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Biomaterials and Magnetic Stem Cell Delivery in the Treatment of Spinal Cord Injury

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Abstract

Spinal cord injury (SCI) is a serious trauma, which often results in a permanent loss of motor and sensory functions, pain and spasticity. Despite extensive research, there is currently no available therapy that would restore the lost functions after SCI in human patients. Advanced treatments use regenerative medicine or its combination with various interdisciplinary approaches such as tissue engineering or biophysical methods. This review summarizes and critically discusses the research from specific interdisciplinary fields in SCI treatment such as the development of biomaterials as scaffolds for tissue repair, and using a magnetic field for targeted cell delivery. We compare the treatment effects of synthetic non-degradable methacrylate-based hydrogels and biodegradable biological scaffolds based on extracellular matrix. The systems using magnetic fields for magnetically guided delivery of stem cells loaded with magnetic nanoparticles into the lesion site are then suggested and discussed.

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References

  1. Varma AK, Das A, Gt Wallace, Barry J, Vertegel AA, Ray SK, Banik NL (2013) Spinal cord injury: a review of current therapy, future treatments, and basic science frontiers. Neurochem Res 38:895–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fitch MT, Silver J (2008) CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Exp Neurol 209:294–301

    Article  CAS  PubMed  Google Scholar 

  3. Kubinova S, Sykova E (2012) Biomaterials combined with cell therapy for treatment of spinal cord injury. Regen Med 7:207–224

    Article  CAS  PubMed  Google Scholar 

  4. Pego AP, Kubinova S, Cizkova D, Vanicky I, Mar FM, Sousa MM, Sykova E (2012) Regenerative medicine for the treatment of spinal cord injury: more than just promises? J Cell Mol Med 16:2564–2582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Straley KS, Foo CW, Heilshorn SC (2010) Biomaterial design strategies for the treatment of spinal cord injuries. J Neurotrauma 27:1–19

    Article  PubMed  PubMed Central  Google Scholar 

  6. Liu S, Schackel T, Weidner N, Puttagunta R (2017) Biomaterial-supported cell transplantation treatments for spinal cord injury: challenges and perspectives. Front Cell Neurosci 11:430

    Article  PubMed  CAS  Google Scholar 

  7. Kubinova S (2015) New trends in spinal cord tissue engineering. Future Neurol 10:129–145

    Article  CAS  Google Scholar 

  8. Fuhrmann T, Anandakumaran PN, Shoichet MS (2017) Combinatorial therapies after spinal cord injury: how can biomaterials help? Adv Healthc Mater 6:1601130

    Article  CAS  Google Scholar 

  9. Theodore N, Hlubek R, Danielson J, Neff K, Vaickus L, Ulich TR, Ropper AE (2016) First human implantation of a bioresorbable polymer scaffold for acute traumatic spinal cord injury: a clinical pilot study for safety and feasibility. Neurosurgery 79:E305 E312

    Article  Google Scholar 

  10. Assuncao-Silva RC, Gomes ED, Sousa N, Silva NA, Salgado AJ (2015) Hydrogels and cell based therapies in spinal cord injury regeneration. Stem Cells Int 2015:948040

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Spang MT, Christman KL (2018) Extracellular matrix hydrogel therapies: in vivo applications and development. Acta Biomater 68:1–14

    Article  CAS  PubMed  Google Scholar 

  12. Sun Y, Li W, Wu X, Zhang N, Zhang Y, Ouyang S, Song X, Fang X, Seeram R, Xue W, He L, Wu W (2016) Functional self-assembling peptide nanofiber hydrogels designed for nerve degeneration. ACS Appl Mater Interfaces 8:2348–2359

    Article  CAS  PubMed  Google Scholar 

  13. Hejcl A, Lesny P, Pradny M, Michalek J, Jendelova P, Stulik J, Sykova E (2008) Biocompatible hydrogels in spinal cord injury repair. Physiol Res 57(Suppl 3):S121–132

    CAS  PubMed  Google Scholar 

  14. Kubinova S, Horak D, Hejcl A, Plichta Z, Kotek J, Proks V, Forostyak S, Sykova E (2015) SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores for spinal cord injury repair. J Tissue Eng Regen Med 9:1298–1309

    Article  CAS  PubMed  Google Scholar 

  15. Kubinova S, Horak D, Kozubenko N, Vanecek V, Proks V, Price J, Cocks G, Sykova E (2010) The use of superporous Ac-CGGASIKVAVS-OH-modified PHEMA scaffolds to promote cell adhesion and the differentiation of human fetal neural precursors. Biomaterials 31:5966–5975

