Abstract

Hemoglobin-based oxygen carriers (HBOCs) were developed with the aim of substituting transfusions in emergency events. However, they exhibit adverse events, such as nitric oxide (NO) scavenging, vasoactivity, enhanced platelet aggregation, presently hampering their clinical application. The impact of two prototypical PEGylated HBOCs, Euro-PEG-Hb and PEG-HbO2, endowed by different oxygen affinities and hydrodynamic volumes, was assessed on the cerebrocortical parenchymal microhemodynamics, and extravasation through the blood-brain-barrier (BBB) by laser speckle contrast imaging (LSCI) method and near-infrared (NIR) imaging, respectively. By evaluating voxel-wise cerebrocortical red blood cell velocity, non-invasively for its mean kernel-wise value (${\overline{\textrm{v}} _{\textrm{RBC}}}$), and model-derived kernel-wise predictions for microregional tissue hematocrit, THt, and fractional change in hematocrit-corrected vascular resistance, R’, as measures of potential adverse effects (enhanced platelet aggregation and vasoactivity, respectively) we found i) no significant difference between tested HBOCs in the systemic and microregional parameters, and in the relative spatial dispersion of THt, and R’ as additional measures of HBOC-related adverse effects, and ii) no extravasation through BBB by Euro-PEG-Hb. We conclude that Euro-PEG-Hb does not exhibit adverse effects in the brain microcirculation that could be directly attributed to NO scavenging.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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2018 (1)

E. Alomari, L. Ronda, and S. Bruno, “Hemoglobin-based oxygen carriers: Differential oxidative stress in a Guinea pig transfusion model,” Free Radical Biol. Med. 124, 299–310 (2018).
[Crossref]

2017 (2)

L. Terraneo, P. Bianciardi, A. Malavalli, G. Mkrtchyan, S. N. Spann, J. Lohman, M. Samaja, and K. D. Vandegriff, “Hemoglobin extravasation in the brain of rats exchange-transfused with hemoglobin-based oxygen carriers,” Artif. Cells, Nanomed., Biotechnol. 45(4), 710–716 (2017).
[Crossref]

I. G. Gould, P. Tsai, D. Kleinfeld, and A. Linninger, “The capillary bed offers the largest hemodynamic resistance to the cortical blood supply,” J. Cereb. Blood Flow Metab. 37(1), 52–68 (2017).
[Crossref]

2016 (2)

Z. D. Qiu, G. Deng, J. Yang, Z. Min, D. Y. Li, Y. Fang, and S. M. Zhang, “A new method for evaluating regional cerebral blood flow changes: Laser speckle contrast imaging in a C57BL/6J mouse model of photothrombotic ischemia,” J. Huazhong Univ. Sci. Technol., Med. Sci. 36(2), 174–180 (2016).
[Crossref]

P. G. Vaz, A. Humeau-Heurtier, E. Figueiras, C. Correia, and J. Cardoso, “Laser Speckle Imaging to Monitor Microvascular Blood Flow: A Review,” IEEE Rev. Biomed. Eng. 9, 106–120 (2016).
[Crossref]

2015 (1)

D. D. Postnov, O. Sosnovtseva, and V. V. Tuchin, “Improved detectability of microcirculatory dynamics by laser speckle flowmetry,” J. Biophotonics 8(10), 790–794 (2015).
[Crossref]

2014 (4)

A. F. Palmer and M. Intaglietta, “Blood Substitutes,” Annu. Rev. Biomed. Eng. 16(1), 77–101 (2014).
[Crossref]

K. Roghani, R. Holtby, and J. Jahr, “Effects of Hemoglobin-Based Oxygen Carriers on Blood Coagulation,” J. Funct. Biomater. 5(4), 288–295 (2014).
[Crossref]

N. Procter, C. Chong, A. Sverdlov, W. Chan, Y. Chirkov, and J. Horowitz, “Aging of platelet nitric oxide signaling: pathogenesis, clinical implications, and therapeutics,” Semin. Thromb. Hemostasis 40(06), 660–668 (2014).
[Crossref]

A. Alayash, “Blood substitutes: why haven't we been more successful?” Trends Biotechnol. 32(4), 177–185 (2014).
[Crossref]

2013 (2)

R. Liu, J. Qin, and R. K. Wang, “Motion-contrast laser speckle imaging of microcirculation within tissue beds in vivo,” J. Biomed. Opt. 18(6), 060508 (2013).
[Crossref]

A. Linninger, I. Gould, T. Marinnan, C. Hsu, A. Alaraj, and M. Chojecki, “Cerebral microcirculation and oxygen tension in the human secondary cortex,” Ann. Biomed. Eng. 41(11), 2264–2284 (2013).
[Crossref]

2012 (3)

A. Y. Shih, J. D. Driscoll, P. J. Drew, N. Nishimura, C. B. Schaffer, and D. Kleinfeld, “Two-photon microscopy as a tool to study blood flow and neurovascular coupling in the rodent brain,” J. Cereb. Blood Flow Metab. 32(7), 1277–1309 (2012).
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A. M. Walker, K. Lee, G. M. Dobson, and C. R. Johnston, “The viscous behaviour of HES 130/0.4 (Voluven®) and HES 260/0.45 (Pentaspan®),” Can J Anesth 59(3), 288–294 (2012).
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W. Zhang, K. Yan, P. Dai, J. Tian, H. Zhu, and C. Chen, “A novel hemoglobin-based oxygen carrier, polymerized porcine hemoglobin, inhibits H(2)O(2)-induced cytotoxicity of endothelial cells,” Artif. Organs 36(2), 151–160 (2012).
[Crossref]

