Calcium Alginate

  • Hua Yang
  • James R. WrightJr.


The concept of using semipermeable capsules for delivery of therapeutic biological reagents was pioneered by T. M. S. Chang over 30 years ago (Chang 1964). Over the next 15 years, a number of immunoisolation systems were developed in an attempt to protect transplanted tissues or cells from host immune rejection; most of these were hollow fibers that were loaded with isolated pancreatic islets and then transplanted into diabetic rodents as bioartificial pancreas devices (Chick 1977, Tze 1976). In 1980, Lim and Sun successfully applied an alginate-polylysine microencapsulation system to islet transplantation in a rodent model (Lim and Sun 1980). This report attracted more attention to the concept of microencapsulation, especially the alginate-polylysine system. During the last 15 years, much effort has been devoted to the study of this system (reviewed by Lanza and Chick 1997). Most of the procedures for producing these microcap sules involve extruding a mixture of cells and sodium alginate into a divalent cation solution to form water-insoluble gel droplets. The negatively charged gel droplets are then coated with positively charged polymers, such as poly-L-lysine (PLL), through ionic interaction. The primary function of the coating is to form a strong complex membrane that reduces and controls the permeability of the alginate gel sphere. Recently, Lanza et al (1995a) reported prolongation of porcine and bovine islet xenograft survival in diabetic mice without immunosuppression, using uncoated alginate gel spheres—that is, alginate droplets that have under-gone gelation in calcium chloride but have not been coated with a synthetic PLL membrane. Sub-sequently, we applied this method to an even more discordant xenograft model, fish islets transplanted into rodents. In our laboratory, fish islet xenograft survival was significantly prolonged in both diabetic mouse and rat recipients without immunosuppression (Yang et al 1996, 1997b). Further studies revealed that uncoated alginate encapsulation, in combination with immunosuppression, permitted long-term fish islet xenograft survival in diabetic mice and rats (Yang et al 1996, Yang et al 1997b), as well as long-term islet allograft survival in spontaneously diabetic dogs (Lanza et al 1995b). It was surprising that uncoated alginate gel spheres could markedly prolong islet xenograft survival, because data clearly indicate that uncoated alginate gel has sufficient porosity to permit antibodies and complement to enter (Lanza et al 1995a, Martinsen et al 1992, Tanaka et al 1984). It is clear that the immunoprotective effect could not be explained solely by the capsule’s mechanical barrier (i.e., porosity of capsule versus molecular weight of diffusents) and that more complex mechanism(s), such as biological and diffusion modulation effects by the encapsulation materials, must also play significant roles. In this chapter, we will focus on technological advances and insights that have been gained through the study of uncoated calcium alginate gel encapsulation systems.


Sodium Alginate Calcium Alginate Islet Graft Islet Tissue Islet Xenograft 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adaniya GK, Roblero L, Rawlins RG, Miller IF, Quigg JM, Zaneveld LJD. 1993. First pregnancies and live births from transfer of sodium alginate encapsulated embryos in a rodent model. Fertil Steril 59:652–655.PubMedGoogle Scholar
