Table 5.

Comparison of 3D in vitro model platforms of breast cancer microenvironments.

Model	Defining feature	Advantages	Disadvantages	Areas of interest	References
Natural matrices	Matrix composed of naturally derived ECM proteins (collagen, laminin, HA, Matrigel™, fibrin) or polysaccharides (alginate, chitosan)	High biocompatibility, high adhesion properties, remodeled and modulated by cells, variable stiffness, including secreted ECMs	Batch-to-batch variability, complex molecular composition, uncontrolled degradation, spatially random without proper care	Fiber alignment, stiffness, multi-culture, hypoxia, formation of spheroids, invasion, migration, angiogenesis	Gu and Mooney, 2016; Pradhan et al., 2016; Regier et al., 2016; Roudsari and West, 2016
Synthetic matrices	Matrix composed of synthetic polymers (PEG, PLGA, PCL, polyurethane to name a few)	Highly tunable biophysical and biochemical properties	Poor cell adhesion, often difficult for cells to degrade, cytotoxicity	Fiber alignment, stiffness, co-culture, formation of spheroids, EMT, CSC generation, migration, angiogenesis	Gu and Mooney, 2016; Morgan et al., 2016; Pradhan et al., 2016; Roudsari and West, 2016; Samavedi and Joy, 2017
Composite matrices	Matrix composed of both synthetic and natural materials	Maintains high tunability of biophysical and biochemical properties with adjusted biocompatibility	Cytotoxicity, batch-to-batch variability, complex molecular composition, custom systems which promotes inaccessibility	Porosity, stiffness, co-culture, hypoxia, formation of spheroids, invasion, migration	Gu and Mooney, 2016; Pradhan et al., 2016; Samavedi and Joy, 2017; Yue et al., 2018
Spheroids	Self-arrange/assembly and proliferation into spherical shapes	Recapitulating early development of in vivo conditions, producible in other models	Reliance on spontaneous cell interaction	Multi-culture, vasculature, migration	Gu and Mooney, 2016; Morgan et al., 2016; Regier et al., 2016; Roudsari and West, 2016
3D microfluidics	Precise control over fluids, structure, and cells on the submillimeter scale	Very high spatial and temporal control, reduced sample volume, fluidic patterning of cells and matrix allowing close cell-cell contacts and complex geometries	Difficulty in maintaining continuous fluid flow, exaggeration of certain fluidic properties, advanced systems are inaccessible to most	Porosity, stiffness, multi-culture, formation of spheroids, invasion, chemotaxis, tissue patterning, vasculature, metastasis (extravasation, intravasation), “on-a-chip” technologies	Zervantonakis et al., 2012; Sackmann et al., 2014; Sung and Beebe, 2014; Gu and Mooney, 2016; Morgan et al., 2016; Regier et al., 2016
Perfusable tumor model	Introduction of continuous fluid flow akin to vasculature (incorporating multiple forms of bioreactors)	Ameliorating issue with transport problems in traditional culture by removing wastes and supplying oxygen and nutrients to cells	Lack of complete controls to transport problems	Co-culture, recellularization of scaffolds, vasculature	Mishra et al., 2015; Guller et al., 2016; Pence et al., 2017; Kulkarni et al., 2018