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Blood Cell Interactions and Segregation in Flow

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Abstract

For more than a century, pioneering researchers have been using novel experimental and computational approaches to probe the mysteries of blood flow. Thanks to their efforts, we know that blood cells generally prefer to migrate to the axis of flow, that red and white cells segregate in flow, and that cell deformability and their tendency to reversibly aggregate contribute to the non-Newtonian nature of this unique fluid. All of these properties have beneficial physiological consequences, allowing blood to perform a variety of critical functions. Our current understanding of these unusual flow properties of blood have been made possible by the ingenuity and diligence of a number of researchers, including Harry Goldsmith, who developed novel technologies to visualize and quantify the flow of blood at the level of individual cells. Here we summarize efforts in our lab to continue this tradition and to further our understanding of how blood cells interact with each other and with the blood vessel wall.

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References

  1. Bell G. I. Models for the specific adhesion of cells to cells. Science 200:618–627, 1978

    Article  PubMed  CAS  Google Scholar 

  2. Bishop J. J., P. Nance, A. S. Popel, M. Intaglietta, P. C. Johnson. Effect of erythrocyte aggregation on velocity profiles in venules. Am. J. Physiol. Heart Circ. Physiol. 280:H222–H236, 2001

    PubMed  CAS  Google Scholar 

  3. Bishop J. J., A. S. Popel, M. Intaglietta, P. C. Johnson. Effects of erythrocyte aggregation and venous network geometry on red blood cell axial migration. Am. J. Physiol. Heart Circ. Physiol. 281:H939–H950, 2001

    PubMed  CAS  Google Scholar 

  4. Brown E. B., R. B. Campbell, Y. Tsuzuki, L. Xu, P. Carmeliet, D. Fukumura, R. K. Jain. In vivo measurement of gene expression, angiogenesis and physiological function in tumors using multiphoton laser scanning microscopy. Nat. Med. 7:864–868, 2001

    Article  PubMed  CAS  Google Scholar 

  5. Butcher E. C., D. Lewinsohn, A. Duijvestijn, R. Bargatze, N. Wu, S. Jalkanen. Interactions between endothelial cells and leukocytes. J. Cell. Biochem. 30:121–131, 1986

    Article  PubMed  CAS  Google Scholar 

  6. Chapman G. B., G. R. Cokelet. Flow resistance and drag forces due to multiple adherent leukocytes in postcapillary vessels. Biophys. J. 74:3292–3301, 1998

    PubMed  CAS  Google Scholar 

  7. Chen B. P., Y. S. Li, Y. Zhao, K. D. Chen, S. Li, J. Lao, S. Yuan, J. Y. Shyy, S. Chien DNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress. Physiol. Genomics 7:55–63, 2001

    Article  PubMed  CAS  Google Scholar 

  8. Chien S. The Benjamin W. Zweifach award lecture. Blood cell deformability, interactions: from molecules to micromechanics and microcirculation. Microvasc. Res. 44:243–254, 1992

    Article  PubMed  CAS  Google Scholar 

  9. Chien S., S. Usami, R. J. Dellenback, M. I. Gregersen Blood viscosity: influence of erythrocyte deformation. Science 157:827–829, 1967

    Article  PubMed  Google Scholar 

  10. Chien S., S. Usami, R. J. Dellenback, M. I. Gregersen, L. B. Nanninga, M. M. Guest. Blood viscosity: influence of erythrocyte aggregation. Science 157:829–831, 1967

    Article  PubMed  Google Scholar 

  11. Chien, S., S. Usami, and R. Skalak. Blood flow in small tubes. In: Handbook of Physiology—The Cardiovascular System IV, edited by E. M. Renkin and C. C. Michel. Bethesda, MD: American Physiological Society, 1984

  12. Cokelet, G. R. The rheology and tube flow of blood. In: Handbook of Bioengineering, edited by R. Skalak and S. Chien. New York: McGraw-Hill, pp. 14.1–14.17, 1987

  13. Cokelet G. R., H. L. Goldsmith Decreased hydrodynamic resistance in the two-phase flow of blood through small vertical tubes at low flow rates. Circ. Res. 68:1–17, 1991

    PubMed  CAS  Google Scholar 

  14. Das B., P. Johnson, A. Popel Computational fluid dynamic studies of leukocyte adhesion effects on non-Newtonian blood flow through microvessels. Biorheology 37:239–258, 2000

    PubMed  CAS  Google Scholar 

  15. Dewitz T. S., R. R. Martin, R. T. Solis, J. D. Hellums, L. V. McIntire Microaggregate formation in whole blood exposed to shear stress. Microvasc. Res. 16:263–271, 1978

    Article  PubMed  CAS  Google Scholar 

  16. Dong C., R. Skalak. Leukocytes deformability: finite element modeling of large viscoelastic deformation. J. Theor. Biol. 158:173–193, 1992

