Generation of cell-laden hydrogel microspheres using 3D printing-enabled microfluidics
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3D printing has been shown to be a robust and inexpensive manufacturing tool for a range of applications within biomedical science. Here we report the design and fabrication of a 3D printerenabled microfluidic device used to generate cell-laden hydrogel microspheres of tunable sizes. An inverse mold was printed using a 3D printer, and replica molding was used to fabricate a PDMS microfluidic device. Intersecting channel geometry was used to generate perfluorodecalin oil-coated gelatin methacrylate (GelMA) microspheres of varying sizes (35–250 lm diameters). Process parameters such as viscosity profile and UV cross-linking times were determined for a range of GelMA concentrations (7–15% w/v). Empirical relationships between flow rates of GelMA and oil phases, microspheres size, and associated swelling properties were determined. For cell experiments, GelMA was mixed with human osteosarcoma Saos-2 cells, to generate cell-laden GelMA microspheres with high long-term viability. This simple, inexpensive method does not require the use of traditional cleanroom facilities and when combined with the appropriate flow setup is robust enough to yield tunable cell-laden hydrogel microspheres for potential tissue engineering applications.
I. INTRODUCTION
Over the past decade, different strategies have been pursued to develop cell-culture systems to understand fundamental cell–cell and cell–extracellular interaction in the third dimension (3D). Cell-laden microspheres using microfluidic technology has been widely used as model cell-culture platform as it integrates the extracellularmatrix mimicking properties of hydrogels with the miniaturization capability of microfluidics.1–4 To incorporate cells within microspheres, living cells are dispersed in a biocompatible hydrogel and the micrometer scale of the spheres allows for sufficient nutrient to support high viability of encapsulated cells.4–6 Biochemical and biophysical properties of the hydrogel can also be modulated to ensure ideal environment for short- and long-term 3D cell culture. As a result, cell-laden microspheres have used a variety of synthetic, semi-synthetic, and natural hydrogels that provide the necessary mechanical properties, cytocompatibility, and nutrient permeability for different cell types, and have been widely used as a reproducible high-throughput cost-effective platform in cell biology and biomedical engineering. Conventional methods to fabricate hydrogel microspheres involve the emulsification of a prepolymer hydrogel solution within an immiscible continuous phase, a)
Address all correspondence to this author. e-mail: [email protected] b) These authors contributed equally to this work. DOI: 10.1557/jmr.2018.77
followed by gelation of emulsion particles.7,8 Gelation is performed using sonication; however, this results in polydisperse sphere sizes and damages the encapsulated cells. As a result, microfluidic flow-focusing devices have been used to generate monodisperse microspheres with tunable sizes for various biomedical applications.9–11 In these devices, an inter
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