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Published in: Acta Neurochirurgica 3/2018

01-03-2018 | Original Article - Spine

Non-functionalized soft alginate hydrogel promotes locomotor recovery after spinal cord injury in a rat hemimyelonectomy model

Published in: Acta Neurochirurgica | Issue 3/2018

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Abstract

Background

Spinal cord injury (SCI) and the consecutive devastating neurological sequelae have an enormous individual and economic impact. Implantation of functionalized hydrogels is a promising approach, because they can serve as a matrix for the regenerating tissue, carry and release bioactive molecules and various cell types. We already demonstrated that non-functionalized soft alginate hydrogel supported axonal outgrowth and protected neurons against oxidative stress in vitro. Here, we investigated the effects of such soft alginate hydrogels on locomotor recovery in small and large spinal cord lesions.

Method

Hemimyelonectomy of 2 mm or 4 mm length was performed in rats and soft alginate hydrogel was implanted. Functional recovery of the hindlimbs was assessed in the open field [Batto Beattie Bresnahan (BBB) score] and using swimming test [Louisville Swim score (LSS)] for 140 days post injury (DPI). Reference histology was performed.

Results

Rats that received an alginate implant into 2 mm spinal cord lesions demonstrated significantly improved locomotor recovery compared to controls detectable already at 10 DPI. At 140 DPI, they reached higher LSS and BBB scores in swimming and open field tests, respectively. However, this beneficial effect of alginate was lacking in animals with larger (4 mm) lesions. Histological examination suggested that fibrous scarring in the spinal cord was reduced after alginate implantation in comparison to controls.

