Disposable Bioreactors pp 55-87

Part of the Advances in Biochemical Engineering / Biotechnology book series (ABE, volume 115)

Bag Bioreactor Based on Wave-Induced Motion: Characteristics and Applications

Abstract

Today wave-mixed bag bioreactors are common devices in modern biotechnological processes where simple, safe and flexible production has top priority. Numerous studies that have been published on ex vivo generation of cells, viruses and therapeutic agents during the last 10 years have confirmed their suitability and even superiority to stirred bioreactors made from glass or stainless steel for animal as well as plant cell cultivations. In these studies the wave-mixed bag bioreactors enabled middle to high cell density and adequate productivity in laboratory and pilot scale. This mainly results from low-shear conditions and highly efficient oxygen transfer for cell cultures, as demonstrated for the widely used BioWave®.Starting with an overview of wave-mixed bag bioreactors and their common operation strategies, this chapter delineates engineering aspects of BioWave®, which like Wave Reactor™ and BIOSTAT®CultiBag RM originates from the prototype of a wave-mixed bag bioreactor introduced in 1998. Subsequently, the second part of the chapter focuses on reported BioWave® applications. Conditions and results from cultivations with animal cells, plant cells, microbial cells and nematodes are presented and discussed.

Keywords

Animal cells Biological insecticides Biotransformation Immunomodulator Plant cells Seed inoculum Wave-mixed bag bioreactor 

Abbreviations

AO

surface area of the fluid;

Aq

hydraulic cross-section of culture bag;

ADV

adeno-associated virus;

BEV

baculovirus expression vector;

BHK

baby hamster kidney;

B

width of culture bag;

BY-2

cultivar Bright Yellow-2 from the tobacco plant;

C1

correction factor considering influence of bag type, rocking angle, rocking rate and culture volume on volumetric flow rate;

C2

correction factor depending on bag type and describing the correlation of BioWave®’s Remod and stirred bioreactor’s Remod;

CAD

computer-aided design;

CD

chemically defined;

CFD

computational fluid dynamics;

CHO cells

Chinese hamster ovary cells;

CO2

carbon dioxide;

D

dilution rate (ratio of volumetric flow rate to culture volume);

DO

dissolved oxygen;

dw

dry weight;

E-FL cells

embryogenic feline lung fibroblast cells;

E.

coli Escherichia coli;

E. neophadidis Erynia neophadidis;

fw fresh weight;

GMP

good manufacturing practice;

H

height of culture bag (inflated);

HEK cells

human embryogenic kidney cells;

H.

megidis Heterorhabditis megidis;

H.

muticus Hyoscyamus muticus;

H. procumbens Harpagophytum procumbens;

h liquid level of culture bag;

i

culture bag geometry, given by the ratio of L to B;

KCl

potassium chloride;

k

rocking rate;

kL

a volumetric oxygen transfer coefficient;

L

length of culture bag;

l

characteristic length of culture bag;

M

momentum;

MDCK cells

Madin–Darby kidney cells (cocker spaniel);

M.

domestica Malus domestica;

MOI

multiplicity of infection or optimal ratio of virus particles per cell;

MEV

mink enteritis virus;

mab

monoclonal antibody;

NaCl

sodium chloride;

N.

tabacum Nicotiana tabacum;

P.

ginseng Panax ginseng;

P/V

power input per volume (specific power input);

Re

Reynolds number;

Remod

modified Reynolds number;

r

recombinant;

rpm

revolution per minute;

Sf

Spodoptera frugiperda;

S.

cerevisiae Saccharomyces cerevisiae;

SEAP

secreted alkaline phosphatase;

S.

feltiae Steinernema feltiae;

SH medium

Schenk and Hildebrandt medium; S.U.B. single use bioreactor;

T 408

tobacco strain with uracil transporter-like protein;

T.

baccata Taxus baccata;

TCID50

tissue culture infectious dose;

TOI

optimal density of cells at infection;

tPA

tissue plasminogen activator;

U

true length of culture bag;

V

culture volume; volumetric flow rate;

Vero cells

kidney epithelial cells from African green monkey;

VOF method

volume of fluid method;

V.

vinifera Vitis vinifera;

vvm

volume per volume per minute;

W

work;

WUB

wave and undertow bioreactor;

w

fluid velocity;

