Skip to main content
SpringerLink
Log in

Design of Nonhypertensive Conjugated Hemoglobins as Novel Resuscitation Fluids

  • Chapter
  • First Online:
Hemoglobin-Based Oxygen Carriers as Red Cell Substitutes and Oxygen Therapeutics

Abstract

Enhancing the molecular size/volume Hb was introduced, as a simple molecular approach to overcome or attenuate the extravasation mediated NO scavenging activity of Hb in vivo. Conjugation of Hb, as a chemical tool to achieve this objective, has now advanced beyond this initial concept. It requires us now to recognize that engineering of resuscitation fluids like properties to Hb is a novel concept and simple approach to neutralize/attenuate the in vivo hypertensive activity of acellular Hb. Development of conjugated hemoglobins is reviewed here as it lead to the development of this concept along with future perspectives. Extension Arm chemistry, that integrates the concepts of click chemistry into the various conjugation approaches of relevance to this aspect of blood substitute research is discussed. Bridging these approaches to increase the efficacy of engineering resuscitation fluid like properties to Hb is suggested as the future direction of designing conjugated Hbs as oxygen therapeutics. The integration of site directed mutagenesis to tame the molecular properties of Hb with the extension arm facilitated PEGylation to attenuate the impact of conjugation chemistry and/or conjugated polymer on the tertiary/quaternary structure of the Hb molecule is discussed in detail as applied to PEGylation of Hb as the conjugation approach of choice to generate nonhypertensive Hb as oxygen therapeutics. We conclude that such a synergistic approach will result in the attenuation of heme degradation product dependent and oxidative stress mediated in vivo toxicity as well as facilitating an increase in the oxygen delivering capacity of the conjugated Hb.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abuchowski A, van Es T, Palczuk NC, Davis FF (1977) Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J Biol Chem 252(11):3578–3581

    Google Scholar 

  • Abuchowski A, Davis FF (1979) Preparation and properties of polyethylene glycol-trypsin adducts. Biochim Biophys Acta 578(1):41–46

    Google Scholar 

  • Acharya AS, Manjula BN, Smith PK (1996) Hemoglobin crosslinkers. US Patent 5, 585, 484

    Google Scholar 

  • Acharya AS, Manjula BN, Smith PK (1998) Hemoglobin crosslinkers. US Patent 5,750,725

    Google Scholar 

  • Acharya AS, Manjula BN, Smith PK (2000) Hemoglobin crosslinkers, US patent 6, 017, 943

    Google Scholar 

  • Acharya SA, Friedman JM, Manjula BN, Intaglietta M, Tsai AG, Winslow RM, Malavalli A, Vandegriff K, Smith PK (2005) Enhanced molecular volume of conservatively pegylated Hb: (SP-PEG5 K)6-HbA is non-hypertensive. Artif Cells Blood Substit Immobil Biotechnol 33(3):239–255

    Google Scholar 

  • Acharya AS, Manjula BN (2006) Size enhanced hemoglobins: surface decoration and crosslinking of the protein with polyoxy alkylene glycols US patent 7, 019, 117

    Google Scholar 

  • Acharya AS, Manjula BN (2007) Size enhanced hemoglobins: surface decoration and crosslinking of the protein with polyoxy alkylene glycols. US Patent 7,169,900

    Google Scholar 

  • Acharya SA, Acharya VN, Kanika ND, Tsai AG, Intaglietta M, Manjula BN (2007a) Non-hypertensive tetraPEGylated canine haemoglobin: correlation between PEGylation, O2 affinity and tissue oxygenation. Biochem J 405(3):503–511

    Google Scholar 

  • Acharya SA, Intaglietta M, Tsai AG (2007b) Modulation of the polyethylene glycol-hemoglobin structure to increase the efficiency of plasma expansion and O2 carrying capacity. Trans Altern Trans Med 9(4):254–264

    Google Scholar 

  • Acharya SA, Intaglietta M, Tsai AG, Ananda K, Meng F (2011) Design of novel PEGylated hemoglobins as oxygen-carrying plasma expanders: Engineering the structure of PEG-Hb adducts for supraperfusion. In: Bettati S, Mozzarelli A (eds) Chemistry and biochemistry of oxygen therapeutics: from transfusion to artificial blood.Wiley, New Jersey, pp 345–369

    Google Scholar 

  • Acharya SA, Acharya VN, Meng FT, Ananda K, Tsai AG, Cantrill A, Intaglietta M (2011) Molecular aspects of in vivo “active supra perfusion” by P5K6 Alb and P5K6 Hb: Deformabilty of PEG-Protein and its potential role in enhancing perfusion Abstracts from 2011 XIII International Symposium on Blood Substitutes and Oxygen Therapeutics Boston, Massachusette, pp. 27–29

    Google Scholar 

  • Acharya VN, Ananda K, Meng FT, Intaglietta M, Acharya SA (2011) Nonconservative EAF-PEGylation of albumin: conjugation chemistry influences structure of protein core and has no influence on PEG-shell packing density. In: Abstracts from 2011 XIII international symposium on blood substitutes and oxygen therapeutics Boston, Massachusette, pp. 27–29

    Google Scholar 

  • Adachi K, Rappaport E, Eck HS, Konitzer P, Kim J, Surrey S (1991) Polymerization and solubility of recombinant hemoglobins α2β2(6Val) (Hb S) and α2β2(6Leu) (Hb Leu). Hemoglobin 15(5):417–430

    Google Scholar 

  • Agishi T, Funakoshi Y, Honda H, Yamagata K, Kobayashi M, Takahashi M (1988) (Pyridoxylated hemoglobin)-(polyoxyethylene) conjugate solution as blood substitute for normothermic whole body rinse-out. Biomater Artif Cells Artif Organs 16(1–3):261–270

    Google Scholar 

  • Alayash AI (2010) Setbacks in blood substitutes research and development: a biochemical perspective. Clin Lab Med 30(2):381–389

    Google Scholar 

  • Ananda K, Manjula BN, Meng F, Acharya VN, Intaglietta M, Acharya SA (2012) Packing density of the PEG-shell in PEG-albumins: PEGylation induced viscosity and COP is inverse correlate of packing density. Artif Cells Blood Substit Immobil Biotechnol 40(1–2):14–27

    Google Scholar 

  • Bakker JC, Berbers GA, Bleeker WK, den Boer PJ, Biessels PT (1992) Preparation and characterization of crosslinked and polymerized hemoglobin solutions. Biomater Artif Cells Immobilization Biotechnol 20(2–4):233–241

    Google Scholar 

  • Baldwin AL, Chien S (1988) Effect of dextran 40 on endothelial binding and vesicle loading of ferritin in rabbit aorta. Arteriosclerosis 8(2):140–146

    Google Scholar 

  • Benesch R, Benesch RE (1981) Preparation and properties of hemoglobin modified with derivatives of pyridoxal. Methods Enzymol 76:147–159

    Google Scholar 

  • Berbers GA, Bleeker WK, Stekkinger P, Agterberg J, Rigter G, Bakker JC (1991) Biophysical characteristics of hemoglobin intramolecularly cross-linked and polymerized. J Lab Clin Med 117(2):157–165

    Google Scholar 

  • Bobofchak KM, Mito T, Texel SJ, Bellelli A, Nemoto M, Traystman RJ, Koehler RC, Brinigar WS, Fronticelli C (2003) A recombinant polymeric hemoglobin with conformational, functional, and physiological characteristics of an in vivo O2 transporter. Am J Physiol Heart Circ Physiol 285(2):H549–H561

    Google Scholar 

  • Bonneaux F, Labrude P, Dellacherie E (1981) Preparation and oxygen binding properties of soluble covalent hemoglobin-dextran conjugates. Experientia 37(8):884–886

    Google Scholar 

  • Bonneaux F, Dellacherie E (1995) Fixation of various aldehydic dextrans onto human hemoglobin: study of conjugate stability. J Protein Chem 14(1):1–5

    Google Scholar 

  • Bradley R, Sloshberg S, Nho K, Czuba B, Szesko D, Shorr R (1994) Production of PEG-modified bovine hemoglobin: economics and feasibility. Artif Cells Blood Substit Immobil Biotechnol 22(3):657–667

