Medial osteoarthritis (OA) and lateral OA have distinct characteristic cartilage lesion locations and knee flexion angles associated with lesion development. These types of OA are suggested to be caused by loading when the knee is in extension and mid-range flexion, respectively. This project used subject-specific finite element (FE) models to investigate contact conditions within the extended and flexed knee. A method of creating subject-specific FE models by combining geometry (derived from magnetic resonance imaging scans) and load cases (calculated from motion analysis data) collected from the same subject was developed. This model creation method was validated by comparing experimentally-measured pressure data to contact data calculated by FE models. Models of normal knees in three subjects were created first. Models with larger subject-specific loads had larger displacements and higher stresses and contact pressures. Contact occurred over most of the articulating cartilage surfaces, both in areas of typical cartilage lesions and outside areas of typical cartilage lesions. Parameters in the normal models were then altered to reflect three mechanical changes hypothesized to lead to OA: increased loading, globally decreased cartilage stiffness, and locally decreased cartilage stiffness. Increased loading led to increased displacements, stresses, and contact pressures. Contact shifted anteriorly in the extended knee models to locations of typical medial OA cartilage lesions; contact remained stationary with elevated stress magnitudes in the flexed knee models. Globally decreasing cartilage stiffness had limited effects on contact results. Locally decreased cartilage stiffness led to locally increased displacement and strain and locally decreased stress and contact pressure. Contact again shifted anteriorly in the extended knee models. Potential mechanisms of OA initiation were then proposed. Increased weight or locally decreased cartilage stiffness increased strains within the cartilage. High strains can damage the cartilage matrix fibres, further decreasing cartilage stiffness and eventually leading to cartilage lesions and OA.

Osteoarthritis (OA) is a common, multifactorial disease that is characterized by focal degeneration of the smooth articular cartilage in any of the synovial joints. Although the underlying molecular mechanisms for OA are still not fully understood, epidemiological studies have evidenced a significant genetic component to OA susceptibility. Genome-wide linkage scans and large-scale association studies have had success in unraveling the genetic architecture underlying OA with the identification of a number of susceptibility genes. In this work, functional analyses are reported of OA associated polymorphisms within two susceptibility genes: BMP5 and GDF5, both members of the TGF-β superfamily of secreted proteins. The extent of differential allelic expression (DAE) of BMP5 in human mesenchymal tissues was first examined with significant differences in BMP5 allelic output observed (allelic ratios exceeding 4:1 in the tissues of some donors). Significant variability in allelic expression within the different tissues of donors was also observed, suggesting that polymorphism in cis-regulation of BMP5 expression is common and that there is a considerable effect of tissue specific elements on BMP5 expression. DAE was then used as a phenotype to map tissue-specific cis-regulatory polymorphisms with the identification of a single nucleotide polymorphism (SNP) located downstream of BMP5 that was significantly associated with DAE as well as OA, suggesting that variability in cis-regulation of BMP5 is important in OA susceptibility. Moreover, the functional effect of a previously identified OA associated microsatellite within intron 1 of BMP5 was investigated using luciferase reporter assays and electrophoretic mobility shift assays (EMSAs) with significant differences observed both in the ability of various microsatellite alleles to modulate BMP5 promoter activity and to bind GATA-3 nuclear proteins, further suggesting a role for variability in BMP5 expression in OA susceptibility that may in part be due to altered GATA-3 binding. Finally, functional characterization of a previously reported OA associated SNP in the 5′ UTR of GDF5 is presented in which EMSAs show differential binding of nuclear factors between the two SNP alleles, strengthening the possible functional contribution of this SNP to OA susceptibility. Overall, this work demonstrates that polymorphism in cis-regulation is likely to play a role in OA susceptibility.

