ORTHOGONAL ANALYSIS OF PHYSICAL PARAMETERS OPTIMIZATION OF MICROBUBBLE-ENHANCED SONO-THROMBOLYSIS_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHOU Xiang ¹ , YU Qinmei ² , LIU Ting ² , WANG Hong ¹ , ZHUANG Hua ¹ , LUO Yan ¹ , PENG Yulan ¹

1Department of Ultrasound, 2Department of Hematology &;
Hematology Research Laboratory, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China. Corresponding author: ZHOU Xiang, E-mail: zhou.xiang@yeah.net;

Corresponding author：

Keywords：

Microbubble-enhanced sono-thrombolysis; Physical parameter; Orthogonal analysis; Rat

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ObjectiveTo investigate the main influence factors of microbubble-enhanced sono-thrombolysis by an orthogonal array experimental design (OAD) and to confirm the optimal parameters of microbubble-enhanced sono-thrombolysis in vitro. Methods The peripheral blood was collected from 50 female Sprague Dawley rats to prepare the standard plasma, and then 100 μL standard plasma and 25 μL thrombin (0.15 U/μL) were mixed and incubated in 37℃ water bath for 3, 6, 12, and 24 hours respectively to prepare corresponding standardized thrombus. The physical parameters for the designed experiments included transmit powers of ultrasound (factor A: 5%, 25%, 50%, and 100%), microbubble volume (factor B: 50, 100, 200, and 400 μL), urokinase (UK) concentration (factor C: 100, 200, 400, and 800 U/mL), and thrombolysis time (factor D: 10, 20, 30, and 40 minutes), respectively. Then an OAD based on four parameters and four levels [L16(45)] was employed to optimize the thrombolysis conditions. The ultrasound frequency was 1.82 MHz. HE staining and scanning electron microscope (SEM) were used to observe the clots before and after thrombolysis. The thrombolysis rate was measured. ResultsHE staining and SEM observation showed that the fibrin was dissolved after thrombolysis. According to the OAD, the optimal parameter combination was C4-D4-A1-B4, indicating UK concentration 800 U/mL, thrombolysis time 40 minutes, transmit power of ultrasound 5%, and microbubble volume 400 μL, respectively. The four factors above had significant influence on thrombolysis (P lt; 0.05), and UK concentration was the most significant. There were significant differences in thrombolysis between different thrombolysis time (P lt; 0.05). ConclusionUnder the condition of fixed ultrasound frequency, microbubble-enhanced sono-thrombolysis efficiency is better in lower transmit power of ultrasound, higher UK concentration, longer thrombolysis time, higher microbubble volume, and shorter thrombolysis time

Citation： ZHOU Xiang,YU Qinmei,LIU Ting,WANG Hong,ZHUANG Hua,LUO Yan,PENG Yulan. ORTHOGONAL ANALYSIS OF PHYSICAL PARAMETERS OPTIMIZATION OF MICROBUBBLE-ENHANCED SONO-THROMBOLYSIS. Chinese Journal of Reparative and Reconstructive Surgery, 2012, 26(9): 1098-1101. doi: Copy

1.	Shaw GJ, Bavani N, Dhamija A, et al. Effect of mild hypothermia on the thrombolytic efficacy of 120 kHz ultrasound enhanced thrombolysis in an in-vitro human clot model. Thromb Res, 2006, 117(5): 603-608.
2.	Holland CK, Vaidya SS, Datta S, et al. Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model. Thromb Res, 2008, 121(5): 663-673.
3.	Mehta RH, Stebbins A, Lopes RD, et al. Race, bleeding, and outcomes in STEMI patients treated with fibrinolytic therapy. Am J Med, 2011, 124(1): 48-57.
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5.	Donnan GA, Davis SM, Parsons MW, et al. How to make better use of thrombolytic therapy in acute ischemic stroke. Nat Rev Neurol, 2011, 7(7): 400-409.
6.	Torno MD, Kaminski MD, Xie Y, et al. Improvement of in vitro thrombolysis employing magnetically-guided microspheres. Thromb Res, 2008, 121(6): 799-811.
7.	Hua X, Liu P, Gao YH, et al. Construction of thrombus-targeted microbubbles carrying tissue plasminogen activator and their in vitro thrombolysis efficacy: a primary research. J Thromb Thrombolysis, 2010, 30(1): 29-35.
8.	Culp WC, Erdem E, Roberson PK, et al. Microbubble potentiated ultrasound as a method of stroke therapy in a pig model: preliminary findings. J Vasc Interv Radiol, 2003, 14(11): 1433-1436.
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12.	Pfaffenberger S, Devcic-Kuhar B, Kollmann C, et al. Can a commercial diagnostic ultrasound device accelerate thrombolysis? An in vitro skull model. Stroke, 2005, 36(1): 124-128.
13.	Alexandrov AV. Ultrasound enhanced thrombolysis for stroke. Int J Stroke, 2006, 1(1): 26-29.
14.	陈冉, 任卫东, 吴瑕, 等. 诊断超声介导自制微泡造影剂的溶栓效应及参数优化体外实验研究. 中国医学影像技术, 2008, 24(1): 9-12.
15.	Kirchhof K, Welzel T, Zoubaa S, et al. New method of embolus preparation for standardized embolic stroke in rabbits. Stroke, 2002, 33(9): 2329-2333.
16.	Trübestein G, Engel C, Etzel F, et al. Thrombolysis by ultrasound. Clin Sci Mol Med Suppl, 1976, 3: 697s-698s.
17.	Prokop AF, Soltani A, Roy RA. Cavitational mechanisms in ultrasound-accelerated fibrinolysis. Ultrasound Med Biol, 2007, 33(6): 924-933.
18.	华兴, 高云华, 刘政, 等. 辐照时间与血栓凝龄对超声波体外溶栓的影响. 临床超声医学杂志, 2007, 9(4): 193-195.
19.	Xie F, Everbach EC, Gao S, et al. Effects of attenuation and thrombus age on the success of ultrasound and microbubble-mediated thrombus dissolution. Ultrasound Med Biol, 2011, 37 (2): 280-288.
20.	Beythien C, Terres W, Gutensohn K, et al. Thrombus age as a determinant of lysis efficacy of in vitro produced platelet-fibrin thrombi. Z Kardiol, 1996, 85(9): 661-667.
21.	Krueger K, Deissler P, Coburger S, et al. How thrombus model impacts the in vitro study of interventional thrombectomy procedures. Invest Radiol, 2004, 39(10): 641-648.
22.	杜宝琮, 杜宝民, 翟桂琴. 体外治疗量超声对血栓溶解效应的影响. 中华物理医学与康复杂志, 2002, 24(7): 417-420.

