Growth factors such as brain-derived neurotrophic factor (BDNF) are widely used in the recovery of spinal cord injury (SCI) for promoting axonal regeneration or improving neuron survival. However, the lack of efficient delivery approaches limits their clinical applications. In this study, we constructed an efficient delivery system including collagen-binding BDNF and linear ordered collagen scaffolds (LOCS). A collagen-binding domain (CBD) was utilized to construct collagen-targeting BDNF (CBD-BDNF) to allow its specific binding to the collagen. In vitro activity assay showed that CBD-BDNF had similar bioactivity in neurite outgrowth of dorsal root ganglia and the survival of PC12 cells. CBD-BDNF was shown to have specific binding activity to collagen. Using the rat hemisection SCI model, we found that LOCS loaded with CBD-BDNF significantly improved the SCI recovery evaluated by the Basso, Beattie, and Bresnahan scale and immunohistochemical staining with anti-neurofilament antibody. Thus, this targeting drug delivery system consisting of CBD-BDNF and LOCS could be an effective strategy for the repair of SCI.
BenraissA., ArsantoJ.P., CoulonJ., ThouvenyY.Neurogenesis during caudal spinal cord regeneration in adult newts. Dev Genes Evol, 209:363. 1999.
4.
NovikovaL.N., NovikovL.N., KellerthJ.O.Survival effects of BDNF and NT-3 on axotomized rubrospinal neurons depend on the temporal pattern of neurotrophin administration. Eur J Neurosci, 12:776. 2000.
5.
OudegaM., HaggT.Neurotrophins promote regeneration of sensory axons in the adult rat spinal cord. Brain Res, 818:431. 1999.
6.
JoostenE.A., HouwelingD.A.Local acute application of BDNF in the lesioned spinal cord anti-inflammatory and anti-oxidant effects. Neuroreport, 15:1163. 2004.
7.
MitsuiT., FischerI., ShumskyJ.S., MurrayM.Transplants of fibroblasts expressing BDNF and NT-3 promote recovery of bladder and hindlimb function following spinal contusion injury in rats. Exp Neurol, 194:410. 2005.
8.
JainA., KimY.T., McKeonR.J., BellamkondaR.V.In situ gelling hydrogels for conformal repair of spinal cord defects, and local delivery of BDNF after spinal cord injury. Biomaterials, 27:497. 2006.
9.
BoccafoschiF., HabermehlJ., VesentiniS., MantovaniD.Biological performances of collagen-based scaffolds for vascular tissue engineering. Biomaterials, 26:7410. 2005.
10.
LiX., FengQ., LiuX., DongW., CuiF.Collagen-based implants reinforced by chitin fibres in a goat shank bone defect model. Biomaterials, 27:1917. 2006.
11.
JuY.E., JanmeyP.A., McCormickM.E., SawyerE.S., FlanaganL.A.Enhanced neurite growth from mammalian neurons in three-dimensional salmon fibrin gels. Biomaterials, 28:2097. 2007.
12.
LinH., ChenB., WangB., ZhaoY., SunW., DaiJ.Novel nerve guidance material prepared from bovine aponeurosis. J Biomed Mater Res A, 79:591. 2006.
13.
KrewsonC.E., KlarmanM.L., SaltzmanW.M.Distribution of nerve growth factor following direct delivery to brain interstitium. Brain Res, 680:196. 1995.
14.
SayerF.T., OudegaM., HaggT.Neurotrophins reduce degeneration of injured ascending sensory and corticospinal motor axons in adult rat spinal cord. Exp Neurol, 175:282. 2002.
15.
ChenB., LinH., WangJ., ZhaoY., WangB., ZhaoW., SunW., DaiJ.Homogeneous osteogenesis and bone regeneration by demineralized bone matrix loading with collagen-targeting bone morphogenetic protein-2. Biomaterials, 28:1027. 2007.
16.
SunW., LinH., XieH., ChenB., ZhaoW., HanQ., ZhaoY., XiaoZ., DaiJ.Collagen membranes loaded with collagen-binding human PDGF-BB accelerate wound healing in a rabbit dermal ischemic ulcer model. Growth Factors, 25:309. 2007.
17.
LinH., ChenB., SunW., ZhaoW., ZhaoY., DaiJ.The effect of collagen-targeting platelet-derived growth factor on cellularization and vascularization of collagen scaffolds. Biomaterials, 27:5708. 2006.
18.
JonesK.R., ReichardtL.F.Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc Natl Acad Sci USA, 87:8060. 1990.
19.
SinghS.M., PandaA.K.Solubilization and refolding of bacterial inclusion body proteins. J Biosci Bioeng, 99:303. 2005.
20.
NimniM.E.The molecular organization of collagen and its role in determining the biophysical properties of the connective tissues. Biorheology, 17:51. 1980.
21.
TullaM., PentikainenO.T., ViitasaloT., KapylaJ., ImpolaU., NykvistP., NissinenL., JohnsonM.S., HeinoJ.Selective binding of collagen subtypes by integrin alpha 1I, alpha 2I, and alpha 10I domains. J Biol Chem, 276:48206. 2001.
22.
KalcheimC., BardeY.A., ThoenenH., Le DouarinN.M.In vivo effect of brain-derived neurotrophic factor on the survival of developing dorsal root ganglion cells. EMBO J, 6:2871. 1987.
23.
YamadaM., SuzukiK., MizutanM., AsadaA., MatozakiT., IkeuchiT., KoizumiS., HatanakaH.Brain-derived neurotrophic factor stimulates interactions of Shp2 with phosphatidylinositol 3-kinase and Grb2 in cultured cerebral cortical neurons. J Neurochem, 73:41. 1999.
24.
HapnerS.J., NielsenK.M., ChaverraM., EsperR.M., LoebJ.A., LefcortF.NT-3 and CNTF exert dose-dependent, pleiotropic effects on cells in the immature dorsal root ganglion: neuregulin-mediated proliferation of progenitor cells and neuronal differentiation. Dev Biol, 297:182. 2006.
25.
BassoD.M., BeattieM.S., BresnahanJ.C.A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma, 12:1. 1995.
26.
GorioA., MadaschiL., Di StefanoB., CarelliS., Di GiulioA.M., De BiasiS., ColemanT., CeramiA., BrinesM.Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci USA, 102:16379. 2005.
27.
SongX.Y., LiF., ZhangF.H., ZhongJ.H., ZhouX.F.Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury. PLoS ONE, 3:e1707. 2008.
YingZ., RoyR.R., ZhongH., ZdunowskiS., EdgertonV.R., Gomez-PinillaF.BDNF-exercise interactions in the recovery of symmetrical stepping after a cervical hemisection in rats. Neuroscience, 155:1070. 2008.