Conclusions

Implantation of soft alginate hydrogel in small spinal cord lesions improved functional recovery. Possible underlying mechanisms include the mechanical stabilization of the wound, reduction of secondary damage and inhibition of fibrous scarring.
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Literature
1.
go back to reference Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME (2004) The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 7(3):269–277CrossRefPubMed Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME (2004) The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 7(3):269–277CrossRefPubMed
2.
go back to reference Vipin A, Thow XY, Mir H, Kortelainen J, Manivannan J, Al-Nashash H, All AH (2016) Natural progression of spinal cord transection injury and reorganization of neural pathways. J Neurotrauma 33(24):2191–2201CrossRefPubMed Vipin A, Thow XY, Mir H, Kortelainen J, Manivannan J, Al-Nashash H, All AH (2016) Natural progression of spinal cord transection injury and reorganization of neural pathways. J Neurotrauma 33(24):2191–2201CrossRefPubMed
4.
go back to reference Metz GA, Merkler D, Dietz V, Schwab ME, Fouad K (2000) Efficient testing of motor function in spinal cord injured rats. Brain Res 883(2):165–177CrossRefPubMed Metz GA, Merkler D, Dietz V, Schwab ME, Fouad K (2000) Efficient testing of motor function in spinal cord injured rats. Brain Res 883(2):165–177CrossRefPubMed
5.
go back to reference Bunge RP, Puckett WR, Becerra JL, Marcillo A, Quencer RM (1993) Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol 59:75–89PubMed Bunge RP, Puckett WR, Becerra JL, Marcillo A, Quencer RM (1993) Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol 59:75–89PubMed
6.
go back to reference Bunge RP, Puckett WR, Hiester ED (1997) Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries. Adv Neurol 72:305–315PubMed Bunge RP, Puckett WR, Hiester ED (1997) Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries. Adv Neurol 72:305–315PubMed
8.
go back to reference Brazda N, Müller HW (2009) Pharmacological modification of the extracellular matrix to promote regeneration of the injured brain and spinal cord. Prog Brain Res 175:269–281CrossRefPubMed Brazda N, Müller HW (2009) Pharmacological modification of the extracellular matrix to promote regeneration of the injured brain and spinal cord. Prog Brain Res 175:269–281CrossRefPubMed
11.
go back to reference Novikova LN, Novikov LN, Kellerth J-O (2003) Biopolymers and biodegradable smart implants for tissue regeneration after spinal cord injury. Curr Opin Neurol 16(6):711–715CrossRefPubMed Novikova LN, Novikov LN, Kellerth J-O (2003) Biopolymers and biodegradable smart implants for tissue regeneration after spinal cord injury. Curr Opin Neurol 16(6):711–715CrossRefPubMed
12.
go back to reference DeVolder R, Kong H-J (2012) Hydrogels for in vivo-like three-dimensional cellular studies. Wiley Interdiscip Rev Syst Biol Med 4(4):351–365CrossRefPubMed DeVolder R, Kong H-J (2012) Hydrogels for in vivo-like three-dimensional cellular studies. Wiley Interdiscip Rev Syst Biol Med 4(4):351–365CrossRefPubMed
14.
go back to reference McKay CA, Pomrenke RD, McLane JS, Schaub NJ, DeSimone EK, Ligon LA, Gilbert RJ (2014) An injectable, calcium responsive composite hydrogel for the treatment of acute spinal cord injury. ACS Appl Mater Interfaces 6(3):1424–1438CrossRefPubMedPubMedCentral McKay CA, Pomrenke RD, McLane JS, Schaub NJ, DeSimone EK, Ligon LA, Gilbert RJ (2014) An injectable, calcium responsive composite hydrogel for the treatment of acute spinal cord injury. ACS Appl Mater Interfaces 6(3):1424–1438CrossRefPubMedPubMedCentral
15.
go back to reference Suzuki Y, Kitaura M, Wu S, Kataoka K, Suzuki K, Endo K, Nishimura Y, Ide C (2002) Electrophysiological and horseradish peroxidase-tracing studies of nerve regeneration through alginate-filled gap in adult rat spinal cord. Neurosci Lett 318(3):121–124CrossRefPubMed Suzuki Y, Kitaura M, Wu S, Kataoka K, Suzuki K, Endo K, Nishimura Y, Ide C (2002) Electrophysiological and horseradish peroxidase-tracing studies of nerve regeneration through alginate-filled gap in adult rat spinal cord. Neurosci Lett 318(3):121–124CrossRefPubMed
16.