  2. Al-Shamkhani A, Duncan R. 1995. Radioiodination of alginate via covalently-bound tyrosinamide allows monitoring of its fate in vivo. J Bioact Compat Polymers 10:4–13.Google Scholar
  3. Bodmeier R, Paertakul O. 1989. Spherical agglomerates of water insoluble drugs. J Pharm Sei 78:964–967.CrossRefGoogle Scholar
  4. Bowersock TL, HogenEsch H, Suckow M, Porter RE, Jackson R, Park H, Park K. 1996. Oral vaccination with alginate microsphere systems. J Controlled Release 39:209–220.CrossRefGoogle Scholar
  5. Chang TMS. 1964. Semipermeable microcapsules. Science 146:524–525.PubMedCrossRefGoogle Scholar
  6. Chick WL, Perna J, Lauris W, Low D, Galletti PM, Whittemore A, Like A, Colton CK, Lysaght M. 1977. Artificial pancreas using living beta cells: effects on glucose homeostasis in diabetic rats. Science 197:780–782.PubMedCrossRefGoogle Scholar
  7. Downs EC, Robertson NE, Riss IL, Plunkett ML. 1992. Calcium alginate beads as a slow-release system for delivering angiogenic molecules in vivo and in vitro. J Cell Physiol 152:422–429.PubMedCrossRefGoogle Scholar
  8. Falorni A, Basta G, Santeusanio F, Brunetti P, Calafiore R. 1996. Culture maintenance of isolated adult porcine pancreatic islets in three-dimensional gel matrices: morphologic and functional results. Pancreas 12:221–229PubMedCrossRefGoogle Scholar
  9. Flessner MF, Dedrick RL, Schultz JS. 1985. Exchange of macromolecules between peritoneal cavity and plasma. Amer J Physiol 248:H15–25.PubMedGoogle Scholar
  10. Fraser RB, MacAulay MA, Wright JR Jr, Sun AM, Rowden G. 1995. Migration of macrophage-like cells within encapsulated islets of Langerhans maintained in tissue culture. Cell Transplant 4:529–534.PubMedCrossRefGoogle Scholar
  11. Hering BJ. 1992. Islet xenotransplantation. In: Ricordi C, ed. Pancreatic islet cell transplantation: 1892-1992— one century of transplantation for diabetes. Austin, Texas: RG Landes Company, p. 313–335.Google Scholar
  12. Jankovsky M, Vasakova L. 1996. Immobilization in alginate gels. Vet Med Praha 41:159–164.PubMedGoogle Scholar
  13. Kneafsey B, O’Shaughnessy M, Condon KC. 1996. The use of calcium alginate dressings in deep hand burns. Burns 22:40–43.PubMedCrossRefGoogle Scholar
  14. Lanza RP, Butler DH, Borland KM, Staruk JE, Faustman DL, Solomon BA, Muller TE, Rupp RG, Maki T, Monaco AP, Chick WL. 1991. Xenotransplantation of canine, bovine, and porcine islets in diabetic rats without immunosuppression. Proc Natl Acad Sei USA 88:11100–11104.CrossRefGoogle Scholar
  15. Lanza RP, Chick WL. 1997. Transplantation of encapsulated cells and tissues. Surgery 121:1–9.PubMedCrossRefGoogle Scholar
  16. Lanza RP, Kühtreiber WM, Ecker D, Staruk JE, Chick WL. 1995a. Xenotransplantation of porcine and bovine islets without immunosuppression using uncoated alginate microspheres. Transplantation 59:1377–1384.PubMedCrossRefGoogle Scholar
  17. Lanza RP, Kühtreiber WM, Ecker D, Staruk JE, Marsh J, Chick WL. 1995b. A simple method for transplanting discordant islets into rats using alginate gel spheres. Transplantation 59:1486–1487.Google Scholar
  18. Lim F, Sun AM. 1980. Microencapsulated islets as bioartifical endocrine pancreas. Science 210:908–10.PubMedCrossRefGoogle Scholar
  19. Mackenzie D. 1996. Doctors farm fish for insulin. New Scientist 152(2056):20.Google Scholar
