Long-term compatibility of albumin capsules based on perfluorocarbon (A-AOCs) and improvement of the regenerative capacity of the organism after the application of albumin capsules in operations with high blood losses in the rat.

Blood substitutes have the advantages of simple composition, ease of formulation, easy storage, longer shelf life and no group matching requirement and easy screening over the allogenic blood1. Donated allogenic blood resources do not meet the demand of health care and research sectors due to rapid demographic changes and other challenges. For these and many other purposes, a blood substitute is urgently sought. The two main types of blood substitutes, which are already tested, or being available in the market are hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon-based oxygen carriers (PFOCs). Our albumin-derived perfluorocarbon-based artificial oxygen carriers (A-AOCs) have already shown promising results in isolated organs/short-term in vivo experiments2

In this current pre-clinical study, we have investigated the compatibility of these A-AOCs in a clinically relevant setting in rats. Through moderate normovolemic hemodilution, 50-60% of the blood from the rats was stepwise exchanged, through femoral vessels with A-AOCs, in order to reduce the hematocrit level to the target range of 18±1%, while the animals were breathing 100% O2 or 21% O2. Four major groups A (A-AOCs - 100% O2), B (control, plasma-like carrier solution - 100% O2), C (A-AOCs - 21% O2) and D (A-AOCs - 100% O2 - Monofer) each comprising of 42 rats were divided into 3 subgroups. Group-1 rats were euthanized directly after the hemodilution. Group 2 and 3 were let to survive for 7 and 14 days, respectively. Blood samples were collected before, during and after the hemodilution and at regular intervals throughout the survival period; and were used for measuring different vital parameters e.g. blood-gases, blood count and enzymes (e.g. ASAT, ALAT). At the end of the survival period, group-AA animals were scanned with 19F/1H 7-tesla ultra-high field magnetic resonance imaging (7T UHF MRI) to track the bio-distribution and organ retention time of A-AOCs in the body by measuring the fluorine present in the core of the A-AOCs. In the non-MRI groups, organs (i.e. heart, liver etc.) were collected at the end of survival period and were used for further analysis such as hematoxylin & eosin (H&E) staining etc.

The results show that after two weeks, the A-AOCs successfully bridged the hematocrit (Hct) gap created (from 45% to 18±1%) during the hemodilution phase of this experimental design. The Hct level doubled (~35%) after a week of survival and reached back to its basal value (~44%) within two weeks survival period. White blood cells (WBCs) increased transiently after 24 and 48 hrs. up to three-fold in group A and doubled in group B and C; importantly group A already reached baseline level after 7 days, whereas group B needed 14 days and group C still presented elevated WBC after 14 days. Lactate level of both A-AOCs treated groups were much lower (~20 mg/dl) in comparison to the control group (~30 mg/dl) after 7 days but decreased in all groups after 14 days. Remaining parameters did not show much variations among all threevigroups; e.g. AST increased only transiently in all groups at 24 and 48 hrs. and normalized after 7 days. H&E staining of the organs showed no differences (in group A, C or D) in comparison to the control (group B). The 19F/1H 7T MRI scans revealed accumulation of A-AOCs mainly in liver and partially in heart and kidneys in the group AA (0-days survival) group, which is significantly (more than the half) reduced after 7 days and restricted only to the liver and to very small extent in the kidney and spleen. After 14 days, there is hardly any detectable traces of the A-AOCs found in the body.


In conclusion, hemodilution with A-AOCs was well tolerated. The overall survival ratio is >95% in A-AOCs-treated groups. The animals recovered quickly within the observation period of 2 weeks with no serious damage to the organs. Slight increases in some of the parameters returned to the normal levels mostly in the first few days or at least in the experiment’s survival window of two weeks.



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