Three-dimensional cell culture: nearing the gap between in vitro and in vivo models

Introduction: Biotechnological advances in association with the pressure to substitute animal experimentation impelled the development of in vitro models that are more physiological and predictive of in vivo response. Objective: To discuss advantages and limitations of three-dimensional (3D) cell culture models. Method: Review of the scientific literature at PubMed using the keywords "3D culture", spheroid, organoid, "organotypic culture", "alternative model", microfluidic, organ-on-a-chip and biotechnology, individually and in different combinations. The search period was from 1971 to 2017. Results: Traditional monolayer cell culture assays, although extensively used, do not reproduce the cell-cell and cell-extracellular matrix interactions that create physical and chemical gradients and that control cell functions, such as survival, proliferation, differentiation, migration, and protein and gene expression. 3D cell culture models are able to mimic more physiological microenvironment. The number of manuscripts published in this period reflects the scientific interest in the field. Conclusions: Although 3D models have unequivocally contributed to the bioengineering, morphogenesis, oncology, and toxicology fields, many challenges remain. The high cost of some of these models, to reproduce the mechanical spatiotemporal features of the tissues, as wells as the lack of standard protocols should be taken into account. Here we discuss the advantages and limitations of some 3D cell culture models.