Femtosecond Lasers in Ophthalmology

Transcription

1 Femtosecond Lasers in Ophthalmology Precise cutting using adaptive optics is pushing the limits Ben Matthias, Uwe Oberheide, Alexander Krüger, Tammo Ripken and Holger Lubatschowski Presbyopia is the most common visual defect of the human eye. Beginning with the age of 45 years, most people lose the ability to focus on near objects due to the loss of accommodation ability of the crystalline lens. Within the research network IKARUS, a femtosecond laser system has been realized, which is able to generate microscopic sliding into the crystalline lens, to restore the accommodative capacity of the eye. The surgical procedure only takes a few seconds and is non-invasive. As a consequence, there is no risk of infection for the patient and the procedure can be carried out in non-sterile environment. In addition, other clinical applications with extremely high market potential were evaluated in the context of ex vivo investigations. It could be shown that, using adaptive optics, it is possible to create precise cuts even in the posterior segment of the eye (retina) and thus open up a multitude of new treatment options. Femtosecond lasers in ophthalmology Since the launch of the first commercial femtosecond laser system for corneal surgery in 2001 by IntraLase, more than thousand systems have been sold and more than twenty million patients have been treated for refractive corneal surgery. Today, femtosecond lasers have developed from a pure Flap-maker for LASIK surgery to a multiple tool for corneal surgery [1] as well as for cataract surgery [2, 3]. In cataract surgery, the laser has extended its field of action from the cornea to the crystalline lens where it is used to open the capsular bag (capsulotomy) and performing lens fragmentation. But, there is even more potential of femto -applications in ophthalmic Fig. 1 Restoring crystalline lens flexibility by generating smooth cuts inside the crystalline lens acting as sliding planes. Left: principle of the procedure. Right: extracted crystalline lens with sliding planes inside surgery. On presbyopic eyes, where accommodation fail, due to the age related hardening of the crystalline lens, pulses might have the chance to regain accommodation by creating micro-incisions inside the lens without surgically opening the eye (Fig. 1). These micro-channels could reduce the inner friction of the lens tissue, acting as sliding planes [4]. When delivered to rabbit eyes, these laser incisions did not cause cataract growth or wound-healing abnormalities. When applied to human autopsy eyes, an average increase of 100 µm in the antero-posterior lens thickness was seen, corresponding to a 2.00 to 3.00 D gain in accommodative amplitude. Moreover, ultrashort laser pulses may replace posterior vitrectomy for the treatment of tractional vitreous attachments in the near future. The traditional method for treating vitreoretinal traction is a posterior vitrectomy, an invasive procedure in which the band of vitreous Fig. 2 Sketch of a vitreoretinal traction, specifically a posterior hyaloid traction exhibiting retinoschisis. In this condition, a portion of the vitreous tissue of the eye has adhered to the retinal tissue, causing the retinal tissue to lift away from the underlying retinal pigment epithelium. Left: untreated, vitreoretinal traction can lead to damage to the retina as well as retinal detachment. Middle: conventional posterior vitrectomy. Right: Cutting the strands with a. Best of Applications OPTIK & PHOTONIK Invited Article Optik&Photonik 2/

2 tissue in traction with the retina is removed. The rate of post-operative morbidity in this invasive procedure is significant, with a high incidence of cataract formation due to the invasive nature of the procedure. Using fs-pulses, the vitreous tissue could be removed without any surgical opening of the eye, avoiding the known post-operative side effects (Fig. 2). Far 55 cm 25 cm Surveying the crystalline lens during accommodation During accommodation, there is a change in the shape of the crystalline lens leading to an increase in refractive power. In order to understand the effects of the laser generated sliding planes inside the lens, it is helpful to record shape of the lens at different refractive states as well as the correlating