Professor Palmer is interested in the application of chemical and biomolecular engineering principles to address key issues in transfusion medicine, tissue engineering and therapeutic macromolecular delivery systems.

In particular, his research program focuses on three primary areas: 1) engineering artificial blood substitutes (oxygen carriers) for various transfusion applications; 2) utilizing oxygen carriers to improve oxygenation of mammalian cell cultures and 3) engineering mechanically strengthened and shape changing vesicles for specialized drug/protein/gene delivery applications. More details of these areas follow.

Engineering Artificial Blood Substitutes
Several commercial hemoglobin-based oxygen carriers (HBOCs) possess low oxygen affinities (high P₅₀s), which has been hypothesized to be one of the root causes of hypertension observed in patients administered with these products. This phenomenon is elicited by supraphysiological amounts of O₂ being delivered to tissues. Hence, in order to reduce the increased amounts of O₂ being delivered to tissues, blood vessels constrict, thus reducing the available surface area for O₂ transport. In contrast, the HBOCs that we are developing possess high oxygen affinities (low P₅₀s), which, when administered, should not elicit hypertension. Essentially, our low P₅₀ O₂ carriers target O₂ delivery to tissues with low pO₂s, thus ensuring that O₂ is delivered to tissues that need it, versus tissues that are well oxygenated.

In the laboratory, three complementary approaches are being used to design artificial blood substitutes: 1) polymerizing tetrameric hemoglobin into intermolecularly cross-linked hemoglobin polymers; 2) encapsulation of hemoglobin inside the aqueous core of vesicles and 3) encapsulation of hemoglobin inside pH and temperature sensitive nanoscale hydrogel particles. The ultimate goal of this three-pronged approach is to design artificial blood substitutes that: 1) specifically target oxygen delivery to tissues with low pO₂s' and 2) exhibit extended circulatory half-lives.

The second root cause of the hypertensive effect stems from HBOC scavenging of NO. HBOC scavenging of NO in the vasculature will also lead to the development of hypertension. Hence another strategy to limit the hypertensive effect entails reducing the rate of NO binding to the HBOC. In order to fine tune our control over HBOC oxygen affinity and NO binding rate, we plan to modify the chemical structure of hemoglobin using protein engineering to produce hemoglobin mutants with high oxygen affinities and low rates of NO binding. This approach in combination with the hemoglobin carriers we are developing will lead to novel types of HBOCs.

Engineering oxygen carriers for improved oxygenation of mammalian cell cultures
Oxygen transport has been identified as one of the main limiting factors in mammalian cell culture. When mammalian cells are placed in aqueous media, their growth is severely constrained by the availability of oxygen. Since oxygen is not very soluble in water, research in the laboratory focuses on methods to better improve oxygen transport to mammalian cells. To this end, red blood cells have been used to deliver increased levels of O₂ to C3A hepatocytes housed in hollow fiber bioreactors.

Our long-range goal is to create an extracorporeal artificial liver with physiological densities of hepatocytes for use in patients suffering from acute liver failure, and a high-density lymphocyte culture for the production of large amounts of killer T cells and interleukin 2 for cancer therapy applications. Future research will also focus on the effect of oxygen tension on the expansion and differentiation of hematopoietic stem cells in various types of bioreactors.

Engineering Mechanically Strengthened and Shape Changing Liposomes
The major problem associated with the use of liposome dispersions as potential long-term therapeutic delivery vehicles is their short half-life (<24 hours) in the circulatory system. In this project, we have demonstrated that mechanically strengthened and shape changing liposomes (actin-containing liposomes) are able to respond dynamically to blood shear forces, and exhibit increased half-lives in the mammalian circulatory system.

Future studies will focus on the use of actin-containing liposomes and polymer vesicles "polymersomes" as hemoglobin carriers. These synthetic vesicles are interesting because unlike vesicles composed of natural lipids, which possess a universal bilayer thickness of 3-4nm, the bilayer thickness of these synthetic vesicles can be engineered between 4-40 nm. This can be achieved by simply utilizing the appropriately sized hydrophobic block and maintaining the weight fraction of the hydrophilic poly(ethylene oxide) block at ~ 30%. The ability to generate thicker membranes improves the mechanical stability of these vesicles towards shear in the blood stream relative to vesicles composed of natural lipids. In addition, these vesicles are 100% PEGylated, unlike liposomes in which only ~ 10% of the bilayer lipids can be PEGylated. PEGylation of the entire vesicle surface improves the biocompatibility of these particles, and reduces the ability of the reticuloendothelial system to recognize them.