Mechanism of hard-nanomaterial clearance by the liver.

The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.

High preoperative bilirubin values protect against reperfusion injury after live donor liver transplantation.

Heme Oxygenase-1 and its product biliverdin/bilirubin have been demonstrated to protect against ischemia/reperfusion injury (IRI). We investigated whether increased preoperative bilirubin values of transplant recipients decrease IRI. Preoperative bilirubin levels of live donor liver recipients were correlated to postoperative liver transaminase as a marker of IRI. Additionally, two recipient groups with pretransplant bilirubin levels >24 µmol/l (n = 348) and ≤24 µmol/l (n = 118) were compared. Post-transplant liver function, complications, length of hospital stay, and patient and graft survival were assessed. Preoperative bilirubin levels were negatively correlated to the postoperative increase in transaminases suggesting a protective effect against IRI. The maximal rise of ALT after transplantation in high versus low bilirubin patients was 288 (-210-2457) U/l vs. 375 (-11-2102) U/l, P = 0.006. Bilirubin remained a significant determining factor in a multivariate linear regression analysis. The MELD score and its individual components as a marker of severity of chronic liver disease were significantly higher in the high versus low bilirubin group (P < 0.001). Despite this, overall complication rate (21.0% vs. 21.2%, P = 0.88), hospital stay [13 (4-260) vs. 14 (6-313) days, P = 0.93), and 1-year graft survival (90.8% vs. 89.0%, P = 0.62) were similar in both groups. High bilirubin levels of liver recipients before live donor transplantation is associated with decreased postoperative IRI.