  20. Marshall E. 1995. Gene therapy’s growing pains. Science 269:1050–1055.PubMedCrossRefGoogle Scholar
  21. Martinsen A, Skjak-Braek G, Smidsrod O. 1989. Alginate as immobilization material: I. Correlation between chemical and physical properties of alginate gel beads. Biotechnol Bioeng 33:79–89.PubMedCrossRefGoogle Scholar
  22. Martinsen A, Storro I, Skjak-Braek G. 1992. Alginate as immobilization material: III. Diffusional properties. Biotechnol Bioeng 39:186–194.PubMedCrossRefGoogle Scholar
  23. McNeely WH, Pettitt DJ. 1973. Algin. In: Whistler RL, ed. Industrial gums—polysaccharides and their derivatives. New York, Academic Press, p 49–81.Google Scholar
  24. Morris VJ. 1986. Gelation of polysaccharides. In: Mitchell JR and Ledward DA, ed. Functional properties of food macromolecules. New York, Elsevier Applied Science, p 121–128.Google Scholar
  25. Mumper RJ, Hoffman AS, Poulakkainen PA, Bouchard LS, Gombotz WR. 1994. Calcium-alginate beads for the oral delivery of transforming growth factor-β2 (TGF-β1: stabilisation of TGF-β1 by the addition of poly aery lie acid within acid-treated beads. J Controlled Rel 30:241–251.CrossRefGoogle Scholar
  26. Otterlei M, Espevik T, Ostgaard K, Skjak-Braek G, Soon-Shiong P, Smidsrod O. 1991. Induction of cytokine production from human monocytes stimulated with alginate. J Immunother 10:286–291.PubMedCrossRefGoogle Scholar
  27. Paige KT, Cima LG, Yaremchuk MJ, Schloo BL, Vacanti JP, Vacanti CA. 1996. De novo cartilage generation using calcium alginate-chondrocyte constructs. Plast Reconstr Surg 97:168–178.PubMedCrossRefGoogle Scholar
  28. Piacquadio D, Nelson DB. 1992. Alginates. A “new” dressing alternative. J Dermatol Surg Oncol 18:992–995.PubMedGoogle Scholar
  29. Pier GB. 1991. Vaccine potential of Pseudomonas aeruginosa mucoid exopolysaccharide (alginate). Antibiot Chemother 44:134–142.Google Scholar
  30. Prisant LM, Bottini B, DiPiro JT, Carr AA. 1992. Novel drug-delivery systems for hypertension. Am J Med 93:459–559.CrossRefGoogle Scholar
  31. Seymour LW, Duncan R, Strohalm J, Kopecek J. 1987. Effect of molecular weight (Mw) of N-(2-hydroxypropyl) methacrylamide copolymers on body distribution and rate of excretion after subcutaneous, intraperitoneal, and intravenous administration to rats. J Biomed Mater Res 21:1341–58.PubMedCrossRefGoogle Scholar
  32. Shimi SM, Newman EL, Hopwood D, Cushieri A. 1991. Semi-permeable microcapsules for cell culture: ultrastructural characterization. J Microencapsul 8:307–316.PubMedCrossRefGoogle Scholar
  33. Smidsrod O, Skjak-Braek G. 1990. Alginate as immobilization matrix for cells. TIBTECH 8(3):71–78.CrossRefGoogle Scholar
  34. Smidsrod O, Draget KI. Alginate gelation technologies. 1997. Special Publications of the Royal Society of Chemistry. 192:279–294.Google Scholar
  35. Soon-Shiong P, Otterlie M, Skjak-Braek G, Smidsrod O, Heintz R, Lanza RP, Espevik T. 1991. An immunological basis for the fibrotic reaction to implanted microcapsules. Transplant Proc 23:758–759.PubMedGoogle Scholar
  36. Soon-Shiong P, Feldman E, Nelson R, Komtebedde J, Smidsrod O, Skjak-Braek G, Espevik T, Heintz R, Lee M. 1992. Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets. Transplantation 5:769–774.CrossRefGoogle Scholar
