Search

Background: The mechanism and clinical significance of low circulating 25-hydroxyvitamin D [25(OH)D] in obese people are unknown. Low total 25(OH)D may be due to low vitamin D–binding proteins (DBPs) or faster metabolic clearance. However, obese people have a higher bone mineral density (BMD), which suggests that low 25(OH)D may not be associated with adverse consequences for bone.\ud \ud Objective: We sought to determine whether 1) vitamin D metabolism and 2) its association with bone health differ by body weight.\ud \ud Design: We conducted a cross-sectional observational study of 223 normal-weight, overweight, and obese men and women aged 25–75 y in South Yorkshire, United Kingdom, in the fall and spring. A subgroup of 106 subjects was also assessed in the winter. We used novel techniques, including an immunoassay for free 25(OH)D, a stable isotope for the 25(OH)D3 half-life, and high-resolution quantitative tomography, to make a detailed assessment of vitamin D physiology and bone health.\ud \ud Results: Serum total 25(OH)D was lower in obese and overweight subjects than in normal-weight subjects in the fall and spring (geometric means: 45.0 and 40.8 compared with 58.6 nmol/L, respectively; P < 0.001) but not in the winter. Serum 25(OH)D was inversely correlated with body mass index (BMI) in the fall and spring and in the winter. Free 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were lower in obese subjects. DBP, the DBP genotype, and the 25(OH)D3 half-life did not differ between BMI groups. Bone turnover was lower, and bone density was higher, in obese people.\ud \ud Conclusions: Total and free 25(OH)D and 1,25(OH)2D are lower at higher BMI, which cannot be explained by lower DBP or the shorter half-life of 25(OH)D3. We speculate that low 25(OH)D in obesity is due to a greater pool of distribution. Lower 25(OH)D may not reflect at-risk skeletal health in obese people, and BMI should be considered when interpreting serum 25(OH)D as a marker of vitamin D status.

Many of the materials used today for cardiovascular implants exhibit good bulk mechanical properties but fail to provide desirable surface properties for reducing thrombogenicity and promoting tissue integration. In fact, biological responses at the blood-material interface, including non-specific protein adsorption, coagulation, and platelet adhesion and activation significantly limit the use of currently available materials in many blood contacting applications. As our understanding of the biological responses to foreign materials has grown, so too has the potential for creating 'bioactive' materials capable of inducing and directing beneficial cellular processes. One promising technique for circumventing undesirable blood-biomaterial interactions involves seeding vascular endothelial cells (ECs) onto synthetic vascular grafts as a means of exploiting the physiological anticoagulant characteristics of the endothelium. Methods for improving cell retention on these constructs include immobilization of cell recognition motifs on the biomaterial surface in order to improve interactions between cells and the synthetic substrate. However, there remains the need to better understand the interactions between surface bound ligands and cells, and the role of linker molecule chemistry on ligand bioactivity and cellular response. In the current work, a novel method was optimized for modifying poly (dimethylsiloxane) (PDMS) with cell adhesion peptides tethered via a heterobifunctional allyl-, NSC-terminated polyethylene oxide (PEO) linker molecule. These novel surfaces combine the protein repellant property of PEO with the cell binding property of cell adhesion peptides. It was found that surfaces modified in this manner reduced protein adsorption to PDMS while increasing cell adhesion. Therefore the use of a generic PEO linker molecule was shown to be a very promising method of reducing non-specific protein interactions while maintaining ligand bioactivity. Silicone surfaces were also modified with diaminobutane (DAB) dendrimers in an attempt to increase the surface capacity for attachment of biomolecules and to compare the effect of surface peptide density with ligand mobility. Grafting cell adhesion peptides via surface bound dendrimers was found to increase the surface peptide density when compared to peptides grafted via the PEO spacer alone. However, cell adhesion was not significantly improved on the dendrimer-peptide modified surfaces compared to PDMS controls. This observation provides evidence that the properties of the linker molecule used for attachment of cell adhesion peptides to a biomaterial surface may be a critical factor in determining peptide bioactivity. In this case the peptides bound to the surface via the highly mobile linear PEO linker showed increased cell adhesion when compared to peptides linked via the rigid, highly branched dendrimer. It is therefore hypothesized that ligand mobility on a biomaterial surface may significantly influence ligand-cell receptor interactions to an even greater extent than surface peptide density. Thesis Master of Applied Science (MASc)