TY - JOUR
T1 - Cell spheroids as a versatile research platform
T2 - formation mechanisms, high throughput production, characterization and applications
AU - Decarli, Monize Caiado
AU - Amaral, Robson
AU - dos Santos, Diogo Peres
AU - Tofani, Larissa Bueno
AU - Katayama, Eric
AU - Rezende, Rodrigo Alvarenga
AU - Lopes da Silva, Jorge Vicente
AU - Swiech, Kamilla
AU - Torres Suazo, Claudio Alberto
AU - Mota, Carlos
AU - Moroni, Lorenzo
AU - Moraes, Angela Maria
N1 - Publisher Copyright:
© 2021 IOP Publishing Ltd.
PY - 2021/7
Y1 - 2021/7
N2 - Three-dimensional (3D) cell culture has tremendous advantages to closely mimic the in vivo architecture and microenvironment of healthy tissue and organs, as well as of solid tumors. Spheroids are currently the most attractive 3D model to produce uniform reproducible cell structures as well as a potential basis for engineering large tissues and complex organs. In this review we discuss, from an engineering perspective, processes to obtain uniform 3D cell spheroids, comparing dynamic and static cultures and considering aspects such as mass transfer and shear stress. In addition, computational and mathematical modeling of complex cell spheroid systems are discussed. The non-cell-adhesive hydrogel-based method and dynamic cell culture in bioreactors are focused in detail and the myriad of developed spheroid characterization techniques is presented. The main bottlenecks and weaknesses are discussed, especially regarding the analysis of morphological parameters, cell quantification and viability, gene expression profiles, metabolic behavior and high-content analysis. Finally, a vast set of applications of spheroids as tools for in vitro study model systems is examined, including drug screening, tissue formation, pathologies development, tissue engineering and biofabrication, 3D bioprinting and microfluidics, together with their use in high-throughput platforms.
AB - Three-dimensional (3D) cell culture has tremendous advantages to closely mimic the in vivo architecture and microenvironment of healthy tissue and organs, as well as of solid tumors. Spheroids are currently the most attractive 3D model to produce uniform reproducible cell structures as well as a potential basis for engineering large tissues and complex organs. In this review we discuss, from an engineering perspective, processes to obtain uniform 3D cell spheroids, comparing dynamic and static cultures and considering aspects such as mass transfer and shear stress. In addition, computational and mathematical modeling of complex cell spheroid systems are discussed. The non-cell-adhesive hydrogel-based method and dynamic cell culture in bioreactors are focused in detail and the myriad of developed spheroid characterization techniques is presented. The main bottlenecks and weaknesses are discussed, especially regarding the analysis of morphological parameters, cell quantification and viability, gene expression profiles, metabolic behavior and high-content analysis. Finally, a vast set of applications of spheroids as tools for in vitro study model systems is examined, including drug screening, tissue formation, pathologies development, tissue engineering and biofabrication, 3D bioprinting and microfluidics, together with their use in high-throughput platforms.
KW - 3D bioprinting
KW - 3D cell culture
KW - cell aggregation
KW - cell spheroids
KW - drug screening
KW - spheroids as in vitro models
KW - tissue engineering
KW - VITRO TISSUE MODELS
KW - DRUG DISCOVERY
KW - MULTICELLULAR TUMOR SPHEROIDS
KW - E-CADHERIN
KW - OVARIAN-CANCER
KW - ON-A-CHIP
KW - IN-VITRO
KW - 3D SPHEROIDS
KW - EMBRYONIC STEM-CELLS
KW - TREATMENT RESPONSE
U2 - 10.1088/1758-5090/abe6f2
DO - 10.1088/1758-5090/abe6f2
M3 - (Systematic) Review article
C2 - 33592595
SN - 1758-5082
VL - 13
JO - Biofabrication
JF - Biofabrication
IS - 3
M1 - 032002
ER -