Medical care costs can reach an estimated value of $4 billion for spinal cord injuries (SCI) each year in the USA alone. With no viable treatment options available, care remains palliative and aims to minimize lifelong disabilities and complications, such as immobility, bladder and bowel dysfunction, breathing problems, and blood clots. Human hair keratin biomaterials have demonstrated efficacy in peripheral nerve injury models and were shown to improve conduction delay and increase axon number and density. In this study, a keratin hydrogel was tested in a central nervous system (CNS) application of spinal cord hemisection injury. Keratin-treated rats showed increased survival rates as well as a better functional recovery of gait properties and bladder function. Histological results demonstrated reduced glial scar formation with keratin treatment and suggested a greater degree of beneficial remodeling and cellular influx. The data provided in this pilot study suggest the possibility of using a keratin-based treatment for SCI and warrant further investigation. 1. Introduction More than 2.5 million people worldwide are effected by spinal cord injuries (SCI), with approximately 12,000 new cases each year in USA alone [1]. The majority of these cases are caused by motor vehicle accidents (36.5%) and falls (28.5%) and predominantly affect young males (80.7%) [1]. Depending on the extent of the injury, survivors can experience severe lifelong disabilities, including immobility, pressure sores, autonomic dysreflexia, neurogenic pain, and breathing problems. Most SCIs will interrupt bladder and bowel functions because the nerves controlling these processes originate in the lower segments of the spinal cord and are subsequently cut off from brain input. In the case of the bladder, loss of neural input causes voiding to become abnormal and thus requires the chronic use of catheters. SCI injury has an even greater impact when lifetime costs are considered, which easily reach millions per patient. Medical care costs alone reach an estimated value of $4 billion per year in USA [2]. Taking into account the fact that the majority of patients are young, active people who are now relegated to long-term palliative care, these numbers increase even more when considering loss of productivity and income wages [1]. Treatment options after SCI are limited, and life expectancies have not improved for patients since the 1980s. The use of the steroid methylprednisolone sodium succinate (MPSS) has fallen out of favor for many clinicians because of the lack of neurological
References
[1]
National Spinal Cord Injury Statistical Center, Facts and Figures at a Glance, University of Alabama at Birmingham, Birmingham, Ala, USA, 2013.
[2]
A. Blesch and M. H. Tuszynski, “Spinal cord injury: plasticity, regeneration and the challenge of translational drug development,” Trends in Neurosciences, vol. 32, no. 1, pp. 41–47, 2009.
[3]
M. G. Fehlings, “Editorial: recommendations regarding the use of methylprednisolone in acute spinal cord injury: making sense out of the controversy,” Spine, vol. 26, supplement 24, pp. S56–S57, 2001.
[4]
S. J. Gerndt, J. L. Rodriguez, J. W. Pawlik et al., “Consequences of high-dose steroid therapy for acute spinal cord injury,” The Journal of Trauma, vol. 42, no. 2, pp. 279–284, 1997.
[5]
R. J. Hurlbert and M. G. Hamilton, “Methylprednisolone for acute spinal cord injury: 5-year practice reversal,” The Canadian Journal of Neurological Sciences, vol. 35, no. 1, pp. 41–45, 2008.
[6]
A. M. Bagnall, L. Jones, S. Duffy, and R. P. Riemsma, “Spinal fixation surgery for acute traumatic spinal cord injury,” The Cochrane Database of Systematic Reviews, no. 1, Article ID CD004725, 2008.
[7]
M. G. Fehlings and R. G. Perrin, “The role and timing of early decompression for cervical spinal cord injury: update with a review of recent clinical evidence,” Injury, vol. 36, no. 2, supplement, pp. S13–S26, 2005.
[8]
P. Gál, P. Kravcuková, M. Mokry, and D. Kluchová, “Chemokines as possible targets in modulation of the secondary damage after acute spinal cord injury: a review,” Cellular and Molecular Neurobiology, vol. 29, no. 6-7, pp. 1025–1035, 2009.
[9]
N. Olby, “Current concepts in the management of acute spinal cord injury,” Journal of Veterinary Internal Medicine, vol. 13, no. 5, pp. 399–407, 1999.
[10]
G. Cantarella, G. di Benedetto, M. Scollo, et al., “Neutralization of tumor necrosis factor-related apoptosis-inducing ligand reduces spinal cord injury damage in mice,” Neuropsychopharmacology, vol. 10, no. 4, pp. 1–13, 2010.
