Skip to main content
Log in

Fractal Dimension of Erythrocyte Membranes: A Highly Useful Precursor for Rapid Morphological Assay

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

Morphology of erythrocyte membrane has been recognized as an alternative biomarker of several patho-physiological states. Numerous attempts have been made to upgrade the existing method of primitive manual counting, particularly exploring the light scattering properties of erythrocyte. All the techniques are at best semi-empirical and heavily rely on the effectiveness of the statistical correlations. Precisely, this is due to the lack of a non-empirical scale of the so-called “morphological scores”. In this article, fractal dimension of erythrocyte membrane has been used to formulate a suitable scoring scale. Subsequently, the rapid experimental output of flow-cytometry has been functionally related to the mean morphological quantifier of the whole cell population via an optimum neural network model (R2 = 0.98). Moreover, the fractal dimension has been further demonstrated to be an important parameter in early detection of an abnormal patho-physiological state, even without any noticeable poikilocytic transformation in micrometric domain.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Abbas, N., D. Mohamad, and A. H. Abdullah. Automated erythrocytes counting in microscopic thin blood smear digital images. J. Telemat. Inform. 3:49–59, 2015.

    Google Scholar 

  2. Ahlgrim, C., T. Pottgiesser, T. Sander, Y. O. Schumacher, and M. W. Baumstark. Flow cytometric assessment of erythrocyte shape through analysis of FSC histograms: use of kurtosis and implications for longitudinal evaluation. PLoS ONE 8:e59862, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Antonio, P. D., M. Lasalvia, G. Perna, and V. Capozzi. Scale-independent roughness value of cell membranes studied by means of AFM technique. Biochim. Biophys. Acta Biomembr. 3141–3148:2012, 1818.

    Google Scholar 

  4. Bessis, M., R. I. Weed, and P. F. Leblond. Red Cell Shape: Physiology, Pathology, Ultrastructure. New York: Springer, p. 180, 1973.

    Book  Google Scholar 

  5. Blank, M. E., and H. Ehmke. Aquaporin-1 and HCO3(-)-Cl(-) transporter-mediated transport of CO2 across the human erythrocyte membrane. J. Physiol. 550:419–429, 2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Buys, A. V., M.-J. Van Rooy, P. Soma, D. Van Papendorp, B. Lipinski, and E. Pretorius. Changes in red blood cell membrane structure in type 2 diabetes: a scanning electron and atomic force microscopy study. Cardiovasc. Diabetol. 12(1):25, 2013.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cybenko, G. Approximation by superpositions of a sigmoidal function. Math. Control Signals Syst. 2:303–314, 1989.

    Article  Google Scholar 

  8. Diez-Silva, M., M. Dao, J. Han, C.-T. Lim, and S. Suresh. Shape and biomechanical characteristics of human red blood cells in health and disease. MRS Bull. 35:382–388, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fauci, A. S., E. Braunwald, D. L. Kasper, S. L. Hauser, D. L. Longo, J. L. Jameson, and J. Loscalzo. Harrison’s Principles of Internal Medicine. New York: Mcgraw-hill, p. 2958, 2008.

    Google Scholar 

  10. Ferrell, J. E., and W. H. Huestis. Phosphoinositide metabolism and the morphology of human erythrocytes. J. Cell Biol. 98:1992–1998, 1984.

    Article  CAS  PubMed  Google Scholar 

  11. Gagnepain, J. J., and C. Roques-Carmes. Fractal approach to two-dimensional and three-dimensional surface roughness. Wear 109:119–126, 1986.

    Article  Google Scholar 

  12. Girasole, M., G. Pompeo, A. Cricenti, A. Congiu-Castellano, F. Andreola, A. Serafino, B. H. Frazer, G. Boumis, and G. Amiconi. Roughness of the plasma membrane as an independent morphological parameter to study RBCs: a quantitative atomic force microscopy investigation. Biochim. Biophys. Acta Biomembr. 1768:1268–1276, 2007.

    Article  CAS  Google Scholar 

  13. Girasole, M., G. Pompeo, A. Cricenti, G. Longo, G. Boumis, A. Bellelli, and S. Amiconi. The how, when, and why of the aging signals appearing on the human erythrocyte membrane: an atomic force microscopy study of surface roughness. Nanomed. Nanotechnol. Biol. Med. 6:760–768, 2010.

