In vitro microscale systems for systematic drug toxicity study

Sung, Jong Hwan; Shuler, Michael L.

doi:10.1007/s00449-009-0369-y

Cited by 74 publications

(61 citation statements)

References 109 publications

(134 reference statements)

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“…Although micro-fabricated micro-fluidic bioreactors and micro cell culture systems (e.g., the cell-on-a-chip developed by Lee et al [16] or the body-on-a-chip proposed by the Shuler's group [17]) are highly cited and several reports demonstrate that they are capable of mimicking physiological interactions between cells [18,19], these devices remain a niche research tool. The cell culture surface in a micro-bioreactor is generally around 0.5-0.8 mm 2 [20] and is seeded with a few thousand cells.…”

Section: Scaling: Nano Micro and Millimentioning

confidence: 99%

Design Criteria for Generating Physiologically Relevant In Vitro Models in Bioreactors

2014

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Abstract:In this paper, we discuss the basic design requirements for the development of physiologically meaningful in vitro systems comprising cells, scaffolds and bioreactors, through a bottom up approach. Very simple micro-and milli-fluidic geometries are first used to illustrate the concepts, followed by a real device case-study. At each step, the fluidic and mass transport parameters in biological tissue design are considered, starting from basic questions such as the minimum number of cells and cell density required to represent a physiological system and the conditions necessary to ensure an adequate nutrient supply to tissues. At the next level, we consider the use of three-dimensional scaffolds, which are employed both for regenerative medicine applications and for the study of cells in environments which better recapitulate the physiological milieu. Here, the driving need is the rate of oxygen supply which must be maintained at an appropriate level to ensure cell viability throughout the thickness of a scaffold. Scaffold and bioreactor design are both critical in defining the oxygen profile in a cell construct and are considered together. We also discuss the oxygen-shear stress trade-off by considering the levels of mechanical stress required for hepatocytes, which are the limiting cell type in a multi-organ model. Similar considerations are also made for glucose consumption in cell constructs. Finally, the allometric approach for generating multi-tissue systemic models using bioreactors is described.

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Section: Scaling: Nano Micro and Millimentioning

confidence: 99%

Design Criteria for Generating Physiologically Relevant In Vitro Models in Bioreactors

2014

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“…Each compartment corresponds to a tissue or organ in the PBPK and the body. We call this approach a micro cell culture analog or ''Body-on-a-Chip'' 17,22 and was the first description of a multi-compartment cell-containing system that attempted to arrange the various ''organ'' compartments in a physiologically realistic manner.…”

Section: Living Cell Models Of Humansmentioning

confidence: 99%

“…Details of design and operation are given elsewhere. 17,22,25,28 The system has been used to determine response to naphthalene as a model toxicant. Naphthalene is not toxic itself, but activated in the liver to a reactive form, which causes cell death in other organs, such as the lung.…”

Section: Living Cell Models Of Humansmentioning

confidence: 99%

Modeling Life

Shuler

2012

Ann Biomed Eng

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Abstract-We seek to construct physical and mathematical models of life. Such models allow us to test our understanding of how living systems function and how they respond to human imposed stimuli. One system is a genomically and chemically complete model of a minimal cell. This cell is a hypothetical bacterium with the fewest number of genes possible. Such a minimal cell provides a platform to ask about the essential features of a living cell and forms a platform to investigate ''synthetic biology.'' A second system is ''Body-on-a-Chip'' which is a microfabricated microfluidic system with cells or tissue constructs representing various organs in the body. It can be constructed from human or animal cells and used in drug discovery development. That model is a physical representation of a physiologically based pharmacokinetic model. Both the computer and the physical models provide insight into the underlying biology and provide new tools to make use of that understanding to provide benefits to society.

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“…18 Finally, an in-depth description of the potential that microfluidic technologies can add to systematic drug toxicity studies was written by Sung and Shuler. 19 In this review, we stress the tight relationship between liver architecture and its biological function and, consequently, DILI. We critically review existing chip-based liver equivalents regarding their equivalence to the human liver lobule, the smallest functional unit of the liver.…”

Section: Introductionmentioning

confidence: 99%

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

2013

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Drug-induced liver toxicity dominates the reasons for pharmaceutical product ban, withdrawal or nonapproval since the thalidomide disaster in the late-1950s. Hopes to finally solve the liver toxicity test dilemma have recently risen to a historic level based on the latest progress in human microfluidic tissue culture devices. Chip-based human liver equivalents are envisaged to identify liver toxic agents regularly undiscovered by current test procedures at industrial throughput. In this review, we focus on advanced microfluidic microscale liver equivalents, appraising them against the level of architectural and, consequently, functional identity with their human counterpart in vivo. We emphasise the inherent relationship between human liver architecture and its drug-induced injury. Furthermore, we plot the current socio-economic drug development environment against the possible value such systems may add.Finally, we try to sketch a forecast for translational innovations in the field.

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In vitro microscale systems for systematic drug toxicity study

Cited by 74 publications

References 109 publications

Design Criteria for Generating Physiologically Relevant In Vitro Models in Bioreactors

Design Criteria for Generating Physiologically Relevant In Vitro Models in Bioreactors

Modeling Life

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

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