22 Mar An Eye on Ophthalmic Lasers

According to the World Health Organization (WHO), the major cause of visual impairment is linked to refractive errors (myopia, hyperopia, astigmatism, presbyopia), showing a global incidence of about 285 million people. If we focus specifically on causes leading to blindness (about 40 million people around the globe), cataracts are by far at the top of the list with more than 50% of the cases, followed by glaucoma, age-related macular degeneration (AMD), corneal opacities, childhood blindness, uncorrected vision errors, trachoma and diabetic retinopathy [5]. Wherever a treatment or therapy is applicable, laser-based or laser-assisted techniques are part of it in most of the cases. However, medical laser technology is usually associated with complex and expensive equipment, non-affordable for many population sectors. But the truth is that blindness incidence is by far more prevalent in developing countries compared to high-income regions, either in percentage and absolute numbers [6]. Hence cost-effectiveness, energy-efficiency or long lifetime gain sense as main drivers for present and future R&D strategies concerning ophthalmological lasers.

Laser-tissue interaction

Laser interaction with eye tissue (and all biological tissues, indeed) can be divided into photothermal, photochemical and photoionizing (see figure 1). When photothermal interaction takes place, the radiation absorbed leads to a sudden temperature rise, causing protein denaturalization (photocoagulation) or even the vaporization of the water surrounding or contained within the affected cells (photovaporization). Such processes enable precise and localized cauterization. However, the pulse duration is in the order of the time necessary for the heat to spread towards adjacent tissues. Within the photochemical category, photoablation implies breaking polymeric tissue into smaller volatile molecules. On another hand, photoradiation comprises the previous administration of a photosensitizer which is selectively attached to a targeted tissue. Once irradiated with its excitation wavelength, the agent is activated and triggers specific biochemical reactions that lead to cell destruction (this is also known as photodynamic therapy). Finally, photoionization (or photodisruption) consists of applying a pulse intense enough to cause the ionization of the irradiated zone. In the process, an acoustic shock wave is generated, which literally tears the tissue apart. The pulse time is so short that the heat affected volume is almost coincident with the beam volume around the focus point. 

Figure 1. Laser-tissue interaction characterized by pulse duration and power density, according to [7]

Lasers in ophthalmology: still the ultimate surgery tool

Globally, laser-assisted refractive surgery for vision correction (myopia, hyperopia and astigmatism) is probably the most popular technique nowadays concerning lasers in Ophthalmology, at least in developed countries. In fact, more than 1 million interventions per year are carried out worldwide [4], only accounting for the variant known as laser-assisted in-situ keratomileusis (LASIK). The most widespread laser used in this technique is an ArF excimer laser, emitting nanosecond pulses at 193 nm. However, femtosecond-pulsed lasers (emitting in the 10XX nm region) have experienced an important growth in the last two decades, and they can be considered certainly as the next generation lasers for refractive surgery.

Although the main goal in modern cataracts treatment comprises the substitution of the human lens by an artificial one, femtosecond lasers can play an important role in key steps of the process. Such is the case when fragmentation of the damaged human lens takes place, or when corneal incisions must be performed for lens substitution.

But if we go back to the beginnings of laser in Ophthalmology, the first laser-assisted therapy clinically tested and validated was retinal photocoagulation (in the early 70s), driven by the discovery of the argon ion laser in 1964. This continuous wave (CW) laser has two intense emission lines at 488nm and 514nm, both showing an excellent absorption by haemoglobin

Laser photocoagulation: a gold standard in ophthalmology

In Ophthalmology, laser photocoagulation is a photothermal-based technique with the main purpose to finely cauterize abnormal leaking blood vessels in the retina (see figure 2), which are related to several eye diseases like diabetic retinopathy or diabetic macular edema  [7].

