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Designing a Novel Drug Delivering Nerve Guide: A Preliminary Study

  • Scott Ho
  • Pratima Labroo
  • Keng-Min Lin
  • Himanshu Sant
  • Jill Shea
  • Bruce Gale
  • Jay Agarwal
Original Article
  • 14 Downloads

Abstract

Peripheral nerve lesions caused by trauma often require the removal of the injured segment of nerve and subsequent surgical repair. Nerve injuries that produce large gaps require a “bridge” to guide axon growth. Autografts are currently the gold standard for bridging that gap but they have drawbacks including donor site morbidity and limited donor sites. Surgically implanting a nerve guidance conduit is an alternative solution to grafting. The conduits can provide guidance for the regenerating axons and allow for tension free bridging. We present a bioresorbable drug delivery conduit that relies on the mechanics of diffusion to locally deliver neurotrophins to the regeneration site. The drug delivery conduit was fabricated using solvent casting and tested for release kinetics using dextran and nerve growth factor. A drug diffusion model was also developed to test the reliability and predictability of our device, and finally the bioactivity of the released media was evaluated by measuring neurite extension in dorsal root ganglia (DRG). The results of the in vitro drug release tests showed that diffusion of drug through our conduits could be tuned by varying the hole size and reservoir size. Linear scaling can be achieved by modifying the initial concentration of drug loaded in the reservoir. The drug delivery nerve conduit was able to release bioactive NGF for 8 days and enhance DRG neurite extension. The drug delivery nerve conduit can release bioactive drugs predictably and has the potential to improve nerve regeneration following a peripheral nerve injury.

Keywords

Poly lactic-co-glycolic acid (PLGA) Nerve conduit Drug delivery Diffusion model 

Notes

Acknowledgements

The authors thank their colleagues at the State of Utah Center of Excellence for Biomedical Microfluidics and the Department of Surgery Research Laboratory for their assistance in this work.

Funding

This work is funded by the DOD Award Number W81XWH1310363.

