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Культивирование клеток in vitro FiberCell Systems, Inc.

             Компания FiberCell Systems Inc. (США) является лидером в производстве перфузионных биореакторов на основе полого, гидрофильного, полисульфонового волокна для решения научно-исследовательских и промышленных задач.

             Компания FiberCell Systems Inc. (США) разработала технологию культивирования клеток, направленную на повышение выхода биомассы с единицы объема модифицированной культуральной среды и на повышение выхода целевого белка путем оптимизации процесса культивирования культуры клеток различных штаммов.

             Система FiberCell Systems™ (США) используется для проточного культивирования клеток в картридже и получения продуцентов. Картридж , заполненный пустотелыми волокнами, дает возможность получать количества клеток и клеточных продуктов, недоступные с помощью стандартных технологий. Технология культивирования клеток и выделения белков успешно используется для проведения анатомических, физиологических, фармакологические и молекулярных исследований.

Перфузионный биореактор с картриджем FiberCell Systems™

Краткие видео презентации по технологии FiberCell Systems™.

            Современные тенденции развития селекции продуцентов – конструирование промышленных штаммов с заданными свойствами с использованием новейших достижений фундаментальных отраслей биологии в сочетании с приемами классической селекции. Клетки выращивают в специальных питательных средах, при постоянной температуре. Для культур растительных клеток используется регулируемое освещение, а для клеток млекопитающих обычно необходима также специальная газовая среда, поддерживаемая в инкубаторе клеточных культур. Как правило, регулируется концентрация в воздухе углекислого газа и паров воды, но иногда также и кислорода. Питательные среды для разных культур клеток различаются по составу, pH, концентрации глюкозы, составу факторов роста и др. Факторы роста, используемые в питательных средах для клеток млекопитающих, чаще всего добавляют вместе с сывороткой крови. Одним из факторов риска при этом является возможность заражения культуры клеток прионами или вирусами. При культивировании одной из важных задач является исключение или сведение к минимуму использование заражённых ингредиентов. Однако на практике это бывает достигнуто не всегда. Наилучшим, но и наиболее дорогостоящим способом является добавление вместо сыворотки очищенных факторов роста.

            Наиболее эффективным типом биореактора для культивирования клеток, является биореактор с системой полых волокон. Полые волокна представляют собой полупроницаемую мембрану из растяжимого материала, на поверхности которого возможна фиксация клеток. Преимущество биореакторов на полых волокнах перед биореакторами других типов заключается в щадящем режиме культивирования. Для повышения безопасности клеточного продукта и упрощения процесса его производства используются биореакторы, изготовленные из стандартных одноразовых модулей, имеющие большое соотношение поверхности для культивирования клеток к объему реактора, закрытую систему культивирования, стандартизованные процессы выполнения инокуляции посевного материала и сбора клеток, постоянный контроль параметров культивирования. Использование закрытых систем культивирования клеток позволяет осуществлять процесс получения клеточных линий в производственных помещениях класса чистоты C или D.

             В состав комплекта системы культивирования Hollow Fiber Cell Culture Systems™, FiberCell Systems, Inc. (США) входит: картридж, насос, сухая питательная смесь, крышка для культурального флакона.

             Картридж FiberCell Systems™ имеет разные физические характеристики полого волокна, что позволяют осуществлять выделение белков с MW более 100 кДа.

             Насос DUET™ обеспечивает газообмен и процесс циркуляции жидкости. Скорость потока внутри системы может достигать 200 мл/мин.

             Сухая питательная смесь CDM-HD™ обеспечивает высокие выходы продуцентов, не содержит в составе белки животного происхождения, детергенты, производится по стандартам GMP, может храниться  при 4°C в течении одного месяца после вскрытия, рекомендуется для использования при работе с вирусами, прионами и микоплазмой.

             Основным компонентом для роста клеток является источник углеродного питания в виде раствора глюкозы. Для точного измерения количества глюкозы в культуральной среде при работе с системой FiberCell Systems рекомендуется использовать электрохимический анализатор GlucCell™ FiberCell Systems. 

             Клетки вводятся в систему Hollow Fiber Cell Culture Systems™,  супернатант, содержащий целевой продукт, отбирается в стерильные шприцы, соединенные резьбовым соединением Люэра с картриджем. Все манипуляции проводятся в стерильной зоне ламинарного шкафа.

Общая схема культивирования Hollow Fiber Cell Culture Systems™, FiberCell Systems Inc. (США)

 

Картридж и культуральный флакон можно отсоединить от насоса, не нарушая стерильности внутри замкнутой системы FiberCell Systems.

