Biology on a Chip: Microfabrication for Studying the Behavior of Cultured Cells

Abstract

The ability to culture cells in vitro has revolutionized hypothesis testing in basic cell and molecular biology research and has become a standard methodology in drug screening and toxicology assays. However, the traditional cell culture methodology-consisting essentially of the immersion of a large population of cells in a homogeneous fluid medium-has become increasingly limiting, both from a fundamental point of view (cells in vivo are surrounded by complex spatiotemporal microenvironments) and from a practical perspective (scaling up the number of fluid handling steps and cell manipulations for high-throughput studies in vitro is prohibitively expensive). Micro fabrication technologies have enabled researchers to design, with micrometer control, the biochemical composition and topology of the substrate, the medium composition, as well as the type of neighboring cells surrounding the microenvironment of the cell. In addition, microtechnology is conceptually well suited for the development of fast, low-cost in vitro systems that allow for high-throughput culturing and analysis of cells under large numbers of conditions. Here we review a variety of applications of microfabrication in cell culture studies, with an emphasis on the biology of various cell types.

A high-throughput microfluidic assay to study neurite response to growth factor gradients

“…Over the past decade, microfluidic devices have gained popularity in cell culture applications, because they offer a great platform for studying how cells respond to alterations of their physical and chemical milieu 15,16,17 . These devices are also useful for creating well-defined 2D and 3D cell culture environments with micrometer precision, quantifiable characterization and experimental reproducibility.…”

Biomolecular gradients in cell culture systems

“…BioMEMS and μF research have provided a plethora of ways to explore how cells respond to micrometer-scale modifications of their physical and chemical environments. [76][77][78][79][80][81] Because microfabrication allows creation of cell culture environments that are well-defined with micrometer precision, quantitative characterization and experimental reproducibility are greatly enhanced.…”

An open-chamber flow-focusing device for focal stimulation of micropatterned cells

“…[1][2][3] Microfluidics offers a high degree of control of the cell microenvironment because transport phenomena such as diffusion and laminar flow can be mathematically modeled, allowing for simulations of local concentrations and flow velocities that can be used to optimize device design. Micropatterning and microfabrication allow single cells to be confined within well-defined geometries, allowing for precise interrogation.…”

“…Therefore, microfluidic devices provide key advantages over traditional cell culture platforms in their ability to recapitulate the physiological conditions at the microscale. 2,3,6,7 Microfluidic manipulation has been utilized for the focal stimulation of microdomains of single cells, subcellular compartments, or tissues in a wide range of applications including: in vitro models for tissue development that necessitate spatiotemporal presentation of soluble and physical signals, 8,9 single cell analysis for multiplexed drug testing, 10,11 localized chemical stimulation of tissue slices for neural electrophysiology and cancer drug screening, [12][13][14] and localized neurochemical stimulation of muscle cells. [15][16][17] Classical microfluidic approaches for localized stimulation in cellular assays have utilized pressure-driven laminar flow in enclosed channels.…”