GelMA Core-Shell Microgel Preparation Based on a Droplet Microfluidic Device for Three-Dimensional Tumor Ball Culture and Its Drug Testing

Abstract

Gelatin methacrylate (GelMA) microgels serve as promising bioscaffolds for tissue engineering and drug screening. However, conventional solid GelMA microgels often exhibit limited mass transfer efficiency and provide insufficient protection for embedded cells. In this study, we developed a droplet-based microfluidic platform to fabricate core-shell structured GelMA microgels. This system enabled precise control over microgel size and core-to-shell ratio by modulating flow rates. Encapsulation of A549 cells within these core-shell microgels preserved cellular viability and facilitated the formation of three-dimensional tumor spheroids. These outcomes confirmed both the protective function of the core-shell architecture during encapsulation and the overall biocompatibility of the microgels. The developed GelMA core-shell microgel system presents considerable applicability in research domains such as organoid modeling and high-throughput pharmacological screening.

Keywords: 3D cell culture; GelMA; core–shell microgel; droplet microfluidic; drug testing.

Figure 1

Schematic and physical layout of the droplet microfluidic chip used for generating core–shell microgels. (A) Chip layout overview. (B) Photograph of the fabricated device. (C) Diagram of the core–shell droplet generation process at the flow-focusing junction.

Figure 2

Influence of phase flow rates on microgel diameter and shell thickness. (A) Effect of MC phase flow rate. (B) Effect of GelMA phase flow rate. (C) Effect of oil phase flow rate. (D) Combined effect of MC and GelMA flow rates at a fixed oil phase flow rate (scale bar: 50 μm).

Figure 3

Characterization of GelMA core–shell microgel permeability. (A) GelMA shell before emulsion destabilization(red fluorescence); (B) GelMA shell after emulsion destabilization; (C) FITC-Dextran core before emulsion destabilization (green fluorescence); (D) Non-fluorescent core after emulsion destabilization; (E) Merged fluorescence image before emulsion destabilization; (F) Merged fluorescence image after emulsion destabilization (scale bar: 50 μm).

Figure 4

Morphological characterization of GelMA core−shell microgels. (A) Z−axis section and cross-sectional fluorescence intensity distribution of a core−shell microgel. (B) Schematic illustration of core−shell microgel formation. (C) Size distribution of the microgels (123 ± 4.2 μm). (Scale bar: 50 μm).

Figure 5

Droplet microfluidic chip for cell-loaded core–shell microgel generation. (A) Bright-field image of a cell-encapsulated microgel. (B) Fluorescence image of live/dead stained microgel; green indicates live cells, red indicates dead cells. (Scale bar: 50 μm).

Figure 6

Evaluation of the viability and proliferation of A549 cells encapsulated in core–shell microgels. (A) Bright-field and fluorescence images of microgels on days 1, 4, 7, and 9; green fluorescence indicates live cells. (B) Size distribution of cell-loaded microgels (125 ± 5.2 µm). (C) Core diameter of microgels as a function of culture time. (Scale bar: 50 μm.).

Figure 7

Comparison of drug sensitivity to doxorubicin (DOX) in 2D-cultured cells and 3D tumor spheroids derived from GelMA core–shell microgels.