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Cited by 383D Printing in Biomedical ResearchTissue Engineering and Regenerative MedicineCellular Mechanics and Interactions

3D bioprinting of dECM-incorporated hepatocyte spheroid for simultaneous promotion of cell-cell and -ECM interactions

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Kim, Min Kyeong, Jeong, Wonwoo, Jeon, Seunggyu, Kang, Hyun-Wook·2023·Frontiers in Bioengineering and Biotechnology
DOI 10.3389/fbioe.2023.1305023PMC PMC10679743
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Abstract

The cell spheroid technology, which greatly enhances cell-cell interactions, has gained significant attention in the development of in vitro liver models. However, existing cell spheroid technologies still have limitations in improving hepatocyte-extracellular matrix (ECM) interaction, which have a significant impact on hepatic function. In this study, we have developed a novel bioprinting technology for decellularized ECM (dECM)-incorporated hepatocyte spheroids that could enhance both cell-cell and -ECM interactions simultaneously. To provide a biomimetic environment, a porcine liver dECM-based cell bio-ink was developed, and a spheroid printing process using this bio-ink was established. As a result, we precisely printed the dECM-incorporated hepatocyte spheroids with a diameter of approximately 160–220 μm using primary mouse hepatocyte (PMHs). The dECM materials were uniformly distributed within the bio-printed spheroids, and even after more than 2 weeks of culture, the spheroids maintained their spherical shape and high viability. The incorporation of dECM also significantly improved the hepatic function of hepatocyte spheroids. Compared to hepatocyte-only spheroids, dECM-incorporated hepatocyte spheroids showed approximately 4.3- and 2.5-fold increased levels of albumin and urea secretion, respectively, and a 2.0-fold increase in CYP enzyme activity. These characteristics were also reflected in the hepatic gene expression levels of ALB, HNF4A, CPS1, and others. Furthermore, the dECM-incorporated hepatocyte spheroids exhibited up to a 1.8-fold enhanced drug responsiveness to representative hepatotoxic drugs such as acetaminophen, celecoxib, and amiodarone. Based on these results, it can be concluded that the dECM-incorporated spheroid printing technology has great potential for the development of highly functional in vitro liver tissue models for drug toxicity assessment.

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  • Fourteen articles cited their usage in printing complicated, cell-based constructs, the shear thinning and fast gelation allowing high resolution printing.

    “Fourteen articles cited their usage in printing complicated, cell-based constructs, the shear thinning and fast gelation allowing high resolution printing [18,58].”

    From From scaffold to function: A systematic review on dLECM-based hydrogels for liver tissue engineering — Fabrication, properties, and translational applications (2026) · cites this paper as [58]

    The Results (§3.2; page unavailable) report shear-thinning bio-inks used to print hepatocyte spheroids, and the Discussion (§4; page unavailable) links bio-ink composition to improved printability and more uniform spheroids. The paper does not establish that fast gelation enabled high-resolution printing. The count of fourteen articles appears to be the citing authors’ tally, not a finding attributed to this individual paper. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • dLECM can be developed into bioinks with tunable rheometric properties, allowing printing of structurally intricate, functionally active, and potentially implantable liver constructs.

    “Exemplar studies by Khati et al. (2022), Tabatabaei Rezaei et al. (2025), and Kim et al. (2023) have shown that dLECM can be developed into bioinks with tunable rheometric properties, allowing the printing of structurally intricate, functionally active, and potentially implantable liver constructs [20,25,58].”

    From From scaffold to function: A systematic review on dLECM-based hydrogels for liver tissue engineering — Fabrication, properties, and translational applications (2026) · cites this paper as [58]

    Methods §2.2 and Discussion §4 describe a liver dECM bio-ink whose viscosity and printed spheroid shape varied with gelatin and dECM concentration. The Introduction §1 and Discussion §4 report enhanced hepatic functionality in the printed spheroids. The paper does not show printing of structurally intricate or implantable liver constructs; Discussion §4 presents liver regeneration only as a future potential. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Kim, M. K., Jeong, W., Jeon, S., & Kang, H.-W.
Affiliations
  • Korea Basic Science Institute (KR)
  • Wake Forest University Health Sciences (US)
  • Ulsan National Institute of Science and Technology (KR)
Corresponding author
Kang, Hyun-Wook
ORCID
Venue
Frontiers in Bioengineering and Biotechnology
Publisher
Frontiers Media SA
Published
2023-11-13
Volume
11
Pages
1305023-1305023
ISSN
2296-4185 (ISSN-L)
DOI
10.3389/fbioe.2023.1305023
PMC
PMC10679743
OpenAlex
W4388646375
Cited by
38
References
7
Citations by year
2026: 13 · 2025: 15 · 2024: 9 · 2023: 1
FWCI
3.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Bioengineering and Biotechnology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Research Foundation
  • National Research Foundation of Korea (2018K1A4A3A01063890, NRF-2018K1A4A3A01063890, 2021R1A2C2012808)
  • Ministry of Science and ICT, South Korea
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
3D bioprinting, decellularized extracellular matrix, hepatocyte spheroids, cell-cell interactions, cell-matrix interactions, bioinks, in vitro liver models, hepatocyte function, drug toxicity assessment, hepatotoxic drugs, paracetamol, celecoxib, amiodarone, drug response

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