Microfluidics as a cutting-edge technique for drug delivery applications

Journal of Drug Delivery Science and Technology

Volumn 34, Issue , 2016, Pages 76-87

  Fontana, Flavia ^a   Ferreira, Mónica P A ^a   Correia, Alexandra ^a   Hirvonen, Jouni ^a   Santos, Hélder A ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

Author keywords

Double emulsion; Drug delivery; Glass capillary; Microfluidics; Multiple emulsion; Single emulsion

Indexed keywords

GLASS; LIPOSOME; MICROSPHERE;

DRUG DELIVERY SYSTEM; DRUG FORMULATION; EMULSION; MICROCAPSULE; MICROFLUIDICS; PHYSICAL CHEMISTRY; PHYSICS; REVIEW; SYNTHESIS;

EID: 84990038913     PISSN: 17732247     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jddst.2016.01.010     Document Type: Review

References (96)

1. [1] Craighead, H., Future lab-on-a-chip technologies for interrogating individual molecules. Nature 442:7101 (2006), 387–393.
2. [2] deMello, A.J., Control and detection of chemical reactions in microfluidic systems. Nature 442:7101 (2006), 394–402.
3. [3] Nguyen, N.-T., Shaegh, S.A.M., Kashaninejad, N., Phan, D.-T., Design, fabrication and characterization of drug delivery systems based on lab-on-a-chip technology. Adv. Drug Deliv. Rev. 65:11–12 (2013), 1403–1419.
4. [4] Tiwari, G., Tiwari, R., Sriwastawa, B., Bhati, L., Pandey, S., Pandey, P., Bannerijee, S.K., Drug delivery systems: an updated review. Int. J. Pharm. Invest. 2:1 (2012), 2–11.
5. [5] Yang, W.W., Pierstorff, E., Reservoir-based polymer drug delivery systems. J. Lab. Autom. 17:1 (2012), 50–58.
6. [6] Wadhwa, J., Nair, A., Kumria, R., Emulsion forming drug delivery system for lipophilic drugs. Acta Pol. Pharm. 69:2 (2012), 179–191.
7. [7] Santos, H.A., Microfluidics technique to revolutionize the drug delivery field: current developments and applications. Curr. Drug Deliv. 13 (2016), 1–3.
8. [8] Kalepu, S., Nekkanti, V., Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm. Sin. B 5:5 (2015), 442–453.
9. [9] Vladisavljević, G.T., Kobayashi, I., Nakajima, M., Production of uniform droplets using membrane, microchannel and microfluidic emulsification devices. Microfluid. Nanofluid 13:1 (2012), 151–178.
10. [10] Whitesides, G.M., The origins and the future of microfluidics. Nature 442:7101 (2006), 368–373.
11. [11] MEMS, I.G., Microfluidics Sector Poised for 23% Growth. 2012 [accessed November 6, 2015] http://blog.memsindustrygroup.org/2012/02/16/microfluidics-sector-poised-for-23-growth/.
12. [12] Valencia, P.M., Farokhzad, O.C., Karnik, R., Langer, R., Microfluidic technologies for accelerating the clinical translation of nanoparticles. Nat. Nanotechnol. 7:10 (2012), 623–629.
13. [13] Zhao, C.X., Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery. Adv. Drug Deliv. Rev. 65:11–12 (2013), 1420–1446.
14. [14] Coltro, W.K., Lunte, S.M., Carrilho, E., Comparison of the analytical performance of electrophoresis microchannels fabricated in PDMS, glass, and polyester-toner. Electrophoresis 29:24 (2008), 4928–4937.
15. [15] Zhao, C.-X., Middelberg, A.P.J., Two-phase microfluidic flows. Chem. Eng. Sci. 66:7 (2011), 1394–1411.
16. [16] Pessi, J., Santos, H.A., Miroshnyk, I., Yliruusi, J., Weitz, D.A., Mirza, S., Microfluidics-assisted engineering of polymeric microcapsules with high encapsulation efficiency for protein drug delivery. Int. J. Pharm. 472:1–2 (2014), 82–87.
