Daniel Palanker, PhD

All Publications

• Accelerated Simulation of Multi-Electrode Arrays Using Sparse and Low-Rank Matrix Techniques. bioRxiv : the preprint server for biology Jensen, N., Charles Chen, Z., Kochnev Goldstein, A., Palanker, D. 2024

  Abstract

  Modeling of Multi-Electrode Arrays used in neural stimulation can be computationally challenging since it may involve incredibly dense circuits with millions of interconnected resistors, representing current pathways in an electrolyte (resistance matrix), coupled to nonlinear circuits of the stimulating pixels themselves. Here, we present a method for accelerating the modeling of such circuits while minimizing the error of a simplified simulation by using a sparse plus low-rank approximation of the resistance matrix. Specifically, we prove that thresholding of the resistance matrix elements enables its sparsification with minimized error. This is accomplished with a sorting algorithm implying efficient O (N log (N)) complexity. The eigenvalue-based low-rank compensation then helps achieve greater accuracy without adding significantly to the problem size. Utilizing these matrix techniques, we accelerated the simulation of multi-electrode arrays by an order of magnitude, reducing the computation time by about 10-fold, while maintaining an average error of less than 0.3% in the current injected from each electrode. We also show a case where acceleration reaches at least 133 times with additional error in the range of 4%, demonstrating the ability of this algorithm to perform under extreme conditions. Although the techniques presented here are used for simulations of photovoltaic retinal prostheses, they are also immediately applicable to any circuit involving dense connections between nodes, and, with modifications, more generally to any systems involving non-sparse matrices. This approach promises significant improvements in the efficiency of modeling the next-generation retinal implants having thousands of pixels, enabling iterative design with broad applicability.

  View details for DOI 10.1101/2024.07.29.605687

  View details for PubMedID 39131271

• Light-evoked deformations in rod photoreceptors, pigment epithelium and subretinal space revealed by prolonged and multilayered optoretinography. Nature communications Tan, B., Li, H., Zhuo, Y., Han, L., Mupparapu, R., Nanni, D., Barathi, V. A., Palanker, D., Schmetterer, L., Ling, T. 2024; 15 (1): 5156

  Abstract

  Phototransduction involves changes in concentration of ions and other solutes within photoreceptors and in subretinal space, which affect osmotic pressure and the associated water flow. Corresponding expansion and contraction of cellular layers can be imaged using optoretinography (ORG), based on phase-resolved optical coherence tomography (OCT). Until now, ORG could reliably detect only photoisomerization and phototransduction in photoreceptors, primarily in cones under bright stimuli. Here, by employing a phase-restoring subpixel motion correction algorithm, which enables imaging of the nanometer-scale tissue dynamics during minute-long recordings, and unsupervised learning of spatiotemporal patterns, we discover optical signatures of the other retinal structures' response to visual stimuli. These include inner and outer segments of rod photoreceptors, retinal pigment epithelium, and subretinal space in general. The high sensitivity of our technique enables detection of the retinal responses to dim stimuli: down to 0.01% bleach level, corresponding to natural levels of scotopic illumination. We also demonstrate that with a single flash, the optoretinogram can map retinal responses across a 12° field of view, potentially replacing multifocal electroretinography. This technique expands the diagnostic capabilities and practical applicability of optoretinography, providing an alternative to electroretinography, while combining structural and functional retinal imaging in the same OCT machine.

  View details for DOI 10.1038/s41467-024-49014-5

  View details for PubMedID 38898002

  View details for PubMedCentralID PMC11186825

• 3D electronic implants in subretinal space: Long-term follow-up in rodents. Biomaterials Bhuckory, M. B., Wang, B. Y., Chen, Z. C., Shin, A., Pham-Howard, D., Shah, S., Monkongpitukkul, N., Galambos, L., Kamins, T., Mathieson, K., Palanker, D. 2024; 311: 122674

  Abstract

  Clinical results with photovoltaic subretinal prosthesis (PRIMA) demonstrated restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution matching the 100 μm pixel size. Since scaling the pixels below 75 μm in the current bipolar planar geometry will significantly limit the penetration depth of the electric field and increase stimulation threshold, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 32-36 weeks post-implantation in aged rats. With both flat and 3D implants, signals elicited in the visual cortex decreased after the day of implantation by more than 3-fold, and gradually recovered over the next 12-16 weeks. With 25 μm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the retina. Retinal thickness and full-field stimulation threshold with 40 μm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10 ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 μm-wide wells, and stimulation threshold increased over 12-16 weeks, before stabilizing at about 0.08 mW/mm2. Such threshold is still significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

  View details for DOI 10.1016/j.biomaterials.2024.122674

  View details for PubMedID 38897028

• On selectivity of neural stimulation with subretinal photovoltaic implants Goldstein, A., Jensen, N., Wang, B., Bhuckory, M., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001313316205328

• Non-Damaging Laser Retinal Therapy (NRT) for Type 2 Macular Telangiectasia: Three years follow-up Lavinsky, D., Chaves, A., Schneider, W., Oliveira, M., Luz, P., Lavinsky, F., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001312227702124

• Transcriptional and Translational Profiling of Reactive Muller Glia Following Cell-type specific Retinal Injury Ashouri, M., Bhuckory, M., Xia, X., Nahmou, M., Tsien, C., Huie, E., Li, B., Cameron, E., Wang, S., Palanker, D. V., Goldberg, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001312227704300

• Letter Acuity and Reading with a Subretinal Photovoltaic Implant in Geographic Atrophy Muqit, M., Le Mer, Y., de Koo, L., Holz, F. G., Sahel, J., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001313316208339

• Mapping the retinal resistivity with electrical impedance tomography for modeling of retinal stimulation Shah, S., Goldstein, A., Chen, Z., Vasireddy, P., Bhuckory, M., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001313316205324

• Replacement of a subretinal prosthesis with a higher-resolution array improves grating acuity in the same animal Bhuckory, M., Monkongpitukkul, N., Shin, A., Goldstein, A., Shah, S., Pham-Howard, D., Dalal, R., Galambos, L., Kamins, T., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001313316205325

• Enhancing Prosthetic Vision by Upgrade of a Subretinal Photovoltaic Implant in situ. bioRxiv : the preprint server for biology Bhuckory, M. B., Monkongpitukkul, N., Shin, A., Goldstein, A. K., Jensen, N., Shah, S. V., Pham-Howard, D., Butt, E., Dalal, R., Galambos, L., Mathieson, K., Kamins, T., Palanker, D. 2024

  Abstract

  In patients with atrophic age-related macular degeneration, subretinal photovoltaic implant (PRIMA) provided visual acuity up to 20/440, matching its 100mum pixels size. Next-generation implants with smaller pixels should significantly improve the acuity. This study in rats evaluates removal of a subretinal implant, replacement with a newer device, and the resulting grating acuity in-vivo. Six weeks after the initial implantation with planar and 3-dimensional devices, the retina was re-detached, and the devices were successfully removed. Histology demonstrated a preserved inner nuclear layer. Re-implantation of new devices into the same location demonstrated retinal re-attachment to a new implant. New devices with 22mum pixels increased the grating acuity from the 100mum capability of PRIMA implants to 28mum, reaching the limit of natural resolution in rats. Reimplanted devices exhibited the same stimulation threshold as for the first implantation of the same implants in a control group. This study demonstrates the feasibility of safely upgrading the subretinal photovoltaic implants to improve prosthetic visual acuity.

  View details for DOI 10.1101/2024.04.15.589465

  View details for PubMedID 38659843

• Prosthetic Visual Acuity with the PRIMA Subretinal Microchip in Patients with Atrophic Age-Related Macular Degeneration at 4 Years Follow-up. Ophthalmology science Muqit, M. M., Le Mer, Y., Olmos de Koo, L., Holz, F. G., Sahel, J. A., Palanker, D. 2024; 4 (5): 100510

  Abstract

  To assess the efficacy and safety of the PRIMA neurostimulation system with a subretinal microchip for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months postimplantation.Feasibility clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.govNCT03333954).Five patients with GA, no foveal light perception, and VA of logarithm of the minimum angle of resolution (logMAR) 1.3 to 1.7 (20/400-20/1000) in their worse-seeing "study" eye.In patients subretinally implanted with a photovoltaic neurostimulation array containing 378 pixels of 100 μm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 m. The system's external components, augmented reality glasses, and pocket computer provide image processing capabilities, including zoom.Visual acuity using ETDRS charts with and without the system, as well as light sensitivity in the central visual field, measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and OCT up to 48 months postimplantation.All 5 subjects met the primary end point of light perception elicited by the implant in the scotoma area. In 1 patient, the implant was incorrectly inserted into the choroid. One subject died 18 months postimplantation due to study-unrelated reasons. ETDRS VA results for the remaining 3 subjects are reported here. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to a mean logMAR of 1.39, or Snellen of 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (standard error 5.1) 95% confidence intervals (13.4, 49.9; P < 0.0001). Natural peripheral visual function in the treated eye did not decline after surgery or during the 48-month follow-up period (P = 0.08).Subretinal implantation of PRIMA in subjects with GA experiencing profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48 months. Prosthetic central vision provided by photovoltaic neurostimulation enabled patients to reliably recognize letters and sequences of letters, and with zoom, it improved VA of up to 8 ETDRS lines.Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

  View details for DOI 10.1016/j.xops.2024.100510

  View details for PubMedID 38881600

  View details for PubMedCentralID PMC11179408

• Three-dimensional electro-neural interfaces electroplated on subretinal prostheses. Journal of neural engineering Butt, E., Wang, B. Y., Shin, A., Chen, Z. C., Bhuckory, M., Shah, S., Galambos, L., Kamins, T., Palanker, D., Mathieson, K. 2024

  Abstract

  High-resolution retinal prosthetics offer partial sight restoration to patients blinded by retinal degenerative diseases through electrical stimulation of remaining neurons. Decreasing pixel size enables increasing prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigated 3-dimensional structures on top of photovoltaic arrays for enhanced penetration of the electric field, permitting higher resolution implants. Approach. 3D COMSOL models of subretinal photovoltaic arrays were developed to accurately quantify the electrodynamics during stimulation and verified through comparison to flat photovoltaic arrays. Models were applied to optimize the design of 3D electrode structures (pillars and honeycombs). Return electrodes on honeycomb walls vertically align the electric field with bipolar cells for optimal stimulation. Pillars elevate the active electrode improving proximity to target neurons. The optimized 3D structures were electroplated onto existing flat subretinal prostheses based on modelling results. Main results. Simulations demonstrate that despite exposed conductive sidewalls, charge mostly flows via high-capacitance sputtered Iridium Oxide films topping the 3D structures. The 24 µm height of honeycomb structures was optimized for integration with the inner nuclear layers cells in the rat retina, whilst 35 µm tall pillars were optimized for penetrating the debris layer in human patients. Implantation of released 3D arrays demonstrates mechanical robustness with histology demonstrating successful integration of 3D structures with the rat retina in-vivo. Significance. Electroplated 3D honeycomb structures produce vertically oriented electric fields, providing low stimulation thresholds, high spatial resolution, and contrast for pixel sizes down to 20 µm. Pillar electrodes offer alternatives for extending past debris layers. Electroplating of 3D structures is compatible with the fabrication process of flat photovoltaic arrays, enabling much more efficient stimulation. .

  View details for DOI 10.1088/1741-2552/ad2a37

  View details for PubMedID 38364290

• Three-dimensional electro-neural interfaces electroplated on subretinal prostheses. bioRxiv : the preprint server for biology Butt, E., Wang, B., Shin, A., Chen, Z. C., Bhuckory, M., Shah, S., Galambos, L., Kamins, T., Palanker, D., Mathieson, K. 2023

  Abstract

  Objective: High-resolution retinal prosthetics offer partial restoration of sight to patients blinded by retinal degenerative diseases through electrical stimulation of the remaining neurons. Decreasing the pixel size enables an increase in prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigate 3-dimensional structures on top of the photovoltaic arrays for enhanced penetration of electric field to permit higher-resolution implants.Approach: We developed 3D COMSOL models of subretinal photovoltaic arrays that accurately quantify the device electrodynamics during stimulation and verified it experimentally through comparison with the standard (flat) photovoltaic arrays. The models were then applied to optimise the design of 3D electrode structures (pillars and honeycombs) to efficiently stimulate the inner retinal neurons. The return electrodes elevated on top of the honeycomb walls surrounding each pixel orient the electric field inside the cavities vertically, aligning it with bipolar cells for optimal stimulation. Alternatively, pillars elevate the active electrode into the inner nuclear layer, improving proximity to the target neurons. Modelling results informed a microfabrication process of electroplating the 3D electrode structures on top of the existing flat subretinal prosthesis.Main results: Simulations demonstrate that despite the conductive sidewalls of the 3D electrodes being exposed to electrolyte, most of the charge flows via the high-capacitance sputtered Iridium Oxide film that caps the top of the 3D structures. The 24 m height of the electroplated honeycomb structures was optimised for integration with the inner nuclear layer cells in rat retina, while 35 m height of the pillars was optimized for penetrating the debris layer in human patients. Release from the wafer and implantation of the 3D arrays demonstrated that they are mechanically robust to withstand the associated forces. Histology demonstrated successful integration of the 3D structures with the rat retina in-vivo.Significance: Electroplated 3D honeycomb structures produce a vertically oriented electric field that offers low stimulation threshold, high spatial resolution and high contrast for the retinal implants with pixel sizes down to 20m in width. Pillar electrodes offer an alternative configuration for extending the stimulation past the debris layers. Electroplating of the 3D structures is compatible with the fabrication process of the flat photovoltaic arrays, thereby enabling much more efficient stimulation than in their original flat configuration.

  View details for DOI 10.1101/2023.11.09.566003

  View details for PubMedID 38014082

• Prosthetic Visual Acuity with the PRIMA System in Patients with Atrophic Age-related Macular Degeneration at 4 years follow-up. medRxiv : the preprint server for health sciences Muqit, M., Le Mer, Y., Olmos de Koo, L., Holz, F. G., Sahel, J. A., Palanker, D. 2023

  Abstract

  Objective: To assess the efficacy and safety of the PRIMA subretinal neurostimulation system 48-months post-implantation for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months post-implantation.Design: First-in-human clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.gov NCT03333954 ).Subjects: Five patients with GA, no foveal light perception and VA of logMAR 1.3 to 1.7 in their worse-seeing "study" eye.Methods: In patients implanted with a subretinal photovoltaic neurostimulation array containing 378 pixels of 100 mum in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 meter. The system's external components: augmented reality glasses and pocket computer, provide image processing capabilities, including zoom.Main Outcome Measures: VA using ETDRS charts with and without the system. Light sensitivity in the central visual field, as measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and optical coherence tomography up to 48-months post- implantation.Results: All five subjects met the primary endpoint of light perception elicited by the implant in the scotoma area. In one patient the implant was incorrectly inserted into the choroid. One subject died 18-months post-implantation due to study-unrelated reason. ETDRS VA results for the remaining three subjects are reported herein. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to mean logMAR 1.39, or Snellen 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (SE 5.1) 95% CI[13.4,49.9], p<0.0001. Natural peripheral visual function in the treated eye did not decline after surgery compared to the fellow eye (p=0.08) during the 48 months follow-up period.Conclusions: Subretinal implantation of PRIMA in subjects with GA suffering from profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48-months. Using prosthetic central vision through photovoltaic neurostimulation, patients reliably recognized letters and sequences of letters,and with zoom it provided a clinically meaningful improvement in VA of up to eight ETDRS lines.

  View details for DOI 10.1101/2023.11.12.23298227

  View details for PubMedID 38014146

• Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision. Proceedings of the National Academy of Sciences of the United States of America Bhuckory, M. B., Wang, B. Y., Chen, Z. C., Shin, A., Huang, T., Galambos, L., Vounotrypidis, E., Mathieson, K., Kamins, T., Palanker, D. 2023; 120 (42): e2307380120

  Abstract

  In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 μm and reaches the 27 μm limit of natural resolution in rats with 20 μm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.

  View details for DOI 10.1073/pnas.2307380120

  View details for PubMedID 37831740

• 3D electronic implants in subretinal space: long-term follow-up in rodents. bioRxiv : the preprint server for biology Bhuckory, M., Wang, B. Y., Chen, Z. C., Shin, A., Pham-Howard, D., Shah, S., Monkongpitukkul, N., Galambos, L., Kamins, T., Mathieson, K., Palanker, D. 2023

  Abstract

  Photovoltaic subretinal prosthesis (PRIMA) enables restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution limited by the 100 μm pixel size. Since decreasing the pixel size below 75 μm in the current bipolar geometry is impossible, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 9 months post-implantation in aged rats. With both flat and 3D implants, VEP amplitude decreased after the day of implantation by more than 3-fold, and gradually recovered over about 3 months. With 25 µm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the second-order neurons. Retinal thickness and full-field stimulation threshold with 40 µm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 µm-wide wells, and stimulation threshold increased over 5 months, before stabilizing at about 0.08 mW/mm2. Such threshold is significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

  View details for DOI 10.1101/2023.07.25.550561

  View details for PubMedID 37546971

  View details for PubMedCentralID PMC10402070

• The role of stimulation selectivity in visual acuity with subretinal prostheses Wang, B., Bhuckory, M., Chen, Z., Shin, A., Jensen, N., Galambos, L., Mathieson, K., Kamins, T., Werginz, P., Palanker, D. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2023

  View details for Web of Science ID 001053795605134

• Explantation of subretinal prostheses with planar and 3-D configurations Bhuckory, M., Shin, A., Wang, B., Galambos, L., Kamins, T., Palanker, D. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2023

  View details for Web of Science ID 001053795605136

• Optimal Photovoltaic Pixels for High-Resolution Subretinal Prosthesis Chen, Z., Wang, B., Goldstein, A., Palanker, D. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2023

  View details for Web of Science ID 001053795605138

• Electronic Retinal Prostheses. Cold Spring Harbor perspectives in medicine Palanker, D. 2023

  Abstract

  Retinal prostheses are a promising means for restoring sight to patients blinded by photoreceptor atrophy. They introduce visual information by electrical stimulation of the surviving inner retinal neurons. Subretinal implants target the graded-response secondary neurons, primarily the bipolar cells, which then transfer the information to the ganglion cells via the retinal neural network. Therefore, many features of natural retinal signal processing can be preserved in this approach if the inner retinal network is retained. Epiretinal implants stimulate primarily the ganglion cells, and hence should encode the visual information in spiking patterns, which, ideally, should match the target cell types. Currently, subretinal arrays are being developed primarily for restoration of central vision in patients impaired by age-related macular degeneration (AMD), while epiretinal implants-for patients blinded by retinitis pigmentosa, where the inner retina is less preserved. This review describes the concepts and technologies, preclinical characterization of prosthetic vision and clinical outcomes, and provides a glimpse into future developments.

  View details for DOI 10.1101/cshperspect.a041525

  View details for PubMedID 36781222

• Interferometric thermometry of ocular tissues for retinal laser therapy. Biomedical optics express Veysset, D., Zhuo, Y., Hattori, J., Buckhory, M., Palanker, D. 2023; 14 (1): 37-53

  Abstract

  Controlling the tissue temperature rise during retinal laser therapy is highly desirable for predictable and reproducible outcomes of the procedure, especially with non-damaging settings. In this work, we demonstrate a method for determining the optical absorption, the thermal conductivity, and the thermal expansion coefficients of RPE and choroid using phase-resolved optical coherence tomography (pOCT). These parameters are extracted from the measured changes in the optical path length (DeltaOPL) using an axisymmetric thermo-mechanical model. This allows the calculation of the temperature rise during hyperthermia, which was further validated by imaging the temperature-sensitive fluorescence at the same location. We demonstrate that, with a temperature uncertainty of ±0.9°C and a peak heating of about 17°C following a laser pulse of 20 ms, this methodology is expected to be safe and sufficiently precise for calibration of the non-damaging retinal laser therapy. The method is directly translatable to in-vivo studies, where we expect a similar precision.

  View details for DOI 10.1364/BOE.475705

  View details for PubMedID 36698667

• Electronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats. Nature communications Wang, B., Chen, Z. C., Bhuckory, M., Huang, T., Shin, A., Zuckerman, V., Ho, E., Rosenfeld, E., Galambos, L., Kamins, T., Mathieson, K., Palanker, D. 2022; 13 (1): 6627

  Abstract

  Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal crosstalk from the neighboring electrodes. Local return electrodes within each pixel limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 55mum. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated the computational modeling of the field confinement in such an optically-controlled circuit by in-vitro and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40mum pixels matches the pixel pitch, while with 20mum pixels, it reaches the 28mum limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.

  View details for DOI 10.1038/s41467-022-34353-y

  View details for PubMedID 36333326

• Photovoltaic implant simulator reveals resolution limits in subretinal prosthesis. Journal of neural engineering Chen, Z. C., Wang, B., Kochnev Goldstein, A., Butt, E., Mathieson, K., Palanker, D. 2022

  Abstract

  OBJECTIVE: PRIMA, the photovoltaic subretinal prosthesis, restores central vision in patients blinded by atrophic age-related macular degeneration (AMD), with a resolution closely matching the 100mum pixel size of the implant. Improvement in resolution requires smaller pixels, but the resultant electric field may not provide sufficient stimulation strength in the inner nuclear layer (INL) or may lead to excessive crosstalk between neighboring electrodes, resulting in low contrast stimulation patterns. We study the approaches to electric field shaping in the retina for prosthetic vision with higher resolution and improved contrast.APPROACH: We present a new computational framework, RPSim, that efficiently computes the electric field in the retina generated by a photovoltaic implant with thousands of electrodes. Leveraging the PRIMA clinical results as a benchmark, we use RPSim to predict the stimulus strength and contrast of the electric field in the retina with various pixel designs and stimulation patterns.MAIN RESULTS: We demonstrate that by utilizing monopolar pixels as both anodes and cathodes to suppress crosstalk, most patients may achieve resolution no worse than 48mum. Closer proximity between the electrodes and the INL, achieved with pillar electrodes, enhances the stimulus strength and contrast and may enable 24mum resolution with 20mum pixels, at least in some patients.SIGNIFICANCE: A resolution of 24mum on the retina corresponds to a visual acuity of 20/100, which is over 4 times higher than the current best prosthetic acuity of 20/438, promising a significant improvement of central vision for many AMD patients.

  View details for DOI 10.1088/1741-2552/ac8ed8

  View details for PubMedID 36055219

• Pixel size limit of the PRIMA implants: from humans to rodents and back. Journal of neural engineering Wang, B. Y., Chen, Z. C., Bhuckory, M., Kochnev Goldstein, A., Palanker, D. 2022

  Abstract

  Retinal prostheses aim at restoring sight in patients with retinal degeneration by electrically stimulating the inner retinal neurons. Clinical trials with patients blinded by atrophic Age-related Macular Degeneration (AMD) using the PRIMA subretinal implant, a 2x2 mm array of 100µm-wide photovoltaic pixels, have demonstrated a prosthetic visual acuity closely matching the pixel size. Further improvement in resolution requires smaller pixels, which, with the current bipolar design, necessitates more intense stimulation.We examine the lower limit of the pixel size for PRIMA implants by modeling the electric field, leveraging the clinical benchmarks, and using animal data to assess the stimulation strength and contrast of various patterns. Visually evoked potentials measured in RCS rats with photovoltaic implants composed of 100µm and 75µm pixels were compared to clinical thresholds with 100µm pixels. Electrical stimulation model calibrated by the clinical and rodent data was used to predict the performance of the implant with smaller pixels.PRIMA implants with 75µm bipolar pixels under the maximum safe near-infrared (880nm) illumination of 8mW/mm2 with 30% duty cycle (10ms pulses at 30Hz) should provide a similar perceptual brightness as with 100µm pixels under 3mW/mm2 irradiance, used in the current clinical trials. Contrast of the Landolt C pattern scaled down to 75µm pixels is also similar under such illumination to that with 100µm pixels, increasing the maximum acuity from 20/420 to 20/315.Computational modelling defines the minimum pixel size of the PRIMA implants as 75µm. Increasing the implant width from 2 to 3 mm and reducing the pixel size from 100 to 75µm will nearly quadrupole the number of pixels, which should be very beneficial for patients. Smaller pixels of the same bipolar flat geometry would require excessively intense illumination, and therefore a different pixel design should be considered for further improvement in resolution.

  View details for DOI 10.1088/1741-2552/ac8e31

  View details for PubMedID 36044878

• Interferometric imaging of thermal expansion for temperature control in retinal laser therapy BIOMEDICAL OPTICS EXPRESS Veysset, D., Ling, T., Zhuo, Y., Pandiyan, V., Sabesan, R., Palanker, D. 2022; 13 (2): 728-743

  View details for DOI 10.1364/BOE.448803

  View details for Web of Science ID 000750862400003

• A Smartphone-Based Near-Vision Testing System: Design, Accuracy, and Reproducibility Compared With Standard Clinical Measures OPHTHALMIC SURGERY LASERS & IMAGING RETINA Kim, D., Webel, A. D., Blumenkranz, M. S., Kim, Y., Yang, J., Yu, S., Kwak, H., Palanker, D., Toy, B., Myung, D. 2022; 53 (2): 79-84

  Abstract

  Ophthalmologic telemedicine has emerged during the COVID-19 pandemic. The objective of this study is to assess the accuracy and reproducibility of a smartphone-based home vision monitoring system (Sightbook) and to compare it with existing clinical standards.Near Snellen visual acuity (VA) was measured with Sightbook and compared with conventional measurements for distance and near VA at an academic medical center ophthalmology clinic in 200 patients with a variety of different specified preexisting ocular conditions. Measurements of contrast sensitivity were also compared by using an existing commercially available chart system in 15 normal patients and 15 patients with age-related macular degeneration.Sightbook VA tests were reproducible (SD = ±0.054 logMAR), and correlation with standard VA methods was significant (R > 0.87 and P < .001). Sightbook contrast sensitivity measurements were reproducible (SD/mean ratio, 0.02 to 0.04), yielding results similar to those of standard tests (R2 > 0.87 and P < .001).Smartphone-based VA and contrast sensitivity are highly correlated with standard charts and may be useful in augmenting limited inoffice care. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:79-84.].

  View details for DOI 10.3928/23258160-20220121-05

  View details for Web of Science ID 000768759200002

  View details for PubMedID 35148218

• Interferometric imaging of thermal expansion for temperature control in retinal laser therapy. Biomedical optics express Veysset, D., Ling, T., Zhuo, Y., Pandiyan, V. P., Sabesan, R., Palanker, D. 2022; 13 (2): 728-743

  Abstract

  Precise control of the temperature rise is a prerequisite for proper photothermal therapy. In retinal laser therapy, the heat deposition is primarily governed by the melanin concentration, which can significantly vary across the retina and from patient to patient. In this work, we present a method for determining the optical and thermal properties of layered materials, directly applicable to the retina, using low-energy laser heating and phase-resolved optical coherence tomography (pOCT). The method is demonstrated on a polymer-based tissue phantom heated with a laser pulse focused onto an absorbing layer buried below the phantom's surface. Using a line-scan spectral-domain pOCT, optical path length changes induced by the thermal expansion were extracted from sequential B-scans. The material properties were then determined by matching the optical path length changes to a thermo-mechanical model developed for fast computation. This method determined the absorption coefficient with a precision of 2.5% and the temperature rise with a precision of about 0.2°C from a single laser exposure, while the peak did not exceed 8°C during 1 ms pulse, which is well within the tissue safety range and significantly more precise than other methods.

  View details for DOI 10.1364/BOE.448803

  View details for PubMedID 35284191

  View details for PubMedCentralID PMC8884207

• Simultaneous perception of prosthetic and natural vision in AMD patients NATURE COMMUNICATIONS Palanker, D., Le Mer, Y., Mohand-Said, S., Sahel, J. A. 2022; 13 (1): 513

  Abstract

  Loss of photoreceptors in atrophic age-related macular degeneration (AMD) results in severe visual impairment. Since the low-resolution peripheral vision is retained in such conditions, restoration of central vision should not jeopardize the surrounding healthy retina and allow for simultaneous use of the natural and prosthetic sight. This interim report, prespecified in the study protocol, presents the first clinical results with a photovoltaic substitute of the photoreceptors providing simultaneous use of the central prosthetic and peripheral natural vision in atrophic AMD. In this open-label single group feasibility trial (NCT03333954, recruitment completed), five patients with geographic atrophy have been implanted with a wireless 2 x 2 mm-wide 30 µm-thick device, having 378 pixels of 100 µm in size. All 5 patients achieved the primary outcome of the study by demonstrating the prosthetic visual perception in the former scotoma. The four patients with a subretinal placement of the chip demonstrated the secondary outcome: Landolt acuity of 1.17 ± 0.13 pixels, corresponding to the Snellen range of 20/460-20/565. With electronic magnification of up to a factor of 8, patients demonstrated prosthetic acuity in the range of 20/63-20/98. Under room lighting conditions, patients could simultaneously use prosthetic central vision and their remaining peripheral vision in the implanted eye and in the fellow eye.

  View details for DOI 10.1038/s41467-022-28125-x

  View details for Web of Science ID 000747407100007

  View details for PubMedID 35082313

  View details for PubMedCentralID PMC8792035

• Questions about the role of P3HT nanoparticles in retinal stimulation. Nature nanotechnology Palanker, D., Glowacki, E. D., Ghezzi, D. 2021

  View details for DOI 10.1038/s41565-021-01044-6

  View details for PubMedID 34887532

• Simultaneous Perception of Prosthetic and Natural Vision in Patients with Geographic Atrophy Palanker, D. V., Le Mer, Y., Hornig, R., Buc, G., Mohand-Said, S., Sahel, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021

  View details for Web of Science ID 000690761600795

• Dynamic Transcriptional and Translational Profiling of Reactive Muller Glia Following Retinal Injury Ashouri, M., Bhuckory, M., Nahmou, M., Hay, S., Knasel, C. M., Cameron, E. G., Wang, S., Palanker, D. V., Goldberg, J. L. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021

  View details for Web of Science ID 000690761100769

• Optically configurable confinement of electric field with photovoltaic retinal prosthesis Chen, Z., Wang, B., Bhuckory, M., Huang, T., Galambos, L., Mathieson, K., Kamins, T., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021

  View details for Web of Science ID 000690761600406

• Subretinal monopolar photovoltaic arrays provide pixel size-independent stimulation threshold and 40 mu m resolution under spatiotemporal modulation Wang, B., Bhuckory, M., Chen, Z., Huang, T., Galambos, L., Mathieson, K., Kamins, T., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021

  View details for Web of Science ID 000690761600405

• Retinal integration with a subretinal honeycomb-shaped prosthesis Bhuckory, M., Chen, Z., Wang, B., Huang, T., Galambos, L., Shin, A., Kamins, T., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021

  View details for Web of Science ID 000690761600452

• Vertical-junction photodiodes for smaller pixels in retinal prostheses. Journal of neural engineering Huang, T. W., Kamins, T. n., Chen, Z. C., Wang, B. Y., Bhuckory, M. n., Galambos, L. n., Ho, E. n., Ling, T. n., Afshar, S. n., Shin, A. n., Zuckerman, V. n., Harris, J. S., Mathieson, K. n., Palanker, D. n. 2021

  Abstract

  Objective.To restore central vision in patients with atrophic age-related macular degeneration, we replace the lost photoreceptors with photovoltaic pixels, which convert light into current and stimulate the secondary retinal neurons. Clinical trials demonstrated prosthetic acuity closely matching the sampling limit of the 100 μm pixels, and hence smaller pixels are required for improving visual acuity. However, with smaller flat bipolar pixels, the electric field penetration depth and the photodiode responsivity significantly decrease, making the device inefficient. Smaller pixels may be enabled by (1) increasing the diode responsivity using vertical p-n junctions and (2) directing the electric field in tissue vertically. Here, we demonstrate such novel photodiodes and test the retinal stimulation in a vertical electric field.Approach.Arrays of silicon photodiodes of 55, 40, 30, and 20 μm in width, with vertical p-n junctions, were fabricated. The electric field in the retina was directed vertically using a common return electrode at the edge of the devices. Optical and electronic performance of the diodes was characterized in-vitro, and retinal stimulation threshold measured by recording the visually evoked potentials (VEPs) in rats with retinal degeneration.Main results.The photodiodes exhibited sufficiently low dark current (<10 pA) and responsivity at 880 nm wavelength as high as 0.51 A/W, with 85% internal quantum efficiency, independent of pixel size. Field mapping in saline demonstrated uniformity of the pixel performance in the array. The full-field stimulation threshold was as low as 0.057±0.029 mW/mm2with 10 ms pulses, independent of pixel size.Significance.Photodiodes with vertical p-n junctions demonstrated excellent charge collection efficiency independent of pixel size, down to 20 μm. Vertically-oriented electric field provides a stimulation threshold that is independent of pixel size. These results are the first steps in validation of scaling down the photovoltaic pixels for subretinal stimulation.

