Intensive studies are being carried out to use devices made of bioresorbable polymers inside the human body to provide various temporary functions. Typical examples include scaffolds for tissue engineering, fixation screws for broken bones and drug-loaded matrices for controlled-release. The development is entirely based on trial and error. The degradation rate strongly depends on the shape and size of the devices, making it difficult to transfer experience from one device to another. The degradation time ranges from weeks to years; animal and ultimately human trials have to be carried out, making the trial and error approach time-consuming and expensive. The entire field would benefit enormously from mathematical models capable of predicting the degradation and property change of the devices. This PhD project will develop such models as following: a) A multi-scale model for degradation of bioresorbable polyesters was developed. Events that occur at the molecular scale are modelled at the molecular scale using the kinetic Monte Carlo schemes while events that occur at the device scale are modelled using macroscopic diffusion model. b) A phenomenological model for simultaneous crystallisation and biodegradation of biodegradable polymers was developed. This model completed the degradation theory developed by Wang et al. at University of Leicester. c) The model in (b) was improved and applied to the analysis of accelerated degradation data. Temperature effects were taking into account by using Arrhenius relations. d) A model for the biodegradation of composite materials made of polyesters and calcium phosphates was developed. A calcium phosphate effectiveness map is established to show the conditions under which incorporating calcium phosphates into polyesters is effective, saturated or ineffective. f) A phase field model was developed for drug release from a swelling Hydroxypropyl methylcellulose matrix. This model can be readily extended to full three dimensional problems.

This thesis describes three studies investigating biomechanical responses to changes in shoe-surface combinations in soccer. In the first study, six male participants (21.7 [S.D. 2.2] yrs, 74.0 [S.D. 6.9] kg [March], 74.6 [S.D. 6.9] kg (May), footwear size 10 -11) performed running and turning movements on natural and third generation artificial surfaces whilst wearing different soccer specific footwear. This was performed at two times of the year where contrasting weather conditions were experienced. It was observed that there were significant differences when the natural and third generation artificial turf surfaces were compared. These differences however, were dependent on the type of movement, time of year and biomechanical measurement used. Each surface was also compared between the two test occasions. The main finding was that for both running and turning peak pressures and peak pressure loading rates were significantly greater in May (when the surfaces were mechanically hard) compared with the same surface in March. It was concluded that comparisons of third generation surfaces with natural turf are dependent on the specific properties of the surfaces and cannot be generalized for all such surfaces. A critical design feature of third generation surfaces that will influence biomechanical comparisons with other playing surfaces is the shock pad layer. In the second experimental chapter, ten male participants (20.9 yrs [S.D. 2.5], 83.2 kg [S.D. 7.1], footwear size 10 -11) were used to assess the effect of two different shock pad densities (55g and 65g) (Arpro® Expanded polypropylene BF2455W, 24mm S.D. 0.5mm thick, Brock International) on the lower extremity loading. These participants were also used to assess the biomechanical adaptations that occur with the inclusion of a 10 mm Sorbothane® heel insert or a Sorbothane® cushioning insole (Sorbo products division, Lancashire, UK), which have been associated with reducing overuse injury including that to the Achilles tendon. The footwear was also assessed for the risk of sustaining lateral ankle ligament damage. It was shown that whilst turning, peak impact force (taken using in-shoe pressure system) was significantly lower on the more cushioned shock pad as was peak pressure at the first metatarsal. Likewise, the time to peak impact force was significantly longer with the heel insert. However, despite the association between the heel insert and reduced dorsi-flexion, no significant differences were observed for this measurement between the footwear conditions. Peak plantar flexion was significantly greater with the heel insert whilst turning suggesting an increased loading of the lateral ankle ligaments, although rearfoot inversion was not significantly different. This study demonstrated the potential role of shock pad cushioning in providing protection from impact related injury in soccer, whilst cushioning inserts were not found to provide a protective effect. For heel inserts, the possibility of a negative influence on rearfoot stability was highlighted. It was suggested that the estimation of internal loads may reveal more regarding the specific role of cushioning interfaces and heel inserts in protecting from injury. In the final research chapter, nine male soccer players (83.4 kg [S.D. 5.8], 23 yrs [S.D. 3.7]) performed running and turning movements for the same conditions described in study two. The peak plantar flexion moment, Achilles tendon force and average loading rate of these measurements, were used to assess Achilles tendon loading. Likewise, peak dorsi-flexion and eversion moments were collected to assess the lateral ankle