    Google Scholar 

  • Bucci E, Razynska A, Kwansa H, Matheson-Urbaitis B, O’Hearne M, Ulatowski JA, Koehler RC (1996a) Production and characteristics of an infusible oxygen-carrying fluid based on hemoglobin intramolecularly cross-linked with sebacic acid. J Lab ClinMed 28(2):146–153

    Google Scholar 

  • Bucci E, Razynska A, Kwansa H, Matheson-Urbaitis B, O’Hearne M, Ulatowski JA, Koehler RC (1996b) Production and characteristics of an infusible oxygen-carrying fluid based on hemoglobin intramolecularly cross-linked with sebacic acid. J Lab Clin Med 128(2):146–153

    Google Scholar 

  • Buehler PW, Mehendale S, Wang H, Xie J, Ma L, Trimble CE, Hsia CJ, Gulati A (2000) Resuscitative effects of polynitroxylated αα-cross-linked hemoglobin following severe hemorrhage in the rat. Free Radic Biol Med 29(8):764–774

    Google Scholar 

  • Buehler PW, Boykins RA, Norris S, Alayash AI (2006) Chemical characterization of diaspirin cross-linked hemoglobin polymerized with poly (ethylene glycol). Anal Chem 78(13):4634–4641

    Google Scholar 

  • Buehler PW, Alayash AI (2008) All hemoglobin-based oxygen carriers are not created equally. Biochim Biophys Acta 1784(10):1378–1381

    Google Scholar 

  • Bunn HF, Esham WT, Bull RW (1969) The renal handling of hemoglobin I. Glomerular filtration. J Exp Med 129(5):909–923

    Google Scholar 

  • Cabrales P, Tsai AG, Intaglietta M (2004) Microvascular pressure and functional capillary density in extreme hemodilution with low- and high-viscosity dextran and a low-viscosity Hb-based O2 carrier. Am J Physiol Heart Circ Physiol 287(1):H363–H373

    Google Scholar 

  • Cabrales P, Tsai AG, Intaglietta M (2007) Resuscitation from emorrhagic shock with hydroxyethyl starch and coagulation changes. Shock 28(4):461–467

    Google Scholar 

  • Cabrales P, Tsai AG, Intaglietta M (2008) Increased plasma viscosity prolongs icrohemodynamic conditions during small volume resuscitation from hemorrhagic shock. Resuscitation 77(3):379–386

    Google Scholar 

  • Cabrales P, Friedman JM. HBOC vasoactivity: Interplay between nitric oxide scavenging and capacity to generate bioactive nitric oxide species. Antioxid Redox Signal. 2013 Feb 12 [Epub ahead of print]

    Google Scholar 

  • Caccia D, Ronda L, Frassi R, Perrella M, Del Favero E, Bruno S, Pioselli B, Abbruzzetti S, Viappiani C, Mozzarelli A (2009) PEGylation promotes hemoglobin tetramer dissociation. Bioconjug Chem 20(7):1356–1366

    Google Scholar 

  • Chang TMS (1964) Semipermeable microcapsules. Science 146:524

    Google Scholar 

  • Chang TMS (1971) Stabilization of enzyme by microencapsulation with a concentrated protein solution or by crosslinking with glutaraldehyde. Biochem Biophys Res Com 44:1531–1533

    Google Scholar 

  • Chang JE, Wong JT (1977) Synthesis of soluble dextran-hemoglobin complexes of different molecular sizes. Can J Biochem 55(4):398–403

    Google Scholar 

  • Chen JY, Scerbo M, Kramer G (2009) A review of blood substitutes: examining the history, clinical trial results, and ethics of Hemoglobin-based oxygen carriers. Clinics (Sao Paulo) 64(8):803–813

    Google Scholar 

  • Cole RH, Vandegriff KD (2011) MP4, a vasodilatory PEGylated hemoglobin. Adv Exp Med Biol 701:85–90

    Google Scholar 

  • Cumber AJ, Forrester JA, Foxwell BM, Ross WC, Thorpe PE (1985) Preparation of antibody-toxin conjugates. Methods Enzymol 112:207–225