  View details for DOI 10.1088/1741-2552/abe6b8

  View details for PubMedID 33592588

• Real-Time Optimization of the Current Steering for Visual Prosthesis Chen, Z., Wang, B., Palanker, D., IEEE IEEE. 2021: 592-596

  View details for DOI 10.1109/NER49283.2021.9441400

  View details for Web of Science ID 000681358200118

• Reply to Farrell: Experimental evidence is the ultimate judge for model assumptions. Proceedings of the National Academy of Sciences of the United States of America Ling, T., Boyle, K. C., Palanker, D. 2020

  View details for DOI 10.1073/pnas.2017702117

  View details for PubMedID 33051290

• On optimal coupling of the "electronic photoreceptors" into the degenerate retina. Journal of neural engineering Werginz, P., Wang, B., Chen, Z. C., Palanker, D. 2020

  Abstract

  ObjectiveTo restore sight in atrophic age-related macular degeneration, the lost photoreceptors can be replaced with electronic implants, which replicate their two major functions: (1) converting light into an electric signal, and (2) transferring visual information to the secondary neurons in the retinal neural network - the bipolar cells (BC). We study the selectivity of BC activation by subretinal implants and dynamics of their response to pulsatile waveforms in order to optimize the electrical stimulation scheme such that retinal signal processing with "electronic photoreceptors" remains as close to natural as possible.ApproachA multicompartmental model of a BC was implemented to simulate responses of the voltage-gated calcium channels and subsequent synaptic vesicle release under continuous and pulsatile stimuli. We compared the predicted response under various frequencies, pulse durations, and alternating gratings to the corresponding experimental measurements. In addition, electric field was computed for various electrode configurations in a 3-d finite element model to assess the stimulation selectivity via spatial confinement of the field.Main ResultsThe modeled BC-mediated retinal responses were, in general, in good agreement with previously published experimental results. Kinetics of the calcium pumps and of the neurotransmitter release in ribbon synapses, which underpin the BC's temporal filtering and rectifying functions, allow mimicking the natural BC response with high frequency pulsatile stimulation, thereby preserving features of the retinal signal processing, such as flicker fusion, adaptation to static stimuli and non-linear summation of subunits in receptive field. Selectivity of the BC stimulation while avoiding direct activation of the downstream neurons (amacrine and ganglion cells - RGCs) is improved with local return electrodes.SignificanceIf the retinal neural network is preserved to a large extent in age-related macular degeneration, selective stimulation of BCs with proper spatial and temporal modulation of the extracellular electric field may retain many features of the natural retinal signal processing and hence allow highly functional restoration of sight.

  View details for DOI 10.1088/1741-2552/aba0d2

  View details for PubMedID 32613948

• Photovoltaic Restoration of Central Vision in Atrophic Age-Related Macular Degeneration. Ophthalmology Palanker, D., Le Mer, Y., Mohand-Said, S., Muqit, M., Sahel, J. A. 2020

  Abstract

  PURPOSE: Loss of photoreceptors in atrophic age-related macular degeneration results in severe visual impairment, although some peripheral vision is retained. To restore central vision without compromising the residual peripheral field, we developed a wireless photovoltaic retinal implant (PRIMA; Pixium Vision, Paris, France) in which pixels convert images projected from video glasses using near-infrared light into electric current to stimulate the nearby inner retinal neurons.DESIGN: We carried out a first-in-human clinical trial to test the safety and efficacy of the prosthesis in patients with geographic atrophy (ClinicalTrials.gov identifier, NCT03333954).PARTICIPANTS: Five patients with geographic atrophy zone of at least 3 optic disc diameters, no foveal light perception, and best-corrected visual acuity of 20/400 to 20/1000 in the worse-seeing study eye.METHODS: The 2-mm wide, 30-mum thick chip, containing 378 pixels (each 100 mum in diameter), was implanted subretinally in the area of atrophy (absolute scotoma).MAIN OUTCOME MEASURES: Anatomic outcomes were assessed with fundus photography and OCT for up to 12 months of follow-up. Prosthetic vision was assessed by mapping light perception, bar orientation, letter recognition, and Landolt C acuity.RESULTS: In all patients, the prosthesis was implanted successfully under the macula, although in 2 patients, it was implanted in unintended locations: within the choroid and off center by 2 mm. All 5 patients could perceive white-yellow prosthetic visual patterns with adjustable brightness in the previous scotomata. The 3 with optimal placement of the implant demonstrated prosthetic acuity of 20/460 to 20/550, and the patient with the off-center implant demonstrated 20/800 acuity. Residual natural acuity did not decrease after implantation in any patient.CONCLUSIONS: Implantation of the PRIMA did not decrease the residual natural acuity, and it restored visual sensitivity in the former scotoma in each of the 5 patients. In 3 patients with the proper placement of the chip, prosthetic visual acuity was only 10% to 30% less than the level expected from the pixel pitch (20/420). Therefore, the use of optical or electronic magnification in the glasses as well as smaller pixels in future implants may improve visual acuity even further.

  View details for DOI 10.1016/j.ophtha.2020.02.024

  View details for PubMedID 32249038

• Current Distribution on Capacitive Electrode-Electrolyte Interfaces PHYSICAL REVIEW APPLIED Chen, Z., Ryzhik, L., Palanker, D. 2020; 13 (1)

  View details for DOI 10.1103/PhysRevApplied.13.014004

  View details for Web of Science ID 000505497800002

• Local photoreceptor degeneration causes local pathophysiological remodeling of retinal neurons. JCI insight Denlinger, B. n., Helft, Z. n., Telias, M. n., Lorach, H. n., Palanker, D. n., Kramer, R. H. 2020; 5 (2)

  Abstract

  Vision loss in age-related macular degeneration (AMD) stems from disruption of photoreceptor cells in the macula, the central retinal area required for high-acuity vision. Mice and rats have no macula, but surgical insertion of a subretinal implant can induce localized photoreceptor degeneration due to chronic separation from retinal pigment epithelium, simulating a key aspect of AMD. We find that the implant-induced loss of photoreceptors in rat retina leads to local changes in the physiology of downstream retinal ganglion cells (RGCs), similar to changes in RGCs of rodent models of retinitis pigmentosa (RP), an inherited disease causing retina-wide photoreceptor degeneration. The local implant-induced changes in RGCs include enhanced intrinsic excitability leading to accelerated spontaneous firing, increased membrane permeability to fluorescent dyes, and enhanced photosensitization by azobenzene photoswitches. The local physiological changes are correlated with an increase in retinoic acid receptor-induced (RAR-induced) gene transcription, the key process underlying retinal remodeling in mouse models of RP. Hence the loss of photoreceptors, whether by local physical perturbation or by inherited mutation, leads to a stereotypical set of pathophysiological consequences in RGCs. These findings implicate RAR as a possible common therapeutic target for reversing the signal-corrupting effects of retinal remodeling in both RP and AMD.

  View details for DOI 10.1172/jci.insight.132114

  View details for PubMedID 31846440

• Sensory Particles with Optical Telemetry Ganesan, K., Flores, T. A., Le, B. Q., Muratore, D. G., Patel, N., Mitra, S., Murmann, B., Palanker, D., IEEE IEEE. 2020

  View details for Web of Science ID 000706854700088

• The optoretinogram reveals the primary steps of phototransduction in the living human eye. Science advances Pandiyan, V. P., Maloney-Bertelli, A. n., Kuchenbecker, J. A., Boyle, K. C., Ling, T. n., Chen, Z. C., Park, B. H., Roorda, A. n., Palanker, D. n., Sabesan, R. n. 2020; 6 (37)

  Abstract

  Photoreceptors initiate vision by converting photons to electrical activity. The onset of the phototransduction cascade is marked by the isomerization of photopigments upon light capture. We revealed that the onset of phototransduction is accompanied by a rapid (<5 ms), nanometer-scale electromechanical deformation in individual human cone photoreceptors. Characterizing this biophysical phenomenon associated with phototransduction in vivo was enabled by high-speed phase-resolved optical coherence tomography in a line-field configuration that allowed sufficient spatiotemporal resolution to visualize the nanometer/millisecond-scale light-induced shape change in photoreceptors. The deformation was explained as the optical manifestation of electrical activity, caused due to rapid charge displacement following isomerization, resulting in changes of electrical potential and surface tension within the photoreceptor disc membranes. These all-optical recordings of light-induced activity in the human retina constitute an optoretinogram and hold remarkable potential to reveal the biophysical correlates of neural activity in health and disease.

  View details for DOI 10.1126/sciadv.abc1124

  View details for PubMedID 32917686

• High-speed interferometric imaging reveals dynamics of neuronal deformation during the action potential. Proceedings of the National Academy of Sciences of the United States of America Ling, T. n., Boyle, K. C., Zuckerman, V. n., Flores, T. n., Ramakrishnan, C. n., Deisseroth, K. n., Palanker, D. n. 2020

  Abstract

  Neurons undergo nanometer-scale deformations during action potentials, and the underlying mechanism has been actively debated for decades. Previous observations were limited to a single spot or the cell boundary, while movement across the entire neuron during the action potential remained unclear. Here we report full-field imaging of cellular deformations accompanying the action potential in mammalian neuron somas (-1.8 to 1.4 nm) and neurites (-0.7 to 0.9 nm), using high-speed quantitative phase imaging with a temporal resolution of 0.1 ms and an optical path length sensitivity of <4 pm per pixel. The spike-triggered average, synchronized to electrical recording, demonstrates that the time course of the optical phase changes closely matches the dynamics of the electrical signal. Utilizing the spatial and temporal correlations of the phase signals across the cell, we enhance the detection and segmentation of spiking cells compared to the shot-noise-limited performance of single pixels. Using three-dimensional (3D) cellular morphology extracted via confocal microscopy, we demonstrate that the voltage-dependent changes in the membrane tension induced by ionic repulsion can explain the magnitude, time course, and spatial features of the phase imaging. Our full-field observations of the spike-induced deformations shed light upon the electromechanical coupling mechanism in electrogenic cells and open the door to noninvasive label-free imaging of neural signaling.

  View details for DOI 10.1073/pnas.1920039117

  View details for PubMedID 32341158

• Decoding network-mediated retinal response to electrical stimulation: implications for fidelity of prosthetic vision. Journal of neural engineering Ho, E. n., Shmakov, A. n., Palanker, D. n. 2020

  Abstract

  Patients with photovoltaic subretinal implant PRIMA demonstrated letter acuity ~0.1 logMAR worse than sampling limit for 100μm pixels (1.3 logMAR) and performed slower than healthy subjects tested with equivalently pixelated images. To explore the underlying differences between natural and prosthetic vision, we compare the fidelity of retinal response to visual and subretinal electrical stimulation through single-cell modeling and ensemble decoding.Responses of retinal ganglion cells (RGC) to optical or electrical white noise stimulation in healthy and degenerate rat retinas were recorded via MEA. Each RGC was fit with linear-nonlinear (LN) and convolutional neural network (CNN) models. To characterize RGC noise, we compared statistics of spike-triggered averages (STA) in RGCs responding to electrical or visual stimulation of healthy and degenerate retinas. At the population level, we constructed a linear decoder to determine the accuracy of the ensemble of RGCs on N-way discrimination tasks.Although computational models can match natural visual responses well (correlation ~0.6), they fit significantly worse to spike timings elicited by electrical stimulation of the healthy retina (correlation ~0.15). In the degenerate retina, response to electrical stimulation is equally bad. The signal-to-noise ratio of electrical STAs in degenerate retinas matched that of the natural responses when 78±6.5% of the spikes were replaced with random timing. However, the noise in RGC responses contributed minimally to errors in ensemble decoding. The determining factor in accuracy of decoding was the number of responding cells. To compensate for fewer responding cells under electrical stimulation than in natural vision, more presentations of the same stimulus are required to deliver sufficient information for image decoding.Slower-than-natural pattern identification by patients with the PRIMA implant may be explained by the lower number of electrically activated cells than in natural vision, which is compensated by a larger number of the stimulus presentations.

  View details for DOI 10.1088/1741-2552/abc535

  View details for PubMedID 33108781

• Harmonic-balance circuit analysis for electro-neural interfaces. Journal of neural engineering Chen, Z. C., Wang, B. Y., Palanker, D. n. 2020

  Abstract

  Objective. Avoidance of the adverse electrochemical reactions at the electrode-electrolyte interface defines the voltage safety window and limits the charge injection capacity (CIC) of an electrode material. For an electrode that is not ideally capacitive, the CIC depends on the waveform of the stimulus. We study the modeling of the charge injection dynamics to optimize the waveforms for efficient neural stimulation within the electrochemical safety limits.Approach. The charge injection dynamics at the electrode-electrolyte interface is typically characterized by the electrochemical impedance spectrum, and is often approximated by discrete-element circuit models. We compare the modeling of the complete circuit, including a non-linear driver such as a photodiode, based on the harmonic-balance (HB) analysis with the analysis based on various discrete element approximations. To validate the modeling results, we performed experiments with iridium-oxide electrodes driven by a current source with diodes in parallel, which mimics a photovoltaic circuit.Main results. Application of HB analysis based on a full impedance spectrum eliminates the complication of finding the discrete-element circuit model in traditional approaches. HB-based results agree with the experimental data better than the discrete-element circuit. HB technique can be applied not only to demonstrate the circuit response to periodic stimulation, but also to describe the initial transient behavior when a burst waveform is applied.Significance. HB-based circuit analysis accurately describes the dynamics of electrode-electrolyte interfaces and driving circuits for all pulsing schemes. This allows optimizing the stimulus waveform to maximize the CIC, based on the impedance spectrum alone.

  View details for DOI 10.1088/1741-2552/ab89fd

  View details for PubMedID 32299074

• FUNCTIONAL AND STRUCTURAL EFFECTS OF NONDAMAGING RETINAL LASER THERAPY FOR MACULAR TELANGIECTASIA TYPE 2: A Randomized Sham-Controlled Clinical Trial. Retina (Philadelphia, Pa.) Lavinsky, D. n., Silva, M. O., Chaves, A. E., Schneider, W. F., Lavinsky, F. n., Palanker, D. n. 2020

  Abstract

  Macular telangiectasia (MacTel) Type 2 is a progressing neurovascular disease of the macula, currently lacking effective treatment. This study assessed the effect of nondamaging retinal laser therapy (NRT) compared with sham.Twelve MacTel patients were enrolled in this double-masked, controlled, randomized clinical trial. For the nine patients with both eyes eligible, one eye was randomized to NRT or sham and the other received alternate treatment. For three patients with only one eye eligible, that eye was randomly assigned either NRT or sham. Ellipsoid zone disruption, best-corrected visual acuity, and macular automated perimetry at 12 months served as structural and functional measures.Eleven eyes were randomized to sham and 10 to NRT. Baseline best-corrected visual acuity was 66 letters (20/50) for sham and 72 letters (20/40) for NRT (P = 0.245). Ellipsoid zone disruption area was 298 µm in sham and 368 µm in NRT (P = 0.391). At 12 months, ellipsoid zone disruption increased by 24% in sham and decreased by 34% in NRT (P < 0.001). Best-corrected visual acuity measures remained stable during follow-up compared with baseline. At 1 year, the mean macular sensitivity was 28 dB in the NRT group, compared with 26 dB in sham.Nondamaging retinal laser therapy was safe and well tolerated in patients with MacTel and resulted in structural and functional improvements, which could represent a protective effect of laser-induced hyperthermia. Longer follow-up and larger number of patients should help corroborate these effects.

  View details for DOI 10.1097/IAE.0000000000002882

  View details for PubMedID 33370517

• Cortical Interactions between Prosthetic and Natural Vision. Current biology : CB Arens-Arad, T., Farah, N., Lender, R., Moshkovitz, A., Flores, T., Palanker, D., Mandel, Y. 2019

  Abstract

  Outer retinal degenerative diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), are among the leading causes of incurable blindness in the Western world [1]. Retinal prostheses have been shown to restore some useful vision by electrically stimulating the remaining retinal neurons [2]. In contrast to inherited retinal degenerative diseases (e.g., RP), typically leading to a complete loss of the visual field, in AMD patients the disease is localized to the macula, leaving the peripheral vision intact. Implanting a retinal prosthesis in the central macula in AMD patients [3, 4] leads to an intriguing situation where the patient's central retina is stimulated electrically, whereas the peripheral healthy retina responds to natural light stimulation. An important question is whether the visual cortex responds to these two concurrent stimuli similarly to the interaction between two adjacent natural light stimuli projected onto healthy retina. Here, we investigated the cortical interactions between prosthetic and natural vision based on visually evoked potentials (VEPs) recorded in rats implanted with photovoltaic subretinal implants. Using this model, where prosthetic and natural vision information are combined in the visual cortex, we observed striking similarities in the interactions of natural and prosthetic vision, including similar effect of background illumination, linear summation of non-patterned stimuli, and lateral inhibition with spatial patterns [5], which increased with target contrast. These results support the idea of combined prosthetic and natural vision in restoration of sight for AMD patients.

  View details for DOI 10.1016/j.cub.2019.11.028

  View details for PubMedID 31883811

• Performance of complex visual tasks using simulated prosthetic vision via augmented-reality glasses. Journal of vision Ho, E., Boffa, J., Palanker, D. 2019; 19 (13): 22

  Abstract

  Photovoltaic subretinal prosthesis is designed for restoration of central vision in patients with age-related macular degeneration (AMD). We investigated the utility of prosthetic central vision for complex visual tasks using augmented-reality (AR) glasses simulating reduced acuity, contrast, and visual field. AR glasses with blocked central 20° of visual field included an integrated video camera and software which adjusts the image quality according to three user-defined parameters: resolution, corresponding to the equivalent pixel size of an implant; field of view, corresponding to the implant size; and number of grayscale levels. The real-time processed video was streamed on a screen in front of the right eye. Nineteen healthy participants were recruited to complete visual tasks including vision charts, sentence reading, and face recognition. With vision charts, letter acuity exceeded the pixel-sampling limit by 0.2 logMAR. Reading speed decreased with increasing pixel size and with reduced field of view (7°-12°). In the face recognition task (four-way forced choice, 5° angular size) participants identified faces at >75% accuracy, even with 100 mum pixels and only two grayscale levels. With 60 mum pixels and eight grayscale levels, the accuracy exceeded 97%. Subjects with simulated prosthetic vision performed slightly better than the sampling limit on the letter acuity tasks, and were highly accurate at recognizing faces, even with 100 mum/pixel resolution. These results indicate feasibility of reading and face recognition using prosthetic central vision even with 100 mum pixels, and performance improves further with smaller pixels.

  View details for DOI 10.1167/19.13.22

  View details for PubMedID 31770773

• Chronic Electrical Stimulation for Tear Secretion: Lacrimal vs. anterior ethmoid nerve. The ocular surface Kossler, A. L., Brinton, M., Patel, Z. M., Dalal, R., Ta, C. N., Palanker, D. 2019

  Abstract

  PURPOSE: To evaluate and compare the effect of lacrimal nerve stimulation (LNS) and anterior ethmoid nerve stimulation (AENS) on aqueous tear secretion, and tissue condition following chronic implantation.METHODS: A neurostimulator was implanted in rabbits adjacent to the (1) lacrimal nerve, and (2) anterior ethmoid nerve. Tear volume was measured with Schirmer test strips after stimulation (2.3-2.8 mA pulses at 30 Hz for 3-5 min), and scores were compared to sham stimulation. Lacrimal gland and nasal septal tissue were evaluated histologically after chronic stimulation (2 weeks-7 months).RESULTS: LNS increases tear volume by 32% above sham (p < 0.05, n = 5), compared with 133% for AENS (p ≤ 0.01, n = 6). AENS also significantly increases tear secretion in the fellow, non-stimulated eye (p ≤ 0.01, n = 6), as expected from the tearing reflex pathway. Histologically, chronic LNS is well tolerated by surrounding tissues while chronic AENS results in nasal mucosal fibrosis and implant extrusion within 3 weeks.CONCLUSIONS: AENS is significantly more effective than LNS at enhancing aqueous tear secretion, including the fellow eye. The lacrimal implant is well tolerated, while the nasal implant requires further design optimization to improve tolerability.

  View details for DOI 10.1016/j.jtos.2019.08.012

  View details for PubMedID 31476515

• Characteristics of prosthetic vision in rats with subretinal flat and pillar electrode arrays. Journal of neural engineering Ho, E., Lei, X., Flores, T. A., Lorach, H., Huang, T. W., Galambos, L., Kamins, T., Harris, J. S., Mathieson, K., Palanker, D. 2019

  Abstract

  OBJECTIVE: Retinal prostheses aim to restore sight by electrically stimulating the surviving retinal neurons. In clinical trials of the current retinal implants, prosthetic visual acuity does not exceed 20/550. However, to provide meaningful restoration of central vision in patients blinded by age-related macular degeneration (AMD), prosthetic acuity should be at least 20/200, necessitating a pixel pitch of about 50 m or lower. With such small pixels, stimulation thresholds are high due to limited penetration of electric field into tissue. Here, we address this challenge with our latest photovoltaic arrays and evaluate their performance in-vivo. &#13; Approach. We fabricated photovoltaic arrays with 55 and 40 m pixels (a) in flat geometry, and (b) with active electrodes on 10 m tall pillars. The arrays were implanted subretinally into rats with degenerate retina. Stimulation thresholds and grating acuity were evaluated using measurements of the visually evoked potentials (VEP). &#13; Main Results. With 55 mum pixels, we measured grating acuity of 48±11 mum, which matches the linear pixel pitch of the hexagonal array. This geometrically corresponds to a visual acuity of 20/192 in a human eye, matching the threshold of legal blindness in the US (20/200). With pillar electrodes, the irradiance threshold was nearly halved, and duration threshold reduced by more than 3-fold, compared to flat pixels. With 40 mum pixels, VEP was too low for reliable measurements of the grating acuity, even with pillar electrodes. &#13; Significance. While being helpful for treating a complete loss of sight, current prosthetic technologies are insufficient for addressing the leading cause of untreatable visual impairment - AMD. Subretinal photovoltaic arrays may provide sufficient visual acuity for restoration of central vision in patients blinded by AMD.&#13.

  View details for DOI 10.1088/1741-2552/ab34b3

  View details for PubMedID 31341094

• Retinal Laser Therapy Preserves Photoreceptors in a Rodent Model of MERTK-Related Retinitis Pigmentosa. Translational vision science & technology Kang, S., Lorach, H., Bhuckory, M. B., Quan, Y., Dalal, R., Palanker, D. 2019; 8 (4): 19

  Abstract

  Purpose: We investigated the effects of various retinal laser therapies on preservation of the photoreceptors in an animal model of Mer tyrosine kinase receptor (MERTK)-related retinitis pigmentosa (RP). These modalities included photocoagulation with various pattern densities, selective RPE therapy (SRT), and nondamaging retinal therapy (NRT).Methods: Laser treatments were performed on right eyes of RCS rats, using one of three laser modalities. For photocoagulation, six pattern densities (spot spacings of 0.5, 1, 1.5, 3, 4, and 5 spot diameters) were delivered in 19-day-old animals, prior to the onset of photoreceptor degeneration, to determine the optimal treatment density for the best preservation of photoreceptors. The left eye was used as control. Rats were monitored for 6 months after treatment using electroretinography, optical coherence tomography, and histology.Results: Photocoagulation resulted in long-term preservation of photoreceptors, manifested morphologically and functionally, with the extent of the benefit dependent on the laser pattern density. Eyes treated with a 1.5 spot size spacing showed the best morphologic and functional preservation during the 6-month follow-up. SRT-treated eyes exhibited short-term morphologic preservation, but no functional benefit. NRT-treated eyes did not show any observable preservation benefit from the treatment.Conclusions: In a rodent model of MERTK-related RP, pattern photocoagulation of about 15% of the photoreceptors (1.5 spot diameter spacing) provides long-term preservation of photoreceptors in the treatment area.Translational Relevance: Availability of retinal lasers in ophthalmic practice enables rapid translation of our study to clinical testing and may help preserve the sight in patients with photoreceptor degeneration.

  View details for DOI 10.1167/tvst.8.4.19

  View details for PubMedID 31402999

• Restoration of Sight in Geographic Atrophy using a Photovoltaic Subretinal Prosthesis Palanker, D. V., Le Mer, Y., Hornig, R., Buc, G., Deterre, M., Bismuth, V., Sahel, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628102143

• Effect of Proliferative Diabetic Retinopathy on Development of Neovascular AMD: a Big Data Analysis Brodie, F., Stell, L., Bhuckory, M., Zuckerman, V., Vounotrypidis, E., Sanislo, S., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628100060

• Optoretinogram: stimulus-induced optical changes in photoreceptors observed with phase-resolved line-scan OCT Pandiyan, V., Bertelli, A., Kuchenbecker, J. A., Park, B., Palanker, D. V., Roorda, A., Sabesan, R. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628103201

• Photovoltaic restoration of sight in age-related macular degeneration Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628100003

• Pillar electrodes reduce in-vivo stimulation thresholds for subretinal prosthesis Ho, E., Huang, T., Lei, X., Flores, T., Lorach, H., Kamins, T., Galambos, L., Mathieson, K., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800703314

• Honeycomb-shaped subretinal prosthesis enables cellular-scale pixels Flores, T., Huang, T., Bhuckory, M., Lorach, H., Chen, Z., Dalal, R., Lei, X., Galambos, L., Kamins, T., Mathieson, K., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800703309

• Cortical response to combined prosthetic and visible stimuli exhibits similarities to natural visual processing Mandel, Y., Arens-Arad, T., Farah, N., Moshkovitz, A., Lender, R., Flores, T., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800703317

• Titration for selective RPE therapy using a continuous line scanning laser Bhuckory, M., Flores, T., Shao, X., Dalal, R., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800700240

• Non-Damaging Laser Therapy (NRT) for Macular Telangiectasia Type 2: Randomized Clinical Trial Lavinsky, D., Chaves, A., Schneider, W., Oliveira, M., Lavinsky, F., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800700244

• STEM CELL THERAPIES, GENE-BASED THERAPIES, OPTOGENETICS, AND RETINAL PROSTHETICS: CURRENT STATE AND IMPLICATIONS FOR THE FUTURE RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Wood, E. H., Tang, P. H., De la Huerta, I., Korot, E., Muscat, S., Palanker, D. A., Williams, G. A. 2019; 39 (5): 820–35

  View details for DOI 10.1097/IAE.0000000000002449

  View details for Web of Science ID 000480749600013

• Feasibility of Intraocular Projection for Treatment of Intractable Corneal Opacity CORNEA Shim, S. Y., Gong, S., Rosenblatt, M. I., Palanker, D., Al-Qahtani, A., Sun, M. G., Zhou, Q., Kanu, L., Chau, F., Yu, C. Q. 2019; 38 (4): 523–27

  View details for DOI 10.1097/1CO.0000000000001852

  View details for Web of Science ID 000467774200029

• Feasibility of Intraocular Projection for Treatment of Intractable Corneal Opacity. Cornea Shim, S. Y., Gong, S., Rosenblatt, M. I., Palanker, D., Al-Qahtani, A., Sun, M. G., Zhou, Q., Kanu, L., Chau, F., Yu, C. Q. 2019

  Abstract

  Despite many decades of research and development, corneal opacity remains a leading cause of reversible blindness worldwide. Corneal transplantation and keratoprosthesis can restore corneal clarity, but both have well-known limitations. High-resolution electronic microdisplays may offer an alternative to traditional methods of treating corneal disease using an intraocular implant to project imagery onto the retina, obviating the need for a clear cornea. In this study, we review previous work and recent technologic developments relevant to the development of such an intraocular projection system.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

  View details for PubMedID 30664047

• STEM CELL THERAPIES, GENE-BASED THERAPIES, OPTOGENETICS, AND RETINAL PROSTHETICS: CURRENT STATE AND IMPLICATIONS FOR THE FUTURE. Retina (Philadelphia, Pa.) Wood, E. H., Tang, P. H., De la Huerta, I., Korot, E., Muscat, S., Palanker, D. A., Williams, G. A. 2019

  Abstract

  PURPOSE: To review and discuss current innovations and future implications of promising biotechnology and biomedical offerings in the field of retina. We focus on therapies that have already emerged as clinical offerings or are poised to do so.METHODS: Literature review and commentary focusing on stem cell therapies, gene-based therapies, optogenetic therapies, and retinal prosthetic devices.RESULTS: The technologies discussed herein are some of the more recent promising biotechnology and biomedical developments within the field of retina. Retinal prosthetic devices and gene-based therapies both have an FDA-approved product for ophthalmology, and many other offerings (including optogenetics) are in the pipeline. Stem cell therapies offer personalized medicine through novel regenerative mechanisms but entail complex ethical and reimbursement challenges.CONCLUSION: Stem cell therapies, gene-based therapies, optogenetics, and retinal prosthetic devices represent a new era of biotechnological and biomedical progress. These bring new ethical, regulatory, care delivery, and reimbursement challenges. By addressing these issues proactively, we may accelerate delivery of care to patients in a safe, efficient, and value-based manner.

  View details for PubMedID 30664120

• Honeycomb-shaped electro-neural interface enables cellular-scale pixels in subretinal prosthesis. Scientific reports Flores, T. n., Huang, T. n., Bhuckory, M. n., Ho, E. n., Chen, Z. n., Dalal, R. n., Galambos, L. n., Kamins, T. n., Mathieson, K. n., Palanker, D. n. 2019; 9 (1): 10657

  Abstract

  High-resolution visual prostheses require small, densely packed pixels, but limited penetration depth of the electric field formed by a planar electrode array constrains such miniaturization. We present a novel honeycomb configuration of an electrode array with vertically separated active and return electrodes designed to leverage migration of retinal cells into voids in the subretinal space. Insulating walls surrounding each pixel decouple the field penetration depth from the pixel width by aligning the electric field vertically, enabling a decrease of the pixel size down to cellular dimensions. We demonstrate that inner retinal cells migrate into the 25 μm deep honeycomb wells as narrow as 18 μm, resulting in more than half of these cells residing within the electrode cavities. Immune response to honeycombs is comparable to that with planar arrays. Modeled stimulation threshold current density with honeycombs does not increase substantially with reduced pixel size, unlike quadratic increase with planar arrays. This 3-D electrode configuration may enable functional restoration of central vision with acuity better than 20/100 for millions of patients suffering from age-related macular degeneration.

  View details for DOI 10.1038/s41598-019-47082-y

  View details for PubMedID 31337815

• Transplantation of Mature Photoreceptors in Rodents With Retinal Degeneration. Translational vision science & technology Lorach, H. n., Kang, S. n., Bhuckory, M. B., Trouillet, A. n., Dalal, R. n., Marmor, M. n., Palanker, D. n. 2019; 8 (3): 30

  Abstract

  To demonstrate survival and integration of mature photoreceptors transplanted with the retinal pigment epithelium (RPE).Full-thickness retina with attached RPE was harvested from healthy adult rats. Grafts were implanted into two rat models of retinal degeneration, Royal College of Surgeons (RCS) and S334ter-3. Survival of the host and transplanted retina was monitored using optical coherence tomography (OCT) for up to 6 months. The retinal structure and synaptogenesis between the host and transplant was assessed by histology and immunohistochemistry.OCT and histology demonstrated a well-preserved photoreceptor layer with inner and outer segments, while the inner retinal layers of the transplant largely disappeared. Grafts, including RPE, survived better than without and the transplanted RPE appeared as a monolayer integrated with the native one. Synaptogenesis was observed through sprouting of new dendrites from the host bipolar cells and synaptic connections forming with cells of the transplant. However, in many samples, a glial fibrillary acidic protein-positive membrane separated the host retina and the graft.Presence of RPE in the graft improved the survival of transplanted photoreceptors. Functional integration between the transplant and the host retina is likely to be further enhanced if formation of a glial seal could be prevented. Transplantation of the mature photoreceptors with RPE may be a practical approach to restoration of sight in retinal degeneration.This approach to restoration of sight in patients with photoreceptor degeneration can be rapidly advanced to clinical testing. In patients with central scotoma, autologous transplantation of the peripheral retina can be an option.

  View details for DOI 10.1167/tvst.8.3.30

  View details for PubMedID 31171997

  View details for PubMedCentralID PMC6543858

• Full-field interferometric imaging of propagating action potentials LIGHT-SCIENCE & APPLICATIONS Ling, T., Boyle, K. C., Goetz, G., Zhou, P., Quan, Y., Alfonso, F. S., Huang, T. W., Palanker, D. 2018; 7

  View details for DOI 10.1038/s41377-018-0107-9

  View details for Web of Science ID 000452920800004

• Femtosecond Lasers for Ophthalmic Surgery Enabled by Chirped-Pulse Amplification. The New England journal of medicine Palanker, D. 2018; 379 (23): 2267-2269

  View details for DOI 10.1056/NEJMcibr1813334

  View details for PubMedID 30575460

• Femtosecond Lasers for Ophthalmic Surgery Enabled by Chirped-Pulse Amplification NEW ENGLAND JOURNAL OF MEDICINE Palanker, D. 2018; 379 (23): 2267–69

  View details for DOI 10.1056/NEJMcibr1813334

  View details for Web of Science ID 000452259200016

• Restoring sight with RETINAL PROSTHESES PHYSICS TODAY Palanker, D., Goetz, G. 2018; 71 (7): 26–32

  View details for DOI 10.1063/PT.3.3967

  View details for Web of Science ID 000437282800010

• Vertical walls surrounding pixels in subretinal space reduce stimulation threshold and improve contrast Flores, T., Huang, T., Lorach, H., Dalal, R., Lei, X., Kamins, T., Mathieson, K., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932802145

• Long-term survival and integration of the retina/RPE allograft in rat models of retinal degeneration Lorach, H., Kang, S., Trouillet, A., Dalal, R., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932805049

• Grating Acuity of Prosthetic Vision in Blind Rats Matches the Pixel Pitch of Photovoltaic Subretinal Arrays Below 50 mu m Ho, E., Lorach, H., Huang, T., Lei, X., Flores, T., Kamins, T., Galambos, L., Mathieson, K., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932802147

• Long-term Rescue of Photoreceptors in a Rodent Model of Retinitis Pigmentosa Associated with MERTK Gene Mutation Palanker, D. V., Kang, S., Dalal, R., Quan, Y., Lorach, H. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912502269

• Stereotyped synaptic connectivity is restored during circuit repair in the adult mammalian retina Beier, C., Palanker, D. V., Sher, A. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912505184

• Stereotyped Synaptic Connectivity Is Restored during Circuit Repair in the Adult Mammalian Retina CURRENT BIOLOGY Beier, C., Palanker, D., Sher, A. 2018; 28 (11): 1818-+

  Abstract

  Proper function of the central nervous system (CNS) depends on the specificity of synaptic connections between cells of various types. Cellular and molecular mechanisms responsible for the establishment and refinement of these connections during development are the subject of an active area of research [1-6]. However, it is unknown if the adult mammalian CNS can form new type-selective synapses following neural injury or disease. Here, we assess whether selective synaptic connections can be reestablished after circuit disruption in the adult mammalian retina. The stereotyped circuitry at the first synapse in the retina, as well as the relatively short distances new neurites must travel compared to other areas of the CNS, make the retina well suited to probing for synaptic specificity during circuit reassembly. Selective connections between short-wavelength sensitive cone photoreceptors (S-cones) and S-cone bipolar cells provides the foundation of the primordial blue-yellow vision, common to all mammals [7-18]. We take advantage of the ground squirrel retina, which has a one-to-one S-cone-to-S-cone-bipolar-cell connection, to test if this connectivity can be reestablished following local photoreceptor loss [8, 19]. We find that after in vivo selective photoreceptor ablation, deafferented S-cone bipolar cells expand their dendritic trees. The new dendrites randomly explore the proper synaptic layer, bypass medium-wavelength sensitive cone photoreceptors (M-cones), and selectively synapse with S-cones. However, non-connected dendrites are not pruned back to resemble unperturbed S-cone bipolar cells. We show, for the first time, that circuit repair in the adult mammalian retina can recreate stereotypic selective wiring.