[11]
D. Gupta, C. H. Tator, and M. S. Shoichet, “Fast-gelling injectable blend of hyaluronan and methylcellulose for intrathecal, localized delivery to the injured spinal cord,” Biomaterials, vol. 27, no. 11, pp. 2370–2379, 2006.
[12]
S. Woerly, V. D. Doan, N. Sosa, J. de Vellis, and A. Espinosa-Jeffrey, “Prevention of gliotic scar formation by NeuroGel allows partial endogenous repair of transected cat spinal cord,” Journal of Neuroscience Research, vol. 75, no. 2, pp. 262–272, 2004.
[13]
D. D. Pearse, F. C. Pereira, A. E. Marcillo et al., “cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury,” Nature Medicine, vol. 10, no. 6, pp. 610–616, 2004.
[14]
S. Thuret, L. D. Moon, and F. H. Gage, “Therapeutic interventions after spinal cord injury,” Nature Reviews Neuroscience, vol. 7, no. 8, pp. 628–643, 2006.
[15]
F. Z. Cui, W. M. Tian, S. P. Hou, Q. Y. Xu, and I.-S. Lee, “Hyaluronic acid hydrogel immobilized with RGD peptides for brain tissue engineering,” Journal of Materials Science: Materials in Medicine, vol. 17, no. 12, pp. 1393–1401, 2006.
[16]
J. Park, E. Lim, S. Back, H. Na, Y. Park, and K. Sun, “Nerve regeneration following spinal cord injury using matrix metalloproteinase-sensitive, hyaluronic acid-based biomimetic hydrogel scaffold containing brain-derived neurotrophic factor,” Journal of Biomedical Materials Research A, vol. 93, no. 3, pp. 1091–1099, 2010.
[17]
G. A. Silva, C. Czeisler, K. L. Niece et al., “Selective differentiation of neural progenitor cells by high-epitope density nanofibers,” Science, vol. 303, no. 5662, pp. 1352–1355, 2004.
[18]
V. M. Tysseling-Mattiace, V. Sahni, K. L. Niece et al., “Self-assembling nanofibers inhibit glial scar formation and promote axon elongation after spinal cord injury,” The Journal of Neuroscience, vol. 28, no. 14, pp. 3814–3823, 2008.
[19]
P. Sierpinski, J. Garrett, J. Ma et al., “The use of keratin biomaterials derived from human hair for the promotion of rapid regeneration of peripheral nerves,” Biomaterials, vol. 29, no. 1, pp. 118–128, 2008.
[20]
L. A. Pace, J. F. Plate, T. L. Smith, and M. E. van Dyke, “The effect of human hair keratin hydrogel on early cellular response to sciatic nerve injury in a rat model,” Biomaterials, vol. 34, no. 24, pp. 5907–5914, 2013.
[21]
R. C. de Guzman, M. R. Merrill, J. R. Richter, R. I. Hamzi, O. K. Greengauz-Roberts, and M. E. van Dyke, “Mechanical and biological properties of keratose biomaterials,” Biomaterials, vol. 32, no. 32, pp. 8205–8217, 2011.
[22]
D. Burmeister, T. Aboushwareb, J. Tan, K. Link, K.-E. Andersson, and G. Christ, “Early stages of in situ bladder regeneration in a rodent model,” Tissue Engineering A, vol. 16, no. 8, pp. 2541–2551, 2010.
[23]
T. C. Chai, H. Gemalmaz, K.-E. Andersson, J. B. Tuttle, and W. D. Steers, “Persistently increased voiding frequency despite relief of bladder outlet obstruction,” The Journal of Urology, vol. 161, no. 5, pp. 1689–1693, 1999.
[24]
A. Malmgren, C. Sj？gren, B. Uvelius, et al., “Cystometrical evaluation of bladder instability in rats with infravesical outflow obstruction,” The Journal of Urology, vol. 137, no. 6, pp. 1291–1294, 1987.
[25]
J. E. Beare, J. R. Morehouse, W. H. DeVries et al., “Gait analysis in normal and spinal contused mice using the treadscan system,” Journal of Neurotrauma, vol. 26, no. 11, pp. 2045–2056, 2009.
[26]
P. J. Apel, J. P. Garrett, P. Sierpinski et al., “Peripheral nerve regeneration using a keratin-based scaffold: long-term functional and histological outcomes in a mouse model,” The Journal of Hand Surgery, vol. 33, no. 9, pp. 1541–1547, 2008.
