Bioreactor-based advances in plant tissue and cell culture: challenges and prospects

Abstract Bioreactors are engineered systems capable of supporting a biologically active situation for conducting aerobic or anaerobic biochemical processes. Stability, operational ease, improved nutrient uptake capacity, time- and cost-effectiveness, and large quantities of biomass production, make bioreactors suitable alternatives to conventional plant tissue and cell culture (PTCC) methods. Bioreactors are employed in a wide range of plant research, and have evolved over time. Such technological progress, has led to remarkable achievements in the field of PTCC. Since the classification of bioreactors has been extensively reviewed in numerous reviews, the current article avoids repeating the same material. Alternatively, it aims to highlight the principal advances in the bioreactor hardware s used in PTCC rather than classical categorization. Furthermore, our review summarizes the most significant steps as well as current state-of-the-art of PTCC carried out in various types of bioreactor.

[1]  A. Valdiani,et al.  Analysis of the Anticancer Phytochemicals in Andrographis paniculata Nees. under Salinity Stress , 2013, BioMed research international.

[2]  Milen I Georgiev,et al.  Bioactive metabolite production and stress-related hormones in Devil’s claw cell suspension cultures grown in bioreactors , 2011, Applied Microbiology and Biotechnology.

[3]  M. Cañal,et al.  Temporary immersion systems (RITA®) for the improvement of cork oak somatic embryogenic culture proliferation and somatic embryo production , 2013, Trees.

[4]  S. Carpentier,et al.  Somatic Embryogenesis in Coffee: The Evolution of Biotechnology and the Integration of Omics Technologies Offer Great Opportunities , 2017, Front. Plant Sci..

[5]  Pamela J. Weathers,et al.  Mist reactors: principles, comparison of various systems, and case studies , 2008 .

[6]  T. Bley,et al.  Temporary immersion systems in plant biotechnology , 2014 .

[7]  S. Florez,et al.  A temporary immersion plant propagation bioreactor with decoupled gas and liquid flows for enhanced control of gas phase , 2016, Biotechnology progress.

[8]  A. Bandehagh,et al.  Production of therapeutic proteins through plant tissue and cell culture , 2016 .

[9]  B. Terrier,et al.  Two new disposable bioreactors for plant cell culture: The wave and undertow bioreactor and the slug bubble bioreactor , 2007, Biotechnology and bioengineering.

[10]  H. Fu,et al.  Disarming and sequencing of Agrobacterium rhizogenes strain K599 (NCPPB2659) plasmid pRi2659 , 2007, In Vitro Cellular & Developmental Biology - Plant.

[11]  C. Delwiche,et al.  Directional Auxin Transport Mechanisms in Early Diverging Land Plants , 2014, Current Biology.

[12]  Stephan Kaiser,et al.  Disposable bioreactors: the current state-of-the-art and recommended applications in biotechnology , 2010, Applied Microbiology and Biotechnology.

[13]  A. K. Kukreja,et al.  In vitro manipulations in St. John’s wort (Hypericum perforatum L.) for incessant and scale up micropropagation using adventitious roots in liquid medium and assessment of clonal fidelity using RAPD analysis , 2008, Plant Cell, Tissue and Organ Culture.

[14]  R. Costa,et al.  Castanea spp. hybrid clones in vitro conservation: synthetic seeds vs. slow growth storage , 2017 .

[15]  P. Briza,et al.  Expression and Characterization of Functional Recombinant Bet v 1.0101 in the Chloroplast of Chlamydomonas reinhardtii , 2017, International Archives of Allergy and Immunology.

[16]  Jost Weber,et al.  Bioreactors for plant cells: hardware configuration and internal environment optimization as tools for wider commercialization , 2014, Biotechnology Letters.

[17]  B. Rehm,et al.  Bacterial exopolysaccharides: biosynthesis pathways and engineering strategies , 2015, Front. Microbiol..

[18]  Hans-Gerd Löhmannsröben,et al.  Optical Oxygen Micro- and Nanosensors for Plant Applications , 2012, Sensors.

[19]  P. Verma,et al.  Over-expression of Catharanthus roseus tryptophan decarboxylase and strictosidine synthase in rol gene integrated transgenic cell suspensions of Vinca minor , 2014, Protoplasma.

[20]  N. Tuteja,et al.  High frequency regeneration via direct somatic embryogenesis and efficient Agrobacterium- mediated genetic transformation of tobacco , 2013, Plant signaling & behavior.

