- Email: [email protected]
Mini-review on the properties and possible applications of therapeutic oxygen carrier Hemarina-M101
Journal Pre-proof Mini-review on the Properties and Possible Applications of Therapeutic Oxygen Carrier Hemarina-M101 Joseph Varney (Conceptualization)Writing-original draft)Writing- review and editing), Amanda Rivera (Conceptualization)Writing-original draft)Writing- review and editing), Vinh Dong (Conceptualization)Writing-original draft)Writing- review and editing), Paul Tieu (Conceptualization)Writing-original draft), Sairah Zia (Conceptualization)Writing-original draft), Nguyen Tien Huy (Conceptualization)Writing- review and editing) (Supervision)
PII:
S1473-0502(20)30339-6
DOI:
https://doi.org/10.1016/j.transci.2020.103016
Reference:
TRASCI 103016
To appear in:
Transfusion and Apheresis Science
Received Date:
23 July 2020
Revised Date:
7 November 2020
Accepted Date:
11 November 2020
Please cite this article as: Varney J, Rivera A, Dong V, Tieu P, Zia S, Huy NT, Mini-review on the Properties and Possible Applications of Therapeutic Oxygen Carrier Hemarina-M101, Transfusion and Apheresis Science (2020), doi: https://doi.org/10.1016/j.transci.2020.103016
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier.
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Title: Mini-review on the Properties and Possible Applications of Therapeutic Oxygen Carrier Hemarina-M101 Joseph Varney 1+, Amanda Rivera 1+, Vinh Dong 1+, Paul Tieu2, Sairah Zia 1, and Nguyen Tien Huy3* 1 American University of the Caribbean Medical School, Cupe Coy, Saint Maarten 2 Faculty of Health Sciences, McMaster University 3 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan *Corresponding author: Nguyen Tien Huy, School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan (E-Mail: [email protected]) Tel: +81-95-819-7558 Fax: +81-95-819-7846 + Authors contributed equally
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Authors’ emails: JV: [email protected] AT: [email protected] VD: [email protected] PT: [email protected] SZ: [email protected] NH: [email protected]
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Abstract: Therapeutic Oxygen Carriers (TOCs) have been studied in the past for utilization in resuscitation fluid, treatment of organ ischemia, and as an alternative to red blood cell transfusion. One TOC, Hemarina-M101, seems promising in transplantation and oxygenation due its capability as a nonimmunogenic, nontoxic, high-oxygen-carrying capacity TOC with little to no side effects. This minireview focuses on Hemarina-M101 and explores its characteristics and possible utilities through past and recent studies.
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Keywords: Hemoglobin-based artificial oxygen carriers; Therapeutic Oxygen Carriers; Arenicola marina; Hemarina-M101; TOCs Introduction
Ever since the United States Food and Drug Agency put all human trials of hemoglobin-based oxygen carriers on hold in 2008, therapeutic oxygen carriers (TOCs) became a neglected topic. Therapeutic oxygen carriers are theorized to be useful as a blood substitute and replacement during trauma, a temporary bridge to red blood cell
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transfusion, a rescue to organ ischemia secondary to arterial insufficiency, or even as an enhancement to preserving donor organs for transplant. However, there are reported side effects such as hypertension, vasoconstriction, and an increased risk of myocardial infarction and death.1 Hemarina-M101 is a therapeutic oxygen carrier that made headlines in 2020 for its possible application in
critical COVID-19 patients in a severe respiratory state. It is manufactured from the extracellular hemoglobin of marine animal, Arenicola marina, and is part of the formulated HemoxyCarrier® as a therapeutic oxygen carrier (AOC).2-3 A Phase I clinical trial named MONACO was aimed to take place in April 2020 in France for use in 10 critically ill COVID-19 patients to see if injection of Hemarina-M101 can improve the oxygenation in these patients. However, the clinical trial was suspended due to a prior 2011 preliminary study showing a 100% lethality rate of the
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pig subjects.4 In this review, we investigate current literature on Hemarina-M101 and explore its properties and utilities. Properties of Hemarina-M101 Hemarina-M101, a natural extracellular biopolymer hemoglobin derived from Arenicola marina blood, has a ~3.6MDa structure made of complex globin and non-linker chains.5 Each globin chain surrounds and protects its own O2-binding heme group consisting of a protoporphyrin ring with an iron atom in the center reversibly bound to one O2 molecule.6 One hemoglobin molecule of this large complex can carry up to 156 O 2 molecules when fully saturated compared to a single human hemoglobin molecule that can carry a maximum of 4 O2 molecules.2-3 It was
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found that the p50 of Arenicola marina hemoglobin (AmHb) is around 7.05 ± 0.93 mmHg compared to human blood which is between 26-30 mmHg. This means that it takes less partial pressure of oxygen for Hemarina-M101 to saturate half of the O2 binding sites compared to human blood.7 Due to this property, Hemarina-M101 releases oxygen to
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hypoxic tissues only, which is generally believed to begin when pO2 goes below 10 mmHg.
