The goal of the present grant is to develop and validate the effectiveness of artificial microRNA-mimic/inhibitor (a- miR-m/i)-based coatings to suppress foreign body reactions to S.Q. injected micro-beads in vivo. If these pre- translational studies of a-miR-m/i coatings in mice are successful, in the future we will evaluate their effectiveness in vivo using porcine models of implantable medical devices. The explosion of implantable medical devices has been ?god sent? by dramatically improving the quality and length of life for a wide variety of patients worldwide. These devices range from simple metal screws, to the artificial pancreas (glucose sensor & insulin pump infusion sets) that help control blood glucose levels in patients with diabetes. Unfortunately, the functional lifespan of these medical implants are frequently shortened by implant-induced chronic inflammation referred to as foreign body reactions (FBR). Although there have been decades of research and development to discover a ?rosette stone? to defeat FBR, no true breakthroughs or disruptive technology has been developed to overcome FBR. There is a clear need for the development of a truly disruptive technology, we believe that a-miR-m/i coatings are that disruptive technology. The original discovery of powerful micro-RNAs, which regulate a wide range of cells and network functions, led to the creation of micro-RNA-m/i, which in turn led to the development of modified synthetic microRNA we have designated as artificial microRNA-mimic (a-miR-m) and inhibitor (a-miR-i) based therapeutics. We propose to use these a-miR-m/i as micro-bead coatings to control FBR in vivo by 1) suppressing inflammation and pathologic fibrosis, as well as 2) induce neovascularization (blood and lymphatic vessels) to enhance successful integration of medical devices into healthy surrounding tissue. To our knowledge, there are currently no publications related to the use of a-miR-m/i to enhance implantable device biocompatibility in the literature. The goal of the present application is to develop foundational data on the ability of a-miR-m and a-miR-i (with and without basement membrane (BM) adjunct coatings), to enhance the biocompatibility in a simple FBR model, i.e. subcutaneous micro-bead injections (murine MB model). For the present studies, BM adjuvants represent a prototype coating, but in the future studies, we will consider various other natural and synthetic coatings for depoting a-miR-m/i. Initially, we will use cell culture models to determine the ability of specific a-miR-m and a-miR-i in suppressing pro- inflammatory activity by targeting 1) M1/M2 macrophages, 2) fibrosis by targeting fibroblasts, and 3) neovascularization by targeting M2 macrophages and vascular endothelial cells (VEC) in vitro. The a-miR-m/i optimized in vitro will then be evaluated in vivo. Using the mouse model, we will evaluate a-miR-m/i only coated micro-beads (i.e. non-BM-coated (Wo) and a-miR-m/i BM-coated (W) micro-beads of varying sizes injected in the subcutaneous tissue of mice, followed by histopathology evaluations, with the most successful in vitro versions of a-miR-m/i (W&Wo BM) being evaluated in vivo. We believe that successful development & validation of a-miR-m/i-BM based coatings will represent a disruptive technology to enhance medical device performance in the future, and dramatically improve quality of life for patients.
The goal of the present application is to develop a totally new paradigm in biocompatibility coatings for implantable devices that will utilize anti-inflammatory a-miR-m/i (with and without basement membrane) based coatings to prevent inflammation and fibrosis, as well as promote tissue regeneration.