Retinal photocoagulation with diode lasers

Introduction

A little physics and technology

Semiconductor lasers (also called diode or junction lasers) belong to the family of solid-state lasers, where the active medium responsible for laser emission is a piece of solid material. Unlike their companions (to name a few that have relevance to ophthalmology: the historical ruby laser, the ubiquitous Nd:YAG, and the more exotic Er:YAG), energy excitation (or ‘pumping’) in diode lasers is not optical, e.g., by means of a lamp, but electrical through a current injected through the sample. Another remarkable difference is that the laser medium is not an insulating crystal (like ruby), but rather a material where electrons are only loosely bonded to the lattice atoms, so that current flow is possible (‘semiconductor’ because the electrical properties are intermediate between those of insulators and conductors, such as metals).

Pure semiconductors, such as silicon and germanium, are of little or no utility in electronics. For effective operation, a junction has to be realized, that is a boundary region between two sides of a semiconductor slab, each of which is doped with different impurity atoms (for silicon, for example, arsenic and indium can be used). This doped slab realizes a diode, i.e., a device in which, after application of voltage across its ends, current flow is only allowed in one direction and is inhibited in the opposite one.

In order for the junction to emit light, silicon and germanium do not work, and more complex semiconductor materials are required, in the form of binary, ternary, or quaternary compounds (with two, three, or four constituents); dopant elements vary accordingly. The simplest structure is the light

emitting diode (LED), which radiates light incoherently in all directions, just like a tiny bulb. LEDs are used in electronics as indicators and displays, and have become so bright that they are used instead of filament lamps in traffic lights and stop lights.

In order to realize a laser device, which operates on stimulated rather than spontaneous emission, semiconductor physics imposes severe material selection, because only a few LED materials match the necessary requirements for laser action. Furthermore, an optical resonator comprising two mirrors must be realized in order to provide regenerative amplification and to generate a spatially collimated beam. Finally, the efficiency and lifetime of the device must be maximized in order to allow, not only pulsed, but also continuous wave operation at room temperature, to reduce threshold and operating currents, and to improve the optical quality of the laser beam. All such requirements result in a very complex structure, comprising many semiconductor layers (at least three), of different composition, doping, and thickness, a typical example of which is sketched in Figure 1.

The structure is implemented on a single monolithic ‘chip’, with typical dimensions of 0.5 mm length, 0.2 mm width, and some 1 µm thickness. Such a device, capable of emitting several watts of optical power, is placed in contact with massive copper heatsinks, and packaged in metal cases which look like power transistors (see Fig. 2). To increase the power output level, many parallel stripes can be grown in a single chip, leading to monolithic laser diode arrays, however, with degradation of the optical quality of the beam. Higher powers are commonly available if the laser is operated in a repetitively pulsed mode.

The laser emission wavelength strictly depends

upon the semiconductor composition: with ternary and quaternary materials, the resulting wavelength varies if the relative concentration of the constituting elements is changed. In general, laser diode wavelengths are concentrated in the infrared portion of the spectrum (up to 2000 nm), and in the visible, only the red part is covered. It is physically and technologically difficult to obtain emission from semiconductor lasers below 600 nm, except at very low powers and possibly at cryogenic temperatures. The laser diodes in use in ophthalmology mostly use the ernary semiconductor GaAlAs, emitting at 810 nm and capable of a few watts of power from a single stripe; the red wavelengths at 670690 nm for Photo-Dynamic Therapy (PDT) treatments are obtained from the quaternary material AlGaInP.

Diode laser beam

The characteristics of the beam coming out of semiconductor lasers markedly differ from those of other types of lasers, particularly of gas lasers (such as argon and helium-neon). In fact, these emit a round, well-shaped beam which stays collimated for long distances: the typical divergence of 1 milliradian implies that the beam size grows by 1 mm after 1 m propagation. Diode lasers, on the other hand, generate noncircular beams which spread out very rapidly. This is mostly due to the fact that the emitting area (the section of the active layer) is slit-shaped, a fraction of a micrometer high and several tens or hundreds of micrometers long. Concurrently, the beam divergence is extremely high, some 10 × 40° typically (i.e., 0.17 × 0.7 radians)

parallel and perpendicular to the active layer, respectively (see Fig. 1). External optics are necessary to compensate for this high divergence (collimation), and cylindrical optics to transform the beam shape from oval to round (equalization).

Intrinsic to the structure of the semiconductor junction are also two other specific features of diode laser emission, namely the large spectral linewidth (some 100-1000 times greater than in ion gas lasers), and the dependence of the peak wavelength on the operating temperature of the junction (λ tends to increase with temperature).

However, there is no doubt that the most distinctive characteristic of diode lasers is their small size combined with their high level of output power. The comparison with argon or krypton ion lasers, capable of emitting the same output power, is dramatic: a few cubic centimeters of solid state material on one side compared to liters and liters of sealed laser tube on the other. The ability of being able to generate watt-level power from such a small volume necessarily implies a relevant efficiency, in terms of output optical power divided by the input electrical power required. Indeed, diode lasers exhibit efficiencies of up to 30-40%, a factor some 1000 times larger than that for an ion laser tube. Since all the input power not converted into useful output must be dissipated as heat in some way, it is clear that the requirements of a semiconductor laser are far less stringent: there is no need for liquid cooling, heat exchangers, or fans. The consequence is that the power supply must provide an electrical power at most three times larger than the optical power output, and thus it can be dimensioned very compactly, with the advantage of working at low voltages (2-3 Volts) and moderate currents (a few Amperes).