Основные преимущества биореактора для культивирования клеток с системой полых волокон:

  • Возможность концентрирования клеточного продукта в небольшом объеме
  • Одинаковый рост клеток в объеме между волокнами, равномерное распределение клеточной массы по всей поверхности волокна, улучшенные гидродинамические характеристики культуральной среды CDM-HD для максимального роста клеток внутри всего биореактора
  • Возможность быстрого масштабирования культурального процесса
  • Возможность получения больших количеств клеток ( до 1011)
  • Полностью закрытая и стерильная система культивирования
  • Использование сухой смеси CDM-HD вместо стандартной сыворотки для приготовления жидкой культуральной среды. CDM-HD не содержит белков, состав компонентов подобран для максимального роста клеточных культур
  • Оптимизированный обмен питательными веществами и выведение  отходов с помощью насоса “Duet”.
  • Минимальные размеры системы для помещения в стандартный CO2-инкубатор
  • Полые волокна обладают обладают высокой степенью эффективности при фильтрации и повышенной пропускной способностью для улучшения жизнеспособности и роста клеток

Области исследований 

  • Онкология
  • Иммунология
  • Генная и клеточная терапия
  • Фармакология
  • Токсикология
  • Неврология

Объекты исследований

  • Моноклональные антитела
  • Рекомбинантные белки
  • Экзосомы (внеклеточные везикулы)
  • 3D- клеточные культуры и секретомы клеточных линий
  • Вирусы
  • Модели кишечного эпителия
  • Культуры эндотелиальных клеток в потоке
  • Фармакокинетические/фармакодинамические (PK/PD) моделирования in vitro

Производство моноклональных антител FiberCell HFBR:

Homeostatic pruning and activity of epidermal nerves are dysregulated in barrier-impaired skin during chronic itch development: Okada, T. et al; Nature Scientific Reports, Jun 2019, vol 9(1) pg: 8625 [Open Access]

A GMCSF-Neuroantigen Tolerogenic Vaccine Elicits Systemic Lymphocytosis of CD4+ CD25high FOXP3+ Regulatory T Cells in Myelin-Specific TCR Transgenic Mice Contingent Upon Low-Efficiency T Cell Antigen Receptor Recognition: Moorman, C.D. et al; Front Immunol. 2018; 9: 3119. [Open Access]

Differential Inhibition of Nav1.7 and Neuropathic Pain by Hybridoma-Produced and Recombinant Monoclonal Antibodies that Target Nav1.7:  Bang,S., Yoo, J., Gong, X. ; Neuroscience Bulletin 2018 Jan 1-20 [Abstract]

Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis: Tati, S. et al.; Neoplasia,2017 19:716-733 [Open Access]

Depletion of CD4+ CD25+ regulatory T cells confers susceptibility to experimental autoimmune encephalomyelitis (EAE) in GM-CSF-deficient Csf2-/- mice.: Ghosh, D. et al.; J Leukoc Biol. 2016 Oct;100(4):747-760 [Abstract]

IFN-β Facilitates Neuroantigen-Dependent Induction of CD25+ FOXP3+ Regulatory T Cells That Suppress Experimental Autoimmune Encephalomyelitis: Wang,D. et al; J. Immunol., 2016; 197: 2992 – 3007 [Abstract]

A Humanized Anti-CD22-Onconase Antibody-Drug Conjugate Mediates Highly Potent Destruction of Targeted Tumor Cells: Weber, T. et al; Journal of Immunology Research Volume 2015 (2015), Article ID 561814. [Open Access]

A Fully Human Inhibitory Monoclonal Antibody to the Wnt Receptor RYK : Halford, M.M. et al; PLOSone 2013. [Open Access]

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody: Krawczyk, A. et al.; 2013 100 (17): 6760-6765 [open access] [materials and methods]

GRB2 Interaction with the Ecotropic Murine Leukemia Virus Receptor, mCAT-1, Controls Virus Entry and Is Stimulated by Virus Binding: Chen, Z. et al; J Virol. 2012 Feb; 86(3): 1421–1432. [Open Access]

Human monoclonal antibodies to West Nile virus identify epitopes on the prM protein: Calvert, A.E. et al; Volume 410, Issue 1, Pages 30-37. [Open Access]

Contemporary Seasonal Influenza A (H1N1) Virus Infection Primes for a More Robust Response To Split Inactivated Pandemic Influenza A (H1N1) Virus Vaccination in Ferrets: Ellebedy,A.; Clin Vaccine Immunol December 2010 vol. 17 (12) 1998-2006 [Open Access]