ϕ

rocking angle;

τ

residence time distribution;

ν

kinematic viscosity; mixing time (time required to achieve 95% homogeneity);

μmax

maximum specific growth rate;

2D

two-dimensional;

3D

three-dimensional

References

  1. 1.
    Eibl R, Eibl D (2002) Bioreactors for plant cell and tissue cultures. In: Oksman-Caldentey KM, Barz WH (eds.) Plant biotechnology and transgenic plants. Marcel Dekker, New York, p. 163Google Scholar
  2. 2.
    Palazón J, Mallol A, Eibl R, Lettenbauer C, Cusidó RM Piñol MT (2003) Planta Med 69:344CrossRefGoogle Scholar
  3. 3.
    Bentebibel S, Moyano E, Palazón J, Cusidó RM, Bonfill M, Eibl R, PiñolMT (2005) Biotechnol Bioeng 89:647CrossRefGoogle Scholar
  4. 4.
    Eibl R, Eibl D (2006) Design and use of the Wave Bioreactor for plant cell culture. In: Dutta Gupta S, (eds.) IbarakiYPlant tissue culture engineering, series: focus on biotechnology, vol 6. Springer, Dordrecht, p. 203Google Scholar
  5. 5.
    Eibl R, Eibl D (2007) Phytochem Rev, DOI 10.1007/s11101-007-9083-z Google Scholar
  6. 6.
    Cuperus S, Eibl R, Hühn T, Amado R (2007) BioForum Europe 6:2Google Scholar
  7. 7.
    Bonfill M, Bentebibel S, Moyano E, Palazón J, Cusidó RM, Eibl R, Piñol MT (2007) Biol Plant 51:647CrossRefGoogle Scholar
  8. 8.
    Eibl R, Eibl D (2006) Disposable bioreactors for pharmaceutical research and manufacturing. Proceedings second international conference on bioreactor technology in cell, tissue culture and biomedical applications. Saariselkä, FinlandGoogle Scholar
  9. 9.
    Genzel Y, Behrendt I, Koenig S, Sann H, Reichl U (2004) Vaccine 22:2202CrossRefGoogle Scholar
  10. 10.
    Genzel Y, Olmer RM, Schaefer B, Reichl U (2006) Vaccine 24:6074CrossRefGoogle Scholar
  11. 11.
    Hundt B, Best C, Schlawin N, Kassner H, Genzel Y, Reichl U (2007) Vaccine 25:3987CrossRefGoogle Scholar
  12. 12.
    Schlaeppi JM, Henke M, Mahnke M, Hartmann S, Schmitz R, Pouliquen Y, Kerins B, Weber E, Kolbinger F, Kocher HP (2006) Protein Expres Purif 50:185CrossRefGoogle Scholar
  13. 13.
    Slivac I, Srɩek VG, RadoŠevic K, Kmetiɩ I, Kniewald Z (2006) J Biosci 3:363CrossRefGoogle Scholar
  14. 14.
    Weber W, Weber E, Geisse S, Memmert K (2002) Cytotechnology 38:77CrossRefGoogle Scholar
  15. 15.
    Mikola M, Seto J, Amanullah A (2007) Bioprocess Biosyst Eng 30:231CrossRefGoogle Scholar
  16. 16.
    Laderman K, Quezada V, Dunphy N, Anderson J, Derecho J, McMahom R, Hsu D, Couture L (2007) DNA production in the Wave Bioreactor under cGMP conditions. http://www.wavebiotech.com/pdfs/press/pDNA_Poster_COH2007.pfd. Accessed 06 November 2007
  17. 17.
    Amanullah A, Burden E, Jug-Dujakovic M, Mikola M, Pearre C, Herber W (2004) Development of a large-scale cell bank in cryobags for the production of biologics. http://www.wavebiotech.com/pdfs/literature/Merck_Cancun-2004.pfd. Accessed 04 November 2007
  18. 18.
    Cronin CN, Lim KB, Rogers J (2007) Protein Sci 16:2023CrossRefGoogle Scholar
  19. 19.
    Singh V (1999) Cytotechnology 30:149CrossRefGoogle Scholar
  20. 20.
    Ohashi R, Singh V, Hammel JF (2001) Perfusion cell culture in disposable bioreactors. Tylösand, Sweden17th ESACT meeting June 2001.Google Scholar
  21. 21.
    Tang YJ, Ohashi R, Hamel JP (2007) Biotechnol Prog 23:255CrossRefGoogle Scholar
  22. 22.
    Fries S, Glazomitsky K, Woods A, Forrest G, Hsu A, Olewinski R, Robinson D, Chartrain M (2005) BioProcess Int 3:36Google Scholar
