Publications by authors named "Reginald Birngruber"

52 Publications

Investigations on Retinal Pigment Epithelial Damage at Laser Irradiation in the Lower Microsecond Time Regime.

Invest Ophthalmol Vis Sci 2021 Mar;62(3):32

Medical Laser Center Lübeck, Lübeck, Germany.

Purpose: New lasers with a continuous wave power exceeding 15 W are currently investigated for retinal therapies, promising highly localized effects at and close to the Retinal Pigment Epithelium (RPE). The goal of this work is to evaluate mechanisms and thresholds for RPE cell damage by means of pulse durations up to 50 µs.

Methods: A diode laser with a wavelength of 514 nm, a power of 15 W, and adjustable pulse durations between 2 µs and 50 µs was used. Porcine RPE-choroidal explants (ex vivo) and chinchilla bastard rabbits (in vivo) were irradiated to determine threshold radiant exposures for RPE damage \({\bar H_{Cell}}\) by calcein vitality staining and fluorescence angiography, respectively. Thresholds for microbubble formation (MBF) \({\bar H_{MBF}}\) were evaluated by time-resolved optoacoustics. Exemplary histologies support the findings.

Results: \({\bar H_{{{MBF}}}}\) is significantly higher than \({\bar H_{Cell}}\) at pulse durations ≥ 5 µs (P < 0.05) ex vivo, while at 2 µs, no statistically significant difference was found. The ratios between \({\bar H_{{{MBF}}}}\) and \({\bar H_{Cell}}\) increase with pulse duration from 1.07 to 1.48 ex vivo and 1.1 to 1.6 in vivo, for 5.2 and 50 µs.

Conclusions: Cellular damage with and without MBF related disintegration are both present and very likely to play a role for pulse durations ≥ 5 µs. With the lower µs pulses, selective RPE disruption might be possible, while higher values allow achieving spatially limited thermal effects without MBF. However, both modi require a very accurate real-time dosing control in order to avoid extended retinal disintegration in this power range.
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http://dx.doi.org/10.1167/iovs.62.3.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991964PMC
March 2021

Micro-optical coherence tomography for high-resolution morphologic imaging of cellular and nerval corneal micro-structures.

Biomed Opt Express 2020 Oct 28;11(10):5920-5933. Epub 2020 Sep 28.

Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA.

We demonstrate the highest resolution (1.5×1.5×1 µm) micrometer optical coherence tomography (µOCT) imaging of the morphologic micro-structure of excised swine and non-human primate corneas. Besides epithelial, stromal, and endothelial cell morphology, this report focuses on investigating the most peripheral corneal nerve fibers, the nerve fibers of the subbasal plexus (SBP). Alterations of SBP nerve density and composition are reportedly linked to major neurologic disorders, such as diabetic neuropathy, potentially indicating earliest onsets of denervation. Here, the fine, hyperreflective, epithelial nerve structures located just above Bowman's membrane, are i) visualized using our µOCT prototype, ii) validated by comparison to fluorescence confocal microscopy (including selective immunohistochemical staining), and iii) segmented using state-of-the-art image processing. Here, we also introduce polarization sensitive (PS) µOCT imaging, demonstrating, to the best of our knowledge, the highest resolution corneal PS-OCT scans reported to date.
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http://dx.doi.org/10.1364/BOE.402971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587290PMC
October 2020

Corneal Stromal Filler Injection as a Novel Approach to Correct Presbyopia-An Pilot Study.

Transl Vis Sci Technol 2020 06 25;9(7):30. Epub 2020 Jun 25.

Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: To evaluate the feasibility of corneal stromal filler injection to create bifocality to correct presbyopia by flattening the central posterior corneal surface and thus increase refractive power.

Methods: Femtosecond laser-assisted corneal stromal pockets of varying diameters close to the posterior corneal curvature were cut into rabbit eyes . Subsequently, hyaluronic acid was injected to flatten the central posterior curvature. Refractive parameters were determined using perioperatively acquired three-dimensional optical coherence tomography (OCT) scans. Using micrometer-resolution OCT, corneal endothelial cell morphology and density were evaluated.

Results: Following filler injection into the corneal stromal pockets, a fair volume-dependent increase of central refractive power up to 4 diopters (dpt) was observed. Unremarkable refractive changes of the peripheral posterior (3 mm, 0.20 ± 0.11 dpt; 2 mm, 0.11 ± 0.10 dpt) and the anterior corneal curvature (3 mm, 0.20 ± 0.34 dpt; 2 mm, 0.33 ± 0.31 dpt) occurred. Only negligible changes in astigmatism were observed. Different sizes of optical zones could be established. Furthermore, no alterations of corneal endothelial morphology or endothelial cell density (2831 ± 356 cells/mm vs. 2734 ± 292 cells/mm; = 0.552) due to the adjacent laser treatment were observed.

Conclusions: The investigations proved the principle of injecting a filler material into femtosecond laser-created corneal stromal pockets close to the posterior corneal curvature as an efficacious, individually adjustable, and novel approach to correct presbyopia without ablating corneal tissue.

Translational Relevance: Due to the aging population worldwide, presbyopia is an increasing problem; thus, our study may encourage further exploration to extend the treatment spectrum of clinically used femtosecond laser systems to correct presbyopia.
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http://dx.doi.org/10.1167/tvst.9.7.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414620PMC
June 2020

Stromal Nerve Imaging and Tracking Using Micro-Optical Coherence Tomography.

Transl Vis Sci Technol 2020 04 15;9(5). Epub 2020 Apr 15.

Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA.

Purpose: To image, track and map the nerve fiber distribution in excised rabbit corneas over the entire stromal thickness using micro-optical coherence tomography (µOCT) to develop a screening tool for early peripheral neuropathy.

Methods: Excised rabbit corneas were consecutively imaged by a custom-designed µOCT prototype and a commercial laser scanning fluorescence confocal microscope. The µOCT images with a field of view of approximately 1 × 1 mm were recorded with axial and transverse resolutions of approximately 1 µm and approximately 4 µm, respectively. In the volumetric µOCT image data, network maps of hyper-reflective, branched structures traversing different stromal compartments were segmented using semiautomatic image processing algorithms. Furthermore, the same corneas received βIII-tubulin antibody immunostaining before digital confocal microscopy, and a comparison between µOCT image data and immunohistochemistry analysis was performed to validate the nerval origin of the tracked network structures.

