title: Microfabricated grooved substrates as platforms for bioartificial liver reactors.
abstract: An extracorporeal bioartificial liver device has the potential to provide temporary hepatic support for patients with liver failure. Our goal was to optimize the flow environment for the cultured hepatocytes in a flat-plate bioreactor, specifically focusing on oxygen delivery using high medium flow rates while reducing the detrimental effects of the resulting shear stresses. We used photolithographic techniques to fabricate microgrooves onto the underlying glass substrate. The microgrooves, perpendicular to the axial flow direction, protected the hepatocytes from the shear stress induced by the flowing medium. Using finite element analysis, we found that the velocity gradient change near the cell surface (i.e., bottom of the grooves) was smaller than that near the top surface of the flow channel, indicating that the grooves would provide protection to the attached cells from the mechanical effects of the flowing medium. We also determined that the shear stress at the cell surface could be reduced by as much as 30 times (channel height of 100 microm) in the grooved-substrate (0.5 dyn/cm(2)) bioreactor compared to the flat-substrate (15 dyn/cm(2)) bioreactor for a medium flow rate of 4.0 mL/min. Albumin and urea synthesis rates of hepatocytes cocultured with 3T3-J2 fibroblasts remained stable over 5 days of perfusion in the grooved-substrate bioreactor, whereas in the flat-substrate bioreactor they decreased over the same time period. These studies indicate that under "high" flow conditions the microgrooved-substrate in the bioreactor can decrease the detrimental effects of shear stress on the hepatocytes while providing adequate oxygenation, thereby resulting in stable liver-specific function.
authors.affiliation: Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Shriners Hospitals for Children and Harvard Medical School, 51 Blossom Street, Boston, Massachusetts 02114, USA.
authors.forename: Jaesung
authors.initials: J
authors.lastname: Park
authors.forename: François
authors.initials: F
authors.lastname: Berthiaume
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.forename: Arno W
authors.initials: AW
authors.lastname: Tilles
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019149:Bioreactors; D018929:Cell Culture Techniques / Q000295:instrumentation* / Q000379:methods; D049109:Cell Proliferation; D002470:Cell Survival; D017076:Computer-Aided Design; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology*; D019164:Liver, Artificial; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation* / Q000379:methods; D051381:Rats; D011917:Rats, Inbred Lew; D033081:Shear Strength; D013499:Surface Properties; D023822:Tissue Engineering / Q000295:instrumentation* / Q000379:methods