Interfacial Nanoprecipitation toward Stable and Responsive Microbubbles and Their Use as a Resuscitative Fluid

Abstract

A new approach has been developed to prepare stable microbubbles (MBs) by interfacial nanoprecipitation of bioabsorbable polymers at air/liquid interfaces. This facile method offers robust control over the morphology and chemophysical properties of MBs by simple chemical modifications. This approach is amenable to large-scale manufacturing, and is useful to develop functional MBs for advanced biomedical applications. To demonstrate this, a MB-based intravenous oxygen carrier was created that undergoes pH-triggered self-elimination. Intravenous injection of previous MBs increased the risk of pulmonary vascular obstruction. However, we show, for the first time, that our current design is superior, as they 1) yielded no evidence of acute risks in rodents, and 2) improved the survival in a disease model of asphyxial cardiac arrest (from 0 to 100 %), a condition that affects more than 100 000 in-hospital patients, and carries a mortality of about 90 %.

Injectable Oxygen: Interfacing Materials Chemistry with Resuscitative Science

“…infusion of LOMs requires careful titration of the delivered gas fraction to avoid depletion of the local oxygen sink conditions within the vasculature; failure to do so results in prolonged microbubble persistence leading to pulmonary emboli and increased incidences of cardiac arrest (Figure D) Our laboratory has also shown that i.v. delivery of LOMs in a swine model of CA causes in vivo formation of lethal large gas emboli . As mentioned above, this is likely because i.v.…”

“…Despite the increased mechanical advantages over LOMs, i.v. injection of higher doses of PHMs lead to increased incidences of pulmonary obstruction and death in a dose‐dependent manner . While not useful for CA, PLGA‐based PHMs would likely be ideal carriers for local or targeted oxygen (or other medical gas) delivery.…”

“…This was demonstrated in a recent study by Peng et al. that reported a new method of interfacial nanoprecipitation of biocompatible polymers to manufacture pH‐responsive self‐eliminating MBs . Nanoprecipitation is a process to produce nanoparticles in bulk solution through solvent exchange .…”

“…The majority of work in this area aims to minimize bulk nanoparticle aggregation through controlling a range of parameters such as viscosity and polymer concentration and structure . Peng et al., on the other hand, leveraged this concept by inducing nanoprecipitation at the air/liquid (a/l) interface to yield ultra‐stable MBs stabilized by shells composed of polymer nanoaggregates (Figure A) . To do this, the team designed a family of water‐insoluble dextran‐based surfactants that readily foamed (i.e., dextran polymers self‐assembled at the a/l interface) when dissolved in a co‐solvent system (DMSO/H 2 O).…”

“…Motivated by the need for an effective solution to treat patients suffering from severe hypoxemia, our laboratory has developed oxygen microbubbles (Ox‐MBs) as an alternative i.v. oxygen carrier . This article will provide a brief review of several biomaterial‐based technologies available for intravascular oxygen delivery in the context of treating severe hypoxemia, with an emphasis on cardiac arrest.…”