  23. 23.
    Negrete A, Kotin RM (2007) J Virol 145:155Google Scholar
  24. 24.
    Rios M (2006) PharmaTech 4:1Google Scholar
  25. 25.
    Pierce LN, Sabraham PW (2004) BioProc J 3:51Google Scholar
  26. 26.
    Hami LS, Chana H, Yuan V, Craig S (2003) BioProc J 2:23Google Scholar
  27. 27.
    Hamis LS, Green C, Leshinsky N, Markham E, Miller K, Craig S (2004) Cytotherapy 6:554CrossRefGoogle Scholar
  28. 28.
    Levine B (2007) Making waves in cell therapy: the Wave bioreactor for the generation of adherent and non-adherent cells for clinical use. http://www.wavebiotech.com/pdf/literature/ISCT_2007_Levine_Final.pdf. Accessed 04 November 2007
  29. 29.
    Matthews T, Wolk B (2005) The use of disposable technologies in antibody manufacturing processes. http://www.wavebiotech.com/pdfs/literature/IBCDisposables_2005.pdf. Accessed 04 November 2007
  30. 30.
    Hallmann S, Bertelsen HP, Scheffler U, Luttmann R (2007) Einsatz von Massflow-Controllern zur Steuerung von Bioreaktionsprozessen. Biotechnica October 2007. Hannover, Germany (poster)Google Scholar
  31. 31.
    Morrow KJ (2006) GEN 26:42Google Scholar
  32. 32.
    Houtzager E, van der Linden R, de Roo G, Huurman S, Priem P, Sijmons C (2005) BioProcess Int 3:60Google Scholar
  33. 33.
    CeLLution Biotech BV (2007) Mass transfer in the CELL-tainer® disposable bioreactor. http://www.cellutionbiotech.com. Accessed 20 October 2007
  34. 34.
    CeLLution Biotech BV (2007) Cultivation of PER.C6®-cells in the CELL-tainer® disposable bioreactor. www.cellutionbiotech.com. Accessed 20 October 2007
  35. 35.
    CeLLution Biotech BV (2007) Cultivation of CHO-cells in the CELL-tainer® disposable bioreactor. www.cellutionbiotech.com. Cited October 20, 2007
  36. 36.
    Terrier B, Courtois D, Hénault N, Cuvier A, Bastin M, Aknin A, Dubreuil J, Pétiard V (2006) Biotechnol Bioeng 96:914CrossRefGoogle Scholar
  37. 37.
    Girard LS, Fabis MJ, Bastin M, Courtois D, Pétiard V, Koprowski H (2006) Biochem Biophys Res Commun 345:602CrossRefGoogle Scholar
  38. 38.
    Kilani J, Lebeault JM (2007) Appl Microbiol Biotechnol 74:324CrossRefGoogle Scholar
  39. 39.
    Eibl R, Eibl D (2007) Disposable bioreactors for inoculum production and protein expression. In: Pörtner R(ed.) Animal cell biotechnology: methods and protocols. Humana Press, Totowa, NJ, p. 321Google Scholar
  40. 40.
    Eibl R, Eibl D, Pechmann G, Ducommun C, Lisica L, Lisica S, Blum P, Schär M, Wolfram L, Rhiel M, Emmerling M, Röll M, Lettenbauer C, Rothmaier M, Flükiger M (2003) Produktion pharmazeutischer Wirkstoffe in disposable Systemen bis zum 100 L Massstab, Teil 1. KTI-Projekt 5844.2 FHS, Final report, primary data of the experiments and summary of calculations, University of Applied Sciences Wädenswil, Switzerland, unpublishedGoogle Scholar
  41. 41.
    Voisard D, Meuly F, Ruffieux PA, Baer G, Kadouri A (2003) Biotechnol Bioeng 82:751CrossRefGoogle Scholar
  42. 42.
    Christi Y (2001) Crit Rev Biotechnol 21:67CrossRefGoogle Scholar
  43. 43.
    Davidson KM, Sushil S, Eggleton CD, Marten MR (2003) Biotechnol Prog 19:1480CrossRefGoogle Scholar
  44. 44.
    Henzler HJ (2000) Particle stress in bioreactors. In: Schügerl K, Kretzmer G(eds.) Influence of stress on cell growth and product formation, series: advances in biochemical engineering/biotechnology, vol.67. Springer, Berlin Heidelberg New York, p 38Google Scholar