Another notable feature of diode lasers is that they are monolithic devices, and as such do not require internal adjustments or maintenance. They have shown reliability performances typical of electronic components, with a lifetime exceeding 20,000 hours of continuous operation.

A short history

The semiconductor laser was conceived by the Nobel prize winner Basov in 1961,1 and operated for the first time in 1962,2 shortly after the invention of the ruby laser. Within a short time, laser action was being demonstrated in many different semiconductor materials, but at the beginning, they could only be operated in pulsed mode, at cryogenic temperatures, and for a short time. It was only in 1970 that a diode laser was able to produce a continuous-wave beam at room temperature. The state-of-the-art in semiconductor lasers continued to advance at an amazing rate. In the mid 1980s, specific technological advancements (molecular beam epitaxy and quantum-well structures) boosted the output power capabilities well beyond the watt

limit, and operation could be maintained for thousands of hours without the risk of self-destruction.

Such achievements made the semiconductor laser suitable for applications in the biomedical field, mainly as a replacement for conventional laser sources. In 1984, Pratesi was the first to realize the enormous potential offered by diode lasers, and suggested the possibility of using them in several fields of photomedicine.3 Shortly after, in 1986, the first retinal photocoagulation experiments with diode lasers were performed on animal eyes.4,5 In 1990, the first commercial photocoagulators based on semiconductor laser sources appeared on the market.

At the beginning, also because of power output restrictions, the laser beam was directly coupled from the diode source to the spot-forming optics of the photocoagulator: this sometimes resulted in hot spots being present within the irradiated area, as a consequence of a non-uniform emission across the active layer. Later, when increased power became available, the beam was injected into, and transmitted through, an optic fiber in the same way this usually occurred with ion photocoagulators, thus achieving a smooth and uniform power density at the focal spot. The difference with ion lasers is that a larger core fiber must be used (typically, 200 versus 50 µm), as a result of the multimode nature of the beam emitted from semiconductor lasers, which therefore cannot be as tightly focused as single mode laser sources. This is commonly reflected in the smallest spot size selectable, which usually is 100 µm instead of 50 µm with argon and krypton laser photocoagulators.

At the present time, several companies produce diode laser photocoagulators commercially that emit at 810 nm. Possibly the greatest merit of these instruments is to be found in their ergonomic advantages (compactness, portability, reliability) and economic savings compared to bulky and expensive ion systems. This made a wide diffusion of laser photocoagulator systems available to general ophthalmologists, not only retina specialists, thus increasing the therapy chances for a number of patients.

Laser-tissue interaction

The adoption of a near-infrared wavelength for retinal photocoagulation in place of visible radiation brings with it slight modifications to the picture of the physical interaction of light with tissue, and consequently to the clinical protocols to be followed for effective therapeutic effects.

In general, the transmission through the refractive ocular media is rather flat all across the visible spectrum, with a broad relative peak at around 850 nm (Fig. 3). The transmittances at diode and krypton laser lines are almost identical (about 97%), and are definitely higher than that for the argon green line (85%). Such a 12% difference is partly

due to the higher reflectance of the ocular interfaces at short wavelengths, but mostly to the scattering losses suffered by radiation in propagating through the refractive media. Scattering (or diffusion) has a much stronger dependence on wavelength: the scattering effect is six times greater for the argon green wavelength relative to the diode laser, and eight times greater for the argon blue line (only two and a half times for the krypton red line).

This markedly different behavior is not usually appreciated in normal subjects, but it can make a difference in mild cataractous eyes, in which the diode laser infrared radiation is definitely superior in concentrating more power at the retinal spot, being less dispersed when passing through the lens. In this way, the diode laser is able to perform retinal photocoagulation in conditions in which an argon laser would be unsuccessful.

A similar advantage can be observed in the presence of intravitreal or intraretinal hemorrhages, because the attenuation coefficient of hemoglobin is 25 times higher for argon green than for semiconductor lasers. Thus, the diode laser can be used more safely for performing photocoagulation through mild hemorrhages, in the same way that krypton lasers are preferred to argon ones for this task.

The specific therapeutic action of laser radiation is achieved through absorption in the retinal layers and the consequent heating of the surrounding tissue to the coagulation temperature (typically 6070°C). Here, the chromophore responsible for the absorption of light is essentially melanin, whose

granules are mainly concentrated in the retinal pigment epithelium. The spectral absorbance behavior of melanin is regular, constantly declining from the ultraviolet to the infrared. As a result, at the diode laser wavelength of 810 nm, the overall absorption in the retinal pigment epithelium (Fig. 3) is about one half the value at the argon green line, and 60% that at the krypton red line. This fact has some important consequences.

Being less absorbed in the retina, the diode laser wavelength requires a higher dose (energy = power × exposure time) to obtain the same temperature rise in the tissue compared to the argon green wavelength. The threshold dose for photocoagulation was shown to be three to four times higher for the diode laser, as a combined result of reduced absorption and greater absorbing volume. In fact, the penetration depth is definitely higher with the diode laser because the absorption coefficient (absorption per unit length) is markedly lower than at the green wavelength. Since coagulation takes place deeper in the tissue, involving the choroid as well as the retinal pigment epithelium, it is somewhat more difficult to detect it: while, with the argon laser, whitening of the retina (due to protein denaturation) clearly indicates when the irradiation should be stopped, with the diode laser, the effect of coagulation is seen rather more as a slight graying of the area being treated. More caution is therefore necessary, in order to avoid the risk of overexposure.

In principle, more power, released deeper in the tissue, should result in more pain during treatment, and indeed discomfort to patients was sometimes

reported, particularly in the first years of diode laser photocoagulation. However, it was also shown that, with optimized treatment parameters, no significant difference in pain was experienced by patients undergoing diode compared to argon laser treatment, but rather some preference emerged for the infrared wavelength because of the absence of bright flashes during treatment.6

The pioneering days of diode laser photocoagulation

Among different medical applications, ophthalmology requires the lowest laser intensity for therapeutic effects and was therefore the first to benefit from the availability of diode lasers.

Until then, photocoagulation of the retina had only been carried out using the (blue-)green or red lines of ion lasers; dye lasers were very useful, thanks to their tunability over the entire visible and near-infrared spectrum. Transmission of these wavelengths through the eye was high, and absorption by melanin and hemoglobin great enough to permit coagulation with short exposure times.

As outlined above, the infrared radiation emitted by diode lasers appeared to be appealing for chorioretinal photocoagulation, by using either transpupillary irradiation with standard slit-lamps, or contact transscleral irradiation with suitably shaped fiber tips.

The first coagulations of the chorioretina with diode lasers (cw/pulsed) were reported in 1986 in connection with endophotocoagulation4 and transpupillary photocoagulation5 of rabbit eyes.

Brancato et al.5 used a GaAlAs diode laser emitting at 901 nm; the average input laser power was

30 mW, and the exposure time varied between four and ten seconds. The lesions obtained with a fivesecond exposure were minimal, whitish, and pointlike, while with an irradiation of ten seconds, the chorioretinal photocoagulation appeared white, surrounded by a slightly darker grayish area about 50 µm wide. Histological examination, carried out three days later, showed an alteration mainly located at the pigment epithelium with vacuolization and karyolysis of the outer nuclear layer which was more evident in longer exposure photocoagulations. Diode laser retinal photocoagulations were similar, both ophthalmoscopically and in histological lesions, to the photocoagulations obtained with standard visible lasers at shorter wavelengths.5,7 Similar histological data were reported by Puliafito et al. in 1987 when performing retinal endophotocoagulations using a semiconductor diode prototype laser at 808 nm.8 In 1988, Brancato et al.9 presented their results obtained on rabbit eyes with a transpupillary slit-lamp photocoagulator coupled to a semiconductor laser emitting at 811 nm in the continuous wave (Figs 4-7).

In 1989, the histopathology of diode lesions in rabbit retina was reported in a comparative study with the argon laser.10 Lesions ophthalmoscopically similar to those obtained therapeutically in humans were obtained with a diode and an argon laser. Twenty-four hours after treatment, these lesions were studied by light and electron microscopy: argon irradiations resulted in damage to all the retinal layers, but especially the retinal pigment epithelium, while diode laser radiation produced damage to the outer retina and choriocapillaris; most internal retinal structures and the internal limiting membrane were spared. A sufficient fraction of diode laser radiation could propagate into the choroid in-

ducing irregular obliteration of the choriocapillaris, a certain degree of disorganization of the choroidal pigment, and/or edema. The minimal structural cellular reaction at the vitreoretinal interface could prevent the postphotocoagulative appearance of proliferative vitreoretinopathy.

In the same study,10 Brancato et al. showed that opthalmoscopically similar retinal lesions could be produced with argon and diode lasers at comparable irradiation levels (about 120 W/cm²), although the argon laser exposure time was slightly shorter. This result was rather unexpected, since it was well known that melanin absorption decreases as the radiation wavelength approaches the infrared spectral region. On the other hand, it was reported that, in addition to a radiation range between 800 and 900 nm, low energy levels were required to produce threshold retinal lesions.8,11 Furthermore, diode laser radiation is well transmitted by the ocular optic media, thus reducing the total amount of energy needed to produce a photocoagulative effect.

Other histopathological studies were undertaken

to assess diode laser-induced retinal thermal damage, mainly in rabbit eyes; all the results demonstrated the clinically evident dose-response effect, namely sparing of inner retinal elements with mild burns and full-thickness retinal cell loss with severe burns. Longer irradiation exposure appeared to be a safer way of producing a severe burn than higher power; burns characteristically bloomed in the few seconds following laser application, indicating the deep localization of energy absorp- tion.12-17

Other groups employed fluorescein angiography to control laser-induced thermal damage, using the quantification of fluorescence staining in terms of both intensity and time.18,19 The diode laser was also tested to evaluate its efficacy in obtaining retinochoroidal adhesions.20,21

All these experimental results had the effect of opening a fascinating new era for laser applications in ophthalmology, offering almost ideal laser systems for the treatment of a variety of eye pathologies.

Initial experiments to investigate the clinical use of diode lasers for the treatment of chorioretinal diseases were carried out in 1989,22,23 and these opened the way for several extended studies, reported below.

Transpupillary photocoagulation

Retinal vascular diseases

Preliminary results on the efficacy of diode laser photocoagulation in the treatment of retinal vascular diseases were reported in 1989-1992,22,24-31 and confirmed its potential technical and clinical advantages.

