Development of a peripheral nerve repair device

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

This thesis focuses on engineering a repair strategy for use in peripheral nerve tissue after transection injuries. With an estimated 300,000 new cases of peripheral nerve injury reported in Europe each year, the socioeconomic cost of these injuries is multifactorial (Chiardelli and Chiono, 2006). Loss of nerve function often leads to long-term disability and chronic neuropathic pain, which dramatically reduces the number of quality adjusted life years (QALYs) post-injury (Siemionow and Brzezicki., 2009; Ciaramitaro et al., 2010). Some research suggests that nerve repair surgery results in a cost effective increase in number of QALYs and suggests that this field warrants further research (Wali et al., 2017). Further, nerve injury has been shown to correlate with post-traumatic stress disorder, especially when loss of function persists longer than 12 months (Miller et al., 2017). 360,000 people in the US suffer paralysis resulting from upper limb trauma alone, which suggests that the total number of patients with peripheral nerve injury (PNI) is much larger and means a large proportion of the population suffer with a nerve defects and their complications. Often, PNI is concomitant with multiple other acute traumas resulting from incidents such as motor vehicle accidents. Therefore peripheral nerve repair (PNR) is withheld as repair of other traumas is prioritised (Gin-Shaw and Jorden, 2002). Evidence suggests withholding PNR reduces the efficacy of regeneration and if subfunctional repair occurs this has a long-term negative effect on patient well-being and ability to self-care (Faroni et al., 2015). Nerve tissue injury leads to degeneration of functional neural cells and the loss of effective communication between the peripheral nerve and nervous system at large, meaning many vital neurological reflexes are lost. Effective nerve repair strategies that expedite recovery are vital to preventing long term disability and improving patient quality of life. The current gold-standard of PNR involves use of autologous nerve tissue, which results in comorbidities, and lack of reliable results (autograft repair methods) (di Summa et al., 2014). However, the development of tissue engineering constructs to encourage peripheral nerve regeneration represents an alternative therapy to autograft. Provision of a synthetic implant, a Nerve Guidance Conduit (NGC), is designed to mimic nerve tissue and encourage infiltration by endogenous glial cells (Schwann cells) and neural cell processes (axons) across the graft (Barton et al., 2017). In contrast to studies that solely focus on the biological events that take part following peripheral nerve injury, this thesis presents an engineering approach to create a more functional design for a synthetic NGC. There is a lack of information related to how regenerating nerve tissue extends through synthetic graft environments and the longterm effect on the regenerated tissue function. This thesis provides a physical solution to the problems encountered in guiding axonal regeneration to establish re-connection with its effector organ. The proposed implant provides a platform for healthy nerve growth within the critical time and length requirements for the animal model studied (the rat Sciatic nerve repair model). If the injury is greater than a critical length (which varies between the specific nerve and specific species), the probability of complete regeneration is low (Petcu et al., 2018). For example, in the rat model the critical length has been evaluated as 1.0 cm and often repaired within 3 months in the rat Sciatic nerve (Mokarizadeh et al., 2016; Tsujimoto et al., 2017). A novel NGC was designed, featuring properties of flexibility, inertness, biocompatibility and capability of fast implantation with a surgery time of 15 minutes. These design criteria were the focus for the material selection process of poly(amide-6,6) (PA6,6), collagen Type 1 and chitosan, which was validated for in vivo use by in vitro assays, and designed to assess factors including cell adhesion, cytotoxicity, cell differentiation and cell migration. The NG108-15 neuroblastoma/glioma cell line was used in conjunction with primary Schwann cells to assess the biological response. It was demonstrated that PA6,6 can be used as a substrate for neural tissue engineering applications, showing that neurons remain excitable when cultured on these substrates. Further, PA6,6 supported significant levels of cell proliferation and neurite extension. A bovine collagen Type 1/ chitosan hydrogel was also investigated, demonstrating a supportive substrate for neuroglial interaction and growth, which was validated using Dorsal Root Ganglia explant cultures. These data were used to translate these materials into the novel NGC, which was further examined in vivo with functional assessment (algesimetry, mechanical sensation, paw spreading and histology).
Date of Award1 Feb 2020
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorIan Thompson (Supervisor) & Eileen Gentleman (Supervisor)

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