Lasers and photothermal therapy

Lasers and Photothermal Therapy 

Petras Juzėnas 

2005.06.22 

Biophysics and PDT Group 

Department of Radiation Biology, Radiumhospital, Oslo, Norway 

http://radium.no/moan

A laser is a powerful tool 

A weapon against pain and disease

Photodynamic therapy (PDT) 

Energy 

transfer 

Absorption 

Fluorescence 

Phosphorescence 

1270 nm 

0.98 eV 

UV 

I R 

400 nm 700 nm

Photothermal therapy (PTT) 

Absorption Heat 

1270 nm 

0.98 eV 

UV 

I R 

400 nm 700 nm

Photothermal Therapy 

ϕωζ 

, ϕωτα- 

θερµη 

θεραπία 

- light 

- warmth, heat 

- treatment, cure

Photothermal therapy (PTT) 

Heat generated by laser can be used for: 

Biostimulation - accelerates healing of wounds 

Thermal therapy - heating (>45 o C) of maligant tissue 

Coagulation - sealing blood vessels, stopping bleeding 

Welding - joining of tissues, blood vessels 

Vaporisation - abblation of tissue (laser surgery) 

Shock-waves - removal of biliary, urinary, kidney stones

Photosensitizers 

- Low toxicity 

- Accumulation in biological targets 

- A large extinction coefficient 

- Photochemical stability 

PDT 

Generation of singlet oxygen 

Fluorescence diagnostics 

Photochemistry 

PTT 

Thermal relaxation 

No fluorescence 

No photochemical activity

Background 

Light 

Amplification by 

Stimulated 

Emission of 

Radiation

Background 

Pulsed mode -10 -3 ÷ 10 -15 s 

up to 10 9 W·pulse -1 

Light 

Amplification by 

Stimulated 

Emission of 

Radiation

Background 

1924 - Einstein and Bose - light could also 

stimulate atoms or molecules to emit light 

of the same kind. The basis of the laser ! 

1954 - Microwave Amplification by 

Stimulated Emission of Radiation 

Townes and Shawlow 

Basov and Prokhorov 

1960 - The first successful 

optical LASER by Maiman 

1964 - the Nobel Prize in Physics “Laser Stars” http://home.achilles.net/~jtalbot/history/

Light-tissue tissue interaction 

Absorption of electromagnetic energy 

by a chromophore 

Absorption: P + hν → P*


Deactivation of excited states 

Absorption: P + hν → P* 

Deactivation: P* + M → P + M* 

E + ∆ E


Reflection, absorption, scattering. 

Chromophores - water, hemoglobin, melanin, etc. 

- photosensitizers (porphyrins, chlorins, etc.)


Therapeutic window 

A.Katzir (1993) Lasers and Optical Fibers in Medicine. 

J.-L.Boulnois (1986) Lasers Med. Sci. 1, 47-66.


A.Katzir (1993) Lasers and Optical Fibers in Medicine.


Photochemical - causes target molecules (photosensitizers) to 

start light-induced chemical reactions (eg. PDT) 

Photothermal - conversion of light energy into heat 

Photomechanical - rapid tissue heating with very short and high 

energy pulses resulting in tissue rupture 

photoablation - removal of tissue 

photoacoustic - shock-waves (bile, kidney stones)


W·cm -2 



Photothermal damage 

Thermal parameters 

Diffusion length 

L 2 = 4κ t 

κ -diffusivity 

1.4 ·10 -3 cm2·s-1 

in water 

t = 1 s, L = 0.8 mm 





Relaxation time 

τ 

R = 

d 

4 

2 

κ 


d - characteristic 

dimension 






τ 

R = 

d 

4 

2 

κ 



dimension 

For small targets d is 

linear dimension of tissue volume to be heated 






1 

τ = 

R 

4α 

2 

κ 



dimension 

α - tissue absorption 

For large targets d = α -1 






τ 

R = 

d 

4 

2 

κ 



dimension 

t pulse < τ R 


J.-L.Boulnois (1986) Lasers Med. Sci. 1, 47-66. 

P.Rol et al. (2000) Graefe’s Arch. Clin. Exp. Ophthalmol. 238, 249-272.


Single pulse of duration t pulse 


1 

τ = 

R 

4α 

2 

κ 

κ -10 -3 cm2·s-1 

α - 500 cm -1 

λ=10.6 µm CO 2 

τ R = 1 ms 

t pulse < 1 ms 




Pulses with repetition rate f 


1 

τ = 

R 

4α 

2 

κ 

κ -10 -3 cm2·s-1 

α - 500 cm -1 

λ=10.6 µm CO 2 

f -1 > τ R = 1 ms 

f < 1000 Hz 




Pulses with repetition rate f 


1 

τ = 

R 

4α 

2 

κ 

κ -10 -3 cm2·s-1 

α - 500 cm -1 

λ=10.6 µm CO 2 

f -1 > τ R = 1 ms 

f > 1000 Hz → CW 




Selective photothermolysis (SP) 

confined damage to the specific tissue structures 

by regulating pulse duration and repetition rate 

target 0.1 1-10 100 1000 µm 

pulse 10 -9 10 -6 10 -3 10 -1 s 

R.R.Anderson and J.A.Parish (1983) Science 220, 524-527.


