Research Papers

Fabrication of Double-Layered Alginate Capsules Using Coaxial Nozzle

[+] Author and Article Information
Yifei Jin

Department of Mechanical
and Aerospace Engineering,
University of Florida,
Gainesville, FL 32611

Danyang Zhao

Department of Mechanical Engineering,
Dalian University of Technology,
Dalian, Liaoning 116023, China

Yong Huang

Department of Mechanical
and Aerospace Engineering,
University of Florida,
Gainesville, FL 32611
e-mail: yongh@ufl.edu

1Corresponding author.

Contributed by the Manufacturing Engineering Division of ASME for publication in the JOURNAL OF MICRO- AND NANO-MANUFACTURING. Manuscript received March 23, 2017; final manuscript received August 8, 2017; published online September 28, 2017. Assoc. Editor: Martin Jun.

J. Micro Nano-Manuf 5(4), 041007 (Sep 28, 2017) (9 pages) Paper No: JMNM-17-1014; doi: 10.1115/1.4037646 History: Received March 23, 2017; Revised August 08, 2017

Multilayered encapsulation has been of great interest for various pharmaceutical, chemical, and food industries. Fabrication of well-defined capsules with more than one shell layer still poses a significant fabrication challenge. This study aims to investigate the feasibility of using a coaxial nozzle to fabricate double-layered (core–shell–shell) capsules during vibration-assisted dripping. A three-layered coaxial nozzle has been designed, manufactured, and tested for double-layered capsule fabrication when using sodium alginate solutions as the model liquid material for inner and outer shell layers and calcium chloride solution as the core fluid. To facilitate the droplet formation process, a vibrator has been integrated into the fabrication system to provide necessary perturbation for effective breakup of the fluid flow. It is demonstrated that double-layered alginate capsules can be successfully fabricated using the proposed three-layered coaxial nozzle fabrication system. During fabrication, increasing the core flow rate leads to an increase in capsule and core diameters while the inner and outer shell layer thicknesses decrease. Increasing annular flow rate results in an increase in capsule diameter and inner shell layer thickness while the outer shell layer thickness decreases. An increase in the sheath flow rate leads to an increase in capsule diameter and outer shell layer thickness but has no significant effect on the core diameter and inner shell layer thickness.