Results: Semiautomatic tracing of the nerves with a high range of different thicknesses was possible through the whole corneal volumes, creating a skeleton of the traced nerves. There was a good conformity between the hyper-reflective structures in the µOCT data and the stained nerval structures in the immunohistochemistry data.

Conclusions: This article demonstrates nerval imaging and tracking as well as a spatial correlation between µOCT and a fluorescence corneal nerve standard for larger nerves throughout the full thickness of the cornea ex vivo.

Translational Relevance: Owing to its advantageous properties, µOCT may become useful as a noncontact method for assessing nerval structures in humans to screen for early peripheral neuropathy.
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http://dx.doi.org/10.1167/tvst.9.5.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401960PMC
April 2020

Refractive Changes After Corneal Stromal Filler Injection for the Correction of Hyperopia.

J Refract Surg 2020 Jun;36(6):406-413

Purpose: To evaluate a new non-ablative and adjustable procedure for laser ablative refractive corneal surgery in hyperopia using the injection of a biocompatible liquid filler material into a stromal pocket.

Methods: A total of 120 stromal pockets were created using a clinical femtosecond laser system in 96 rabbit corneoscleral discs and 24 whole globes. Pockets were cut at a depth of 120 or 250 µm below the epithelial surface. Hyaluronic acid was injected manually into the pocket. To determine the refractive changes, three-dimensional optical coherence tomography images and a specifically developed picture recognition Matlab (The Mathworks) routine were used.

Results: After injection, a steepening of the anterior and flattening of the posterior corneal surface was observed, which led to hyperopic correction. The two main factors determining the amount of correction were the pocket depth and the injected volume. After the pocket was homogeneously filled, an initial refractive increase was observed, followed by a linear relation between the injected volume and the refraction increase.

Conclusions: This possible clinical protocol for controlled refraction correction of hyperopia suggests a potential readjustable clinical application. [J Refract Surg. 2020;36(6):406-414.].
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http://dx.doi.org/10.3928/1081597X-20200429-01DOI Listing
June 2020

First Assessment of a Carbon Monoxide Laser and a Thulium Fiber Laser for Fractional Ablation of Skin.

Lasers Surg Med 2020 10 14;52(8):788-798. Epub 2020 Jan 14.

Institute of Biomedical Optics, University of Luebeck, Luebeck, 23562, Germany.

Background And Objectives: A recent generation of 5,500 nm wavelength carbon monoxide (CO) lasers could serve as a novel tool for applications in medicine and surgery. At this wavelength, the optical penetration depth is about three times higher than that of the 10,600 nm wavelength carbon dioxide (CO ) laser. As the amount of ablation and coagulation is strongly influenced by the wavelength, we anticipated that CO lasers would provide extended coagulation zones, which could be beneficial for several medical applications, such as tissue tightening effects after laser skin resurfacing. Until now, the 1,940 nm wavelength thulium fiber (Tm:fiber) laser is primarily known as a non-ablative laser with an optical penetration depth that is eight times higher than that of the CO laser. The advantage of lasers with shorter wavelengths is the ability to create smaller spot sizes, which has a determining influence on the ablation outcome. In this study, the ablation and coagulation characteristics of a novel CO laser and a high power Tm:fiber laser were investigated to evaluate their potential application for fractional ablation of the skin.

Study Design/materials And Methods: Laser-tissue exposures were performed using a novel CO laser, a modified, pulse-width-modulated CO laser, and a Tm:fiber laser. We used discarded ex vivo human skin obtained from abdominoplasty as tissue samples. Similar exposure parameters, such as spot size (108-120 μm), pulse duration (2 milliseconds), and pulse energy (~10-200 mJ) were adjusted for the different laser systems with comparable temporal pulse structures. Laser effects were quantified by histology.

Results: At radiant exposures 10-fold higher than the ablation threshold, the CO laser ablation depth was almost two times deeper than that of the CO laser. At 40-fold of the ablation threshold, the CO laser ablation was 47% deeper. The ablation craters produced by the CO laser exhibited about two times larger coagulation zones when compared with the CO laser. In contrast, the Tm:fiber laser exhibited superficial ablation craters with massive thermal damage.

Conclusions: The tissue ablation using the Tm:fiber laser was very superficial in contrast to the CO laser and the CO laser. However, higher etch depths should be obtainable when the radiant exposure is increased by using higher pulse energies and/or smaller spot sizes. At radiant exposures normalized to the ablation threshold, the CO laser was capable of generating deeper ablation craters with extended coagulation zones compared with the CO laser, which is possibly desirable depending on the clinical goal. The effect of deep ablation combined with additional thermal damage on dermal remodeling needs to be further confirmed with in vivo studies. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23215DOI Listing
October 2020

Selective Equatorial Sclera Crosslinking in the Orbit Using a Metal-Coated Polymer Waveguide.

Invest Ophthalmol Vis Sci 2019 06;60(7):2563-2570

Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, United States.

Purpose: Photochemical crosslinking of the sclera is an emerging technique that may prevent excessive eye elongation in pathologic myopia by stiffening the scleral tissue. To overcome the challenge of uniform light delivery in an anatomically restricted space, we previously introduced the use of flexible polymer waveguides. We presently demonstrate advanced waveguides that are optimized to deliver light selectively to equatorial sclera in the intact orbit.

Methods: Our waveguides consist of a polydimethylsiloxane cladding and a polyurethane core, coupled to an optical fiber. A reflective silver coating deposited on the top and side surfaces of the waveguide prevents light leakage to nontarget, periorbital tissue. Postmortem rabbits were used to test the feasibility of in situ equatorial sclera crosslinking. Tensometry measurements were performed on ex vivo rabbit eyes to confirm a biomechanical stiffening effect.

Results: Metal-coated waveguides enabled efficient light delivery to the entire circumference of the equatorial sclera with minimal light leakage to the periorbital tissues. Blue light was delivered to the intact orbit with a coefficient of variation in intensity of 22%, resulting in a 45 ± 11% bleaching of riboflavin fluorescence. A 2-fold increase in the Young's modulus at 5% strain (increase of 92% P < 0.05, at 25 J/cm2) was achieved for ex vivo crosslinked eyes.

