Annals of Biomedical Engineering

, Volume 46, Issue 7, pp 1038–1046 | Cite as

Quantitative Dual Contrast CT Technique for Evaluation of Articular Cartilage Properties

  • Abhisek BhattaraiEmail author
  • Juuso T. J. Honkanen
  • Katariina A. H. Myller
  • Mithilesh Prakash
  • Miitu Korhonen
  • Annina E. A. Saukko
  • Tuomas Virén
  • Antti Joukainen
  • Amit N. Patwa
  • Heikki Kröger
  • Mark W. Grinstaff
  • Jukka S. Jurvelin
  • Juha Töyräs


Impact injuries of cartilage may initiate post-traumatic degeneration, making early detection of injury imperative for timely surgical or pharmaceutical interventions. Cationic (positively-charged) CT contrast agents detect loss of cartilage proteoglycans (PGs) more sensitively than anionic (negatively-charged) or non-ionic (non-charged, i.e., electrically neutral) agents. However, degeneration related loss of PGs and increase in water content have opposite effects on the diffusion of the cationic agent, lowering its sensitivity. In contrast to cationic agents, diffusion of non-ionic agents is governed only by steric hindrance and water content of cartilage. We hypothesize that sensitivity of an iodine(I)-based cationic agent may be enhanced by simultaneous use of a non-ionic gadolinium(Gd)-based agent. We introduce a quantitative dual energy CT technique (QDECT) for simultaneous quantification of two contrast agents in cartilage. We employ this technique to improve the sensitivity of cationic CA4+ (q =+4) by normalizing its partition in cartilage with that of non-ionic gadoteridol. The technique was evaluated with measurements of contrast agent mixtures of known composition and human osteochondral samples (n = 57) after immersion (72 h) in mixture of CA4+ and gadoteridol. Samples were arthroscopically graded and biomechanically tested prior to QDECT (50/100 kV). QDECT determined contrast agent mixture compositions correlated with the true compositions (R2= 0.99, average error = 2.27%). Normalizing CA4+ partition in cartilage with that of gadoteridol improved correlation with equilibrium modulus (from ρ = 0.701 to 0.795). To conclude, QDECT enables simultaneous quantification of I and Gd contrast agents improving diagnosis of cartilage integrity and biomechanical status.


Biomechanics Cartilage Cationic contrast agent Contrast enhanced computed tomography Dual energy CT 



Sandra Sefa (B.Sc.) is acknowledged for assistance with the biomechanical measurements. Jaakko Sarin, M.Sc.(Tech) is acknowledged for assistance in sample extraction. Academy of Finland (Projects 269315, 307932), Kuopio University Hospital (VTR 5041746, 5041757, PY210), Instrumentarium Science Foundation (170033) and Doctoral Program in Science, Technology and Computing (SCITECO, University of Eastern Finland) are acknowledged for financial support.

Conflicts of interests

The authors have no conflicts of interest.


