Bulk Manufacture of Concentrated Oxygen Gas‐Filled Microparticles for Intravenous Oxygen Delivery

Abstract

Self-assembling, concentrated, lipid-based oxygen microparticles (LOMs) have been developed to administer oxygen gas when injected intravenously, preventing organ injury and death from systemic hypoxemia in animal models. Distinct from blood substitutes, LOMs are a one-way oxygen carrier designed to rescue patients who experience life-threatening hypoxemia, as caused by airway obstruction or severe lung injury. Here, we describe methods to manufacture large quantities of LOMs using an in-line, recycling, high-shear homogenizer, which can create up to 4 liters of microparticle emulsion in 10 minutes, with particles containing a median diameter of 0.93 microns and 60 volume% of gas phase. Using this process, we screen 30 combinations of commonly used excipients for their ability to form stable LOMs. LOMs composed of DSPC and cholesterol in a 1:1 molar ratio are stable for a 100 day observation period, and the number of particles exceeding 10 microns in diameter does not increase over time. When mixed with blood in vitro, LOMs fully oxygenate blood within 3.95 seconds of contact, and do not cause hemolysis or complement activation. LOMs can be manufactured in bulk by high shear homogenization, and appear to have a stability and size profile which merit further testing.

Bio‐inspired nanomedicine strategies for artificial blood components

“…31,[96][97][98] Interestingly, instead of encapsulating Hb, some research approaches have also attempted to encapsulate oxygen (O 2 ) directly within phospholipid microvesicles (2-4 μm in diameter) to deliver O 2 to deoxygenated RBCs in circulation. 99,100 Although these oxygen-loaded microbubbles were found to be stable for a few weeks in storage with only small extent of oxygen loss, in vivo they have a very short circulation lifetime (<1 h). Therefore, treatment with these systems would require multiple or repeated dosing, which may then lead to negative effects of dysregulated oxidative stress and associated immune response.…”

Oxygen delivery using engineered microparticles

“…To confirm that O 2 release from PHMs was diffusion controlled, we desaturated donated human red blood cells (hRBCs) with nitrogen gas and maintained them under stagnant conditions in an airtight water-jacketed (37°C) reaction vessel equipped with a stir bar and an oximetric probe (16)(17)(18)(19). The latter enabled the real-time continuous monitoring of oxyhemoglobin concentration (Fig.…”

“…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.…”

“…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.…”

Lights! Oxygen! Action! Hollywood anaesthesia is coming to a theatre near you

“…to asphyxiated rabbits, lipid oxygen-containing microparticles maintained full-body oxygenation and normal vital signs, preventing organ injury and death from systemic hypoxaemia. 48 It may not be long until this product becomes commercially available, 49 potentially forcing us to readdress the whole concept of difficult airway management. Novel efficient extracorporeal CO 2 -removal devices requiring simple percutaneous venous access, no systemic anticoagulation, and minimal blood flow rates of <0.5 litres min À1 have been developed.…”