Graduate Thesis Or Dissertation
 

Synthesis and function of bioactive, block copolymer surfactant constructs as relevant to the preparation of anticoagulant and antibacterial medical implant surfaces.

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  • Nisin, an antibacterial peptide proven to be an effective inhibitor of Gram-positive bacteria, was incorporated into novel block copolymer constructs and tested for retained antibacterial activity. Covalent coupling was achieved by chemical modification of the N-terminal isoleucine to introduce a thiol group. Thiolated nisin derivatives were then linked to poly[ethylene oxide]-poly[propylene oxide]-poly[ethylene oxide] (PEO-PPO-PEO) triblocks that had been end-activated such that terminal hydroxyl groups of the PEO chains were replaced with pyridyl disulfide moieties. The nisin-containing block copolymers were separated from unreacted nisin by dialysis, and showed antimicrobial activity against the Gram positive indicator strain Pediococcus pentosaceus. Antimicrobial activity was determined to be due to a combination of disulfide-linked nisin, and nisin that was not covalently associated with the PEO-PPO-PEO triblocks. While the extent to which nisin retained antimicrobial activity in its disulfide-linked, copolymer form is not clear, reduction of the nisin-containing copolymer constructs with dithiothreitol demonstrated that nisin released from the copolymer constructs did show antimicrobial activity. Thiol groups were also introduced to unfractionated heparin, an anticoagulant glycosaminoglycan, by reaction of carboxyl groups in its iduronic residues with 3, 3’dithiobis (propanoic) hydrazide. Thiolated heparin derivatives were then linked to pyridyl disulfide-activated PEO-PPO-PEO triblocks which had previously been coated onto the surfaces of polystyrene microspheres (1 m diameter). In addition to monitoring the heparin linking reaction spectrophotometrically, the zeta potential of uncoated, triblock-coated, and heparin-containing microsphere suspensions was recorded to provide an indication of the successful surface attachment of heparin. While the surface attachment of heparin in this manner significantly increased the anticoagulant activity of the microsphere suspensions as determined by the Activated Partial Thromboplastin Time (APTT) assay, this result was not fully reproducible due to the random nature of the thiol-modification process, which, after heparin surface attachment, may interfere with heparin function.
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