UNIVE D RS N IT U Y L MEDICAL Lund University Medical Laser Centre, Sweden
LASER CENTRE 1991
SWEDEN Challenges in Biophotonics
Therapeutic and Diagnostic applications of light in medicine
Laser therapy
• Laser surgery and ablation • Thermo therapy and photocoagulation therapy • Tatoo removal • Cosmetic hair removal • Photodynamic therapy
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
1 Why are lasers used for medical treatments?
– Effective local treatment – Minimally invasive – Minimal side-effects – No bleeding – Non-contact
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Log10 absorption coefficient
H2 O Adenine HbO2 DOPA-Melanin
H O 2 Photofrin
100 200 300 500 700 1000 2000 3000 5000 10,000
UNIVER D SI Wavelength (nm) N T U Y L MEDICAL Ar- LASERUV CENTRE Lund University Medical Laser Centre,PDT Sweden IR 1991 ion SWEDEN Pulsed CO ArF XeCl dye Nd:YAG 2
2 Medical Laser Therapy
• Laser surgery – Eye (Ar-ion , Nd:YAG, Excimer lasers)
– Dermatological (CO2, Dye, Ruby, Ar-ion lasers)
– General surgery (Nd:YAG, diode, CO2 lasers) • Thermo therapy • Photodynamic therapy
UNIVE D RS N IT U Y L Dosimetry is essential!! MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
LASIK Laser-Assited In Situ Keratomileusis
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
3 LASIK Laser-Assited In Situ Keratomileusis Seven steps towards a perfect sight
1. Mark the cornea with inc. Apply anaesthetic eye drops!
UNIVE D RS N IT U Y L MEDICAL From www.eyesurgeryeducation.com
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
LASIK Laser-Assited In Situ Keratomileusis Seven steps towards a perfect sight
2a. Fixate the eye with a suction ring (Option: 2b. Wavefront analysis of the eye) UNIVE D RS N IT U Y L MEDICAL From www.eyesurgeryeducation.com
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
4 LASIK Laser-Assited In Situ Keratomileusis Seven steps towards a perfect sight
3. Peel a slice of the cornea with a microkeratome
UNIVE D RS N IT U Y L MEDICAL From www.eyesurgeryeducation.com
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
LASIK Laser-Assited In Situ Keratomileusis Seven steps towards a perfect sight
4. Expose the underlying layer of the cornea.
UNIVE D RS N IT U Y L MEDICAL From www.eyesurgeryeducation.com
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
5 LASIK Laser-Assited In Situ Keratomileusis Seven steps towards a perfect sight
5. Laser alignment of the eye.
UNIVE D RS N IT U Y L MEDICAL From www.eyesurgeryeducation.com
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
LASIK Laser-Assited In Situ Keratomileusis Seven steps towards a perfect sight
Typical values
Wpulse= 3mJ, tpulse= 18 ns λ=193 nm f = 50Hz 6. Reshape the cornea! (Excimer laser) ∅beam= 0.9 mm
UNIVE D RS N IT U Y L MEDICAL From www.eyesurgeryeducation.com
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
6 LASIK Laser-Assited In Situ Keratomileusis Seven steps towards a perfect sight
7. Put the flap back, wait 5 minutes, then go home!
UNIVE D RS N IT U Y L MEDICAL From www.eyesurgeryeducation.com
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Medical Laser Therapy
• Laser surgery – Eye (Ar-ion , Nd:YAG, Excimer lasers)
– Dermatological (CO2, Dye, Ruby, Ar-ion lasers)
– General surgery (Nd:YAG, diode, CO2 lasers) • Thermo therapy • Photodynamic therapy
UNIVE D RS N IT U Y L Dosimetry is essential!! MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
7 Laser Skin Resurfacing
UNIVE D RS N IT U Y L MEDICAL Wrinkles
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN Courtesy: Stuart Nelson, UC Irvine
Laser Skin Resurfacing
UNIVE D RS N IT U Y L MEDICAL Rhinophyma
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN Courtesy: Stuart Nelson, UC Irvine
8 Laser Skin Resurfacing
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN Courtesy: Stuart Nelson, UC Irvine
Formation of New Collagen
Pre Treatment
UNIVE D RS N IT U Y 6 Months Post Treatment L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN Courtesy: Stuart Nelson, UC Irvine
9 What is Non-Ablative Skin Rejuvenation? Epidermal protection New collagen deposition
UNIVE D RS N IT U Y L MEDICAL Heating of upper dermis New collagen deposition LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN Courtesy: Stuart Nelson, UC Irvine
Port Wine Stains
DEEP RED/PURPLE PWS
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN Courtesy Lars Svaasand, NTNU Trondheim
10 NORMAL SKIN
Stratum corneum EPIDERMIS 0.1 mm Melanosomes Papillary dermis Upper vascular plexus
1 mm DERMIS
Lower vascular plexus
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN Courtesy Lars Svaasand, NTNU Trondheim
PORT WINE STAIN
EPIDERMIS
Papillary dermis Upper vascular plexus