    Google Scholar 

  • Dellacherie E, Bonneaux F, Labrude P, Vigneron C (1983) Modification of human hemoglobin by covalent association with soluble dextran. Biochim Biophys Acta 749(1):106–114

    Google Scholar 

  • Dellacherie E, Vigneron C (1991) Hemoglobin-based artificial blood: new polymeric derivatives of hemoglobin with low oxygen affinity. Int J Artif Organs 14(1):28–32

    Google Scholar 

  • Doherty DH, Doyle MP, Curry SR, Vali RJ, Fattor TJ, Olson JS, Lemon DD (1998) Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nat Biotechnol 16(7):672–676

    Google Scholar 

  • Doyle MP, Apostol I, Kerwin BA (1999) Glutaraldehyde modification of recombinant human hemoglobin alters its hemodynamic properties. J Biol Chem 274(4):2583–2591

    Google Scholar 

  • D’Agnillo F, Chang TM (1993) Cross-linked hemoglobin-superoxide dismutase-catalase scavenges oxygen-derived free radicals and prevents methemoglobin formation and iron release. Biomater Artif Cells Immobilization Biotechnol 21(5):609–621

    Google Scholar 

  • D’Agnillo F, Chang TM (1998) Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties. Nat Biotechnol 16(7):667–671

    Google Scholar 

  • Eich RF, Li T, Lemon DD, Doherty DH, Curry SR, Aitken JF, Mathews AJ, Johnson KA, Smith RD, Phillips GN Jr, Olson JS (1996) Mechanism of NO-induced oxidation of myoglobin and hemoglobin. Biochemistry 35(22):6976–6983

    Google Scholar 

  • Eike JH, Palmer AF (2004) Oxidized mono-, di-, tri-, and polysaccharides as potential hemoglobin cross-linking reagents for the synthesis of high oxygen affinity artificial blood substitutes. Biotechnol Prog 20(3):953–962

    Google Scholar 

  • Elmer J, Alam HB, Wilcox SR (2012) Hemoglobin-based oxygen carriers for hemorrhagic shock. Resuscitation 83(3):285–292

    Google Scholar 

  • Epstein CJ, Anfinsen CB (1962) The reversible reduction of disulfide bonds in trypsin and ribonuclease coupled to carboxymethyl cellulose. J Biol Chem 237:2175–2179

    Google Scholar 

  • Faggiano S, Ronda L, Bruno S, Jankevics H, Mozzarelli A (2010) Polymerized and polyethylene glycol-conjugated hemoglobins: a globin-based calibration curve for dynamic light scattering analysis. Anal Biochem 401(2):266–270

    Google Scholar 

  • Fronticelli C, Bucci E, Razynska A, Sznajder J, Urbaitis B, Gryczynski Z (1990) Bovine hemoglobin pseudo-crosslinked with mono(3,5-dibromosalicyl)-fumarate. Eur J Biochem 193(2):331–336

    Google Scholar 

  • Gourianov N, Kluger R (2003) Cross-linked bis-hemoglobins: connections and oxygen binding. J Am Chem Soc 125(36):10885–10892

    Google Scholar 

  • Hai TT, Nelson D, Pereira D, Srnak A (1994) Diaspirin crosslinked hemoglobin (DCLHb) polymerization. Artif Cells Blood Substit Immobil Biotechnol 22(3):923–931

    Google Scholar 

  • Hai TT, Pereira DE, Nelson DJ, Srnak A, Catarello J (1999) Polymerization of diaspirin cross-linked hemoglobin (DCLHb) with water-soluble, nonimmunogenic polyamide cross-linking agents. Bioconjug Chem 10(6):1013–1020

    Google Scholar 

  • Harrington JP, Wollocko J, Kostecki E, Wollocko H (2011) Physicochemical characteristics of OxyVita hemoglobin, a zero-linked polymer: liquid and powder preparations. Artif Cells Blood Substit Immobil Biotechnol 39(1):12–18

    Google Scholar 

  • Hsia CJ, Ma L (2012) A hemoglobin-based multifunctional therapeutic: polynitroxylated pegylated hemoglobin. Artif Organs 36(2):215–220

