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3-D cell-based high-throughput screening for drug discovery and cell culture process development

Zhang, Xudong
http://rave.ohiolink.edu/etdc/view?acc_num=osu1204701561

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Based on three-dimensional (3-D) cultures of GFP-expressing mammalian cells, a novel microbiorector array capable of online monitoring of biological activities was developed. The 3-D microbioreactor array can afford parallel, automated, and long-term (over one month) cell bioactivity assays. It can also increase signal to noise ratio (SNR) by at least one order of magnitude as compared to the conventional 2-D culture system and at the same time remove most of the detection interference caused by cell activities. It used inexpensive materials and proven tissue engineering principles, and can be used for fast cell culture media development and cytotoxicity assays for drug screening. Toxicity of embryotoxic reference chemicals and anti-cancer drugs was measured in the 3-D multicellular models and the predicted toxicity was compared to that from monolayer cultures. It showed that the 3-D system was a more realistic pharmacotoxicological test system than 2-D monolayer cultures. With the 3-D system, acquired tissue resistance in the treatment of bulky tumor tissues could be revealed in a high-throughput manner. As a bridge over the gap between monolayer cell cultures and animal models, this 3-D system can improve the drug discovery process when being applied in toxicity and efficacy tests prior to animal experiments. Besides high-throughput toxicity screening, autofluorescence detection of 3-D tissue cultures could also be extended to immobilized cell culture process development. Butyrate treatment was used as a case study to demonstrate the performance of the new system. The microbioreactor array developed was used for high-throughput cell process development to improve monoclonal antibody (MAb) production in a fibrous bed bioreactor (FBB) using CHO cells. A novel online fluorescence probe was developed and used in spinner flasks and a lab-scale perfusion fibrous bed bioreactor to non-invasively quantify cell growth and MAb productivity. The results from this study showed that GFP fluorescence could indicate recombinant protein production and thus provide a fast, reliable and robust platform for cell culture process development to optimize target protein productivity without cell counting or protein analysis.
Shang-Tian Yang, PhD (Advisor)
Jeffrey Chalmers, PhD (Committee Member)
Jiyan Ma, PhD (Committee Member)
Peng Wang, PhD (Committee Member)
254 p.
Biochemistry; Biology; Biomedical Research; Cellular Biology; Chemical Engineering; Pharmaceuticals; Toxicology
3-D; cell-based; high-throughput screening; drug discovery; cell culture process development; autofluorescence

Recommended Citations

Citations

  • Zhang, X. (2008). 3-D cell-based high-throughput screening for drug discovery and cell culture process development [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1204701561

    APA Style (7th edition)

  • Zhang, Xudong. 3-D cell-based high-throughput screening for drug discovery and cell culture process development. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1204701561.

    MLA Style (8th edition)

  • Zhang, Xudong. "3-D cell-based high-throughput screening for drug discovery and cell culture process development." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1204701561

    Chicago Manual of Style (17th edition)

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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.