    Article  PubMed  CAS  Google Scholar 

  17. Dupin M. M., I. Halliday, C. M. Care, L. Alboul, L. L. Munn. Modeling the flow of dense suspensions of deformable particles in three dimensions. Phys. Rev. E 75:066707, 2007

    Article  CAS  Google Scholar 

  18. Dupin, M. M., and L. L. Munn. Lateral Migration of Blood Cells in Flow Depends on Rheology and Size: Insights from Simulations. Los Angeles, CA: Biomedical Engineering Society, p 4.56, 2007

  19. Fahraeus R. The suspension stability of the blood. Physiol. Rev. 9:241–274, 1929

    Google Scholar 

  20. Fahraeus R., T. Lindqvist. The viscosity of the blood in narrow capillary tubes. Am. J. Physiol. 96:562–568, 1931

    CAS  Google Scholar 

  21. Frangos J. A., S. G. Eskin, L. V. McIntire, C. L. Ives. Flow effects on prostacyclin production by cultured human endothelial cells. Science 227:1477–1479, 1985

    Article  PubMed  CAS  Google Scholar 

  22. Giorgio T. D., J. D. Hellums. A cone and plate viscometer for the continuous measurement of blood platelet activation. Biorheology 25:605–624, 1988

    PubMed  CAS  Google Scholar 

  23. Goldsmith H. L. Microscopic flow properties of red cells. Fed. Proc. 26:1813–1820, 1967

    PubMed  CAS  Google Scholar 

  24. Goldsmith H. L. Red cell motions and wall interactions in tube flow. Fed. Proc. 30:1578–1588, 1971

    PubMed  CAS  Google Scholar 

  25. Goldsmith H. L., D. N. Bell, S. Braovac, A. Steinberg, F. McIntosh. Physical and chemical effects of red cells in the shear-induced aggregation of human platelets. Biophys. J. 69:1584–1595, 1995

    PubMed  CAS  Google Scholar 

  26. Goldsmith H. L., D. N. Bell, S. Spain, F. A. McIntosh. Effect of red blood cells and their aggregates on platelets and white cells in flowing blood. Biorheology 36:461–468, 1999

    PubMed  CAS  Google Scholar 

  27. Goldsmith H. L., G. R. Cokelet, P. Gaehtgens. Robin Fahraeus: evolution of his concepts in cardiovascular physiology. Am. J. Physiol. 257:H1005–H1015, 1989

    PubMed  CAS  Google Scholar 

  28. Goldsmith H. L., T. Karino. Interactions of human blood cells with the vascular endothelium. Ann. N. Y. Acad. Sci. 516:468–483, 1987

    Article  PubMed  CAS  Google Scholar 

  29. Goldsmith H. L., J. C. Marlow. Flow behaviour of erythrocytes. I. Rotation and deformation in dilute suspensions. Proc. R. Soc. Lond. B 182:351–384, 1972

    Google Scholar 

  30. Goldsmith H. L., J. C. Marlow. Flow behavior of erythrocytes II. Particle motions in concentrated suspensions of ghost cells. J. Colloid Interface Sci. 71:383–407, 1979

    Article  Google Scholar 

  31. Goldsmith H. L., S. G. Mason. The flow of suspensions through tubes. I. Single spheres, rods and discs. J. Colloid Sci. 17:448–476, 1962

    Article  Google Scholar 

  32. Goldsmith H. L., S. G. Mason. The flow of suspensions through tubes II. Single large bubbles. J. Colloid Sci. 18:237–261, 1963

    Article  CAS  Google Scholar 

  33. Goldsmith H. L., S. G. Mason. Further comments on the radial migration of spheres in Poiseuille flow. Biorheology 3:33–36, 1965

    PubMed  CAS  Google Scholar 

  34. Goldsmith H. L., S. Spain. Margination of leukocytes in blood flow through small tubes. Microvasc. Res. 27:204–222, 1984

    Article  PubMed  CAS  Google Scholar 

  35. Helmke B. P., S. N. Bremne, B. W. Zweifach, R. Skalak, G. W. Schmid-Schonbein. Mechanisms for increased blood flow resistance due to leukocytes. Am. J. Physiol. 273:H2884–H2890, 1997

    PubMed  CAS  Google Scholar 

  36. Hubbell J. A., L. V. McIntire. Platelet active concentration profiles near growing thrombi. A mathematical consideration. Biophys. J. 50:937–945, 1986

    PubMed  CAS  Google Scholar 

  37. Jain R. K. Determinants of tumor blood flow: a review. Cancer Res. 48:2641–2658, 1988

    PubMed  CAS  Google Scholar 

  38. Jain, R. K., L. L. Munn, and D. Fukumura. Transparent window models and intravital microscopy. In: Tumor Models in Cancer Research, edited by B. A. Teicher. Totowa: Humana Press Inc, pp. 647–671, 2001