Tissue damage function 

63% damage at Ω = 1 

∆E ≈ 290-630 kJ·mol -1 

F.C.Henriques, 1947 

Ω 

= 

A 

τ 

denat 

e 

− 

∆ E 

RT 

R.Birngruber, 1985 

t pulse ≥τ denat 




Thermal tissue damage 

100 s 

1 s 

54 o C 68 o C 




Modifications induced by the photothermic process 

Temperature 

43-45°C 

Histological modifications 

Conformational changes, shrinkage, hyperthermia (cell death) 

50°C Reduction of enzymatic activity 

60°C 

Denaturation of the proteins, coagulation of the collagens, 

membrane permeabilisation 

100°C Formation of extracellular vacuoles 

> 100°C Breaking of the vacuoles, carbonisation 

300-1000°C 

Thermoablation of the tissue 

60-100 o C 

> 300 o C 

3350°C Vaporisation of carbon 

37-45 o C 

100-300 o C 

J.-L.Boulnois (1986) Lasers Med. Sci. 1, 47-66. 

S.Thomsen (1991) Photochem. Photobiol. 53, 825-835.







Excimer 

Ar 

Ruby 

Alexandrite 

Dye 

Diode 

Nd:YAG 

Ho:YAG 

Er:YAG 

CO 2 

- Ar:F 193 nm, Kr:F 248 nm nm (microscopic surgery) 

- 488, 514 nm (retinal and ear surgery, birthmarks, facial veins) 

- 694 nm (freckles, naevus, hair removal) 

- 755 nm (hair and tattoo removal) 

- 577-585 nm(vascular lesions, PWS) 

- 800-900 nm (hair removal, dental surgery, treatment of veins) 

- 1064 (tissue cut, hair, tattoo removal), 532 nm (vascular lesions) 

- 2070 nm (bone and cartilage ablation, urology, dental fields) 

- 2940 nm (cosmetic skin resurfacing, dental drill) 

- 10600 nm (first laser used by surgeons) 

- (moles, warts, keratoses; tumours; wrinkles)

Clinical applications 

- Pigmented tumours 

- Vascular lesions 

- Reshaping of cornea 

- Atherosclerotic plaques 

- Hair removal 

- Bleaching of birthmarks 

- Skin resurfacing 

- Tattoo removal 

- Tooth drilling and whitening, gum surgery

Endogenous photosensitizers 

Melanin 

Pigmented tumours 

Bleaching of naevus 

Hair removal 

K.G.Klavuhn and D.Green (2002) Lasers Surg. Med. 31, 97-105. 

V.V.Tuchin Ed. (2002) Handbook of Optical Biomedical Diagnostics

Photothermal therapy in 

Ophthalmology 

Pupillary and retinal melanomas 

Retinal detachment 

P.Rol et al. (2000) Graefe’s Arch. Clin. Exp. Ophthalmol. 238, 249-272. 

A.Pirracchio et al. (2001) J. Bombay Ophthalmol. Assoc. 11, 135-144.

Hair Removal 

Selective Absorption in the follicles 

Destruction of the follicle structure 

K.G.Klavuhn and D.Green (2002) Lasers Surg. Med. 31, 97-105.

Hair Removal 

Series of clinical photographs from one subject showing 

the results of a 60-J/cm2, 30 ms, 800 nm pulse 

Pre-cooling 

+ 

Heat-sinking 

Heat-sinking 

only 

No 

cooling 

K.G.Klavuhn and D.Green (2002) Lasers Surg. Med. 31, 97-105.


Hemoglobin 

Vascular lesions 


V.V.Tuchin Ed. (2002) Handbook of Optical Biomedical Diagnostics


Ophthalmology 

Macular degeneration 

Glaucoma 

Diode 810 nm 

Nd:YAG 532, 1064 nm 

Ar 488, 514 nm 


A.Pirracchio et al. (2001) J. Bombay Ophthalmol. Assoc. 11, 135-144.

