Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities
Introduction: Pediatric patients with cardiac congenital diseases require heart valve implants that can grow with their natural somatic increase in size. Current artificial valves perform poorly in children and cannot grow; thus, living-tissue-engineered valves capable of sustaining matrix homeostas...
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Frontiers Media S.A.
2021-08-01
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Series: | Frontiers in Cardiovascular Medicine |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2021.707892/full |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ionela Movileanu Ionela Movileanu Marius Harpa Marius Harpa Hussam Al Hussein Hussam Al Hussein Lucian Harceaga Alexandru Chertes Hamida Al Hussein Georg Lutter Thomas Puehler Terezia Preda Carmen Sircuta Ovidiu Cotoi Dan Nistor Dan Nistor Adrian Man Bogdan Cordos Radu Deac Horatiu Suciu Horatiu Suciu Klara Brinzaniuc Klara Brinzaniuc Megan Casco Leslie Sierad Margarita Bruce Dan Simionescu Dan Simionescu Agneta Simionescu |
spellingShingle |
Ionela Movileanu Ionela Movileanu Marius Harpa Marius Harpa Hussam Al Hussein Hussam Al Hussein Lucian Harceaga Alexandru Chertes Hamida Al Hussein Georg Lutter Thomas Puehler Terezia Preda Carmen Sircuta Ovidiu Cotoi Dan Nistor Dan Nistor Adrian Man Bogdan Cordos Radu Deac Horatiu Suciu Horatiu Suciu Klara Brinzaniuc Klara Brinzaniuc Megan Casco Leslie Sierad Margarita Bruce Dan Simionescu Dan Simionescu Agneta Simionescu Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities Frontiers in Cardiovascular Medicine acellular scaffolds autologous cells bioreactor conditioning orthotopic implantation cell seeding |
author_facet |
Ionela Movileanu Ionela Movileanu Marius Harpa Marius Harpa Hussam Al Hussein Hussam Al Hussein Lucian Harceaga Alexandru Chertes Hamida Al Hussein Georg Lutter Thomas Puehler Terezia Preda Carmen Sircuta Ovidiu Cotoi Dan Nistor Dan Nistor Adrian Man Bogdan Cordos Radu Deac Horatiu Suciu Horatiu Suciu Klara Brinzaniuc Klara Brinzaniuc Megan Casco Leslie Sierad Margarita Bruce Dan Simionescu Dan Simionescu Agneta Simionescu |
author_sort |
Ionela Movileanu |
title |
Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities |
title_short |
Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities |
title_full |
Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities |
title_fullStr |
Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities |
title_full_unstemmed |
Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities |
title_sort |
preclinical testing of living tissue-engineered heart valves for pediatric patients, challenges and opportunities |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cardiovascular Medicine |
issn |
2297-055X |
publishDate |
2021-08-01 |
description |
Introduction: Pediatric patients with cardiac congenital diseases require heart valve implants that can grow with their natural somatic increase in size. Current artificial valves perform poorly in children and cannot grow; thus, living-tissue-engineered valves capable of sustaining matrix homeostasis could overcome the current drawbacks of artificial prostheses and minimize the need for repeat surgeries.Materials and Methods: To prepare living-tissue-engineered valves, we produced completely acellular ovine pulmonary valves by perfusion. We then collected autologous adipose tissue, isolated stem cells, and differentiated them into fibroblasts and separately into endothelial cells. We seeded the fibroblasts in the cusp interstitium and onto the root adventitia and the endothelial cells inside the lumen, conditioned the living valves in dedicated pulmonary heart valve bioreactors, and pursued orthotopic implantation of autologous cell-seeded valves with 6 months follow-up. Unseeded valves served as controls.Results: Perfusion decellularization yielded acellular pulmonary valves that were stable, no degradable in vivo, cell friendly and biocompatible, had excellent hemodynamics, were not immunogenic or inflammatory, non thrombogenic, did not calcify in juvenile sheep, and served as substrates for cell repopulation. Autologous adipose-derived stem cells were easy to isolate and differentiate into fibroblasts and endothelial-like cells. Cell-seeded valves exhibited preserved viability after progressive bioreactor conditioning and functioned well in vivo for 6 months. At explantation, the implants and anastomoses were intact, and the valve root was well integrated into host tissues; valve leaflets were unchanged in size, non fibrotic, supple, and functional. Numerous cells positive for a-smooth muscle cell actin were found mostly in the sinus, base, and the fibrosa of the leaflets, and most surfaces were covered by endothelial cells, indicating a strong potential for repopulation of the scaffold.Conclusions: Tissue-engineered living valves can be generated in vitro using the approach described here. The technology is not trivial and can provide numerous challenges and opportunities, which are discussed in detail in this paper. Overall, we concluded that cell seeding did not negatively affect tissue-engineered heart valve (TEHV) performance as they exhibited as good hemodynamic performance as acellular valves in this model. Further understanding of cell fate after implantation and the timeline of repopulation of acellular scaffolds will help us evaluate the translational potential of this technology. |