In 1993, Bandello et al.32 published data on a randomized study of diode versus argon-green panretinal laser photocoagulation in proliferative diabetic retinopathy, with a mean follow-up of two years: the long-term efficacy of the diode laser turned out to be similar to that of the argon laser (100% of new vessel regression versus 91%). The complications resulting from the overdosage of diode energy observed in preliminary reports (Figs. 8, 9) were partially reduced thanks to the lower energy used, but were still high (choroidal detachment, neurotrophic keratopathy, troublesome pain, severe field loss).

When performing panretinal photocoagulation at 810 nm radiation, three problems were encountered: (1) it was difficult to judge the intensity of the burn by its appearance; (2) only a narrow power range was shown to produce satisfactory retinal thermal damage; and (3) pigmentation of the treated areas strongly influenced the thermal response. These effects made it possible to produce an unintentional variation in retinal exposure (Fig. 10). These features, together with the complications observed, forced investigators to perform diode

laser treatment using lower energy levels than in preliminary reports, in order to obtain non-contigu- ous gray laser spots only.32

Moreover, the chronic fluorangiographic aspects observed after diode laser irradiation (i.e., marked chorioretinal atrophy larger than acute lesions and greater size and intensity of the chorioretinal atrophy than those produced by the argon laser, see Figs 11-13) deserved some consideration. Initially, these findings were attributed to a higher energy deposit in the choroid because of overdose treatments. However, similar aspects of chorioretinal atrophy were found in eyes treated with lower diode energy; this phenomenon seemed to be wavelengthdependent rather than energy-related: approaching longer wavelengths, absorption by the retinal pigment epithelium decreases and the thermal effect moves to the choroid, as previously demonstrated histologically.10,33 Therefore, the pronounced damage to the choriocapillaris produced by the diode laser in the acute phase contributes to the suffering of the overlying retinal layers, resulting, in the chronic stage, in complete retinal atrophy.10,12

Moreover, Ulbig and Hamilton34 underlined the fluorangiographically-deeper effects of the diode laser in the choroid; compared to the argon laser, their diabetic patients found diode laser treatment more painful, but appreciated the absence of bright flashes during therapy. Altering the pulse configuration resulted in affecting the pain response during diode laser photocoagulation.35

Again, in patients with proliferative diabetic retinopathy, a tendency towards lower decline in color contrast sensitivity and pattern electroretinogram recordings was reported after diode laser compared to argon laser photocoagulation.36,37 The diode laser was also shown to be a viable tool for managing macular edema secondary to diabetes or retinal vein occlusion.22,28,37-42

Fig. 9. Choroidal detachment after an overdose of diode laser photocoagulation.

Retinopathy of prematurity

Diode laser photocoagulation for retinopathy of prematurity was applied for the first time in 1992, in nine infants by means of an indirect ophthalmoscopic delivery system;43 the anatomical and functional results were satisfactory and encouraged the following trials.44-52 Some side-effects were re-

a.

b.

ported, such as lens changes, phthisis bulbi, hyphema, and angle-closure glaucoma.

Other authors proposed transscleral diode laser retinal photocoagulation for threshold retinopathy of prematurity, and reported a favorable outcome. The technique proved to be as effective as transpupillary diode laser photocoagulation, but minor side-effects were noted. However, the technique turned out to be a technically straightforward alternative to cryotherapy.

In 1997, Young et al.63 reported histopathology and vascular endothelial growth factor (VEGF) expression in untreated and diode laser-treated eyes of an infant with stage 3 retinopathy of prematurity. In the treated eye, the histopathological results demonstrated the clinically evident dose-response effect, i.e., sparing of inner retinal elements with mild laser burns, and full-thickness retinal cell disruption with severe burns; scleral and ciliary nerve effects were absent. VEGF mRNA was found to be elevated in the peripheral avascular retina of the untreated eye, consistent with the hypothesis that retinal hypoxia stimulates VEGF expression. In the treated eye, VEGF mRNA was not detected in the photocoagulated areas, but increased between laser scars.

The histopathological study reported by Park et al.64 in diode laser photocoagulated eyes disclosed segmental areas of chorioretinal scarring with retinal atrophy and gliosis, loss of retinal pigment epithelium, and extensive atrophy of the choroid and its vasculature, resembling lesions described after transscleral cryotherapy, but with less severe chorioretinal damage.

Although advances in scleral buckling and vitrectomy techniques offer hope for infants suffering from stage 4 or 5 retinopathy of prematurity,

prevention of progression to these stages offers the greatest promise for favorable structural and visual outcomes. Technological advances in screening tools and portable diode lasers enable ophthalmologists to successfully manage threshold retinopathy of prematurity.

Macular degeneration

Diode laser photocoagulation was applied in patients with macular degeneration, and it turned out

to be at least as effective as that using conventional lasers; advantages were found when performing indocyanine green dye-enhanced diode laser photocoagulation of new choroidal vessels or feeder ves-

sels.40,65-70

Olk et al.71 reported therapeutic benefits from diode laser macular grid photocoagulation in the prophylactic treatment of non-exudative macular degeneration, significantly reducing drusen levels and improving visual acuity when either visible endpoint burns or subthreshold endpoint lesions were used. Complications were fewer using sub-

threshold endpoint lesions. Data from this clinical pilot study have been used to design the Prophylactic Treatment of AMD Trial (PTAMD), a multicenter, randomized, prospective, clinical trial currently in progress, which compares subthreshold (invisible) treatment with observation in eyes with nonexudative AMD.

