Visual disruption using the thermal lensing effect in the human eye: pilot study.

At select wavelengths, near infrared (IR) light is absorbed in the preretinal media of the eye. This produces small transient increases in temperature that temporarily alter the local index of refraction. If the IR exposure is sufficiently high, a momentary reduction in the focusing power of the eye can be induced through an effect known as thermal lensing. Fundamental optical interaction and safety aspects of this phenomenon have been demonstrated previously in animal and artificial eye models. However, whether the effect will induce an observable visual change in human subjects has not been explored. Here, results of a pilot study are shown where eight human subjects were exposed to an IR laser at levels that were below the safe exposure limit. The exposures did induce a transient visual distortion if sufficiently high levels were used. While the description of the visual change varied between subjects, this experiment was able to determine a general guideline for power needed to induce significant effects in human subjects.

Micro-patterned drug delivery device for light-activated drug release.

BACKGROUND: The primary goal of this study was the fabrication, long-term stability, and measured release of a marker dye from a micro-patterned drug delivery device using (i) mechanical puncture and (ii) photodisruption with an ophthalmic Nd:YAG laser. MATERIALS AND METHODS: A drug delivery device was made from a transparent bio-compatible polymer. The device consisted of two 2.6 mm diameter reservoirs containing 10% Na fluorescein dye. The device was implanted in the rabbit's eye (n = 2) with the cap of the device facing toward the exterior of the eye. Once the animals recovered from the implant surgery, 100% anhydrous glycerol was topically applied to the eye at the implantation site to decrease light scattering in the conjunctiva and sclera. The dye was released from one of the reservoir either using a 28 G ½ needle or an ophthalmic Q-switched Nd:YAG laser. A fluorescence spectrophotometer (FS) with fiber optic probe was used to measure the half-life of the dye in the eye. Measurements of fluorescence intensity were collected until the measurements return to baseline and histology was done on the tissue surrounded the device. RESULTS: None of the devices leaked of 10% Na fluorescein dye after implant. The ablation threshold of the drug delivery device was between 6 and 10 mJ to create 100-500 µm holes. The half-life measurement of the dye was found to be 13 days at the vitreous chamber after measuring the fluorescence intensity through the dilated cornea. Histology study showed minimal immune and foreign body response such as mild inflammation. CONCLUSION: This study established that the drug delivery device seemed to elicit minimal inflammatory response and retained its fluidic content until it was released with relatively longer retention time (half-life). Thus, similar device could be used for controlled release of drugs for certain ocular diseases.

Changes in morphology and optical properties of sclera and choroidal layers due to hyperosmotic agent.

Light scattering in the normally white sclera prevents diagnostic imaging or delivery of a focused laser beam to a target in the underlying choroid layer. In this study, we examine optical clearing of the sclera and changes in blood flow resulting from the application of glycerol to the sclera of rabbits. Recovery dynamics are monitored after the application of saline. The speed of clearing for injection delivery is compared to the direct application of glycerol through an incision in the conjunctiva. Although, the same volume of glycerol was applied, the sclera cleared much faster (5 to 10 s) with the topical application of glycerol compared to the injection method (3 min). In addition, the direct topical application of glycerol spreads over a larger area in the sclera than the latter method. A diffuse optical spectroscopy system provided spectral analysis of the remitted light every two minutes during clearing and rehydration. Comparison of measurements to those obtained from phantoms with various absorption and scattering properties provided estimates of the absorption coefficient and reduced scattering coefficient of rabbit eye tissue.

Variation of fluorescence in tissue with temperature.

