Patient derived organoids have emerged as robust preclinical models for screening anti-cancer therapeutics. Current 2D culturing methods do not provide physiological responses to therapeutics, therefore 3D models are being developed to better reproduce physiological responses. 3D culturing however often requires large initial cell populations and one week to one month to grow tumors ready for therapeutic testing. As a solution a 3D culturing system has been developed capable of producing physiologically relevant tumors in an expedited fashion while only requiring a small number of initial cancer cells. A bi-layer microfluidic system capable of facilitating active convective nutrient supply to populations of cancer cells facilitates expedited growth of cancer cells when starting with populations as small as 8 cells. The system has been shown to function well with adherent and non-adherent cell types by expediting cell growth by a factor ranging from 1.27 to 4.76 greater than growth under static conditions. Utilizing such an approach has enable to formation of tumors ready for therapeutic screening within 3 days and the ability to perform therapeutic screening within the microfluidic system is demonstrated. A mathematical model has been developed which allows for adjustments to be made to the dynamic delivery of nutrients in order to efficiently use culture media without excessive waste. We believe this work to be the first attempt to grow cancers in an expedited fashion utilizing only a convective nutrient supply within a microfluidic system which also facilitates on-device therapeutic screening. The developed microfluidic system and cancer growth method have the potential to offer improved drug screening for patients in clinical settings.
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Morphological instability and roughening of growing 3D bacterial colonies
How do growing bacterial colonies get their shapes? While colony morphogenesis is well studied in two dimensions, many bacteria grow as large colonies in three-dimensional (3D) environments, such as gels and tissues in the body or subsurface soils and sediments. Here, we describe the morphodynamics of large colonies of bacteria growing in three dimensions. Using experiments in transparent 3D granular hydrogel matrices, we show that dense colonies of four different species of bacteria generically become morphologically unstable and roughen as they consume nutrients and grow beyond a critical size—eventually adopting a characteristic branched, broccoli-like morphology independent of variations in the cell type and environmental conditions. This behavior reflects a key difference between two-dimensional (2D) and 3D colonies; while a 2D colony may access the nutrients needed for growth from the third dimension, a 3D colony inevitably becomes nutrient limited in its interior, driving a transition to unstable growth at its surface. We elucidate the onset of the instability using linear stability analysis and numerical simulations of a continuum model that treats the colony as an “active fluid” whose dynamics are driven by nutrient-dependent cellular growth. We find that when all dimensions of the colony substantially exceed the nutrient penetration length, nutrient-limited growth drives a 3D morphological instability that recapitulates essential features of the experimental observations. Our work thus provides a framework to predict and control the organization of growing colonies—as well as other forms of growing active matter, such as tumors and engineered living materials—in 3D environments.
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- NSF-PAR ID:
- 10394413
- Date Published:
- Journal Name:
- Proceedings of the National Academy of Sciences
- Volume:
- 119
- Issue:
- 43
- ISSN:
- 0027-8424
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1073/pnas.2208019119