1. Shaw GJ, Bavani N, Dhamija A, et al. Effect of mild hypothermia on the thrombolytic efficacy of 120 kHz ultrasound enhanced thrombolysis in an in-vitro human clot model. Thromb Res, 2006, 117(5): 603-608.
2. Holland CK, Vaidya SS, Datta S, et al. Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model. Thromb Res, 2008, 121(5): 663-673.
3. Mehta RH, Stebbins A, Lopes RD, et al. Race, bleeding, and outcomes in STEMI patients treated with fibrinolytic therapy. Am J Med, 2011, 124(1): 48-57.
4. Stein PD, Matta F, Steinberger DS, et al. Intracerebral hemorrhage with thrombolytic therapy for acute pulmonary embolism. Am J Med, 2012, 125(1): 50-56.
5. Donnan GA, Davis SM, Parsons MW, et al. How to make better use of thrombolytic therapy in acute ischemic stroke. Nat Rev Neurol, 2011, 7(7): 400-409.
6. Torno MD, Kaminski MD, Xie Y, et al. Improvement of in vitro thrombolysis employing magnetically-guided microspheres. Thromb Res, 2008, 121(6): 799-811.
7. Hua X, Liu P, Gao YH, et al. Construction of thrombus-targeted microbubbles carrying tissue plasminogen activator and their in vitro thrombolysis efficacy: a primary research. J Thromb Thrombolysis, 2010, 30(1): 29-35.
8. Culp WC, Erdem E, Roberson PK, et al. Microbubble potentiated ultrasound as a method of stroke therapy in a pig model: preliminary findings. J Vasc Interv Radiol, 2003, 14(11): 1433-1436.
9. Culp WC, Porter TR, Lowery J, et al. Intracranial clot lysis with intravenous microbubbles and transcranial ultrasound in swine. Stroke, 2004, 35(10): 2407-2411.
10. Tsivgoulis G, Eggers J, Ribo M, et al. Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke, 2010, 41(2): 280-287.
11. Siegel RJ, Luo H. Ultrasound thrombolysis. Ultrasonics, 2008, 48(4): 312-320.
12. Pfaffenberger S, Devcic-Kuhar B, Kollmann C, et al. Can a commercial diagnostic ultrasound device accelerate thrombolysis? An in vitro skull model. Stroke, 2005, 36(1): 124-128.
13. Alexandrov AV. Ultrasound enhanced thrombolysis for stroke. Int J Stroke, 2006, 1(1): 26-29.
14. 陈冉, 任卫东, 吴瑕, 等. 诊断超声介导自制微泡造影剂的溶栓效应及参数优化体外实验研究. 中国医学影像技术, 2008, 24(1): 9-12.
15. Kirchhof K, Welzel T, Zoubaa S, et al. New method of embolus preparation for standardized embolic stroke in rabbits. Stroke, 2002, 33(9): 2329-2333.
16. Trübestein G, Engel C, Etzel F, et al. Thrombolysis by ultrasound. Clin Sci Mol Med Suppl, 1976, 3: 697s-698s.
17. Prokop AF, Soltani A, Roy RA. Cavitational mechanisms in ultrasound-accelerated fibrinolysis. Ultrasound Med Biol, 2007, 33(6): 924-933.
18. 华兴, 高云华, 刘政, 等. 辐照时间与血栓凝龄对超声波体外溶栓的影响. 临床超声医学杂志, 2007, 9(4): 193-195.
19. Xie F, Everbach EC, Gao S, et al. Effects of attenuation and thrombus age on the success of ultrasound and microbubble-mediated thrombus dissolution. Ultrasound Med Biol, 2011, 37 (2): 280-288.
20. Beythien C, Terres W, Gutensohn K, et al. Thrombus age as a determinant of lysis efficacy of in vitro produced platelet-fibrin thrombi. Z Kardiol, 1996, 85(9): 661-667.
21. Krueger K, Deissler P, Coburger S, et al. How thrombus model impacts the in vitro study of interventional thrombectomy procedures. Invest Radiol, 2004, 39(10): 641-648.
22. 杜宝琮, 杜宝民, 翟桂琴. 体外治疗量超声对血栓溶解效应的影响. 中华物理医学与康复杂志, 2002, 24(7): 417-420.

Chinese Journal of Reparative and Reconstructive Surgery

ORTHOGONAL ANALYSIS OF PHYSICAL PARAMETERS OPTIMIZATION OF MICROBUBBLE-ENHANCED SONO-THROMBOLYSIS

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