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Approximately one-third of trauma patients are coagulopathic on arrival to the emergency department. Acute traumatic coagulopathy and systemic inflammatory responses are serious secondary consequences of severe trauma and are linked to increased morbidity and mortality. Early tissue hypoxia is a major component in the aetiology of both complications. New resuscitation strategies are aimed at improving tissue oxygenation in the pre-hospital phase, and may attenuate coagulopathy and inflammatory sequelae. This is of particular importance in military personnel who suffer complex injuries, often from blast exposure, and may have extended evacuation times. This thesis evaluates the effect of a novel hybrid (NH) resuscitation strategy on coagulation and inflammation. Terminally anaesthetised pigs were randomised to one of two injury strands of haemorrhage +/- blast injury; initially resuscitated with 0.9% Saline to a hypotensive systolic blood pressure of 80mmHg for one hour. This was followed by either a return to a normotensive pressure (110mmHg) (NH) or a continuation at the hypotensive level. Over both injury strands NH significantly reduced Prothrombin Time, PT (mean proportion of baseline: 1.40±0.05 vs. 1.80±0.09; p=0.001) and interleukin-6 (IL6) levels (mean 1106±153 vs. 429±79 pg/ml; p=0.001) compared to the hypotensive groups. PT was positively correlated with IL6 (p=0.002) and base deficit (p=0.0004). These findings indicate that improving tissue oxygenation reduces the coagulation derangement and the pro-inflammatory response. No difference in coagulopathy was found between injury strands although blast did cause greater inflammation. Early identification of coagulopathic casualties is essential and a separate feasibility field study was preformed to assess the use of thromboelastometry in a deployed military hospital, evaluating the degree of coagulopathy in battlefield casualties and to monitor the coagulation status during the resuscitation process. In conclusion, NH attenuated the acute traumatic coagulopathy and inflammatory responses and therefore should be considered when an extended casualty evacuation is enforced.

Stabbing is the most common way of committing murder in the UK. Sharp implements are used in stabbing attacks with the intent to cause injury and death. The number of deaths that result from stabs is high, partly because major organs and major blood vessels are relatively close to the skin and easily penetrated. Knight in the late 1970s used a spring loaded device to make stab tests into cadavers. He concluded that skin was easily penetrated by sharp knives and that skin offered the most resistance to penetration, with underlying fat and muscle requiring less force to penetrate. Knight concluded that the sharpness of the tip was the most important factor in determining whether a knife penetrated. Various other investigators have since investigated the effect of skin and various skin simulants, concluding that most items of clothing are easily penetrated by a knife, and considered how the geometry of the knife affects it sharpness. This thesis has looked at the effect of clothing on forces required for stabbing and the use of glass bottles as impulsive weapons. It has been found that clothing does influence the force required for stabbing. For the glass bottles it was found that there was no simple method for predicting how sharp a particular bottle would be once it was fractured. A novel dynamometer has been developed to accurately mimic a stabbing event and record the forces generated. The data shows that there are considerable differences in the forces generated by males and females; discernable differences between the dominant and non-dominant hand and that stabbing, even with blunt weapons can cause considerable penetration in most cases. The data also shows that the traditional ranking of mild, moderate and severe used by forensic pathologists lacks meaning in interpreting stabbing events.

Chronic wounds have an exaggerated inflammatory response which disrupts the proteolytic microenvironment, increasing proteases, particularly matrix metalloproteinases (MMPs). This causes degradation of vital matrix components which prevent wound healing. It was therefore hypothesised that a dressing incorporating a peptide based MMP inhibitor may promote healing. Novel peptides designed to chelate the active site zinc, were successfully synthesised using Solid Phase Peptide Synthesis (SPPS) and the inhibitory potential of each evaluated against MMPs associated with chronic wounds (MMP-1, -2, -8 and -9). Results indicated that three peptides, namely A1, A2 and T2A inhibited MMPs in a reversible, competitive manner with Ki values in the sub-micromolar range. Furthermore, biocompatibility studies suggested that the compounds did not affect cell viability or migration. The lead compound, T2A, was then manipulated in order to bind it to a number of solid supports. The most successful of those analysed were in the form of resins designed for use in SPPS, namely NovaPEG and Spheritide. MMP inhibitor peptides were immobilised onto each via standard SPPS methods before optimisation of TFA promoted removal of the protecting trityl group. A further inhibitor was designed to increase the projection of the inhibitor from Spheritide resin (peptide T2A-PEG). Enzyme inhibition assays suggested both NovaPEG and Spheritide resins, with immobilised peptides successfully acted as broad spectrum MMP inhibitors with preference given to Spheritide bound T2A-PEG (S -T2A-PEG). The use of this combination in further studies was vindicated by promising cytotoxicity outcomes from indirect cell viability analysis. Finally, S-T2A-PEG significantly removed MMPs from biologically relevant human and equine chronic wound fluid. Development of a prototype dressing was accomplished by enclosing the immobilised compound within a sealed nylon 'bag' which enabled retention of the peptides' inhibitory ability. In conclusion, the advanced material and resulting prototype emerging from this project is a commercially important and novel wound care product.

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Angiogenesis is an essential process in wound healing. An insufficient angiogenic response can result in chronic wounds, whilst an overzealous response can contribute to scarring and cancer metastasis. Beta-adrenoceptors (β-AR) are G protein-coupled receptors (GPCR) and have previously been shown to play a role in wound healing, however their role in angiogenesis, is currently unknown. It was hypothesised that β-AR activation or blockade will reduce and promote human dermal microvascular endothelial cell (HDMEC) angiogenic functions and angiogenesis. β-AR activation was both anti-motogenic and anti-mitogenic. In addition, protein kinase A and exchange proteins directly activated by cAMP (EPAC) played a role in modulating the β-AR-mediated decrease in migration rate. Meanwhile, immunoprecipitation studies revealed that both the β1-AR and β2-AR co-localised with EPAC. Finally, inhibiting cyclic adenosine monophosphate (cAMP) signalling pathways reduced proliferation. Perhaps a decrease in cAMP underpinned the β-AR-mediated decrease in proliferation rate. In more complex environments, β-AR activation both promoted and delayed, whilst β-AR blockade promoted tubule formation. Meanwhile, β-AR activation and blockade both increased and reduced aortic outgrowth. In the chick chorio-allantoic membrane assay, β-AR activation and blockade both reduced and increase angiogenesis. Finally, enzyme linked-immunosorbent assays demonstrated that β-AR modulation altered vascular endothelial growth factor A secretion from human neonatal keratinocytes and fibroblast growth factor 2 secretion from HDMECs and human dermal fibroblasts. In conclusion, activating or inhibiting β-ARs can modulate HDMEC function and angiogenesis in vitro, ex vivo and in vivo. Therefore, the use of β-AR agonists and antagonists could be promising modulators of angiogenesis.

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