AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB026140130
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RESEARCH ARTICLE

Digital light processing-printed macroencapsulated human liver organoids preserve hepatic stellate cell quiescence for transplantation in immunocompetent mice

Zhi Zhou1† Ruitong Li1† Xiaodong Ding1 Yixuan Li1 Yixue Luo2* Shaojun Liang1*
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1 Tianjin Key Laboratory of Life and Health Detection, Life and Health Intelligent Research Institute, School of Materials Science & Engineering, Tianjin University of Technology, Tianjin, China
2 Biomanufacturing and Rapid Forming Technology Key Laboratory of Beijing, Department of Mechanical Engineering, School of Mechanical Engineering, Tsinghua University, Beijing, China
†These authors contributed equally to this work.
Received: 5 April 2026 | Revised: 14 May 2026 | Accepted: 22 May 2026 | Published online: 22 May 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Digital light processing (DLP) bioprinting enables the fabrication of stem cell-derived liver organoids into biomimetic architectures. However, preserving quiescent hepatic stellate cells (HSCs) within human liver organoids during DLP printing remains challenging, as the mechanical requirements for print fidelity often conflict with the compliant microenvironment necessary for maintaining HSC quiescence. To address this limitation, we delineated the printable window of induced pluripotent stem cell (iPSC)-derived HSCs that balances printability with resistance to activation. Notably, day 10 HSCs retained a quiescent phenotype, contributing to the assembly of multicellular organoids without fibrotic activation. We subsequently evaluated the stress-relaxation properties of poly(ethylene glycol) diacrylate (PEGDA)–gelatin methacryloyl (GelMA) and F127DA–GelMA hydrogels, demonstrating that fast-relaxing inner hydrogels preserved the compact cellular morphology of liver organoids, suppressed activation-associated gene expression, and protected HSCs from fibrotic conversion. This highlights that stress relaxation, rather than stiffness alone, is critical for cellular adaptation. Then, we developed a DLP-bioprinted macroencapsulation platform integrating stage-selected iPSC-derived HSCs, stress relaxation-tuned hydrogels, and a protective outer shell. The DLP-printed outer shell conferred structural integrity to the macroencapsulated construct, enabling successful implantation in immunocompetent mice with high graft viability and minimal alpha-smooth muscle actin (α-SMA) expression in iPSC-derived liver organoids containing HSCs. In summary, this study establishes a coordinated strategy harmonizing HSC selection, matrix mechanics, and bioprinting design to balance biological and mechanical demands, yielding structurally stable, physiologically relevant liver organoids while preventing fibrotic activation during biofabrication.

Graphical abstract
Keywords
Human liver organoids
Hepatic stellate cells
Digital light processing bioprinting
Stress relaxation
Macroencapsulation
Funding
This work was supported by the National Natural Science Foundation of China (22534006) and the Tianjin Natural Science Foundation Project (23JCQNJC00790).
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing