Applied Microbiology and Biotechnology

, Volume 102, Issue 22, pp 9403–9409 | Cite as

Bioproduction, purification, and application of polysialic acid

  • Jianrong WuEmail author
  • Xiaobei Zhan
  • Liming Liu
  • Xiaole XiaEmail author
Mini Review


Polysialic acid (PSA) is a negatively charged linear homopolymer linked by N-acetylneuraminic acid and widely present in vertebrates and some pathogens. PSA, commonly found on cell surfaces as glycoproteins and glycolipids, plays important roles in intercellular adhesion, cell migration, and formation and remodeling of the neural system by regulating the adhesive property of nerve cell adhesion molecules. PSA with a molecular weight that can reach as high as 260 kDa also belongs to the group II capsule polysaccharide of neonatal meningitis-causing Escherichia coli K1. To date, much effort has been devoted to developing the biotechnological production of PSA. As a non-glycosaminoglycan, PSA is a non-immunogenic and biodegradable polysaccharide that can be used as a biomaterial in protein polysialylation, tissue engineering, and drug delivery. PSA can also combine with other macromolecules to form multifunctional composites. In this mini-review, the production, purification, and application of PSA are summarized to provide a basis for further PSA applications.


Polysialic acid Non-immunogenicity Biomaterial Drug-controlled release Biological functions Biomaterial Fermentative production 


Funding information

This work is supported by the National Natural Science Foundation of China (No. 21778022), the Program of Introducing Talents of Discipline to Universities (111-2-06), the Fundamental Research Funds for the Central Universities (JUSRP51632A), and the National First-class Discipline Program of Light Industry Technology and Engineering (LITE2018-17).

Compliance with ethical standards

Ethical statement

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflicts of interest

The authors declare that they have no conflict of interest.