Conclusions: Flexible polymer waveguides with reflective, biocompatible surfaces are useful for sclera crosslinking to achieve targeted light delivery. We anticipate that our demonstrated procedure will be applicable to sclera crosslinking in live animal models and, potentially, humans in vivo.
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http://dx.doi.org/10.1167/iovs.19-26709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586079PMC
June 2019

Correction of hyperopia by intrastromal cutting and liquid filler injection.

J Biomed Opt 2019 05;24(5):1-7

University of Luebeck, Institute of Biomedical Optics, Peter-Monnik Weg 4, Luebeck, Germany.

Correction of hyperopia requires an increase of the refractive power by steepening of the corneal surface. Present refractive surgical techniques based on corneal ablation (LASIK) or intrastromal lenticule extraction (SMILE) are problematic due to epithelial regrowth. Recently, it was shown that correction of low hyperopia can be achieved by implanting intracorneal inlays or allogeneic lenticules. We demonstrate a steepening of the anterior corneal surface after injection of a transparent, liquid filler material into a laser-dissected intrastromal pocket. We performed the study on ex-vivo porcine eyes. The increase of the refractive power was evaluated by optical coherence tomography (OCT). For a circular pocket, injection of 1 μl filler material increased the refractive power by +4.5 diopters. An astigmatism correction is possible when ellipsoidal intrastromal pockets are created. Injection of 2 μl filler material into an ellipsoidal pocket increased the refractive power by +10.9  dpt on the short and +5.1  dpt on the long axis. OCT will enable to monitor the refractive change during filler injection and is thus a promising technique for real-time dosimetry.
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http://dx.doi.org/10.1117/1.JBO.24.5.058001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992961PMC
May 2019

Optimization-based vessel segmentation pipeline for robust quantification of capillary networks in skin with optical coherence tomography angiography.

J Biomed Opt 2019 04;24(4):1-11

Institut für Biomedizinische Optik, Univ. zu Lübeck, Germany.

Optical coherence tomography angiography (OCTA) provides in-vivo images of microvascular perfusion in high resolution. For its application to basic and clinical research, an automatic and robust quantification of the capillary architecture is mandatory. Only this makes it possible to reliably analyze large amounts of image data, to establish biomarkers, and to monitor disease developments. However, due to its optical properties, OCTA images of skin often suffer from a poor signal-to-noise ratio and contain imaging artifacts. Previous work on automatic vessel segmentation in OCTA mostly focuses on retinal and cerebral vasculature. Its applicability to skin and, furthermore, its robustness against imaging artifacts had not been systematically evaluated. We propose a segmentation method that improves the quality of vascular quantification in OCTA images even if corrupted by imaging artifacts. Both the combination of image processing methods and the choice of their parameters are systematically optimized to match the manual labeling of an expert for OCTA images of skin. The efficacy of this optimization-based vessel segmentation is further demonstrated on sample images as well as by a reduced error of derived quantitative vascular network characteristics.
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http://dx.doi.org/10.1117/1.JBO.24.4.046005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990060PMC
April 2019

Selective retina therapy: toward an optically controlled automatic dosing.

J Biomed Opt 2018 11;23(11):1-12

Medizinisches Laserzentrum Lübeck GmbH, Lübeck, Germany.

Selective retina therapy (SRT) targets the retinal pigment epithelium (RPE) with pulsed laser irradiation by inducing microbubble formation (MBF) at the intracellular melanin granula, which leads to selective cell disruption. The following wound healing process rejuvenates the chorio-retinal junction. Pulse energy thresholds for selective RPE effects vary intra- and interindividually. We present the evaluation of an algorithm that processes backscattered treatment light to detect MBF as an indicator of RPE cell damage since these RPE lesions are invisible during treatment. Eleven patients with central serous chorioretinopathy and four with diabetic macula edema were treated with a SRT system, which uses a wavelength of 527 nm, a repetition rate of 100 Hz, and a pulse duration of 1.7 μs. Fifteen laser pulses with stepwise increasing pulse energy were applied per treatment spot. Overall, 4626 pulses were used for algorithm parameter optimization and testing. Sensitivity and specificity were the metrics maximized through an automatic optimization process. Data were verified by fluorescein angiography. A sensitivity of 1 and a specificity of 0.93 were achieved. The method introduced in this paper can be used for guidance or automatization of microbubble-related treatments like SRT or selective laser trabeculoplasty.
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http://dx.doi.org/10.1117/1.JBO.23.11.115002DOI Listing
November 2018

Simple approach for aberration-corrected OCT imaging of the human retina.

Opt Lett 2018 Sep;43(17):4224-4227

Aberration-corrected imaging of human photoreceptor cells, whether hardware or software based, presently requires a complex and expensive setup. Here we use a simple and inexpensive off-axis full-field time-domain optical coherence tomography (OCT) approach to acquire volumetric data of an in vivo human retina. Full volumetric data are recorded in 1.3 s. After computationally correcting for aberrations, single photoreceptor cells were visualized. In addition, the numerical correction of ametropia is demonstrated. Our implementation of full-field optical coherence tomography combines a low technical complexity with the possibility for computational image correction.
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http://dx.doi.org/10.1364/OL.43.004224DOI Listing
September 2018

Enhanced quantification of metabolic activity for individual adipocytes by label-free FLIM.

Sci Rep 2018 06 8;8(1):8757. Epub 2018 Jun 8.

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.

Fluorescence lifetime imaging microscopy (FLIM) of intrinsic fluorophores such as nicotinamide adenine dinucleotide (NADH) allows for label-free quantification of metabolic activity of individual cells over time and in response to various stimuli, which is not feasible using traditional methods due to their destructive nature and lack of spatial information. This study uses FLIM to measure pharmacologically induced metabolic changes that occur during the browning of white fat. Adipocyte browning increases energy expenditure, making it a desirable prospect for treating obesity and related disorders. Expanding from the traditional two-lifetime model of NADH to a four-lifetime model using exponential fitting and phasor analysis of the fluorescence decay results in superior metabolic assessment compared to traditional FLIM analysis. The four lifetime components can also be mapped to specific cellular compartments to create a novel optical ratio that quantitatively reflects changes in mitochondrial and cytosolic NADH concentrations and binding states. This widely applicable approach constitutes a powerful tool for studies where monitoring cellular metabolism is of key interest.
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http://dx.doi.org/10.1038/s41598-018-27093-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993796PMC
June 2018

Assessment of skin lesions produced by focused, tunable, mid-infrared chalcogenide laser radiation.