Additionally, Hemarina-M101 has certain properties that make it suitable in the human body. For example,
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Hemarina-M101 is non-immunogenic because it does not contain red blood cells. Therefore, cross matching and typing would not be required.7 Also, Hemarina-M101 functions in the temperature range between 4°C - 37°C. Its oxygen affinity is only modified by Mg2+ and Ca 2+ at concentrations greater than 9 mM at 7.5 pH, levels higher than
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that in human blood. Under human physiological conditions, temperature does not significantly affect the oxygen binding of Hemarina-M101 with cooperativity being unaffected (n 50= 2.5). 7 Hemarina-M101 was also shown to have
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antioxidant properties through its intrinsic Cu/Zn- superoxide dismutase (SOD) activity.7 This study, published in 2006, also tested the hemoglobin of Arenicola marina by incubating Arenicola marina hemoglobin with KO2, a substrate for superoxide dismutase.7 This superoxide dismutase-like activity (SOD-like activity) was measured to be 3.53 ± 0.02 U/mg Hb compared to the literature value of 1-2 U/mg Hb for human red blood cell. Having higher SOD-
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like activity, the hemoglobin of the Arenicola marina may scavenge oxygen radicals and have a protective effect inside the body.7
In 2012, animal studies using rats and hamsters investigated Hemarina-M101’s effects inside the body. A top-load experiment giving 10% total blood volume (estimated as 7% of total body weight) using Hemarina-M101 in a hamster skinfold window chamber model showed no effect on both the heart rate and mean arterial pre ssure.2 Injection of Hemarina-M101 (600 mg/kg over 5 min) did not significantly increase the heart rate or myocardial
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contractility in the rat model compared to the saline treated control group. 2 This suggests that Hemarina-M101 causes minimal to no vasocontraction which is in contrast to other hemoglobin-based oxygen carriers such as PBH4 and ααHb which can cause vasoconstriction and reduced microvascular perfusion. In addition, the binding properties for nitric oxide (NO) of Hemarina-M101 was found to be less than that of human hemoglobin, polymerized bovine hemoglobin Oxyglobin, and Hemoglobin Vesicles.2 This means more bioavailability of NO, which may explain why vasoconstriction is not a problem for Hemarina-M101 as NO vasodilates vascular smooth muscles and other hemoglobin-based carriers can scavenge NO leading to hypertension. 7,9
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Hemarina-M101 can oxygenate hypoxic tissue and may be stable inside the body. In one study, HemarinaM101 was able to remain in the circulation of mice for several hours and showed the ability to improve oxygenation in poorly vascularized tissues.3 Administration did not lead to allergic reactions and no apparent behavioral or pathophysiological changes were reported.2 When tagged with a fluorescent dye, Hemarina-M101 was observed to circulate for several hours reaching all the organs including the brain with no observable side effects before naturally breaking down. Using subcutaneously implanted HT29 human colorectal adenocarcinoma tumors in mice, HemarinaM101 was observed to oxygenate the poorly vascularized tissue, reducing tissue hypoxia upwards of 23%. 3 Furthermore, the dynamic regimen provided by machine perfusion was shown to effectively distribute HemarinaM101 within the vascular compartments leading to a more efficient delivery of its oxygen to the graft.10
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Finally, Arenicola marina hemoglobin has been shown to degrade into hemin and is picked up by abundant plasma protein human serum albumin (HSA), avoiding renal toxicity. 7
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Utility for Transplantation
In terms of transplantation, Hemarina-M101 may have several useful properties that can be used for
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preserving the donor organ. For instance, Hemarina-M101 is compatible with hypothermic conditions, which may be useful for static cold storage organ or hypothermic machine perfusion preservation. In a recent study done in 2019 using 60 large white male pigs, different amounts Hemarina-M101 were used in solutions of ice-cold UW® (University
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of Wisconsin) or KPS® (Kidney Perfusion Solution) for cold preservation and machine perfusion of pig kidneys intended for auto-transplantation. The serum and urinary creatinine and urinary protein was then measured during the
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3-month post-transplantation period.10 Adenosine triphosphate (ATP) content from the kidneys was also measured from obtained biopsies before and after warm ischemia and at the end of preservation phase. A western blot was used to determine expression of vascular endothelial growth factor (VEGF) to determine the microvascular status of the
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transplanted organ, in which a higher VEGF was associated with more favorable outcomes post transplantation. It was found that the highest dose of Hemarina-M101 (2 g/l M101) when supplemented in either the ice-cold UW® or KPS® compared to the control 1-month and 3-month post-transplantation saw significantly lower creatinine levels, which means a better long term outcome. Both ATP content and VEGF expression increased for machine perfusion when KPS® was supplemented with Hemarina-M101, which ended up being higher than that of the control.10 However, results were not as clearly defined for cold solution preservation, as supplementing ice -cold UW ® with
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Hemarina-M101 at the highest dose did not yield an ATP increase, and VEGF expression did not increase significantly compared to the control at the highest dose (2 g/l M101). VEGF’s expression, however, did increase significantly at a lower dose (1 g/l M101).10 In an experiment conducted by Kasil et al. using preclinical porcine models, using Hemarina-M101 in
Waves® machine perfusion during the 23 hour hypothermic preservation following 1 hour of warm ischemia, saw a lower glomerular filtration rate and lower blood creatinine first week post -transplantation as well as lower renal vascular resistance. Early follow-up demonstrated the capability of Hemarina-M101 supplemented solutions in lowering the peak of serum creatinine and increasing the speed of functional recovery in vivo and limiting fibrosis.10,15
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Hemarina-M101’s superoxide dismutase-like property may be responsible for the lower renal resistance observed versus those without M101 by limiting the oxidative damage done to the blood vessels. In comparison, groups perfused with just 100% O2 were unable to limit kidney fibrosis.13,15,21 These findings suggest that there are benefits to Hemarina-M101 supplementation.21 Hemarina-M101 also had promising results during its investigations for its efficacy and safety in organ preservation with the development of the class III medical device (HEMO2life). 11,12 Transmission electron microscopic evaluation of cultured human primary aortic endothelium cells were semi-quantitatively scored upon observation. After 24 hours of cold hypoxia and 12 hours of synchronization, the presence of autophagosomes instead of necrotic bodies indicated that the cells were able to mount a better response against stress. This led to improved
