Laser Thermal Therapy
26th Annual Meeting
American College of Medical Physics (ACMP)
Virginia Beach
May 2 – 5, 2009
Gal Shafirstein, DSc
Associate Professor
Director of Vascular Anomalies Research
Department of Otolaryngology, Jackson T. Stephens Spine Center
University of Arkansas for Medical Sciences
e-mail: shafirsteingal@uams.edu
Tel.
501 526 4917
Laser Therapy
Selective Photothermolysis
Selective photothermolysis is the
premise underlying current laser
treatments
At select laser wavelengths, laser
energy is primarily absorbed by the
target absorption site (e.g. hemoglobin,
fluorescence dye)
Linear Absorption
as Function Wavelength
Subcutaneous
Tissue Cutting
Laser Types
Intravital Microscopy
Window Chamber Model
Titanium window chamber attached to the dorsal skin of anesthetized mouse
(left), placed at heated (37 oC) microscope (Nikon Eclipse 50i) stage (right).
Low power double frequency Nd:YAG laser (532 nm)
Intravital Microscopy
Window Chamber Model
In vivo
Laser Treatment
Prior to laser
Immediately after laser
24 hrs post laser
Laser Therapy
Key Parameters
Wavelength
575 – 1064 nm
Pulse time
0.45 -300 ms
Radiant exposure
6 – 600 J/cm2
Beam diameter
1.5-18 mm
Laser Therapy
Laser Systems
Selective Photothermolysis - Pulsed Lasers
Laser
Wave
length
(nm)
Pulse time
(ms)
Peak
Power
(W)
Radiant
Exposure
J/cm2
Pulsed Dye
Laser
575, 585,
595, 600
0.45 to 60
50,000
6 - 40
Nd:YAG
1064
0.25-300
26,333
6 - 600
Diode
800, 805,
808
5-400
2,900
5 - 100
Alexandrite
755
0.25-300
17,666
6 - 600
Laser Thermal Therapy
Treatment of Benign Lesions
Clinical goal:
Induce irreversible damage of the ectatic
vessels wall without damaging adjacent skin
constituents.
Benign Lesions
Vascular Malformations
Vascular Malformations
Birthmarks
Located on the head and neck in 90% of
the cases
Can cause significant disfigurement,
functional deficits and psychological
impairment
Benign Lesions
Vascular Malformations
Clinical categories:
Hemangioma
Common (10% of new born)
Involutes in 90% of the cases
Venous, Arteriovenous, Lymphatic and mix
malformations
Never resolved without treatment (rare)
Venular (Port-Wine Stains)
Never resolved without treatment (0.3-0.5%)
Benign Lesions
Vascular Malformations
Arteriovenous Malformation
Hemangiomia
Venous Malformation
Port-Wine Stain (PWS)
4 months
56 years
23 years
54 years
Modeling Laser Treatment
of Port-Wine stains (PWS)
There are no animal models of PWS;
therefore, the laser parameters for
selective photothermolysis have been
determined largely through
mathematical modeling
Modeling is used to elucidate the optimal
laser parameters
Laser Therapy
Mathematical Modeling
MODEL – aim to explain tendencies
Assist physicians in selecting the right laser
and settings
Associate clinical outcomes (i.e. reality)
with laser parameters
Enables to test multiple parameters to
find the optimal working window
Laser Therapy
Photothermal Modeling
Finite element method (FEM).
