From hemoglobin allostery to hemoglobin-based oxygen carriers

Abuchowski, 2016, PEGylated bovine carboxyhemoglobin (SANGUINATE): results of clinical safety testing and use in patients, Adv. Exp. Med. Biol., 876, 461, 10.1007/978-1-4939-3023-4_58 Abuchowski, 2017, SANGUINATE (PEGylated carboxyhemoglobin bovine): mechanism of action and clinical update, Artif. Organs, 41, 346, 10.1111/aor.12934 Aburawi, 2019, Synthetic hemoglobin-based oxygen carriers are an acceptable alternative for packed red blood cells in normothermic kidney perfusion, Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg., 19, 2814, 10.1111/ajt.15375 Ackers, 1992, Molecular code for cooperativity in hemoglobin, Science, 255, 54, 10.1126/science.1553532 Alayash, 2017, Hemoglobin-based blood substitutes and the treatment of sickle cell disease: more harm than help?, Biomolecules, 7 Alayash, 2019, Mechanisms of toxicity and modulation of hemoglobin-based oxygen carriers, Shock, 52, 41, 10.1097/SHK.0000000000001044 Alomari, 2018, High- and low-affinity PEGylated hemoglobin-based oxygen carriers: differential oxidative stress in a Guinea pig transfusion model, Free Radic. Biol. Med., 124, 299, 10.1016/j.freeradbiomed.2018.06.018 Antonini, 1971 Belcher, 2017, Mixtures of tense and relaxed state polymerized human hemoglobin regulate oxygen affinity and tissue construct oxygenation, PLoS One, 12, 10.1371/journal.pone.0185988 Belcher, 2018, The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: a theoretical and experimental study, PLoS One, 13, 10.1371/journal.pone.0191275 Belcher, 2013, MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice, Blood, 122, 2757, 10.1182/blood-2013-02-486282 Bellelli, 2011, Hemoglobin allostery: variations on the theme, Biochim. Biophys. Acta, 1807, 1262, 10.1016/j.bbabio.2011.04.004 Benitez Cardenas, 2019, Current challenges in the development of acellular hemoglobin oxygen carriers by protein engineering, Shock, 52, 28, 10.1097/SHK.0000000000001053 Bettati, 1997, T state hemoglobin binds oxygen noncooperatively with allosteric effects of protons, inositol hexaphosphate, and chloride, J. Biol. Chem., 272, 32050, 10.1074/jbc.272.51.32050 Bettati, 1998, Allosteric mechanism of haemoglobin: rupture of salt-bridges raises the oxygen affinity of the T-structure, J. Mol. Biol., 281, 581, 10.1006/jmbi.1998.1983 Bhattacharjee, 2020, Renal protection against ischemia reperfusion injury: hemoglobin-based oxygen carrier-201 versus blood as an oxygen carrier in ex vivo subnormothermic machine perfusion, Transplantation, 104, 482, 10.1097/TP.0000000000002967 Birukou, 2010, Distal histidine stabilizes bound O2 and acts as a gate for ligand entry in both subunits of adult human hemoglobin, J. Biol. Chem., 285, 8840, 10.1074/jbc.M109.053934 Bobofchak, 2003, A recombinant polymeric hemoglobin with conformational, functional, and physiological characteristics of an in vivo O2 transporter, Am. J. Physiol. Heart Circ. Physiol., 285, H549, 10.1152/ajpheart.00037.2003 Boteon, 2019, The impact on the bioenergetic status and oxidative-mediated tissue injury of a combined protocol of hypothermic and normothermic machine perfusion using an acellular haemoglobin-based oxygen carrier: the cold-to-warm machine perfusion of the liver, PLoS One, 14, 10.1371/journal.pone.0224066 Bradley, 1994, Production of PEG-modified bovine hemoglobin: economics and feasibility, Artif. Cells Blood Substit. Immobil. Biotechno., 22, 657, 10.3109/10731199409117896 Bruno, 2001, High and low oxygen affinity conformations of T state hemoglobin, Protein Sci. : Pub. Protein Soc., 10, 2401, 10.1110/ps.20501 Buehler, 2010, Synthesis, biophysical properties and pharmacokinetics of ultrahigh molecular weight tense and relaxed state polymerized bovine hemoglobins, Biomaterials, 31, 3723, 10.1016/j.biomaterials.2010.01.072 Bunn, 1986 Caccia, 2009, PEGylation promotes hemoglobin