Figure 2. Eye structure 

In order to do so, green or yellow lasers can be chosen, depending on the typology of the photocoagulation therapy. But in the end, from a light-tissue interaction perspective, it is a question of the chromophore contained in the tissue under treatment (see figure 4). Notice that although blue wavelengths ([8]. Although the whole therapeutic process is not fully understood, the photocoagulated tissue contributes to slow down or even stop the generation in excess of new blood vessels (neovascularisation), which in turns prevents further retinal detachment and progressive vision loss [9]. The most employed wavelength in panretinal photocoagulation (PRP) so far is 532 nm, for many reasons. First of all, it is better absorbed by melanin than yellow, the absorption of haemoglobin is still acceptable, and also light scattering is not a problem. On the other hand, it corresponds to the SHG of Nd:YAG emission (when 1064nm is the selected gain band), one of the most popular solid state lasers ever, which means well-established and widespread technology. In this sense, A multipath solid state laser, MP-532, from Monocrom is an example of compact, reliable and cost-effective solution for PRP, which is beyond traditional Nd:YAG lasers in many senses. Its unique resonator design and the use of Nd:GdVO4 as the active medium allows more than 5 W of peak power in pulsed operation (QCW) at 532nm, with a pulse modulation from 1ms to continous wave (CW) [1]. Nd:GdVO4 combines much larger pump absorption than Nd:YAG with comparable thermal conductivity and emission cross section. Therefore, Nd:GdVO4 represents the best choice (even over Nd:YVO4) for compact and high power laser heads, operating either in CW or QCW. High and stable power, low noise (<1% rms) and high efficiency are combined in a compact, air-cooled and cost-effective laser head ideal for its integration into PRP equipment.

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[1] Maximum nominal power in CW operation is 3 W

Figure 4. Absorption of haemoglobin and eye melanin depending on photon wavelength. 527nm, 532nm and 577nm are laser emission wavelengths corresponding to typical commercial lasers employed in retinal photocoagulation.

Figure 4. Absorption of haemoglobin and eye melanin depending on photon wavelength. 527nm, 532nm and 577nm are laser emission wavelengths corresponding to typical commercial lasers employed in retinal photocoagulation.

Selective retinal therapy: a new era of ultra-precise laser treatments

Despite the broadly extended and well-established technique of panretinal photocoagulation (PRP), a new approach was proposed in the 90s and developed in the past decade. The idea was to selectively destroy dysfunctional tissue in the retinal pigment epithelium (RPE), leaving unaltered the adjacent neural retina and photoreceptors, as well as the choroid. This new technique was named selective retinal therapy (SRT). It relied on the fact that RPE cell recovery was observed after regular laser photocoagulation treatments, which pointed out to a crucial role of the RPE in the proliferation of retinal vascular diseases. According to this, the destruction of adjacent tissues could be considered as an unwanted side-effect of traditional laser panretinal photocoagulation (PRP) [10]. According to the previous theoretical studies, selective retinal therapy (SRT) demanded a well defined laser pulse in the μs range with pulse energy around 1 mJ [11], and a wavelength well absorbed by the melanin contained in the RPE tissue. In fact, the laser-tissue interaction mechanism under such conditions could no longer be considered photocoagulation, but photovaporization instead.  Laser pulses requiring mJ and μs together meant peak power in the kW range. At the time when selective retinal therapy (SRT) was developed, green diode lasers where only a research topic, so the direct diode solution was discarded, and most probably it will remain like this for the next five to ten years to come. On the other hand, high peak power pulses in solid state lasers require Q-switching, but the duration of the pulses usually falls into the ns-range, mainly due to the resonator length, but also influenced by the gain of the active medium.  Therefore, alternative solutions were explored. The need for green wavelengths presented an advantage here. In lasers with active media emitting in the 1μm region of the spectrum, the insertion of an intra-cavity SHG crystal along with an active Q-switching element in the resonator allows the stretching of the Q-pulses from the ns to the μs range. Such technique is based on a physical phenomenon called “mode overcoupling”. When placing an SHG crystal within the resonator, the dynamics of optical gain and losses during Q-pulse formation are altered. As a result, the outcoming pulse can be stretched from a few ns to more than 1 μs [11]. However, the shape of the pulse is far from a nice sharp and symmetric peak. Instead, it consists of a sudden rise followed by a slow exponential-like decay (see figure 5). This represents a drawback for selective retinal therapy (SRT), since the power distribution is far from constant along the pulse. To overcome this, something more had to be done. For this, the Q-switching element must be operated in a smart and tailored way. Monocrom diode-pumped solid state laser, LQ-527, head combines a compact U-shaped resonator, with intracavity SHG crystal and an acoustic-optical modulator (AOM) as the Q-switching element. A particular smart signal was designed to drive the AOM, which is applied during laser adjustment. In particular, the conversion efficiency of the intracavity SHG crystal is tuned through the adjustment of its operating temperature and relative angle between the optical axis and the laser beam, iteratively. This leads to the formation a stretched laser pulse of 1.7 μs at 527 nm (see figure 6). The maximum energy per pulse is 1 mJ and the instant power shows a maximum difference of 25%. In addition, the frequency of operation can be as high as 200 Hz. The effectiveness of such laser parameters for selective retinal therapy (SRT) has been already demonstrated by several clinical studies [12, 13, 14]. Another important fact is that given its precise actuation over the RPE layer, LQ-527 solid state laser is a suitable laser head to perform treatments in the macula, where the destruction of photoreceptors is a critical issue in traditional photocoagulation approaches.