    Google Scholar 

  • Hu T, Prabhakaran M, Acharya SA, Manjula BN (2005) Influence of the chemistry of conjugation of poly (ethylene glycol) to Hb on the oxygen binding and solution properties of the PEG-Hb conjugate. Biochem J 392(Pt 3):555–564

    Google Scholar 

  • Hu T, Li D, Manjula BN, Acharya SA (2008) Autoxidation of the site-specifically PEGylated hemoglobins: role of the PEG chains and the sites of PEGylation in the autoxidation. Biochemistry 47(41):10981–10990

    Google Scholar 

  • Hu D, Kluger R (2008) Functional cross-linked hemoglobin bis-tetramers: geometry and cooperativity. Biochemistry 47(47):12551–12561

    Google Scholar 

  • Jahr JS, Akha AS, Holtby RJ (2012) Crosslinked, polymerized, and PEG-conjugated hemoglobin-based oxygen carriers: Clinical safety and efficacy of recent and current products. Curr Drug Discov Technol 9(3):158–165

    Google Scholar 

  • Jia Y, Wood F, Menu P, Faivre B, Caron A, Alayash AI (2004) Oxygen binding and oxidation reactions of human hemoglobin conjugated to carboxylate dextran. Biochim Biophys Acta 1672(3):164–173

    Google Scholar 

  • Jones MW, Strickland RA, Schumacher FF, Caddick S, Baker JR, Gibson MI, Haddleton DM (2012) Polymeric dibromomaleimides as extremely efficient disulfide bridging biconjugation and pegylation agents. J Am Chem Soc 134(3):1847–1852

    Google Scholar 

  • Kaul DK, Hebbel RP (2000) Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Invest 106(3):411–420

    Google Scholar 

  • Kaul DK, Liu XD, Zhang X, Ma L, Hsia CJ, Nagel RL (2006) Inhibition of sickle red cell adhesion and vasoocclusion in the microcirculation by antioxidants. Am J Physiol Heart Circ Physiol 291(1):H167–H175

    Google Scholar 

  • Keipert PE, Olofsson C, Winslow RM (2008) Hemoglobin-based blood substitutes and risk of myocardial infarction and death. JAMA 300(11):1295–1296

    Google Scholar 

  • Khan I, Dantsker D, Samuni U, Friedman AJ, Bonaventura C, Manjula B, Acharya SA, Friedman JM (2001) Beta 93 modified hemoglobin: kinetic and conformational consequences. Biochemistry 40(25):7581–7592

    Google Scholar 

  • Klett D, Grandgeorge M, Dellacherie E (1992) Fixation of aldehydic dextrans onto human deoxyhemoglobin. Biopolymers 32(5):517–522

    Google Scholar 

  • Kluger R, Zhang J (2003) Hemoglobin dendrimers: functional protein clusters. J Am Chem Soc 125(20):6070–6071

    Google Scholar 

  • Li D, Manjula BN, Acharya AS (2006) Extension arm facilitated PEGylation of hemoglobin: correlation of the properties with the extent of PEGylation. Protein J 25(4):263–274

    Google Scholar 

  • Li D, Manjula BN, Ho NT, Simplaceanu V, Ho C, Acharya AS (2007) Molecular aspects of the high oxygen affinity of non-hypertensive hexa pegylated hemoglobin, [(SP-PEG5 K)(6)-Hb]. Artif Cells Blood Substit Immobil Biotechnol 35(1):19–29

    Google Scholar 

  • Li D, Hu T, Manjula BN, Acharya SA (2008) Non-conservative surface decoration of hemoglobin: influence of neutralization of positive charges at PEGylation sites on molecular and functional properties of PEGylated hemoglobin. Biochim Biophys Acta 1784(10):1395–1401

    Google Scholar 

  • Lui FE, Kluger R (2009) Enhancing nitrite reductase activity of modified hemoglobin: bis-tetramers and their PEGylated derivatives. Biochemistry 48(50):11912–11919

    Google Scholar 

  • MacDonald SL, Pepper DS (1994) Hemoglobin polymerization. Methods Enzymol 231:287–308

