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Spinal cord injury repair by implantation of structured hyaluronic acid scaffold with PLGA microspheres in the rat

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Abstract

In order to create an optimal microenvironment for neural regeneration in the lesion area after spinal cord injury (SCI), we fabricated a novel scaffold composed of a hyaluronic acid (HA) hydrogel with a longitudinal multi-tubular conformation. The scaffold was modified by binding with an anti-Nogo receptor antibody (antiNgR) and mixed further with poly(lactic-co-glycolic acid) (PLGA) microspheres containing brain-derived neurotrophic factor and vascular endothelial growth factor (HA+PLGA). In the rat, after implantation of this composite into an injured area created by a dorsal hemisection at T9-10 of the spinal cord, favorable effects were seen with regard to the promotion of spinal repair, including excellent integration of the implants with host tissue, inhibition of inflammation, and gliosis. In particular, large numbers of new blood vessels and regenerated nerve fibers were found within and around the implants. Simultaneously, the implanted rats exhibited improved locomotor recovery. Thus, this novel composite material might provide a suitable microenvironment for neural regeneration following SCI.

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References

  • Ban DX, Ning GZ, Feng SQ, Wang Y, Zhou XH, Liu Y, Chen JT (2011) Combination of activated Schwann cells with bone mesenchymal stem cells: the best cell strategy for repair after spinal cord injury in rats. Regen Med 6:707–720

    Article  CAS  PubMed  Google Scholar 

  • Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21

    Article  CAS  PubMed  Google Scholar 

  • Blight AR (1983) Cellular morphology of chronic spinal cord injury in the cat: analysis of myelinated axons by line-sampling. Neuroscience 10:521–543

    Article  CAS  PubMed  Google Scholar 

  • Chen MS, Huber AB, Haar ME van der, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403:434–439

  • Davies SJ, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390:680–683

    CAS  PubMed  Google Scholar 

  • Dray C, Rougon G, Debarbieux F (2009) Quantitative analysis by in vivo imaging of the dynamics of vascular and axonal networks in injured mouse spinal cord. Proc Natl Acad Sci U S A 106:9459–9464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ergul A, Alhusban A, Fagan SC (2012) Angiogenesis: a harmonized target for recovery after stroke. Stroke 43:2270–2274

    Article  PubMed  PubMed Central  Google Scholar 

  • Fitch MT, Doller C, Combs CK, Landreth GE, Silver J (1999) Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci 19:8182–8198

    CAS  PubMed  Google Scholar 

  • Graumann U, Ritz MF, Hausmann O (2011) Necessity for re-vascularization after spinal cord injury and the search for potential therapeutic options. Curr Neurovasc Res 8:334–341

    Article  CAS  PubMed  Google Scholar 

  • Hamers FP, Koopmans GC, Joosten EA (2006) CatWalk-assisted gait analysis in the assessment of spinal cord injury. J Neurotrauma 23:537–548

    Article  PubMed  Google Scholar 

  • Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Gröne HJ, Hämmerling GJ, Arnold B, Ganss R (2008) Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453:410–414

    Article  CAS  PubMed  Google Scholar 

  • Hou S, Xu Q, Tian W, Cui F, Cai Q, Ma J, Lee IS (2005) The repair of brain lesion by implantation of hyaluronic acid hydrogels modified with laminin. J Neurosci Methods 148:60–70

    Article  CAS  PubMed  Google Scholar 

  • Hou S, Tian W, Xu Q, Cui F, Zhang J, Lu Q, Zhao C (2006) The enhancement of cell adherence and inducement of neurite outgrowth of dorsal root ganglia co-cultured with hyaluronic acid hydrogels modified with Nogo-66 receptor antagonist in vitro. Neuroscience 137:519–529

    Article  CAS  PubMed  Google Scholar 

  • Huang YC, Huang YY (2006) Biomaterials and strategies for nerve regeneration. Artif Organs 30:514–522

