Laser in Ophthamology Laser Tissue Interaction Class

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1 Laser in Ophthamology Laser Tissue Interaction Class Hoang Phuong Lien Department of Biomedical Science and Engineering Single Molecule Biology and Cellular Dynamics Lab

2 Content Introduction Structure of a human eye LASER Application of laser in Ophthamology Photothermal therapy Photodynamic therapy Photomechanical interaction

3 Introduction: Structure of human eye Fig 1. Scheme of a human eye

4 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.

5 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.

6 Vitreous Body Transparent gel, Consists of % 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.

$Lens Transparent Helps to refract light to be focused on the retina.$

7 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.

8 Iris Thin, circular structure (diameter: 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.

9 Trabeculum Open - angle glaucoma: induced by a malfunction of the trabecular meshwork. -> Laser trabeculoplasty

$Avascular About 70% of the overall refraction arises from cornea.$

10 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

11 Introduction Table 1: Common medical laser

12 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.

13 Content Introduction Structure of a human eye LASER Application of laser in Ophthamology Photothermal therapy Photodynamic therapy Photomechanical interaction

14 Photothermal Therapy: Photothermal Interaction

15 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.

16 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.

17 Retinal plasticity following photocoagulation Fig 7. Intense burn (a, b), and light burn (c, d) (100ms laser pulses)

18 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).

19 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.

are applied to the 180 on TM with pulses of 100 ms in duration.

20 Laser trabeculoplasty Fig 10. Iris before and after laser treatment. 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. Laser burns in TM: much larger than the beam size and they scar over time -> impossible retreatment of the same areas.

21 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

22 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.

tracking Useful for image-guided targeting

23 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

24 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).

25 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 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

26 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.

27 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).

28 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.

29 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.

30 PHOTOCHEMICAL INTERACTIONS: PHOTODYNAMIC THERAPY Photochemical interactions: based on nonthermal lightinduced 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

31 PHOTOCHEMICAL INTERACTIONS: PHOTODYNAMIC THERAPY The far-red peak ( 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).

32 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: 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.

33 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).

34 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

35 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.

36 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.

37 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.

38 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).

$Photorefractive keratectomy Problems$

39 REFRACTIVE SURGERY Fig 17. Radial keratotomy Fig 18. Photorefractive keratectomy Problems of slow and rather uncomfortable recovery of the epithelial layer.

40 REFRACTIVE SURGERY Laser-assisted in situ keratomileusis (LASIK) (Pallikaris et al. 1991).

41 REFRACTIVE SURGERY Fig 19. Femtosecond laser for corneal flap cutting. Advantage: this improved the consistency of refractive outcomes.

42 TRANSPARENT TISSUE SURGERY WITH ULTRASHORT - PULSE LASERS Dielectric breakdown: Using extremely high irradiances ( 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.

43 Cataract Surgery Fig 20. Posterior Capsulotomy: using ultrashort-pulse laser

44 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.

45 Cataract Surgery Fig 22. A scanning femtosecond laser for anterior capsulotomy

46 References Daniel Palanker Evolution of Concepts and Technologies in Ophthalmic Laser Therapy, Annu. Rev. Vis. Sci. 2: Projects/Photodynamic-therapy/

47 Thank you!

49 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

50 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 (1) 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 (2)

51 Paper: Noninvasive optoacoustic temperature determination at the fundus of the eye during laser irradiation (Schuele et al. 2004) B 0 : determined by the first laser pulse applied, if the start temperature T0 and T RPE p=0 are known. Applying I0 and measuring P0 max, B0 is given by (3) T 0 : the body temperature

52 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 T rep(ti), which is given by

53 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)

LASERS AND LATTE Richard G. Orlando, M.D., F.A.C.S.

LASER LASERS AND LATTE Richard G. Orlando, M.D., F.A.C.S. Light Amplification by Stimulated Emission of Radiation Photons are in phase to produce high intensity polarized light Modification by shutters