  1. Azurmendi HF, Vionnet J, Wrightson L, Trinh LB, Shiloach J, Freedberg DI (2007) Extracellular structure of polysialic acid explored by on cell solution NMR. Proc Natl Acad Sci U S A 104:11557–11561CrossRefGoogle Scholar
  2. Azurmendi HF, Battistel MD, Zarb J, Lichaa F, Negrete Virgen A, Shiloach J, Freedberg DI (2017) The β-reducing end in α(2-8)-polysialic acid constitutes a unique structural motif. Glycobiology 27:900–911CrossRefGoogle Scholar
  3. Bader RA, Silvers AL, Zhang N (2011) Polysialic acid-based micelles for encapsulation of hydrophobic drugs. Biomacromolecules 12:314–320CrossRefGoogle Scholar
  4. Berski S, van Bergeijk J, Schwarzer D, Stark Y, Kasper C, Scheper T, Grothe C, Gerardy-Schahn R, Kirschning A, Dräger G (2008) Synthesis and biological evaluation of a polysialic acid-based hydrogel as enzymatically degradable scaffold material for tissue engineering. Biomacromolecules 9:2353–2359CrossRefGoogle Scholar
  5. Bice I, Celik H, Wolff C, Beutel S, Zahid M, Hitzmann B, Rinas U, Kasper C, Gerardy-Schahn R, Scheper T (2013) Downstream processing of high chain length polysialic acid using membrane adsorbers and clay minerals for application in tissue engineering. Eng Life Sci 13:140–148CrossRefGoogle Scholar
  6. Bruns S, Stark Y, Röker S, Wieland M, Dräger G, Kirschning A, Stahl F, Kasper C, Scheper T (2007) Collagen biomaterial doped with colominic acid for cell culture applications with regard to peripheral nerve repair. J Biotechnol 28:335–345CrossRefGoogle Scholar
  7. Chen R, John J, Rode B, Hitzmann B, Gerardy-Schahn R, Kasper C, Scheper T (2011) Comparison of polysialic acid production in Escherichia coli K1 during batch cultivation and fed-batch cultivation applying two different control strategies. J Biotechnol 154:222–229CrossRefGoogle Scholar
  8. Chen F, Tao Y, Jin C, Xu Y, Lin BX (2015) Enhanced production of polysialic acid by metabolic engineering. Appl Microbiol Biotechnol 99:2603–2611CrossRefGoogle Scholar
  9. Colley KJ, Kitajima K, Sato C (2014) Polysialic acid: biosynthesis, novel functions and applications. Crit Rev Biochem Mol Biol 49:498–532CrossRefGoogle Scholar
  10. Constantinou A, Epenetos AA, Hreczuk-Hirst D, Jain S, Deonarain MP (2008) Modulation of antibody pharmacokinetics by chemical polysialylation. Bioconjug Chem 19:643–650CrossRefGoogle Scholar
  11. Constantinou A, Epenetos AA, Hreczuk-Hirst D, Jain S, Wright M, Chester KA, Deonarain MP (2009) Site-specific polysialylation of an antitumor single-chain Fv fragment. Bioconjug Chem 20:924–931CrossRefGoogle Scholar
  12. De Vries I, Busse C, Kopatz J, Neumann H, Beutel S, Scheper T (2017) Polysialic acid production using Escherichia coli K1 in a disposable bag reactor. Eng Life Sci 17:723–731CrossRefGoogle Scholar
  13. El Maarouf A, Petridis AK, Rutishauser U (2006) Use of polysialic acid in repair of the central nervous system. Proc Natl Acad Sci U S A 103:16989–16994CrossRefGoogle Scholar
  14. Fernandes AI, Gregoriadis G (1996) Synthesis, characterization and properties of sialylated catalase. Biochim Biophys Acta 1293:90–96CrossRefGoogle Scholar
  15. Fernandes AI, Gregoriadis G (1997) Polysialylated asparaginase: preparation, activity and pharmacokinetics. Biochim Biophys Acta 1341(1):26–34CrossRefGoogle Scholar
  16. Greco F, Arif I, Botting R, Fante C, Quintieri L, Clementi C, Schiavon O, Pasut G (2013) Polysialic acid as a drug carrier: evaluation of a new polysialic acid-epirubicin conjugate and its comparison against established drug carriers. Polym Chem-UK 4:1600–1609CrossRefGoogle Scholar
  17. Haastert-Talini K, Schaper-Rinkel J, Schmitte R, Bastian R, Mühlenhoff M, Schwarzer D, Draeger G, Su Y, Scheper T, Gerardy-Schahn R, Grothe C (2010) In vivo evaluation of polysialic acid as part of tissue-engineered nerve transplants. Tissue Eng Part A 16:3085–3098CrossRefGoogle Scholar
  18. Haile Y, Haastert K, Cesnulevicius K, Stummeyer K, Timmer M, Berski S, Dräger G, Gerardy-Schahn R, Grothe C (2007) Culturing of glial and neuronal cells on polysialic acid. Biomaterials 28:1163–1173CrossRefGoogle Scholar
  19. Haile Y, Berski S, Dräger G, Nobre A, Stummeyer K, Gerardy-Schahn R, Grothe C (2008) The effect of modified polysialic acid based hydrogels on the adhesion and viability of primary neurons and glial cells. Biomaterials 29:1880–1891CrossRefGoogle Scholar
  20. Jain S, Hreczuk-Hirst DH, McCormack B, Mital M, Epenetos A, Laing P, Gregoriadis G (2003) Polysialylated insulin: synthesis, characterization and biological activity in vivo. Biochim Biophys Acta 1622:42–49CrossRefGoogle Scholar