DERMIS
Lower vascular plexus
UNIVE D RS N IT U Y L MEDICAL Ectactic venules/abnormal density of vessel LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN Courtesy Lars Svaasand, NTNU Trondheim
11 ABSORPTION and SCATTERING SPECTRA
Melanin (arb.units)
Scattering (arb. units)
UV IR UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Medical Laser Therapy
• Laser surgery – Eye (Ar-ion , Nd:YAG, Excimer lasers)
– Dermatological (CO2, Dye, Ruby, Ar-ion lasers)
– General surgery (Nd:YAG, diode, CO2 lasers) • Thermo therapy • Photodynamic therapy
UNIVE D RS N IT U Y L Dosimetry is essential!! MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
12 Laser Medical pen
•Both for cutting tissue and for coagulation of bleedings •Laser characteristics: P = 5W, λ = 980 nm
UNIVE D RS N IT U Y L Developed by the US Air Force MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Laser-Tissue Interaction Mechanisms Power density (W/cm2) 1015 Electro- 1012 mechanics Ophthalmology Ablation 109 Angioplasty 104 J/cm2
106 1 J/cm2 Thermal effects Surgery 103 Tissue welding Hyperthermia 1 Photochemistry PDT Biostimulation
UNIVE D RS N IT -9 -6 -3 3 U Y L 10 10 10 1 10 MEDICAL Pulse duration (s) LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
13 Optical measurements of tissue •Morphological measurements – White light imaging and Microscopy – Optical coherence tomography (OCT) – Optical mammography •Physiological measurements – Oxygenation – Optical biopsy – Transcutaneous glucose measurements – Body fluid constituents (dialysis monitoring, blood vials analysis) •Velocity measurements – Laser Doppler – Breathing UNIVE D RS N IT U Y L MEDICAL – Photoplethysmography (PPG)
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
“OCT for dummies” Optical Coherence Tomography
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
14 Commercial OCT system
Humphrey® Optical Coherence Tomography Scanner
UNIVE D RS N IT U Y at Herlev Hospital. L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991 Courtesy Peter Andersen, Risø, Denmark
SWEDEN
Applications: Ophthalmology
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991 Courtesy Peter Andersen, Risø, Denmark
SWEDEN
15 Incoming light
Nerve fiber layer Ganglion cell layer Inner plexiform layer
Inner nuclear layer
Outer plexiform layer Outer nuclear layer
External limiting membrane Layers of rods and cones Retinal pigment epithelium Choroid
Sclera UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991 Courtesy Peter Andersen, Risø, Denmark
SWEDEN
Opportunities for New Technologies
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
16 Consequences of Age Related Changes
m x-ray mammograms (normal breasts)
t
h
.
1
5
y
t
h
b
8
a
/
h
t
l
a
e
h
/
s
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d
/
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o
c
.
s
t
r
a MILDY
e
m FATTY o DENSE DENSE
h
/
/
:
p
t
t
h
UNIV AGE E D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Mammography: Good and Bad Overall ~90% sensitivity, specificity Post-Menopause Pre-Menopause
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
17 PTB Multi-Channel Scanning Laser Pulse Mammograph
(mark #2, 2003) 652 nm
• 4 (8) detection channels Æ off-axis data (zT) 684 nm • 4 wavelengths ÆcHb, cHbO2 + water + lipid 797 nm Æscatter power 839 nm
now: 4 λ multiplexed
planned:
y+2cm
UNIVE D RS N IT U Y L MEDICAL x-2cm x x+2cm
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Patients #144: Cysts (Mammot3)
Thickness: 4.8 cm (CC) 5.0 cm (OB) Scattering 637 nm 656 nm 683 nm 785 nm
Lesion size: 20 mm
Lesion size: 40 mm
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991 SWEDEN Courtesy Alessandro Torrecelli, POLIMI
18 Patient #130: Cyst (Scattering)
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991 SWEDEN Courtesy Alessandro Torrecelli, POLIMI
Construction of 3D scanning bed
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991 SWEDEN Courtesy Jeremy Hebden, UCL London
19 Evaluation of contrast & spatial resolution
Absorbing / scattering target
165 mm
50 mm Extra section
Hemisphere
UNIVE D RS N IT Scattering fluid U Y L MEDICAL Intralipid + dye LASER CENTRE Lund University Medical Laser Centre, Sweden 1991 SWEDEN Courtesy Jeremy Hebden, UCL London
NETWORK Hand-Held ANALYZER spectrometer Optical Scanner BIAS DC NETWORK
DIODE OPTICAL LASERS SWITCH
CW Source
APD
OPTICAL 2.8 CM FIBER APD
2.2 CM 5 CM
UNIVE D RS N IT U Y L MEDICAL TO LASER CENTRE Lund University Medical Laser Centre, Sweden INSTRUMENT Pham,1991 TH., et al. Review of Scientific Instruments, 71 , 1 – 14, (2000). SWEDEN Courtesy Bruce Tromberg, UC Irvine Bevilacqua, F., et al. Applied Optics, 39, 6498-6507, (2000).
