Engineering of biomaterials with controlled biomolecule delivery for cardiovascular applications

Project Summary Currently, cardiovascular disease ranks as the leading cause of death in the United States. It is projected that by 2035, over 130 million adults in the U.S. will have some form of cardiovascular disease. Vascular graft technologies with patency rates equivalent to the clinical success of autologous grafting are lacking. Our goal is to utilize novel biomaterial surface modifications and develop nucleic acid delivery technology to improve host- biomaterial interactions with particular focus on the failure mechanism of neointimal hyperplasia resulting from smooth muscle cell proliferation and migration. Previous work by our team has optimized surface characteristics (physical topographies and biochemical modifications) to promote endothelialization without increasing thrombosis. However, the addition of controlled therapeutic nucleic acid delivery with this proposal will address intimal hyperplasia by directly altering smooth muscle cell phenotype. This work will develop the material surface delivery techniques to alter host-biomaterial responses, which occur after graft implantation. Our use of poly(vinyl alcohol) (PVA) biomaterials is integral to these studies because it is a highly modifiable material; however, these results can be readily translated to other modifiable off-the-shelf materials. Our aims are to: (1) develop nonviral delivery of miR145 with surface- and sustained-release via nanoparticles complexed to our novel PVA-CDI immobilized aminated fucoidan (PCAF) biomaterials, (2) characterize the effects of PCAF delivered miR145 on vascular cell responses, including endothelial cells, neutrophils, macrophages, and fibroblasts and (3) characterize the in vivo effects of PCAF-delivered miR145 on neointimal formation under healthy and diseased states. Using PCAF with previously established topographies and surface chemistries known to support endothelialization while maintaining hemocompatibility, we will utilize innovative gene delivery technologies in conjunction with our clinically relevant animal models. These strict models have the potential to improve translation by testing the material modifications in a whole, non-anticoagulated, flowing blood model of thrombosis and a clinically relevant end-to-side model of vascular grafting implantation. The deliverables for this project will include (1) efficient and sustainable delivery of miRNA-145 from our previously optimized PCAF to smooth muscle cells (SMCs), (2) induction of the SMC contractile phenotype without causing endothelial dysfunction, inflammation, or thrombosis, and (3) confirming a reduction of neointima formation in vivo without harmful “off-target” effects or harmful accumulation in organs. The potential significance of this translational project is the improved design of novel, functional biomaterial surfaces for cardiovascular applications. While we are focused on vascular graft applications in this proposal, the principles of surface controlled responses can be applied to multiple blood contacting devices. Our research will enable development and optimization of vascular biomaterials for use in humans.