Decellularized extracellular matrix‐rich hydrogel–silver nanoparticle mixture as a potential treatment for acute liver failure model

Abstract

Acute liver failure (ALF) occurs due to severe liver damage that triggers rapid loss of normal liver function. Here, we investigate the usefulness of an injectable liver extracellular matrix (LECM)-rich hydrogel generated from an optimized decellularization protocol incorporated with silver nanoparticles (AgNPs) as a promising therapy for ALF. First, we optimized a non-destructive protocol for rat liver decellularization to obtain ECM-rich well-preserved scaffold. Then, LECM hydrogel generated from two commonly used decellularization protocols were compared by LECM hydrogel obtained from our optimized protocol. The ALF model was induced by an intraperitoneal (IP) thioacetamide (TAA) injection followed by the IP injection of LECM hydrogel, collagen-AgNP mixture, or LECM hydrogel-AgNP mixture. LECM-rich scaffold and hydrogel were successfully obtained using our optimized decellularization protocol. Use of the LECM hydrogel-AgNP mixture to treat TAA-induced ALF greatly improved liver injury and histological liver regeneration. Interleukin-6 and transforming growth factor-beta expressions were significantly reduced, while albumin, hepatocyte growth factor, and Ki67-positive cells were highly expressed. Moreover, aspartate transaminase and alanine transaminase plasma levels and liver homogenate nitric oxide level were significantly lowered. In conclusion, the LECM hydrogel-AgNP mixture has potential efficient therapeutic and regenerative effects on TAA-induced liver injury.

Photocrosslinkable liver extracellular matrix hydrogels for the generation of 3D liver microenvironment models

“…ECM has been predominantly obtained through animal organ and tissue decellularization using different chemical detergents 62 . This is a critical step because the choice of detergent treatment has been shown to affect gelation kinetics, mechanical properties and biological activity of the resulting ECM hydrogels 35 , 58 , 63 . While some studies have reported the use of a single detergent treatment for successful decellularization of liver tissues 27 , 29 , 34 , other studies have shown improved efficiency of decellularization by combinational use of detergents 20 , 22 , 31 .…”

“…In accordance with previous studies, however, we achieved complete solubilization at room temperature 30 , 64 . The majority of previous studies have used unfunctionalized, solubilized liver ECM to encapsulate liver cells by spontaneous gelation at 37°C 22 , 26 , 27 , 31 , 32 , 34 , 35 . While these studies have collectively demonstrated maintenance of liver-specific functions, thermal self-assembly of ECM hydrogels is a largely uncontrolled, time-consuming process which leaves little room to tune key physicochemical matrix parameters such as stiffness and porosity.…”

“…Predominantly, studies have used solubilized liver ECM to create collagenous hydrogels fabricated by thermal gelation, resulting in a biomimetic microenvironment for the cells to attach and grow 21 , 22 , 27 – 33 . Yet, despite several related studies published in the last decade 22 , 27 , 31 – 35 , there is little consensus on the most effective decellularization method to generate liver ECM hydrogels with relevant biochemical and biomechanical properties.…”

Decellularised scaffolds: just a framework? Current knowledge and future directions

“…These cell-containing hydrogels can then be injected for minimally invasive delivery into irregular spaces, [68][69][70] applied topically or used for 3D printing or electrospinning. 57,71 Some of the medical conditions for which decellularised ECM-based hydrogels have been investigated include type 1 diabetes, 70 myocardial infarction by replacing damaged cardiac tissue, 68,69 peripheral artery disease, 72 skin wound healing, 73 keratoconus by bioprinting a corneal stromal substitute, 71 acute liver failure, 74 chronic fibrotic diseases 75 and inflammatory bowel disease. 76 The impact of the decellularisation method on the ECM-derived hydrogel has been shown by several studies.…”

Cell Therapy and Bioengineering in Experimental Liver Regenerative Medicine: In Vivo Injury Models and Grafting Strategies

“…These forms are fabricated using digested ECM, homogenized ECM, or ECM ink, respectively. These ECM forms could be used for cell delivery, but they have relevant limitations, mainly due to the additional loss of biochemical components during the digestion and fabrication processes [97,[109][110][111][112][113][114][115][116].…”