Dose-Ranging Study of the Performance of the Natural Oxygen Transporter HEMO₂Life in Organ Preservation

Abstract

The intensity of ischemia-reperfusion injury of the donor organ during the preservation phase and after anastomosis is acknowledged as being a key factor for long-term graft outcome. We previously showed that the addition of 5 g/L of the natural oxygen carrier HEMO2 Life was beneficial for the cold static preservation of kidney grafts in both University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate solutions. Herein, we refined these findings by evaluating HEMO2 Life at various dose levels in UW, both in vitro with endothelial cells and in vivo in a pig kidney autotransplantation preclinical model. We showed in vitro that cells were significantly better preserved with HEMO2 Life in a dose-dependent manner, with benefits in terms of survival, metabolic activity, and cellular integrity. In vivo, serum creatinine measurements at reperfusion confirmed the important benefits of HEMO2 Life treatment on function recovery at the dose levels of 1, 2, and 5 g/L. Likewise, histological analysis of kidney parenchyma biopsies from day 7 confirmed the superiority of HEMO2 Life-supplemented UW over UW alone, and there was no difference between the doses. Three months' follow-up confirmed the trend of the first 2 weeks, with creatinine and fibrosis levels similar to those in pretransplant kidneys.

Cerebral Vasoactivity and Oxygenation with Oxygen Carrier M101 in Rats

“…This product did not cause cerebral vasoconstriction when administered to healthy rats suggesting it may also possess the safety profile necessary to progress to the next stage of clinical development for early treatment from TBI. Previous studies have shown a reduction in organ damage during renal graft preservation by supplementing classical organ preservation solution with M101, 12,14 but this is the first in vivo study to show improvement in an animal model of tissue hypoxia with M101 administration.…”

“…It is active over a wide range of temperatures 12 and has a half-life, determined using M101 tagged with fluorescent dye, of age 3 of 39 4 ~24 h in rats. 13 M101 has been shown to improve organ preservation 12,14 and a recent study, measuring arterioles and venules in the hamster dorsal skin fold, reports that M101 does not have vasoconstrictive properties. 10 These product characteristics and pharmacodynamic data make M101 a candidate for further development for pre-hospital treatment for TBI if the product 1) does not cause cerebral arteriolar vasoconstriction (safety) and 2) shows evidence of reducing brain injury (efficacy) in TBI models.…”

Beneficial effects of the novel marine oxygen carrier M101 during cold preservation of rat and human pancreas

“…M101 possesses a high affinity for oxygen and can carry up to 156 oxygen molecules, compared to the four oxygen molecules carried by human haemoglobin . Oxygen release occurs over a gradient without any allosteric effectors, and according to the p50 of the molecule . The p50 reflects haemoglobin affinity for oxygen, and the value corresponds to the oxygen tension at which 50% of the O 2 ‐binding sites are saturated.…”

“…19 Oxygen release occurs over a gradient without any allosteric effectors, and according to the p50 of the molecule. 20 The p50 reflects haemoglobin affinity for oxygen, and the value corresponds to the oxygen tension at which 50% of the O 2 -binding sites are saturated. This is a crucial advantage of M101 over other types of haemoglobin-based oxygen carriers (HBOC).…”

New Approaches in Commercial Development of Artificial Oxygen Carriers

“…Based on remarkable properties of this Hb, it was proposed that such an oxygen carrier could have numerous therapeutic applications wherever oxygen is necessary, mainly in hypothermia. The initial studies proved that this product can be effectively used as an oxygen carrying solution in organ preservation and wound healing .…”