Final Report Summary - TECAS (Towards Tissue Engineering Solutions for Cardiovascular Surgery)
The TECAS-ITN integrated the major European contributors in the field of cardiovascular tissue engineering (TE) and regenerative medicine (RM), to facilitate the training and career development of 13 early stage researchers (ESRs). The TECAS-ITN was focused on the clinical needs of cardiac valve replacement/repair, myocardium reconstruction and patch graft angioplasty of the great blood vessels, with a view to developing the underpinning expertise and technology for manufacturing functional implants for clinical use in the near future. Along these lines, the TECAS-ITN was aimed at developing numerical and experimental models for interrogating mechanotransduction and the capacity of stromal- and stem-cells to populate fibrin and decellularised scaffolds. Moreover, the work was aimed at establishing experimental models for interrogating the calcification and fatigue of decellularised scaffolds, as well as methodologies for assessing the maturation of cell-seeded constructs grown in a bioreactor and the quality of scaffolds. With a view to facilitating the safe and effective clinical translation of TE scaffolds and cell-seeded constructs, the work in this ITN aimed at assessing a number of approaches for scaffold sterilisation, and scaffold and cell-seeded construct preservation and storage. Based on the research of the TECAS-ITN, the training programme was aimed at providing the ESRs with advanced multidisciplinary and intersectorial training in the field of cardiovascular TE and RM, facilitated by host-based and Network-wide training activities, and supplemented by a rigorous complementary and transferrable skills and secondment programmes, including Exchange Secondments to other TECAS-ITN Partners, Clinical Secondments to the affiliated hospitals, Laboratory Secondments to external institutions and Industrial Secondments to the industrial TECAS-ITN Partners, designed and delivered specifically for the TECAS-ITN ESRs.
During the first year of the TECAS-ITN, the website (http://doctoralacademy.mh-hannover.de/) was established and the ESRs were recruited in two cohorts, together with the Project Manager and Administrator. In total, 7 female and 6 male ESRs from 8 nationalities were selected. All ESRs were enrolled in PhD programmes at their host institutions and followed the local training requirements for the award of the PhD degree. Moreover, the ESRs followed the TECAS-ITN Joint PhD Rules and Regulations, and attended 300 elective hours from the TECAS-ITN Joint Curriculum, which were designed and agreed between the participating institutions in order to harmonise doctoral training across the TECAS-ITN. The Joint Curriculum included a portfolio of postgraduate-level academic courses, seminars and workshops, pre-existed in the participating academic institutions, and special short-fat courses that were designed specifically for the TECAS-ITN ESRs. The Joint PhD Rules and Regulations described provisions for ESR supervision, personal development plan, examination procedures, secondments, mentoring and Joint Curriculum attendance, and were designed to fulfil at least the minimum requirements for the award of a PhD degree of each of the participating academic institutions. Moreover, a Pre-financing Meeting and the Kick-off Meeting were organised, together with 2 Annual and 1 Mid-year Work-in-Progress (WiP) meetings, and the Final meeting, which was combined with the End-of-Network Conference. The Mid-year WiP meeting also hosted the mid-term intermediate examination of the ESRs. During the course of the TECAS-ITN, the Consortium organised 2 Complementary and Transferable Skills workshops, 2 Translation-Exploitation-Standardisation and Commercialisation workshops, and a School in Mathematical Modelling and Mechanobiology, which were designed specifically for the TECAS-ITN ESRs. The Consortium organised 4 Industrial Stakeholder meetings, which were attended by external industrialists and clinicians, 6 Patient Focus seminars for the general public, 6 Women in Science and Engineering (WISE) seminars delivered by prominent female academics and clinicians in the field of TE and RM, 5 Summer Schools for secondary education pupils and teachers, and 9 primary school workshops. Moreover, the TECAS-ITN ESRs contributed 7 Wikipedia articles and a number of publications in the non-scientific online and printed press. The Consortium also organised 6 cardiovascular-focused symposia in international conferences, participated in 7 science fairs and published 9 quarterly Newsletters, which were distributed to key external academics, clinicians, industrialists and politicians. Three press conferences were also organised, which were attended by a significant number of media representatives and resulted in substantial coverage of the TECAS-ITN by the Italian, German, Dutch and Greek Media. The TECAS-ITN was selected and featured as a “best practice” example for Lower Saxony at the Regional portal of the European Commission for Germany, whereas it was also highlighted by the European Commission's Project Officer and selected by the CORDIS Editorial Team to be written about in a “Results in Brief” article.