Although the tensile mechanical properties of tendon have been well characterised, the viscoelastic and anisotropic properties remain uncertain. This thesis addresses the anisotropic and viscoelastic material properties of tendon. A method to characterise the three-dimensional shape of tendon is reported and experiments to characterise the fibre-aligned and fibre-transverse viscoelastic properties of tendon are presented. The cross-sectional profiles of bovine digital extensor tendons were determined by a laser-slice method. Linear dimensions were measured within 0.15 mm and cross-sectional areas within 1.7 mm². Tendons were compressed between two glass plates in creep loading at multiple loads. Compression was then modelled in a finite element environment. Tendon was found to be nearly incompressible and reproduction of its isochronal load-displacement curve was achieved with a neo-Hookean material model (E ≃ 0.3 MPa). The fibre-aligned tensile mechanical properties were described using a Quasi-Linear Viscoelastic model. The model was effective at reproducing cyclic loading; however, it was ineffective at predicting stress relaxation outside the scope of data used to fit the model. When all experimental results are considered together, two significant conclusions are made: (1) tendon is much stiffer in fibre-aligned tension than in fibre-transverse compression and (2) the fibre-aligned tensile response is strain dependant, while the transverse response is not.

Medial Oxford unicompartmental knee replacement (UKR) is an established and successful treatment for patients with antero-medial knee osteoarthritis. However, following the operation some patients have pain which compromises their functional outcome. The aims of this thesis were to determine the incidence of pain, to identify the patient, disease and surgical risk factors associated with this pain and to try and understand why it occurs. The clinical studies were performed using patients operated on by experienced surgeons. The incidence of post-operative severe pain was 3% at six weeks and 2% at one year and the incidence remained unchanged at subsequent follow ups. The overall incidence of pain has reduced over the years. In patients who had UKR between 1998 and 2001, the incidence of severe pain was 5%; this reduced to 2.3% for the period between 2008 and 2011. As the indications have not changed, the improvement is probably due to modifications in the surgical technique and due to improvements in instrumentation. Patients with severe pain at the final follow up had a worse neuropathic pain score, and the patients with possible pre-operative neuropathic pain achieved significantly worse outcome. To explore the effect of disease severity on outcome, matched cohorts of patients with partial thickness cartilage loss (PTCL), bone-on-bone and bone loss were compared. All those with bone-on-bone and bone loss did well, whereas 20% of those with PTCL did not benefit from the surgery; 7% had severe pain and 17% had pain related complications. Although component and leg alignment, and component overhang have a profound effect on the outcome of total knee replacement (TKR), their effect on the outcome of the Oxford UKR are not known. It was found that malalignment in the coronal or sagittal planes of the femoral component within ±10° and of the tibial component within ±5° did not compromise the outcome. Leg alignment was not related to outcome even though 18% were in 5° varus and 8% were in 10° varus. In contrast, tibial component overhang ≥3 mm compromised the outcome and 21% of these patients continue to suffer from pain. The presence of radiolucent lines (RLL) following a joint replacement is usually deemed to be indicative, or predictive, of loosening. 63% of Oxford UKRs were found to have RLL under the tibial component. No correlation was found between RLL and outcome, particularly pain. It has been suggested that post-operative pain, which is commonly antero-medial over the proximal tibia, may be related to bone overload. This was explored using the finite element (FE) analysis. Following implantation of the Oxford UKR, the strains in the antero-medial region doubled. Various implantation, loading and alignment variables were studied and the findings correlated with the clinical studies, suggesting that high strain is an important cause of pain. With time, the bone will remodel, so the strains will decrease but individual differences in the remodeling threshold may explain resolution of symptoms in some, but not in all, patients. In conclusion, this work has shown that following the Oxford UKR, pain is a rare but important complication. The chance of pain can be decreased by operating only on patients with bone-on-bone arthritis and taking care with the surgical technique. Bone overload is likely to be an important cause of pain, and further modification to the implant or technique, such as achieving fixation of the tibial component vertical wall to bone, may further decrease the incidence of pain.