2011 (2)

D. Buerk, K. Barbee, and D. Jaron, “Nitric oxide signaling in the microcirculation,” Crit Rev Biomed Eng 39(5), 397–433 (2011).
[Crossref]

A. R. Pries and T. W. Secomb, “Blood Flow in Microvascular Networks,” Compr Physiol 9, 3–36 (2011).
[Crossref]

2010 (2)

D. A. Boas and A. K. Dunn, “Laser speckle contrast imaging in biomedical optics,” J. Biomed. Opt. 15(1), 011109 (2010).
[Crossref]

A. Mozzarelli, L. Ronda, S. Faggiano, S. Bettati, and S. Bruno, “Haemoglobin-based oxygen carriers: research and reality towards an alternative to blood transfusions,” Blood Transfusion = Trasfusione del Sangue 8(Suppl 3), s59–68 (2010).
[Crossref]

2009 (5)

B. Yu, K. D. Bloch, and W. M. Zapol, “Hemoglobin-based red blood cell substitutes and nitric oxide,” Trends Cardiovasc. Med. 19(3), 103–107 (2009).
[Crossref]

B. Allen, J. Stamler, and C. Piantadosi, “Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation,” Trends Mol. Med. 15(10), 452–460 (2009).
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H. W. Kim, C. M. Hai, and A. G. Greenburg, “Acellular Hemoglobin-Based Oxygen Carrier Induced Vasoactivity: a Brief Review of Potential Pharmacologic Remedies,” Artificial Blood 147, 713–733 (2009).
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M. Moallempour, J. Jahr, J. Lim, D. Weeks, A. Butch, and B. Driessen, “Methemoglobin effects on coagulation: a dose-response study with HBOC-200 (Oxyglobin) in a thrombelastogram model,” J. Cardiothorac. Vasc. Anesth. 23(1), 41–47 (2009).
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D. Caccia, L. Ronda, R. Frassi, M. Perrella, E. Del Favero, S. Bruno, B. Pioselli, S. Abbruzzetti, C. Viappiani, and A. Mozzarelli, “PEGylation promotes hemoglobin tetramer dissociation,” Bioconjugate Chem. 20(7), 1356–1366 (2009).
[Crossref]

2008 (3)

C. Stowell, “Blood substitutes: time for a deep breath,” Transfusion 48(4), 574–575 (2008).
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I. Portoro, L. Kocsis, P. Herman, D. Caccia, M. Perrella, L. Ronda, S. Bruno, S. Bettati, C. Micalella, A. Mozzarelli, A. Varga, M. Vas, K. C. Lowe, and A. Eke, “Towards a novel haemoglobin-based oxygen carrier: Euro-PEG-Hb, physico-chemical properties, vasoactivity and renal filtration,” Biochim. Biophys. Acta, Proteins Proteomics 1784(10), 1402–1409 (2008).
[Crossref]

P. Buehler and A. Alayash, “All hemoglobin-based oxygen carriers are not created equally,” Biochim Biophys Acta 1784, 1378–1381 (2008).
[Crossref]

2006 (4)

A. Tsai, P. Cabrales, B. Manjula, S. Acharya, R. Winslow, and M. Intaglietta, “Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers,” Blood 108(10), 3603–3610 (2006).
[Crossref]

P. Herman and A. Eke, “Nonlinear analysis of blood cell flux fluctuations in the rat brain cortex during stepwise hypotension challenge,” J. Cereb. Blood Flow Metab. 26(9), 1189–1197 (2006).
[Crossref]

P. Herman and A. Eke, “Nonlinear analysis of blood cell flux fluctuations in the rat brain cortex during stepwise hypotension challenge,” J. Cereb. Blood Flow Metab. 26(9), 1189–1197 (2006).
[Crossref]

L. Kocsis, P. Herman, and A. Eke, “Mathematical model for the estimation of hemodynamic and oxygenation variables by tissue spectroscopy,” J. Theor. Biol. 241(2), 262–275 (2006).
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2005 (5)

H. Lipowsky, “Microvascular Rheology and Hemodynamics,” Microcirculation 12(1), 5–15 (2005).
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M. A. Young, L. Riddez, B. T. Kjellström, J. Bursell, F. Winslow, J. Lohman, and R. M. Winslow, “MalPEG-hemoglobin (MP4) improves hemodynamics, acid-base status, and survival after uncontrolled hemorrhage in anesthetized swine,” Crit. Care Med. 33(8), 1794–1804 (2005).
[Crossref]

A. R. Pries and T. W. Secomb, “Microvascular blood viscosity in vivo and the endothelial surface layer,” American journal of physiology. Heart and circulatory physiology 289(6), H2657–H2664 (2005).
[Crossref]

A. G. Tsai, C. Acero, P. R. Nance, P. Cabrales, J. A. Frangos, D. G. Buerk, and M. Intaglietta, “Elevated plasma viscosity in extreme hemodilution increases perivascular nitric oxide concentration and microvascular perfusion,” Am J Physiol Heart Circ Physiol 288(4), H1730–H1739 (2005).
[Crossref]

