Healing of chronic wounds such as diabetic foot ulcers is a significant clinical problem. Methods of accelerating healing in these difficult lower extremity sites include use of growth factor-loaded gels, hyperbaric oxygen, grafts, and artificial skin replacements. Nitric oxide (NO) has been proposed as a possible active agent for enhancing wound healing. This study examines the in vitro and in vivo responses to a novel hydrogel that produces therapeutic levels of NO. A hydrogel wound dressing was fabricated using ultraviolet light-initiated polymerization from poly(vinyl alcohol) with a NO donor covalently coupled to the polymer backbone. NO release from the NO-modified hydrogel was shown to occur over a time period of up to 48 hours, and there was no associated decrease in fibroblast growth or viability in vitro associated with NO hydrogels. Fibroblasts in culture with NO hydrogels had an increased production of extracellular matrix compared with cells cultured without the NO hydrogels. Preliminary animal studies in a diabetic mouse, impaired wound healing model were conducted comparing low (0.5 mM) and high (5 mM) doses of NO. Time to complete closure was similar in control wounds and NO-treated wounds; however, at 8 days control wounds were significantly smaller than NO-treated wounds. By days 10 to 13 this delay was no longer apparent. Granulation tissue thickness within the wounds at days 8 and 15 and scar tissue thickness after wound closure were increased in animals exposed to higher dose NO hydrogels. The results of this study suggest that exogenous NO released from a hydrogel wound dressing has potential to modulate wound healing.

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A porous polyurethane vascular prosthesis with an internal diameter of 5 mm was studied. The graft carries a coating of immobilized dipyridamole (Persantin(R)) on the surface of its lumen. Dipyridamole is a potent nontoxic inhibitor of platelet activation/aggregation, and also a strong inhibitor of vascular smooth muscle cell proliferation. The polyurethane material is also known as Chronoflex(R), and already finds use as a vascular access graft. The coated vascular graft was studied in vitro (hemocompatibility, interaction with blood platelets and cultured endothelial cells), as well as in two established in vivo models. In the first in vivo study, coated grafts were implanted in goats, as a bypass of the carotid artery (four animals, eight grafts, length of the graft was approximately 12 cm). Four uncoated grafts were used as controls in otherwise identical experiments. In the second in vivo experiment, eight sheep were used. Each animal received one coated and one uncoated prosthesis as an interposition graft in the carotid artery (length of the graft was 4 cm). The in vitro experiments revealed that the dipyridamole coating has three beneficial effects: reduced thrombogenicity, reduced adherence of blood platelets, and accommodation of a confluent monolayer of endothelial cells. The goat experiments showed patency of the coated grafts in three of the eight cases. The sheep experiments were not useful for the evaluation of the dipyridamole coating because deterioration of the polyurethane material was observed. The in vivo results indicate that the dipyridamole coating may positively influence the patency rate, probably because the coating promotes the growth of an endothelial cell lining. The sheep data show, however, that the limited stability of the Chronoflex(R) material precludes its issue for the construction of permanent small-bore vascular grafts.

ABSTRACT:We have previously reported on a hydrogel system fabricated from poly(vinyl alcohol) (PVA) functionalized with tyramine groups (PVA-Tyr) that has the ability to co-polymerize with proteins in their native state. These gels were also shown to be hydrolytically degradable through the ester groups present in the functional groups. In this article, the hydrolytic degradation of the PVA-Tyr gels is shown to be strongly dependant on pH, where at pH < 7.4 the lack of ionization of the tyramine groups resulted in slower hydrolysis. The gels' degradation was also highly influenced by temperature, where heat (>25 C) was required to facilitate the hydrolysis of the ester bonds. Moreover, the degradation rates were successfully tailored between 19 to 27 days by varying the hydrogels' initial macromer concentration. It was highlighted that the cross-linking density was dependant on the sodium persulphate to tyramine ratio, as well as the viscosity of the macromer solution.

The term nanocomposite refers to organic:inorganic composites where one phase, typically the inorganic phase, has dimensions on the nanoscale. Several authors have noted the potential benefit of biomedical application of nanocomposite technology, and have suggested using quaternary ammonium compounds (QAC) as an organic modification to enhance dispersion of nanoparticles within polymer matrices. This study aimed to examine fibroblast responses in vitro to a range of nanocomposites using different organic modifiers. Composite materials were prepared from a polyether urethane (PEU) and various unmodified and organically modified montmorillonite (MMT) nanoparticles. QAC and amino undecanoic acid (AUA) modified-MMT were added to PEU at loadings ranging from approximately 1 to 15 wt %. Composites with organically modified QAC and AUA particles displayed partially exfoliated and intercalated silicate morphology, respectively. Nanocomposites showed increases in ultimate tensile properties for materials with lower QACMMT loadings. However QAC was shown to significantly inhibit cell growth following release from PEU-QACMMT under extraction conditions mimicking those of the physiological environment. Materials containing silicate modified using AUA were cytocompatible. The results of this study suggest that QAC may be unsuitable as organic modifiers for nanoparticles destined for biomedical use. Alternative modifiers based on AUA confer equivalent dispersion and are of low toxicity.