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www.ibme.ox.ac.uk/bubbl
Theracoustics: how sound and bubbles can cure our troubles
Professor Constantin-C. CoussiosDirector, Institute of Biomedical Engineering, University of Oxford
CTO & Founder, OrganOx Ltd., OxSonics Ltd. and OrthoSon Ltd.
Sheffield, 7th January 2019
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I set out to study this (with J.E. Ffowcs Williams) in 1998…
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… and ended up working on this over the next 20 years…
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Towards Acoustics-Led Medicine: Surgery, Oncology, Orthopaedics,…
Oncological drug delivery£8bn/year in EuropeSurgical Ablation
Primary Liver Cancer: 15,000 cases pa in EuropePrimary Kidney: 40,000 cases pa in Europe
Colorectal Cancer 144,000 cases pa in EuropePancreatic Cancer: 20,000 cases pa in Europe
Lower Back Pain >70% of adults
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Part I: Non-Invasive Surgery
Surgery(only feasible in 10-25% cases)
Drug delivery / chemotherapy(20-50% response, 12-month survival)
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Therapeutic Focused Ultrasound: Thermal Effects
[Thermal Denaturation Video: Prof. Larry Crum, CIMU, Univ. of Washington ]
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Target organ (e.g. liver)
Tumour
‘Lesion’ of coagulative necrosis at focusSkin
Transducer
Undamaged tissue in front of focus
(12x3mm)
Histology of a liver lesion(24 hours) Courtesy of Gail ter Haar
J. Kennedy, Nat. Cancer Reviews, 2005.
High-Intensity Focussed Ultrasound (HIFU)
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HIFU in the Clinic (Churchill Hospital-Oxford)
2 days Pre-HIFU 1 day post-HIFU
Plane of surgical resection
Plane of histological slice
Inferior / Free edge
Superior /Dome
R L
JC 200 - Chongqing
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Part II: Oncological Drug Delivery
Surgery(only feasible in 10-25% cases)
Drug delivery / chemotherapy(20-50% response, 12-month survival)
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Drug Delivery for Cancer
“Among 68 cancer drug indications approved by the EMA in the period 2009-13, and with a median of 5.4 years’ follow-up,
only 35 (51%) were associated with significant improvement in survival or quality of life over alternative treatment options, placebo, or as add-on treatment.
For 33 (49%), uncertainty remains over whether the drugs extend survival or improve quality of life.”
Davis et al., BMJ 2017;359:j4530
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15nm 90-140nm
➢Typically, 0.5-1.4% of the administered drug dose reaches the target tumour
CHEMO-THERAPEUTICS
ANTIBODIES /IMMUNO-ONCOLOGY
LIPOSOMES /POLYMERIC VEHICLES
<1nm 100-300nm
ONCOLYTIC VIRUSES /IMMUNO-ONCOLOGY
Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, et al. 2016. Analysis of nanoparticle delivery to tumours. Nature Reviews Materials 1:16014
A Common Problem Across All Cancer Drug Classes
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“Physicians pour drugs of which they know little,
to cure diseases of which they know less,
into humans of which they know nothing.”
François Voltaire (1694 – 1778)
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Tumour Physiology as a Barrier to Drug Delivery
▪ Size selectivity of the tumour endothelium (100-600 nm)
▪ Elevated intratumoral pressure (~ 20 mm Hg)
▪ Highly irregular tumour vasculature
▪ Increased distance between nearest blood vessel and farthest cell (~ 200 µm in tumours vs 90 µm in tissue)
Irregular Vasculature
high vascular
density
low vascular
density
(hypoxic region)
high vascular
density
100 µm vasculature
cancer cells
therapeutic
agents
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Active or PassiveAccumulation
Triggered Release
(with Monitoring)
EnhancedExtravasation
(with Monitoring)
Therapy
Manufacturingof Stimulus Responsive
Nano & Micro Particles
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TarDox Clinical Trial
P.C. Lyon, C-
C. Coussios,
et al. “Clinical
Trial Protocol
for TarDox: A
Phase I Study
to Investigate
the Feasibility
of Targeted
Release of
Lyso-
thermosensitiv
e Liposomal
Doxorubicin
(ThermoDox®)
Using Focused
Ultrasound in
Patients with
Liver
Tumours”, J.
Therapeutic
Ultrasound –
in press
(2017).
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Extracorporeal FUS for Targeted Volumetric Hyperthermia
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Extracorporeal FUS for Targeted Volumetric Hyperthermia17
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Target (TD+FUS)
Control (TD)
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Thermally Triggered Release & Drug Delivery by UltrasoundIn first 10 patients (4 without thermistor), using a clinical USgFUS system
• Mild hyperthermia > 39.5 C successfully sustained for 23-79 minutes over volumes of 14-73cc in 5/6
patients with CEM43<15 minutes.
• Mean intratumoural dox concentration increase of 3.7x achieved following FUS exposure, with 7/10
patients demonstrating at least a 2x increase.
• Notable therapeutic response (PET/CT) observed in 6/10 patients even after a single cycle of chemo.
‘Big picture’ challenges:
• Liposomal delivery requires drug re-formulation
• Thermal delivery may not be suitable for certain types of biologics
• Using current systems, FUS-hyperthermia is difficult to scale up to
thousands of patients in each hospital.
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Active or PassiveAccumulation
Triggered Release
(with Monitoring)
EnhancedExtravasation
(with Monitoring)
Therapy
Manufacturingof Stimulus Responsive
Nano & Micro Particles
Avoiding Drug Reformulation
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The Ultrasonic Pump: Cavitation-Mediated Drug Transport
Coussios C. and Roy R., “Applications of Acoustics and Cavitation to Non-Invasive
Therapy and Drug Delivery” Annual Review of Fluid Mechanics 40: 395-420 (2008).
