Hollow fiber bioreactors are used extensively in biomedical research to produce large quantities of cells or cellular products. The system consists of a bundle of hollow fibers encased in a plastic cartridge. The fibers are fabricated from porous material that permits the passage of nutrients and low molecular weight species but excludes cells and high molecular weight cellular products such as monoclonal antibodies. The cells are sequestered in the extracapillary space between the exterior of the fibers and the cartridge body. Fresh media is continuously recirculated through the interior of the fibers. Nutrients freely pass into the extracapillary space, providing an environment that promotes maximal cell growth.

Examples of (left to right) a fungal pathogen, a bacterial pathogen and a viral pathogen that can be grown and studied in our hollow fiber pharmacodynamic model system.

Investigators at Ordway Research Institute have adapted the application of the hollow fiber bioreactors to develop a novel experimental system in which sophisticated computer programs and pumps are used to continuously change the concentration of drug to simulate almost any pharmacokinetic profile in vitro. With this system it is possible to delineate the effect of continuously changing concentrations of drug on a target cell, whether that target cell is a microorganism, a mammalian neoplastic cell, or the production of a cell product such as a protein, a hormone, or mRNA. Other target cells can be considered.

The Hollow Fiber Core offers expertise in designing and implementing studies in our novel hollow fiber system to characterize the dose-response relationship and the pharmacodynamic parameter linked with efficacy of commercially available and investigational antimicrobial agents against a variety of viral, fungal, and bacterial pathogens. Drug exposures that amplify or suppress the selection of drug-resistant mutants also can be explored. When the data generated with the hollow fiber infection model is analyzed by Ordway Research Institutes’ Mathematical Modeling Core, breakpoint exposures maximizing treatment success and/or the prevention of the emergence of drug-resistant mutants can be calculated. The predictive value of the results generated from the hollow fiber system has been validated in animal infection models and in human disease.

The microorganisms that the Hollow Fiber Core has studied using the hollow fiber infection system are listed in Table 1. However, currently Ordway Research Institute only has the infrastructure to work with Biosafety Level-2 pathogens. Since the hollow fiber system is highly adaptable, we will be modifying the system for evaluation of drug effect on other pathogens. Furthermore, we plan to adapt the hollow fiber system to characterize the dose-response effect, the pharmacodynamic parameter linked with efficacy, and/or resistance prevention of non-antimicrobial agents for other target cells and the production of cell products. In the near future we will initiate studies to define the dose-response effect of anti-neoplastic drugs against oncologic cell lines.

Table 1. Pathogens previously studied in the hollow fiber system.

Biodefense Pathogens: Bacillus anthracis (agent of anthrax), Yersinia pestis (agent of plague), Francisella tularensis (agent of tularemia), cowpox [under development] Human Immunodeficiency Virus (HIV) Mycobacterium tuberculosis - extracellular and within macrophages Nosocomial pathogens: A) Bacteria: Pseudomonas aeruginosa, Klebsiella species, vancomycin-susceptible and -resistant Enterococcal species, multi-drug resistant Staphylococcus aureus B) Fungi: Candida albicans, Candida glabrata, Aspergillus species Community-acquired Pathogens:   A) Bacteria: Streptococcus pneumoniae, E. coli, Staphylococcus aureus B) Viruses: Herpes simplex virus and Influenza virus

Photographs of a complete hollow fiber system used to define the dose-response effect of a drug against a pathogen or target cell. Photo A shows the rack of computer controlled pumps that dispense the drug at timed intervals and that drive the simulated elimination of the
drug from the system. Photo B shows four hollow fiber experiments set up in a single incubator. Photo C is a close-up of a single setup, showing the cartridge, recirculating pump, and central reservoir of media.

Hollow Fiber Core Director
Arnold Louie, M.D.

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