R. Rother, L. Bell, P. Hillmen, and M. Gladwin, “The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease,” JAMA 293(13), 1653–1662 (2005).
[Crossref]

2004 (3)

J. Olson, E. Foley, C. Rogge, A. Tsai, M. Doyle, and D. Lemon, “No scavenging and the hypertensive effect of hemoglobin-based blood substitutes,” Free Radical Biol. Med. 36(6), 685–697 (2004).
[Crossref]

M. Gladwin, J. Crawford, and R. Patel, “The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation,” Free Radical Biol. Med. 36(6), 707–717 (2004).
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M. Kavdia and A. S. Popel, “Contribution of nNOS-and eNOS-derived NO to microvascular smooth muscle NO exposure,” J. Appl. Physiol. 97(1), 293–301 (2004).
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2003 (4)

O. YIldirim, “Changes in nitric oxide level of different tissues in diabetic rats,” Biotechnol. Biotechnol. Equip. 17(1), 131–135 (2003).
[Crossref]

U. Windberger, A. Bartholovitsch, R. Plasenzotti, K. J. Korak, and G. Heinze, “Whole blood viscosity, plasma viscosity and erythrocyte aggregation in nine mammalian species: reference values and comparison of data,” Exp Physiol 88(3), 431–440 (2003).
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A. G. Tsai, K. D. Vandegriff, M. Intaglietta, and R. M. Winslow, “Targeted O2 delivery by low-P50 hemoglobin: a new basis for O2 therapeutics,” Am J Physiol Heart Circ Physiol 285(4), H1411–H1419 (2003).
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K. D. Vandegriff, A. Malavalli, J. Wooldridge, J. Lohman, and R. M. Winslow, “MP4, a new nonvasoactive PEG-Hb conjugate,” Transfusion 43(4), 509–516 (2003).
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2002 (3)

M. Feelisch, T. Rassaf, S. Mnaimneh, N. Singh, N. Bryan, D. Jourd’Heuil, and M. Kelm, “Concomitant S-, N-, and heme-nitros(yl)ation in biological tissues and fluids: implications for the fate of NO in vivo,” FASEB J. 16(13), 1775–1785 (2002).
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L. Baumane, M. Dzintare, L. Zvejniece, D. Meirena, L. Lauberte, V. Sile, I. Kalvinsh, and N. Sjakste, “Increased synthesis of nitric oxide in rat brain cortex due to halogenated volatile anesthetics confirmed by EPR spectroscopy,” Acta Anaesthesiol. Scand. 46(4), 378–383 (2002).
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S. Kashiwagi, M. Kajimura, Y. Yoshimura, and M. Suematsu, “Nonendothelial source of nitric oxide in arterioles but not in venules: alternative source revealed in vivo by diaminofluorescein microfluorography,” Circ. Res. 91(12), e55–64 (2002).
[Crossref]

2001 (5)

W. Alderton, C. Cooper, and R. Knowles, “Nitric oxide synthases: structure, function and inhibition,” Biochem. J. 357(3), 593–615 (2001).
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D. D. Thomas, X. Liu, S. P. Kantrow, and J. R. Lancaster, “The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2,” Proc. Natl. Acad. Sci. 98(1), 355–360 (2001).
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M. Dzintare, L. Baumane, D. Meirena, L. Lauberte, I. Kalvinsh, and N. Sjakste, “Nitric oxide production in different organs of intact white rats,” Baltic J. Lab. Anim. Sci 11, 218–224 (2001).

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab. 21(3), 195–201 (2001).
[Crossref]

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab. 21(3), 195–201 (2001).
[Crossref]

2000 (2)

A. R. Pries, T. W. Secomb, and P. Gaehtgens, “The endothelial surface layer,” Pfluegers Arch. 440(5), 653–666 (2000).
[Crossref]

L. Brown, B. Key, and T. Lovick, “Fluorescent imaging of nitric oxide production in neuronal varicosities associated with intraparenchymal arterioles in rat hippocampal slices,” Neurosci. Lett. 294(1), 9–12 (2000).
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1999 (2)

J. W. Denninger and M. A. Marletta, “Guanylate cyclase and the⋅ NO/cGMP signaling pathway,” Biochim. Biophys. Acta, Bioenerg. 1411(2-3), 334–350 (1999).
[Crossref]

A. Alayash, “Hemoglobin-based blood substitutes: oxygen carriers, pressor agents, or oxidants?” Nat. Biotechnol. 17(6), 545–549 (1999).
[Crossref]

1998 (7)

