Award Abstract # 1903933
EAGER: Understanding Nano-Cardio Interactions Using 3D Bioprinted Human Heart Tissue

NSF Org: CBET
Division of Chemical, Bioengineering, Environmental, and Transport Systems
Recipient: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Initial Amendment Date: July 2, 2019
Latest Amendment Date: July 2, 2019
Award Number: 1903933
Award Instrument: Standard Grant
Program Manager: Nora Savage
nosavage@nsf.gov
 (703)292-7949
CBET
 Division of Chemical, Bioengineering, Environmental, and Transport Systems
ENG
 Directorate for Engineering
Start Date: July 1, 2019
End Date: June 30, 2022 (Estimated)
Total Intended Award Amount: $200,000.00
Total Awarded Amount to Date: $200,000.00
Funds Obligated to Date: FY 2019 = $200,000.00
History of Investigator:
  • Shaochen Chen (Principal Investigator)
    chen168@eng.ucsd.edu
  • Vicki Grassian (Co-Principal Investigator)
Recipient Sponsored Research Office: University of California-San Diego
9500 GILMAN DR
LA JOLLA
CA  US  92093-0021
(858)534-4896
Sponsor Congressional District: 50
Primary Place of Performance: University of California, San Diego
9500 Gilman Dr., MC 0448
LA JOLLA
CA  US  92093-0934
Primary Place of Performance
Congressional District:
50
Unique Entity Identifier (UEI): UYTTZT6G9DT1
Parent UEI:
NSF Program(s): Nanoscale Interactions Program,
ENG NNI Special Studies
Primary Program Source: 01001920DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 7237, 7916
Program Element Code(s): 117900, 768100
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.041

ABSTRACT

While nanotechnology is revolutionizing many industry sectors and having significant impact to our daily lives, investigating the potential negative impacts of nanomaterials becomes ever more important. Most studies that focus on understanding potential health effects are carried out with cells cultured in a petri-dish. While such studies have provided a wealth of information about the importance of nanomaterial's physical, mechanical, and chemical properties in toxicity to cells, they inform less about the interactions of the nanoparticles with human tissues and organs. This project aims to create an engineered 3-dimensional human heart tissue model generated by a novel bioprinting technique, and to use this model to study the impact of nanoparticles on the heart. Success of this this project will eliminate the need for expensive animal model systems in studies of tissue and organ toxicity to nanomaterials. The highly interdisciplinary nature of the project will involve training students across the traditional boundaries, offering exciting topics including bioprinting, tissue engineering, nanotechnology, and biological interactions of nanoparticles. Also, the project will facilitate training broadly across multiple stages of professional and academic development by including graduate students, undergraduate students, and high school students of diverse backgrounds.

