The potential use of porcine hepatocytes in a bioartificial liver device requires large quantities of viable and highly active cells. To facilitate the scaling up of the system, liver specific activities of hepatocytes should be maximized. One way of enhancing the specific activities is to cultivate hepatocytes as multicellular spheroids. Freshly isolated porcine hepatocytes form spheroids when cultivated in suspended cultures. These spheroids exhibit higher activities for a number of liver specific functions compared to hepatocytes cultivated as monolayers. However, these activities decreased in a few days in culture. Entrappment of spheroids in collagen gel sustained their metabolic activities at a stable level over 21 days. Production of albumin and urea by spheroid hepatocytes entrapped in collagen gels were 2 to 3 times higher than those by freshly isolated single cells. P-450 activity was demonstrated by metabolism of lidocaine to its main metabolite, monoethylglycinexylidide. Phase II drug metabolism was demonstrated by glucuronidation of 4-methylumbelliferone. This work shows that porcine hepatocyte spheroids entrapped in collagen maintain differentiated functions for an extended time period. Such hepatocyte spheroid entrappment system may facilitate the development of a bioartificial liver support device.
Changing clinical practice is sometimes as difficult as the basic science and clinical trials work that led to the discovery of beneficial therapies. Investigators are now beginning to develop and test more theory-based implementation models that are relevant to the clinical environment. A proportion of the resources used in developing an ICU guideline or protocol must be dedicated to the implementation strategy for successful adoption. ICUs are ideal organizations to test new approaches in implementation science. Intensive care professionals should insist that their practice environment have both a culture that is supportive of adopting new practices and adequate resources to implement them into patient care.
Suppression of the gut luminal aerobic flora to reduce nosocomial infections was tested in a prospective, randomized, double-blind, placebo-controlled clinical trial in patients in a surgical intensive care unit who had persistent hypermetabolism. Forty-six patients were randomized to receive either norfloxacin, 500-mg suspension every 8 hours, together with nystatin, 1 million units every 6 hours, or matching placebo solutions administered through a nasogastric tube within 48 hours of surgical intensive care unit admission. Selective gut decontamination with the experimental therapy or placebo solutions continued for at least 5 days or until the time of surgical intensive care unit discharge. Patients were monitored with routine surveillance cultures for the development of nosocomial infections, as defined by criteria from the Centers for Disease Control. All other therapy was given as clinically indicated, including systemic antibiotics. The selective gut decontamination group experienced a significant reduction in the incidence of nosocomial infections and a reduced length of stay. However, these results were not associated with a concomitant decrease in progressive multiple organ failure syndrome, adult respiratory distress syndrome, or mortality.
Metabolic activity of a gel-entrapment, hollow fiber, bioartificial liver was evaluated in vitro and during extracorporeal hemoperfusion in an anhepatic rabbit model. The bioartificial liver contained either 100 million rat hepatocytes (n = 12), fibroblasts (n = 3), or no cells (n = 7) during hemoperfusion of anhepatic rabbits. Eight other anhepatic rabbits were studied without hemoperfusion as anhepatic controls, and three sham rabbits served as normal controls. Albumin production rates (mean +/- SEM) were similar during in vitro (17.0 +/- 2.8 micrograms/h) and extracorporeal (18.0 +/- 4.0 micrograms/h) application of the hepatocyte bioartificial liver. Exogenous glucose requirements were reduced (p < 0.01) and euglycemia was prolonged (p < 0.001) in anhepatic rabbits treated with the hepatocyte bioartificial liver. The maximum rate of glucose production by the hepatocyte bioartificial liver ranged from 50-80 micrograms/h. Plasma concentrations of aromatic amino acids, proline, alanine, and ammonia were normalized in anhepatic rabbits during hepatocyte hemoperfusion. Gel-entrapped hepatocytes in the bioartifical liver performed sulfation and glucuronidation of 4-methylumbelliferone. P450 activity was demonstrated during both in vitro and extracorporeal application of the BAL device by the formation of 3-hydroxy-lidocaine, the major metabolite of lidocaine biotransformation by gel-entrapped rat hepatocytes. In summary, a gel-entrapment, bioartificial liver performed multiple hepatocyte-specific functions without adverse side effects during extracorporeal application in an anhepatic, small animal model. With its potential for short term support of acute liver failure, scale-up of the current bioartificial liver device is indicated for further investigations in large animal, preclinical trials.
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