Lasers Surg Med 2018 09 25;50(9):961-972. Epub 2018 May 25.

Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Traditionally, fractional laser treatments are performed with focused laser sources operating at a fixed wavelength. Using a tunable laser in the mid-infrared wavelength range, wavelength-dependent absorption properties on the ablation process and thermal damage formation were assessed with the goal to obtain customizable tissue ablations to provide guidance in finding optimized laser exposure parameters for clinical applications.

Methods: Laser tissue experiments were carried out on full thickness ex vivo human abdominal skin using a mid-infrared tunable chromium-doped zinc selenide/sulfide chalcogenide laser. The laser has two independent channels: a continuous wave (CW) output channel which covers a spectrum ranging from 2.4 μm to 3.0 μm with up to 9.2 W output power, and a pulsed output channel which ranges from 2.35 μm to 2.95 μm. The maximum pulse energy of the pulsed channel goes up to 2.8 mJ at 100 Hz to 1,000 Hz repetition rate with wavelength-dependent pulse durations of 4-7 ns.

Results: Total ablation depth, ablation efficiency, and coagulation zone thickness were highly correlated to wavelength, pulse width, and pulse energy. Using the same total radiant exposure at 2.85 μm wavelength resulted in 10-times smaller coagulation zones and 5-times deeper ablation craters for one hundred 6 ns pulses compared to one 100 ms pulse. For a fixed pulse duration of 6 ns and a total radiant exposure of 2.25 kJ/cm the ablation depth increased with longer wavelengths.

Conclusion: The tunable laser system provides a useful research tool to investigate specific laser parameters such as wavelength on lesion shape, ablation depth and thermal tissue damage. It also allows for customization of the characteristics of laser lesions and therefore facilitates the selection of suitable laser parameters for optimized fractional laser treatments. Lasers Surg. Med. 50:961-972, 2018.© 2018 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.22935DOI Listing
September 2018

Interface Bonding With Corneal Crosslinking (CXL) After LASIK Ex Vivo.

Invest Ophthalmol Vis Sci 2017 12;58(14):6292-6298

Wellman Center for Photomedicine-Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States.

Purpose: Interface bonding with corneal crosslinking (CXL) after LASIK using two different photosensitizers was studied ex vivo.

Methods: A LASIK flap was created in enucleated rabbit eyes using a femtosecond laser. After the dissection, CXL was performed to seal the interface. In one group interface CXL was performed using rose bengal and green light, whereas in a second group riboflavin and UV-A light was used. In both groups irradiance, radiant exposure, dye concentration, and imbibition time was varied. In a control group, LASIK only was performed. After the procedures, the maximal shear-force required to separate the flap from the stroma was measured. Additionally, corneal transmission spectra were recorded.

Results: Optimized parameters for rose bengal/green-light bonding lead to a 2.1-fold increase in shear-force compared with untreated control eyes (P < 0.01). The optimal parameter combination was: irradiance of 180 mW/cm2 for 14 minutes (total radiant exposure 150 J/cm2), rose bengal concentration 0.1%, and an imbibition time of 2 minutes. Optimized riboflavin/UV-A light parameters were 0.5% for 2 minutes with a radiant exposure of 8.1 J/cm2 obtained by an irradiance of 30 mW/cm2 for 4.5 minutes. These optimized parameters lead to a 2-fold increase compared with untreated control eyes (P < 0.01). Optical transmission experiments suggest safety for more posterior structures.

Conclusions: Based on ex-vivo results, interface bonding after LASIK using crosslinking with either rose bengal or riboflavin increases the adhesion between flap and stromal bed. In vivo trials are needed to evaluate the temporal evolution of the effect.
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http://dx.doi.org/10.1167/iovs.17-22426DOI Listing
December 2017

Power-controlled temperature guided retinal laser therapy.

J Biomed Opt 2017 Nov;22(11):1-11

Medizinisches Laserzentrum Lübeck GmbH, Lübeck, Germany.

Laser photocoagulation has been a treatment method for retinal diseases for decades. Recently, studies have demonstrated therapeutic benefits for subvisible effects. A treatment mode based on an automatic feedback algorithm to reliably generate subvisible and visible irradiations within a constant irradiation time is introduced. The method uses a site-individual adaptation of the laser power by monitoring the retinal temperature rise during the treatment using optoacoustics. This provides feedback to adjust the therapy laser power during the irradiation. The technique was demonstrated on rabbits in vivo using a 532-nm continuous wave Nd:YAG laser. The temperature measurement was performed with 523-nm Q-switched Nd:YLF laser pulses with 75-ns pulse duration at 1-kHz repetition rate. The beam diameter on the fundus was 200  μm for both lasers, respectively. The aim temperatures ranged from 50°C to 75°C in 11 eyes of 7 rabbits. The results showed ophthalmoscopically invisible effects below 55°C with therapy laser powers over a wide range. The standard deviation for the measured temperatures ranged from 2.1°C for an aim temperature of 50°C to 4.7°C for 75°C. The ED50 temperature value for ophthalmoscopically visible lesions in rabbits was determined as 65.3°C. The introduced method can be used for retinal irradiations with adjustable temperature elevations.
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http://dx.doi.org/10.1117/1.JBO.22.11.118001DOI Listing
November 2017

Biomedical optics centers: forty years of multidisciplinary clinical translation for improving human health.

J Biomed Opt 2016 12;21(12):124001

Wellman Center for Photomedicine and Harvard Medical School, Massachusetts General Hospital, Research Institute, Department of Dermatology, 40 Blossom Street, Boston, Massachusetts 02114, United States.