20 Fluorescence? Molecular energy
Absorption Fluorescence of light emission
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Clinical questions ∗ Discriminate adenoumatous and hyperplastic polyps in the colon ∗ Identify premalignant and malignant lesions of the vocal fold ∗ Identify malignant tissue in the brain ∗ Visualize the borders of malignant skin lesions
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
21 Fluorescence diagnostics
• Optical contact fibre or through surgical microscope • Non-invasive • Real-time diagnosis • Provide “optical biopsy” information • Endoscopy UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
• Autofluorescence Collagen Elastin NADH...
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
22 Fluorescence: Tissue autofluorescence Protoporphyrin IX
337 nm excitation 405 nm excitation
Collagen ElastinNADH Carotene Protoporphyrin IX Fluorescence [a.u.] intensity
400 500 600 700 500 550 600 650 700 750 Wavelength (nm) Wavelength (nm)
UNIVE D RS N IT U Y L J. Johansson, Dissertation thesis, LTH (1993). MEDICAL af Klinteberg et al. (1999)
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Clinical measurements
Hyperplastic: Adenomatous:
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
23 Gated Fluorosensor
Synkronisation
Trigger fibre Nitrogen laser
337 nm
Detector
Dye laser (405 nm) Spectrometer
1998- Optics wheel UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden Optical fibre 1991
SWEDEN
Fluorosensors
Nitrogen laser based fluorosensor
UNIVE D RS N IT U Y L MEDICAL Diode laser based fluorosensor LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
24 Diode laser fluorosensor 1999 Diode laser 396 nm
Beam splitter Optical fibre
Spectrometer
2001 Shutter Software
Lap top controlled
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Old, old systems
1986 1990
1999 2003 R.I.P. R.I.P.
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
25 Fluorescence larynx
Ventricular fold anterior Vocal fold
~5 mm
• 337 nm excitation • Multivariate methods for classification: SIMCA, PCA, PLS, logistic regression. • Malignant and premalignant lesions vs. normal tissue UNIVE D RS N IT U Y L ⇒ up to 88% sens. and 93% spec. MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Autofluorescence spectra from tissue
337 nm excitation
Normal
Intensity [a.u.] Pre-malignant
400 450 500 550 600 650 Emission wavelength [nm]
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
26 • Autofluorescence Collagen Elastin NADH...
• Fluorescence induced by tumour marker e.g. ALA-induced PpIX
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Typical fluorescence spectra
Normal Malignant Intensity
400 500 600 700nm UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
27 Exogenous fluorescence and Photodynamic therapy (PDT) 1. Administration of ALA 3. Diagnostics
Haem 635 nm
Iron
ALA Protoporfyrin IX Blue laser
2. Production of PpIX
UNIVE D RS N IT U Y L Tumour MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Fluorescence diagnostics of skin tumour following ALA administration
35 Border
35 Healthy skin 35 Tumour 0 500 600 700
0 0 500 600 700 500 600 700
UNIVE D RS N IT U Y L MEDICAL Basal Cell Carcinoma of the skin
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
28 Fluorescence spectra
1 hour post PDT Post PDT Pre PDT Normal skin 4 hours post ALA 10 mm outside lesion 400 450 500 550 600 650 700 750 2 hours post ALA
Wavelength (nm) 1 hour post ALA Pre ALA
BCC
Centre of lesion Intensity Intensity
UNIVE D RS N IT U Y L MEDICAL 400 450 500 550 600 650 700 750
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Tissue fluorescence with ALA-PpIX as tumour marker
405 nm excitation
Normal Adenoma Intensity [a.u.]
