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Bio-Design and Manufacturing  2021 Vol.4 No.4 P.790-805

http://doi.org/10.1007/s42242-021-00137-4


Biofabrication of size‑controlled liver microtissues incorporated with ECM‑derived microparticles to prolong hepatocyte function


Author(s):  Zahra Heydari, Ibrahim Zarkesh, Mohammad‑Hossein Ghanian, Mahdokht H. Aghdaei, Svetlana Kotova, Ensieh Zahmatkesh, Zahra Farzaneh, Abbas Piryaei, Iman Akbarzadeh, Anastasia Shpichka, Roberto Gramignoli, Peter Timashev, Hossein Baharvand, Massoud Vosough

Affiliation(s):  Department of Developmental Biology, University of Science and Culture, ACECR, 14155-4364 Tehran, Iran; more

Corresponding email(s):   masvos@royaninstitute.org

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Zahra Heydari, Ibrahim Zarkesh, Mohammad‑Hossein Ghanian, Mahdokht H. Aghdaei, Svetlana Kotova, Ensieh Zahmatkesh, Zahra Farzaneh, Abbas Piryaei, Iman Akbarzadeh, Anastasia Shpichka, Roberto Gramignoli, Peter Timashev, Hossein Baharvand, Massoud Vosough. Biofabrication of size‑controlled liver microtissues incorporated with ECM‑derived microparticles to prolong hepatocyte function[J]. Journal of Zhejiang University Science D, 2021, 4(4): 790-805.

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author="Zahra Heydari, Ibrahim Zarkesh, Mohammad‑Hossein Ghanian, Mahdokht H. Aghdaei, Svetlana Kotova, Ensieh Zahmatkesh, Zahra Farzaneh, Abbas Piryaei, Iman Akbarzadeh, Anastasia Shpichka, Roberto Gramignoli, Peter Timashev, Hossein Baharvand, Massoud Vosough",
journal="Journal of Zhejiang University Science D",
volume="4",
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%A Zahra Heydari
%A Ibrahim Zarkesh
%A Mohammad‑Hossein Ghanian
%A Mahdokht H. Aghdaei
%A Svetlana Kotova
%A Ensieh Zahmatkesh
%A Zahra Farzaneh
%A Abbas Piryaei
%A Iman Akbarzadeh
%A Anastasia Shpichka
%A Roberto Gramignoli
%A Peter Timashev
%A Hossein Baharvand
%A Massoud Vosough
%J Journal of Zhejiang University SCIENCE D
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%P 790-805
%@ 1869-1951
%D 2021
%I Zhejiang University Press & Springer
%DOI 10.1007/s42242-021-00137-4

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T1 - Biofabrication of size‑controlled liver microtissues incorporated with ECM‑derived microparticles to prolong hepatocyte function
A1 - Zahra Heydari
A1 - Ibrahim Zarkesh
A1 - Mohammad‑Hossein Ghanian
A1 - Mahdokht H. Aghdaei
A1 - Svetlana Kotova
A1 - Ensieh Zahmatkesh
A1 - Zahra Farzaneh
A1 - Abbas Piryaei
A1 - Iman Akbarzadeh
A1 - Anastasia Shpichka
A1 - Roberto Gramignoli
A1 - Peter Timashev
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A1 - Massoud Vosough
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DOI - 10.1007/s42242-021-00137-4


Abstract: 
Multicellular microtissues of primary human hepatocytes (PHHs) co-cultured with other supporting cell types are a promising model for drug screening and toxicological studies. However, these liver microtissues (LMs) rapidly lose their functions during ex vivo culture. Here, in order to mimic the cellular and structural hepatic microenvironment, we co-cultured PHHs with human mesenchymal stromal cells (MSCs) and human umbilical vein endothelial cells (HUVECs) in the presence of cell-sized microparticles (MPs) derived from liver extracellular matrix (LEMPs). The microwell culture platform enabled biofabrication of size-controlled multicellular microtissues (PHH:HUVEC:MSC=3:2:1) with efcient LEMP incorporation (about 70% at a 2:1 ratio of cells:MP). The biofabricated liver microtissues (BLMs) were cultured ex vivo for 14 days and compared to the cell-only LM in terms of gene and protein expression, functional activity, cytochrome P450 (CYP450) enzyme inducibility, and drug sensitivity. The results supported superior hepatic-related gene expression, functional activity, and polarity for PHH in BLM compared to LM. CYP450 enzyme inducibility and dose-responsive sensitivity to toxic drugs were signifcantly higher in the BLM group. In conclusion, microtissue engineering by incorporation of tissue-specifc microparticles within a multicellular microtissue can ofer some advantages for drug discovery studies and cell transplantation applications. In the near future, this approach could generate a scalable platform of several functional biofabricated microtissues representing diferent organs.

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