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recovery from hypoxia/hypothermia which was confirmed by functional tests and hypothesized to be due to increased ATP levels.13 The first human trials of Hemarina-M101 for organ preservation have recently been conducted after promising results both in vitro and in vivo.11-12,14-15 Development of Hemarina-M101 as an additive to organ
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preservation solutions has been indicated due to its passive release of O2 in an oxygen gradient without requiring any allosteric effector when in an environment that has the right amount of oxygen. 16
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In a study published in 2020, an additive to organ preservation fluid, Hemo2Life ®, was mixed with low potassium dextrane solution (LPD solution) in the experimental group using cold preservation to preserve the lungs taken from pigs which was then evaluated after 36 hours using 12 hours of normothermic ex-vivo perfusion followed
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by transplant and reperfusion. Analyzing the tissue samples obtained after 36 hours of cold preservation, lungs that received LPD with Hemo2Life ® showed significantly less apoptotic death. During ex-vivo perfusion, Hemo2Life®
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supplemented LPD treated lungs were better than the control (LPD treated lungs) in terms of dynamic and static lung compliances, peak and plateau airway pressures, oxygenation, and decreased edema with preservation of tight junctions. After transplantation into the pig, the Hemo2Life ® supplemented LPD treated lungs compared to just LPD treated lungs showed lower peak airway pressures, higher dynamic and static compliances, as well as peak
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compliances. Additionally, inflammatory markers IL-6 and IL-β were significantly lower compared to the control after transplantation. With the role of IL-6 being known to cause airway inflammation and increased airway resistance; the reduction observed may indicate a protective role of Hemo2Life ®.17 In summary, the use of a solution containing Hemarina-M101 has led to significantly superior early post-transplant lung function.17 Hemarina-M101 may have protective effects from ischemic reperfusion injury which results in protection against primary graft dysfunction (PGD) in the early post-transplant period. The result of this protection speeds up the recovery of the transplant recipient
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from various insults to pulmonary function and proposes an explanation linked to the inhibition of significant triggers to inflammation pathway activation.16 A recent study by Florent et al. showed that adding Hemarina-M101 to the preservation solution for rat
pancreas used for transplant cold preservation, islet quality after isolation following cold ischemia in presence of M101 and M101 injection into the pancreatic duct saw insulin secretion higher in presence of glucose. Additionally, when Hemarina-M101 was injected in the pancreas of rats in a preservation solution during ischemia, there was an observed decrease in oxidative stress, necrosis, and cellular stress pathway activity. 18 Human pancreases exposed to Hemarina-M101 showed an increase in complex 1 mitochondrial activity for 3 hours as well as marked activation of
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AKT activity (a cell survival marker) with isolated islets secretion of insulin shown to be upregulated. Notably, even after 6 hours of cold ischemia, the Hemarina-M101 group showed a 25% decrease in pancreatic reactive oxygen species production when compared to the control. The SOD-like activity of Hemarina-M101 may be responsible for this.18 During preservation, it is crucial to provide oxygen to avoid an imbalance of oxygen supply and/or metabolic disturbances. Normothermia preservation appears to be the leading edge of preservation technology based on the recent advances in machine perfusion technology with hypothermia preservation only recently being considered with the use of a therapeutic oxygen carrier.16 It was found in a recent study that Hemarina-M101 is the only oxygen transporter that is not only compatible with normothermia but has also been shown to be compatible with standard
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hypothermic preservation.16 As opposed to other TOC that are manufactured using vertebrate hemoglobin that work only at 21–37°C, Hemarina-M101 is the only TOC that has been shown to function in the large temperature range of 4–37°C.7 Furthermore, using Hemarina-M101 in the preservation solution is shown to maintain mitochondrial
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complex 1 activity in the transplant organ, which allows for oxidative phosphorylation during the beginning hours of cold ischemia.18 This demonstrates the ability of cells to use the Hemarina-M101 released oxygen in the preservation
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solution in a gradient-dependent manner.18
Supplementing preservation solutions using Hemarina-M101 allows for maintenance of energetic metabolism by increasing cellular ATP content. This decreases the need to switch from mitochondrial respiration to
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anaerobic glycolysis in turn protecting the mitochondria. High adenosine triphosphate (ATP) level maintenance during preservation by M101 may also prove to be beneficial upon reperfusion due to less metabolic stress on oxidative
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pathways, allowing for the restoration of energy homeostasis. 15 However, Lemaire et. al showed no correlation between the maintenance of respiration in M101 and an increase in ATP despite increased glucose uptake in the islet
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cells.18 More research is needed to clarify the mechanism.
Utility for Oxygenation
Hemarina-M101 was studied to see whether it could improve brain tissue oxygenation after a traumatic brain injury by using controlled cortical impact in rats. An increased mean arterial pressure without cerebral vasoconstriction was observed after transfusion in healthy rats. It was reported that when Hemarina-M101 was
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given soon after controlled cortical impact of traumatic brain injury (CCI-TBI), it was able to restore brain tissue oxygen tension (PbtO2) to 86% of pre-injury for at least 80 min by restoring brain tissue oxygen tension. When Hemarina-M101 is given to healthy rats, an increased systemic blood pressure without any concurrent vasoconstriction in the small-and-medium-sized cerebral pial vessels was reported.19 These vessels were seen to constrict over time in the control group of this study, while most first and second-generation HBOCs also possessed vasoconstrictive side-effects limiting their clinical usage.19 These findings suggest Hemarina-M101 may possess the necessary safety profile for clinical development in the early treatment of traumatic brain injury patients. 19 The protective effects on the brain suggest that Hemarina-M101 may aid in hypoxic brain injury patients.
