Described as one of the most challenging events an individual can face (Evans et al., in press), the legacy of impairment following Spinal Cord Injury (SCI) often has lifelong consequences. Appraisals have been highlighted as a potentially important, but under researched construct, with regard to adjustment to SCI (Pollard & Kennedy, 2007). Furthermore, it has been argued that self-report measures specifically designed for SCI should be developed (Elfstrom et al, 2002). The current study aimed to develop a -reliable and valid appraisal scale (The Primary and Secondary Appraisals of Disability Scale; PSADS) for adult SCI populations.

Spinal cord injury (SCI) affects approximately 40,000 people in the UK; the most common type of SCI is a contusion injury and the majority of these cases are male and aged between 16 and 30 years old. The initial physical trauma to the spinal cord during injury leads to substantial damage and loss of neurones. After the primary traumatic insult has occurred a sequence of events is initiated that sets off a cascade of biochemical, cellular and inflammatory events that are massively destructive and continue for weeks to months after the initial SCI. This phenomenon is known as “secondary death” and leads to an increase in the size of the damaged area. Infiltrating monocytes and monocyte-derived macrophage have been implicated as a crucial component in the perpetration of secondary death. It was demonstrated in this thesis that staphylococcus protein A (SpA), when in complex with IgG forms homogeneous small immune complexes (SIC) that can polarize macrophages in vitro to an anti-inflammatory phenotype, resulting in increased production of the immune-suppressive cytokine IL-10 and reduced ability to produce the pro-inflammatory cytokine IL-12. SIC treatment of IFNγ-primed macrophages in conjunction with LPS also induces a down-regulation of MHC II surface expression; however, the macrophages still exhibit normal levels of co-stimulatory molecule CD86 compared to a classically-activated macrophage. In an in vivo setting it was demonstrated that SpA binds to monocytes and preferentially to the “inflammatory” Ly6Chi monocyte sub-set. The binding of SpA to this monocyte population induced the maturation of the Ly6Chi “inflammatory” monocyte into Ly6Clow “anti-inflammatory” monocytes within the steady state and in the sterile inflammatory setting of SCI. In the inflammatory environment of the damaged spinal cord, SpA treatment induced a higher percentage of Ly6Clow monocytes to produce the immune-modulatory cytokine IL-10 compared to the control treated group. These observations indicate when SpA and IgG form SIC they interact with macrophages and monocytes in vitro or in vivo polarizing them to an anti-inflammatory phenotype. In conclusion, it has been shown in this thesis that SIC has the potential to be used as a method of polarizing monocytes and macrophages to an anti-inflammatory phenotype, which in turn has the potential to modify the overt inflammatory response that is responsible for the death of neurons days to weeks after the initial injury and is responsible for reduced functional recovery in SCI patients.

Spinal cord injury (SCI) causes a lesion-dependent impairment in cardiorespiratory function that may limit exercise capacity. The aims of this thesis were to describe cardiorespiratory function in highly-trained athletes with low-cervical SCI, and to investigate whether abdominal binding enhances cardiorespiratory function at rest and during exercise in this population. Using body plethysmography, bilateral phrenic nerve stimulation and transthoracic ultrasound, it was demonstrated that Paralympic athletes with cervical SCI exhibit a restrictive pulmonary defect, impaired diaphragm and expiratory muscle function, and low left ventricular mass and ejection fraction compared to able-bodied controls. Using the same methods, it was shown that abdominal binding improves resting cardiorespiratory function by reducing operating lung volumes, and increasing vital capacity, twitch transdiaphragmatic pressure, expiratory muscle strength and cardiac output. A further finding was a positive relationship between binder tightness and cardiorespiratory function. During a field-based assessment of fitness, abdominal binding reduced the time taken to complete an acceleration/deceleration test and increased the distance covered during a repeated maximal 4-min push test. During laboratory-based incremental wheelchair propulsion, abdominal binding altered breathing mechanics by reducing operating lung volumes and attenuating the rise in the pressure-time index of the diaphragm. Furthermore, abdominal binding increased peak oxygen uptake and reduced peak blood lactate concentration, despite no change in peak work rate. Peak oxygen uptake in the laboratory was related to the distance covered during the maximal 4-min push, suggesting that the improvement in field-based performance with binding was due to an improvement in aerobic capacity. In conclusion, this thesis demonstrates that abdominal binding significantly enhances cardiorespiratory function at rest, improves exercise performance in the field, and improves operating lung volumes, breathing mechanics and peak oxygen uptake during incremental treadmill exercise. Thus, abdominal binding provides a simple, easy-to-use tool that can be used to enhance cardiorespiratory function at rest and during exercise in highly-trained athletes with cervical SCI.

Injuries to the central nervous system (CNS) have traumatic consequences such as irreparable disability due to the inability of the CNS to regenerate injured nerve fibres. The aim of the work presented here was to develop a scaffold which potentially provides guidance to axons in the injured spinal cord thus facilitating signal transduction. A poly-(lactic-co-glycolic acid) (PLGA, PLA:PGA ratio of 75:25) flat sheet membrane scaffold was created using phase inversion with N-methyl pyrrolidinone (NMP) as the solvent and water as the non-solvent for immersion precipitation. PLGA flat sheet membranes were exposed to surface treatments including aminolysis, peptide immobilisation and ozonation in order to achieve higher cell attachment of PC12 cells, a cell line which was cloned from a solid pheochromocytoma tumour of white rats, and used as a tool for measurement of regeneration. Cell attachment studies revealed no significant difference in cell attachment between modified and not-modified PLGA flat sheet membranes. However, the absence of foetal calf serum (FCS) resulted in fivefold higher cell attachment compared to medium supplemented with 10% FCS. A second scaffold was produced by electrospinning 10% (w/w) PLGA in a chloroform:methanol (CHCl3:MeOH) mixture in ratio of 3:1 resulting in a nanofibrous scaffold. Optimum settings for electrospinning were found to be 3 ml/h feeding rate, 15kV applied voltage and 11cm collector-to-needle distance. Random and aligned PLGA nanofibres were produced, with a fibre diameter of 530±140nm. PC12 cells attached and differentiated to the nanofibrous scaffold. When exposed to NGF these cells stopped dividing and extended neurites. On random fibres, neurite orientation was random, whereas on aligned fibres 63% of neurites grew with the fibre orientation ±15��ᵒ. After 7 days of exposure to NGF, cells had 1-4 neurites on random fibres, reaching a maximum length of 188μm, whereas on aligned fibres, cells had 1-2 neurites, reaching a maximum length of 400μm. PLGA nanofibres were also investigated as a delivery vehicle for bioactive molecules. For this, poly-L-lysine (PLL) was incorporated into electrospun PLGA nanofibres via emulsion electrospinning. PLGA-PLL nanofibres were significantly larger than PLGA nanofibres having a diameter of 830±190nm. In order to visualise the incorporation of PLL, FITC-PLL was electrospun und the resulting nanofibres fluoresced greed. Attachment of PC12s to PLGA-PLL nanofibres was not significantly different compared to PLGA nanofibres. Aligned PLGA-PLL nanofibres were shown to promote neurite outgrowth of PC12s with resulting neurites of up to twice the length compared to aligned PLGA nanofibres. The results suggest that PLGA nanofibres strongly influences neurite organisation, which is potentially useful for future therapeutic approaches. The work in this thesis has shown that electrospun PLGA nanofibre mats have the potential to be used as scaffolds for spinal cord repair addressing topographical guidance and delivery of bioactive molecules to the site of injury.