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Jain A, McKeon RJ, Brady-Kalnay SM, Bellamkonda RV (2011) Sustained delivery of activated Rho GTPases and BDNF promotes axon growth in CSPG-rich regions following spinal cord injury. PLoS One 6:e16135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koehn R, Mann B, Atzet S, Prestwich G (2014) Cross-linked hyaluronic acid based gel and wound healing. Vet Surg 43:227

    Article  PubMed  Google Scholar 

  • Kosako H, Amano M, Yanagida M, Tanabe K, Nishi Y, Kaibuchi K, Inagaki M (1997) Phosphorylation of glial fibrillary acidic protein at the same sites by cleavage furrow kinase and Rho-associated kinase. J Biol Chem 272:10333–10336

    Article  CAS  PubMed  Google Scholar 

  • Lai BQ, Wang JM, Ling EA, Wu JL, Zeng YS (2014) Graft of a tissue engineered neural scaffold serves as a promising strategy to restore myelination after rat spinal cord transection. Stem Cells Dev 23:910–921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laurent TC, Laurent UB, Fraser JR (1996) The structure and function of hyaluronan: an overview. Immunol Cell Biol 74:A1–A7

    Article  CAS  PubMed  Google Scholar 

  • Li SX, Liu BP, Budel S, Li M, Ji B, Walus L, Li W, Jirik A, Rabacchi S, Choi E, Worley D, Sah DW, Pepinsky B, Lee D, Relton J, Strittmatter SM (2004) Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury. J Neurosci 24:10511–10520

    Article  CAS  PubMed  Google Scholar 

  • Ma J, Tian WM, Hou SP, Xu QY, Spector M, Cui FZ (2007) An experimental test of stroke recovery by implanting a hyaluronic acid hydrogel carrying a Nogo receptor antibody in a rat model. Biomed Mater 2:233–240

    Article  CAS  PubMed  Google Scholar 

  • McKeon RJ, Jurynec MJ, Buck CR (1999) The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J Neurosci 19:10778–10788

    CAS  PubMed  Google Scholar 

  • Muramatsu R, Takahashi C, Miyake S, Fujimura H, Mochizuki H, Yamashita T (2012) Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin. Nat Med 18:1658–1664

    Article  CAS  PubMed  Google Scholar 

  • Ning G, Tang L, Wu Q, Li Y, Zhang C, Feng S (2013) Human umbilical cord blood stem cells for spinal cord injury: early transplantation results in better local angiogenesis. Regen Med 8:271–281

    Article  CAS  PubMed  Google Scholar 

  • Nordblom J, Persson JK, Aberg J, Blom H, Engqvist H, Brismar H, Sjödahl J, Josephson A, Frostell A, Thams S, Brundin L, Svensson M, Mattsson P (2012) FGF1 containing biodegradable device with peripheral nerve grafts induces corticospinal tract regeneration and motor evoked potentials after spinal cord resection. Restor Neurol Neurosci 30:91–102

    CAS  PubMed  Google Scholar 

  • Ohab JJ, Fleming S, Blesch A, Carmichael ST (2006) A neurovascular niche for neurogenesis after stroke. J Neurosci 26:13007–13016

    Article  CAS  PubMed  Google Scholar 

  • Oudega M (2012) Molecular and cellular mechanisms underlying the role of blood vessels in spinal cord injury and repair. Cell Tissue Res 349:269–288

    Article  CAS  PubMed  Google Scholar 

  • Phng LK, Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16:196–208

    Article  CAS  PubMed  Google Scholar 

  • Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873–887

    Article  CAS  PubMed  Google Scholar 

  • Schira J, Gasis M, Estrada V, Hendricks M, Schmitz C, Trapp T, Kruse F, Kögler G, Wernet P, Hartung HP, Müller HW (2012) Significant clinical, neuropathological and behavioural recovery from acute spinal cord trauma by transplantation of a well-defined somatic stem cell from human umbilical cord blood. Brain 135:431–446

    Article  PubMed  Google Scholar 

  • Sharp KG, Dickson AR, Marchenko SA, Yee KM, Emery PN, Laidmåe I, Uibo R, Sawyer ES, Steward O, Flanagan LA (2012) Salmon fibrin treatment of spinal cord injury promotes functional recovery and density of serotonergic innervation. Exp Neurol 235:345–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, Vincent P, Pumiglia K, Temple S (2004) Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304:1338–1340