tetramer dissociation, Bioconjugate Chem., 20, 1356, 10.1021/bc900130f Caron, 1999, Cardiovascular and hemorheological effects of three modified human hemoglobin solutions in hemodiluted rabbits, J. Appl. Physiol., 86, 541, 10.1152/jappl.1999.86.2.541 Chang, 1997, Blood substitutes, vols. 1 and 2 Chang, 1992 Chatterjee, 1986, Isolation and characterization of a new hemoglobin derivative cross-linked between the alpha chains (lysine 99 alpha 1----lysine 99 alpha 2), J. Biol. Chem., 261, 9929, 10.1016/S0021-9258(18)67605-7 Chen, 2009, A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers, Clinics, 64, 803, 10.1590/S1807-59322009000800016 Cooper, 2021, Stability of maleimide-PEG and mono-sulfone-PEG conjugation to a novel engineered cysteine in the human hemoglobin alpha subunit, Front Chem, 9, 707797, 10.3389/fchem.2021.707797 Cooper, 2008, Peroxidase activity of hemoglobin towards ascorbate and urate: a synergistic protective strategy against toxicity of Hemoglobin-Based Oxygen Carriers (HBOC), Biochim. Biophys. Acta, 1784, 1415, 10.1016/j.bbapap.2008.03.019 Cooper, 2020, Engineering hemoglobin to enable homogenous PEGylation without modifying protein functionality, Biomaterials science, 8, 3896, 10.1039/C9BM01773A Cooper, 2019, Engineering tyrosine residues into hemoglobin enhances heme reduction, decreases oxidative stress and increases vascular retention of a hemoglobin based blood substitute, Free Radic. Biol. Med., 134, 106, 10.1016/j.freeradbiomed.2018.12.030 Coppola, 2011, Low affinity PEGylated hemoglobin from Trematomus bernacchii, a model for hemoglobin-based blood substitutes, BMC Biochem., 12, 66, 10.1186/1471-2091-12-66 D'Agnillo, 1998, Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties, Nat. Biotechnol., 16, 667, 10.1038/nbt0798-667 Das, 1999, Temperature dependent quaternary state relaxation in sol-gel encapsulated hemoglobin, Biospectroscopy, 5, S64, 10.1002/(SICI)1520-6343(1999)5:5+<S64::AID-BSPY7>3.0.CO;2-W de Vries, 2019, Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution, Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg., 19, 1202, 10.1111/ajt.15228 Devineau, 2018, Manipulating hemoglobin oxygenation using silica nanoparticles: a novel prospect for artificial oxygen carriers, Blood advances, 2, 90, 10.1182/bloodadvances.2017012153 di Masi, 2020, Haptoglobin: from hemoglobin scavenging to human health, Mol. Aspect. Med., 73, 100851, 10.1016/j.mam.2020.100851 Doherty, 1998, Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin, Nat. Biotechnol., 16, 672, 10.1038/nbt0798-672 Dolgin, 2017, Bioengineering: doing without donors, Nature, 549, S12, 10.1038/549S12a Dou, 2002, Myoglobin as a model system for designing heme protein based blood substitutes, Biophys. Chem., 98, 127, 10.1016/S0301-4622(02)00090-X Dube, 2019, Relative efficacies of HBOC-201 and polyheme to increase oxygen transport compared to blood and crystalloids, Shock, 52, 100, 10.1097/SHK.0000000000001058 Eaton, 1980, The relationship between coding sequences and function in haemoglobin, Nature, 284, 183, 10.1038/284183a0 Eaton, 2007, Evolution of allosteric models for hemoglobin, IUBMB Life, 59, 586, 10.1080/15216540701272380 Eaton, 1999, Is cooperative oxygen binding by hemoglobin really understood?, Nat. Struct. Biol., 6, 351, 10.1038/7586 Eich, 1996, Mechanism of NO-induced oxidation of myoglobin and hemoglobin, Biochemistry, 35, 6976, 10.1021/bi960442g Elmer, 2012, Hypervolemic infusion of Lumbricus terrestris erythrocruorin purified by tangential-flow filtration, Transfusion, 52, 1729, 10.1111/j.1537-2995.2011.03523.x Faggiano, 2011, Modulation of expression and polymerization of hemoglobin Polytaur, a potential blood substitute, Arch. Biochem. Biophys., 505, 42, 10.1016/j.abb.2010.09.027 Friedman, 1985, Structure, dynamics, and reactivity in hemoglobin, Science, 228, 1273, 10.1126/science.4001941 Fronticelli, 2009, Design