Frontiers of Engineering Reports on Leading-Edge Engineering from the 2012 Symposium (2013) / Chapter Skim
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Engineering 3D Tissue Systems to Better Mimic Human Biology--Matthew Gevaert
Engineering 3D Tissue Systems to Better Mimic Human Biology--Matthew Gevaert
Pages 137-148
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From page 137... ...
, was already commonplace when cells were first widely cultured in the mid-20th century and remains the standard of cell culture today. The vast majority of human cell types are adhesion dependent, and after fluid transfer to a Petri dish or well plate they attach to the bottom.
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From page 138... ...
ENGINEERING CELL SHAPE THROUGH MATERIAL INTERACTION As a living entity, each cell has the potential to sense and respond to physical stimulus at each point in all its transecting planes -- i.e., its entire surface in three dimensions. When an adhesion-dependent cell is presented with a flat surface to which it can favorably attach, it tends to maximize its adhesion and adopts a primarily flat morphology.
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From page 139... ...
Stem cells' differentiation pathway has historically been controlled by soluble factor interactions, either from a second "feeder" layer cell type or as a result of soluble factors added to the cells' media. Surprisingly, forcing a cell into a particular shape (e.g., the stars and flowers shown in Figure 1)
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From page 140... ...
Schematic representation of focal adhesion visualization (stars on cell surface) in live HT-1080 cells cultured at increasing distances (a-d)
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From page 141... ...
With frequent media changes to compensate for evaporation, depletion of nutrients, and generation of wastes, compromised viability of 2D cell cultures due to insufficient soluble environment interaction is rarely a concern. However, inherent in soluble environment interactions and the frequent replacement of cell media is a cyclic change in the media pH and a "feast to famine" dynamic with respect to nutrient access.
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From page 142... ...
by the presence of soluble factors from cell "B." Rivaling and perhaps surpassing stem cell cocultures for scientific a ctivity are cancer cocultures, particularly cancer-stroma cocultures: it is increasingly being demonstrated that the incorporation of a second cell type materially affects cancer cells in culture (Khodarev et al.
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From page 143... ...
Yet, in the absence of their purposed integration into drug delivery processes, correlation of in vitro models to in vivo results is poor, 88% of drug candidates fail in clinical trials, and each successful drug costs approximately $1 billion to develop and launch (Deloitte 2011)
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From page 144... ...
"layered complexity" in vitro systems. Both are perfusion based and incorporate 3D microenvironments and coculture interactions, but they differ in scale, manufacturing techniques, potential applications for cell-scaffold constructs, cost, and throughput.
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From page 145... ...
The mesofluidic approach inherits the benefits of more traditional bioreactors, including the highest cell viability over time, best potential to model complexity, and broadest incorporation and recovery of diverse 3D scaffold materials, the latter being an important bridge to biomanufacturing applications such as regenerative medicine, tissue engineering, and some forms of cell therapy. Layered complexity is achieved through inherent accommodation of both mixed and segregated cocultures and more controlled management of the soluble environment through active perfusion.
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From page 146... ...
the emergence of viable business models in related industries (regen TABLE 1 Evolving Paradigm Through Which the Value of In Vitro Models Is Perceived Traditional Paradigm New Paradigm 2D static monolayer More complex 2D static monolayer Layered complexity cell culture cell culture: 3D cell culture cell culture (e.g., 3D or perfusion or perfused coculture) coculture • High throughput • Lower throughput • Higher • Higher relevance but throughput but lower throughput lower relevance • Acute cost • Costs more than • Cost and value of • Overall cost minimization 2D data both matter reduction potential • Synch with past • Past data • Oversimplified • Managed complexity data disconnect • Convenience • Interesting but • Use when can get • Use when value impractical away with justifies cost NET EFFECT: Very heavy reliance on 2D NET EFFECT: Balanced approach that static monolayer methods with emphasis on recognizes throughput/relevance tradeoffs and throughput and acute cost minimization.
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From page 147... ...
aligned nontechnical trends, including increased emphasis on funding clearly relevant research and on further refining, reducing, and replacing the use of animals. The combination of these factors results in unprecedented opportunity and provides the required foundation to usher in a new era of better in vitro models.
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From page 148... ...
2008. Prognostic breast cancer signature identified from 3D culture model accurately predicts clinical outcome across independent datasets.
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