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VMI
 


Vascular Medicine Institute
University of Pittsburgh
BST E1240
200 Lothrop Street
Pittsburgh, PA 15261
Phone: 412-383-5853
Fax: 412-648-5980

Xucai Chen, PhD

 

xucai chen phd

 

Xucai Chen, MD

Research Associate Professor of Medicine, Division of Cardiology

S-969 Scaife Hall
200 Lothrop Street
Pittsburgh, PA 15213

Phone: 412-648-9512
Email: chenxx2@upmc.edu


Center for Ultrasound Molecular Imaging and Therapeutics

   

Bio

Dr. Chen specializes in biological ultrasound applications. His current research interests concentrate on developing new technologies for ultrasound molecular imaging and therapeutics, radiation force assisted cell therapy, ultrasound assisted drug and gene delivery, and microbubble dynamics using high speed imaging.


Education and Training

B.Eng., China University of Mining and Technology, 1982

Ph.D., Yale University, 1991

Postdoctoral Fellow, University of Rochester, Electrical & Computer Eng. and Cardiology, 1993


Research Interests

Ultrasound molecular imaging and therapy

Radiation force theory and application

Nonlinear IVUS imaging

Drug and gene delivery

High speed imaging and microbubble dynamics


Lab

Center for Ultrasound Molecular Imaging and Therapeutics

Acoustic radiation force on microbubbles can be used to delivery stem cells for vascular cell therapy. (Toma C, Fisher A, Wang J, Chen X, Grata M, Leeman J, Winston B, Kaya M, Fu H, Lavery L, Fischer D, Wagner WR, and Villanueva FS, Vascular endoluminal delivery of mesenchymal stem cells using acoustic radiation force. Tissue Eng Part A, 2011. 17(9-10): p. 1457-64; Kaya M, Toma C, Wang J, Grata M, Fu H, Villanueva FS, and Chen X, Acoustic radiation force for vascular cell therapy: in vitro validation. Ultrasound Med Biol, 2012. 38(11): p. 1989-97.)

Chen Fig 1

Flow trajectories of microbubble-cell complexes for various acoustic pressures and duty cycles after maximum intensity persistence was applied to the recorded images. Adapted from Kaya et al, Ultrasound Med Biol, 2012. 38.

 

UPMC Cam, the ultrafast multiframe imaging system developed at the Center of Molelcualr Imaging and Therapeutics directed by Dr. Villanueva is well suited for the study of dynamic behaviors of microbubbles and other microscopic objects (Chen X, Wang J, Versluis M, de Jong N, and Villanueva FS, Ultra-fast bright field and fluorescence imaging of the dynamics of micrometer-sized objects. Rev Sci Instrum, 2013. 84(6): p. 063701). This system is capable of imaging microscopic bright field and fluorescence movies at 25 million frames per second for 128 frames, with a frame size of 920×616 pixels.

Chen Fig 2
 

Overview of UPMC Cam. This system is capable of imaging microscopic bright field and fluorescence movies at 25 million frames per second for 128 frames, with a frame size of 920×616 pixels. Adapted from Chen X et al, Rev Sci Instrum, 2013. 84(6)

 
 
Chen Fig 3
 

Optical design of the UPMC Cam. For clarity, all USB hubs and relay circuits were removed from this drawing.  Adapted from Chen X et al, Rev Sci Instrum, 2013. 84(6).

 

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This is a bright field movie of lipid microbubbles under ultrasound excitation (f=2.25 MHz, Pa=0.5 MPa), demonstrating ultrasound-induced microbubble oscillation. Imaging is at 25 million fps, and playback is at 30 fps. Frame size is 22 µm × 22 µm.

 
 

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This is a brightfield movie of multiple microbubbles oscillating adjacent to a thrombus (left) during ultrasound exposure (1 MHz, 1.5 MPa).  Acoustic radiation force causes oscillating microbubbles to migrate towards the thrombus (a new microbubble enters the field of view from the right).  Note the marked cyclic thrombus deformation in response to ultrasound-induced microbubble oscillations compressing the thrombus, and ultimate microbubble destruction or formation of smaller microbubbles.    Imaging is at 5 million fps, and playback is at 8 fps.  Frame size is 55 µm x 55 µm. Adapted from Chen X et al, Ultrasound Med Biol 2014;40).

