Skip to main content

Advertisement

SpringerLink
Log in

Delivery of chemotropic proteins and improvement of dopaminergic neuron outgrowth through a thixotropic hybrid nano-gel

  • Published:
Journal of Materials Science: Materials in Medicine Aims and scope Submit manuscript

Abstract

Chemotropic proteins guide neuronal projections to their final target during embryo development and are useful to guide axons of neurons used in transplantation therapies. Site-specific delivery of the proteins however is needed for their application in the brain to avoid degradation and pleiotropic affects. In the present study we report the use of Poly (ethylene glycol)-Silica (PEG-Si) nanocomposite gel with thixotropic properties that make it injectable and suitable for delivery of the chemotropic protein semaphorin 3A. PEG-Si gel forms a functional gradient of semaphorin that enhances axon outgrowth of dopaminergic neurons from rat embryos or differentiated from stem cells in culture. It is not cytotoxic and its properties allowed its injection into the striatum without inflammatory response in the short term. Long term implantation however led to an increase in macrophages and glial cells. The inflammatory response could have resulted from non-degraded silica particles, as observed in biodegradation assays.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Check E. Harmful potential of viral vectors fuels doubts over gene therapy. Nature. 2003;423:573–4.

    CAS  Google Scholar 

  2. Sawyer AJ, Piepmeier JM, Saltzman WM. New methods for direct delivery of chemotherapy for treating brain tumors. Yale J Biol Med. 2006;79:141–52.

    CAS  Google Scholar 

  3. Morris MI, Fischer SA, Ison MG. Infections transmitted by transplantation. Infect Dis Clin North Am. 2010;24:497–514.

    Article  Google Scholar 

  4. McRae A, Hjorth S, Mason DW, Dillon L, Tice TR. Microencapsulated dopamine (DA)-induced restitution of function in 6-OHDA-denervated rat striatum in vivo: comparison between two microsphere excipients. J Neural Transplant Plast. 1991;2:165–73.

    Article  CAS  Google Scholar 

  5. Maysinger D, Jalsenjak I, Cuello AC. Microencapsulated nerve growth factor: effects on the forebrain neurons following devascularizing cortical lesions. Neurosci Lett. 1992;140:71–4.

    Article  CAS  Google Scholar 

  6. Klose D, Siepmann F, Willart JF, Descamps M, Siepmann J. Drug release from PLGA-based microparticles: effects of the “microparticle:bulk fluid” ratio. Int J Pharm. 2009;383:123–31.

    Article  Google Scholar 

  7. Nkansah MK, Tzeng SY, Holdt AM, Lavik EB. Poly(lactic-co-glycolic acid) nanospheres and microspheres for short- and long-term delivery of bioactive ciliary neurotrophic factor. Biotechnol Bioeng. 2008;100:1010–9.

    Article  CAS  Google Scholar 

  8. Burdick JA, Ward M, Liang E, Young MJ, Langer R. Stimulation of neurite outgrowth by neurotrophins delivered from degradable hydrogels. Biomaterials. 2006;27:452–9.

    Article  CAS  Google Scholar 

  9. Jain A, Kim YT, McKeon RJ, Bellamkonda RV. In situ gelling hydrogels for conformal repair of spinal cord defects, and local delivery of BDNF after spinal cord injury. Biomaterials. 2006;27:497–504.

    Article  CAS  Google Scholar 

  10. Piantino J, Burdick JA, Goldberg D, Langer R, Benowitz LI. An injectable, biodegradable hydrogel for trophic factor delivery enhances axonal rewiring and improves performance after spinal cord injury. Exp Neurol. 2006;201:359–67.

    Article  CAS  Google Scholar 

  11. Jhaveri SJ, Hynd MR, Dowell-Mesfin N, Turner JN, Shain W, Ober CK. Release of nerve growth factor from HEMA hydrogel-coated substrates and its effect on the differentiation of neural cells. Biomacromolecules. 2009;10:174–83.

    Article  CAS  Google Scholar 

  12. Lee K, Silva EA, Mooney DJ. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. J R Soc Interface. 2011;8:153–70.

    Article  CAS  Google Scholar 

  13. Bagnard D, Lohrum M, Uziel D, Puschel AW, Bolz J. Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections. Development. 1998;125:5043–53.