Despite widespread government and public interest, there are significant barriers to translating basic science discoveries into clinical practice. Biophotonics and biomedical optics technologies can be used to overcome many of these hurdles, due, in part, to offering new portable, bedside, and accessible devices. The current JBO special issue highlights promising activities and examples of translational biophotonics from leading laboratories around the world. We identify common essential features of successful clinical translation by examining the origins and activities of three major international academic affiliated centers with beginnings traceable to the mid-late 1970s: The Wellman Center for Photomedicine (Mass General Hospital, USA), the Beckman Laser Institute and Medical Clinic (University of California, Irvine, USA), and the Medical Laser Center Lübeck at the University of Lübeck, Germany. Major factors driving the success of these programs include visionary founders and leadership, multidisciplinary research and training activities in light-based therapies and diagnostics, diverse funding portfolios, and a thriving entrepreneurial culture that tolerates risk. We provide a brief review of how these three programs emerged and highlight critical phases and lessons learned. Based on these observations, we identify pathways for encouraging the growth and formation of similar programs in order to more rapidly and effectively expand the impact of biophotonics and biomedical optics on human health.
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http://dx.doi.org/10.1117/1.JBO.21.12.124001DOI Listing
December 2016

In-vivo retinal imaging with off-axis full-field time-domain optical coherence tomography.

Opt Lett 2016 Nov;41(21):4987-4990

With a simple setup, mainly composed of a low coherence light source and a camera, full-field optical coherence tomography (FF-OCT) allows volumetric tissue imaging. However, fringe washout constrains its use in retinal imaging. Here, we present a novel motion-insensitive approach to FF-OCT, which introduces path-length differences between the reference and the sample light in neighboring pixels using an off-axis reference beam. The temporal carrier frequency in scanned time-domain OCT is replaced by a spatial carrier frequency. Volumetric in-vivo FF-OCT measurements of the human retina were acquired in only 1.3 s, comparable to the acquisition times of current clinically used OCT devices.
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http://dx.doi.org/10.1364/OL.41.004987DOI Listing
November 2016

Lesion strength control by automatic temperature guided retinal photocoagulation.

J Biomed Opt 2016 09;21(9):98001

University of Lübeck, Institute of Biomedical Optics, Peter-Monnik-Weg 4, 23562 Lübeck, Germany.

Laser photocoagulation is an established treatment for a variety of retinal diseases. However, when using the same irradiation parameter, the size and strength of the lesions are unpredictable due to unknown inter- and intraindividual optical properties of the fundus layers. The aim of this work is to investigate a feedback system to generate desired lesions of preselectable strengths by automatically controlling the irradiation time. Optoacoustics were used for retinal temperature monitoring. A 532-nm continuous wave Nd:YAG laser was used for photocoagulation. A 75-ns/523-nm Q-switched Nd:YLF laser simultaneously excited temperature-dependent pressure transients, which were detected at the cornea by an ultrasonic transducer embedded in a contact lens. The temperature data were analyzed during the irradiation by a LabVIEW routine. The treatment laser was switched off automatically when the required lesion strength was achieved. Five different feedback control algorithms for different lesion sizes were developed and tested on rabbits in vivo. With a laser spot diameter of 133???m, five different lesion types with ophthalmoscopically visible diameters ranging mostly between 100 and 200???m, and different appearances were achieved by automatic exposure time control. The automatically controlled lesions were widely independent of the treatment laser power and the retinal pigmentation.
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http://dx.doi.org/10.1117/1.JBO.21.9.098001DOI Listing
September 2016

Polyacrylamide gel substrates that simulate the mechanical stiffness of normal and malignant neuronal tissues increase protoporphyin IX synthesis in glioma cells.

J Biomed Opt 2015 Sep;20(9):098002

Princess Margaret Cancer Centre, 101 College Street, Toronto, Ontario M5G1L7, CanadabUniversity of Toronto, Department of Medical Biophysics, 101 College Street, Toronto, Ontario M5G1L7, Canada.

Protoporphyrin IX (PPIX) produced following the administration of exogenous 5d-aminolevulinic acid is clinically approved for photodynamic therapy and fluorescence-guided resection in various jurisdictions around the world. For both applications, quantification of PPIX forms the basis for accurate therapeutic dose calculation and identification of malignant tissues for resection. While it is well established that the PPIX synthesis and accumulation rates are subject to the cell’s biochemical microenvironment, the effect of the physical microenvironment, such as matrix stiffness, has received little attention to date. Here we studied the proliferation rate and PPIX synthesis and accumulation in two glioma cell lines U373 and U118 cultured under five different substrate conditions, including the conventional tissue culture plastic and polyacrylamide gels that simulated tissue stiffness of normal brain (1 kPa) and glioblastoma tumors (12 kPa). We found that the proliferation rate increased with substrate stiffness for both cell lines, but not in a linear fashion. PPIX concentration was significantly higher in cells cultured on tissue-simulating gels than on the much stiffer tissue culture plastic for both cell lines. These findings, albeit preliminary, suggest that the physical microenvironment might be an important determinant of tumor aggressiveness and PPIX synthesis in glioma cells.
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http://dx.doi.org/10.1117/1.JBO.20.9.098002DOI Listing
September 2015

Light-Controlled Delivery of Monoclonal Antibodies for Targeted Photoinactivation of Ki-67.

Mol Pharm 2015 Sep 13;12(9):3272-81. Epub 2015 Aug 13.

Institute of Biomedical Optics , University of Lübeck, Peter-Monnik-Weg 4, 23562 Lübeck, Germany.

The selective inhibition of intracellular and nuclear molecules such as Ki-67 holds great promise for the treatment of cancer and other diseases. However, the choice of the target protein and the intracellular delivery of the functional agent remain crucial challenges. Main hurdles are (a) an effective delivery into cells, (b) endosomal escape of the delivered agents, and (c) an effective, externally triggered destruction of cells. Here we show a light-controlled two-step approach for selective cellular delivery and cell elimination of proliferating cells. Three different cell-penetrating nano constructs, including liposomes, conjugates with the nuclear localization sequence (NLS), and conjugates with the cell penetrating peptide Pep-1, delivered the light activatable antibody conjugate TuBB-9-FITC, which targets the proliferation associated protein Ki-67. HeLa cells were treated with the photosensitizer benzoporphyrin monoacid derivative (BPD) and the antibody constructs. In the first optically controlled step, activation of BPD at 690 nm triggered a controlled endosomal escape of the TuBB-9-FITC constructs. In more than 75% of Ki-67 positive, irradiated cells TuBB-9-FITC antibodies relocated within 24 h from cytoplasmic organelles to the cell nucleus and bound to Ki-67. After a second light irradiation at 490 nm, which activated FITC, cell viability decreased to approximately 13%. Our study shows an effective targeting strategy, which uses light-controlled endosomal escape and the light inactivation of Ki-67 for cell elimination. The fact that liposomal or peptide-assisted delivery give similar results leads to the additional conclusion that an effective mechanism for endosomal escape leaves greater variability for the choice of the delivery agent.
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http://dx.doi.org/10.1021/acs.molpharmaceut.5b00260DOI Listing
September 2015

Non-invasive transdermal two-dimensional mapping of cutaneous oxygenation with a rapid-drying liquid bandage.