Timescales of Seconds (Real Time) and Length scales of mm
Timescales of Microseconds
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Clinical Challenges : Matching Biological Length Scales
Co
uss
ens
et a
l., 2
01
7
Leaky vasculature
100-1000 nm
Need for acoustic
cavitation nucleation
agents in the size
range 100-500 nm
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Co
uss
ens
et a
l., 2
01
7
Leaky vasculature
100-600 nm
Matching the Engineering to the Biological Length Scales
0 200 400 600 800 1000 12000.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
IC T
hre
shold
(M
Pa)
Cavity Diameter (nm)
Theoretical (AR = 0.45)
NC (Flow)
NC (Static)
f = 0.5 MHz
*
[1] J.J. Kwan …, E Stride and C. C. Coussios, “Ultrasound‐Propelled Nanocups for Drug Delivery,” Small 11(39):5305-5314 (2015).[2] J.J. Kwan, ..., E. Stride, and C. Coussios, “Ultrasound-induced inertial cavitation from gas-stabilizing nanoparticles,” Physical Review E 92(2) (2015)[3] J. Kwan, R Myers, A. Shah and C Coussios, “Cavitation-Inducing Polymeric Nanoparticles”, EP3071183 A1 (2014).
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Treatment Monitoring: Passive Acoustic Mapping of Cavitation
5-15 MHz ultrasound array receiver
0.5-1.5 MHz focussed ultrasound source array
[1] C. Coussios, M .Gyöngy, M. Arora and R. Roy, US Patent 9238152 B2 (2008). [2] M. Gyöngy and C. Coussios, "Passive spatial mapping of inertial cavitation during HIFU exposure", IEEE Trans on Biom.Eng, 57(1): 48 - 56 (2010).[3] C. Coviello, R. Kozick and C.-C. Coussios, “Passive acoustic mapping utilizing optimal beamforming in ultrasound therapy monitoring,” J. Acoustc. Soc. Am. 137(5): 2573-2585 (2015).
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Towards Clinical Translation (CEeDD Clinical Trial)
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Conquering the Whole Tumour with US-Mediated Transport
Without ultrasound
With ultrasound
Blood vessels Polymeric cups Cancer Cell
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1 x
10
5V
V
1 day 5 days 20 days
1 x
10
5V
V +
cu
ps
+ u
ltra
sou
nd
x10,000
X 50
Improving Delivery of Novel Oncology Drugs into Tumours
Myers, R., Kwan,J., Coviello, C., Carlisle, R. & Coussios, C. C. et al., (2016) Polymeric cups for cavitation mediated delivery of oncolytic vaccinia virus. Molecular Therapy
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The Value of Real-Time Mapping of Drug Delivery28
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Enhanced Anti-PD-L1 Therapy in CT-26/Balbc (IV)
0 20 40 60 800
50
100
Time
Pe
rce
nt su
rviv
al
Survival Data
IgGs
IgGs+Cavitation
aPDL1
aPDL1+Cavitation
aPD1
aPD1+Cavitation
(Days)
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Part III: Spinal Therapies
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Surgery for Discogenic Back Pain
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UltraSpine: Minimally Invasive Disc Replacement
HIFU Transducer )
US Imaging Array
HIFU Transducer
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Restoring Function of Repaired Degenerate Discs
0
10
20
30
40
50
60
70
80
90
0 30 60 90 120 150
Load
(lb
)
Time (min)
0
10
20
30
40
50
60
70
80
90
0 30 60 90 120 150
Load
(lb
)
Time (min)
0
10
20
30
40
50
60
70
80
90
0 50 100 150
Load
(lb
)
Time (min)
0
10
20
30
40
50
60
70
80
90
0 50 100 150
Load
(lb
)
Time (min)
Healthy Disc
Hydrogel InjectedUS-Treated Disc
Degenerate Disc
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“Sound
will be the future
of medicine…”
Edgar Cayce (1877 – 1945)Father of Hollistic Medicine
… and it is (nano) bubbly!
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Acknowledgements 2009-2018DLs and Post-docs:Manish AroraCostas ArvanitisMiriam Bazan-PeregrinoOlga BoubriakBob CarlisleChristian CovielloJames ChoiJamie CollinDelphine ElbesMichael GrayCarl JensenJames KwanStephane LabouretEramia LykaChristophoros MannarisEleonora MylonopoulouShan Qiao
•EP/L024012/1
•EP/F02617X/1
•EP/F01564X/1
•EP/F011547/1
•EP/D06127X/1 •07/010/22307
DPhils:Sunali Bhatnagar
Susan Graham
Miklos Gyongy
Susan Graham
Stuart Faragher
Natalie Hockham
David Holroyd
Prateek Katti
Zoe Kyriakou
Paul Lyon
Mike Molinari
Rachel Myers
Sacha Nandlall
Catherine Paverd
Bassel Rifai
Rob RitchieAnne Charlotte van Blokland
Ian Webb
Steven Mo
Industry:AstraZeneca, Pfizer, GSK, Medimmune
OrganOx Ltd.
OxSonics Ltd.
Psioxus, Transgene
Celsion
Academic Collaborators:BUBBL Faculty (Carlisle, Cleveland, Stride)Oxford Oncology (Seymour, Vallis, Sibson, MIddleton)Oxford Radiology (Gleeson)Weatherall (Eggeling, Sezgin, de la Serna)Clinical HIFU Unit (Tom Leslie, David Cranston)Dept of Surgical Sciences (Peter Friend)University of Twente (Versluis, Lajoinie)University of Colorado (Borden)University of Leeds (Wilcox)