laser-tissue interaction and its medical...

2016/4/26 No. 1

Quantum Beam Engineering E (Kenichi ISHIKAWA) for internal use only (Univ. of Tokyo)

based on M. Niemz, “Laser-Tissue Interactions,” Springer

Quantum Beam Engineering E 量子ビーム発生工学特論E

Laser-tissue interaction and its medical applications

Kenichi Ishikawa（石川顕一）http://ishiken.free.fr/english/lecture.html

[email protected]

レーザーの生体組織への影響と医療応用

2016/4/26 No. 2


Interaction mechanismsn Photochemical interaction

n Thermal interactionn Photoablationn Plasma-induced ablation

n Photodisruption

All these seemingly different interaction types share the energy density (fluence) ranges between 1 and 1000 J/cm2 → Exposure duration largely matters!

Map of laser-tissue interactions

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Photochemical interactionLight can induce chemical effects and reactions within macromolecules or tissues.• In nature → photosynthesis• Medical application → significant role during photodynamic therapy (PDT)• takes place at very low intensity ～ 1 W/cm2 and long exposure (seconds to

CW)• in the visible ranges – high efficiency and optical penetration depth

Photodynamic therapy (PDT)

Tumor Injection of photosensitizer

Laser irradiation

Excitation of photosensitizer

Production of highly cytotoxic reactants through intramoleculartransfer reactions

Oxidation of essential cell structures

Necrosis

chromophore compound causing light-induced reactions in other non-absorbing molecules

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Kinetics of photosensitizationExcitation• Singlet state absorptionDecays• Fluorescence• Nonradiative singlet decay• Intersystem crossing• Phosphorescence• Nonradiative triplet decayType I reactions• Hydrogen transfer• Electron transfer• Formation of HO2 radicals• Formation O2

- radicalsType II reactions• Intramolecular exchange• Cellular oxidation

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1S + hν ⇒ 1S*

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1S* ⇒ 1S + h # ν

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1S* ⇒ 1S

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1S* ⇒ 3S*

FIG.3.6

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3S* ⇒ 1S + h # # ν

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3S* ⇒ 1S

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3S* + RH ⇒ SH• + R•

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3S* + RH ⇒ S•− + RH•+

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SH• + 3O2 ⇒ 1S+ HO2•

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S•− + 3O2 ⇒ 1S+ O2•−

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3S* + 3O2 ⇒ 1S + 1O2*

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1O2* + cell⇒ cellox

cytotoxic

Energy level diagram of hematoporphyrin derivative(HpD)

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Photodynamic therapy (PDT)

method

• Intravenous injection of photosensitizer (typically porfimer sodium, sold as photofrin)– Photofrin concentration in tumor is ca. four times higher than in healthy tissues.

– Photofrin stays in tumor longer than 48 hours.– Photofrin is excreted from healthy tissues (except for liver and kidney) within 24

hours.

• Laser irradiation after 48-72 hours after Photofrin injection – 630 nm wavelength– introduced to the tumor by optical fiber

a form of cancer therapy using nontoxic light-sensitive compounds that are exposed selectively to light, whereupon they become toxic to targeted tumor cells.

Photofrin

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光線力学的治療法Photodynamic therapy (PDT)

特長• PDTに使用するレーザーは、出力がレーザーメスの1／100程度と低く、フォトフリンはがん組織に多く集積するので、正常組織への障害を最小限に抑え、がん病巣のみを選択的に治療することができる。

• 切ったり、焼いたりする事のない局所的非侵襲的治療法。麻酔の必要が無く、痛み、出血もほとんどない。

• 抗ガン剤のようなきつい副作用がない。• 他の治療を妨げないため、外科手術・放射線療法・化学療法との合併療法が可能。

副作用• 日光過敏症‒ フォトフリン投与後２～３週間は直射日光を避け、必要に応じて日焼け止めクリームの塗布。

‒ 暗室等に滞在する必要はない。

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光線力学的治療法Photodynamic therapy (PDT)