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Conclusions Hemarina-M101, derived from the extracellular hemoglobin of marine animal Arenicola marina, has potential in organ transplantation as well as in oxygenation. Hemarina-M101 showed its protective effects on organ preservation due to increased oxygenation, increased ATP, decreased fibrosis, positive vascular effects such as increased VEGF, antioxidant properties, and its unique compatibility with standard hypothermic preservation. It is non-immunogenic while having a high oxygen-carrying capacity. Most studies cited on Hemarina-M101 were in vivo, utilizing small animals (i.e. rats, mice, and hamster models). More studies are needed in larger animal models, which
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may pave the way for further utility of Hemarina-M101.
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CRediT author statement
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Sources of Funding: None
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Joseph Varney: Conceptualization, Writing-Original Draft, Writing- Review and Editing Amanda Rivera: Conceptualization, Writing-Original Draft, Writing- Review and Editing Vinh Dong: Conceptualization, Writing-Original Draft, Writing- Review and Editing. Paul Tieu: Conceptualization, Writing-Original Draft Sairah Zia: Conceptualization, Writing-Original Draft Nguyen Tien Huy: Conceptualization, WritingReview and Editing, Supervision
Compliance with ethical standards: Yes
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Conflict of interest statement by authors: None
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Acknowledgments: None
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Superior microvascular perfusion of infused liposome-encapsulated hemoglobin prior to reductions in infarctions after transient focal cerebral ischemia. Journal of Stroke and Cerebrovascular Diseases. 2017 Dec 1;26(12):2994-3003. 27. Kawaguchi AT, Okamoto Y, Kise Y, Takekoshi S, Murayama C, Makuuchi H. Effects of liposome‐ encapsulated hemoglobin on gastric wound healing in the rat. Artificial organs. 2014 Aug;38(8):641-9. 28. Njoku, Mary, Deidre St Peter, and Colin F. Mackenzie. "Haemoglobin-based oxygen carriers: indications and future applications." (2015): 78-83. 29. George I, Yi GH, Schulman AR, Morrow BT, Cheng Y, Gu A, et al. A polymerized bovine hemoglobin oxygen carrier preserves regional myocardial function and reduces infarct size after acute myocardial ischemia. American Journal of Physiology-Heart and Circulatory Physiology. 2006 Sep;291(3):H1126-37. 30. te Lintel Hekkert M, Dubé GP, Regar E, de Boer M, Vranckx P, van der Giessen WJ, et al. 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The Journal of Thoracic and Cardiovascular Surgery. 1995 Sep 1;110(3):774-85. 34. Kleen M, Habler O, Hutter J, Kemming G, Podtschaske A, Tiede M, et al. Hemodilution and hyperoxia locally change distribution of regional pulmonary perfusion in dogs. American Journal of Physiology-Heart and Circulatory Physiology. 1998 Feb 1;274(2):H520-8. 35. Stern SA, Dronen SC, McGoron AJ, Wang X, Chaffins K, Millard R, et al. Effect of supplemental perfluorocarbon administration on hypotensive resuscitation of severe uncontrolled hemorrhage. The American journal of emergency medicine. 1995 May 1;13(3):269-75. 36. Manning JE, Batson DN, Payne FB, Adam N, Murphy CA, Perretta SG, et al. Selective aortic arch perfusion during cardiac arrest: enhanced resuscitation using oxygenated perflubron emulsion, with and without aortic arch epinephrine. Annals of emergency medicine. 1997 May 1;29(5):580-7. 37. Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. 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39. Chatauret N, Coudroy R, Delpech PO, Vandebrouck C, Hosni S, Scepi M, et al. Mechanistic analysis of nonoxygenated hypothermic machine perfusion's protection on warm ischemic kidney uncovers greater eNOS phosphorylation and vasodilation. American Journal of Transplantation. 2014 Nov;14(11):2500-14. 40. Rubini A. Interleukin-6 and lung inflammation: evidence for a causative role in inducing respiratory system resistance increments. Inflammation & Allergy-Drug Targets (Formerly Current Drug Targets-Inflammation & Allergy). 2013 Oct 1;12(5):315-21.
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FIGURES AND TABLES. Table 1. Summary of Studies on M101
Title
Year of research Model
Finding(s)
Le Meur et al. France
First-in-human use of a marine oxygen carrier (M101) for organ preservation: A safety and proof-ofprinciple study. Beneficial effects of the novel marine oxygen carrier M101 during cold preservation of rat and human pancreas.
2020
Human kidney transplant
M101 added to the preservation solution had no reported adverse events and resulted in better renal function.
2019
Rat and human pancreas
Individual and 2019 Combined Impact of Oxygen and Oxygen Transporter Supplementation during Kidney Machine Preservation in a Porcine Preclinical Kidney Transplantation Model. Efficacy of the 2019 natural oxygen transporter HEMO2 life® in cold
Jo Kaminski et al. France
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M101 improved post-isolation islet quality when added to the preservation solution of rat pancreas during ischemia or exposed to the human pancreas.
Porcine kidney transplant
M101 added to the preservation solution improved kidney recovery and late graft outcomes.
Porcine kidney transplant
M101 added to the preservation solution improved functional
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Kasil et al. France
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Lemaire F et al. France
of
Country of corresponding author
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2011
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Supplementation with a new therapeutic oxygen carrier reduces chronic fibrosis and organ dysfunction in kidney static preservation.
M101 infusion increased blood pressure without causing vasoconstriction of pial vasculature and improves brain tissue oxygen.