  View details for PubMedID 29804805

• Optimization of pillar electrodes in subretinal prosthesis for enhanced proximity to target neurons JOURNAL OF NEURAL ENGINEERING Flores, T., Lei, X., Huang, T., Lorach, H., Dalal, R., Galambos, L., Kamins, T., Mathieson, K., Palanker, D. 2018; 15 (3)

  View details for DOI 10.1088/1741-2552/aaac39

  View details for Web of Science ID 000426955200002

• Optimization of pillar electrodes in subretinal prosthesis for enhanced proximity to target neurons. Journal of neural engineering Flores, T., Lei, X., Huang, T., Lorach, H., Dalal, R., Galambos, L., Kamins, T., Mathieson, K., Palanker, D. 2018; 15 (3): 036011

  Abstract

  High-resolution prosthetic vision requires dense stimulating arrays with small electrodes. However, such miniaturization reduces electrode capacitance and penetration of electric field into tissue. We evaluate potential solutions to these problems with subretinal implants based on utilization of pillar electrodes.To study integration of three-dimensional (3D) implants with retinal tissue, we fabricated arrays with varying pillar diameter, pitch, and height, and implanted beneath the degenerate retina in rats (Royal College of Surgeons, RCS). Tissue integration was evaluated six weeks post-op using histology and whole-mount confocal fluorescence imaging. The electric field generated by various electrode configurations was calculated in COMSOL, and stimulation thresholds assessed using a model of network-mediated retinal response.Retinal tissue migrated into the space between pillars with no visible gliosis in 90% of implanted arrays. Pillars with 10 μm height reached the middle of the inner nuclear layer (INL), while 22 μm pillars reached the upper portion of the INL. Electroplated pillars with dome-shaped caps increase the active electrode surface area. Selective deposition of sputtered iridium oxide onto the cap ensures localization of the current injection to the pillar top, obviating the need to insulate the pillar sidewall. According to computational model, pillars having a cathodic return electrode above the INL and active anodic ring electrode at the surface of the implant would enable six times lower stimulation threshold, compared to planar arrays with circumferential return, but suffer from greater cross-talk between the neighboring pixels.3D electrodes in subretinal prostheses help reduce electrode-tissue separation and decrease stimulation thresholds to enable smaller pixels, and thereby improve visual acuity of prosthetic vision.

  View details for DOI 10.1088/1741-2552/aaac39

  View details for PubMedID 29388561

• Mechanisms of electrical vasoconstriction JOURNAL OF NEUROENGINEERING AND REHABILITATION Brinton, M., Mandel, Y., Schachar, I., Palanker, D. 2018; 15: 43

  Abstract

  Electrical vasoconstriction is a promising approach to control blood pressure or restrict bleeding in non-compressible wounds. We explore the neural and non-neural pathways of electrical vasoconstriction in-vivo.Charge-balanced, asymmetric pulses were delivered through a pair of metal disc electrodes. Vasoconstriction was assessed by measuring the diameter of rat saphenous vessels stimulated with low-voltage (20 V, 1 ms) and high-voltage (150 V, 10 μs) stimuli at 10 Hz for 5 min. Activation pathways were explored by topical application of a specific neural agonist (phenylephrine, alpha-1 receptor), a non-specific agonist (KCl) and neural inhibitors (phenoxybenzamine, 25 mg/ml; guanethidine, 1 mg/ml). Acute tissue damage was assessed with a membrane permeability (live-dead) fluorescent assay. The Joule heating in tissue was estimated using COMSOL Multiphysics modeling.During stimulation, arteries constricted to 41 ± 8% and 37 ± 6% of their pre-stimulus diameter with low- and high-voltage stimuli, while veins constricted to 80 ± 18% and 40 ± 11%, respectively. In arteries, despite similar extent of constriction, the recovery time was very different: about 30 s for low-voltage and 10 min for high-voltage stimuli. Neural inhibitors significantly reduced low-voltage arterial constriction, but did not affect high-voltage arterial or venous constriction, indicating that high-voltage stimuli activate non-neural vasoconstriction pathways. Adrenergic pathways predominantly controlled low-voltage arterial but not venous constriction, which may involve a purinergic pathway. Viability staining confirmed that stimuli were below the electroporation threshold. Modeling indicates that heating of the blood vessels during stimulation (< 0.2 °C) is too low to cause vasoconstriction.We demonstrate that low-voltage stimuli induce reversible vasoconstriction through neural pathways, while high-voltage stimuli activate non-neural pathways, likely in addition to neural stimulation. Different stimuli providing precise control over the extent of arterial and venous constriction as well as relaxation rate could be used to control bleeding, perfusion or blood pressure.

  View details for PubMedID 29843762

• Interferometric mapping of material properties using thermal perturbation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Goetz, G., Ling, T., Gupta, T., Kang, S., Wang, J., Gregory, P. D., Park, B., Palanker, D. 2018; 115 (11): E2499–E2508

  Abstract

  Optical phase changes induced by transient perturbations provide a sensitive measure of material properties. We demonstrate the high sensitivity and speed of such methods, using two interferometric techniques: quantitative phase imaging (QPI) in transmission and phase-resolved optical coherence tomography (OCT) in reflection. Shot-noise-limited QPI can resolve energy deposition of about 3.4 mJ/cm2 in a single pulse, which corresponds to 0.8 °C temperature rise in a single cell. OCT can detect deposition of 24 mJ/cm2 energy between two scattering interfaces producing signals with about 30-dB signal-to-noise ratio (SNR), and 4.7 mJ/cm2 when SNR is 45 dB. Both techniques can image thermal changes within the thermal confinement time, which enables accurate single-shot mapping of absorption coefficients even in highly scattering samples, as well as electrical conductivity and many other material properties in biological samples at cellular scale. Integration of the phase changes along the beam path helps increase sensitivity, and the signal relaxation time reveals the size of hidden objects. These methods may enable multiple applications, ranging from temperature-controlled retinal laser therapy or gene expression to mapping electric current density and characterization of semiconductor devices with rapid pump-probe measurements.

  View details for PubMedID 29483276

• Temporal structure in spiking patterns of ganglion cells defines perceptual thresholds in rodents with subretinal prosthesis SCIENTIFIC REPORTS Ho, E., Lorach, H., Goetz, G., Laszlo, F., Lei, X., Kamins, T., Mariani, J., Sher, A., Palanker, D. 2018; 8: 3145

  Abstract

  Subretinal prostheses are designed to restore sight in patients blinded by retinal degeneration using electrical stimulation of the inner retinal neurons. To relate retinal output to perception, we studied behavioral thresholds in blind rats with photovoltaic subretinal prostheses stimulated by full-field pulsed illumination at 20 Hz, and measured retinal ganglion cell (RGC) responses to similar stimuli ex-vivo. Behaviorally, rats exhibited startling response to changes in brightness, with an average contrast threshold of 12%, which could not be explained by changes in the average RGC spiking rate. However, RGCs exhibited millisecond-scale variations in spike timing, even when the average rate did not change significantly. At 12% temporal contrast, changes in firing patterns of prosthetic response were as significant as with 2.3% contrast steps in visible light stimulation of healthy retinas. This suggests that millisecond-scale changes in spiking patterns define perceptual thresholds of prosthetic vision. Response to the last pulse in the stimulation burst lasted longer than the steady-state response during the burst. This may be interpreted as an excitatory OFF response to prosthetic stimulation, and can explain behavioral response to decrease in illumination. Contrast enhancement of images prior to delivery to subretinal prosthesis can partially compensate for reduced contrast sensitivity of prosthetic vision.

  View details for PubMedID 29453455

• y Spatiotemporal characteristics of retinal response to network-mediated photovoltaic stimulation JOURNAL OF NEUROPHYSIOLOGY Ho, E., Smith, R., Goetz, G., Lei, X., Galambos, L., Kamins, T. I., Harris, J., Mathieson, K., Palanker, D., Sher, A. 2018; 119 (2): 389–400

  Abstract

  Subretinal prostheses aim at restoring sight to patients blinded by photoreceptor degeneration using electrical activation of the surviving inner retinal neurons. Today, such implants deliver visual information with low-frequency stimulation, resulting in discontinuous visual percepts. We measured retinal responses to complex visual stimuli delivered at video rate via a photovoltaic subretinal implant and by visible light. Using a multielectrode array to record from retinal ganglion cells (RGCs) in the healthy and degenerated rat retina ex vivo, we estimated their spatiotemporal properties from the spike-triggered average responses to photovoltaic binary white noise stimulus with 70-μm pixel size at 20-Hz frame rate. The average photovoltaic receptive field size was 194 ± 3 μm (mean ± SE), similar to that of visual responses (221 ± 4 μm), but response latency was significantly shorter with photovoltaic stimulation. Both visual and photovoltaic receptive fields had an opposing center-surround structure. In the healthy retina, ON RGCs had photovoltaic OFF responses, and vice versa. This reversal is consistent with depolarization of photoreceptors by electrical pulses, as opposed to their hyperpolarization under increasing light, although alternative mechanisms cannot be excluded. In degenerate retina, both ON and OFF photovoltaic responses were observed, but in the absence of visual responses, it is not clear what functional RGC types they correspond to. Degenerate retina maintained the antagonistic center-surround organization of receptive fields. These fast and spatially localized network-mediated ON and OFF responses to subretinal stimulation via photovoltaic pixels with local return electrodes raise confidence in the possibility of providing more functional prosthetic vision. NEW & NOTEWORTHY Retinal prostheses currently in clinical use have struggled to deliver visual information at naturalistic frequencies, resulting in discontinuous percepts. We demonstrate modulation of the retinal ganglion cells (RGC) activity using complex spatiotemporal stimuli delivered via subretinal photovoltaic implant at 20 Hz in healthy and in degenerate retina. RGCs exhibit fast and localized ON and OFF network-mediated responses, with antagonistic center-surround organization of their receptive fields.

  View details for PubMedID 29046428

  View details for PubMedCentralID PMC5867391

• Full-field interferometric imaging of propagating action potentials. Light, science & applications Ling, T., Boyle, K. C., Goetz, G., Zhou, P., Quan, Y., Alfonso, F. S., Huang, T. W., Palanker, D. 2018; 7: 107

  Abstract

  Currently, cellular action potentials are detected using either electrical recordings or exogenous fluorescent probes that sense the calcium concentration or transmembrane voltage. Ca imaging has a low temporal resolution, while voltage indicators are vulnerable to phototoxicity, photobleaching, and heating. Here, we report full-field interferometric imaging of individual action potentials by detecting movement across the entire cell membrane. Using spike-triggered averaging of movies synchronized with electrical recordings, we demonstrate deformations up to 3nm (0.9mrad) during the action potential in spiking HEK-293 cells, with a rise time of 4ms. The time course of the optically recorded spikes matches the electrical waveforms. Since the shot noise limit of the camera (~2mrad/pix) precludes detection of the action potential in a single frame, for all-optical spike detection, images are acquired at 50kHz, and 50 frames are binned into 1ms steps to achieve a sensitivity of 0.3mrad in a single pixel. Using a self-reinforcing sensitivity enhancement algorithm based on iteratively expanding the region of interest for spatial averaging, individual spikes can be detected by matching the previously extracted template of the action potential with the optical recording. This allows all-optical full-field imaging of the propagating action potentials without exogeneous labels or electrodes.

  View details for PubMedID 30564313

• Comparison of Continuous-Wave and Micropulse Modulation in Retinal Laser Therapy INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Wang, J., Quan, Y., Dalal, R., Palanker, D. 2017; 58 (11): 4722–32

  Abstract

  Recent progress in retinal laser therapy has centered upon using thermal stress below damage threshold or selective destruction of targeted tissue layers as a stimulus for retinal repair. Temporal modulation, including micropulse, is thought to increase the selectivity of laser treatment, but has not been carefully analyzed. We measure and model the tissue response to continuous-wave (CW) and micropulse laser to evaluate the advantages and drawbacks of temporal modulation.Thresholds of ophthalmoscopic visibility, which indicates damage to photoreceptors, and fluorescein angiography (FA), indicating damage to retinal pigment epithelium (RPE), were measured with 577-nm laser in rabbits for duty cycles ranging from 3% to 100% (CW) and pulse envelopes of 20 and 200 ms. Heat shock protein (HSP) expression was measured in rats. Thresholds were compared to a computational model of tissue response based on the Arrhenius integral.Damage to photoreceptors was defined by average power, regardless of the duty cycle, as predicted by the model. The average power for FA threshold was lower with 5% duty cycle than with CW laser by 22 ± 15% for 200-ms and 35 ± 21.5% for 20-ms envelopes, demonstrating some heat localization to RPE. The ratio of RPE damage threshold to HSP expression threshold was 1.30 ± 0.15 and 1.39 ± 0.11 for 20 ms at 5% duty cycle and CW, respectively.Micropulse modulation with sufficiently short envelope and duty cycle can help reduce the spread of heat from the light-absorbing RPE and choroid. However, this localization does not benefit nondamaging retinal laser therapy, which is intended to avoid any cell death.

  View details for PubMedID 28910825

• Deafferented Adult Rod Bipolar Cells Create New Synapses with Photoreceptors to Restore Vision JOURNAL OF NEUROSCIENCE Beier, C., Hovhannisyan, A., Weiser, S., Kung, J., Lee, S., Lee, D. Y., Huie, P., Dalal, R., Palanker, D., Sher, A. 2017; 37 (17): 4635-4644

  Abstract

  Upon degeneration of photoreceptors in the adult retina, interneurons, including bipolar cells, exhibit a plastic response leading to their aberrant rewiring. Photoreceptor reintroduction has been suggested as a potential approach to sight restoration, but the ability of deafferented bipolar cells to establish functional synapses with photoreceptors is poorly understood. Here we use photocoagulation to selectively destroy photoreceptors in adult rabbits while preserving the inner retina. We find that rods and cones shift into the ablation zone over several weeks, reducing the blind spot at scotopic and photopic luminances. During recovery, rod and cone bipolar cells exhibit markedly different responses to deafferentation. Rod bipolar cells extend their dendrites to form new synapses with healthy photoreceptors outside the lesion, thereby restoring visual function in the deafferented retina. Secretagogin-positive cone bipolar cells did not exhibit such obvious dendritic restructuring. These findings are encouraging to the idea of photoreceptor reintroduction for vision restoration in patients blinded by retinal degeneration. At the same time, they draw attention to the postsynaptic side of photoreceptor reintroduction; various bipolar cell types, representing different visual pathways, vary in their response to the photoreceptor loss and in their consequent dendritic restructuring.SIGNIFICANCE STATEMENT Loss of photoreceptors during retinal degeneration results in permanent visual impairment. Strategies for vision restoration based on the reintroduction of photoreceptors inherently rely on the ability of the remaining retinal neurons to correctly synapse with new photoreceptors. We show that deafferented bipolar cells in the adult mammalian retina can reconnect to rods and cones and restore retinal sensitivity at scotopic and photopic luminances. Rod bipolar cells extend their dendrites to form new synapses with healthy rod photoreceptors. These findings support the idea that bipolar cells might be able to synapse with reintroduced photoreceptors, thereby restoring vision in patients blinded by retinal degeneration.

  View details for DOI 10.1523/JNEUROSCI.2570-16.2017

  View details for Web of Science ID 000401038400018

  View details for PubMedID 28373392

• Enhanced Tearing by Electrical Stimulation of the Anterior Ethmoid Nerve INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Brinton, M., Kossler, A. L., Patel, Z. M., Loudin, J., Franke, M., Ta, C. N., Palanker, D. 2017; 58 (4): 2341-2348

  Abstract

  Electrical neurostimulation enhances tear secretion, and can be applied to treatment of dry eye disease. Using a chronic implant, we evaluate the effects of stimulating the anterior ethmoid nerve on the aqueous, lipid, and protein content of secreted tears.Neurostimulators were implanted beneath the nasal mucosa in 13 New Zealand white rabbits. Stimulations (2.3-2.8 mA pulses of 75-875 μs in duration repeated at 30-100 Hz for 3 minutes) were performed daily, for 3 weeks to measure changes in tear volume (Schirmer test), osmolarity (TearLab osmometer), lipid (Oil-Red-O staining), and protein (BCA assay, mass spectrometry).Stimulation of the anterior ethmoid nerve in the frequency range of 30 to 90 Hz increased tear volume by 92% to 133% (P ≤ 0.01). Modulating the treatment with 50% duty cycle (3 seconds of stimulation repeated every 6 seconds) increased tear secretion an additional 23% above continuous stimulation (P ≤ 0.01). Tear secretion returned to baseline levels within 7 minutes after stimulation ended. Tear film osmolarity decreased by 7 mOsmol/L, tear lipid increased by 24% to 36% and protein concentration increased by 48% (P ≤ 0.05). Relative abundance of the lacrimal gland proteins remained the same, while several serum and corneal proteins decreased with stimulation (P ≤ 0.05).Electrical stimulation of the anterior ethmoid nerve increased aqueous tear volume, reduced tear osmolarity, added lipid, and increased the concentration of normal tear proteins. Human studies with an intranasal stimulator should verify these effects in patients with aqueous- and lipid-deficient forms of dry eye disease.

  View details for DOI 10.1167/iovs.16-21362

  View details for PubMedID 28431436

• Optophysiology of cardiomyocytes: characterizing cellular motion with quantitative phase imaging. Biomedical optics express Cordeiro, C. n., Abilez, O. J., Goetz, G. n., Gupta, T. n., Zhuge, Y. n., Solgaard, O. n., Palanker, D. n. 2017; 8 (10): 4652–62

  Abstract

  Quantitative phase imaging enables precise characterization of cellular shape and motion. Variation of cell volume in populations of cardiomyocytes can help distinguish their types, while changes in optical thickness during beating cycle identify contraction and relaxation periods and elucidate cell dynamics. Parameters such as characteristic cycle shape, beating frequency, duration and regularity can be used to classify stem-cell derived cardiomyocytes according to their health and, potentially, cell type. Unlike classical patch-clamp based electrophysiological characterization of cardiomyocytes, this interferometric approach enables rapid and non-destructive analysis of large populations of cells, with longitudinal follow-up, and applications to tissue regeneration, personalized medicine, and drug testing.

  View details for PubMedID 29082092

  View details for PubMedCentralID PMC5654807

• Characterizing Cardiomyocytes Motion with Quantitative Phase Imaging Cordeiro, C., Abilez, O., Gupta, T., Goetz, G., Solgaard, O., Palanker, D., IEEE IEEE. 2017

  View details for Web of Science ID 000427296200175

• NONDAMAGING RETINAL LASER THERAPY FOR TREATMENT OF CENTRAL SEROUS CHORIORETINOPATHY: What is the Evidence? Retina (Philadelphia, Pa.) Wood, E. H., Karth, P. A., Sanislo, S. R., Moshfeghi, D. M., Palanker, D. V. 2016: -?

  Abstract

  To summarize the literature addressing subthreshold or nondamaging retinal laser therapy (NRT) for central serous chorioretinopathy (CSCR) and to discuss results and trends that provoke further investigation.Analysis of current literature evaluating NRT with micropulse or continuous wave lasers for CSCR.Sixteen studies including 398 patients consisted of retrospective case series, prospective nonrandomized interventional case series, and prospective randomized clinical trials. All studies but one evaluated chronic CSCR, and laser parameters varied greatly between studies. Mean central macular thickness decreased, on average, by ∼80 μm by 3 months. Mean best-corrected visual acuity increased, on average, by about 9 letters by 3 months, and no study reported a decrease in acuity below presentation. No retinal complications were observed with the various forms of NRT used, but six patients in two studies with micropulse laser experienced pigmentary changes in the retinal pigment epithelium attributed to excessive laser settings.Based on the current evidence, NRT demonstrates efficacy and safety in 12-month follow-up in patients with chronic and possibly acute CSCR. The NRT would benefit from better standardization of the laser settings and understanding of mechanisms of action, as well as further prospective randomized clinical trials.

  View details for PubMedID 27841848

• Evolution of Concepts and Technologies in Ophthalmic Laser Therapy. Annual review of vision science Palanker, D. 2016; 2: 295-319

  Abstract

  Ophthalmology was the first medical specialty to adopt lasers right after their invention more than 50 years ago, and they gradually revolutionized ocular imaging, diagnostics, therapy, and surgery. Challenging precision, safety, and selectivity requirements for ocular therapeutic and surgical procedures keep advancing the laser technologies, which in turn continue enabling novel applications for the preservation and restoration of sight. Modern lasers can provide single-cell-layer selectivity in therapy, submicrometer precision in three-dimensional image-guided surgery, and nondamaging retinal therapy under optoacoustic temperature control. This article reviews the evolution of laser technologies; progress in understanding of the laser-tissue interactions; and concepts, misconceptions, and accidental discoveries that led to modern therapeutic and surgical applications of lasers in ophthalmology. It begins with a brief historical overview, followed by a description of the laser-tissue interactions and corresponding ophthalmic applications.

  View details for DOI 10.1146/annurev-vision-111815-114358

  View details for PubMedID 28532364

• Electronic approaches to restoration of sight. Reports on progress in physics. Physical Society (Great Britain) Goetz, G. A., Palanker, D. V. 2016; 79 (9): 096701-?

  Abstract

  Retinal prostheses are a promising means for restoring sight to patients blinded by the gradual atrophy of photoreceptors due to retinal degeneration. They are designed to reintroduce information into the visual system by electrically stimulating surviving neurons in the retina. This review outlines the concepts and technologies behind two major approaches to retinal prosthetics: epiretinal and subretinal. We describe how the visual system responds to electrical stimulation. We highlight major differences between direct encoding of the retinal output with epiretinal stimulation, and network-mediated response with subretinal stimulation. We summarize results of pre-clinical evaluation of prosthetic visual functions in- and ex vivo, as well as the outcomes of current clinical trials of various retinal implants. We also briefly review alternative, non-electronic, approaches to restoration of sight to the blind, and conclude by suggesting some perspectives for future advancement in the field.

  View details for DOI 10.1088/0034-4885/79/9/096701

  View details for PubMedID 27502748

• SiC protective coating for photovoltaic retinal prosthesis. Journal of neural engineering Lei, X., Kane, S., Cogan, S., Lorach, H., Galambos, L., Huie, P., Mathieson, K., Kamins, T., Harris, J., Palanker, D. 2016; 13 (4): 046016-?

  Abstract

  To evaluate plasma-enhanced, chemically vapor deposited (PECVD) amorphous silicon carbide (α-SiC:H) as a protective coating for retinal prostheses and other implantable devices, and to study their failure mechanisms in vivo.Retinal prostheses were implanted in rats sub-retinally for up to 1 year. Degradation of implants was characterized by optical and scanning electron microscopy. Dissolution rates of SiC, SiN x and thermal SiO2 were measured in accelerated soaking tests in saline at 87 °C. Defects in SiC films were revealed and analyzed by selectively removing the materials underneath those defects.At 87 °C SiN x dissolved at 18.3 ± 0.3 nm d(-1), while SiO2 grown at high temperature (1000 °C) dissolved at 0.104 ± 0.008 nm d(-1). SiC films demonstrated the best stability, with no quantifiable change after 112 d. Defects in thin SiC films appeared primarily over complicated topography and rough surfaces.SiC coatings demonstrating no erosion in accelerated aging test for 112 d at 87 °C, equivalent to about 10 years in vivo, can offer effective protection of the implants. Photovoltaic retinal prostheses with PECVD SiC coatings exhibited effective protection from erosion during the 4 month follow-up in vivo. The optimal thickness of SiC layers is about 560 nm, as defined by anti-reflective properties and by sufficient coverage to eliminate defects.

  View details for DOI 10.1088/1741-2560/13/4/046016

  View details for PubMedID 27323882

  View details for PubMedCentralID PMC4967360

• Optimization of return electrodes in neurostimulating arrays JOURNAL OF NEURAL ENGINEERING Flores, T., Goetz, G., Lei, X., Palanker, D. 2016; 13 (3)

  Abstract

  High resolution visual prostheses require dense stimulating arrays with localized inputs of individual electrodes. We study the electric field produced by multielectrode arrays in electrolyte to determine an optimal configuration of return electrodes and activation sequence.To determine the boundary conditions for computation of the electric field in electrolyte, we assessed current dynamics using an equivalent circuit of a multielectrode array with interleaved return electrodes. The electric field modeled with two different boundary conditions derived from the equivalent circuit was then compared to measurements of electric potential in electrolyte. To assess the effect of return electrode configuration on retinal stimulation, we transformed the computed electric fields into retinal response using a model of neural network-mediated stimulation.Electric currents at the capacitive electrode-electrolyte interface redistribute over time, so that boundary conditions transition from equipotential surfaces at the beginning of the pulse to uniform current density in steady state. Experimental measurements confirmed that, in steady state, the boundary condition corresponds to a uniform current density on electrode surfaces. Arrays with local return electrodes exhibit improved field confinement and can elicit stronger network-mediated retinal response compared to those with a common remote return. Connecting local return electrodes enhances the field penetration depth and allows reducing the return electrode area. Sequential activation of the pixels in large monopolar arrays reduces electrical cross-talk and improves the contrast in pattern stimulation.Accurate modeling of multielectrode arrays helps optimize the electrode configuration to maximize the spatial resolution, contrast and dynamic range of retinal prostheses.

  View details for DOI 10.1088/1741-2560/13/3/036010

  View details for Web of Science ID 000375701200014

  View details for PubMedID 27098048

• Nondamaging Retinal Laser Therapy: Rationale and Applications to the Macula INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Lavinsky, D., Wang, J., Huie, P., Dalal, R., Lee, S. J., Lee, D. Y., Palanker, D. 2016; 57 (6): 2488-2500

  Abstract

  Retinal photocoagulation and nondamaging laser therapy are used for treatment of macular disorders, without understanding of the response mechanism and with no rationale for dosimetry. To establish a proper titration algorithm, we measured the range of tissue response and damage threshold. We then evaluated safety and efficacy of nondamaging retinal therapy (NRT) based on this algorithm for chronic central serous chorioretinopathy (CSCR) and macular telangiectasia (MacTel).Retinal response to laser treatment below damage threshold was assessed in pigmented rabbits by expression of the heat shock protein HSP70 and glial fibrillary acidic protein (GFAP). Energy was adjusted relative to visible titration using the Endpoint Management (EpM) algorithm. In clinical studies, 21 eyes with CSCR and 10 eyes with MacTel were treated at 30% EpM energy with high spot density (0.25-diameter spacing). Visual acuity, retinal and choroidal thickness, and subretinal fluid were monitored for 1 year.At 25% EpM energy and higher, HSP70 was expressed acutely in RPE, and GFAP upregulation in Müller cells was observed at 1 month. Damage appeared starting at 40% setting. Subretinal fluid resolved completely in 81% and partially in 19% of the CSCR patients, and visual acuity improved by 12 ± 3 letters. Lacunae in the majority of MacTel patients decreased while preserving the retinal thickness, and vision improved by 10 letters.Heat shock protein expression in response to hyperthermia helps define the therapeutic window for NRT. Lack of tissue damage enables high-density treatment to boost clinical efficacy, therapy in the fovea, and retreatments to manage chronic diseases.

  View details for DOI 10.1167/iovs.15-18981

  View details for PubMedID 27159441

• Implantation of Modular Photovoltaic Subretinal Prosthesis. Ophthalmic surgery, lasers & imaging retina Lee, D. Y., Lorach, H., Huie, P., Palanker, D. 2016; 47 (2): 171-174

  Abstract

  Establish the surgical procedure for subretinal implantation of multiple photovoltaic arrays for the restoration of sight.Multiple silicon photovoltaic arrays of 1 mm in diameter and 30 µm in thickness were implanted subretinally via single retinotomy in rabbits. Ophthalmoscopic imaging and optical coherence tomography (OCT) were used to validate the implants' placement.Vitrectomy, followed by subretinal fluid injection for retinal detachment and retinotomy, allowed accurate placement of seven modules in the bleb, covering approximately a 3.5-mm diameter area on the retina via a single 1.5-mm retinotomy. OCT confirmed complete reattachment of the retina over the implants.Subretinal implantation of multiple photovoltaic arrays via a single retinotomy, followed by their tiling, minimizes the scleral and retinal incisions and provides better fit to the spherical shape of the eye ball, compared to a single, larger module. Such minimally traumatic procedure can be performed with 20-gauge intraocular instruments.

  View details for DOI 10.3928/23258160-20160126-11

  View details for PubMedID 26878451

• Photovoltaic Pixels for Neural Stimulation: Circuit Models and Performance. IEEE transactions on biomedical circuits and systems Boinagrov, D., Lei, X., Goetz, G., Kamins, T. I., Mathieson, K., Galambos, L., Harris, J. S., Palanker, D. 2016; 10 (1): 85-97

  Abstract

  Photovoltaic conversion of pulsed light into pulsed electric current enables optically-activated neural stimulation with miniature wireless implants. In photovoltaic retinal prostheses, patterns of near-infrared light projected from video goggles onto subretinal arrays of photovoltaic pixels are converted into patterns of current to stimulate the inner retinal neurons. We describe a model of these devices and evaluate the performance of photovoltaic circuits, including the electrode-electrolyte interface. Characteristics of the electrodes measured in saline with various voltages, pulse durations, and polarities were modeled as voltage-dependent capacitances and Faradaic resistances. The resulting mathematical model of the circuit yielded dynamics of the electric current generated by the photovoltaic pixels illuminated by pulsed light. Voltages measured in saline with a pipette electrode above the pixel closely matched results of the model. Using the circuit model, our pixel design was optimized for maximum charge injection under various lighting conditions and for different stimulation thresholds. To speed discharge of the electrodes between the pulses of light, a shunt resistor was introduced and optimized for high frequency stimulation.

  View details for DOI 10.1109/TBCAS.2014.2376528

  View details for PubMedID 25622325

• Electronic enhancement of tear secretion. Journal of neural engineering Brinton, M., Chung, J. L., Kossler, A., KooK, K. H., Loudin, J., Franke, M., Palanker, D. 2016; 13 (1): 016006-?

  Abstract

  To study electrical stimulation of the lacrimal gland and afferent nerves for enhanced tear secretion, as a potential treatment for dry eye disease. We investigate the response pathways and electrical parameters to safely maximize tear secretion.We evaluated the tear response to electrical stimulation of the lacrimal gland and afferent nerves in isofluorane-anesthetized rabbits. In acute studies, electrical stimulation was performed using bipolar platinum foil electrodes, implanted beneath the inferior lacrimal gland, and a monopolar electrode placed near the afferent ethmoid nerve. Wireless microstimulators with bipolar electrodes were implanted beneath the lacrimal gland for chronic studies. To identify the response pathways, we applied various pharmacological inhibitors. To optimize the stimulus, we measured tear secretion rate (Schirmer test) as a function of pulse amplitude (1.5-12 mA), duration (0.1-1 ms) and repetition rate (10-100 Hz).Stimulation of the lacrimal gland increased tear secretion by engaging efferent parasympathetic nerves. Tearing increased with stimulation amplitude, pulse duration and repetition rate, up to 70 Hz. Stimulation with 3 mA, 500 μs pulses at 70 Hz provided a 4.5 mm (125%) increase in Schirmer score. Modulating duty cycle further increased tearing up to 57%, compared to continuous stimulation in chronically implanted animals (36%). Ethmoid (afferent) nerve stimulation increased tearing similar to gland stimulation (3.6 mm) via a reflex pathway. In animals with chronically implanted stimulators, a nearly 6 mm increase (57%) was achieved with 12-fold less charge density per pulse (0.06-0.3 μC mm(-2) with 170-680 μs pulses) than the damage threshold (3.5 μC mm(-2) with 1 ms pulses).Electrical stimulation of the lacrimal gland or afferent nerves may be used as a treatment for dry eye disease. Clinical trials should validate this approach in patients with aqueous tear deficiency, and further optimize electrical parameters for maximum clinical efficacy.

  View details for DOI 10.1088/1741-2560/13/1/016006

  View details for PubMedID 26655141

• Retinal safety of near infrared radiation in photovoltaic restoration of sight. Biomedical optics express Lorach, H., Wang, J., Lee, D. Y., Dalal, R., Huie, P., Palanker, D. 2016; 7 (1): 13-21

  Abstract

  Photovoltaic restoration of sight requires intense near-infrared light to effectively stimulate retinal neurons. We assess the retinal safety of such radiation with and without the retinal implant. Retinal damage threshold was determined in pigmented rabbits exposed to 880nm laser radiation. The 50% probability (ED50) of retinal damage during 100s exposures with 1.2mm diameter beam occurred at 175mW, corresponding to a modeled temperature rise of 12.5°C. With the implant, the same temperature was reached at 78mW, close to the experimental ED50 of 71mW. In typical use conditions, the retinal temperature rise is not expected to exceed 0.43°C, well within the safety limits for chronic use.

