Abstract
Human tumour progression is a dynamic process involving diverse biological and biochemical events such as genetic mutation and selection in addition to physical, chemical, and mechanical events occurring between cells and the tumour microenvironment. Using 3D bioprinting we have developed a method to embed MDA-MB-231 triple negative breast cancer cells, and IMR-90 fibroblast cells, within a cross-linked alginate/gelatin matrix at specific initial locations relative to each other. After 7 days of co-culture the MDA-MB-231 cells begin to form multicellular tumour spheroids (MCTS) that increase in size and frequency over time. After ~15 days the IMR-90 stromal fibroblast cells migrate through a non-cellularized region of the hydrogel matrix and infiltrate the MDA-MB-231 spheroids creating mixed MDA-MB-231/IMR-90 MCTS. This study provides a proof-of-concept that biomimetic in vitro tissue co-culture models bioprinted with both breast cancer cells and fibroblasts will result in MCTS that can be maintained for durations of several weeks.
Highlights
To accurately determine the magnitude of the influence CAFs contribute in these roles the precise control over the localization, cell density, and matrix biochemistry of the stromal cells and tumour epithelial cells need to be highly controlled. 3D cell culture, co-culture of cancer cells, and cancer associated cells, grown in polymeric matrices have been shown to more accurately represent the physiological environment of tumours due to the cell-cell and cell-matrix interactions that can occur[10,11,12]
We report the ability of an extrusion bioprintable composite hydrogel formulation composed of ionically cross-linked alginate and gelatin hydrogels drives the formation of multicellular tumour spheroids (MCTS) without the use of additional chemical, biological, or physical stresses
The cells were mixed individually into a composite hydrogel solution comprised of 3% alginate/7% gelatin (w/v%)
Summary
To accurately determine the magnitude of the influence CAFs contribute in these roles the precise control over the localization, cell density, and matrix biochemistry of the stromal cells and tumour epithelial cells need to be highly controlled. 3D cell culture, co-culture of cancer cells, and cancer associated cells, grown in polymeric matrices have been shown to more accurately represent the physiological environment of tumours due to the cell-cell and cell-matrix interactions that can occur[10,11,12]. To accurately determine the magnitude of the influence CAFs contribute in these roles the precise control over the localization, cell density, and matrix biochemistry of the stromal cells and tumour epithelial cells need to be highly controlled. Bioprinting is advantageous in that more complex geometric matrices can be printed with high cell density and viability and cell-laden samples can be created directly, with precise reproducibility, from cell-hydrogel suspensions[16,17,18,19,20,21,22,23]. Ejection bioprinted ovarian cancer co-culture models including CAFs demonstrated that the ovarian cells were able to proliferate and spontaneously form multicellular acini[24]. Using Multi-cartridge extrusion bioprinting allows us to develop cellularly heterogeneous samples comprised of both TN breast cancer cells and fibroblasts in specific initial locations with controlled density. The development of MCTS is quantitatively analyzed during 30-day culture periods by monitoring the MCTS surface area, frequency, and cell viability
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