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Harvard Medical School, Massachusetts Institute of Technology

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ACS Nano, Publication Date : October 17, 2019 | https://doi.org/10.1021/acsnano.9b03050 Nanoparticle-Based Hybrid Scaffolds for Deciphering the Role of Multimodal Cues in Cardiac Tissue Engineering

Junmin Lee,^{†,‡,§,⊥,+} Vijayan Manoharan,^{†,‡,∥,+} Louis Cheung,^# Seungkyu Lee,^¶ Byung-Hyun Cha,^†,‡,□Peter Newman,^†,‡ Razieh Farzad,^†,‡ Shreya Mehrotra,^{†,‡,▽,★} Kaizhen Zhang,^○ Fazal Khan,^●Masoumeh Ghaderi,^†,‡ Yi-Dong Lin,^⬡ Saira Aftab,^†,‡ Pooria Mostafalu,^†,‡ Mario Miscuglio,^Δ Joan Li,^∥Biman B. Mandal,^▽ Mohammad Asif Hussain,^■Kai-tak Wan,^○Xiaowu Shirley Tang,^*,# Ali Khademhosseini,^{*,†,‡,§,⊥,▼,⬢} and Su Ryon Shin^*,†,‡

^†Division of Engineering in Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, United States
^‡ Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
^§ Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California−Los Angeles, Los Angeles, California 90095, United States
^⊥Center for Minimally Invasive Therapeutics (C-MIT), University of California−Los Angeles, Los Angeles, California 90095, United States
^∥ Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia
^# Department of Chemistry & Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada
^¶ F. M. Kirby Neurobiology Center, Children’s Hospital Boston, and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, United States
^□Division of Cardio-Thoracic Surgery, Department of Surgery, University of Arizona College of Medicine, Room 4302D, 1501 N. Campbell Avenue, Tucson, Arizona 85724, United States
^▽ Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati-781039, Assam, India
^○ Department of Mechanical and Industrial Engineering, Northeastern University, Boston, Massachusetts 02115, United States
^●Department of Biochemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
^⬡ Divisions of Genetics and Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
^Δ Department of Electrical and Computer Engineering, George Washington University, Washington, D.C. 20052, United States
^■Department of Electrical and Computer Engineering, King Abdulaziz University, Jeddah 21569, Saudi Arabia
^▼Department of Chemical and Biomolecular Engineering, Henry Samueli School of Engineering and Applied Sciences, University of California−Los Angeles, Los Angeles, California 90095, United States
^⬢ Department of Radiology, David Geffen School of Medicine, University of California−Los Angeles, Los Angeles, California 90095, United States

^*Corresponding Authors

Author Contributions
⁺J.L. and V.M. contributed equally.

Present Address
^★Centre for Nanotechnology, Indian Institute of Technology Guwahati, Guwahati-781039, Assam, India.

Abstract

Myocardial microenvironment plays a decisive role in guiding the function and fate of cardiomyocytes, and engineering this extracellular niche holds great promise for cardiac tissue regeneration. Platforms utilizing hybrid hydrogels containing various types of conductive nanoparticles have been a critical tool for constructing engineered cardiac tissues with outstanding mechanical integrity and improved electrophysiological properties. However, there has been no attempt to directly compare the efficacy of these hybrid hydrogels and decipher the mechanisms behind how these platforms differentially regulate cardiomyocyte behavior. Here, we employed gelatin methacryloyl (GelMA) hydrogels containing three different types of carbon-based nanoparticles: carbon nanotubes (CNTs), graphene oxide (GO), and reduced GO (rGO), to investigate the influence of these hybrid scaffolds on the structural organization and functionality of cardiomyocytes. Using immunofluorescent staining for assessing cellular organization and proliferation, we showed that electrically conductive scaffolds (CNT- and rGO-GelMA compared to relatively nonconductive GO-GelMA) played a significant role in promoting desirable morphology of cardiomyocytes and elevated the expression of functional cardiac markers, while maintaining their viability. Electrophysiological analysis revealed that these engineered cardiac tissues showed distinct cardiomyocyte phenotypes and different levels of maturity based on the substrate (CNT-GelMA: ventricular-like, GO-GelMA: atrial-like, and rGO-GelMA: ventricular/atrial mixed phenotypes). Through analysis of gene-expression patterns, we uncovered that the engineered cardiac tissues matured on CNT-GelMA and native cardiac tissues showed comparable expression levels of maturation markers. Furthermore, we demonstrated that engineered cardiac tissues matured on CNT-GelMA have increased functionality through integrin-mediated mechanotransduction (via YAP/TAZ) in contrast to cardiomyocytes cultured on rGO-GelMA.

KEYWORDS : carbon-based nanoparticles, cardiomyocytes, tissue engineering, extracellular matrix, gelatin methacryloyl, echanotransduction

논문정보

형식Research article
게재일2019년 10월 (BRIC 등록일 2019-11-06)
연구진국외 연구진
분야 바이오·의료융합 > 바이오소재

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