Tumors

In 1989, a patient with choroidal melanoma, whose eye was about to be enucleated, was briefed about

the aim of human experimental diode laser retinal photocoagulation, which first demonstrated the possibility of obtaining therapeutically useful chorioretinal photocoagulation, ophthalmoscopically and histologically similar to that produced by ion lasers.23

The diode laser has proved to be effective in the treatment of choroidal hemangiomas,72 and has been tested in capillary papillary hemangiomas.73

Transscleral diode laser retinal photocoagulation

The transscleral application of semiconductor diode lasers was first reported in 1990;74,75 Peyman et al.75 achieved retinal photocoagulation in rabbit eyes using energy levels of 200-500 mW for 0.5 seconds; chorioretinal scar formation was observed clinically and histologically within two to three weeks.

Mouries et al.76 examined laser burns obtained

with transscleral diode laser photocoagulation in rabbits by light and electron microscopy and found them to be similar to those produced by argon and krypton lasers. Histopathological evaluation of the lesions demonstrated an intact sclera overlying the chorioretinal lesions.

The results of experimental studies support the hypothesis that transscleral retinal photocoagulation using the diode laser in selected indications may be a valuable alternative to cryotreatment and diathermy in the human eye. The absence of scleral damage and pigmented epithelium cell dispersion, as well as the decreased breakdown of the blood ocular barrier after transscleral diode laser photocoagulation, were the main advantages of the technique.

Various studies showed that transscleral diode laser photocoagulation of retinal breaks is effective and safe;77-80 in particular, Bonnet and Mouries77 demonstrated that it is a valuable alternative to cryotreatment in eyes at high risk of postoperative proliferative vitreo-retinopathy (PVR), and/or when argon laser photocoagulation cannot be used, and/ or in retinal detachments after previous failed surgery. Effective diode laser retinopexy has been reported in retinal detachment surgery.

Transscleral diode laser retinal photocoagulation turned out to be an effective and safe treatment in proliferative sickle cell retinopathy with vitreous and in rubeosis iridis/neovascular

Endo-ocular diode laser retinal photocoagulation

The first coagulations of the chorioretina with a diode endolaser were reported in 1986 in rabbits.5 Some years later, diode endolaser photocoagulation was applied in 25 patients with proliferative diabetic retinopathy, proliferative vitreoretinopathy, complex retinal detachments, or retinal breaks.87 Good retinal and retinal pigment epithelium laser uptake was observed in all cases; the clinical appearance of the burns was similar to that with the argon laser, but it was subtly lighter, especially in less-pigmented areas and in eyes. The logistical advantages offered by this system have been confirmed by other studies,38,88 and it is now routinely applied in vitreoretinal surgery.

Conclusions

The development of diode laser photocoagulators represented a major technological breakthrough relative to conventional ion laser devices, and opened a new era in the field of retinal photocoagulation. The technical and ergonomic advantages of diode laser sources are well evident and certain: compactness, portability, long lifetime, reduced main-

tenance costs. Their attractiveness for a variety of microsurgical procedures has led to a widespread diffusion of the diode laser in the field of vitreoretinal surgery.

In transpupillar retinal photocoagulation, the diode laser fully demonstrated its efficacy and a substantial overlap of its therapeutic results with argon and krypton laser sources, despite a few differences experienced in the course of the treatment. In the last years, the diode laser has been progressively surpassed in the current practice by the diodepumped frequency-doubled Nd:YAG laser photocoagulators, which combine the compactness and reliability of a solid-state laser source with the advantage of a visible wavelength (532 nm), closely resembling the emission line of argon green photocoagulators (514.5 nm).

References

1.Basov NG, Krokhin ON, Popov YM: Production of negative temperature states in P-N junctions of degenerate semiconductors. Journal Experimental Theoretical Physics 40: 1320, 1961

2.Hall RN, Fenner GE, Kingsley JD, Soltys TJ, Carlson RO: Coherent light emission from GaAs junctions. Phys Rev Lett 9:366, 1962

3.Pratesi R: Diode lasers in photomedicine. J Quantum Electronics 20:1433-1439, 1984

4.Deutsch TF, Boll J, Puliafito CA, To K: Semiconductor laser photocoagulation of the retina. In: Technical Digest, Conference on Lasers and Electro-Optics, pp 150-151. San Francisco, CA: OSA/IEEE 1986

5.Brancato R, Giovannoni L, Pratesi R, Vanni U: New lasers for ophthalmology: retinal photocoagulation with pulsed and diode lasers. In: Proceedings of the 1986 Conference on Optics, Optical Systems and Applications (ECOOSA), Florence. SPIE 701:365-366, 1986

6.Goebel W, Pfeiffer N, Grehn F: Patient discomfort during laser treatment, a comparison between diode and argon laser. Invest Ophthalmol Vis Sci 35(Suppl):553, 1994

7.Brancato R, Pratesi R: Applications of diode lasers in Ophthalmology. Lasers Ophthalmol 1:119-129, 1987

8.Puliafito CA, Deutsch TF, Boll J, To K: Semiconductor lasers endophotocoagulation of the retina. Arch Ophthalmol 105:424-428, 1987

9.Brancato R, Pratesi R, Leoni G, Trabucchi G, Giovannoni L, Vanni U: Retinal photocoagulation with diode lasers operating from a slit lamp microscope. Lasers Light Ophthalmol 2:73, 1988