  View details for DOI 10.1364/BOE.7.000013

  View details for PubMedID 26819813

• Evolution of Concepts and Technologies in Ophthalmic Laser Therapy ANNUAL REVIEW OF VISION SCIENCE, VOL 2 Palanker, D. 2016; 2: 295-319

  View details for DOI 10.1146/annurev-vision-111815-114358

  View details for Web of Science ID 000389589000014

• Finesse of transparent tissue cutting by ultrafast lasers at various wavelengths JOURNAL OF BIOMEDICAL OPTICS Wang, J., Schuele, G., Palanker, D. 2015; 20 (12)

  Abstract

  Transparent ocular tissues, such as the cornea and crystalline lens, can be ablated or dissected using short-pulse lasers. In refractive and cataract surgeries, the cornea, lens, and lens capsule can be cut by producing dielectric breakdown in the focus of a near-infrared (IR) femtosecond laser, which results in explosive vaporization of the interstitial water, causing mechanical rupture of the surrounding tissue. Here, we compare the texture of edges of lens capsule cut by femtosecond lasers with IR and ultraviolet (UV) wavelengths and explore differences in interactions of these lasers with biological molecules. Scanning electron microscopy indicates that a 400-nm laser is capable of producing very smooth cut edges compared to 800 or 1030 nm at a similar focusing angle. Using gel electrophoresis and liquid chromatography/mass spectrometry, we observe laser-induced nonlinear breakdown of proteins and polypeptides by 400-nm femtosecond pulses above and below the dielectric breakdown threshold. On the other hand, 800-nm femtosecond lasers do not produce significant dissociation even above the threshold of dielectric breakdown. However, despite this additional interaction of UV femtosecond laser with proteins, we determine that efficient cutting requires plasma-mediated bubble formation and that remarkably smooth edges are the result of reduced thresholds and smaller focal volume.

  View details for DOI 10.1117/1.JBO.20.12.125004

  View details for Web of Science ID 000368440300021

• Finesse of transparent tissue cutting by ultrafast lasers at various wavelengths. Journal of biomedical optics Wang, J., Schuele, G., Palanker, D. 2015; 20 (12): 125004

  Abstract

  Transparent ocular tissues, such as the cornea and crystalline lens, can be ablated or dissected using short-pulse lasers. In refractive and cataract surgeries, the cornea, lens, and lens capsule can be cut by producing dielectric breakdown in the focus of a near-infrared (IR) femtosecond laser, which results in explosive vaporization of the interstitial water, causing mechanical rupture of the surrounding tissue. Here, we compare the texture of edges of lens capsule cut by femtosecond lasers with IR and ultraviolet (UV) wavelengths and explore differences in interactions of these lasers with biological molecules. Scanning electron microscopy indicates that a 400-nm laser is capable of producing very smooth cut edges compared to 800 or 1030 nm at a similar focusing angle. Using gel electrophoresis and liquid chromatography/mass spectrometry, we observe laser-induced nonlinear breakdown of proteins and polypeptides by 400-nm femtosecond pulses above and below the dielectric breakdown threshold. On the other hand, 800-nm femtosecond lasers do not produce significant dissociation even above the threshold of dielectric breakdown. However, despite this additional interaction of UV femtosecond laser with proteins, we determine that efficient cutting requires plasma-mediated bubble formation and that remarkably smooth edges are the result of reduced thresholds and smaller focal volume.

  View details for DOI 10.1117/1.JBO.20.12.125004

  View details for PubMedID 26720869

• Interactions of Prosthetic and Natural Vision in Animals With Local Retinal Degeneration INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Lorach, H., Lei, X., Galambos, L., Kamins, T., Mathieson, K., Dalal, R., Huie, P., Harris, J., Palanker, D. 2015; 56 (12): 7444-7450

  Abstract

  Prosthetic restoration of partial sensory loss leads to interactions between artificial and natural inputs. Ideally, the rehabilitation should allow perceptual fusion of the two modalities. Here we studied the interactions between normal and prosthetic vision in a rodent model of local retinal degeneration.Implantation of a photovoltaic array in the subretinal space of normally sighted rats induced local degeneration of the photoreceptors above the chip, and the inner retinal neurons in this area were electrically stimulated by the photovoltaic implant powered by near-infrared (NIR) light. We studied prosthetic and natural visually evoked potentials (VEP) in response to simultaneous stimulation by NIR and visible light patterns.We demonstrate that electrical and natural VEPs summed linearly in the visual cortex, and both responses decreased under brighter ambient light. Responses to visible light flashes increased over 3 orders of magnitude of contrast (flash/background), while for electrical stimulation the contrast range was limited to 1 order of magnitude. The maximum amplitude of the prosthetic VEP was three times lower than the maximum response to a visible flash over the same area on the retina.Ambient light affects prosthetic responses, albeit much less than responses to visible stimuli. Prosthetic representation of contrast in the visual scene can be encoded, to a limited extent, by the appropriately calibrated stimulus intensity, which also depends on the ambient light conditions. Such calibration will be important for patients combining central prosthetic vision with natural peripheral sight, such as in age-related macular degeneration.

  View details for DOI 10.1167/iovs.15-17521

  View details for Web of Science ID 000368238200056

  View details for PubMedCentralID PMC5110201

• Interactions of Prosthetic and Natural Vision in Animals With Local Retinal Degeneration. Investigative ophthalmology & visual science Lorach, H., Lei, X., Galambos, L., Kamins, T., Mathieson, K., Dalal, R., Huie, P., Harris, J., Palanker, D. 2015; 56 (12): 7444-50

  Abstract

  Prosthetic restoration of partial sensory loss leads to interactions between artificial and natural inputs. Ideally, the rehabilitation should allow perceptual fusion of the two modalities. Here we studied the interactions between normal and prosthetic vision in a rodent model of local retinal degeneration.Implantation of a photovoltaic array in the subretinal space of normally sighted rats induced local degeneration of the photoreceptors above the chip, and the inner retinal neurons in this area were electrically stimulated by the photovoltaic implant powered by near-infrared (NIR) light. We studied prosthetic and natural visually evoked potentials (VEP) in response to simultaneous stimulation by NIR and visible light patterns.We demonstrate that electrical and natural VEPs summed linearly in the visual cortex, and both responses decreased under brighter ambient light. Responses to visible light flashes increased over 3 orders of magnitude of contrast (flash/background), while for electrical stimulation the contrast range was limited to 1 order of magnitude. The maximum amplitude of the prosthetic VEP was three times lower than the maximum response to a visible flash over the same area on the retina.Ambient light affects prosthetic responses, albeit much less than responses to visible stimuli. Prosthetic representation of contrast in the visual scene can be encoded, to a limited extent, by the appropriately calibrated stimulus intensity, which also depends on the ambient light conditions. Such calibration will be important for patients combining central prosthetic vision with natural peripheral sight, such as in age-related macular degeneration.

  View details for DOI 10.1167/iovs.15-17521

  View details for PubMedID 26618643

  View details for PubMedCentralID PMC5110201

• Contrast Sensitivity With a Subretinal Prosthesis and Implications for Efficient Delivery of Visual Information. Investigative ophthalmology & visual science Goetz, G., Smith, R., Lei, X., Galambos, L., Kamins, T., Mathieson, K., Sher, A., Palanker, D. 2015; 56 (12): 7186-94

  Abstract

  To evaluate the contrast sensitivity of a degenerate retina stimulated by a photovoltaic subretinal prosthesis, and assess the impact of low contrast sensitivity on transmission of visual information.We measure ex vivo the full-field contrast sensitivity of healthy rat retina stimulated with white light, and the contrast sensitivity of degenerate rat retina stimulated with a subretinal prosthesis at frequencies exceeding flicker fusion (>20 Hz). Effects of eye movements on retinal ganglion cell (RGC) activity are simulated using a linear-nonlinear model of the retina.Retinal ganglion cells adapt to high frequency stimulation of constant intensity, and respond transiently to changes in illumination of the implant, exhibiting responses to ON-sets, OFF-sets, and both ON- and OFF-sets of light. The percentage of cells with an OFF response decreases with progression of the degeneration, indicating that OFF responses are likely mediated by photoreceptors. Prosthetic vision exhibits reduced contrast sensitivity and dynamic range, with 65% contrast changes required to elicit responses, as compared to the 3% (OFF) to 7% (ON) changes with visible light. The maximum number of action potentials elicited with prosthetic stimulation is at most half of its natural counterpart for the ON pathway. Our model predicts that for most visual scenes, contrast sensitivity of prosthetic vision is insufficient for triggering RGC activity by fixational eye movements.Contrast sensitivity of prosthetic vision is 10 times lower than normal, and dynamic range is two times below natural. Low contrast sensitivity and lack of OFF responses hamper delivery of visual information via a subretinal prosthesis.

  View details for DOI 10.1167/iovs.15-17566

  View details for PubMedID 26540657

  View details for PubMedCentralID PMC4640473

• Contrast Sensitivity With a Subretinal Prosthesis and Implications for Efficient Delivery of Visual Information INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Goetz, G., Smith, R., Lei, X., Galambos, L., Kamins, T., Mathieson, K., Sher, A., Palanker, D. 2015; 56 (12): 7186-7194

  Abstract

  To evaluate the contrast sensitivity of a degenerate retina stimulated by a photovoltaic subretinal prosthesis, and assess the impact of low contrast sensitivity on transmission of visual information.We measure ex vivo the full-field contrast sensitivity of healthy rat retina stimulated with white light, and the contrast sensitivity of degenerate rat retina stimulated with a subretinal prosthesis at frequencies exceeding flicker fusion (>20 Hz). Effects of eye movements on retinal ganglion cell (RGC) activity are simulated using a linear-nonlinear model of the retina.Retinal ganglion cells adapt to high frequency stimulation of constant intensity, and respond transiently to changes in illumination of the implant, exhibiting responses to ON-sets, OFF-sets, and both ON- and OFF-sets of light. The percentage of cells with an OFF response decreases with progression of the degeneration, indicating that OFF responses are likely mediated by photoreceptors. Prosthetic vision exhibits reduced contrast sensitivity and dynamic range, with 65% contrast changes required to elicit responses, as compared to the 3% (OFF) to 7% (ON) changes with visible light. The maximum number of action potentials elicited with prosthetic stimulation is at most half of its natural counterpart for the ON pathway. Our model predicts that for most visual scenes, contrast sensitivity of prosthetic vision is insufficient for triggering RGC activity by fixational eye movements.Contrast sensitivity of prosthetic vision is 10 times lower than normal, and dynamic range is two times below natural. Low contrast sensitivity and lack of OFF responses hamper delivery of visual information via a subretinal prosthesis.

  View details for DOI 10.1167/iovs.15-17566

  View details for Web of Science ID 000368238200024

  View details for PubMedCentralID PMC4640473

• Safety of cornea and iris in ocular surgery with 355-nm lasers. Journal of biomedical optics Wang, J., Chung, J. L., Schuele, G., Vankov, A., Dalal, R., Wiltberger, M., Palanker, D. 2015; 20 (9): 095005-?

  Abstract

  A recent study showed that 355-nm nanosecond lasers cut cornea with similar precision to infrared femtosecond lasers. However, use of ultraviolet wavelength requires precise assessment of ocular safety to determine the range of possible ophthalmic applications. In this study, the 355-nm nanosecond laser was evaluated for corneal and iris damage in rabbit, porcine, and human donor eyes as determined by minimum visible lesion (MVL) observation, live/dead staining of the endothelium, and apoptosis assay. Single-pulse damage to the iris was evaluated on porcine eyes using live/dead staining. In live rabbits, the cumulative median effective dose (ED50) for corneal damage was 231 J/cm2, as seen by lesion observation. Appearance of endothelial damage in live/dead staining or apoptosis occurred at higher radiant exposure of 287 J/cm2. On enucleated rabbit and porcine corneas, ED50 was 87 and 52 J/cm2, respectively, by MVL, and 241 and 160 J/cm2 for endothelial damage. In human eyes, ED50 for MVL was 110 J/cm2 and endothelial damage at 453 J/cm2. Single-pulse iris damage occurred at ED 50 of 208 mJ/cm2. These values determine the energy permitted for surgical patterns and can guide development of ophthalmic laser systems. Lower damage threshold in corneas of enucleated eyes versus live rabbits is noted for future safety evaluation.

  View details for DOI 10.1117/1.JBO.20.9.095005

  View details for PubMedID 26359809

• Safety of cornea and iris in ocular surgery with 355-nm lasers. Journal of biomedical optics Wang, J., Chung, J. L., Schuele, G., Vankov, A., Dalal, R., Wiltberger, M., Palanker, D. 2015; 20 (9): 95005-?

  Abstract

  A recent study showed that 355-nm nanosecond lasers cut cornea with similar precision to infrared femtosecond lasers. However, use of ultraviolet wavelength requires precise assessment of ocular safety to determine the range of possible ophthalmic applications. In this study, the 355-nm nanosecond laser was evaluated for corneal and iris damage in rabbit, porcine, and human donor eyes as determined by minimum visible lesion (MVL) observation, live/dead staining of the endothelium, and apoptosis assay. Single-pulse damage to the iris was evaluated on porcine eyes using live/dead staining. In live rabbits, the cumulative median effective dose (ED50) for corneal damage was 231 J/cm2, as seen by lesion observation. Appearance of endothelial damage in live/dead staining or apoptosis occurred at higher radiant exposure of 287 J/cm2. On enucleated rabbit and porcine corneas, ED50 was 87 and 52 J/cm2, respectively, by MVL, and 241 and 160 J/cm2 for endothelial damage. In human eyes, ED50 for MVL was 110 J/cm2 and endothelial damage at 453 J/cm2. Single-pulse iris damage occurred at ED 50 of 208 mJ/cm2. These values determine the energy permitted for surgical patterns and can guide development of ophthalmic laser systems. Lower damage threshold in corneas of enucleated eyes versus live rabbits is noted for future safety evaluation.

  View details for DOI 10.1117/1.JBO.20.9.095005

  View details for PubMedID 26359809

• Integration of Perforated Subretinal Prostheses With Retinal Tissue. Translational vision science & technology Adekunle, A. N., Adkins, A., Wang, W., Kaplan, H. J., de Castro, J. F., Lee, S. J., Huie, P., Palanker, D., McCall, M., Pardue, M. T. 2015; 4 (4): 5-?

  Abstract

  To investigate the integration of subretinal implants containing full-depth perforations of various widths with rat and pig retina across weeks of implantation.In transgenic P23H rhodopsin line 1 (TgP23H-1) rats and wild-type (WT) pigs, we examined four subretinal implant designs: solid inactive polymer arrays (IPA), IPAs with 5- or 10-μm wide perforations, and active bipolar photovoltaic arrays (bPVA) with 5-μm perforations. We surgically placed the implants into the subretinal space using an external approach in rats or a vitreoretinal approach in pigs. Implant placement in the subretinal space was verified with optical coherence tomography and retinal perfusion was characterized with fluorescein angiography. Rats were sacrificed 8 or 16 weeks post-implantation (wpi) and pigs 2, 4, or 8 wpi, and retinas evaluated at the light microscopic level.Regardless of implant design, retinas of both species showed normal vasculature. In TgP23H-1 retinas implanted with 10-μm perforated IPAs, inner nuclear layer (INL) cells migrated through the perforations by 8 wpi, resulting in significant INL thinning by 16 wpi. Additionally, these retinas showed greater pseudo-rosette formation and fibrosis compared with retinas with solid or 5-μm perforated IPAs. TgP23H-1 retinas with bPVAs showed similar INL migration to retinas with 5-μm perforated IPAs, with less fibrosis and rosette formation. WT pig retina with perforated IPAs maintained photoreceptors, showed no migration, and less pseudo-rosette formation, but more fibrosis compared with implanted TgP23H-1 rat retinas.In retinas with photoreceptor degeneration, solid implants, or those with 5-μm perforations lead to the best biocompatibility.

  View details for PubMedID 26290776

• Development of Animal Models of Local Retinal Degeneration. Investigative ophthalmology & visual science Lorach, H., Kung, J., Beier, C., Mandel, Y., Dalal, R., Huie, P., Wang, J., Lee, S., Sher, A., Jones, B. W., Palanker, D. 2015; 56 (8): 4644-4652

  Abstract

  Development of nongenetic animal models of local retinal degeneration is essential for studies of retinal pathologies, such as chronic retinal detachment or age-related macular degeneration. We present two different methods to induce a highly localized retinal degeneration with precise onset time, that can be applied to a broad range of species in laboratory use.A 30-μm thin polymer sheet was implanted subretinally in wild-type (WT) rats. The effects of chronic retinal separation from the RPE were studied using histology and immunohistochemistry. Another approach is applicable to species with avascular retina, such as rabbits, where the photoreceptors and RPE were thermally ablated over large areas, using a high power scanning laser.Photoreceptors above the subretinal implant in rats degenerated over time, with 80% of the outer nuclear layer disappearing within a month, and the rest by 3 months. Similar loss was obtained by selective photocoagulation with a scanning laser. Cells in the inner nuclear layer and ganglion cell layer were preserved in both cases. However, there were signs of rewiring and decrease in the size of the bipolar cell terminals in the damaged areas.Both methods induce highly reproducible degeneration of photoreceptors over a defined area, with complete preservation of the inner retinal neurons during the 3-month follow-up. They provide a reliable platform for studies of local retinal degeneration and development of therapeutic strategies in a wide variety of species.

  View details for DOI 10.1167/iovs.14-16011

  View details for PubMedID 26207299

• Integration of Perforated Subretinal Prostheses With Retinal Tissue TRANSLATIONAL VISION SCIENCE & TECHNOLOGY Adekunle, A. N., Adkins, A., Wang, W., Kaplan, H. J., de Castro, J. F., Lee, S. J., Huie, P., Palanker, D., McCall, M., Pardue, M. T. 2015; 4 (4)

  Abstract

  To investigate the integration of subretinal implants containing full-depth perforations of various widths with rat and pig retina across weeks of implantation.In transgenic P23H rhodopsin line 1 (TgP23H-1) rats and wild-type (WT) pigs, we examined four subretinal implant designs: solid inactive polymer arrays (IPA), IPAs with 5- or 10-μm wide perforations, and active bipolar photovoltaic arrays (bPVA) with 5-μm perforations. We surgically placed the implants into the subretinal space using an external approach in rats or a vitreoretinal approach in pigs. Implant placement in the subretinal space was verified with optical coherence tomography and retinal perfusion was characterized with fluorescein angiography. Rats were sacrificed 8 or 16 weeks post-implantation (wpi) and pigs 2, 4, or 8 wpi, and retinas evaluated at the light microscopic level.Regardless of implant design, retinas of both species showed normal vasculature. In TgP23H-1 retinas implanted with 10-μm perforated IPAs, inner nuclear layer (INL) cells migrated through the perforations by 8 wpi, resulting in significant INL thinning by 16 wpi. Additionally, these retinas showed greater pseudo-rosette formation and fibrosis compared with retinas with solid or 5-μm perforated IPAs. TgP23H-1 retinas with bPVAs showed similar INL migration to retinas with 5-μm perforated IPAs, with less fibrosis and rosette formation. WT pig retina with perforated IPAs maintained photoreceptors, showed no migration, and less pseudo-rosette formation, but more fibrosis compared with implanted TgP23H-1 rat retinas.In retinas with photoreceptor degeneration, solid implants, or those with 5-μm perforations lead to the best biocompatibility.

  View details for DOI 10.1167/tvst.4.4.5

  View details for Web of Science ID 000388659900005

  View details for PubMedCentralID PMC4539203

• Performance of photovoltaic arrays in-vivo and characteristics of prosthetic vision in animals with retinal degeneration VISION RESEARCH Lorach, H., Goetz, G., Mandel, Y., Lei, X., Kamins, T. I., Mathieson, K., Huie, P., Dalal, R., Harris, J. S., Palanker, D. 2015; 111: 142-148

  Abstract

  Loss of photoreceptors during retinal degeneration leads to blindness, but information can be reintroduced into the visual system using electrical stimulation of the remaining retinal neurons. Subretinal photovoltaic arrays convert pulsed illumination into pulsed electric current to stimulate the inner retinal neurons. Since required irradiance exceeds the natural luminance levels, an invisible near-infrared (915 nm) light is used to avoid photophobic effects. We characterized the thresholds and dynamic range of cortical responses to prosthetic stimulation with arrays of various pixel sizes and with different number of photodiodes. Stimulation thresholds for devices with 140 μm pixels were approximately half those of 70 μm pixels, and with both pixel sizes, thresholds were lower with 2 diodes than with 3 diodes per pixel. In all cases these thresholds were more than two orders of magnitude below the ocular safety limit. At high stimulation frequencies (>20 Hz), the cortical response exhibited flicker fusion. Over one order of magnitude of dynamic range could be achieved by varying either pulse duration or irradiance. However, contrast sensitivity was very limited. Cortical responses could be detected even with only a few illuminated pixels. Finally, we demonstrate that recording of the corneal electric potential in response to patterned illumination of the subretinal arrays allows monitoring the current produced by each pixel, and thereby assessing the changes in the implant performance over time.

  View details for DOI 10.1016/j.visres.2014.09.007

  View details for PubMedID 25255990

• Photovoltaic restoration of sight with high visual acuity. Nature medicine Lorach, H., Goetz, G., Smith, R., Lei, X., Mandel, Y., Kamins, T., Mathieson, K., Huie, P., Harris, J., Sher, A., Palanker, D. 2015; 21 (5): 476-482

  Abstract

  Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration.

  View details for DOI 10.1038/nm.3851

  View details for PubMedID 25915832

• Photovoltaic restoration of sight with high visual acuity NATURE MEDICINE Lorach, H., Goetz, G., Smith, R., Lei, X., Mandel, Y., Kamins, T., Mathieson, K., Huie, P., Harris, J., Sher, A., Palanker, D. 2015; 21 (5): 476-U254

  Abstract

  Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration.

  View details for DOI 10.1038/nm.3851

  View details for Web of Science ID 000354068800014

  View details for PubMedID 25915832

• Serum Inflammatory Markers After Rupture Retinal Laser Injury in Mice OPHTHALMIC SURGERY LASERS & IMAGING RETINA Paulus, Y. M., Kuo, C., Morohoshi, K., Nugent, A., Zheng, L. L., Nomoto, H., Blumenkranz, M. S., Palanker, D., Ono, S. J. 2015; 46 (3): 362-368

  Abstract

  To characterize the cellular, immunological, and inflammatory response to retinal photocoagulation of intense rupture laser lesions as a model of retinal degenerative diseases.Seven C57BL/6 mice were irradiated using a 532-nm laser to induce 10 retinal burns per eye that ruptured Bruch's membrane. Blood was drawn from the saphenous vein before and 2 months after laser treatment. The serum was run on antigen microarrays with 85 molecular markers associated with retinal degenerative diseases.Rupture laser resulted in dramatic changes in the immunoglobulin reactivity of most inflammatory markers 2 months after laser injury. Approximately two-thirds increased expression and one-third decreased expression. Notable markers that were increased included complement C3, CRP, PKM2, and aldolase.Rupture laser injury causes a change in the serum inflammatory markers after 2 months similar to macular degeneration, diabetic retinopathy, and cancer-associated retinopathy. This animal model could be used as a biomarker for disease stage and activity in retinal degenerations.

  View details for DOI 10.3928/23258160-20150323-11

  View details for Web of Science ID 000359291400012

  View details for PubMedID 25856824

• NONDAMAGING PHOTOTHERMAL THERAPY FOR THE RETINA Initial Clinical Experience With Chronic Central Serous Retinopathy RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Lavinsky, D., Palanker, D. 2015; 35 (2): 213-222

  Abstract

  To assess safety and clinical efficacy of the nondamaging photothermal therapy for the macula for the treatment of chronic central serous retinopathy.Sixteen eyes of 16 patients with persistent central serous retinopathy (>4 months of duration) were treated with the PASCAL Streamline) at 577-nm wavelength, using 200-μm retinal spot sizes. Using Endpoint Management Software, the laser power was first titrated for a barely visible burn with 15-ms pulses, which was defined as 100% pulse energy. Treatment was then applied over the area of serous retinal detachment and adjacent nonthickened retina, using 30% pulse energy with the spot spacing of 0.25 beam diameter. Changes in subretinal fluid, Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, and central macular thickness were measured over 6 months of follow-up. Pretreatment and posttreatment fluorescein angiography and fundus autofluorescence were also assessed.On average, 532 spots have been applied per treatment. No visible laser marks could be detected by clinical observation, optical coherence tomography, fundus autofluorescence, or fluorescein angiography. On average, 12 Early Treatment Diabetic Retinopathy Study letters gain was achieved at 2 months and was sustained by 6 months (P < 0.001). Central macular thickness decreased from 350 μm to 282 μm (P = 0.004). Subretinal fluid completely resolved in 37% of the patients after first treatment, whereas 44% of the patients required retreatment after 3 months because of recurrent fluid or incomplete resolution. The remaining 19% of the patients received a second retreatment. By 6 months, in 75% of the patients, the subretinal fluid was completely resolved, whereas in 25%, there was some minimal fluid left.Photothermal therapy using 577-nm PASCAL laser with Endpoint Management graphic user interface was safe, and it improved visual acuity and resolution of subretinal fluid in chronic central serous retinopathy. Lack of tissue damage allows periodic retreatment without cumulative scaring, characteristic to conventional photocoagulation. This technique should be tested in the treatment of other macular disorders and may offer an alternative to conventional laser coagulation of the macula and to anti-vascular endothelial growth factor pharmacological treatments of macular diseases.

  View details for Web of Science ID 000348764200008

  View details for PubMedID 25158944

• Role of molecular photodissociation in ultrafast laser surgery Conference on Optical Interactions with Tissue and Cells XXVI Wang, J., Schuele, G., Huie, P., Palanker, D. V. SPIE-INT SOC OPTICAL ENGINEERING. 2015

  View details for DOI 10.1117/12.2077004

  View details for Web of Science ID 000353616800005

• Photovoltaic Restoration of Sight with High Visual Acuity in Rats with Retinal Degeneration 25th Conference on Ophthalmic Technologies held as a part of the SPIE Photonics West BiOS Meeting Palanker, D., Goetz, G., Lorach, H., Mandel, Y., Smith, R., Boinagrov, D., Lei, X., KAMINS, T., Harris, J., Mathieson, K., Sher, A. SPIE-INT SOC OPTICAL ENGINEERING. 2015

  View details for DOI 10.1117/12.2081068

  View details for Web of Science ID 000353411700013

• Reply to Rattay. Journal of neurophysiology Boinagrov, D., Palanker, D. 2014; 112 (10): 2666-?

  View details for DOI 10.1152/jn.z9k-2655-reply.2014

  View details for PubMedID 25399449

  View details for PubMedCentralID PMC4233274

• Inner retinal preservation in rat models of retinal degeneration implanted with subretinal photovoltaic arrays EXPERIMENTAL EYE RESEARCH Light, J. G., Fransen, J. W., Adekunle, A. N., Adkins, A., Pangeni, G., Loudin, J., Mathieson, K., Palanker, D. V., Mccall, M. A., Pardue, M. T. 2014; 128: 34-42

  Abstract

  Photovoltaic arrays (PVA) implanted into the subretinal space of patients with retinitis pigmentosa (RP) are designed to electrically stimulate the remaining inner retinal circuitry in response to incident light, thereby recreating a visual signal when photoreceptor function declines or is lost. Preservation of inner retinal circuitry is critical to the fidelity of this transmitted signal to ganglion cells and beyond to higher visual targets. Post-implantation loss of retinal interneurons or excessive glial scarring could diminish and/or eliminate PVA-evoked signal transmission. As such, assessing the morphology of the inner retina in RP animal models with subretinal PVAs is an important step in defining biocompatibility and predicting success of signal transmission. In this study, we used immunohistochemical methods to qualitatively and quantitatively compare inner retinal morphology after the implantation of a PVA in two RP models: the Royal College of Surgeons (RCS) or transgenic S334ter-line 3 (S334ter-3) rhodopsin mutant rat. Two PVA designs were compared. In the RCS rat, we implanted devices in the subretinal space at 4 weeks of age and histologically examined them at 8 weeks of age and found inner retinal morphology preservation with both PVA devices. In the S334ter-3 rat, we implanted devices at 6-12 weeks of age and again, inner retinal morphology was generally preserved with either PVA design 16-26 weeks post-implantation. Specifically, the length of rod bipolar cells and numbers of cholinergic amacrine cells were maintained along with their characteristic inner plexiform lamination patterns. Throughout the implanted retinas we found nonspecific glial reaction, but none showed additional glial scarring at the implant site. Our results indicate that subretinally implanted PVAs are well-tolerated in rodent RP models and that the inner retinal circuitry is preserved, consistent with our published results showing implant-evoked signal transmission.

  View details for DOI 10.1016/j.exer.2014.09.004

  View details for Web of Science ID 000344312300006

  View details for PubMedCentralID PMC4566954

• Inner retinal preservation in rat models of retinal degeneration implanted with subretinal photovoltaic arrays. Experimental eye research Light, J. G., Fransen, J. W., Adekunle, A. N., Adkins, A., Pangeni, G., Loudin, J., Mathieson, K., Palanker, D. V., Mccall, M. A., Pardue, M. T. 2014; 128: 34-42

  Abstract

  Photovoltaic arrays (PVA) implanted into the subretinal space of patients with retinitis pigmentosa (RP) are designed to electrically stimulate the remaining inner retinal circuitry in response to incident light, thereby recreating a visual signal when photoreceptor function declines or is lost. Preservation of inner retinal circuitry is critical to the fidelity of this transmitted signal to ganglion cells and beyond to higher visual targets. Post-implantation loss of retinal interneurons or excessive glial scarring could diminish and/or eliminate PVA-evoked signal transmission. As such, assessing the morphology of the inner retina in RP animal models with subretinal PVAs is an important step in defining biocompatibility and predicting success of signal transmission. In this study, we used immunohistochemical methods to qualitatively and quantitatively compare inner retinal morphology after the implantation of a PVA in two RP models: the Royal College of Surgeons (RCS) or transgenic S334ter-line 3 (S334ter-3) rhodopsin mutant rat. Two PVA designs were compared. In the RCS rat, we implanted devices in the subretinal space at 4 weeks of age and histologically examined them at 8 weeks of age and found inner retinal morphology preservation with both PVA devices. In the S334ter-3 rat, we implanted devices at 6-12 weeks of age and again, inner retinal morphology was generally preserved with either PVA design 16-26 weeks post-implantation. Specifically, the length of rod bipolar cells and numbers of cholinergic amacrine cells were maintained along with their characteristic inner plexiform lamination patterns. Throughout the implanted retinas we found nonspecific glial reaction, but none showed additional glial scarring at the implant site. Our results indicate that subretinally implanted PVAs are well-tolerated in rodent RP models and that the inner retinal circuitry is preserved, consistent with our published results showing implant-evoked signal transmission.

  View details for DOI 10.1016/j.exer.2014.09.004

  View details for PubMedID 25224340

  View details for PubMedCentralID PMC4566954

• Miniature Electrical Stimulator for Hemorrhage Control IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Brinton, M. R., Mandel, Y., Dalal, R., Palanker, D. 2014; 61 (6): 1765-1771

  View details for DOI 10.1109/TBME.2014.2306672

  View details for Web of Science ID 000337736000020

• Miniature electrical stimulator for hemorrhage control. IEEE transactions on bio-medical engineering Brinton, M. R., Mandel, Y., Dalal, R., Palanker, D. 2014; 61 (6): 1765-1771

  Abstract

  Noncompressible hemorrhage is currently the most common cause of preventable death in battlefield and in civilian trauma injuries. Tourniquets, specialized wound dressings, and hemorrhage-inhibiting biomaterials are not sufficiently effective in arrest of noncompressible hemorrhage and often cause collateral tissue damage. An effective, easy-to-use, portable device is needed to reduce blood loss in trauma patients immediately following injury and to maintain hemorrhage control up to several hours-until the injured is evacuated to a medical facility. We developed a miniature electrical stimulator to induce vascular constriction and, thereby, reduce hemorrhage. Vasoconstriction of the rat femoral arteries and veins was studied with pulse durations in the range of 1 μs to 10 ms and repetition rate of 10 Hz. Pulse amplitude of 20 V, duration of 1 ms, and repetition rate of 10 Hz were found sufficient to induce rapid constriction down to 31 ± 2% of the initial diameter, which could be maintained throughout a two-hour treatment. Within one minute following treatment termination the artery dilated back to 88 ± 3% of the initial diameter, providing rapid restoration of blood perfusion. Histology indicated no damage to the vessel wall and endothelium seven days after stimulation. The same treatment reduced the blood loss following complete femoral artery resection by 68 ± 11%, compared to untreated vessels. Very low power consumption during stimulation (<10 mW per 1.6 mm electrode) allows miniaturization of the stimulator for portable battery-powered operation in the field to control the blood loss following vascular trauma.

  View details for DOI 10.1109/TBME.2014.2306672

  View details for PubMedID 24845287

• Selectivity of direct and network-mediated stimulation of the retinal ganglion cells with epi-, sub- and intraretinal electrodes. Journal of neural engineering Boinagrov, D., Pangratz-Fuehrer, S., Goetz, G., Palanker, D. 2014; 11 (2): 026008-?

  View details for DOI 10.1088/1741-2560/11/2/026008

  View details for PubMedID 24608166

• Selectivity of direct and network-mediated stimulation of the retinal ganglion cells with epi-, sub- and intraretinal electrodes. Journal of neural engineering Boinagrov, D., Pangratz-Fuehrer, S., Goetz, G., Palanker, D. 2014; 11 (2): 026008-?