  1. 1.
    Adair, G. S. On the Donnan equilibrium and the equations of Gibbs. Science 58:13, 1923.CrossRefPubMedGoogle Scholar
  2. 2.
    Anderson, D. D., S. Chubinskaya, F. Guilak, J. A. Martin, T. R. Oegema, S. A. Olson, and J. A. Buckwalter. Post-traumatic osteoarthritis: improved understanding and opportunities for early intervention. J. Orthop. Res. 29:802–809, 2011.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Arkill, K. P., and C. P. Winlove. Solute transport in the deep and calcified zones of articular cartilage. Osteoarthr. Cartil. 16:708–714, 2008.CrossRefPubMedGoogle Scholar
  4. 4.
    Bansal, P. N., N. S. Joshi, V. Entezari, B. C. Malone, R. C. Stewart, B. D. Snyder, and M. W. Grinstaff. Cationic contrast agents improve quantification of glycosaminoglycan (GAG) content by contrast enhanced CT imaging of cartilage. J. Orthop. Res. 29:704–709, 2011.CrossRefPubMedGoogle Scholar
  5. 5.
    Bansal, P. N., R. C. Stewart, V. Entezari, B. D. Snyder, and M. W. Grinstaff. Contrast agent electrostatic attraction rather than repulsion to glycosaminoglycans affords a greater contrast uptake ratio and improved quantitative CT imaging in cartilage. Osteoarthr. Cartil. 19:970–976, 2011.CrossRefPubMedGoogle Scholar
  6. 6.
    Bay-Jensen, A.-C., S. Hoegh-Madsen, E. Dam, K. Henriksen, B. C. Sondergaard, P. Pastoureau, P. Qvist, and M. A. Karsdal. Which elements are involved in reversible and irreversible cartilage degradation in osteoarthritis? Rheumatol. Int. 30:435–442, 2010.CrossRefPubMedGoogle Scholar
  7. 7.
    Berberat, J. E., M. J. Nissi, J. S. Jurvelin, and M. T. Nieminen. Assessment of interstitial water content of articular cartilage with T1 relaxation. Magn. Reson. Imaging 27:727–732, 2009.CrossRefPubMedGoogle Scholar
  8. 8.
    Brittberg, M., and C. S. Winalski. Evaluation of cartilage injuries and repair. J. Bone Jt Surg. Am. 85-A(Suppl):58–69, 2003.CrossRefGoogle Scholar
  9. 9.
    Brocklehurst, R., M. T. Bayliss, A. Maroudas, H. L. Coysh, M. A. Freeman, P. A. Revell, and S. Y. Ali. The composition of normal and osteoarthritic articular cartilage from human knee joints. With special reference to unicompartmental replacement and osteotomy of the knee. J. Bone Jt Surg. Am. 66:95–106, 1984.CrossRefGoogle Scholar
  10. 10.
    Buckwalter, J. A., H. J. Mankin, and A. J. Grodzinsky. Articular cartilage and osteoarthritis. Instr. Course Lect. 54:465–480, 2005.PubMedGoogle Scholar
  11. 11.
    Correa, D., and S. A. Lietman. Articular cartilage repair: current needs, methods and research directions. Semin. Cell Dev. Biol. 62:67–77, 2017.CrossRefPubMedGoogle Scholar
  12. 12.
    Ewers, B. J., V. M. Jayaraman, R. F. Banglmaier, and R. C. Haut. Rate of blunt impact loading affects changes in retropatellar cartilage and underlying bone in the rabbit patella. J. Biomech. 35:747–755, 2002.CrossRefPubMedGoogle Scholar
  13. 13.
    Hayes, W. C., L. M. Keer, G. Herrmann, and L. F. Mockros. A mathematical analysis for indentation tests of articular cartilage. J. Biomech. 5:541–551, 1972.CrossRefPubMedGoogle Scholar
  14. 14.
    Honkanen, J. T. J., M. J. Turunen, J. D. Freedman, S. Saarakkala, M. W. Grinstaff, J. H. Ylärinne, J. S. Jurvelin, and J. Töyräs. Cationic contrast agent diffusion differs between cartilage and meniscus. Ann. Biomed. Eng. 44:2913–2921, 2016.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Honkanen, J. T. J., M. J. Turunen, V. Tiitu, J. S. Jurvelin, and J. Töyräs. Transport of iodine is different in cartilage and meniscus. Ann. Biomed. Eng. 44:2114–2122, 2016.CrossRefPubMedGoogle Scholar
  16. 16.
    Julkunen, P., R. K. Korhonen, W. Herzog, and J. S. Jurvelin. Uncertainties in indentation testing of articular cartilage: a fibril-reinforced poroviscoelastic study. Med. Eng. Phys. 30:506–515, 2008.CrossRefPubMedGoogle Scholar
  17. 17.
    Kokkonen, H. T., J. S. Jurvelin, V. Tiitu, and J. Töyräs. Detection of mechanical injury of articular cartilage using contrast enhanced computed tomography. Osteoarthr. Cartil. 19:295–301, 2011.CrossRefPubMedGoogle Scholar
  18. 18.
    Kokkonen, H. T., J.-S. Suomalainen, A. Joukainen, H. Kröger, J. Sirola, J. S. Jurvelin, J. Salo, and J. Töyräs. In vivo diagnostics of human knee cartilage lesions using delayed CBCT arthrography. J. Orthop. Res. 32:403–412, 2014.CrossRefPubMedGoogle Scholar
  19. 19.
    Kokkonen, H. T., H. C. Chin, J. Töyräs, J. S. Jurvelin, and T. M. Quinn. Solute transport of negatively charged contrast agents across articular surface of injured cartilage. Ann. Biomed. Eng. 45:973–981, 2016.CrossRefPubMedGoogle Scholar
  20. 20.
    Korhonen, R. K., M. S. Laasanen, J. Töyräs, R. Lappalainen, H. J. Helminen, and J. S. Jurvelin. Fibril reinforced poroelastic model predicts specifically mechanical behavior of normal, proteoglycan depleted and collagen degraded articular cartilage. J. Biomech. 36:1373–1379, 2003.CrossRefPubMedGoogle Scholar
  21. 21.