of recombinant hemoglobins for use in transfusion fluids, Crit. Care Clin., 25, 357, 10.1016/j.ccc.2008.12.010 Frost, 2018, How synthetic biology and metabolic engineering can boost the generation of artificial blood using microbial production hosts, Front. Bioeng. Biotechnol., 6, 186, 10.3389/fbioe.2018.00186 Funaki, 2019, Hemoglobin−Albumin clusters prepared using N-succinimidyl 3-maleimidopropionate as an appropriate cross-linker, ACS Omega, 4, 3228, 10.1021/acsomega.8b03474 Gelin, 1983, Hemoglobin tertiary structural change on ligand binding. Its role in the co-operative mechanism, J. Mol. Biol., 171, 489, 10.1016/0022-2836(83)90042-6 Gibson, 1955, The kinetics of dissociation of the first oxygen molecule from fully saturated oxyhaemoglobin in sheep blood solutions, Proc. R. Soc. Lond. Ser. B Biol. Sci., 143, 310 Gladwin, 2017, How red blood cells process nitric oxide: evidence for the nitrite hypothesis, Circulation, 135, 177, 10.1161/CIRCULATIONAHA.116.024752 Gould, 1998, The first randomized trial of human polymerized hemoglobin as a blood substitute in acute trauma and emergent surgery, J. Am. Coll. Surg., 187, 113, 10.1016/S1072-7515(98)00095-7 Graves, 2008, Enhancing stability and expression of recombinant human hemoglobin in E. coli: progress in the development of a recombinant HBOC source, Biochim. Biophys. Acta, 1784, 1471, 10.1016/j.bbapap.2008.04.012 Greenburg, 2004, Hemoglobin-based oxygen carriers, Crit. Care, 8, S61, 10.1186/cc2455 Gu, 2021 Guerci, 2020, Resuscitation with PEGylated carboxyhemoglobin preserves renal cortical oxygenation and improves skeletal muscle microcirculatory flow during endotoxemia, Am. J. Physiol. Ren. Physiol., 318, F1271, 10.1152/ajprenal.00513.2019 Harrington, 2011, Physicochemical characteristics of OxyVita hemoglobin, a zero-linked polymer: liquid and powder preparations, Artif. Cells Blood Substit. Immobil. Biotechno., 39, 12, 10.3109/10731199.2010.501753 Harris, 2008, Modern cross-linking strategies for synthesizing acellular hemoglobin-based oxygen carriers, Biotechnol. Prog., 24, 1215, 10.1002/btpr.85 Haruki, 2015, Safety evaluation of hemoglobin-albumin cluster "HemoAct" as a red blood cell substitute, Sci. Rep., 5, 12778, 10.1038/srep12778 Henry, 2002, A tertiary two-state allosteric model for hemoglobin, Biophys. Chem., 98, 149, 10.1016/S0301-4622(02)00091-1 Henry, 1997, Can a two-state MWC allosteric model explain hemoglobin kinetics?, Biochemistry, 36, 6511, 10.1021/bi9619177 Henry, 2015, Experiments on hemoglobin in single crystals and silica gels distinguish among allosteric models, Biophys. J., 109, 1264, 10.1016/j.bpj.2015.04.037 Hofrichter, 1983, Nanosecond absorption spectroscopy of hemoglobin: elementary processes in kinetic cooperativity, Proc. Natl. Acad. Sci. U.S.A., 80, 2235, 10.1073/pnas.80.8.2235 Hu, 2009, PEGylation of Val-1(alpha) destabilizes the tetrameric structure of hemoglobin, Biochemistry, 48, 608, 10.1021/bi801880y Hu, 2011, Increased inter dimeric interaction of oxy hemoglobin is necessary for attenuation of reductive pegylation promoted dissociation of tetramer, Artif. Cells Blood Substit. Immobil. Biotechno., 39, 69, 10.3109/10731199.2010.501756 Hu, 2012, Propylbenzmethylation at Val-1(alpha) markedly increases the tetramer stability of the PEGylated hemoglobin: a comparison with propylation at Val-1(alpha), Biochim. Biophys. Acta, 1820, 2044, 10.1016/j.bbagen.2012.09.013 Iafelice, 2007, Identification of the sites of deoxyhaemoglobin PEGylation, Biochem. J., 403, 189, 10.1042/BJ20061556 Imai, 1982 Inayat, 2006, Oxygen carriers: a selected review, Transfus. Apher. Sci. Off. J. World Apheresis Assoc. Off. J. Eur. Soc. Haemapheresis, 34, 25 Jahr, 2012, Crosslinked, polymerized, and PEG-conjugated hemoglobin-based oxygen carriers: clinical safety and efficacy of recent and current products, Curr. Drug Discov. Technol., 9, 158, 10.2174/157016312802650742 