    CAS  Google Scholar 

  14. Bagnard D, Thomasset N, Lohrum M, Puschel AW, Bolz J. Spatial distributions of guidance molecules regulate chemorepulsion and chemoattraction of growth cones. J Neurosci. 2000;20:1030–5.

    CAS  Google Scholar 

  15. Rosentreter SM, Davenport RW, Loschinger J, Huf J, Jung J, Bonhoeffer F. Response of retinal ganglion cell axons to striped linear gradients of repellent guidance molecules. J Neurobiol. 1998;37:541–62.

    Article  CAS  Google Scholar 

  16. Isbister CM, Mackenzie PJ, To KC, O’Connor TP. Gradient steepness influences the pathfinding decisions of neuronal growth cones in vivo. J Neurosci. 2003;23:193–202.

    CAS  Google Scholar 

  17. Unified nomenclature for the semaphorins/collapsins. Semaphorin Nomenclature Committee. Cell. 1999;97:551–52.

    Google Scholar 

  18. Tessier-Lavigne M, Goodman CS. The molecular biology of axon guidance. Science. 1996;274:1123–33.

    Article  CAS  Google Scholar 

  19. Messersmith EK, Leonardo ED, Shatz CJ, Tessier-Lavigne M, Goodman CS, Kolodkin AL. Semaphorin III can function as a selective chemorepellent to pattern sensory projections in the spinal cord. Neuron. 1995;14:949–59.

    Article  CAS  Google Scholar 

  20. Moreno-Flores MT, Martin-Aparicio E, Martin-Bermejo MJ, Agudo M, McMahon S, Avila J, Diaz-Nido J, Wandosell F. Semaphorin 3C preserves survival and induces neuritogenesis of cerebellar granule neurons in culture. J Neurochem. 2003;87:879–90.

    Article  CAS  Google Scholar 

  21. Polleux F, Morrow T, Ghosh A. Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature. 2000;404:567–73.

    Article  CAS  Google Scholar 

  22. Hernandez-Montiel HL, Tamariz E, Sandoval-Minero MT, Varela-Echavarria A. Semaphorins 3A, 3C, and 3F in mesencephalic dopaminergic axon pathfinding. J Comp Neurol. 2008;506:387–97.

    Article  CAS  Google Scholar 

  23. Mann F, Chauvet S, Rougon G. Semaphorins in development and adult brain: implication for neurological diseases. Prog Neurobiol. 2007;82:57–79.

    Article  CAS  Google Scholar 

  24. Song H, Ming G, He Z, Lehmann M, McKerracher L, Tessier-Lavigne M, Poo M. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science. 1998;281:1515–8.

    Article  CAS  Google Scholar 

  25. Terman JR, Kolodkin AL. Nervy links protein kinase a to plexin-mediated semaphorin repulsion. Science. 2004;303:1204–7.

    Article  CAS  Google Scholar 

  26. Castellani V, De Angelis E, Kenwrick S, Rougon G. Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. EMBO J. 2002;21:6348–57.

    Article  CAS  Google Scholar 

  27. Falk J, Bechara A, Fiore R, Nawabi H, Zhou H, Hoyo-Becerra C, Bozon M, Rougon G, Grumet M, Puschel AW, Sanes JR, Castellani V. Dual functional activity of semaphorin 3B is required for positioning the anterior commissure. Neuron. 2005;48:63–75.

    Article  Google Scholar 

  28. Schlomann U, Schwamborn JC, Muller M, Fassler R, Puschel AW. The stimulation of dendrite growth by Sema3A requires integrin engagement and focal adhesion kinase. J Cell Sci. 2009;122:2034–42.

    Article  CAS  Google Scholar 

  29. Tamariz E, Diaz-Martinez NE, Diaz NF, Garcia-Pena CM, Velasco I, Varela-Echavarria A. Axon responses of embryonic stem cell-derived dopaminergic neurons to semaphorins 3A and 3C. J Neurosci Res. 2010;88:971–80.

    CAS  Google Scholar 

  30. Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature. 2002;418:50–6.