Technically, this project will be the first attempt in the field to investigate how nanoparticles interact with 3-dimensional human heart tissues, created by 3-dimensional bioprinting. The first research task aims to establish the bioprinted microscale human heart tissue model and evaluate cell alignment, morphology, gene expression, and cardiac function. The second research task will focus on the synthesis of a suite of monodispersed nanoparticles with varying compositions and surface coatings. Assessment of nano-cardio interactions will be carried out to investigate the effects of these nanoparticles on cell viability, morphology, gene expression, and cardiac force output. From this project, the feasibility of using these engineered human tissue models for nanotoxicity studies will be established. The project is of high-risk. But if successful, the outcomes of the project will lead to high reward since it will provide significant insights into the biocompatibility of nanoparticles to 3-dimensional human tissues. Using human induced pluripotent stem cells derived cardiomyocytes, the project will further reveal individual effects of these nanoparticles. The investigators are well situated and uniquely positioned to tackle these issues. The principal investigator is a pioneer in 3-dimensional bioprinting with an excellent track record for cutting-edge research in biomaterials, bioprinting, and tissue engineering. The co-principal investigator is a leading expert in studying the environmental and health implications of nanomaterials. Such a unique collaboration will lead to transformative results. The highly interdisciplinary nature of the project will enable student training across the traditional boundaries, offering exciting topics including biomanufacturing, nanotechnology and biological interactions of nanoparticles. Also, the project will facilitate training graduate students, undergraduate students, and high school students of diverse backgrounds.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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Hwang, Henry H and You, Shangting and Ma, Xuanyi and Kwe, Leilani and Victorine, Grace and Lawrence, Natalie and Wan, Xueyi and Shen, Haixu and Zhu, Wei and Chen, Shaochen "High throughput direct 3D bioprinting in multiwell plates" Biofabrication , v.13 , 2021 https://doi.org/10.1088/1758-5090/ab89ca Citation Details
Kiratitanaporn, Wisarut and Berry, David B. and Mudla, Anusorn and Fried, Trevor and Lao, Alison and Yu, Claire and Hao, Nan and Ward, Samuel R. and Chen, Shaochen "3D printing a biocompatible elastomer for modeling muscle regeneration after volumetric muscle loss" Biomaterials Advances , v.142 , 2022 https://doi.org/10.1016/j.bioadv.2022.213171 Citation Details
Liu, Justin and Miller, Kathleen and Ma, Xuanyi and Dewan, Sukriti and Lawrence, Natalie and Whang, Grace and Chung, Peter and McCulloch, Andrew D. and Chen, Shaochen "Direct 3D bioprinting of cardiac micro-tissues mimicking native myocardium" Biomaterials , v.256 , 2020 https://doi.org/10.1016/j.biomaterials.2020.120204 Citation Details
Miller, Kathleen L. and Xiang, Yi and Yu, Claire and Pustelnik, Jacob and Wu, Jerry and Ma, Xinyue and Matsui, Toshikatsu and Imahashi, Kenichi and Chen, Shaochen "Rapid 3D BioPrinting of a human iPSC-derived cardiac micro-tissue for high-throughput drug testing" Organs-on-a-Chip , v.3 , 2021 https://doi.org/10.1016/j.ooc.2021.100007 Citation Details
Wang, Pengrui and Berry, David B. and Song, Zhaoqiang and Kiratitanaporn, Wisarut and Schimelman, Jacob and Moran, Amy and He, Frank and Xi, Brian and Cai, Shengqiang and Chen, Shaochen "3D Printing of a Biocompatible Double Network Elastomer with Digital Control of Mechanical Properties" Advanced Functional Materials , v.30 , 2020 https://doi.org/10.1002/adfm.201910391 Citation Details
Yu, Claire and Miller, Kathleen L. and Schimelman, Jacob and Wang, Pengrui and Zhu, Wei and Ma, Xuanyi and Tang, Min and You, Shangting and Lakshmipathy, Deepak and He, Frank and Chen, Shaochen "A sequential 3D bioprinting and orthogonal bioconjugation approach for precision tissue engineering" Biomaterials , v.258 , 2020 https://doi.org/10.1016/j.biomaterials.2020.120294 Citation Details
Yu, Claire and Schimelman, Jacob and Wang, Pengrui and Miller, Kathleen L. and Ma, Xuanyi and You, Shangting and Guan, Jiaao and Sun, Bingjie and Zhu, Wei and Chen, Shaochen "Photopolymerizable Biomaterials and Light-Based 3D Printing Strategies for Biomedical Applications" Chemical Reviews , 2020 10.1021/acs.chemrev.9b00810 Citation Details
Y. Xiang, K. Miller "3D Bioprinting of complex tissue in vitro: state-of-the-art and future perspectives" Archives of toxicology , v.96 , 2022 Citation Details

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

The objective of this research is to investigate the interactions of nanoparticles and cardiac tissue using a 3D bioprinted human micro-heart model. The research approach includes: 1) establishing a cardiac tissue model using 3D bioprinting for nano-cardio interaction studies, 2) synthesizing a suite of monodispersed nanoparticles of similar size but of different bulk compositions and of different surface coatings, 3) investigating the impacts of nanoparticles on heart tissue viability, maturation, and function.

This work has led to significant outcomes including: 1) successful bioprinting of 3D functional micro-heart tissues using human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), 2) successful synthesis of a suite of monodispersed nanoparticles and characterization  using various techniques such as transmission electron microscopy, X-ray diffraction, and dynamic light scattering, 3) detailed studies of the nanoparticle toxicity against the human micro-heart tissues in terms of heart beating frequency, force output, and the pathways of cardiac toxicity. 

During the course of the project, three graduate students have worked in the multi-disciplinary team with significant training in bioprinting, nanoparticle synthesis and characterization, cell culture and tissue function and toxicity studies. Three undergraduate researchers have been involved in this project. The undergraduate students learned how to team up with the graduate students, and learned how to conduct scientific experiments. Eight peer-reviewed journal papers and one book chapter have been published with support from this grant. 

Results from this project has been presented in a variety of society meetings, including the Society of Engineering Science Annual Meeting, Select Biosciences Organ-on-a-Chip and 3D-Printing World Congress, American Heart Association Scientific SessionSPIE Photonic West, American Institute of Chemical Engineers meeting, and American Chemical Society meetings. The investigators have also been invited to present the results in several departmental seminars at several universities. Results from this project have also been used as a part of course materials for graduate and undergraduate courses, including Nano 206 - "Nanomanufacturing" (average enrollment 50 students per year), NANO 112 - "Synthesis and Fabrication of Nanoengineering Systems" (average enrollment 80 students per year) at the University of California San Diego. 

 


Last Modified: 10/30/2022
Modified by: Shaochen Chen

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