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Marison, I. , Peters, A. , and Heinzen, C. , 2004, “ Liquid Core Capsules for Applications in Biotechnology,” Fundamentals of Cell Immobilisation Biotechnology, V. Nedovic and R. Willaert, eds., Springer, Dordrecht, The Netherlands, pp. 185–204.
Service, R. F. , 1997, “ Drug Delivery Takes a Deep Breath,” Science, 277(5330), pp. 1199–1200. [CrossRef] [PubMed]
Kuang, T. , Chang, L. , Peng, X. , Hu, X. , and Gallego-Perez, D. , 2017, “ Molecular Beacon Nano-Sensors for Probing Living Cancer Cells,” Trends Biotechnol., 35(4), pp. 347–359. [CrossRef] [PubMed]
Chang, L. , Hu, J. , Chen, F. , Chen, Z. , Shi, J. , Yang, Z. , and Lee, L. J. , 2016, “ Nanoscale Bio-Platforms for Living Cell Interrogation: Current Status and Future Perspectives,” Nanoscale, 8(6), pp. 3181–3206. [CrossRef] [PubMed]
Chan, E. S. , Lee, B. B. , Ravindra, P. , and Poncelet, D. , 2009, “ Prediction Models for Shape and Size of Ca-Alginate Macrobeads Produced Through Extrusion-Dripping Method,” J. Colloid Interface Sci., 338(1), pp. 63–72. [CrossRef] [PubMed]
Lopez-Herrera, J. M. , Barrero, A. , Lopez, A. , Loscertales, I. G. , and Marquez, M. , 2003, “ Coaxial Jets Generated From Electrified Taylor Cones,” J. Aerosol Sci., 34(5), pp. 535–552. [CrossRef]
Utada, A. S. , Lorenceau, E. , Link, D. R. , Kaplan, P. D. , Stone, H. A. , and Weitz, D. A. , 2005, “ Monodisperse Double Emulsions Generated From a Microcapillary Device,” Science, 308(5721), pp. 537–541. [CrossRef] [PubMed]
Bocanegra, R. , Luis Sampedro, J. , Gañán-Calvo, A. , and Marquez, M. , 2005, “ Monodisperse Structured Multi-Vesicle Microencapsulation Using Flow-Focusing and Controlled Disturbance,” J. Microencapsulation, 22(7), pp. 745–759. [CrossRef]
Berkland, C. , Pollauf, E. , Varde, N. , Pack, D. W. , and Kim, K. K. , 2007, “ Monodisperse Liquid-Filled Biodegradable Capsules,” Pharm. Res., 24(5), pp. 1007–1013. [CrossRef] [PubMed]
Wang, W. , Herran, C. L. , Coutris, N. , Huang, Y. , Mironov, V. , and Markwald, R. , 2013, “ Methodology for the Evaluation of Double-Layered Capsule Formability Zone in Compound Nozzle Jetting Based on Growth Rate Ratio,” ASME J. Fluids Eng., 135(5), p. 051203. [CrossRef]
Nikoo, A. M. , Kadkhodaee, R. , Ghorani, B. , Razzaq, H. , and Tucker, N. , 2015, “ Electrohydrodynamic Atomization Assisted Encapsulation of Bioactive Compounds,” MOJ Food Process. Technol., 1(2), p. 00010. [CrossRef]
Gao, Y. , Zhao, D. , Chang, M. W. , Ahmad, Z. , and Li, J. S. , 2016, “ Optimizing the Shell Thickness-to-Radius Ratio for the Fabrication of Oil-Encapsulated Polymeric Microspheres,” Chem. Eng. J., 284, pp. 963–971. [CrossRef]
Davarci, F. , Turan, D. , Ozcelik, B. , and Poncelet, D. , 2017, “ The Influence of Solution Viscosities and Surface Tension on Calcium-Alginate Microbead Formation Using Dripping Technique,” Food Hydrocolloids, 62, pp. 119–127. [CrossRef]
Yeo, Y. , Chen, A. U. , Basaran, O. A. , and Park, K. , 2004, “ Solvent Exchange Method: A Novel Microencapsulation Technique Using Dual Microdispensers,” Pharm. Res., 21(8), pp. 1419–1427. [CrossRef] [PubMed]
Jain, R. A. , 2000, “ The Manufacturing Techniques of Various Drug Loaded Biodegradable Poly (Lactide-Co-Glycolide) (PLGA) Devices,” Biomaterials, 21(23), pp. 2475–2490. [CrossRef] [PubMed]
Chan, E. S. , Hong, W. O. , Lee, B. B. , Yim, Z. H. , and Ravindra, P. , 2006, “ Formation of Alginate-Membrane Capsules by Using Co-Extrusion Dripping Technique,” XIVth International Workshop on Bioencapsulation, Lausanne, Switzerland, Oct. 6–7, pp. 321–325.
Berkland, C. , Pollauf, E. , Pack, D. W. , and Kim, K. K. , 2004, “ Uniform Double-Walled Polymer Microspheres of Controllable Shell Thickness,” J. Controlled Release, 96(1), pp. 101–111. [CrossRef]
Loscertales, I. G. , Barrero, A. , Guerrero, I. , Cortijo, R. , Marquez, M. , and Ganan-Calvo, A. M. , 2002, “ Micro/Nano Encapsulation Via Electrified Coaxial Liquid Jets,” Science, 295(5560), pp. 1695–1698. [CrossRef] [PubMed]
Yao, R. , Zhang, R. , Luan, J. , and Lin, F. , 2012, “ Alginate and Alginate/Gelatin Microspheres for Human Adipose-Derived Stem Cell Encapsulation and Differentiation,” Biofabrication, 4(2), p. 025007. [CrossRef] [PubMed]
Yao, R. , Zhang, R. , Lin, F. , and Luan, J. , 2012, “ Injectable Cell/Hydrogel Microspheres Induce the Formation of Fat Lobule-Like Microtissues and Vascularized Adipose Tissue Regeneration,” Biofabrication, 4(4), p. 045003. [CrossRef] [PubMed]
