title: Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip.
abstract: Engineering cardiac tissues and organ models remains a great challenge due to the hierarchical structure of the native myocardium. The need of integrating blood vessels brings additional complexity, limiting the available approaches that are suitable to produce integrated cardiovascular organoids. In this work we propose a novel hybrid strategy based on 3D bioprinting, to fabricate endothelialized myocardium. Enabled by the use of our composite bioink, endothelial cells directly bioprinted within microfibrous hydrogel scaffolds gradually migrated towards the peripheries of the microfibers to form a layer of confluent endothelium. Together with controlled anisotropy, this 3D endothelial bed was then seeded with cardiomyocytes to generate aligned myocardium capable of spontaneous and synchronous contraction. We further embedded the organoids into a specially designed microfluidic perfusion bioreactor to complete the endothelialized-myocardium-on-a-chip platform for cardiovascular toxicity evaluation. Finally, we demonstrated that such a technique could be translated to human cardiomyocytes derived from induced pluripotent stem cells to construct endothelialized human myocardium. We believe that our method for generation of endothelialized organoids fabricated through an innovative 3D bioprinting technology may find widespread applications in regenerative medicine, drug screening, and potentially disease modeling.
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02139, USA. Electronic address: yszhang@research.bwh.harvard.edu.
authors.forename: Yu Shrike
authors.initials: YS
authors.lastname: Zhang
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan 20133, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arneri
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Cell and Tissue Engineering Lab, IRCCS Istituto Ortopedico Galeazzi, Milan 20161, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Bersini
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02139, USA.
authors.forename: Su-Ryon
authors.initials: SR
authors.lastname: Shin
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biomedical Engineering, Amirkabir University of Technology, Tehran 64540, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Goli-Malekabadi
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Aleman
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Sapienza Università di Roma, Rome 00185, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Colosi
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electronics and Telecommunications, Politecnico di Torino, Torino 10129, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Busignani
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biomedical Engineering, Politecnico di Torino, Torino 10129, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Dell'Erba
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Bishop
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Shupe
authors.affiliation: Department of Electronics and Telecommunications, Politecnico di Torino, Torino 10129, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Demarchi
authors.affiliation: Cell and Tissue Engineering Lab, IRCCS Istituto Ortopedico Galeazzi, Milan 20161, Italy; Swiss Institute for Regnerative Medicine, Lugano 6900, Switzerland; Cardiocentro Ticino, Lugano 6900, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Moretti
authors.affiliation: Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan 20133, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rasponi
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02139, USA.
authors.forename: Mehmet Remzi
authors.initials: MR
authors.lastname: Dokmeci
authors.affiliation: Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02139, USA; Department of Bioindustrial Technologies, College of Animal Bioscience and Technology, Konkuk University, Seoul 143-701, Republic of Korea; Department of Physics, King Abdulaziz University, Jeddah 21569, Saudi Arabia. Electronic address: alik@bwh.harvard.edu.
authors.forename: Ali
authors.initials: A
authors.lastname: Khademhosseini
mesh_terms: D062028:Bioprinting / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000737:chemistry / Q000166:cytology; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D020894:Microfibrils / Q000737:chemistry; D009206:Myocardium; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000378:metabolism; D009940:Organoids / Q000737:chemistry / Q000254:growth & development* / Q000378:metabolism; D066330:Printing, Three-Dimensional; D044968:Regenerative Medicine; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D020100:Hydrogels
keywords: Bioprinting; Cardiac tissue engineering; Cardiovascular toxicity; Heart-on-a-chip; Vascularization