  Abstract

  Objective. Intra-retinal placement of stimulating electrodes can provide close and stable proximity to target neurons. We assessed improvement in stimulation thresholds and selectivity of the direct and network-mediated retinal stimulation with intraretinal electrodes, compared to epiretinal and subretinal placements. Approach. Stimulation thresholds of the retinal ganglion cells (RGCs) in wild-type rat retina were measured using the patch-clamp technique. Direct and network-mediated responses were discriminated using various synaptic blockers. Main results. Three types of RGC responses were identified: short latency (SL, τ < 5 ms) originating in RGCs, medium latency (ML, 3 < τ < 70 ms) originating in the inner nuclear layer and long latency (LL, τ > 40 ms) originating in photoreceptors. Cathodic epiretinal stimulation exhibited the lowest threshold for direct RGC response and the highest direct selectivity (network/direct thresholds ratio), exceeding a factor of 3 with pulse durations below 0.5 ms. For network-mediated stimulation, the lowest threshold was obtained with anodic pulses in OPL position, and its network selectivity (direct/network thresholds ratio) increased with pulse duration, exceeding a factor of 4 at 10 ms. Latency of all three types of responses decreased with increasing strength of the stimulus. Significance. These results define the optimal range of pulse durations, pulse polarities and electrode placement for the retinal prostheses aiming at direct or network-mediated stimulation of RGCs.

  View details for DOI 10.1088/1741-2560/11/2/026008

  View details for PubMedID 24608166

• Subvisible retinal laser therapy: titration algorithm and tissue response. Retina (Philadelphia, Pa.) Lavinsky, D., Sramek, C., Wang, J., Huie, P., Dalal, R., Mandel, Y., Palanker, D. 2014; 34 (1): 87-97

  Abstract

  Laser therapy for diabetic macular edema and other retinal diseases has been used within a wide range of laser settings: from intense burns to nondamaging exposures. However, there has been no algorithm for laser dosimetry that could determine laser parameters yielding a predictable extent of tissue damage. This multimodal imaging and structural correlation study aimed to verify and calibrate a computational model-based titration algorithm for predictable laser dosimetry ranging from nondamaging to intense coagulative tissue effects.Endpoint Management, an algorithm based on a computational model of retinal photothermal damage, was used to set laser parameters for various levels of tissue effect. The algorithm adjusts both power and pulse duration to vary the expected level of thermal damage at different percentages of a reference titration energy dose. Experimental verification was conducted in Dutch Belted rabbits using a PASCAL Streamline 577 laser system. Titration was performed by adjusting laser power to produce a barely visible lesion at 20 ms pulse duration, which is defined as the nominal (100%) energy level. Tissue effects were then determined for energy levels of 170, 120, 100, 75, 50, and 30% of the nominal energy at 1 hour and 3, 7, 30, and 60 days after treatment. In vivo imaging included fundus autofluorescence, fluorescein angiography, and spectral-domain optical coherence tomography. Morphologic changes in tissue were analyzed using light microscopy, as well as scanning and transmission electron microscopy.One hundred and seventy percent and 120% levels corresponded to moderate and light burns, respectively, with damage to retinal pigment epithelium, photoreceptors, and at highest settings, to the inner retina. 50% to 75% lesions were typically subvisible ophthalmoscopically but detectable with fluorescein angiography and optical coherence tomography. Histology in these lesions demonstrated some selective damage to retinal pigment epithelium and photoreceptors. The 30% to 50% lesions were invisible with in vivo multimodal imaging, and damage was limited primarily to retinal pigment epithelium, visible best with scanning electron microscopy. Over time, photoreceptors shifted into the coagulated zone, reestablishing normal retinal anatomy in lesions ≤100%, as seen in optical coherence tomography and light microscopy. Transmission electron microscopy at 2 months demonstrated restoration of synapses between shifted-in photoreceptors and bipolar cells in these lesions. Retinal pigment epithelium monolayer restored its continuity after 1 week in all lesions. No damage could be seen <30% level.A retinal laser dosimetry protocol based on the Endpoint Management algorithm provides reproducible changes in retinal morphology in animals with various levels of pigmentation. This algorithm opens doors to clinical trials of well-defined subvisible and nondestructive regimes of retinal therapy, especially important for treatment of macular disorders.

  View details for DOI 10.1097/IAE.0b013e3182993edc

  View details for PubMedID 23873164

• Non-damaging Laser Therapy of the Macula: Titration Algorithm and Tissue Response 24th Conference on Ophthalmic Technologies as a part of the SPIE Photonics West BiOS Meeting Palanker, D., Lavinsky, D., Dalal, R., Huie, P. SPIE-INT SOC OPTICAL ENGINEERING. 2014

  View details for DOI 10.1117/12.2036870

  View details for Web of Science ID 000334350000021

• Holographic display system for restoration of sight to the blind. Journal of neural engineering Goetz, G. A., Mandel, Y., Manivanh, R., Palanker, D. V., Cižmár, T. 2013; 10 (5): 056021-?

  Abstract

  Objective. We present a holographic near-the-eye display system enabling optical approaches for sight restoration to the blind, such as photovoltaic retinal prosthesis, optogenetic and other photoactivation techniques. We compare it with conventional liquid crystal displays (LCD) or digital light processing (DLP)-based displays in terms of image quality, field of view, optical efficiency and safety. Approach. We detail the optical configuration of the holographic display system and its characterization using a phase-only spatial light modulator. Main results. We describe approaches to controlling the zero diffraction order and speckle related issues in holographic display systems and assess the image quality of such systems. We show that holographic techniques offer significant advantages in terms of peak irradiance and power efficiency, and enable designs that are inherently safer than LCD or DLP-based systems. We demonstrate the performance of our holographic display system in the assessment of cortical response to alternating gratings projected onto the retinas of rats. Significance. We address the issues associated with the design of high brightness, near-the-eye display systems and propose solutions to the efficiency and safety challenges with an optical design which could be miniaturized and mounted onto goggles.

  View details for DOI 10.1088/1741-2560/10/5/056021

  View details for PubMedID 24045579

• Vasoconstriction by Electrical Stimulation: New Approach to Control of Non-Compressible Hemorrhage SCIENTIFIC REPORTS Mandel, Y., Manivanh, R., Dalal, R., Huie, P., Wang, J., Brinton, M., Palanker, D. 2013; 3

  Abstract

  Non-compressible hemorrhage is the most common preventable cause of death on battlefield and in civilian traumatic injuries. We report the use of microsecond pulses of electric current to induce rapid constriction in femoral and mesenteric arteries and veins in rats. Electrically-induced vasoconstriction could be induced in seconds while blood vessels dilated back to their original size within minutes after stimulation. At higher settings, a blood clotting formed, leading to complete and permanent occlusion of the vessels. The latter regime dramatically decreased the bleeding rate in the injured femoral and mesenteric arteries, with a complete hemorrhage arrest achieved within seconds. The average blood loss from the treated femoral artery during the first minute after injury was about 7 times less than that of a non-treated control. This new treatment modality offers a promising approach to non-damaging control of bleeding during surgery, and to efficient hemorrhage arrest in trauma patients.

  View details for DOI 10.1038/srep02111

  View details for Web of Science ID 000321287200001

  View details for PubMedID 23828130

  View details for PubMedCentralID PMC3701318

• Cortical responses elicited by photovoltaic subretinal prostheses exhibit similarities to visually evoked potentials. Nature communications Mandel, Y., Goetz, G., Lavinsky, D., Huie, P., Mathieson, K., Wang, L., Kamins, T., Galambos, L., Manivanh, R., Harris, J., Palanker, D. 2013; 4: 1980-?

  Abstract

  We have previously developed a wireless photovoltaic retinal prosthesis, in which camera-captured images are projected onto the retina using pulsed near-IR light. Each pixel in the subretinal implant directly converts pulsed light into local electric current to stimulate the nearby inner retinal neurons. Here we report that implants having pixel sizes of 280, 140 and 70 μm implanted in the subretinal space in rats with normal and degenerate retina elicit robust cortical responses upon stimulation with pulsed near-IR light. Implant-induced eVEP has shorter latency than visible light-induced VEP, its amplitude increases with peak irradiance and pulse duration, and decreases with frequency in the range of 2-20 Hz, similar to the visible light response. Modular design of the arrays allows scalability to a large number of pixels, and combined with the ease of implantation, offers a promising approach to restoration of sight in patients blinded by retinal degenerative diseases.

  View details for DOI 10.1038/ncomms2980

  View details for PubMedID 23778557

• Restoration of retinal morphology and residual scarring after photocoagulation. Acta ophthalmologica Lavinsky, D., Cardillo, J. A., Mandel, Y., Huie, P., Melo, L. A., Farah, M. E., Belfort, R., Palanker, D. 2013; 91 (4): e315-23

  Abstract

  Purpose:  To study healing of retinal laser lesions in patients undergoing PRP using SD-OCT. Methods:  Moderate, light and barely visible retinal burns were produced in patients with proliferative diabetic retinopathy scheduled for PRP using 100-, 20- and 10-ms pulses of 532-nm laser, with retinal spot sizes of 100, 200 and 400 μm. Lesions were measured with OCT at 1 hr, 1 week, 1, 2, 4, 6, 9 and 12 months. OCT imaging was correlated with histology in a separate study in rabbits. Results:  Lesions produced by the standard 100-ms exposures exhibited steady scarring, with the damage zone stabilized after 2 months. For 400- and 200-μm spots and 100-ms pulses, the residual scar area at 12 months was approximately 50% of the initial lesion size for moderate, light and barely visible burns. In contrast, lesions produced by shorter exposures demonstrated enhanced restoration of the photoreceptor layer, especially in smaller burns. With 20-ms pulses, the damage zone decreased to 32%, 24% and 20% for moderate, light and barely visible burns of 400 μm, respectively, and down to 12% for barely visible burns of 200 μm. In the 100-μm spots, the residual scar area of the moderate 100-ms burns was 41% of the initial lesion, while barely visible 10-ms burns contracted to 6% of the initial size. Histological observations in rabbits were useful for proper interpretation of the damage zone boundaries in OCT. Conclusions:  Traditional photocoagulation parameters (400 μm, 100 ms and moderate burn) result in a stable scar similar in size to the beam diameter. Restoration of the damaged photoreceptor layer in lighter lesions produced by shorter pulses should allow reducing the common side-effects of photocoagulation such as scotomata and scarring.

  View details for DOI 10.1111/aos.12045

  View details for PubMedID 23557390

• Restoration of Retinal Structure and Function after Selective Photocoagulation JOURNAL OF NEUROSCIENCE Sher, A., Jones, B. W., Huie, P., Paulus, Y. M., Lavinsky, D., Leung, L. S., Nomoto, H., Beier, C., Marc, R. E., Palanker, D. 2013; 33 (16): 6800-6808

  Abstract

  CNS neurons change their connectivity to accommodate a changing environment, form memories, or respond to injury. Plasticity in the adult mammalian retina after injury or disease was thought to be limited to restructuring resulting in abnormal retinal anatomy and function. Here we report that neurons in the mammalian retina change their connectivity and restore normal retinal anatomy and function after injury. Patches of photoreceptors in the rabbit retina were destroyed by selective laser photocoagulation, leaving retinal inner neurons (bipolar, amacrine, horizontal, ganglion cells) intact. Photoreceptors located outside of the damaged zone migrated to make new functional connections with deafferented bipolar cells located inside the lesion. The new connections restored ON and OFF responses in deafferented ganglion cells. This finding extends the previously perceived limits of restorative plasticity in the adult retina and allows for new approaches to retinal laser therapy free of current detrimental side effects such as scotomata and scarring.

  View details for DOI 10.1523/JNEUROSCI.1044-12.2013

  View details for Web of Science ID 000317723000012

  View details for PubMedID 23595739

• Optical patient interface in femtosecond laser-assisted cataract surgery: Contact corneal applanation versus liquid immersion JOURNAL OF CATARACT AND REFRACTIVE SURGERY Talamo, J. H., Gooding, P., Angeley, D., Culbertson, W. W., Schuele, G., Andersen, D., Marcellino, G., Essock-Burns, E., Batlle, J., Feliz, R., Friedman, N. J., Palanker, D. 2013; 39 (4): 501-510

  Abstract

  To compare 2 optical patient interface designs used for femtosecond laser-assisted cataract surgery.Optimedica Corp., Santa Clara, California, USA, and Centro Laser, Santo Domingo, Dominican Republic.Experimental and clinical studies.Laser capsulotomy was performed during cataract surgery with a curved contact lens interface (CCL) or a liquid optical immersion interface (LOI). The presence of corneal folds, incomplete capsulotomy, subconjunctival hemorrhage, and eye movement during laser treatment were analyzed using video and optical coherence tomography. The induced rise of intraocular pressure (IOP) was measured in porcine and cadaver eyes.Corneal folds were identified in 70% of the CCL cohort; 63% of these had areas of incomplete capsulotomies beneath the corneal folds. No corneal folds or incomplete capsulotomies were identified in the LOI cohort. The mean eye movement during capsulotomy creation (1.5 sec) was 50 μm with a CCL and 20 μm with an LOI. The LOI cohort had 36% less subconjunctival hemorrhage than the CCL cohort. During suction, the mean IOP rise was 32.4 mm Hg ± 3.4 (SD) in the CCL group and 17.7 ± 2.1 mm Hg in the LOI group.Curved contact interfaces create corneal folds that can lead to incomplete capsulotomy during laser cataract surgery. A liquid interface eliminated corneal folds, improved globe stability, reduced subconjunctival hemorrhage, and lowered IOP rise.

  View details for DOI 10.1016/j.jcrs.2013.01.021

  View details for Web of Science ID 000317871900004

  View details for PubMedID 23434216

• Modulation of Transgene Expression in Retinal Gene Therapy by Selective Laser Treatment INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Lavinsky, D., Chalberg, T. W., Mandel, Y., Huie, P., Dalal, R., Marmor, M., Palanker, D. 2013; 54 (3): 1873-1880

  Abstract

  To develop a method for modulation of transgene expression in retinal pigment epithelium (RPE) using scanning laser that spares neurosensory retina.Fifteen pigmented rabbits received subretinal injection of recombinant adeno-associated virus (rAAV-2) encoding green fluorescent protein (GFP). GFP expression was measured using confocal scanning laser ophthalmoscopy (cSLO) fluorescence imaging and immunohistochemistry. To reduce the total expression in RPE by half, 50% of the transfected RPE cells were selectively destroyed by microsecond exposures to scanning laser with 50% pattern density. The selectivity of RPE destruction and its migration and proliferation were monitored using fluorescein angiography, spectral-domain optical coherence tomography (SD-OCT), and light, transmission, and scanning electron microscopy. 5-Bromo-2'-dioxyuridine (BrdU) assay was performed to evaluate proliferation of RPE cells.RPE cells were selectively destroyed by the line scanning laser with 15 μs exposures, without damage to the photoreceptors or Bruch's membrane. RPE cells started migrating after the first day, and in 1 week there was complete restoration of RPE monolayer. Selective laser treatment decreased the GFP fluorescence by 54% as compared to control areas; this was further decreased by an additional 48% following a second treatment 1 month later. BrdU assay demonstrated proliferation in approximately half of the RPE cells in treatment areas.Microsecond exposures produced by scanning laser destroyed RPE cells selectively, without damage to neural retina. Continuity of RPE layer is restored within days by migration and proliferation, but transgene not integrated into the nucleus is not replicated. Therefore, gene expression can be modulated in a precise manner by controlling the laser pattern density and further adjusted using repeated applications.

  View details for DOI 10.1167/iovs.12-10933

  View details for PubMedID 23422827

• EFFECT OF INTRAVITREAL TRIAMCINOLONE ACETONIDE ON HEALING OF RETINAL PHOTOCOAGULATION LESIONS RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Nomoto, H., Lavinsky, D., Paulus, Y. M., Leung, L., Dalal, R., Blumenkranz, M. S., Palanker, D. 2013; 33 (1): 63-70

  Abstract

  To evaluate the effect of intravitreal triamcinolone acetonide (TA) on healing of retinal photocoagulation lesions using drug and laser dosing typically employed in clinical practice.Laser burns with a 267-μm retinal beam size at 532-nm wavelength were applied to 40 eyes of Dutch belted rabbits. Barely visible to intense lesions were produced with pulses of 5, 10, 20, and 50 milliseconds and power of 175 mW. Eyes received intravitreal injections of either 2 mg TA/50 μL or balanced salt solution administered either 1 week before or immediately after laser treatment. Lesion grades were assessed acutely ophthalmoscopically and by a masked observer histologically at 1, 3, 7, 30, and 60 days.Both TA groups demonstrated significant reduction in retinal thickness throughout follow-up compared with balanced salt solution groups (P < 0.001). The width of the lesions at 1 day after injection was not significantly different between groups. However, by 7 days, the lesions in balanced salt solution groups contracted much more than in the TA groups, especially the more intense burns, and this difference persisted to 2 months. The healing rate of the barely visible burns was not significantly affected by TA compared with the balanced salt solution control eyes.Triamcinolone acetonide injection previously or concurrently with photocoagulation significantly decreases laser-induced edema but interferes with lesions healing, thereby leaving wider residual scarring, especially persistent in more intense burns.

  View details for DOI 10.1097/IAE.0b013e318261e34b

  View details for Web of Science ID 000313422500008

  View details for PubMedID 23026846

• Ocular safety limits for 1030 nm femtosecond laser cataract surgery Conference on Ophthalmic Technologies XXIII as a part of the SPIE Photonics West BiOS Meeting Wang, J., Sramek, C., Paulus, Y. M., Lavinsky, D., Schuele, G., Anderson, D., Dewey, D., Palanker, D. V. SPIE-INT SOC OPTICAL ENGINEERING. 2013

  View details for DOI 10.1117/12.2001895

  View details for Web of Science ID 000325430800004

• Hemorrhage Control by Microsecond Electrical Pulses Conference on Terahertz and Ultrashort Electromagnetic Pulses for Biomedical Applications Mandel, Y., Manivanh, R., Dalal, R., Huie, P., Wang, J., Brinton, M., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2013

  View details for DOI 10.1117/12.2002303

  View details for Web of Science ID 000325500100010

• Optical Modulation of Transgene Expression in Retinal Pigment Epithelium Conference on Ophthalmic Technologies XXIII as a part of the SPIE Photonics West BiOS Meeting Palanker, D., Lavinsky, D., Chalberg, T., Mandel, Y., Huie, P., Dalal, R., Marmor, M. SPIE-INT SOC OPTICAL ENGINEERING. 2013

  View details for DOI 10.1117/12.2001923

  View details for Web of Science ID 000325430800006

• In-vivo Performance of Photovoltaic Subretinal Prosthesis Conference on Ophthalmic Technologies XXIII as a part of the SPIE Photonics West BiOS Meeting Mandel, Y., Goetz, G., Lavinsky, D., Huie, P., Mathieson, K., Wang, L., Kamins, T., Manivanh, R., Harris, J., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2013

  View details for DOI 10.1117/12.2001750

  View details for Web of Science ID 000325430800005

• Vasoconstriction by electrical stimulation: new approach to control of non-compressible hemorrhage. Scientific reports Mandel, Y., Manivanh, R., Dalal, R., Huie, P., Wang, J., Brinton, M., Palanker, D. 2013; 3: 2111-?

  Abstract

  Non-compressible hemorrhage is the most common preventable cause of death on battlefield and in civilian traumatic injuries. We report the use of microsecond pulses of electric current to induce rapid constriction in femoral and mesenteric arteries and veins in rats. Electrically-induced vasoconstriction could be induced in seconds while blood vessels dilated back to their original size within minutes after stimulation. At higher settings, a blood clotting formed, leading to complete and permanent occlusion of the vessels. The latter regime dramatically decreased the bleeding rate in the injured femoral and mesenteric arteries, with a complete hemorrhage arrest achieved within seconds. The average blood loss from the treated femoral artery during the first minute after injury was about 7 times less than that of a non-treated control. This new treatment modality offers a promising approach to non-damaging control of bleeding during surgery, and to efficient hemorrhage arrest in trauma patients.

  View details for DOI 10.1038/srep02111

  View details for PubMedID 23828130

  View details for PubMedCentralID PMC3701318

• Cortical responses elicited by photovoltaic subretinal prostheses exhibit similarities to visually evoked potentials. Nature communications Mandel, Y., Goetz, G., Lavinsky, D., Huie, P., Mathieson, K., Wang, L., Kamins, T., Galambos, L., Manivanh, R., Harris, J., Palanker, D. 2013; 4: 1980-?

  Abstract

  We have previously developed a wireless photovoltaic retinal prosthesis, in which camera-captured images are projected onto the retina using pulsed near-IR light. Each pixel in the subretinal implant directly converts pulsed light into local electric current to stimulate the nearby inner retinal neurons. Here we report that implants having pixel sizes of 280, 140 and 70 μm implanted in the subretinal space in rats with normal and degenerate retina elicit robust cortical responses upon stimulation with pulsed near-IR light. Implant-induced eVEP has shorter latency than visible light-induced VEP, its amplitude increases with peak irradiance and pulse duration, and decreases with frequency in the range of 2-20 Hz, similar to the visible light response. Modular design of the arrays allows scalability to a large number of pixels, and combined with the ease of implantation, offers a promising approach to restoration of sight in patients blinded by retinal degenerative diseases.

  View details for DOI 10.1038/ncomms2980

  View details for PubMedID 23778557

• Femtosecond plasma mediated laser ablation has advantages over mechanical osteotomy of cranial bone LASERS IN SURGERY AND MEDICINE Lo, D. D., Mackanos, M. A., Chung, M. T., Hyun, J. S., Montoro, D. T., Grova, M., Liu, C., Wang, J., Palanker, D., Connolly, A. J., Longaker, M. T., Contag, C. H., Wan, D. C. 2012; 44 (10): 805-814

  Abstract

  Although mechanical osteotomies are frequently made on the craniofacial skeleton, collateral thermal, and mechanical trauma to adjacent bone tissue causes cell death and may delay healing. The present study evaluated the use of plasma-mediated laser ablation using a femtosecond laser to circumvent thermal damage and improve bone regeneration.Critical-size circular calvarial defects were created with a trephine drill bit or with a Ti:Sapphire femtosecond pulsed laser. Healing was followed using micro-CT scans for 8 weeks. Calvaria were also harvested at various time points for histological analysis. Finally, scanning electron microscopy was used to analyze the microstructure of bone tissue treated with the Ti:Sapphire laser, and compared to that treated with the trephine bur.Laser-created defects healed significantly faster than those created mechanically at 2, 4, and 6 weeks post-surgery. However, at 8 weeks post-surgery, there was no significant difference. In the drill osteotomy treatment group, empty osteocyte lacunae were seen to extend 699 ± 27 µm away from the edge of the defect. In marked contrast, empty osteocyte lacunae were seen to extend only 182 ± 22 µm away from the edge of the laser-created craters. Significantly less ossification and formation of irregular woven bone was noted on histological analysis for drill defects.We demonstrate accelerated bone healing after femtosecond laser ablation in a calvarial defect model compared to traditional mechanical drilling techniques. Improved rates of early regeneration make plasma-mediated ablation of the craniofacial skeleton advantageous for applications to osteotomy.

  View details for DOI 10.1002/lsm.22098

  View details for Web of Science ID 000312941600004

  View details for PubMedID 23184427

• Upper threshold of extracellular neural stimulation JOURNAL OF NEUROPHYSIOLOGY Boinagrov, D., Pangratz-Fuehrer, S., Suh, B., Mathieson, K., Naik, N., Palanker, D. 2012; 108 (12): 3233-3238

  Abstract

  It is well known that spiking neurons can produce action potentials in response to extracellular stimulation above certain threshold. It is widely assumed that there is no upper limit to somatic stimulation, except for cellular or electrode damage. Here we demonstrate that there is an upper stimulation threshold, above which no action potential can be elicited, and it is below the threshold of cellular damage. Existence of this upper stimulation threshold was confirmed in retinal ganglion cells (RGCs) at pulse durations ranging from 5 to 500 μs. The ratio of the upper to lower stimulation thresholds varied typically from 1.7 to 7.6, depending on pulse duration. Computational modeling of extracellular RGC stimulation explained the upper limit by sodium current reversal on the depolarized side of the cell membrane. This was further confirmed by experiments in the medium with a low concentration of sodium. The limited width of the stimulation window may have important implications in design of the electro-neural interfaces, including neural prosthetics.

  View details for DOI 10.1152/jn.01058.2011

  View details for Web of Science ID 000312589100006

  View details for PubMedID 22993266

  View details for PubMedCentralID PMC3544878

• Retinal safety of near-infrared lasers in cataract surgery JOURNAL OF BIOMEDICAL OPTICS Wang, J., Sramek, C., Paulus, Y. M., Lavinsky, D., Schuele, G., Anderson, D., Dewey, D., Palanker, D. 2012; 17 (9)

  Abstract

  Femtosecond lasers have added unprecedented precision and reproducibility to cataract surgery. However, retinal safety limits for the near-infrared lasers employed in surgery are not well quantified. We determined retinal injury thresholds for scanning patterns while considering the effects of reduced blood perfusion from rising intraocular pressure and retinal protection from light scattering on bubbles and tissue fragments produced by laser cutting. We measured retinal damage thresholds of a stationary, 1030-nm, continuous-wave laser with 2.6-mm retinal spot size for 10- and 100-s exposures in rabbits to be 1.35 W (1.26 to 1.42) and 0.78 W (0.73 to 0.83), respectively, and 1.08 W (0.96 to 1.11) and 0.36 W (0.33 to 0.41) when retinal perfusion is blocked. These thresholds were input into a computational model of ocular heating to calculate damage threshold temperatures. By requiring the tissue temperature to remain below the damage threshold temperatures determined in stationary beam experiments, one can calculate conservative damage thresholds for cataract surgery patterns. Light scattering on microbubbles and tissue fragments decreased the transmitted power by 88% within a 12 deg angle, adding a significant margin for retinal safety. These results can be used for assessment of the maximum permissible exposure during laser cataract surgery under various assumptions of blood perfusion, treatment duration, and scanning patterns.

  View details for DOI 10.1117/1.JBO.17.9.095001

  View details for Web of Science ID 000309905700007

  View details for PubMedID 23085903

• Photovoltaic retinal prosthesis: implant fabrication and performance JOURNAL OF NEURAL ENGINEERING Wang, L., Mathieson, K., Kamins, T. I., Loudin, J. D., Galambos, L., Goetz, G., Sher, A., Mandel, Y., Huie, P., Lavinsky, D., Harris, J. S., Palanker, D. V. 2012; 9 (4)

  Abstract

  The objective of this work is to develop and test a photovoltaic retinal prosthesis for restoring sight to patients blinded by degenerative retinal diseases. A silicon photodiode array for subretinal stimulation has been fabricated by a silicon-integrated-circuit/MEMS process. Each pixel in the two-dimensional array contains three series-connected photodiodes, which photovoltaically convert pulsed near-infrared light into bi-phasic current to stimulate nearby retinal neurons without wired power connections. The device thickness is chosen to be 30 µm to absorb a significant portion of light while still being thin enough for subretinal implantation. Active and return electrodes confine current near each pixel and are sputter coated with iridium oxide to enhance charge injection levels and provide a stable neural interface. Pixels are separated by 5 µm wide trenches to electrically isolate them and to allow nutrient diffusion through the device. Three sizes of pixels (280, 140 and 70 µm) with active electrodes of 80, 40 and 20 µm diameter were fabricated. The turn-on voltages of the one-diode, two-series-connected diode and three-series-connected diode structures are approximately 0.6, 1.2 and 1.8 V, respectively. The measured photo-responsivity per diode at 880 nm wavelength is ∼0.36 A W(-1), at zero voltage bias and scales with the exposed silicon area. For all three pixel sizes, the reverse-bias dark current is sufficiently low (<100 pA) for our application. Pixels of all three sizes reliably elicit retinal responses at safe near-infrared light irradiances, with good acceptance of the photodiode array in the subretinal space. The fabricated device delivers efficient retinal stimulation at safe near-infrared light irradiances without any wired power connections, which greatly simplifies the implantation procedure. Presence of the return electrodes in each pixel helps to localize the current, and thereby improves resolution.

  View details for DOI 10.1088/1741-2560/9/4/046014

  View details for Web of Science ID 000306759600027

  View details for PubMedID 22791690

  View details for PubMedCentralID PMC3419261

• Therapeutic Window of Retinal Photocoagulation With Green (532-nm) and Yellow (577-nm) Lasers Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) Sramek, C. K., Leung, L. B., Paulus, Y. M., Palanker, D. V. SLACK INC. 2012: 341–47

  Abstract

  The 577-nm (yellow) laser provides an alternative to the 532-nm (green) laser in retinal photocoagulation, with potential benefits in macular treatment and through ocular opacities. To assess relative risk of thermomechanical rupture of Bruch's membrane with yellow laser in photocoagulation, the therapeutic window, the ratio of threshold powers for mild coagulation and rupture, was measured.Retinal coagulation and rupture thresholds, visualized ophthalmoscopically, were measured with 577- and 532-nm lasers using 10- to 100-ms pulses in 34 rabbit eyes. Lesions at 1 and 7 days were assessed histologically.Coagulation threshold with yellow laser was 26% lower than with green laser. The therapeutic window increased linearly with log-duration for both wavelengths with a difference in parallel-slope intercept of 0.36 ± 0.20, corresponding to 8% to 15% wider therapeutic window for yellow wavelength.The therapeutic window of retinal photocoagulation in rabbits at 577 nm is slightly wider than at 532 nm, whereas histologically the lesions are similar.

  View details for DOI 10.3928/15428877-20120426-05

  View details for Web of Science ID 000312366000012

  View details for PubMedID 22589338

• Photovoltaic retinal prosthesis with high pixel density NATURE PHOTONICS Mathieson, K., Loudin, J., Goetz, G., Huie, P., Wang, L., Kamins, T. I., Galambos, L., Smith, R., Harris, J. S., Sher, A., Palanker, D. 2012; 6 (6): 391-397

  Abstract

  Retinal degenerative diseases lead to blindness due to loss of the "image capturing" photoreceptors, while neurons in the "image processing" inner retinal layers are relatively well preserved. Electronic retinal prostheses seek to restore sight by electrically stimulating surviving neurons. Most implants are powered through inductive coils, requiring complex surgical methods to implant the coil-decoder-cable-array systems, which deliver energy to stimulating electrodes via intraocular cables. We present a photovoltaic subretinal prosthesis, in which silicon photodiodes in each pixel receive power and data directly through pulsed near-infrared illumination and electrically stimulate neurons. Stimulation was produced in normal and degenerate rat retinas, with pulse durations from 0.5 to 4 ms, and threshold peak irradiances from 0.2 to 10 mW/mm(2), two orders of magnitude below the ocular safety limit. Neural responses were elicited by illuminating a single 70 μm bipolar pixel, demonstrating the possibility of a fully-integrated photovoltaic retinal prosthesis with high pixel density.

  View details for DOI 10.1038/NPHOTON.2012.104

  View details for Web of Science ID 000304598200017

  View details for PubMedCentralID PMC3462820

• Photovoltaic Retinal Prosthesis with High Pixel Density. Nature photonics Mathieson, K., Loudin, J., Goetz, G., Huie, P., Wang, L., Kamins, T. I., Galambos, L., Smith, R., Harris, J. S., Sher, A., Palanker, D. 2012; 6 (6): 391-397

  Abstract

  Retinal degenerative diseases lead to blindness due to loss of the "image capturing" photoreceptors, while neurons in the "image processing" inner retinal layers are relatively well preserved. Electronic retinal prostheses seek to restore sight by electrically stimulating surviving neurons. Most implants are powered through inductive coils, requiring complex surgical methods to implant the coil-decoder-cable-array systems, which deliver energy to stimulating electrodes via intraocular cables. We present a photovoltaic subretinal prosthesis, in which silicon photodiodes in each pixel receive power and data directly through pulsed near-infrared illumination and electrically stimulate neurons. Stimulation was produced in normal and degenerate rat retinas, with pulse durations from 0.5 to 4 ms, and threshold peak irradiances from 0.2 to 10 mW/mm(2), two orders of magnitude below the ocular safety limit. Neural responses were elicited by illuminating a single 70 μm bipolar pixel, demonstrating the possibility of a fully-integrated photovoltaic retinal prosthesis with high pixel density.

  View details for DOI 10.1038/nphoton.2012.104

  View details for PubMedID 23049619

  View details for PubMedCentralID PMC3462820

• Panretinal Photocoagulation for Proliferative Diabetic Retinopathy AMERICAN JOURNAL OF OPHTHALMOLOGY Palanker, D., Blumenkranz, M. S. 2012; 153 (4): 780-781

  View details for Web of Science ID 000302387100035

  View details for PubMedID 22445637

• LONG-TERM SAFETY, HIGH-RESOLUTION IMAGING, AND TISSUE TEMPERATURE MODELING OF SUBVISIBLE DIODE MICROPULSE PHOTOCOAGULATION FOR RETINOVASCULAR MACULAR EDEMA RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Luttrull, J. K., Sramek, C., Palanker, D., Spink, C. J., Musch, D. C. 2012; 32 (2): 375-386

  Abstract

  To determine the long-term safety of high-density subvisible diode micropulse photocoagulation (810 nm), compare the clinical findings with computational modeling of tissue hyperthermia and to report results for a subset of eyes treated for diabetic macular edema (ME) documented pre- and postoperatively by spectral-domain optical coherence tomography.All eyes treated for ME from diabetic retinopathy (diabetic ME) and branch retinal vein occlusion between April 2000 and January 2010 were reviewed for subvisible diode micropulse laser-induced retinal damage. Therapeutic outcomes were reviewed for a subgroup treated for diabetic ME with pre- and postoperative spectral-domain optical coherence tomography. Laser-induced retinal thermal effects were modeled computationally using Arrhenius formalism.A total of 252 eyes (212 diabetic ME, 40 branch retinal vein occlusion) of 181 patients qualified. None of the 168 eyes treated at irradiance <350 W/cm2 and 7 of 84 eyes at ≥ 590 W/cm2 had retinal damage (P = 0.0001) (follow-up 3-120 months, median, 47). Sixty-two eyes of 48 patients treated for diabetic ME with pre- and postoperative spectral-domain optical coherence tomography with median 12 months follow-up had no retinal injury by infrared, red-free, or fundus autofluorescence photos; fluorescein angiography or indocyanine green angiography; or spectral-domain optical coherence tomography. Central foveal thickness (P = 0.04) and maximum macular thickness decreased (P < 0.0001). Modeling of retinal hyperthermia demonstrates that the sublethal clinical regimen corresponds to Arrhenius integral >0.05, while damage is likely to occur if it exceeds 1.Subvisible diode micropulse can effectively treat retinovascular ME without laser-induced retinal damage, consistent with Arrhenius modeling of pulsed hyperthermia.