    Article  CAS  PubMed  Google Scholar 

  • Silva NA, Sousa N, Reis RL, Salgado AJ (2014) From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol 114:25–57

    Article  PubMed  Google Scholar 

  • Spanevello MD, Tajouri SI, Mirciov C, Kurniawan N, Pearse MJ, Fabri LJ, Owczarek CM, Hardy MP, Bradford RA, Ramunno ML, Turnley AM, Ruitenberg MJ, Boyd AW, Bartlett PF (2013) Acute delivery of EphA4-Fc improves functional recovery after contusive spinal cord injury in rats. J Neurotrauma 30:1023–1034

    Article  PubMed  PubMed Central  Google Scholar 

  • Stokols S, Tuszynski MH (2006) Freeze-dried agarose scaffolds with uniaxial channels stimulate and guide linear axonal growth following spinal cord injury. Biomaterials 27:443–451

    Article  CAS  PubMed  Google Scholar 

  • Struve J, Maher PC, Li YQ, Kinney S, Fehlings MG, Kuntz C 4th, Sherman LS (2005) Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferation. Glia 52:16–24

    Article  PubMed  Google Scholar 

  • Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S, Woodard EJ, Snyder EY, Eichler ME, Friedlander RM (2004) Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci U S A 101:3071–3076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang M, Zhai P, Chen X, Schreyer DJ, Sun X, Cui F (2011) Bioengineered scaffolds for spinal cord repair. Tissue Eng B Rev 17:177–194

    Article  Google Scholar 

  • Wang Y, Wei YT, Zu ZH, Ju RK, Guo MY, Wang XM, Xu QY, Cui FZ (2011) Combination of hyaluronic acid hydrogel scaffold and PLGA microspheres for supporting survival of neural stem cells. Pharm Res 28:1406–1414

    Article  CAS  PubMed  Google Scholar 

  • Wei YT, He Y, Xu CL, Wang Y, Liu BF, Wang XM, Sun XD, Cui FZ, Xu QY (2010) Hyaluronic acid hydrogel modified with nogo-66 receptor antibody and poly-L-lysine to promote axon regrowth after spinal cord injury. J Biomed Mater Res B Appl Biomater 95:110–117

    Article  PubMed  Google Scholar 

  • Xiong Y, Mahmood A, Chopp M (2010) Angiogenesis, neurogenesis and brain recovery of function following injury. Curr Opin Investig Drugs 11:298–308

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou L, Shine HD (2003) Neurotrophic factors expressed in both cortex and spinal cord induce axonal plasticity after spinal cord injury. J Neurosci Res 74:221–226

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurobiology, Beijing Institute for Brain Disorders, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Capital Medical University, 10 Xitoutiao, Youanmen, Beijing, 100069, China

    Yujun Wen, Shukui Yu, Yanhong Wu, Rongkai Ju, Hao Wang, Yujun Liu, Ying Wang & Qunyuan Xu

  2. On leave from Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China

    Yujun Wen

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  1. Yujun Wen
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  2. Shukui Yu
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  3. Yanhong Wu
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  4. Rongkai Ju
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  5. Hao Wang
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  7. Ying Wang
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Correspondence to Qunyuan Xu.

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Additional information

This study was supported by grants from the National Natural Science Foundation of China (Fund no. 81070977, no. 81200931, no. 81271388), the National Basic Research Program of China (Fund no. 2012CBA01307), and Capital Medical University Key Laboratory Research (Fund no. 2011SJZS05, no. 2012SJZS03).

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Wen, Y., Yu, S., Wu, Y. et al. Spinal cord injury repair by implantation of structured hyaluronic acid scaffold with PLGA microspheres in the rat. Cell Tissue Res 364, 17–28 (2016). https://doi.org/10.1007/s00441-015-2298-1

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  • DOI: https://doi.org/10.1007/s00441-015-2298-1

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