go back to reference Suzuki K, Suzuki Y, Ohnishi K, Endo K, Tanihara M, Nishimura Y (1999) Regeneration of transected spinal cord in young adult rats using freeze-dried alginate gel. Neuroreport 10(14):2891–2894CrossRefPubMed Suzuki K, Suzuki Y, Ohnishi K, Endo K, Tanihara M, Nishimura Y (1999) Regeneration of transected spinal cord in young adult rats using freeze-dried alginate gel. Neuroreport 10(14):2891–2894CrossRefPubMed
17.
go back to reference Matyash M, Despang F, Ikonomidou C, Gelinsky M (2014) Swelling and mechanical properties of alginate hydrogels with respect to promotion of neural growth. Tissue Eng Part C Methods 20(5):401–411CrossRefPubMed Matyash M, Despang F, Ikonomidou C, Gelinsky M (2014) Swelling and mechanical properties of alginate hydrogels with respect to promotion of neural growth. Tissue Eng Part C Methods 20(5):401–411CrossRefPubMed
18.
go back to reference Matyash M, Despang F, Mandal R, Fiore D, Gelinsky M, Ikonomidou C (2012) Novel soft alginate hydrogel strongly supports neurite growth and protects neurons against oxidative stress. Tissue Eng Part A 18(1–2):55–66CrossRefPubMed Matyash M, Despang F, Mandal R, Fiore D, Gelinsky M, Ikonomidou C (2012) Novel soft alginate hydrogel strongly supports neurite growth and protects neurons against oxidative stress. Tissue Eng Part A 18(1–2):55–66CrossRefPubMed
19.
go back to reference Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R, Snyder EY (2002) Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci U S A 99(5):3024–3029CrossRefPubMedPubMedCentral Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R, Snyder EY (2002) Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci U S A 99(5):3024–3029CrossRefPubMedPubMedCentral
20.
go back to reference Brechtel K, Tura A, Abdibzadeh M, Hirsch S, Conrad S, Schwab JM (2006) Intrinsic locomotor outcome in dorsal transection of rat spinal cord: predictive value of minimal incision depth. Spinal Cord 44(10):605–613CrossRefPubMed Brechtel K, Tura A, Abdibzadeh M, Hirsch S, Conrad S, Schwab JM (2006) Intrinsic locomotor outcome in dorsal transection of rat spinal cord: predictive value of minimal incision depth. Spinal Cord 44(10):605–613CrossRefPubMed
21.
go back to reference Konya D, Liao W-L, Choi H et al (2008) Functional recovery in T13-L1 hemisected rats resulting from peripheral nerve rerouting: role of central neuroplasticity. Regen Med 3(3):309–327CrossRefPubMed Konya D, Liao W-L, Choi H et al (2008) Functional recovery in T13-L1 hemisected rats resulting from peripheral nerve rerouting: role of central neuroplasticity. Regen Med 3(3):309–327CrossRefPubMed
22.
go back to reference Smith RR, Burke DA, Baldini AD, Shum-Siu A, Baltzley R, Bunger M, Magnuson DSK (2006) The Louisville swim scale: a novel assessment of hindlimb function following spinal cord injury in adult rats. J Neurotrauma 23(11):1654–1670CrossRefPubMedPubMedCentral Smith RR, Burke DA, Baldini AD, Shum-Siu A, Baltzley R, Bunger M, Magnuson DSK (2006) The Louisville swim scale: a novel assessment of hindlimb function following spinal cord injury in adult rats. J Neurotrauma 23(11):1654–1670CrossRefPubMedPubMedCentral
23.
go back to reference Lee Y-S, Lin C-Y, Jiang H-H, Depaul M, Lin VW, Silver J (2013) Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. J Neurosci 33(26):10591–10606CrossRefPubMedPubMedCentral Lee Y-S, Lin C-Y, Jiang H-H, Depaul M, Lin VW, Silver J (2013) Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. J Neurosci 33(26):10591–10606CrossRefPubMedPubMedCentral
24.
go back to reference Kataoka K, Suzuki Y, Kitada M, Hashimoto T, Chou H, Bai H, Ohta M, Wu S, Suzuki K, Ide C (2004) Alginate enhances elongation of early regenerating axons in spinal cord of young rats. Tissue Eng 10(3–4):493–504CrossRefPubMed Kataoka K, Suzuki Y, Kitada M, Hashimoto T, Chou H, Bai H, Ohta M, Wu S, Suzuki K, Ide C (2004) Alginate enhances elongation of early regenerating axons in spinal cord of young rats. Tissue Eng 10(3–4):493–504CrossRefPubMed
25.
go back to reference Kataoka K, Suzuki Y, Kitada M, Ohnishi K, Suzuki K, Tanihara M, Ide C, Endo K, Nishimura Y (2001) Alginate, a bioresorbable material derived from brown seaweed, enhances elongation of amputated axons of spinal cord in infant rats. J Biomed Mater Res 54(3):373–384CrossRefPubMed Kataoka K, Suzuki Y, Kitada M, Ohnishi K, Suzuki K, Tanihara M, Ide C, Endo K, Nishimura Y (2001) Alginate, a bioresorbable material derived from brown seaweed, enhances elongation of amputated axons of spinal cord in infant rats. J Biomed Mater Res 54(3):373–384CrossRefPubMed
