Polar application of test substances in an organotypic environment and under continuous medium flow: A new tissue-based test concept for a broad range of applications in pharmacotoxicology

Kloth, Sabine; Kobuch, Karin; Domokos, Judit; Wanke, Christiane; Monzer, Jan

doi:10.1016/s0887-2333(00)00010-2

Cited by 8 publications

(3 citation statements)

References 20 publications

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“…Notable is the effort to establish patient-specific therapeutic test systems for specific tumor entities, such as the ex vivo ATP-based chemosensitivity assay (ATP-TCA), which is based on the 2-D culturing of tumor cells isolated from primary tissue biopsies. [26][27][28][29] Also, in parallel to improvements in the tissue engineering field, diverse culture approaches have been developed that may allow reproducible maintenance of viability and differentiation in isolated primary tissue material of different origin in a 3-D format, such as the NASA bioreactor, [30][31][32][33] various perfusion-type or gradient container systems, [34][35][36][37][38][39][40][41] or the tumor fragment spheroid model. [42][43][44] Some of the above-mentioned systems are still under refinement to better match specific properties of differentiated tissues.…”

Section: Rationale For Using Complex Cell Systems In Antitumor Drug Testingmentioning

confidence: 99%

The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model

et al. 2004

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Over the past few years, establishment and adaptation of cell-based assays for drug development and testing has become an important topic in high-throughput screening (HTS). Most new assays are designed to rapidly detect specific cellular effects reflecting action at various targets. However, although more complex than cell-free biochemical test systems, HTS assays using monolayer or suspension cultures still reflect a highly artificial cellular environment and may thus have limited predictive value for the clinical efficacy of a compound. Today's strategies for drug discovery and development, be they hypothesis free or mechanism based, require facile, HTS-amenable test systems that mimic the human tissue environment with increasing accuracy in order to optimize preclinical and preanimal selection of the most active molecules from a large pool of potential effectors, for example, against solid tumors. Indeed, it is recognized that 3-dimensional cell culture systems better reflect the in vivo behavior of most cell types. However, these 3-D test systems have not yet been incorporated into mainstream drug development operations. This article addresses the relevance and potential of 3-D in vitro systems for drug development, with a focus on screening for novel antitumor drugs. Examples of 3-D cell models used in cancer research are given, and the advantages and limitations of these systems of intermediate complexity are discussed in comparison with both 2-D culture and in vivo models. The most commonly used 3-D cell culture systems, multicellular spheroids, are emphasized due to their advantages and potential for rapid development as HTS systems. Thus, multicellular tumor spheroids are an ideal basis for the next step in creating HTS assays, which are predictive of in vivo antitumor efficacy. (Journal of Biomolecular Screening 2004:273-285)

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Section: Rationale For Using Complex Cell Systems In Antitumor Drug Testingmentioning

confidence: 99%

The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model

et al. 2004

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“…Most of the administered pharmaceuticals have to pass an epithelial barrier in the organism. To test the transport of newly developed drugs through an epithelial cell layer long term gradient perfusion culture experiments were performed [99,100]. In these series of experiments it was found that Caco‐2 cells are forming a tightly sealing epithelial cell layer [101,102].…”

Section: Reviewmentioning

confidence: 99%

Supportive development of functional tissues for biomedical research using the MINUSHEET® perfusion system

Minuth

Denk

2012

Clinical & Translational Med

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Functional tissues generated under in vitro conditions are urgently needed in biomedical research. However, the engineering of tissues is rather difficult, since their development is influenced by numerous parameters. In consequence, a versatile culture system was developed to respond the unmet needs. Optimal adhesion for cells in this system is reached by the selection of individual biomaterials. To protect cells during handling and culture, the biomaterial is mounted onto a MINUSHEET® tissue carrier. While adherence of cells takes place in the static environment of a 24 well culture plate, generation of tissues is accomplished in one of several available perfusion culture containers. In the basic version a continuous flow of always fresh culture medium is provided to the developing tissue. In a gradient perfusion culture container epithelia are exposed to different fluids at the luminal and basal sides. Another special container with a transparent lid and base enables microscopic visualization of ongoing tissue development. A further container exhibits a flexible silicone lid to apply force onto the developing tissue thereby mimicking mechanical load that is required for developing connective and muscular tissue. Finally, stem/progenitor cells are kept at the interface of an artificial polyester interstitium within a perfusion culture container offering for example an optimal environment for the spatial development of renal tubules. The system presented here was evaluated by various research groups. As a result a variety of publications including most interesting applications were published. In the present paper these data were reviewed and analyzed. All of the results point out that the cell biological profile of engineered tissues can be strongly improved, when the introduced perfusion culture technique is applied in combination with specific biomaterials supporting primary adhesion of cells.

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“…Pharmaceuticals were applied in gradient perfusion culture [71,[96][97][98]. It was found for example that the gradient perfusion culture with Caco-2 cells generated sealing epithelia and revealed reproducible results much earlier than traditional 21-day static cultures.…”

Section: Pharmaceutical Applicationmentioning

confidence: 99%

Gradient Perfusion Culture - Simulating a Tissue-Specific Environment for Epithelia in Biomedicine

Minuth¹,

Denk²,

Roessger³

2009

JEBP

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Epithelia act in the organism as biological barriers. All of them are exposed to different environments at the luminal and basal side. To simulate such a tissue-specific situation Minusheet ® gradient perfusion culture was developed. For pharmaceutical research, biomaterial testing and tissue engineering epithelial cells are cultured on individually selected supports (1). Growing epithelia are stabilized within a tissue carrier (2). Long term culture is performed in a gradient perfusion container (3). To expose epithelia to a tissue-specific environment fresh media of different composition are transported parallel to the luminal and basal compartment of the gradient container. During culture leakage, edge damage and pressure differences have to be avoided. Harvest of intact epithelia is promoted by the use of biocompatible supports and innovative equipment such as transport of oxygen-rich and gas bubble-free medium. Actual literature demonstrates that gradient perfusion culture is an effective method to investigate barrier functions under realistic conditions. Examples of application comprise renal epithelia, retina, blood-air barrier, blood-brain barrier including aspects of tissue-specific development and regeneration.

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Polar application of test substances in an organotypic environment and under continuous medium flow: A new tissue-based test concept for a broad range of applications in pharmacotoxicology

Cited by 8 publications

References 20 publications

The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model

The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model

Supportive development of functional tissues for biomedical research using the MINUSHEET® perfusion system

Gradient Perfusion Culture - Simulating a Tissue-Specific Environment for Epithelia in Biomedicine

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