  21. Jung B, Shim MK, Park MJ, Jang EH, Yoon HY, Kim K, Kim JH (2017) Hydrophobically modified polysaccharide-based on polysialic acid nanoparticles as carriers for anticancer drugs. Int J Pharm 520:111–118CrossRefGoogle Scholar
  22. Kapre SV, Shaligram U (2012) Process for the preparation of highly pure polysialic acid of high molecular weights. WO Patent 0353732008Google Scholar
  23. Karlstetter M, Kopatz J, Aslanidis A, Shahraz A, Caramoy A, Linnartz-Gerlach B, Lin Y, Lückoff A, Fauser S, Düker K, Claude J, Wang Y, Ackermann J, Schmidt T, Hornung V, Skerka C, Langmann T, Neumann H (2016) Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina. EMBO Mol Med 9:154–166CrossRefGoogle Scholar
  24. Kawai Y, Takemoto M, Oda Y, Kakehi K, Ohta Y, Yamaguchi S, Miyake M (2000) Inhibition of in vitro fertilization of mouse gametes by sulfated sialic polymers. Biol Pharm Bull 23:936–940CrossRefGoogle Scholar
  25. Lassalle B, Testart J (1994) Human zona pellucida recognition associated with removal of sialic acid from human sperm surface. J Reprod Fertil 101:703–711CrossRefGoogle Scholar
  26. Lin SL, Inoue Y, Inoue S (1999) Evaluation of high-performance anion-exchange chromatography with pulsed electrochemical and fluorometric detection for extensive application to the analysis of homologous series of oligo- and polysialic acids in bioactive molecules. Glycobiology 9:807–814CrossRefGoogle Scholar
  27. Liu JL, Zhan XB, Wu JR, Lin CC, Yu DF (2010) An efficient and large-scale preparation process for polysialic acid by Escherichia coli CCTCC M208088. Biochem Eng J 53:97–103CrossRefGoogle Scholar
  28. Luo X, Hu L, Zheng H, Liu M, Liu X, Li C, Qiu Q, Zhao Z, Cheng X, Lai C, Su Y, Deng Y, Song Y (2018) Neutrophil-mediated delivery of pixantrone-loaded liposomes decorated with poly(sialic acid)-octadecylamine conjugate for lung cancer treatment. Drug Deliv 25:1200–1212CrossRefGoogle Scholar
  29. Marx M, Rivera-Milla E, Stummeyer K, Gerardy-Schahn R, Bastmeyer M (2007) Divergent evolution of the vertebrate polysialyltransferase Stx and Pst genes revealed by fish-to-mammal comparison. Dev Biol 306:560–571CrossRefGoogle Scholar
  30. Masand SN, Chen J, Perron IJ, Hammerling BC, Loers G, Schachner M, Shreiber DI (2012) The effect of glycomimetic functionalized collagen on peripheral nerve repair. Biomaterials 33:8353–8362CrossRefGoogle Scholar
  31. Miyata S, Sato C, Kitamura S, Toriyama M, Kitajima K (2004) A major flagellum sialoglycoprotein in sea urchin sperm contains a novel polysialic acid, an α2,9-linked poly-N-acetylneuraminic acid chain, capped by an 8-O-sulfated sialic acid residue. Glycobiology 14:827–840CrossRefGoogle Scholar
  32. Neyra C, Paladino J, Le BM (2014) Oxidation of sialic acid using hydrogen peroxide as a new method to tune the reducing activity. Carbohydr Res 386:92–98CrossRefGoogle Scholar
  33. Nomoto H, Iwasaki M, Endo T, Inoue S, Inoue Y, Matsumura G (1982) Structures of carbohydrate units isolated from Trout egg polysialoglycoproteins: short-cored units with oligosialosyl groups. Arch Biochem Biophys 218:335–341CrossRefGoogle Scholar
  34. Puente-Polledo L, Reglero A, González-Clemente C, Rodríguez-Aparicio LB, Ferrero MA (1998) Biochemical conditions for the production of polysialic acid by Pasteurella haemolytica A2. Glycoconj J 15:855–861CrossRefGoogle Scholar
  35. Rode B, Endres C, Ran C, Stahl F, Beutel S, Kasper C, Galuska S, Geyer R, Mühlenhoff M, Gerardy-Schahn R, Scheper T (2008) Large-scale production and homogenous purification of long chain polysialic acids from E. coli K1. J Biotechnol 135:202–209CrossRefGoogle Scholar
  36. Rodriguez-Aparicio LB, Reglero A, Ortiz AI, Luengo JM (1988) Effect of physical and chemical conditions on the production of colominic acid by Escherichia coli in a defined medium. Appl Microbiol Biotechnol 27:474–483CrossRefGoogle Scholar
  37. Shahraz A, Kopatz J, Mathy R, Kappler J, Winter D, Kapoor S, Schütza V, Scheper T, Gieselman V, Neumann H (2015) Anti-inflammatory activity of low molecular weight polysialic acid on human macrophages. Sci Rep 5:16800CrossRefGoogle Scholar
  38. Stark Y, Bruns S, Stahl F, Kasper C, Wesemann M, Grothe C, Scheper T (2008) A study on polysialic acid as a biomaterial for cell culture applications. J Biomed Mater Res A 85((1):1–13CrossRefGoogle Scholar
  39. Tecle E, Gagneux P (2015) Sugar-coated sperm: unraveling the functions of the mammalian sperm glycocalyx. Mol Reprod Dev 82:635–650CrossRefGoogle Scholar
  40. De Vries I, Schreiber S, Boßmann D, Hellmanna Z, Kopatzb J, Neumannb H, Beutel S (2018) Single-use membrane adsorbers for endotoxin removal and purification of endogenous polysialic acid from Escherichia coli K1. Biotechnol Rep, 2018, 17:110–116Google Scholar
