Laser in OphthamologyLaser – Tissue Interaction Class

Hoang Phuong Lien

20161009

Department of Biomedical Science and Engineering

Single Molecule Biology and Cellular Dynamics Lab

Content

Introduction

Structure of a human eye

LASER

Application of laser in Ophthamology

Photothermal therapy

Photodynamic therapy

Photomechanical interaction

Introduction: Structure of human eye

Fig 1. Scheme of a human eye

Retina

Fig 2. Cross-section of a human retina

Retinal problems

Retinal hole and tear

Retinal detachment

Diabetic retinopathy (neovascularization)

Central vein occlusion: retinal vascular disorder.

Senile macula degeneration

-> cause vision problems -> treated by retinal coagulation.

Retinal tumor or retinoblastoma-> treated by converting laser energy to heat, or mechanical excision or implants of radioactive substance.

Vitreous Body

Transparent gel,

Consists of 98-99.7 % of waters

The formation of new membranes and

neovascularizations extending from retina into

vitreous body could be problems.

-> Thermally acting lasers should be used for treatment

due to the direct vicinity of the retina.

Lens

• Transparent

• Helps to refract light to be focused on the

retina.

• In a cataract, the transparency of the lens is

strongly decreasing. -> Cataract surgery

Iris

Thin, circular structure (diameter: 1.5 – 8 mm)

Responsible for controlling the diameter and size of the

pupil

Closed – angle glaucoma due to dislocation of iris

-> induce strong headaches, severe edema, loss in vision

- > Laser iridotomy.

Trabeculum

Open - angle glaucoma: induced by a

malfunction of the trabecular meshwork.

-> Laser trabeculoplasty

Cornea

The transparent front part of the eye.

Avascular

About 70% of the overall refraction arises

from cornea.

Refractive surgery

Fig. 3. Cross-section of a human cornea

Introduction

Table 1: Common medical laser

Introduction

Fig 4A. Absorption spectra of the major ocular

chromophores

Fig 4B: Absorption spectra of the major ocular chromophores in

the visible part of the spectrum, including Hemoglobin, Melanin

and Xantrophyll.

Content

Introduction

Structure of a human eye

LASER

Application of laser in Ophthamology

Photothermal therapy

Photodynamic therapy

Photomechanical interaction

Photothermal Therapy:

Photothermal Interaction

Photocoagulation

Laser energy : Absorbed primarily by

Melanin in the RPE and choroid

Hemoglobin in blood.

Common lasers in photocoagulation

Frequency-doubled Nd:YAG (532 nm)

Yellow semiconductor lasers (577 nm).

Safe and effective for proliferative diabetic retinopathy.

Beetham (1970) observed that patients with retinal scars (lack photoreceptors) do not develop neovascularization.

Figure 5. Histology of the rabbit retina, with major

chromophores, and the fraction of the laser beam absorbed in

various retinal layers. CH- horiocapillaris, PC – pigmented

choroid, NPC – non-pigmented choroid.

Photocoagulation

Fig 6. Fundus of a patient with diabetic retinopathy after panretinal photocoagulation. All the peripheral retina beyond the vascular arcades is

treated with lesions (light round spots) coagulating photoreceptors and retinal pigmented epithelium, but preserving the inner retina.

Elimination of up to 30% of the photoreceptors, the metabolically most active and numerous cells in the retina, reduces oxygen consumption

and thereby decreases angiogenic signaling, preventing neovascularization and sparing the central vision.

Retinal plasticity following photocoagulation

Fig 7. Intense burn (a, b), and light burn (c, d) (100ms laser pulses)

Retinal plasticity following photocoagulation

Fig 8. Migration of the photoreceptors into the very light lesion of 200 μm in width restores continuity of the photoreceptor layer over

time and prevents formation of a scotoma and scarring. Shifted rods and cones rewire to the local rod- and cone-bipolar cells, restoring

retinal neural network in the lesion, including proper function of the on and off pathways. Figure adapted from Sher et al. (2013).