BACKGROUND AND OBJECTIVE: Previous studies demonstrated a decrease in fluorescence intensity as tissue temperature increased. In vitro samples were increased from room temperature and in vivo canine liver from body temperature. This study investigated variations in fluorescence intensity with temperatures starting at 14°C and compared in vivo and in vitro results for consistency. STUDY DESIGN/MATERIAL AND METHODS: A fiber optic-based noninvasive system was used to characterize the temperature effect on tissue fluorescence in hamster dorsal skin in vivo, and in sclera and cornea of enucleated pig eyes in vitro. As tissue was allowed to progress through the temperature range of 14-42°C, the spectra of auto-fluorescence with respect to temperature was sampled every 1-2 minutes. A pulsed nitrogen laser was used to excite fluorescence through a fiber optic probe with a source-detector aperture separation of 370 µm. RESULTS: Fluorescence intensity decreased as temperature increased from 14 to 42°C in a phantom containing Rhodamine B dye. Results from both in vivo and in vitro tissue followed the same trend of decreasing intensity as tissue temperature increased from 14°C. Spectral intensity lineshape changed around 450 nm due to absorption from tissue. CONCLUSION: Cooling a tissue increased fluorescence intensity of skin in vivo, in all experiments. In vitro results were consistent with in vivo measurements.

Perfusion in hamster skin treated with glycerol.

BACKGROUND AND OBJECTIVE: The objective of this article is to quantify the effect of hyper-osmotic agent (glycerol) on blood velocity in hamster skin blood vessels measured with a dynamic imaging technique, laser speckle contrast imaging (LSCI). STUDY DESIGN/MATERIALS AND METHODS: In this study a dorsal skin-flap window was implanted on the hamster skin. The hyper-osmotic drug, that is, glycerol was delivered to the skin through the open dermal end of the window model. A two-dimensional map of blood flow of skin blood vessels was obtained from the speckle contrast (SC) images. RESULTS: Preliminary studies demonstrated that hyper-osmotic agents such as glycerol not only make tissue temporarily transparent, but also reduce blood flow. The blood perfusion was measured every 3 minutes for 36-66 minutes after diffusion of anhydrous glycerol. Blood flow in small capillaries was found to be reduced significantly within 3-9 minutes. Blood flow in larger blood vessels (i.e., all arteries and veins) decreased over time and some veins had significantly reduced blood flow within 36 minutes. At 24 hours, there was a further reduction in capillary blood perfusion whereas larger blood vessels regained flow compared to an hour after initial application of glycerol. CONCLUSION: Blood flow velocity and vessel diameter of the micro-vasculatures of hamster skin were reduced by the application of 100% anhydrous glycerol. At 24 hours, capillary perfusion remained depressed.

Trends in retinal damage thresholds from 100-millisecond near-infrared laser radiation exposures: a study at 1,110, 1,130, 1,150, and 1,319 nm.

BACKGROUND AND OBJECTIVES: Retinal damage thresholds from 100-millisecond exposures to laser radiation for wavelengths between 1,100 and 1,350 nm have never previously been established. We sought to determine the retinal damage threshold for 100-millisecond exposures of near-infrared (NIR) laser radiation wavelengths at 1,110, 1,130, 1,150, and 1,319 nm. These data were then used to create trends for retinal damage thresholds over the 1,100-1,350 nm NIR region based upon linear absorption of laser radiation in ocular media and chromatic dispersion of the eye. MATERIALS AND METHODS: The paramacula and macula areas of the retina in Macaca mulatta (rhesus) subjects were exposed for 100 milliseconds to NIR laser radiation wavelengths using a Coherent OPO laser for 1,110, 1,130, and 1,150 nm and a Lee laser for 1,319 nm. Probit analysis was used to establish the estimated damage threshold in the retina for 50% of exposures (ED(50)). Using trends of transmitted energy to the retina, refractive error of the eye and linear absorption of the retina, a scaling factor (SF) method was created to fit the experimental data, predicting retinal damage thresholds over the 1,100-1,350 nm region. RESULTS: The experimental retinal damage threshold, ED(50), for 100-millisecond exposures for laser radiation wavelengths at 1,110, 1,130, and 1,319 nm were determined to be 193, 270, and 13,713 mW of power delivered to the cornea, respectively. The retinal damage threshold for the 1,150 nm wavelength was statistically undetermined due to laser-power limitations, but was achieved in one out of three subjects tested. CONCLUSION: The SF predicts the experimental 100- millisecond NIR ED(50) value for wavelengths between 1,100 and 1,350 nm.