    Article  CAS  Google Scholar 

  14. Goodman, S. R., and K. Shiffer. The spectrin membrane skeleton of normal and abnormal human erythrocytes: a review. Am. J. Physiol. Cell Physiol. 244:121–141, 1983.

    Article  Google Scholar 

  15. Higuchi, T. Approach to an irregular time series on the basis of the fractal theory. Phys. D 31:277–283, 1988.

    Article  Google Scholar 

  16. Ionescu, C., A. Lopes, D. Copot, J. A. T. Machado, and J. H. T. Bates. The role of fractional calculus in modeling biological phenomena: a review. Commun. Nonlinear Sci. Numer. Simulat. 51:141–159, 2017.

    Article  Google Scholar 

  17. Jackups, Jr, R. Deep learning makes its way to the clinical laboratory. Clin. Chem. 63:1790–1791, 2017.

    Article  CAS  PubMed  Google Scholar 

  18. Jin, H., X. Xing, H. Zhao, Y. Chen, X. Huang, S. Ma, H. Ye, and J. Cai. Detection of erythrocytes influenced by aging and type 2 diabetes using atomic force microscope. Biochem. Biophys. Res. Commun. 391:1698–1702, 2010.

    Article  CAS  PubMed  Google Scholar 

  19. Jing, J., P. Feng, S. Wei, H. Zhao, and Y. Liu. Investigation on the surface morphology of Si3N4 ceramics by a new fractal dimension calculation method. Appl. Surf. Sci. 387:812–821, 2016.

    Article  CAS  Google Scholar 

  20. Kim, Y., K. Kim, and Y. Park. Measurement techniques for red blood cell deformability: recent advances. In: Blood Cell—An Overview of Studies in Hematology, edited by T. E. Moschandreou. Rijeka: InTech, 2012, pp. 167–194.

    Google Scholar 

  21. Knauf, P. A., F.-Y. Law, T.-W. V. Leung, A. U. Gehret, and M. L. Perez. Substrate-dependent reversal of anion transport site orientation in the human red blood cell anion-exchange protein, AE1. Proc. Natl. Acad. Sci. USA 99:10861–10864, 2002.

    Article  CAS  PubMed  Google Scholar 

  22. Kubisztal, J., M. Kubisztal, and G. Haneczok. Quantitative characterization of material surface—application to Ni + Mo electrolytic composite coatings. Mater. Charact. 122:45–53, 2016.

    Article  CAS  Google Scholar 

  23. Mandelbrot, B. B. The Fractal Geometry of Nature. New York: W. H. Freeman and Co., 1982.

    Google Scholar 

  24. Melzak, K. A., G. R. Lázaro, A. Hernández-Machado, I. Pagonabarraga, J. M. de Espada, and J. L. Toca-Herrera. AFM measurements and lipid rearrangements: evidence from red blood cell shape changes. Soft Matter 8:7716–7726, 2012.

    Article  CAS  Google Scholar 

  25. Méndez-Vilas, A., J. M. Bruque, and M. L. González-Martín. Sensitivity of surface roughness parameters to changes in the density of scanning points in multi-scale AFM studies. Application to a biomaterial surface. Ultramicroscopy 107:617–625, 2007.

    Article  CAS  PubMed  Google Scholar 

  26. Mohandas, N., Y. R. Kim, D. H. Tycko, J. Orlik, J. Wyatt, and W. Groner. Accurate and independent measurement of volume and hemoglobin concentration of individual red cells by laser light scattering. Blood 68:506–513, 1986.

    CAS  PubMed  Google Scholar 

  27. Mosior, M., T. Krawczak-Sadowska, A. Wróbel, W. A. Bialas, and J. Gomulkiewicz. The effect of arsenate and vanadate ions on the critical cell volume of bovine erythrocytes. Gen. Physiol. Biophys. 11:337–343, 1992.

    CAS  PubMed  Google Scholar 

  28. Mukherjee, R., K. Chaudhury, and C. Chakraborty. Topological features of erythrocytes in thalassemic patients: quantitative characterization by scanning electron and atomic force microscopy. Anal. Quant. Cytol. Pathol. 36:91–99, 2014.

    Google Scholar 

  29. Mukherjee, R., M. Saha, A. Routray, and C. Chakraborty. Nanoscale surface characterization of human erythrocytes by atomic force microscopy: a critical review. IEEE Trans. Nanobiosci. 14:625–633, 2015.