UNIVE 450 500 R 550 600 650 D S 700 N IT U Y L MEDICAL Emission wavelength [nm] LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
29 PpIX fluorescence Autofluorescence
5 mm 5 mm
7000 70000 6000 Astrocytoma 60000 5000
4000 50000
3000 40000
2000 30000 1000 20000 0 440 490 540 590 640 690 -1000 10000
-2000 0 400 450 500 550 600 650 700 15 mm 15 mm 140000 120000 120000 100000 100000 80000 80000 60000 60000 40000 40000 20000 20000 0 0 400 450 500 550 600 650 700 440 490 540 590 640 690
35 mm 35 mm 90000 30000 80000 70000 25000 60000
20000 50000 40000 15000 30000 20000 10000 10000 0 5000 UNIVE D RS 400 450 500 550 600 650 700 N IT U Y L MEDICAL0 440 490 540 590 640 690
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
30 Fluorescence diagnostics
Point monitoring: Whole spectrum in one small tissue site
Imaging: Less spectral information but in larger area
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Fluorescence specrum
Fitted curve PpIX peak A Ratio = A Autofluorescence B Intensity
B
400 450 500 550 600 650 700 750 Wavelength (nm) UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
31 Fluorescence imaging
TAE nBCC
G R Intensified B sBCC CCD camera nBCC
TAE Laser
5 Optical A 4 fiber 3 Beam 2 splitterD White-light 1 Fluorescence Intensity (a.u.) Intensity Fluorescence CCD camera 0 450500550600650700750 Wavelength (nm)
8 7 6 Lens 5 4 3 2 UNIVE D RS N IT 1 U Y L MEDICAL 0
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Multicolour Fluorescence Imaging
White light image
Digitally processed image
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
32 Hyperspectral imaging system
Sagnac interferometer
CCD detector
INTERFEROGRAM collimating lens 0.8 light source 0.6
barrier filter 0.4 dichroic filter 0.2 0.0 excitation filter -0.2
-0.4 objective -0.6
-0.8 UNIVE D RS -10 -5 0 5 10 N IT U Y L MEDICAL Patient Fluorescence intensity Interferometer rotation angle LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Hyperspectral imaging
Fluorescence image using White light photo visual colour scale Fluorescence intensity (a.u.)
400 500 600 700 800 Wavelength (nm)
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
33 Hyperspectral fluorescence imaging of a Basal Cell Carcinoma
Pre ALA Pre PDT Post PDT
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Hyperspectral fluorescence imaging of a BCC pre PDT
Photo Visual colour coding
Similarity plot PLS analysis
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
34 Hyper Spectral Diagnostic Imager
Combines: • video image • reflectance scan • fluorescence scan
Aim: • interactive diagnostics • integrated colposcope
UNIVE D RS N IT U Y L MEDICAL Under development by Science & Technology Inc, USA
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Fibre endoscope
•Coherent fibre bundle
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
35 Cross-section of the distal end
Air/fluid channel
Image channel Guided light fibre bundle
Biopsy channel
Guided light fibre bundle
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
The diagnosis
White-light mode Blue-light mode
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
36 Measurements at Ear-Nose- Throat clinic
Larynx
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Fluorescence diagnostics of skin tumour following ALA administration 1. Administration of ALA 3. Diagnostics
Haem 635 nm
Iron
ALA Protoporfyrin IX Blue laser
2. Production of PpIX 4. Treatment
Red laser
UNIVE D RS N IT U Y L Tumour MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
37 Energy level diagram for PDT
Hp O2
S2 1 + T2 B Σ g
IX S1 T1 1 630 A Δ g nm γ F 1270 P nm
3 - X Σ g S0
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Course of healing
Cryosurgery
Pre 8 days post 7 weeks post 3 months post ALA-PDT
Pre 7 days post 7 weeks post 3 months post
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
38 ALA-PDT of non-melanoma malignant lesions in the region close to the eye
Pre treatment Post treatment
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Parameters of concern in photodynamic therapy
PHOTOSENSITIZER ILLUMINATION Pre-formed agent/porphyrin precursor Wavelength Dose Light dose Mode of administration Fluence rate Tissue localization 1 02 Split-dose regimen Selectivity Photoproduct generation Kinetics
UNIVE D RS N IT U Y L MEDICAL OPTIMIZED TREATMENT OUTCOME
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
39 The synthesis of haem
Mitochondria Ferrochelatase dback Haem e fee tiv ga Ne Fe 2+
Glycine Protoporphyrin IX + (PpIX) Succinyl-CoA δ-aminolevulinic acid
synthase O OH H2N O δ-aminolevulinic acid Cytosol (ALA) Protoporphyrinogen III
Porphobilinogen Coproporphyrinogen III