承認の略歴• 1993年（カナダ）：膀胱ガンの治療の承認• 1994年（オランダ）：肺ガンと食道ガンの治療の承認• 1994年（日本）：手術等の他の根治的治療が不可能な場合、あるいは、肺または子宮頸部の機能温存が必要な患者に他の治療法が使用できない場合で、かつ内視鏡的に病巣全容が観察でき、レーザー光照射が可能な下記疾患‒ 早期肺ガン‒ 表在型食道ガン‒ 表在型早期胃ガン‒ 子宮頸部初期ガンおよび異形成

• 1995年（アメリカ）：食道ガンの治療の承認

• 日本では、まだ早期ガンに対してしか承認されていない。‒ このため、なかなかメジャーな治療法にならない。‒ 進行または再発食道ガン・大腸ガンに対する治癒例はある。

• 外国では、進行ガンに対しても承認している国もある。

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Summary of photochemical interaction

• Main idea– use a photosensitizer acting as catalyst

• Observations– no macroscopic observations

• Typical lasers– red dye lasers, semiconductor lasers

• Pulse exposure duration– 1 sec ~ CW

• Intensity– 0.01 ~ 50 W/cm2

• Medical application– Photodynamic therapy of cancer

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Thermal interaction

Microscopic two-step process1. Absorption: A + hν→ A*

– Absorption of a photon promotes molecule A to an excited state A*– Free water molecules, proteins, pigments, and other macromolecules

have many vibrational levels, leading to efficient photoabsorption.2. Deactivation: A* + M(Ekin) → A + M(Ekin+ΔEkin)

– Inelastic collisions with some partner M of the surrounding medium– deactivation of A* and simultaneous increase in kinetic energy of M

Heat generation

Heat transport

Heat effects

Laser & optical tissue parameters

Thermal tissue parameters

Type of tissue

Transfer of photon energy to kinetic energy

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Thermal interaction

Heat generation

Heat transport

Heat effects

凝固(coagulation) 60℃

蒸発・気化(vaporization) 100℃

炭化(carbonization) ＞100℃

融解(melting) ＞300℃

Laser & optical tissue parameters

Thermal tissue parameters

Type of tissue

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coagulation vaporization

Uterine tissue of a wistar rat (CW, Nd:YAG, 10 W)

Human tooth (20 pulses, Er:YAG, 90 µs, 100 mJ, 1Hz)

80µm

Human tooth (Enlargement)Human cornea (120 pulses, Er:YAG, 90 µs, 5 mJ, 1 Hz)

100µm

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carbonization meltingTumor metastases on human skin (CW CO2, 40 W)

1 mm

Human tooth (CW CO2, 1W)

1 mm

Human tooth (100 pulses, Ho:YAG, 3.8 µs, 18 mJ, 1Hz)

Human tooth (Enlargement)

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Heat generation• Absorption mainly by free water molecules, proteins, pigments, and other macromolecules

• Absorption governed by Lambert-Beer’s law

• Absorption by water molecules plays a significant role.‒ Peak at 3µm due to symmetric and asymmetric vibrational modes

‒ Er:[email protected]µm, Er:[email protected]µm, Er:[email protected]µm

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S(z,t)Δz = I(z,t)− I(z+Δz)

fig.3.14

z z+dz

I(z) I(z+dz)

dz

Energy deposition per unit area and time SΔz (W/cm2)

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S(z,t) = −∂I(z,t)∂z

= αI(z,t) (W/cm3)

absorption coefficient

heat source

heat content change dQ vs temperature change dT

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dQ = mcdT m : mass, c : specific heat capacity

Good approximation for most tissues

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c = 1.55 + 2.8 ρWρ

#

$ %

&

' (

kJkg ⋅K

ρ : tissue density (kg/m3)ρW : water content (kg/m3)Absorption spectrum of water

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Heat transportMainly due to heat conduction, except for that due to blood flow (heat convection)