optical power and the resulting aberrations. At the start of IKARUS several diagnosis systems existed to monitor either the shape of the crystalline lens or its optical properties [5, 6]. However, so far there was no method for the direct correlation of optical with the anatomical changes. To allow such a simultaneous measurement, a combination of an optical coherence tomography (OCT) and an aberrometer was realized. For this, the beam paths of a commercially available time-domain OCT for clinical measurements of the anterior segment of the eye (SL-OCT, Heidelberg Engineering, Germany) and clinical aberrometer using raytracing (itrace,tracey Technologies, USA) were combined collinearly with a dichroic beam splitter due to the wavelengths of 785 nm and 1300 nm used by the aberrometer and the OCT, respectively. Fig. 3 shows OCT images of the shape of the lens at three different accommodative states and the simultaneously measured spherical aberrations as an example. On average, the lens thickness increased by 82 ± 3 microns per diopter of accommodative power. During the accommodation process, the spherical aberrations of the entire eye change toward negative spherical aberrations, for the measured group ± µm per diopter accommodative power. With these measurements, the changes of the wavefront are correlated with changes in the lens thickness and shape for the first time. Fig. 3 OCT images (top) of the shape of the lens at three different accommodative states (far, intermediate, near) and the simultaneously measured spherical aberrations (bottom) Integrating OCT-Technology Since inter-individual anatomical differences lead to variations in the lens position and geometry, the integration of an intraoperative depth-resolved imaging is vital to the safety and success of lens surgery. Internal structures must be reliably addressed in adherence to safety zones to the lens capsule. Optical coherence tomography has been originally introduced as such a measurement technique for intraocular distances and has evolved into a versatile diagnostic imaging tool used in numerous medical disciplines. The realized clinical prototype for lens surgery utilizes a customized spectrometer-based Fourier-domain OCT (FD-OCT) system to guide laser beam positioning in the anterior SLD spectrometer attenuation eye (Fig. 4). A detailed system description is given in [7]. Compared to time domain OCT (TD-OCT), FD-OCT has considerable advantages regarding signal-to-noise ratio and imaging speed. But it has two drawbacks that restrict the measuring depth. First, there is a sensitivity rolloff with increasing measuring depth in FD-OCT. The most sensitive measuring range is close to the zero delay position, where the OCT interferometer arms are matched in length. Second, conventional FD-OCT images suffer from disturbing mirror artifacts due to a complex ambiguity in the Fourier analysis of the real-valued measured spectral signals. Different full range OCT methods exist to eliminate mirror artifacts and effectively double the usable imaging range. Most of them use phase shifting dichr. mirror sample arm reference arm scanning x-y z focusing sample Fig. 4 Schematic setup of the OCT-guided surgery system for cutting the crystalline lens. The customized FD-OCT system (840 nm central wavelength) and the (1040 nm) are in common path configuration sharing the scanning unit and the focusing optics. The coupling interface is a dichroic mirror. Dispersion compensation glasses are deliberately omitted in the OCT reference arm to create a dispersion imbalance in the OCT interferometer required for dispersion encoded full range (DEFR) processing [7]. 50 Optik&Photonik 2/2016

