The need for microphysiological systems
[The need for MPS]
The advances in drug discovery are severely impacted by limitations of workhorse in vitro model systems, such as immortalized cell lines / 2D culture. These and other study systems, such as PDx, are characterized by modest translational value, arising form to lack of 3D environment, cell-heterogeneity and matrix in the former, and interspecies differences in the latter.
The search for improved biological screening system has led to efforts to created microphysiological systems, which are more representative of human physiology and pathology. In addition, these systems promise greater standardization, lower costs, as well as reduced vivisection. Such model systems have included spheroids, organoids, and organ-on-a-chip systems among others. The latter had the advantage of microfluidic fluid exchange, while the latter have used are traditional static medica in multi-well plates.
Organoids are more sophisticated than spheroids, although they also generally have a roughly spherical shape. The latter are characterized by the presence of stem cells, or pluripotent cells, which differentiate and propagate, growing into a mass of cells with organization that resembles organs in certain key aspects. Epithelial organoids, such as for liver, lung or pancreas, are characterized by mesenchyme core (inner mass), and the early development resembles a blastocyst.
[Benefits of MPS]
Microphysiological systems (MPS) enabling organoid growth address a critical need. These systems not only facilitate the growth of organoids, their improve their culture conditions due to perfusion, in preference for shaking, resulting in better organoid growth, due to improved delivery of nutrients, and more consistent shear flow. Microfluidic culture also results in more uniform growth of organoids. This is an important feature, because variation of the differentiation of organoids grown in batch format cannot be controlled.
Microphysiological systems also can facilitate and improve optical imaging by distributing organoids in a more uniform fashion compare with gel matrix in a multi-well plate (which can result in high-content confocal imaging acquisition of z-stack with mostly empty space, slowing down acquisition of data, and wasting terabytes of storage).
MPS systems enable 3D cell culture with perfusion of media. This technology can enable organoid growth for:
- Study organ development
- Drug development platform (safety/ toxicity, efficacy)
- Precision/personalized medicine (patient response prediction)
- Regeneration technology
The application for drug development includes infectious and genetic diseases, as well as cancer. Examples of established organoid cultures for study of healthy and disease tissue in various organs include:
|Gastric||Architecture, cancer markers: morphology, transcriptomics, “mutational landscape”||Seidlitz et al
|Instestinal||Architecture, transcriptomics||Vlachogiannis et al. Science. 2018;359:920–6.|
|Liver||Architecture, transcriptomics||Broutier et al.
Nat Med. 2017; 23:1424–35.
|Pancreas||Gene (expression?) alterations, tumoroid formation/morphology||Seino et al
Cell Stem Cell. 2018;22(454–67):e6
|Prostate||Histological patterns in PDx models, similar genetic diversity in tumoroids to PDx||Gao et al
|Bladder||Mutational profile similarity in vitro and in vivo||Lee et al
|Breast||morphology, histopathology and gene profiles||Sachs et al