Hemoglobin Based Oxygen Carriers (HBOC)
Universal oxygen carrying solutions that can replace the oxygen storage and transport functions of red blood cells will greatly improve clinical outcomes both for trauma victims and patients undergoing high-blood-loss surgical procedures. These oxygen carriers also will prevent the serious complications associated with blood transfusions. In my lab, we utilize three engineering approaches for designing HBOCs. Our design strategy is based on the observation that transfusion of hemoglobin results in vasoconstriction and the development of systemic hypertension.
The root cause of this effect stems from the ability of hemoglobin to extravasate through pores in the wall of blood vessels and scavenge Nitric Oxide (NO) from the surrounding vasculature. This leads to blood vessel constriction and results in the observed hypertensive effect. Therefore, our design strategy focuses on increasing the size of HBOCs so that they are unable to traverse across the wall of blood vessels. In my lab, we engineer polymersome encapsulated hemoglobins (PEHs), polymerized hemoglobins (PolyHbs) and surface conjugated hemoglobins. We are also developing a modeling framework to assess the ability of these oxygen carriers to transport oxygen and NO in an arteriole. This work is significant in that it will lead to the development of novel oxygen carriers for therapeutic use.
In the case of PEHs, we encapsulate hemoglobin in the aqueous core of polymer vesicles that are composed of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene oxide) (PEG) block and a hydrophobic block consisting of either poly(butadiene), poly(caprolactone) or poly(lactic acid). PEHs in essence, function as red blood cell mimics, with a tunable glycocalyx (PEG corona) and red blood cell membrane (hydrophobic copolymer).
Other groups have observed that HBOC oxygen affinity is highly correlated with the degree of blood loss, and hence the oxygen requirements of the various tissues and organs in the body. To address this issue, we are designing novel polymerized hemoglobins with low to high oxygen affinities. For example in the case of hemorrhagic shock (at least 50% blood loss), the pO2 in key organs like the brain, heart and liver drop to precipitously low levels. In this situation, the emergency room doctor is concerned with delivering oxygen to these low pO2 organs, before oxygen is delivered systemically throughout the body.
Therefore, the need by transfusion of high oxygen affinity polymerized hemoglobins which target oxygen delivery to these low pO2 organs. In our work with polymerized hemoglobins, we have utilized cross-linking reagents to freeze the quaternary structure of hemoglobin in either the high oxygen affinity state (R-state) or low oxygen affinity (T-state), while simultaneously increasing the molecular radius of the polymerized hemoglobin with intermolecular cross-links. Our design is both unique and innovative, since acellular hemoglobin is intrinsically vaso-active, while polymerized hemoglobins exhibit significantly less vaso-activity.
Our group is also designing glycosylated hemoglobins. In this work, we have site-specifically conjugated saccharides to surface cysteine residues on hemoglobin which can hydrogen bond with amino acids in the α1β2 interface of the hemoglobin tetramer. This prevents the hemoglobin tetramer from dissociating into αβ dimers which cannot cross the lumen of blood vessels, and thus provides another strategy for mitigating the hypertensive effect.
- A. F. Palmer and M. Intaglietta, “Blood Substitutes,” Annual Review of Biomedical Engineering 16: 77-101 (2014)