 

Chen FIg 4
 

High speed fluorescence recordings with UPMC Cam reveal a variety of microbubble coating behaviors not evident from brightfield recordings. For microbubble with a homogeneous coating before ultrasound (50 kPa), we observed homogeneous fluorescence during oscillation (A), “hot spots” (focal areas of increased fluorescence intensity) only during compression (B), or hot spots during oscillation that persisted after US (C), suggesting that lipids can reach speeds on the order of 1 m/s. For microbubble with hot spots before US, the hot spots persisted or intensified (D). Occurrence of hot spots during ultrasound could be due to buckling. At higher acoustic pressures, we also observed other phenomena: formation of a tail (E) that was not evident in BF, or a non-continuous lipid coating during the expansion phase (F), suggesting a ruptured coating correlating with deflation. Adapted from Kooiman et al, IEEE IUS 2014.


Publications

Chen X, Schwarz KQ, and Parker KJ, Radiation pattern of a focused transducer: a numerically convergent solution. J Acoust Soc Am, 1993. 94(5): p. 2979-91.

Harpaz D, Chen X, Francis CW, Marder VJ, and Meltzer RS, Ultrasound enhancement of thrombolysis and reperfusion in vitro. J Am Coll Cardiol, 1993. 21(6): p. 1507-11.

Schwarz KQ, Bezante GP, Chen X, Mottley JG, and Schlief R, Volumetric arterial flow quantification using echo contrast. An in vitro comparison of three ultrasonic intensity methods: radio frequency, video and Doppler. Ultrasound Med Biol, 1993. 19(6): p. 447-60.

Schwarz KQ, Bezante GP, Chen X, and Schlief R, Quantitative echo contrast concentration measurement by Doppler sonography. Ultrasound Med Biol, 1993. 19(4): p. 289-97.

Brayman AA, Azadniv M, Miller MW, and Chen X, Bubble recycling and ultrasonic cell lysis in a stationary exposure vessel. J Acoust Soc Am, 1994. 96(2 Pt 1): p. 627-33.

Chen X, Schwarz KQ, and Parker KJ, Acoustic coupling from a focused transducer to a flat plate and back to the transducer. J Acoust Soc Am, 1994. 95(6): p. 3049-54.

Harpaz D, Chen X, Francis CW, and Meltzer RS, Ultrasound accelerates urokinase-induced thrombolysis and reperfusion. Am Heart J, 1994. 127(5): p. 1211-9.

Schwarz KQ, Bezante GP, and Chen X, When can Doppler be used in place of integrated backscatter as a measure of scattered ultrasound intensity? Ultrasound Med Biol, 1995. 21(2): p. 231-42.

Chen X and Apfel RE, Radiation force on a spherical object in an axisymmetric wave field and its application to the calibration of high-frequency transducers. J Acoust Soc Am, 1996. 99(2): p. 713-24.

Schwarz KQ, Bezante GP, Chen X, Phillips D, and Schlief R, Hemodynamic effects of microbubble echo contrast. J Am Soc Echocardiogr, 1996. 9(6): p. 795-804.

Schwarz KQ, Chen X, Bezante GP, Phillips D, and Schlief R, The Doppler kinetics of microbubble echo contrast. Ultrasound Med Biol, 1996. 22(4): p. 453-62.

Chen X and Apfel RE, Radiation force on a spherical object in the field of a focused cylindrical transducer. J Acoust Soc Am, 1997. 101(5 Pt 1): p. 2443-7.

Chen X, Phillips D, Schwarz KQ, Mottley JG, and Parker KJ, The measurement of backscatter coefficient from a broadband pulse-echo system: a new formulation. IEEE Trans Ultrason Ferroelectr Freq Control, 1997. 44(2): p. 515-25.

Schwarz KQ, Chen X, Steinmetz S, and Phillips D, Harmonic imaging with Levovist. J Am Soc Echocardiogr, 1997. 10(1): p. 1-10.

Chen X, Schwarz KQ, Phillips D, Steinmetz SD, and Schlief R, A mathematical model for the assessment of hemodynamic parameters using quantitative contrast echocardiography. IEEE Trans Biomed Eng, 1998. 45(6): p. 754-65.

Phillips D, Chen X, Baggs R, Rubens D, Violante M, and Parker KJ, Acoustic backscatter properties of the particle/bubble ultrasound contrast agent. Ultrasonics, 1998. 36(8): p. 883-92.

Schwarz KQ, Chen X, and Steinmetz S, Methods for quantifying ultrasound backscatter and two-dimensional video intensity: implications for contrast-enhanced sonography. J Am Soc Echocardiogr, 1998. 11(2): p. 155-68.