  39. Jiang Y., M. N. Myers, J. C. Giddings. Separation behavior of blood cells in sedimentation field-flow fractionation. J. Liq. Chromatogr. Relat. Technol. 22:1213–1234, 2005

    Google Scholar 

  40. Karino T., H. L. Goldsmith. Flow behaviour of blood cells and rigid spheres in an annular vortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 279:413–445, 1977

    Article  PubMed  CAS  Google Scholar 

  41. Karino T., H. L. Goldsmith, M. Motomiya, S. Mabuchi, Y. Sohara. Flow patterns in vessels of simple and complex geometries. Ann. N. Y. Acad. Sci. 516:422–441, 1987

    Article  PubMed  CAS  Google Scholar 

  42. Karnis A., H. L. Goldsmith, S. G. Mason. Axial migration of particles in Poiseuille flow. Nature 200:159–160, 1963

    Article  Google Scholar 

  43. Konstantopoulos K., L. V. McIntire. Effects of fluid dynamic forces on vascular cell adhesion. J. Clin. Invest. 98:2661–2665, 1996

    Article  PubMed  CAS  Google Scholar 

  44. Konstantopoulos K., S. Neelamegham, A. R. Burns, E. Hentzen, G. S. Kansas, K. R. Snapp, E. L. Berg, J. D. Hellums, C. W. Smith, L. V. McIntire, S. I. Simon. Venous levels of shear support neutrophil–platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin. Circulation 98:873–882, 1998

    PubMed  CAS  Google Scholar 

  45. Kroll M. H., J. D. Hellums, L. V. McIntire, A. I. Schafer, J. L. Moake. Platelets and shear stress. Blood 88:1525–1541, 1996

    PubMed  CAS  Google Scholar 

  46. Lawrence M. B., T. A. Springer. Leukocytes roll on a selectin at physiological flow rates: distinction from and prerequisite for adhesion through integrins. Cell 65:859–873, 1991

    Article  PubMed  CAS  Google Scholar 

  47. Lipowsky, H. H., S. D. House, and J. C. Firrell (eds). (1988). In: Leukocyte Endothelium Adhesion and Microvascular Hemodynamics. Vascular Endothelium in Health and Disease. New York, Plenum Press

  48. Maude A. D., R. L. Whitmore. Theory of the flow of blood in narrow tubes. J. Appl. Pysiol. 12:105–113, 1958

    CAS  Google Scholar 

  49. Mayrovitz H. N., S. J. Kang, B. Herscovici, R. N. Sampsell. Leukocyte adherence initiation in skeletal muscle capillaries and venules. Microvasc. Res. 33:22–34, 1987

    Article  PubMed  CAS  Google Scholar 

  50. Migliorini C., Y. Qian, H. Chen, E. Brown, R. Jain, L. Munn. Red blood cells augment leukocyte rolling in a virtual blood vessel. Biophys. J. 83:1834–1841, 2002

    PubMed  CAS  Google Scholar 

  51. Munn L. L., R. J. Melder, R. K. Jain. Role of erythrocytes in leukocyte–endothelial interactions: mathematical model and experimental validation. Biophys. J. 71:466–478, 1996

    PubMed  CAS  Google Scholar 

  52. Munn L., A. W. Mulivor, M. Dupin, S. S. Shevkoplyas, C. Sun. Tumor vessel abnormalities affect blood cell dynamics and flow distribution. J. Biomech. 39:S396, 2006

    Article  Google Scholar 

  53. Pearson M. J., H. H. Lipowsky. Influence of erythrocyte aggregation on leukocyte margination in postcapillary venules of rat mesentery. Am. J. Physiol. Heart Circ. Physiol. 279:H1460–H1471, 2000

    PubMed  CAS  Google Scholar 

  54. Pries A. R., D. Neuhaus, P. Gaehtgens. Blood viscosity in tube flow: dependence on diameter and hematocrit. Am. J. Physiol. 263:H1770–H1778, 1992

    PubMed  CAS  Google Scholar 

  55. Pries A. R., T. W. Secomb. Microcirculatory network structures and models. Ann. Biomed. Eng. 28:916–921, 2000

    Article  PubMed  CAS  Google Scholar 

  56. Reinke W., P. Gaehtgens, P. C. Johnson. Blood viscosity in small tubes: effect of shear rate, aggregation, and sedimentation. Am. J. Physiol. 253:H540–H547, 1987

    PubMed  CAS  Google Scholar 

  57. Sasaki A., R. K. Jain, A. A. Maghazachi, R. H. Goldfarb, R. B. Herberman. Low deformability of lymphokine-activated killer cells as a possible determinant of in vivo distribution. Cancer Res. 49:3742–3746, 1989

