Targeted Nanobubble Technology to Control Diabetic Macrophage Function
Abstract
Rationale: According to estimates from the Centers for Disease Control and Prevention, 30.2 million people, or 9.4% of the U.S. population, have diabetes. The key threat to the society is diabetic complications. Wounds and inflammation are the critical components of diabetic complications. Further, inflammatory response is critical in wound healing in scenarios like blast injuries and extremity trauma. Inflammation is a necessary and critical post-injury but must undergo timely resolution to enable healing. Macrophages play a key role in mounting and resolving inflammation. The function and fate of wound monocyte/macrophages hold the key to the outcome of wound inflammation. Research Strategy: This application focuses on the regulation of macrophage polarization and plasticity at the site of injury using targeted gas nanobubble technology with reprogramming cargo. Macrophages exhibit diversity and plasticity. They undergo polarization to anti-inflammatory subtype from pro-inflammatory. They are plastic and can switch fate to endothelial and fibroblasts at the site of injury. Such fate change is critical for the resolution of inflammation, failing which they get stalled in pro-inflammatory phase, resulting in chronic inflammation as observed in diabetes. However, such can be overcome by delivery of macrophage reprogramming factors. Use of gas nanobubble technology as a gene delivery platform has advantages. First, it is a non-viral system and hence does not pose challenges like integration in chromosomes or adverse immunologic reactions. Second, they are easily trackable through ultrasound (US) imaging. Third, the delivery of genetic material can be regulated unlike any other gene-delivery platforms. When required, US can be used to trigger and deliver factors to tissue of interest via sonoporation. We propose to test two specific aims. In the first aim, we develop gas nanobubble as a vehicle to carry genetic factors targeted to macrophages. In the second aim, we utilize such macrophage targeting gas nanobubbles to alter macrophage fate at the site of injury and resolve inflammation. Potential Clinical Applications and Impact: The project aims to resolve chronic inflammation associated with diabetes and other traumatic injuries by regulating macrophage fate. Such regulation will be mediated via delivery of genes through targeted gas nanobubbles. The proposed project will be completed in 18 months. Because of the simplicity of the technology and safety of the gas nanobubbles, we anticipate that it will be used for clinical applications. Reportedly, 8.7% of women and 10% of men who served the U.S. military during 2013-2014 were diagnosed with diabetes. Wounds like diabetic foot ulcer and inflammation are major complications arising from diabetes. Therefore, regulation of macrophage fate using targeted gas-based nanobubbles will offer a novel therapy towards addressing the diabetic complications. The technology can be also leveraged to accelerate wound healing post blast injuries and extremity trauma by ensuring faster resolution of inflammation. For military personnel, such chronic wounds constitute a serious barrier to the high level of functioning required to return to duty. Therefore, the ability to treat such individuals to facilitate full functional recovery and the highest possible quality of life is a key goal envisioned through this proposal.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910120
Entities
People
- Sashwati Roy
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army