title: The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors.
abstract: Whole animal testing is an essential part in evaluating the toxicological and pharmacological profiles of chemicals and pharmaceuticals, but these experiments are expensive and cumbersome. A cell culture analog (CCA) system, when used in conjunction with a physiologically based pharmacokinetic (PBPK) model, provides an in vitro supplement to animal studies and the possibility of a human surrogate for predicting human response in clinical trials. A PBPK model mathematically simulates animal metabolism by modeling the absorption, distribution, metabolism, and elimination kinetics of a chemical in interconnected tissue compartments. A CCA uses mammalian cells cultured in interconnected chambers to physically represent the corresponding PBPK. These compartments are connected by recirculating tissue culture medium that acts as a blood surrogate. The purpose of this article is to describe the design and basic operation of the microscale manifestation of such a system. Microscale CCAs offer the potential for inexpensive, relatively high throughput evaluation of chemicals while minimizing demand for reagents and cells. Using microfabrication technology, a three-chamber ("lung"-"liver"-"other") microscale cell culture analog (microCCA) device was fabricated on a 1 in. (2.54 cm) square silicon chip. With a design flow rate of 1.76 microL/min, this microCCA device achieves approximate physiological liquid-to-cell ratio and hydrodynamic shear stress while replicating the liquid residence time parameters in the PBPK model. A dissolved oxygen sensor based on collision quenching of a fluorescent ruthenium complex by oxygen molecules was integrated into the system, demonstrating the potential to integrate real-time sensors into such devices.
authors.affiliation: School of Chemical and Biomolecular Engineering, Cornell University, 120 Olin Hall, Ithaca, New York 14850, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Sin
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Chin
authors.forename: Muhammad F
authors.initials: MF
authors.lastname: Jamil
authors.forename: Yordan
authors.initials: Y
authors.lastname: Kostov
authors.forename: Govind
authors.initials: G
authors.lastname: Rao
authors.forename: Michael L
authors.initials: ML
authors.lastname: Shuler
mesh_terms: D000818:Animals; D032701:Biomimetics / Q000295:instrumentation* / Q000379:methods; D015374:Biosensing Techniques / Q000295:instrumentation* / Q000379:methods; D018929:Cell Culture Techniques / Q000295:instrumentation* / Q000379:methods; D002460:Cell Line; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005240:Feasibility Studies; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D044085:Microfluidics / Q000295:instrumentation* / Q000379:methods; D008904:Miniaturization / Q000379:methods; D009928:Organ Specificity; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology*; D051381:Rats; D020545:Respiratory Mucosa / Q000502:physiology*; D013045:Species Specificity
chemical_list: D010100:Oxygen