loading. Group analysis did not reveal any significant differences in these variables. Individual data showed that the response to heel insert intervention was specific to the participant. Some participants exhibited a reduced Achilles tendon force or average loading rate, suggesting a reduced risk of injury with the heel insert. However, it was observed that eversion and dorsi-flexion moment and average loading rates increased in some participants, suggesting that these participants were at an increased risk of lateral ankle ligament injury with the heel insert. Likewise, one participant experienced significantly greater peak Achilles tendon force, also indicating a greater risk of injury to this structure. The overall conclusions gained from these studies are that the design of the footwear and playing surfaces are worth considering in the quest to reduce injury risk. It was also highlighted that the choice of shock pad density for a third generation artificial surface can be influential in the protection of the athlete even when the surface is new, particularly when turning. Finally, although the use of heel inserts has proven successful in the reduction the Achilles tendon injury, the lack of significant differences for group comparisons suggests that the mechanisms behind the success is still unclear. However, although heel inserts may prove useful in the reduction of Achilles tendon injury, the observation that significant increases in the measurements associated with acute ankle ligament damage and chronic Achilles tendon injury, suggests that heel lift may not be suitable for some individuals.

The main concern of this thesis was to evaluate the effects of strenuous eccentric exercise on specific indices of neuromuscular and sensorimotor performance. The effects and symptoms of exercise-induced muscle damage (EIMD) have been very well documented in adult populations. They include impairments in muscle function (isometric and dynamic strength, power and rate of force development and flexibility), an increase in the release of muscle proteins (e.g. creatine kinase), delayed onset muscle soreness and an increase in perceived exertion. However, very little research has focussed on the effects of EIMD on electromechanical delay and sensorimotor performance. Even less attention has focussed on the effects of strenuous eccentric exercise on children populations. To date, only four studies have investigated the effects of EIMD in children, although these studies did not assess the effects of EIMD on sensorimotor performance. This thesis comprises six chapters: • Chapter 1: Introduction • Chapter 2: Review of Literature • Chapter 3: Reproducibility and Single Measurement Reliability of Indices of Neuromuscular and Sensorimotor Performance of the Knee Flexors in Adults and Children. • Chapter 4: Evaluation of the Effects of two bouts of strenuous isokinetic eccentric exercise on Sensorimotor and Neuromuscular Performance of the knee flexors in Men and Women. • Chapter 5: Evaluation of the effects of a bout of strenuous eccentric exercise on sensorimotor and neuromuscular performance of the knee flexors in young athletes. • Chapter 6: Further thoughts, conclusions and limitations. Chapter 3 examined the single-measurement reliability and reproducibility of selected indices of neuromuscular and sensorimotor performance that were deployed in the subsequent chapters of this thesis in adults and children. The results demonstrated no statistically significant differences (P > 0.05) between groups (males, females, boys and girls), which suggested that considerations regarding the testing protocols could be made on the same basis for all the selected groups. Similarly, no significant differences were observed between legs (preferred, non-preferred) in any of the involved groups. Furthermore, the findings demonstrated that single-trial protocols are not powerful enough for the accurate discrimination of intra-session differences in performance capabilities especially during intra-individual assessments and moreover are insufficient for the correct interpretation of neuromuscular and sensorimotor performance between days. Chapter 4 assessed the effects of two bouts of exercise-induced muscle damage on neuromuscular and sensorimotor performance of the knee flexors of both legs in males and females. The eccentric exercise protocols were associated with impaired peak force, elevated soreness, decreased passive flexibility, prolonged electromechanical delay and preserved sensorimotor performance. However, no significant differences between men and women were observed. Interestingly, the prolonged electromechanical delay and the preserved sensorimotor performance were the novel and most important findings of this study and were contrary to previous observations. Finally chapter 5 assessed the effects of a strenuous eccentric exercise protocol on neuromuscular and sensorimotor performance of the knee flexors of both legs in boys and girls (aged 11-14 years) who were members of the Exeter Tennis Centre. The eccentric exercise protocol was associated with impaired peak force, elevated soreness, decreased passive flexibility, and preserved electromechanical delay and sensorimotor performance. Interestingly, all impaired indices of muscle function returned to baseline 72 hours after the damaging protocol. Moreover, there were no significant sex differences. Further analysis revealed that boys and girls experienced milder symptoms of muscle damage than men and women, with the adult participants demonstrating higher levels of peak force decrease and of delayed onset muscle soreness.

