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Development of Acellular Porcine Peripheral Nerves

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Development of Acellular Porcine Peripheral Nerves Development of Acellular Porcine Peripheral Nerves Thesis submitted to the University of Sheffield for the degree of Doctor of Philosophy Department of Materials Science and Engineering Leyla Žilić October 2016 Acknowledgments I would like to firstly thank my supervisors, Professor John Haycock and Dr Stacy-Paul Wilshaw for their guidance and support throughout my years at the University of Sheffield and University of Leeds. I would also like to acknowledge Dr James Phillips for his guidance and contribution in the TEM and in vivo studies carried out in this study. I would like to say a thank you to all the staff members with a special mention to Mark Wagner, Dr Adam Glen and Dr Sabiniano Roman who have helped me on numerous occasions in the labs. I would also like to give thanks to all the people in the Ingham and Kroto labs who have helped me and given me support throughout the years with a special mention to Ruth Craven, Lindsey Dew, Giulia Gigliobianco Ahtasham Raza, Dharaminder Singh and Assad Fiaz. Lastly I would like to give a special mention to my family especially my mother Dudiya. She has provided me with endless support and is my role model, for which I will be eternally grateful. i Abstract Peripheral nerve injuries can lead to a major loss of function and affect quality of life. Current autologous treatments and commercially available products such as nerve guide conduits all have limitations. The aim of this study was to develop biocompatible, non-immunogenic nerve grafts using low concentration SDS to decellularise porcine peripheral nerves. Initially the porcine nerve anatomy was defined. Acellular nerves were then used as the basis for an in vitro study of perfused flow within the tissue for the introduction of Schwann cells - as the delivery of these cells is reported to stimulate axon regeneration. Furthermore, an in vivo study using a rat sciatic nerve injury model was conducted to evaluate the regenerative capacity of acellular porcine grafts. Histology confirmed an absence of cells and retention of the native nerve histioarchitecture. DNA levels were reduced by >95 % throughout the decellularised tissue. Immunohistochemistry showed retention of important extracellular matrix proteins such as collagen, laminin and fibronectin. In vitro biocompatibility studies indicated the acellular nerves were not cytotoxic to human dermal fibroblasts and primary rat Schwann cells. Uniaxial tensile testing showed a significant increase in ultimate tensile strength (UTS) and strain between native and acellular nerve tissues. In addition, mechanical testing of the nerves revealed porcine peroneal nerves to have a higher UTS value in comparison to the porcine tibial nerves. Analysis of the nerves using transmission electron microscopy concluded that the mechanical properties of nerves could not be determined exclusively by their ultrastructure or collagen fibril diameter. Porcine acellular nerve grafts were used as an in vitro and in vivo model for the introduction of primary rat Schwann cells. The in vitro nerve model confirmed that reseeded Schwann cells under perfusion maintained their phenotype and had a lower rate of cell death when compared to static conditions. A rat sciatic nerve in vivo gap injury model demonstrated that porcine grafts were able to promote axonal regeneration; however, they were not as effective as the autologous graft. In summary, acellular peripheral nerve tissue was found to have excellent potential for development of a tissue engineered graft to aid peripheral nerve regeneration. ii Contents Page Acknowledgments......................................................................... i Abstract ........................................................................................ ii Contents Page ............................................................................. iii Presentations and Publications ...................................................x List of Tables ............................................................................... xi List of Figures ........................................................................... xiii Abbreviations ........................................................................... xvii 1. Introduction ..............................................................................1 1.1 Physiology of the nervous system ............................................................................... 3 1.2 Cellular components of the nervous system ................................................................ 4 1.2.1 Cellular components of the CNS ............................................................................... 5 1.3 Anatomy of the nervous system: spinal cord and peripheral nerve ................................. 6 1.3.1 Anatomy of the spinal cord ....................................................................................... 6 1.3.2 Anatomy of the peripheral nerve ............................................................................... 7 1.3.3 Peripheral nerve extracellular matrix (ECM) ............................................................ 8 1.4 Nerve injury and regeneration ........................................................................................ 11 1.4.1 Peripheral nerve regeneration .................................................................................. 11 1.4.2 Classifications of nerve injury ................................................................................. 14 1.4 Clinical need for peripheral nerve repair................................................................... 16 1.5 Current clinical approaches for treating peripheral nerve injuries ................................. 17 1.6 Nerve guides conduits (NGCs) and grafts to aid peripheral nerve regeneration ........... 18 1.6.1 Naturally derived nerve guides ................................................................................ 21 1.6.2 Synthetic nerve guides ............................................................................................. 23 1.6.3 Motor outcomes after reconstruction of nerve defect using NGCs ......................... 25 1.6.4 Clinical efficacy of autografts and NGCS in treating peripheral nerve repair ........ 28 iii 1.6.5 Limitations of NGCs in promoting regeneration across critical gap length ............ 30 1.7 Importance of ECM and Schwann cell basal lamina in nerve regeneration .................. 30 1.8 Tissue decellularisation .................................................................................................. 31 1.8.1 Clinical relevance for the use of acellular scaffolds ................................................ 32 1.8.2 Decellularisation methods ....................................................................................... 34 1.8.3 Decellularisation solutions and agents .................................................................... 36 1.9 Sterilisation of acellular tissue ....................................................................................... 39 1.10 Immune response to biological scaffolds ..................................................................... 40 1.10.1 Constructive remodelling versus pro-inflammatory response to biological scaffolds .......................................................................................................................................... 40 1.10.2 Degradation of biological scaffolds ....................................................................... 41 1.11 Acellular nerve grafts .................................................................................................. 42 1.11.1 Avance® Nerve Graft ............................................................................................ 42 1.11.2 Clinical studies on Avance® Nerve Graft .............................................................. 42 1.11.3 Use of xenogeneic acellular nerve grafts ............................................................... 47 1.11.4 Limitations of acellular nerve grafts ...................................................................... 49 1.12 Importance of cellular therapies for nerve regeneration .............................................. 50 1.12.1 Role of Schwann cells in nerve regeneration ........................................................ 50 1.12.2 Use of cellular therapy in nerve tissue engineering applications .......................... 51 1.12.2.1 Current cellular therapy for NGCs ..................................................................... 51 1.12.3 Introduction of cells into acellular grafts ............................................................... 55 1.13 In vitro acellular nerve model ...................................................................................... 56 1.14 Conclusion .................................................................................................................... 57 1.15 Aims and Objectives .................................................................................................... 59 Chapter 2. Materials and Methods ...........................................60 2.1 Materials ......................................................................................................................... 60 2.1.1 Equipment ................................................................................................................ 60 iv 2.1.2 General consumables ............................................................................................... 61 2.1.3
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