Biomed Opt Express 2014 Nov 1;5(11):3748-64. Epub 2014 Oct 1.

Wellman Center for Photomedicine, Harvard Medical School, Massachusetts General Hospital, 149 13th Street, Charlestown, Massachusetts 02129, USA ; Harvard University Program in Biophysics, Building C2 Room 112, 240 Longwood Avenue, Boston, MA 02115, USA.

Oxygen plays an important role in wound healing, as it is essential to biological functions such as cell proliferation, immune responses and collagen synthesis. Poor oxygenation is directly associated with the development of chronic ischemic wounds, which affect more than 6 million people each year in the United States alone at an estimated cost of $25 billion. Knowledge of oxygenation status is also important in the management of burns and skin grafts, as well as in a wide range of skin conditions. Despite the importance of the clinical determination of tissue oxygenation, there is a lack of rapid, user-friendly and quantitative diagnostic tools that allow for non-disruptive, continuous monitoring of oxygen content across large areas of skin and wounds to guide care and therapeutic decisions. In this work, we describe a sensitive, colorimetric, oxygen-sensing paint-on bandage for two-dimensional mapping of tissue oxygenation in skin, burns, and skin grafts. By embedding both an oxygen-sensing porphyrin-dendrimer phosphor and a reference dye in a liquid bandage matrix, we have created a liquid bandage that can be painted onto the skin surface and dries into a thin film that adheres tightly to the skin or wound topology. When captured by a camera-based imaging device, the oxygen-dependent phosphorescence emission of the bandage can be used to quantify and map both the pO2 and oxygen consumption of the underlying tissue. In this proof-of-principle study, we first demonstrate our system on a rat ischemic limb model to show its capabilities in sensing tissue ischemia. It is then tested on both ex vivo and in vivo porcine burn models to monitor the progression of burn injuries. Lastly, the bandage is applied to an in vivo porcine graft model for monitoring the integration of full- and partial-thickness skin grafts.
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http://dx.doi.org/10.1364/BOE.5.003748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242015PMC
November 2014

Validation of two-dimensional and three-dimensional measurements of subpleural alveolar size parameters by optical coherence tomography.

J Biomed Opt 2012 Dec;17(12):126015

Harvard Medical School and Massachusetts General Hospital, Wellman Center for Photomedicine, 40 Parkman Street, RSL 160, Boston, Massachusetts 02114, USA.

Optical coherence tomography (OCT) has been increasingly used for imaging pulmonary alveoli. Only a few studies, however, have quantified individual alveolar areas, and the validity of alveolar volumes represented within OCT images has not been shown. To validate quantitative measurements of alveoli from OCT images, we compared the cross-sectional area, perimeter, volume, and surface area of matched subpleural alveoli from microcomputed tomography (micro-CT) and OCT images of fixed air-filled swine samples. The relative change in size between different alveoli was extremely well correlated (r>0.9, P<0.0001), but OCT images underestimated absolute sizes compared to micro-CT by 27% (area), 7% (perimeter), 46% (volume), and 25% (surface area) on average. We hypothesized that the differences resulted from refraction at the tissue-air interfaces and developed a ray-tracing model that approximates the reconstructed alveolar size within OCT images. Using this model and OCT measurements of the refractive index for lung tissue (1.41 for fresh, 1.53 for fixed), we derived equations to obtain absolute size measurements of superellipse and circular alveoli with the use of predictive correction factors. These methods and results should enable the quantification of alveolar sizes from OCT images in vivo.
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http://dx.doi.org/10.1117/1.JBO.17.12.126015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519489PMC
December 2012

Correlation of temperature rise and optical coherence tomography characteristics in patient retinal photocoagulation.

J Biophotonics 2012 Nov 16;5(11-12):889-902. Epub 2012 Aug 16.

Department of Ophthalmology, University of Kiel, Kiel, Germany.

We conducted a study to correlate the retinal temperature rise during photocoagulation to the afterward detected tissue effect in optical coherence tomography (OCT). 504 photocoagulation lesions were examined in 20 patients. The retinal temperature increase was determined in real-time during treatment based on thermoelastic tissue expansion which was probed by repetitively applied ns laser pulses. The tissue effect was examined on fundus images and OCT images of individualized lesions. We discerned seven characteristic morphological OCT lesion classes. Their validity was confirmed by increasing visibility and diameters. Mean peak temperatures at the end of irradiation ranged from approx. 60 °C to beyond 100 °C, depending on burn intensity.
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http://dx.doi.org/10.1002/jbio.201200091DOI Listing
November 2012

Automatic temperature controlled retinal photocoagulation.

J Biomed Opt 2012 Jun;17(6):061223

University of Lübeck, Institute of Biomedical Optics, Peter-Monnik-Weg 4, D-23562, Lübeck, Germany.

Laser coagulation is a treatment method for many retinal diseases. Due to variations in fundus pigmentation and light scattering inside the eye globe, different lesion strengths are often achieved. The aim of this work is to realize an automatic feedback algorithm to generate desired lesion strengths by controlling the retinal temperature increase with the irradiation time. Optoacoustics afford non-invasive retinal temperature monitoring during laser treatment. A 75 ns/523 nm Q-switched Nd:YLF laser was used to excite the temperature-dependent pressure amplitudes, which were detected at the cornea by an ultrasonic transducer embedded in a contact lens. A 532 nm continuous wave Nd:YAG laser served for photocoagulation. The ED50 temperatures, for which the probability of ophthalmoscopically visible lesions after one hour in vivo in rabbits was 50%, varied from 63°C for 20 ms to 49°C for 400 ms. Arrhenius parameters were extracted as ΔE=273 J mol(-1) and A=3 x 10(44) s(-1). Control algorithms for mild and strong lesions were developed, which led to average lesion diameters of 162 ± 34 μm and 189 ± 34 μm, respectively. It could be demonstrated that the sizes of the automatically controlled lesions were widely independent of the treatment laser power and the retinal pigmentation.
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http://dx.doi.org/10.1117/1.JBO.17.6.061223DOI Listing
June 2012

Real-time temperature determination during retinal photocoagulation on patients.