Cell-free Assays for HIV-1 Uncoating: Aiken, C; Methods Mol Biol. 2009; 485 [Open Access]

Human antibodies for immunotherapy development generated via a human B cell hybridoma technology: Li, J; PNAS. 2006; 103(10)[Open Access]

Выделение и производство белков:

Interaction of Pregnancy-Specific Glycoprotein 1 With Integrin Α5β1 Is a Modulator of Extravillous Trophoblast Functions.:Rattila, S. et al. ; Cells. 2019 Oct 31;8(11) [Open Access]

Immunization of Rabbits with Recombinant Human Cytomegalovirus Trimeric versus Monomeric gH/gL Protein Elicits Markedly Higher Titers of Antibody and Neutralization Activity:Cui, X. et al; Int J Mol Sci. 2019 Jul; 20 (13):3158 [Open Access]

Effects of copper occupancy on the conformational landscape of peptidylglycine α-hydroxylating monooxygenase: Maheshwari et al.; Nature Communications Biology volume 1, Article number: 74 (2018) [Open Access]

Novel trimeric human cytomegalovirus glycoprotein B elicits a high-titer neutralizing antibody response: Cui, X et al.; Vaccine 2018 36(37):5580-5590 [Open Access]

Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis: Tati, S. et al.; Neoplasia,2017 19:716-733 [Open Access]

PSG9 Stimulates Increase in FoxP3+ Regulatory T-Cells through the TGF-β1 Pathway: Jones, K. et al. PLOSone 2016 July [Open Access]

Rabbits immunized with Epstein-Barr virus gH/gL or gB recombinant proteins elicit higher serum virus neutralizing activity than gp350: Cui, X. et al. Vaccine. 2016 Jul 25;34(34):4050-5 [Open Access]

Kinetic and Spectroscopic Study of Peptidylglycine Monooxygenase: Chauhan,S.. 2016 [Open Access]

Antigenicity and Immunogenicity of a Trimeric Envelope Protein from an Indian Clade C HIV-1 Isolate: Priya, R.S. The Journal of Biological Chemistry 2015 290: 9195-9208 [Open Access]

A Humanized Anti-CD22-Onconase Antibody-Drug Conjugate Mediates Highly Potent Destruction of Targeted Tumor Cells: Weber, T. et al; Journal of Immunology Research Volume 2015 (2015), Article ID 561814. [Open Access]

Induction and Activation of Latent Transforming Growth Factor-β1 Are Carried out by Two Distinct Domains of Pregnancy-specific Glycoprotein 1 (PSG1): Ballesteros, A. et al.; The Journal of Biological Chemistry 2015 290: 4422-4431 [Open Access]

Better and faster: improvements and optimization for mammalian recombinant protein production: Almo,S., Love, J.; Curr Opin Struct Biol 2014 ; 26: 39–4 [Open Access]

Efficient production and purification of recombinant human interleukin-12 (IL-12) overexpressed in mammalian cells without affinity tag: Jayanthi S. et al.; Protein Expr Purif. 2014 Oct; 102: 76–84. [Open Access]

Free IL-12p40 Monomer Is a Polyfunctional Adaptor for Generating Novel IL-12–like Heterodimers Extracellularly: Abdi, K. et al.; The Journal of Immunology 2014 192 (12): 6028-6036 [Open Access]

A novel tetrameric gp350(1-470) as a potential Epstein-Barr virus vaccine: Cui,X. et al.; Vaccine 2013 31(30): 3039-3045 [Open Access]

The HHM Motif at the CuH-site of Peptidylglycine Monooxygenase is a pH-Dependent Conformational Switch: Kline, C.D. et al, Biochemistry 2013 52(15): 2586–2596
[Open Access]

Overcoming drug-resistant herpes simplex virus (HSV) infection by a humanized antibody: Krawczyk, A. et al.; 2013 100 (17): 6760-6765 [open access] [materials and methods]

Cloning, Expression, and Functional Characterization of TL1A-Ig:
Khan, S. et al.; The Journal of Immunology 2013 190 (4): 1540-1550 [Open Access]

Comparison of intradermal and intramuscular delivery followed by in vivo electroporation of SIV Env DNA in macaques: Kulkarni, V. et al.; Human Vaccines & Immunotherapeutics Vol 9, 2013 (10). [Open Access]

Characterization and Favorable in Vivo Properties of Heterodimeric Soluble IL-15•IL-15Rα Cytokine Compared to IL-15 Monomer: Chertova, E. et al.; The Journal of Biological Chemistry 2013 288: 18093-18103. [Open Access]

Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum: Bergamaschi, C.. et al.; Blood 2012 120 (1) [Open Access]