10.Brancato R, Pratesi R, Leoni G, Trabucchi G, Vanni U: Histopathology of diode and argon laser lesions in rabbit retina: a comparative study. Invest Ophthalmol Vis Sci 30: 1504-1510, 1989

11.Lund DJ, Beatrice ES, Schuschereba ST: Bioeffects concerning the safe use of GaAs laser training devices. In: Beatrice ES (ed) Combat Ocular Problems, pp 15-29. San Francisco, CA: Letterman Army Institute of Research 1985

12.Smiddy WE, Hernandez E: Histopathologic results of retinal diode laser photocoagulation in rabbit eyes. Arch Ophthalmol 110:693-698, 1992

13.Benner JD, Huang M, Morse LS, Hjelmeland LM, Landers MB III: Comparison of photocoagulation with the argon, krypton, and diode laser indirect ophthalmoscopes in rabbit eyes. Ophthalmology 99:1554-1563, 1992

14.Cho HK, Park YW, Kim YJ, Shyn KH: Histopathologic and ultrastructural findings of photocoagulation lesions produced by transpupillary diode laser in the rabbit retina. J Korean Med Sci 8:420-430, 1993

15.McHugh D, England C, Van der Zypen E, Marshall J, Fankhauser F, Fankhauser-Kwasniewska: Irradiation of rabbit retina with diode and Nd:YAG lasers. Br J Ophthalmol 79:672-677, 1995

16.Richardson PR, Boulton ME, Duvall-Young J, McLeod D: Immunocytochemical study of retinal diode laser photocoagulation in the rat. Br J Ophthalmol 80:1092-1098, 1996

17.Pollack JS, Kim JE, Pulido JS, Burke JM: Tissue effects of subclinical diode laser treatment of the retina. Arch Ophthalmol 116:1633-1639, 1998

18.Desmettre T, Devoisselle JM, Soulie-Begu S, Mordon S: Value of fluorescein angiography in control of retinal thermal damage due to diode laser. J Fr Ophtalmol 22:730-737, 1999

19.Desmettre TJ, Soulie-Begu S, Devoisselle JM, Mordon SR: Diode laser-induced thermal damage evaluation on the retina with a liposome dye system. Lasers Surg Med 24:61-68, 1999

20.Aso S: Retinochoroidal adhesions of diode laser endophotocoagulation lesions. 1. Histopathology of rabbit eyes. Nippon Ganka Gakkai Zasshi 96:479-485, 1992

21.Smiddy WE, Hernandez E: Histopathologic characteristics of diode laser-induced chorioretinal adhesions for experimental retinal detachment in rabbit eyes. Arch Ophthalmol 110:1630-1633, 1992

22.McHugh JD, Marshall J, Ffytche TJ, Hamilton AM, Raven A, Keeler CR: Initial clinical experience using a diode laser in the treatment of retinal vascular disease. Eye 3:516527, 1989

23.Brancato R, Pratesi R, Leoni G, Trabucchi G, Vanni U: Semiconductor diode laser photocoagulation of human malignant melanoma. Am J Ophthalmol 107:295-296, 1989

24.Noyori K, Noyori S, Ryutaro O: Clinical trial of diode laser photocoagulation: a preliminary report. Laser Light Ophthalmol 2:81-87, 1990

25.Brancato R, Bandello F, Trabucchi G, Leoni G, Lattanzio

R:Argon and diode laser photocoagulation in proliferative diabetic retinopathy: a preliminary report. Lasers Light Ophthalmol 3:233-237, 1990

26.Puliafito CA: Semiconductor diode laser photocoagulation in retinal vascular diseases. Laser Surg Med 2:S67, 1990

27.Balles MW, Puliafito CA: Semiconductor diode lasers: a new laser light source in ophthalmology. Int Ophthalmol Clin 30:77-83, 1990

28.Balles MW, Puliafito CA, D’Amico DJ, Jacobson JJ, Birngruber R: Semiconductor diode laser photocoagulation in retinal vascular disease. Ophthalmology 97:15531561, 1990

29.Noyori S, Iijima M, Ohki R, Noyori K, Yoneya S: Effects on the retina and choroid of transpupillary diode laser photocoagulation. Nippon Ganka Gakkai Zasshi 95:758766, 1991

30.Brancato R, Bandello F: New laser modalities for posterior segment treatment. Curr Opin Ophthalmol 2:299-305, 1991

31.Buckley S, Jenkins L, Benjamin L: Field loss after pan retinal photocoagulation with diode and argon lasers. Doc Ophthalmol 82:317-322, 1992

32.Bandello F, Brancato R, Trabucchi G, Lattanzio R, Malegori

A:Diode versus argon-green laser panretinal photocoagulation in proliferative diabetic retinopathy: a randomized study in 44 eyes with a long follow-up time. Graefe’s Arch Clin Exp Ophthalmol 231:491-494, 1993

33.Puliafito CA, Deutsch TF, Boll J, To K: Semiconductor

laser endophotocoagulation of the retina. Arch Ophthalmol 105:424-427, 1987

34.Ulbig MW, Hamilton AM: Comparative use of diode and argon laser for panretinal photocoagulation in diabetic retinopathy. Ophthalmologe 90:457-462, 1993

35.Friberg TR, Venkatesh S: Alteration of pulse configuration affects the pain response during diode laser photocoagulation. Lasers Surg Med 16:380-383, 1995