Optimization of pulse duration

Fig 9. (a) Laser power required to create retinal lesions increases with decreasing pulse duration (measured with 132-μm spot

size on the retina). (b) The range of powers between photocoagulation and rupture (the therapeutic window) decreases with

decreasing pulse duration, making visible photocoagulation unsafe with pulses shorter than 10 ms.

Laser trabeculoplasty

Fig 11. Using argon laser (514 nm) or more recently with the

equivalent 532-nm Nd:YAG laser, 50 spots of 50 μm in

diameter are applied to the 180◦ on TM with pulses of 100 ms in

duration.

Fig 10. Iris before and after laser treatment.

• Laser burns in TM: much larger than the beam size and they scar over time -> impossible retreatment of the

same areas.

Real-time monitoring of tissue temperature

To provide uniform outcomes, because:

The strong variation in fundus pigmentation

Different transparency

Transducer: detect acoustic waves generated in

melanosomes irradiated with nanosecond laser

pulses (Schuele et al. 2004)

Fig 12. Setup for optoacoustic measurements during selective RPE

treatment. A standard contact lens is modified with a piezoelectric

transducer

Pattern-scanning laser photocoagulation

OptiMedicaCorp (2005) introduced a semiautomatic pattern-scanning

photocoagulator.

• Patterns: square arrays (5×5 spots )

• Each exposure: shorter than in

conventional photocoagulation.

• Higher power density

Fig 13. (A) Modified grid by conventional laser. (B) PRP for PDR with

combined conventional laser and Pascal photocoagulation for comparison.

Pattern-scanning laser photocoagulation

Navilas Laser system introduced an automatic laser delivery:

Guided by diagnostic imaging

Stabilized using eye tracking

Useful for image-guided targeting of the leaking microaneurysms - hallmark of

diabetic retinopathy

Nondamaging Laser Therapy of the Macula

Intense photocoagulation outcome:

Destroys the invading vasculature

Leaves a chorioretinal scar -> blind spot (scotoma).

Reichel (1999) attemped to make the nondamaging approach to retinal laser

therapy

Using near-infrared diode laser (810 nm)

Very long exposures (60 s)

A millimeter-wide spot on the retina

Hypothesis: a selective damaging effect of heating on actively dividing cells

in newly formed blood vessels owing to their higher susceptibility to thermal

injury than nondividing cells have in normal tissue.

Difficulties with reliable titration -> frequent occurrences of significant

retinal damage (Benner et al. 2002).

Nondamaging Laser Therapy of the Macula

Nondamaging retinal therapy: using a pulsed version of near-infrared diode laser

(micropulse laser )

Smaller spot size (125 μm) was applied to.

100–300-ms long bursts composed of 0.1- to 0.3-ms pulses

Repeated at a 500-Hz rate.

Sivaprasad (2010) showed significant advantages of the nondamaging retinal

phototherapy

The absence of scotomata and scarring,

The ability to treat foveal areas, and

Improved preservation of color vision and contrast sensitivity.

Nondamaging Laser Therapy of the Macula

Sramek (2011) established dynamic

range of the retinal response to

nondamaging hyperthermia by

monitoring expression of the heat

shock protein HSP-70 in mice.

Endpoint Management (EpM): a

titration protocol for adjustment of

the laser power and duration was

developed (Lavinsky et al. 2014).

Fig 14. Endpoint Management algorithm.

Nondamaging Laser Therapy of the Macula

Fig. 15. Resolution of subretinal fluid in a patient with chronic central serous chorioretinopathy after nondamaging retinal laser

therapy. Approximately 400 spots have been applied at 30% Endpoint Management energy, and no tissue damage has been detected

during the 12-month follow-up. Figure adapted from Lavinsky & Palanker (2015).

Patterned laser trabeculoplasty

Computer guides patterns

Dense coverage of TM with 5-ms-long subvisible

exposures - a strategy similar to the nondamaging

retinal laser therapy.

Laser power is titrated to a barely visible burn in the

area of highest pigmentation (the inferior segment)

using 10-ms pulses,

Pulse duration is decreased by half to reduce the

energy below the visible damage threshold.