First-order model of thermal lensing in a virtual eye.

An ABCD beam-propagation method was used to build a first-order mathematical model of a thermal lens effect from a near-infrared laser beam in water and ocular media. The model was found to fit experimental z-scan data best when the thermo-optic coefficient dn/dT of liquid water at 292 K was -4.46x10(-5) K(-1). The physiological parameters of the human eye were simulated in a simple eye model using this fitted dn/dT value. Conservative model simulations for 1150 and 1318 nm laser radiation include parameter sets used in experimental ocular exposures performed by Zuclich et al. [Health Phys.92, 15 (2007)] to illustrate the transient response of the thermal lens approaching the limits of the retinal damage thresholds for equivalent laser radiation sources.

Thermal lensing in ocular media exposed to continuous-wave near-infrared radiation: the 1150-1350-nm region.

Ocular damage threshold data remain sparse in the continuous wave (CW), near-infrared (NIR) radiation region save for the 1300-nm area that has been investigated in the past several decades. The 1300-nm ocular damage data have yielded unusual characteristics where CW retinal damage was observed in rabbit models, but never in nonhuman primate models. This paper reviews the existing 1300-nm ocular damage threshold data in terms of the fundamental criteria of an action spectrum to assist in explaining laser-tissue effects from near-infrared radiation in the eye. Reviewing the action spectrum criteria and existing NIR retinal lesion data lend evidence toward the significant presence of thermal lensing in ocular media affecting damage, a relatively unexplored mechanism of laser-tissue interaction.

Histological and modeling study of skin thermal injury to 2.0 microm laser irradiation.

BACKGROUND AND OBJECTIVE: Qualitative and quantitative gross histopathologic studies of skin damage were performed at 48 hours after irradiation with a 2.0 microm thulium CW laser to determine the mechanisms of laser effects in the skin under various exposure conditions. STUDY DESIGN/MATERIALS AND METHODS: Pig skin lesions were created at, below and beyond the threshold irradiation conditions for grossly apparent thermal lesions. Histological sections of these lesions were studied. For each threshold lesion, four quantitative histopathological parameters were measured: the widths of (1) epidermal necrosis at the surface, (2) the outer boundary of the thrombosis zone, (3) the depth of vascular thrombosis, and (4) the depth of perivascular inflammation (increased infiltrates of inflammatory cells) and edema. The quantitative histopathologic data were compared with predictions using an optical-thermal-damage model. RESULTS: Histologically, the thermal damage mechanisms for grossly apparent threshold lesions of persistent redness at 48 hours included necrosis of the epidermal cells, intravascular thrombosis and perivascular inflammation and edema in dermal blood vessels. At irradiation levels just below 'gross threshold', non-lethal thermal effects, such as perivascular inflammation and edema were found in the histological sections. When the radiation reached about 1.5-2.5 times beyond the threshold, decrease of dermal collagen birefringence was observed. CONCLUSIONS: A sequence of damage endpoints was defined in the skin as power increased. By choosing rate process coefficients to match specific mechanisms of lethal thermal damage, the optical-thermal-damage model is capable of predicting various types of thermal injury in the skin, such as epidermal necrosis, vascular thrombosis, and dermal collagen coagulation.

Use of hyperosmotic chemical agent to improve the laser treatment of cutaneous vascular lesions.