Femlab® (Comsol, Burlington, MA)
Diffusion Approximation
Validated in animal models and in agreement with
clinical observations
Validated by independent research groups
Lasers in Surgery and Medicine 34:335–347 (2004)
Medical Laser Application 20, 247–254 (2005)
J Invest Dermatol 125, 343 –352 (2005)
British Journal of Dermatology; 155(2):364-371 (2006)
Lasers Surg Med; 39(2):132-9, (2007)
Lasers Med Sci. 22(2):111-8, (2007)
Lasers Surg Med. 39(4):341-352, (2007)
Medical Laser Application 23, 71–78 (2008)
Laser Therapy
Diffusion Approximation
The source is represented as flux of
photons at the epidermis
Heating of blood vessels is mainly by
diffuse light
Accurate for energy densities larger
than 0.1 J/cm2 (number of photons >
1019)
Accurate for t >>10-12 sec
Photothermal Modeling
Diffusion Approximation
The diffuse light is created at about 1
transport mean free path (MFP) from the
surface
MFP= 1/(Ka + (1-g)Ks)
Ka is the linear absorption coefficient (1/m)
Ks is the linear scattering coefficient (1/m)
g is the optical anisotropic factor
Laser Therapy
Light Diffusion Approximation (2D)
∂
Φ ( x, z , t ) − ∇(α n ∇Φ ( x, z , t )) = −cn µ an Φ ( x, z , t )
∂t
Φ( x, z, t ) Photons flux, Photons/m2/s
cn
Speed of light in tissue n, m/s
α =
cn
n
3( µ a + (1 − g ) µ s )
n
(1− rr )P(t)laserc0
hf
z=0,0≥x≤3.5mm
t >0
n
Optical diffusivity in tissue n, m2/s
= −αn∇Φ(x, z,t)
Surface Boundary condition
P(t) - Laser power density, W/m2
h– Plank constant, 6.626M1034, JMs
f – Laser frequency, 1/s
r- Reflection
Laser Therapy
The Thermal Equation (2D)
∂T
ρ C (T ) p
− ∇(k n∇T ) = ρ nC (T ) np v p(Tv − T ) + µan Φ( x, z, t )hf
∂t
n
n
ρ n Tissue density, kg/m3
kn
Thermal conductivity, W/m/C
v p Blood perfusion, mb3/m3/s
Tv
Core body (blood) temperature
exp(-(T - 100)2 / ∆T 2 )
n
C (T ) = Cp + L ⋅
p
π∆T 2
∆T = 1 o C
Specific heat capacity, J/Kg/C and
Latent heat (L) J/Kg,
Laser Therapy
The Geometrical Model
Schematic geometrical model of a cross section of normal skin, including two
dilated vessels at 0.5 and 1.2 mm depth
Laser Therapy
Temporal Pulse Profile
The pulses delivered during the heating time vary from three
pulses (top), two pulses (lower left), 0.1 ms each, to one
continuous pulse (lower right) of 0.45 ms.
Optical Properties
FPDL 585 and 595 nm
Optical properties
Laser wavelength 585 nm
µa (1/m)
µs (1/m)
Refraction index
g
Laser wavelength 595 nm
µa (1/m)
µs (1/m)
Refraction index
g
(*)Epidermis
Dermis
Blood (0.4
(bloodless) hematocrit)
1800
47000
1.37
0.79
24
12900
1.37
0.79
19100
46700
1.33
0.995
1550
48000
1.37
0.8
24.5
12000
1.37
0.8
4930
46600
1.33
0.995
van Gemert, M.J.C., et al., Laser treatment of port wine stains, in Optical-thermal response of laser-irradiated tissue, A.J.
Welch and M.J.C.v. Gemert, Editors. 1995, Plenum Press: New York. p. 789-829.
Photon and Temperature
Distribution
Calculated photon flux distribution (left) and corresponding temperature field
(right) at the end of a 0.45-ms continuous pulse of FPDL with a 585-nm
wavelength and an energy density of 6 J/cm2.