Patterned laser trabeculoplasty

Reduction in IOP following this treatment (∼25%) was similar to the results of ALT

(Turati et al. 2010) and, owing to lack of tissue scarring, it allows periodic retreatments.

PHOTOCHEMICAL INTERACTIONS:

PHOTODYNAMIC THERAPY

Photochemical interactions: based on nonthermal light-

induced chemical reactions.

PDT is performed at very low power densities (typically

<1W/cm2) and using minute-long exposures.

This differential accumulation is the basis for selectivity

of PDT against neovascularization, compared with the

normal choroidal and retinal vasculature

PHOTOCHEMICAL INTERACTIONS:

PHOTODYNAMIC THERAPY

The far-red peak (688–691 nm) of the verteporfin absorption spectrum is typically

utilized in clinical practice because of the lower retinal sensitivity and its superior

penetration into the choroid (Woodburn et al. 2002).

Schmidt-Erfurth (1994) showed closure of the abnormal blood vessels occurs within

approximately 6-12 weeks inmost patients

Reperfusion is common, and multiple treatments are often required.

Since the recent advent of anti-vascular endothelial growth factor pharmacotherapy,

which has proven to be much more efficient in the prevention of neovascularization,

PDT has fallen out of favor (Oh & Yu 2015).

PHOTOMECHANICAL INTERACTIONS

Vapor bubbles produced when tissue temperature exceeds the

vaporization threshold may rupture cells within a zone comparable

to the bubble size.

Temperature for vaporization:100 - 305◦C, depending on pulse

duration and on the presence of the bubble nucleation sites

(Vogel&Venugopalan 2003).

For efficient heating, the energy should be delivered fast enough to

avoid heat diffusion during the pulse, a condition called thermal

confinement.

Selective retinal pigmented epithelium

(RPE) Therapy

Light is strongly absorbed by melanosomes in the RPE (μa ≈8,000

cm−1) (Brinkmann et al. 2000).

Application of microsecond laser pulses allows for confinement of

the thermal and mechanical effects of this absorption within the RPE

layer, thus sparing the photoreceptors and the inner retina (Roider et

al. 1992, 1993).

Microsecond and nanosecond pulses can selectively damage RPE by

formation of small cavitation bubbles around melanosomes (Schuele

et al. 2005).

Selective retinal pigmented epithelium

(RPE) Therapy

Fig 16. Retinal pigmented epithelium (RPE) is selectively damaged by a rapidly scanning 532-nm laser

Selective Laser Trabeculoplasty

Latina & Park (1995) introduced selective laser

trabeculoplasty (SLT)

The short pulses of light absorbed in pigmented cells cause

explosive vaporization of melanosomes:

Destruction of the pigmented endothelial cells lining the

meshwork beams

Sparing the nearby nonpigmented tissue.

SLT systems:

Q-switched,

532-nm laser delivers 3-ns pulses in a 400-μm spot.

Selective Laser Trabeculoplasty

Hypothesis:

Remove clogging the TM

Improved permeability to aqueous outflow,

Leading to reduction of IOP.

Latina (1998), Melamed (2003), Nagar (2005)

shown effeciency of SLT in treatment of open angle

glaucoma

Improve permeability of TM to aqueous flow

Without destruction of its microstructure.

Selective Laser Trabeculoplasty

The IOP-lowering effect of SLT lasts for several years, but it also diminishes over

time.

Lack of scarring in SLT allows retreatment.

.

REFRACTIVE SURGERY

Lendeer Jans Lans (1896) published the first ideas for reshaping the

cornea to correct refractive errors

Using penetrating corneal cuts to correct astigmatism.

In 1981, Srinivasan and Wynne put turkey cartilage under the laser

beam (193-nm ArF excimer) and observed a beautiful crater formed

by ablation—much cleaner than any other laser they had tested

(Srinivasan et al. 1983).

REFRACTIVE SURGERY

Fig 17. Radial keratotomy Fig 18. Photorefractive keratectomy

Problems of slow and rather uncomfortable recovery of the epithelial layer.