G.-R. Wang, Y. Zhu, P. V. Halushka, T. M. Lincoln, and M. E. Mendelsohn, “Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase,” Proc. Natl. Acad. Sci. 95(9), 4888–4893 (1998).
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X. Liu, M. J. S. Miller, M. S. Joshi, H. Sadowska-Krowicka, D. A. Clark, and J. R. Lancaster, “Diffusion-limited reaction of nitric oxide with erythrocytes,” J. Biol. Chem. 273(30), 18709–18713 (1998).
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D. H. Doherty, M. P. Doyle, S. R. Curry, R. J. Vali, T. J. Fattor, J. S. Olson, and D. D. Lemon, “Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin,” Nat. Biotechnol. 16(7), 672–676 (1998).
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A. R. Pries, T. W. Secomb, M. Sperandio, and P. Gaehtgens, “Blood flow resistance during hemodilution: Effect of plasma composition,” Cardiovasc. Res. 37(1), 225–235 (1998).
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Y. Asano, R. C. Koehler, J. A. Ulatowski, R. J. Traystman, and E. Bucci, “Effect of cross-linked hemoglobin Transfusion on endothelial-dependent dilation in cat pial arterioles,” Am J Physiol 275(3), C669–C674 (1998).
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B. Goins, R. Klipper, C. Martin, P. Jerabek, S. Khalvati, P. T. Fox, C. R. O. V. Kwasiborski, A. S. Rudolph, and W. T. Phillips, “Use of oxygen-15-labeled molecular oxygen for oxygen delivery studies of blood and blood substitutes,” Adv Exp Med Biol 454, 643–652 (1998).
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J. A. Ulatowski, E. Bucci, A. Razynska, R. J. Traystman, R. C. Koehler, A. John, and R. C. K. Cere, “Cerebral blood flow during hypoxic hypoxia with plasma-based hemoglobin at reduced hematocrit,” Am J Physiol Heart Circ Physiol 274(6), H1933–H1942 (1998).
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1997 (3)

W. T. Phillips, L. Lemen, B. Goins, A. S. Rudolph, R. Klipper, D. Fresne, P. A. Jerabek, M. E. Emch, C. Martin, P. T. Fox, and C. A. McMahan, “Use of oxygen-15 to measure oxygen-carrying capacity of blood substitutes in vivo,” Am J Physiol Heart Circ Physiol 272(5), H2492–H2499 (1997).
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A. Eke, P. Herman, J. Bassingthwaighte, G. Raymond, I. Balla, and C. Ikrenyi, “Temporal fluctuations in regional red blood cell flux in the rat brain cortex is a fractal process,” Adv Exp Med Biol 428, 703–709 (1997).
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H. Kim and A. Greenburg, “Ferrrous hemoglobin scavenging of endothelium derived nitric oxide is a principal mechanism for hemoglobin mediated vasoactivities in isolated rat thoracic aorta,” Artif. Cells, Blood Substitutes, Biotechnol. 25(1-2), 121–133 (1997).
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1996 (1)

A. Pries, T. Secomb, and P. Gaehtgens, “Biophysical aspects of blood flow in the microvasculature,” Cardiovasc Res. 32(4), 654–667 (1996).
[Crossref]

1995 (1)

P. F. Davies, “Flow-mediated endothelial mechanotransduction,” Physiol. Rev. 75(3), 519–560 (1995).
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1994 (1)

D. Bredt and S. Snyder, “Nitric oxide: a physiologic messenger molecule,” Annu. Rev. Biochem. 63(1), 175–195 (1994).
[Crossref]

1993 (1)

H. Koenig, D. Pelligrino, and R. Albrecht, “Halothane vasodilation,” J Neurosurg Anesth 5(4), 264–271 (1993).
[Crossref]

1992 (2)

A. R. Pries, D. Neuhaus, and P. Gaehtgens, “Blood viscosity in tube flow: dependence on diameter and hematocrit.,” Am J Physiol Heart Circ Physiol 263(6), H1770–H1778 (1992).
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M. M. Todd, J. B. Weeks, and D. S. Warner, “Cerebral blood flow, blood volume, and brain tissue hematocrit during isovolemic hemodilution with hetastarch in rats,” Am J Physiol Heart Circ Physiol 263(1), H75–H82 (1992).
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1991 (2)

P. Kubes, M. Suzuki, and D. Granger, “Nitric oxide: an endogenous modulator of leukocyte adhesion,” Proc. Natl. Acad. Sci. 88(11), 4651–4655 (1991).
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S. Moncada, R. M. Palmer, and E. A. Higgs, “Nitric oxide: physiology, pathophysiology, and pharmacology,” Pharmacol Rev 43, 109–142 (1991).

1990 (2)

C. Desjardins and B. R. Duling, “Heparinase treatment suggests a role for the endothelial cell glycocalyx in regulation of capillary hematocrit.,” Am J Physiol Heart Circ Physiol 258(3), H647–H654 (1990).
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A. Pries, T. W. Secomb, P. Gaehtgens, and J. F. Gross, “Blood flow in microvascular networks: Experiments and simulation,” Circ. Res. 67(4), 826–834 (1990).
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1988 (1)

J. M. Sneddon and J. R. Vane, “Endothelium-derived relaxing factor reduces platelet adhesion to bovine endothelial cells,” Proc. Natl. Acad. Sci. 85(8), 2800–2804 (1988).
[Crossref]

1987 (3)

M. Radomski, R. Palmer, and S. Moncada, “Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium,” Lancet 330(8567), 1057–1058 (1987).
[Crossref]

R. M. Palmer, A. G. Ferrige, and S. Moncada, “Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor,” Nature 327(6122), 524–526 (1987).
[Crossref]

C. Desjardins and B. R. Duling, “Microvessel hematocrit: measurement and implications for capillary oxygen transport,” Am J Physiol Heart Circ Physiol 252(3), H494–H503 (1987).
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1985 (1)