Laser treatment of port wine stains, 

hemangiomas and vascular birth marks 

Port wine stain (PWS) is a natural, congenital vascular lesion 

that occurs in approximately 0.3% of population. Laser treatment 

of port wine stains (PWS) utilises selective photothermolysis for 

irreversible damage of subsurface blood vessels. Pulsed dye 

lasers are often used in clinical practice. 

before 

after 

before 

after 

PWS 

Hemangioma 

http://www.lasaway.com/home/portwinenew.html

Vascular diseases 

Photocoagulation of 

hemorrhage and bleeding 

Photothermal destruction 

of atherosclerotic plaques 

E.B.Diethrich (2002) 

T.S.Alster et al. (1998) South. Med. J. 91, 806-814.


Collagen 

Water 

Tissue ablation 

for cosmetic skin 

resurfacing 

http://www.entdr.com/ http://www.sbu.ac.uk/water/ 

http://www.stanford.edu/group/FEL/results/ablation.htm

Skin rejuvenation 

Wrinkle removal 

Lasers emitting 

in µm region 

(CO 2 , Er:YAG) 

K.Karpowicz (2002)


Ophthalmology 

LASIK 

- laser assisted 

in situ keratomileusis 

Correction of 

nearsightedness and 

farsightedness 

Excimer lasers 

C.Gorman (1999) Time 154(18), 60-65

Clinical applications 

Exogenous photosensitizers

Exogenous photosensitizers 

Porphyrins, chlorins, phthalocyanines 

λ ε max = 400-650 nm 

before 

after 

25000 

20000 

15000 

ν , cm -1 

Absorption 

Fluorescence 

Intensity 

http://www.photocure.no 

400 600 

λ , nm


Indocyanine green 

ICG 

λ ε max = 780 nm 

Wistar rats with implanted DMBA-4 tumours 

ICG 10 min. and 24 h intratumourally 

808 nm diode laser, 5-10 W, 3-5 min., 60 o C 

control (untreated) 

31.5 ± 3.7 days survival 

treated (ICG + laser) 29.9 ± 3.8 days survival 

lower rate of tumour growth 

W.R.Chen et al. (1996) Cancer Lett. 98, 169-173. 

M.Gurfinkel et al (2000) Photochem. Photobiol. 72, 94-102.


Ni-octabutoxy-naphthalocyanine 

NiNc(Obu) 8 


Ni 

Amelanotic melanoma B78H1 cells in vitro 

NiNc 1.3-7.7 µM for 2, 18, 48 h 

C57/BL6 mice B78H1 tumour, NiNc 3.6 mg·kg -1 i.p. for 24 h 

850 nm Q-switched Ti:saphire laser, 30 ns, 200mJ·pulse -1 , 10 Hz 

treated (in vitro) 

1.7% cell survival for t = 140s 

treated (in vivo) 5 day delay to reach 0.2 cm 3 

A.Busetti et al. (1999) J.Photochem. Photobiol. B:Biol. 53, 103-109.


Pd-octabutoxy-naphthalocyanine 

PdNc(Obu) 8 


BALB/c mice EMT6 tumour 

PdNc 0.6 ± 0.1 mg·kg -1 i.p. for 0-305 h 

Pharmacokinetics measured 

highest tumour / normal skin ratio 

highest tumour / muscle ratio 

~ 12 at 48-175 h 

20 ± 9 at 48-175 h 

M.Bucking et al. (2000) J.Photochem. Photobiol. B:Biol. 58, 87-93.


Cu(II)-hematoporphyrin 

CuHp 

λ ε max = 400 nm; 500-550 nm 

Amelanotic melanoma B78H1 cells in vitro 

CuHp 3-26 µM for 3, 6, 9, 14, 18 h 

532 nm Q-switched Nd:YAG laser, 10 ns, >50mJ·pulse -1 , 10 Hz 

treated (CuHp + pulsed laser) 

treated (CuHp + CW laser) 

50% cell survival for t > 120 s 

no cell killing, t = 40 min. 

M.Soncin et al. (1999) Photochem. Photobiol. 69, 708-712.


Merocyanine dyes 

λ ε max = 380 nm; 589 nm 

Azo dyes 

λ ε max = 530-635 nm 

A.Planner and D.Frąckowiak (2001) J.Photochem. Photobiol. A:Chem. 140, 223-228. 

S.J.Isak et al. (2000) J.Photochem. Photobiol. A:Chem. 134, 77-85.

Conclusions 

Photothermal laser therapy is attractive because: 

- wide range of applications 

- no prolonged cutaneous photosensitivity 

- possibility to treat pigmented tumours 

- does not depend on reactive oxygen species

Conclusions 

Photothermal therapy is attractive because: 

- wide range of applications 

- no prolonged cutaneous photosensitivity 

- possibility to treat pigmented tumours 

- does not depend on reactive oxygen species 

Disadvantages: 

- tissue burning due to “over-treatment” (retinal burns) 

- hemorrhage (especially in retina) 

- light penetration in large tumours 

- fluorescence cannot be used for diagnosis

Thank you !

Lasers and photothermal therapy

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