Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.

Ilustraciones

Autores:
López Taborda, Juan David
Tipo de recurso:
Fecha de publicación:
2021
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/80353
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/80353
https://repositorio.unal.edu.co/
Palabra clave:
570 - Biología
Células y tejidos vegetales - Cultivo
Metabolitos
Metabolites
Cell culture
Cultivo de celulas
Azadirachta indica
Escala de Kolmogorov
Estrés celular
Oferta de oxígeno
Sistema de control
Velocidad de disipación de energía
Kolmogorov microscale
Cell stress
Oxygen transferrate
Energy dissipation rate
Rights
openAccess
License
Atribución-NoComercial 4.0 Internacional
id UNACIONAL2_3a47a5f448840da3a90429b90b1b36ee
oai_identifier_str oai:repositorio.unal.edu.co:unal/80353
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.
dc.title.translated.eng.fl_str_mv A strategy to study hydrodynamic and oxygen stress in plant cell biorreactors.
title Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.
spellingShingle Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.
570 - Biología
Células y tejidos vegetales - Cultivo
Metabolitos
Metabolites
Cell culture
Cultivo de celulas
Azadirachta indica
Escala de Kolmogorov
Estrés celular
Oferta de oxígeno
Sistema de control
Velocidad de disipación de energía
Kolmogorov microscale
Cell stress
Oxygen transferrate
Energy dissipation rate
title_short Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.
title_full Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.
title_fullStr Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.
title_full_unstemmed Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.
title_sort Estrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.
dc.creator.fl_str_mv López Taborda, Juan David
dc.contributor.advisor.none.fl_str_mv Orozco-Sanchez, Fernando
Ocampo Betancur, Maritza
dc.contributor.author.none.fl_str_mv López Taborda, Juan David
dc.subject.ddc.spa.fl_str_mv 570 - Biología
topic 570 - Biología
Células y tejidos vegetales - Cultivo
Metabolitos
Metabolites
Cell culture
Cultivo de celulas
Azadirachta indica
Escala de Kolmogorov
Estrés celular
Oferta de oxígeno
Sistema de control
Velocidad de disipación de energía
Kolmogorov microscale
Cell stress
Oxygen transferrate
Energy dissipation rate
dc.subject.armarc.none.fl_str_mv Células y tejidos vegetales - Cultivo
dc.subject.lemb.none.fl_str_mv Metabolitos
Metabolites
Cell culture
Cultivo de celulas
dc.subject.proposal.other.fl_str_mv Azadirachta indica
dc.subject.proposal.spa.fl_str_mv Escala de Kolmogorov
Estrés celular
Oferta de oxígeno
Sistema de control
Velocidad de disipación de energía
dc.subject.proposal.eng.fl_str_mv Kolmogorov microscale
Cell stress
Oxygen transferrate
Energy dissipation rate
description Ilustraciones
publishDate 2021
dc.date.accessioned.none.fl_str_mv 2021-10-01T19:55:43Z
dc.date.available.none.fl_str_mv 2021-10-01T19:55:43Z
dc.date.issued.none.fl_str_mv 2021
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/80353
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/80353
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.indexed.spa.fl_str_mv Agrovoc
dc.relation.references.spa.fl_str_mv Acedos, M. G., Hermida, A., Gomez, E., Santos, V. E., & Garcia-Ochoa, F. (2019). Effects of fluid-dynamic conditions in Shimwellia blattae (p424IbPSO)cultures in stirred tank bioreactors: Hydrodynamic stress and change of metabolic routes by oxygen availability. Biochemical Engineering Journal, 149(May), 107238. https://doi.org/10.1016/j.bej.2019.107238
Akesson, M., & Hagander, P. (1998). Control of Dissolved Oxygen in Stirred Bioreactors (Technical Reports TFRT-7571).
Akesson, M., & Hagander, P. (1999). A Gain-Scheduling Approach for Control of Dissolved Oxygen in Stirred Bioreactors.
Al-Whaibi, M. H. (2011). Plant heat-shock proteins: A mini review. Journal of King Saud University - Science, 23(2), 139-150. https://doi.org/10.1016/j.jksus.2010.06.022
Alvarez-Yela, A. C., Chiquiza-Montaño, L. N., Hoyos, R., & Orozco-Sánchez, F. (2016). Rheology and mixing analysis of plant cell cultures (Azadirachta indica, Borojoa patinoi and Thevetia peruviana) in shake flasks. Biochemical Engineering Journal, 114, 18-25. https://doi.org/10.1016/j.bej.2016.06.019
Arias, M., Aguirre, A., Angarita, M., Montoya, C., & Restrepo, J. (2009). Engineering aspects of the in vitro plant cell culture for the production of secondary metabolites. Dyna, 76(157), 109-121.
Armstrong, W. (1994). Polarographic oxygen electrodes and their use in plant aeration studies. Proceedings of the Royal Society of Edinburgh. Section B. Biological Sciences, 102(May 2015), 511-527. https://doi.org/10.1017/s0269727000014548
Arrua, L. A., McCoy, B. J., & Smith, J. M. (1990). Gas-liquid mass transfer in stirred tanks. AICHE Journal, 36(11), 1768-1772. https://doi.org/10.1002/aic.690361121
Arteaga, H., & Vazquez, V. (2012). Control difuso del oxígeno disuelto, pH y temperatura de un biorreactor columna de burbujas en la producción de biomasa de Candida utilis. Departamento de Ciencias Agroindustriales, Universidad Nacional de Trujillo, 2, 10.
Arya, S. S., Rookes, J. E., Cahill, D. M., & Lenka, S. K. (2020). Next-generation metabolic engineering approaches towards development of plant cell suspension cultures as specialized metabolite producing biofactories. Biotechnology Advances, 45(July), 107635. https://doi.org/10.1016/j.biotechadv.2020.107635
Babich, O., Sukhikh, S., Pungin, A., Ivanova, S., Asyakina, L., & Prosekov, A. (2020). Modern Trends in the In Vitro Production and Use of Callus, Suspension Cells and Root Cultures of Medicinal Plants. Molecules (Basel, Switzerland), 25(24), 1-18. https://doi.org/10.3390/molecules25245805
Balaji, K., Veeresham, C., Srisilam, K., & Kokate, C. (2003). Azadirachtin, a Novel Biopesticide from Cell Cultures of Azadirachta indica. Journal of Plant Biotechnology, 5(2), 121-129.
Barbosa, M. J., Albrecht, M., & Wijffels, R. H. (2003). Hydrodynamic stress and lethal events in sparged microalgae cultures. Biotechnology and Bioengineering, 83(1), 112-120. https://doi.org/10.1002/bit.10657
Benavides-López, S., Oviedo-Ramírez, J., López-Taborda, J.-D. D., Martínez-Mira, A., Vásquez-Rivera, A., Hoyos-Sánchez, R., & Orozco-Sánchez, F. (2020). Bioprocess plant design and economic analysis of an environmentally friendly insect controller agent produced with Azadirachta indica cell culture. Biochemical Engineering Journal, 159(March), 107579. https://doi.org/10.1016/j.bej.2020.107579
Bhambhani, S., Lakhwani, D., Gupta, P., Pandey, A., Dhar, Y. V., Kumar Bag, S., Asif, M. H., & Kumar Trivedi, P. (2017). Transcriptome and metabolite analyses in Azadirachta indica: Identification of genes involved in biosynthesis of bioactive triterpenoids. Scientific Reports, 7(1), 1-12. https://doi.org/10.1038/s41598-017-05291-3
Boulton-Stone, J. M., & Blake, J. R. (1993). Gas bubbles bursting at a free surface. Journal of Fluid Mechanics, 254(I), 437-466. https://doi.org/10.1017/S0022112093002216
Braga, T. M., Rocha, L., Chung, T. Y., Oliveira, R. F., Pinho, C., Oliveira, A. I., Morgado, J., & Cruz, A. (2021). Azadirachta indica A. Juss. In Vivo Toxicity-An Updated Review. Molecules (Basel, Switzerland), 26(2), 1-21. https://doi.org/10.3390/molecules26020252
Buitrago H, G., Otálvaro A, Á. M., & Duarte B., P. G. (2013). Evaluación de la transferencia de oxígeno en un biorreactor convencional con aireador externo. Revista Colombiana de Biotecnología, 15(2), 106-114. https://doi.org/10.15446/rev.colomb.biote.v15n2.41272
Busciglio, A., Grisafi, F., Scargiali, F., & Brucato, A. (2013). On the measurement of local gas hold-up, interfacial area and bubble size distribution in gas-liquid contactors via light sheet and image analysis: Imaging technique and experimental results. Chemical Engineering Science, 102, 551-566. https://doi.org/10.1016/j.ces.2013.08.029
Busto, V. D., Calabró-López, A., Rodríguez-Talou, J., Giulietti, A. M., & Merchuk, J. C. (2013). Anthraquinones production in Rubia tinctorum cell suspension cultures: Down scale of shear effects. Biochemical Engineering Journal, 77, 119-128. https://doi.org/10.1016/j.bej.2013.05.013
Çalik, P., Yilgör, P., Ayhan, P., & Demir, A. S. (2004). Oxygen transfer effects on recombinant benzaldehyde lyase production. Chemical Engineering Science, 59(22-23), 5075-5083. https://doi.org/10.1016/j.ces.2004.07.070
Cantor del Angel, J. A. (2011). Cultivo de Beta vulgaris L. por lote alimentado para la producción de arabinogalactano-proteínas. Instituto Politécnico Nacional.
Capataz Tafur, J., Orozco-Sánchez, F., Vergara Ruiz, R., & Hoyos Sanchez, R. (2007). Efecto antialimentario de los extractos de suspensiones celulares de Azadiractha indica sobre Spodoptera frugiperda en condiciones de laboratorio. Revista Fac, 60(1), 2008.
