Author + information
- Received May 13, 2019
- Revision received September 16, 2019
- Accepted September 16, 2019
- Published online January 27, 2020.
- Emanuela S. Fioretta, PhDa,∗,
- Valentina Lintas, PhDa,b,∗,
- Anna Mallone, PhDa,
- Sarah E. Motta, PhDa,
- Lisa von Boehmer, DVMa,
- Petra E. Dijkman, PhDa,
- Nikola Cesarovic, DVM, PhDc,d,
- Etem Caliskan, MDe,f,
- Héctor Rodriguez Cetina Biefer, MDd,
- Miriam Lipiski, DVMc,
- Mareike Sauer, DVMc,
- Matilde Putti, PhDg,h,
- Henk M. Janssen, PhDi,
- Serge H. Söntjens, PhDi,
- Anthal I.P.M. Smits, PhDg,h,
- Carlijn V.C. Bouten, PhDg,h,
- Maximilian Y. Emmert, MD, PhDa,b,e,f,†∗ ( and )
- Simon P. Hoerstrup, MD, PhDa,b,g,†∗∗ ()
- aInstitute for Regenerative Medicine, University of Zürich, Zürich, Switzerland
- bWyss Translational Center Zürich, University of Zürich and ETH Zürich, Zürich, Switzerland
- cDivision of Surgical Research, University of Zürich, Zürich, Switzerland
- dDepartment of Cardiovascular Surgery, University Hospital Zürich, Zürich, Switzerland
- eDepartment of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
- fDepartment of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
- gDepartment of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands
- hInstitute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
- iSyMO-Chem B.V., Eindhoven, the Netherlands
• Bone marrow mononuclear cell pre-seeding of polycarbonate bisurea–based tissue-engineered heart valves has detrimental effects on long-term performance and in situ remodeling and, therefore, should be avoided.
• Leaflet-specific analysis revealed pronounced remodeling differences with regard to cell infiltration, scaffold resorption, and extracellular matrix deposition within the same valve explant.
• The heterogeneity in remodeling of polycarbonate bisurea–based tissue-engineered heart valves may have important safety implications in terms of clinical translation.
• An in-depth understanding of the mechanobiological mechanisms involved in the in situ remodeling is required to limit the risk of unpredictable (maladaptive) remodeling.
This study showed that bone marrow mononuclear cell pre-seeding had detrimental effects on functionality and in situ remodeling of bioresorbable bisurea-modified polycarbonate (PC-BU)-based tissue-engineered heart valves (TEHVs) used as transcatheter pulmonary valve replacement in sheep. We also showed heterogeneous valve and leaflet remodeling, which affects PC-BU TEHV safety, challenging their potential for clinical translation. We suggest that bone marrow mononuclear cell pre-seeding should not be used in combination with PC-BU TEHVs. A better understanding of cell–scaffold interaction and in situ remodeling processes is needed to improve transcatheter valve design and polymer absorption rates for a safe and clinically relevant translation of this approach.
- cardiovascular regenerative medicine
- endogenous tissue regeneration
- in situ tissue engineering
- supramolecular polymer
- tissue-engineered heart valve
↵∗ Drs. Fioretta and Lintas contributed equally to this work and are joint first authors.
↵† Drs. Emmert and Hoestrup contributed equally to this work and are joint senior authors.
This research forms part of Project P1.01 iValve of the research program of the BioMedical Materials institute, co-funded by the Dutch Ministry of Economic Affairs (grant number DHF-2008T089), and of project iValve-II, powered by Health∼Holland, top sector of Life Science and Health (grant number TTTI1403B), supported by the Dutch Ministry of Economic Affairs. Dr. Fioretta was partly supported by the Swiss National Science Foundation (grant number PZ00P3_180138). Drs. Bouten and Hoerstrup are shareholders of Xeltis BV. Drs. Söntjens and Janssen are employed by SyMO-Chem B.V. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received May 13, 2019.
- Revision received September 16, 2019.
- Accepted September 16, 2019.
- 2020 The Authors