17. [17] Wang, W., Zhang, M.J., Chu, L.Y., Functional polymeric microparticles engineered from controllable microfluidic emulsions. Acc. Chem. Res. 47:2 (2014), 373–384.
18. [18] Zhang, Y., Chan, H.F., Leong, K.W., Advanced materials and processing for drug delivery: the past and the future. Adv. Drug Deliv. Rev. 65:1 (2013), 104–120.
19. [19] Utada, A.S., Fernandez-Nieves, A., Gordillo, J.M., Weitz, D.A., Absolute instability of a liquid jet in a coflowing stream. Phys. Rev. Lett., 100(1), 2008, 014502.
20. [20] Gunther, A., Jensen, K.F., Multiphase microfluidics: from flow characteristics to chemical and materials synthesis. Lab. Chip 6:12 (2006), 1487–1503.
21. [21] Utada, A.S., Fernandez-Nieves, Stone, H.A., Weitz, D.A., Dripping to jetting transitions in coflowing liquid streams. Phys. Rev. Lett., 99(9), 2007, 094502.
22. [22] Ambravaneswaran, B., Subramani, H.J., Phillips, S.D., Basaran, O.A., Dripping-jetting transitions in a dripping faucet. Phys. Rev. Lett., 93(3), 2004, 034501.
23. [23] Utada, A.S., Lorenceau, E., Link, D.R., Kaplan, P.D., Stone, H.A., Weitz, D.A., Monodisperse double emulsions generated from a microcapillary device. Science 308:5721 (2005), 537–541.
24. [24] Polenz, I., Weitz, D.A., Baret, J.C., Polyurea microcapsules in microfluidics: surfactant control of soft membranes. Langmuir 31:3 (2015), 1127–1134.
25. [25] Mazutis, L., Vasiliauskas, R., Weitz, D.A., Microfluidic production of alginate hydrogel particles for antibody encapsulation and release. Macromol. Biosci. 15 (2015), 1641–1646.
26. [26] Mittal, N., Cohen, C., Bibette, J., Bremond, N., Dynamics of step-emulsification: from a single to a collection of emulsion droplet generators. Phys. Fluids, 26(8), 2014, 082109.
27. [27] Nabavi, S.A., Vladisavljević, G.T., Gu, S., Ekanem, E.E., Double emulsion production in glass capillary microfluidic device: parametric investigation of droplet generation behaviour. Chem. Eng. Sci. 130 (2015), 183–196.
28. [28] Datta, S.S., Abbaspourrad, A., Amstad, E., Fan, J., Kim, S.-H., Romanowsky, M., Shum, H.C., Sun, B., Utada, A.S., Windbergs, M., Zhou, S., Weitz, D.A., Double emulsion templated solid microcapsules: mechanics and controlled release. Adv. Mater. 26:14 (2014), 2205–2218.
29. [29] Duncanson, W.J., Lin, T., Abate, A.R., Seiffert, S., Shah, R.K., Weitz, D.A., Microfluidic synthesis of advanced microparticles for encapsulation and controlled release. Lab. Chip 12:12 (2012), 2135–2145.
30. [30] Liu, D., Herranz-Blanco, B., Mäkilä, E., Arriaga, L.R., Mirza, S., Weitz, D.A., Sandler, N., Salonen, J., Hirvonen, J., Santos, H.A., Microfluidic templated mesoporous silicon–solid lipid microcomposites for sustained drug delivery. ACS Appl. Mater. Interfaces 5:22 (2013), 12127–12134.
31. [31] Wang, J.T., Wang, J., Han, J.J., Fabrication of advanced particles and particle-based materials assisted by droplet-based microfluidics. Small 7:13 (2011), 1728–1754.
32. [32] Yang, S., Guo, F., Kiraly, B., Mao, X., Lu, M., Leong, K.W., Huang, T.J., Microfluidic synthesis of multifunctional Janus particles for biomedical applications. Lab. Chip 12:12 (2012), 2097–2102.
33. [33] Seiffert, S., Functional microgels tailored by droplet-based microfluidics. Macromol. Rapid Commun. 32:20 (2011), 1600–1609.