[21]  I. Farag,et al.  TUBULAR PHOTOBIOREACTOR FOR MICROALGAE BIODIESEL PRODUCTION , 2012 .

[22]  J. Alegre,et al.  Influence of culture vessel characteristics and agitation rate on gaseous exchange, hydrodynamic stress, and growth of embryogenic cork oak (Quercus suber L.) cultures , 2011, In Vitro Cellular & Developmental Biology - Plant.

[23]  S. Alok,et al.  Effect of Different Impellers and Baffles on Aerobic Stirred Tank Fermenter using Computational Fluid Dynamics , 2014 .

[24]  R. Reski,et al.  Optimisation of a bioreactor culture of the moss Physcomitrella patens for mass production of protoplasts , 2002 .

[25]  Xiangyang Li,et al.  Gas‐Liquid Mass Transfer Characteristics with Microbubble Aeration – I. Standard Stirred Tank , 2016 .

[26]  Joost T. van Dongen,et al.  Regulation of Respiration and Fermentation to Control the Plant Internal Oxygen Concentration1[OA] , 2008, Plant Physiology.

[27]  R Y K Yang,et al.  Plant-cell bioreactors with simultaneous electropermeabilization and electrophoresis. , 2003, Journal of biotechnology.

[28]  Michael Pedersen,et al.  From tissue to silicon to plastic: three-dimensional printing in comparative anatomy and physiology , 2016, Royal Society Open Science.

[29]  M. Cardarelli,et al.  Influence of ozone treatments on in vitro propagation ofLiliumin bioreactor , 2017 .

[30]  A. Dhingra,et al.  In vitro cultures and regeneration of Bienertia sinuspersici (Chenopodiaceae) under increasing concentrations of sodium chloride and carbon dioxide , 2011, Plant Cell Reports.

[31]  A. Hvoslef-Eide,et al.  Bioreactor design for propagation of somatic embryos , 2005, Plant Cell, Tissue and Organ Culture.

[32]  Jianfeng Xu,et al.  Towards high-yield production of pharmaceutical proteins with plant cell suspension cultures. , 2011, Biotechnology advances.

[33]  E. Nyaboga,et al.  Factors influencing somatic embryogenesis, regeneration, and Agrobacterium-mediated transformation of cassava (Manihot esculenta Crantz) cultivar TME14 , 2015, Front. Plant Sci..

[34]  Milen I Georgiev,et al.  Hosting the plant cells in vitro: recent trends in bioreactors , 2013, Applied Microbiology and Biotechnology.

[35]  Elisa Quiala,et al.  Improved production of potato microtubers using a temporary immersion system , 1999, Plant Cell, Tissue and Organ Culture.

[36]  L. Harvey,et al.  Operating bioreactors for microbial exopolysaccharide production , 2011, Critical reviews in biotechnology.

[37]  The effect of immobilization on recombinant protein production in plant cell culture , 2001, Plant Cell Reports.

[38]  G. Andrews,et al.  Fluidized-bed bioreactors , 1988 .

[39]  R. Mallón,et al.  Improving secondary embryogenesis in Quercus robur: application of temporary immersion for mass propagation , 2012, Trees.

[40]  Jose R. Vallejos,et al.  A case study in converting disposable process scouting devices into disposable bioreactors as a future bioprocessing tool , 2012, Biotechnology and bioengineering.

[41]  T. Wysokinski,et al.  Factors influencing real time internal structural visualization and dynamic process monitoring in plants using synchrotron-based phase contrast X-ray imaging , 2015, Scientific Reports.

[42]  Huasun Huang,et al.  Micropropagation of self‐rooting juvenile clones by secondary somatic embryogenesis in Hevea brasiliensis , 2010 .

[43]  W. Fang,et al.  Hyperhydricity in shoot cultures of Scrophularia yoshimurae can be effectively reduced by ventilation of culture vessels. , 2005, Journal of plant physiology.

[44]  K N Yogalakshmi,et al.  Effect of transient sodium chloride shock loads on the performance of submerged membrane bioreactor. , 2010, Bioresource technology.

[45]  A. Scragg,et al.  Somatic embryo production in bioreactors , 1992 .

[46]  Julia Thom Oxford,et al.  Optimal 3D culture of primary articular chondrocytes for use in the rotating wall vessel bioreactor. , 2014, Aviation, space, and environmental medicine.