Heinzen, C. , Berger, A. , and Marison, I. , 2004, “ Use of Vibration Technology for Jet Break-Up for Encapsulation of Cells and Liquids in Monodisperse Capsules,” Fundamentals of Cell Immobilisation Biotechnology, V. Nedovic and R. Willaert, eds., Springer, Dordrecht, The Netherlands, pp. 257–275.
Berkland, C. , Kim, K. K. , and Pack, D. W. , 2001, “ Fabrication of PLG Microspheres with Precisely Controlled and Monodisperse Size Distributions,” J. Controlled Release, 73(1), pp. 59–74. [CrossRef]
Goubault, C. , Pays, K. , Olea, D. , Gorria, P. , Bibette, J. , Schmitt, V. , and Leal-Calderon, F. , 2001, “ Shear Rupturing of Complex Fluids: Application to the Preparation of Quasi-Monodisperse Water-in-Oil-in-Water Double Emulsions,” Langmuir, 17(17), pp. 5184–5188. [CrossRef]
Herran, C. L. , Wang, W. , Huang, Y. , Mironov, V. , and Markwald, R. , 2010, “ Parametric Study of Acoustic Excitation-Based Glycerol-Water Microsphere Fabrication in Single Nozzle Jetting,” ASME J. Manuf. Sci. Eng., 132(5), p. 051001. [CrossRef]
Herran, C. L. , Huang, Y. , and Chai, W. , 2012, “ Performance Evaluation of Bipolar and Tripolar Excitations During Nozzle-Jetting-Based Alginate Microsphere Fabrication,” J. Micromech. Microeng., 22(8), p. 085025. [CrossRef]
Herran, C. L. , and Huang, Y. , 2012, “ Alginate Microsphere Fabrication Using Bipolar Wave-Based Drop-on-Demand Jetting,” J. Manuf. Processes, 14(2), pp. 98–106. [CrossRef]
Dowding, P. J. , Atkin, R. , Vincent, B. , and Bouillot, P. , 2004, “ Oil Core-Polymer Shell Capsules Prepared by Internal Phase Separation From Emulsion Droplets. I. Characterization and Release Rates for Capsules With Polystyrene Shells,” Langmuir, 20(26), pp. 11374–11379. [CrossRef] [PubMed]
Luginbuehl, V. , Wenk, E. , Koch, A. , Gander, B. , Merkle, H. P. , and Meinel, L. , 2005, “ Insulin-Like Growth Factor I—Releasing Alginate-Tricalciumphosphate Composites for Bone Regeneration,” Pharm. Res., 22(6), pp. 940–950. [CrossRef] [PubMed]
Ramadas, M. , Paul, W. , Dileep, K. J. , Anitha, M. R. Y. , and Sharma, C. P. , 2000, “ Lipoinsulin Encapsulated Alginate-Chitosan Capsules: Intestinal Delivery in Diabetic Rats,” J. Microencapsulation, 17(4), pp. 405–411. [CrossRef]
Jiang, Z. , Zhang, Y. , Li, J. , Jiang, W. , Yang, D. , and Wu, H. , 2007, “ Encapsulation of β-Glucuronidase in Biomimetic Alginate Capsules for Bioconversion of Baicalin to Baicalein,” Ind. Eng. Chem. Res., 46(7), pp. 1883–1890. [CrossRef]
Ghidoni, I. , Chlapanidas, T. , Bucco, M. , Crovato, F. , Marazzi, M. , Vigo, D. , and Faustini, M. , 2008, “ Alginate Cell Encapsulation: New Advances in Reproduction and Cartilage Regenerative Medicine,” Cytotechnology, 58(1), pp. 49–56. [CrossRef] [PubMed]
Mei, L. , Xie, R. , Yang, C. , Ju, X. J. , Wang, W. , Wang, J. Y. , and Chu, L. Y. , 2013, “ pH-Responsive Ca-Alginate-Based Capsule Membranes With Grafted Poly (Methacrylic Acid) Brushes for Controllable Enzyme Reaction,” Chem. Eng. J., 232, pp. 573–581. [CrossRef]
Xiong, R. , Zhang, Z. , Chai, W. , Huang, Y. , and Chrisey, D. B. , 2015, “ Freeform Drop-on-Demand Laser Printing of 3D Alginate and Cellular Constructs,” Biofabrication, 7(4), p. 045011. [CrossRef] [PubMed]
Braschler, T. , Valero, A. , Colella, L. , Pataky, K. , Brugger, J. , and Renaud, P. , 2011, “ Link Between Alginate Reaction Front Propagation and General Reaction Diffusion Theory,” Anal. Chem., 83(6), pp. 2234–2242. [CrossRef] [PubMed]
Morris, E. R. , Rees, D. A. , Thom, D. , and Boyd, J. , 1978, “ Chiroptical and Stoichiometric Evidence of a Specific, Primary Dimerisation Process in Alginate Gelation,” Carbohydr. Res., 66(1), pp. 145–154. [CrossRef]
Li, L. , Davidovich, A. E. , Schloss, J. M. , Chippada, U. , Schloss, R. R. , Langrana, N. A. , and Yarmush, M. L. , 2011, “ Neural Lineage Differentiation of Embryonic Stem Cells Within Alginate Microbeads,” Biomaterials, 32(20), pp. 4489–4497. [CrossRef] [PubMed]
Wang, J. H. , 1953, “ Tracer-Diffusion in Liquids. IV. Self-Diffusion of Calcium Ion and Chloride Ion in Aqueous Calcium Chloride Solutions,” J. Am. Chem. Soc., 75(7), pp. 1769–1770. [CrossRef]
Jin, Y. , Compaan, A. , Bhattacharjee, T. , and Huang, Y. , 2016, “ Granular Gel Support-Enabled Extrusion of Three-Dimensional Alginate and Cellular Structures,” Biofabrication, 8(2), p. 025016. [CrossRef] [PubMed]


