title: Early detection of heterotopic ossification using near-infrared optical imaging reveals dynamic turnover and progression of mineralization following Achilles tenotomy and burn injury.
abstract: Heterotopic ossification (HO) is the abnormal formation of bone in soft tissue. Current diagnostics have low sensitivity or specificity to incremental progression of mineralization, especially at early time points. Without accurate and reliable early diagnosis and intervention, HO progression often results in incapacitating conditions of limited range of motion, nerve entrapment, and pain. We hypothesized that non-invasive near-infrared (NIR) optical imaging can detect HO at early time points and monitor heterotopic bone turnover longitudinally. C57BL6 mice received an Achilles tenotomy on their left hind limb in combination with a dorsal burn or sham procedure. A calcium-chelating tetracycline derivative (IRDye 680RD BoneTag) was injected bi-weekly and imaged via NIR to measure accumulative fluorescence for 11 wk and compared to in vivo microCT images. Percent retention of fluorescence was calculated longitudinally to assess temporal bone resorption. NIR detected HO as early as five days and revealed a temporal response in HO formation and turnover. MicroCT could not detect HO until 5 wk. Confocal microscopy confirmed fluorophore localization to areas of HO. These findings demonstrate the ability of a near-infrared optical imaging strategy to accurately and reliably detect and monitor HO in a murine model.
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Perosky
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Peterson
authors.forename: Owulatobi N
authors.initials: ON
authors.lastname: Eboda
authors.forename: Michael D
authors.initials: MD
authors.lastname: Morris
authors.forename: Stewart C
authors.initials: SC
authors.lastname: Wang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Levi
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kozloff
mesh_terms: D000125:Achilles Tendon / Q000000981:diagnostic imaging / Q000503:physiopathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001862:Bone Resorption; D001842:Bone and Bones / Q000000981:diagnostic imaging; D002056:Burns / Q000503:physiopathology*; D002118:Calcium / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry; D003287:Contrast Media / Q000737:chemistry; D018450:Disease Progression; D005456:Fluorescent Dyes / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009999:Ossification, Heterotopic / Q000000981:diagnostic imaging / Q000503:physiopathology*; D016059:Range of Motion, Articular; D012680:Sensitivity and Specificity; D019265:Spectroscopy, Near-Infrared; D058971:Tenotomy; D013752:Tetracycline / Q000737:chemistry; D055114:X-Ray Microtomography
chemical_list: D015415:Biomarkers; D002614:Chelating Agents; D003287:Contrast Media; D005456:Fluorescent Dyes; D013752:Tetracycline; D002118:Calcium
keywords: biomarkers; heterotopic Ossification; microCT; molecular imaging
references.citation: J Bone Miner Res. 2007 Aug;22(8):1208-16
references.pmid: 17488196
references.citation: Paraplegia. 1982 Aug;20(4):208-16
references.pmid: 6215609
references.citation: J Orthop Trauma. 2012 Nov;26(11):e204-13
references.pmid: 22588530
references.citation: J Bone Joint Surg Am. 1997 May;79(5):749-55
references.pmid: 9160948
references.citation: Clin Orthop Relat Res. 2009 Feb;467(2):526-30
references.pmid: 18820982
references.citation: Eur J Surg Oncol. 2011 Jan;37(1):32-9
references.pmid: 21106329
references.citation: Radiology. 2007 Nov;245(2):523-31
references.pmid: 17940307
references.citation: Nat Biotechnol. 2005 Mar;23(3):313-20
references.pmid: 15765087
references.citation: Skeletal Radiol. 2012 Jan;41(1):61-6
references.pmid: 21331512
references.citation: Mol Imaging Biol. 2014 Apr;16(2):147-51
references.pmid: 24249642
references.citation: J Trauma Acute Care Surg. 2012 May;72(5):1399-403
references.pmid: 22673273
references.citation: Anal Biochem. 2011 Sep 15;416(2):167-73
references.pmid: 21645491
references.citation: J Rehabil Med. 2005 May;37(3):129-36
references.pmid: 16040468
references.citation: Nat Med. 2003 Jan;9(1):123-8
references.pmid: 12514725
references.citation: Bone. 2013 May;54(1):28-34
references.pmid: 23314070
references.citation: Radiology. 2002 Jan;222(1):189-95
references.pmid: 11756725
references.citation: Metab Bone Dis Relat Res. 1983-1984;5(1):41-5
references.pmid: 6200748
references.citation: J Bone Joint Surg Am. 2001 Dec;83(12):1783-8
references.pmid: 11741055
references.citation: Radiology. 1977 Apr;123(1):217-21
references.pmid: 403570
references.citation: AJR Am J Roentgenol. 2010 Jun;194(6):1559-67
references.pmid: 20489097
references.citation: Mol Imaging Biol. 2014 Oct;16(5):652-60
references.pmid: 24609633
references.citation: AJR Am J Roentgenol. 2010 Aug;195(2):321-32
references.pmid: 20651186
references.citation: Arthritis Rheumatol. 2014 Jan;66(1):121-9
references.pmid: 24431283
references.citation: Ann Surg. 2014 May;259(5):993-8
references.pmid: 23673767
references.citation: J Orthop Res. 2003 May;21(3):529-34
references.pmid: 12706027
references.citation: J Bone Miner Res. 2010 Aug;25(8):1748-58
references.pmid: 20200982
references.citation: Clin Orthop Relat Res. 1989 Aug;(245):269-81
references.pmid: 2502346
references.citation: J Head Trauma Rehabil. 2009 Jan-Feb;24(1):69-71
references.pmid: 19158599
references.citation: Paraplegia. 1993 Jan;31(1):40-50
references.pmid: 8446447
references.citation: Eur J Nucl Med Mol Imaging. 2011 May;38 Suppl 1:S69-77
references.pmid: 21484383
references.citation: Bone. 2009 Feb;44(2):190-8
references.pmid: 19007918
references.citation: Curr Protoc Mouse Biol. 2013 Jun;3:39-67
references.pmid: 24634803
references.citation: Insights Imaging. 2013 Oct;4(5):595-603
references.pmid: 23828230
references.citation: J Orthop Trauma. 2012 Dec;26(12):684-8
references.pmid: 23010648
references.citation: Eur Radiol. 2005 Sep;15(9):1867-75
references.pmid: 15856244
references.citation: Am J Roentgenol Radium Ther Nucl Med. 1973 Aug;118(4):865-9
references.pmid: 4205823
references.citation: Int J Exp Pathol. 2012 Oct;93(5):319-31
references.pmid: 22974213
references.citation: J Bone Joint Surg Br. 1998 Mar;80(2):259-63
references.pmid: 9546456