Photons Flux (Photons/m2/s) For FPDL
0.45 ms continuous pulse
and 6 J/cm2 energy density
Heating and Cooling Cycle for FPDL
0.45 ms continuous pulse
and 6 J/cm2 energy density
Photons Flux (Photons/m2/s) for FPDL at 585
nm wavelength and 3 pulses of 0.1 ms for 1.5
ms heating time and 12 J/cm2 energy density
Heating and Cooling Cycle for FPDL at 585 nm
wavelength and 3 pulses of 0.1 ms for 1.5 ms
heating time and 12 J/cm2 energy density
FPDL 595-nm wavelength
Test in Animal Models
12 J/cm2,
1.5 ms
8J/cm2,
0.45 ms
Temperature calculated
at the center of a vessel
8J/cm2,
1.5 ms
24 hours post
treatment
Laser Therapy
Histology
A
A
BB
CC
DD
Small vessels are spared (A x400) while large vessels (170 Km) are
coagulated (B, x600) for FPDL 12 J/cm2 1.5 ms. No damage for 8 J/cm2
with 1.5 ms 3P was seen (C, x200) in contrast to 0.45 ms (D, x200)
Laser Therapy
of PWS - Clinical Settings
FPDL 585 nm delivering 3 consecutive pulses of 0.1 ms within
1.5 ms (top) and one continuous pulse of 0.45 ms (lower)
12 J/cm2 and 1.5 ms vs.
6 J/cm2 and 0.45ms
Calculated maximum temperature at
the center of vessels as a function
of vessel diameter
Temperature as a function of time
calculated at the center of a 150
Km dilated vessel 1.2 mm deep
Clinical Results, FPDL 585nm,
Before and After 12 J/cm2, 1.5 ms, 3P
Before treatment
After 6 treatments at 12
J/cm2 and 1.5 ms pulse time
with 3 pulses of 0.1 ms
Clinical Results, FPDL 585nm,
Before and After 6 J/cm2, 0.45 ms, 1P
Before treatment
After 6 treatments at 6 J/cm2
and 0.45 ms continuous pulse
Temporal Laser Pulse Contour
Clinical Application
ScleroPlusTM with single pulse at low
energy and power density (6 J/cm2 at
0.45 ms) is equivalent to V-beamTM multi
pluses at high radiant exposure (12 J/cm2
with three 0.1 ms within 1.5 ms)
Laser Thermal Therapy
Laser Efficiency
Laser efficiency: the ratio of the thermal dose
(degMsec) to the applied laser energy (Joule)
ThermalDose
Laser efficiency =
LaserEnergy
tf
ThermalDose = T (t )dt
0
tf= heating and cooling time (sec)
British Journal of Dermatology; 155(2):364-371 (2006)
(oCMsec)
o
C
W
Laser Thermal Therapy
Laser Efficiency
Optimal temperature range
70o C< Tmax < 100o C
Black JF, Barton JK. Chemical and structural changes in blood undergoing
laser photocoagulation. Photochem Photobiol 2004;80:89-7.
Maximum Efficiency
Minimize adverse events
Laser Thermal Therapy
Laser Efficiency
Efficiency= 36 oC/W
Efficiency= 7 oC/W
a
b
The temperature distribution for a 1 mm vessel at the end of the laser pulse
(1064 nm, 60 ms, 100 J/cm²), for 2.5 mm spot size (a) and 6 mm spot size
(b)
Laser Parameters
256 different combinations of laser parameters and vessel sizes
Radiant
Vessel
Beam
Exposure Diameter diameter
(J/cm2)
(mm)
Laser
type
Wavelength
(nm)
Pulse time
(Milliseconds)
FPDL
585
595
0.45 (*), 1.5
6, 8, 12
7
Nd:YAG
1064
10, 30,
60, 100
100, 200
300, 400
2.5, 6
10,
100,
200,
400,
50
150
250
500
400
1000
1500
(*) One set was calculated assuming one continuous pulse of 0.45
milliseconds (Photogenica VTM) and another set was run assuming two or
three pulses of 0.1 ms are delivered within 0.45 ms (V-BeamTM)
Laser – Malformation
Multiple Laser Systems
Vessel Size
(.m)
50-150
150-500
500-1000
Vascular
Malformation
Laser
PWS (early stage)
Hemangioma(*)
FPDL 585, 6 J/cm2 , 0.45 ms, 1P
FPDL 595, 8 J/cm2 , 0.45 ms, 1P
PWS (developed)
Telangiectases
Spider angioma
Venous malformation
Cherry angioma
FPDL 585, 8 J/cm2 , 0.45 ms, 1P
FPDL 595, 8 J/cm2 , 0.45 ms, 1P
FPDL 595, >12 J/cm2, 0.45 ms, 3P
Nd:YAG, 100 J/cm2, 10-100 ms,
2.5 mm spot size
Cherry angioma
Nd:YAG, 100 - 200 J/cm2, 30 -100
Venous malformation ms, 2.5 mm spot size
(*) small vessels (<50 Km) hemangioma will have very poor response to any of
these lasers
Summary
Multiple lasers could be use (consecutively) to
improve clinical outcomes in laser treatments
of vascular malformations
Laser efficiency (oC/W) is a useful parameter
to compare between different laser settings
Simple to calculate
Could be measured (thermal imaging) to monitor
laser treatments in real time
Skin cooling is essential to protect the
epidermal/dermal junction
Laser Therapy of
Malignant Lesions
Induce coagulation necrosis
Laser Concomitant with Drug
Administration
Indocyanine green (ICG) is a water-soluble
tricarbocyanine dye (775 g/mol) FDA
approved for diagnosis, that absorbs NIR
laser light (750-810 nm) four times more
than other blood constituents.