J Biomed Opt 2012 Jun;17(6):061219

University of Lübeck, Institute of Biomedical Optics, Lübeck, Germany.

The induced thermal damage in retinal photocoagulation depends on the temperature increase and the time of irradiation. The temperature rise is unknown due to intraocular variations in light transmission, scattering and grade of absorption in the retinal pigment epithelium (RPE) and the choroid. Thus, in clinical practice, often stronger and deeper coagulations are applied than therapeutically needed, which can lead to extended neuroretinal damage and strong pain perception. This work focuses on an optoacoustic (OA) method to determine the temperature rise in real-time during photocoagulation by repetitively exciting thermoelastic pressure transients with nanosecond probe laser pulses, which are simultaneously applied to the treatment radiation. The temperature-dependent pressure amplitudes are non-invasively detected at the cornea with an ultrasonic transducer embedded in the contact lens. During clinical treatment, temperature courses as predicted by heat diffusion theory are observed in most cases. For laser spot diameters of 100 and 300 μm, and irradiation times of 100 and 200 ms, respectively, peak temperatures range between 70°C and 85°C for mild coagulations. The obtained data look very promising for the realization of a feedback-controlled treatment, which automatically generates preselected and reproducible coagulation strengths, unburdens the ophthalmologist from manual laser dosage, and minimizes adverse effects and pain for the patient.
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http://dx.doi.org/10.1117/1.JBO.17.6.061219DOI Listing
June 2012

Imaging thermal expansion and retinal tissue changes during photocoagulation by high speed OCT.

Biomed Opt Express 2012 May 19;3(5):1025-46. Epub 2012 Apr 19.

Visualizing retinal photocoagulation by real-time OCT measurements may considerably improve the understanding of thermally induced tissue changes and might enable a better reproducibility of the ocular laser treatment. High speed Doppler OCT with 860 frames per second imaged tissue changes in the fundus of enucleated porcine eyes during laser irradiation. Tissue motion, measured by Doppler OCT with nanometer resolution, was correlated with the temperature increase, which was measured non-invasively by optoacoustics. In enucleated eyes, the increase of the OCT signal near the retinal pigment epithelium (RPE) corresponded well to the macroscopically visible whitening of the tissue. At low irradiance, Doppler OCT revealed additionally a reversible thermal expansion of the retina. At higher irradiance additional movement due to irreversible tissue changes was observed. Measurements of the tissue expansion were also possible in vivo in a rabbit with submicrometer resolution when global tissue motion was compensated. Doppler OCT may be used for spatially resolved measurements of retinal temperature increases and thermally induced tissue changes. It can play an important role in understanding the mechanisms of photocoagulation and, eventually, lead to new strategies for retinal laser treatments.
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http://dx.doi.org/10.1364/BOE.3.001025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342180PMC
May 2012

Temperature-controlled retinal photocoagulation--a step toward automated laser treatment.

Invest Ophthalmol Vis Sci 2012 Jun 14;53(7):3605-14. Epub 2012 Jun 14.

Department of Ophthalmology, University of Kiel, Kiel, Germany.

Purpose: Retinal laser photocoagulation carries the risk of overtreatment due to effect variation of identically applied lesions. The degree of coagulation depends on the induced temperature increase and on exposure time. We introduce temperature controlled photocoagulation (TCP), which uses optoacoustics to determine individually exposure times necessary to create reproducible lesions.

Methods: Optoacoustic temperature measurement relies on pressure waves that are excited in the retinal tissue by repetitive low-energy laser pulses. Signal amplitudes correlate with tissue temperature and are detected by a transducer in the laser contact lens. We used a continuous wave (CW) photocoagulator for treatment irradiation and superimposed probe laser pulses for simultaneous temperature measurement. Optoacoustic data of 1500 lesions (rabbit) were evaluated to develop an algorithm that controls exposure times automatically in TCP. Lesion diameters of 156 TCP lesions were compared to 156 non-controlled lesions. Histology was performed after 1 hour, and 1 and 4 weeks.

Results: TCP resulted in exposure times from 4 to 800 ms depending on laser power chosen. Ophthalmoscopic and histologic lesion diameters were independent of power between 14 and 200 mW. TCP lesions barely were visible with a mean diameter equal to the treatment beam (130 μm). In contrast, standard lesion diameters increased linearly and statistically significantly with power. Histology confirmed sparing of the ganglion and nerve fiber layers in TCP.

Conclusions: TCP facilitates uniform retinal lesions over a wide power range. In a clinical setting, it should generate soft and reproducible lesions independently of local tissue variation and improve safety, particularly at short exposure times.
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http://dx.doi.org/10.1167/iovs.11-8588DOI Listing
June 2012

Selective retina therapy (SRT) for clinically significant diabetic macular edema.

Graefes Arch Clin Exp Ophthalmol 2010 Sep;248(9):1263-72

Department of Ophthalmology, University Medical Center Schleswig-Holstein, Campus Kiel, Arnold-Heller Strasse 3, Kiel, Germany.

Purpose: To test selective retina therapy (SRT) as a treatment of clinically significant diabetic macular edema (DME).

Methods: Prospective two-center interventional uncontrolled phase II pilot study. Thirty-nine eyes of 39 patients with previously untreated non-ischemic DME were treated with focal laser treatment using a Q-switched frequency doubled Nd:YLF laser which selectively affects the retinal pigment epithelium while sparing the photoreceptor layer. Optoacoustic measurements, fundus fluorescein angiography (FFA), and funduscopy were used to determine the individual threshold of RPE damage of each patient. The pulse energy was adjusted to apply angiographically visible but funduscopically invisible effects. Optoacoustic measurements were correlated with funduscopy and FFA. Follow-up examinations at 3 and 6 months post-treatment included best-corrected ETDRS visual acuity (BCVA), FFA, fundus photography, and retinal thickness measured by optical coherence tomography. The primary outcome measure was change of BCVA. Other outcome measures were change of retinal thickness, presence of hard exudates, leakage in FFA, accuracy of optoacoustic measurements, and correlation of BCVA with change of anatomical and systemic parameters.