Cash, T. P., Pan, Y., & Simon, M. C. (2007). Reactive oxygen species and cellular oxygen sensing. 43, 1219-1225. https://doi.org/10.1016/j.freeradbiomed.2007.07.001
Chen, J., Fan, X., Zhu, J., Song, L., Li, Z., Lin, F., Yu, R., Xu, H., & Zi, J. (2018). Limonoids from seeds of Azadirachta indica A. Juss. and their cytotoxic activity. Acta Pharmaceutica Sinica B, 2018, 0-5. https://doi.org/10.1016/j.apsb.2017.12.009
Chisti, Y. (2000). Animal-cell damage in sparged bioreactors. Trends in Biotechnology, 18(10), 420-432. https://doi.org/10.1016/S0167-7799(00)01474-8
Choudhury, F. K., Rivero, R. M., Blumwald, E., & Mittler, R. (2017). Reactive oxygen species , abiotic stress and stress combination. 856-867. https://doi.org/10.1111/tpj.13299
Cragg, G. M., & Newman, D. J. (2013). Natural products : A continuing source of novel drug leads. Biochimica et Biophysica Acta, 1830(6), 3670-3695. https://doi.org/10.1016/j.bbagen.2013.02.008
Dat, J. F., Capelli, N., Folzer, H., Bourgeade, P., & Badot, P. (2004). Sensing and signalling during plant flooding. 42, 273-282. https://doi.org/10.1016/j.plaphy.2004.02.003
de Jesús, S. S., Moreira Neto, J., & Maciel Filho, R. (2017). Hydrodynamics and mass transfer in bubble column, conventional airlift, stirred airlift and stirred tank bioreactors, using viscous fluid: A comparative study. Biochemical Engineering Journal, 118, 70-81. https://doi.org/10.1016/j.bej.2016.11.019
De León-Rodríguez, A., Galindo, E., & Ramírez, O. T. (2010). Design and characterization of a one-compartment scale-down system for simulating dissolved oxygen tension gradients. Journal of Chemical Technology and Biotechnology, 85(7), 950-956. https://doi.org/10.1002/jctb.2384
De León, a, Mayani, H., & Ramírez, O. T. (1998). Design, characterization and application of a minibioreactor for the culture of human hematopoietic cells under controlled conditions. Cytotechnology, 28(1-3), 127-138. https://doi.org/10.1023/A:1008042000744
De León, A., Barba-De La Rosa, A. P., Mayani, H., Galindo, E., & Ramírez, O. T. (2001). Two useful dimensionless parameters that combine physiological, operational and bioreactor design parameters for improved control of dissolved oxygen. Biotechnology Letters, 23(13), 1051-1056. https://doi.org/10.1023/A:1010598121587
Doran, P. (1995). Bioprocess Engineering Principles. Academic Press.
Doran, P. (1999). Design of mixing systems for plant cell suspensions in stirred reactors. Biotechnology progress, 15(3), 319-335.
Doran, P. M. (2013). Bioprocess engineering principles (Second). Elsevier.
DuBois, M., Gilles, K. a., Hamilton, J. K., Rebers, P. a., & Smith, F. (1956). Colorimetric Method for Determination of Sugars and Related Substances. Analytical Chemistry, 28(3), 350-356. https://doi.org/10.1021/ac60111a017
Dunlop, E. H., & Namdev, P. K. (1994). Effect of fluid shear forces on plant cell suspensions. Chemical Engineering Science, 49(14), 2263-2276. https://doi.org/10.1016/0009-2509(94)E0043-P
Dunlop, E. H., Namdev, P. K., & Rosenberg, M. Z. (1994). Effect of fluid shear forces on plant cell suspensions. Chemical Engineering Science, 49(14), 2263-2276. https://doi.org/10.1016/0009-2509(94)E0043-P
Edahiro, J. ichi, & Seki, M. (2006). Phenylpropanoid metabolite supports cell aggregate formation in strawberry cell suspension culture. Journal of Bioscience and Bioengineering, 102(1), 8-13. https://doi.org/10.1263/jbb.102.8
Eibl, R., Meier, P., Stutz, I., Schildberger, D., Hühn, T., & Eibl, D. (2018). Plant cell culture technology in the cosmetics and food industries: current state and future trends. Applied Microbiology and Biotechnology, 102(20), 8661-8675. https://doi.org/10.1007/s00253-018-9279-8
Farjaminezhad, R., & Garoosi, G. (2021). Improvement and prediction of secondary metabolites production under yeast extract elicitation of Azadirachta indica cell suspension culture using response surface methodology. AMB Express, 11(1). https://doi.org/10.1186/s13568-021-01203-x
Flickinger, M. C., & Doran, P. M. (2010). Bioreactors, Stirred Tank for Culture of Plant Cells. Encyclopedia of Industrial Biotechnology. https://doi.org/10.1002/9780470054581.eib150
Garcia-Ochoa, F., Gomez, E., Alcon, A., & Santos, V. E. (2012). The effect of hydrodynamic stress on the growth of Xanthomonas campestris cultures in a stirred and sparged tank bioreactor. Bioprocess Biosyst Eng, 1. https://doi.org/10.1007/s00449-012-0825-y
Garcia-Ochoa, F., Gomez, E., Alcon, A., & Santos, V. E. (2013). The effect of hydrodynamic stress on the growth of Xanthomonas campestris cultures in a stirred and sparged tank bioreactor. Bioprocess and Biosystems Engineering, 36(7), 911-925. https://doi.org/10.1007/s00449-012-0825-y
Garcia-ochoa, F., Gomez, E., Santos, V. E., & Merchuk, J. C. (2010). Oxygen uptake rate in microbial processes : An overview. Biochemical Engineering Journal, 49(3), 289-307. https://doi.org/10.1016/j.bej.2010.01.011
Garcia-Ochoa, Felix, Escobar, S., & Gomez, E. (2015). Specific oxygen uptake rate as indicator of cell response of Rhodococcus erythropolis cultures to shear effects. Chemical Engineering Science, 122, 491-499. https://doi.org/10.1016/j.ces.2014.10.016
Geigenberger, P. (2003). Response of plant metabolism to too little oxygen. Current Opinion in Plant Biology, 6(3), 247-256. https://doi.org/10.1016/S1369-5266(03)00038-4
Georgiev, M., & Weber, J. (2014). Bioreactors for plant cells: Hardware configuration and internal environment optimization as tools for wider commercialization. Biotechnology Letters, 36(7), 1359-1367. https://doi.org/10.1007/s10529-014-1498-1
Georgiev, V., Slavov, A., Vasileva, I., & Pavlov, A. (2018). Plant cell culture as emerging technology for production of active cosmetic ingredients. Engineering in Life Sciences, 18(11), 779-798. https://doi.org/10.1002/elsc.201800066
Gill, S. S., & Tuteja, N. (2010). Reactive oxygen species and antioxidant machinery in abiotic stress tolerance in crop plants. Plant Physiology and Biochemistry, 48(12), 909-930. https://doi.org/10.1016/j.plaphy.2010.08.016
Gomes, J., & Menawat, A. S. (2000). Precise control of dissolved oxygen in bioreactors - a model-based geometric algorithm. Chemical Engineering Science, 55(1), 67-78. https://doi.org/10.1016/S0009-2509(99)00305-X
Gomez, E., Santos, V. E., Alcon, A., & Garcia-Ochoa, F. (2006). Oxygen transport rate on Rhodococcus erythropolis cultures: Effect on growth and BDS capability. Chemical Engineering Science, 61(14), 4595-4604. https://doi.org/10.1016/j.ces.2006.02.025
Gong, Y. W., Li, S. Y., Han, R. Bin, & Yuan, Y. J. (2006). Age-related responses of suspension cultured Taxus cuspidata to hydrodynamic shear stress. Biochemical Engineering Journal, 32(2), 113-118. https://doi.org/10.1016/j.bej.2006.09.010
Gupta, S. C., Prasad, S., Tyagi, A. K., Kunnumakkara, A. B., & Aggarwal, B. B. (2017). Neem (Azadirachta indica): An indian traditional panacea with modern molecular basis. Phytomedicine, 34(May), 14-20. https://doi.org/10.1016/j.phymed.2017.07.001
Gurib-fakim, A. (2006). Medicinal plants : Traditions of yesterday and drugs of tomorrow. 27, 1-93. https://doi.org/10.1016/j.mam.2005.07.008
Halliwell, B. (2007). Biochemistry of oxidative stress. Biochemical society transactions. 1147-1150.
Hazen, T. C., & Stahl, D. A. (2006). Using the stress response to monitor process control : pathways to more effective bioremediation. Current opinion in biotechnology. 285-290. https://doi.org/10.1016/j.copbio.2006.03.004
Hodgson, H., De La Peña, R., Stephenson, M. J., Thimmappa, R., Vincent, J. L., Sattely, E. S., & Osbourn, A. (2019). Identification of key enzymes responsible for protolimonoid biosynthesis in plants: Opening the door to azadirachtin production. Proceedings of the National Academy of Sciences of the United States of America, 116(34), 17096-17104. https://doi.org/10.1073/pnas.1906083116
Hong, J. K., Yeo, H. C., Lakshmanan, M., Han, S. hyuk, Cha, H. M., Han, M., & Lee, D. Y. (2020). In silico model-based characterization of metabolic response to harsh sparging stress in fed-batch CHO cell cultures. Journal of Biotechnology, 308(August 2019), 10-20. https://doi.org/10.1016/j.jbiotec.2019.11.011
Hu, W., Berdugo, C., & Chalmers, J. J. (2011). The potential of hydrodynamic damage to animal cells of industrial relevance : current understanding. 445-460. https://doi.org/10.1007/s10616-011-9368-3
Hua, J., Erickson, L. E., Yiin, T. Y., & Glasgow, L. a. (1993). A review of the effects of shear and interfacial phenomena on cell viability. Critical reviews in biotechnology, 13(4), 305-328. https://doi.org/10.3109/07388559309075700
Huang, S. Y., & Chou, C. J. (2000). Effect of gaseous composition on cell growth and secondary metabolite production in suspension culture of Stizolobium hassjoo cells. Bioprocess Engineering, 23(6), 585-593. https://doi.org/10.1007/s004490000204
Huang, Shih Yow, Shen, Y. W., & Chan, H. S. (2002). Development of a bioreactor operation strategy for L-DOPA production using Stizolobium hassjoo suspension culture. Enzyme and Microbial Technology, 30(6), 779-791. https://doi.org/10.1016/S0141-0229(02)00058-3
Islas, J. F., Acosta, E., G-Buentello, Z., Delgado-Gallegos, J. L., Moreno-Treviño, M. G., Escalante, B., & Moreno-Cuevas, J. E. (2020). An overview of Neem (Azadirachta indica) and its potential impact on health. Journal of Functional Foods, 74(September), 104171. https://doi.org/10.1016/j.jff.2020.104171
Jackson, J. R., Overbeck, P. K., & Overby, J. M. (1999). Dissolved Oxygen Control by Pressurized Side Stream Ozone Contacting and Degassing. 623.
Jonelis, K., Brazauskas, K., & Levišauskas, D. (2012). A system for dissolved oxygen control in industrial aeration tank. Information Technology and Control, 41(1), 46-52. https://doi.org/10.5755/j01.itc.41.1.921
Kaboré, A. K., Delaunay, S., Blanchard, F., Guedon, E., Fick, M., & Olmos, E. (2019). Study and modeling of fluctuating dissolved oxygen concentration impact on Corynebacterium glutamicum growth in a scale-down bioreactor. Process Biochemistry, 77(November 2018), 8-17. https://doi.org/10.1016/j.procbio.2018.10.016
Karimi, A., Golbabaei, F., Mehrnia, M. R., Neghab, M., Mohammad, K., Nikpey, A., & Pourmand, M. R. (2013). Oxygen mass transfer in a stirred tank bioreactor using different impeller configurations for environmental purposes. Iranian journal of environmental health science & engineering, 10(1), 6. https://doi.org/10.1186/1735-2746-10-6
Kieran, P. M., Malone, D. M., & MacLoughlin, P. F. (2000). Effects of hydrodynamic and interfacial forces on plant cell suspension systems. Advances in biochemical engineering/biotechnology, 67, 139-177. https://doi.org/10.1007/3-540-47865-5_5
Koul, O. (2009). Azadirachtin. Zeitschrift für Angewandte Entomologie, 98(1-5), 221-223. https://doi.org/10.1111/j.1439-0418.1984.tb02703.x
Krasteva, G., Georgiev, V., & Pavlov, A. (2020). Recent applications of plant cell culture technology in cosmetics and foods. Engineering in Life Sciences, October, 1-9. https://doi.org/10.1002/elsc.202000078
Krishnan, N. M., Pattnaik, S., Deepak, S. A., Hariharan, A. K., Gaur, P., Chaudhary, R., Jain, P., Vaidyanathan, S., Krishna, P. G. B., & Panda, B. (2011). De novo sequencing and assembly of Azadirachta indica fruit transcriptome. Current Science, 101(12), 1553-1561.
