Thrombolysis and Bubble Coalescing

The overall goal of this project is to improve efficacy for histotripsy thrombolysis using an integrated histotripsy and bubble coalescing (HBC) transducer system.

Background

Histotripsy has exhibited the ability to break up clots to debris, and has been investigated as a noninvasive, drug-free, and image guided thrombolysis method in vitro and in vivo. However, histotripsy treatment has low efficiency for aged or retracted clot. During histotripsy treatment, the cavitation memory effect can cause bubble clouds to repeatedly form at the same discrete set of sites. This effect limits the efficiency of histotripsy-based tissue fractionation. The cavitation memory effect can be removed passively by reducing histotripsy pulse repetition frequency (PRF), which allows residual cavitation nuclei enough time to dissolve between successive pulses. However, the treatment rate over time is very low using such a low PRF and may not be reasonable in a clinical setting.

The lesion patterns observed during and after the treatments when the time intervals between pulses decreased from (a) 200 to (c) 2 ms. (Ultrasound in Medicine and Biology 38.5 (2012): 753-766.)

Integration of histotripsy and bubble coalescence (HBC)

In our previous work, the cavitation memory effect at high rate was mitigated by using 1000-cycle 1-MPa bursts transmitted by a secondary transducer confocal with the histotripsy therapy transducer. This work present and integrated HBC transducer system to deliver both high amplitude (P- >= 30 MPa) histotripsy pulses and low amplitude (~1-2 MPa) BC sequences to achieve rapid, homogenous ablation. The integrated transducer design dispenses with the need for a second bubble coalescing (BC) transducer and driving system, minimizing the aperture of histotripsy transducer, and allowing in-line ultrasound imaging for thrombolysis. For histotripsy pulses, all the elements of the transducer were excited simultaneously. For BC pulses, each element was excited individually in sequence to produce a high PRF burst.

HBC transducer (a) and general pulse scheme (b) used to study the thrombolysis by using HBC sequence. 

Enhanced thrombolysis

The HBC transducer system was used to restore flow channels through eight retracted clots in an in vitro deep vein thrombosis model. The histotripsy treatment efficiency using BC was measured and compared to that using histotripsy alone. The results indicated significant increases in the cross-sectional areas of flow channel generated using the HBC sequence versus histotripsy alone at both scan speeds (p<0.001).

Representative ultrasound images of the cross sections of the flow channels generated using histotripsy pulses alone (left) and HBC sequences (right) at scan speeds of 0.2 mm/s (a) and 0.5 mm/s (b).

We investigated the in vivo feasibility of the microtripsy thrombolysis. Microtripsy uses 1-cycle ultrasound pulses with only one high amplitude negative pressure phase to initiate cavitation when the negative pressure directly exceeds the intrinsic threshold of generating cavitation (26-30MPa in water-based tissue). Acute thrombi were formed in the left femoral veins of pigs (~35 kg) by occluding the vessel using two balloon catheters and infusing with thrombin. Guided by ultrasound imaging, microtripsy thrombolysis treatment was conducted in 14 pigs using 1 µs-long pulses at a pulse repetition frequency of 100Hz and a peak negative pressure of 30 MPa by a 1 MHz transducer. 10 pigs were euthanized on the same day (acute) and 4 at 2 weeks (subacute). To evaluate the vessel damage, 30-min free-flow treatment (no thrombus) in the right femoral vein was also conducted in 8 acute pigs. Blood flow was restored or significantly increased after treatment in 13 out of the 14 pigs confirmed by ultrasound color Doppler. One treatment was not effective due to a technical issue with clot formation. The flow channels reopened by microtripsy had a diameter up to 64% of the vessel diameter (~6mm). The average treatment time was 16 minute per cm-long thrombus. Minor hemolysis was observed in both thrombolysis and free-flow treatments. Histology showed no vessel damage and only microscopic hemorrhage outside the veins for the free-flow treatments with nothing abnormal observed for the subacute treatments.

Representative US B-mode images (first row) and color Doppler images (second row) taken before, right after and two weeks after microtripsy thrombolysis treatment in a subacute pig. Blood flow was increased  after two weeks of recovery compared that right after the treatment. Since a relatively smaller velocity scale was chosen to be consistent throughout all the color Doppler images, velocity aliasing occurred on the two-week color Doppler image (g) with an increased blood flow.

Please add the References.

  1. Shi A, Xu Z, Lundt J, Tamaddoni HA, Worlikar T, Hall TL. Integrated Histotripsy and Bubble Coalescence Transducer for Rapid Tissue Ablation. IEEE Trans Ultrason Ferroelectr Freq Control. 2018.
  2. Zhang X, Owens GE, Cain CA, Gurm HS, Macoskey J, Xu Z. Histotripsy Thrombolysis on Retracted Clots. Ultrasound Med Biol. 2016;42(8):1903-18. PMCID: 4912870.
  3. Miller RM, Zhang X, Maxwell AD, Cain CA, Xu Z. Bubble-Induced Color Doppler Feedback for Histotripsy Tissue Fractionation. IEEE Trans Ultrason Ferroelectr Freq Control. 2016;63(3):408-19. PMCID: 4838481.
  4. Zhang X, Macoskey JJ, Ives K, Owens GE, Gurm HS, Shi J, Pizzuto M, Cain CA, Xu Z. Non-invasive Thrombolysis Using Microtripsy in a Porcine Deep Vein Thrombosis Model. Ultrasound Medicine & Biology. 2017; 43 (6), 1237-1251.
  5. Zhang X, Jin L, Vlaisavljevich E, Owens GE, Gurm HS, Cain CA, Xu Z. Noninvasive thrombolysis using microtripsy: a parameter study. IEEE Trans Ultrason Ferroelectr Freq Control. 2015;62(12):2092-105.
  6. Maxwell AD, Owens G, Gurm HS, Ives KA, Myer DD, Xu Z. Noninvasive treatment of deep venous thrombosis using pulsed ultrasound cavitation therapy (histotripsy) in a porcine model. Journal of Vascular and Interventional Radiology. 2011;22(3):369-77.
  7. Maxwell AD, Cain CA, Duryea A, Yuan L, Gurm HS, Xu Z. Non-invasive thrombolysis using pulsed ultrasound cavitation therapy – histotripsy. Ultrasound in Medicine and Biology. 2009;35(12):1982-94.