    Article  Google Scholar 

  30. Pages, G., T. W. Yau, and P. W. Kuchel. Erythrocyte shape reversion from echinocytes to discocytes: kinetics via fast-measurement NMR diffusion-diffraction. Magn. Reson. Med. 64:645–652, 2010.

    Article  CAS  PubMed  Google Scholar 

  31. Piagnerelli, M., K. Z. Boudjeltia, D. Brohee, A. Vereerstraeten, P. Piro, J. L. Vincent, and M. Vanhaeverbeek. Assessment of erythrocyte shape by flow cytometry techniques. J. Clin. Pathol. 60:549–554, 2007.

    Article  CAS  PubMed  Google Scholar 

  32. Pretorius, E., and D. B. Kell. Diagnostic morphology: biophysical indicators for iron-driven inflammatory diseases. Integr. Biol. 6:486–510, 2014.

    Article  CAS  Google Scholar 

  33. Pretorius, E., A. C. Swanepoel, A. V. Buys, N. Vermeulen, W. Duim, and D. B. Kell. Eryptosis as a marker of Parkinson’s disease. Aging (Albany NY) 6:788–819, 2014.

    Article  CAS  Google Scholar 

  34. Santacruz-Gomez, K., E. Silva-Campa, S. Álvarez-García, V. Mata-Haro, D. Soto-Puebla, and M. Pedroza-Montero. An AFM approach of RBC micro and nanoscale topographic features during storage. Int. J. Med. Health Biomed. Bioeng. Pharm. Eng. 8:478–481, 2014.

    Google Scholar 

  35. Scarabelli, L., F. Giovanardi, E. Gervasi, G. Prati, D. Pezzuolo, and L. Scaltriti. Increased mean corpuscular volume of red blood cells in patients treated with capecitabine for advanced breast and colon cancer. Chemotherapy 59:369–372, 2013.

    Article  CAS  PubMed  Google Scholar 

  36. Steck, T. L. The organization of proteins in the human red blood cell membrane. A review. J. Cell Biol. 62:1–19, 1974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Takeuchi, M., H. Miyamoto, Y. Sako, H. Komizu, and A. Kusumi. Structure of the erythrocyte membrane skeleton as observed by atomic force microscopy. Biophys. J. 74:2171–2183, 1998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ţălu, Ş., S. Stach, V. Sueiras, and N. M. Ziebarth. Fractal analysis of AFM images of the surface of Bowman’s membrane of the human cornea. Ann. Biomed. Eng. 43:906–916, 2015.

    Article  PubMed  Google Scholar 

  39. Wong, P. A hypothesis of the disc-sphere transformation of the erythrocytes between glass surfaces and of related observations. J. Theor. Biol. 233:127–135, 2005.

    Article  PubMed  Google Scholar 

  40. Wu, Y., J. Cai, L. Cheng, Y. Xu, Z. Lin, C. Wang, and Y. Chen. Atomic force microscope tracking observation of Chinese hamster ovary cell mitosis. Micron 37:139–145, 2006.

    Article  PubMed  Google Scholar 

  41. Zhang, Y., W. Zhang, S. Wang, C. Wang, J. Xie, X. Chen, Y. Xu, and P. Mao. Detection of erythrocytes in patients with multiple myeloma using atomic force microscopy. Scanning 34:295–301, 2012.

    Article  PubMed  Google Scholar 

  42. Zhang, Y., W. Zhang, S. Wang, C. Wang, J. Xie, X. Chen, Y. Xu, and P. Mao. Detection of human erythrocytes influenced by iron deficiency anemia and thalassemia using atomic force microscopy. Micron 43:1287–1292, 2012.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The present work has been carried out utilizing the infrastructures developed under the project, entitled “Quantifying morphological alteration of RBC population”, funded by TEQIP, phase-II, University of Calcutta (Vide Sanction Letter No. TEQIP-II/R&D/13/105(4) dated November, 2013). The contribution of TEQIP is gratefully acknowledged. We are also grateful to the Centre for Research in Nanoscience and Nanotechnology (CRNN), IIT Kharagpur and the University of Calcutta for the infrastructural support.

Conflict of interest

No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Debasish Sarkar.

Additional information

Associate Editor Umberto Morbiducci oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1486 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghosh, S., Roy, A., Chakraborty, I. et al. Fractal Dimension of Erythrocyte Membranes: A Highly Useful Precursor for Rapid Morphological Assay. Ann Biomed Eng 46, 1362–1375 (2018). https://doi.org/10.1007/s10439-018-2050-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-018-2050-6

Keywords

Navigation