Krishnan, N. M., Pattnaik, S., Jain, P., Gaur, P., Choudhary, R., Vaidyanathan, S., Deepak, S., Hariharan, A. K., Krishna, P. G. B., Nair, J., Varghese, L., Valivarthi, N. K., Dhas, K., Ramaswamy, K., & Panda, B. (2012). A draft of the genome and four transcriptomes of a medicinal and pesticidal angiosperm Azadirachta indica. BMC Genomics, 13(1). https://doi.org/10.1186/1471-2164-13-464
Kumar, B. (2010). Energy Dissipation and Shear Rate with Geometry of Baffled Surface Aerator. Chemical Engineering Research Bulletin, 14(2), 92-96. https://doi.org/10.3329/cerb.v14i2.4910
Kuravadi, N. A., Yenagi, V., Rangiah, K., Mahesh, H. B., Rajamani, A., Shirke, M. D., Russiachand, H., Loganathan, R. M., Lingu, C. S., Siddappa, S., Ramamurthy, A., Sathyanarayana, B. N., & Gowda, M. (2015). Comprehensive analyses of genomes, transcriptomes and metabolites of neem tree. PeerJ, 2015(8), 1-25. https://doi.org/10.7717/peerj.1066
Landau, L., & Lifhitz, E. M. (1976). Fluid Mechanist (P. Press (ed.); 2nd ed.
Lara, A. R., Galindo, E., Ramírez, O. T., & Palomares, L. A. (2006). Living with heterogeneities in bioreactors: Understanding the effects of environmental gradients on cells. Molecular Biotechnology, 34(3), 355-381. https://doi.org/10.1385/MB:34:3:355
Lee-Parsons, C. W. T. (2007). Gas composition strategies for the successful scale-up of Catharanthus roseus cell cultures for the production of ajmalicine. Phytochemistry Reviews, 6(2-3), 419-433. https://doi.org/10.1007/s11101-006-9046-9
Lee-Parsons, C. W. T., & Shuler, M. L. (2005). Sparge gas composition affects biomass and ajmalicine production from immobilized cell cultures of Catharanthus roseus. Enzyme and Microbial Technology, 37(4), 424-434. https://doi.org/10.1016/j.enzmictec.2005.02.016
Lindblon, T. (2009). Qualitative comparison of optical and electrochemical sensors for measuring dissolved oxygen in bioreactors. En In Situ. Linkoping University.
Liu, Y., Li, F., Hu, W., Wiltberger, K., & Ryll, T. (2014). Effects of bubble-liquid two-phase turbulent hydrodynamics on cell damage in sparged bioreactor. Biotechnology Progress, 30(1), 48-58. https://doi.org/10.1002/btpr.1790
Liu, Y. S., Wu, J. Y., & Ho, K. P. (2006). Characterization of oxygen transfer conditions and their effects on Phaffia rhodozyma growth and carotenoid production in shake-flask cultures. Biochemical Engineering Journal, 27(3), 331-335. https://doi.org/10.1016/j.bej.2005.08.031
López-Taborda, J., Vargas Zapata, A., Ramirez Vargas, J., Valdez Cruz, N., Trujillo Roldán, M., & Orozco Sánchez, F. (2018). A novel system to control dissolved oxygen in bioreactors minimizing variation on hydrodynamic stress. Universidad Nacional de Colombia- Sede Medellín.
MacLennan, D. G., & Pirt, S. J. (1966). Automatic control of dissolved oxygen concentration in stirred microbial cultures. Journal of general microbiology, 45(2), 289-302. https://doi.org/10.1099/00221287-45-2-289
Martins, F. G. (2005). Tuning PID Controllers using the ITAE Criterion. International Journal of Engineering Education, 21(5), 867-873.
Meijer, J. J., ten Hoopen, H. J. G., Luyben, K. C. A. M., & Libbenga, K. R. (1993). Effects of hydrodynamic stress on cultured plant cells: A literature survey. Enzyme and Microbial Technology, 15(3), 234-238. https://doi.org/10.1016/0141-0229(93)90143-P
Mittler, R. (2002). Oxidative stress , antioxidants and stress tolerance. Trends in Plant Science, 7(9), 405-410.
Mittler, R. (2017). ROS Are Good. Trends in Plant Science, 22(1), 11-19. https://doi.org/10.1016/j.tplants.2016.08.002
Mohan, R., Kumar, M. S. M., & Rao, L. (2021). Numerical modelling of oxygen mass transfer in diffused aeration systems: A CFD-PBM approach. Journal of Water Process Engineering, 40(September 2020), 101920. https://doi.org/10.1016/j.jwpe.2021.101920
Mulabagal, V., & Tsay, H. (2004). Plant Cell Cultures - An Alternative and Efficient Source for the Production of Biologically Important Secondary Metabolites. September 2015, 29-48.
Muñoz-Cruz, W., Vanegas-Monterrosa, O. A., Guzmán-Rosas, A. A., Capataz-Tafur, J., Hoyos-Sánchez, R., & Orozco-Sánchez, F. (2006). Estimación de variables de operación de un biorreactor con células de Azadirachta indica A. Juss. Revista Facultad Nacional de Agronomía, 59(2), 3467-3478.
Namdev, P. K., & Dunlop, E. H. (1995). Shear sensitivity of plant cells in suspensions present and future. Applied Biochemistry and Biotechnology, 54(1-3), 109-131. https://doi.org/10.1007/BF02787914
Neunstoecklin, B., Stettler, M., Solacroup, T., Broly, H., Morbidelli, M., & Soos, M. (2015). Determination of the maximum operating range of hydrodynamic stress in mammalian cell culture. Journal of Biotechnology, 194, 100-109. https://doi.org/10.1016/j.jbiotec.2014.12.003
Nienow, A. W. (1998). Hydrodynamics of stirred bioreactors. Applied Mechanics Reviews, 51(1), 3-32. https://doi.org/10.1115/1.3098990
Nock, V., Blaikie, R. J., & David, T. (2009). Oxygen control for bioreactors and in-vitro cell assays. AIP Conference Proceedings, 1151(February 2017), 67-70. https://doi.org/10.1063/1.3203249
O’Leary, B. M., Asao, S., Millar, A. H., & Atkin, O. K. (2019). Core principles which explain variation in respiration across biological scales. New Phytologist, 222(2), 670-686. https://doi.org/10.1111/nph.15576
Oksman-Caldentey, K. M., & Inzé, D. (2004). Plant cell factories in the post-genomic era: New ways to produce designer secondary metabolites. Trends in Plant Science, 9(9), 433-440. https://doi.org/10.1016/j.tplants.2004.07.006
Orozco-Sánchez, F. (2009). Efecto de la oferta de oxígeno sobre el crecimiento y la producción de terpenoides con células de Azadirachta indica en un biorreactor. 96.
Orozco-Sanchez, F., & Rodríguez-Monroy, M. (2007). Cell suspension culture of Azadirachta indica for the production of a bioinsecticide. Revista Mexicana de Ingeniería Química, 6(3), 251-258.
Orozco-Sánchez, F., Sepúlveda-Jimenez, G., Trejo-Tapia, G., Zamilpa, A., & Rodríguez-Monroy, M. (2011). Oxygen limitations to growth Azadirachta indica cell culture in shake flask. Revista Mexicana de Ingeniería Química, 10(1), 17-28.
Pandreka, A., Chaya, P. S., Kumar, A., Aarthy, T., Mulani, F. A., Bhagyashree, D. D., B, S. H., Jennifer, C., Ponnusamy, S., Nagegowda, D., & Thulasiram, H. V. (2021). Limonoid biosynthesis 3: Functional characterization of crucial genes involved in neem limonoid biosynthesis. Phytochemistry, 184(September 2020), 112669. https://doi.org/10.1016/j.phytochem.2021.112669
Patel, S. M., Nagulapalli Venkata, K. C., Bhattacharyya, P., Sethi, G., & Bishayee, A. (2016). Potential of neem (Azadirachta indica L.) for prevention and treatment of oncologic diseases. Seminars in Cancer Biology, 40_41, 100-115. https://doi.org/10.1016/j.semcancer.2016.03.002
Pérez-Hernández, J., Nicasio-Torres, M. del P., Sarmiento-López, L. G., & Rodríguez-Monroy, M. (2019). Production of anti-inflammatory compounds in Sphaeralcea angustifolia cell suspension cultivated in stirred tank bioreactor. Engineering in Life Sciences, 19(3), 196-205. https://doi.org/10.1002/elsc.201800134
Prakash, G., Emmannuel, C. J. S. K., & Srivastava, A. K. (2005). Variability of Azadirachtin in Azadirachta indica (neem) and batch kinetics studies of cell suspension culture. Biotechnology and Bioprocess Engineering, 10, 198-204.
Prakash, G., & Srivastava, A. K. (2007). Azadirachtin production in stirred tank reactors by Azadirachta indica suspension culture. Process Biochemistry, 42(1), 93-97. https://doi.org/10.1016/j.procbio.2006.06.020
Rafiq, M., & Dahot, M. U. (2010). Callus and azadirachtin related limonoids production through in vitro culture of neem (Azadirachta indica A. Juss). African Journal of Biotechnology, 9(4), 449-453. https://doi.org/10.5897/AJB09.1091
Ramaswamy, S., Cutright, T. J., & Qammar, H. K. (2005). Control of a continuous bioreactor using model predictive control. Process Biochemistry, 40(8), 2763-2770. https://doi.org/10.1016/j.procbio.2004.12.019
Raposo, S., & Lima-Costa, M. E. (2012). Effects of the hydrodynamic environment and oxygen mass transfer on plant cell growth and milk-clotting protease production in a stirred-tank reactor. Engineering in Life Sciences, 12(4), 441-449. https://doi.org/10.1002/elsc.201100087
Raval, K., Hellwig, S., & Srivastava, A. (2003). Necessity of a Two-Stage Process for the Production of Azadirachtin-Related Limonoids in Suspension Cultures of Azadirachta indica. Journal of Bioscience and Bioengineering, 96(I).