    Article  CAS  PubMed  Google Scholar 

  16. Kubinova S, Horak D, Vanecek V, Plichta Z, Proks V, Sykova E (2014) The use of new surface-modified poly(2-hydroxyethyl methacrylate) hydrogels in tissue engineering: treatment of the surface with fibronectin subunits versus Ac-CGGASIKVAVS-OH, cysteine, and 2-mercaptoethanol modification. J Biomed Mater Res A 102:2315–2323

    Article  PubMed  CAS  Google Scholar 

  17. Mackova H, Plichta Z, Proks V, Kotelnikov I, Kucka J, Hlidkova H, Horak D, Kubinova S, Jirakova K (2016) RGDS- and SIKVAVS-modified superporous poly(2-hydroxyethyl methacrylate) scaffolds for tissue engineering applications. Macromol Biosci 16:1621–1631

    Article  CAS  PubMed  Google Scholar 

  18. Woerly S, Petrov P, Sykova E, Roitbak T, Simonova Z, Harvey AR (1999) Neural tissue formation within porous hydrogels implanted in brain and spinal cord lesions: ultrastructural, immunohistochemical, and diffusion studies. Tissue Eng 5:467–488

    Article  CAS  PubMed  Google Scholar 

  19. Woerly S, Pinet E, de Robertis L, Van Diep D, Bousmina M (2001) Spinal cord repair with PHPMA hydrogel containing RGD peptides (NeuroGel). Biomaterials 22:1095–1111

    Article  CAS  PubMed  Google Scholar 

  20. Hejcl A, Sedy J, Kapcalova M, Toro DA, Amemori T, Lesny P, Likavcanova-Masinova K, Krumbholcova E, Pradny M, Michalek J, Burian M, Hajek M, Jendelova P, Sykova E (2010) HPMA-RGD hydrogels seeded with mesenchymal stem cells improve functional outcome in chronic spinal cord injury. Stem Cells Dev 19:1535–1546

    Article  CAS  PubMed  Google Scholar 

  21. Lesny P, Pradny M, Jendelova P, Michalek J, Vacik J, Sykova E (2006) Macroporous hydrogels based on 2-hydroxyethyl methacrylate. Part 4: growth of rat bone marrow stromal cells in three-dimensional hydrogels with positive and negative surface charges and in polyelectrolyte complexes. J Mater Sci Mater Med 17:829–833

    Article  CAS  PubMed  Google Scholar 

  22. Hejcl A, Lesny P, Pradny M, Sedy J, Zamecnik J, Jendelova P, Michalek J, Sykova E (2009) Macroporous hydrogels based on 2-hydroxyethyl methacrylate. Part 6: 3D hydrogels with positive and negative surface charges and polyelectrolyte complexes in spinal cord injury repair. J Mater Sci Mater Med 20:1571–1577

    Article  CAS  PubMed  Google Scholar 

  23. Kubinova S, Horak D, Sykova E (2009) Cholesterol-modified superporous poly(2-hydroxyethyl methacrylate) scaffolds for tissue engineering. Biomaterials 30:4601–4609

    Article  CAS  PubMed  Google Scholar 

  24. Kubinova S, Horak D, Hejcl A, Plichta Z, Kotek J, Sykova E (2011) Highly superporous cholesterol-modified poly(2-hydroxyethyl methacrylate) scaffolds for spinal cord injury repair. J Biomed Mater Res Part A 99:618–629

    Article  CAS  Google Scholar 

  25. Ruzicka J, Romanyuk N, Hejcl A, Vetrik M, Hruby M, Cocks G, Cihlar J, Pradny M, Price J, Sykova E, Jendelova P (2013) Treating spinal cord injury in rats with a combination of human fetal neural stem cells and hydrogels modified with serotonin. Acta Neurobiol Exp (Wars) 73:102–115

    Google Scholar 

  26. Hejcl A, Ruzicka J, Proks V, Mackova H, Kubinova S, Tukmachev D, Cihlar J, Horak D, Jendelova P (2018) Dynamics of tissue ingrowth in SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores after bridging a spinal cord transection. J Mater Sci-Mater Med 29:89

