Ongoing clinical trials are evaluating the use of stem cells as a way to treat traumatic spinal cord injury (SCI). However, the inhibitory environment present in the injured spinal cord makes it challenging to achieve the survival of these cells along with desired differentiation into the appropriate phenotypes necessary to regain function. Transplanting stem cells along with an instructive biomaterial scaffold can increase cell survival and improve differentiation efficiency. This study reviews the literature discussing different types of instructive biomaterial scaffolds developed for transplanting stem cells into the injured spinal cord. We have chosen to focus specifically on biomaterial scaffolds that direct the differentiation of neural stem cells and pluripotent stem cells since they offer the most promise for producing the cell phenotypes that could restore function after SCI. In terms of biomaterial scaffolds, this article reviews the literature associated with using hydrogels made from natural biomaterials and electrospun scaffolds for differentiating stem cells into neural phenotypes. It then presents new data showing how these different types of scaffolds can be combined for neural tissue engineering applications and provides directions for future studies.

1.
Abbasi, N., S.M. Hashemi, M. Salehi, H. Jahani, S.J. Mowla, M. Soleimani, H. Hosseinkhani (2016) Influence of oriented nanofibrous PCL scaffolds on quantitative gene expression during neural differentiation of mouse embryonic stem cells. J Biomed Mater Res A 104: 155-164.
2.
Assuncao-Silva, R.C., E.D. Gomes, N. Sousa, N.A. Silva, A.J. Salgado (2015) Hydrogels and cell based therapies in spinal cord injury regeneration. Stem Cells Int 2015: 948040.
3.
Ballios, B.G., M.J. Cooke, L. Donaldson, B.L. Coles, C.M. Morshead, D. van der Kooy, M.S. Shoichet (2015) A hyaluronan-based injectable hydrogel improves the survival and integration of stem cell progeny following transplantation. Stem Cell Reports 4: 1031-1045.
4.
Brown, A.C., T.H. Barker (2014) Fibrin-based biomaterials: modulation of macroscopic properties through rational design at the molecular level. Acta Biomater 10: 1502-1514.
5.
Bunge, M.B. (2001) Bridging areas of injury in the spinal cord. Neuroscientist 7: 325-339.
6.
Cheung, V., R. Hoshide, V. Bansal, E. Kasper, C.C. Chen (2015) Methylprednisolone in the management of spinal cord injuries: lessons from randomized, controlled trials. Surg Neurol Int 6: 142.
7.
Chew, S.Y., J. Wen, E.K. Yim, K.W. Leong (2005) Sustained release of proteins from electrospun biodegradable fibers. Biomacromolecules 6: 2017-2024.
8.
Christopherson, G.T., H. Song, H.Q. Mao (2009) The influence of fiber diameter of electrospun substrates on neural stem cell differentiation and proliferation. Biomaterials 30: 556-564.
9.
Davis, A.A., S. Temple (1994) A self-renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372: 263-266.
10.
Fawcett, J.W., R.A. Asher (1999) The glial scar and central nervous system repair. Brain Res Bull 49: 377-391.
11.
Fukushima, K., M. Enomoto, S. Tomizawa, M. Takahashi, Y. Wakabayashi, S. Itoh, Y. Kuboki, K. Shinomiya (2008) The axonal regeneration across a honeycomb collagen sponge applied to the transected spinal cord. J Med Dent Sci 55: 71-79.
12.
Greitz, D. (2006) Unraveling the riddle of syringomyelia. Neurosurg Rev 29: 251-263; discussion 264.
13.
Han, S., B. Wang, W. Jin, Z. Xiao, X. Li, W. Ding, M. Kapur, B. Chen, B. Yuan, T. Zhu, H. Wang, J. Wang, Q. Dong, W. Liang, J. Dai (2015) The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. Biomaterials 41: 89-96.
14.
Hu, B.-Y., S.-C. Zhang (2009) Differentiation of spinal motor neurons from pluripotent human stem cells. Nature Protocols 4: 1295-1304.
15.
Hutmacher, D.W., P.D. Dalton (2011) Melt electrospinning. Chem Asian J 6: 44-56.