A method is presented for decreasing radiant exposures required for photocoagulation of cutaneous blood vessels using a hyperosmotic agent applied to skin prior to laser irradiation. The 50% probability for a given radiant exposure (RE50) to result in photocoagulation of vessels classified by type (arteriole, venule) and diameter was determined following direct (subcutaneous) laser irradiation of 84 vessels in a dorsal skin preparation pretreated with glycerol. Values were compared against results without glycerol pretreatment. A second set of experiments involved irradiation of blood vessels through the skin from the epidermal surface after application of glycerol. Subcutaneous RE50s for vessels treated with glycerol were typically several factors lower than untreated vessels. For example, arterioles in the 80- to 110-microm-diam range in untreated skin had RE50 values approximately 12 J/cm(2), compared to approximately 2 J/cm(2) in glycerol-treated cases. Results from epidermal irradiations also indicate that pretreatment with glycerol decreases radiant exposures required for photocoagulation. Vessels were successfully coagulated from the epidermal side in glycerol-treated samples using radiant exposures ranging from 1.6 J/cm(2) to 5 Jcm(2), compared to the 12 to >16 J/cm(2) range for control cases. We believe that this method could be a powerful technique for reducing the radiant exposures required for vessel photocoagulation.

Corneal minimal visible lesion thresholds for 2.0 microm laser radiation.

To support refinement of the ANSI Maximum Permissible Exposure safety limits, a series of experiments were conducted in vivo on Dutch Belted rabbit corneas to determine corneal minimum visible lesion thresholds for 2.0 microm continuous-wave laser irradiation. Single pulse radiant exposures were made at specified pulse durations of 0.1, 0.25, 0.5, 1.0, 2.0, and 4.0 s for spot 1/e(2) diameters of 1.17 mm and 4.02 mm. Threshold lesions were defined as the presence of a superficial surface whitening one hour after irradiation. Temperature measurements indicated that threshold peak temperatures were dependent on spot size and exposure duration. The exposure duration dependence of threshold average radiant exposure was described by an empirical power law equation: threshold radiant exposure[J/cm(2)]=a x exposure duration[s](b).

Effect of pigmentation density upon 2.0 microm laser irradiation thermal response.

Yucatan mini-pigs with predominantly dark skin have been used to determine skin safety standards for infrared (IR) wavelength irradiation due to its anatomical similarity to all human skin. It has generally been argued that water is the principle absorber in the IR-B band and melanin has relatively low absorbance. To accept dark pigmented damage thresholds for skin with various melanin densities, it is necessary to investigate the potential role of melanin in producing skin injury as characterized by an erythermal response. A Yucatan mini-pig covered with lightly pigmented pink and darkly pigmented brown skin was used in this study. The significance of skin pigmentation was investigated by comparing the transient thermal response, absorption coefficient, and the threshold damage of instant redness within 1 min and persistent redness at 48 h post exposure for dark and light skin areas at 2.0 microm wavelength. The density of melanin granules did not significantly alter the thermal and optical properties of in vivo skin exposed to 2.0 microm laser irradiation. For Gaussian shaped beam radiation at 1 s exposure duration and 4.83 mm 1/e spot diameter, the average radiant exposures at instant and persistent redness thresholds were 3.88 J cm and 5.08 J cm for dark skin, respectively, as well as 4.09 J cm and 4.09 J cm for light colored skin. Subjectively speaking, however, lightly pigmented mini-pig skin was more suitable for damage threshold estimation because of the increased contrast for visual determination of redness on light skin.

Design and development of a computer-assisted retinal laser surgery system.

Since the mid-1980s, the development of a therapeutic, computer-assisted laser photocoagulation system to treat retinal disorders has progressed under the guidance of Dr. Welch, the Marion E. Forsman Centennial Professor of Engineering, Department of Biomedical Engineering, the University of Texas at Austin. This paper reviews the development of the system, related research in eye movement and laser-tissue interaction, and system implementation and testing. While subsets of these topics have been reported in prior publications, this paper brings the entire evolutionary design of the system together. We also discuss other recent "spinoff" uses of the system technology that have not been reported elsewhere and describe the impact of the latest technical advances on the overall system design.

Dependence of calculus retropulsion on pulse duration during Ho: YAG laser lithotripsy.