The research of the TECAS-ITN has produced 19 original-research manuscripts, with 19 additional original-research manuscripts in preparation, whereas the ESRs have contributed 47 podium or poster presentations in major national and international conferences. These contributions have been based on the significant output of the TECAS-ITN in terms of new methodologies and technologies. Specifically, the research of the ESRs has produced analytical and numerical 3D models for predicting intracellular alpha-actin distribution/orientation in response to cyclic strain, experimental 3D micro-tissue models for investigating alpha-actin and collagen remodelling, and a non-destructive method for the quality control of cell-seeded TE constructs cultured in bioreactors, using the split-off products in the culture medium. In the field of quality control, another method that was based on a semi-automatic pattern recognition technique for the histopathological assessment of decellularised scaffolds was developed, alongside a method for the preclinical long-term fatigue testing of decellularised pulmonary and aortic scaffolds. Moreover, a static and a near-physiological pulsatile flow bioreactor for assessing the calcification potential of valvular scaffolds and scaffolds suitable for cardiovascular patching were developed, reducing the need for animal testing, together with a treatment inducing anticalcific resistance to decellularised cardiovascular tissue scaffolds. The work also developed a functional bioreactor capable of providing electromechanical stimulation and medium perfusion for the conditioning/maturation of cell-seeded myocardial patches. Using this functional simulation system, a living myocardial patch comprising a myocardial contractile component and a perfusable vascular system was generated. Moreover, 3 novel heart valve prostheses were developed, including a textile-reinforced fibrin-gel cell-seeded mitral valve, a decellularised whole mitral valve, and a decellularised-pericardium percutaneous heart valve (PHV) based on a trileaflet configuration and a novel collapsible stent. Focusing on decellularised scaffolds, a method for replenishing extracellular matrix (ECM) proteins that can be depleted during decellularisation and sterilisation was developed, together with methods for the sterilisation and preservation of decellularised scaffolds and cell-seeded constructs.
The TECAS-ITN was focused on the rapidly emerging and disruptive technological area of TE and RM, in which there is a shortage of trained multidisciplinary scientists and engineers, especially in Europe. The TECAS-ITN developed a multidisciplinary and intersectorial training programme that provided formal accreditation to its ESRs through their PhD degrees. Effectively, the TECAS-ITN structured doctoral training in cardiovascular TE at a European level by creating a cross-European research and training infrastructure that will form the basis for further European and national doctoral programmes, further enhancing European competitiveness in TE and RM. This intersectorial infrastructure provides a direct route for the commercial exploitation and clinical translation of the methodologies and technologies developed in the TECAS-ITN. Specifically, this infrastructure has enabled the rapid translation of the semi-automatic pattern recognition method for the histopathological assessment of histological images in the clinical practice of Hannover Medical School, and the industrial translation of the developed sterilisation and preservation methodologies for decellularised valvular scaffolds by Corlife oHG. These technologies can be potentially applied to additional tissues than those researched in the TECAS-ITN. In addition to the readily translatable methodologies with an immediate impact on the clinical and industrial practice, the TECAS-ITN generated a number of additional disruptive technologies that are poised to generate a significant impact in the near future. Among those, the developed methodologies for the functional assessment of valvular scaffolds in terms of long-term fatigue and calcification are expected to significantly streamline the development, quality control and production monitoring of valvular scaffolds for safe clinical use, significantly reducing the need for animal testing. In addition, the novel valve prostheses and the living myocardial patch developed in the TECAS-ITN will provide further options for valve replacement and myocardial repair, with the potential to remodel and regenerate in the patient, reducing the need for costly revision surgery. Furthermore, the developed anticalcification and ECM protein replenishment treatments have the potential to further enhance the performance of valvular scaffolds for implantation by reducing calcification incidents and enhancing ECM integrity and cell colonisation. In addition to the translatable technologies, the TECAS-ITN also developed important model systems with resonance to the wider scientific community. In particular, the numerical and experimental models for predicting and investigating alpha-actin and collagen distribution/orientation, and the living myocardial patch, offer important tools for elucidating the process of mechanotransduction, by which the cells transduce mechanical stresses into biochemical signals to regulate their function. Similarly, the in vitro calcification bioreactor and the living myocardial patch offer important models for studying the onset and progression of calcification and myocardial infraction, respectively, by enabling the investigation of relevant disease parameters in isolation or in combinations, as well as for the assessment of therapeutic regimes for these conditions. Overall, the TECAS-ITN produced a cohort of translatable and enabling technologies that will produce significant and direct scientific, clinical and commercial benefits to a range of different stakeholders, including the wider academic and cardiothoracic surgeon communities, and the medical devices industrial sector, with the ultimate beneficiaries being the patient population, who will in the near future receive safer implants with a remodelling and regeneration potential, reducing the need for revision surgery.
