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

Abstract

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.

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

“…The scaffolds crosslinked with nanographene oxide show high resistance to enzymatic degradation via direct inhibition of MMPs activity and increased M2-like macrophage polarization, which reduces graft-elicited inflammation (Table 2). Overall, nano-graphene oxide offers an alternative for donor organs [43].…”

“…In addition, quantum dots (QDs) are used for imaging and drug-targeted delivery, which allow rapid absorption in the small intestine after oral administration and is highly specific targeting to LSECs or hepatocytes [164]. Moreover, graphene oxide (GO) enables efficient liver regeneration via immunomodulation [43].…”

Electroactive scaffolds of biodegradable polyurethane/polydopamine-functionalized graphene oxide regulating the inflammatory response and revitalizing the axonal growth cone for peripheral nerve regeneration

“…46–48 For instance, Kim et al reported that M2 polarization of macrophages was enhanced in the GO-crosslinked decellularized extracellular matrix (dECM), thereby reducing the implantation-induced foreign body response. 49 In addition, the abundant reductive functional groups (imine and catechol) in PDA can significantly decrease the inflammatory response by scavenging reactive oxygen species (ROS), which may also contribute to the M2 polarization of macrophages. 34…”

Decellularized extracellular matrix-based composite scaffolds for tissue engineering and regenerative medicine

“…Likely, Kim et al . [ 200 ] crosslinked the dECM scaffold with nano-graphene oxide to alleviate the enzymatic degradation activity and enhance the mechanical rigidity. Integrating nano-graphene oxide within dECM scaffolds has shown high stability after implantation for 60 days, alleviating the graft-elicited inflammation responses by regulating macrophage polarity.…”