Antiviral Breadth and Combination Potential of Peptide Triazole HIV-1 Entry Inhibitors: McFadden, K. et al.; Antimicrob. Agents Chemother. 2012 56 (2): 1073-1080 [Open Access]

T Cell Costimulation by TNFR Superfamily (TNFRSF)4 and TNFRSF25 in the Context of Vaccination: Schreiber, T. et al.; The Journal of Immunology 2012 189 (7): 3311-3318 [Open Access]

Proteolytic processing of vascular endothelial growthfactor-D is essential for its capacity to promote the growth and spread of cancer: Harris N.C. et al.; The Faseb Journal 2011 pp. 2615-2625.  [Open Access]

Insights into egg coat assembly and egg-sperm interaction from the X-ray structure of full-length ZP3: Han, L. et al.; Cell 2010 143(3):404-15 [Open Access]

1.8 Å structure of murine GITR ligand dimer expressed in Drosophila melanogaster S2 cells: Kausik Chattopadhyay et al.; Acta Crystallogr D Biol Crystallogr.2009; 65(Pt 5): 434–439. [Open Access]

Purification and characterization of recombinant human renin for X-ray crystallization studies: Wu, Z. et al.; BMC Biochemistry 2008 9:19 [Open Access]

Murine Pregnancy-Specific Glycoprotein 23 Induces the Proangiogenic Factors Transforming-Growth Factor Beta 1 and Vascular Endothelial Growth Factor A in Cell Types Involved in Vascular Remodeling in Pregnancy: Wu JA et al., Biol Reprod. 2008 Dec;79(6):1054-1061 [Open Access]

Expression of SEAP (secreted alkaline phosphatase) by baculovirus mediated transduction of HEK 293: Jardin BA et al., J Biotechnol. 2008 Jun 30;135(3):272-80. [Abstract]

Purification of soluble CD14 fusion proteins and use in an electrochemiluminescent assay for lipopolysaccharide binding: Burkhardt, M. et al., Protein Expr Purif. 2007 Jan;51(1):96-101 [Abstract]

Recombinant-protein production in insect cells utilizing a hollow-fibre bioreactor: Baxter SC et al., Biotechnol Appl Biochem. 2006 Nov;45(Pt 3):167-72. [Abstract]

Biochemical and biological characterization of a dodecameric CD4-Ig fusion protein. Implications for therapeutic and vaccine strategies: Arthos, J.; Cicala, C et al., JBC 2002;277(13):11, 456-464 [Open Access]

Alteration of Hepatitis A Virus (HAV) Particles by a Soluble Form of HAV Cellular Receptor 1 containing the Immunoglobulin- and Mucin-Like Regions: Silverstein, E., Journal of Virology, 2003 p. 8765-8774 [Open Access]

Производство экзосом:

Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury: Cao et al; Stem Cell Research and Therapy (2020) 11:206 [open access]

Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications: Tsiapalis, D. & O’Driscoll, L.; Cells 2020, 9, 991[open access]

Exosomes produced from 3D cultures of umbilical cord mesenchymal stem cells in a hollow-fiber bioreactor show improved osteochondral regeneration activity: Litao Yan & Xing Wu; Cell Biol Toxico (Dec 09 2019) [open access]… 

Urine-derived stem cells facilitate endogenous spermatogenesis restoration of busulfan-induced non-obstructive azoospermic mice by paracrine exosomes. Cuncan DengYun Xie et al.; Stem Cells and Development (Jul 16 2019) [abstract]… 

Extracellular Vesicles From Human Urine-Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA: Ouyang B. et al.; Sexual Medicine (2019) [open access]...

Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift: Park, JE et al.; Oncogene (2019) [abstract] ... 

Large-scale preparation of extracellular vesicles enriched with specific micro-RNA: Yoo, KW et al. ; Tissue Engineering. 2018 [abstract]

Scalable, cGMP-compatible purification of extracellular vesicles carrying bioactive human heterodimeric IL-15/lactadherin complexes: Watson,D.C. et al.; J Extracell Vesicles. 2018 Feb 28;7(1) [open acccess]

Use of a Hollow Fiber Bioreactor to Collect Extracellular Vesicles from Cells in Culture: Yan IK et al.; Methods Mol Biol. 2018;1740:35-41 [abstract]

Clinical Scale Production and Wound Healing Activity of Human Adipose Derived Mesenchymal Stem Cell Extracellular Vesicles from a Hollow Fiber Bioreactor. [Fibercell Poster ISEV2017]