    Google Scholar 

  • Mahaseth H, Vercellotti GM, Welch TE, Bowlin PR, Sonbol KM, Hsia CJ, Li M, Bischof JC, Hebbel RP, Belcher JD (2005) Polynitroxyl albumin inhibits inflammation and vasoocclusion in transgenic sickle mice. J Lab Clin Med 145(4):204–211

    Google Scholar 

  • Manjula BN, Smith PK, Malavalli A, Acharya AS (1995) Intramolecular cross-linking of oxy hemoglobin by bis sulfosuccinimidyl suberate and sebacate: generation of cross-linked hemoglobin with reduced oxygen affinity. Artif Cells Blood Substit Immobil Biotechnol 23(3):311–318

    Google Scholar 

  • Manjula BN, Malavalli A, Smith PK, Chan NL, Arnone A, Friedman JM, Acharya AS (2000) Cys-93-betabeta-succinimidophenyl polyethylene glycol 2000 hemoglobin A. Intramolecular cross bridging of hemoglobin outside the central cavity. J Biol Chem 275(8):5527–5534

    Google Scholar 

  • Manjula BN, Tsai A, Upadhya R, Perumalsamy K, Smith PK, Malavalli A, Vandegriff K, Winslow RM, Intaglietta M, Prabhakaran M, Friedman JM, Acharya AS (2003) Site-specific PEGylation of hemoglobin at Cys-93(β): Correlation between the colligative properties of the PEGylated protein and the length of the conjugated PEG chain. Bioconjug Chem 14(2):464–472

    Google Scholar 

  • Manjula BN, Tsai AG, Intaglietta M, Tsai CH, Ho C, Smith PK, Perumalsamy K, Kanika ND, Friedman JM, Acharya SA (2005) Conjugation of multiple copies of polyethylene glycol to hemoglobin facilitated through thiolation: influence on hemoglobin structure and function. Protein J 24(3):133–146

    Google Scholar 

  • Matheson B, Kwansa HE, Bucci E, Rebel A, Koehler RC (2002) Vascular response to infusions of a nonextravasating hemoglobin polymer. J Appl Physiol 93(4):1479–1486

    Google Scholar 

  • Marini M, Moore G, Fishman R, Jesse R, Medina F, Snell S et al (1989) A critical examination of the reaction of pyridoxal 5-phosphate with human hemoglobin A0. Biopolymers 28:2071–2083

    Google Scholar 

  • McCarthy MR, Vandegriff KD, Winslow RM (2001) The role of facilitated diffusion in oxygen transport by cell-free hemoglobins: implications for the design of hemoglobin-based oxygen carriers. Biophys Chem 92(1–2):103–117

    Google Scholar 

  • Menu P, Faivre B, Labrude P, Riffard P, Grandgeorge M, Vigneron C (1994) Human hemoglobin conjugated to carboxylate dextran as a potential red blood cell substitute. II–Pharmacotoxicological evaluation. Artif Cells Blood Substit Immobil Biotechnol 22(3):543–549

    Google Scholar 

  • Miralles G, Verdié P, Puget K, Maurras A, Martinez J, Subra G (2013) Microwave-mediated reduction of disulfide bridges with supported (Tris(2- carboxyethyl)phosphine) as resin-bound reducing agent. ACS Comb Sci 15(4):169–173

    Google Scholar 

  • Mito T, Nemoto M, Kwansa H, Sampei K, Habeeb M, Murphy SJ, Bucci E, Koehler RC (2009) Decreased damage from transient focal cerebral ischemia by transfusion of zero-link hemoglobin polymers in mouse. Stroke 40(1):278–284

    Google Scholar 

  • Nho K, Linberg R, Johnson M, Gilbert C, Shorr R (1994) PEG-hemoglobin: an efficient oxygen-delivery system in the rat exchange transfusion and hypovolemic shock models. Artif Cells Blood Substit Immobil Biotechnol 22(3):795–803

    Google Scholar 

  • Olofsson C, Nygårds EB, Ponzer S, Fagrell B, Przybelski R, Keipert PE, Winslow N, Winslow RM (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(1):28–39

    Google Scholar 

  • Payne J (1973) Polymerization of proteins with glutaraldehyde Soluble molecular-weight markers. Biochem J 135:867–873