Jahr, 2007, Blood substitutes as pharmacotherapies in clinical practice, Curr. Opin. Anaesthesiol., 20, 325, 10.1097/ACO.0b013e328172225a Jahr, 2008, HBOC-201, hemoglobin glutamer-250 (bovine), Hemopure (Biopure Corporation), Expet Opin. Biol. Ther., 8, 1425, 10.1517/14712598.8.9.1425 Jana, 2020, The providence mutation (betaK82D) in human hemoglobin substantially reduces betaCysteine 93 oxidation and oxidative stress in endothelial cells, Int. J. Mol. Sci., 21, 10.3390/ijms21249453 Jani, 2017, Polyethylene glycol camouflaged earthworm hemoglobin, PLoS One, 12, 10.1371/journal.pone.0170041 Jansman, 2018, Recent and prominent examples of nano- and microarchitectures as hemoglobin-based oxygen carriers, Adv. Colloid Interface Sci., 260, 65, 10.1016/j.cis.2018.08.006 Jones, 2012, Heme reactivity is uncoupled from quaternary structure in gel-encapsulated hemoglobin: a resonance Raman spectroscopic study, J. Am. Chem. Soc., 134, 3461, 10.1021/ja210126j Jones, 2014, Differential control of heme reactivity in alpha and beta subunits of hemoglobin: a combined Raman spectroscopic and computational study, J. Am. Chem. Soc., 136, 10325, 10.1021/ja503328a Juszczak, 1999, UV resonance Raman spectra of ligand binding intermediates of sol-gel encapsulated hemoglobin, J. Biol. Chem., 274, 30357, 10.1074/jbc.274.43.30357 Kaminski, 2019, Efficacy of the natural oxygen transporter HEMO2 life((R)) in cold preservation in a preclinical porcine model of donation after cardiac death, Transpl. Int. : official journal of the European Society for Organ Transplantation, 32, 985, 10.1111/tri.13434 Kendrew, 1960, Structure of myoglobin: a three-dimensional Fourier synthesis at 2 A. resolution, Nature, 185, 422, 10.1038/185422a0 Khan, 2020, Artificial blood: the history and current perspectives of blood substitutes, Discoveries, 8, e104, 10.15190/d.2020.1 Khan, 2000, Sol-gel trapping of functional intermediates of hemoglobin: geminate and bimolecular recombination studies, Biochemistry, 39, 16099, 10.1021/bi000536x Kim, 2013 Kister, 1987, An expanded two-state allosteric model for interactions of human hemoglobin A with nonsaturating concentrations of 2,3-diphosphoglycerate, J. Biol. Chem., 262, 12085, 10.1016/S0021-9258(18)45319-7 Kocian, 2008, Haemoglobin, oxygen carriers and perioperative organ perfusion. Best practice & research, Clinical anaesthesiology, 22, 63 Komiyama, 1995, Transplanting a unique allosteric effect from crocodile into human haemoglobin, Nature, 373, 244, 10.1038/373244a0 Koshland, 1966, Comparison of experimental binding data and theoretical models in proteins containing subunits, Biochemistry, 5, 365, 10.1021/bi00865a047 Krafft, 2009, Chemistry, physical chemistry, and uses of molecular fluorocarbon--hydrocarbon diblocks, triblocks, and related compounds--unique "apolar" components for self-assembled colloid and interface engineering, Chem. Rev., 109, 1714, 10.1021/cr800260k Laing, 2017, The use of an acellular oxygen carrier in a human liver model of normothermic machine perfusion, Transplantation, 101, 2746, 10.1097/TP.0000000000001821 Lalezari, 1990, New effectors of human hemoglobin: structure and function, Biochemistry, 29, 1515, 10.1021/bi00458a024 Lamy, 2000, Randomized trial of diaspirin cross-linked hemoglobin solution as an alternative to blood transfusion after cardiac surgery, Anesthesiology, 92, 646, 10.1097/00000542-200003000-00007 Le Coeur, 2015, Conformation of the poly(ethylene glycol) chains in DiPEGylated hemoglobin specifically probed by SANS: correlation with PEG length and in vivo efficiency, Langmuir : the ACS journal of surfaces and colloids, 31, 8402, 10.1021/acs.langmuir.5b01121 Li, 2009, Extension arm facilitated pegylation of alphaalpha-hemoglobin with modifications targeted exclusively to amino groups: functional and structural advantages of free Cys-93(beta) in the PEG-Hb adduct, Bioconjugate