    Article  CAS  Google Scholar 

  31. Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol. 2000;18:675–9.

    Article  CAS  Google Scholar 

  32. Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell. 2009;136:964–77.

    Article  CAS  Google Scholar 

  33. Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA. 2008;105:5856–61.

    Article  CAS  Google Scholar 

  34. Bjorklund A, Stenevi U, Schmidt RH, Dunnett SB, Gage FH. Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites. Acta Physiol Scand Suppl. 1983;522:9–18.

    CAS  Google Scholar 

  35. Isacson O, Bjorklund LM, Schumacher JM. Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson’s disease by stem cells. Ann Neurol. 2003;53(Suppl 3):S135–46.

    Article  CAS  Google Scholar 

  36. Pek YS, Wan AC, Shekaran A, Zhuo L, Ying JY. A thixotropic nanocomposite gel for three-dimensional cell culture. Nat Nanotechnol. 2008;3:671–5.

    Article  CAS  Google Scholar 

  37. Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD. Neuropilin is a semaphorin III receptor. Cell. 1997;90:753–62.

    Article  CAS  Google Scholar 

  38. Diaz NF, Guerra-Arraiza C, Diaz-Martinez NE, Salazar P, Molina-Hernandez A, Camacho-Arroyo I, Velasco I. Changes in the content of estrogen alpha and progesterone receptors during differentiation of mouse embryonic stem cells to dopamine neurons. Brain Res Bull. 2007;73:75–80.

    Article  CAS  Google Scholar 

  39. Kokubo T, Kushitani H, Sakka S, Kitsugi T, Yamamuro T. Solutions able to reproduce in vivo surface-structure changes in bioactive glass-ceramic A-W. J Biomed Mater Res. 1990;24:721–34.

    Article  CAS  Google Scholar 

  40. Luo Y, Raible D, Raper JA. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell. 1993;75:217–27.

    Article  CAS  Google Scholar 

  41. Dupeyron D, Rieumont J, González M, Castaño VM. Protein delivery by enteric copolymer nanoparticles. J Dispers Sci Technol. 2009;30:1–7.

    Article  Google Scholar 

  42. Colthup BN, Daly HL, Wiberley ES. Introduction to infrared and Raman spectroscopy. 3rd ed. San Diego: Academic Press; 1990.

    Google Scholar 

  43. Nakamoto K. Infrared and Raman spectra of inorganic and coordination compounds. 3rd ed. New York: Wiley; 1978.

    Google Scholar 

  44. Hargus G, Cooper O, Deleidi M, Levy A, Lee K, Marlow E, Yow A, Soldner F, Hockemeyer D, Hallett PJ, Osborn T, Jaenisch R, Isacson O. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats. Proc Natl Acad Sci USA. 2010;107:15921–6.

    Article  CAS  Google Scholar 

  45. Mendez I, Sadi D, Hong M. Reconstruction of the nigrostriatal pathway by simultaneous intrastriatal and intranigral dopaminergic transplants. J Neurosci. 1996;16:7216–27.

    CAS  Google Scholar 

  46. Thompson LH, Grealish S, Kirik D, Bjorklund A. Reconstruction of the nigrostriatal dopamine pathway in the adult mouse brain. Eur J Neurosci. 2009;30:625–38.

    Article  Google Scholar 

  47. Gaillard A, Decressac M, Frappe I, Fernagut PO, Prestoz L, Besnard S, Jaber M. Anatomical and functional reconstruction of the nigrostriatal pathway by intranigral transplants. Neurobiol Dis. 2009;35:477–88.

    Article  Google Scholar 

  48. Baker KA, Sadi D, Hong M, Mendez I. Simultaneous intrastriatal and intranigral dopaminergic grafts in the parkinsonian rat model: role of the intranigral graft. J Comp Neurol. 2000;426:106–16.

    Article  CAS  Google Scholar 

  49. Nikkhah G, Cunningham MG, Cenci MA, McKay RD, Bjorklund A. Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. I. Evidence for anatomical reconstruction of the nigrostriatal pathway. J Neurosci. 1995;15:3548–61.