16.
Jain, N.B., G.D. Ayers, E.N. Peterson, M.B. Harris, L. Morse, K.C. O'Connor, E. Garshick (2015) Traumatic spinal cord injury in the United States, 1993-2012. JAMA 313: 2236-2243.
17.
Johnson, P.J., A. Tatara, D.A. McCreedy, A. Shiu, S.E. Sakiyama-Elbert (2010a) Tissue-engineered fibrin scaffolds containing neural progenitors enhance functional recovery in a subacute model of SCI. Soft Matter 6: 5127-5137.
18.
Johnson, P.J., A. Tatara, A. Shiu, S.E. Sakiyama-Elbert (2010b) Controlled release of neurotrophin-3 and platelet-derived growth factor from fibrin scaffolds containing neural progenitor cells enhances survival and differentiation into neurons in a subacute model of SCI. Cell Transplant 19: 89-101.
19.
Kandel, E.R., J.H. Schwartz, T.M. Jessell (2013) Principles of Neural Science. New York, McGraw-Hill.
20.
Kaneko, A., A. Matsushita, Y. Sankai (2015) A 3D nanofibrous hydrogel and collagen sponge scaffold promotes locomotor functional recovery, spinal repair, and neuronal regeneration after complete transection of the spinal cord in adult rats. Biomed Mater 10: 015008.
21.
Khaing, Z.Z., C.E. Schmidt (2012) Advances in natural biomaterials for nerve tissue repair. Neurosci Lett 519: 103-114.
22.
Ko, J., N.K. Mohtaram, F. Ahmed, A. Montgomery, M. Carlson, P.C. Lee, S.M. Willerth, M.B. Jun (2014a) Fabrication of poly (ε- caprolactone) microfiber scaffolds with varying topography and mechanical properties for stem cell-based tissue engineering applications. J Biomater Sci Polym Ed 25: 1-17.
23.
Ko, J., S.K. Bhullar, N.K. Mohtaram, S.M. Willerth, M.B.G. Jun (2014b) Using mathematical modeling to control topographical properties of poly (ε-caprolactone) melt electrospun scaffolds. J Micromech Microeng 24: 065009.
24.
Kolehmainen, K., S.M. Willerth (2012) Preparation of 3D fibrin scaffolds for stem cell culture applications. J Vis Exp 61: e3641.
25.
Li, X., H. Liang, J. Sun, Y. Zhuang, B. Xu, J. Dai (2015) Electrospun collagen fibers with spatial patterning of SDF1α for the guidance of neural stem cells. Adv Healthc Mater 4: 1869-1876.
26.
Liu, C., Y. Huang, M. Pang, Y. Yang, S.F. Li, L.S. Liu, T. Shu, W. Zhou, X. Wang, L.M. Rong, B. Liu (2015) Tissue-engineered regeneration of completely transected spinal cord using induced neural stem cells and gelatin-electrospun poly (lactide-co-glycolide)/polyethylene glycol scaffolds. PLoS One 10: e0117709.
27.
Low, W.C., P.O. Rujitanaroj, F. Wang, J. Wang, S.Y. Chew (2015) Nanofiber-mediated release of retinoic acid and brain-derived neurotrophic factor for enhanced neuronal differentiation of neural progenitor cells. Drug Deliv Transl Res 5: 89-100.
28.
Lu, P., L. Graham, Y. Wang, D. Wu, M. Tuszynski (2014a) Promotion of survival and differentiation of neural stem cells with fibrin and growth factor cocktails after severe spinal cord injury. J Vis Exp 89: e50641.
29.
Lu, P., Y. Wang, L. Graham, K. McHale, M. Gao, D. Wu, J. Brock, A. Blesch, E.S. Rosenzweig, L.A. Havton, B. Zheng, J.M. Conner, M. Marsala, M.H. Tuszynski (2012) Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150: 1264-1273.
30.
Lu, P., G. Woodruff, Y. Wang, L. Graham, M. Hunt, D. Wu, E. Boehle, R. Ahmad, G. Poplawski, J. Brock, L.S. Goldstein, M.H. Tuszynski (2014b) Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 83: 789-796.