Chem., 20, 2062, 10.1021/bc900170e Li, 2006, Extension arm facilitated PEGylation of hemoglobin: correlation of the properties with the extent of PEGylation, Protein J., 25, 263, 10.1007/s10930-006-9010-y Lui, 2008, Polyethylene glycol conjugation enhances the nitrite reductase activity of native and cross-linked hemoglobin, Biochemistry, 47, 10773, 10.1021/bi801116k Lui, 2009, Enhancing nitrite reductase activity of modified hemoglobin: bis-tetramers and their PEGylated derivatives, Biochemistry, 48, 11912, 10.1021/bi9014105 Lukin, 2003, Quaternary structure of hemoglobin in solution, Proc. Natl. Acad. Sci. U.S.A., 100, 517, 10.1073/pnas.232715799 Mahboub, 2020, The efficacy of HBOC-201 in ex situ gradual rewarming kidney perfusion in a rat model, Artif. Organs, 44, 81, 10.1111/aor.13534 Mallet, 2014, Dose-ranging study of the performance of the natural oxygen transporter HEMO2 Life in organ preservation, Artif. Organs, 38, 691, 10.1111/aor.12307 Manjula, 2000, Cys-93-betabeta-succinimidophenyl polyethylene glycol 2000 hemoglobin A. Intramolecular cross-bridging of hemoglobin outside the central cavity, J. Biol. Chem., 275, 5527, 10.1074/jbc.275.8.5527 Manjula, 2003, Site-specific PEGylation of hemoglobin at Cys-93(beta): correlation between the colligative properties of the PEGylated protein and the length of the conjugated PEG chain, Bioconjugate Chem., 14, 464, 10.1021/bc0200733 Manjula, 2005, Conjugation of multiple copies of polyethylene glycol to hemoglobin facilitated through thiolation: influence on hemoglobin structure and function, Protein J., 24, 133, 10.1007/s10930-005-7837-2 Marden, 1990, Effectors of hemoglobin. Separation of allosteric and affinity factors, Biophys. J., 57, 397, 10.1016/S0006-3495(90)82556-X McConachie, 2020, Early experiences with PEGylated carboxyhemoglobin bovine in anemic Jehovah's Witnesses: a case series and review of the literature, J. Pharm. Pract., 33, 372, 10.1177/0897190018815373 Meng, 2018, Comprehensive biochemical and biophysical characterization of hemoglobin-based oxygen carrier therapeutics: all HBOCs are not created equally, Bioconjugate Chem., 29, 1560, 10.1021/acs.bioconjchem.8b00093 Miele, 2013, Hemoglobin allostery: new views on old players, J. Mol. Biol., 425, 1515, 10.1016/j.jmb.2012.12.018 Misra, 2017, A Phase Ib open label, randomized, safety study of SANGUINATE in patients with sickle cell anemia, Rev. Bras. Hematol. Hemoter., 39, 20, 10.1016/j.bjhh.2016.08.004 Mollan, 2013, Redox reactions of hemoglobin: mechanisms of toxicity and control, Antioxidants Redox Signal., 18, 2251, 10.1089/ars.2013.5195 Monod, 1965, On the nature of allosteric transitions: a plausible model, J. Mol. Biol., 12, 88, 10.1016/S0022-2836(65)80285-6 Moore, 2009, Human polymerized hemoglobin for the treatment of hemorrhagic shock when blood is unavailable: the USA multicenter trial, J. Am. Coll. Surg., 208, 1, 10.1016/j.jamcollsurg.2008.09.023 Mozzarelli, 2011 Mozzarelli, 1997, Allosteric effectors do not alter the oxygen affinity of hemoglobin crystals, Protein Sci. : Pub. Protein Soc., 6, 484, 10.1002/pro.5560060230 Mozzarelli, 1991, Crystals of haemoglobin with the T quaternary structure bind oxygen noncooperatively with no Bohr effect, Nature, 351, 416, 10.1038/351416a0 Mozzarelli, 2010, Haemoglobin-based oxygen carriers: research and reality towards an alternative to blood transfusions, Blood Transfus., 8, s59 Muirhead, 1963, Structure of haemoglobin. A three-dimensional fourier synthesis of reduced human haemoglobin at 5,5 Å, Nature, 199, 633, 10.1038/199633a0 Natanson, 2008, Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis, Jama, 299, 2304, 10.1001/jama.299.19.jrv80007 Noble, 1972, A strctural comparison of ligand-saturated hemoglobin with protoporphyrin globin. I. Reaction with bromothymol blue and sulfhydryl reagents, J. Mol. Biol., 70, 689, 10.1016/0022-2836(72)90567-0 Olofsson, 