3 techniques which can roughly be classified into alternating phase shifts between stationary A-scans (Inter-A-Phaseshift) and continuous phase shifts during laterally scanning the sample (BM-Mode- Scan). These techniques try to generate or reconstruct a complex-valued analytical signal which is unambiguous under Fourier transform. Phase shifting methods usually make use of additional hardware and thereby increase the system complexity. Within IKARUS, a version of the dispersion encoded full-range (DEFR) technique [8] was implemented. Moving and error-prone elements for artifact suppression are unnecessary and system complexity is not increased. The DEFR algorithm removes mirror artifacts by exploiting a dispersion mismatch between the OCT interferometer arms. True structure and mirror terms get distinguishable after numerical dispersion compensation and mirror artifacts can be removed iteratively. Despite a high computational effort, OCT B-mode frames are displayed in real time by highly parallelized image processing on a graphics processing unit. The full range imaging capability of the clinical prototype is demonstrated in Fig 5. The OCT B-mode images show the whole anterior eye segment of a porcine eye ex vivo including the cornea and the rear lens surface. DEFR-processing clearly reduces the mirror artifacts and the true sample structure is retained. By Fig. 5 OCT B-mode images of the anterior segment of a porcine eye ex vivo after conventional processing (left) and DEFR processing (right). Disturbing mirror artifacts symmetrical to the zero delay position (dashed horizontal line) are suppressed and image interpretation is facilitated. The shown A-scan signals are generated along the blue vertical lines. Imaging is performed by composing two B-scans with two different z-focus positions; one B-scan is acquired in the front and one in the rear part of the anterior segment while the zero delay position remains unchanged (modified from [7]). means of the full range OCT images a surgeon is capable to define the following surgical procedure more reliably. Adaptive optics Extending the field of application even deeper into the posterior eye segment, individual eye aberrations have a noticeable impact and surgery is impaired by focus degradation. The induced aberrations considerably increase the focal volume and lead to higher threshold energies that are required for laser cutting. Furthermore, the eye pupil limits the usable numerical aperture down to about 0.2, increasing the focal spot and threshold energy as well. Thus, the risk of retinal damage is increased. Because target structures may be in the direct vicinity of the retina, cutting precision and retinal safety are even more critical than in the established applications in the anterior eye. In prior studies, it could be shown that the threshold energy for laser induced optical breakdown (LIOB) in water can be reduced and cutting precision can be SLD spectrometer target eye model deformable mirror flip mirror PBS beam expander attenuator lens wheel dispersion compensation Hartmann-Shack sensor y-scanner x-scanner Fig. 6 Schematic overview of an AO-assisted system extended by a spectrometer based FD-OCT system for image-guided cutting in an eye model (modified from [9]). λ/2 IKARUS Innovative cataract, presbyopia and retinal treatment using ultrashort laser pulses The German joint research project IKARUS has realized an ultrashort pulse laser scalpel, which enables minimally invasive laser cuts with high precision in order to induce microscopic sliding planes within the aged lens. Due to the gain in lens flexibility, the accommodation ability will be restored by up to three diopters. The system will be controlled by the surgeon via a simple interface and enables online monitoring of the therapy due to OCT (optical coherence tomography) imaging. Project partners are ROWIAK GmbH, Hannover (coordinator), ARGES GmbH, Wackersdorf, QIOPTIQ Photonics GmbH & Co. KG, Göttingen, Laserforum Köln e.v., Cologne, and Laser Zentrum Hannover e.v., Hannover. Optik&Photonik 2/

4 Value in µm Zernike polynomial decomposition Modal coefficient collecting lens water LIOB PBS focusing lens (EFL 17.0 mm) λ/2 enhanced using adaptive optics (AO) for aberration correction. The presented functional prototype for image-guided vitreo-retinal surgery combines AO for spatial beam shaping and OCT for focus positioning (Fig. 6). A detailed description of the laboratory setup is given in [9]. The AO-assisted system at 800 nm is extended by a spectrometer-based FD-OCT system with 890 nm central wavelength and 150 nm spectrum width. The path of the OCT sample beam is mostly identical to the sharing the deformable mirror, the scanners and the focusing optics. The coupling interface is a flip mirror. A Hartmann-Shack sensor (HASO3-first, Imagine Eyes, France) is used for aberration measurement and a deformable mirror (mirao 52-e, Imagine Eyes, France) for aberration correction. A