  View details for DOI 10.1097/IAE.0b013e3182206f6c

  View details for Web of Science ID 000300182700022

  View details for PubMedID 21971077

• Photovoltaic retinal prosthesis for restoring sight to the blind: implant design and fabrication Conference on Micromachining and Microfabrication Process Technology XVII Wang, L., Mathieson, K., Kamins, T. I., Loudin, J., Galambos, L., Harris, J. S., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2012

  View details for DOI 10.1117/12.909104

  View details for Web of Science ID 000302640000004

• Fifty Years of Ophthalmic Laser Therapy ARCHIVES OF OPHTHALMOLOGY Palanker, D. V., Blumenkranz, M. S., Marmor, M. F. 2011; 129 (12): 1613-1619

  View details for Web of Science ID 000297995000016

  View details for PubMedID 22159684

• Femtosecond laser capsulotomy Reply JOURNAL OF CATARACT AND REFRACTIVE SURGERY Friedman, N. J., Palanker, D. V., Schuele, G., Andersen, D., Marcellino, G., Seibel, B. S., Battle, J., Feliz, R., Talaino, J. H., Blumenkranz, M. S., Culbertson, W. W. 2011; 37 (12): 2231-2232

  View details for Web of Science ID 000298026000025

• Photodiode Circuits for Retinal Prostheses IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS Loudin, J. D., Cogan, S. F., Mathieson, K., Sher, A., Palanker, D. V. 2011; 5 (5): 468-480

  Abstract

  Photodiode circuits show promise for the development of high-resolution retinal prostheses. While several of these systems have been constructed and some even implanted in humans, existing descriptions of the complex optoelectronic interaction between light, photodiode, and the electrode/electrolyte load are limited. This study examines this interaction in depth with theoretical calculations and experimental measurements. Actively biased photoconductive and passive photovoltaic circuits are investigated, with the photovoltaic circuits consisting of one or more diodes connected in series, and the photoconductive circuits consisting of a single diode in series with a pulsed bias voltage. Circuit behavior and charge injection levels were markedly different for platinum and sputtered iridium-oxide film (SIROF) electrodes. Photovoltaic circuits were able to deliver 0.038 mC/cm(2) (0.75 nC/phase) per photodiode with 50- μm platinum electrodes, and 0.54-mC/cm(2) (11 nC/phase) per photodiode with 50-μ m SIROF electrodes driven with 0.5-ms pulses of light at 25 Hz. The same pulses applied to photoconductive circuits with the same electrodes were able to deliver charge injections as high as 0.38 and 7.6 mC/cm(2) (7.5 and 150 nC/phase), respectively. We demonstrate photovoltaic stimulation of rabbit retina in-vitro, with 0.5-ms pulses of 905-nm light using peak irradiance of 1 mW/mm(2). Based on the experimental data, we derive electrochemical and optical safety limits for pixel density and charge injection in various circuits. While photoconductive circuits offer smaller pixels, photovoltaic systems do not require an external bias voltage. Both classes of circuits show promise for the development of high-resolution optoelectronic retinal prostheses.

  View details for DOI 10.1109/TBCAS.2011.2144980

  View details for Web of Science ID 000296251500009

  View details for PubMedID 23852178

• THE IMPACT OF PULSE DURATION AND BURN GRADE ON SIZE OF RETINAL PHOTOCOAGULATION LESION Implications for Pattern Density RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Palanker, D., Lavinsky, D., Blumenkranz, M. S., Marcellino, G. 2011; 31 (8): 1664-1669

  Abstract

  Shorter pulses used in pattern scanning photocoagulation (10-20 milliseconds [ms]) tend to produce lighter and smaller lesions than the Early Treatment Diabetic Retinopathy Study standard 100-ms exposures. Smaller lesions result in fewer complications but may potentially reduce clinical efficacy. It is worthwhile to reevaluate existing standards for the number and size of lesions needed.The width of the coagulated zone in patients undergoing retinal photocoagulation was measured using optical coherence tomography. Lesions of "moderate," "light," and "barely visible" clinical grades were compared for 100, 200, and 400 μm spot sizes and pulse durations of 20 ms and 100 ms.To maintain the same total area as in 1,000 standard burns (100 ms, moderate) with a 400-μm beam, a larger number of 20-ms lesions are required: 1,464, 1,979, and 3,520 for moderate, light, and barely visible grades, respectively. Because of stronger relative effect of heat diffusion with a smaller beam, with 200 μm this ratio increases: 1,932, 2,783, and 5,017 lesions of 20 ms with moderate, light, and barely visible grades correspond to the area of 1,000 standard burns.A simple formula is derived for calculation of the required spot spacing in the laser pattern for panretinal photocoagulation with various laser parameters to maintain the same total coagulated area.

  View details for Web of Science ID 000294456100027

  View details for PubMedID 21642898

• Femtosecond laser capsulotomy JOURNAL OF CATARACT AND REFRACTIVE SURGERY Friedman, N. J., Palanker, D. V., Schuele, G., Andersen, D., Marcellino, G., Seibel, B. S., Battle, J., Feliz, R., Talamo, J. H., Blumenkranz, M. S., Culbertson, W. W. 2011; 37 (7): 1189-1198

  Abstract

  To evaluate a femtosecond laser system to create the capsulotomy.Porcine and cadaver eye studies were performed at OptiMedica Corp., Santa Clara, California, USA; the human trial was performed at the Centro Laser, Santo Domingo, Dominican Republic.Experimental and clinical study.Capsulotomies performed by an optical coherence tomography-guided femtosecond laser were evaluated in porcine and human cadaver eyes. Subsequently, the procedure was performed in 39 patients as part of a prospective randomized study of femtosecond laser-assisted cataract surgery. The accuracy of the capsulotomy size, shape, and centration were quantified and capsulotomy strength was assessed in the porcine eyes.Laser-created capsulotomies were significantly more precise in size and shape than manually created capsulorhexes. In the patient eyes, the deviation from the intended diameter of the resected capsule disk was 29 μm ± 26 (SD) for the laser technique and 337 ± 258 μm for the manual technique. The mean deviation from circularity was 6% and 20%, respectively. The center of the laser capsulotomies was within 77 ± 47 μm of the intended position. All capsulotomies were complete, with no radial nicks or tears. The strength of laser capsulotomies (porcine subgroup) decreased with increasing pulse energy: 152 ± 21 mN for 3 μJ, 121 ± 16 mN for 6 μJ, and 113 ± 23 mN for 10 μJ. The strength of the manual capsulorhexes was 65 ± 21 mN.The femtosecond laser produced capsulotomies that were more precise, accurate, reproducible, and stronger than those created with the conventional manual technique.

  View details for DOI 10.1016/j.jcrs.2011.04.022

  View details for Web of Science ID 000292783100004

  View details for PubMedID 21700099

• Non-damaging Retinal Phototherapy: Dynamic Range of Heat Shock Protein Expression INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Sramek, C., Mackanos, M., Spitler, R., Leung, L., Nomoto, H., Contag, C. H., Palanker, D. 2011; 52 (3): 1780-1787

  Abstract

  Subthreshold retinal phototherapy demonstrated clinical efficacy for the treatment of diabetic macular edema without visible signs of retinal damage. To assess the range of cellular responses to sublethal hyperthermia, expression of the gene encoding a 70 kDa heat shock protein (HSP70) was evaluated after laser irradiation using a transgenic reporter mouse.One hundred millisecond, 532 nm laser exposures with 400 μm beam diameter were applied to the retina surrounding the optic nerve in 32 mice. Transcription from the HSP70 promoter was assessed relative to the control eye using a bioluminescence assay at 7 hours after laser application. The retinal pigmented epithelium (RPE) viability threshold was determined with a fluorescence assay. A computational model was developed to estimate temperature and the extent of cell damage.A significant increase in HSP70 transcription was found at exposures over 20 mW, half the threshold power for RPE cell death. Computational modeling estimated peak temperature T = 49°C at HSP70 expression threshold. At RPE viability threshold, T = 57°C. Similar temperatures and damage indices were calculated for clinical subvisible retinal treatment parameters.Beneficial effects of laser therapy have been previously shown to extend beyond those resulting from destruction of tissue. One hundred millisecond laser exposures at approximately half the threshold power of RPE damage induced transcription of HSP70, an indication of cellular response to sublethal thermal stress. A computational model of retinal hyperthermia can guide further optimization of laser parameters for nondamaging phototherapy.

  View details for DOI 10.1167/iovs.10-5917

  View details for Web of Science ID 000288965300070

  View details for PubMedID 21087969

• SELECTIVE RETINAL THERAPY WITH MICROSECOND EXPOSURES USING A CONTINUOUS LINE SCANNING LASER RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Paulus, Y. M., Jain, A., Nomoto, H., Sramek, C., Gariano, R. F., Andersen, D., Schuele, G., Leung, L., Leng, T., Palanker, D. 2011; 31 (2): 380-388

  Abstract

  To evaluate the safety, selectivity, and healing of retinal lesions created using a continuous line scanning laser.A 532-nm Nd:YAG laser (PASCAL) with retinal beam diameters of 40 μm and 66 μm was applied to 60 eyes of 30 Dutch-belted rabbits. Retinal exposure duration varied from 15 μs to 60 μs. Lesions were acutely assessed by ophthalmoscopy and fluorescein angiography. Retinal pigment epithelial (RPE) flatmounts were evaluated with live-dead fluorescent assay. Histological analysis was performed at 7 time points from 1 hour to 2 months.The ratios of the threshold of rupture and of ophthalmoscopic visibility to fluorescein angiography visibility (measures of safety and selectivity) increased with decreasing duration and beam diameter. Fluorescein angiography and live-dead fluorescent assay yielded similar thresholds of RPE damage. Above the ophthalmoscopic visibility threshold, histology showed focal RPE damage and photoreceptor loss at 1 day, without inner retinal effects. By 1 week, photoreceptor and RPE continuity was restored. By 1 month, photoreceptors appeared normal.: Retinal therapy with a fast scanning continuous laser achieves selective targeting of the RPE and, at higher power, of the photoreceptors without permanent scarring or inner retinal damage. Continuous scanning laser can treat large retinal areas within standard eye fixation time.

  View details for DOI 10.1097/IAE.0b013e3181e76da6

  View details for Web of Science ID 000286586500024

  View details for PubMedID 20930656

• Improving the therapeutic window of retinal photocoagulation by spatial and temporal modulation of the laser beam JOURNAL OF BIOMEDICAL OPTICS Sramek, C., Leung, L., Leng, T., Brown, J., Paulus, Y. M., Schuele, G., Palanker, D. 2011; 16 (2)

  Abstract

  Decreasing the pulse duration helps confine damage, shorten treatment time, and minimize pain during retinal photocoagulation. However, the safe therapeutic window (TW), the ratio of threshold powers for thermomechanical rupture of Bruch's membrane and mild coagulation, also decreases with shorter exposures. Two potential approaches toward increasing TW are investigated: (a) decreasing the central irradiance of the laser beam and (b) temporally modulating the pulse. An annular beam with adjustable central irradiance was created by coupling a 532-nm laser into a 200-μm core multimode optical fiber at a 4-7 deg angle to normal incidence. Pulse shapes were optimized using a computational model, and a waveform generator was used to drive a PASCAL photocoagulator (532 nm), producing modulated laser pulses. Acute thresholds for mild coagulation and rupture were measured in Dutch-Belted rabbit in vivo with an annular beam (154-163 μm retinal diameter) and modulated pulse (132 μm, uniform irradiance "flat-top" beam) with 2-50 ms pulse durations. Thresholds with conventional constant-power pulse and a flat-top beam were also determined. Both annular beam and modulated pulse provided a 28% increase in TW at 10-ms duration, affording the same TW as 20-ms pulses with conventional parameters.

  View details for DOI 10.1117/1.3542045

  View details for Web of Science ID 000288939200056

  View details for PubMedID 21361711

• New Horizons in Retinal Laser Treatment: Sublethal Laser Therapy. Retinal Physician Y. M. Paulus, C. Sramek, M.S. Blumenkranz, D. Palanker 2011
• Photovoltaic Retinal Prosthesis Conference on Ophthalmic Technologies XXI Loudin, J., Mathieson, K., Kamins, T., Wang, L., Galambos, L., Huie, P., Sher, A., Harris, J., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2011

  View details for DOI 10.1117/12.876560

  View details for Web of Science ID 000297590500028

• Impact of Pulse Duration and Burn Grade on Size of Retinal Photocoagulation Lesion: Implications for Pattern Density. RETINA D. Palanker, D. Lavinsky, M.S. Blumenkranz, G. Marcellino. 2011
• Optical breakdown in transparent media with adjustable axial length and location OPTICS EXPRESS Toytman, I., Simanovski, D., Palanker, D. 2010; 18 (24): 24688-24698

  Abstract

  We demonstrate a highly elongated (aspect ratio over 500:1) optical breakdown in water produced by a single pulse of a picosecond laser focused with a combination of an axicon and a lens. Locations of the proximal and distal ends of the breakdown region can be adjusted by modifying radial intensity distribution of the incident beam with an amplitude mask. Using Fresnel diffraction theory we derive a transmission profile of the amplitude mask to create a uniform axial intensity distribution in the breakdown zone. Experimentally observed dynamics of the bubbles obtained with the designed mask is in agreement with the theoretical model. A system producing an adjustable cylindrical breakdown can be applied to fast linear or planar dissection of transparent materials. It might be useful for ophthalmic surgical applications including cataract surgery and crystalline lens softening.

  View details for Web of Science ID 000285586800048

  View details for PubMedID 21164815

• Femtosecond Laser-Assisted Cataract Surgery with Integrated Optical Coherence Tomography SCIENCE TRANSLATIONAL MEDICINE Palanker, D. V., Blumenkranz, M. S., Andersen, D., Wiltberger, M., Marcellino, G., Gooding, P., Angeley, D., Schuele, G., Woodley, B., Simoneau, M., Friedman, N. J., Seibel, B., Batlle, J., Feliz, R., Talamo, J., Culbertson, W. 2010; 2 (58)

  Abstract

  About one-third of people in the developed world will undergo cataract surgery in their lifetime. Although marked improvements in surgical technique have occurred since the development of the current approach to lens replacement in the late 1960s and early 1970s, some critical steps of the procedure can still only be executed with limited precision. Current practice requires manual formation of an opening in the anterior lens capsule, fragmentation and evacuation of the lens tissue with an ultrasound probe, and implantation of a plastic intraocular lens into the remaining capsular bag. The size, shape, and position of the anterior capsular opening (one of the most critical steps in the procedure) are controlled by freehand pulling and tearing of the capsular tissue. Here, we report a technique that improves the precision and reproducibility of cataract surgery by performing anterior capsulotomy, lens segmentation, and corneal incisions with a femtosecond laser. The placement of the cuts was determined by imaging the anterior segment of the eye with integrated optical coherence tomography. Femtosecond laser produced continuous anterior capsular incisions, which were twice as strong and more than five times as precise in size and shape than manual capsulorhexis. Lens segmentation and softening simplified its emulsification and removal, decreasing the perceived cataract hardness by two grades. Three-dimensional cutting of the cornea guided by diagnostic imaging creates multiplanar self-sealing incisions and allows exact placement of the limbal relaxing incisions, potentially increasing the safety and performance of cataract surgery.

  View details for DOI 10.1126/scitranslmed.3001305

  View details for Web of Science ID 000288441800003

  View details for PubMedID 21084720

• Multifocal laser surgery: Cutting enhancement by hydrodynamic interactions between cavitation bubbles PHYSICAL REVIEW E Toytman, I., Silbergleit, A., Simanovski, D., Palanker, D. 2010; 82 (4)

  Abstract

  Transparent biological tissues can be precisely dissected with ultrafast lasers using optical breakdown in the tight focal zone. Typically, tissues are cut by sequential application of pulses, each of which produces a single cavitation bubble. We investigate the hydrodynamic interactions between simultaneous cavitation bubbles originating from multiple laser foci. Simultaneous expansion and collapse of cavitation bubbles can enhance the cutting efficiency, by increasing the resulting deformations in tissue, and the associated rupture zone. An analytical model of the flow induced by the bubbles is presented and experimentally verified. The threshold strain of the material rupture is measured in a model tissue. Using the computational model and the experimental value of the threshold strain one can compute the shape of the rupture zone in tissue resulting from application of multiple bubbles. With the threshold strain of 0.7 two simultaneous bubbles produce a continuous cut when applied at the distance 1.35 times greater than that required in sequential approach. Simultaneous focusing of the laser in multiple spots along the line of intended cut can extend this ratio to 1.7. Counterpropagating jets forming during collapse of two bubbles in materials with low viscosity can further extend the cutting zone-up to approximately a factor of 1.5.

  View details for DOI 10.1103/PhysRevE.82.046313

  View details for Web of Science ID 000283540900002

  View details for PubMedID 21230396

• Strength-Duration Relationship for Extracellular Neural Stimulation: Numerical and Analytical Models JOURNAL OF NEUROPHYSIOLOGY Boinagrov, D., Loudin, J., Palanker, D. 2010; 104 (4): 2236-2248

  Abstract

  The strength-duration relationship for extracellular stimulation is often assumed to be similar to the classical intracellular stimulation model, with a slope asymptotically approaching 1/τ at pulse durations shorter than chronaxy. We modeled extracellular neural stimulation numerically and analytically for several cell shapes and types of active membrane properties. The strength-duration relationship was found to differ significantly from classical intracellular models. At pulse durations between 4 μs and 5 ms stimulation is dominated by sodium channels, with a slope of -0.72 in log-log coordinates for the Hodgkin-Huxley ion channel model. At shorter durations potassium channels dominate and slope decreases to -0.13. Therefore the charge per phase is decreasing with decreasing stimulus duration. With pulses shorter than cell polarization time (∼0.1-1 μs), stimulation is dominated by polarization dynamics with a classical -1 slope and the charge per phase becomes constant. It is demonstrated that extracellular stimulation can have not only lower but also upper thresholds and may be impossible below certain pulse durations. In some regimes the extracellular current can hyperpolarize cells, suppressing rather than stimulating spiking behavior. Thresholds for burst stimuli can be either higher or lower than that of a single pulse, depending on pulse duration. The modeled thresholds were found to be comparable to published experimental data. Electroporation thresholds, which limit the range of safe stimulation, were found to exceed stimulation thresholds by about two orders of magnitude. These results provide a biophysical basis for understanding stimulation dynamics and guidance for optimizing the neural stimulation efficacy and safety.

  View details for DOI 10.1152/jn.00343.2010

  View details for Web of Science ID 000282649900039

  View details for PubMedID 20702740

  View details for PubMedCentralID PMC2957463

• Patterned Laser Trabeculoplasty OPHTHALMIC SURGERY LASERS & IMAGING Turati, M., Gil-Carrasco, F., Morales, A., Quiroz-Mercado, H., Andersen, D., Marcellino, G., Schuele, G., Palanker, D. 2010; 41 (5): 538-545

  View details for DOI 10.3928/15428877-20100910-02

  View details for Web of Science ID 000208416900008

• Patterned laser trabeculoplasty. Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye Turati, M., Gil-Carrasco, F., Morales, A., Quiroz-Mercado, H., Andersen, D., Marcellino, G., Schuele, G., Palanker, D. 2010; 41 (5): 538-545

  Abstract

  A novel computer-guided laser treatment for open-angle glaucoma, called patterned laser trabeculoplasty, and its preliminary clinical evaluation is described.Forty-seven eyes of 25 patients with open-angle glaucoma received 532-nm laser treatment with 100-μm spots. Power was titrated for trabecular meshwork blanching at 10 ms and sub-visible treatment was applied with 5-ms pulses. The arc patterns of 66 spots rotated automatically after each laser application so that the new pattern was applied at an untreated position.Approximately 1,100 laser spots were placed per eye in 16 steps, covering 360° of trabecular meshwork. The intraocular pressure decreased from the pretreatment level of 21.9 ± 4.1 to 16.0 ± 2.3 mm Hg at 1 month (n = 41) and remained stable around 15.5 ± 2.7 mm Hg during 6 months of follow-up (n = 30).Patterned laser trabeculoplasty provides rapid, precise, and minimally traumatic (sub-visible) computer-guided treatment with exact abutment of the patterns, exhibiting a 24% reduction in intraocular pressure during 6 months of follow-up (P < .01).

  View details for DOI 10.3928/15428877-20100910-02

  View details for PubMedID 20968276

• Anterior capsulotomy with a pulsed-electron avalanche knife JOURNAL OF CATARACT AND REFRACTIVE SURGERY Palanker, D., Nomoto, H., Huie, P., Vankov, A., Chang, D. F. 2010; 36 (1): 127-132

  Abstract

  To evaluate a new pulsed-electron avalanche knife design for creating a continuous curvilinear capsulotomy (CCC) and compare the CCC with a mechanical capsulorhexis.Department of Ophthalmology, Stanford University, Stanford, California, USA.In this study, CCCs were created in freshly enucleated bovine eyes and in rabbit eyes in vivo. The cutting velocity was adjusted by controlling the burst repetition rate, voltage amplitude, and burst duration. Tissue samples were fixed and processed for histology and scanning electron microscopy (SEM) immediately after surgery.The study included 50 bovine eyes and 10 rabbit eyes. By adjusting the electrosurgical waveforms, gas-bubble formation was minimized to permit good surgical visualization. The optimum voltage level was determined to be +/-410 V with a burst duration of 20 mus. Burst repetition rate, continuously adjustable from 20 to 200 Hz with footpedal control, allowed the surgeon to vary linear cutting velocity up to 2.0 mm/s. Histology and SEM showed that the pulsed-electron avalanche knife produced sharp-edged capsule cutting without radial nicks or tears.The probe of the pulsed-electron avalanche knife duplicated the surgical feel of a 25-gauge cystotome and created a histologically smooth capsule cut. It may improve precision and reproducibility of creating a CCC, as well as improve its proper sizing and centration, especially in the face of surgical risk factors, such as weak zonules or poor visibility. FINANCIAL DISCLOSURES: Drs. Palanker and Vankov hold patents to the pulsed electron avalanche knife technology, which are licensed to PEAK Surgical by Stanford University. Drs. Palanker and Chang are consultants to PEAK Surgical. Dr. Vankov is an employee of PEAK Surgical. Neither of the other authors has a financial or proprietary interest in any material or method mentioned.

  View details for DOI 10.1016/j.jcrs.2009.07.046

  View details for Web of Science ID 000277410700021

  View details for PubMedID 20117716

  View details for PubMedCentralID PMC2818865

• Selective retinal therapy with a continuous line scanning laser Conference on Ophthalmic Technologies XX Paulus, Y. M., Jain, A., Gariano, R. F., Nomoto, H., Schuele, G., Sramek, C., Charalel, R., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2010

  View details for DOI 10.1117/12.840574

  View details for Web of Science ID 000283928200018

• Improved safety of retinal photocoagulation with a shaped beam and modulated pulse Conference on Ophthalmic Technologies XX Sramek, C., Brown, J., Paulus, Y. M., Nomoto, H., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2010

  View details for DOI 10.1117/12.841079

  View details for Web of Science ID 000283928200017

• Tissue Dissection with Ultrafast Laser Using Extended and Multiple Foci Conference on Optical Interactions with Tissue and Cells XXI Toytman, I., Silbergleit, A., Simanovski, D., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2010

  View details for DOI 10.1117/12.842438

  View details for Web of Science ID 000284359500029

• Patterned Laser Trabeculoplasty. Ophthalmic Surgery Lasers and Imaging M. Turati, F. Gil-Carrasco, A. Morales, H. Quiroz-Mercado, D. Andersen, G. Marcellino, G. Schuele, D. Palanker. 2010; 41: 538-545
• Short-pulse Laser Treatment: Redefining Retinal Therapy. Retinal Physician Y. Paulus, D. Palanker, M.S. Blumenkranz. 2010; 7 (1): 54-59
• Comparative Healing of Surgical Incisions Created by the PEAK PlasmaBlade, Conventional Electrosurgery, and a Scalpel PLASTIC AND RECONSTRUCTIVE SURGERY Loh, S. A., Carlson, G. A., Chang, E. I., Huang, E., Palanker, D., Gurtner, G. C. 2009; 124 (6): 1849-1859

  Abstract

  The PEAK PlasmaBlade is a new electrosurgical device that uses pulsed radiofrequency to generate a plasma-mediated discharge along the exposed rim of an insulated blade, creating an effective cutting edge while the blade stays near body temperature.Full-thickness incisions were made on the dorsums of pigs with the PlasmaBlade, a conventional electrosurgical device, and a scalpel, and blood loss was quantified. Wounds were harvested at designated time points, tested for wound tensile strength, and examined histologically for scar formation and tissue damage.Bleeding was reduced significantly (59 percent) in PlasmaBlade incisions compared with scalpel incisions, and acute thermal damage from the PlasmaBlade (66 +/- 5 microm) was significantly less than both cut and coagulation mode electrosurgical incisions (456 +/- 35 microm and 615 +/- 22 microm, respectively). Histologic scoring for injury and wound strength was equivalent between the PlasmaBlade and scalpel incisions. By 6 weeks, the healed PlasmaBlade and scalpel incisions were approximately three times stronger, and scar cosmetic appearance was significantly better compared with electrosurgical incisions.The PlasmaBlade is a promising new surgical instrument that provides atraumatic, scalpel-like cutting precision and electrosurgical-like hemostasis, resulting in minimal bleeding, tissue injury, and scar formation.

  View details for DOI 10.1097/PRS.0b013e3181bcee87

  View details for Web of Science ID 000272615600015

  View details for PubMedID 19952641

• Dynamics of retinal photocoagulation and rupture JOURNAL OF BIOMEDICAL OPTICS Sramek, C., Paulus, Y., Nomoto, H., Huie, P., Brown, J., Palanker, D. 2009; 14 (3)

  Abstract

  In laser retinal photocoagulation, short (<20 ms) pulses have been found to reduce thermal damage to the inner retina, decrease treatment time, and minimize pain. However, the safe therapeutic window (defined as the ratio of power for producing a rupture to that of mild coagulation) decreases with shorter exposures. To quantify the extent of retinal heating and maximize the therapeutic window, a computational model of millisecond retinal photocoagulation and rupture was developed. Optical attenuation of 532-nm laser light in ocular tissues was measured, including retinal pigment epithelial (RPE) pigmentation and cell-size variability. Threshold powers for vaporization and RPE damage were measured with pulse durations ranging from 1 to 200 ms. A finite element model of retinal heating inferred that vaporization (rupture) takes place at 180-190 degrees C. RPE damage was accurately described by the Arrhenius model with activation energy of 340 kJ/mol. Computed photocoagulation lesion width increased logarithmically with pulse duration, in agreement with histological findings. The model will allow for the optimization of beam parameters to increase the width of the therapeutic window for short exposures.

  View details for DOI 10.1117/1.3130282

  View details for Web of Science ID 000268536300016

  View details for PubMedID 19566300

• On illumination schemes for wide-field CARS microscopy OPTICS EXPRESS Toytman, I., Simanovskii, D., Palanker, D. 2009; 17 (9): 7339-7347

  Abstract

  New system for a wide-field CARS microscopy is demonstrated, including two schemes of non-phase-matching illumination. Several advantages including high Stokes pulse energy, pulse-to-pulse stability and inherent synchronization between pump and Stokes pulses were brought by use of methane-filled Raman converter. Spatial resolution of the system with axially symmetric illumination, 0.5 microm, was found to correspond to diffraction limit of the imaging objective. Selective sensitivity to lipid-rich myelin sheaths in the nerve tissue has been demonstrated and confirmed by comparison with histological samples stained with myelin-specific dye. Single-shot imaging capability of the system has been demonstrated with a speckling-free illumination on a monolayer of 3 microm polystyrene beads.

  View details for Web of Science ID 000266381700049

  View details for PubMedID 19399112

• Effect of shape and coating of a subretinal prosthesis on its integration with the retina EXPERIMENTAL EYE RESEARCH Butterwick, A., Huie, P., Jones, B. W., Marc, R. E., Marmor, M., Palanker, D. 2009; 88 (1): 22-29

  Abstract

  Retinal stimulation with high spatial resolution requires close proximity of electrodes to target cells. This study examines the effects of material coatings and 3-dimensional geometries of subretinal prostheses on their integration with the retina. A trans-scleral implantation technique was developed to place microfabricated structures in the subretinal space of RCS rats. The effect of three coatings (silicon oxide, iridium oxide and parylene) and three geometries (flat, pillars and chambers) on the retinal integration was compared using passive implants. Retinal morphology was evaluated histologically 6 weeks after implantation. For 3-dimensional implants the retinal cell phenotype was also evaluated using Computational Molecular Phenotyping. Flat implants coated with parylene and iridium oxide were generally well tolerated in the subretinal space, inducing only a mild gliotic response. However, silicon-oxide coatings induced the formation of a significant fibrotic seal around the implants. Glial proliferation was observed at the base of the pillar electrode arrays and inside the chambers. The non-traumatic penetration of pillar tips into the retina provided uniform and stable proximity to the inner nuclear layer. Retinal cells migrated into chambers with apertures larger than 10 mum. Both pillars and chambers achieved better proximity to the inner retinal cells than flat implants. However, isolation of retinal cells inside the chamber arrays is likely to affect their long-term viability. Pillars demonstrated minimal alteration of the inner retinal architecture, and thus appear to be the most promising approach for maintaining close proximity between the retinal prosthetic electrodes and target neurons.

  View details for DOI 10.1016/j.exer.2008.09.018

  View details for Web of Science ID 000262395800004

  View details for PubMedID 18955050

• Solid state lasers for wide-field CARS microscopy Conference on Solid State Lasers XVIII - Technology and Devices Simanovskii, D., Toytman, I., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2009

  View details for DOI 10.1117/12.812187

  View details for Web of Science ID 000284870500064

• Computational model of retinal photocoagulation and rupture Conference on Ophthalmic Technologies XIX Sramek, C., Paulus, Y. M., Nomoto, H., Huie, P., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2009

  View details for DOI 10.1117/12.808556

  View details for Web of Science ID 000284821000019

• Finite element model of thermal processes in retinal photocoagulation Conference on Optical Interactions with Tissue and Cells XX Sramek, C., Paulus, Y. M., Nomoto, H., Huie, P., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2009

  View details for DOI 10.1117/12.828888

  View details for Web of Science ID 000285714500035

• High resolution optoelectronic retinal prosthesis Conference on Ophthalmic Technologies XIX Loudin, J., Dinyari, R., Huie, P., Butterwick, A., Peumans, P., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2009

  View details for DOI 10.1117/12.807668

  View details for Web of Science ID 000284821000029

• On mechanisms of interaction in electrosurgery NEW JOURNAL OF PHYSICS Palanker, D., Vankov, A., Jayaraman, P. 2008; 10

  View details for DOI 10.1088/1367-2630/10/12/123022

  View details for Web of Science ID 000264869500008

• Healing of Retinal Photocoagulation Lesions INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Paulus, Y. M., Jain, A., Gariano, R. F., Stanzel, B. V., Marmor, M., Blumenkranz, M. S., Palanker, D. 2008; 49 (12): 5540-5545

  Abstract

  To systematically assess the changes in retinal morphology during the healing of retinal photocoagulation lesions of various clinical grades.Rabbits were irradiated with a 532-nm Nd:YAG laser with a beam diameter of 330 microm at the retinal surface, a power of 175 mW, and pulse durations between 5 and 100 ms. Retinal lesions were clinically graded 1 minute after placement as invisible, barely visible, light, moderate, intense, very intense, and rupture and were assessed histologically at six time points from 1 hour to 4 months.At all pulse durations, the width of the retinal lesions decreased over time. At clinical grades of light and more severe (pulse durations, 10-100 ms), retinal scarring stabilized at 1 month at approximately 35% of the initial lesion diameter. Lesions clinically categorized as barely visible and invisible (pulse durations of 7 and 5 ms) exhibited coagulation of the photoreceptor layer but did not result in permanent scarring. In these lesions, photoreceptors completely filled in the damaged areas by 4 months.The decreasing width of the retinal damage zone suggests that photoreceptors migrating from unaffected areas fill in the gap in the photoreceptor layer. Laser photocoagulation parameters can be specified to avoid not only the inner retinal damage, but also permanent disorganization and scarring in the photoreceptor layer. These data may facilitate studies to determine those aspects of laser treatment necessary for beneficial clinical response and those that result in extraneous retinal damage.

