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Image-guidance for Therapeutic Ultrasound:
Passive Cavitation Imaging for Drug
Delivery and Tissue Ablation
Kevin J. Haworth, PhDDepartment of Internal Medicine,
University of Cincinnati
Disclosures
• Current Research Support
– NIH-NHLBI (PI: K25 HL133452)
– NIH-NHLBI (PI: R01 HL148451)
– NIH-NHLBI (Co-I: R01 HL133334)
– NIH-NHLBI (Co-I: R01 HL135092)
• Research Support from Boston Scientific (EKOS)
2
Clinical Trials of Cavitation-Based
Therapeutic Ultrasound
3
Dimcevski et al. 2016
J Control Release
Enhanced Chemotherapy Blood Brain
Barrier Disruption
Lipsman et al. 2018
Nature Comm
Vidal Jove et al. 2019
Int Symp Ther US
Mechanical Tumor Ablation
4
Wilson and Burns (2010) Radiology
Exogenous Microbubbles
Maxwell J Acoust Soc Am 2011
Microbubbles and Cavitation
5
Raymond et al.
2016 PMB
‘Traditional’ Cavitation Detection
6
z
Standard Contrast-enhanced
Ultrasound imaging
7
Combining Cavitation Detection & CEUS
8
Unfocused PCDFocused PCD
Insensitive
Sensitive
9
-60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60Lateral [mm]
30
40
50
60
70
De
pth
[m
m]
−15
−10
−5
0
En
erg
y [d
B re
ma
x]
Beamformed Inharmonic Energy
-60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60Lateral [mm]
30
40
50
60
70
De
pth
[m
m]
−15
−10
−5
0
En
erg
y [d
B re
ma
x]
Beamformed Ultraharmonic Energy
Haworth et al. (2017) IEEE UFFC
Passive Cavitation Imaging
10Haworth et al. (2017) IEEE UFFC
Passive Cavitation Imaging
Artifact!
-60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60Lateral [mm]
30
40
50
60
70
De
pth
[m
m]
−15
−10
−5
0
En
erg
y [d
B re
ma
x]
Beamformed Inharmonic Energy
-60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60Lateral [mm]
30
40
50
60
70
De
pth
[m
m]
−15
−10
−5
0
En
erg
y [d
B re
ma
x]
Beamformed Ultraharmonic Energy
• Image formation can be
done in real-time (GPU)
Advanced Algorithms
11Coviello et al. 2015
J Acoust Soc Am
Jones et al. 2016
Phys Med Biol
Abadi et al. 2018
J Acoust Soc Am
Salido et al. 2019
Int Soc Therap Ultrasound
Adaptive
Beamforming
Spatial Filtering Nonlinear
BeamformingAberration
Correction
Cavitation Mapping for
Drug Delivery
12
• Intra-arterial infusion of fluorophore-labeled echogenic liposomes
Drug Delivery: Setup
• Porcine Femoral Artery w/ bare metal stent a
13
Vantage ultrasound
system
Stent Vessel
Drive Electronics
60 mm
Phased Imaging/PCI
array
500-kHz therapeutic
transducer
OFP-ELIP 70 mm
Transducer holder
Haworth et al. (2016) UMBHaworth et al. (2016) Ultrasound Med Biol
500-kHz exposure
10 20 30 40 50
OFP-ELIP infusion
Time (s)
40 PCI frames 15 B-mode
frames
0
Drug Delivery: Results
• Identifying and mapping cavitation can assist in predicting
delivery to vascular tissue
Haworth et al. (2016) Ultrasound Med Biol14
Cavitation Mapping for
Histotripsy
(Mechanical Ablation)
15
PCI: Histotripsy
Liquefaction
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Histotripsy
Transducer
L7-4
Imaging Array
Verasonics
PC Controlled Excitation
Signal
Three Axis
Positioning
System
Trig
ge
r O
ut
Water
Tank
Azimuthal
Dimension
Ra
ng
e
Dim
en
sio
n
Phantom2 cm3 cm
Histotripsy Pulse
Trigger
PCI Acquisition: 60 µs
Histotripsy Focal
Insonation: 5-20 µs
B-Mode Acquisition: 40 µs53 µs
1 ms
(A)
(B)
Bader et al. (2018) IEEE Med Imaging
Histotripsy
Transducer
L7-4
Imaging Array
Verasonics
PC Controlled Excitation
Signal
Three Axis
Positioning
System
Trig
ge
r O
ut
Water
Tank
Azimuthal
Dimension
Ra
ng
e
Dim
en
sio
n
Phantom2 cm3 cm
Histotripsy Pulse
Trigger
PCI Acquisition: 60 µs
Histotripsy Focal
Insonation: 5-20 µs
B-Mode Acquisition: 40 µs53 µs
1 ms
(A)
(B)
PCI: Histotripsy
Liquefaction
17
Ra
ng
eAzimuth
Stained Phantom
B-mode Imaging Overlay
PCI Overlay
PCI AUROC: 0.93
Bmode AUROC: 0.82
Bader et al. (2018) IEEE Med Imaging
Final thoughts
• Sources of cavitation can be mapped in a quantitative manner
• The image is diffraction limited– Poor axial resolution for a clinical diagnostic array
– Alternate transducer geometries or beamforming algorithms improve image quality
• The ability of PCI to guide a therapy depends on how central cavitation activity is to inducing bioeffects
18
Acknowledgements
19
http://med.uc.edu/ultrasound