point source for performing wavefront aberration correction is produced by focusing pulses at low energy levels on a diffuse reflecting target within the eye model. The eye model consists of a water filled chamber with two lenses in water contact towards Irradiance Transmission Point spread function Distance from center in µm Pulse transmission measurement Incident pulse energy in µj Fig. 7 Waveform errors are reduced by closed loop AO correction from 270 nm rms down to 64 nm rms, ignoring tilts and defocus aberrations. The Zernike polynomial decomposition of the waveform (top left) clearly shows the improvement. The focus quality is enhanced after AO correction demonstrated by the point spread functions calculated from the wavefront maps (top right). The Strehl ratio is improved from 0.11 up to The LIOB threshold energy in water measured at the entrance of the eye model is reduced from about 3.0 µj pulse energy in the case down to about 1.3 µj in the case (bottom right). The LIOB thresholds were determined by transmission measurements comparing the energy values at two energy calibrated s (bottom left). The onset of a reduced transmission through the eye model is used as LIOB threshold their inner sides. The entrance lens is an uncoated aspheric condenser lens with effective focus length of 17.0 mm in air and models the refractive power of the human eye. Different targets can be dipped into the chamber from above. By means of AO aberration correction wavefront errors are reduced, the focus is improved and the LIOB threshold energy is lowered (Fig. 7). The waveform errors are reduced from 270 nm rms (root mean square) down to 64 nm rms, ignoring tilts and defocus aberrations. The point spread function narrows down to a sharp peak; the Strehl ratio is improved from 0.11 to The LIOB threshold energy in water is decreased from about 3.0 μj pulse energy, measured at the entrance of the eye model, down to about 1.3 μj. LIOB thresholds were determined by transmission measurements comparing the energy values at two energy calibrated s before and behind the eye model. The onset of a reduced transmission through the eye model is used as LIOB threshold. A proof of concept for epiretinal cutting at animal tissue is demonstrated in Fig. 8. Targeted cutting of a membranelike phantom in front of retinal tissue is performed with the system. The tissue sample was excised carefully from a porcine eye ex vivo. The OCT images were used to target the onto the membrane prior cutting and to inspect the cutting afterwards. The used pulse energy for cutting of about 1.3 μj at the entrance lens of the eye model was Fig. 8 Targeted line cutting of a membrane like phantom (synthetic foil) in front of excised retinal pigment epithelium (RPE) on choroid of a porcine eye ex vivo. The AO system was operated in open loop configuration with the deformable mirror held in the shape. The line cut was programmed along the x-axis with 550 µm length. To cut reliably through the foil the laser focus was shifted ±10 μm around the middle position in twenty steps along the z-axis using the deformable mirror. The laser pulse energy was near the LIOB threshold of 1.3 µj at the entrance of the eye model. The foil is separated well about 300 µm in length as indicated in the B-scans along and perpendicular to the line cut. A laser lesion or modification of the RPE is not visible in the OCT images [9]. 52 Optik&Photonik 2/2016

5 near the LIOB threshold. The foil is separated well about 300 μm in length. At each edge, ± 125 μm in length are partially cut. A laser lesion or modification in the retinal tissue is not visible in the OCT images. Detailed risk analyses, like neurophysiological studies in an animal model, could provide greater insights concerning retinal safety. Acknowledgements The work was part of the research project IKARUS (innovative cataract, age related presbyopia and retina treatment with ultrashort pulsed lasers; NOs. 13N11847, 13N11848, 13N11850, 13N11851, 19AP9HIz) and was sponsored by the German Federal Ministry of Education and Research (BMBF). The authors thank Dorothee Brockmann for helpful discussions and assistance regarding the preparation of the ocular tissue. DOI: /opph [1] G. D. Kymionis et al.: Femtosecond Laser Technology in Corneal Refractive Surgery: A Review, J Refract Surg 28 (2012) 12 [2] R. G. Abell et al.: Femtosecond laser assisted cataract surgery versus standard phacoemulsification cataract surgery: Outcomes and safety in more than 4000 cases at a single center, Journal of Cataract & Refractive Surgery 41 (2015) 1 [3] D. V. Palanker et al.: Femtosecond Laser-Assisted Cataract Surgery with Integrated Optical Coherence Tomography, Sci Transl Med 2(58):58ra85 (2010) [4] H. Lubatschowski et al.: Femtosecond lentotomy: generating gliding planes inside the crystalline lens to regain accommodation ability, J. Biophoton. 