26.
go back to reference Ansorena E, De Berdt P, Ucakar B et al (2013) Injectable alginate hydrogel loaded with GDNF promotes functional recovery in a hemisection model of spinal cord injury. Int J Pharm 455(1):148–158CrossRefPubMed Ansorena E, De Berdt P, Ucakar B et al (2013) Injectable alginate hydrogel loaded with GDNF promotes functional recovery in a hemisection model of spinal cord injury. Int J Pharm 455(1):148–158CrossRefPubMed
27.
go back to reference Krishna V, Konakondla S, Nicholas J, Varma A, Kindy M, Wen X (2013) Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: a systematic review. J Spinal Cord Med 36(3):174–190CrossRefPubMedPubMedCentral Krishna V, Konakondla S, Nicholas J, Varma A, Kindy M, Wen X (2013) Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: a systematic review. J Spinal Cord Med 36(3):174–190CrossRefPubMedPubMedCentral
28.
go back to reference Silva NA, Sousa N, Reis RL, Salgado AJ (2014) From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol 114:25–57CrossRefPubMed Silva NA, Sousa N, Reis RL, Salgado AJ (2014) From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol 114:25–57CrossRefPubMed
29.
go back to reference Deng B, Shen L, Wu Y, Shen Y, Ding X, Lu S, Jia J, Qian J, Ge J (2015) Delivery of alginate-chitosan hydrogel promotes endogenous repair and preserves cardiac function in rats with myocardial infarction. J Biomed Mater Res A 103(3):907–918CrossRefPubMed Deng B, Shen L, Wu Y, Shen Y, Ding X, Lu S, Jia J, Qian J, Ge J (2015) Delivery of alginate-chitosan hydrogel promotes endogenous repair and preserves cardiac function in rats with myocardial infarction. J Biomed Mater Res A 103(3):907–918CrossRefPubMed
30.
go back to reference Sarker B, Singh R, Silva R, Roether JA, Kaschta J, Detsch R, Schubert DW, Cicha I, Boccaccini AR (2014) Evaluation of fibroblasts adhesion and proliferation on alginate-gelatin crosslinked hydrogel. PLoS One 9(9):e107952CrossRefPubMedPubMedCentral Sarker B, Singh R, Silva R, Roether JA, Kaschta J, Detsch R, Schubert DW, Cicha I, Boccaccini AR (2014) Evaluation of fibroblasts adhesion and proliferation on alginate-gelatin crosslinked hydrogel. PLoS One 9(9):e107952CrossRefPubMedPubMedCentral
31.
go back to reference Birbrair A, Zhang T, Files DC, Mannava S, Smith T, Wang Z-M, Messi ML, Mintz A, Delbono O (2014) Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner. Stem Cell Res Ther 5(6):122CrossRefPubMedPubMedCentral Birbrair A, Zhang T, Files DC, Mannava S, Smith T, Wang Z-M, Messi ML, Mintz A, Delbono O (2014) Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner. Stem Cell Res Ther 5(6):122CrossRefPubMedPubMedCentral
32.
go back to reference Fernández-Klett F, Priller J (2014) The fibrotic scar in neurological disorders. Brain Pathol Zurich Switz 24(4):404–413CrossRef Fernández-Klett F, Priller J (2014) The fibrotic scar in neurological disorders. Brain Pathol Zurich Switz 24(4):404–413CrossRef
33.
go back to reference Ahmed Z, Bansal D, Tizzard K, Surey S, Esmaeili M, Gonzalez AM, Berry M, Logan A (2014) Decorin blocks scarring and cystic cavitation in acute and induces scar dissolution in chronic spinal cord wounds. Neurobiol Dis 64:163–176CrossRefPubMed Ahmed Z, Bansal D, Tizzard K, Surey S, Esmaeili M, Gonzalez AM, Berry M, Logan A (2014) Decorin blocks scarring and cystic cavitation in acute and induces scar dissolution in chronic spinal cord wounds. Neurobiol Dis 64:163–176CrossRefPubMed
34.
go back to reference Estrada V, Brazda N, Schmitz C, Heller S, Blazyca H, Martini R, Müller HW (2014) Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiol Dis 67:165–179CrossRefPubMed Estrada V, Brazda N, Schmitz C, Heller S, Blazyca H, Martini R, Müller HW (2014) Long-lasting significant functional improvement in chronic severe spinal cord injury following scar resection and polyethylene glycol implantation. Neurobiol Dis 67:165–179CrossRefPubMed
35.
go back to reference Klapka N, Hermanns S, Straten G, Masanneck C, Duis S, Hamers FPT, Müller D, Zuschratter W, Müller HW (2005) Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery. Eur J Neurosci 22(12):3047–3058CrossRefPubMed Klapka N, Hermanns S, Straten G, Masanneck C, Duis S, Hamers FPT, Müller D, Zuschratter W, Müller HW (2005) Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery. Eur J Neurosci 22(12):3047–3058CrossRefPubMed