Efficient production and enhanced tumor delivery of engineered extracellular vesicles: Watson DC et al.; Biomaterials 105, 2016: 195-205 [open access]…

In vitro toxicology studies of extracellular vesicles: Maji,S. et al.; Journal of Applied Toxicology (2016) [abstract]

Comparative Secretome Analyses Using a Hollow Fiber Culture System with Label-Free Quantitative Proteomics Indicates the Influence of PARK7 on Cell Proliferation and Migration/Invasion in Lung Adenocarcinoma: Ying-Hua Chang et al, J. Proteome Res. 2012, 11, 11, 5167-5185 [abstract]

Получение 3D культур секретома:

Secretomic profiling of cells from hollow fiber bioreactor reveals PSMA3 as a potential cholangiocarcinoma biomarker: Verathamjamras,C. et al; Int J Oncol. 2017 51(1):269-280. [Abstract]

Analysis of colorectal cancer glyco-secretome identifies laminin Beta-1 (LAMB1) as a potential serological biomarker for colorectal cancer: lIN,Q. et al.; Proteomics 2015, 15, 3905–3920 [Abstract]

Effective enrichment of cholangiocarcinoma secretomes using the hollow fiber bioreactor culture system: Weeraphan, C.; Talanta. 2012 Sep 15;99:294-301 [Abstract]

Collection of in vivo-like liver cell secretome with alternative sample enrichment method using a hollow fiber bioreactor culture system combined with tangential flow filtration for secretomics analysis: Wen,Y-T et al.; Analytica Chimica Acta 2011 Vol. 684, p81-88 [Abstract]

Cell Secretome Analysis Using Hollow Fiber Culture System Leads to the Discovery of CLIC1 Protein as a Novel Plasma Marker for Nasopharangeal Carcinoma: Chang,YH et al.; J Proteome Res. 2009 8(12):5465-74. [Abstract]

Proteomics Analysis of Nasopharyngeal Carcinoma Cell Secretome Using a Hollow Fiber Culture System and Mass Spectrometry: Wu, HJ et al.; Journal of Proteome Research, 2009,8 (1), 380-389 [Open Access]

Производство вирусных частиц:

High density Huh7.5 cell hollow fiber bioreactor culture for high-yield production of hepatitis C virus and studies of antivirals: Pihl, A. et al., Nature Scientific Reports volume 8, Article number: 17505 (2018) [Open Access]

Clinical Regimens of Favipiravir Inhibit Zika Virus Replication in the Hollow-Fiber Infection Model: Camilly P. Pires de Mello et al.; Antimicrob Agents Chemother 2018 62 [abstract]

Oseltamivir-zanamivir combination therapy suppresses drug-resistant H1N1 influenza A viruses in the hollow fiber infection model (HFIM) system: Pires de Mello, C.P.; European Journal of Pharmaceutical Sciences 111 (2018) 443-449 [open access]

Antiviral Effects of Clinically-Relevant Interferon-alpha and Ribavirin Regimens against Dengue Virus in the Hollow Fiber Infection Model (HFIM): Pires de Mello, C.P. et al; Viruses 2018, 10, 317 [open access]

Production of high-titer human influenza A virus with adherent and suspension MDCK cells cultured in a single-use hollow fiber bioreactor: Tapia, F. et al.; Vaccine 2014 Feb 12;32(8):1003-11 [Open Access]

Considerations in Scale-Up of Viral Vaccine Production: William G. Whitford and Alain Fairbank; BioProcess International 2011 September [PDF]

Effect of Half-Life on the Pharmacodynamic Index of Zanamivir against Influenza Virus Delineated by a Mathematical Model: Brown, A. et al.; Antimicrob. Agents Chemother. 2011 55 (4) 1747-1753[open access]

Antiviral pharmacodynamics in hollow fibre Bioreactors: McSharry, J. et al.; Antiviral Chemistry & Chemotherapy 2011; 21:183–192 [open access]

A Hollow fiber bioreactor for expanding HIV-1 in human lymphocytes used in preparing an inactivated vaccine candidate: Leong M, Bobbitt W, Vyas G, Biologicals, 2007 35 (4):227-233.

