Modelo Sistémico

The development of biocompatible materials has remained an elusive goal for the scientific community due to the numerous fouling mechanisms inherent to an implant surface. As such, the amount of research funding devoted to developing such materials has initiated a biomaterial revolution. The design of new materials has encompassed all facets of polymer science ranging from absorbable to persistent polymers with applications ranging from coatings for electrochemical sensors to prosthetic implants. Unfortunately, many biomaterial design approaches only look to solve one of the numerous fouling mechanisms. The inherent advantages of NO-releasing materials lie in their ability to combat numerous issues ranging from infection and thrombosis to the foreign body response and neointimal hyperplasia. Even with the numerous advances made to NO-releasing materials in the past 15 to 20 years, the development of materials resistant to fouling remains a long-term goal. While numerous NO-releasing materials have shown great promise, the development of materials with application specific properties combined is a critical step toward the development of NO-releasing biomaterials.

The physical incorporation of NO-releasing dopants into polymeric materials is a promising avenue for the development of better biomaterials.80 Diffusion-mediated NO release of diazeniumdiolated additives embedded within these materials provides a method for significantly prolonging the therapeutic effects of NO.76 Furthermore, tunable NO release may

be achieved by controlling the dopant type and amount dispersed within the polymeric matrix. Unfortunately, many of the dopants to date actually leach from their polymeric scaffold, liberating potentially carcinogenic nitrosamine byproducts into the body.76 As a result, the development of diazeniumdiolated additives with increased polymeric retention is an important factor for the fabrication of NO-releasing material coatings. Increasing the hydrophobicity of low molecular weight additives may provide enhanced polymeric retention of the additives thereby avoiding leaching of potentially carcinogenic diazeniumdiolate degradation byproducts. Although previous reports have investigated this correlation, the elusiveness of a non-leaching NO-releasing polymer additive warrants the synthesis of diazeniumdiolate precursors with even greater alkyl content. The synthesis and characterization of lipophilic diamine diazeniumdiolates as potential polymer additives was one goal of my dissertation research.

The first reports of using degradable polymers as sutures occurred over 50 years ago.8, 9 Since that time, advancements in polymer science have led to the development of unique polymeric materials with well-defined degradation rates capable of use for a variety of new medical applications including gene therapy, drug delivery, and tissue engineering.7 However, problems associated with persistent implants, such as infection and the foreign body response also plague degradable implant materials.10, 12 Although bulk degradation of the polymeric materials enables controlled release of antibacterial agents and other drugs to facilitate material integration into the body, the realization of a fouling-resistant material is yet to be achieved.9 As such, introducing the physiological benefits of NO release to a material that can be absorbed by its host is an interesting avenue of research. The proven benefits shown by persistent NO- releasing implants may be extended to materials with new applications where material

degradation is also essential. The development and characterization of NO-releasing degradable materials was a second focus of my dissertation research.

Blood compatibility is an important aspect for the development of intravascular implants such as catheters, stents, and sensors.11 Polyurethanes represent one of the most popular blood-contacting materials as their low surface energy segments significantly reduce blood protein and platelet adhesion. The inherent anti-platelet characteristics of polyurethanes have been shown to be enhanced by the addition of NO release in the form of polymer additives and diazeniumdiolate modification.102-104 However, leaching of polymer additives and protein adhesion caused by surface charge accumulation of diazeniumdiolate-modified materials pose compatibility risks for implants.103 Additionally, these materials suffer from low NO storage capacities (up to 0.02 µmol mg-1_).102-104

S-nitrosothiol modification of polyurethanes is a

promising avenue for the development of blood compatible materials. Nitric oxide release from these surfaces should enhance blood compatibility of the material, and the absence of surface charge accumulation may prevent the adhesion of blood proteins at the polymer interface. Furthermore, the incorporation of NO donors at different places (hard vs. soft segment) along the polymer backbone, which has yet to be investigated, may increase total NO storage and influence the kinetics of NO release. The design and synthesis of S-nitrosothiol-modified polyurethanes

and NO-release dependence on NO donor position along the polymer backbone was another aspect of my research.

An important design aspect for therapeutic materials is matching morphological and chemical characteristics of the material with its intended application. For example, tissue engineering is most effective using high surface area scaffolds to maximize cell seeding and promote differentiation. Unfortunately, current NO-releasing materials lack morphological

diversity required for numerous therapeutic applications. In order to extender the therapeutic benefits of NO to high surface areas materials coupling the electrospinning technique, used to make well defined monodisperse, micro and nanofibers, with NO release represents a promising avenue for the development of biomaterials. Diversity of electrospun materials may easily be attained by varying fiber composition, size, and NO donor type giving rise to numerous therapeutic platforms. Investigating the NO release dependence on size, composition, and morphology of electrospun polymer microfibers doped with various NO donors is the final aspect of my dissertation research.