[47]  C. C. Giri,et al.  Progress in tissue culture, genetic transformation and applications of biotechnology to trees: an overview , 2004, Trees.

[48]  W. Powell,et al.  Application of airlift bioreactors to accelerate genetic transformation in American chestnut , 2014, Plant Cell, Tissue and Organ Culture (PCTOC).

[49]  Lingxue Kong,et al.  CFD modeling of hydrodynamic characteristics of slug bubble flow in a flat sheet membrane bioreactor , 2013 .

[50]  Enrique Durán-Páramo,et al.  Shear rate and microturbulence effects on the synthesis of proteases by Jacaratia mexicana cells cultured in a bubble column, airlift, and stirred tank bioreactors , 2013, Biotechnology and Bioprocess Engineering.

[51]  N. Paiva,et al.  Bioreactors for surface-immobilized cells , 1995, Plant Cell, Tissue and Organ Culture.

[52]  R. Reiter,et al.  A new balancing act: The many roles of melatonin and serotonin in plant growth and development , 2015, Plant signaling & behavior.

[53]  J. Bello-Bello,et al.  Assessment of somaclonal variation during sugarcane micropropagation in temporary immersion bioreactors by intersimple sequence repeat (ISSR) markers , 2017, In Vitro Cellular & Developmental Biology - Plant.

[54]  M. Ellis,et al.  Overexpression of alcohol dehydrogenase or pyruvate decarboxylase improves growth of hairy roots at reduced oxygen concentrations. , 2002, Biotechnology and bioengineering.

[55]  R Thibeaux,et al.  Using X-ray computed tomography for quantification of cell proliferation within a perfusion bioreactor , 2015, Computer methods in biomechanics and biomedical engineering.

[56]  Václav Tesař,et al.  Design of an airlift loop bioreactor and pilot scales studies with fluidic oscillator induced microbubbles for growth of a microalgae Dunaliella salina , 2011 .

[57]  S. Takayama,et al.  Mass Propagation of Begonia × hiemalis Plantlets by Shake Culture , 1981 .

[58]  Smita Srivastava,et al.  In Vitro Azadirachtin Production by Hairy Root Cultivation of Azadirachta indica in Nutrient Mist Bioreactor , 2011, Applied Biochemistry and Biotechnology.

[59]  J.-J. Zhong,et al.  2.14 – Bioreactor Engineering , 2011 .

[60]  R. E. Harris,et al.  TWO MACHINES FOR IN VITRO PROPAGATION OF PLANTS IN LIQUID MEDIA , 1983 .

[61]  H. Byrne,et al.  Mathematical modelling of cell layer growth in a hollow fibre bioreactor. , 2017, Journal of theoretical biology.

[62]  Regine Eibl,et al.  Design And Use Of The Wave Bioreactor For Plant Cell Culture , 2008 .

[63]  J. A. Teixeira da Silva The role of thin cell layers in regeneration and transformation in orchids , 2013 .

[64]  M. Shuler Bioreactors for plant cell culture , 1988 .

[65]  M. Lila,et al.  Plant-Based Vaccines: Production and Challenges , 2016 .

[66]  Amine Kamen,et al.  Design parameters and performance of a surface baffled helical ribbon impeller bioreactor for the culture of shear sensitive cells , 1992 .

[67]  Michael C. Flickinger,et al.  Encyclopedia of industrial biotechnology : bioprocess, bioseparation, and cell technology , 2010 .

[68]  P. Saxena,et al.  An efficient temporary immersion system for micropropagation of hybrid hazelnut , 2016 .

[69]  J. Simpson,et al.  High Genetic and Epigenetic Stability in Coffea arabica Plants Derived from Embryogenic Suspensions and Secondary Embryogenesis as Revealed by AFLP, MSAP and the Phenotypic Variation Rate , 2013, PloS one.

[70]  F. Acevedo,et al.  Development of grapevine somatic embryogenesis using an air-lift bioreactor as an efficient tool in the generation of transgenic plants. , 2009, Journal of biotechnology.

[71]  S. Gantait,et al.  Synthetic seed production of medicinal plants: a review on influence of explants, encapsulation agent and matrix , 2015, Acta Physiologiae Plantarum.

[72]  Chin-Wen Ho,et al.  Plant regeneration via somatic embryogenesis from suspension cell cultures of Lilium×formolongi hort. Using a bioreactor system , 2006, In Vitro Cellular & Developmental Biology - Plant.