L. Ditenfass, “Red cell aggregation in cardiovascular diseases and crucial role of inversion phenomenon,” Angiology 36(5), 315–326 (1985).
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1982 (1)

H. R. Weiss, E. Buchweitz, T. J. Murtha, and M. Auletta, “Quantitative Regional Determination of Morphometric Indices of the Total and Perfused Capillary Network in the Rat Brain,” Circ. Res. 51(4), 494–503 (1982).
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1979 (2)

K. Albrecht, P. Gaehtgens, A. Pries, and M. Heuser, “The Fahraeus effect in narrow capillaries (i.d. 3.3 to 11.0 micrometer),” Microvasc. Res. 18(1), 33–47 (1979).
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A. Eke, G. Hutiray, and A. G. Kovach, “Induced hemodilution detected by reflectometry for measuring microregional blood flow and blood volume in cat brain cortex,” Am J Physiol-Heart C 236(5), H759–H768 (1979).
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1968 (1)

H. Schmid-Schönbein, P. Gaehtgens, and H. Hirsch, “On the shear rate dependence of red cell aggregation in vitro,” J. Clin. Invest. 47(6), 1447–1454 (1968).
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1967 (1)

H. Nagashima, “Studies on Blood Viscosity During,” Nagoya J Med Sci 31, 25–50 (1967).

1964 (1)

L. Ditenfass, “Viscosity and clotting of blood in venous thrombosis and coronary occlusions,” Circ. Res. 14(1), 1–16 (1964).
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1963 (1)

L. Ditenfass, “Blood rheology in cardio-vascular disease,” Nature 4895, 813–815 (1963).

1929 (1)

R. Fahraeus, “The suspension stability of blood,” Physiol. Rev. 9(2), 241–274 (1929).
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1928 (1)

R. Fahraeus, “Die Strömungsverhältnisse und die Vertailung der Blutzellen in Gefässsystem. Zur Frage der Bedeutung der intra-vaskulären Erythrozytenaggregation,” Klin. Wochenschr. 7(3), 100–106 (1928).
[Crossref]

Abbruzzetti, S.

D. Caccia, L. Ronda, R. Frassi, M. Perrella, E. Del Favero, S. Bruno, B. Pioselli, S. Abbruzzetti, C. Viappiani, and A. Mozzarelli, “PEGylation promotes hemoglobin tetramer dissociation,” Bioconjugate Chem. 20(7), 1356–1366 (2009).
[Crossref]

Acero, C.

A. G. Tsai, C. Acero, P. R. Nance, P. Cabrales, J. A. Frangos, D. G. Buerk, and M. Intaglietta, “Elevated plasma viscosity in extreme hemodilution increases perivascular nitric oxide concentration and microvascular perfusion,” Am J Physiol Heart Circ Physiol 288(4), H1730–H1739 (2005).
[Crossref]

Acharya, S.

A. Tsai, P. Cabrales, B. Manjula, S. Acharya, R. Winslow, and M. Intaglietta, “Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers,” Blood 108(10), 3603–3610 (2006).
[Crossref]

Alaraj, A.

A. Linninger, I. Gould, T. Marinnan, C. Hsu, A. Alaraj, and M. Chojecki, “Cerebral microcirculation and oxygen tension in the human secondary cortex,” Ann. Biomed. Eng. 41(11), 2264–2284 (2013).
[Crossref]

Alayash, A.

A. Alayash, “Blood substitutes: why haven't we been more successful?” Trends Biotechnol. 32(4), 177–185 (2014).
[Crossref]

P. Buehler and A. Alayash, “All hemoglobin-based oxygen carriers are not created equally,” Biochim Biophys Acta 1784, 1378–1381 (2008).
[Crossref]

A. Alayash, “Hemoglobin-based blood substitutes: oxygen carriers, pressor agents, or oxidants?” Nat. Biotechnol. 17(6), 545–549 (1999).
[Crossref]

Albrecht, K.

K. Albrecht, P. Gaehtgens, A. Pries, and M. Heuser, “The Fahraeus effect in narrow capillaries (i.d. 3.3 to 11.0 micrometer),” Microvasc. Res. 18(1), 33–47 (1979).
[Crossref]

Albrecht, R.

H. Koenig, D. Pelligrino, and R. Albrecht, “Halothane vasodilation,” J Neurosurg Anesth 5(4), 264–271 (1993).
[Crossref]

Alderton, W.

W. Alderton, C. Cooper, and R. Knowles, “Nitric oxide synthases: structure, function and inhibition,” Biochem. J. 357(3), 593–615 (2001).
[Crossref]

Allen, B.

B. Allen, J. Stamler, and C. Piantadosi, “Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation,” Trends Mol. Med. 15(10), 452–460 (2009).
[Crossref]

Alomari, E.

E. Alomari, L. Ronda, and S. Bruno, “Hemoglobin-based oxygen carriers: Differential oxidative stress in a Guinea pig transfusion model,” Free Radical Biol. Med. 124, 299–310 (2018).
[Crossref]

Asano, Y.

