| Autor: |
Dwyer KD; School of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USA., Kant RJ; School of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USA., Soepriatna AH; School of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USA., Roser SM; School of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USA., Daley MC; School of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USA., Sabe SA; Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.; Division of Cardiothoracic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA., Xu CM; Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.; Division of Cardiothoracic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA., Choi BR; Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA., Sellke FW; Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.; Division of Cardiothoracic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA., Coulombe KLK; School of Engineering, Brown University Center for Biomedical Engineering, Providence, RI 02912, USA.; Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA. |
| Abstrakt: |
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. |