Further details and updates can be found on the TECAS-ITN website (http://doctoralacademy.mh-hannover.de/) and Facebook profile (https://www.facebook.com/EuropeanDoctoralAcademyInRegenerativeEngineering/timeline). The TECAS-ITN management team can be contacted at doctoral.academy@mh-hannover.de and the TECAS-ITN coordinator at korossis.sotirios@mh-hannover.de.
During the first year of the TECAS-ITN, the website (http://doctoralacademy.mh-hannover.de/) was established and the ESRs were recruited in two cohorts, together with the Project Manager and Administrator. In total, 7 female and 6 male ESRs from 8 nationalities were selected. All ESRs were enrolled in PhD programmes at their host institutions and followed the local training requirements for the award of the PhD degree. Moreover, the ESRs followed the TECAS-ITN Joint PhD Rules and Regulations, and attended 300 elective hours from the TECAS-ITN Joint Curriculum, which were designed and agreed between the participating institutions in order to harmonise doctoral training across the TECAS-ITN. The Joint Curriculum included a portfolio of postgraduate-level academic courses, seminars and workshops, pre-existed in the participating academic institutions, and special short-fat courses that were designed specifically for the TECAS-ITN ESRs. The Joint PhD Rules and Regulations described provisions for ESR supervision, personal development plan, examination procedures, secondments, mentoring and Joint Curriculum attendance, and were designed to fulfil at least the minimum requirements for the award of a PhD degree of each of the participating academic institutions. Moreover, a Pre-financing Meeting and the Kick-off Meeting were organised, together with 2 Annual and 1 Mid-year Work-in-Progress (WiP) meetings, and the Final meeting, which was combined with the End-of-Network Conference. The Mid-year WiP meeting also hosted the mid-term intermediate examination of the ESRs. During the course of the TECAS-ITN, the Consortium organised 2 Complementary and Transferable Skills workshops, 2 Translation-Exploitation-Standardisation and Commercialisation workshops, and a School in Mathematical Modelling and Mechanobiology, which were designed specifically for the TECAS-ITN ESRs. The Consortium organised 4 Industrial Stakeholder meetings, which were attended by external industrialists and clinicians, 6 Patient Focus seminars for the general public, 6 Women in Science and Engineering (WISE) seminars delivered by prominent female academics and clinicians in the field of TE and RM, 5 Summer Schools for secondary education pupils and teachers, and 9 primary school workshops. Moreover, the TECAS-ITN ESRs contributed 7 Wikipedia articles and a number of publications in the non-scientific online and printed press. The Consortium also organised 6 cardiovascular-focused symposia in international conferences, participated in 7 science fairs and published 9 quarterly Newsletters, which were distributed to key external academics, clinicians, industrialists and politicians. Three press conferences were also organised, which were attended by a significant number of media representatives and resulted in substantial coverage of the TECAS-ITN by the Italian, German, Dutch and Greek Media. The TECAS-ITN was selected and featured as a “best practice” example for Lower Saxony at the Regional portal of the European Commission for Germany, whereas it was also highlighted by the European Commission's Project Officer and selected by the CORDIS Editorial Team to be written about in a “Results in Brief” article.