Massage was professionalised in Britain in 1895 by the Society of Trained Masseuses (STM), a small group of nurses and midwives mainly concerned with giving general massage to neurasthenic women. By the end of the First World War the massage profession had been transformed - a key participant in the rehabilitation of the nation’s wounded soldiers; publically, medically and politically acclaimed; and a specialism fully embryonic of physiotherapy. This thesis examines the professionalisation of massage from c.1880-1920. It argues that in order to fully understand the development of the profession in this period we have to move away from institutional teleologies, linear narratives of ‘medical control’ and embrace the myriad of socio-cultural, economic, political and professional forces driving and shaping this process. To explore these wider forces this thesis looks beyond internal institutional dynamics and examines a number of locations where massage was practised. Beginning with an examination of how massage was translated from a traditionally lay-treatment into the language of medical orthodoxy, this thesis considers its adoption into British medicine, its development as a practice and a profession, and its entry into the First World War. Fiercely contested both medically and ethically throughout the period, the practice of massage offers a new lens through which to examine the complex socio-cultural and professional negotiations shaping the course of professionalisation. This thesis argues that debates about massage, gender and intimacy were intricately woven into the formulation of professional boundaries, conditioning the relationship between patient and masseuse as well as the masseuse and medical practitioner. Focus on practice also yields insights into broader socio-economic and political concerns about disability, productivity and military efficiency. It situates the evolution of massage, practically and professionally, as part of the wider development of rehabilitation within society and medicine during this period. By contextualising the early professionalisation of massage in this way, this thesis offers new perspectives on the complex interplay between the development of physiotherapy, society and medicine.

In order to investigate growth modifications of the temporomandibular joint (TMJ) during dentofacial orthopaedic treatment, various functional appliances have been used to prompt the mandible into a protrusive position in various animal experimental models. The general purpose of this project was (i) to test the effectiveness of a functional appliance specially designed for sheep; (ii) to clarify whether or not forward mandibular displacement in sheep is associated with faster and/or redirected condylar growth; (iii) to evaluate the sheep as a model for dentofacial orthopaedic research by comparing the similarities of mandibular condylar growth in sheep and humans; (iv) to detail the position of the mandible during forward mandibular posturing and the effects of mandibular forward displacement on modelling and remodelling of the mandibular condyle. The specific purpose of this project was to reveal whether functional appliance treatment increases the quantity of bone formed during the treatment, or changes the distribution of the bone, or both. Eight, 4-month old, castrated male Merino sheep were randomly assigned to experimental or control groups with 4 in each group. Cast functional appliances were fabricated for the animals in the experimental group. The treatment period was 15 weeks. Calcein (day 1) tetracycline (13 weeks) and alizarin red S (3 days before sacrifice) fluorochromes were administered to all animals. Dental casts, endosseous implant markers and cephalograms were used to analyse the 3-D displacement of the mandible. Undecalcified mid-sagittal sections of TMJ were used to evaluate the tissue responses induced by the appliances. Dynamic parameters of bone formation, static indices of bone-forming and resorbing activity as well as structural indices of trabecular bone were estimated using histomorphometry. The trabecular bone was sampled from two regions: (i) a subchondral region; (determined by 2nd and 3rd labels), believed to comprise bone newly-formed during the experimental period; and (ii) a central region (labelled by all the three fluorochromes), believed to comprise bone which existed before the experiment. The cortical bone was divided into anterior and posterior regions for analysis. The weight of the animals was measured monthly to monitor their growth. Metacarpus growth was also evaluated. During the experimental period, the animals were found to maintain their weight within the normal range and grew normally. The appliance was found to displace the mandible to a downward and forward position with a net condylar displacement of 2.4 mm. The observed adaptive responses in the TMJ induced by the appliances included; the condylar process was less tapered and rounder in the experimental group than in the controls, and anteriorly thickened condylar cartilage and a thickened compact bone layer along the anterior surface of the posterior wall of the glenoid fossa. The mandibular condylar growth vector in sheep was found to be in a postero-superior direction. Condylar growth in the control sheep during the experimental period varied from 8.8 to 11.9 mm, with the mean being 10.6 mm, which is quantitatively similar to two years of condylar growth in human adolescents. In the experimental sheep, the condylar growth varied from 8.5 to 13.3 mm, with the mean being 11.4 mm. When metacarpal growth and weight gain were taken into consideration using multivariant analysis, the coefficients for growth in the postero-superior and posterior direction were found to be high, with adjusted r2 as 0.84 and 0.82 respectively. The induced condylar growth was estimated to be largest in the posterior direction (2.3 mm), which is also similar to previous reports in humans. Regional differences in adaptive response within the mandibular condyle were found in this study. In the experimental group, bone volume fraction (BV/TV) of the subchondral regions decreased, although the specific bone surface and bone formation rates increased. This low BV/TV was associated with decreased trabecular thickness and increased trabecular separation. In the central region of the experimental group's condyle, BV/TV was unchanged. However, an increased osteoid surface (OS/BS) was defined when the eroded surface (ES/BS) was taken into consideration. The sheep were found to cope well with the experimental procedures and the appliance used in this study has been effective in inducing adaptive responses in the TMJ. Consequently, it is believed that the sheep is an appropriate animal model for quantitative histological analysis of the responses to functional appliance treatment. The first null hypothesis, that functional appliance treatment has no effect on bone matrix mineralisation was rejected. The second null hypothesis, functional appliance treatment has no effect on the mineralisation lag time, was rejected. The results indicated that the treatment effects of functional appliances involve reorganisation of the TMJ through bone modelling and remodelling. An important mechanism of functional appliance treatment is, therefore, suggested to be a change in the distribution of bone rather than an increase in the quantity of bone. Posterior rotation of the principle tensile strain angle (Et) suggested an posteriorly altered direction of the condylar growth. Increased new bone formation in the glenoid fossa suggested an anterior re-positioning of the temporomandibular joint. / Thesis (Ph.D.)--Dental School, 2002.

