A bioengineered three-dimensional cell culture platform integrated with microfluidics to address antimicrobial resistance in tuberculosis

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Title: A bioengineered three-dimensional cell culture platform integrated with microfluidics to address antimicrobial resistance in tuberculosis
Author(s): Bielecka, MK
Tezera, LB
Zmijan, R
Drobniewski, F
Zhang, X
Jayasinghe, S
Elkington, P
Item Type: Journal Article
Abstract: Antimicrobial resistance presents one of the most significant threats to human health, with the emergence of totally drug-resistant organisms. We have combined bioengineering, genetically modified bacteria, longitudinal readouts, and fluidics to develop a transformative platform to address the drug development bottleneck, utilizing Mycobacterium tuberculosis as the model organism. We generated microspheres incorporating virulent reporter bacilli, primary human cells, and an extracellular matrix by using bioelectrospray methodology. Granulomas form within the three-dimensional matrix, and mycobacterial stress genes are upregulated. Pyrazinamide, a vital first-line antibiotic for treating human tuberculosis, kills M. tuberculosis in a three-dimensional culture but not in a standard two-dimensional culture or Middlebrook 7H9 broth, demonstrating that antibiotic sensitivity within microspheres reflects conditions in patients. We then performed pharmacokinetic modeling by combining the microsphere system with a microfluidic plate and demonstrated that we can model the effect of dynamic antibiotic concentrations on mycobacterial killing. The microsphere system is highly tractable, permitting variation of cell content, the extracellular matrix, sphere size, the infectious dose, and the surrounding medium with the potential to address a wide array of human infections and the threat of antimicrobial resistance.
Publication Date: 7-Feb-2017
Date of Acceptance: 12-Jan-2017
URI: http://hdl.handle.net/10044/1/45024
DOI: https://dx.doi.org/10.1128/mBio.02073-16
ISSN: 2150-7511
Publisher: American Society for Microbiology
Journal / Book Title: MBIO
Volume: 8
Issue: 1
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: 515330101
Copyright Statement: © 2017 Bielecka et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
MYCOBACTERIUM-TUBERCULOSIS
ANTIBIOTIC-RESISTANCE
EXTRACELLULAR-MATRIX
IN-VITRO
ANTITUBERCULOSIS DRUGS
HOST
PYRAZINAMIDE
EXPRESSION
EVOLUTION
PATHOGEN
0605 Microbiology
Publication Status: Published
Article Number: ARTN e02073-16
Appears in Collections:Department of Medicine
Faculty of Medicine



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