2008, A randomized, single-blind, increasing dose safety trial of an oxygen-carrying plasma expander (Hemospan) administered to orthopaedic surgery patients with spinal anaesthesia, Transfus. Med., 18, 28, 10.1111/j.1365-3148.2007.00811.x Olofsson, 2011, Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: a randomized, double-blind, multicenter study, Anesthesiology, 114, 1048, 10.1097/ALN.0b013e318215e198 Olson, 1997, Protein engineering strategies for designing more stable hemoglobin-based blood substitutes, Artif. Cells Blood Substit. Immobil. Biotechno., 25, 227, 10.3109/10731199709118912 Olson, 2004, No scavenging and the hypertensive effect of hemoglobin-based blood substitutes, Free Radic. Biol. Med., 36, 685, 10.1016/j.freeradbiomed.2003.11.030 Panetta, 2008, Hb(alpha alpha,beta beta): A novel fusion construct for a dimeric, four-domain hemoglobin, Biochim. Biophys. Acta Protein Proteonomics, 1784, 1462, 10.1016/j.bbapap.2008.01.003 Parak, 1988, Protein structural dynamics as determined by Mössbauer spectroscopy, Hyperfine Interact., 40, 147, 10.1007/BF02049086 Pauling, 1935, The oxygen equilibrium of hemoglobin and its structural interpretation, Proc. Natl. Acad. Sci. U.S.A., 21, 186, 10.1073/pnas.21.4.186 Perutz, 1964, Structure of haemoglobin. An X-ray examination of reduced horse haemoglobin, Nature, 203, 687, 10.1038/203687a0 Peterson, 2004, Domain-specific effector interactions within the central cavity of human adult hemoglobin in solution and in porous sol-gel matrices: evidence for long-range communication pathways, Biochemistry, 43, 4832, 10.1021/bi035481o Pillai, 2020, Origin of complexity in haemoglobin evolution, Nature, 581, 480, 10.1038/s41586-020-2292-y Portoro, 2008, Towards a novel haemoglobin-based oxygen carrier: euro-PEG-Hb, physico-chemical properties, vasoactivity and renal filtration, Biochim. Biophys. Acta, 1784, 1402, 10.1016/j.bbapap.2008.03.005 Powanda, 2002, Cross-linked polyhemoglobin-superoxide dismutase-catalase supplies oxygen without causing blood-brain barrier disruption or brain edema in a rat model of transient global brain ischemia-reperfusion, Artif. Cells Blood Substit. Immobil. Biotechno., 30, 23, 10.1081/BIO-120002725 Premont, 2020, Role of nitric oxide carried by hemoglobin in cardiovascular physiology: developments on a three-gas respiratory cycle, Circ. Res., 126, 129, 10.1161/CIRCRESAHA.119.315626 Pusateri, 2019, Reassessment of the need for an oxygen carrier for the treatment of traumatic hemorrhage when blood is not an option, Shock, 52, 55, 10.1097/SHK.0000000000001417 Rajesh, 2018, Glutaraldehyde cross-linking increases the stability of Lumbricus terrestris erythrocruorin, Biotechnol. Prog., 34, 521, 10.1002/btpr.2593 Reeder, 2008, Tyrosine residues as redox cofactors in human hemoglobin: implications for engineering nontoxic blood substitutes, J. Biol. Chem., 283, 30780, 10.1074/jbc.M804709200 Rivetti, 1993, Oxygen binding by single crystals of hemoglobin, Biochemistry, 32, 2888, 10.1021/bi00062a021 Roamcharern, 2019, Physicochemical properties and oxygen affinity of glutaraldehyde polymerized crocodile hemoglobin: the new alternative hemoglobin source for hemoglobin-based oxygen carriers, Artificial cells, nanomedicine, and biotechnology, 47, 852, 10.1080/21691401.2019.1579733 Roberts, 2002, Chemistry for peptide and protein PEGylation, Adv. Drug Deliv. Rev., 54, 459, 10.1016/S0169-409X(02)00022-4 Ronda, 2008, Ligand reactivity and allosteric regulation of hemoglobin-based oxygen carriers, Biochim. Biophys. Acta, 1784, 1365, 10.1016/j.bbapap.2008.04.021 Ronda, 2006, Circular dichroism spectroscopy of tertiary and quaternary conformations of human hemoglobin entrapped in wet silica gels, Protein Sci. : Pub. Protein Soc., 15, 1961, 10.1110/ps.062272306 Ronda, 2011, Electrophoretic analysis of PEGylated hemoglobin-based blood substitutes, Anal. Biochem., 408, 118, 