Date of Award

8-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical and Chemical Engineering

Advisor(s)

Patrick T. Mather

Subject Categories

Biomedical Engineering and Bioengineering

Abstract

Nitric oxide [NO] is an endogenous gas involved in a multitude of physiological functions, ranging from vasodilatation, inflammatory response to inhibition of platelet aggregation. Significant interest exists for therapeutic application of exogenous NO, particularly for the improvement of foreign-body responses of biomaterials. One challenge amongst several others that must be taken into consideration is NO's short half-life, ranging from 2-3 s, in physiological systems. Researchers have worked on synthesizing materials, formally referred to as NO donors/NONOates capable of preserving NO and spontaneous gas release upon contact with blood under physiological conditions. Two groups of these commercially available NO donors known as diazeniumdiolates and nitrosothiols have been shown to be biological active. Unfortunately, current commercially available NO donors, particularly diazeniumdiolates have short half-lives, ranging from a few seconds to a maximum of 20 h under physiological conditions. Many studies have shown diverse approaches for slowing down NO release for appropriate therapeutic application unfortunately, elimination of undesirable spontaneous NO release, still remains an elusive goal. In the first chapter, a POSS-based NO donor capable of 8-fold more NO-loading efficiency per mol of donor, in comparison to current commercially available NO donors is presented. Various characterization techniques were used to confirm successful NO-modification and determination of NO-loading efficiency. Ten mols of NO were successfully detected on the POSS/NO compound, which is higher than the loading efficiency of commercial NO donors.

The inadequacy associated with commercially available NO donors is not only related with their NO-loading inefficiency, but also in the delivery of sustained and controlled NO release. Motivated by this problem we introduce a biomimetic approach with the development of a novel NO-releasing elastomeric composite system capable of controlled and sustained NO release under physiological conditions. The NO donor was incorporated into a two-part elastomeric composite system comprised of hydrophobic electrospun fibers and a silicone-based elastomeric polymer. Utilization of a fibrous elastomeric composite, permeable to gas and water molecules, enabled very gradual penetration of water into the system thus, preventing immediate NO donor hydrolysis in aqueous medium. Experimental results showed the control group, without the elastomeric component, released NO spontaneously whilst the fibrous composite system exhibited remarkable controlled and sustained NO release. Considering the biomimetic and NO-releasing properties of our elastomeric composite system, utilization of the system towards vascular graft application was also studied. The idea behind this NO-based therapy was to provide a material that will not only mimic native blood vessels, but would also enable endothelial cell [EC] proliferation, promoted by long-term NO release post-surgical intervention. In collaboration with a vascular surgeon, the composite grafts were tested under in vitro and in vivo conditions. The mechanical properties of the NO-releasing elastomeric tubes were comparable to native blood vessels and showed adequate suturability and suture retention strength.

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Open Access

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