[73]  Kevin Voll,et al.  Which Impeller Is Right for Your Cell Line? A Guide to Impeller Selection for Stirred-Tank Bioreactors , 2009 .

[74]  A. Quainoo,et al.  The Effect of Abscisic Acid in the Conversion of Cocoa Somatic Embryos into Plantlets , 2012 .

[75]  B. N. Mishra,et al.  Growth of hairy‐root cultures in various bioreactors for the production of secondary metabolites , 2008, Biotechnology and applied biochemistry.

[76]  O. Toldi,et al.  Membranes to reduce adherence of somatic embryos to the cell lift impeller of a bioreactor , 2005 .

[77]  Ingo Klimant,et al.  An optical multifrequency phase-modulation method using microbeads for measuring intracellular oxygen concentrations in plants. , 2005, Biophysical journal.

[78]  S. W. Park,et al.  The role of silicon in plant tissue culture , 2014, Front. Plant Sci..

[79]  H. Issa Oxygen Mass Transfer in an Aerated Stirred Tank with Double Impellers: A Generalized Correlation Including Spacing Impact , 2016 .

[80]  N. Qi,et al.  Influence of mist intervals and aeration rate on growth and second metabolite production of Pseudostellaria heterophylla adventitious roots in a siphon-mist bioreactor , 2010 .

[81]  G. Loake,et al.  Plant cell culture strategies for the production of natural products , 2016, BMB reports.

[82]  J. A. Teixeira da Silva,et al.  Plant thin cell layers: update and perspectives , 2015 .

[83]  M. Akita,et al.  Bioengineering Aspects Of Bioreactor Application In Plant Propagation , 2008 .

[84]  K. McDonald,et al.  Molecular Farming Using Bioreactor-Based Plant Cell Suspension Cultures for Recombinant Protein Production , 2012 .

[85]  CO2-enriched atmosphere and supporting material impact the growth, morphophysiology and ultrastructure of in vitro Brazilian-ginseng [Pfaffia glomerata (Spreng.) Pedersen] plantlets , 2014, Plant Cell, Tissue and Organ Culture (PCTOC).

[86]  E. Déchamp,et al.  Bioreactors in coffee micropropagation , 2006 .

[87]  M. Ganapathy Plants as Bioreactors- A Review , 2016 .

[88]  Octavio T. Ramírez,et al.  Bioreactor Scale-Up , 2003 .

[89]  Chunzhao Liu,et al.  Hairy root culture: bioreactor design and process intensification. , 2013, Advances in biochemical engineering/biotechnology.

[90]  Jürg Schönenberger,et al.  Plant Tissues in 3D via X-Ray Tomography: Simple Contrasting Methods Allow High Resolution Imaging , 2013, PloS one.

[91]  Y. Chisti,et al.  Shear rate in stirred tank and bubble column bioreactors , 2006 .

[92]  P. Saxena,et al.  Elicitation of secondary metabolism in Echinacea purpurea L. by gibberellic acid and triazoles , 2009 .

[93]  Shui-gen Li,et al.  Application of Somatic Embryogenesis in Woody Plants. , 2016, Front. Plant Sci..

[94]  M. Pomeroy,et al.  Production of vigorous, desiccation tolerant white spruce (Picea glauca [Moench.] Voss.) synthetic seeds in a bioreactor , 1994, Plant Cell Reports.

[95]  S. Rao,et al.  Plant cell cultures: Chemical factories of secondary metabolites. , 2002, Biotechnology advances.

[96]  H. Krishna,et al.  Somaclonal variations and their applications in horticultural crops improvement , 2016, 3 Biotech.

[97]  D. Martens,et al.  Effect of O2:CO2 ratio on the primary metabolism of Chlamydomonas reinhardtii , 2011, Biotechnology and bioengineering.

[98]  W. Zimmerman,et al.  Airlift bioreactor for biological applications with microbubble mediated transport processes , 2015 .

[99]  Zanmin Hu,et al.  The Potential for Microalgae as Bioreactors to Produce Pharmaceuticals , 2016, International journal of molecular sciences.

[100]  J. Linden,et al.  Shear stress effects on plant cell suspension cultures in a rotating wall vessel bioreactor , 1999, Journal of Industrial Microbiology and Biotechnology.

[101]  W. Teng,et al.  Somatic Embryogenesis of Carrot in Bioreactor Culture Systems , 1994 .