31.
Mahairaki, V., S.H. Lim, G.T. Christopherson, L.Y. Xu, I. Nasonkin, C. Yu, H.Q. Mao, V.E. Koliatsos (2011) Nanofiber matrices promote the neuronal differentiation of human embryonic stem cell-derived neural precursors in vitro. Tissue Eng Part A 17: 855-863.
32.
Martin, G.R. (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78: 7634-7638.
33.
McCreedy, D.A., T.S. Wilems, H. Xu, J.C. Butts, C.R. Brown, A.W. Smith, S.E. Sakiyama-Elbert (2014) Survival, differentiation, and migration of high-purity mouse embryonic stem cell-derived progenitor motor neurons in fibrin scaffolds after sub-acute spinal cord injury. Biomater Sci 2: 1672-1682.
34.
Mohtaram, N.K., J. Ko, A. Agbay, D. Rattray, P.O. Neill, A. Rajwani, R. Vasandani, H.L. Thu, M.B.G. Jun, S.M. Willerth (2015a) Development of a glial cell-derived neurotrophic factor-releasing artificial dura for neural tissue engineering applications. J Mater Chem B 3: 7974-7985.
35.
Mohtaram, N.K., J. Ko, C. King, L. Sun, N. Muller, M.B. Jun, S.M. Willerth (2015b) Electrospun biomaterial scaffolds with varied topographies for neuronal differentiation of human-induced pluripotent stem cells. J Biomed Mater Res A 103: 2591-2601.
36.
Mohtaram, N.K., J. Ko, A. Montgomery, M. Carlson, L. Sun, A. Wong, M. Robinson, M.B.G. Jun, S.M. Willerth (2014) Multifunctional electrospun scaffolds for promoting neuronal differentiation of induced pluripotent stem cells. J Biomater Tissue Eng 4: 906-914.
37.
Mohtaram, N.K., A. Montgomery, S.M. Willerth (2013) Biomaterial-based drug delivery systems for the controlled release of neurotrophic factors. Biomed Mater 8: 022001.
38.
Montgomery, A., A. Wong, N. Gabers, S.M. Willerth (2015) Engineering personalized neural tissue by combining induced pluripotent stem cells with fibrin scaffolds. Biomater Sci 3: 401-413.
39.
Rajangam, T., S.S. An (2013) Fibrinogen and fibrin based micro and nano scaffolds incorporated with drugs, proteins, cells and genes for therapeutic biomedical applications. Int J Nanomedicine 8: 3641-3662.
40.
Raspa, A., R. Pugliese, M. Maleki, F. Gelain (2016) Recent therapeutic approaches for spinal cord injury. Biotechnol Bioeng 113: 253-259.
41.
Robinson, M., S. Yau, L. Sun, N. Gabers, E. Bibault, B.R. Christie, S.M. Willerth (2015) Optimizing differentiation protocols for producing dopaminergic neurons from human induced pluripotent stem cells for tissue engineering applications. Biomark Insights suppl 1: 61-70.
42.
Schaub, N.J., C. Le Beux, J. Miao, R.J. Linhardt, J.G. Alauzun, D. Laurencin, R.J. Gilbert (2015) The effect of surface modification of aligned poly-L-lactic acid electrospun fibers on fiber degradation and neurite extension. PLoS One 10: e0136780.
43.
Scott, C.T., D. Magnus (2014) Wrongful termination: lessons from the Geron clinical trial. Stem Cells Transl Med 3: 1398-1401.
44.
Sill, T.J., H.A. von Recum (2008) Electrospinning: applications in drug delivery and tissue engineering. Biomaterials 29: 1989-2006.
45.
Silver, J., M.E. Schwab, P.G. Popovich (2014) Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb Perspect Biol 7: a020602.
46.
Sugai, K., S. Nishimura, M. Kato-Negishi, H. Onoe, S. Iwanaga, Y. Toyama, M. Matsumoto, S. Takeuchi, H. Okano, M. Nakamura (2015) Neural stem/progenitor cell-laden microfibers promote transplant survival in a mouse transected spinal cord injury model. J Neurosci Res 93: 1826-1838.
