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One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration

Despite the overwhelming use of cellularized therapeutics in cardiac regenerative engineering, approaches to biomanufacture engineered cardiac tissues (ECTs) at clinical scale remain limited. This study aims to evaluate the impact of critical biomanufacturing decisions—namely cell dose, hydrogel com...

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Autores principales: Dwyer, Kiera D., Kant, Rajeev J., Soepriatna, Arvin H., Roser, Stephanie M., Daley, Mark C., Sabe, Sharif A., Xu, Cynthia M., Choi, Bum-Rak, Sellke, Frank W., Coulombe, Kareen L. K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215511/
https://www.ncbi.nlm.nih.gov/pubmed/37237658
http://dx.doi.org/10.3390/bioengineering10050587
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author Dwyer, Kiera D.
Kant, Rajeev J.
Soepriatna, Arvin H.
Roser, Stephanie M.
Daley, Mark C.
Sabe, Sharif A.
Xu, Cynthia M.
Choi, Bum-Rak
Sellke, Frank W.
Coulombe, Kareen L. K.
author_facet Dwyer, Kiera D.
Kant, Rajeev J.
Soepriatna, Arvin H.
Roser, Stephanie M.
Daley, Mark C.
Sabe, Sharif A.
Xu, Cynthia M.
Choi, Bum-Rak
Sellke, Frank W.
Coulombe, Kareen L. K.
author_sort Dwyer, Kiera D.
collection PubMed
description Despite the overwhelming use of cellularized therapeutics in cardiac regenerative engineering, approaches to biomanufacture engineered cardiac tissues (ECTs) at clinical scale remain limited. This study aims to evaluate the impact of critical biomanufacturing decisions—namely cell dose, hydrogel composition, and size-on ECT formation and function—through the lens of clinical translation. ECTs were fabricated by mixing human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) and human cardiac fibroblasts into a collagen hydrogel to engineer meso-(3 × 9 mm), macro- (8 × 12 mm), and mega-ECTs (65 × 75 mm). Meso-ECTs exhibited a hiPSC-CM dose-dependent response in structure and mechanics, with high-density ECTs displaying reduced elastic modulus, collagen organization, prestrain development, and active stress generation. Scaling up, cell-dense macro-ECTs were able to follow point stimulation pacing without arrhythmogenesis. Finally, we successfully fabricated a mega-ECT at clinical scale containing 1 billion hiPSC-CMs for implantation in a swine model of chronic myocardial ischemia to demonstrate the technical feasibility of biomanufacturing, surgical implantation, and engraftment. Through this iterative process, we define the impact of manufacturing variables on ECT formation and function as well as identify challenges that must still be overcome to successfully accelerate ECT clinical translation.
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spelling pubmed-102155112023-05-27 One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration Dwyer, Kiera D. Kant, Rajeev J. Soepriatna, Arvin H. Roser, Stephanie M. Daley, Mark C. Sabe, Sharif A. Xu, Cynthia M. Choi, Bum-Rak Sellke, Frank W. Coulombe, Kareen L. K. Bioengineering (Basel) Article Despite the overwhelming use of cellularized therapeutics in cardiac regenerative engineering, approaches to biomanufacture engineered cardiac tissues (ECTs) at clinical scale remain limited. This study aims to evaluate the impact of critical biomanufacturing decisions—namely cell dose, hydrogel composition, and size-on ECT formation and function—through the lens of clinical translation. ECTs were fabricated by mixing human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) and human cardiac fibroblasts into a collagen hydrogel to engineer meso-(3 × 9 mm), macro- (8 × 12 mm), and mega-ECTs (65 × 75 mm). Meso-ECTs exhibited a hiPSC-CM dose-dependent response in structure and mechanics, with high-density ECTs displaying reduced elastic modulus, collagen organization, prestrain development, and active stress generation. Scaling up, cell-dense macro-ECTs were able to follow point stimulation pacing without arrhythmogenesis. Finally, we successfully fabricated a mega-ECT at clinical scale containing 1 billion hiPSC-CMs for implantation in a swine model of chronic myocardial ischemia to demonstrate the technical feasibility of biomanufacturing, surgical implantation, and engraftment. Through this iterative process, we define the impact of manufacturing variables on ECT formation and function as well as identify challenges that must still be overcome to successfully accelerate ECT clinical translation. MDPI 2023-05-13 /pmc/articles/PMC10215511/ /pubmed/37237658 http://dx.doi.org/10.3390/bioengineering10050587 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dwyer, Kiera D.
Kant, Rajeev J.
Soepriatna, Arvin H.
Roser, Stephanie M.
Daley, Mark C.
Sabe, Sharif A.
Xu, Cynthia M.
Choi, Bum-Rak
Sellke, Frank W.
Coulombe, Kareen L. K.
One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration
title One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration
title_full One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration
title_fullStr One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration
title_full_unstemmed One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration
title_short One Billion hiPSC-Cardiomyocytes: Upscaling Engineered Cardiac Tissues to Create High Cell Density Therapies for Clinical Translation in Heart Regeneration
title_sort one billion hipsc-cardiomyocytes: upscaling engineered cardiac tissues to create high cell density therapies for clinical translation in heart regeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215511/
https://www.ncbi.nlm.nih.gov/pubmed/37237658
http://dx.doi.org/10.3390/bioengineering10050587
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