Results: Mean BCVA improved from 43.7 letters (standard deviation, SD=9.1) at baseline to 46.1 letters (SD=10.5) at the 6-month follow-up (p=0.02). BCVA improved (>5 letters) or remained stable (+/-5 letters) in 84% of eyes. Thirteen percent of eyes improved by > or =10 letters, while 16% of eyes lost more than 5 letters. There was no severe loss of vision (> or =15 letters). Overall, retinal thickness, hard exudates, and leakage in FFA did not change significantly (p> 0.05), while improvement of BCVA correlated with a reduction of hard exudates (p=0.01) and central retinal thickness (p=0.01). Specificity and sensitivity of detecting the angiographic visible threshold of RPE damage by optoacoustic measurements were 86% and 70% respectively. No adverse effects or pain were noted during or after treatment. Conclusions Functional and anatomical improvement or stabilization was observed in most patients. SRT appears to be safe. Optoacoustic measurements accurately detect the individual threshold of RPE damage. A randomized trial is required to further test efficacy and safety of SRT as a treatment of clinically significant diabetic macular edema (DME).
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http://dx.doi.org/10.1007/s00417-010-1356-3DOI Listing
September 2010

Selective retina therapy (SRT) in patients with geographic atrophy due to age-related macular degeneration.

Graefes Arch Clin Exp Ophthalmol 2010 May 22;248(5):651-8. Epub 2009 Dec 22.

University Eye Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg, Germany.

Background: For geographic atrophy (GA) due to age-related macular degeneration (AMD) there is so far no approved treatment option. Usually, increased autofluorescence (AF) levels of different patterns adjacent to the atrophic area indicate lipofuscin-laden retinal pigment epithelium (RPE) cells at a high risk for apoptosis. Herein, SRT was used to selectively treat these cells to stimulate RPE proliferation, in order to reduce or ideally stop further growth of the atrophic area.

Material And Methods: Six eyes of six patients with bilateral equally pronounced GA were treated by SRT, while the fellow eye served as control. Irradiation was performed using a prototype SRT laser (Medical Laser Center Lübeck, Nd:YLF laser; 527 nm; 200 ns/1.7 micros pulse duration; 30 repetitive pulses at 100 Hz). Test lesions with increasing energies were applied at the lower vessel arcade to determine the individual angiographic and ophthalmoscopic threshold radiant exposures. Treatment was then performed in the area of increased AF adjacent to the GA using energies between both thresholds. The GA progression rates of treated and fellow eyes were evaluated.

Results: After a 1-year follow-up, a progression of the atrophic area was observed in the treated eyes (0.7-8.0 mm(2)/yr, mean 3.0 mm(2)/yr; 46%/yr) whereas the progression rates of the fellow eyes were insignificantly lower (0.46-4.04 mm(2)/yr, mean 1.9 mm(2)/yr; 30%/yr; p = 0.134). The progression rate in the treated eyes of two patients increased significantly, while in the other four patients, the progression rates were nearly the same between both eyes. Moreover, one of these two eyes showed an unexpected RPE reaction after treatment, since all laser lesions led to RPE atrophy and thus an accelerated enlargement of the GA occurred.

Conclusion: SRT in the hyperautofluorescent areas of GA was not able to stop or slow down the progression of GA. However, modified treatment strategies might be more promising, e.g. placing the spots outside the hyperautofluorescent areas where RPE apoptosis is postulated. Moreover, SRT studies on GA might be more successfully performed on specific subgroups of GA, based on autofluorescence and other findings.
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http://dx.doi.org/10.1007/s00417-009-1208-1DOI Listing
May 2010

Effects on choroidal neovascularization after anti-VEGF Upload using intravitreal ranibizumab, as determined by spectral domain-optical coherence tomography.

Invest Ophthalmol Vis Sci 2010 Mar 29;51(3):1671-6. Epub 2009 Oct 29.

University Eye Hospital, Regensburg, Germany.

Purpose: It is unclear whether anti-VEGF monotherapy in age-related macular degeneration (AMD) achieves morphologic CNV regression or only stops further CNV growth. In this study, spectral domain-optical coherence tomography (SD-OCT) was used to image CNV structure before and after anti-VEGF treatment.

Methods: Out of 107 consecutive patients, a prospective CNV evaluation was possible in 78 of them. Newly diagnosed CNV (classic CNV: n = 16; occult CNV: n = 54; minimal classic CNV: n = 8) due to AMD was imaged before and 4 weeks after anti-VEGF upload in three intravitreal injections of ranibizumab. Qualitative (structural changes) and quantitative measurements (diameter and thickness) of the CNV were obtained from the OCT images.

Results: Classic CNV components were observed above the RPE/photoreceptor complex, whereas occult CNVs stayed below. Of all postoperative OCTs, 59% revealed complete dry retinal structures, 27% showed reduced edema, and 14% showed edema remaining unchanged. Mean macular thickness decreased significantly from 427 to 303 microm (P = 0.000). Qualitatively, overall CNV architecture appeared to be unchanged in 78%, was reduced in thickness in 18%, and became larger in 4%. Quantitatively, in all CNV subtypes, the diameter of the CNV lesions (preoperative, 2813 microm; postoperative, 2804 microm) did not change after treatment (classic CNV: P = 0.390; occult CNV: P = 0.405, minimal classic CNV: P = 0.092) independent of postoperative retinal edema. The overall thickness of the lesion, however, was reduced from 205 to 175 microm (P = 0.000). Thickness reduction was significantly enhanced especially in CNV with classic components (n = 24; 252 to 197 microm; P = 0.000; reduction, 22%), whereas reduction was smaller but also significant in occult CNV (183 to 164 microm; P = 0.003; reduction, 10%).

Conclusions: With SD-OCT, CNV size can be two-dimensionally determined and followed up after intravitreal anti-VEGF treatment. In only 4% of CNV was enlargement observed, whereas in 78%, CNV architecture appeared qualitatively unchanged, independent of retinal edema. Quantitative measurements underlined stable CNV diameters for all subtypes but revealed significant reduction of thickness especially for classic CNV components. In this series, ranibizumab monotherapy was able to morphologically stop further CNV growth but, in most patients, did not lead to a major regression of CNV, especially of its occult components.
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http://dx.doi.org/10.1167/iovs.09-4496DOI Listing
March 2010