Skip to main content
    • Aa
    • Aa

Biochemical and molecular aspects of spectral diagnosis in calcinosis cutis

  • Shan-Yang Lin (a1)

Calcinosis cutis (CC) is a type of calcinosis wherein insoluble compounds or salts deposited on the skin. Clinical diagnosis of CC is usually achieved through time consuming histopathological or immunohistochemical procedures, but it can only be empirically identified by experienced practitioners. The use of advanced vibrational spectroscopy has been recently shown to have great potential as a diagnostic technique for various diseased tissues because it analyses the chemical composition of diseased tissue rather than its anatomy and predicts disease progression. This review article includes a summary of the application of Fourier transform infrared (FT-IR) and Raman spectroscopic or microspectroscopic analysis for the rapid diagnosis and identification of the chemical composition of skin calcified deposits in patients with various CC symptoms. Both advanced techniques not only can detect the types of insoluble salts such as calcium phosphate, calcium carbonate, and monosodium urate, and β-carotene in the calcified deposits of human skin tissue but also can directly differentiate the carbonate substitution in the apatite structure of the skin calcified deposits. In particular, the combination of both vibrational techniques may provide complementary information to simultaneously assess the intact components of the calcified deposits. In the future, both FT-IR and Raman vibrational microspectroscopic techniques will become available tools to support the standard test techniques currently used in some clinical diagnoses. Molecular spectroscopy technique is rapidly changing disease diagnosis and management.

Corresponding author
Corresponding author: Prof. Shan-Yang Lin, PhD., Lab. Pharm. Biopharm., Department of Biotechnology and Pharmaceutical Technology, Yuanpei University, Hsin Chu, Taiwan, Republic of China. + 886-3-610-2439; + 886-3-610-2328; E-mail:
Hide All
1 N.B. Colthup , L.H. Daly and S.E. Wiberely (1990) Introduction to IR and Raman Spectroscopy (3rd edn), Academic Press Inc., New York, USA

3 W. Petrich (2001) Mid-infrared and Raman spectroscopy for medical diagnostics. Applied Spectroscopy Reviews 36, 181-237

4 H.H. Mantsch , L.P. Choo-Smith and R.A. Shaw (2002) Vibrational spectroscopy and medicine: an alliance in the making. Vibrational Spectroscopy 30, 31-41

5 L.G. Thygesen (2003) Vibrational microspectroscopy of food. Raman vs. FT-IR. Trends in Food Science & Technology 14, 50-57

9 C. Krafft (2004) Bioanalytical applications of Raman spectroscopy. Analytical and Bioanalytical Chemistry 378, 60-62

10 S.Y. Lin , M.J. Li and W.T. Cheng (2007) FT-IR and Raman vibrational microspectroscopies used for spectral biodiagnosis of human tissues Spectroscopy-An International Journal 21, 1-30

11 S.Y. Lin (2014) Vibrational spectral biodiagnosis of ocular calcification. Applied Spectroscopy Reviews 49, 11-63

12 E.R. Blout and M. Fields (1948) On the infrared spectra of nucleic acids and certain of their components. Science. 107, 252-254

13 E.R. Blout and R.C. Mellors (1949) Infrared spectra of tissues. Science. 110, 137-138

14 A. Elliot and E.J. Ambrose (1950) Structure of synthetic polypeptides. Nature. 165, 921-922

17 D.I. Ellis and R. Goodacre (2006) Metabolic fingerprinting in disease diagnosis: biomedical applications of infrared and Raman spectroscopy. Analyst. 131, 875-885

18 C. Krafft and V. Sergo (2006) Biomedical applications of Raman and infrared spectroscopy to diagnose tissues. Spectroscopy-An International Journal 20, 195-218

19 M.J. Walsh (2007) IR microspectroscopy: potential applications in cervical cancer screening. Cancer Letters. 246, 1-11