    Google Scholar 

  • Portöro I, Kocsis L, Hermán P, Caccia D, Perrella M, Ronda L, Bruno S, Bettati S, Micalella C, Mozzarelli A, Varga A, Vas M, Lowe KC, Eke A (2008) Towards a novel haemoglobin-based oxygen carrier: Euro-PEG-Hb, physico-chemical properties, vasoactivity and renal filtration. Biochim Biophys Acta 1784(10):1402–1409

    Google Scholar 

  • Quellec P, Léonard M, Grandgeorge M, Dellacherie E (1994) Human hemoglobin conjugated to carboxylate dextran as a potential red blood cell substitute. I. Further physico-chemical characterization. Artif Cells Blood Substit Immobil Biotechnol 22(3):669–676

    Google Scholar 

  • Razack S, D’Agnillo F, Chang TM (1997) Crosslinked hemoglobin-superoxide dismutase-catalase scavenges free radicals in a rat model of intestinal ischemia-reperfusion injury. Artif Cells Blood Substit Immobil Biotechnol 25(1–2):181–192

    Google Scholar 

  • Salazar Vázquez BY, Wettstein R, Cabrales P, Tsai AG, Intaglietta M (2008) Microvascular experimental evidence on the relative significance of restoring oxygen carrying capacity vs. blood viscosity in shock resuscitation. Biochim Biophys Act 1784(10):1421–1427

    Google Scholar 

  • Sampei K, Ulatowski JA, Asano Y, Kwansa H, Bucci E, Koehler RC (2005) Role of nitric oxide scavenging in vascular response to cell-free hemoglobin transfusion. Am J Physiol Heart Circ Physiol 289(3):H1191–H1201

    Google Scholar 

  • Savoca KV, Abuchowski A, van Es T, Davis FF, Palczuk NC (1979) Preparation of a non-immunogenic arginase by the covalent attachment of polyethylene glycol. Biochim Biophys Acta 578(1):47–53

    Google Scholar 

  • Scatena R, Giardina B (2001) O-raffinose-polymerised haemoglobin. A biochemical and pharmacological profile of an oxygen carrier. Expert Opin Biol Ther 1(1):121–127

    Google Scholar 

  • Scurtu F, Zolog O, Iacob B, Silaghi-Dumitrescu R. Hemoglobin-albumin cross-linking with disuccinimidyl suberate (DSS) and/or glutaraldehyde for blood substitutes. Artif Cells Nanomed Biotechnol. 2013 Jan 23. [Epub ahead of print]

    Google Scholar 

  • Sriram K, Tsai AG, Cabrales P, Meng F, Acharya SA, Tartakovsky DM, Intaglietta M (2012) PEG-albumin supraplasma expansion is due to increased vessel wall shear stress induced by blood viscosity shear thinning. Am J Physiol Heart Circ Physiol 302(12):H2489–H2497

    Google Scholar 

  • Styslinger TJ, Zhang N, Bhatt VS, Pettit N, Palmer AF, Wang PG (2012) Site-selective glycosylation of hemoglobin with variable molecular weight oligosaccharides: potential alternative to PEGylation. J Am Chem Soc 134(17):7507–7515

    Google Scholar 

  • Tarasov E, Blaszak MM, LaMarre JM, Olsen KW (2007) Synthesis of a hemoglobin polymer containing antioxidant enzymes using complementary chemistry of maleimides and sulfhydryls. Artif Cells Blood Substit Immobil Biotechnol 35(1):31–43

    Google Scholar 

  • Tsai AG, Friesenecker B, McCarthy M, Sakai H, Intaglietta M (1998) Plasma viscosity regulates capillary perfusion during extreme hemodilution in hamster skinfold model. Am J Physiol 275(6 Pt 2):H2170–H2180

    Google Scholar 

  • Tsai AG, Intaglietta M (2002) The unusual properties of effective blood substitutes. Keio J Med 51(1):17–20

    Google Scholar 

  • Tsai AG, Vandegriff KD, Intaglietta M, Winslow RM (2003) Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics. Am J Physiol Heart Circ Physiol 285(4):H1411–H1419