47.
Takahashi, K., K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda, S. Yamanaka (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861-872.
48.
Takahashi, K., S. Yamanaka (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676.
49.
Tetzlaff, W., E.B. Okon, S. Karimi-Abdolrezaee, C.E. Hill, J.S. Sparling, J.R. Plemel, W.T. Plunet, E.C. Tsai, D. Baptiste, L.J. Smithson, M.D. Kawaja, M.G. Fehlings, B.K. Kwon (2011) A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma 28: 1611-1682.
50.
Thomson, J.A., J. Itskovitz-Eldor, S.S. Shapiro, M.A. Waknitz, J.J. Swiergiel, V.S. Marshall, J.M. Jones (1998) Embryonic stem cell lines derived from human blastocysts. Science 282: 1145-1147.
51.
Tsukamoto, A., N. Uchida, A. Capela, T. Gorba, S. Huhn (2013) Clinical translation of human neural stem cells. Stem Cell Res Ther 4: 102.
52.
Wang, J., X. Wang, J. Wei, M. Wang (2015) Hyaluronan tetrasaccharide exerts neuroprotective effect and promotes functional recovery after acute spinal cord injury in rats. Neurochem Res 40: 98-108.
53.
Wilems, T.S., J. Pardieck, N. Iyer, S.E. Sakiyama-Elbert (2015) Combination therapy of stem cell derived neural progenitors and drug delivery of anti-inhibitory molecules for spinal cord injury. Acta Biomater 28: 23-32.
54.
Wilems, T.S., S.E. Sakiyama-Elbert (2015) Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury. J Control Release 213: 103-111.
55.
Willerth, S.M., K.J. Arendas, D.I. Gottlieb, S.E. Sakiyama-Elbert (2006) Optimization of fibrin scaffolds for differentiation of murine embryonic stem cells into neural lineage cells. Biomaterials 27: 5990-6003.
56.
Willerth, S.M., T.E. Faxel, D.I. Gottlieb, S.E. Sakiyama-Elbert (2007) The effects of soluble growth factors on embryonic stem cell differentiation inside of fibrin scaffolds. Stem Cells 25: 2235-2244.
57.
Willerth, S.M., A. Rader, S.E. Sakiyama-Elbert (2008) The effect of controlled growth factor delivery on embryonic stem cell differentiation inside fibrin scaffolds. Stem Cell Res 1: 205-218.
58.
Wilmut, I., A.E. Schnieke, J. McWhir, A.J. Kind, K.H.S. Campbell (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385: 810-813.
59.
Xie, J., M.R. Macewan, S.M. Willerth, X. Li, D.W. Moran, S.E. Sakiyama-Elbert, Y. Xia (2009a) Conductive core-sheath nanofibers and their potential application in neural tissue engineering. Adv Funct Mater 19: 2312-2318.
60.
Xie, J.W., S.M. Willerth, X.R. Li, M.R. Macewan, A. Rader, S.E. Sakiyama-Elbert, Y.N. Xia (2009b) The differentiation of embryonic stem cells seeded on electrospun nanofibers into neural lineages. Biomaterials 30: 354-362.
61.
Yang, F., C.Y. Xu, M. Kotaki, S. Wang, S. Ramakrishna (2004) Characterization of neural stem cells on electrospun poly(L-lactic acid) nanofibrous scaffold. J Biomater Sci Polym Ed 15: 1483-1497.
62.
Yuan, N., W. Tian, L. Sun, R. Yuan, J. Tao, D. Chen (2014) Neural stem cell transplantation in a double-layer collagen membrane with unequal pore sizes for spinal cord injury repair. Neural Regen Res 9: 1014-1019.
63.
Zhang, N., Y. Yin, S.J. Xu, Y.P. Wu, W.S. Chen (2012) Inflammation & apoptosis in spinal cord injury. Indian J Med Res 135: 287-296.
64.
Zhang, X., C.T. Huang, J. Chen, M.T. Pankratz, J. Xi, J. Li (2010) Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell 7: 90-100.
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