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Cited by 84Tissue Engineering and Regenerative Medicine3D Printing in Biomedical ResearchBone Tissue Engineering Materials

Improving functional re-endothelialization of acellular liver scaffold using REDV cell-binding domain

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Devalliere, Julie, Chen, Yibin, Dooley, Kevin, Yarmush, Martin L., Uygun, Basak E.·2018·Acta Biomaterialia
DOI 10.1016/j.actbio.2018.07.046PMC PMC6261340
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Abstract

Engineering of functional vascularized liver tissues holds great promise in addressing donor organ shortage for transplantation. Whole organ decellularization is a cell removal method that retains the native vascular structures of the organ such that it can be anastomosed with the recipient circulation after recellularization with healthy cells. However, a main hurdle to successful implantation of bioengineered organ is the inability to efficiently re-endothelialize the vasculature with a functional endothelium, resulting in blood clotting which is the primary cause of failure in early transplant studies. Here, we present an efficient approach for enhancing re-endothelialization of decellularized rat liver scaffolds by conjugating the REDV cell-binding domain to improve attachment of endothelial cells (EC) on vascular wall surfaces. In order to facilitate expression and purification of the peptide, REDV was fused with elastin-like peptide (ELP) that confers thermally triggered aggregation behavior to the fusion protein. After validating the adhesive properties of the REDV-ELP peptide, we covalently coupled REDV-ELP to the blood vasculature of decellularized rat livers and seeded EC using perfusion of the portal vein. We showed that REDV-ELP increased cell attachment, spreading and proliferation of EC within the construct resulting in uniform endothelial lining of the scaffold vasculature. We further observed that REDV-ELP conjugation dramatically reduced platelet adhesion and activation. Altogether, our results demonstrate that this method allowed functional re-endothelialization of liver scaffold and show great potential toward the generation of functional bioengineered liver for long-term transplantation. Statement of significance There is a critical need for novel organ replacement therapies as the grafts for transplantation fall short of demand. Recent advances in tissue engineering, through the use of decellularized scaffolds, have opened the possibility that engineered grafts could be used as substitutes for donor livers. However, successful implantation has been challenged by the inability to create a functional vasculature. Our research study reports a new strategy to increase efficiency of endothelialization by increasing the affinity of the vascular matrix for endothelial cells. We functionalized decellularized liver scaffold using elastin-like peptides grafted with REDV cell binding domain. We showed that REDV-ELP conjugation improve endothelial cell attachment and proliferation within the scaffold, demonstrating the feasibility of re-endothelializing a whole liver vasculature using our technique.

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  • Both HUVECs and EA. hy926 cells were able to line the blood vessels of decellularized livers, with a significant reduction in platelet adhesion and clot formation during ex vivo blood perfusion, and demonstrated the ability to withstand blood flow after in vivo transplantation in pigs.

    “Both cell types were able to line the blood vessels of decellularized livers, with a significant reduction in platelet adhesion and clot formation during ex vivo blood perfusion and demonstrated the ability to withstand blood flow after in vivo transplantation in pigs.”

    From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [10]

    Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • 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 [10]

    The Introduction (page not provided) says endothelial coverage of the vascular network is needed to prevent thrombosis, supporting the coagulation part of the claim. The Discussion discusses flow shear stress on endothelial cells, but does not say the endothelial layer protects hepatocytes from shear stress caused by blood flowing outside vascular spaces. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • HUVECs and EA. hy926 cells have been extensively used for reendothelization of decellularized livers due to relative ease of accessibility, non-invasive harvesting from medical waste, and high yield following isolation.

    “Cell lines, including HUVECs and EA. hy926 cells, have been extensively used for reendothelization of decellularized livers due to their relative ease of accessibility and the non-invasive harvesting from medical waste, in addition to a high yield following isolation [10,13,14,235].”

    From Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities (2024) · cites this paper as [10]

    The Methods section (‘Re-endothelialization of decellularized liver scaffold’; page unavailable) confirms that this study used EA.hy926 cells to re-endothelialize liver scaffolds. The Discussion (page unavailable) discusses HUVECs but describes their availability as poor, contrary to the claimed ease of access. It does not support non-invasive harvesting from medical waste, high isolation yield, or extensive use of both cell types. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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 [10]

  • 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 [10]

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Cited by

Sorted by citations

Authors
Devalliere, J., Chen, Y., Dooley, K., Yarmush, M. L., & Uygun, B. E.
Affiliations
  • Harvard University (US)
  • Rutgers, The State University of New Jersey (US)
Corresponding author
Uygun, Basak E.
ORCID
Venue
Acta Biomaterialia
Publisher
Elsevier BV
Published
2018-09
Volume
78
Pages
151-164
ISSN
1742-7061 (ISSN-L)
DOI
10.1016/j.actbio.2018.07.046
PMC
PMC6261340
OpenAlex
W2887837569
Cited by
84
References
5
Citations by year
2026: 6 · 2025: 9 · 2024: 12 · 2023: 13 · 2022: 8 · 2021: 10 · 2020: 14 · 2019: 12
FWCI
9.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Biomaterialia (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (K99DK088962, R01DK084053, R00DK088962)
Topics
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
Keywords
re-endothelialization, decellularized liver scaffold, elastin-like peptides, endothelial cell adhesion, vascularization, platelet adhesion, coagulation, tissue engineering, rat liver
MeSH terms
Protein Domains, Animals, Cell Line, Humans, Liver, Oligopeptides, Endothelial Cells, Rats, Tissue Scaffolds

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