Essential operating principles for tumor spheroid growth

Engelberg, Jesse A.; Ropella, Glen E. P.; Hunt, C. Anthony

doi:10.1186/1752-0509-2-110

Cited by 41 publications

(46 citation statements)

References 36 publications

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“…2: cycles of ISECC synthesis, testing and evaluation, validation or falsification, assessment, cogitation, and system revision until one satisfied predetermined similarity criteria. We have used the protocol successfully Tang et al, 2007;Engelberg et al, 2008;. It strives to adhere to the guideline of parsimony, which is important when building agent-oriented analogs that are expected to become increasingly complex.…”

Section: Methodsmentioning

confidence: 99%

Mechanistic Insight from In Silico Pharmacokinetic Experiments: Roles of P-glycoprotein, Cyp3A4 Enzymes, and Microenvironments

Lam

Hunt²

2009

J Pharmacol Exp Ther

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Saquinavir exhibits paradoxical transport across modified Caco-2 cell monolayers (doi: 10.1124/jpet.103.056390) expressing P-glycoprotein and Cyp3A4. The data implicate complicated intracellular transport mechanisms. Drawing on recent discrete event modeling and simulation advances, we built an in silico analog of the confluent, asymmetric cell monolayer used in the cited work. We call it in silico experimental Caco-2 (cell monolayer) culture (ISECC). Concrete, working, hypothesized spatial mechanisms were implemented. Validation was achieved when in silico experimental results met similarity measure (SM) expectations that targeted 16 wet-lab experimental conditions. Initial mechanistic hypotheses turned out to be necessary parts of a more complicated explanation. We progressed through four stages of an iterative refinement and validation protocol that enabled and facilitated discovery of plausible, new mechanistic details. The process exercised abductive reasoning, a primary means of scientific knowledge creation and creative cognition. The ISECC that survived the most stringent SM challenge produced transport data that was statistically indistinguishable from referent wet-lab observations. It required a 7:1 ratio of apical transporters to metabolizing enzymes, a 97% reduction of efflux activity by an inhibitor, a biased distribution of metabolizing enzymes, heterogeneous intracellular spaces, and restrictions on intracellular drug movement. Experimenting on synthetic analogs such as ISECC provides a former unavailable means of discovering new mechanistic details and testing their plausibility. The approach thus provides a powerful new expansion of the scientific method: an independent, scientific means to challenge, explore, better understand, and improve any inductive mechanism and, importantly, the assumptions on which it rests. et al. (2004) reported paradoxical observations after a vectorial study of saquinavir transport across a monolayer of modified P-glycoprotein (P-gp) and Cyp3A4-expressing Caco-2 cells: there were higher intracellular levels of saquinavir, yet less metabolite formation after apical compared with basal dosing. The data clearly indicated that the intracellular mechanisms during transport were more complicated than anticipated. Mouly

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Section: Methodsmentioning

confidence: 99%

Mechanistic Insight from In Silico Pharmacokinetic Experiments: Roles of P-glycoprotein, Cyp3A4 Enzymes, and Microenvironments

Lam

Hunt²

2009

J Pharmacol Exp Ther

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“…Similarity measures typically begin weak and are then strengthened as done by Lam and Hunt [2010]. We have used the protocol successfully for different types of analogues [Yan et al, 2008b;Engelberg et al, 2008;Kim et al, 2010;Tang and Hunt, 2010;Lam and Hunt, 2010]. For ISLs, step 1 is to assemble a set of hepatic and dispositional attributes, static and dynamic, which the ISL and its components will need to closely mimic in order to begin being scientifically useful.…”

Section: Building and Iteratively Revising Analoguesmentioning

confidence: 99%

Moving beyond in silico tools to in silico science in support of drug development research

Hunt

Ropella

2010

Drug Development Research

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Exploitation of concretized mechanistic models and simulation methods enables the acquisition of a competitive advantage through deeper, easily shared, mechanistic insight into the disease and/or health phenomena that are the focus of the research and development (R&D) organization. The models are analogues of the biological wet-lab models used to support that R&D. An analogue is an explanatory and evolving hypothesis about the mechanistic consequences of xenobiotic or biologic interventions. As such, it is fundamentally different from the familiar inductive, equation-based, pharmacokinetic, pharmacodynamic, and related models. Analogues are designed for experimentation and to be useful in the face of incomplete data and multiple uncertainties. These models use interchangeable components and require iterative refinement. They enable linking coarse-grained systemic phenomena to fine-grained molecular details, including molecular targets. To simplify and focus this discussion, we describe one example of the new class of models, in silico livers (ISLs). We present a vision of how the biological wet-lab side of the R&D process might function when these models and methods are fully implemented within a common computational framework. Accumulated mechanistic knowledge is easily measured and visualized in action; thus, it can be easily challenged. Components within analogues that have been validated for many compounds can use programmed ''intelligence'' to automatically parameterize for, and respond to, a new, not previously seen compound based on its physicochemical properties. Each analogue can be tuned to reflect differences in experimental conditions and individuals, making translational research more concrete, while moving closer to personalized medicine. Drug Dev Res 72:153-161, 2011.

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“…The cell spheroids generated by the highfrequency excitation have a slightly faster growth rate (2.05 fold in 7 days) than that by the low-frequency excitation (1.79 fold in 7 days). For large cell spheroids, the cells at the center may be less exposed to the nutrient and oxygen from the culture medium [62][63][64] , which may slow down cell growth and lead to necrotic death [65] . After being transferred out of the PDMS cavity and collected in a culture dish, the fresh cell spheroids have clear outlines of individual cells.…”

Section: Growth Of Cell Spheroidsmentioning

confidence: 99%

Formation of cell spheroids using Standing Surface Acoustic Wave (SSAW)

Sriphutkiat¹,

Kasetsirikul²,

Zhou³

2024

IJB

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3D bioprinting becomes one of the popular approaches in the tissue engineering. In this emerging application, bioink is crucial for fabrication and functionality of constructed tissue. The use of cell spheroids as bioink can enhance the cell-cell interaction and subsequently the growth and differentiation of cells in the 3D printed construct with the minimum amount of other biomaterials. However, the conventional methods of preparing the cell spheroids have several limitations, such as long culture time, low-throughput, and medium modification. In this study, the formation of cell spheroids by SSAW was evaluated both numerically and experimentally in order to overcome the aforementioned limitations. The effects of excitation frequencies on the cell accumulation time, diameter of the formed cell spheroids, and subsequently, the growth and viability of cell spheroids in the culture medium over time were studied. Using the high-frequency (23.8 MHz) excitation, cell accumulation time to the pressure nodes could be reduced in comparison to that of the low-frequency (10.4 MHz) excitation, but in a smaller spheroid size. SSAW excitation at both frequencies does not affect the cell viability up to 7 days, > 90% with no statistical difference compared with the control group. In summary, SSAW can effectively prepare the cell spheroids as bioink for the future 3D bioprinting and various biotechnology applications (e.g., pharmaceutical drug screening and tissue engineering).

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Essential operating principles for tumor spheroid growth

Cited by 41 publications

References 36 publications

Mechanistic Insight from In Silico Pharmacokinetic Experiments: Roles of P-glycoprotein, Cyp3A4 Enzymes, and Microenvironments

Mechanistic Insight from In Silico Pharmacokinetic Experiments: Roles of P-glycoprotein, Cyp3A4 Enzymes, and Microenvironments

Moving beyond in silico tools to in silico science in support of drug development research

Formation of cell spheroids using Standing Surface Acoustic Wave (SSAW)

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