10.1016/j.ab.2010.08.043 Rumsey, 1998, Absorption, transport, and disposition of ascorbic acid in humans, J. Nutr. Biochem., 9, 116, 10.1016/S0955-2863(98)00002-3 Sakai, 2005, Oxygen release from low and normal P50 Hb vesicles in transiently occluded arterioles of the hamster window model, Am. J. Physiol. Heart Circ. Physiol., 288, H2897, 10.1152/ajpheart.01184.2004 Sakai, 2001, Hemoglobin-vesicles as oxygen carriers: influence on phagocytic activity and histopathological changes in reticuloendothelial system, Am. J. Pathol., 159, 1079, 10.1016/S0002-9440(10)61783-X Samuni, 2004, Spectroscopic and functional characterization of T state hemoglobin conformations encapsulated in silica gels, Biochemistry, 43, 13674, 10.1021/bi048531d Samuni, 2006, Modulation of reactivity and conformation within the T-quaternary state of human hemoglobin: the combined use of mutagenesis and sol-gel encapsulation, Biochemistry, 45, 2820, 10.1021/bi050010i Scatena, 2001, O-raffinose-polymerised haemoglobin. A biochemical and pharmacological profile of an oxygen carrier, Expet Opin. Biol. Ther., 1, 121, 10.1517/14712598.1.1.121 Schiro, 2007, Quaternary relaxations in sol-gel encapsulated hemoglobin studied via NIR and UV spectroscopy, Biochemistry, 46, 11568, 10.1021/bi701166m Sen Gupta, 2019, Hemoglobin-based oxygen carriers: current state-of-the-art and novel molecules, Shock, 52, 70, 10.1097/SHK.0000000000001009 Shibayama, 2020, Allosteric transitions in hemoglobin revisited. Biochimica et biophysica acta, General subjects, 1864, 129335, 10.1016/j.bbagen.2019.03.021 Shibayama, 1995, Fixation of the quaternary structures of human adult haemoglobin by encapsulation in transparent porous silica gels, J. Mol. Biol., 251, 203, 10.1006/jmbi.1995.0427 Silkstone, 2016, Engineering tyrosine electron transfer pathways decreases oxidative toxicity in hemoglobin: implications for blood substitute design, Biochem. J., 473, 3371, 10.1042/BCJ20160243 Simoni, 2014, Artificial oxygen carrier with pharmacologic actions of adenosine-5'-triphosphate, adenosine, and reduced glutathione formulated to treat an array of medical conditions, Artif. Organs, 38, 684, 10.1111/aor.12337 Simoni, 2012, ATP-adenosine-glutathione cross-linked hemoglobin as clinically useful oxygen carrier, Curr. Drug Discov. Technol., 9, 173, 10.2174/157016312802650797 Simons, 2018, Comparison of the oxidative reactivity of recombinant fetal and adult human hemoglobin: implications for the design of hemoglobin-based oxygen carriers, Biosci. Rep., 38, 10.1042/BSR20180370 Spivack, 2018, Increasing the stability of Lumbricus terrestris erythrocruorin via poly(acrylic acid) conjugation, Artificial cells, nanomedicine, and biotechnology, 46, 1137, 10.1080/21691401.2018.1480491 Strader, 2017, Exploring oxidative reactions in hemoglobin variants using mass spectrometry: lessons for engineering oxidatively stable oxygen therapeutics, Antioxidants Redox Signal., 26, 777, 10.1089/ars.2016.6805 Strader, 2017, Engineering oxidative stability in human hemoglobin based on the Hb providence (betaK82D) mutation and genetic cross-linking, Biochem. J., 474, 4171, 10.1042/BCJ20170491 Taguchi, 2020, Use of hemoglobin for delivering exogenous carbon monoxide in medicinal applications, Curr. Med. Chem., 27, 2949, 10.2174/0929867325666181113122340 Thuillier, 2011, Supplementation with a new therapeutic oxygen carrier reduces chronic fibrosis and organ dysfunction in kidney static preservation, Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg., 11, 1845, 10.1111/j.1600-6143.2011.03614.x Tomita, 2013, Covalent core-shell architecture of hemoglobin and human serum albumin as an artificial O2 carrier, Biomacromolecules, 14, 1816, 10.1021/bm400204y Tsuneshige, 2002, Heterotropic effectors control the hemoglobin function by interacting with its T and R states--a new view on the principle of allostery, Biophys. Chem., 