3 (2012) 5-6 [5] M. Dubbelman et al.: Change in shape of the aging human crystalline lens with accommodation, Vision Research (2005) [6] D. M. Win-Hall, A. Glasser: Objective accommodation measurements in pseudophakic subjects using an autorefractor and an aberrometer, Journal of Cataract and Refractive Surgery (35) (2009) [7] B. Matthias, T. Ripken, A. Krüger: Dispersion Encoded Full Range Fourier Domain Optical Coherence Tomography for Image-Guidance of Fs-Laser Lens Surgery, Biomed. Tech. 59 (2014) s1 [8] B. Hofer et al.: Fast dispersion encoded full range optical coherence tomography for retinal imaging at 800 nm and 1060 nm, Opt. Express 18 (2010) 5, [9] B. Matthias et al.: Concept for image-guided vitreo-retinal surgery adaptive optics and optical coherence tomography for laser beam shaping and positioning, Proc. SPIE 9307, Ophthalmic Technologies XXV, 93070Z (2015) Authors Ben Matthias was born in Hannover in 1986, graduated in technical physics at Leibniz Universität Hannover in Since 2010, He is working at the Laser Zentrum Hannover e.v. in the Biomedical Optics Department. His research is focused on image-guided surgery in the field of ophthalmic technologies taking advantage of optical coherence tomography and adaptive optics. Uwe Oberheide studied physics at the University of Hannover and finished his PhD at the Laser Zentrum Hannover in He worked in medical research at the Laserforum Köln and the Augenklinik am Neumarkt, in Cologne. Since 2014, he is full professor at the TH Köln, focusing on optical technologies and biomedical optics. Alexander Krüger (née Popp), born 1970, graduated in physics in 1998 and finished his dissertation about optical parametric oscillators in January 2003 at the University of Bonn. Optical coherence tomography became one of his mayor interests in the years at the Medical Faculty of Technical University Dresden. Since 2008, he has worked at the Laser Zentrum Hannover e.v., and is now Head of the Image-guided Laser Surgery Group in the Biomedical Optics Department. Tammo Ripken was born in Hannover in Study of Physics with diploma, PhD obtained from the Leibniz Universität Hannover in Since 2001, he is working at the Laser Zentrum Hannover e.v. (LZH), from 2005 to 2008 as project leader for in ophthalmology, and from 2008 to 2010, as Head of the Laser Medicine Group. Since 2011 Ripken acts as Head of the Biomedical Optics Department. His main research areas are laser-assisted medicine, laser-tissue interaction and laser-based medical imaging. Holger Lubatschowski studied physics at the University of Bonn, Germany. After his PhD he moved to Hannover and became Head of Medical Laser Group at the Laser Zentrum Hannover e.v. (LZH). In 2001, he completed his postdoctoral lecture qualification for physics at the physics faculty of the University of Hannover and became assistant professor. Since then, Lubatschowski has headed the department of Biomedical Optics at the LZH. Here, he acquired expertise in laser processing of biological tissue which is demonstrated by more than 200 scientific publications in the area of laser medicine and laser-tissue interaction in leading scientific journals. Since 2010, Lubatschowski concentrates his work on his own company ROWIAK GmbH, a spin-off from the LZH. ROWIAK develops and produces ultrafast laser systems for ophthalmic surgery. Holger Lubatschowski, ROWIAK GmbH, Garbsener Landstr. 10, D Hannover, h.lubatschowski@rowiak.de, Phone: Ben Matthias, Tammo Ripken, Alexander Krüger, Laser Zentrum Hannover e.v., Hollerithallee 8, Hannover, b.matthias@lzh.de, Phone: Uwe Oberheide, Institut für Angewandte Optik und Elektronik, Technische Hochschule Köln, Campus Deutz, Betzdorfer Straße 2, Köln; uwe.oberheide@ th-koeln.de, Phone: Optik&Photonik 2/