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Effective repair of traumatically injured spinal cord by nanoscale block copolymer micelles

Abstract

Spinal cord injury results in immediate disruption of neuronal membranes, followed by extensive secondary neurodegenerative processes. A key approach for repairing injured spinal cord is to seal the damaged membranes at an early stage. Here, we show that axonal membranes injured by compression can be effectively repaired using self-assembled monomethoxy poly(ethylene glycol)-poly(d,l-lactic acid) di-block copolymer micelles. Injured spinal tissue incubated with micelles (60 nm diameter) showed rapid restoration of compound action potential and reduced calcium influx into axons for micelle concentrations much lower than the concentrations of polyethylene glycol, a known sealing agent for early-stage spinal cord injury. Intravenously injected micelles effectively recovered locomotor function and reduced the volume and inflammatory response of the lesion in injured rats, without any adverse effects. Our results show that copolymer micelles can interrupt the spread of primary spinal cord injury damage with minimal toxicity.

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Figure 1: Immediate CAP restoration in compression-injured spinal cords after treatment with mPEG–PDLLA di-block copolymer micelles.
Figure 2: Calcium influx into axons.
Figure 3: Efficiency of CAP restoration depends on micelle structure and concentration.
Figure 4: Recovery of locomotor function in rats after compression injury.
Figure 5: Lesion volume and immunoreactivity analysis of rat tissue.
Figure 6: Toxicity analysis.

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Acknowledgements

The authors cordially thank W. S. Shim for preparation of mPEG–PDLLA di-block copolymers, G. Leung for isolation of spinal cord white matter strips from guinea pigs, J. Li for fabrication of the CAP recording chamber, K. Cheng and H. Lou for help in immunostaining and image analysis, Y. Zhang for histological examination and intracerebroventricular injection of dextran–FITC, X.-M. Xu and X. Wang for instructions on immunostaining, D. Bohnert for training of survival surgery, and C. Dowell, M. Bible, G. Brock and A. Peterson for help in blood draw. The work was supported by a Showalter Trust grant from Purdue University, an Indiana Spinal Cord and Brain Injury Research Fund from the State of Indiana, and partially supported by a fund from State of Indiana (HB 1444) to R.B.B. and R01 EB7243 to J.X.C.

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J.X.C., R.S., R.B.B. and K.P. equally contributed to the concept, experimental design, materials, equipment and conduct of the study. Y.S., S.K. and T.B.H. performed the experiments. Y.S. analyzed the data. Y.S. and J.X.C. co-wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Ji-Xin Cheng.

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Shi, Y., Kim, S., Huff, T. et al. Effective repair of traumatically injured spinal cord by nanoscale block copolymer micelles. Nature Nanotech 5, 80–87 (2010). https://doi.org/10.1038/nnano.2009.303

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