36.Ulbig MR, Arden GB, Hamilton AM: Color contrast sensitivity and pattern electroretinographic findings after diode and argon laser photocoagulation in diabetic retinopathy. Am J Ophthalmol 117:583-588, 1994

37.Moorman CM, Hamilton AM: Clinical applications of the MicroPulse diode laser. Eye 13:145-150, 1999

38.Moriarty AP: Diode lasers in ophthalmology. Int Ophthalmol 17:297-304, 1993/94

39.Ulbig MW, McHugh DA, Hamilton AM: Diode laser photocoagulation for diabetic macular oedema. Br J Ophthalmol 79:318-321, 1995

40.Friberg TR, Karatza EC: The treatment of macular disease using a micropulsed and continuous wave 810-nm diode laser. Ophthalmology 104:2030-2038, 1997

41.Bandello F, Lanzetta P, Menchini U: When and how to do a grid laser for diabetic macular edema. Doc Ophthalmol 97:415-419, 1999

42.Tewari HK, Gupta V, Kumar A, Verma L: Efficacy of diode laser for managing diabetic macular oedema. Acta Ophthalmol Scand 76:363-366, 1998

43.Fleming TN, Runge PE, Charles ST: Diode laser photocoagulation for prethreshold, posterior retinopathy of prematurity. Am J Ophthalmol 114:589-592, 1992

44.Capone A Jr, Diaz-Rohena R, Sternberg P Jr, Mandell B, Lambert HM, Lopez PF: Diode-laser photocoagulation for zone 1 threshold retinopathy of prematurity. Am J Ophthalmol 116:444-450, 1993

45.Hunter DG, Repka MX: Diode laser photocoagulation for threshold retinopathy of prematurity: a randomized study. Ophthalmology 100:238-244, 1993

46.Goggin M, O’Keefe M: Diode laser for retinopathy of prematurity-early outcome. Br J Ophthalmol 77:559-562, 1993

47.Yang CM: Diode laser photocoagulation for retinopathy of prematurity. J Formos Med Assoc 94:56-59, 1995

48.Tsitsis T, Tasman W, McNamara JA, Brown G, Vander J: Diode laser photocoagulation for retinopathy of prematurity. Trans Am Ophthalmol Soc 95:231-236; discussion 237-245, 1997

49.McGregor ML, Wherley AJ, Fellows RR, Bremer DL, Rogers GL, Letson AD: A comparison of cryotherapy versus diode laser retinopexy in 100 consecutive infants treated for threshold retinopathy of prematurity. J AAPOS 2:360364, 1998

50.Hautz W, Prost ME: Treating retinopathy of prematurity with laser diode photocoagulation. Klin Oczna 102:355359, 2000

51.Foroozan R, Connolly BP, Tasman WS: Outcomes after laser therapy for threshold retinopathy of prematurity. Ophthalmology 108:1644-1646, 2001

52.Banach MJ, Berinstein DM: Laser therapy for retinopathy of prematurity. Curr Opin Ophthalmol 12:164-170, 2001

53.Capone A: Transient lens changes after diode laser retinal photocoagulation for retinopathy of prematurity. Am J Ophthalmol 15:533-535, 1994

54.Lee GA, Lee LR, Gole GA: Angle-closure glaucoma after laser treatment for retinopathy of prematurity. J AAPOS 2:383-384, 1998

55.Simons BD, Wilson MC, Hertle RW, Schaefer DB: Bilateral hyphemas and cataracts after diode laser retinal photoablation

for retinopathy of prematurity. J Pediatr Ophthalmol Strabismus 35:185-187, 1998

56.Lambert SR, Capone A Jr, Cingle KA, Drack AV: Cataract and phthisis bulbi after laser photoablation for threshold retinopathy of prematurity. Am J Ophthalmol 129: 585-591, 2000

57.Obana A, Lorenz B, Birngruber R: Transscleral and indirect ophthalmoscope diode laser retinal photocoagulation: experimental quantification of the therapeutic range for their application in the treatment of retinopathy of prematurity. Graefe’s Arch Clin Exp Ophthalmol 231:378-383, 1993

58.Seiberth V, Linderkamp O, Vardarli I, Knorz MC, Liesenhoff

H:Diode laser photocoagulation for stage 3+ retinopathy of prematurity. Graefe’s Arch Clin Exp Ophthalmol 233:489493, 1995

59.Seiberth V, Linderkamp O, Vardarli I, Knorz MC, Liesenhoff

H:Diode laser coagulation of stage 3+ retinopathy of prematurity. Ophthalmologe 93:182-189, 1996

60.Seiberth V, Linderkamp O, Vardarli I: Transscleral vs transpupillary diode laser photocoagulation for the treatment of threshold retinopathy of prematurity. Arch Ophthalmol 115:1270-1275, 1997

61.Seiberth V, Woldt C, Linderkamp O: Transscleral diode laser coagulation for therapy of acute retinopathia praematurorum. Klin Mbl Augenheilk 215:241-246, 1999

62.Davis AR, Jackson H, Trew D, McHugh JD, Aclimandos WA: Transscleral diode laser in the treatment of retinopathy of prematurity. Eye 13:571-576, 1999

63.Young TL, Anthony DC, Pierce E, Foley E, Smith LE: Histopathology and vascular endothelial growth factor in untreated and diode laser-treated retinopathy of prematurity. J AAPOS 1:105-110, 1997