Heat flux jQ (diffusion equation)

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jQ = −k∇T k : heat conductivity

Good approximation for most tissues

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k = 0.06 + 0.57 ρWρ

#

$ %

&

' (

Wm ⋅K

ρ : tissue densityρW : water content

Equation of continuity

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div jQ = −ρm∂Q∂t

= −ρc∂T∂t

Heat conduction equation

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∂T∂t

=kρc∇2T

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∂T∂t

= κ∇2T

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κ ≡kρc

≈1.4 ×10−7 m2 /s

in water and most tissues

Heat conduction with heat source S

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∂T∂t

= κ∇2T +Sρc

2016/4/26 No. 15


Treatment of lumbar disk herniation

normal disk herniation

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Percutaneous Laser Disc Decompression (PLDD)“minimally invasive” treatment modalities for lumbar disk herniation

http://www.spinesurgeon.co.uk/content/laserdiscoplasty/

on an outpatient basis using a gentle, relaxing medicineand local anesthetic

STEP 1 : After some anesthetic is injected to numb thearea, a thin needle called a cannula is inserted throughthe back and into the herniated disc.STEP 2 : A small laser probe is carefully insertedthrough the cannula and into the disc. Pulses of laserlight are shined into the problem area of the disc.STEP 3 : The laser light creates enough heat to shrinkthe disc wall area.END OF PROCEDURE : The probe and needle areremoved, and the insertion area in the skin is coveredwith a small bandage. Because no muscles or bone arecut during the procedure , recovery is fast and scarringis minimized.

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Summary of thermal interaction• Main idea: Achieving a certain temperature which leads to the desired thermal effect

• Observation：coagulation, vaporization, carbonization, melting

• Typical lasers：CO2, Nd:YAG, Er:YAG, Ho:YAG, argon ion, semiconductor lasers

• Pulse duration：1µs～1min• Intensity：10～106 W/cm2• Medical application‒ Laser-induced interstitial themotherapy (LITT)‒ Treatment of retinal detachment‒ Laser bruise treatment

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Photoablation• Removal of tissue in a very clean

and exact fashion without thermal damage

• Tissue is very precisely “etched.”

• Takes place over threshold intensity (107～108 W/cm2)

Fig. 3.30

Cross section of corneal tissue (ArF [email protected] (193nm), 14 ns, 180 mJ/cm2)

Advantages• Precision of the etching process • Excellent predictability• No thermal damage to adjacent tissueMedical application• Laser-Assisted in situ Keratomileusis (LASIK) - myopia,

hypermetropia, and astigmatism.

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Mechanism of photoablation

1. Absorption of a UV photon 2. Excitation of repulsive states

• AB + hν→ (AB)*3. Dissociation

• (AB)* → A + B + Ekin4. Ejection of fragments

C-C bond : 3.5 eVC-N bond : 3.0 eV

Polymethyl-metacrylate (PMMA)

needs UV light

~ 3 – 7 eV

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Ablation depthLambert-Beer’s law

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I(z) = I0 exp(−αz) I0 : incident intensity α : absorption coefficient

Photoablation takes place only when I(z) is above a certain threshold Ith .

Ablation depth d

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I0 exp(−αd) = I th

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d =1αln I0I th

=2.3αlog10

I0I th

Plasma formation

Photoablation

Ablation curve of rabbit cornea (ArF excimer, 14ns)

