Gadolinium-based contrast agents (GBCAs) are in widespread use to enhance magnetic resonance angiography images for evaluating vascular pathology. However, there are safety concerns and limitations regarding the use of GBCAs. It has been shown that the magnetic resonance imaging (MRI) signal intensity (T1-weighted images) in some of the brain's tissues is higher for patients who had multiple exposures to GBCAs compared to patients who had never had exposure to GBCAs. This implies that GBCAs are not sufficiently removed from body such that GBCAs may potentially have long-term effects on the human body. These potential safety concerns have led to an increased interest in alternative contrast agents. Methemoglobin (metHb) and oxygen-free hemoglobin (HHb) are two forms of hemoglobin with paramagnetic properties. It has been shown that the T1-weighted signal intensity of blood is changed during MRI scans for metHb and HHb, leading to enhanced contrast of MRI images. The ability of metHb and HHb to change the signal intensity has led to the idea that they can be used as effective contrast agents. MetHb can be made by exposing oxyhemoglobin (oxyHb) to nitric oxide (NO) and HHb can be made by removing the oxygen from hemoglobin using nitrogen (N2). In this study, a new gas delivery system was developed to make metHb and HHb. The new gas delivery system was developed to have greater experimental control compared to the PermSelect hollow-fiber module that was used in preliminary studies to make metHb. The same system can be used to make HHb. Initial experiments showed significant amounts of undesired nitrite (NO2-) formation during metHb formation due to the presence of contaminants in the NO gas source. To minimize this problem, flow of NO from the gas source was bubbled in a sodium hydroxide solution in order to reduce the NO2- concentration. Following metHb formation, continuous delivery of NO also led to the formation of ferrous nitrosyl hemoglobin (HbIINO). MRI studies showed that HbIINO can also increase the signal intensity of an MRI image. It is unknown as to whether metHb, HHb, or HbIINO would be a stronger and more appropriate contrast agent and to what extent the T1-weighted signal is affected by the concentration. This study evaluated T1-weighted images of blood samples over a range of metHb and HHb concentrations, as well as HbIINO concentrations. Comparison of T1 values showed that metHb is the strongest contrast agent and that HHb is a relatively weak contrast agent. This study showed for the first time that HbIINO can provide a contrast effect, although not as strong as metHb but stronger than HHb. With metHb providing a viable contrast between 10-20%, metHb has the potential to be a safe and effective contrast agent since it can be naturally converted back to hemoglobin.



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Chemical Engineering



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Roya Ayati, methemoglobin, deoxyhemoglobin, ferrous nitrosyl hemoglobin, ferric nitrosyl hemoglobin, magnetic resonance imaging, MRI, T1 relaxation time, T1-weighted, gadolinium-based contrast agents, nitrite, nitric oxide, hemoglobin, contrast agent



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