Y. Asano, R. C. Koehler, J. A. Ulatowski, R. J. Traystman, and E. Bucci, “Effect of cross-linked hemoglobin Transfusion on endothelial-dependent dilation in cat pial arterioles,” Am J Physiol 275(3), C669–C674 (1998).
[Crossref]

Auletta, M.

H. R. Weiss, E. Buchweitz, T. J. Murtha, and M. Auletta, “Quantitative Regional Determination of Morphometric Indices of the Total and Perfused Capillary Network in the Rat Brain,” Circ. Res. 51(4), 494–503 (1982).
[Crossref]

Balla, I.

A. Eke, P. Herman, J. Bassingthwaighte, G. Raymond, I. Balla, and C. Ikrenyi, “Temporal fluctuations in regional red blood cell flux in the rat brain cortex is a fractal process,” Adv Exp Med Biol 428, 703–709 (1997).
[Crossref]

Barbee, K.

D. Buerk, K. Barbee, and D. Jaron, “Nitric oxide signaling in the microcirculation,” Crit Rev Biomed Eng 39(5), 397–433 (2011).
[Crossref]

Bartholovitsch, A.

U. Windberger, A. Bartholovitsch, R. Plasenzotti, K. J. Korak, and G. Heinze, “Whole blood viscosity, plasma viscosity and erythrocyte aggregation in nine mammalian species: reference values and comparison of data,” Exp Physiol 88(3), 431–440 (2003).
[Crossref]

Bassingthwaighte, J.

A. Eke, P. Herman, J. Bassingthwaighte, G. Raymond, I. Balla, and C. Ikrenyi, “Temporal fluctuations in regional red blood cell flux in the rat brain cortex is a fractal process,” Adv Exp Med Biol 428, 703–709 (1997).
[Crossref]

Baumane, L.

L. Baumane, M. Dzintare, L. Zvejniece, D. Meirena, L. Lauberte, V. Sile, I. Kalvinsh, and N. Sjakste, “Increased synthesis of nitric oxide in rat brain cortex due to halogenated volatile anesthetics confirmed by EPR spectroscopy,” Acta Anaesthesiol. Scand. 46(4), 378–383 (2002).
[Crossref]

M. Dzintare, L. Baumane, D. Meirena, L. Lauberte, I. Kalvinsh, and N. Sjakste, “Nitric oxide production in different organs of intact white rats,” Baltic J. Lab. Anim. Sci 11, 218–224 (2001).

Bell, L.

R. Rother, L. Bell, P. Hillmen, and M. Gladwin, “The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease,” JAMA 293(13), 1653–1662 (2005).
[Crossref]

Bettati, S.

A. Mozzarelli, L. Ronda, S. Faggiano, S. Bettati, and S. Bruno, “Haemoglobin-based oxygen carriers: research and reality towards an alternative to blood transfusions,” Blood Transfusion = Trasfusione del Sangue 8(Suppl 3), s59–68 (2010).
[Crossref]

I. Portoro, L. Kocsis, P. Herman, D. Caccia, M. Perrella, L. Ronda, S. Bruno, S. Bettati, C. Micalella, A. Mozzarelli, A. Varga, M. Vas, K. C. Lowe, and A. Eke, “Towards a novel haemoglobin-based oxygen carrier: Euro-PEG-Hb, physico-chemical properties, vasoactivity and renal filtration,” Biochim. Biophys. Acta, Proteins Proteomics 1784(10), 1402–1409 (2008).
[Crossref]

Bianciardi, P.

L. Terraneo, P. Bianciardi, A. Malavalli, G. Mkrtchyan, S. N. Spann, J. Lohman, M. Samaja, and K. D. Vandegriff, “Hemoglobin extravasation in the brain of rats exchange-transfused with hemoglobin-based oxygen carriers,” Artif. Cells, Nanomed., Biotechnol. 45(4), 710–716 (2017).
[Crossref]

Bloch, K. D.

B. Yu, K. D. Bloch, and W. M. Zapol, “Hemoglobin-based red blood cell substitutes and nitric oxide,” Trends Cardiovasc. Med. 19(3), 103–107 (2009).
[Crossref]

Boas, D. A.

D. A. Boas and A. K. Dunn, “Laser speckle contrast imaging in biomedical optics,” J. Biomed. Opt. 15(1), 011109 (2010).
[Crossref]

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab. 21(3), 195–201 (2001).
[Crossref]

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab. 21(3), 195–201 (2001).
[Crossref]

Bolay, H.

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab. 21(3), 195–201 (2001).
[Crossref]

A. K. Dunn, H. Bolay, M. A. Moskowitz, and D. A. Boas, “Dynamic imaging of cerebral blood flow using laser speckle,” J. Cereb. Blood Flow Metab. 21(3), 195–201 (2001).
[Crossref]

Bredt, D.

D. Bredt and S. Snyder, “Nitric oxide: a physiologic messenger molecule,” Annu. Rev. Biochem. 63(1), 175–195 (1994).
[Crossref]

Brown, L.

L. Brown, B. Key, and T. Lovick, “Fluorescent imaging of nitric oxide production in neuronal varicosities associated with intraparenchymal arterioles in rat hippocampal slices,” Neurosci. Lett. 294(1), 9–12 (2000).
[Crossref]

Bruno, S.

