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Evaluation Methods and Design for Bioartificial Liver Based on Perfusion Model
Yueng Guen Park,류화원 한국생물공학회 2005 Biotechnology and Bioprocess Engineering Vol.10 No.1
A bioartificial liver (BAL) is a medical device entrapping living hepatocytes or immortalized cells derived from hepatocytes. Many efforts have already been made to maintain the functions of the hepatocytes in a BAL device over a long term. However, there is still some uncertainty as to their efficacy, and their limitations are unclear. Therefore, it is important to quantitatively evaluate the metabolic functions of a BAL. In previous studies on in vitro BAL devices, two test methods, an initial bolus loading and constant-rate infusion plus initial bolus loading, were theoretically carried out to obtain physiologic data on drugs. However, in the current study, the same two methods were used as a perfusion model and derived the same clearance characterized by an interrelationship between the perfusate flow rate and intrinsic clearance. The interrelationship indicated that the CL increased with an increasing perfusate flow rate and approached its maximum value, i.e. intrinsic clearance. In addition, to set up an in vivo BAL system, the toxic plateau levels in the BAL system were calculated for both series and parallel circuit models. The series model had a lower plateau level than the parellel model. The difference in the toxic plateau levels between the parallel and series models increased with an increasing number of BAL cartridges.
Evaluation Methods and Design for Bioartificial Liver Based on Perfusion Model
Park Yueng Guen,Ryu Hwa-Won The Korean Society for Biotechnology and Bioengine 2005 Biotechnology and Bioprocess Engineering Vol.10 No.1
A bioartificial liver (BAL) is a medical device entrapping living hepatocytes or immortalized cells derived from hepatocytes. Many efforts have already been made to maintain the functions of the hepatocytes in a BAL device over a long term. However, there is still some uncertainty as to their efficacy. and their limitations are unclear. Therefore, it is important to quantitatively evaluate the metabolic functions of a BAL. In previous studies on in vitro BAL devices, two test methods, an initial bolus loading and constant-rate infusion plus initial bolus loading, were theoretically carried out to obtain physiologic data on drugs. However, in the current study, the same two methods were used as a perfusion model and derived the same clearance characterized by an interrelationship between the perfusate flow rate and intrinsic clearance. The interrelationship indicated that the CL increased with an increasing perfusate flow rate and approached its maximum value, i.e. intrinsic clearance. In addition, to set up an in vivo BAL system, the toxic plateau levels in the BAL system were calculated for both series and parallel circuit models. The series model had a lower plateau level than the parellel model. The difference in the toxic plateau levels between the parallel and series models increased with an increasing number of BAL cartridges.
류화원,Yueng Guen Park,Takehiko Tosha,Satoshi Fujita,Boru Zhu,Hiroo Iwata 한국생물공학회 2003 Biotechnology and Bioprocess Engineering Vol.8 No.1
Difficulties associated with bioartificial liver (BAL) preservation limit not only the commercialization of BAL, but also its clinical trials. In this study, the possibility of cold preservation of BAL cartridges containing porcine hepatocytes was examined at 4 oC. In an in vitro perfusion culture system, BAL cartridges maintained cytochrome P450 metabolic function for at least 50 days. However, all BAL cartridges completely lost their ammonia eliminating ability when stored at 4oC. We also studied the effect of cell density on the maintenance of BAL liver function in a highly differentiated and healthy state. As expected, BALs containing a larger number of hepatocytes demonstrated higher metabolic functions. When metabolic functions were compared per gram of hepatocytes, no large differences were observed between devices containing different densities of hepatocytes. Decreased cell density did not successfully prolong BAL function. The viability and function of isolated hepatocytes highly depend on the culture conditions, such as cell density, substrata, culture media, and additives to the culture media. Perfusion culture of BAL cartridges at 4oC gave a promosing result with respect to the maintenance of P450 activity. However, as indicated by the rapid loss of ammonia metabolic activity, many factors still remain to be optimized for preservation of BAL keeping high metabolic functions for a longer time.
Method for Evaluating Metabolic Functions of Drugs in Bioartificial Liver
류화원,Yueng Guen Park,Hiroo Iwata,Seiji Satoh,Takehiko Uesugi 한국생물공학회 2003 Biotechnology and Bioprocess Engineering Vol.8 No.5
Lidocaine and galactose loading tests were performed on a bioartificial liver (BAL), an extracorporeal medical device incorporating living hepatocytes in a cartridge without a transport barrier across the membranes. The concentration changes were analyzed using pharmacokinetic equations to evaluate the efficacy and limitation of the proposed method. Lidocaine and galactose were found to be suitable drugs for a quantitative evaluation of the BAL functions, as they did not interact with the plasma proteins or blood vessels, making their concentrations easy to determine. The drug concentration changes after drug loading were easily analyzed using pharmacokinetic equations, and the BAL functions quantitatively expressed by pharmacokinetic parameters, such as the clearance (CL) and galactose elimination capacity (GEC). In addition, these two drugs have already been used in clinical tests to evaluate human liver functions over long periods, and lidocaine CL values and GEC values reported for a normal human liver. Thus, a comparison of the CL and GEC values for the BAL and a natural liver revealed what proportion of normal liver functions could be replaced by the BAL.