Porphobilinogen deaminase UNIVE D RS N IT U Y L MEDICAL Uroporphyrinogen III
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Benefits & Disadvantages of PDT
Superficial PDT + Selective treatment + Good cosmetic results + Fast healing + Repeated many times + Outpatient basis + “Simple” method (cooling with water as anaesthetics, occasionally) – Thin and superficial tumours
…compared to conventional methods
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
40 Benefits & Disadvantages of I-PDT
Interstitial PDT
+ Large and/or deeply lying tumours
– Mechanical damage – Insertion of fibres – Dosimetry
...compared to superficial PDT UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Concept Action: InsertionStartContinueMeasureTreatment treatment fluence oftreatment finished optical rate fibres in predetermined Recalculatepositions treatment time
Tumour Healthy tissue
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
41 Calculations of delivered light dose
Not fully treated tumour tissue
Treated tumour tissue
High dose surrounding tissue
UNIVE D RS 20092 minutes N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Benefits & Disadvantages of IPDT
Interstitial PDT
+ Large and/or deeply lying tumours
– Minimally invasive – Positioning of the fibres – Dosimetry
...compared to superficial PDT UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
42 Our patented technology
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Dosimetry measurements during treatment
Fluence rate - fibre positions - optical feedback Fluorescence - build-up of PpIX - PpIX bleaching Temperature -IR camera Tissue perfusion - laser Doppler imaging
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
43 PpIX photobleaching
Pre PDT 40361218251 minutesminute Fluorescence intensity (a.u.)
Excitation wavelength
UNIVE D RS N IT U Y 400 500 600 700 L MEDICAL Wavelength (nm)
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Temperature measurements
• Monitor the heating during PDT
• Observe vascular effects
• Thermal imaging camera (AGEMA
• Resolution 0.1 ºC
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
44 Temperature measurements
Basal cell carcinoma on the chest. 127 mW/cm2, 60 J/cm2
PDT fiber
Pre PDT 3 cm 140 s 33,6ºC 36,4ºC
Temp. measurement area
320 s 480 s, post PDT 37,0ºC 36,7ºC
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Temperature measurement
Temperature increase (ºC) Laser off Basal cells cancer 4 127 mW/cm2
3 Chest, ALA Back, ALA-ME 2
1
0 0 100 200 300 400 500 600 UNIVE D RS N IT U Y L MEDICAL Time (seconds)
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
45 Laser Doppler Perfusion Imaging
Laser
λem: 633 nm
Scanning
Detector Signal
UNIVE D RS Processing N IT U Y L MEDICAL Computer
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Laser Doppler Perfusion Imaging
Pre PDT Im. post PDT 1 w post PDT
1.52 0.00 2.30 0.00 0.51 0.10 Tissue perfusion (a. u.) - PDT 1 m post PDT1.2 13 m post PDT
Superficial BCC 1.0 Normal tissue
0.8
0.6
0.4
UNIVE D RS N IT U Y L 0.2 MEDICAL 0.0 LASER CENTRE Lund University Medical Laser Centre, SwedenPre Im post 1w 1m 2m 3m 13m 1991 0.91 0.08 1.73 0.37
SWEDEN
46 Set-up for spatially resolved diffuse reflectance
Lamp Mirror log(I/I0) Fibre CCD -25 0 25 r(mm)
Tissue
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Diffuse Reflectance from Skin at 630 nm
log(I/I0)
-25 0 25 r(mm)
Diffuse reflectance of normal skin irradiated with a pencil beam UNIVE D RS N IT U Y L MEDICAL of light at 630 nm, measured as line across the irradiated spot.
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
47 Models and methods
- Spatially resolved CW reflectance
Constant µ’s Constant µa
Optimal distances : one at the “Hinge” and one beyond the “Pivot”
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Spatially resolved CW measurements
Diffusion equation - curve fitting Monte Carlo method - curve fitting Calibration against known standards
r
tissue
μa , μs’
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
48 Results Fit of MCS to diffuse reflectance
120 profile
100
80
60
40 intensity (CCD count) (CCD intensity
Intensity (CCD counts) (CCD Intensity 20
0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 ρρ (mm)
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
Fit versus expected optical Results properties 0.06 1.20
0.05 1.05
) 0.04 ) -1 ) ) -1 -1 -1 0.03 0.90 (mm ' (mm (mm s a a μ μ ’ (mm μ s
0.02 μ 0.75 0.01
0.00 0.60 550 600 650 700 750 800 850 550 600 650 700 750 800 850 Wavelengthwavelength (nm) (nm) Wavelengthwavelength (nm) (nm)
UNIVE D RS N IT U Y L MEDICAL
LASER CENTRE Lund University Medical Laser Centre, Sweden 1991
SWEDEN
49