  View details for DOI 10.1167/iovs.08-1928

  View details for PubMedID 18757510

• Pulsed electrical stimulation for control of vasculature: Temporary vasoconstriction and permanent thrombosis BIOELECTROMAGNETICS Palanker, D., Vankov, A., Freyvert, Y., Huie, P. 2008; 29 (2): 100-107

  Abstract

  A variety of medical procedures is aimed to selectively compromise or destroy vascular function. Such procedures include cancer therapies, treatments of cutaneous vascular disorders, and temporary hemostasis during surgery. Currently, technologies such as lasers, cryosurgery and radio frequency coagulation, produce significant collateral damage due to the thermal nature of these interactions and corresponding heat exchange with surrounding tissues. We describe a non-thermal method of inducing temporary vasoconstriction and permanent thrombosis using short pulse (microseconds) electrical stimulation. The current density required for vasoconstriction increases with decreasing pulse duration approximately as t(-0.25). The threshold of electroporation has a steeper dependence on pulse duration-exceeding t(-0.5). At pulse durations shorter than 5 micros, damage threshold exceeds the vasoconstriction threshold, thus allowing for temporary hemostasis without direct damage to surrounding tissue. With a pulse repetition rate of 0.1 Hz, vasoconstriction is achieved approximately 1 min after the beginning of treatment in both arteries and veins. Thrombosis occurs at higher electric fields, and its threshold increases with vessel diameter. Histology demonstrated a lack of tissue damage during vasoconstriction, but vascular endothelium was damaged during thrombosis. The temperature increase does not exceed 0.1 degrees C during these treatments.

  View details for DOI 10.1002/bem.20368

  View details for Web of Science ID 000253250000003

  View details for PubMedID 17918191

• Electrosurgery with cellular precision IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Palanker, D. V., Vankov, A., Huie, P. 2008; 55 (2): 838-841

  Abstract

  Electrosurgery, one of the most-often used surgical tools, is a robust but somewhat crude technology that has changed surprisingly little since its invention almost a century ago. Continuous radiofrequency is still used for tissue cutting, with thermal damage extending to hundreds of micrometers. In contrast, lasers developed 70 years later, have been constantly perfected, and the laser-tissue interactions explored in great detail, which has allowed tissue ablation with cellular precision in many laser applications. We discuss mechanisms of tissue damage by electric field, and demonstrate that electrosurgery with properly optimized waveforms and microelectrodes can rival many advanced lasers. Pulsed electric waveforms with burst durations ranging from 10 to 100 micros applied via insulated planar electrodes with 12 microm wide exposed edges produced plasma-mediated dissection of tissues with the collateral damage zone ranging from 2 to 10 microm. Length of the electrodes can vary from micrometers to centimeters and all types of soft tissues-from membranes to cartilage and skin could be dissected in liquid medium and in a dry field. This technology may allow for major improvements in outcomes of the current surgical procedures and development of much more refined surgical techniques.

  View details for DOI 10.1109/TBME.2007.914539

  View details for Web of Science ID 000252622500006

  View details for PubMedID 18270030

• Effect of pulse duration on size and character of the lesion in retinal photocoagulation ARCHIVES OF OPHTHALMOLOGY Jain, A., Blumenkranz, M. S., Paulus, Y., Wiltberger, M. W., Andersen, D. E., Huie, P., Palanker, D. 2008; 126 (1): 78-85

  Abstract

  To systematically evaluate the effects of laser beam size, power, and pulse duration of 1 to 100 milliseconds on the characteristics of ophthalmoscopically visible retinal coagulation lesions.A 532-nm Nd:YAG laser was used to irradiate 36 retinas in Dutch Belt rabbits with retinal beam sizes of 66, 132, and 330 mum. Lesions were clinically graded 1 minute after placement, their size measured by digital imaging, and their depth assessed histologically at different time points.Retinal lesion size increased linearly with laser power and logarithmically with pulse duration. The width of the therapeutic window, defined by the ratio of the threshold power for producing a rupture to that of a mild coagulation, decreased with decreasing pulse durations. For 132- and 330-mum retinal beam sizes, the therapeutic window declined from 3.9 to 3.0 and 5.4 to 3.7, respectively, as pulse duration decreased from 100 to 20 ms. At pulse durations of 1 millisecond, the therapeutic window decreased to unity, at which point rupture and a mild lesion were equally likely to occur.At shorter pulse durations, the width and axial extent of the retinal lesions are smaller and less dependent on variations in laser power than at longer durations. The width of the therapeutic window, a measure of relative safety, increases with the beam size.Pulse durations of approximately 20 milliseconds represent an optimal compromise between the favorable impact of speed, higher spatial localization, and reduced collateral damage on one hand, and sufficient width of the therapeutic window (> 3) on the other.

  View details for Web of Science ID 000252312800011

  View details for PubMedID 18195222

• On Mechanisms of Interaction in Electrosurgery New Journal of Physics D. Palanker, A. Vankov, P. Jayaraman 2008; 10: 123022
• Tissue damage by pulsed electrical stimulation IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Butterwick, A., Vankov, A., Huie, P., Freyvert, Y., Palanker, D. 2007; 54 (12): 2261-2267

  Abstract

  Repeated pulsed electrical stimulation is used in a multitude of neural interfaces; damage resulting from such stimulation was studied as a function of pulse duration, electrode size, and number of pulses using a fluorescent assay on chick chorioallontoic membrane (CAM) in vivo and chick retina in vitro. Data from the chick model were verified by repeating some measurements on porcine retina in-vitro. The electrode size varied from 100 microm to 1 mm, pulse duration from 6 micros to 6 ms, and the number of pulses from 1 to 7500. The threshold current density for damage was independent of electrode size for diameters greater than 300 microm, and scaled as 1/r2 for electrodes smaller than 200 microm. Damage threshold decreased with the number of pulses, dropping by a factor of 14 on the CAM and 7 on the retina as the number of pulses increased from 1 to 50, and remained constant for a higher numbers of pulses. The damage threshold current density on large electrodes scaled with pulse duration as approximately 1/t0.5, characteristic of electroporation. The threshold current density for repeated exposure on the retina varied between 0.061 A/cm2 at 6 ms to 1.3 A/cm2 at 6 micros. The highest ratio of the damage threshold to the stimulation threshold in retinal ganglion cells occurred at pulse durations near chronaxie-around 1.3 ms.

  View details for DOI 10.1109/TBME.2007.908310

  View details for Web of Science ID 000251226200016

  View details for PubMedID 18075042

• Wide-field coherent anti-Stokes Raman scattering microscopy with non-phase-matching illumination OPTICS LETTERS Toytman, I., Cohn, K., Smith, T., Simanovskii, D., Palanker, D. 2007; 32 (13): 1941-1943

  Abstract

  We have developed and tested a wide-field coherent anti-Stokes Raman scattering (CARS) microscopy technique, which provides the simultaneous imaging of an extended illuminated area without scanning. This method is based on the non-phase-matching illumination of a sample and imaging of a CARS signal with a CCD camera using conventional microscope optics. We have identified a set of conditions on the illumination and imaging optics, as well as on sample preparation. Imaging of test objects proved high spatial resolution and chemical selectivity of this technique.

  View details for Web of Science ID 000248348300059

  View details for PubMedID 17603621

• Pulsed electron avalanche knife: new technology for cataract surgery BRITISH JOURNAL OF OPHTHALMOLOGY Priglinger, S. G., Palanker, D., Alge, C. S., Kreutzer, T. C., Haritoglou, C., Grueterich, M., Kampik, A. 2007; 91 (7): 949-954

  Abstract

  The pulsed electron avalanche knife (PEAK-fc) is a new pulsed electrosurgical device that allows for precise, "cold" and traction-free tissue dissection.To evaluate the surgical applicability, safety and potential complications of PEAK-fc in complicated cataract surgery.The study included five children with congenital cataracts, two patients with advanced senile cataracts, six adults with mature cataracts, three of them with posterior iris synechia, three patients with post-traumatic cataracts with zonulolysis, one patient with intumescent traumatic cataract and three patients with massive anterior capsule opacification. Anterior and posterior capsulotomies, iris synechiolysis, dissection of anterior capsule opacification and fibrotic scar tissue were performed. PEAK-fc was set at voltages of 500-700 V, pulse duration of 0.1 m and repetition rate of 40-100 Hz.Anterior and posterior capsulotomies were successfully and safely performed in all eyes. The edges of capsulotomies appeared sharp, showing only limited collateral damage. PEAK-fc worked best by just gently touching the capsule, thereby avoiding tractional forces or pressure on the lens capsule. Posterior iris synechiae could be released and anterior capsule opacification was dissected without complications.PEAK-fc is a very helpful cutting device for complicated cases of cataract surgery, especially for mature and congenital cataracts, traumatic zonulolysis or anterior segment complications after intraocular inflammation.

  View details for DOI 10.1136/bjo.2006.109546

  View details for Web of Science ID 000247347700028

  View details for PubMedID 17229798

• Nanosecond plasma-mediated electrosurgery with elongated electrodes JOURNAL OF APPLIED PHYSICS Vankov, A., Palanker, D. 2007; 101 (12)

  View details for DOI 10.1063/1.2738374

  View details for Web of Science ID 000247625700134

• Image processing for a high-resolution optoelectronic retinal prosthesis IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Asher, A., Segal, W. A., Baccus, S. A., Yaroslavsky, L. P., Palanker, D. V. 2007; 54 (6): 993-1004

  Abstract

  In an effort to restore visual perception in retinal diseases such as age-related macular degeneration or retinitis pigmentosa, a design was recently presented for a high-resolution optoelectronic retinal prosthesis having thousands of electrodes. This system requires real-time image processing fast enough to convert a video stream of images into electrical stimulus patterns that can be properly interpreted by the brain. Here, we present image-processing and tracking algorithms for a subretinal implant designed to stimulate the second neuron in the visual pathway, bypassing the degenerated first synaptic layer. For this task, we have developed and implemented: 1) A tracking algorithm that determines the implant's position in each frame. 2) Image cropping outside of the implant boundaries. 3) A geometrical transformation that distorts the image appropriate to the geometry of the fovea. 4) Spatio-temporal image filtering to reproduce the visual processing normally occurring in photoceptors and at the photoreceptor-bipolar cell synapse. 5) Conversion of the filtered visual information into a pattern of electrical current. Methods to accelerate real-time transformations include the exploitation of data redundancy in the time domain, and the use of precomputed lookup tables that are adjustable to retinal physiology and allow flexible control of stimulation parameters. A software implementation of these algorithms processes natural visual scenes with sufficient speed for real-time operation. This computationally efficient algorithm resembles, in some aspects, biological strategies of efficient coding in the retina and could provide a refresh rate higher than fifty frames per second on our system.

  View details for DOI 10.1109/TBME.2007.894828

  View details for Web of Science ID 000246821500005

  View details for PubMedID 17554819

• Optoelectronic retinal prosthesis: system design and performance Eye and the Chip World Congress on Artificial Vision Loudin, J. D., Simanovskii, D. M., VijayRaghavan, K., Sramek, C. K., Butterwick, A. F., Huie, P., McLean, G. Y., Palanker, D. V. IOP PUBLISHING LTD. 2007: S72–S84

  Abstract

  The design of high-resolution retinal prostheses presents many unique engineering and biological challenges. Ever smaller electrodes must inject enough charge to stimulate nerve cells, within electrochemically safe voltage limits. Stimulation sites should be placed within an electrode diameter from the target cells to prevent 'blurring' and minimize current. Signals must be delivered wirelessly from an external source to a large number of electrodes, and visual information should, ideally, maintain its natural link to eye movements. Finally, a good system must have a wide range of stimulation currents, external control of image processing and the option of either anodic-first or cathodic-first pulses. This paper discusses these challenges and presents solutions to them for a system based on a photodiode array implant. Video frames are processed and imaged onto the retinal implant by a head-mounted near-to-eye projection system operating at near-infrared wavelengths. Photodiodes convert light into pulsed electric current, with charge injection maximized by applying a common biphasic bias waveform. The resulting prosthesis will provide stimulation with a frame rate of up to 50 Hz in a central 10 degrees visual field, with a full 30 degrees field accessible via eye movements. Pixel sizes are scalable from 100 to 25 microm, corresponding to 640-10,000 pixels on an implant 3 mm in diameter.

  View details for DOI 10.1088/1741-2560/4/1/S09

  View details for Web of Science ID 000245612700010

  View details for PubMedID 17325419

• Nanosecond plasma-mediated electrosurgery with elongated electrodes Journal of Applied Physics A. Vankov, D. Palanker 2007; 101: 124701
• Patterned retinal coagulation with a scanning laser 17th Conference on Ophthalmic Technologies Palanker, D., Jain, A., Paulus, Y., Andersen, D., Blumenkranz, M. S. SPIE-INT SOC OPTICAL ENGINEERING. 2007

  View details for DOI 10.1117/12.701708

  View details for Web of Science ID 000246519000036

• Non-scanning CARS microscopy using wide-field geometry Conference on Multiphoton Microscopy in the Biomedical Sciences VII Toytman, I., Cohn, K., Smith, T., Simanovskii, D., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2007

  View details for DOI 10.1117/12.701617

  View details for Web of Science ID 000246520500006

• Progress towards a high-resolution retinal prosthesis 17th Conference on Ophthalmic Technologies Butterwick, A., Vankov, A., Huie, P., Vijayraghavan, K., Loudin, J., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2007

  View details for DOI 10.1117/12.701787

  View details for Web of Science ID 000246519000018

• Pulsed Electron Avalanche Knife (PEAK-fc): New Technology for Cataract Surgery British Journal of Ophthalmology S.G. Priglinger, D. Palanker, C.S. Alge, T.C. Kreutzer, C. Haritoglou, M. Grueterich, A. Kampik 2007; 91: 949-954
• Image processing for a high-resolution optoelectronic retinal prosthesis IEEE Transactions on Biomedical Engineering A Asher, WA Segal, SA Baccus, LP Yaroslavsky, DV Palanker 2007; 54 (6): 993-1004
• Gene transfer to rabbit retina with electron avalanche transfection INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Chalberg, T. W., Vankov, A., Molnar, F. E., Butterwick, A. F., Huie, P., Calos, M. P., Palanker, D. V. 2006; 47 (9): 4083-4090

  Abstract

  Nonviral gene therapy represents a promising treatment for retinal diseases, given clinically acceptable methods for efficient gene transfer. Electroporation is widely used for transfection, but causes significant collateral damage and a high rate of cell death, especially in applications in situ. This study was conducted in the interest of developing efficient and less toxic forms of gene transfer for the eye.A novel method for nonviral DNA transfer, called electron avalanche transfection, was used that involves microsecond electric plasma-mediated discharges applied via microelectrode array. This transfection method, which produces synchronized pulses of mechanical stress and high electric field, was first applied to chorioallantoic membrane as a model system and then to rabbit RPE in vivo. Gene transfer was measured by using luciferase bioluminescence and in vivo fluorescent fundus photography. Safety was evaluated by performing electroretinograms and histology.In chorioallantoic membrane, electron avalanche transfection was approximately 10,000-fold more efficient and produced less tissue damage than conventional electroporation. Also demonstrated was efficient plasmid DNA transfer to the rabbit retina after subretinal DNA injection and transscleral electron avalanche transfection. Electroretinograms and histology showed no evidence of damage from the procedure.Electron avalanche transfection is a powerful new technology for safe DNA delivery that has great promise as a nonviral system of gene transfer.

  View details for DOI 10.1167/iovs.06-0092

  View details for Web of Science ID 000240050700055

  View details for PubMedID 16936128

• Cellular tolerance to pulsed hyperthermia PHYSICAL REVIEW E Simanovskii, D. M., Mackanos, M. A., Irani, A. R., O'Connell-Rodwell, C. E., Contag, C. H., Schwettman, H. A., Palanker, D. V. 2006; 74 (1)

  Abstract

  Transient heating of tissues leading to cellular stress or death is very common in medicine and biology. In procedures involving a mild (below 70 degrees C) and prolonged (minutes) heating, such as hyperthermal tumor therapy, the cellular response to thermal stress is relatively well studied. However, there is practically no data on cell viability at higher temperatures and shorter exposures, while the demand for this knowledge is growing. Two main reasons motivate this research: (i) a growing number of laser therapies and surgical procedures involving pulsed heating, and (ii) cellular viability data at short exposures to high temperatures provide a unique insight into the understanding of processes leading to thermally induced cellular death. We designed a technique and performed a study of cell viability under pulses of heat from 0.3 to 100 ms in duration with peak temperatures as high as 130 degrees C. We found that the threshold of cellular death in this range can be accurately approximated by the Arrhenius law with the activation energy of 1 eV, a significantly lower value than was reported in studies based on multisecond exposures.

  View details for DOI 10.1103/PhysRevE.74.011915

  View details for Web of Science ID 000239425600098

  View details for PubMedID 16907135

• Pulsed electron avalanche knife for capsulotomy in congenital and mature cataract 23rd Congress of the European-Society-of-Cataract-and-Refractive-Surgeons Priglinger, S. G., Haritoglou, C., Palanker, D., Kook, D., Grueterich, M., Mueller, A., Alge, C. S., Kampik, A. ELSEVIER SCIENCE INC. 2006: 1085–88

  Abstract

  The pulsed electron avalanche knife (PEAK-fc, Carl Zeiss Meditec) is an electrosurgical cutting device that allows precise "cold" and traction-free tissue dissection. We describe its applicability and safety for anterior capsulotomy in a child with congenital cataract and an adult patient with mature cataract. The PEAK-fc was set at a voltage of 600 V and a pulse repetition rate of 80 Hz. Anterior capsulotomies were successfully and safely performed in both cases, with the edges of capsulotomies appearing sharp and showing only limited collateral damage. The PEAK-fc appears to be a helpful cutting device for complicated cases of cataract surgery, especially for mature and congenital cataracts.

  View details for DOI 10.1016/j.jcrs.2006.03.020

  View details for Web of Science ID 000239334000010

  View details for PubMedID 16857491

• Semiautomated patterned scanning laser for retinal photocoagulation RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Blumenkranz, M. S., Yellachich, D., Andersen, D. E., Wiltberger, M. W., Mordaunt, D., Marcellino, G. R., Palanker, D. 2006; 26 (3): 370-376

  View details for Web of Science ID 000241684700024

  View details for PubMedID 16508446

• Plasma-mediated transfection of RPE 16th Conference on Ophthalmic Technologies Palanker, D., Chalberg, T., Vankov, A., Huie, P., Molnar, F. E., Butterwick, A., Calos, M., Marmor, M., Blumenkranz, M. S. SPIE-INT SOC OPTICAL ENGINEERING. 2006

  View details for DOI 10.1117/12.649624

  View details for Web of Science ID 000237708800038

• Noninvasive dosimetry and monitoring of TTT using spectral imaging 16th Conference on Ophthalmic Technologies Schuele, G., Molnar, F. E., Yellachich, D., Vitkin, E., Perelman, L. T., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2006

  View details for DOI 10.1117/12.642338

  View details for Web of Science ID 000237708800039

• Dynamic range of safe electrical stimulation of the retina 16th Conference on Ophthalmic Technologies Butterwick, A. F., Vankov, A., Huie, P., Palanker, D. V. SPIE-INT SOC OPTICAL ENGINEERING. 2006

  View details for DOI 10.1117/12.650652

  View details for Web of Science ID 000237708800018

• Pulsed electron avalanche knife (PEAK-fc) for dissection of retinal tissue ARCHIVES OF OPHTHALMOLOGY Priglinger, S. G., Haritoglou, C., Palanker, D. V., Alge, C. S., Gandorfer, A., Kampik, A. 2005; 123 (10): 1412-1418

  Abstract

  To evaluate the effectiveness and precision of tractionless retinal tissue dissection by the advanced version of the pulsed electron avalanche knife for fine cutting (PEAK-fc; Carl Zeiss Meditec, Jena, Germany).Porcine retina (in vivo) and human retina (in vitro) were incised with the PEAK-fc using various pulse parameters. The globes were then processed for light microscopy. Evaluation of all specimens focused on depth of the retinal cuts and on the degree of collateral damage.Retinal cuts performed both in vivo on porcine eyes and on human donor eyes showed very sharp edges with only little collateral damage. With probes of 600 mum in length, the optimal pulse parameters for precise and reproducible cutting of the retina were an amplitude of 350 to 380 V, a repetition rate of 300 Hz, and 30 "minipulses" per pulse of 100-microsecond duration. With increasing voltage, cuts also affected the retinal pigment epithelium and the choroid, followed by intravitreal bleeding during in vivo application.We demonstrated that PEAK-fc is capable of precisely cutting retinal tissue in vivo and in vitro using optimal pulse parameters. Further in vivo studies will be necessary to determine the efficacy of this new tractionless cutting device in vitreoretinal surgery.

  View details for Web of Science ID 000232502700014

  View details for PubMedID 16219733

• Pulsed electron avalanche knife in vitreoretinal surgery 108th Annual Meeting of the American-Academy-of-Ophthalmology Priglinger, S. G., Haritoglou, C., Mueller, A., Grueterich, M., Strauss, R. W., Alge, C. S., Gandorfer, A., Palanker, D., Kampik, A. LIPPINCOTT WILLIAMS & WILKINS. 2005: 889–96

  Abstract

  To evaluate the advantages, disadvantages, safety, and surgical applicability of the pulsed electron avalanche knife (PEAK-fc), a new electrosurgical knife for "cold" and tractionless cutting, in vitreoretinal surgery. PEAK-fc is equipped with an integrated fiberoptic that makes bimanual procedures in intraocular surgery possible.A prospective consecutive trial of 18 eyes in 18 patients who underwent vitreoretinal surgery for proliferative diabetic retinopathy, proliferative vitreoretinopathy, subretinal macular hemorrhage, or macular pucker was performed. The following specific maneuvers were performed with PEAK-fc: transection of epiretinal membranes, retinotomies, retinal vessel coagulation, and posterior membranectomy.Detached and attached retina could be dissected successfully in eight cases. Intraoperatively, incision edges were sharply demarcated, showing no visible collateral damage. Deeper layers than the neurosensory retina were not affected. With the bimanual approach, epiretinal avascular and vascular membranes could be removed in 10 cases. Hemorrhages occurring during transection of vascularized membranes could be stopped immediately using the coagulation mode of PEAK-fc. Posterior capsule fibrosis was successfully excised in one patient. No complications were observed.PEAK-fc offers precise and tractionless tissue cutting during ocular surgery. Using different waveform parameters, the same device performs cold cutting and/or "hot" coagulation, thus improving the precision, safety, and ergonomics of vitreoretinal surgery.

  View details for Web of Science ID 000235012900012

  View details for PubMedID 16205569

• Optical spectroscopy noninvasively monitors response of organelles to cellular stress 4th Inter Workshop on Optical Imaging from Bench to Bedside Schuele, G., Vitkin, E., Huie, P., O'Connell-Rodwell, C., Palanker, D., Perelman, L. T. SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS. 2005

  Abstract

  Fast and noninvasive detection of cellular stress is extremely useful for fundamental research and practical applications in medicine and biology. We discovered that light scattering spectroscopy enables us to monitor the transformations in cellular organelles under thermal stress. At the temperatures triggering expression of heat shock proteins, the refractive index of mitochondria increase within 1 min after the onset of heating, indicating enhanced metabolic activity. At higher temperatures and longer exposures, the organelles increase in size. This technique provides an insight into metabolic processes within organelles larger than 50 nm without exogenous staining and opens doors for noninvasive real-time assessment of cellular stress.

  View details for DOI 10.1117/1.2075207

  View details for Web of Science ID 000233711300006

  View details for PubMedID 16292941

• Design of a high-resolution optoelectronic retinal prosthesis. Journal of neural engineering Palanker, D., Vankov, A., Huie, P., Baccus, S. 2005; 2 (1): S105-20

  Abstract

  It has been demonstrated that electrical stimulation of the retina can produce visual percepts in blind patients suffering from macular degeneration and retinitis pigmentosa. However, current retinal implants provide very low resolution (just a few electrodes), whereas at least several thousand pixels would be required for functional restoration of sight. This paper presents the design of an optoelectronic retinal prosthetic system with a stimulating pixel density of up to 2500 pix mm(-2) (corresponding geometrically to a maximum visual acuity of 20/80). Requirements on proximity of neural cells to the stimulation electrodes are described as a function of the desired resolution. Two basic geometries of sub-retinal implants providing required proximity are presented: perforated membranes and protruding electrode arrays. To provide for natural eye scanning of the scene, rather than scanning with a head-mounted camera, the system operates similar to 'virtual reality' devices. An image from a video camera is projected by a goggle-mounted collimated infrared LED-LCD display onto the retina, activating an array of powered photodiodes in the retinal implant. The goggles are transparent to visible light, thus allowing for the simultaneous use of remaining natural vision along with prosthetic stimulation. Optical delivery of visual information to the implant allows for real-time image processing adjustable to retinal architecture, as well as flexible control of image processing algorithms and stimulation parameters.

  View details for PubMedID 15876646

• Design of a high-resolution optoelectronic retinal prosthesis JOURNAL OF NEURAL ENGINEERING Palanker, D., Vankov, A., Huie, P., Baccus, S. 2005; 2 (1): S105-S120

  View details for DOI 10.1088/1741-2560/2/1/012

  View details for Web of Science ID 000209672200012

• Cellular tolerance to pulsed heating Conference on Optical Interactions with Tissue and Cells XVI Simanovskii, D., Sarkar, M., Irani, A., O'Connell-Rodwell, C., Contag, C., SCHWETTMAN, A., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2005: 254–259

  View details for DOI 10.1117/12.601774

  View details for Web of Science ID 000229361500030

• Optical monitoring of thermal effects in RPE during heating 15th Conference on Ophthalmic Technologies Schuele, G., Huie, P., Yellachich, D., Molnar, F. E., O'Conell-Rodwell, C., Vitkin, E., Perelman, L. T., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2005: 194–200

  View details for DOI 10.1117/12.591068

  View details for Web of Science ID 000229038000024

• Towards high-resolution optoelectronic retinal prosthesis 15th Conference on Ophthalmic Technologies Palanker, D., Huie, P., Vankov, A., Asher, A., Baccus, S. SPIE-INT SOC OPTICAL ENGINEERING. 2005: 223–233

  View details for DOI 10.1117/12.590964

  View details for Web of Science ID 000229038000028

• Migration of retinal cells through a perforated membrane: Implications for a high-resolution prosthesis INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Palanker, D., Huie, P., Vankov, A., Aramant, R., Seiler, M., Fishman, H., Marmor, M., Blumenkranz, M. 2004; 45 (9): 3266-3270

  Abstract

  One of the critical difficulties in design of a high-resolution retinal implant is the proximity of stimulating electrodes to the target cells. This is a report of a phenomenon of retinal cellular migration into a perforated membrane that may help to address this problem.Mylar membranes with an array of perforations (3-40 microm in diameter) were used as a substrate for in vitro retinal culture (chicken, rats) and were also transplanted into the subretinal space of adult RCS rats. A membrane was also constructed with a seal on one side to restrict the migration.Retinal tissue in vitro grew within 3 days through perforations of greater than 5 microm in diameter when the membranes were positioned on the photoreceptor side, but no migration occurred if the implant was placed on the inner retinal surface. Histology with light microscopy and transmission electron microscopy (TEM) demonstrated that migrating cells retain neuronal structures for signal transduction. Similar growth of RCS rat retinal cells occurred in vivo within 5 days of implantation. A basal seal kept the migrating tissue within a small membrane compartment.Retinal neurons migrate within a few days into perforations (> 5 microm in diameter) of a membrane placed into the subretinal space. This may provide a means of gaining close proximity between electrodes in a retinal prosthetic chip and target cells, and thus allow a greater density of stimulating elements to subserve higher resolution. Further studies are needed to explore the long-term stability of the retinal migration.

  View details for DOI 10.1167/iovs.03-1327

  View details for PubMedID 15326150

• The chick chorioallantoic membrane as a model tissue for surgical retinal research and simulation RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES Leng, T., MILLER, J. M., Bilbao, K. V., Palanker, D. V., Huie, P., Blumenkranz, M. S. 2004; 24 (3): 427-434

  Abstract

  We describe the use of chick chorioallantoic membrane (CAM) as a model system for the study of the precision and safety of vitreoretinal microsurgical instruments and techniques.The CAM was prepared for experimentation with and without its inner shell membrane (ISM) attached for in vivo and in vitro experiments that simulated medical and surgical interventions on the retina.The CAM's ease of use, low cost, and anatomic structure make it a convenient model for surgical retinal and retinal vascular modeling.While CAM has been used extensively in the past for ocular angiogenesis studies, we describe the tissue as a useful tool for a variety of other applications, including (1) testing of novel surgical tools and techniques for cutting and coagulating retina and its vasculature, (2) testing vessel cannulation and injection techniques, (3) angiographic studies, and (4) endoscopic surgery.

  View details for Web of Science ID 000222156800014

  View details for PubMedID 15187666

• Design of a neurotransmitter-based retinal prosthetic chip powered by the ambient light. Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Fishman, H. A., Palanker, D. V., Mehenti, N. Z., Marmor, M. F., Bent, S. F., Blumenkranz, M. S. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2004: U126–U126

  View details for Web of Science ID 000223338200600

• A genetic reporter of thermal stress defines physiologic zones over a defined temperature range FASEB JOURNAL O'Connell-Rodwell, C. E., Shriver, D., Simanovskii, D. M., Mcclure, C., Cao, Y. A., Zhang, W. S., Bachmann, M. H., Beckham, J. T., Jansen, E. D., Palanker, D., Schwettman, H. A., Contag, C. H. 2004; 18 (2): 264-271

  Abstract

  We define five unique cellular responses to thermal stress using a reporter construct generated using the stress-inducible promoter from the gene encoding a murine 70 kDa heat shock protein (Hsp70A.1) to express luciferase (luc). Thermal stress was delivered over a range of temperatures (42-68 degrees C) for 5 s to 20 min and luciferase activity was measured in live cells using a cooled CCD camera as a measure of reporter gene transcription. Reporter gene expression was assessed every 2 h for 10 h, and at 24 h post-stress. Expression patterns were validated for selected temperatures. A transition zone where cells lose the ability to produce light and beyond which >50% of cells die was observed to occur within a narrow (2.5 degrees C) temperature window. Although luc and hsp70 mRNA levels in this transition zone were high, there were reduced levels of Luc and Hsp70 protein and ATP levels. Cells treated at these temperatures recovered the ability to produce light in response to a secondary stress at 30 h. This Hsp70-luc reporter gene construct may be useful for defining zones of physiologic responses and assessing collateral thermal damage generated during treatment of biological tissue with lasers and other sources of heat.

  View details for DOI 10.1096/fj.03-0585com

  View details for Web of Science ID 000220425000006

  View details for PubMedID 14769820

• Electro-adhesive forceps for tissue manipulation 14th Conference on Ophthalmic Technologies Vankov, A., Huie, P., Blumenkranz, M., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2004: 270–274

  View details for DOI 10.1117/12.529723

  View details for Web of Science ID 000223299200035

• Attracting retinal cells to electrodes for high-resolution stimulation 14th Conference on Ophthalmic Technologies Palanker, D. V., Huie, P., Vankov, A., Freyvert, Y., Fishman, H., Marmor, M. F., Blumenkranz, M. S. SPIE-INT SOC OPTICAL ENGINEERING. 2004: 306–314

  View details for DOI 10.1117/12.529757

  View details for Web of Science ID 000223299200039

• Non-invasive monitoring of the thermal stress in RPE using light scattering spectroscopy 14th Conference on Ophthalmic Technologies Schuele, G., Huie, P., Vankov, A., Vitkin, E., Fang, H., Hanlon, E. B., Perelman, L. T., Palanker, D. SPIE-INT SOC OPTICAL ENGINEERING. 2004: 95–99

  View details for DOI 10.1117/12.529415

  View details for Web of Science ID 000223299200012

• Prevention of tissue damage by water jet during cavitation JOURNAL OF APPLIED PHYSICS Palanker, D., Vankov, A., Miller, J., Friedman, M., Strauss, M. 2003; 94 (4): 2654-2661

  View details for DOI 10.1063/1.1593803

  View details for Web of Science ID 000184469800083

• Precision and safety of the pulsed electron avalanche knife in vitreoretinal surgery ARCHIVES OF OPHTHALMOLOGY MILLER, J. M., Palanker, D. V., Vankov, A., Marmor, M. F., Blumenkranz, M. S. 2003; 121 (6): 871-877

  Abstract

  We have developed a new surgical instrument, called the pulsed electron avalanche knife (PEAK; Carl Zeiss Meditec, Jena, Germany), for precise, "cold," and tractionless dissection of tissue in liquid media.To evaluate the 3-dimensional damage zone induced by the PEAK compared with 2 other standard intraocular surgical instruments, diathermy and retinal scissors.Damage zone and minimum safe distance were measured in vitro on chick chorioallantoic membrane and in vivo on rabbit retina with the use of propidium iodide staining.The PEAK produced a paracentral zone of cellular structure disruption surrounding a crater and a peripheral zone of structurally intact but abnormally permeable cells. The instrument induced a damage radius that varied from 55 to 300 micro m for the range of voltages and pulses typically used during surgery. For comparison, damage radius for microsurgical scissors was 50 micro m, and for diathermy, 400 to 850 micro m. The PEAK also damaged tissue up to 1.4 mm away by the creation of water flow that formed at the tip of convex probes during collapse of a cavitation bubble. Concave probes, which prevent formation of the water jet, eliminated this effect.The PEAK operated well within accept-able safety limits and may greatly facilitate both posterior segment surgeries (eg, membrane dissection and sheathotomy) and anterior segment procedures (eg, capsulotomy, nonpenetrating trabeculectomy, and iridectomy).

  View details for PubMedID 12796261

• Transient optical elements: application to near-field microscopy JOURNAL OF MICROSCOPY-OXFORD Simanovskii, D., Palanker, D., Cohn, K., Smith, T. 2003; 210: 307-310

  Abstract

  We report methods of near-field infrared microscopy with transient optically induced probes. The first technique - a transient aperture (TA) - uses photoinduced reflectivity in semiconductors to generate a relatively large transient mirror (TM) with a small aperture at its centre. We report the optical properties of the TM and TA and experiments performed on near-field imaging with the TA. The second technique is based on solid immersion microscopy, in which high resolution is achieved when light is focused inside a solid with a high refractive index. By creating a transient Fresnel lens on the surface of a semiconductor wafer via photoinduction, we were able to form a solid immersion lens (SIL) for use as a near-field probe. The use of transient probes eliminates the need for mechanical scanning of the lens or sample, and thus provides a much faster scanning rate and the possibility to work with soft and liquid objects.