36.
go back to reference Kwon BK, Okon E, Hillyer J, Mann C, Baptiste D, Weaver LC, Fehlings MG, Tetzlaff W (2011) A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J Neurotrauma 28(8):1545–1588CrossRefPubMedPubMedCentral Kwon BK, Okon E, Hillyer J, Mann C, Baptiste D, Weaver LC, Fehlings MG, Tetzlaff W (2011) A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J Neurotrauma 28(8):1545–1588CrossRefPubMedPubMedCentral
37.
go back to reference Vogelaar CF, König B, Krafft S, Estrada V, Brazda N, Ziegler B, Faissner A, Müller HW (2015) Pharmacological suppression of CNS scarring by Deferoxamine reduces lesion volume and increases regeneration in an in vitro model for Astroglial-fibrotic scarring and in rat spinal cord injury in vivo. PLoS One 10(7):e0134371CrossRefPubMedPubMedCentral Vogelaar CF, König B, Krafft S, Estrada V, Brazda N, Ziegler B, Faissner A, Müller HW (2015) Pharmacological suppression of CNS scarring by Deferoxamine reduces lesion volume and increases regeneration in an in vitro model for Astroglial-fibrotic scarring and in rat spinal cord injury in vivo. PLoS One 10(7):e0134371CrossRefPubMedPubMedCentral
38.
go back to reference Tamosaityte S, Galli R, Uckermann O et al (2015) Biochemical monitoring of spinal cord injury by FT-IR spectroscopy—effects of therapeutic alginate implant in rat models. PLoS One 10(11):e0142660CrossRefPubMedPubMedCentral Tamosaityte S, Galli R, Uckermann O et al (2015) Biochemical monitoring of spinal cord injury by FT-IR spectroscopy—effects of therapeutic alginate implant in rat models. PLoS One 10(11):e0142660CrossRefPubMedPubMedCentral
39.
go back to reference Steward O, Willenberg R (2017) Rodent spinal cord injury models for studies of axon regeneration. Exp Neurol 287(Pt 3):374–383CrossRefPubMed Steward O, Willenberg R (2017) Rodent spinal cord injury models for studies of axon regeneration. Exp Neurol 287(Pt 3):374–383CrossRefPubMed
40.
go back to reference Cheriyan T, Ryan DJ, Weinreb JH, Cheriyan J, Paul JC, Lafage V, Kirsch T, Errico TJ (2014) Spinal cord injury models: a review. Spinal Cord 52(8):588–595CrossRefPubMed Cheriyan T, Ryan DJ, Weinreb JH, Cheriyan J, Paul JC, Lafage V, Kirsch T, Errico TJ (2014) Spinal cord injury models: a review. Spinal Cord 52(8):588–595CrossRefPubMed
41.
go back to reference Brownstone RM, Bui TV, Stifani N (2015) Spinal circuits for motor learning. Curr Opin Neurobiol 33:166–173CrossRefPubMed Brownstone RM, Bui TV, Stifani N (2015) Spinal circuits for motor learning. Curr Opin Neurobiol 33:166–173CrossRefPubMed
42.
go back to reference Marder E, Bucher D (2001) Central pattern generators and the control of rhythmic movements. Curr Biol CB 11(23):R986–R996CrossRefPubMed Marder E, Bucher D (2001) Central pattern generators and the control of rhythmic movements. Curr Biol CB 11(23):R986–R996CrossRefPubMed
43.
45.
go back to reference Yoshida Y, Kataoka H, Kanchiku T, Suzuki H, Imajyo Y, Kato H, Taguchi T (2013) Transection method for shortening the rat spine and spinal cord. Exp Ther Med 5(2):384–388CrossRefPubMed Yoshida Y, Kataoka H, Kanchiku T, Suzuki H, Imajyo Y, Kato H, Taguchi T (2013) Transection method for shortening the rat spine and spinal cord. Exp Ther Med 5(2):384–388CrossRefPubMed
46.
go back to reference Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12(1):1–21CrossRefPubMed Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12(1):1–21CrossRefPubMed
47.
go back to reference Syková E, Jendelová P (2005) Magnetic resonance tracking of implanted adult and embryonic stem cells in injured brain and spinal cord. Ann N Y Acad Sci 1049:146–160CrossRefPubMed Syková E, Jendelová P (2005) Magnetic resonance tracking of implanted adult and embryonic stem cells in injured brain and spinal cord. Ann N Y Acad Sci 1049:146–160CrossRefPubMed
Metadata
Title
Non-functionalized soft alginate hydrogel promotes locomotor recovery after spinal cord injury in a rat hemimyelonectomy model
Publication date
01-03-2018
Published in
Acta Neurochirurgica / Issue 3/2018
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
DOI
https://doi.org/10.1007/s00701-017-3389-4

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