Mice model of subcutaneous tumors
M101 rapidly diffused in the whole body for several hours without causing side-effects and reduced hypoxia in poorly vascularized tissues. M101 added to the preservation solution reduced cold-storage cell death, reduced kidney inflammation levels, increased function recovery and in the long term slowed fibrosis
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Thuillier et al. France
2014
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In vivo biodistribution and oxygenation potential of a new generation of oxygen carrier.
Rat model of traumatic brain injury
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Le Gall et al. France
outcomes and tissue integrity.
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Moon-Massat et al. USA
preservation in a preclinical porcine model of donation after cardiac death. Cerebral 2017 Vasoactivity and Oxygenation with Oxygen Carrier M101 in Rats.
Porcine kidney transplant
Table 1. Summary of studies investigating the effect of Hemarina-M101 in various applications.
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PII:
S1473-0502(20)30339-6
DOI:
https://doi.org/10.1016/j.transci.2020.103016
Reference:
TRASCI 103016
To appear in:
Transfusion and Apheresis Science
Received Date:
23 July 2020
Revised Date:
7 November 2020
Accepted Date:
11 November 2020
Please cite this article as: Varney J, Rivera A, Dong V, Tieu P, Zia S, Huy NT, Mini-review on the Properties and Possible Applications of Therapeutic Oxygen Carrier Hemarina-M101, Transfusion and Apheresis Science (2020), doi: https://doi.org/10.1016/j.transci.2020.103016
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier.
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Title: Mini-review on the Properties and Possible Applications of Therapeutic Oxygen Carrier Hemarina-M101 Joseph Varney 1+, Amanda Rivera 1+, Vinh Dong 1+, Paul Tieu2, Sairah Zia 1, and Nguyen Tien Huy3* 1 American University of the Caribbean Medical School, Cupe Coy, Saint Maarten 2 Faculty of Health Sciences, McMaster University 3 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan *Corresponding author: Nguyen Tien Huy, School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan (E-Mail: [email protected]) Tel: +81-95-819-7558 Fax: +81-95-819-7846 + Authors contributed equally
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Authors’ emails: JV: [email protected] AT: [email protected] VD: [email protected] PT: [email protected] SZ: [email protected] NH: [email protected]
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Abstract: Therapeutic Oxygen Carriers (TOCs) have been studied in the past for utilization in resuscitation fluid, treatment of organ ischemia, and as an alternative to red blood cell transfusion. One TOC, Hemarina-M101, seems promising in transplantation and oxygenation due its capability as a nonimmunogenic, nontoxic, high-oxygen-carrying capacity TOC with little to no side effects. This minireview focuses on Hemarina-M101 and explores its characteristics and possible utilities through past and recent studies.
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Keywords: Hemoglobin-based artificial oxygen carriers; Therapeutic Oxygen Carriers; Arenicola marina; Hemarina-M101; TOCs Introduction
Ever since the United States Food and Drug Agency put all human trials of hemoglobin-based oxygen carriers on hold in 2008, therapeutic oxygen carriers (TOCs) became a neglected topic. Therapeutic oxygen carriers are theorized to be useful as a blood substitute and replacement during trauma, a temporary bridge to red blood cell
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transfusion, a rescue to organ ischemia secondary to arterial insufficiency, or even as an enhancement to preserving donor organs for transplant. However, there are reported side effects such as hypertension, vasoconstriction, and an increased risk of myocardial infarction and death.1 Hemarina-M101 is a therapeutic oxygen carrier that made headlines in 2020 for its possible application in
critical COVID-19 patients in a severe respiratory state. It is manufactured from the extracellular hemoglobin of marine animal, Arenicola marina, and is part of the formulated HemoxyCarrier® as a therapeutic oxygen carrier (AOC).2-3 A Phase I clinical trial named MONACO was aimed to take place in April 2020 in France for use in 10 critically ill COVID-19 patients to see if injection of Hemarina-M101 can improve the oxygenation in these patients. However, the clinical trial was suspended due to a prior 2011 preliminary study showing a 100% lethality rate of the
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pig subjects.4 In this review, we investigate current literature on Hemarina-M101 and explore its properties and utilities. Properties of Hemarina-M101 Hemarina-M101, a natural extracellular biopolymer hemoglobin derived from Arenicola marina blood, has a ~3.6MDa structure made of complex globin and non-linker chains.5 Each globin chain surrounds and protects its own O2-binding heme group consisting of a protoporphyrin ring with an iron atom in the center reversibly bound to one O2 molecule.6 One hemoglobin molecule of this large complex can carry up to 156 O 2 molecules when fully saturated compared to a single human hemoglobin molecule that can carry a maximum of 4 O2 molecules.2-3 It was
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found that the p50 of Arenicola marina hemoglobin (AmHb) is around 7.05 ± 0.93 mmHg compared to human blood which is between 26-30 mmHg. This means that it takes less partial pressure of oxygen for Hemarina-M101 to saturate half of the O2 binding sites compared to human blood.7 Due to this property, Hemarina-M101 releases oxygen to
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hypoxic tissues only, which is generally believed to begin when pO2 goes below 10 mmHg.