The design of biomechanical devices is often difficult because it is not feasible to test them within human or animal patients. Initial designs may be tested using mechanical rigs or finite element models to simulate the complex loading conditions within biological environments. Recent advances in computer technology have allowed computer simulations to become more detailed. However, educated assumptions must be made to simplify the conditions that will effect the device. Highly accurate results can be obtained but it is essential that these results are verified using a mechanical test rig. This will identify if human error or inaccurate assumptions have occurred. Mechanical test rigs were designed to simulate the forces acting within four different biomechanical systems. This involved simulating the forces applied to the lumbar spine, the greater trochanter of the hip, and to the shin; for the testing of inter-vertebral cages, hip protectors and floor coverings, and shin pads respectively. Load cells were used to measure the resultant impact forces applied to the hip and shin. The time-domain data were recorded for each impact and from these data it was possible to calculate the maximum impact force and the total energy absorbed by the greater trochanter. Mechanical testing of intervertebral cages involved pressure sensitive paper to measure resultant pressure trends at the interface between the vertebral end plate and the cages. This instantly revealed pressure trends and computer programs were written to determine the contact area, calibrate pressure values, and to allow the improved visualisation of results. Results from the mechanical test rigs are also suitable for validation of finite element analysis studies. New information has been generated to improve understanding about the pressure trends under intervertebral cages and the key design features have been identified. The hip test rig was used in the design of a novel hip protector, to determine the role of floor coverings in an impact, and to compare numerous hip protectors using typical impact conditions. Results show that a combination of energy absorbent flooring with a hip protector is the best environment for a reduced risk of a hip fracturing. Design recommendations were made regarding the material composition and the thickness of the materials used. This allowed the novel hip protector to be designed as small as possible but still sufficiently reduces the impact force from a person falling onto their hip. The hip test rig was modified to simulate the shin and was used to compare several commercially available shin guards. New information was generated to identify which design features are best to reduce impact forces. Further developments have been made to the first version of the hip impact test rig. The latest version of this hip test rig is currently being used as a benchmark for all hip protectors and is a likely contender as the basis of a standard testing system for a European Standard.

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Phosphorylation is a key regulator of protein function and activity, and aberrant kinase activity is implicated in a wide range of malignancies, of which the bcr:abl fusion kinase found in chronic myeloid leukaemia is a classic example. As phosphopeptides are known to be presented by both the MHC class-I and class- II pathways, against which specific CD4+ and CD8+ T cell responses may be generated, study of MHC-presented phosphopeptides may reveal unique cancer antigens with direct links to the neoplastic state. Mild acid cell-surface elution is a rapid and effective method for MHC class-I peptide capture, though complicated by contamination with non-MHC peptides and poor downstream compatibility, especially with IMAC, a popular method for phosphopeptide enrichment. As an alternative to the citrate-phosphate elution buffer, a TMA-formate elution buffer is proposed. This was developed for IMAC compatibility, and osmotically balanced and supplemented to minimise cell lysis, (assessed by several assays) and used with a pH 5.5 prewash to reduce non- MHC peptide contamination. MALDI-MS/MS of MHC class-I peptides from K562- A3 cells found a sequence with high homology to a known cancer antigen as the common peak for both citrate-phosphate and TMA-formate eluted cells. Currently there are no published mechanisms for cell-surface elution of MHC class-II peptides (immunoprecipitation is widely used), though previous work at NTU led to the development of an IMAC compatible MHC class-II protocol. This was also subjected to supplementation and optimisation, reducing cell death to a level corresponding to that of the widely accepted citrate-phosphate class-I protocol. Various chromatographic approaches were tested for phosphopeptide retention. Fe3+ IMAC remains optimal; methods were adjusted to increase peak fraction concentration (assessed by a modification the BCA protein assay improving suitability for peptides). Though further method development may be required to optimise mass spectrometry, a number of phosphopeptides were found in both MHC class-I and class-II eluates, many with known links to malignancy. It is hoped that these improved methods will be of use in the ongoing search for novel cancer antigens.