Optimization and mathematical modeling of the transtubular bioreactor for the production of monoclonal antibodies from a hybridoma cell line

Craig R. Halberstadt*, Bernhard O. Palsson, A. Rees Midgley, Rane L. Curl

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

This report describes the use of a transtubular bioreactor to study the relative effects of diffusion versus perfusion of medium on antibody production by a hybridoma cell line. The study was performed with a high-density cell culture maintained in a serum-free, low-protein medium for 77 days. It was determined that the reactor possessed a macro-mixing pattern residence time distribution similar to a continuous stirred tank reactor (CSTR). However, due to the arrangement of the medium lines in the reactor, the flow patterns for nutrient distribution consist of largely independent medium path lengths ranging from short to long. When operated with cyclic, reversing, transtubular medium flow, some regions of the reactor (with short residence times) are more accessible to medium than others (with long residence times). From this standpoint, the reactor can be divided into three regions: a captive volume, which consists of medium primarily delivered via diffusion; a lapped volume, which provides nutrients through unilateral convection; and a swept volume, which operates through bilateral convection. The relative sizes of these three volumes were modified experimentally by changing the period over which the direction of medium flow was reversed from 15 min (larger captive volume) to 9 h (larger swept volume). The results suggest that antibody concentration increases as the size of the diffusion-limited (captive) volume is increased to a maximum at around 30 min with a sharp decrease thereafter. As reflected by changes in measured consumption of glucose and production of lactate, no significant difference in cellular metabolism occurred as the reactor was moved between these different states. These results indicate that the mode of operation of the transtubular bioreactor may influence antibody productivity under serum-free, low-protein conditions with minimal effects on cellular metabolism.

Original languageEnglish
Pages (from-to)163-170
Number of pages8
JournalBiotechnology and Bioprocess Engineering
Volume7
Issue number3
DOIs
Publication statusPublished - 2002

Bibliographical note

Funding Information:
Acknowledgments The authors gratefully acknowledge the financial support provided from NSF grants EET-8712756 and BCS-P009389 and Rackham Graduate School, the University of Michigan, Ann Arbor, Michigan. The authors would also like to thank Mark Kamin-ski, MD, Internal Medicine, University of Michigan for providing the cell line and valuable assistance.

Other keywords

  • Antibody production
  • Bioreactor design
  • Cell communication
  • Modeling
  • Perfusion

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