Development of highly functional bioengineered human liver with perfusable vasculature
Abstract
Liver tissue engineering offers a promising strategy for liver failure patients. Since transplantation rejection resulting in vessel thrombosis is regarded as a major hurdle, vascular reconstruction is one of indispensable requirements of whole organ engineering. Here we demonstrated a novel strategy for reconstruction of a vascularized bioengineered human liver (VBHL) using decellularized liver scaffolds in an efficient manner. First we achieved fully functional endothelial coverage of scaffolds by adopting the anti-CD31 aptamer as a potent coating agent for re-endothelialization. Through an ex vivo human blood perfusion that recapitulates the blood coagulation response in humans, we demonstrated significantly reduced platelet aggregation in anti-CD31 aptamer coated scaffolds. We then produced VBHL constructs using liver parenchymal cells and nonparenchymal cells, properly organized into liver-like structures with an aligned vasculature. Interestingly, VBHL constructs displayed prominently enhanced long-term liver-specific functions that are affected by vascular functionality. The VBHL constructs formed perfusable vessel networks in vivo as evidenced by the direct vascular connection between the VBHL constructs and the renal circulation. Furthermore, heterotopic transplantation of VBHL constructs supported liver functions in a rat model of liver fibrosis. Overall, we proposed a new strategy to generate transplantable bioengineered livers characterized by highly functional vascular reconstruction.
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Bioengineered livers produced with dECM scaffolds and liver-composing cells have been extensively developed to replace or regenerate injured liver tissues.
“bioengineered livers produced with dECM scaffolds and liver-composing cells have been extensively developed to replace or regenerate injured liver tissues8,9.”
From Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation (2023) · cites this paper as [9]
Over the last two decades, livers from mice, rats, ferrets, rabbits, sheep, pigs, and humans have been used for decellularization.
“Over the last two decades, livers from mice, rats, ferrets, rabbits, sheep, pigs, and humans have been used for decellularization [[8], [9], [10], [11],[13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [9]
Several published studies have demonstrated promising results in generating bioengineered livers.
“Several published studies have demonstrated promising results in generating bioengineered livers [[8], [9], [10], [11], [12], [13], [14]].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [9]
The combined DNase and chemical detergent approach has led to complete depletion of cellular and nuclear materials, with more than 95% DNA removal.
“This combined approach has led to complete depletion of cellular and nuclear materials, with more than 95 % DNA removal [9,149].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [9]
The endothelial layer reduces the risk of blood coagulation and protects the hepatocytes from shear stress resulting from blood flow outside the vascular spaces.
“This endothelial layer reduces the risk of blood coagulation and protects the hepatocytes from shear stress resulting from blood flow outside the vascular spaces [9,10,108,168].”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [9]
Coating decellularized rat liver with anti-CD31 aptamer led to formation of continuous endothelium along vascular lumens and more efficient endothelization throughout the liver construct than with anti-CD31 antibody.
“Formation of continuous endothelium along the vascular lumens was observed in the presence of the anti-CD31 aptamer coating, leading to more efficient endothelization throughout the liver construct than with the anti-CD31 antibody as shown in Fig. 4.”
From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [9]
Cites
The use of whole organ decellularization for the generation of a vascularized liver organoid
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Integrin β1 controls VE-cadherin localization and blood vessel stability
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Recent advances in liver engineering with decellularized scaffold
Dai, Q., Jiang, W., Huang, F., Song, F., Zhang, J., & Zhao, H. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.831477 · Cited by 57 · see citing works
Kim, D.-H., Kim, M.-J., Kwak, S.-Y., Jeong, J., Choi, D., Choi, S. W., Ryu, J., & Kang, K.-S. (2023) · Nature Communications · doi:10.1038/s41467-023-35941-2 · Cited by 53 · see citing works
Self-citationHussein, K. H., Ahmadzada, B., Correa, J. C., Sultan, A., Wilken, S., Amiot, B., & Nyberg, S. L. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.06.001 · Cited by 28 · see citing works
“Scale bar for the top images: 200 μ m, and for the bottom: 100 μ m [Adapted from Kim et al. [9], with a permission from Elsevier].”
BackgroundMethodInfluentialYadav, C. J., Yadav, U., Afrin, S., Lee, J.-Y., Kamel, J., & Park, K.-M. (2026) · Biomaterials Science · doi:10.1039/d5bm01589h · Cited by 2 · see citing works
- Authors
- Kim, D.-H., Ahn, J., Kang, H. K., Kim, M.-S., Kim, N.-G., Kook, M. G., Choi, S. W., Jeon, N. L., Woo, H.-M., & Kang, K.-S.
- Affiliations
- Seoul National University (KR)
- Kangwon National University (KR)
- Corresponding author
- Kang, Kyung-Sun
- ORCID
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 265
- Pages
- 120417
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W3088414730
- Cited by
- 48
- References
- 4
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 6 · 2023: 12 · 2022: 7 · 2021: 6
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation of Korea
- Rural Development Administration
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- vascular reconstruction, decellularized liver scaffold, re-endothelialization, platelet aggregation, blood perfusion, liver parenchymal cells, non-parenchymal cells, heterotopic transplantation, liver fibrosis, liver failure
- MeSH terms
- Animals, Biomedical Engineering, Humans, Liver, Tissue Engineering, Endothelial Cells, Rats, Tissue Scaffolds
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