[102]  J. Vargas,et al.  Life cycle assessment of biomass production in microalgae compact photobioreactors , 2015 .

[103]  R. Luttman,et al.  Silicone-tubing aerated bioreactors for somatic embryo production , 1994, Plant Cell, Tissue and Organ Culture.

[104]  A. Valdiani,et al.  SOMATIC EMBRYOGENESIS AND IN-VITRO REGENERATION OF RICE (ORYZA SATIVA L.) CULTIVARS UNDER ONE-STEP AND MULTIPLE-STEP SALINITY STRESSES , 2017 .

[105]  J. Mihelcic,et al.  Application of denitrifying wood chip bioreactors for management of residential non-point sources of nitrogen , 2017, Journal of Biological Engineering.

[106]  A. Scragg,et al.  Alfalfa embryo production in airlift vessels via direct somatic embryogenesis , 1994, Plant Cell, Tissue and Organ Culture.

[107]  P. Saxena,et al.  Improvement of Ginseng by In Vitro Culture: Challenges and Opportunities , 2011 .

[108]  M. Shuler,et al.  Stimulation of ajmalicine production and excretion from Catharanthus roseus: effects of adsorption in situ, elicitors and alginate immobilization , 1989, Applied Microbiology and Biotechnology.

[109]  José Carlos Lorenzo,et al.  Temporary Immersion for Plant Tissue Culture , 1999 .

[110]  H. Etienne,et al.  Temporary immersion systems in plant micropropagation , 2002, Plant Cell, Tissue and Organ Culture.

[111]  Regine Eibl,et al.  Design of bioreactors suitable for plant cell and tissue cultures , 2008, Phytochemistry Reviews.

[112]  Regine Eibl,et al.  Effects of immobilization by entrapment in alginate and scale-up on paclitaxel and baccatin III production in cell suspension cultures of Taxus baccata. , 2005, Biotechnology and bioengineering.

[113]  P. Bozhkov,et al.  Somatic embryogenesis: life and death processes during apical-basal patterning. , 2014, Journal of experimental botany.

[114]  U. Langer,et al.  Improving bioreactor cultivation conditions for sensitive cell lines by dynamic membrane aeration , 2009, Cytotechnology.

[115]  M. Taherzadeh,et al.  Reverse membrane bioreactor: Introduction to a new technology for biofuel production. , 2016, Biotechnology advances.

[116]  Jochen Büchs,et al.  Orbitally shaken single-use bioreactors. , 2014, Advances in biochemical engineering/biotechnology.

[117]  T. Xiang,et al.  Transgenic hairy roots of Tetrastigma hemsleyanum: induction, propagation, genetic characteristics and medicinal components , 2015, Plant Cell, Tissue and Organ Culture (PCTOC).

[118]  S. Rasmussen,et al.  Genoproteomics-assisted improvement of Andrographis paniculata: toward a promising molecular and conventional breeding platform for autogamous plants affecting the pharmaceutical industry , 2017, Critical reviews in biotechnology.

[119]  P. Sowiński,et al.  Production of tropane alkaloids in Hyoscyamus niger (black henbane) hairy roots grown in bubble-column and spray bioreactors , 2013, Biotechnology Letters.

[120]  L. A. Erland,et al.  Melatonin Natural Health Products and Supplements: Presence of Serotonin and Significant Variability of Melatonin Content. , 2017, Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine.

[121]  R. D. Williams,et al.  Production of somatic embryos in a helical ribbon impeller bioreactor , 1994, Biotechnology and bioengineering.

[122]  W. Xing,et al.  Large scale preparation of microbubbles by multi‐channel ceramic membranes: Hydrodynamics and mass transfer characteristics , 2017 .

[123]  C. Chavarie,et al.  Development of a helical‐ribbon impeller bioreactor for high‐density plant cell suspension culture , 1992, Biotechnology and bioengineering.

[124]  H. Chang,et al.  Membrane bioreactors: present and prospects. , 1991, Advances in biochemical engineering/biotechnology.

[125]  S. Moorhouse,et al.  A plant cell bioreactor with medium-perfusion for control of somatic embryogenesis in liquid cell suspensions , 1996, Plant Growth Regulation.

[126]  Li-Hua Zhu,et al.  Evaluation of a new vessel system based on temporary immersion system for micropropagation , 2014 .

[127]  Beatriz Brena,et al.  Immobilization of enzymes: a literature survey. , 2013, Methods in molecular biology.

