A Nanobubble-Based Resuscitative Fluid for the Treatment of Hemorrhagic Shock
Abstract
FY21 DMRDP JPC-6/CCCRP BRISCC Focus Areas: Novel and/or advanced blood products or volume expanders with oxygen-carrying capacity that offer physiological, logistical, or cost advantages over current products. Background: Hemorrhage following traumatic injury is the most common cause of preventable death in Warfighters on the battlefield, with the majority of deaths occurring in the pre-hospital setting. Severe bleeding results in a sudden drop in blood volume, known as hemorrhagic shock (HS), and it disrupts the ability of the body to deliver oxygen to tissues, particularly the brain and heart. Oxygen is essential to life, and even brief disruptions in its supply can result in irreversible organ damage—and in the setting of uncontrolled bleeding, death can occur in minutes. Administration of blood or blood components (e.g., albumin, freeze-dried plasma) are the current gold standard for the treatment of HS; however, they have extremely limited availability, especially in austere environments. In the absence of blood products, frontline caregivers are forced to administer other fluids, such as saline or sugar solutions, to buy the time necessary for transport to a higher echelon of care for definitive treatment. However, these fluids lack the intrinsic oxygen carrying capacity needed to compensate for the severe blood loss commonly seen in HS and, in fact, often result in worse clinical outcomes. In response to this, the scientific community sought to create artificial oxygen carriers (OCs) that could be added to existing resuscitative fluids, creating the field of blood substitutes. The most well known OCs include the hemoglobin (HBOCs) and perfluorocarbon (PRCOCs)-based systems. HOBCs typically employ a heme derivative that binds and releases dissolved oxygen in a manner similar to red blood cells. PROCOCs, on the other hand, are tiny fluid-filled particles that dissolve oxygen gas within their liquid cores. However, despite decades of research and development and numerous clinical trials, there remain no FDA-approved OCs. In general, this is because HBOCs and PFCOCs continue to be plagued by low efficacy and toxicity problems, such as deleterious vasoconstriction due to heme-related NO scavenging, heme toxicity, and oxidative stress injuries that exacerbate existing inflammatory conditions, which are common in traumatically injured Warfighters. Further, oxygen loading and delivery from HOBCs and PFCOCs can be delayed or even inhibited by the altered physiology of HS patients and the lack of specialized equipment (e.g., PFCOCs require inspiration of high oxygen concentrations to work, which may not be readily accessible on the battlefield). Innovation: In this proposal, we will create an entirely new class of OCs based on circulating polymeric nanobubbles (pNBs). Over the past decade, our laboratory has pioneered the use of gas-based micro- and nanocarriers for rapid intravenous oxygen delivery to rescue patients suffering from cardiac arrest. pNBs contain a pure gaseous core encapsulated within a thin, gas-permeable polymeric shell (e.g., oxygen can pass through the shell within seconds). In this way, they function as circulating microscopic lungs, where they become rapidly loaded with oxygen as they pass through the lungs before entering the systemic circulation. When they encounter oxygen-deprived tissues, oxygen is released from the pNBs, thus permitting the tissue to breathe normally. Importantly, pNBs can be functionalized with ligands that simultaneously increase the blood volume while rendering them virtually invisible to the immune system. This maximizes oxygen delivery while minimizing the volume of fluid needed for resuscitation, which is important, as excessive fluid can be fatal in the setting of HS. It also reduces the risk of drug toxicity due to undesired interaction with immune cells or blood components known to plaque nanomedicines. In Aim 1, we will optimize the pharmaceutic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210111
Entities
People
- Yifeng Peng
Organizations
- United States Army