2012:15thSESSION of ESMP€¦ · • 1946 US + X-ray (1st report) • 1967 US + Chemotherapy 3....

Lecture presented in Archamps (Salève Building) by :

2012 :15th SESSION of ESMP

Jean-Martial MARI (INSERM Lyon)

European School of Medical Physics - Archamps

Bio-effects of ultrasound&

Applications to therapy

Jean Martial Mari

David Melo de LimaInserm 1032, LabTAU, Lyon France


Paul Langevin 1872-1946

Toulon, 1917 : Research on sonar by Paul Langevin in order to detect U-boats.

If high amplitude ultrasound waves can kill fish, it may be possible to apply these waves with therapeutic objectives.

Historical anecdote

2


History of Ultrasound in Medicine

• 1880 Piezoelectricity Pierre & Jacques Curie

• 1918 Transducer Patent Paul Langevin

• 1920 First bioeffects report RW Wood + AL Loomis

• 1928 Medical use suggested

• 1932 Therapeutic heating H. Freundlich

• 1933 Cancer therapy report A. Szent-Györgyi

• 1937 Patent on NDT

• 1942 Focused US (H.I.F.U.) J.G. Lynn

• 1942 First medical diagnosis report

• 1946 US + X-ray (1st report)

• 1967 US + Chemotherapy 3


Exposure conditions for diagnosis and therapy

Frequency

(MHz)

Intensity

W/cm2

Duration

(s)

Pulse-Echo 1 - 20 1.8 < 1 µs

Doppler 1 - 20 16 < 10 ms

Physiotherapy 0.5 - 3 2.5 Continuous

Surgery 0.5 - 10 > 100 1 – 20 s

• The frequency range is similar for diagnosis and therapy.• To achieve a therapeutic effect, a more important dose of ultrasound is deposited by increasing the intensity and/or the exposure duration. 4


Overview of the seminar

• US – Tissues Interactions

• Clinical applications of ultrasound:

– Extracorporeal Lithotripsy

– High Intensity Focused Ultrasound

• Recent trends in therapeutic ultrasound

5


Ultrasound - Tissue Interactions

Thermal Effects

Cavitation

Chemical Effects

Non thermal Effects

Mechanical Effects

For most cases:

Interactions between effects6


Thermal Effects (1)• In an absorbing medium, ultrasound energy is continuously

converted into heat (due to viscosity).• Because of this phenomenon, the intensity of the wave

decreases exponentially with distance

I(z) = I0 e-2αfz

• The energy “lost” along a distance ∆z is converted to heat (locally)

• Quantity of heat deposited in a volume with thickness ∆z :

• Note that heat deposition is proportional to frequency f

)(2)(

)( zIfdz

zdIzq α−==

Peak pressure decreases as exp( - α f z )

Intensity decreases as exp( - 2 α f z )

7


Thermal Effects (2)

• Thermal response of biological tissues can be calculated by the Bio Heat Transfer Equation:

• The thermal effects depend on the:– Applied temperature– Exposure duration– Size and shape of the heated volume (Conduction)– Perfusion

Qckt

c abbttt +−+∇∇= )().( θθωθ∂

∂θρ

Heat Conduction(heat propagates in

adjacent tissues)

Blood Perfusion(acts as ‘cooling

radiator’ effect)

Volumetric

heat rate(energy brought

by the ultrasound

wave)

Rate of change of

temperature

8


Thermal Effects (3)

• Threshold for thermal damage as a function of exposure duration and temperature (Lele 1977)

• The thermal effects depend on the:– Applied temperature– Exposure duration– Size and shape of the heated volume (Conduction)– Perfusion

0.1 1 10 10 2 10 3 10 4 10 5

Temps d'exposition (s)

70

60

50

40

Temperature en °C

Dommages irréversibles

Pas de dommages

Chirurgie

ultrasonore

Hyperthermie

No damage

Irreversible damagesThermal ablation

Hyperthermia

Temperature °C

Exposure duration (s)

Dependent on perfusion Independent of

perfusion

9European School of Medical Physics - Archamps


Non linearity enhanced thermal effect

Linear waveclose to the transducer

p B

Time

AC

p

p

Time

Time

f

f+

f++

A

A

B

B

Distorted waveaway from the transducer

Where pressure is high, density increases and the wave propagates faster.Inversely, the wave propagates slower where pressure is low.B (max of pressure) gets closer to A (p=0). The sine wave gets distorted,high harmonics occur and absorption increases.

10


• Ultrasound causes particle motion which results in local mechanical stress and strain

Mechanical Effects (1)

∆

-∆

Displacement

Distance

λ/2 Direction of propagation

Pressurep = ρ c v

Negative pressure(Rarefaction = Stretching)

Positive pressure (Compression)

11


• Case of linear wave

f = 1 MHz, I = 1000 W.cm-2

Displacement = 0.58 µm, v = 3.65 m.s-1 over λ/2 = 0.75 mm

Strain = Variation in length / Original length

Strain = 2 x 0.58 µm / 0.75 mm = 0.15 %


∆

-∆

Displacement

x

λ/2Direction of propagation

Stretching of tissues12



• Shock wave (non linear)

I > 50,000 W.cm-2

Displacement >10 µm, v > 250 m.s-1 over < 0.1 mm

Strain > 20%

Displacement

x

Compressionof tissues

Direction of propagation

13



When a wave propagates in a dispersive medium or hit an object, the gradient of energy leads to a steady force: Acoustic streaming and radiation pressure.

14


Cavitation (1)

• Interaction of ultrasound with micro-bubbles

• When a medium that hosts gaseous nuclei is sonicated, micro-bubbles start to expand and contract in a way inversely proportional to the acoustical pressure.

15


f/2, f, 2f, 3f…,f±f0

Medium : α = α(f)

fTransducer Bubble

• Stable cavitation = bubbles oscillate (f0) around their resonant size.

Stable Cavitation

• During stable cavitation, bubbles pumps the US energy which is then scattered at different frequencies. Thereby, bubbly tissuesabsorb much more US power than would pass through normal tissues.

16


Cavitation (2)

• Bubbles radius changes toward the resonant size: Rµm x fMHz =3

• R increases by rectified diffusion = process in which more gas diffused into the bubble from the surrounding medium during the expansion phase than during the compression phase (surface and shell effects)

• R decreases by bubble normal dissolution.

Gas

P < 0

P > 0

Time

Pre

ssu

re

17


Stable Cavitation

18


– Local emission of a shock wave (P > 20,000 Atm) and jets

– Local temperature > 5,000 °K

– Sonoluminescence

– Formation of free radicals (-H and -OH) which are chemically active

– Transient cavitation is associated with hemorrhage and tissue disintegration.

Local shock waves

fTransducer

Medium

Bubble

• Transient cavitation = bubbles expand and collapse violently.

Transient Cavitation

19


Transient Cavitation

20


Transient cavitation – Micro jets

Time

Pressure

Pv

Po + Pa

Po - Pa

Po

Po + Pa

21


Therapeutic applications of ultrasound / involved effect

PhysiotherapyT < 42°C

Hyperthermia42°C < T < 60°C

HIFU or US SurgeryT > 60°C

Non Thermal effectsThermal effects

LithotripsyCavitation - Mechanical effects -

Shock Waves

Sonoporation

Drug DeliveryCavitation

22








23


Treatment urinary stones

• In France:

– Female: 36 cases for 100000 inhabitants

– Male: 78 cases for 100000 inhabitants

– 60000 new cases per year

• Available treatments:

Open surgery, per

cutaneous surgery and

extracorporeal lithotripsy24


Extracorporeal lithotripsy

• Principle: Shock waves generated by extracorporeal

lithotripter focused on the stones

• Mechanisms for stones destruction: Transient

cavitation and shock waves (squeezing, spallation)

• Image guided treatment

25


Shockwave for lithotripsy

1. Very high positive pressure

2. Followed by a long pressure release

3. Pulse repetition frequency # 1Hz

1

2

26

European School of Medical Physics - ArchampsTypical form of the applied wave

Direction of propagation

Damage in the rear of the stone

cS

cW

cS>cW

Ultrasound Ultrasound

Shockwave

« Spalliation » and « Squeezing »

27


Bubbles on stoneduring Shock Wave Lithotripsy

Sokolov, Bailey

28


Bailey, Cleveland et al.

