Oxygen Gas–Filled Microparticles Provide Intravenous Oxygen Delivery

Abstract

We have developed an injectable foam suspension containing self-assembling, lipid-based microparticles encapsulating a core of pure oxygen gas for intravenous injection. Prototype suspensions were manufactured to contain between 50 and 90 ml of oxygen gas per deciliter of suspension. Particle size was polydisperse, with a mean particle diameter between 2 and 4 μm. When mixed with human blood ex vivo, oxygen transfer from 70 volume % microparticles was complete within 4 s. When the microparticles were infused by intravenous injection into hypoxemic rabbits, arterial saturations increased within seconds to near-normal levels; this was followed by a decrease in oxygen tensions after stopping the infusions. The particles were also infused into rabbits undergoing 15 min of complete tracheal occlusion. Oxygen microparticles significantly decreased the degree of hypoxemia in these rabbits, and the incidence of cardiac arrest and organ injury was reduced compared to controls. The ability to administer oxygen and other gases directly to the bloodstream may represent a technique for short-term rescue of profoundly hypoxemic patients, to selectively augment oxygen delivery to at-risk organs, or for novel diagnostic techniques. Furthermore, the ability to titrate gas infusions rapidly may minimize oxygen-related toxicity.

Oxygen delivery using engineered microparticles

“…One potential solution to this problem is to use a gas-stabilizing agent to contain the oxygen gas and to prevent bubble coalescence during and following injection (16)(17)(18)(19). From a theoretical perspective, this approach is preferred as it overcomes the concentration limits of dissolved or bound oxygen.…”

“…From a theoretical perspective, this approach is preferred as it overcomes the concentration limits of dissolved or bound oxygen. Our group first demonstrated the feasibility of this approach by packaging oxygen gas within lipid-coated microbubbles (LOMs) (17). Similar to microbubble-based contrast agents, LOMs consist of an oxygen gas core stabilized by a lipid shell.…”

“…Similar to microbubble-based contrast agents, LOMs consist of an oxygen gas core stabilized by a lipid shell. Oxygen transport across the shell occurs via passive diffusion and is triggered when the bubble encounters blood with low oxygen tensions (i.e., relative to the oxygen-rich LOM core, pO 2 < 740 mmHg) (16)(17)(18). Because LOMs contain large gas volume fractions [i.e., >70% (vol/vol)], they can deliver substantially larger gas payloads than other particle-based systems that use hemoglobin, heme derivatives, or PFCs.…”

“…In fact, i.v. infusion of LOMs rapidly raised arterial blood saturations and decreased the incidence of death in several animal models of severe hypoxemia (17,20). However, despite the effectiveness of lipid-based stabilizing agents, several challenges must be addressed before clinical translation.…”

“…First, the fluid nature of lipid shells renders LOMs mechanically fragile and introduces the possibility of rupture during rapid injections, releasing free gas to the bloodstream. Second, LOMs, like other lipid-based carriers, are susceptible to coalescence, Ostwald ripening, and Laplace overpressure during storage (21,22), which leads to significant product loss and undesirable changes in size distributions (17). Design strategies that reduce the risk of free gas release, and improve the drug shelf life while preserving a high oxygen carrying capacity,…”