REFRACTIVE SURGERY

Laser-assisted in situ keratomileusis (LASIK)

(Pallikaris et al. 1991).

REFRACTIVE SURGERY

Fig 19. Femtosecond laser for corneal flap cutting.

Advantage: this improved the consistency of refractive outcomes.

TRANSPARENT TISSUE SURGERY WITH

ULTRASHORT - PULSE LASERS

Dielectric breakdown:

Using extremely high irradiances (108–1011 W/cm2), short-pulsed (ns or fs)

tightly focused laser beam (nanosecond Nd:YAG lasers)

Transparent material can be ionized, and ions absorbing the laser light reach very

high temperatures.

Cataract Surgery

Fig 20. Posterior Capsulotomy: using ultrashort-pulse laser

Cataract Surgery

Fig 21. Anterior capsulotomy: Left: system diagram, including the OCT and femtosecond laser combined by a common

scanner. Right: Side and top views of the eye, with overlay of the planned laser patterns.

Cataract Surgery

Fig 22. A scanning femtosecond laser for anterior capsulotomy

References

Daniel Palanker. 2016. Evolution of Concepts and Technologies in Ophthalmic Laser

Therapy, Annu. Rev. Vis. Sci. 2:295–319

http://web.stanford.edu/~palanker/publications/Ophthalmic_Laser_Therapy.pdf

https://en.wikipedia.org/wiki/Retinoblastoma

http://www.summitmedicalgroup.com/library/adult_health/oph_retinal_holes_and_tears/

http://www.slideshare.net/FUTUREDESIGNER/anatomy-of-the-lens-38752158

http://www.selectspecs.com/info/structure-of-the-eye/

https://www.od-os.com/en-US/home/

http://portal.faf.cuni.cz/Groups/Azaphthalocyanine-group/Research-

Projects/Photodynamic-therapy/

Thank you!

Paper: Noninvasive optoacoustic temperature determination at

the fundus of the eye during laser irradiation (Schuele et al. 2004)

Nanosecond laser pulses melanosome thermal

expansion Thermoelastic pressure wave.

Acoustic transducer: detect pressure wave.

Using a constant pulse energy, the amplitude of the

pressure wave increases linearly with an increase in the

base temperature of between 30 and 80°C.

Fig 12. Setup for optoacoustic measurements during selective RPE treatment.

A standard contact lens is modified with a piezoelectric transducer

Paper: Noninvasive optoacoustic temperature

determination at the fundus of the eye during laser

irradiation (Schuele et al. 2004)Sigrist showed that the maximum peak pressure is proportional to the laser intensity I0 and to the Gru¨neisen

parameter Γ under conditions of no acoustic confinement but thermal confinement.For small variations in the

laser intensity I0 , it follows that

For water, Γ increases nearly linearly in the temperature range from 20

to 60°C.Therefore the maximum pressure amplitude emitted after

pulsed heating increases linearly with the base temperature in this

range. A linear approximation (1) leads to

(1)

(2)

Paper: Noninvasive optoacoustic temperature determination at the

fundus of the eye during laser irradiation (Schuele et al. 2004)

B0: determined by the first laser pulse applied, if the start temperature T0 and TRPEp=0 are known.

Applying I0 and measuring P0 max , B0 is given by

T0: the body temperature

(3)

Paper: Noninvasive optoacoustic temperature determination at the

fundus of the eye during laser irradiation (Schuele et al. 2004)

The increase in the baseline temperature at the i’th laser pulse:

(4)

In the case of repetitive laser irradiation with a repetition rate f rep, the baseline temperature of the i’th laser

pulse is determined at time ti = i*1/f rep . The mean temperature achieved by the previous laser pulses sums

to Trep(ti), which is given by

Grüneisen parameter

The Grüneisen parameter, a constitutive parameter in photoacoustics, is usually measured from isobaric

thermal expansion. It tells us how temperature varies

(where β is the isobaric volume expansion coefficient, Cp is the specific heat, vs is the acoustic

speed, κ is the isothermal compressibility, and ρ is the mass density)