[128]  T. Scheper,et al.  Evaluation of a new mist‐chamber bioreactor for biotechnological applications , 2015, Biotechnology and bioengineering.

[129]  F. Steward,et al.  Investigations on Growth and Metabolism of Plant CellsI. New Techniques for the Investigation of Metabolism, Nutrition and Growth in Undifferentiated Cells , 1952 .

[130]  S. Schillberg,et al.  Plant Cell-Based Recombinant Antibody Manufacturing with a 200 L Orbitally Shaken Disposable Bioreactor. , 2016, Methods in molecular biology.

[131]  Youngjin Kim,et al.  Performance of a Novel Fertilizer-Drawn Forward Osmosis Aerobic Membrane Bioreactor (FDFO-MBR): Mitigating Salinity Build-Up by Integrating Microfiltration , 2017 .

[132]  A. Steinfeld,et al.  Micro-Computed Tomography Based Computational Fluid Dynamics for the Determination of Shear Stresses in Scaffolds Within a Perfusion Bioreactor , 2014, Annals of Biomedical Engineering.

[133]  J. A. Teixeira da Silva The role of thin cell layers in regeneration and transformation in orchids , 2013, Plant Cell, Tissue and Organ Culture (PCTOC).

[134]  A. Bhatt,et al.  ESTABLISHMENT OF A SHOOT PROLIFERATION PROTOCOL FOR BANANA (ABB GROUP) CV. ‘PISANG AWAK’ VIA TEMPORARY IMMERSION SYSTEM , 2013 .

[135]  WeyandBirgit,et al.  Noninvasive Oxygen Monitoring in Three-Dimensional Tissue Cultures Under Static and Dynamic Culture Conditions , 2015 .

[136]  R. G. Kosky,et al.  Production of yam microtubers using a temporary immersion system , 2005, Plant Cell, Tissue and Organ Culture.

[137]  A. Tong,et al.  Treatment of 2,4-D, mecoprop, and dicamba using membrane bioreactor technology , 2013, Environmental Science and Pollution Research.

[138]  B. Chiancone,et al.  Encapsulation of black mulberry microcuttings: Studies on capsules and synthetic seeds , 2017 .

[139]  K. Hnatuszko-Konka,et al.  Tomato (Solanum lycopersicum L.) in the service of biotechnology , 2015, Plant Cell, Tissue and Organ Culture (PCTOC).

[140]  M. Ziv Silicon Effects on Growth Acclimatization and Stress Tolerance of Bioreactor Cultured Ornithogalum dubium Plants , 2010 .

[141]  N. Durán,et al.  Nanodevices for the immobilization of therapeutic enzymes , 2015, Critical reviews in biotechnology.

[142]  C. Deschamps,et al.  Influence of calcium content of tissue on hyperhydricity and shoot-tip necrosis of in vitro regenerated shoots of Lavandula angustifolia Mill. , 2014 .

[143]  Inn H. Yuk,et al.  Overcoming challenges in WAVE bioreactors without feedback controls for pH and dissolved oxygen , 2011, Biotechnology progress.

[144]  Jiahua Xie,et al.  Efficient somatic embryogenesis and Agrobacterium-mediated transformation of pothos (Epipremnum aureum) ‘Jade’ , 2013, Plant Cell, Tissue and Organ Culture (PCTOC).

[145]  Maritza Escalona,et al.  Temporary immersion bioreactors (TIB) provide a versatile, cost-effective and reproducible in vitro analysis of the response of pineapple shoots to salinity and drought , 2017, Acta Physiologiae Plantarum.

[146]  U. Göransson,et al.  Micropropagation of Viola uliginosa (Violaceae) for endangered species conservation and for somaclonal variation-enhanced cyclotide biosynthesis , 2014, Plant Cell, Tissue and Organ Culture (PCTOC).

[147]  T. Scheper,et al.  Tubular membrane bioreactors for biotechnological processes , 2013, Applied Microbiology and Biotechnology.

[148]  Francesc Gòdia,et al.  Fluidized‐Bed Bioreactors , 1995 .

[149]  F. D. D'Auria,et al.  In vitro antifungal activity of extracts obtained from Hypericum perforatum adventitious roots cultured in a mist bioreactor against planktonic cells and biofilm of Malassezia furfur , 2016, Natural product research.

[150]  Daniele Mazzei,et al.  Environmental Control in Flow Bioreactors , 2017 .