topic |
acellular scaffolds autologous cells bioreactor conditioning orthotopic implantation cell seeding |
url |
https://www.frontiersin.org/articles/10.3389/fcvm.2021.707892/full |
work_keys_str_mv |
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doaj-3941edf86721482fabef76e1788269e02021-08-19T08:20:52ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2021-08-01810.3389/fcvm.2021.707892707892Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and OpportunitiesIonela Movileanu0Ionela Movileanu1Marius Harpa2Marius Harpa3Hussam Al Hussein4Hussam Al Hussein5Lucian Harceaga6Alexandru Chertes7Hamida Al Hussein8Georg Lutter9Thomas Puehler10Terezia Preda11Carmen Sircuta12Ovidiu Cotoi13Dan Nistor14Dan Nistor15Adrian Man16Bogdan Cordos17Radu Deac18Horatiu Suciu19Horatiu Suciu20Klara Brinzaniuc21Klara Brinzaniuc22Megan Casco23Leslie Sierad24Margarita Bruce25Dan Simionescu26Dan Simionescu27Agneta Simionescu28Regenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaInstitute of Cardiovascular Diseases and Transplant, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaInstitute of Cardiovascular Diseases and Transplant, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaInstitute of Cardiovascular Diseases and Transplant, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaDepartment for Experimental Cardiac Surgery and Heart Valve Replacement, School of Medicine, University of Kiel, Kiel, GermanyDepartment for Experimental Cardiac Surgery and Heart Valve Replacement, School of Medicine, University of Kiel, Kiel, GermanyRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaInstitute of Cardiovascular Diseases and Transplant, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaInstitute of Cardiovascular Diseases and Transplant, Târgu Mureş, RomaniaRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaInstitute of Cardiovascular Diseases and Transplant, Târgu Mureş, RomaniaBiocompatibility and Tissue Regeneration Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, United StatesAptus Bioreactors, LLC, Clemson, SC, United StatesBiocompatibility and Tissue Regeneration Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, United StatesRegenerative Medicine Laboratory, University of Medicine, Pharmacy, Science and Technology “George Emil Palade”, Târgu Mureş, RomaniaBiocompatibility and Tissue Regeneration Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, United StatesTissue Engineering Laboratory, Department of Bioengineering, Clemson University, Clemson, SC, United StatesIntroduction: Pediatric patients with cardiac congenital diseases require heart valve implants that can grow with their natural somatic increase in size. Current artificial valves perform poorly in children and cannot grow; thus, living-tissue-engineered valves capable of sustaining matrix homeostasis could overcome the current drawbacks of artificial prostheses and minimize the need for repeat surgeries.Materials and Methods: To prepare living-tissue-engineered valves, we produced completely acellular ovine pulmonary valves by perfusion. We then collected autologous adipose tissue, isolated stem cells, and differentiated them into fibroblasts and separately into endothelial cells. We seeded the fibroblasts in the cusp interstitium and onto the root adventitia and the endothelial cells inside the lumen, conditioned the living valves in dedicated pulmonary heart valve bioreactors, and pursued orthotopic implantation of autologous cell-seeded valves with 6 months follow-up. Unseeded valves served as controls.Results: Perfusion decellularization yielded acellular pulmonary valves that were stable, no degradable in vivo, cell friendly and biocompatible, had excellent hemodynamics, were not immunogenic or inflammatory, non thrombogenic, did not calcify in juvenile sheep, and served as substrates for cell repopulation. Autologous adipose-derived stem cells were easy to isolate and differentiate into fibroblasts and endothelial-like cells. Cell-seeded valves exhibited preserved viability after progressive bioreactor conditioning and functioned well in vivo for 6 months. At explantation, the implants and anastomoses were intact, and the valve root was well integrated into host tissues; valve leaflets were unchanged in size, non fibrotic, supple, and functional. Numerous cells positive for a-smooth muscle cell actin were found mostly in the sinus, base, and the fibrosa of the leaflets, and most surfaces were covered by endothelial cells, indicating a strong potential for repopulation of the scaffold.Conclusions: Tissue-engineered living valves can be generated in vitro using the approach described here. The technology is not trivial and can provide numerous challenges and opportunities, which are discussed in detail in this paper. Overall, we concluded that cell seeding did not negatively affect tissue-engineered heart valve (TEHV) performance as they exhibited as good hemodynamic performance as acellular valves in this model. Further understanding of cell fate after implantation and the timeline of repopulation of acellular scaffolds will help us evaluate the translational potential of this technology.https://www.frontiersin.org/articles/10.3389/fcvm.2021.707892/fullacellular scaffoldsautologous cellsbioreactor conditioningorthotopic implantationcell seeding |