The research of the TECAS-ITN has produced 19 original-research manuscripts, with 19 additional original-research manuscripts in preparation, whereas the ESRs have contributed 47 podium or poster presentations in major national and international conferences. These contributions have been based on the significant output of the TECAS-ITN in terms of new methodologies and technologies. Specifically, the research of the ESRs has produced analytical and numerical 3D models for predicting intracellular alpha-actin distribution/orientation in response to cyclic strain, experimental 3D micro-tissue models for investigating alpha-actin and collagen remodelling, and a non-destructive method for the quality control of cell-seeded TE constructs cultured in bioreactors, using the split-off products in the culture medium. In the field of quality control, another method that was based on a semi-automatic pattern recognition technique for the histopathological assessment of decellularised scaffolds was developed, alongside a method for the preclinical long-term fatigue testing of decellularised pulmonary and aortic scaffolds. Moreover, a static and a near-physiological pulsatile flow bioreactor for assessing the calcification potential of valvular scaffolds and scaffolds suitable for cardiovascular patching were developed, reducing the need for animal testing, together with a treatment inducing anticalcific resistance to decellularised cardiovascular tissue scaffolds. The work also developed a functional bioreactor capable of providing electromechanical stimulation and medium perfusion for the conditioning/maturation of cell-seeded myocardial patches. Using this functional simulation system, a living myocardial patch comprising a myocardial contractile component and a perfusable vascular system was generated. Moreover, 3 novel heart valve prostheses were developed, including a textile-reinforced fibrin-gel cell-seeded mitral valve, a decellularised whole mitral valve, and a decellularised-pericardium percutaneous heart valve (PHV) based on a trileaflet configuration and a novel collapsible stent. Focusing on decellularised scaffolds, a method for replenishing extracellular matrix (ECM) proteins that can be depleted during decellularisation and sterilisation was developed, together with methods for the sterilisation and preservation of decellularised scaffolds and cell-seeded constructs.
The TECAS-ITN was focused on the rapidly emerging and disruptive technological area of TE and RM, in which there is a shortage of trained multidisciplinary scientists and engineers, especially in Europe. The TECAS-ITN developed a multidisciplinary and intersectorial training programme that provided formal accreditation to its ESRs through their PhD degrees. Effectively, the TECAS-ITN structured doctoral training in cardiovascular TE at a European level by creating a cross-European research and training infrastructure that will form the basis for further European and national doctoral programmes, further enhancing European competitiveness in TE and RM. This intersectorial infrastructure provides a direct route for the commercial exploitation and clinical translation of the methodologies and technologies developed in the TECAS-ITN. Specifically, this infrastructure has enabled the rapid translation of the semi-automatic pattern recognition method for the histopathological assessment of histological images in the clinical practice of Hannover Medical School, and the industrial translation of the developed sterilisation and preservation methodologies for decellularised valvular scaffolds by Corlife oHG. These technologies can be potentially applied to additional tissues than those researched in the TECAS-ITN. In addition to the readily translatable methodologies with an immediate impact on the clinical and industrial practice, the TECAS-ITN generated a number of additional disruptive technologies that are poised to generate a significant impact in the near future. Among those, the developed methodologies for the functional assessment of valvular scaffolds in terms of long-term fatigue and calcification are expected to significantly streamline the development, quality control and production monitoring of valvular scaffolds for safe clinical use, significantly reducing the need for animal testing. In addition, the novel valve prostheses and the living myocardial patch developed in the TECAS-ITN will provide further options for valve replacement and myocardial repair, with the potential to remodel and regenerate in the patient, reducing the need for costly revision surgery. Furthermore, the developed anticalcification and ECM protein replenishment treatments have the potential to further enhance the performance of valvular scaffolds for implantation by reducing calcification incidents and enhancing ECM integrity and cell colonisation. In addition to the translatable technologies, the TECAS-ITN also developed important model systems with resonance to the wider scientific community. In particular, the numerical and experimental models for predicting and investigating alpha-actin and collagen distribution/orientation, and the living myocardial patch, offer important tools for elucidating the process of mechanotransduction, by which the cells transduce mechanical stresses into biochemical signals to regulate their function. Similarly, the in vitro calcification bioreactor and the living myocardial patch offer important models for studying the onset and progression of calcification and myocardial infraction, respectively, by enabling the investigation of relevant disease parameters in isolation or in combinations, as well as for the assessment of therapeutic regimes for these conditions. Overall, the TECAS-ITN produced a cohort of translatable and enabling technologies that will produce significant and direct scientific, clinical and commercial benefits to a range of different stakeholders, including the wider academic and cardiothoracic surgeon communities, and the medical devices industrial sector, with the ultimate beneficiaries being the patient population, who will in the near future receive safer implants with a remodelling and regeneration potential, reducing the need for revision surgery.
Further details and updates can be found on the TECAS-ITN website (http://doctoralacademy.mh-hannover.de/) and Facebook profile (https://www.facebook.com/EuropeanDoctoralAcademyInRegenerativeEngineering/timeline). The TECAS-ITN management team can be contacted at doctoral.academy@mh-hannover.de and the TECAS-ITN coordinator at korossis.sotirios@mh-hannover.de.