34. [34] Foster, T., Dorfman, K.D., Davis, H.T., Giant biocompatible and biodegradable PEG-PMCL vesicles and microcapsules by solvent evaporation from double emulsion droplets. J. Colloid Interface Sci. 351:1 (2010), 140–150.
35. [35] Shum, H.C., Abate, A.R., Lee, D., Studart, A.R., Wang, B., Chen, C.-H., Thiele, J., Shah, R.K., Krummel, A., Weitz, D.A., Droplet microfluidics for fabrication of non-spherical particles. Macromol. Rapid Commun. 31:2 (2010), 108–118.
36. [36] Zhang, H., Liu, D., Shahbazi, M.-A., Mäkilä, E., Herranz-Blanco, B., Salonen, J., Hirvonen, J., Santos, H.A., Fabrication of a multifunctional nano-in-micro drug delivery platform by microfluidic templated encapsulation of porous silicon in polymer matrix. Adv. Mater. 26:26 (2014), 4497–4503.
37. [37] Herranz-Blanco, B., Arriaga, L.R., Mäkilä, E., Correia, A., Shrestha, N., Mirza, S., Weitza, D.A., Salonen, J., Hirvonen, J., Santos, H.A., Microfluidic assembly of multistage porous silicon-lipid vesicles for controlled drug release. Lab. Chip 14:6 (2014), 1083–1086.
38. [38] Teh, S.Y., Lin, R., Hung, L.H., Lee, A.P., Droplet microfluidics. Lab. Chip 8:2 (2008), 198–220.
39. [39] Jeong, W.C., Lim, J.M., Choi, J.-H., Kim, J.-H., Lee, Y.J., Kim, S.-H., Lee, G., Kim, J.-D., Yi, G.-R., Yang, S.-M., Controlled generation of submicron emulsion droplets via highly stable tip-streaming mode in microfluidic devices. Lab. Chip 12:8 (2012), 1446–1453.
40. [40] Cristini, V., Tan, Y.C., Theory and numerical simulation of droplet dynamics in complex flows–a review. Lab. Chip 4:4 (2004), 257–264.
41. [41] Kong, T., Wu, J., To, M., Yeung, K.W.K., Shum, H.C., Wang, L., Droplet based microfluidic fabrication of designer microparticles for encapsulation applications. Biomicrofluidics, 6(3), 2012, 34104.
42. [42] Min, N.G., Kim, B., Lee, T.Y., Kim, D., Lee, D.C., Kim, S.-H., Anisotropic microparticles created by phase separation of polymer blends confined in monodisperse emulsion drops. Langmuir 31:3 (2015), 937–943.
43. [43] Hu, Y., Wang, S., Abbaspourrad, A., Ardekani, A.M., Fabrication of shape controllable Janus alginate/pNIPAAm microgels via microfluidics technique and off-chip ionic cross-linking. Langmuir 31:6 (2015), 1885–1891.
44. [44] Vladisavljević, G.T., Shahmohamadi, H., Das, D.B., Ekanem, E.E., Tauanow, Z., Sharma, L., Glass capillary microfluidics for production of monodispersed poly (DL-lactic acid) and polycaprolactone microparticles: experiments and numerical simulations. J. Colloid Interface Sci. 418 (2014), 163–170.
45. [45] Park, J., Byun, A., Kim, D.-H., Shin, S.S., Kim, J.-H., Kim, J.W., Microfluidic fabrication and permeation behaviors of uniform zwitterionic hydrogel microparticles and shells. J. Colloid Interface Sci. 426 (2014), 162–169.
46. [46] Park, J., Jeong, E.S., Kim, S., Kim, Y.-J., Jeong, H.-J., Kim, J.W., Microfluidic immobilization of polyglycerin-b-poly(ε-caprolactone) polymeric micelles in uniform zwitterionic hydrogel microparticles for molecular network-mediated drug release. Colloid Polym. Sci. 293:4 (2015), 1121–1127.
47. [47] Mangin, D., Puel, F., Veesler, S., Polymorphism in processes of crystallization in solution: a practical review. Org. Process Res. Dev. 13:6 (2009), 1241–1253.
48. [48] Leon, R.A.L., Badruddoza, A.Z.M., Zheng, L., Yeap, E.W.Q., Toldy, A.I., Wong, K.Y., Hatton, A., Khan, S.A., Highly selective, kinetically driven polymorphic selection in microfluidic emulsion-based crystallization and formulation. Cryst. Growth Des. 15:1 (2015), 212–218.