    Article  PubMed  CAS  Google Scholar 

  27. Hejcl A, Ruzicka J, Kekulova K, Svobodova B, Proks V, Mackova H, Jirankova K, Karova K, Machova Urdzikova L, Kubinova S, Cihlar J, Horak D, Jendelova P (2018) Modified methacrylate hydrogels improve tissue repair after spinal cord injury. Int J Mol Sci 19:2481

    Article  PubMed Central  CAS  Google Scholar 

  28. Hejcl A, Ruzicka J, Kapcalova M, Turnovcova K, Krumbholcova E, Pradny M, Michalek J, Cihlar J, Jendelova P, Sykova E (2013) Adjusting the chemical and physical properties of hydrogels leads to improved stem cell survival and tissue ingrowth in spinal cord injury reconstruction: a comparative study of four methacrylate hydrogels. Stem Cells Dev 22:2794–2805

    Article  CAS  PubMed  Google Scholar 

  29. Machova Urdzikova L, Ruzicka J, Karova K, Kloudova A, Svobodova B, Amin A, Dubisova J, Schmidt M, Kubinova S, Jhanwar-Uniyal M, Jendelova P (2017) A green tea polyphenol epigallocatechin-3-gallate enhances neuroregeneration after spinal cord injury by altering levels of inflammatory cytokines. Neuropharmacology 126:213–223

    Article  CAS  PubMed  Google Scholar 

  30. Zhao RR, Fawcett JW (2013) Combination treatment with chondroitinase ABC in spinal cord injury–breaking the barrier. Neurosci Bull 29:477–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Saldin LT, Cramer MC, Velankar SS, White LJ, Badylak SF (2017) Extracellular matrix hydrogels from decellularized tissues: structure and function. Acta Biomater 49:1–15

    Article  CAS  PubMed  Google Scholar 

  32. Kubinova S (2017) Extracellular matrix based biomaterials for central nervous system tissue repair: the benefits and drawbacks. Neural Regen Res 12:1430–1432

    Article  PubMed  PubMed Central  Google Scholar 

  33. Swinehart IT, Badylak SF (2016) Extracellular matrix bioscaffolds in tissue remodeling and morphogenesis. Dev Dyn 245:351–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Medberry CJ, Crapo PM, Siu BF, Carruthers CA, Wolf MT, Nagarkar SP, Agrawal V, Jones KE, Kelly J, Johnson SA, Velankar SS, Watkins SC, Modo M, Badylak SF (2013) Hydrogels derived from central nervous system extracellular matrix. Biomaterials 34:1033–1040

    Article  CAS  PubMed  Google Scholar 

  35. Cornelison RC, Gonzalez-Rothi EJ, Porvasnik SL, Wellman SM, Park JH, Fuller DD, Schmidt CE (2018) Injectable hydrogels of optimized acellular nerve for injection in the injured spinal cord. Biomed Mater 13:034110

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ghuman H, Massensini AR, Donnelly J, Kim SM, Medberry CJ, Badylak SF, Modo M (2016) ECM hydrogel for the treatment of stroke: characterization of the host cell infiltrate. Biomaterials 91:166–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ghuman H, Gerwig M, Nicholls FJ, Liu JR, Donnelly J, Badylak SF, Modo M (2017) Long-term retention of ECM hydrogel after implantation into a sub-acute stroke cavity reduces lesion volume. Acta Biomater 63:50–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Raeder RH, Badylak SF, Sheehan C, Kallakury B, Metzger DW (2002) Natural anti-galactose alpha 1,3 galactose antibodies delay, but do not prevent the acceptance of extracellular matrix xenografts. Transpl Immunol 10:15–24

    Article  CAS  PubMed  Google Scholar 

  39. Badylak SF, Gilbert TW (2008) Immune response to biologic scaffold materials. Semin Immunol 20:109–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kurtz A, Oh SJ (2012) Age related changes of the extracellular matrix and stem cell maintenance. Prev Med 54(Suppl):S50–56

    Article  CAS  PubMed  Google Scholar 

  41. Koci Z, Vyborny K, Dubisova J, Vackova I, Jager A, Lunov O, Jirakova K, Kubinova S (2017) Extracellular matrix hydrogel derived from human umbilical cord as a scaffold for neural tissue repair and its comparison with extracellular matrix from porcine tissues. Tissue Eng Part C Methods 23:333–345