  45. 45.
    Ho C, Henderson K, Rorrer G (1995) Biotechnol Prog 11:140CrossRefGoogle Scholar
  46. 46.
    Kieran PM, Malone DM, MacLoughlin PF (2000) Effects of hydrodynamic and interfacial forces in plant cell suspension systems. In: Schügerl K, Kretzmer G(eds.) Influence of stress on cell growth and product formation, series: advances in biochemical engineering/biotechnology, vol.67. Springer, Berlin Heidelberg New York, p 141Google Scholar
  47. 47.
    Leckie F, Scraggs H, Cliffe K (1991) Enzyme Microb Technol 13:801CrossRefGoogle Scholar
  48. 48.
    Marks DM (2003) Cytotechnology 42:21CrossRefGoogle Scholar
  49. 49.
    Nienow AW (1998) Hydrodynamics of stirred bioreactors. In: Pohorecki R (ed.) Fluid mechanics problems in biotechnology. App Mech Rev 51:3Google Scholar
  50. 51.
    Takeda T, Seki M, Furusaki S (1994) J Chem Eng Jpn 27:466CrossRefGoogle Scholar
  51. 52.
    Kunas KT, Keating J (2005) Stirred tank-single-use bioreactor: comparison to traditional stirred tank bioreactor. bioLOGIC Europe May 2005. Geneva, SwitzerlandGoogle Scholar
  52. 53.
    Knevelman C, Hearle DC, Osman JJ, Khan M, Dean M, Smith M, Aiyedebinu Cheung K (2002) Characterization and operation of a disposable bioreactor as a replacement for conventional steam-in-place inoculum bioreactors for mammalian cell culture processes. 224th National Meeting of the American Chemical Society. American Chemical Society, Washington DC, USA (poster), Boston, MAGoogle Scholar
  53. 54.
    Heidemann R, Riese U, Lütkemeyer D, Büntemeyer H, Lehmann J (1994) Cytotechnology 14:1CrossRefGoogle Scholar
  54. 55.
    Eibl D, Eibl R, Frefel J, Hans D, Jenny D (1996) Erprobung und Bewertung eines Zellkulturreaktors für die Produktion von Sekundärmetaboliten mittels pflanzlicher Zellen. Final report, Ingenieurschule Wädenswil, Switzerland, unpublishedGoogle Scholar
  55. 56.
    Studer A (2003) Bioverfahrenstechnische Untersuchungen an einem 2 L-BIOSTAT® B Plus Zellkulturreaktorsystem der Firma Sartorius BBI Systems. Semester thesis, University of Applied Sciences Wädenswil, Switzerland, unpublishedGoogle Scholar
  56. 57.
    Czermak P, Weber C, Nehring D (2005) A ceramic microsparging aeration system for cell culture reactors. Scientific report, FH Giessen, Germany, http://kmubser.tg.fh-giessen.de/pm/IBPT/Czermak-et-al-Sparger.pdf. Cited February 21, 2008
  57. 58.
    Ries C (2008) Untersuchungen zum Einsatz von Einwegbioreaktoren für die auf animalen Zellen basierte Produktion von internen und externen Proteinen. Diploma thesis, Zurich University of Applied Sciences, Department for Life Sciences and Facility Management. Wädenswil, Switzerland, unpublishedGoogle Scholar
  58. 59.
    Ries C (2008) Verfahrenstechnische Charakterisierung des Single Use Bioreactor 50 L von Thermo Fisher Scientific. Scientific report, Zurich University of Applied Sciences, Department for Life Sciences and Facility Management. Wädenswil, Switzerland, unpublishedGoogle Scholar
  59. 60.
    Applikon biotechnology (2005) Application note: kLa valuesGoogle Scholar
  60. 61.
    Pechmann G (2002) Disposable Wirkstoffproduktion im Wave-Reaktor mit animalen Suspensionszellen. Diploma thesis, Hochschule Anhalt (FH), Germany, unpublishedGoogle Scholar
  61. 62.