49. [49] Duncanson, W.J., Zieringer, M., Wagner, O., Wilking, J.N., Abbaspourrad, A., Haag, R., Weitz, D.A., Microfluidic synthesis of monodisperse porous microspheres with size-tunable pores. Soft Matter 8:41 (2012), 10636–10640.
50. [50] Danhier, F., Ansorena, E., Silva, J.M., Coco, R., Le Breton, A., Préat, V., PLGA-based nanoparticles: an overview of biomedical applications. J. Control. Release 161:2 (2012), 505–522.
51. [51] Leon, R.A.L., Somasundar, A., Badruddoza, A.Z.M., Khan, S.A., Microfluidic fabrication of multi-drug-loaded polymeric microparticles for topical glaucoma therapy. Part. Part. Syst. Charact. 32:5 (2015), 567–572.
52. [52] Liu, D., Bimbo, L.M., Mäkilä, E., Villanova, F., Kaasalainen, M., Herranz-Blanco, B., Caramella, C.M., Lehto, V.-P., Salonen, J., Herzig, K.-H., Santos, H.A., Co-delivery of a hydrophobic small molecule and a hydrophilic peptide by porous silicon nanoparticles. J. Control. Release 170:2 (2013), 268–278.
53. [53] Liu, D., Herranz-Blanco, B., Mäkilä, E., Lehto, V.-P., Salonen, J., Hirvonen, J., Santos, H.A., Microfluidic assembly of monodisperse multistage pH-responsive polymer/porous silicon composites for precisely controlled multi-drug delivery. Small 10:10 (2014), 2029–2038.
54. [54] Shahbazi, M.-A., Herranz, B., Santos, H.A., Nanostructured porous Si-based nanoparticles for targeted drug delivery. Biomatter 2:4 (2012), 296–312.
55. [55] Araújo, F., Shrestha, N., Shahbazi, M.-A., Liu, D., Herranz-Blanco, B., Mäkilä, E.M., Salonen, J.J., Hirvonen, J.T., Granja, P.L., Sarmento, B., Santos, H.A., Microfluidic assembly of a multifunctional tailorable composite system designed for site specific combined oral delivery of peptide drugs. ACS Nano 9:8 (2015), 8291–8302.
56. [56] Song, Y.S., Choi, Y.H., Kim, H., Microextraction in a tetrabutylammonium bromide/ammonium sulfate aqueous two-phase system and electrohydrodynamic generation of a micro-droplet. J. Chromatogr. A 1162:2 (2007), 180–186.
57. [57] Ziemecka, I., van Steijn, V., Koper, G.J.M., Rosso, M., Brizard, A.M., van Esch, J.H., Kreutzer, M.T., Monodisperse hydrogel microspheres by forced droplet formation in aqueous two-phase systems. Lab. Chip 11:4 (2011), 620–624.
58. [58] Cheung Shum, H., Varnell, J., Weitz, D.A., Microfluidic fabrication of water-in-water (w/w) jets and emulsions. Biomicrofluidics 6:1 (2012), 12808–128089.
59. [59] Wei, J., Ju, X.J., Xie, R., Mou, C.-L., Lin, X., Chu, L.-Y., Novel cationic pH-responsive poly(N,N-dimethylaminoethyl methacrylate) microcapsules prepared by a microfluidic technique. J. Colloid Interface Sci. 357:1 (2011), 101–108.
60. [60] Chen, P.W., Erb, R.M., Studart, A.R., Designer polymer-based microcapsules made using microfluidics. Langmuir 28:1 (2011), 144–152.
61. [61] Tu, F., Lee, D., Controlling the stability and size of double-emulsion-templated poly(lactic-co-glycolic) acid microcapsules. Langmuir 28:26 (2012), 9944–9952.
62. [62] Kim, S.H., Kim, J.W., Cho, J.C., Weitz, D.A., Double-emulsion drops with ultra-thin shells for capsule templates. Lab. Chip 11:18 (2011), 3162–3166.
63. [63] Zhao, Y., Shum, H.C., Adams, L.L.A., Sun, B., Holtze, C., Gu, Z., Weitz, D.A., Enhanced encapsulation of actives in self-sealing microcapsules by precipitation in capsule shells. Langmuir 27:23 (2011), 13988–13991.