22 V.F. Kalasinsky , H. Marie Jenkins and F.B. Johnson (2002) Applications of vibrational microspectroscopy to pathology specimens. Vibrational Spectroscopy 28, 199-207

23 M. Diem (2004) A decade of vibrational micro-spectroscopy of human cells and tissue. Analyst. 129, 880-885

24 C. Krafft (2009) Disease recognition by infrared and Raman spectroscopy. Journal of Biophotonics 2, 13-28

26 M. Diem (2012) Applications of infrared and Raman microspectroscopy of cells and tissue in medical diagnostics: present status and future promises. Spectroscopy-An International Journal 27, 463-496

28 A. Carden and M.D. Morris (2000) Application of vibrational spectroscopy to the study of mineralized tissues. Journal of Biomedical Optics 5, 259-268

30 A.L. Boskey and R. Mendelsohn (2005) Infrared spectroscopic characterization of mineralized tissues. Vibrational Spectroscopy 38, 107-114

32 E.E. Golub (2011) Biomineralization and matrix vesicles in biology and pathology. Seminars in Immunopathology 33, 409-417

33 S. Chander and P. Gordon (2012) Soft tissue and subcutaneous calcification in connective tissue diseases. Current Opinion in Rheumatology 24, 158-164

34 T. Kirsch (2012) Biomineralization–an active or passive process? Connective Tissue Research 53, 438-445

35 E.J. O'Flaherty (2000) Modeling normal aging bone loss, with consideration of bone loss in osteoporosis. Toxicological Sciences 55, 171-188

37 H. Chen (2008) Regional variations of vertebral trabecular bone microstructure with age and gender. Osteoporosis International 19, 1473-1483

38 H. Orimo (2010) The mechanism of mineralization and the role of alkaline phosphatase in health and disease. Journal of Nippon Medical School. 77, 4-12

42 F. Atzeni , P. Sarzi-Puttini and M. Bevilacqua (2006) Calcium deposition and associated chronic diseases (atherosclerosis, diffuse idiopathic skeletal hyperostosis, and others). Rheumatic Disease Clinics of North America 32, 413–26, viii

43 T. Kirsch (2006) Determinants of pathological mineralization. Current Opinion in Rheumatology 18, 174-180

44 M. Peacock (2010) Calcium metabolism in health and disease. Clinical Journal of the American Society of Nephrology 5, S23-S30

45 I. Masuda (2004) Calcium crystal deposition diseases: lessons from histochemistry. Current Opinion in Rheumatology 16, 279-281

46 C.M. Giachelli (1999) Ectopic calcification: gathering hard facts about soft tissue mineralization. The American Journal of Pathology 154, 671-675

48 K. Kawasaki , A.V. Buchanan and K.M. Weiss (2009) Biomineralization in humans: making the hard choices in life. Annual Review of Genetics 43, 119-142

49 S.V. Dorozhkin (2009) Calcium orthophosphates in nature, biology and medicine. Materials 2, 399-498

50 S.V. Dorozhkin (2010) Bioceramics of calcium orthophosphates. Biomaterials 31, 1465-1485

51 M.S. Sader (2013) Simultaneous incorporation of magnesium and carbonate in apatite: effect on physico-chemical properties. Materials Research 16, 779-784

52 H. Pan and B.W. Darvell (2010) Effect of carbonate on hydroxyapatite solubility. Crystal Growth & Design 10, 845-850

54 R.Z. LeGeros (1995) Synergistic effects of magnesium and carbonate on properties of biological and synthetic apatites. Connective Tissue Research 33, 203-209

55 F. Ren (2010) Synthesis, characterization and ab initio simulation of magnesium-substituted hydroxyapatite. Acta Biomaterialia 6, 2787-2796

56 G. Xu , I.A. Aksay and J.T. Groves (2001) Continuous crystalline carbonate apatite thin films. A biomimetic approach. Journal of the American Chemical Society 123, 2196-2203