    Eibl R, Eibl D (2008) Application of disposable bag-bioreactors in tissue engineering and for the production of therapeutic agents. In: Kasper G, (eds.) PörtnerR,van GriensvenMBioreactor systems for tissue engineering, series: advances in biochemical engineering/biotechnology, vol. 110. Springer, Berlin Heidelberg New York (in pressGoogle Scholar
  62. 63.
    Bauer I, Lamp J, Eibl R (2007) Influence of BioWave’s culture bag pre-treatment on CHO cell growth and protein expression in chemically defined minimal medium. Biotech May 2007. Wädenswil, Switzerland, (poster)Google Scholar
  63. 64.
    Eibl R, Bauer I (2007) Application note: cultivation of serum-free growing CHO XM 111 suspension cells in the BioWave 20 SPS or BIOSTAT CultiBag RM 20 (fed batch/feeding mode) operating with CultiBag RM 2 LGoogle Scholar
  64. 65.
    Eibl R, Rutschmann K, Lisica L, Eibl D (2003) BioWorld 5:22Google Scholar
  65. 66.
    Eibl R, Bauer I (2007) Application note: cultivation and SEAP secretion of serum-free growing CHO XM 111 suspension cells in the BioWave 20 SPS or BIOSTAT CultiBag RM 20 (fed batch) operating with CultiBag RM 20 LGoogle Scholar
  66. 67.
    Mazur X, Fussenegger M, Renner WA, Bailey JE (1998) Biotechnol Prog 14:705CrossRefGoogle Scholar
  67. 68.
    Eibl D, Eibl R (2002) Entwicklungsstand und trends in der Zellkulturtechnologie. In: Beckmann D, (eds.) MeisterM,HeidenS,ErbRTechnische Systeme für die Biotechnologie und Umwelt-Biosensorik. Erich Schmidt Verlag, Berlin, p. 255Google Scholar
  68. 69.
    Kaufmann H, Mazur X, Fussenegger M, Bailey JE (1999) Biotechnol Bioeng 63:573CrossRefGoogle Scholar
  69. 70.
    Rhiel M, Eibl R (2004) Der Wave als System zur Prozessentwicklung für Proteinexpressionen. Biotech May 2004, Wädenswil, SwitzerlandGoogle Scholar
  70. 71.
    Wernli U, Eibl R, Eibl D (2008) Quest 5:18Google Scholar
  71. 72.
    Weber W, Fussenegger M (2005) Baculovirus-based production of biopharmaceuticals using insect cell cultures. In: Knäblein J (ed.) Modern biopharmaceuticals. Wiley VCH, Weinheim, p. 1045CrossRefGoogle Scholar
  72. 73.
    Dietzsch C, Genzel Y, Reichl U (2007) Vero or MDCK cells for influenza A virus production in microcarrier systems? European BioPerspectives May 2007. Cologne, Germany (poster)Google Scholar
  73. 74.
    Kreis W, Baron D, Stoll G (2001) Biotechnologie der Arzneistoffe. Deutscher Apotheker Verlag, StuttgartGoogle Scholar
  74. 75.
    Hibino K, Ushiyama K (1999) Commercial production of ginseng by plant tissue culture technology. In: Fu TJ, Curtis WR (eds.) Plant cell and tissue culture for the production of food ingredients. Kluwer Academic, New York, p. 215Google Scholar
  75. 76.
    Wink M, Alfermann AW, Franke R, Wetterauer B, Distl M, Windhoevel J, Krohn O, Fuss E, Garden H, Mohagheghzadeh A, Wildi E, Ripplinger P (2005) Plant Gene Res 3:90CrossRefGoogle Scholar
  76. 77.
    Evans J (2006) Plant-derived drug. http://www.rsc.org/chemistryworld/News/2006/February/07020602.asp. Accessed 10 April 2007
  77. 78.
    Hess D (1992) Biotechnologie der Pflanzen. Eugen Ulmer, StuttgartGoogle Scholar
  78. 79.
    Deus-Neumann B, Zenk HM (1984) Planta Med 50:427CrossRefGoogle Scholar
  79. 80.
    Oksman-Caldentey KM, Hiltunen R (1996) Field Crops Res 45:57CrossRefGoogle Scholar
  80. 81.
    Sharp JM, Doran PM (2001) Biotechnol Prog 17:979CrossRefGoogle Scholar
  81. 82.