Reyes, C. R., Barrales-cureño, H. J., Hoyos, P. A., Luna-cruz, A., Terrón-mejía, K. A., López-valdez, L. G., Sánchez-herrera, L. M., Cortes-ruíz, J. A., Calderon-caballero, M. C., Orlando, J., Osuna, G., Ingeniería, D. De, Politécnica, U., Naturales, D. D. P., Comunitaria, I. F., & Intercultural, U. (2017). Software Simulator Bioprocess (SSBP) to estimate hydrodynamic stress conditions in cell cultures performed in shaking bioreactors. International Journal of Biosciences (IJB), 10(3), 143-156. https://doi.org/10.12692/ijb/10.3.143-156
Rodríguez-Monroy, M., & Galindo, E. (1999). Broth rheology, growth and metabolite production of Beta vulgaris suspension culture: A comparative study between cultures grown in shake flasks and in a stirred tank. Enzyme and Microbial Technology, 24(10), 687-693. https://doi.org/10.1016/S0141-0229(99)00002-2
Rodríguez-Monroy, M., & Orozco-Sánchez, F. (2014). Caracterización, operación y escalado de biorreactores (F. Orozco-Sánchez & M. Rodríguez-Monroy (eds.); 2.a ed.). Universidad Nacional de Colombia.
Rodríguez-Monroy, M., Trejo-Espino, J. L., Jiménez-Aparicio, A., De La Luz Morante, M., Villarreal, M. L., & Trejo-Tapia, G. (2004). Evaluation of morphological properties of Solanum chrysotrichum cell cultures in a shake flask and fermenter and rheological properties of broths. Food Technology and Biotechnology, 42(3), 153-158.
Rodríguez Torres, M. I. (2013). Condiciones de cultivo para el crecimiento de Rhizopus oryzae NRRL-395 y la producción de ácido L (+) láctico en un reactor de tanque agitado. En Tesis de maestría, Universidad Nacional de Colombia (Vol. 26, Número 4). Universidad Nacional de Colombia.
Saleem, S., Muhammad, G., Hussain, M. A., & Bukhari, S. N. A. (2018). A comprehensive review of phytochemical profile, bioactives for pharmaceuticals, and pharmacological attributes of Azadirachta indica. Phytotherapy Research, 32(7), 1241-1272. https://doi.org/10.1002/ptr.6076
Santos, R. B., Abranches, R., Fischer, R., Sack, M., & Holland, T. (2016). Putting the Spotlight Back on Plant Suspension Cultures. Frontiers in Plant Science, 7(March), 1-12. https://doi.org/10.3389/fpls.2016.00297
Schaepe, S., Kuprijanov, A., Sieblist, C., Jenzsch, M., Simutis, R., & Lübbert, A. (2013). KLa of stirred tank bioreactors revisited. Journal of Biotechnology, 168(4), 576-583. https://doi.org/10.1016/j.jbiotec.2013.08.032
Shuler, M. L., & Kargi, F. (2017). Bioprocess Engineering: Basic Concepts (Third). Prentice Hall.
Smith, C., & Corripio, A. (1991). Control automático de procesos, teoría y práctica.
Smith, J. M., Davison, S. W., & Payne, G. F. (1990). Development of a strategy to control the dissolved concentrations of oxygen and carbon dioxide at constant shear in a plant cell bioreactor. Biotechnology and Bioengineering, 35(11), 1088-1101. https://doi.org/10.1002/bit.260351104
Soler, A., & Buitrago Hurtado, G. (2010). Evaluación de la transferencia de oxígeno en cultivos con lactococcus lactis empleando un sistema de fermentación con aireación externa. Revista Colombiana de Biotecnología, 12(2), 124-138.
Sowana, D. D., Williams, D. R. G., Dunlop, E. H., Dally, B. B., O’Neill, B. K., & Fletcher, D. F. (2001). Turbulent Shear Stress Effects on Plant Cell Suspension Cultures. Chemical Engineering Research and Design, 79(8), 867-875. https://doi.org/10.1205/02638760152721370
Sujanya, S., Devi, B. P., & Sai, I. (2008). In vitro production of azadirachtin from cell suspension cultures of Azadirachta indica. Journal of Biosciences, 33(1), 113-120. https://doi.org/10.1007/s12038-008-0027-6
Suresh, S., Srivastava, V. C., & Mishra, I. M. (2009). Techniques for oxygen transfer measurement in bioreactors: A review. Journal of Chemical Technology and Biotechnology, 84(8), 1091-1103. https://doi.org/10.1002/jctb.2154
Takeda, T., Tamura, M., Ohtaki, M., & Matsuoka, H. (2003). Gene expression in cultured strawberry cells subjected to hydrodynamic stress. Biochemical Engineering Journal, 15(3), 211-215. https://doi.org/10.1016/S1369-703X(02)00214-0
Taylan, E., Kose, A., Celik, Y., & Oncel, S. S. (2021). Design of a horizontal-dual bladed bioreactor for low shear stress to improve hydrodynamic responses in cell cultures : A pilot study in Chlamydomonas reinhardtii. Biochemical Engineering Journal, 169(February), 107970. https://doi.org/10.1016/j.bej.2021.107970
Thakore, D., & Srivastava, A. K. (2017). Production of biopesticide azadirachtin using plant cell and hairy root cultures. 997-1005. https://doi.org/10.1002/elsc.201700012
Trejo-Tapia, G., & Rodríguez-Monroy, M. (2007). La agregación celular en la producción de metabolitos secundarios en cultivos vegetales in vitro. Interciencia, 32(10), 669-674.
Trujillo-Roldán, M. A., & Valdez-Cruz, N. A. (2006). El estrés hidrodinámico: Muerte y daño celular en cultivos agitados. Revista Latinoamericana de Microbiologia, 48(3-4), 269-280.
Trujillo Roldán, M. A., Peña, C., Ramirez, O. T., & Galindo, E. (2001). Effect of oscillating dissolved oxygen tension on the production of alginate by Azotobacter vinelandii. Biotechnology Progress, 17(6), 1042-1048. https://doi.org/10.1021/bp010106d
Van Dongen, J. T., & Licausi, F. (2015). Oxygen sensing and signaling. Annual Review of Plant Biology, 66, 345-367. https://doi.org/10.1146/annurev-arplant-043014-114813
Vásquez-Rivera, A., Chicaiza-Finley, D., Hoyos, R. A., & Orozco-Sánchez, F. (2015). Production of Limonoids with Insect Antifeedant Activity in a Two-Stage Bioreactor Process with Cell Suspension Culture of Azadirachta indica. Applied Biochemistry and Biotechnology, 177(2), 334-345.
Verma, R., Mehan, L., Kumar, R., Kumar, A., & Srivastava, A. (2019). Computational fluid dynamic analysis of hydrodynamic shear stress generated by different impeller combinations in stirred bioreactor. Biochemical Engineering Journal, 151(July), 107312. https://doi.org/10.1016/j.bej.2019.107312
Verpoorte, R., Contin, A., & Memelink, J. (2002). Biotechnology for the production of plant secondary metabolites. Phytochemistry Reviews, 1(1), 13-25. https://doi.org/10.1023/A:1015871916833
Villegas-Velásquez, S., Martínez-Mira, A. D., Hoyos, R., Rojano, B., & Orozco-Sánchez, F. (2017). Hydrodynamic stress and limonoid production in Azadirachta indica cell culture. Biochemical Engineering Journal, 122, 75-84. https://doi.org/10.1016/j.bej.2017.03.004
Villiger, T. K., Neunstoecklin, B., Karst, D. J., Lucas, E., Stettler, M., Broly, H., Morbidelli, M., & Soos, M. (2018). Experimental and CFD physical characterization of animal cell bioreactors: From micro- to production scale. Biochemical Engineering Journal, 131, 84-94. https://doi.org/10.1016/j.bej.2017.12.004
Walls, P. L. L., McRae, O., Natarajan, V., Johnson, C., Antoniou, C., & Bird, J. C. (2017). Quantifying the potential for bursting bubbles to damage suspended cells. Scientific Reports, 7(1), 1-9. https://doi.org/10.1038/s41598-017-14531-5
Wang, Guan, Haringa, C., Tang, W., Noorman, H., Chu, J., Zhuang, Y., & Zhang, S. (2020). Coupled metabolic-hydrodynamic modeling enabling rational scale-up of industrial bioprocesses. En Biotechnology and Bioengineering (Vol. 117, Número 3). https://doi.org/10.1002/bit.27243
Wang, Guichao, Yang, F., Wu, K., Ma, Y., Peng, C., Liu, T., & Wang, L. (2021). Estimation of the dissipation rate of turbulent kinetic energy : A review. Chemical Engineering Science, 229(229). https://doi.org/10.1016/j.ces.2020.116133
Wilson, S. A., & Roberts, S. C. (2012). Recent advances towards development and commercialization of plant cell culture processes for the synthesis of biomolecules. Plant Biotechnology Journal, 10(3), 249-268. https://doi.org/10.1111/j.1467-7652.2011.00664.x
Wink, M. (2003). Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. 64, 3-19. https://doi.org/10.1016/S0031-9422(03)00300-5
Wu, J. (1995). Mechanisms of animal cell damage associated with gas bubbles and cell protection by medium additives. Journal of Biotechnology, 43(2), 81-94. https://doi.org/10.1016/0168-1656(95)00133-7
Zhao, J., Davis, L. C., & Verpoorte, R. (2005). Elicitor signal transduction leading to production of plant secondary metabolites. Biotechnology Advances, 23(4), 283-333. https://doi.org/10.1016/j.biotechadv.2005.01.003
Zhong, C., & Yuan, Y. J. (2009). Responses of Taxus cuspidata to hydrodynamics in bubble column bioreactors with different sparging nozzle sizes. Biochemical Engineering Journal, 45(2), 100-106. https://doi.org/10.1016/j.bej.2009.03.001
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.license.spa.fl_str_mv Atribución-NoComercial 4.0 Internacional
dc.rights.uri.spa.fl_str_mv http://creativecommons.org/licenses/by-nc/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv Atribución-NoComercial 4.0 Internacional
http://creativecommons.org/licenses/by-nc/4.0/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.spa.fl_str_mv xxi, 97 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv Medellín - Ciencias - Maestría en Ciencias - Biotecnología
dc.publisher.department.spa.fl_str_mv Escuela de biociencias
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias
dc.publisher.place.spa.fl_str_mv Medellín, Colombia
dc.publisher.branch.spa.fl_str_mv Universidad Nacional de Colombia - Sede Medellín
institution Universidad Nacional de Colombia
bitstream.url.fl_str_mv https://repositorio.unal.edu.co/bitstream/unal/80353/3/license.txt
https://repositorio.unal.edu.co/bitstream/unal/80353/4/1152199306.2021.pdf
https://repositorio.unal.edu.co/bitstream/unal/80353/5/1152199306.2021.pdf.jpg
bitstream.checksum.fl_str_mv cccfe52f796b7c63423298c2d3365fc6
3700f390b3990cdcf1e08dcfb0e3a321
3cce5c6aa99c0c7dd53cc4a78f27b88a
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