Additionally, Hemarina-M101 has certain properties that make it suitable in the human body. For example,
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Hemarina-M101 is non-immunogenic because it does not contain red blood cells. Therefore, cross matching and typing would not be required.7 Also, Hemarina-M101 functions in the temperature range between 4°C - 37°C. Its oxygen affinity is only modified by Mg2+ and Ca 2+ at concentrations greater than 9 mM at 7.5 pH, levels higher than
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that in human blood. Under human physiological conditions, temperature does not significantly affect the oxygen binding of Hemarina-M101 with cooperativity being unaffected (n 50= 2.5). 7 Hemarina-M101 was also shown to have
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antioxidant properties through its intrinsic Cu/Zn- superoxide dismutase (SOD) activity.7 This study, published in 2006, also tested the hemoglobin of Arenicola marina by incubating Arenicola marina hemoglobin with KO2, a substrate for superoxide dismutase.7 This superoxide dismutase-like activity (SOD-like activity) was measured to be 3.53 ± 0.02 U/mg Hb compared to the literature value of 1-2 U/mg Hb for human red blood cell. Having higher SOD-
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like activity, the hemoglobin of the Arenicola marina may scavenge oxygen radicals and have a protective effect inside the body.7
In 2012, animal studies using rats and hamsters investigated Hemarina-M101’s effects inside the body. A top-load experiment giving 10% total blood volume (estimated as 7% of total body weight) using Hemarina-M101 in a hamster skinfold window chamber model showed no effect on both the heart rate and mean arterial pre ssure.2 Injection of Hemarina-M101 (600 mg/kg over 5 min) did not significantly increase the heart rate or myocardial
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contractility in the rat model compared to the saline treated control group. 2 This suggests that Hemarina-M101 causes minimal to no vasocontraction which is in contrast to other hemoglobin-based oxygen carriers such as PBH4 and ααHb which can cause vasoconstriction and reduced microvascular perfusion. In addition, the binding properties for nitric oxide (NO) of Hemarina-M101 was found to be less than that of human hemoglobin, polymerized bovine hemoglobin Oxyglobin, and Hemoglobin Vesicles.2 This means more bioavailability of NO, which may explain why vasoconstriction is not a problem for Hemarina-M101 as NO vasodilates vascular smooth muscles and other hemoglobin-based carriers can scavenge NO leading to hypertension. 7,9
2
Hemarina-M101 can oxygenate hypoxic tissue and may be stable inside the body. In one study, HemarinaM101 was able to remain in the circulation of mice for several hours and showed the ability to improve oxygenation in poorly vascularized tissues.3 Administration did not lead to allergic reactions and no apparent behavioral or pathophysiological changes were reported.2 When tagged with a fluorescent dye, Hemarina-M101 was observed to circulate for several hours reaching all the organs including the brain with no observable side effects before naturally breaking down. Using subcutaneously implanted HT29 human colorectal adenocarcinoma tumors in mice, HemarinaM101 was observed to oxygenate the poorly vascularized tissue, reducing tissue hypoxia upwards of 23%. 3 Furthermore, the dynamic regimen provided by machine perfusion was shown to effectively distribute HemarinaM101 within the vascular compartments leading to a more efficient delivery of its oxygen to the graft.10
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Finally, Arenicola marina hemoglobin has been shown to degrade into hemin and is picked up by abundant plasma protein human serum albumin (HSA), avoiding renal toxicity. 7
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Utility for Transplantation
In terms of transplantation, Hemarina-M101 may have several useful properties that can be used for
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preserving the donor organ. For instance, Hemarina-M101 is compatible with hypothermic conditions, which may be useful for static cold storage organ or hypothermic machine perfusion preservation. In a recent study done in 2019 using 60 large white male pigs, different amounts Hemarina-M101 were used in solutions of ice-cold UW® (University
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of Wisconsin) or KPS® (Kidney Perfusion Solution) for cold preservation and machine perfusion of pig kidneys intended for auto-transplantation. The serum and urinary creatinine and urinary protein was then measured during the
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3-month post-transplantation period.10 Adenosine triphosphate (ATP) content from the kidneys was also measured from obtained biopsies before and after warm ischemia and at the end of preservation phase. A western blot was used to determine expression of vascular endothelial growth factor (VEGF) to determine the microvascular status of the
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transplanted organ, in which a higher VEGF was associated with more favorable outcomes post transplantation. It was found that the highest dose of Hemarina-M101 (2 g/l M101) when supplemented in either the ice-cold UW® or KPS® compared to the control 1-month and 3-month post-transplantation saw significantly lower creatinine levels, which means a better long term outcome. Both ATP content and VEGF expression increased for machine perfusion when KPS® was supplemented with Hemarina-M101, which ended up being higher than that of the control.10 However, results were not as clearly defined for cold solution preservation, as supplementing ice -cold UW ® with
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Hemarina-M101 at the highest dose did not yield an ATP increase, and VEGF expression did not increase significantly compared to the control at the highest dose (2 g/l M101). VEGF’s expression, however, did increase significantly at a lower dose (1 g/l M101).10 In an experiment conducted by Kasil et al. using preclinical porcine models, using Hemarina-M101 in
Waves® machine perfusion during the 23 hour hypothermic preservation following 1 hour of warm ischemia, saw a lower glomerular filtration rate and lower blood creatinine first week post -transplantation as well as lower renal vascular resistance. Early follow-up demonstrated the capability of Hemarina-M101 supplemented solutions in lowering the peak of serum creatinine and increasing the speed of functional recovery in vivo and limiting fibrosis.10,15
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Hemarina-M101’s superoxide dismutase-like property may be responsible for the lower renal resistance observed versus those without M101 by limiting the oxidative damage done to the blood vessels. In comparison, groups perfused with just 100% O2 were unable to limit kidney fibrosis.13,15,21 These findings suggest that there are benefits to Hemarina-M101 supplementation.21 Hemarina-M101 also had promising results during its investigations for its efficacy and safety in organ preservation with the development of the class III medical device (HEMO2life). 11,12 Transmission electron microscopic evaluation of cultured human primary aortic endothelium cells were semi-quantitatively scored upon observation. After 24 hours of cold hypoxia and 12 hours of synchronization, the presence of autophagosomes instead of necrotic bodies indicated that the cells were able to mount a better response against stress. This led to improved