References

  1. 1.
    Burnett, M. G., & Zager, E. L. (2004). Pathophysiology of peripheral nerve injury: A brief review. Neurosurgical Focus, 16(5), E1.CrossRefGoogle Scholar
  2. 2.
    Daly, W., Yao, L., Zeugolis, D., Windebank, A., & Pandit, A. (2012). A biomaterials approach to peripheral nerve regeneration: Bridging the peripheral nerve gap and enhancing functional recovery. Journal of the Royal Society, Interface, 9(67), 202–221.  https://doi.org/10.1098/rsif.2011.0438.CrossRefGoogle Scholar
  3. 3.
    Pabari, A., Lloyd-Hughes, H., Seifalian, A. M., & Mosahebi, A. (2014). Nerve conduits for peripheral nerve surgery. Plastic and Reconstructive Surgery, 133(6), 1420–1430.  https://doi.org/10.1097/PRS.0000000000000226.CrossRefGoogle Scholar
  4. 4.
    Fowler, J. R., Lavasani, M., Huard, J., & Goitz, R. J. (2015). Biologic strategies to improve nerve regeneration after peripheral nerve repair. Journal of Reconstructive Microsurgery, 31(4), 243–248.  https://doi.org/10.1055/s-0034-1394091.Google Scholar
  5. 5.
    Lin, K. M., Sant, H. J., Gale, B. K., & Agarwal, J. P. (2012). New approaches to bridge nerve gaps: Development of a novel drug-delivering nerve conduit. Conference Proceedings IEEE Engineering in Medicine and Biology Society, 2012, 747–750.  https://doi.org/10.1109/EMBC.2012.6346039.Google Scholar
  6. 6.
    Daly, W. T., Knight, A. M., Wang, H., de Boer, R., Giusti, G., Dadsetan, M., et al. (2013). Comparison and characterization of multiple biomaterial conduits for peripheral nerve repair. Biomaterials, 34(34), 8630–8639.  https://doi.org/10.1016/j.biomaterials.2013.07.086.CrossRefGoogle Scholar
  7. 7.
    Kehoe, S., Zhang, X. F., & Boyd, D. (2012). FDA approved guidance conduits and wraps for peripheral nerve injury: A review of materials and efficacy. Injury, 43(5), 553–572.  https://doi.org/10.1016/j.injury.2010.12.030.CrossRefGoogle Scholar
  8. 8.
    Pinho, A. C., Fonseca, A. C., Serra, A. C., Santos, J. D., & Coelho, J. F. (2016). Peripheral nerve regeneration: Current status and new strategies using polymeric materials. Advanced Healthcare Materials, 5(21), 2732–2744.  https://doi.org/10.1002/adhm.201600236.CrossRefGoogle Scholar
  9. 9.
    Zhao, Y. Z., Jiang, X., Xiao, J., Lin, Q., Yu, W. Z., Tian, F. R., et al. (2016). Using NGF heparin-poloxamer thermosensitive hydrogels to enhance the nerve regeneration for spinal cord injury. Acta Biomaterialia, 29, 71–80.  https://doi.org/10.1016/j.actbio.2015.10.014.CrossRefGoogle Scholar
  10. 10.
    Hsieh, S. C., Tang, C. M., Huang, W. T., Hsieh, L. L., Lu, C. M., Chang, C. J., et al. (2011). Comparison between two different methods of immobilizing NGF in poly(DL-lactic acid-co-glycolic acid) conduit for peripheral nerve regeneration by EDC/NHS/MES and genipin. Journal of Biomedical Materials Research Part A, 99(4), 576–585.  https://doi.org/10.1002/jbm.a.33157.CrossRefGoogle Scholar
  11. 11.
    Xu, H., Yan, Y., & Li, S. (2011). PDLLA/chondroitin sulfate/chitosan/NGF conduits for peripheral nerve regeneration. Biomaterials, 32(20), 4506–4516.  https://doi.org/10.1016/j.biomaterials.2011.02.023.CrossRefGoogle Scholar
  12. 12.
    Dong, H., Xu, D., & Xu, Y. (2006). Morphologic research on PDLLA/NGF-controlled release conduit promoting peripheral nerve regeneration. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi, 20(8), 787–790.Google Scholar
  13. 13.
    Fine, E. G., Decosterd, I., Papaloizos, M., Zurn, A. D., & Aebischer, P. (2002). GDNF and NGF released by synthetic guidance channels support sciatic nerve regeneration across a long gap. European Journal of Neuroscience, 15(4), 589–601.CrossRefGoogle Scholar
  14. 14.
    Sun, H., Xu, F., Guo, D., & Yu, H. (2012). Preparation and evaluation of NGF-microsphere conduits for regeneration of defective nerves. Neurological Research, 34(5), 491–497.  https://doi.org/10.1179/1743132812Y.0000000037.CrossRefGoogle Scholar
  15. 15.
    Madduri, S., Feldman, K., Tervoort, T., Papaloizos, M., & Gander, B. (2010). Collagen nerve conduits releasing the neurotrophic factors GDNF and NGF. Journal of Controlled Release, 143(2), 168–174.  https://doi.org/10.1016/j.jconrel.2009.12.017.CrossRefGoogle Scholar
  16. 16.
    Labroo, P., Shea, J., Sant, H., Gale, B., & Agarwal, J. (2016). Effect of combining FK506 and neurotrophins on neurite branching and elongation. Muscle and Nerve.  https://doi.org/10.1002/mus.25370.Google Scholar
  17. 17.
    Jia, X., Romero-Ortega, M. I., & Teng, Y. D. (2014). Peripheral nerve regeneration: Mechanism, cell biology, and therapies. BioMed Research International, 2014, 145304.  https://doi.org/10.1155/2014/145304.Google Scholar
  18. 18.
    Sivak, W. N., White, J. D., Bliley, J. M., Tien, L. W., Liao, H. T., Kaplan, D. L., et al. (2014). Delivery of chondroitinase ABC and glial cell line-derived neurotrophic factor from silk fibroin conduits enhances peripheral nerve regeneration. J Tissue Eng Regen Med.  https://doi.org/10.1002/term.1970.Google Scholar
  19. 19.
    Quarta, S., Baeumer, B. E., Scherbakov, N., Andratsch, M., Rose-John, S., Dechant, G., et al. (2014). Peripheral nerve regeneration and NGF-dependent neurite outgrowth of adult sensory neurons converge on STAT3 phosphorylation downstream of neuropoietic cytokine receptor gp130. Journal of Neuroscience, 34(39), 13222–13233.  https://doi.org/10.1523/JNEUROSCI.1209-13.2014.CrossRefGoogle Scholar