Figure 5. Stretched pulse shape from mode overcoupling (left). Ideal pulse shape combining mode overcoupling and AOM smart driving (right).

igure 6. Stretched pulse shape by mode overcoupling and AOM smart driving. Central oscillogram corresponds to the optimized pulse, while left and right oscillograms corresponds to small variations of the SHG crystal temperature, above and below, respectively

From the laser technician perspective, the suppression of high peak power at the beginning of the pulse represents an inherent advantage. By stretching the Q-pulse in time and flattening its power profile, all optical components are kept well below their catastrophic optical damage (COD) threshold. This contributes decisively to its reliability while reducing criticality in their components, which results in competitive manufacturing costs.

A final remark

The weight of ophthalmologic lasers in the medical industry is remarkable. As usual, this fact represents a precious stimulation for competition in terms of quality, innovation and cost-effectiveness. At the same time, safer and more effective laser-based treatments are being developed continuously, enriching the whole path from research to real application. Indeed, when it comes to medical lasers, it is not the customer who matters, but the patient.

References

[1]. Theodore H. Maiman, “Stimulated emission in ruby” Nature 187, 493-494 (1960) 

[2]. It happened here: the ruby laser (web article accessed online in June of 2018 at: https://healthmatters.nyp.org/ruby-laser/)

[3]. Daniel V. Palanker, Mark S. Blumenkranz, Michael F. Marmor, “Fifty Years of Ophthalmic Laser Therapy”,  Archives of Ophthalmology 129 (12), 1613-19 (2011) (Article accessible online at https://web.stanford.edu/~palanker/publications/History_of_Ophthalmic_Lasers.pdf)

[4]. Kathy Kincade, Allen Nogee, Gail Overton, David Belforte, and Conard Holton, “Annual Laser Market Review & Forecast: Lasers enabling lasers”, LASER FOCUS WORLD, January 2018 (Article accessible online at https://www.laserfocusworld.com/articles/print/volume-54/issue-01/features/annual-laser-market-review-forecast-lasers-enabling-lasers.html)

[5]. World Health Organization, “Global data on visual impairments 2010” (report available online at: https://www.who.int/blindness/GLOBALDATAFINALforweb.pdf?ua=1)

[6]. Gretchen A. Et al., “Global Prevalence of Vision Impairment and Blindness. Magnitude and Temporal Trends, 1990–2010”, American Academy of Ophthalmology Journal 120 (12), 2377?84 (2013)

[7]. Boulnois J. L., “Photophysical processes in recent medical laser developments: A review”, Laser Medical Science 1 (1), 47-66 (1986)

[8]. Jhawer S., Karth P. A.,”Panretinal Photocoagulation”, online article on eye-wiki portal ofr the American Academy of Ophthalmology (2016) (available online at: https://eyewiki.aao.org/Panretinal_Photocoagulation)    

[9]. Stefánsson E., “The mechanism of retinal photocoagulation. How does the laser work?”, European Ophthalmic Review 2 (1), 76-79 (2009)

[10]. Neely K. A. and Gardner T. W., “Ocular neovascularisation”, American Journal of Pathology 153 (3), 665-670 (1998)

[11]. Roider J.et al., “Selective retina therapy (SRT) for clinically significant diabetic macular edema”, Graefe’s Archive for Clinical and Experimental Ophthalmology 248 (9), 1263–1272 (2010)

[12]. Kracht D. Brinkmann R. “Green Q?switched microsecond laser pulses by overcoupled intracavity second harmonic generation”, Optics communications 231, 319-324 (2004)

[13]. Park Y. G., Kim E. Y., Roh Y. J., “Laser-based strategies to treat diabetic macular edema: Hystory and new promising therapies”, Journal of Ophthalmology 2014 Volume 2014, Article ID 769213, 1-9 (2014)

[14]. Kim H.D. et al., “Functional evaluation using multifocal electroretinogram after selective retina therapy with a microsecond-pulsed laser”, Investigative Ophthalmology and Vision Science 56 (1), 122-131 (2014)

[15]. Park Y. G. et al., “Selective retina therapy with automatic real-time feedback-controlled dosimetry for chronic central serous chorioretinopathy in Korean patients”, Graefe’s Archive for Clinical and Experimental Ophthalmology 255, 1375-1383 (2017)