    Google Scholar 

  • Vandegriff KD, McCarthy M, Rohlfs RJ, Winslow RM (1997) Colloid osmotic properties of modified hemoglobins: chemically cross-linked versus polyethylene glycol surface-conjugated. Biophys Chem 69(1):23–30

    Google Scholar 

  • Vandegriff KD, Malavalli A, Wooldridge J, Lohman J, Winslow RM (2003) MP4, a new nonvasoactive PEG-Hb conjugate. Transfusion 43(4):509–516

    Google Scholar 

  • Vandegriff KD, Young MA, Lohman J, Bellelli A, Samaja M, Malavalli A, Winslow RM (2008a) CO-MP4, a polyethylene glycol-conjugated haemoglobin derivative and carbon monoxide carrier that reduces myocardial infarct size in rats. Br J Pharmacol 154(8):1649–1661

    Google Scholar 

  • Vandegriff KD, Malavalli A, Mkrtchyan GM, Spann SN, Baker DA, Winslow RM (2008b) Sites of modification of hemospan, a poly (ethylene glycol)-modified human hemoglobin for use as an oxygen therapeutic. Bioconjug Chem 19(11):2163–2170

    Google Scholar 

  • Vasseur-Godbillon C, Sahu SC, Domingues E, Fablet C, Giovannelli JL, Tam TC, Ho NT, Ho C, Marden MC, Baudin-Creuza V (2006) Recombinant hemoglobin βG83C-F41Y. FEBS J 273(1):230–241

    Google Scholar 

  • Walder RY, Andracki ME, Walder JA (1994) Preparation of intramolecularly cross-linked hemoglobins. Methods Enzymol 231:274–280

    Google Scholar 

  • Winslow RM (2000) αα-crosslinked hemoglobin: was failure predicted by preclinical testing? Vox Sang 79(1):1–20

    Google Scholar 

  • Winslow RM (2003) Current status of blood substitute research: towards a new paradigm. J Intern Med 253(5):508–517

    Google Scholar 

  • Winslow RM (2006) Current status of oxygen carriers (‘blood substitutes’): 2006. Vox Sang 91(2):102–110

    Google Scholar 

  • Winslow RM (2008) Cell-free oxygen carriers: scientific foundations, clinical development, and new directions. Biochim Biophys Acta 1784(10):1382–1386

    Google Scholar 

  • Wong JT (1988) Rightshifted dextran-hemoglobin as blood substitute. Biomater Artif Cells Artif Organs 16(1–3):237–245

    Google Scholar 

  • Yabuki A, Yamaji K, Ohki H, Iwashita Y (1990) Characterization of a pyridoxalated hemoglobin-polyoxyethylene conjugate as a physiologic oxygen carrier. Transfusion 30(6):516–520

    Google Scholar 

  • Young MA, Malavalli A, Winslow N, Vandegriff KD, Winslow RM (2007) Toxicity and hemodynamic effects after single dose administration of Mal PEG-hemoglobin (MP4) in rhesus monkeys. Transl Res 149(6):333–342

    Google Scholar 

  • Zhang N, Palmer AF (2010) Polymerization of human hemoglobin using the crosslinker 1,11-bis(maleimido)triethylene glycol for use as an oxygen carrier. Biotechnol Prog 26(5):1481–1485

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medicine and of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA

    Seetharama A. Acharya & Fantao Meng

  2. Department Bioengineering, University of California, San Diego, La Jolla, CA, USA

    Marcos Intaglietta & Amy G. Tsai

Authors
  1. Seetharama A. Acharya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcos Intaglietta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amy G. Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fantao Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seetharama A. Acharya .

Editor information

Editors and Affiliations

  1. Brown University, Barrington, Rhode Island, USA

    Hae Won Kim

  2. Brown University, Barrington, Rhode Island, USA

    A. Gerson Greenburg

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Acharya, S.A., Intaglietta, M., Tsai, A.G., Meng, F. (2013). Design of Nonhypertensive Conjugated Hemoglobins as Novel Resuscitation Fluids. In: Kim, H., Greenburg, A. (eds) Hemoglobin-Based Oxygen Carriers as Red Cell Substitutes and Oxygen Therapeutics. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40717-8_11

Download citation

Publish with us

Policies and ethics

Search

Navigation