  View details for Web of Science ID 000183307500022

  View details for PubMedID 12787104

• Bubble-free plasma blade for posterior segment surgery Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Sanislo, S. R., Palanker, D., Vankov, A., Bilbao, K., Marmor, M., Blumenkranz, M. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2003: U665–U665

  View details for Web of Science ID 000184607002337

• The pulsed electron avalanche knife in human vitreoretinal surgery; A status report Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Blumenkranz, M. S., Palanker, D., Sanislo, S. S., Marmor, M. H., Quiroz-Mercado, H., Koch, F., Kampik, A., Miesner, H., Amend, P. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2003: U99–U99

  View details for Web of Science ID 000184607000495

• Prevention of tissue damage by water jet during cavitation Journal of Applied Physics D. Palanker, A.Vankov, J. Miller, M. Friedman, M. Strauss 2003; 94 (4): 2654-2661
• Optimization of the pulsed electron avalanche knife for anterior segment surgery 13th Conference on Ophthalmic Technologies Palanker, D., Vankov, A., Bilbao, K., Marmor, M., Blumenkranz, M. SPIE-INT SOC OPTICAL ENGINEERING. 2003: 56–61

  View details for Web of Science ID 000184938700008

• Transient photoinduced diffractive solid immersion lens for infrared microscopy APPLIED PHYSICS LETTERS Cohn, K., Simanovskii, D., Smith, T., Palanker, D. 2002; 81 (19): 3678-3680

  View details for DOI 10.1063/1.1519729

  View details for Web of Science ID 000178935200054

• Intravascular drug delivery with a pulsed liquid microjet ARCHIVES OF OPHTHALMOLOGY Fletcher, D. A., Palanker, D. V., Huie, P., Miller, J., Marmor, M. F., Blumenkranz, M. S. 2002; 120 (9): 1206-1208

  Abstract

  Occlusions of the retinal veins and arteries, associated with diseases such as hypertension and arteriosclerosis, are a major cause of severe and irreversible loss of vision. Treatments for retinal vascular diseases have been unsatisfactory owing in part to the difficulty of delivering drugs to the site of disease within the eye. In this article, we demonstrate that a new device, the vapor bubble-driven pulsed liquid microjet, can deliver drugs into the lumen of small vessels such as those found in the retina. A 15- micro m-diameter liquid jet traveling at more than 60 m/s was shown to penetrate and deliver fluid through the wall of a blood vessel that was 60 micro m in diameter. Perforation of the wall of the blood vessel did not extend beyond the jet diameter.

  View details for Web of Science ID 000178022300013

  View details for PubMedID 12215096

• Effects of the pulsed electron avalanche knife on retinal tissue ARCHIVES OF OPHTHALMOLOGY Palanker, D. V., Marmor, M. F., Branco, A., Huie, P., MILLER, J. M., Sanislo, S. R., Vankov, A., Blumenkranz, M. S. 2002; 120 (5): 636-640

  Abstract

  To evaluate the precision of retinal tissue dissection by the pulsed electron avalanche knife (PEAK) and to assess possible toxic effects from this device.To demonstrate precision of cutting, bovine retina (in vitro) and rabbit retina (in vivo) were incised with the PEAK. Samples were examined by scanning electron microscopy and histologic examination (light microscopy). To evaluate possible toxic effects in rabbit eyes, 30 000 pulses were delivered into the vitreous 1 cm above the retina. Histologic examinations and electroretinography were performed at intervals up to 1 month after exposure.Cuts in postmortem bovine retina showed extremely sharp edges with no signs of thermal damage. Full-thickness cuts in living attached rabbit retina were similarly sharp and were typically less than 100 microm wide. No signs of retinal toxic effects were detected by histologic examination or electroretinography.The PEAK is capable of precise cutting through retinal tissue, and there are no demonstrable retinal toxic effects from its use. The precision and tractionless nature of PEAK cutting offers advantages over mechanical tools and laser-based instrumentation. We believe this new device will prove useful in a variety of vitreoretinal surgical applications.

  View details for PubMedID 12003616

• The Pulsed Electron Avalanche Knife (PEAK (TM)) for intraocular surgery in patients with proliferative vitreoretinal disorders Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Blumenkranz, M. S., Quiroz-Mercado, H., Sanislo, S. R., Garcia, G., Dubnack, S., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2002: U845–U845

  View details for Web of Science ID 000184606700157

• Surgical therapy of central retinal vein occlusion by creation of choroidal retinal anastomosis Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Quiroz-Mercado, H., Blumenkranz, M. S., Palanker, D. V., Sanislo, S. R., Garcia-Aguirre, G., Magdalenic, R., Araya-Munoz, C. E., Ruiz, M. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2002: U431–U431

  View details for Web of Science ID 000184606601829

• A new pulsed liquid microjet lot potential treatment of retinal vascular occlusions Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology Sanislo, S. R., Blumenkranz, M. S., Vankov, A., Palanker, D. V. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2002: U988–U988

  View details for Web of Science ID 000184606700681

• Transient photoinduced diffractive solid immersion lens for infrared microscopy Applied Physics Letters K. Cohn, D. Simanovskii, T. Smith, D. Palanker 2002; 81 (19): 3678-3680
• Effect of the probe geometry on dynamics of cavitation Conference on Laser Tissue Interaction XIII - Photochemical, Photothermal, and Photomechanical Palanker, D., Vankov, A., Miller, J. SPIE-INT SOC OPTICAL ENGINEERING. 2002: 112–117

  View details for Web of Science ID 000177691300014

• Pulsed liquid microjet for intravascular injection 12th Conference on Ophthalmic Technologies Palanker, D., Fletcher, D., Miller, J., Huie, P., Marmor, M., Blumenkranz, M. SPIE-INT SOC OPTICAL ENGINEERING. 2002: 72–75

  View details for Web of Science ID 000177417400010

• Pulsed Electron Avalanche Knife (PEAK) for intraocular surgery INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Palanker, D. V., MILLER, J. M., Marmor, M. F., Sanislo, S. R., Huie, P., Blumenkranz, M. S. 2001; 42 (11): 2673-2678

  Abstract

  To develop a better and more economical instrument for precise, tractionless, "cold" cutting during intraocular surgery. The use of highly localized electric fields rather than laser light as the means of tissue dissection was investigated.A high electric field at the tip of a fine wire can, like lasers, initiate plasma formation. Micrometer-length plasma streamers are generated when an insulated 25 micron (microm) wire, exposed to physiological medium at one end, is subjected to nanosecond electrical pulses between 1 and 8 kV in magnitude. The explosive evaporation of water in the vicinity of these streamers cuts soft tissue without heat deposition into surrounding material (cold cutting). Streamers of plasma and the dynamics of water evaporation were imaged using an inverted microscope and fast flash photography. Cutting effectiveness was evaluated on both polyacrylamide gels, on different tissues from excised bovine eyes, and in vivo on rabbit retina. Standard histology techniques were used to examine the tissue.Electric pulses with energies between 150 and 670 microJ produced plasma streamers in saline between 10 and 200 microm in length. Application of electric discharges to dense (10%) polyacrylamide gels resulted in fracturing of the gel without ejection of bulk material. In both dense and softer (6%) gels, layer by layer shaving was possible with pulse energy rather than number of pulses as the determinant of ultimate cutting depth. The instrument made precise partial or full-thickness cuts of retina, iris, lens, and lens capsule without any evidence of thermal damage. Because different tissues require distinct energies for dissection, tissue-selective cutting on complex structures can be performed if the appropriate pulse energies are used; for example, retina can be dissected without damage to the major retinal vessels.This instrument, called the Pulsed Electron Avalanche Knife (PEAK), can quickly and precisely cut intraocular tissues without traction. The small delivery probe and modest cost make it promising for many ophthalmic applications, including retinal, cataract, and glaucoma surgery. In addition, the instrument may be useful in nonophthalmic procedures such as intravascular surgery and neurosurgery.

  View details for Web of Science ID 000171433300037

  View details for PubMedID 11581215

• Near-field infrared microscopy with a transient photoinduced aperture APPLIED PHYSICS LETTERS Simanovskii, D., Palanker, D., Cohn, K., Smith, T. 2001; 79 (8): 1214-1216

  View details for Web of Science ID 000170429000048

• Refraction contrast imaging with a scanning microlens APPLIED PHYSICS LETTERS Fletcher, D. A., Crozier, K. B., Quate, C. F., Kino, G. S., Goodson, K. E., Simanovskii, D., Palanker, D. V. 2001; 78 (23): 3589-3591

  View details for Web of Science ID 000168996900007

• Pulsed liquid microjet for microsurgery APPLIED PHYSICS LETTERS Fletcher, D. A., Palanker, D. V. 2001; 78 (13): 1933-1935

  View details for Web of Science ID 000167744000044

• Evaluation of toxicity in vitreoretinal application of the Pulsed Electron Avalanche Knife (PEAK). Sanislo, S. R., Palanker, D. V., Miller, J., Marmor, M. F., Huie, P., Vankov, A., Branco, A., Blumenkranz, M. S. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2001: S429–S429

  View details for Web of Science ID 000168392102282

• Refraction Contrast Imaging With A Scanning Microlens. Applied Physics Letters D.A. Fletcher, K.B. Crozier, C.F. Quate, G.S. Kino, K.E. Goodson, D. Simanovskii, D.V. Palanker 2001; 78 (23): 3589-3591
• Pulsed liquid microjet for microsurgical applications Conference on Biomedical Instrumentation Based on Micro- and Nanotechnology Palanker, D. V., Fletcher, D. A. SPIE-INT SOC OPTICAL ENGINEERING. 2001: 36–39

  View details for Web of Science ID 000169777000005

• Near-Field Infrared Microscopy With A Transient Photo-Induced Aperture. Applied Physics Letters D. Simanovski, D. Palanker, K. Cohn, T. Smith 2001; 79 (8): 1214-1216
• Pulsed Liquid Microjet For Microsurgery. Applied Physics Letters D. A. Fletcher, D. V. Palanker 2001; 78 (13): 1933-35
• On contrast parameters and topographic artifacts in near-field infrared microscopy JOURNAL OF APPLIED PHYSICS Palanker, D. V., Simanovskii, D. M., Huie, P., Smith, T. I. 2000; 88 (11): 6808-6814

  View details for Web of Science ID 000165543200102

• Near-field infrared imaging with a microfabricated solid immersion lens APPLIED PHYSICS LETTERS Fletcher, D. A., Crozier, K. B., Quate, C. F., Kino, G. S., Goodson, K. E., Simanovskii, D., Palanker, D. V. 2000; 77 (14): 2109-2111

  View details for Web of Science ID 000089524900010

• Near-field infrared imaging with a microfabricated solid immersion lens. Applied Physics Letters D.A. Fletcher,, K.B. Crozier, C.F. Quate, G.S. Kino, K.E. Goodson, D. Simanovskii, D.V. Palanker 2000; 77 (14): 2109-2111
• Microfabricated solid immersion lens with metal aperture IEEE/LEOS International Conference on Optical MEMS Fletcher, D. A., Simanovskii, D., Palanker, D., Crozier, K. B., Quate, C. F., Kino, G. S., Goodson, F. E. IEEE. 2000: 133–134

  View details for Web of Science ID 000165310300063

• On image formation in near-field infrared microscopy 2nd Conference on Scanning and Force Microscopies for Biomedical Applications Simanovskii, D. M., Palanker, D. V., Huie, P., Smith, T. I. SPIE-INT SOC OPTICAL ENGINEERING. 2000: 182–88

  View details for Web of Science ID 000087779800022

• On Contrast Parameters and Topographic Artifacts in Near-Field Infrared Microscopy. Journal of Applied Physics D.V. Palanker, D.M. Simanovskii, P. Huie, T.I. Smith, H.A. Schwettman 2000; 88 (11): 6808-6814
• Near-field scanning optical microscopy in cell biology TRENDS IN CELL BIOLOGY Lewis, A., Radko, A., Ben Ami, N., Palanker, D., Lieberman, K. 1999; 9 (2): 70-73

  Abstract

  Near-field optics has produced the highest optical resolution that has ever been achieved. The methods involved lie at the interface of far-field optical microscopy and scanned probe microscopy. This article describes the principles behind near-field scanning optical microscopy (NSOM) and highlights its potential in cell biology.

  View details for Web of Science ID 000079416700008

  View details for PubMedID 10087622

• Fast IR imaging with sub-wavelength resolution using a transient near-field probe (Tipless near-field microscopy) Conference on 3-Dimensional and Multidimensional Microscopy - Image Acquisition and Processing VI Palanker, D. V., Smith, T. I., Schwettman, H. A. SPIE-INT SOC OPTICAL ENGINEERING. 1999: 31–39

  View details for Web of Science ID 000080657900004

• Pulse shape measurements using differential optical gating of a picosecond free electron laser source with an unsynchronized femtosecond Ti : sapphire gate OPTICS COMMUNICATIONS Rella, C. W., Knippels, G. M., Palanker, D. V., Schwettman, H. A. 1998; 157 (1-6): 335-342

  View details for Web of Science ID 000077541700051

• Fast IR imaging with sub-wavelength resolution using a transient near-field probe International Symposium on Free Electron Laser Facilities and Applications (FELFA 98) Palanker, D. V., Knippels, G. M., Smith, T. I., Schwettman, H. A. ELSEVIER SCIENCE BV. 1998: 240–45

  View details for Web of Science ID 000076020700037

• IR microscopy with a transient photo-induced near-field probe (tipless near-field microscopy) OPTICS COMMUNICATIONS Palanker, D. V., Knippels, G. M., Smith, T. I., Schwettman, H. A. 1998; 148 (4-6): 215-220

  View details for Web of Science ID 000074007400001

• Early nonsurgical removal of chemically injured tissue enhances wound healing in partial thickness burns BURNS Eldad, A., Weinberg, A., Breiterman, S., Chaouat, M., Palanker, D., Ben-Bassat, H. 1998; 24 (2): 166-172

  Abstract

  Chemical burns are slow healing injuries and their depth is difficult to assess. Tissue destruction continues as long as active material is present in the wound site. The routine therapy for treatment of full thickness chemical burns is early excision; it shortens hospitalization and reduces morbidity. However, presently there is no specific treatment for chemical burns of partial thickness. This study examined several treatment modalities for partial thickness chemical burns: surgical excision; laser ablation and chemical debridement with Debridase or trypsin-linked to gauze. Chemical burns were inflicted with nitrogen mustard (NM -- a nitrogen analog to sulfur mustard -- mustard gas) in an experimental guinea pig model. Debridase was most effective and reduced significantly lesion area of burns after 'humid' exposure to 2 mg NM. The healing action of Debridase was also evident in the significantly higher histopathological score of biopsies from local tissue obtained on day 5. Laser ablation was most effective and accelerated healing of burn lesions after 'dry' exposure to 5 mg NM. The histopathology score of the laser treated burns was higher on day 4 compared to untreated controls. It is concluded that for partial thickness chemical burns early nonsurgical removal of the damaged tissues accelerates wound healing.

  View details for Web of Science ID 000073712900015

  View details for PubMedID 9625245

• IR Microscopy with a Transient Photo-induced Near-field Probe (Tipless Near-field Microscopy). Optics Communications D. V. Palanker, G.M.H. Knippels, T.I. Smith, H.A. Schwettman 1998; 148 (4-6): 215-220
• Pulse Shape Measurements Using Differential Optical Gating Of A Picosecond Free Electron Laser Source With An Unsynchronized Femtosecond Ti:Sapphire Gate. Optics Comm C.W. Rella, G.M.H. Knippels, D. Palanker, H.A. Schwettman 1998; 157 (1-6): 335-42
• Fast IR Imaging with Sub-Wavelength Resolution using a Transient Near-field Probe. Nuclear Instruments and Methods in Physics, Section B: Beam Interactions with Materials and Atoms D. V. Palanker, G.M.H. Knippels, T.I. Smith, H.A. Schwettman 1998; 144: 240-245
• Etched Chalcogenide Fibers for Near-Field IR Scanning Microscopy. Review of Scientific Instruments M.A. Unger, D.A. Kossakovski, R. Kongovi, J.L. Beauchamp, D.V. Palanker 1998; 69 (8): 2988-93
• Vitreoretinal surgery assisted by the 193-nm excimer laser INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Hemo, I., Palanker, D., TUROVETS, I., Lewis, A., Zauberman, H. 1997; 38 (9): 1825-1829

  Abstract

  Ablating and cutting vitreoretinal membranes using a 193-nm excimer laser-based microsurgical system.A 193-nm microsurgical system enables delivery of the beam into a fluid medium to cut preretinal and subretinal membranes. Two patients with proliferative diabetic retinopathy and one patient with proliferative vitreoretinopathy were treated with this new device.Gentle ablation and cutting of the preretinal and subretinal membranes without exerting any traction on or apparent damage to the neighboring tissue was achieved.The technology is applicable to a variety of intraocular vitreoretinal surgical procedures.

  View details for Web of Science ID A1997XU43000020

  View details for PubMedID 9286272

• Electrical alternative to pulsed fiber-delivered lasers in microsurgery JOURNAL OF APPLIED PHYSICS Palanker, D., TUROVETS, I., Lewis, A. 1997; 81 (11): 7673-7680

  View details for Web of Science ID A1997XC34800084

• Nanometer-sized electrochemical sensors ANALYTICAL CHEMISTRY Shao, Y. H., Mirkin, M. V., Fish, G., Kokotov, S., Palanker, D., Lewis, A. 1997; 69 (8): 1627-1634

  View details for Web of Science ID A1997WT63100024

• Electrical Alternative to Pulsed Fiber-Delivered Lasers in Microsurgery. Appl. Phys. Palanker D., Turovets I., Lewis A., J. 1997; 81 (11): 7673-7680
• Electric discharge-induced cavitation: A competing approach to pulsed lasers for performing microsurgery in liquid media Conference on Laser-Tissue Interaction VIII Palanker, D., TUROVETS, I., Lewis, A. SPIE - INT SOC OPTICAL ENGINEERING. 1997: 351–360

  View details for Web of Science ID A1997BJ12Q00040

• Electrical alternative to pulsed lasers in vitreoretinal surgery 7th Conference on Ophthalmic Technologies Palanker, D., TUROVETS, I., Lewis, A. SPIE - INT SOC OPTICAL ENGINEERING. 1997: 67–73

  View details for Web of Science ID A1997BH97Z00011

• Nanometer-Sized Electrochemical Sensors. Anal. Chem. Y. Shao, M. V. Mirkin, G. Fish, S. Kokotov, D. Palanker, A. Lewis 1997; 69: 1627-1634
• Dynamics of ArF excimer laser-induced cavitation bubbles in gel surrounded by a liquid medium LASERS IN SURGERY AND MEDICINE Palanker, D., TUROVETS, I., Lewis, A. 1997; 21 (3): 294-300

  Abstract

  Cavitation bubbles have been shown to be the driving force of tissue cutting in 193 nm ArF excimer laser-based vitreoretinal microsurgery. In the present work we investigate the dynamics of cavitation bubbles inside a gelatin gel in a saline environment using fast flash microphotography.The screening influence of the saline medium was found to restrict the maximal distance between the tip and the tissue at which cavitation bubbles are created to < 100 microns at an energy fluence up to 0.3 J/cm2/pulse (the maximal energy fluence applied in vitreoretinal surgery).Single laser pulses did not cause disruption of gelatin at an energy fluence of up to 0.4 J/cm2/pulse. During the application of repetitive pulses small insoluble gas-containing bubbles were produced and often trapped between the tip and the tissue. They completely changed the shape of the subsequent cavitation bubbles and caused deep crater formation in the gel.

  View details for Web of Science ID A1997XV00300010

  View details for PubMedID 9291087

• Dynamics of cavitation bubble induced by 193 nm ArF excimer laser in concentrated sodium chloride solutions JOURNAL OF APPLIED PHYSICS TUROVETS, I., Palanker, D., Kokotov, Y., Hemo, I., Lewis, A. 1996; 79 (5): 2689-2693

  View details for Web of Science ID A1996TY11900077

• Dynamics of Cavitation Bubble Induced by 193 nm ArF Excimer Laser in Concentrated Sodium Chloride Solutions. Journal of Applied Physics Turovets I., Palanker D., Kokotov Yu, Hemo I., Lewis A 1996; 79 (5): 2689-2693
• ULTRAFAST RESPONSE MICROPIPETTE-BASED SUBMICROMETER THERMOCOUPLE REVIEW OF SCIENTIFIC INSTRUMENTS Fish, G., Bouevitch, O., Kokotov, S., Lieberman, K., Palanker, D., TUROVETS, I., Lewis, A. 1995; 66 (5): 3300-3306

  View details for Web of Science ID A1995QZ06900032

• Ultrafast Response Micropipette-Based Submicron Thermocouple. Review of Scientific Instruments G. Fish, O. Bouevitch, S. Kokotov, K. Lieberman, D. Palanker, I. Turovets, A. Lewis 1995; 66 (5): 3300-3306
• ARF EXCIMER LASER-INDUCED BUBBLE FORMATION DURING IRRADIATION OF NACL SOLUTIONS PHOTOCHEMISTRY AND PHOTOBIOLOGY TUROVETS, I., Palanker, D., Lewis, A. 1994; 60 (5): 412-414

  Abstract

  During application of the 193 nm excimer laser to vitreoretinal surgery, very deep cutting of the retina of about 100 microm/pulse was detected at the energy fluence in the range of 0.25-0.35 J/cm2/pulse. At the surface of the ablating tip insoluble bubbles were observed during the irradiation. In this paper we study production of these bubbles in aqueous solutions of sodium chloride. The yield of gaseous photoproducts was measured as a function of NaCl concentration and energy fluence. At concentrations of 100 g/L powerful water vapor bubbles and shock waves were observed. A mechanism of soft tissue cutting by the 193 nm laser in highly absorbing liquid media is suggested that explains the features of vitreoretinal ablation with this system: (1) the high cutting depth when the tip touches the tissue and (2) the absence of cutting when the tip is not in contact with tissue. The advantages of the ArF laser for microsurgery of internal organs are discussed.

  View details for Web of Science ID A1994PR25800003

  View details for PubMedID 7800714

• VITREORETINAL ABLATION WITH THE 193-NM EXCIMER-LASER IN FLUID MEDIA INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Palanker, D., Hemo, I., TUROVETS, I., Zauberman, H., Fish, G., Lewis, A. 1994; 35 (11): 3835-3840

  Abstract

  To ablate retina and vitreous membranes using the 193-nm argon fluoride excimer laser in a fluid medium.A special delivery system for the 193-nm excimer laser was developed that enabled the delivery of the laser into high-absorption liquid environments. The system was tested on the retina in an in vitro cup preparation of cow's eyes, and also in vivo on retina and vitreous membranes of rabbit eyes. The depth of cut as a function of laser energy was determined for an ablating needle with a 0.25-mm exit diameter.Gentle cutting of retinal tissue and of vitreous membranes was obtained in an energy range of 0.075 to 0.25 mJ/pulse. At the energy level of 0.075 mJ/pulse, four pulses were required for full-depth cut formation in rabbit retina, whereas at energy levels greater than 0.17 mJ/pulse, one pulse was sufficient for full-depth cut formation. The maximal rate of cutting achieved for the bovine retina was 2 mm/sec at a 20-Hz repetition rate of the laser. Ablation occurred only when the tip was held in contact with the tissue.The technology described herein appears to be advantageous and applicable to a variety of vitreoretinal surgical procedures.

  View details for Web of Science ID A1994PM51000008

  View details for PubMedID 7928180

• PERMEABILIZING MILLIONS OF CELLS WITH SINGLE PULSES OF AN EXCIMER-LASER BIOTECHNIQUES TUROVETS, I., Lewis, A., Palanker, D., GILO, H., VILENZ, A., BRODER, J. C., Lewis, S. 1993; 15 (6): 1022-?

  Abstract

  Poration of millions of cells with single laser pulses of an argon fluoride excimer laser is developed and demonstrated on plant cells. The essence of the technique is to use the large beam size (10 x 25 mm) of the excimer laser and to split it using an appropriate mask into millions of micron- or submicron-sized beams of 193-nm radiation with enough energy to perforate cell membranes and walls. The extremely small depth of penetration of the 193-nm radiation in biological tissue (< 1 microns) is used to great advantage in this technique to provide for a gentle method that does not lead to cell death. This is the first laser-based method that has enough throughput to make it viable for biotechnological applications. Of considerable significance is that the method is applicable not only in the case of the single cells in suspension, but also for cells growing on the leaves of living plants.

  View details for Web of Science ID A1993MK53300012

  View details for PubMedID 8292334

• INTERACTION BETWEEN HUMAN SPERM CELLS AND HAMSTER OOCYTES AFTER ARGON FLUORIDE EXCIMER-LASER DRILLING OF THE ZONA-PELLUCIDA FERTILITY AND STERILITY Simon, A., Palanker, D., HARPAZEISENBERG, V., Lewis, A., Laufer, N. 1993; 60 (1): 159-164

  Abstract

  To provide conclusive evidence that sperm cells gain access to the perivitelline space exclusively through a laser-drilled opening. To assess the optimal size of the hole and to evaluate the efficacy of laser drilling in comparison with that of mechanical zona dissection.An interspecies model of human sperm cell that interacts with a laser-drilled or partially zona-dissected hamster oocytes.Penetration rate into the perivitelline space as related to the size of the opening (group A [5 microns], group B [10 microns], and group C [15 microns]) and to the sperm cell concentrations (1 x 10(6), 5 x 10(6), and 10 x 10(6) cells/mL) used for insemination.For each sperm cell concentration, the penetration rate into the perivitelline space was lowest for group A followed by group C and highest for group B. When penetration was compared for each hole size, it was found that sperm concentration had no effect on the rate of penetration in groups A and C but significantly affected this rate in group B. The highest penetration rate of 73% was observed with a concentration of 10 x 10(6) cell/mL and declined to 58% and 23% at 5 x 10(6) cell/mL and 1 x 10(6) cell/mL, respectively. Oocytes drilled by laser (10-microns hole) demonstrated a significantly higher penetration rate when compared with those treated by partial zona dissection (73% versus 20% and 58% versus 21% for sperm densities of 10 x 10(6) cells/mL and 5 x 10(6) cells/mL, respectively).Human sperm cells gain access into the perivitelline space of hamster oocytes exclusively through a hole drilled by an argon fluoride excimer laser. An opening of 10 microns was found to yield optimal results. Laser drilling of the zona pellucida seems to be superior to that of mechanical slitting in terms of sperm oolema interaction.

  View details for Web of Science ID A1993LK48000028

  View details for PubMedID 8513935

• THE EFFICACY AND SAFETY OF ZONA-PELLUCIDA DRILLING BY A 193-NM EXCIMER LASER FERTILITY AND STERILITY Laufer, N., Palanker, D., Shufaro, Y., Safran, A., Simon, A., Lewis, A. 1993; 59 (4): 889-895

  Abstract

  To examine the efficiency of argon fluoride excimer laser drilling of the zona pellucida of mouse oocytes in improving in vitro fertilization (IVF) at low sperm concentrations and to assess its safety.Oocytes obtained from (Balb/c x C57BL6)CB6F1 female mice were drilled by laser and divided into two groups: group I (89 oocytes) were inseminated with 10(5) sperm cells/mL, and group II (94 oocytes) were inseminated with 10(6) sperm cells/mL. Both groups' fertilization rate and development in vitro was compared with control oocytes that underwent the same preparation steps but no drilling (94 and 88 oocytes for group I and group II, respectively).The fertilization rate and the development in vitro of the laser-drilled groups is compared with that of the control. In addition, in vivo development of embryos generated from laser-drilled oocytes after transfer to pseudopregnant recipients is assessed.For both sperm concentrations, laser drilling significantly enhanced fertilization over control (67% versus 31% at 10(5) sperm cells/mL and 90% versus 54% at 10(6) sperm cells/mL). The development into the blastocyst stage after 96 hours of incubation was similar for both the laser-drilled and control groups at any sperm cell concentration. However, complete hatching at this point was significantly enhanced by the drilling procedure. Normal litters were obtained from the transfer of embryos developed from zona-drilled oocytes into pseudopregnant recipients.Excimer laser drilling enhanced IVF at low sperm cell concentration. The procedure is safe and did not interfere with embryo development in vitro or in vivo.

  View details for Web of Science ID A1993KV24900030

  View details for PubMedID 8458512

• MICROSURGERY OF THE RETINA WITH A NEEDLE-GUIDED 193-NM EXCIMER LASER INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Lewis, A., Palanker, D., Hemo, I., Peer, J., Zauberman, H. 1992; 33 (8): 2377-2381

  Abstract

  This article presents a method used to guide the beam from an argon fluoride excimer laser to make it suitable for microsurgical purposes and confine it to areas that can be varied in dimension from 1 micron to tens or hundreds of microns. This approach guides the excimer laser beam with an articulated mechanical arm and confines it with variable-diameter tapered tubes, possibly allowing the use of this laser in in vitro retinal surgery with endolaser techniques. Currently, because of the lack of a delivery and focusing system for the 193-nm argon fluoride beam and its absorption by biologic liquids, this laser is used exclusively in ophthalmology for topical applications, such as corneal sculpting. This new method resolves these problems in a unique way with impressive results. Specifically, it was shown that, with this needle-guided excimer laser, it is possible to remove retinal tissue accurately without detectable damage to surrounding cells. Applications of this new technique in retinal surgery are discussed.

  View details for Web of Science ID A1992JE50900004

  View details for PubMedID 1634334

• EFFECT OF THE ARF EXCIMER LASER ON HUMAN ENAMEL LASERS IN SURGERY AND MEDICINE Feuerstein, O., Palanker, D., FUXBRUNNER, A., Lewis, A., Deutsch, D. 1992; 12 (5): 471-477

  Abstract

  Human enamel surface was irradiated with ArF excimer laser and examined under light microscopy and scanning electron microscopy (SEM). Enamel surface was irradiated at three different areas with different energy fluences. It is demonstrated that the ArF excimer laser causes ablation of the calcified hard enamel tissue. Ablation curves were measured. There was no significant difference found in the etch depth between the three different areas of enamel surface. The morphology of the irradiated areas seen under the SEM was found to be dependent on energy fluence. It changed with increase in energy fluence from being etched to forming a smooth, fused, glaze-like surface and then at very high energy fluences producing a rough surface. The influence of the laser irradiation was confined to the irradiated area only, with no visible heat damage to the surroundings. These results suggest that excimer laser could be applied in a controlled and defined manner for tooth enamel treatments in dentistry.

  View details for Web of Science ID A1992JQ31500002

  View details for PubMedID 1405998

• Statistical Approach for Subwavelength Measurements with a Conventional Light Microscope. Biophysical Journal Palanker D., Lewis A. 1991; 60: 1147-1155
• TECHNIQUE FOR CELLULAR MICROSURGERY USING THE 193-NM EXCIMER LASER LASERS IN SURGERY AND MEDICINE Palanker, D., OHAD, S., Lewis, A., Simon, A., SHENKAR, J., Penchas, S., Laufer, N. 1991; 11 (6): 580-586

  Abstract

  A new cell surgery technique has been developed to produce well-defined alterations in cells and tissue without detectable heating and/or other structural damage in the surroundings. The technique involves the use of an argon fluoride excimer laser, in the deep ultraviolet (UV) region of the spectrum at 193 nm, which is guided through a glass pipette filled with a positive air pressure. To demonstrate the method, holes were drilled in the zona pellucida of mouse oocytes. The diameter of the drilled hole was determined by the pipette tip size, and its depth by an energy emitted per pulse and number of pulses. Scanning electron microscopy of the drilled mouse oocytes showed uniform, round, well-circumscribed holes with sharp edges. Oocytes that had their zona pellucida drilled with this new method fertilized in vitro and developed to the blastocyst stage in a rate similar to that of control group. These results demonstrate the nonperturbing nature of this cold laser microsurgical procedure. In addition to the extension of our results for clinical in vitro fertilization purposes, such as enhancement of fertilization and embryo biopsy, there are wide-ranging possible uses of our method in fundamental and applied investigations that require submicron accuracy in cellular alteration.

  View details for Web of Science ID A1991GR70300012

  View details for PubMedID 1753851

• [Aggregation of cardiolipin liposomes induced by monovalent cations]. Biofizika Atsagortsian, A. Z., Vasiukov, A. E., Palanker, D. V., Nadzharian, G. N. 1989; 34 (1): 49-53

  Abstract

  Monovalent ion induced aggregation of the cardiolipin bilayer liposomes is studied. Derived threshold concentrations (Ck) stimulating fast aggregation testify that the order of effectiveness for monovalent cations to cause this process is: H+ greater than Na+ greater than Li+ greater than K+. The Ck is shown to be nonmonotonously dependent on the temperature discovering a maximum in the range approximately 30-40 degrees C. It is also shown that the liposomes preliminary temperature processing for two hours at approximately 70 degrees C as well as the liposomes incubation for several days at approximately 5 degrees C affect the Ck value. In both cases a considerable Ck increase is accompanied by almost two-fold increase of the lipid oxidation index. The studied process is reversible to both electrolyte concentration dilution and temperature changes. However, unlike the phosphatidylserine (PS) and phosphatidic acid (PA) liposomes the observed changes in the cardiolipin case proceeding considerably slower possibly indicate that the potential must be lower in its depth than that in the case of PS and/or PA.

  View details for PubMedID 2730931

• The Effect of the Discreteness of Charge on the Potential Distribution in the Phospholipid Membrane. Proceedings of the Academy of Sciences of the Armenian Republic. Physical Series Atsagortsjan A., Palanker D., Nadjarjan G.N 1987; 22 (5): 266-272