59 P.N. De Aza , A.H. De Aza and S. De Aza (2005) Crystalline Bioceramic Materials. Boletín de la Sociedad Española de Cerámica 44, 135-145

60 J.C. Elliott , D.W. Holcomb and R.A. Young (1985) Infrared determination of the degree of substitution of hydroxyl by carbonate ions in human dental enamel. Calcified Tissue International 37, 372-375

61 R.Z. LeGeros (1991) Calcium phosphates in oral biology and medicine. Monographs in Oral Science 15, 1-201

62 B. Wopenka and J.D. Pasteris (2005) A mineralogical perspective on the apatite in bone. Materials Science and Engineering C 25, 131-143

63 S. Peroos , Z. Du and N.H. De Leeuw (2006) A computer modelling study of the uptake, structure and distribution of carbonate defects in hydroxyapatite. Biomaterials 27, 2150-2161

64 S. Kannan (2011) Synthesis, mechanical and biological characterization of ionic doped carbonated hydroxyapatite/β-tricalcium phosphate mixtures. Acta Biomaterialia 7, 1835-1843

65 C. Rey (1989) The carbonate environment in bone mineral: a resolution-enhanced Fourier transform infrared spectroscopy study. Calcified Tissue International 45, 157-164

66 E. Landi (2004) Influence of synthesis and sintering parameters on the characteristics of carbonate apatite. Biomaterials 25, 1763-1770

67 J.S. Walsh and J.A. Fairley (1995) Calcifying disorders of the skin. Journal of the American Academy of Dermatology 33, 693-706

69 N. Reiter (2011) Calcinosis cutis. Part I. Diagnostic pathway. Journal of the American Academy of Dermatology 65, 1-12; quiz 13–4

71 S.N. Meloan and H. Puchtler (1985) Chemical mechanisms of staining methods: von Kossa's technique. What von Kossa really wrote and a modified reaction for selective demonstration of inorganic phosphate. Journal of Histotechnology 8, 11-13

72 J. Rungby (1993) The von Kossa reaction for calcium deposits: silver lactate staining increases sensitivity and reduces background. The Histochemical Journal 25, 446-451

73 L.F. Bonewald (2003) Von Kossa staining alone is not sufficient to confirm that mineralization in vitro represents bone formation. Calcified Tissue International 72, 537-547

74 M.D. Morris and W.F. Finney (2004) Recent developments in Raman and infrared spectroscopy and imaging of bone tissue. Spectroscopy-An International Journal 18, 155-159

75 S. Stewart (2002) Trends in early mineralization of murine calvarial osteoblastic cultures: a Raman microscopic study. Journal of Raman Spectroscopy 33, 536-543

76 N.S. Eikje , K. Aizawa and Y. Ozaki (2005) Vibrational spectroscopy for molecular characterisation and diagnosis of benign, premalignant and malignant skin tumours. Biotechnology Annual Review 11, 191-225

77 H.J. Chiou (2010) Correlations among mineral components, progressive calcification process and clinical symptoms of calcific tendonitis. Rheumatology. 49, 548-555

78 C. Kendall (2011) Exploiting the diagnostic potential of biomolecular fingerprinting with vibrational spectroscopy. Faraday Discussions 149, 279-290

83 G. Daculsi , G. Faure and B. Kerebel (1983) Electron microscopy and microanalysis of a subcutaneous heterotopic calcification. Calcified Tissue International 35, 723-727

84 V. Bettoli (1992) Structural and chemical characterization of a cutaneous calcification. Journal of Thermal Analysis 38, 2719-2728

86 W.T. Cheng (2005) Micro-Raman spectroscopy used to identify and grade human skin pilomatrixoma. Microscopy Research & Technique 68, 75-79

87 M. Gniadecka (2001) Cutaneous tophi and calcinosis diagnosed in vivo by Raman spectroscopy. British Journal of Dermatology 145, 672-674