64.Park P, Eagle RC Jr, Tasman WS: Diode laser photocoagulation for retinopathy of prematurity: a histopathologic study. Ophthalmic Surg Lasers 32:63-66, 2001

65.Matsumoto M, Miki T, Obana A, Shiraki K, Suh JH: Indocyanine green enhanced photocoagulation in the pigmented rabbit. Nippon Ganka Gakkai Zasshi 96:742-748, 1992

66.Obana A, Matsumoto M, Miki T, Eckert KG, Birngruber R, Gabel VP: Quantification of indocyanine-green enhancement of diode laser photocoagulation. Nippon Ganka Gakkai Zasshi 97:581-586, 1993

67.Kusaka K, Kishimoto N, Fukushima I, Ohkuma H, Uyama

M:An experimental study of diode laser photocoagulation and indocyanine green dye-enhanced diode laser photocoagulation in the primate retina. Nippon Ganka Gakkai Zasshi 98:224-233, 1994

68.Hope-Ross MW, Gibson JM, Chell PB, Corridan PG, Kritzinger EE: Dye enhanced laser photocoagulation in the treatment of a peripapillary subretinal neovascular membrane. Acta Ophthalmol Scand 72:134-137, 1994

69.Flower RW: Experimental studies of indocyanine green dye-enhanced photocoagulation of choroidal neovascularization feeder vessels. Am J Ophthalmol 129:501-512, 2000

70.Gomez-Ulla F, Gonzalez F, Abelenda D, Rodriguez-Cid MJ: Diode laser photocoagulation of choroidal neovascularization associated with retinal pigment epithelial detachment. Acta Ophthalmol Scand 79:39-44, 2001

71.Olk RJ, Friberg TR, Stickney KL, Akduman L, Wong KL, Chen MC, Levy MH, Garcia CA: Therapeutic benefits of infrared (810-nm) diode laser macular grid photocoagula-

tion in prophylactic treatment of nonexudative age-related macular degeneration: two-year results of a randomized pilot study. Ophthalmology 106:2082-2090, 1999

72.Lanzetta P, Virgili G, Ferrari E, Menchini U: Diode laser photocoagulation of choroidal hemangioma. Int Ophthalmol 19:239-247, 1995

73.Garcia-Arumi J, Sararols LH, Cavero L, Escalada F, Corcostegui BF: Therapeutic options for capillary papillary hemangiomas. Ophthalmology 107:48-54, 2000

74.Jennings T, Fuller T, Vukich JA, Lam TT, Joondeph BC, Ticho B, Blair NP, Edward DP: Transscleral contact retinal photocoagulation with an 810-nm semiconductor diode laser. Ophthalmic Surg 12:492-496, 1990

75.Peyman GA, Naguib KS, Gaasterland D: Transscleral application of a semiconductor diode laser. Lasers Surg Med 10:569-575, 1990

76.Mouries O, Vitrey D, Germain P, Bonnet M: Use of diode laser in transscleral retinal photocoagulation. J Fr Ophtalmol 16:108-113, 1993

77.Bonnet M, Mouries O: Pilot study of transscleral light coagulation of retinal breaks using diode laser. J Fr Ophtalmol 17:739-745, 1994

78.McHugh DA, Schwartz S, Dowler JG, Ulbig M, Blach RK, Hamilton PA: Diode laser contact transscleral retinal photocoagulation: a clinical study. Br J Ophthalmol 79:10831087, 1995

79.Loewenstein A, Lamborne AN, Haller JA, de Juan E Jr: Effect of scleral indentation on diode laser transscleral retinal photocoagulation. Ophthalmic Surg Lasers 29:658662, 1998

80.Duquesne N, Fleury J, Bonnet M: Postoperative proliferative vitreoretinopathy in rhegmatogenous retinal detachment associated with stage B preoperative proliferative vitreoretinopathy: comparative results of transscleral retinopexy with diode laser or transpupillary retinopexy with argon laser. J Fr Ophtalmol 21:555-559, 1998

81.Haller JA, Blair N, De Juan E Jr, De Bustros S, Goldberg MF, Muldoon T, Packo K, Resnick K, Rosen R, Shapiro M, Smiddy W, Walsh J: Transscleral diode laser retinopexy in retinal detachment surgery: results of a multicenter trial. Retina 18:399-404, 1998

82.Steel DH, West J, Campbell WG: A randomized controlled study of the use of transscleral diode laser and cryotherapy in the management of rhegmatogenous retinal detachment. Retina 20:346-357, 2000

83.Seiberth V: Trans-scleral diode laser photocoagulation in proliferative sickle cell retinopathy. Ophthalmology 106: 1828-1829, 1999

84.Seiberth V: Transscleral and transpupillary laser coagulation in proliferative sickle-cell retinopathy. Ophthalmologe 98:199-202, 2001

85.Tsai JC, Bloom PA, Franks WA, Khaw PT: Combined transscleral diode laser cyclophotocoagulation and transscleral retinal photocoagulation for refractory neovascular glaucoma. Retina 16:164-166, 1996

86.Flaxel CJ, Larkin GB, Broadway DB, Allen PJ, Leaver PK: Peripheral transscleral retinal diode laser for rubeosis iridis. Retina 17:421-429, 1997

87.Smiddy WE: Diode endolaser photocoagulation. Arch Ophthalmol 110:1172-1174, 1992

88.Sasoh M, Smiddy WE: Diode laser endophotocoagulation. Retina 15:388-393, 1995