BACKGROUND AND OBJECTIVES: The purpose of this study was to investigate the effect of optical pulse duration on stone retropulsion during Ho:YAG (lambda = 2.12 microm) laser lithotripsy. STUDY DESIGN/MATERIALS AND METHODS: A clinical Ho:YAG laser with pulse durations was employed to fragment calculus phantoms and to evaluate stone phantom retropulsion. At a given pulse energy, optical pulse durations were divided into two discrete conditions: short pulse (tau(p): 120 to approximately 190 microseconds at FWHM) and long pulse (tau(p): 210 to approximately 350 microseconds at FWHM). Plaster of Paris calculus phantoms were ablated at different energy levels using optical fibers of varying diameters (273, 365, and 550 microm in core size). The dynamics of the recoil action of a calculus phantom was monitored using a high-speed camera; the laser-induced craters were evaluated with optical coherent tomography (OCT). Bubble formation and collapse were recorded with a fast flash photography setup, and acoustic transients were measured with a hydrophone. RESULTS: Shorter pulse durations produced more stone retropulsion than longer pulses at any given pulse energy. Regardless of pulse duration, higher pulse energy and larger fibers resulted in larger ablation volume and retropulsion (P<0.05). For shorter pulse durations, more rapid bubble expansion was observed and higher amplitudes of the collapse pressure wave were measured (P<0.05). CONCLUSION: Less retropulsion and equivalent fragmentation occurred when Ho:YAG pulse duration increased.

Urinary calculus fragmentation during Ho: YAG and Er:YAG lithotripsy.

BACKGROUND AND OBJECTIVES: We tested Ho:YAG and Er:YAG laser ablation of human urinary calculi to determine if Er:YAG is a more efficient lithotripsy device. STUDY DESIGN/MATERIALS AND METHODS: Ablation efficiency of Ho:YAG and Er:YAG lasers was tested at varying energy settings, ranging from the damage threshold to clinical energy setting associated with Ho:YAG laser. Stones of known composition (calcium oxalate monohydrate (COM), cystine, and uric acid (UA)) were irradiated. Crater width, depth, and ablation volumes were determined using an optical coherence tomography (OCT). RESULTS: For all stones and energy settings, the Er:YAG laser produced deeper craters and larger ablation volumes than Ho:YAG laser. The Ho:YAG laser created wider craters during the multiple pulse process and the shape of craters was irregular. CONCLUSIONS: The Er:YAG laser is more efficient than the Ho:YAG laser for lithotripsy. The deeper craters produced by the Er:YAG laser is attributed to the high absorption of energy at its wavelength.

Modeling thermal damage in skin from 2000-nm laser irradiation.

An optical-thermal-damage model of the skin under laser irradiation is developed by using finite-element modeling software (FEMLAB 3.1, Comsol, Incorporated, Burlington, Massachusetts). The general model simulates light propagation, heat generation, transient temperature response, and thermal damage produced by a radically symmetric laser beam of normal incidence. Predictions from the model are made of transient surface temperatures and the thermal damage on a pigskin surface generated by 2000-nm laser irradiation, and these predictions are compared to experimental measurements. The comparisons validate the model predictions, boundary conditions, and optical, thermal, and rate process parameters. The model enables the authors to verify the suitability of the American National Standards Institute (ANSI) maximum permissible exposure (MPE) standard for a wavelength of 2000 nm with exposure duration from 0.1 to 1 s and 3.5-mm beam diameter. Compared with the ANSI MPE standard, however, the MPE values predicted by the model are higher for exposure durations less than 0.1 s. The model indicates that it may be necessary to modify the ANSI MPE standard for cases in which the laser-beam diameter is larger than 3.5 mm when a "safety factor" of ten is used. A histopathological analysis of the skin damage is performed to determine the mechanisms of laser-induced damage in the skin.

Porcine skin ED50 damage thresholds for 2,000 nm laser irradiation.

