Bioengineered liver crosslinked with nano-graphene oxide enables efficient liver regeneration via MMP suppression and immunomodulation

• Published in: Nature communications Vol. 14; no. 1; p. 801
• Main Authors: Kim, Da-Hyun, Kim, Min-Ji, Kwak, Seon-Yeong, Jeong, Jaemin, Choi, Dongho, Choi, Soon Won, Ryu, Jaechul, Kang, Kyung-Sun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 13; 13/107; 14; 38/77; 631/61/2035; 631/61/490; 631/61/54/990; 639/166/985; 639/301/54/990; 64/60; 64/86; 82/51; 96/31; Allografts; Animal models; Animals; Bioengineering; Crosslinking; Degradation; Extracellular matrix; Extracellular Matrix - metabolism; Graphene; High resistance; Humanities and Social Sciences; Immunomodulation; Inflammation; Inflammation - metabolism; Liver; Liver diseases; Liver Regeneration; Liver transplantation; Macrophages; Matrix metalloproteinase; Matrix metalloproteinases; Metalloproteinase; Mice; multidisciplinary; Organs; Oxides - metabolism; Rigidity; Scaffolds; Science; Science (multidisciplinary); Tissue Engineering; Tissue inhibitor of metalloproteinases; Tissue Scaffolds; Transplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-35941-2

Decellularized extracellular matrix scaffold, widely utilized for organ engineering, often undergoes matrix decomposition after transplantation and produces byproducts that cause inflammation, leading to clinical failure. Here we propose a strategy using nano-graphene oxide to modify the biophysical properties of decellularized liver scaffolds. Notably, we demonstrate that scaffolds crosslinked with nano-graphene oxide show high resistance to enzymatic degradation via direct inhibition of matrix metalloproteinase activity and increased mechanical rigidity. We find that M2-like macrophage polarization is promoted within the crosslinked scaffolds, which reduces graft-elicited inflammation. Moreover, we show that low activities of matrix metalloproteinases, attributed to both nano-graphene oxide and tissue inhibitors of metalloproteinases expressed by M2c, can protect the crosslinked scaffolds against in vivo degradation. Lastly, we demonstrate that bioengineered livers fabricated with the crosslinked scaffolds remain functional, thereby effectively regenerating damaged livers after transplantation into liver failure mouse models. Overall, nano-graphene oxide crosslinking prolongs allograft survival and ultimately improves therapeutic effects of bioengineered livers, which offer an alternative for donor organs. Bioengineered livers using decellularized scaffolds have been considered as an alternative to donor organs. Here, the authors modulate biophysical properties of decellularized scaffolds by crosslinking with nano-graphene oxide, thereby greatly enhancing therapeutic efficacy of bioengineered livers.