A self-regulating cell culture analog device to mimic animal and human toxicological responses

Shuler, Michael L.; Ghanem, Ahmed N; Quick, Deborah J.; Wong, Ming-Ching; Miller, Paula

doi:10.1002/(sici)1097-0290(19961005)52:1<45::aid-bit5>3.0.co;2-z

Cited by 66 publications

(13 citation statements)

References 27 publications

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“…In a study conducted in 2000, Ghanem and Shuler designed early-generation PBPK-CCA systems to assess naphthalene metabolism [56, 57]. The researchers tested two CCA reactors.…”

Section: 0 Future Directions For In Vitro Developmentmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Models: Integration of In Silico Approaches with Micro Cell Culture Analogues

Chen¹,

Yarmush²,

Maguire³

2012

CDM

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There is a large emphasis within the pharmaceutical industry to provide tools that will allow early research and development groups to better predict dose ranges for and metabolic responses of candidate molecules in a high throughput manner, prior to entering clinical trials. These tools incorporate approaches ranging from PBPK, QSAR, and molecular dynamics simulations in the in silico realm, to micro cell culture analogue (CCAs)s in the in vitro realm. This paper will serve to review these areas of high throughput predictive research, and highlight hurdles and potential solutions. In particular we will focus on CCAs, as their incorporation with PBPK modeling has the potential to replace animal testing, with a more predictive assay that can combine multiple organ analogs on one microfluidic platform in physiologically correct volume ratios. While several advantages arise from the current embodiments of CCAS in a microfluidic format that can be exploited for realistic simulations of drug absorption, metabolism and action, we explore some of the concerns with these systems, and provide a potential path forward to realizing animal-free solutions. Furthermore we envision that, together with theoretical modeling, CCAs may produce reliable predictions of the efficacy of newly developed drugs.

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“…In a study conducted in 2000, Ghanem and Shuler designed early-generation PBPK-CCA systems to assess naphthalene metabolism [56, 57]. The researchers tested two CCA reactors.…”

Section: 0 Future Directions For In Vitro Developmentmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Models: Integration of In Silico Approaches with Micro Cell Culture Analogues

Chen¹,

Yarmush²,

Maguire³

2012

CDM

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“…Models of the blood brain barrier have been reported and successfully implemented for studies involving transport across an endothelium layer 17. Other reports of a cell culture analogue, a device containing different tissue types connected by a series of fluid channels, have also been reported 18, 19…”

Section: Introductionmentioning

confidence: 95%

Interactions between Multiple Cell Types in Parallel Microfluidic Channels: Monitoring Platelet Adhesion to an Endothelium in the Presence of an Anti-Adhesion Drug

Oblak

Spence

2008

Anal. Chem.

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A simple method for immobilizing endothelial cells in the channels of a microfluidic device fabricated with soft lithography is presented that requires no surface oxidation of the substrate material used in conjunction with the microfluidic device and is operable even with a reversible seal. Specifically, optimal conditions for culturing bovine pulmonary artery endothelial cells (bPAECs) to the surface of a Petri dish were investigated. The parameters investigated included fibronectin concentration, temperature, seeding density, and immobilization time. To enhance the utility of the device, all optimization studies, and studies involving platelet adhesion to the immobilized endothelium, were performed in parallel channels, thereby enabling improved throughput over a single channel device. The optimal conditions for cell immobilization included coating the petri dish with 100 μg/mL fibronectin, a seeding cell density of 1.00 × 10 5 cells mL −1 and an immobilization time of 90 min at 37 °C. The device was then employed to monitor the physical interaction (adhesion) of platelets to the immobilized endothelium in the presence of a known platelet activator (ADP) and a drug inhibitor of platelet activation. The number of platelets adhering to the endothelial cells in the channels increased from 17.0 ± 2.3 in the absence of ADP to 63.2 ± 2.4 in the presence of 5.00 μM ADP. Moreover, the data presented here also shows that inhibition of endothelium nitric oxide (NO) production, a recognized inhibitor of platelet adhesion to the endothelium, increased the number of platelets adhering to the surface to 35.4 ± 1.0. In the presence of NO inhibition and 5.00 μM ADP, the affect on platelet adhesion was further increased to 127 ± 5.2. Finally, this device was employed to investigate the effect of a drug known to inhibit platelet adhesion (clopidogrel) and, in the presence of the drug, the platelet adhesion due to activation by 5.00 μM ADP decreased to 24.0 ± 3.8. This work is the first representation of multiple cell types physically interacting in the channels of a microfluidic device and further demonstrates the potential of these devices in the drug discovery process and drug efficacy studies.

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“…Such physical models can be used as alternative methods to predict human response by exposure to chemicals or pharmaceuticals [252]. The basic concepts of CCA devices are described in [253][254]. Viravaidya et al [255], developed a miniaturised CCA device for culturing liver, lung and fat cells in different interconnected compartments to mimic the physiological features such as residence time, of the circulation and exchange of metabolites in the body.…”

Section: Drug and Toxicological Screeningmentioning

confidence: 99%

Microfluidic Bioreactors for Cell Culturing: A Review

Pasirayi

Auger

Scott

et al. 2011

MNS

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A self-regulating cell culture analog device to mimic animal and human toxicological responses

Cited by 66 publications

References 27 publications

Physiologically Based Pharmacokinetic Models: Integration of In Silico Approaches with Micro Cell Culture Analogues

Physiologically Based Pharmacokinetic Models: Integration of In Silico Approaches with Micro Cell Culture Analogues

Interactions between Multiple Cell Types in Parallel Microfluidic Channels: Monitoring Platelet Adhesion to an Endothelium in the Presence of an Anti-Adhesion Drug

Microfluidic Bioreactors for Cell Culturing: A Review

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