Using gold nanorods to modify the extracellular matrix and mechanical properties

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DESCRIPTION (provided by applicant): The atrioventricular valves (AV) divide the mammalian heart into four chambers and, combined with the pulmonary and aortic valves, ensure unidirectional blood flow. AV valve leaflets are composed of a trilaminar structure consisting of both valvular interstitial cells and layers of extracellular matrix (ECM) proteins. Of the ECM proteins present, collagen type I is particularly important because it is responsible for the structural support and mechanical durability of the valves. When the balance of collagen turnover is altered, the mechanical properties of the mitral valve leaflets change. If the leaflets become too stiff, as can occur during adaptation to progressive heart disease, or too floppy, as in degenerative valve diseases, the leaflets do not completely close allowing regurgitation to occur. While there are a number of surgical approaches which can repair or completely replace diseased valves, therapeutic strategies aimed at the biochemical changes leading to valvular dysfunction are limited. Nanomaterials are receiving increased attention for their therapeutic potential, largely in the areas of drug delivery and imaging. Recent work from our group has demonstrated that negatively charged gold nanorods can alter cardiac fibroblast phenotype, preventing their transformation into myofibroblasts, and affecting the production of type I collagen. Preliminary data presented herein demonstrates that surface-modified gold nanorods can alter the assembly of type I collagen fibrils which correlates with changes in the mechanical properties of three-dimensional collagen gels. The proposed study will test the hypothesis that surface-modified gold nanorods can modulate valvular interstitial cell behavior by altering the mechanical properties of collagen. Furthermore, it is proposed that by manipulating the surface charge on the nanorods, the mechanical properties of mitral valve leaflets can be tailored to obtain desired functional properties. Two specific aims are proposed to test this hypothesis: 1) To determine the effect of surface-modified gold nanorods on the mechanical properties of atrioventricular valves ex vivo and 2) To determine the mechanism by which surface-modified gold nanorods alter collagen fibrillogenesis. The work proposed herein represents a multidisciplinary approach to investigating the potential uses of gold nanorods in biomedicine, targeted ultimately at developing a minimally invasive therapy for mitral valve regurgitation. If successful, these studies will demonstrate the efficacy of using surface charges presented by gold nanorods to modulate cell behavior, matrix assembly and tissue mechanical properties. These results will not only impact the cardiovascular field, which is greatly interested in mechanisms associated with matrix remodeling and ways to control it, but also other areas of medicine where the control of fibrosis is essential to preserve organ function. PUBLIC HEALTH RELEVANCE: Collagen is a structural protein found within valve leaflets which is largely responsible for the mechanical properties and proper function of the valves. In response to increased load on the heart or due to genetic defects, the balance between collagen production and degradation, which is maintained by cells within the valve leaflets, becomes shifted and these leaflets can no longer function properly. The work proposed herein will take a novel approach using gold nanorods to regulate cell behavior, collagen assembly and the mechanical properties of heart valves.