  20. 20.
    Wang, Z., Han, N., Wang, J., Zheng, H., Peng, J., Kou, Y., et al. (2014). Improved peripheral nerve regeneration with sustained release nerve growth factor microspheres in small gap tubulization. American Journal of Translational Research, 6(4), 413–421.Google Scholar
  21. 21.
    Griffin, M. F., Malahias, M., Hindocha, S., & Khan, W. S. (2014). Peripheral nerve injury: Principles for repair and regeneration. Open Orthop J, 8, 199–203.  https://doi.org/10.2174/1874325001408010199.CrossRefGoogle Scholar
  22. 22.
    Gentile, P., Chiono, V., Carmagnola, I., & Hatton, P. V. (2014). An overview of poly(lactic-co-glycolic) acid (PLGA)-based biomaterials for bone tissue engineering. International Journal of Molecular Sciences, 15(3), 3640–3659.  https://doi.org/10.3390/ijms15033640.CrossRefGoogle Scholar
  23. 23.
    Miller, R. A., Brady, J. M., & Cutright, D. E. (1977). Degradation rates of oral resorbable implants (polylactates and polyglycolates): Rate modification with changes in PLA/PGA copolymer ratios. Journal of Biomedical Materials Research, 11(5), 711–719.  https://doi.org/10.1002/jbm.820110507.CrossRefGoogle Scholar
  24. 24.
    Hadlock, T. A., Sheahan, T., Cheney, M. L., Vacanti, J. P., & Sundback, C. A. (2003). Biologic activity of nerve growth factor slowly released from microspheres. Journal of Reconstructive Microsurgery, 19(3), 179–184.  https://doi.org/10.1055/s-2003-39831.CrossRefGoogle Scholar
  25. 25.
    Siepmann, J., & Siepmann, F. (2012). Modeling of diffusion controlled drug delivery. Journal of Controlled Release, 161(2), 351–362.  https://doi.org/10.1016/j.jconrel.2011.10.006.CrossRefzbMATHGoogle Scholar
  26. 26.
    Barnard, A. S. (2016). Challenges in modelling nanoparticles for drug delivery. Journal of Physics: Condensed Matter, 28(2), 023002.  https://doi.org/10.1088/0953-8984/28/2/023002.Google Scholar
  27. 27.
    Grassi, M., & Grassi, G. (2005). Mathematical modelling and controlled drug delivery: Matrix systems. Current Drug Delivery, 2(1), 97–116.CrossRefGoogle Scholar
  28. 28.
    Xu, Y., Kim, C. S., Saylor, D. M., & Koo, D. (2016). Polymer degradation and drug delivery in PLGA-based drug-polymer applications: A review of experiments and theories. Journal of Biomedical Materials Research. Part B, Applied Biomaterials.  https://doi.org/10.1002/jbm.b.33648.Google Scholar
  29. 29.
    Lin, K. M., Shea, J., Gale, B., Sant, H., Larrabee, P., & Agarwal, J. (2016). Nerve growth factor released from a novel PLGA nerve conduit can improve axon growth. Journal of Micromechanics and Microengineering, 26(4), 045016.CrossRefGoogle Scholar
  30. 30.
    Crank, J. (1975). The mathematics of diffusion (2d ed.). Oxford, Eng: Clarendon Press.zbMATHGoogle Scholar
  31. 31.
    Astete, C. E., & Sabliov, C. M. (2006). Synthesis and characterization of PLGA nanoparticles. Journal of Biomaterials Science, Polymer Edition, 17(3), 247–289.CrossRefGoogle Scholar
  32. 32.
    Csaba, N., Gonzalez, L., Sanchez, A., & Alonso, M. J. (2004). Design and characterisation of new nanoparticulate polymer blends for drug delivery. Journal of Biomaterials Science, Polymer Edition, 15(9), 1137–1151.CrossRefGoogle Scholar
  33. 33.
    Labroo, P., Ho, S., Sant, H., Shea, J., Gale, B. K., & Agarwal, J. (2016). Controlled delivery of FK506 to improve nerve regeneration. Shock, 46(3 Suppl 1), 154–159.  https://doi.org/10.1097/SHK.0000000000000628.CrossRefGoogle Scholar
  34. 34.
    Stroh, M., Zipfel, W. R., Williams, R. M., Webb, W. W., & Saltzman, W. M. (2003). Diffusion of nerve growth factor in rat striatum as determined by multiphoton microscopy. Biophysical Journal, 85(1), 581–588.  https://doi.org/10.1016/S0006-3495(03)74502-0.CrossRefGoogle Scholar
  35. 35.
    Bilsland, J., Rigby, M., Young, L., & Harper, S. (1999). A rapid method for semi-quantitative analysis of neurite outgrowth from chick DRG explants using image analysis. Journal of Neuroscience Methods, 92(1–2), 75–85.CrossRefGoogle Scholar
  36. 36.
    Madduri, S., Papaloizos, M., & Gander, B. (2009). Synergistic effect of GDNF and NGF on axonal branching and elongation in vitro. Neuroscience Research, 65(1), 88–97.  https://doi.org/10.1016/j.neures.2009.06.003.CrossRefGoogle Scholar
  37. 37.
    Eng, M., Ling, V., Briggs, J. A., Souza, K., Canova-Davis, E., Powell, M. F., et al. (1997). Formulation development and primary degradation pathways for recombinant human nerve growth factor. Analytical Chemistry, 69(20), 4184–4190.CrossRefGoogle Scholar

Copyright information

© Taiwanese Society of Biomedical Engineering 2018

Authors and Affiliations

  • Scott Ho
    • 1
  • Pratima Labroo
    • 1
  • Keng-Min Lin
    • 1
  • Himanshu Sant
    • 1
  • Jill Shea
    • 2
  • Bruce Gale
    • 1
  • Jay Agarwal
    • 3
  1. 1.Department of Mechanical EngineeringUniversity of UtahSalt Lake CityUSA
  2. 2.Department of SurgeryUniversity of UtahSalt Lake CityUSA
  3. 3.Department of SurgeryUniversity of UtahSalt Lake CityUSA

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