Работа c эндотелиальными клетками:

Application of a Flow-Based Hollow-Fiber Co-Culture System to Study Cellular Influences under Hyperglycemic Conditions: Ebrahim, A.S. et al; Nature Scientific Reports [open access]

Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration: Pasikowska, M. et al; Blood 2016 128:563-573

Development and characterization of a physiologically relevant model of lymphocyte migration in chronic lymphocytic leukemia: Walsby, E. et al.; Blood 2014 123:3607-3617 [open access]

PECAM-1 and caveolae form the mechanosensing complex necessary for NOX2 activation and angiogenic signaling with stopped flow in pulmonary endothelium: Noel,J. et al.; Am J Physiol Lung Cell Mol Physiol. 2013 305(11): L805–L818. [open access]

Transcriptional Remodeling of Ion Channel Subunits by Flow Adaptation in Human Coronary Artery Endothelial Cells: Kefaloyianni, E. and Coetzee, W.A.; J Vasc Res. 2011; 48(4): 357–367. [open access]

Endothelial Cell Capture of Heparin-Binding Growth Factors under Flow: Zhao, B. et al.; PLOS Computational Biology, 2010. [open access]

CAVEOLAE ARE AN ESSENTIAL COMPONENT OF THE PATHWAY FOR ENDOTHELIAL CELL SIGNALING ASSOCIATED WITH ABRUPT REDUCTION OF SHEAR STRESS: Milovanova, T. et al.; Biochim Biophys Acta. 2008 1783(10): 1866–1875. [open access]

Lung Ischemia: A Model for Endothelial Mechanotransduction: Chatterjee, S. et al.; Cell Biochem Biophys.2008; 52(3) [open access]

Advanced methods of adenovirus vector production for human gene therapy: roller
bottles, microcarriers, and hollow fibers: T. Isayeva, et al.; BioProcessing Journal 2003 75-81 [PDF]

Создание инфекционных моделей in-vitro для исследования PK/PD:

Modeling of Effective Antimicrobials to Reduce Staphylococcus aureus Virulence Gene Expression Using a Two‐Compartment Hollow Fiber Infection Model: Shukla, S.K. et al Toxins vol. 12 (2) 2020 [open access]

The Effect of Drug Combinations on the Kinetics of the Emergence of Antibiotic Resistance in E. coli CFT073 Using the In Vitro Hollow Fiber Infection Model: Garimella, N. et al, Antimicrobial Agents Dec 2019 [abstract]

Fluconazole Monotherapy Is a Suboptimal Option for InitialTreatment of Cryptococcal Meningitis Because of Emergenceof Resistance: Hope, W. et al, Therapeutics and Preventation Nov-Dec 2019 [open access]

Mimicking in-vivo exposures to drug combinations in-vitro: antituberculosis drugs in lung lesions and the hollow fiber model of infection: Kloprogge, F. et al, www.nature.com/scientificreports 13 Sep 2019 [open access]

P-glycoprotein mediated efflux reduces the in vivo efficacy of a therapeutic targeting the gastrointestinal parasite Cryptosporidium: Arnold SLM et al; J Infect Dis. 2019 Jun 8. [open access]

Pharmacodynamics of 1 Ceftazidime plus Avibactam against KPC-2 Bearing Isolates of Klebsiella pneumoniae in a Hollow Fiber Infection Model: Drusano GL et al; Antimicrob Agents Chemother. 2019 Jun 3 [abstract]

Generating Robust and Informative Nonclinical In Vitro and In Vivo Bacterial Infection Model Efficacy Data To Support Translation to Humans: Antimicrobial Agents and Chemotherapy May 2019 Vol 63 Issue 5 [open access]

Comparison of in vitro static and dynamic assays to evaluate the efficacy of an antimicrobial drug combination against Staphylococcus aureus: Broussou, D. et al; PLOS ONE Jan 2019 [open access]

Clinical Regimens of Favipiravir Inhibit Zika Virus Replication in the Hollow-Fiber Infection Model: Camilly P. Pires de Mello et al.; Antimicrob Agents Chemother 2018 62 [abstract]

Differential Activity of the Combination of Vancomycin and Amikacin on Planktonic vs. Biofilm-Growing Staphylococcus aureus Bacteria in a Hollow Fiber Infection Model: Broussou, D. et al; Front. Microbiol., 27 March 2018 [open access]

Optimization and evaluation of piperacillin plus tobramycin combination dosage regimens against Pseudomonas aeruginosa for patients with altered pharmacokinetics via the hollow-fiber infection model and mechanism-based modelling: Yadav, R. et al; AMS 2018 (62) 3 [abstract]

Evaluation of Activity and Emergence of Resistance of Polymyxin B and ZTI-01 (Fosfomycin for Injection) against KPC-Producing Klebsiella pneumoniae: Diep, J.K. et al; Antimicrob. Agents Chemother. 2018 (62) 2 [open access]

Oseltamivir-zanamivir combination therapy suppresses drug-resistant H1N1 influenza A viruses in the hollow fiber infection model (HFIM) system: Pires de Mello, C.P.; European Journal of Pharmaceutical Sciences 111 (2018) 443-449 [open access]