Grahic Jump Location
Fig. 1

Multilayered capsule fabrication system: (a) double-layered capsule fabrication system (inset: image of the three-layered coaxial nozzle; scale bar: 10 mm) and (b) a double-layered capsule being fabricated (scale bar: 1 mm)

Grahic Jump Location
Fig. 2

Schematic of alginate crosslinking process with the presence of calcium cations: (a) schematic of alginate solution being crosslinked in air, (b) schematic of entire alginate capsule being crosslinked in the CaCl2 bath, and (c) a fabricated alginate capsule (only one layer is shown for illustration)

Grahic Jump Location
Fig. 3

Structure of the three-layered coaxial nozzle and simulation results. (a) Schematic of the nozzle assembly. Structure dimensions of (b) the annular channel and (c) the sheath channel. (d) Points selected to evaluate the velocity uniformity in the channels, and typical simulation results of the velocity distribution of (e) the annular flow and (f) the sheath flow at the outlet of the nozzle.

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Fig. 6

Effects of flow rates on the dimensions of double-layered capsules. (a) Capsule and core diameters and (b) inner and outer shell layer thicknesses as a function of core flow rate, (c) capsule and core diameters and (d) inner and outer shell layer thicknesses as a function of annular flow rate, and (e) capsule and core diameters and (f) inner and outer shell layer thicknesses as a function of sheath flow rate (with one standard deviation error bars and three samples).

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Fig. 5

Double-layered capsules: (a) schematic and (b) representative alginate capsules (inset: fluorescent image showing different layers; scale bars: 1.0 mm)

Grahic Jump Location
Fig. 4

Three-layered coaxial nozzle. (a) Schematic of the three-layered coaxial nozzle structure. Velocity field of alginate solution flowing in the (b) annular channel and (c) sheath channel, (d) and (e) assembly of the assembled three-layered coaxial nozzle (scale bar: 4.0 mm) and the view of its nozzle outlets (scale bars: 4.0 mm for (e) and 0.5 mm for the inset), and (f) the inner set (scale bar: 1.0 mm), (g) the middle set (scale bar: 1.0 mm), and (h) the outer set (scale bar: 2.0 mm) of the three-layered coaxial nozzle.



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