    CAS  Google Scholar 

  50. Nikkhah G, Cunningham MG, McKay R, Bjorklund A. Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. II. Transplant-induced behavioral recovery. J Neurosci. 1995;15:3562–70.

    CAS  Google Scholar 

  51. Lee JK, Geoffroy CG, Chan AF, Tolentino KE, Crawford MJ, Leal MA, Kang B, Zheng B. Assessing spinal axon regeneration and sprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron. 2010;66:663–70.

    Article  CAS  Google Scholar 

  52. Omoto S, Ueno M, Mochio S, Takai T, Yamashita T. Genetic deletion of paired immunoglobulin-like receptor B does not promote axonal plasticity or functional recovery after traumatic brain injury. J Neurosci. 2010;30:13045–52.

    Article  CAS  Google Scholar 

  53. Nakamura Y, Fujita Y, Ueno M, Takai T, Yamashita T. Paired immunoglobulin-like receptor B knockout does not enhance axonal regeneration or locomotor recovery after spinal cord injury. J Biol Chem. 2011;286:1876–83.

    Article  CAS  Google Scholar 

  54. Van den Heuvel DM, Pasterkamp RJ. Getting connected in the dopamine system. Prog Neurobiol. 2008;85:75–93.

    Article  Google Scholar 

  55. Krieglstein K. Factors promoting survival of mesencephalic dopaminergic neurons. Cell Tissue Res. 2004;318:73–80.

    Article  CAS  Google Scholar 

  56. Stromberg I, Bjorklund L, Johansson M, Tomac A, Collins F, Olson L, Hoffer B, Humpel C. Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp Neurol. 1993;124:401–12.

    Article  CAS  Google Scholar 

  57. Tang FI, Tien LT, Zhou FC, Hoffer BJ, Wang Y. Intranigral ventral mesencephalic grafts and nigrostriatal injections of glial cell line-derived neurotrophic factor restore dopamine release in the striatum of 6-hydroxydopamine-lesioned rats. Exp Brain Res. 1998;119:287–96.

    Article  CAS  Google Scholar 

  58. Lu J, Liong M, Li Z, Zink JI, Tamanoi F. Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. Small. 2010;6:1794–805.

    Article  CAS  Google Scholar 

  59. He X, Nie H, Wang K, Tan W, Wu X, Zhang P. In vivo study of biodistribution and urinary excretion of surface-modified silica nanoparticles. Anal Chem. 2008;80:9597–603.

    Article  CAS  Google Scholar 

  60. Burns AA, Vider J, Ow H, Herz E, Penate-Medina O, Baumgart M, Larson SM, Wiesner U, Bradbury M. Fluorescent silica nanoparticles with efficient urinary excretion for nanomedicine. Nano Lett. 2009;9:442–8.

    Article  CAS  Google Scholar 

  61. Hudson SP, Padera RF, Langer R, Kohane DS. The biocompatibility of mesoporous silicates. Biomaterials. 2008;29:4045–55.

    Article  CAS  Google Scholar 

  62. Calandrelli L, Annunziata M, Della Ragione F, Laurienzo P, Malinconico M, Oliva A. Development and performance analysis of PCL/silica nanocomposites for bone regeneration. J Mater Sci Mater Med. 2010;21:2923–36.

    Article  CAS  Google Scholar 

  63. D’Agostino A, Errico ME, Malinconico M, De Rosa M, Avella M, Schiraldi C. Development of nanocomposite based on hydroxyethylmethacrylate and functionalized fumed silica: mechanical, chemico-physical and biological characterization. J Mater Sci Mater Med. 2011;22:481–90.

    Article  Google Scholar 

  64. Witasp E, Kupferschmidt N, Bengtsson L, Hultenby K, Smedman C, Paulie S, Garcia-Bennett AE, Fadeel B. Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells. Toxicol Appl Pharmacol. 2009;239:306–19.

    Article  CAS  Google Scholar 

  65. Kunzmann A, Andersson B, Thurnherr T, Krug H, Scheynius A, Fadeel B. Toxicology of engineered nanomaterials: focus on biocompatibility, biodistribution and biodegradation. Biochim Biophys Acta. 2010;1810:361–73.

    Google Scholar 

  66. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56.