    Article  CAS  PubMed  Google Scholar 

  42. Tukmachev D, Forostyak S, Koci Z, Zaviskova K, Vackova I, Vyborny K, Sandvig I, Sandvig A, Medberry CJ, Badylak SF, Sykova E, Kubinova S (2016) Injectable extracellular matrix hydrogels as scaffolds for spinal cord injury repair. Tissue Eng Part A 22:306–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sung HW, Chang WH, Ma CY, Lee MH (2003) Crosslinking of biological tissues using genipin and/or carbodiimide. J Biomed Mater Res A 64:427–438

    Article  PubMed  CAS  Google Scholar 

  44. Sung HW, Huang RN, Huang LL, Tsai CC, Chiu CT (1998) Feasibility study of a natural crosslinking reagent for biological tissue fixation. J Biomed Mater Res 42:560–567

    Article  CAS  PubMed  Google Scholar 

  45. Wassenaar JW, Braden RL, Osborn KG, Christman KL (2016) Modulating in vivo degradation rate of injectable extracellular matrix hydrogels. J Mater Chem B 4:2794–2802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dalamagkas K, Tsintou M, Seifalian AM (2018) Stem cells for spinal cord injuries bearing translational potential. Neural Regen Res 13:35–42

    Article  PubMed  PubMed Central  Google Scholar 

  47. Pal R, Gopinath C, Rao NM, Banerjee P, Krishnamoorthy V, Venkataramana NK, Totey S (2010) Functional recovery after transplantation of bone marrow-derived human mesenchymal stromal cells in a rat model of spinal cord injury. Cytotherapy 12:792–806

    Article  PubMed  Google Scholar 

  48. Paul C, Samdani AF, Betz RR, Fischer I, Neuhuber B (2009) Grafting of human bone marrow stromal cells into spinal cord injury: a comparison of delivery methods. Spine (Phila Pa 1976) 34:328–334

    Article  Google Scholar 

  49. Krupa P, Vackova I, Ruzicka J, Zaviskova K, Dubisova J, Koci Z, Turnovcova K, Urdzikova LM, Kubinova S, Rehak S, Jendelova P (2018) The effect of human mesenchymal stem cells derived from Wharton's Jelly in spinal cord injury treatment is dose-dependent and can be facilitated by repeated application. Int J Mol Sci 19:1503

    Article  PubMed Central  CAS  Google Scholar 

  50. Cizkova D, Novotna I, Slovinska L, Vanicky I, Jergova S, Rosocha J, Radonak J (2011) Repetitive intrathecal catheter delivery of bone marrow mesenchymal stromal cells improves functional recovery in a rat model of contusive spinal cord injury. J Neurotrauma 28:1951–1961

    Article  PubMed  Google Scholar 

  51. Ruzicka J, Machova-Urdzikova L, Gillick J, Amemori T, Romanyuk N, Karova K, Zaviskova K, Dubisova J, Kubinova S, Murali R, Sykova E, Jhanwar-Uniyal M, Jendelova P (2017) A comparative study of three different types of stem cells for treatment of rat spinal cord injury. Cell Transpl 26:585–603

    Article  Google Scholar 

  52. Cores J, Caranasos TG, Cheng K (2015) Magnetically targeted stem cell delivery for regenerative medicine. J Funct Biomater 6:526–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yanai A, Hafeli UO, Metcalfe AL, Soema P, Addo L, Gregory-Evans CY, Po K, Shan XH, Moritz OL, Gregory-Evans K (2012) Focused magnetic stem cell targeting to the retina using superparamagnetic iron oxide nanoparticles. Cell Transpl 21:1137–1148

    Article  Google Scholar 

  54. Vandergriff AC, Hensley TM, Henry ET, Shen D, Anthony S, Zhang J, Cheng K (2014) Magnetic targeting of cardiosphere-derived stem cells with ferumoxytol nanoparticles for treating rats with myocardial infarction. Biomaterials 35:8528–8539

    Article  CAS  PubMed  Google Scholar 

  55. Kodama A, Kamei N, Kamei G, Kongcharoensombat W, Ohkawa S, Nakabayashi A, Ochi M (2012) In vivo bioluminescence imaging of transplanted bone marrow mesenchymal stromal cells using a magnetic delivery system in a rat fracture model. J Bone Joint Surg Br 94:998–1006

    Article  CAS  PubMed  Google Scholar 

  56. Kamei G, Kobayashi T, Ohkawa S, Kongcharoensombat W, Adachi N, Takazawa K, Shibuya H, Deie M, Hattori K, Goldberg JL, Ochi M (2013) Articular cartilage repair with magnetic mesenchymal stem cells. Am J Sports Med 41:1255–1264