repository.mail.fl_str_mv repositorio_nal@unal.edu.co
_version_ 1806886001515167744
spelling Atribución-NoComercial 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Orozco-Sanchez, Fernando37e38ec772d6fef4caa396db7da872e5600Ocampo Betancur, Maritzac0ee805897e7c15a4de5c644283f7fdfLópez Taborda, Juan Davidf8369e6237a0a11553a7131daa0877a82021-10-01T19:55:43Z2021-10-01T19:55:43Z2021https://repositorio.unal.edu.co/handle/unal/80353Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/IlustracionesLa hidrodinámica y la transferencia de oxígeno en biorreactores son fenómenos multifactoriales que pueden generar estrés en cultivos de células vegetales. En este trabajo se propuso una estrategia para estudiar diferencialmente los efectos de la velocidad de agitación, flujo de gas y concentración de oxígeno utilizando un sistema de control de oxígeno disuelto (OD) con control de flujo másico de gas. El sistema se evaluó en un cultivo modelo de Azadirachta indica con control a 30% de OD, 400 rpm y 0.08 vvm y se comparó con un sistema control convencional que manipula válvulas solenoides con un flujo variable entre 0-0.08 vvm. Con el sistema de flujo constante se encontró un control preciso de OD (± 1%), limitación en la producción de biomasa (5.2 ± 0.4 g L-1 respecto al control 12.3 ± 0.3 g L-1), viabilidad celular de 70 ± 2%, y una producción de azadiractina (0.6 ± 0.2 mg gDCW-1) 3.5 veces mayor al control. El biorreactor se mantuvo a velocidades de disipación de energía de 0.76 W kg-1 y 488-1332 kW mestela-3 produciendo escalas de Kolmogorov entre 26 ± 5 µm y 149 ± 28 µm; mientras que los agregados celulares tuvieron un diámetro de 101 ± 26 µm. No se encontró limitación por transferencia de oxígeno (Damkhöler < 1) pero el tiempo de transferencia de masa fue 14 veces mayor al tiempo de reacción del OD. La estrategia desarrollada representa un avance tecnológico para manipular condiciones operativas y estudiar el efecto de los fenómenos de transporte (movimiento y masa) en cultivos celulares. (texto tomado de la fuente)Hydrodynamics and oxygen transfer in bioreactors cause stress in plant cell cultures. In this work, a strategy to study hydrodynamic and oxygen stress was proposed. It used a dissolved oxygen (DO) control system that maintains constant agitation and gassing. The strategy integrates calculations on hydromechanical, biochemical, geometrical, and DO transfer/uptake parameters. The system was evaluated in a model Azadirachta indica cell culture at 30% DO, 400 rpm and 0.08 vvm, and it was compared with a standard DO controller. By using constant gas flow, a precise DO control was found (± 1%), the biomass production was limited (5.2 ± 0.4 g L-1 in comparison with the control 12.3 ± 0.3 g L-1), cell viability was maintained around 70 ± 2%, and azadirachtin was produced (0.6 ± 0.2 mg gDCW-1). The bioreactor provided energy dissipation rates of 0.76 W kg-1 and 488-1332 kW mwake-3, and Kolmogorov microscales between 26 ± 5 µm and 149 ± 28 µm. Also, the most common cell aggregates size was 101 ± 26 µm. There were not oxygen transfer limitations (Damkhöler < 1), but mass transfer time was 30 times higher than DO reaction time. This strategy represents a technological advance to manipulate culture conditions in bioreactors. In this way, the study of transfer phenomena (mass and mixing) in A. indica and other plant species is possible.MaestríaMagíster en Ciencias- BiotecnologíaSíntesis de bioprocesosxxi, 97 páginasapplication/pdfspaUniversidad Nacional de ColombiaMedellín - Ciencias - Maestría en Ciencias - BiotecnologíaEscuela de biocienciasFacultad de CienciasMedellín, ColombiaUniversidad Nacional de Colombia - Sede Medellín570 - BiologíaCélulas y tejidos vegetales - CultivoMetabolitosMetabolitesCell cultureCultivo de celulasAzadirachta indicaEscala de KolmogorovEstrés celularOferta de oxígenoSistema de controlVelocidad de disipación de energíaKolmogorov microscaleCell stressOxygen transferrateEnergy dissipation rateEstrategia para estudiar estrés hidrodinámico y por oxígeno en biorreactores de células vegetales.A strategy to study hydrodynamic and oxygen stress in plant cell biorreactors.Trabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMAgrovocAcedos, M. G., Hermida, A., Gomez, E., Santos, V. E., & Garcia-Ochoa, F. (2019). Effects of fluid-dynamic conditions in Shimwellia blattae (p424IbPSO)cultures in stirred tank bioreactors: Hydrodynamic stress and change of metabolic routes by oxygen availability. Biochemical Engineering Journal, 149(May), 107238. https://doi.org/10.1016/j.bej.2019.107238Akesson, M., & Hagander, P. (1998). Control of Dissolved Oxygen in Stirred Bioreactors (Technical Reports TFRT-7571).Akesson, M., & Hagander, P. (1999). A Gain-Scheduling Approach for Control of Dissolved Oxygen in Stirred Bioreactors.Al-Whaibi, M. H. (2011). Plant heat-shock proteins: A mini review. Journal of King Saud University - Science, 23(2), 139-150. https://doi.org/10.1016/j.jksus.2010.06.022Alvarez-Yela, A. C., Chiquiza-Montaño, L. N., Hoyos, R., & Orozco-Sánchez, F. (2016). Rheology and mixing analysis of plant cell cultures (Azadirachta indica, Borojoa patinoi and Thevetia peruviana) in shake flasks. Biochemical Engineering Journal, 114, 18-25. https://doi.org/10.1016/j.bej.2016.06.019Arias, M., Aguirre, A., Angarita, M., Montoya, C., & Restrepo, J. (2009). Engineering aspects of the in vitro plant cell culture for the production of secondary metabolites. Dyna, 76(157), 109-121.Armstrong, W. (1994). Polarographic oxygen electrodes and their use in plant aeration studies. Proceedings of the Royal Society of Edinburgh. Section B. Biological Sciences, 102(May 2015), 511-527. https://doi.org/10.1017/s0269727000014548Arrua, L. A., McCoy, B. J., & Smith, J. M. (1990). Gas-liquid mass transfer in stirred tanks. AICHE Journal, 36(11), 1768-1772. https://doi.org/10.1002/aic.690361121Arteaga, H., & Vazquez, V. (2012). Control difuso del oxígeno disuelto, pH y temperatura de un biorreactor columna de burbujas en la producción de biomasa de Candida utilis. Departamento de Ciencias Agroindustriales, Universidad Nacional de Trujillo, 2, 10.Arya, S. S., Rookes, J. E., Cahill, D. M., & Lenka, S. K. (2020). Next-generation metabolic engineering approaches towards development of plant cell suspension cultures as specialized metabolite producing biofactories. Biotechnology Advances, 45(July), 107635. https://doi.org/10.1016/j.biotechadv.2020.107635Babich, O., Sukhikh, S., Pungin, A., Ivanova, S., Asyakina, L., & Prosekov, A. (2020). Modern Trends in the In Vitro Production and Use of Callus, Suspension Cells and Root Cultures of Medicinal Plants. Molecules (Basel, Switzerland), 25(24), 1-18. https://doi.org/10.3390/molecules25245805Balaji, K., Veeresham, C., Srisilam, K., & Kokate, C. (2003). Azadirachtin, a Novel Biopesticide from Cell Cultures of Azadirachta indica. Journal of Plant Biotechnology, 5(2), 121-129.Barbosa, M. J., Albrecht, M., & Wijffels, R. H. (2003). Hydrodynamic stress and lethal events in sparged microalgae cultures. Biotechnology and Bioengineering, 83(1), 112-120. https://doi.org/10.1002/bit.10657Benavides-López, S., Oviedo-Ramírez, J., López-Taborda, J.-D. D., Martínez-Mira, A., Vásquez-Rivera, A., Hoyos-Sánchez, R., & Orozco-Sánchez, F. (2020). Bioprocess plant design and economic analysis of an environmentally friendly insect controller agent produced with Azadirachta indica cell culture. Biochemical Engineering Journal, 159(March), 107579. https://doi.org/10.1016/j.bej.2020.107579Bhambhani, S., Lakhwani, D., Gupta, P., Pandey, A., Dhar, Y. V., Kumar Bag, S., Asif, M. H., & Kumar Trivedi, P. (2017). Transcriptome and metabolite analyses in Azadirachta indica: Identification of genes involved in biosynthesis of bioactive triterpenoids. Scientific Reports, 7(1), 1-12. https://doi.org/10.1038/s41598-017-05291-3Boulton-Stone, J. M., & Blake, J. R. (1993). Gas bubbles bursting at a free surface. Journal of Fluid Mechanics, 254(I), 437-466. https://doi.org/10.1017/S0022112093002216Braga, T. M., Rocha, L., Chung, T. Y., Oliveira, R. F., Pinho, C., Oliveira, A. I., Morgado, J., & Cruz, A. (2021). Azadirachta indica A. Juss. In Vivo Toxicity-An Updated Review. Molecules (Basel, Switzerland), 26(2), 1-21. https://doi.org/10.3390/molecules26020252Buitrago H, G., Otálvaro A, Á. M., & Duarte B., P. G. (2013). Evaluación de la transferencia de oxígeno en un biorreactor convencional con aireador externo. Revista Colombiana de Biotecnología, 15(2), 106-114. https://doi.org/10.15446/rev.colomb.biote.v15n2.41272Busciglio, A., Grisafi, F., Scargiali, F., & Brucato, A. (2013). On the measurement of local gas hold-up, interfacial area and bubble size distribution in gas-liquid contactors via light sheet and image analysis: Imaging technique and experimental results. Chemical Engineering Science, 102, 551-566. https://doi.org/10.1016/j.ces.2013.08.029Busto, V. D., Calabró-López, A., Rodríguez-Talou, J., Giulietti, A. M., & Merchuk, J. C. (2013). Anthraquinones production in Rubia tinctorum cell suspension cultures: Down scale of shear effects. Biochemical Engineering Journal, 77, 119-128. https://doi.org/10.1016/j.bej.2013.05.013Çalik, P., Yilgör, P., Ayhan, P., & Demir, A. S. (2004). Oxygen transfer effects on recombinant benzaldehyde lyase production. Chemical Engineering Science, 59(22-23), 5075-5083. https://doi.org/10.1016/j.ces.2004.07.070Cantor del Angel, J. A. (2011). Cultivo de Beta vulgaris L. por lote alimentado para la producción de arabinogalactano-proteínas. Instituto Politécnico Nacional.Capataz Tafur, J., Orozco-Sánchez, F., Vergara Ruiz, R., & Hoyos Sanchez, R. (2007). Efecto antialimentario de los extractos de suspensiones celulares de Azadiractha indica sobre Spodoptera frugiperda en condiciones de laboratorio. Revista Fac, 60(1), 2008.Cash, T. P., Pan, Y., & Simon, M. C. (2007). Reactive oxygen species and cellular oxygen sensing. 