E. Alomari, L. Ronda, and S. Bruno, “Hemoglobin-based oxygen carriers: Differential oxidative stress in a Guinea pig transfusion model,” Free Radical Biol. Med. 124, 299–310 (2018).
[Crossref]

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D. D. Thomas, X. Liu, S. P. Kantrow, and J. R. Lancaster, “The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2,” Proc. Natl. Acad. Sci. 98(1), 355–360 (2001).
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W. T. Phillips, L. Lemen, B. Goins, A. S. Rudolph, R. Klipper, D. Fresne, P. A. Jerabek, M. E. Emch, C. Martin, P. T. Fox, and C. A. McMahan, “Use of oxygen-15 to measure oxygen-carrying capacity of blood substitutes in vivo,” Am J Physiol Heart Circ Physiol 272(5), H2492–H2499 (1997).
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G.-R. Wang, Y. Zhu, P. V. Halushka, T. M. Lincoln, and M. E. Mendelsohn, “Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase,” Proc. Natl. Acad. Sci. 95(9), 4888–4893 (1998).
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I. G. Gould, P. Tsai, D. Kleinfeld, and A. Linninger, “The capillary bed offers the largest hemodynamic resistance to the cortical blood supply,” J. Cereb. Blood Flow Metab. 37(1), 52–68 (2017).
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A. Linninger, I. Gould, T. Marinnan, C. Hsu, A. Alaraj, and M. Chojecki, “Cerebral microcirculation and oxygen tension in the human secondary cortex,” Ann. Biomed. Eng. 41(11), 2264–2284 (2013).
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X. Liu, M. J. S. Miller, M. S. Joshi, H. Sadowska-Krowicka, D. A. Clark, and J. R. Lancaster, “Diffusion-limited reaction of nitric oxide with erythrocytes,” J. Biol. Chem. 273(30), 18709–18713 (1998).
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L. Brown, B. Key, and T. Lovick, “Fluorescent imaging of nitric oxide production in neuronal varicosities associated with intraparenchymal arterioles in rat hippocampal slices,” Neurosci. Lett. 294(1), 9–12 (2000).
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I. Portoro, L. Kocsis, P. Herman, D. Caccia, M. Perrella, L. Ronda, S. Bruno, S. Bettati, C. Micalella, A. Mozzarelli, A. Varga, M. Vas, K. C. Lowe, and A. Eke, “Towards a novel haemoglobin-based oxygen carrier: Euro-PEG-Hb, physico-chemical properties, vasoactivity and renal filtration,” Biochim. Biophys. Acta, Proteins Proteomics 1784(10), 1402–1409 (2008).
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A. Linninger, I. Gould, T. Marinnan, C. Hsu, A. Alaraj, and M. Chojecki, “Cerebral microcirculation and oxygen tension in the human secondary cortex,” Ann. Biomed. Eng. 41(11), 2264–2284 (2013).
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Figures (7)

Fig. 1.
Fig. 1. Concept and validation of RBC velocity measurement by laser speckle contrast imaging. A: Bright view, laser speckle and color-coded RBC velocity images. B: Intensity-coded velocity maps of a scattering phantom flowing through the same segment of a glass tube is seen on the left. Calculated perfusion values integrated for the imaged segment are displayed as a function of preset perfusion levels on the right. C: RBC velocity maps obtained while perfusion pressure to the brain was lowered in a step-wise manner is shown on the left (parenchymal ROI marked framed in white). RBC velocities plotted as a function of the mean arterial blood pressure from this experiment is shown on the right (open circles) along with our data obtained earlier by a commercially available laser Doppler flowmetry instrument under the same experimental condition (closed circles). For more details, see text.
Fig. 2.
Fig. 2. Scheme of the lumped microregional hemodynamic model developed for predicting the microhemodynamic effects of PEG-HBOC molecules in the brain cortex from RBC velocity image data. The model requires systemic (mean arterial blood pressure and hematocrit) and microregional (RBC velocity) parameters as its inputs. In turn, the model provides predictions for a range of microregional hemodynamic parameters (RBC, plasma and whole blood flows, tube hematocrit and vascular resistance) for each and every voxel within a ROI.
Fig. 3.
Fig. 3. Spatio-temporal dynamics of model-predicted microhemodynamic parameters within an area of the rat brain cortex in a blood-to-Euro-PEG-Hb exchange experiment. RBC velocity (${\overline{\textrm{v}} _{\textrm{RBC}}}$) as input, and tissue tube hematocrit (THt) and vascular resistance (R’) as output parameters of the model are shown intensity-coded according to the scales on the right. Parametric maps of THt and R’ were predicted from kernel-wise ${\overline{\textrm{v}} _{\textrm{RBC}}}$ and MAP data by a lumped microhemodynamic model (Fig. 2) for a parenchymal area marked as ROI on the ${\overline{\textrm{v}} _{\textrm{RBC}}}$maps.
Fig. 4.
Fig. 4. Model-predicted regional hemodynamic parameters following exchange transfusions. HES and various PEG-HBOC molecules were tested for their effects on regional hemodynamics in the brain cortex. Regional parameters were aggregated from the voxel-wise (microregional) values within the ROI are as follows. A: regional tube hematocrit, THt, B: regional wall shear stress, τw’, C: regional vascular resistance, R’ and D: regional blood flow, QWB. Exchange transfusion was carried out at 0 minute. HES: hydroxyethyl starch, EuroPEG-Hb: N-propionyl maleimide-PEGylated Hb, PEG-HbO2: maleimide-PEGylated oxyhemoglobin. Data are plotted as group mean ± SD.
Fig. 5.
Fig. 5. Heterogeneity in regional hemodynamics following exchange transfusions. The impact of exchange transfusion by HES and various HBOC molecules in terms of RBC aggregation and vasoreactivity were evaluated by assessing the regional spatial heterogeneities in microregional tube hematocrit (B) and vascular resistance (C), respectively. Regional to large arterial hematocrit ratio (A) indicates that regional hemodilution exceeds that in the central arterial circulation. Note that RD(THt) and RD(R’) for the HBOC and HES molecules do not differ, which is taken as the lack of adverse effects manifested in RBC aggregation or vasoactivity. Data are plotted as group mean ± SD.
Fig. 6.
Fig. 6. Clearance and extravasation of Euro-PEG-Hb assessed in a nude mouse by NIR fluorescence optical imaging. The animal was top-loaded at 0 min with Euro-PEG-Hb molecules labeled by IRDye800CW. Image sequences are: in vivo (B-E), ex vivo in situ (F), brain and one of the kidneys removed once the blood had been cleared by saline perfusion (F) (1: brain, 2: kidney).
Fig. 7.
Fig. 7. Relations of discharge and tube hematocrits in the cerebral circulation. A dichotomically branched arterial tree was generated by a fractal model for the purpose of this schematics. Discharge (left) and tube hematocrits (right) were plotted in gray scale code (far left) for subsequent segments of the arterial tree from its input in the large arterial circulation (lower index a) all the way to its output at the tissue (capillary) level (lower index t). Note the apparent homogeneity in the distribution of the plotted parameters. Due to the lack of pase separation, discharge (DH) and tube (TH) hematocrits are equal at the input of the system. Owing to the conservation of mass, DH is uniform within the system, hence DHa=D Ht. As a result of dynamic separation of phases along the arterial tree, TH becomes progressively smaller than DH (Fåhræus effect [54,55]) reaching its minimal value at the tissue level within the ROI (THt).