    Doran PM (2002) Properties and application of hairy root cultures. In: Oksman-Caldentey KM, Barz WH (eds.) Plant biotechnology and transgenic plants. Marcel Dekker, New York, p. 143Google Scholar
  82. 83.
    Curtis WR, Emery A (1993) Biotechnol Bioeng 42:520CrossRefGoogle Scholar
  83. 84.
    Su W (2006) Bioreactor engineering for recombinant protein production using plant cell suspension culture. In: Dutta Gupta S, Ibaraki Y (eds.) Plant tissue culture engineering, series: focus on biotechnology, vol 6. Springer, Dordrecht, p. 135Google Scholar
  84. 85.
    Schwarz S (2004) Comparison of different scale-up methods for the production of high value-compounds in selected plant systems. Diploma thesis, University of Applied Sciences Wädenswil, Switzerland, unpublishedGoogle Scholar
  85. 86.
    Zhong JJ (2001) Biochemical engineering of the production of plant-specific secondary metabolites. In: Tscheper T (ed.) Plant cells, series: advances in biochemical engineering/biotechnology, vol. 72. Springer, Berlin Heidelberg New York, p. 1Google Scholar
  86. 87.
    Schürch C, Blum P, Zülli F (2007) Phytochem Rev, DOI 10.1007/s11101-007-9082-0Google Scholar
  87. 88.
    Griehl C, Isdepsky A, Krause-Hielscher S (2007) Establishment of marine macrophytic cell cultures for the production of bioactive metabolites. http://www.wavebiotech.net.Accessed 02 March 2008
  88. 89.
    Jouhikainen K, Lindgren L, Jokelainen T, Hiltunen R, Teeri TM, Oksman-Caldentey KM (1999) Planta Med 208:545Google Scholar
  89. 90.
    Cuperus S, Eibl R, Rischer H, Oksman-Caldentey KM, Cusidó RM, Pinyol MT, Eibl D (2007) Disposable bag bioreactor for plant cell and tissue cultures. PSE congress “Plants for human health in the post-genome era”. Espoo, Finland (poster) August 2007Google Scholar
  90. 91.
    Jablonski-Lorin C, Mellio V, Hungerbühler E (2003) Chimia 57:574CrossRefGoogle Scholar
  91. 92.
    Hess S (2001) Kultivierung von Erynia neoaphidis im Wave-Reaktor. Scientific report, University of Applied Sciences Wädenswil, Switzerland, unpublishedGoogle Scholar
  92. 93.
    Canales R, Hlubina M, Baier U, Tuor U (2001) Evaluation of cultivation parameters for mass production of Erynia neoaphidis. IOBC Meeting “Entomopathogens and insect parasite nematodes” Athens, Greece (poster) June 2001.Google Scholar
  93. 94.
    Hess S, Baier U, Lettenbauer C, Hafner D (2002) A new application for the Wave Bioreactor 20: cultivation of Erynia neoaphidis , a mycel producing fungus. IOBC meeting“Insect pathogens and insect parasitic nematodes” Birmingham, U.K.May 2002.Google Scholar
  94. 95.
    Hirschy O, Schmid T (1999) Flüssigkultivierung von entomopathogenen Nematoden. Scientific report, University of Applied Sciences Wädenswil, Switzerland, unpublishedGoogle Scholar
  95. 96.
    Hirschy O, Schmid T, Grunder JM, Andermatt M, Bollhalder F, Sievers M (2001) Wave reactor and the liquid culture of the entomopathogenic nematode Steinerma feltiae. In: Griffin CT, Burnell AM, Downes MJ, Mulder R (eds.) Developments in entomopathogenic nematode/bacterial research. Brussels, LuxembourgDG XII, COST 819,Google Scholar
  96. 97.
    Hardy J, Priester P (2004) BioProc Int (Supplement series “The disposables option”):32Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Institute of BiotechnologyZurich University of Applied Sciences, School of Life Sciences and Facility ManagementWädenswilSwitzerland

Personalised recommendations