43, 1219-1225. https://doi.org/10.1016/j.freeradbiomed.2007.07.001Chen, J., Fan, X., Zhu, J., Song, L., Li, Z., Lin, F., Yu, R., Xu, H., & Zi, J. (2018). Limonoids from seeds of Azadirachta indica A. Juss. and their cytotoxic activity. Acta Pharmaceutica Sinica B, 2018, 0-5. https://doi.org/10.1016/j.apsb.2017.12.009Chisti, Y. (2000). Animal-cell damage in sparged bioreactors. Trends in Biotechnology, 18(10), 420-432. https://doi.org/10.1016/S0167-7799(00)01474-8Choudhury, F. K., Rivero, R. M., Blumwald, E., & Mittler, R. (2017). Reactive oxygen species , abiotic stress and stress combination. 856-867. https://doi.org/10.1111/tpj.13299Cragg, G. M., & Newman, D. J. (2013). Natural products : A continuing source of novel drug leads. Biochimica et Biophysica Acta, 1830(6), 3670-3695. https://doi.org/10.1016/j.bbagen.2013.02.008Dat, J. F., Capelli, N., Folzer, H., Bourgeade, P., & Badot, P. (2004). Sensing and signalling during plant flooding. 42, 273-282. https://doi.org/10.1016/j.plaphy.2004.02.003de Jesús, S. S., Moreira Neto, J., & Maciel Filho, R. (2017). Hydrodynamics and mass transfer in bubble column, conventional airlift, stirred airlift and stirred tank bioreactors, using viscous fluid: A comparative study. Biochemical Engineering Journal, 118, 70-81. https://doi.org/10.1016/j.bej.2016.11.019De León-Rodríguez, A., Galindo, E., & Ramírez, O. T. (2010). Design and characterization of a one-compartment scale-down system for simulating dissolved oxygen tension gradients. Journal of Chemical Technology and Biotechnology, 85(7), 950-956. https://doi.org/10.1002/jctb.2384De León, a, Mayani, H., & Ramírez, O. T. (1998). Design, characterization and application of a minibioreactor for the culture of human hematopoietic cells under controlled conditions. Cytotechnology, 28(1-3), 127-138. https://doi.org/10.1023/A:1008042000744De León, A., Barba-De La Rosa, A. P., Mayani, H., Galindo, E., & Ramírez, O. T. (2001). Two useful dimensionless parameters that combine physiological, operational and bioreactor design parameters for improved control of dissolved oxygen. Biotechnology Letters, 23(13), 1051-1056. https://doi.org/10.1023/A:1010598121587Doran, P. (1995). Bioprocess Engineering Principles. Academic Press.Doran, P. (1999). Design of mixing systems for plant cell suspensions in stirred reactors. Biotechnology progress, 15(3), 319-335.Doran, P. M. (2013). Bioprocess engineering principles (Second). Elsevier.DuBois, M., Gilles, K. a., Hamilton, J. K., Rebers, P. a., & Smith, F. (1956). Colorimetric Method for Determination of Sugars and Related Substances. Analytical Chemistry, 28(3), 350-356. https://doi.org/10.1021/ac60111a017Dunlop, E. H., & Namdev, P. K. (1994). Effect of fluid shear forces on plant cell suspensions. Chemical Engineering Science, 49(14), 2263-2276. https://doi.org/10.1016/0009-2509(94)E0043-PDunlop, E. H., Namdev, P. K., & Rosenberg, M. Z. (1994). Effect of fluid shear forces on plant cell suspensions. Chemical Engineering Science, 49(14), 2263-2276. https://doi.org/10.1016/0009-2509(94)E0043-PEdahiro, J. ichi, & Seki, M. (2006). Phenylpropanoid metabolite supports cell aggregate formation in strawberry cell suspension culture. Journal of Bioscience and Bioengineering, 102(1), 8-13. https://doi.org/10.1263/jbb.102.8Eibl, R., Meier, P., Stutz, I., Schildberger, D., Hühn, T., & Eibl, D. (2018). Plant cell culture technology in the cosmetics and food industries: current state and future trends. Applied Microbiology and Biotechnology, 102(20), 8661-8675. https://doi.org/10.1007/s00253-018-9279-8Farjaminezhad, R., & Garoosi, G. (2021). Improvement and prediction of secondary metabolites production under yeast extract elicitation of Azadirachta indica cell suspension culture using response surface methodology. AMB Express, 11(1). https://doi.org/10.1186/s13568-021-01203-xFlickinger, M. C., & Doran, P. M. (2010). Bioreactors, Stirred Tank for Culture of Plant Cells. Encyclopedia of Industrial Biotechnology. https://doi.org/10.1002/9780470054581.eib150Garcia-Ochoa, F., Gomez, E., Alcon, A., & Santos, V. E. (2012). The effect of hydrodynamic stress on the growth of Xanthomonas campestris cultures in a stirred and sparged tank bioreactor. Bioprocess Biosyst Eng, 1. https://doi.org/10.1007/s00449-012-0825-yGarcia-Ochoa, F., Gomez, E., Alcon, A., & Santos, V. E. (2013). The effect of hydrodynamic stress on the growth of Xanthomonas campestris cultures in a stirred and sparged tank bioreactor. Bioprocess and Biosystems Engineering, 36(7), 911-925. https://doi.org/10.1007/s00449-012-0825-yGarcia-ochoa, F., Gomez, E., Santos, V. E., & Merchuk, J. C. (2010). Oxygen uptake rate in microbial processes : An overview. Biochemical Engineering Journal, 49(3), 289-307. https://doi.org/10.1016/j.bej.2010.01.011Garcia-Ochoa, Felix, Escobar, S., & Gomez, E. (2015). Specific oxygen uptake rate as indicator of cell response of Rhodococcus erythropolis cultures to shear effects. Chemical Engineering Science, 122, 491-499. https://doi.org/10.1016/j.ces.2014.10.016Geigenberger, P. (2003). Response of plant metabolism to too little oxygen. Current Opinion in Plant Biology, 6(3), 247-256. https://doi.org/10.1016/S1369-5266(03)00038-4Georgiev, M., & Weber, J. (2014). Bioreactors for plant cells: Hardware configuration and internal environment optimization as tools for wider commercialization. Biotechnology Letters, 36(7), 1359-1367. https://doi.org/10.1007/s10529-014-1498-1Georgiev, V., Slavov, A., Vasileva, I., & Pavlov, A. (2018). Plant cell culture as emerging technology for production of active cosmetic ingredients. Engineering in Life Sciences, 18(11), 779-798. https://doi.org/10.1002/elsc.201800066Gill, S. S., & Tuteja, N. (2010). Reactive oxygen species and antioxidant machinery in abiotic stress tolerance in crop plants. Plant Physiology and Biochemistry, 48(12), 909-930. https://doi.org/10.1016/j.plaphy.2010.08.016Gomes, J., & Menawat, A. S. (2000). Precise control of dissolved oxygen in bioreactors - a model-based geometric algorithm. Chemical Engineering Science, 55(1), 67-78. https://doi.org/10.1016/S0009-2509(99)00305-XGomez, E., Santos, V. E., Alcon, A., & Garcia-Ochoa, F. (2006). Oxygen transport rate on Rhodococcus erythropolis cultures: Effect on growth and BDS capability. Chemical Engineering Science, 61(14), 4595-4604. https://doi.org/10.1016/j.ces.2006.02.025Gong, Y. W., Li, S. Y., Han, R. Bin, & Yuan, Y. J. (2006). Age-related responses of suspension cultured Taxus cuspidata to hydrodynamic shear stress. Biochemical Engineering Journal, 32(2), 113-118. https://doi.org/10.1016/j.bej.2006.09.010Gupta, S. C., Prasad, S., Tyagi, A. K., Kunnumakkara, A. B., & Aggarwal, B. B. (2017). Neem (Azadirachta indica): An indian traditional panacea with modern molecular basis. Phytomedicine, 34(May), 14-20. https://doi.org/10.1016/j.phymed.2017.07.001Gurib-fakim, A. (2006). Medicinal plants : Traditions of yesterday and drugs of tomorrow. 27, 1-93. https://doi.org/10.1016/j.mam.2005.07.008Halliwell, B. (2007). Biochemistry of oxidative stress. Biochemical society transactions. 1147-1150.Hazen, T. C., & Stahl, D. A. (2006). Using the stress response to monitor process control : pathways to more effective bioremediation. Current opinion in biotechnology. 285-290. https://doi.org/10.1016/j.copbio.2006.03.004Hodgson, H., De La Peña, R., Stephenson, M. J., Thimmappa, R., Vincent, J. L., Sattely, E. S., & Osbourn, A. (2019). Identification of key enzymes responsible for protolimonoid biosynthesis in plants: Opening the door to azadirachtin production. Proceedings of the National Academy of Sciences of the United States of America, 116(34), 17096-17104. https://doi.org/10.1073/pnas.1906083116Hong, J. K., Yeo, H. C., Lakshmanan, M., Han, S. hyuk, Cha, H. M., Han, M., & Lee, D. Y. (2020). In silico model-based characterization of metabolic response to harsh sparging stress in fed-batch CHO cell cultures. Journal of Biotechnology, 308(August 2019), 10-20. https://doi.org/10.1016/j.jbiotec.2019.11.011Hu, W., Berdugo, C., & Chalmers, J. J. (2011). The potential of hydrodynamic damage to animal cells of industrial relevance : current understanding. 445-460. https://doi.org/10.1007/s10616-011-9368-3Hua, J., Erickson, L. E., Yiin, T. Y., & Glasgow, L. a. (1993). A review of the effects of shear and interfacial phenomena on cell viability. Critical reviews in biotechnology, 13(4), 305-328. https://doi.org/10.3109/07388559309075700Huang, S. Y., & Chou, C. J. (2000). Effect of gaseous composition on cell growth and secondary metabolite production in suspension culture of Stizolobium hassjoo cells. Bioprocess Engineering, 23(6), 585-593. https://doi.org/10.1007/s004490000204Huang, Shih Yow, Shen, Y. W., & Chan, H. S. (2002). Development of a bioreactor operation strategy for L-DOPA production using Stizolobium hassjoo suspension culture. Enzyme and Microbial Technology, 30(6), 779-791. https://doi.org/10.1016/S0141-0229(02)00058-3Islas, J. F., Acosta, E., G-Buentello, Z., Delgado-Gallegos, J. L., Moreno-Treviño, M. G., Escalante, B., & Moreno-Cuevas, J. E. (2020). An overview of Neem (Azadirachta indica) and its potential impact on health. Journal of Functional Foods, 74(September), 104171. https://doi.org/10.1016/j.jff.2020.104171Jackson, J. R., Overbeck, P. K., & Overby, J. M. (1999). Dissolved Oxygen Control by Pressurized Side Stream Ozone Contacting and Degassing. 