Schwarz KQ, Bezante GP, Chen X, Villa G, and Brunelli C, Contrast harmonic color Doppler left ventriculography: machine-interpreted left ventricular ejection fraction compared with equilibrium-gated radionuclide ventriculography. J Am Soc Echocardiogr, 2000. 13(5): p. 368-78.

Gudavalli A, Kalaria VG, Chen X, and Schwarz KQ, Intrapulmonary arteriovenous shunt: diagnosis by saline contrast bubbles in the pulmonary veins. J Am Soc Echocardiogr, 2002. 15(9): p. 1012-4.

Yokoyama N, Schwarz KQ, Chen X, Steinmetz SD, Becher H, Schimpky C, and Schlief R, The effect of echo contrast agent on Doppler velocity measurements. Ultrasound Med Biol, 2003. 29(5): p. 765-70.

Yokoyama N, Schwarz KQ, Steinmetz SD, Li X, and Chen X, Prognostic value of contrast stress echocardiography in patients with image quality too limited for traditional noncontrast harmonic echocardiography. J Am Soc Echocardiogr, 2004. 17(1): p. 15-20.

Bezante GP, Chen X, Molinari G, Valbusa A, Deferrari L, Sebastiani V, Yokoyama N, Steinmetz S, Barsotti A, and Schwarz KQ, Left ventricular myocardial mass determination by contrast enhanced colour Doppler compared with magnetic resonance imaging. Heart, 2005. 91(1): p. 38-43.

Bezante GP, Rosa GM, Bruni R, Chen X, Villa G, Scopinaro A, Balbi M, Barsotti A, and Schwarz KQ, Improved assessment of left ventricular volumes and ejection fraction by contrast enhanced harmonic color Doppler echocardiography. Int J Cardiovasc Imaging, 2005. 21(6): p. 609-16.

Schwarz KQ, Parikh SS, Chen X, Farrar DJ, Steinmetz S, Ramamurthi S, Hallinan W, Massey HT, and Chen L, Non-invasive flow measurement of a rotary pump ventricular assist device using quantitative contrast echocardiography. J Am Soc Echocardiogr, 2010. 23(3): p. 324-9.

Carson AR, McTiernan CF, Lavery L, Hodnick A, Grata M, Leng X, Wang J, Chen X, Modzelewski RA, and Villanueva FS, Gene therapy of carcinoma using ultrasound-targeted microbubble destruction. Ultrasound Med Biol, 2011. 37(3): p. 393-402.

Moguillansky D, Leng X, Carson A, Lavery L, Schwartz A, Chen X, and Villanueva FS, Quantification of plaque neovascularization using contrast ultrasound: a histologic validation. Eur Heart J, 2011. 32(5): p. 646-53.

Toma C, Fisher A, Wang J, Chen X, Grata M, Leeman J, Winston B, Kaya M, Fu H, Lavery L, Fischer D, Wagner WR, and Villanueva FS, Vascular endoluminal delivery of mesenchymal stem cells using acoustic radiation force. Tissue Eng Part A, 2011. 17(9-10): p. 1457-64.

Carson AR, McTiernan CF, Lavery L, Grata M, Leng X, Wang J, Chen X, and Villanueva FS, Ultrasound-targeted microbubble destruction to deliver siRNA cancer therapy. Cancer Res, 2012. 72(23): p. 6191-9.

Kaya M, Toma C, Wang J, Grata M, Fu H, Villanueva FS, and Chen X, Acoustic radiation force for vascular cell therapy: in vitro validation. Ultrasound Med Biol, 2012. 38(11): p. 1989-97.

Kim JS, Leeman JE, Kagemann L, Yu FT, Chen X, Pacella JJ, Schuman JS, Villanueva FS, and Kim K, Volumetric quantification of in vitro sonothrombolysis with microbubbles using high-resolution optical coherence tomography. J Biomed Opt, 2012. 17(7): p. 070502.

Leeman JE, Kim JS, Yu FT, Chen X, Kim K, Wang J, Chen X, Villanueva FS, and Pacella JJ, Effect of acoustic conditions on microbubble-mediated microvascular sonothrombolysis. Ultrasound Med Biol, 2012. 38(9): p. 1589-98.

Wexler O, Morgan MA, Gough MS, Steinmetz SD, Mack CM, Darling DC, Doolin KP, Apostolakos MJ, Graves BT, Frampton MW, Chen X, and Pietropaoli AP, Brachial artery reactivity in patients with severe sepsis: an observational study. Crit Care, 2012. 16(2): p. R38.

