Downregulation of neutrophil extracellular traps by fibrous regeneration template design.

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This application's overall objective is to understand the mechanisms of NETosis, the process of secreting neutrophil extracellular traps (NETs), on fibrous templates and to apply this knowledge gained to engineer novel fibrous templates focused on the attenuation of the degree of acute NETosis. This attenuation will be critical to limit any restriction of marginal tissue integration during in situ regeneration. The central hypothesis of this study is that fibrous templates can be engineered via architecture and therapeutic compound release to attenuate the degree of NETosis by acutely interacting neutrophils. Aim 1 will utilize near-field electrospinning (NFES) to fabricate precision, square-grid templates such that fiber diameter and pore size are the independent variables (template architecture) tested in the role of stimulating in vitro, acute, template-induced NETosis. Aim 2 will elucidate NETosis mechanisms induced by the templates and develop fiber-based, compound releasing vehicles as a supplemental means to architecture design to attenuate acute, template-induced NETosis and potentially minimize NET-induced fibrosis. Finally, in Aim 3, we will determine the in vivo template invoked degree of neutrophil NETosis and thus test whether the in vitro results are correlative in terms of the degree of NETosis-template attenuation in a rat subcutaneous model, in vivo veritas, and if this translates to enhanced marginal tissue integration. In summary, this study's expected outcome and innovation will elucidate the critical structural variables and therapeutic compound delivery in the refinement of fibrous, polydioxanone templates to allow for critical three-dimensional tissue integration, free from the impediment of acute, surface NETs. These results are then expected to translate to various degrees to other polymeric, fibrous tissue template compositions and designs to advance the field of template-induced tissue engineering and in situ regeneration in the treatment options for a wide variety of disorders plaguing our society.