64. [64] Sun, B.J., Shum, H.C., Holtze, C., Weitz, D.A., Microfluidic melt emulsification for encapsulation and release of actives. ACS Appl. Mater. Interfaces 2:12 (2010), 3411–3416.
65. [65] Ren, P.W., Ju, X.J., Xie, R., Chu, L.Y., Monodisperse alginate microcapsules with oil core generated from a microfluidic device. J. Colloid Interface Sci. 343:1 (2010), 392–395.
66. [66] Liu, L., Wu, F., Ju, X.-J., Xie, R., Wang, W., Niu, C.H., Chu, L.-Y., Preparation of monodisperse calcium alginate microcapsules via internal gelation in microfluidic-generated double emulsions. J. Colloid Interface Sci. 404 (2013), 85–90.
67. [67] Liu, L., Yang, J.-P., Ju, X.-J., Xie, R., Liu, Y.-M., Wang, W., Zhang, J.-J., Niu, C.H., Chu, L.-Y., Monodisperse core-shell chitosan microcapsules for pH-responsive burst release of hydrophobic drugs. Soft Matter 7:10 (2011), 4821–4827.
68. [68] Wu, J., Kong, T., Yeung, K.W.K., Shum, H.C., Cheung, K.M.C., Wang, L., To, M.K., Fabrication and characterization of monodisperse PLGA-alginate core-shell microspheres with monodisperse size and homogeneous shells for controlled drug release. Acta Biomater. 9:7 (2013), 7410–7419.
69. [69] Lorenceau, E., Utada, A.S., Link, D.R., Cristobal, G., Joanicot, M., Weitz, D.A., Generation of polymersomes from double-emulsions. Langmuir 21:20 (2005), 9183–9186.
70. [70] Shah, R.K., Shum, H.C., Rowat, A.C., Lee, D., Agresti, J.J., Utada, A.S., Chu, L.-Y., Kim, J.-W., Fernandez-Nieves, A., Martinez, C.J., Weitz, D.A., Designer emulsions using microfluidics. Mater. Today 11:4 (2008), 18–27.
71. [71] Kim, S.H., Kim, J.W., Kim, D.H., Han, S.H., Weitz, D.A., Polymersomes containing a hydrogel network for high stability and controlled release. Small 9:1 (2013), 124–131.
72. [72] Seth, A., Béalle, G., Santanach-Carreras, E., Abou-Hassan, A., Ménager, C., Design of vesicles using capillary microfluidic devices: from magnetic to multifunctional vesicles. Adv. Mater. 24:26 (2012), 3544–3548.
73. [73] Amstad, E., Kim, S.H., Weitz, D.A., Photo- and thermoresponsive polymersomes for triggered release. Angew. Chem. Int. Ed. Engl. 51:50 (2012), 12499–12503.
74. [74] Kong, F., Zhang, X., Hai, M., Microfluidics fabrication of monodisperse biocompatible phospholipid vesicles for encapsulation and delivery of hydrophilic drug or active compound. Langmuir 30:13 (2014), 3905–3912.
75. [75] Kong, F., Zhang, X., Zhang, H., Qu, X., Chen, D., Servos, M., Mäkilä, E., Salonen, J., Santos, H.A., Hai, M., Weitz, D.A., Inhibition of multidrug resistance of cancer cells by co-delivery of DNA nanostructures and drugs using porous silicon nanoparticles@Giant Liposomes. Adv. Funct. Mater. 25:22 (2015), 3330–3340.
76. [76] Al-Lazikani, B., Banerji, U., Workman, P., Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol. 30:7 (2012), 679–692.
77. [77] Windbergs, M., Zhao, Y., Heyman, J., Weitz, D.A., Biodegradable core–shell carriers for simultaneous encapsulation of synergistic actives. J. Am. Chem. Soc. 135:21 (2013), 7933–7937.
78. [78] Wang, W., Liu, L., Ju, X.-J., Zerrouki, D., Xie, R., Yang, L., Chu, L.-Y., A novel thermo-induced self-bursting microcapsule with magnetic-targeting property. Chem. Phys. Chem. 10:14 (2009), 2405–2409.