Displaced femoral neck fractures comprise more than a third of all hip fractures. There is controversy as to the optimal treatment. Despite attempts to improve the methods for internal fixation, complication rates have been almost unchanged: 20-40% non-union and late segmental collapse in another 10-20%. Internal fixation has been the preferred treatment in Scandinavia, whereas primary hemi- or total arthroplasty have been more prevalent in the rest of Europe and North America. In this study, patients 75 years or older, including those with mental impairment, were randomized to either internal fixation or cemented primary total hip arthroplasty (THA). A total of 146 hips in 143 patients were followed for two years. After one year 23% had died, and after two years 29%. Mortality was about the same in both groups. The accumulated mortality was pronounced among the mentally impaired patients. In the internal fixation group, 44% underwent further surgery. In the THA group, 18% dislocated. The dislocation rate was higher for the mentally impaired patients. The Harris hip scores were higher in the THA group, whereas pain was more common in the internal fixation group. The first 50 patients in each treatment group were studied concerning heterotopic ossification (HO), a well-known complication after THA. The incidence of HO in the THA group was similar to what is found after THA due to osteoarthritis. However, only 1/39 developed severe symptoms. A subgroup of 100 patients was included in a study concerning nutritional status and functional capacity using the Modified Norton scale, Katz index of ADL and a questionnaire measuring instrumental activities of daily living. The THA group fared better concerning weight change over time, locomotion and pain. The nutritional intervention did not show any measurable effects. All patients were followed until two years postoperatively and all fracturerelated hospital costs, including reoperations, were calculated. We found no difference in total costs between the treatment groups. Costs to the municipality were calculated comparing the baseline cost before surgery with the average cost per month during the first postoperative year. No difference was found between the treatment groups. On the basis of our results, we recommend arthroplasty for patients in this age group with normal mental function and high functional demands.

This thesis, comprising 5 separate studies, is concerned with fixation of prosthetic components in total hip arthroplasty. The results and conclusions of the studies fol-low; The initial stability of femoral revision components, the long cementless PCA stem and the Exeter standard stem cemented in a bed of impacted bone graft, was com-pared in an experimental study. The PCA stem was more stable than the Exeter stem. However, for both stems initial stability may not be sufficient to allow bone ingrowth. Initial fixation is especially vulnerable to torsion. Identical femoral stems with or without HA-coating were compared in a prospec-tive randomized clinical trial. The long-term stable fixation of a cementless Link RS femoral component was improved by application of hydroxyapatite coating to the femoral stem. In a clinical study the method of extensive impaction of morsellized bone allograft and a hydroxyapatite-coated cementless Mallory-Head acetabular component was found to be advantageous for acetabular revision in the presence of contained or acetabular wall defects. The limited contact between the HA-coated implant and living host bone did not seem to compromise long-term stable fixation. Two different cup designs were compared in a prospective randomized RSA study. At 3 years after implantation the cemented low profile Lubinus FAL cup performed as well as the cemented Lubinus Standard cup in terms of migration and polyethyl-ene wear. In a study of the relationship between radiolucent lines and migration the Lubinus FAL cup displayed more radiolucent lines in the cement bone interface than the Lubinus Standard cup but no difference in migration was found. Early appearance of such radiolucent lines represents an unspecific finding without reliable correla-tion to 3-year migration of the acetabular component.