    Article  PubMed  Google Scholar 

  57. Kamei N, Ochi M, Adachi N, Ishikawa M, Yanada S, Levin LS, Kamei G, Kobayashi T (2018) The safety and efficacy of magnetic targeting using autologous mesenchymal stem cells for cartilage repair. Knee Surg Sports Traumatol Arthrosc 26:3626–3635

    Article  PubMed  Google Scholar 

  58. Sasaki H, Tanaka N, Nakanishi K, Nishida K, Hamasaki T, Yamada K, Ochi M (2011) Therapeutic effects with magnetic targeting of bone marrow stromal cells in a rat spinal cord injury model. Spine (Phila Pa 1976) 36:933–938

    Article  Google Scholar 

  59. Nucci LP, Silva HR, Giampaoli V, Mamani JB, Nucci MP, Gamarra LF (2015) Stem cells labeled with superparamagnetic iron oxide nanoparticles in a preclinical model of cerebral ischemia: a systematic review with meta-analysis. Stem Cell Res Ther 6:27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Vanecek V, Zablotskii V, Forostyak S, Ruzicka J, Herynek V, Babic M, Jendelova P, Kubinova S, Dejneka A, Sykova E (2012) Highly efficient magnetic targeting of mesenchymal stem cells in spinal cord injury. Int J Nanomed 7:3719–3730

    Article  CAS  Google Scholar 

  61. Tukmachev D, Lunov O, Zablotskii V, Dejneka A, Babic M, Sykova E, Kubinova S (2015) An effective strategy of magnetic stem cell delivery for spinal cord injury therapy. Nanoscale 7:3954–3958

    Article  CAS  PubMed  Google Scholar 

  62. Markides H, Rotherham M, El Haj AJ (2012) Biocompatibility and toxicity of magnetic nanoparticles in regenerative medicine. J Nanomater 2012:11

    Article  CAS  Google Scholar 

  63. Jirakova K, Seneklova M, Jirak D, Turnovcova K, Vosmanska M, Babic M, Horak D, Veverka P, Jendelova P (2016) The effect of magnetic nanoparticles on neuronal differentiation of induced pluripotent stem cell-derived neural precursors. Int J Nanomed 11:6267–6281

    Article  CAS  Google Scholar 

  64. Singh N, Jenkins GJ, Asadi R, Doak SH (2010) Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev 1:5358

    Article  CAS  Google Scholar 

  65. Mahmoudi M, Hofmann H, Rothen-Rutishauser B, Petri-Fink A (2012) Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles. Chem Rev 112:2323–2338

    Article  CAS  PubMed  Google Scholar 

  66. Novotna B, Jendelova P, Kapcalova M, Rossner P Jr, Turnovcova K, Bagryantseva Y, Babic M, Horak D, Sykova E (2012) Oxidative damage to biological macromolecules in human bone marrow mesenchymal stromal cells labeled with various types of iron oxide nanoparticles. Toxicol Lett 210:53–63

    Article  CAS  PubMed  Google Scholar 

  67. Smolkova B, Uzhytchak M, Lynnyk A, Kubinova S, Dejneka A, Lunov O (2018) A critical review on selected external physical cues and modulation of cell behavior: magnetic nanoparticles, non-thermal plasma and lasers. J Funct Biomater 10:2

    Article  PubMed Central  CAS  Google Scholar 

  68. Zablotskii V, Dejneka A, Kubinova S, Le-Roy D, Dumas-Bouchiat F, Givord D, Dempsey NM, Sykova E (2013) Life on magnets: stem cell networking on micro-magnet arrays. PLoS ONE 8:e70416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zablotskii V, Lunov O, Kubinova S, Polyakova T, Sykova E, Dejneka A (2016) Effects of high-gradient magnetic fields on living cell machinery. J Phys D 49:493003

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Operational Programme Research, Development and Education in the framework of the Project “Center of Reconstructive Neuroscience”, Registration Number CZ.02.1.01/0.0./0.0/15_003/0000419 and by the Czech Science Foundation 17-03765S, 19-10365S.

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  1. Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 14220, Prague, Czech Republic

    Šárka Kubinová

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Kubinová, Š. Biomaterials and Magnetic Stem Cell Delivery in the Treatment of Spinal Cord Injury. Neurochem Res 45, 171–179 (2020). https://doi.org/10.1007/s11064-019-02808-2

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