Tables (5)

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Table 1. Key parameters for transfusion exchange experiments using various test moleculesa

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Table 2. Systemic and regional input model parameters (MAP, THa) before and after blood-to-plasma expander and blood-to-PEG-HBOC exchange transfusionsa

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Table 3. Significance of various parameters in within group and in between groups relationsa

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Table 4. Regional model prediction for relative apparent viscositya

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Table 5. Symbols, abbreviations and definitions used in the calculations

Equations (24)

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Q WB = k Q RBC T H t = k v ¯ RBC r A 2 π T H t T H t = k v ¯ RBC r A 2 π
k = T H t D H t = T H t T H a .
r A = T H t v ¯ RBC η ( T H a , r A ) ( T H a ) 1 ( PP ) 1
r A = 2 r A D ¯ .
T H t = T H a 2 + T H a ( 1 T H a ) ( 1 + 1.7 e ( 0.415 D ¯ r A ) 0.6 e ( 0.011 D ¯ r A ) )
R = η ( r A ) 4 .
τ w = η v ¯ RBC r A .
Q RBC = V RBC t ¯ RBC ,
Q RBC = L ¯ RBC A RBC t ¯ RBC = v ¯ RBC A RBC ,
Q RBC = v ¯ RBC A = v ¯ RBC r A 2 π T H t ,
Q WB = Q RBC D H t .
T H a = D H a D H t .
k = T H t D H t .
Q WB = k Q RBC T H t = k r A 2 π v ¯ RBC T H t T H t = k r A 2 π v ¯ RBC .
R = MAP ICP Q WB = PP k r A 2 π v ¯ RBC = 8 L ¯ η π r A 4 .
η = [ 1 + ( η 0.45 1 ) ( 1 ( T H a ) ) c 1 ( 1 0.45 ) c 1 ( D D 1.1 ) 2 ] ( D D 1.1 ) 2 .
C = ( 0.8 + e ( 0.075 D ) ) ( 1 + 1 1 + 10 11 D 12 ) + 1 1 + 10 11 D 12 ,
η 0.45 = 6 e ( 0.085 D ) + 3.2 2.44 e ( 0.06 D 0.645 ) .
k = T H t T H a = T H a + ( 1 + T H a ) ( 1 + 1.7 e ( 0.415 D ) 0.6 e ( 0.011 D ) ) .
T H t = T H a 2 + T H a ( 1 + T H a ) ( 1 + 1.7 e ( 0.415 D ) 0.6 e ( 0.011 D ) ) .
r A 4 = T H t r A 2 v ¯ RBC 8 η L ¯ T H a PP ,
r A = T H t v ¯ RBC 8 η L ¯ T H a PP .
r A = T H t v ¯ RBC η ( T H a ) 1 ( PP ) 1 .
r lumen = r lumen ( T ) r lumen ( C ) = tube Hc t tissue ( T ) v ¯ RBC ( T ) η ( T ) Hc t arterial ( C ) PP ( C ) tube Hc t tissue ( C ) v ¯ RBC ( C ) η ( C ) Hc t arterial ( T ) PP ( T )

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