide a lifelong prosthesis, which will be particularly beneficial for children.