88 L.G. Rider and F.W. Miller (1997) Classification and treatment of the juvenile idiopathic inflammatory myopathies. Rheumatic Disease Clinics of North America 23, 619-655

89 B.M. Feldman (2008) Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. The Lancet 371, 2201-2212

90 L.M. Pachman (2006) Composition of calcifications in children with juvenile dermatomyositis: association with chronic cutaneous inflammation. Arthritis & Rheumatism 54, 3345-3350

91 N. Eidelman (2009) Microstructure and mineral composition of dystrophic calcification associated with the idiopathic inflammatory myopathies. Arthritis Research & Therapy 11(5), R159

92 M.T. Liu (2005) Identification of chemical compositions of skin calcified deposit by vibrational microspectroscopies. Archives of Dermatological Research 297, 231-234

93 G. Penel (1998) MicroRaman spectral study of the PO4 and CO3 vibrational modes in synthetic and biological apatites. Calcified Tissue International 63, 475-481

94 E.P. Paschalis (1996) FTIR microspectroscopic analysis of human osteonal bone. Calcified Tissue International 59, 480-487

95 C. Rey (1991) Fourier transform infrared spectroscopic study of the carbonate ions in bone mineral during aging. Calcified Tissue International 49, 251-258

96 M.E. Fleet (2013) The carbonate ion in hydroxyapatite: recent X-ray and infrared results. Frontiers in Bioscience (Elite Edition) 5, 643-652

97 D.M. Niu (2011) Idiopathic calcinosis cutis in a child: chemical composition of the calcified deposits. Dermatology 222, 201-205

99 M. Jackson and H.H. Mantsch (1995) The use and misuse of FTIR spectroscopy in the determination of protein structure. Critical Reviews in Biochemistry and Molecular Biology 30, 95-120

100 I.V. Ermakov (2004) Noninvasive selective detection of lycopene and beta-carotene in human skin using Raman spectroscopy. Journal of Biomedical Optics 9, 332-338

101 B.R. Hammond and B.R. Wooten (2005) Resonance Raman spectroscopic measurement of carotenoids in the skin and retina. Journal of Biomedical Optics 10(5), 054002

103 Q. Li (2013) Review of spectral imaging technology in biomedical engineering: achievements and challenges. Journal of Biomedical Optics 18(10), 100901.

104 R. Bhargava (2012) Infrared spectroscopic imaging: the next generation. Applied Spectroscopy 66, 1091-1120

105 U. Bindig (2002) Fiber-optical and microscopic detection of malignant tissue by use of infrared spectrometry. Journal of Biomedical Optics 7, 100-108

106 J.T. Motz (2006) In vivo Raman spectral pathology of human atherosclerosis and vulnerable plaque. Journal of Biomedical Optics 11(2), 021003

108 C.M. Krishna (2006) Combined Fourier transform infrared and Raman spectroscopic approach for identification of multidrug resistance phenotype in cancer cell lines. Biopolymers 82, 462-470

109 P. Lasch and J. Knwipp (2008) Biomedical Vibrational Spectroscopy, John Wiley & Sons, Hobaken, New Jersey, USA

111 J. Surmacki , J. Musial , R. Kordek and H. Abramczyk (2013) Raman imaging at biological interfaces: applications in breast cancer diagnosis. Molecular Cancer 12, 48

112 P. Matousek and N. Stone (2013) Recent advances in the development of Raman spectroscopy for deep non-invasive medical diagnosis. Journal of Biophotonics 6, 7-19

113 M.J. Pelletier (2013) Sensitivity-enhanced transmission Raman spectroscopy. Applied Spectroscopy 67, 829-840

114 B. Sharma (2013) Seeing through bone with surface-enhanced spatially offset Raman spectroscopy. Journal of the American Chemical Society 135, 17290-17293

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Full text views

Total number of HTML views: 10
Total number of PDF views: 12 *
Loading metrics...

Abstract views

Total abstract views: 146 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 18th October 2017. This data will be updated every 24 hours.