    Kulmala, K. A. M., H. M. Karjalainen, H. T. Kokkonen, V. Tiitu, V. Kovanen, M. J. Lammi, J. S. Jurvelin, R. K. Korhonen, and J. Töyräs. Diffusion of ionic and non-ionic contrast agents in articular cartilage with increased cross-linking—contribution of steric and electrostatic effects. Med. Eng. Phys. 35:1415–1420, 2013.CrossRefPubMedGoogle Scholar
  22. 22.
    Lakin, B. A., H. Patel, C. Holland, J. D. Freedman, J. S. Shelofsky, B. D. Snyder, K. S. Stok, and M. W. Grinstaff. Contrast-enhanced CT using a cationic contrast agent enables non-destructive assessment of the biochemical and biomechanical properties of mouse tibial plateau cartilage. J. Orthop. Res. 34:1130–1138, 2016.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lakin, B. A., B. D. Snyder, and M. W. Grinstaff. Assessing cartilage biomechanical properties: techniques for evaluating the functional performance of cartilage in health and disease. Annu. Rev. Biomed. Eng. 19:27–55, 2017.CrossRefPubMedGoogle Scholar
  24. 24.
    Li, X., V. Pedoia, D. Kumar, J. Rivoire, C. Wyatt, D. Lansdown, K. Amano, N. Okazaki, D. Savic, M. F. Koff, J. Felmlee, S. L. Williams, and S. Majumdar. Cartilage T1rho and T2 relaxation times: longitudinal reproducibility and variations using different coils, MR systems and sites. Osteoarthr. Cartil. 23:2214–2223, 2015.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Link, T. M., J. Neumann, and X. Li. Prestructural cartilage assessment using MRI. J. Magn. Reson. Imaging 45:949–965, 2017.CrossRefPubMedGoogle Scholar
  26. 26.
    Maroudas, A. Biophysical chemistry of cartilaginous tissues with special reference to solute and fluid transport. Biorheology 12:233–248, 1975.CrossRefPubMedGoogle Scholar
  27. 27.
    Maroudas, A., P. Bullough, S. A. Swanson, and M. A. Freeman. The permeability of articular cartilage. J. Bone Jt Surg. Br. 50:166–177, 1968.CrossRefGoogle Scholar
  28. 28.
    Muir, H., P. Bullough, and A. Maroudas. The distribution of collagen in human articular cartilage with some of its physiological implications. J. Bone Jt Surg. Br. 52:554–563, 1970.CrossRefGoogle Scholar
  29. 29.
    Myller, K. A. H., M. J. Turunen, J. T. J. Honkanen, S. P. Vaananen, J. T. Iivarinen, J. Salo, J. S. Jurvelin, and J. Töyräs. In vivo contrast-enhanced cone beam CT provides quantitative information on articular cartilage and subchondral bone. Ann. Biomed. Eng. 45:811–818, 2017.CrossRefPubMedGoogle Scholar
  30. 30.
    Pouran, B., V. Arbabi, A. A. Zadpoor, and H. Weinans. Isolated effects of external bath osmolality, solute concentration, and electrical charge on solute transport across articular cartilage. Med. Eng. Phys. 38:1399–1407, 2016.CrossRefPubMedGoogle Scholar
  31. 31.
    Rangacharyulu, C. Physics of Nuclear Radiations Concepts, Techniques and Applications. Boca Raton: Taylor and Francis, 2013.CrossRefGoogle Scholar
  32. 32.
    Saltybaeva, N., M. E. Jafari, M. Hupfer, and W. A. Kalender. Estimates of effective dose for CT scans of the lower extremities. Radiology 273:153–159, 2014.CrossRefPubMedGoogle Scholar
  33. 33.
    Saukko, A. E. A., J. T. J. Honkanen, W. Xu, S. P. Vaananen, J. S. Jurvelin, V.-P. Lehto, and J. Töyräs. Dual contrast CT method enables diagnostics of cartilage injuries and degeneration using a single CT image. Ann. Biomed. Eng. 2017. Scholar
  34. 34.
    Stewart, R. C., P. N. Bansal, V. Entezari, H. Lusic, R. M. Nazarian, B. D. Snyder, and M. W. Grinstaff. Contrast-enhanced CT with a high-affinity cationic contrast agent for imaging ex vivo bovine, intact ex vivo rabbit, and in vivo rabbit cartilage. Radiology 266:141–150, 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Stewart, R. C., J. T. J. Honkanen, H. T. Kokkonen, V. Tiitu, S. Saarakkala, A. Joukainen, B. D. Snyder, J. S. Jurvelin, M. W. Grinstaff, and J. Töyräs. Contrast-enhanced computed tomography enables quantitative evaluation of tissue properties at intrajoint regions in cadaveric knee cartilage. Cartilage 8:391–399, 2017.CrossRefPubMedGoogle Scholar
  36. 36.
    Stewart, R. C., A. N. Patwa, H. Lusic, J. D. Freedman, M. Wathier, B. D. Snyder, A. Guermazi, and M. W. Grinstaff. Synthesis and preclinical characterization of a cationic iodinated imaging contrast agent (CA4 +) and its use for quantitative computed tomography of ex vivo human hip cartilage. J. Med. Chem. 60:5543–5555, 2017.CrossRefPubMedGoogle Scholar
  37. 37.
    Zou, G. Y. Toward using confidence intervals to compare correlations. Psychol. Methods 12:399–413, 2007.CrossRefPubMedGoogle Scholar

Copyright information

© Biomedical Engineering Society 2018

Authors and Affiliations

  1. 1.Department of Applied PhysicsUniversity of Eastern FinlandKuopioFinland
  2. 2.Diagnostic Imaging CenterKuopio University HospitalKuopioFinland
  3. 3.Center of OncologyKuopio University HospitalKuopioFinland
  4. 4.Department of Orthopedics, Traumatology and Hand SurgeryKuopio University HospitalKuopioFinland
  5. 5.Departments of Biomedical Engineering, Chemistry, and MedicineBoston UniversityBostonUSA
  6. 6.School of Liberal Studies and EducationNavrachana UniversityVadodaraIndia

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