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recovery from hypoxia/hypothermia which was confirmed by functional tests and hypothesized to be due to increased ATP levels.13 The first human trials of Hemarina-M101 for organ preservation have recently been conducted after promising results both in vitro and in vivo.11-12,14-15 Development of Hemarina-M101 as an additive to organ
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preservation solutions has been indicated due to its passive release of O2 in an oxygen gradient without requiring any allosteric effector when in an environment that has the right amount of oxygen. 16
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In a study published in 2020, an additive to organ preservation fluid, Hemo2Life ®, was mixed with low potassium dextrane solution (LPD solution) in the experimental group using cold preservation to preserve the lungs taken from pigs which was then evaluated after 36 hours using 12 hours of normothermic ex-vivo perfusion followed
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by transplant and reperfusion. Analyzing the tissue samples obtained after 36 hours of cold preservation, lungs that received LPD with Hemo2Life ® showed significantly less apoptotic death. During ex-vivo perfusion, Hemo2Life®
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supplemented LPD treated lungs were better than the control (LPD treated lungs) in terms of dynamic and static lung compliances, peak and plateau airway pressures, oxygenation, and decreased edema with preservation of tight junctions. After transplantation into the pig, the Hemo2Life ® supplemented LPD treated lungs compared to just LPD treated lungs showed lower peak airway pressures, higher dynamic and static compliances, as well as peak
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compliances. Additionally, inflammatory markers IL-6 and IL-β were significantly lower compared to the control after transplantation. With the role of IL-6 being known to cause airway inflammation and increased airway resistance; the reduction observed may indicate a protective role of Hemo2Life ®.17 In summary, the use of a solution containing Hemarina-M101 has led to significantly superior early post-transplant lung function.17 Hemarina-M101 may have protective effects from ischemic reperfusion injury which results in protection against primary graft dysfunction (PGD) in the early post-transplant period. The result of this protection speeds up the recovery of the transplant recipient
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from various insults to pulmonary function and proposes an explanation linked to the inhibition of significant triggers to inflammation pathway activation.16 A recent study by Florent et al. showed that adding Hemarina-M101 to the preservation solution for rat
pancreas used for transplant cold preservation, islet quality after isolation following cold ischemia in presence of M101 and M101 injection into the pancreatic duct saw insulin secretion higher in presence of glucose. Additionally, when Hemarina-M101 was injected in the pancreas of rats in a preservation solution during ischemia, there was an observed decrease in oxidative stress, necrosis, and cellular stress pathway activity. 18 Human pancreases exposed to Hemarina-M101 showed an increase in complex 1 mitochondrial activity for 3 hours as well as marked activation of
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AKT activity (a cell survival marker) with isolated islets secretion of insulin shown to be upregulated. Notably, even after 6 hours of cold ischemia, the Hemarina-M101 group showed a 25% decrease in pancreatic reactive oxygen species production when compared to the control. The SOD-like activity of Hemarina-M101 may be responsible for this.18 During preservation, it is crucial to provide oxygen to avoid an imbalance of oxygen supply and/or metabolic disturbances. Normothermia preservation appears to be the leading edge of preservation technology based on the recent advances in machine perfusion technology with hypothermia preservation only recently being considered with the use of a therapeutic oxygen carrier.16 It was found in a recent study that Hemarina-M101 is the only oxygen transporter that is not only compatible with normothermia but has also been shown to be compatible with standard
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hypothermic preservation.16 As opposed to other TOC that are manufactured using vertebrate hemoglobin that work only at 21–37°C, Hemarina-M101 is the only TOC that has been shown to function in the large temperature range of 4–37°C.7 Furthermore, using Hemarina-M101 in the preservation solution is shown to maintain mitochondrial
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complex 1 activity in the transplant organ, which allows for oxidative phosphorylation during the beginning hours of cold ischemia.18 This demonstrates the ability of cells to use the Hemarina-M101 released oxygen in the preservation
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solution in a gradient-dependent manner.18
Supplementing preservation solutions using Hemarina-M101 allows for maintenance of energetic metabolism by increasing cellular ATP content. This decreases the need to switch from mitochondrial respiration to
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anaerobic glycolysis in turn protecting the mitochondria. High adenosine triphosphate (ATP) level maintenance during preservation by M101 may also prove to be beneficial upon reperfusion due to less metabolic stress on oxidative
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pathways, allowing for the restoration of energy homeostasis. 15 However, Lemaire et. al showed no correlation between the maintenance of respiration in M101 and an increase in ATP despite increased glucose uptake in the islet
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cells.18 More research is needed to clarify the mechanism.
Utility for Oxygenation
Hemarina-M101 was studied to see whether it could improve brain tissue oxygenation after a traumatic brain injury by using controlled cortical impact in rats. An increased mean arterial pressure without cerebral vasoconstriction was observed after transfusion in healthy rats. It was reported that when Hemarina-M101 was
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given soon after controlled cortical impact of traumatic brain injury (CCI-TBI), it was able to restore brain tissue oxygen tension (PbtO2) to 86% of pre-injury for at least 80 min by restoring brain tissue oxygen tension. When Hemarina-M101 is given to healthy rats, an increased systemic blood pressure without any concurrent vasoconstriction in the small-and-medium-sized cerebral pial vessels was reported.19 These vessels were seen to constrict over time in the control group of this study, while most first and second-generation HBOCs also possessed vasoconstrictive side-effects limiting their clinical usage.19 These findings suggest Hemarina-M101 may possess the necessary safety profile for clinical development in the early treatment of traumatic brain injury patients. 19 The protective effects on the brain suggest that Hemarina-M101 may aid in hypoxic brain injury patients.