BACKGROUND AND OBJECTIVES: To gain refinement in safe-exposure limits, indicated by the maximum permissible exposure (MPE) limits, the minimum visible lesion thresholds for three spot sizes (5-15 mm) and four exposure durations (0.25-2.5 seconds) were determined for the skin at 2,000 nm continuous wave laser irradiation. STUDY DESIGN/MATERIALS AND METHODS: A series of experiments were conducted in vivo on female Yucatan mini-pigs to determine the ED50 damage thresholds for 2,000 nm continuous wave laser irradiation. The study employed Gaussian laser beam exposures with spot diameters (1/e2) of 4.83, 9.65, and 14.65 mm and exposure durations of 0.25, 0.5, 1.0, and 2.5 seconds as a function of laser power. The effect of each irradiation was evaluated within 1 minute after irradiation and the final determination was made at 48 hours post-exposure. Probit analysis was conducted to estimate the dose for 50% probability of laser-induced damage (ED50), defined as persistent redness at the site of irradiation for the mini-pig skin after 48 hours. RESULTS: The MPE spot size and exposure duration trends for 2,000 nm laser exposure is consistent for exposure diameters less than 3.5 mm. However, for larger exposure diameters of 4.83, 9.65, and 14.65 mm and exposure duration longer than 0.25 second, the current MPEs are bigger than one tenth of our damage thresholds. For Gaussian laser profile, which is common for many laser output irradiance distributions, lower energy is required to generate a lesion on skin for smaller spot sizes and shorter exposure duration. On the other hand, for spot sizes greater than 4.83 mm and exposure duration over 0.25 second, the average radiant exposure at threshold is inversely proportional to spot size. The irradiance-time and temperature-time power law at the threshold were investigated as well and showed that the irradiance-time power law was a close approximation to estimate laser irradiance at ED50 damage threshold. CONCLUSIONS: The thresholds study shows that consideration for lowering the MPE standards should be explored as the laser beam diameter becomes larger than 3.5 mm. Based on the limited experimental data, the duration and size dependences of the ED50 damage thresholds could be described by an empirical equation: Irradiance at the threshold = (5.669-1.81xspot diameter)xexposure duration -0.794.

Quantitative phase-contrast imaging of cells with phase-sensitive optical coherence microscopy.

We describe a method for en face phase-contrast imaging of cells with a fiber-based differential phase-contrast optical coherence microscopy system. Recorded en face images are quantitative phase-contrast maps of cells due to spatial variation of the refractive index and (or) thickness of various cellular components. Quantitative phase-contrast images of human epithelial cheek cells obtained with the fiber-based differential phase-contrast optical coherence microscopy system are presented.

Review of laser fibers: a practical guide for urologists.

Holmium:YAG lithotripsy requires transmission of optical energy using laser fibers. Optical fibers may be subjected to severe angular deflection and bending during flexible nephroscopy or flexible ureteronephroscopy. Irradiation of a deflected fiber in a tight bending radius may produce fiber failure and consequent irradiation of the ureteroscope, with risk of instrument damage and patient injury. We review the physics and engineering aspects of optical fibers to explain why fibers fail.

Morphological changes in blood vessels produced by hyperosmotic agents and measured by optical coherence tomography.

Optical tissue clearing by hyperosmotic chemical agents significantly increases light depth penetration in skin and may improve light-based therapeutics such as laser treatment of cutaneous vascular lesions. A feasibility study was conducted to evaluate the potential role of optical clearing by glycerol in laser treatment of cutaneous vessels. Optical imaging was performed to investigate the morphological effects of glycerol on blood vessels of skin. Blood vessels were imaged using Doppler optical coherence tomography in in vivo hamster skin treated with glycerol. Images were obtained from the subdermal side to assess morphological changes in the blood vessels caused by glycerol and from the epidermal side to assess enhanced Doppler imaging of blood vessels. Application of glycerol to the subdermis resulted in venule stasis and for prolonged treatment times, arteriole stasis. In cases where flow remained in arterioles, an improved Doppler signal was detected from blood vessels when imaging transepidermally compared with the native condition. Intensity images indicated changes in blood optical properties and improved contrast of skin cross sections after glycerol application. The observed optical and morphological effects were reversed upon hydration of the skin with phosphate-buffered saline. The combination of increased depth of light penetration and the temporary slowing or cessation of flow in blood vessels could mean improved laser treatment of vessels.