98, 49, 10.1016/S0301-4622(02)00084-4 Vandegriff, 2003, MP4, a new nonvasoactive PEG-Hb conjugate, Transfusion, 43, 509, 10.1046/j.1537-2995.2003.00341.x Vanholder, 2021, Organ donation and transplantation: a multi-stakeholder call to action, Nat. Rev. Nephrol., 17, 554, 10.1038/s41581-021-00425-3 Varnado, 2013, Development of recombinant hemoglobin-based oxygen carriers, Antioxidants Redox Signal., 18, 2314, 10.1089/ars.2012.4917 Varney, 2021, Mini-review on the properties and possible applications of therapeutic oxygen carrier Hemarina-M101, Transfus. Apher. Sci. Off. J. World Apheresis Assoc. Off. J. Eur. Soc. Haemapheresis, 60, 103016 Viappiani, 2014, Experimental basis for a new allosteric model for multisubunit proteins, Proc. Natl. Acad. Sci. U.S.A., 111, 12758, 10.1073/pnas.1413566111 Viappiani, 2004, New insights into allosteric mechanisms from trapping unstable protein conformations in silica gels, Proc. Natl. Acad. Sci. U.S.A., 101, 14414, 10.1073/pnas.0405987101 Walder, 1979, Diaspirins that cross-link beta chains of hemoglobin: bis(3,5-dibromosalicyl) succinate and bis(3,5-dibromosalicyl) fumarate, Biochemistry, 18, 4265, 10.1021/bi00587a001 Wang, 2014, Reversible protection of Cys-93(beta) by PEG alters the structural and functional properties of the PEGylated hemoglobin, Biochim. Biophys. Acta, 1844, 1201, 10.1016/j.bbapap.2014.04.005 Wang, 2017, Structural, functional and physiochemical properties of dextran-bovine hemoglobin conjugate as a hemoglobin-based oxygen carrier, Process Biochem., 60, 67, 10.1016/j.procbio.2017.05.021 Winslow, 2004, MP4, a new nonvasoactive polyethylene glycol-hemoglobin conjugate, Artif. Organs, 28, 800, 10.1111/j.1525-1594.2004.07392.x Winslow, 2005, Targeted O2 delivery by low-p50 hemoglobin: a new basis for hemoglobin-based oxygen carriers, Artif. Cells Blood Substit. Immobil. Biotechno., 33, 1, 10.1081/BIO-200046634 Winslow, 2006, Current status of oxygen carriers ('blood substitutes'): 2006, Vox Sang., 91, 102, 10.1111/j.1423-0410.2006.00789.x Winslow, 1996 Winslow, 2006 Winslow, 2008, Cell-free oxygen carriers: scientific foundations, clinical development, and new directions, Biochim. Biophys. Acta, 1784, 1382, 10.1016/j.bbapap.2008.04.032 Wollocko, 2017, Zero-link polymerized hemoglobin (OxyVita((R))Hb) stabilizes the heme environment: potential for lowering vascular oxidative stress, Artificial cells, nanomedicine, and biotechnology, 45, 701, 10.1080/21691401.2016.1263639 Wollocko, 2017, OxyVita((R))C, a next-generation haemoglobin-based oxygen carrier, with coagulation capacity (OVCCC). Modified lyophilization/spray-drying process: proteins protection, Artificial cells, nanomedicine, and biotechnology, 45, 1350, 10.1080/21691401.2017.1339052 Yonetani, 2002, Global allostery model of hemoglobin. Modulation of O(2) affinity, cooperativity, and Bohr effect by heterotropic allosteric effectors, J. Biol. Chem., 277, 34508, 10.1074/jbc.M203135200 Yonetani, 2003, The global allostery model of hemoglobin: an allosteric mechanism involving homotropic and heterotropic interactions, Comptes Rendus Biol., 326, 523, 10.1016/S1631-0691(03)00150-1 Young, 2005, MalPEG-hemoglobin (MP4) improves hemodynamics, acid-base status, and survival after uncontrolled hemorrhage in anesthetized swine, Crit. Care Med., 33, 1794, 10.1097/01.CCM.0000172648.55309.13 Yuan, 2015, New look at hemoglobin allostery, Chem. Rev., 115, 1702, 10.1021/cr500495x Zhang, 2011, Biophysical properties and oxygenation potential of high-molecular-weight glutaraldehyde-polymerized human hemoglobins maintained in the tense and relaxed quaternary states, Tissue Eng., 17, 927, 10.1089/ten.tea.2010.0353 Zhou, 2011, Synthesis, biophysical properties, and oxygenation potential of variable molecular weight glutaraldehyde-polymerized bovine hemoglobins with low and high oxygen affinity, Biotechnol. Prog., 27, 1172, 10.1002/btpr.624