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Conclusions Hemarina-M101, derived from the extracellular hemoglobin of marine animal Arenicola marina, has potential in organ transplantation as well as in oxygenation. Hemarina-M101 showed its protective effects on organ preservation due to increased oxygenation, increased ATP, decreased fibrosis, positive vascular effects such as increased VEGF, antioxidant properties, and its unique compatibility with standard hypothermic preservation. It is non-immunogenic while having a high oxygen-carrying capacity. Most studies cited on Hemarina-M101 were in vivo, utilizing small animals (i.e. rats, mice, and hamster models). More studies are needed in larger animal models, which
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may pave the way for further utility of Hemarina-M101.
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CRediT author statement
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Sources of Funding: None
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Joseph Varney: Conceptualization, Writing-Original Draft, Writing- Review and Editing Amanda Rivera: Conceptualization, Writing-Original Draft, Writing- Review and Editing Vinh Dong: Conceptualization, Writing-Original Draft, Writing- Review and Editing. Paul Tieu: Conceptualization, Writing-Original Draft Sairah Zia: Conceptualization, Writing-Original Draft Nguyen Tien Huy: Conceptualization, WritingReview and Editing, Supervision
Compliance with ethical standards: Yes
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Conflict of interest statement by authors: None
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Acknowledgments: None
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Superior microvascular perfusion of infused liposome-encapsulated hemoglobin prior to reductions in infarctions after transient focal cerebral ischemia. Journal of Stroke and Cerebrovascular Diseases. 2017 Dec 1;26(12):2994-3003. 27. Kawaguchi AT, Okamoto Y, Kise Y, Takekoshi S, Murayama C, Makuuchi H. Effects of liposome‐ encapsulated hemoglobin on gastric wound healing in the rat. Artificial organs. 2014 Aug;38(8):641-9. 28. Njoku, Mary, Deidre St Peter, and Colin F. Mackenzie. "Haemoglobin-based oxygen carriers: indications and future applications." (2015): 78-83. 29. George I, Yi GH, Schulman AR, Morrow BT, Cheng Y, Gu A, et al. A polymerized bovine hemoglobin oxygen carrier preserves regional myocardial function and reduces infarct size after acute myocardial ischemia. American Journal of Physiology-Heart and Circulatory Physiology. 2006 Sep;291(3):H1126-37. 30. te Lintel Hekkert M, Dubé GP, Regar E, de Boer M, Vranckx P, van der Giessen WJ, et al. 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The Journal of Thoracic and Cardiovascular Surgery. 1995 Sep 1;110(3):774-85. 34. Kleen M, Habler O, Hutter J, Kemming G, Podtschaske A, Tiede M, et al. Hemodilution and hyperoxia locally change distribution of regional pulmonary perfusion in dogs. American Journal of Physiology-Heart and Circulatory Physiology. 1998 Feb 1;274(2):H520-8. 35. Stern SA, Dronen SC, McGoron AJ, Wang X, Chaffins K, Millard R, et al. Effect of supplemental perfluorocarbon administration on hypotensive resuscitation of severe uncontrolled hemorrhage. The American journal of emergency medicine. 1995 May 1;13(3):269-75. 36. Manning JE, Batson DN, Payne FB, Adam N, Murphy CA, Perretta SG, et al. Selective aortic arch perfusion during cardiac arrest: enhanced resuscitation using oxygenated perflubron emulsion, with and without aortic arch epinephrine. Annals of emergency medicine. 1997 May 1;29(5):580-7. 37. Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. 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FIGURES AND TABLES. Table 1. Summary of Studies on M101
Title
Year of research Model
Finding(s)
Le Meur et al. France
First-in-human use of a marine oxygen carrier (M101) for organ preservation: A safety and proof-ofprinciple study. Beneficial effects of the novel marine oxygen carrier M101 during cold preservation of rat and human pancreas.
2020
Human kidney transplant
M101 added to the preservation solution had no reported adverse events and resulted in better renal function.
2019
Rat and human pancreas
Individual and 2019 Combined Impact of Oxygen and Oxygen Transporter Supplementation during Kidney Machine Preservation in a Porcine Preclinical Kidney Transplantation Model. Efficacy of the 2019 natural oxygen transporter HEMO2 life® in cold
Jo Kaminski et al. France
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M101 improved post-isolation islet quality when added to the preservation solution of rat pancreas during ischemia or exposed to the human pancreas.
Porcine kidney transplant
M101 added to the preservation solution improved kidney recovery and late graft outcomes.
Porcine kidney transplant
M101 added to the preservation solution improved functional
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Kasil et al. France
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Lemaire F et al. France
of
Country of corresponding author
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2011
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of
Supplementation with a new therapeutic oxygen carrier reduces chronic fibrosis and organ dysfunction in kidney static preservation.
M101 infusion increased blood pressure without causing vasoconstriction of pial vasculature and improves brain tissue oxygen.
Mice model of subcutaneous tumors
M101 rapidly diffused in the whole body for several hours without causing side-effects and reduced hypoxia in poorly vascularized tissues. M101 added to the preservation solution reduced cold-storage cell death, reduced kidney inflammation levels, increased function recovery and in the long term slowed fibrosis
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Thuillier et al. France
2014
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In vivo biodistribution and oxygenation potential of a new generation of oxygen carrier.
Rat model of traumatic brain injury
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Le Gall et al. France
outcomes and tissue integrity.
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Moon-Massat et al. USA
preservation in a preclinical porcine model of donation after cardiac death. Cerebral 2017 Vasoactivity and Oxygenation with Oxygen Carrier M101 in Rats.
Porcine kidney transplant
Table 1. Summary of studies investigating the effect of Hemarina-M101 in various applications.
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