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Laser in situ Keratomileusis (LASIK)

typically ArF excimerlaser (10~25 ns)

anesthetic (eye drop)fs laser is used to create a thin, hinged flap of the cornea (15 sec exposure per eye)

corneal flap is flipped open

excimer laser is used to remove tissue from the center of the cornea to correct the refractive error

the flap is replacedthe flap is allowed to heal naturally without stitches

2016/4/26 No. 22

Quantum Beam Engineering E (Kenichi ISHIKAWA) for internal use only (Univ. of Tokyo)femtosecond laser to to create a thin, hinged flap

laser processing by self-focusing

2016/4/26 No. 23


1.0以上90%

その他2%0.7-0.9

8%

角膜屈折異常の矯正Laser in situ Keratomileusis (LASIK, レーシック)

LASIKの特長• 良好なpredictability• 痛みが非常に少ない。• 手術翌日から良好な視力が得られる。• 両眼同時手術が可能（20分ほど）• 術後も長期に渡って安定した視力が得られる。

術後裸眼視力裸眼視力の経過

LASIK

乱視遠視近視

LASIKの適応

-1.0～-12.0D 0.5～6.0D+1.0～6.0D

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Summary of photoablation• Main idea : direct breaking of molecular bonds by UV

photons• Observations : very clean ablation, associated with

audible report and visible fluorescnece• Typical lasers : excimer lasers such as ArF, KrF, XeCl,

XeF

• Pulse duration : 10～100 ns

• Intensity : 107～1010 W/cm2

• Medical application : vision correction (LASIK)

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Plasma-induced ablation• Optical breakdown at laser intensity exceeding 1011W/cm2 in solid and

1014 W/cm2 in air• Ablation is primarily caused by plasma ionization itself.• Very clean and well-defined removal of tissue without evidence of thermal

or mechanical damage by choosing appropriate laser parameters.

Medical application

• Refractive corneal surgery• Caries therapy

Plasma sparking on tooth surface (Nd:YLF, 30 ps, 1 mJ, 5x1012 W/cm2)

1 mm

After 16,000 pulses

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Photodisruption• At even higher laser energy density, shock waves and other

mechanical side effects become more significant.• Shock waves, cavitation bubble, jet formation → mechanical

damage to (adjacent) tissue

Medical application

• Lithotripsy

Cavitation bubble within a human cornea (single pulse, Nd:YLF, 30 ps, 1 mJ)

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Plasma formation by optical breakdown

Plasma formation by optical breakdown

Step I : multi-photon ionization

Ionization threshold

High intensity

Multiphotonionization

Low intensity

No ionization

Ejected electrons are accelerated in laser fields (inverse Bremsstrahlung)

Accelerated electrons collide with other atoms and induce further ionization

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hν + e+A+ → e+A+ +Ekin

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dρedt

= σ N INρatom +η I( )ρe

Electron density

Density of neutral atomsIonization threshold

ground state

ground state

Step II : avalanche ionization

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Plasma formation by optical breakdownElectron density

Density of neutral atoms

d⇢edt

= �NIN⇢atom

+ ⌘(I)⇢e

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Progress of plasma-induced ablation and photodisruption

Laser irradiation

Plasma formation and expansion

Shock wave generation

Cavitation bubble formation

Bubble expansion

(Liquid) jet formation

supersonic→deceleration

bubble collapse

Tissue removal(Plasma-induced

ablation)

Damage to adjacent tissues

(Photodisruption)

Optical breakdown

Cavitation bubble within a human cornea

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Summary of plasma-induced ablation

• Main idea : ablation by ionizing plasma formation

• Observation: very clean ablation, associated with audible report and blueish plasma spaking

• Typical lasers– Nd:YAG

– Nd:YLF– Ti:Sapphire

• Pulse duration : 100 fs ～ 500 ps


• Medical application : refractive corneal surgery, caries therapy

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Summary of photodisruption

• Main idea : fragmentation and cutting of tissue by mechanical forces

• Observation: plasma sparking, generation of shock waves, cavitation, jet formation

• Typical lasers

– Nd:YAG– Nd:YLF– Ti:Sapphire

• Pulse duration : 100 fs ～ 100 ns


• Medical application : lithotripsy

laser-tissue interaction and its medical...

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