623.Jonelis, K., Brazauskas, K., & Levišauskas, D. (2012). A system for dissolved oxygen control in industrial aeration tank. Information Technology and Control, 41(1), 46-52. https://doi.org/10.5755/j01.itc.41.1.921Kaboré, A. K., Delaunay, S., Blanchard, F., Guedon, E., Fick, M., & Olmos, E. (2019). Study and modeling of fluctuating dissolved oxygen concentration impact on Corynebacterium glutamicum growth in a scale-down bioreactor. Process Biochemistry, 77(November 2018), 8-17. https://doi.org/10.1016/j.procbio.2018.10.016Karimi, A., Golbabaei, F., Mehrnia, M. R., Neghab, M., Mohammad, K., Nikpey, A., & Pourmand, M. R. (2013). Oxygen mass transfer in a stirred tank bioreactor using different impeller configurations for environmental purposes. Iranian journal of environmental health science & engineering, 10(1), 6. https://doi.org/10.1186/1735-2746-10-6Kieran, P. M., Malone, D. M., & MacLoughlin, P. F. (2000). Effects of hydrodynamic and interfacial forces on plant cell suspension systems. Advances in biochemical engineering/biotechnology, 67, 139-177. https://doi.org/10.1007/3-540-47865-5_5Koul, O. (2009). Azadirachtin. Zeitschrift für Angewandte Entomologie, 98(1-5), 221-223. https://doi.org/10.1111/j.1439-0418.1984.tb02703.xKrasteva, G., Georgiev, V., & Pavlov, A. (2020). Recent applications of plant cell culture technology in cosmetics and foods. Engineering in Life Sciences, October, 1-9. https://doi.org/10.1002/elsc.202000078Krishnan, N. M., Pattnaik, S., Deepak, S. A., Hariharan, A. K., Gaur, P., Chaudhary, R., Jain, P., Vaidyanathan, S., Krishna, P. G. B., & Panda, B. (2011). De novo sequencing and assembly of Azadirachta indica fruit transcriptome. Current Science, 101(12), 1553-1561.Krishnan, N. M., Pattnaik, S., Jain, P., Gaur, P., Choudhary, R., Vaidyanathan, S., Deepak, S., Hariharan, A. K., Krishna, P. G. B., Nair, J., Varghese, L., Valivarthi, N. K., Dhas, K., Ramaswamy, K., & Panda, B. (2012). A draft of the genome and four transcriptomes of a medicinal and pesticidal angiosperm Azadirachta indica. BMC Genomics, 13(1). https://doi.org/10.1186/1471-2164-13-464Kumar, B. (2010). Energy Dissipation and Shear Rate with Geometry of Baffled Surface Aerator. Chemical Engineering Research Bulletin, 14(2), 92-96. https://doi.org/10.3329/cerb.v14i2.4910Kuravadi, N. A., Yenagi, V., Rangiah, K., Mahesh, H. B., Rajamani, A., Shirke, M. D., Russiachand, H., Loganathan, R. M., Lingu, C. S., Siddappa, S., Ramamurthy, A., Sathyanarayana, B. N., & Gowda, M. (2015). Comprehensive analyses of genomes, transcriptomes and metabolites of neem tree. PeerJ, 2015(8), 1-25. https://doi.org/10.7717/peerj.1066Landau, L., & Lifhitz, E. M. (1976). Fluid Mechanist (P. Press (ed.); 2nd ed.Lara, A. R., Galindo, E., Ramírez, O. T., & Palomares, L. A. (2006). Living with heterogeneities in bioreactors: Understanding the effects of environmental gradients on cells. Molecular Biotechnology, 34(3), 355-381. https://doi.org/10.1385/MB:34:3:355Lee-Parsons, C. W. T. (2007). Gas composition strategies for the successful scale-up of Catharanthus roseus cell cultures for the production of ajmalicine. Phytochemistry Reviews, 6(2-3), 419-433. https://doi.org/10.1007/s11101-006-9046-9Lee-Parsons, C. W. T., & Shuler, M. L. (2005). Sparge gas composition affects biomass and ajmalicine production from immobilized cell cultures of Catharanthus roseus. Enzyme and Microbial Technology, 37(4), 424-434. https://doi.org/10.1016/j.enzmictec.2005.02.016Lindblon, T. (2009). Qualitative comparison of optical and electrochemical sensors for measuring dissolved oxygen in bioreactors. En In Situ. Linkoping University.Liu, Y., Li, F., Hu, W., Wiltberger, K., & Ryll, T. (2014). Effects of bubble-liquid two-phase turbulent hydrodynamics on cell damage in sparged bioreactor. Biotechnology Progress, 30(1), 48-58. https://doi.org/10.1002/btpr.1790Liu, Y. S., Wu, J. Y., & Ho, K. P. (2006). Characterization of oxygen transfer conditions and their effects on Phaffia rhodozyma growth and carotenoid production in shake-flask cultures. Biochemical Engineering Journal, 27(3), 331-335. https://doi.org/10.1016/j.bej.2005.08.031López-Taborda, J., Vargas Zapata, A., Ramirez Vargas, J., Valdez Cruz, N., Trujillo Roldán, M., & Orozco Sánchez, F. (2018). A novel system to control dissolved oxygen in bioreactors minimizing variation on hydrodynamic stress. Universidad Nacional de Colombia- Sede Medellín.MacLennan, D. G., & Pirt, S. J. (1966). Automatic control of dissolved oxygen concentration in stirred microbial cultures. Journal of general microbiology, 45(2), 289-302. https://doi.org/10.1099/00221287-45-2-289Martins, F. G. (2005). Tuning PID Controllers using the ITAE Criterion. International Journal of Engineering Education, 21(5), 867-873.Meijer, J. J., ten Hoopen, H. J. G., Luyben, K. C. A. M., & Libbenga, K. R. (1993). Effects of hydrodynamic stress on cultured plant cells: A literature survey. Enzyme and Microbial Technology, 15(3), 234-238. https://doi.org/10.1016/0141-0229(93)90143-PMittler, R. (2002). Oxidative stress , antioxidants and stress tolerance. Trends in Plant Science, 7(9), 405-410.Mittler, R. (2017). ROS Are Good. Trends in Plant Science, 22(1), 11-19. https://doi.org/10.1016/j.tplants.2016.08.002Mohan, R., Kumar, M. S. M., & Rao, L. (2021). Numerical modelling of oxygen mass transfer in diffused aeration systems: A CFD-PBM approach. Journal of Water Process Engineering, 40(September 2020), 101920. https://doi.org/10.1016/j.jwpe.2021.101920Mulabagal, V., & Tsay, H. (2004). Plant Cell Cultures - An Alternative and Efficient Source for the Production of Biologically Important Secondary Metabolites. September 2015, 29-48.Muñoz-Cruz, W., Vanegas-Monterrosa, O. A., Guzmán-Rosas, A. A., Capataz-Tafur, J., Hoyos-Sánchez, R., & Orozco-Sánchez, F. (2006). Estimación de variables de operación de un biorreactor con células de Azadirachta indica A. Juss. Revista Facultad Nacional de Agronomía, 59(2), 3467-3478.Namdev, P. K., & Dunlop, E. H. (1995). Shear sensitivity of plant cells in suspensions present and future. Applied Biochemistry and Biotechnology, 54(1-3), 109-131. https://doi.org/10.1007/BF02787914Neunstoecklin, B., Stettler, M., Solacroup, T., Broly, H., Morbidelli, M., & Soos, M. (2015). Determination of the maximum operating range of hydrodynamic stress in mammalian cell culture. Journal of Biotechnology, 194, 100-109. https://doi.org/10.1016/j.jbiotec.2014.12.003Nienow, A. W. (1998). Hydrodynamics of stirred bioreactors. Applied Mechanics Reviews, 51(1), 3-32. https://doi.org/10.1115/1.3098990Nock, V., Blaikie, R. J., & David, T. (2009). Oxygen control for bioreactors and in-vitro cell assays. AIP Conference Proceedings, 1151(February 2017), 67-70. https://doi.org/10.1063/1.3203249O’Leary, B. M., Asao, S., Millar, A. H., & Atkin, O. K. (2019). Core principles which explain variation in respiration across biological scales. New Phytologist, 222(2), 670-686. https://doi.org/10.1111/nph.15576Oksman-Caldentey, K. M., & Inzé, D. (2004). Plant cell factories in the post-genomic era: New ways to produce designer secondary metabolites. Trends in Plant Science, 9(9), 433-440. https://doi.org/10.1016/j.tplants.2004.07.006Orozco-Sánchez, F. (2009). Efecto de la oferta de oxígeno sobre el crecimiento y la producción de terpenoides con células de Azadirachta indica en un biorreactor. 96.Orozco-Sanchez, F., & Rodríguez-Monroy, M. (2007). Cell suspension culture of Azadirachta indica for the production of a bioinsecticide. Revista Mexicana de Ingeniería Química, 6(3), 251-258.Orozco-Sánchez, F., Sepúlveda-Jimenez, G., Trejo-Tapia, G., Zamilpa, A., & Rodríguez-Monroy, M. (2011). Oxygen limitations to growth Azadirachta indica cell culture in shake flask. Revista Mexicana de Ingeniería Química, 10(1), 17-28.Pandreka, A., Chaya, P. S., Kumar, A., Aarthy, T., Mulani, F. A., Bhagyashree, D. D., B, S. H., Jennifer, C., Ponnusamy, S., Nagegowda, D., & Thulasiram, H. V. (2021). Limonoid biosynthesis 3: Functional characterization of crucial genes involved in neem limonoid biosynthesis. Phytochemistry, 184(September 2020), 112669. https://doi.org/10.1016/j.phytochem.2021.112669Patel, S. M., Nagulapalli Venkata, K. C., Bhattacharyya, P., Sethi, G., & Bishayee, A. (2016). Potential of neem (Azadirachta indica L.) for prevention and treatment of oncologic diseases. Seminars in Cancer Biology, 40_41, 100-115. https://doi.org/10.1016/j.semcancer.2016.03.002Pérez-Hernández, J., Nicasio-Torres, M. del P., Sarmiento-López, L. G., & Rodríguez-Monroy, M. (2019). Production of anti-inflammatory compounds in Sphaeralcea angustifolia cell suspension cultivated in stirred tank bioreactor. Engineering in Life Sciences, 19(3), 196-205. https://doi.org/10.1002/elsc.201800134Prakash, G., Emmannuel, C. J. S. K., & Srivastava, A. K. (2005). Variability of Azadirachtin in Azadirachta indica (neem) and batch kinetics studies of cell suspension culture. Biotechnology and Bioprocess Engineering, 10, 198-204.Prakash, G., & Srivastava, A. K. (2007). Azadirachtin production in stirred tank reactors by Azadirachta indica suspension culture. Process Biochemistry, 42(1), 93-97. https://doi.org/10.1016/j.procbio.2006.06.020Rafiq, M., & Dahot, M. U. (2010). Callus and azadirachtin related limonoids production through in vitro culture of neem (Azadirachta indica A. Juss). African Journal of Biotechnology, 9(4), 449-453. https://doi.org/10.5897/AJB09.1091Ramaswamy, S., Cutright, T. J., & Qammar, H. K. (2005). Control of a continuous bioreactor using model predictive control. Process Biochemistry, 40(8), 2763-2770. https://doi.org/10.1016/j.procbio.2004.12.019Raposo, S., & Lima-Costa, M. E. (2012). Effects