Indocyanine Green (ICG)
Enhanced NIR laser therapy
Indocyanine Green (ICG) enhanced near infrared (NIR) laser
therapy
ICG Enhanced NIR
Laser Therapy
L9 cells (6 E5) were suspended in 15 KL PBS or 20 Kg/mL ICG. Immediate
cells viability was evaluated with Live/Dead assay using flow cytometry
(Cell Lab Quanta, Beckman Coulter)
ICG Enhanced Laser Thermal Ablation
of SCK Tumors in a Mouse Model
Objective:
Non invasive, fast, thermal ablation
of multiple subcutaneous and small
tumors (<5 mm thickness)
ICG Enhanced Laser Thermal Ablation
of SCK Tumors in Mouse Model
Animals:
Mammary adenocarcinoma cells of A/J mice (SCK
cells) were injected into the flank of the mice
(n=20)
Laser settings:
Wavelength: 805 nm
Power: 85 W
Pulse time: 0.250 seconds
Beam diameter: 5 mm
ICG Enhanced Laser Thermal Ablation
ICG Clearance Rate
Whole body NIR
fluorescence
image of a SCID
mouse, 1
minute after 0.2
mg/kg ICG tail
vain injection.
The change of ICG intensity at the tumor site as function
of time post ICG administration.
ICG Enhanced Laser Thermal Ablation
Temperature Distribution, During Laser
Laser + Saline
Laser + ICG
Laser aiming
beam illuminates
lower left side of
the treated region.
ICG Enhanced Laser Thermal Ablation
Tumor Growth Delay
Relative tumor size, to starting volume, at
day 1 to 6 after laser treatment
ICG Enhanced Laser Thermal Ablation
of SCK Tumors in a Mouse Model
Conclusions
ICG enhanced laser thermal ablation of
SCK tumors
Treatment can be completed within 3-5
minutes
Laser Thermal Therapy
Advantages
Non invasive
Fast (minutes)
Selective damage for benign lesions
Enhanced with drugs to induce coagulation
necrosis
Limitation
Shallow penetration <5mm
Limited to light skin (Fitzpatrick 1-3)
Praise and Thanks
Collaborators and Staff:
Wolfgang Bäumler, PhD and Michael Landthaler MD, Dept of
Dermatology, Regensburg Germany
Ran Friedman BSc, Scott Ferguson BS, James Suen MD, Lisa
Buckmiller MD, Dept of Otolaryngology, UAMS
Robert Griffin PhD and Eduardo Moros PhD, Dept of Radiation
Oncology
Michael Borrelli, PhD, Dept of Radiology
Leah Hennings DVM, Chun-Yang Fan MD PhD Dept of pathology
Funding sources:
Arkansas Children’s Hospital Research Institute
Milton and Benjamin Waner Endowed Chair in Plastic Surgery
NIH/NCI, CA108678
US Army Medical Research, BC033639