  41. Wang XJ, Gao YP, Lu NN, Li WS, Xu JF, Ying XY, Wu G, Liao MH, Tan C, Shao LX, Lu YM, Zhang C, Fukunaga K, Han F, Du YZ (2016) Endogenous polysialic acid based micelles for calmodulin antagonist delivery against vascular dementia. ACS Appl Mater Interfaces 8:35045–35058CrossRefGoogle Scholar
  42. Williams S, Neumann A, Bremer I, Su Y, Dräger G, Kasper C, Behrens P (2015) Nanoporous silica nanoparticles as biomaterials: evaluation of different strategies for the functionalization with polysialic acid by step-by-step cytocompatibility testing. J Mater Sci-Mater M 26:125–141CrossRefGoogle Scholar
  43. Wilson DR, Zhang N, Silvers AL, Forstner MB, Bader RA (2014) Synthesis and evaluation of cyclosporine A-loaded polysialic acid-polycaprolactone micelles for rheumatoid arthritis. Eur J Pharm Sci 51:146–156CrossRefGoogle Scholar
  44. Wu J-R, Zhan X-B, Lin Y (2008) Preparation and application of PEG-PSA block copolymer. CN Patent 201010111612.XGoogle Scholar
  45. Wu JR, Lin Y, Zheng ZY, Lin CC, Zhan XB, Shen YQ (2010a) Improvement of the CuZn-superoxide dismutase enzyme activity and stability as a therapeutic agent by modification with polysialic acids. Biotechnol Lett 32:1939–1945CrossRefGoogle Scholar
  46. Wu JR, Liu JL, Zhan XB, Lin CC, Zhao H (2010b) Enhancement of polysialic acid yield by reduction of initial phosphate and feeding of ammonia water with Escherichia coli CCTCC M208088. Biotechnol Bioprocess Eng 15:657–663CrossRefGoogle Scholar
  47. Wu JR, Zhan XB, Zheng ZY, Zhang HT (2015) Synthesis and characterization of polysialic acid/carboxymethyl chitosan hydrogel with potential for drug delivery. Russ J Bioorg Chem 41:562–567CrossRefGoogle Scholar
  48. Wu J, Lu S, Zheng Z, Zhu L, Zhan X (2016) Modification with polysialic acid-PEG copolymer as a new method for improving the therapeutic efficacy of proteins. Prep Biochem Biotechnol 46:788–797CrossRefGoogle Scholar
  49. Wu J, Fu H, Zhang H, Zheng Z, Zhan X (2017) Preparation and characterization of a novel polysialic acid-hyaluronan graft copolymer potential as dermal filler. Int J Biol Macromol 99:692–698CrossRefGoogle Scholar
  50. Wu JR, Fu X, Jiang Y, Ma X, Zhang HT, Zhan XB (2018) Dipotassium phosphate improves the molecular weight stability of polysialic acid in Escherichia coli K235 culture broth. Bioresour Technol 247:30–35CrossRefGoogle Scholar
  51. Zhan X, Zhu L, Wu J, Zheng Z, Jia W (2002) Production of polysialic acid from fed-batch fermentation with pH control. Biochem Eng J 11:201–204CrossRefGoogle Scholar
  52. Zhang N, Bader RA (2012) Synthesis and characterization of polysialic acid-N-trimethyl chitosan nanoparticles for drug delivery. Nano LIFE 2:1241003CrossRefGoogle Scholar
  53. Zhang RS, Jain S, Rowland M, Hussain N, Agarwal M, Gregoriadis G (2010) Development and testing of solid dose formulations containing polysialic acid insulin conjugate: next generation of long-acting insulin. J Diabetes Sci Technol 4:532–539CrossRefGoogle Scholar
  54. Zhang T, Zhou S, Hu L, Peng B, Liu Y, Luo X, Song Y, Liu X, Deng Y (2016a) Polysialic acid-modifying liposomes for efficient delivery of epirubicin, in-vitro characterization and in-vivo evaluation. Int J Pharm 515:449–459CrossRefGoogle Scholar
  55. Zhang W, Dong D, Li P, Wang D, Mu H, Niu H, Duan J (2016b) Novel pH-sensitive polysialic acid based polymeric micelles for triggered intracellular release of hydrophobic drug. Carbohydr Polym 139:75–81CrossRefGoogle Scholar
  56. Zhang N, Xu C, Li N, Zhang S, Fu L, Chu X, Hua H, Zeng X, Zhao Y (2018a) Folate receptor-targeted mixed polysialic acid micelles for combating rheumatoid arthritis: in vitro and in vivo evaluation. Drug Deliv 25:1182–1191CrossRefGoogle Scholar
  57. Zhang T, Zhou S, Hu L, Peng B, Liu Y, Luo X, Liu X, Song Y, Deng Y (2018b) Polysialic acid-polyethylene glycol conjugate-modified liposomes as a targeted drug delivery system for epirubicin to enhance anticancer efficiency. Drug Deliv Transl Res 8:602–616CrossRefGoogle Scholar
  58. Zheng ZY, Wang SZ, Li GS, Zhan XB, Lin CC, Wu JR, Zhu L (2013) A new polysialic acid production process based on dual-stage pH control and fed-batch fermentation for higher yield and resulting high molecular weight product. Appl Microbiol Biotechnol 97:2405–2412CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of BiotechnologyJiangnan UniversityWuxiChina
  2. 2.State Key Laboratory of Food Science and TechnologyJiangnan UniversityWuxiChina

Personalised recommendations