of the hydrodynamic environment and oxygen mass transfer on plant cell growth and milk-clotting protease production in a stirred-tank reactor. Engineering in Life Sciences, 12(4), 441-449. https://doi.org/10.1002/elsc.201100087Raval, K., Hellwig, S., & Srivastava, A. (2003). Necessity of a Two-Stage Process for the Production of Azadirachtin-Related Limonoids in Suspension Cultures of Azadirachta indica. Journal of Bioscience and Bioengineering, 96(I).Reyes, C. R., Barrales-cureño, H. J., Hoyos, P. A., Luna-cruz, A., Terrón-mejía, K. A., López-valdez, L. G., Sánchez-herrera, L. M., Cortes-ruíz, J. A., Calderon-caballero, M. C., Orlando, J., Osuna, G., Ingeniería, D. De, Politécnica, U., Naturales, D. D. P., Comunitaria, I. F., & Intercultural, U. (2017). Software Simulator Bioprocess (SSBP) to estimate hydrodynamic stress conditions in cell cultures performed in shaking bioreactors. International Journal of Biosciences (IJB), 10(3), 143-156. https://doi.org/10.12692/ijb/10.3.143-156Rodríguez-Monroy, M., & Galindo, E. (1999). Broth rheology, growth and metabolite production of Beta vulgaris suspension culture: A comparative study between cultures grown in shake flasks and in a stirred tank. Enzyme and Microbial Technology, 24(10), 687-693. https://doi.org/10.1016/S0141-0229(99)00002-2Rodríguez-Monroy, M., & Orozco-Sánchez, F. (2014). Caracterización, operación y escalado de biorreactores (F. Orozco-Sánchez & M. Rodríguez-Monroy (eds.); 2.a ed.). Universidad Nacional de Colombia.Rodríguez-Monroy, M., Trejo-Espino, J. L., Jiménez-Aparicio, A., De La Luz Morante, M., Villarreal, M. L., & Trejo-Tapia, G. (2004). Evaluation of morphological properties of Solanum chrysotrichum cell cultures in a shake flask and fermenter and rheological properties of broths. Food Technology and Biotechnology, 42(3), 153-158.Rodríguez Torres, M. I. (2013). Condiciones de cultivo para el crecimiento de Rhizopus oryzae NRRL-395 y la producción de ácido L (+) láctico en un reactor de tanque agitado. En Tesis de maestría, Universidad Nacional de Colombia (Vol. 26, Número 4). Universidad Nacional de Colombia.Saleem, S., Muhammad, G., Hussain, M. A., & Bukhari, S. N. A. (2018). A comprehensive review of phytochemical profile, bioactives for pharmaceuticals, and pharmacological attributes of Azadirachta indica. Phytotherapy Research, 32(7), 1241-1272. https://doi.org/10.1002/ptr.6076Santos, R. B., Abranches, R., Fischer, R., Sack, M., & Holland, T. (2016). Putting the Spotlight Back on Plant Suspension Cultures. Frontiers in Plant Science, 7(March), 1-12. https://doi.org/10.3389/fpls.2016.00297Schaepe, S., Kuprijanov, A., Sieblist, C., Jenzsch, M., Simutis, R., & Lübbert, A. (2013). KLa of stirred tank bioreactors revisited. Journal of Biotechnology, 168(4), 576-583. https://doi.org/10.1016/j.jbiotec.2013.08.032Shuler, M. L., & Kargi, F. (2017). Bioprocess Engineering: Basic Concepts (Third). Prentice Hall.Smith, C., & Corripio, A. (1991). Control automático de procesos, teoría y práctica.Smith, J. M., Davison, S. W., & Payne, G. F. (1990). Development of a strategy to control the dissolved concentrations of oxygen and carbon dioxide at constant shear in a plant cell bioreactor. Biotechnology and Bioengineering, 35(11), 1088-1101. https://doi.org/10.1002/bit.260351104Soler, A., & Buitrago Hurtado, G. (2010). Evaluación de la transferencia de oxígeno en cultivos con lactococcus lactis empleando un sistema de fermentación con aireación externa. Revista Colombiana de Biotecnología, 12(2), 124-138.Sowana, D. D., Williams, D. R. G., Dunlop, E. H., Dally, B. B., O’Neill, B. K., & Fletcher, D. F. (2001). Turbulent Shear Stress Effects on Plant Cell Suspension Cultures. Chemical Engineering Research and Design, 79(8), 867-875. https://doi.org/10.1205/02638760152721370Sujanya, S., Devi, B. P., & Sai, I. (2008). In vitro production of azadirachtin from cell suspension cultures of Azadirachta indica. Journal of Biosciences, 33(1), 113-120. https://doi.org/10.1007/s12038-008-0027-6Suresh, S., Srivastava, V. C., & Mishra, I. M. (2009). Techniques for oxygen transfer measurement in bioreactors: A review. Journal of Chemical Technology and Biotechnology, 84(8), 1091-1103. https://doi.org/10.1002/jctb.2154Takeda, T., Tamura, M., Ohtaki, M., & Matsuoka, H. (2003). Gene expression in cultured strawberry cells subjected to hydrodynamic stress. Biochemical Engineering Journal, 15(3), 211-215. https://doi.org/10.1016/S1369-703X(02)00214-0Taylan, E., Kose, A., Celik, Y., & Oncel, S. S. (2021). Design of a horizontal-dual bladed bioreactor for low shear stress to improve hydrodynamic responses in cell cultures : A pilot study in Chlamydomonas reinhardtii. Biochemical Engineering Journal, 169(February), 107970. https://doi.org/10.1016/j.bej.2021.107970Thakore, D., & Srivastava, A. K. (2017). Production of biopesticide azadirachtin using plant cell and hairy root cultures. 997-1005. https://doi.org/10.1002/elsc.201700012Trejo-Tapia, G., & Rodríguez-Monroy, M. (2007). La agregación celular en la producción de metabolitos secundarios en cultivos vegetales in vitro. Interciencia, 32(10), 669-674.Trujillo-Roldán, M. A., & Valdez-Cruz, N. A. (2006). El estrés hidrodinámico: Muerte y daño celular en cultivos agitados. Revista Latinoamericana de Microbiologia, 48(3-4), 269-280.Trujillo Roldán, M. A., Peña, C., Ramirez, O. T., & Galindo, E. (2001). Effect of oscillating dissolved oxygen tension on the production of alginate by Azotobacter vinelandii. Biotechnology Progress, 17(6), 1042-1048. https://doi.org/10.1021/bp010106dVan Dongen, J. T., & Licausi, F. (2015). Oxygen sensing and signaling. Annual Review of Plant Biology, 66, 345-367. https://doi.org/10.1146/annurev-arplant-043014-114813Vásquez-Rivera, A., Chicaiza-Finley, D., Hoyos, R. A., & Orozco-Sánchez, F. (2015). Production of Limonoids with Insect Antifeedant Activity in a Two-Stage Bioreactor Process with Cell Suspension Culture of Azadirachta indica. Applied Biochemistry and Biotechnology, 177(2), 334-345.Verma, R., Mehan, L., Kumar, R., Kumar, A., & Srivastava, A. (2019). Computational fluid dynamic analysis of hydrodynamic shear stress generated by different impeller combinations in stirred bioreactor. Biochemical Engineering Journal, 151(July), 107312. https://doi.org/10.1016/j.bej.2019.107312Verpoorte, R., Contin, A., & Memelink, J. (2002). Biotechnology for the production of plant secondary metabolites. Phytochemistry Reviews, 1(1), 13-25. https://doi.org/10.1023/A:1015871916833Villegas-Velásquez, S., Martínez-Mira, A. D., Hoyos, R., Rojano, B., & Orozco-Sánchez, F. (2017). Hydrodynamic stress and limonoid production in Azadirachta indica cell culture. Biochemical Engineering Journal, 122, 75-84. https://doi.org/10.1016/j.bej.2017.03.004Villiger, T. K., Neunstoecklin, B., Karst, D. J., Lucas, E., Stettler, M., Broly, H., Morbidelli, M., & Soos, M. (2018). Experimental and CFD physical characterization of animal cell bioreactors: From micro- to production scale. Biochemical Engineering Journal, 131, 84-94. https://doi.org/10.1016/j.bej.2017.12.004Walls, P. L. L., McRae, O., Natarajan, V., Johnson, C., Antoniou, C., & Bird, J. C. (2017). Quantifying the potential for bursting bubbles to damage suspended cells. Scientific Reports, 7(1), 1-9. https://doi.org/10.1038/s41598-017-14531-5Wang, Guan, Haringa, C., Tang, W., Noorman, H., Chu, J., Zhuang, Y., & Zhang, S. (2020). Coupled metabolic-hydrodynamic modeling enabling rational scale-up of industrial bioprocesses. En Biotechnology and Bioengineering (Vol. 117, Número 3). https://doi.org/10.1002/bit.27243Wang, Guichao, Yang, F., Wu, K., Ma, Y., Peng, C., Liu, T., & Wang, L. (2021). Estimation of the dissipation rate of turbulent kinetic energy : A review. Chemical Engineering Science, 229(229). https://doi.org/10.1016/j.ces.2020.116133Wilson, S. A., & Roberts, S. C. (2012). Recent advances towards development and commercialization of plant cell culture processes for the synthesis of biomolecules. Plant Biotechnology Journal, 10(3), 249-268. https://doi.org/10.1111/j.1467-7652.2011.00664.xWink, M. (2003). Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective. 64, 3-19. https://doi.org/10.1016/S0031-9422(03)00300-5Wu, J. (1995). Mechanisms of animal cell damage associated with gas bubbles and cell protection by medium additives. Journal of Biotechnology, 43(2), 81-94. https://doi.org/10.1016/0168-1656(95)00133-7Zhao, J., Davis, L. C., & Verpoorte, R. (2005). Elicitor signal transduction leading to production of plant secondary metabolites. Biotechnology Advances, 23(4), 283-333. https://doi.org/10.1016/j.biotechadv.2005.01.003Zhong, C., & Yuan, Y. J. (2009). Responses of Taxus cuspidata to hydrodynamics in bubble column bioreactors with different sparging nozzle sizes. Biochemical Engineering Journal, 45(2), 100-106. https://doi.org/10.1016/j.bej.2009.03.001InvestigadoresLICENSElicense.txtlicense.txttext/plain; charset=utf-83964https://repositorio.unal.edu.co/bitstream/unal/80353/3/license.txtcccfe52f796b7c63423298c2d3365fc6MD53ORIGINAL1152199306.2021.pdf1152199306.2021.pdfTesis de Maestría en Ciencias- Biotecnologíaapplication/pdf2246722https://repositorio.unal.edu.co/bitstream/unal/80353/4/1152199306.2021.pdf3700f390b3990cdcf1e08dcfb0e3a321MD54THUMBNAIL1152199306.2021.pdf.jpg1152199306.2021.pdf.jpgGenerated Thumbnailimage/jpeg4767https://repositorio.unal.edu.co/bitstream/unal/80353/5/1152199306.2021.pdf.jpg3cce5c6aa99c0c7dd53cc4a78f27b88aMD55unal/80353oai:repositorio.unal.edu.co:unal/803532024-07-30 23:11:09.869Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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