Polymyxin Combinations Combat Escherichia coli Harboring mcr-1 and blaNDM-5: Preparation for a Postantibiotic Era. Bulman Z.PP; mBio 8(4)2017 [open access]

In vitro pharmacodynamic evaluation of ceftolozane/tazobactam against β-lactamase-producing Escherichia coli in a hollow-fibre infection model Soon, R et al. International Journal of Antimicrobial Agents 2017 49(1)[open access]

From lead optimization to NDA approval for a new antimicrobial: Use of pre-clinical effect models and pharmacokinetic/pharmacodynamic mathematical modeling. Drusano G.L.; Bioorg Med Chem. 2016[abstract]

Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps: Deshpande, D. et al.; Clin Infect Dis. 2016, 63 (3)S80-87 [abstract]

Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis: The Dynamic Duo: Deshpande, D. et al.; Clin Infect Dis. 2016, 63 (3): S88-S94.[open access]

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way: Deshpande, D. et al.; Clin Infect Dis. 2016, 63(3): S95-S101.: S88-S94.[open access]

Thioridazine as Chemotherapy for Mycobacterium avium Complex Diseases: Deshpande, D. et al.; Antimicrob. Agents Chemother. 2016 60 (8) 4652-4658 [open access]

Azithromycin Pharmacodynamics Against Non-Typeable H. Influenzae: Fisher, J., Yale University Public Health Theses 2016 [open access]

EMA Qualification opinion: In-vitro hollow fiber system model of tuberculosis (HSF-TB): EMA/CHMP/SAWP/47290/2015

Continuous culture of Cryptosporidium parvum using hollow fiber technology: Morada, M. et al.; Int J Parasitol. 2016 Jan;46(1):21-9 [related presentation PDF]

A long-term Co-perfused Disseminated Tuberculosis-3D Liver Hollow Fiber Model for Both Drug Efficacy and Hepatotoxicity in Babies: Srivastava, S. et al.; EBioMedicine 2016; 6:126-138 [open access]

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy: Brown, A. et al.; mBio vol. 6 (6) [open access]

Strategic Regulatory Evaluation and Endorsement of the Hollow Fiber Tuberculosis System as a Novel Drug Development Tool: Romero, K., Clay, R. and Hanna, D.; Clinical Infectious Diseases 2015 61 (1): S5–9 [open access]

Pharmacokineticdeterminants of virological response to raltegravir in thein vitropharmacodynamic hollow-fiber infection model system: Brown AN, Adams JR, Baluya DL, Drusano G; . Antimicrob AgentsChemother 59:3771–3777 [open access]

In Vitro Pharmacodynamics of Various Antibiotics in Combination against Extensively Drug-Resistant Klebsiella pneumoniae Lim, Tze-Peng et al.; Antimicrobial Agents and Chemother. 2015 59(5): 2515–2524.[open access]

Correlations Between the Hollow Fiber Model of Tuberculosis and Therapeutic Events in Tuberculosis Patients: Learn and Confirm: Gumbo, T.;2015 [open access]

The Hollow Fiber Infection Model: Principles and Practice: Cadwell, J.;J Adv Antibiotics and Antibodies 2015, 1(1) [open access]

Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance:Ly,N.S. et al.; Journal of Antimicrobial Therapy 2015 70(5): 1434-1442 [open access]

Hollow Fiber System Model for Tuberculosis: The European Medicines Agency Experience: Cavaleri, M. and Manolis, E.; Clin Infect Dis. (2015) 61 (suppl 1): S1-S4.[open access]

Rapid Drug Tolerance and Dramatic Sterilizing Effect of Moxifloxacin Monotherapy in a Novel Hollow-Fiber Model of Intracellular Mycobacterium kansasii Disease: Srivastava, S. et al.; Antimicrob. Agents Chemother. 2015, 59(4) [open access]

Model System to Define Pharmacokinetic Requirements for Antimalarial Drug Efficacy: Bakshi R., Shapiro A. et al.; Science Translational Medicine 2013:Vol. 5, Issue 205 [open access]

Thioridazine Pharmacokinetic-Pharmacodynamic Parameters “Wobble” during Treatment of Tuberculosis: a Theoretical Basis for Shorter-Duration Curative Monotherapy with Congeners Musuka, S. et al.; Antimicrob. Agents Chemother. 2013 vol. 57 no. 12 5870-5877 [open access]

PK/PD models in antibacterial development: Velkov, T. et al.; Curr Opin Microbiol . 2013, 16(5) [open access]