    Article  CAS  Google Scholar 

  67. Vallhov H, Gabrielsson S, Stromme M, Scheynius A, Garcia-Bennett AE. Mesoporous silica particles induce size dependent effects on human dendritic cells. Nano Lett. 2007;7:3576–82.

    Article  CAS  Google Scholar 

  68. Huang X, Teng X, Chen D, Tang F, He J. The effect of the shape of mesoporous silica nanoparticles on cellular uptake and cell function. Biomaterials. 2010;31:438–48.

    Article  CAS  Google Scholar 

  69. Dutta D, Sundaram SK, Teeguarden JG, Riley BJ, Fifield LS, Jacobs JM, Addleman SR, Kaysen GA, Moudgil BM, Weber TJ. Adsorbed proteins influence the biological activity and molecular targeting of nanomaterials. Toxicol Sci. 2007;100:303–15.

    Article  CAS  Google Scholar 

  70. Cauda V, Schlossbauer A, Bein T. Bio-degradation study of colloidal mesoporous silica nanoparticles: effect of surface functionalization with organo-silanes and poly(ethylene glycol). Microp Mesop Mater. 2010;132:60–71.

    Article  CAS  Google Scholar 

  71. Xu H, Yan F, Monson EE, Kopelman R. Room-temperature preparation and characterization of poly (ethylene glycol)-coated silica nanoparticles for biomedical applications. J Biomed Mater Res. 2003;A 66:870–9.

    Article  Google Scholar 

  72. Nikkhah G, Olsson M, Eberhard J, Bentlage C, Cunningham MG, Bjorklund A. A microtransplantation approach for cell suspension grafting in the rat Parkinson model: a detailed account of the methodology. Neuroscience. 1994;63:57–72.

    Article  CAS  Google Scholar 

  73. Olanow CW. Surgical therapy for Parkinson’s disease. Eur J Neurol. 2002;9(Suppl 3):31–9.

    Article  Google Scholar 

  74. Steiner B, Winter C, Blumensath S, Paul G, Harnack D, Nikkhah G, Kupsch A. Survival and functional recovery of transplanted human dopaminergic neurons into hemiparkinsonian rats depend on the cannula size of the implantation instrument. J Neurosci Methods. 2008;169:128–34.

    Article  Google Scholar 

Download references

Acknowledgments

We thank to Fabian Diaz, Emmanuel Diaz-Martinez, Soledad Mendoza, Elsa Nydia Hernández, and Martín García-Servín for their technical support. We also thank Dororthy Pless for editing the manuscript style. This work was supported by National Council of Science and Technology of Mexico (CONACYT), grant number 82482; and National University of México (UNAM), grant DGAPA-UNAM IN217810-21 and IMPULSA02-UNAM (stem cell group).

Disclosure

Authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Instituto de Ciencias de la Salud, Universidad Veracruzana, Av. Luis Castelazo Ayala s/n, 91190, Xalapa, VER, México

    Elisa Tamariz

  2. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, 138669, Singapore

    Andrew C. A. Wan & Y. Shona Pek

  3. Instituto de Neurobiología, Universidad Nacional Autónoma de México, Blvd. Juriquilla 3001, 76230, Querétaro, QRO, México

    Magda Giordano & Alfredo Varela-Echavarría

  4. Centro de Física Aplicada y Tecnología Avanzada, Universidad Nacional Autónoma de México, Blvd. Juriquilla 3001, 76230, Querétaro, QRO, México

    Genoveva Hernández-Padrón & Víctor M. Castaño

  5. Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, 04510, México, DF, México

    Iván Velasco

Authors
  1. Elisa Tamariz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew C. A. Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. Shona Pek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Magda Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Genoveva Hernández-Padrón
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alfredo Varela-Echavarría
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Iván Velasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Víctor M. Castaño
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elisa Tamariz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tamariz, E., Wan, A.C.A., Pek, Y.S. et al. Delivery of chemotropic proteins and improvement of dopaminergic neuron outgrowth through a thixotropic hybrid nano-gel. J Mater Sci: Mater Med 22, 2097–2109 (2011). https://doi.org/10.1007/s10856-011-4385-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10856-011-4385-5

Keywords

Search

Navigation