title: Ultrasound-modulated fluorescence based on fluorescent microbubbles.
abstract: Ultrasound-modulated fluorescence (UMF) imaging has been proposed to provide fluorescent contrast while maintaining ultrasound resolution in an optical-scattering medium (such as biological tissue). The major challenge is to extract the weakly modulated fluorescent signal from a bright and unmodulated background. UMF was experimentally demonstrated based on fluorophore-labeled microbubble contrast agents. These contrast agents were produced by conjugating N-hydroxysuccinimide (NHS)-ester-attached fluorophores on the surface of amine-functionalized microbubbles. The fluorophore surface concentration was controlled so that a significant self-quenching effect occurred when no ultrasound was applied. The intensity of the fluorescent emission was modulated when microbubbles were oscillated by ultrasound pulses, presented as UMF signal. Our results demonstrated that the UMF signals were highly dependent on the microbubbles' oscillation amplitude and the initial surface fluorophore-quenching status. A maximum of ∼42% UMF modulation depth was achieved with a single microbubble under an ultrasound peak-to-peak pressure of 675 kPa. Further, UMF was detected from a 500-μm tube filled with contrast agents in water and scattering media with ultrasound resolution. These results indicate that ultrasound-modulated fluorescent microbubble contrast agents can potentially be used for fluorescence-based molecular imaging with ultrasound resolution in the future.
authors.affiliation: University of Texas at Arlington, Department of Bioengineering, Arlington, Texas 76010, United StatesbUniversity of Texas at Arlington and University of Texas Southwestern Medical Center at Dallas, Joint Biomedical Engineering Program, Texas 75390, United.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: University of Colorado, Department of Mechanical Engineering, Boulder, Colorado 80309-0427, United States.
authors.forename: Jameel A
authors.initials: JA
authors.lastname: Feshitan
authors.affiliation: University of Texas at Arlington, Department of Bioengineering, Arlington, Texas 76010, United StatesbUniversity of Texas at Arlington and University of Texas Southwestern Medical Center at Dallas, Joint Biomedical Engineering Program, Texas 75390, United.
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Wei
authors.affiliation: University of Colorado, Department of Mechanical Engineering, Boulder, Colorado 80309-0427, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Borden
authors.affiliation: University of Texas at Arlington, Department of Bioengineering, Arlington, Texas 76010, United StatesbUniversity of Texas at Arlington and University of Texas Southwestern Medical Center at Dallas, Joint Biomedical Engineering Program, Texas 75390, United.
authors.forename: Baohong
authors.initials: B
authors.lastname: Yuan
mesh_terms: D003287:Contrast Media / Q000737:chemistry / Q000528:radiation effects; D005456:Fluorescent Dyes / Q000737:chemistry* / Q000528:radiation effects*; D019220:High-Energy Shock Waves; D045423:Microbubbles; D008856:Microscopy, Fluorescence / Q000295:instrumentation / Q000379:methods*; D057054:Molecular Imaging / Q000295:instrumentation / Q000379:methods*; D061088:Photoacoustic Techniques / Q000295:instrumentation / Q000379:methods*; D013010:Sonication / Q000379:methods*
chemical_list: D003287:Contrast Media; D005456:Fluorescent Dyes
references.citation: Curr Med Chem. 2009;16(5):627-42
references.pmid: 19199927
references.citation: Appl Phys Lett. 2008 Jul 7;93(1):11111
references.pmid: 19079748
references.citation: Clin Cancer Res. 2007 Jan 1;13(1):323-30
references.pmid: 17200371
references.citation: Nat Photonics. 2012 Oct 1;6(10):657-661
references.pmid: 23241552
references.citation: J Nucl Med. 2008 Apr;49(4):511-4
references.pmid: 18375921
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14241-4
references.pmid: 11121030
references.citation: J Acoust Soc Am. 2007 Aug;122(2):1191-200
references.pmid: 17672665
references.citation: Mol Cancer Ther. 2008 Jan;7(1):101-9
references.pmid: 18202013
references.citation: Ultrasound Med Biol. 2007 Dec;33(12):1978-87
references.pmid: 17900793
references.citation: Br J Radiol. 2003;76 Spec No 2:S128-38
references.pmid: 15572335
references.citation: Nat Rev Drug Discov. 2003 Feb;2(2):123-31
references.pmid: 12563303
references.citation: Ultrasound Med Biol. 2008 Jun;34(6):1014-20
references.pmid: 18395962
references.citation: Opt Express. 2008 Aug 18;16(17):12577-90
references.pmid: 18711494
references.citation: Angew Chem Int Ed Engl. 2007;46(12):1999-2001
references.pmid: 17279589
references.citation: Biomed Microdevices. 2012 Apr;14(2):279-89
references.pmid: 22076383
references.citation: Invest Radiol. 2011 Apr;46(4):215-24
references.pmid: 21343825
references.citation: Biomed Opt Express. 2013 Aug 08;4(9):1559-70
references.pmid: 24049677
references.citation: Trends Mol Med. 2007 Jul;13(7):287-97
references.pmid: 17544849
references.citation: Anal Biochem. 1988 Jul;172(1):61-77
references.pmid: 3189776
references.citation: Opt Lett. 2006 Aug 15;31(16):2423-5
references.pmid: 16880843
references.citation: Genes Dev. 2003 Mar 1;17(5):545-80
references.pmid: 12629038
references.citation: Opt Lett. 2004 Nov 1;29(21):2509-11
references.pmid: 15584277
references.citation: J Biomed Opt. 2010 Mar-Apr;15(2):021321
references.pmid: 20459241
references.citation: J Opt Soc Am A Opt Image Sci Vis. 2003 Dec;20(12):2347-54
references.pmid: 14686514
references.citation: J Biomed Opt. 2013 Feb;18(2):20505
references.pmid: 23386195
references.citation: Soft Matter. 2013 Jan 1;9(8):2384-2388
references.pmid: 23526919
references.citation: Dis Markers. 2003-2004;19(2-3):123-38
references.pmid: 15096709
references.citation: Pharm Res. 2007 Jun;24(6):1172-85
references.pmid: 17385018
references.citation: J Nucl Med. 2008 Jun;49 Suppl 2:113S-28S
references.pmid: 18523069
references.citation: Drug Des Devel Ther. 2013 May 03;7:375-88
references.pmid: 23667309
references.citation: J Appl Phys. 2008 Nov 15;104(10):103102
references.pmid: 19337588
references.citation: Nat Commun. 2012 Jun 26;3:928
references.pmid: 22735456
references.citation: J Biomed Opt. 2010 May-Jun;15(3):030515
references.pmid: 20614998
references.citation: J Biomed Opt. 2013 Jan;18(1):15002
references.pmid: 23292610
references.citation: J Biomed Opt. 2009 Mar-Apr;14(2):024043
references.pmid: 19405771
references.citation: Opt Lett. 2012 May 15;37(10):1658-60
references.pmid: 22627528
references.citation: J Ultrasound Med. 2011 Jul;30(7):921-31
references.pmid: 21705725
references.citation: Opt Lett. 2004 Dec 1;29(23):2770-2
references.pmid: 15605500
references.citation: Biomaterials. 2012 Jan;33(1):247-55
references.pmid: 21993236