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J Biomed Mater Res A. 2009 Sep 15;90(4):1107-19. doi: 10.1002/jbm.a.32164.

Histopathological changes of rat brain after direct injection of Hb-vesicles (artificial oxygen carriers) and neurological impact in an intracerebral hemorrhage model.

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Research Institute for Science and Engineering, Waseda University, Tokyo 169-8555, Japan.


For use as artificial oxygen carriers during transfusion, the safety and efficacy of Hb-vesicles (HbV, 250 nm), have been investigated extensively. Nevertheless, their neurotoxicity remains unknown. We explored potential adverse effects of HbV in the brain using a rat intracerebral hemorrhage model. Male Wistar rats were anesthetized with sevoflurane and fixed on a stereotaxic frame. Then HbV or homologous RBC suspension ([Hb] = 8.6 g/dL, 20 microL) was injected into the right caudate nucleus. All animals survived, gained weight, and maintained their well-being until the time of sacrifice; except during the first few days after surgery. However, both groups showed slight weakness in hind leg retraction, occasional ataxia/gait, and piloerection. Neutrophils accumulated at the onset of injury in perihematomal tissues in both groups at 1st day, but had disappeared by 3 days. Infiltration of small HbV in the perihematomal tissue was prominent at 1st day; phagocytized HbV were detected in macrophages. Hemeoxygenase-1 and hemosiderin deposition appeared after 3 days, reflecting the degradation of both HbV and RBC. The HbVs were detectable even after 28 days in the HbV group, but no residual RBCs were detected in the RBC group. Both groups showed proliferation of astrocytes, named gliosis, for tissue reconstruction after 3 days. This study revealed no notable differences in adverse effects between the intra-cerebral injection of HbV and the RBC control on behavioral functions and brain tissue responses.

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