    PubMed  CAS  Google Scholar 

  58. Schmid-Schoenbein G. W., Y.-C. Fung, B. W. Zweifach. Vascular endothelium–leukocyte interaction. Sticking shear force in venules. Circ. Res. 36:173–184, 1975

    PubMed  CAS  Google Scholar 

  59. Schmid-Schoenbein G. W., S. Usami, R. Skalak, S. Chien. The interaction of leukocytes and erythrocytes in capillary and postcapillary vessels. Microvasc. Res. 19:45–70, 1980

    Article  Google Scholar 

  60. Secomb T. W., B. Styp-Rekowska, A. R. Pries. Two-dimensional simulation of red blood cell deformation and lateral migration in microvessels. Ann. Biomed. Eng. 35:755–765, 2007

    Article  PubMed  Google Scholar 

  61. Segre G., A. Silberger. Radial particle displacements in Poiseuille flow of suspensions. Nature 189:209–210, 1961

    Article  Google Scholar 

  62. Shevkoplyas S. S., T. Yoshida, L. L. Munn, M. W. Bitensky. Biomimetic autoseparation of leukocytes from whole blood in a microfluidic device. Anal. Chem. 77:933–937, 2005

    Article  PubMed  CAS  Google Scholar 

  63. Simon S. I., H. L. Goldsmith. Leukocyte adhesion dynamics in shear flow. Ann. Biomed. Eng. 30:315–332, 2002

    Article  PubMed  Google Scholar 

  64. Skalak R., S. Chien (1987). Handbook of Bioengineering. New York, McGraw-Hill

    Google Scholar 

  65. Sun C., R. K. Jain, L. L. Munn. Non-uniform plasma leakage affects local hematocrit and blood flow: implications for inflammation and tumor perfusion. Ann. Biomed. Eng. 35:2121–2129, 2007

    Article  PubMed  Google Scholar 

  66. Sun C. H., C. Migliorini, L. L. Munn. Red blood cells initiate leukocyte rolling in postcapillary expansions: a lattice Boltzmann analysis. Biophys. J. 85:208–222, 2003

    PubMed  CAS  Google Scholar 

  67. Sun C. H., L. L. Munn. Particulate nature of blood determines macroscopic rheology: a 2-D lattice Boltzmann analysis. Biophys. J. 88:1635–1645, 2005

    Article  PubMed  CAS  Google Scholar 

  68. Sun C. H., L. L. Munn. Influence of erythrocyte aggregation on leukocyte margination in postcapillary expansions: a lattice-Boltzmann analysis. Physica A 362:191–196, 2006

    Article  Google Scholar 

  69. Sun, C. H., and L. L. Munn. Lattice Boltzmann simulation of blood flow in digitized vessel networks. Comput. Math. Appl. doi:10.1016/j.camwa.2007.08.019:2007

  70. Willett C. G., Y. Boucher, E. di Tomaso, D. G. Duda, L. L. Munn, R. T. Tong, D. C. Chung, D. V. Sahani, S. P. Kalva, S. V. Kozin, M. Mino, K. S. Cohen, D. T. Scadden, A. C. Hartford, A. J. Fischman, J. W. Clark, D. P. Ryan, A. X. Zhu, L. S. Blaszkowsky, H. X. Chen, P. C. Shellito, G. Y. Lauwers, R. K. Jain. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 10:145–147, 2004

    Article  PubMed  CAS  Google Scholar 

  71. Winkler F., S. V. Kozin, R. T. Tong, S. S. Chae, M. F. Booth, I. Garkavtsev, L. Xu, D. J. Hicklin, D. Fukumura, E. di Tomaso, L. L. Munn, R. K. Jain. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases [see comment]. Cancer Cell 6:553–563, 2004

    PubMed  CAS  Google Scholar 

  72. Yu S. K., H. L. Goldsmith. Behavior of model particles and blood cells at spherical obstructions in tube flow. Microvasc. Res. 6:5–31, 1973

    Article  PubMed  CAS  Google Scholar 

  73. Zao Y., S. Chien, S. Weinbaum. Dynamic contact forces on leukocyte microvilli and their penetration of the endothelial glycocalyx. Biophys. J. 80:1124–1140, 2001

    Google Scholar 

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Acknowledgments

We would like to thank Dr. Harry Goldsmith for laying the foundation for all the work described herein. The studies were supported by NIH grant R01 HL64240 (LLM).

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  1. E.L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom St., COX 7, Boston, MA, 02114, USA

    Lance L. Munn & Michael M. Dupin

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Correspondence to Lance L. Munn.

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Munn, L.L., Dupin, M.M. Blood Cell Interactions and Segregation in Flow. Ann Biomed Eng 36, 534–544 (2008). https://doi.org/10.1007/s10439-007-9429-0

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