The collapse of the bubbles cloud induces erosion of the front face of the stone.

29


Stone comminution during SWL

Bailey, Cleveland

30


Technomed Praktis

31








32



Experimental demonstration

Green light on:Ultrasound on.

Bovine eye lens

HIFUtransducer

34


Imaging position Firing position

Application of HIFU to the treatment of prostate cancer

35


Principle of transrectal ultrasound for treatment of prostate cancer

• Volume to be treated defined by the urologist

• Procedure monitored by computer (ultrasound scan

of the prostate, motion detection, movement of the

transducer)

• Procedure performed

under epidural anesthesia

Ablatherm “maxis”

36


Efficacy of the treatment evaluated by dosage of PSA in blood…

0

5

10

15

20

25

30

35

40

01-95 04-95 07-95 10-95 02-96 05-96

Time

PS

A (

ng/m

l)

HIFU

Final PSA: 0.41 ng/ml

Negative biopsies

37


The treatment can be repeated

0

5

10

15

20

25

30

35

40

45

50

05-90 09-91 01-93 06-94 10-95 03-97

PS

A (

ng

/ml)

Time

HIFU Sessions

Last PSA : 0.24 ng/ml

Negative Biopsies

Positive Biopsies

Additional HIFU Session

38


Extracorporeal applications of HIFU

• Breast cancers

• Uterine fibroids (very large volumes)

• Liver cancers (ribcage, large volumes, very perfused organ)

• Brain tumors (phase aberration and attenuation through the skull)

• …

39





– Lithotripsy



40


• Intra-luminal and interstitial ultrasound

sources

• Haemostasis induced by ultrasound

• Enhanced transfection by ultrasound

New developments in HIFU

41


Intra-luminal and interstitial heating

• Depositing energy by interstitial routes may

be preferable in some cases (gas, bones,

deep position…).

• Miniature non-focused transducers operating

at higher frequencies than HIFU

• Lesions extend from the transducer surface.

42


Esophagus

Bile duct

Intraluminal applicators

43


Bile duct

Pancreas

Tumor

Duodenum

Tumor thermal ablation with an intra-ductal ultrasound applicator

44



sources




45


Haemostasis = Stop of bleeding

Lacerated organ

Damaged vein

Vaezy et al.46


Haemostasis

Sealed vessel Permeable vessel

• Thermal and mechanical effects

47



sources




48


Ultrasound-enhanced transfection

• Integration of a macro

molecular structure

(plasmid) into a cell

• Objective: Obtain the gene

expression in the cell

Mestas et al. 49


Example of transfection

The green fluorescence in the cell demonstrates that the cell has been transfected.

50


Principle of sonoporation

• Presence of a gene, a microbubble and a cell

• US: Stable cavitation (radiation force),

perforation of cell membrane

• Continuous emission of low pressures and low

frequencies

Chang 51


Drug-delivery enhanced by ultrasound

52


Drug-delivery enhanced by ultrasound

• Advantage = Localized treatment

• Molecule attached or encapsulated in ultrasound contrast agent

• Envisaged applications: lyses of blood clots, delivery of insulin without needle, aiming of chemotherapies…

53



sources



The end !


54


Bio-effects of ultrasound&

Applications to therapy

Jean Martial Mari

David Melo de LimaInserm 1032, LabTAU, Lyon France

European School of Medical Physics, Archamps 2012

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2012:15thSESSION of ESMP€¦ · • 1946 US + X-ray (1st report) • 1967 US + Chemotherapy 3....

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