  37. Soon-Shiong P, Feldman E, Nelson R, Heintz R, Yao Q, Yao Z, Zheng T, Merideth N, Skjak-Braek G, Espevik T, Smidsrod O, Sandford P. 1993. Long-term reversal of diabetes by the injection of immunoprotected islets. Proc Natl Acad Sci USA 90:5843–5847.PubMedCrossRefGoogle Scholar
  38. Tanaka H, Matsumura M, Veliky IA. 1984. Diffusion characteristics of substrates in Ca-alginate gel beads. Biotechnol Bioeng 26:53–58.PubMedCrossRefGoogle Scholar
  39. Thu B, Bruheim P, Espevik T, Smidsrod O, Soon-Shiong P, Skjak-Braek G. 1996a. Alginate polycation microcapsules. 1. Interaction between alginate and polycation. Biomaterials 17:1031–1040.PubMedCrossRefGoogle Scholar
  40. Thu B, Bruheim P, Espevik T, Smidsrod O, Soon-Shiong P, Skjak-Braek G. 1996b. Alginate polycation microcapsules. 2. Some functional properties. Biomaterials 17:1069–1079.PubMedCrossRefGoogle Scholar
  41. Tomlinson E. 1986. Site-specific drug carriers. Eng-Med 15:197–202.PubMedCrossRefGoogle Scholar
  42. Tze WJ, Wong FC, Chen LM, O’Young S. 1976. Implantable artificial endocrine pancreas unit used to restore normoglycemia in the diabetic rat. Nature 264:466–467.PubMedCrossRefGoogle Scholar
  43. Wilson PR. 1996. Dressed to heal: new options for graft site dressing. Australas J Dermatol 37:157–8.PubMedCrossRefGoogle Scholar
  44. Wright JR Jr, Polvi S, MacLean H. 1992. Experimental transplantation using principal islets of teleost fish (Brockmann bodies): Long-term function of tilapia islet tissue in diabetic nude mice. Diabetes 41:1528–1532.PubMedCrossRefGoogle Scholar
  45. Wright JR Jr. 1994. Procurement of fish islets (Brockmann bodies). In: Lanza RP, Chick WL, ed. Pancreatic islet transplantation series. Vol. 1. Procurement of pancreatic islets. Austin, Texas: RG Landes, p 123–133.Google Scholar
  46. Wright JR Jr, Yang H. 1997 Tilapia Brockmann bodies: An inexpensive, simple model for discordant islet xenotransplantation. Ann Transplant. 2(3):72–76.PubMedGoogle Scholar
  47. Wright JR Jr, Yang H, Dooley KC. 1998. Tilapia—A source of hypoxia-resistant islets for encapsulation. Cell Transplant. 7:299–307.PubMedCrossRefGoogle Scholar
  48. Yang H, O’Hali W, Kearns H, Wright JR Jr. 1996. Reversal of diabetes in rodents by encapsulated fish islets (abstract). Cell Transplant 5:5S–2.CrossRefGoogle Scholar
  49. Yang H, Wright JR Jr. 1995. A method for mass harvest0ing islets (Brockmann bodies) from teleost fish. Cell Transplant 4:621–628.PubMedCrossRefGoogle Scholar
  50. Yang H, Dickson BC, O’Hali W, Kearns H, Wright JR Jr. 1997a. Functional comparison of mouse, rat, and fish islet grafts transplanted into diabetic nude mice. Gen Comp Endocrinol 106:384–388.PubMedCrossRefGoogle Scholar
  51. Yang H, O’Hali W, Kearns H, Wright JR Jr. 1997b. Long-term function of fish islet xenografts in mice by alginate encapsulation. Transplantation 64:28–32.PubMedCrossRefGoogle Scholar
  52. Yuet PK, Kwok WY, Harries TJ, Goosen MFA. 1993. Mathematical modelling of protein diffusion and cell growth in microcapsules. In: Goosen MFA, ed. Fundamentals in animal cell encapsulation and immobilization. Boca Raton, Florida, CRC Press, p 79–111.Google Scholar
  53. Zekorn T, Siebers U, Bretzel RG, Renardy M, Planck H, Zgchocke P, Federlin K. 1990. Protection of islets of Langerhans from interleukin-1 toxicity by artificial membranes. Transplantation 50:391–394.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Hua Yang
  • James R. WrightJr.

There are no affiliations available

Personalised recommendations