[27]
P. S. Hill, P. J. Apel, J. Barnwell et al., “Repair of peripheral nerve defects in rabbits using keratin hydrogel scaffolds,” Tissue Engineering A, vol. 17, no. 11-12, pp. 1499–1505, 2011.
[28]
K. S. Straley, C. W. Foo, and S. C. Heilshorn, “Biomaterial design strategies for the treatment of spinal cord injuries,” Journal of Neurotrauma, vol. 27, no. 1, pp. 1–19, 2010.
[29]
R. C. de Guzman, J. M. Saul, M. D. Ellenburg, et al., “Bone regeneration with BMP-2 delivered from keratose scaffolds,” Biomaterials, vol. 34, no. 6, pp. 1644–1656, 2013.
[30]
J. Kirfel, T. M. Magin, and J. Reichelt, “Keratins: a structural scaffold with emerging functions,” Cellular and Molecular Life Sciences, vol. 60, no. 1, pp. 56–71, 2003.
[31]
P. L. Ditunno, M. Patrick, M. Stineman, and J. F. Ditunno, “Who wants to walk? Preferences for recovery after SCI: a longitudinal and cross-sectional study,” Spinal Cord, vol. 46, no. 7, pp. 500–506, 2008.
[32]
P. L. Ditunno, M. Patrick, M. Stineman, B. Morganti, A. F. Townson, and J. F. Ditunno, “Cross-cultural differences in preference for recovery of mobility among spinal cord injury rehabilitation professionals,” Spinal Cord, vol. 44, no. 9, pp. 567–575, 2006.
[33]
D. M. Basso, L. C. Fisher, A. J. Anderson, L. B. Jakeman, D. M. McTigue, and P. G. Popovich, “Basso mouse scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains,” Journal of Neurotrauma, vol. 23, no. 5, pp. 635–659, 2006.
[34]
P. L. Kuhn and J. R. Wrathall, “A mouse model of graded contusive spinal cord injury,” Journal of Neurotrauma, vol. 15, no. 2, pp. 125–140, 1998.
[35]
M. Ma, D. M. Basso, P. Walters, B. T. Stokes, and L. B. Jakeman, “Behavioral and histological outcomes following graded spinal cord contusion injury in the C57Bl/6 mouse,” Experimental Neurology, vol. 169, no. 2, pp. 239–254, 2001.
[36]
J. B. Recknor and S. K. Mallapragada, “Nerve regeneration: tissue engineering strategies,” in The Biomedical Engineering Handbook: Tissue Engineering and Artificial Organs, J. D. Bronzino, Ed., pp. 48–41, Taylor & Francis, Boca Raton, Fla, USA, 3rd edition, 2006.
[37]
E. J. Bradbury and S. B. McMahon, “Spinal cord repair strategies: why do they work?” Nature Reviews Neuroscience, vol. 7, no. 8, pp. 644–653, 2006.
[38]
G. Yiu and Z. He, “Glial inhibition of CNS axon regeneration,” Nature Reviews Neuroscience, vol. 7, no. 8, pp. 617–627, 2006.
[39]
T. Karnezis, W. Mandemakers, J. L. McQualter et al., “The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination,” Nature Neuroscience, vol. 7, no. 7, pp. 736–744, 2004.
[40]
H. Wang, Y. Katagiri, T. E. McCann et al., “Chondroitin-4-sulfation negatively regulates axonal guidance and growth,” Journal of Cell Science, vol. 121, part 18, pp. 3083–3091, 2008.
[41]
H. Zhang, K. Uchimura, and K. Kadomatsu, “Brain keratan sulfate and glial scar formation,” Annals of the New York Academy of Sciences, vol. 1086, pp. 81–90, 2006.
[42]
Q. Cao, Y. P. Zhang, C. Iannotti et al., “Functional and electrophysiological changes after graded traumatic spinal cord injury in adult rat,” Experimental Neurology, vol. 191, supplement 1, pp. S3–S16, 2005.
[43]
Y. Li, R. J. Oskouian, Y.-J. Day, J. A. Kern, and J. Linden, “Optimization of a mouse locomotor rating system to evaluate compression-induced spinal cord injury: correlation of locomotor and morphological injury indices,” Journal of Neurosurgery: Spine, vol. 4, no. 2, pp. 165–173, 2006.