Chen X, Wang J, Versluis M, de Jong N, and Villanueva FS, Ultra-fast bright field and fluorescence imaging of the dynamics of micrometer-sized objects. Rev Sci Instrum, 2013. 84(6): p. 063701.

Stephens DN, Mahmoud AM, Ding X, Lucero S, Dutta D, Yu FT, Chen X, and Kim K, Flexible integration of high-imaging-resolution and high-power arrays for ultrasound-induced thermal strain imaging (US-TSI). IEEE Trans Ultrason Ferroelectr Freq Control, 2013. 60(12): p. 2645-56.

Chen X, Leeman JE, Wang J, Pacella JJ, and Villanueva FS, New insights into mechanisms of sonothrombolysis using ultra-high-speed imaging. Ultrasound Med Biol, 2014. 40(1): p. 258-62.

Leng X, Wang J, Carson A, Chen X, Fu H, Ottoboni S, Wagner WR, and Villanueva FS, Ultrasound detection of myocardial ischemic memory using an E-selectin targeting peptide amenable to human application. Mol Imaging, 2014. 13(4): p. 1-9.

Yu FT, Villanueva FS, and Chen X, Radial modulation contrast imaging using a 20-MHz single-element intravascular ultrasound catheter. IEEE Trans Ultrason Ferroelectr Freq Control, 2014. 61(5): p. 779-91.

Pacella JJ, Brands J, Schnatz F, Black JJ, Chen X, Villanueva FS. Treatment of microvascular micro-embolization using microbubbles and long-tone-burst ultrasound: an in vivo study. Ultrasound Med Biol, 2015;41:456-464.

Kopechek JA, Carson AR, McTiernan CF, Chen X, Villanueva FS. Transcription factor decoy-mediated knockdown of STAT3 signaling to inhibit tumor growth using ultrasound targeted microbubble destruction. Theranostics 2015;5(12):1378-1387. Epub 2014 Dec 23. doi: 10.7150/thno.12822. PMID: 25542487.

Chen X, Wang J, Pacella JJ, Villanueva FS. Dynamic behavior of microbubbles during long ultrasound tone-burst excitation: mechanistic insights into ultrasound-microbubble mediated therapeutics using high-speed imaging and cavitation detection. Ultrasound Med Biol 2016;42(2):528-538. Epub 2015 Nov 18. doi: 10.1016/j.ultrasmedbio.2015.09.017. PMID: 26603628.

Yu FTH, Chen X, Wang J, Qin B, Panday R, Villanueva FS. Low intensity ultrasound mediated liposomal doxorubicin delivery using polymer microbubbles. Mol Pharmaceutics 2016;13(1):55-64. Epub 2015 Nov 15. doi: 10.1021/acs.molpharmaceut.5b00421. PMID: 26567985.

Helfield B, Black JJ, Qin B, Pacella J, Chen X, Villanueva FS. Fluid viscosity affects the fragmentation and inertial cavitation threshold of lipid encapsulated microbubbles. Ultrasound Med Biol 2016;42(3):782-794. Epub 2015 Dec 7. doi: 10.1121/1.4939123. PMID: 26674676.

Helfield B, Chen X, Qin B, Villanueva FS. Individual lipid encapsulated microbubble radial oscillations: Effects of fluid viscosity. J Acoust Soc Am 2016;139(1):204-214. Epub 2016 January 11. doi: 10.1121/1.4939123. PMID: 26827018.

Black JJ, Yu FTH, Schnatz RG, Chen X, Villanueva FS, Pacella JJ. Effect of thrombus composition and viscosity on sonoreperfusion efficacy in a model of microvascular obstruction. Ultrasound Med Biol 2016; 42(9):2220-31. Epub 2016 May 17. doi: 10.1016/j.ultrasmedbio.2016.04.004. PMID: 27207018.

Kopechek JA, Carson AR, McTiernan CF, Chen X, Klein EC, Villanueva FS. Cardiac gene expression knockdown using small inhibitory RNA-loaded microbubbles and ultrasound. PLoS ONE 2016;11(7):e0159751. doi: 10.1371/journal.pone.0159751. PMID: 27471848.

Helfield B, Chen X, Watkins S, Villanueva FS. Biophysical insight into mechanisms of sonoporation. PNAS 2016;(in press). EPub 2016 August 22. doi: 10.1073/pnas.1606915113.

Roos ST, Yu FT, Kamp O, Chen X, Villanueva FS, Pacella JJ. Sonoreperfusion therapy kinetics in whole blood using ultrasound, microbubbles and tPA. Ultrasound Med Biol 2016;(in press).