Reactive oxygen species (ROS) induce oxidative stress and although are primarily recognized for playing a deleterious biological role, they can be beneficial to cell systems. ROS are extremely short-lived and normally tightly regulated by antioxidant defence systems. Cells react to oxidative stress in different ways, which primarily depends on cell type, stress severity, or both. There is a general limitation in extrapolating to humans conclusions drawn from in vitro and animal studies because of important species-specific differences. Therefore, the general aim of this thesis was to study the influence of oxidative stress on human muscle and bone in vivo. In paper I we presented a one-step HPLC method optimized for the simultaneous determination of purine degradation products in small microdialysis samples. The clinical utility of the method was successfully tested in a patient with traumatic brain injury. In paper II we evaluated microdialysis as an in vivo method to characterize the relative kinetics of ROS-related metabolites in human skeletal muscle exposed to ischaemia-reperfusion. Results indicated that microdialysis was feasible and safe to use in monitoring metabolic events during tourniquet-assisted surgery. In paper III we investigated the association between an oxidative stress marker (urinary 8-iso-PGF2α) and bone mineral density (BMD) and whether α-tocopherol modified the association. The main finding was the negative association between 8-iso-PGF2α and BMD and that the association was further dependent on serum α-tocopherol level. In paper IV we performed a randomized controlled trial to evaluate the influence of Q10 supplementation on exercise performance and metabolites of muscular damage. We did not observe any effects on exercise capacity after 8 weeks of Q10 administration. Nor did we find a significant effect on serum markers related to oxidative stress. In conclusion we have studied the influence of oxidative stress on muscle and bone in vivo in humans. The oxidative stress was triggered by four different causes (trauma, ischemia-reperfusion, ageing, and exercise exhaustion).

The focus of this dissertation is on the development of a solid freeform fabrication (SFF) process for the design and manufacture of porous biodegradable orthopaedic implants from calcium polyphosphate (CPP). Porous CPP structures are used as bone substitutes for regenerating bone defects and/or as substrates in formation of so-called “biphasic” implants for repair of damaged osteochondral tissues. The CPP implants can be utilized in the treatment of many musculoskeletal diseases, osteochondral defects, and bone tumours while replacement of the defect site is required. In this study, the fabrication of CPP structures was developed through a powder-based SFF technique known as adhesive bonding 3D-printing. SFF is an advanced alternative to the “conventional” fabrication method consisting of gravity sintering of CPP pre-forms followed by machining to final form, as SFF enables rapid manufacturing of complex-shaped bio-structures with controlled internal architecture. To address the physical and structural properties of the porous SFF-made components, they were characterized using scanning electron microscopy, micro-CT scanning and mercury intrusion porosimetry. Specific surface area and permeability of the porous structures were also determined. Additionally, the chemical properties (crystallinity) of the specimens were identified by X-ray diffraction. The mechanical properties of the crystalline CPP material were also measured by micro- and nano-indentation. Moreover, the porous structures were tested by uniaxial and diametral mechanical compression to determine the compressive and tensile strengths, respectively. Furthermore, the effect of the stacked-layer orientation on the mechanical properties of the SFF-made constructs was investigated through the production of samples with horizontal or vertical stacked-layers. The properties of the SFF-made samples were compared with those of the conventionally-made CPP constructs. The SFF-made implants showed drastically higher compressive mechanical strength compared to the conventionally-formed samples with identical porosity. It was also shown that the orientation of the stacked-layer has substantial influence on the mechanical strengths. Moreover, this thesis examined the ability of in vitro forming of cartilaginous tissue on the SFF-made substrates where the chondrocytes cellular response to the CPP implants was evaluated histologically and biochemically. In addition, an initial in vivo assessment of the CPP structures as bone substitutes was conducted using a rabbit medial femoral site model. Significant amount of new-bone was formed within the CPP porous constructs during the 6-week implantation period demonstrating appropriate biological response of SFF-made CPP structures for bone substitute applications. Another accomplishment of this thesis was the development of a mathematical model which predicts the compact density of powder layers spread by a counter-rotating roller in the SFF technique. The results may be used in the control of the apparent density of the final implant. The potential of the developed SFF method as an efficient and reproducible technique for the production of porous CPP structures for use in orthopaedics and musculoskeletal tissue regenerative applications was concluded.