Hollow-fiber pharmacodynamics studies and mathematical modeling to predict the efficacy of amoxicillin for anthrax postexposure prophylaxis in pregnant women and children. Louie, A et al.; Antimicrob Agents Chemother 2013; 57:5946–60. [open access]

Relationship between Ceftolozane-Tazobactam Exposure and Drug Resistance Amplification in a Hollow-Fiber Infection Model: VanScoy, B. et al.; Antimicrobial Agents and Chemotherapy 2013 p 4134 – 4138. [open access]

The Hollow Fiber Infection Model for Antimicrobial Pharmacodynamics and Pharmacokinetics: Cadwell, J.; Adv Pharmacoepidem Drug Safety 2012 [open access]

In Vitro Activity of MK-7655, a Novel Beta-Lactamase Inhibitor, in Combination With Imipenem Against Carbapenem-Resistant Gram-Negative Bacteria: Hirsch,E.B. et al.; Antimicrobial Agents and Chemotherapy 2012; 56(7): 3753–57 [open access]

Simulated Antibiotic Exposures in an In Vitro Hollow-Fiber Infection Model Influence Toxin Gene Expression and Production in Community-Associated Methicillin-Resistant Staphylococcus aureus Strain MW2: Pichereau, S. et al.; Antimicrob Agents Chemother. 2012 Jan; 56(1): 140–147. [open access]

Effect of Half-Life on the Pharmacodynamic Index of Zanamivir against Influenza Virus Delineated by a Mathematical Model: Brown, A. et al.; Antimicrob. Agents Chemother. 2011 55 (4) 1747-1753[open access]

Antiviral pharmacodynamics in hollow fibre Bioreactors: McSharry, J. et al.; Antiviral Chemistry & Chemotherapy 2011; 21:183–192 [open access]

Pharmacokinetic Mismatch Does Not Lead to Emergence of Isoniazid- or Rifampin-Resistant Mycobacterium tuberculosis but to Better Antimicrobial Effect: a New Paradigm for Antituberculosis Drug Scheduling: Srivastava, S. et al; Antimicrob. Agents Chemother. 2011 55 (11): 5085-5089 [open access]

Moxifloxacin Pharmacokinetics/Pharmacodynamics and Optimal Dose and Susceptibility Breakpoint Identification for Treatment of Disseminated Mycobacterium avium Infection :Deshpande,D. et al.;Antimicrob Agents Chemother. 2010 54(6): 2534–2539. [open access]

Optimizing the Culture of Plasmodium Falciparum in Hollow Fiber Bioreactors :Preechapornkul,P. et al.;Southeast Asian J Trop Med Public Health. 2010 41(4): 761–769 [open access]

Ethambutol Optimal Clinical Dose and Susceptibility Breakpoint Identification by Use of a Novel Pharmacokinetic-Pharmacodynamic Model of Disseminated Intracellular Mycobacterium avium: <>Deshpande, D. et al.; Antimicrob Agents Chemother. 2010 54(5): 1728–1733 [open access]

In Vitro System for Modeling Influenza A Virus Resistance under Drug Pressure: Brown, A.; Antimicrob Agents Chemother. 2010 Aug;54(8):3442-50 open access]

Prediction of the Pharmacodynamically Linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow-Fiber Infection Model System. McSharry, J.; Antimicrob. Agents Chemother. 2009 53 (6) 2375-2381 open access]

Pharmacodynamics of Cidofovir for Vaccinia Virus Infection in an In Vitro Hollow-Fiber Infection Model System. McSharry, J.; Antimicrob. Agents Chemother. 2009 53(1) 129-135 [open access– system diagram

Is 60 Days of Ciprofloxacin Administration Necessary for Postexposure Prophylaxis for Bacillus Anthracis?Drusano GL et al. 2008 Antimicrob Agents Chemother 52 (11), 3973- [open access

Pharmacodynamic Characterization of gemcitabine cytotoxicity in an in vitro cell culture bioreactor system. Kirstein MN, Brundage RC, Moore MM, Williams BW, Hillman LA, et al. 2008 Cancer Chemother Pharmacol 61: 291-299.

Comparative Pharmacodynamics of Gentamicin against Staphylococcus aureus and Pseudomonas aeruginosa: Tam, V. et al; Antimicrob Agents Chemother. 2006 50(8): 2626–2631

Selection of a moxifloxacin dose that suppresses drug resistance in Mycobacterium tuberculosis, by use of an in vitro pharmacodynamic infection model and mathematical modeling. Gumbo, T. et al.; J Infect Dis. 2004 Nov 1;190(9):1642-51. [open access]

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