79. [79] Timko, B.P., Dvir, T., Kohane, D.S., Remotely triggerable drug delivery systems. Adv. Mater. 22:44 (2010), 4925–4943.
80. [80] Wang, Y., Byrne, J.D., Napier, M.E., DeSimone, J.M., Engineering nanomedicines using stimuli-responsive biomaterials. Adv. Drug Deliv. Rev. 64:11 (2012), 1021–1030.
81. [81] Lee, M.H., Hribar, K.C., Brugarolas, T., Kamat, N.P., Burdick, J.A., Lee, D., Harnessing interfacial phenomena to program the release properties of hollow microcapsules. Adv. Funct. Mater. 22:1 (2012), 131–138.
82. [82] Duncanson, W.J., Arriaga, L.R., Ung, W.L., Kopechek, J.A., Porter, T.M., Weitz, D.A., Microfluidic fabrication of perfluorohexane-shelled double emulsions for controlled loading and acoustic-triggered release of hydrophilic agents. Langmuir 30:46 (2014), 13765–13770.
83. [83] Abbaspourrad, A., Datta, S.S., Weitz, D.A., Controlling release from pH-responsive microcapsules. Langmuir 29:41 (2013), 12697–12702.
84. [84] Wang, W., Zhang, M.J., Xie, R., Ju, X.-J., Yang, C., Mou, C.L., Weitz, D.A., Chu, L.-Y., Hole–shell microparticles from controllably evolved double emulsions. Angew. Chem. Int. Ed. Engl. 52:31 (2013), 8084–8087.
85. [85] Okochi, H., Nakano, M., Preparation and evaluation of w/o/w type emulsions containing vancomycin. Adv. Drug. Deliv. Rev. 45:1 (2000), 5–26.
86. [86] Vladisavljević, G.T., Shimizu, M., Nakashima, T., Production of multiple emulsions for drug delivery systems by repeated SPG membrane homogenization: influence of mean pore size, interfacial tension and continuous phase viscosity. J. Membr. Sci. 284:1 (2006), 373–383.
87. [87] McClements, D.J., Decker, E.A., Weiss, J., Emulsion-based delivery systems for lipophilic bioactive components. J. Food Sci. 72:8 (2007), R109–R124.
88. [88] Adams, L., Kodger, T.E., Kim, S.-H., Shum, H.C., Franke, T., Weitz, D.A., Single step emulsification for the generation of multi-component double emulsions. Soft Matter 8:41 (2012), 10719–10724.
89. [89] Wang, W., Xie, R., Ju, X.-J., Luo, T., Liu, L., Weitz, D.A., Chu, L.-Y., Controllable microfluidic production of multicomponent multiple emulsions. Lab. Chip 11:9 (2011), 1587–1592.
90. [90] Chu, L.Y., Utada, A.S., Shah, R.K., Kim, J.-W., Weitz, D.A., Controllable monodisperse multiple emulsions. Angew. Chem. Int. Ed. Engl. 46:47 (2007), 8970–8974.
91. [91] Kim, S.H., Shum, H.C., Kim, J.W., Cho, J.-C., Weitz, D.A., Multiple polymersomes for programmed release of multiple components. J. Am. Chem. Soc. 133:38 (2011), 15165–15171.
92. [92] Kim, S.H., Weitz, D.A., One-step emulsification of multiple concentric shells with capillary microfluidic devices. Angew. Chem. Int. Ed. Engl. 50:37 (2011), 8731–8734.
93. [93] Chen, H., Li, J., Wan, J., Weitz, D.A., Gas-core triple emulsions for ultrasound triggered release. Soft Matter 9:1 (2013), 38–42.
94. [94] Dendukuri, D., Hatton, T.A., Doyle, P.S., Synthesis and self-assembly of amphiphilic polymeric microparticles. Langmuir 23:8 (2007), 4669–4674.
95. [95] Herranz-Blanco, B., Liu, D., Mäkilä, E., Shahbazi, M.-A., Ginestar, E., Zhang, H., Aseyev, V., Balasubramanian, V., Salonen, J., Hirvonen, J., Santos, H.A., On-chip self-assembly of a smart hybrid nanocomposite for antitumoral applications. Adv. Funct. Mater. 25:10 (2015), 1488–1497.
96. [96] Zhao, J., Grant, S.F., Advances in whole genome sequencing technology. Curr. Pharm. Biotechnol. 12:2 (2011), 293–305.