Force-based Control for Safe Robot-assisted Retinal Interventions: In Vivo Evaluation in Animal Studies.

In recent years, robotic assistance in vitreoretinal surgery has moved from a benchtop environment to the operating rooms. Emerging robotic systems improve tool manoeuvrability and provide precise tool motions in a constrained intraocular environment and reduce/remove hand tremor. However, often due to their stiff and bulky mechanical structure, they diminish the perception of tool-to-sclera (scleral) forces, on which the surgeon relies, for eyeball manipulation. In this paper we measure these scleral forces and actively control the robot to keep them under a predefined threshold. Scleral forces are measured using a Fiber Bragg Grating (FBG) based force sensing instrument in an in vivo rabbit eye model in manual, cooperative robotic assistance with no scleral force control (NC), adaptive scleral force norm control (ANC) and adaptive scleral force component control (ACC) methods. To the best of our knowledge, this is the first time that the scleral forces are measured in an in vivo eye model during robot assisted vitreoretinal procedures. An experienced retinal surgeon repeated an intraocular tool manipulation (ITM) task 10 times in four in vivo rabbit eyes and a phantom eyeball, for a total of 50 repetitions in each control mode. Statistical analysis shows that the ANC and ACC control schemes restrict the duration of the undesired scleral forces to 4.41% and 14.53% as compared to 43.30% and 35.28% in manual and NC cases, respectively during the in vivo studies. These results show that the active robot control schemes can maintain applied scleral forces below a desired threshold during robot-assisted vitreoretinal surgery. The scleral forces measurements in this study may enable a better understanding of tool-to-sclera interactions during vitreoretinal surgery and the proposed control strategies could be extended to other microsurgery and robot-assisted interventions.

Post-discharge follow-up of patients with COVID-19: A Brazilian experience.

Objective: The objective of this study is to evaluate post-acute symptoms in patients with confirmed severe and critical coronavirus disease 2019 infections. Methods: We evaluated patients with confirmed severe and critical coronavirus disease 2019 infections. Post-acute symptoms were defined as symptoms persisting 4 weeks after the onset of the symptoms and classified as pulmonary, muscular, hematologic, neuropsychiatric, renal, and dermatological. Results: We recovered data from 565 patients (43.7% female) with a mean age of 61.1 years. In 18.2%, at least one hospital readmission was necessary and 11.1% died. In 62.6%, there was at least one persistent symptom, and 28.8% had more than one. Among associated factors, obesity, intensive care support, and mechanical ventilation were related to persistent symptoms. Conclusion: The most prevalent symptoms were pulmonary and neuropsychiatric sequelae, as reported in previous studies. This finding underscores the severity of the coronavirus disease 2019 infection and the need for follow-up after recovery from the initial illness. Obese patients, those requiring mechanical ventilation, female patients, and increased hospital length are at greater chance of having persistent symptoms.

Force and Velocity Based Puncture Detection in Robot Assisted Retinal Vein Cannulation: In-Vivo Study.

OBJECTIVE: Retinal vein cannulation is a technically demanding surgical procedure and its feasibility may rely on using advanced surgical robots equipped with force-sensing microneedles. Reliable detection of the moment of venous puncture is important, to either alert or prevent the clinician from double puncturing the vessel and damaging the retinal surface beneath. This paper reports the first in-vivo retinal vein cannulation trial on rabbit eyes, using sensorized metal needles, and investigates puncture detection. METHODS: We utilized total of four indices including two previously demonstrated ones and two new indices, based on the velocity and force of the needle tip and the correlation between the needle-tissue and tool-sclera interaction forces. We also studied the effect of detection timespan on the performance of detecting actual punctures. RESULTS: The new indices, when used in conjunction with the previous algorithm, improved the detection rate form 75% to 92%, but slightly increased the number of false detections from 37 to 43. Increasing the detection window improved the detection performance, at the cost of adding to the delay. CONCLUSION: The current algorithm can supplement the surgeons' visual feedback and surgical judgment. To achieve automatic puncture detection, more measurements and further analysis are required. Subsequent in-vivo studies in other animals, such as pigs with their more human like eye anatomy, are required, before clinical trials. SIGNIFICANCE: The study provides promising results and the criteria developed may serve as guidelines for further investigation into puncture detection in in-vivo retinal vein cannulation.

Adaptive Control Improves Sclera Force Safety in Robot-Assisted Eye Surgery: A Clinical Study.

The integration of robotics into retinal microsurgery leads to a reduction in surgeon perception of tool-to-tissue interaction forces. This blunting of human tactile sensory input, which is due to the inflexible mass and large inertia of the robotic arm as compared to the milli-Newton scale of the interaction forces and fragile tissues during ophthalmic surgery, identifies a potential iatrogenic risk during robotic eye surgery. In this paper, we aim to evaluate two variants of an adaptive force control scheme implemented on the Steady-Hand Eye Robot (SHER) that are intended to mitigate the risk of unsafe scleral forces. The present study enrolled ten retina fellows and ophthalmology residents into a simulated procedure, which simply asked the trainees to follow retinal vessels in a model retina surgery environment. For this purpose, we have developed a force-sensing (equipped with Fiber Bragg Grating (FBG)) instrument to attach to the robot. A piezo-actuated linear stage for creating random lateral motions to the eyeball phantom has been provided to simulate disturbances during surgery. The SHER and all of its dependencies were set up in an operating room in the Wilmer Eye Institute at the Johns Hopkins Hospital. The clinicians conducted robot-assisted experiments with the adaptive controls incorporated as well as freehand manipulations. The results indicate that the Adaptive Norm Control (ANC) method, is able to maintain scleral forces at predetermined safe levels better than even freehand manipulations. Novice clinicians in robot training however, subjectively preferred freehand maneuvers over robotic manipulations. Clinician preferences once highly skilled with the robot is not assessed in this study.

Deep Learning Detection of Sea Fan Neovascularization From Ultra-Widefield Color Fundus Photographs of Patients With Sickle Cell Hemoglobinopathy.

Importance: Adherence to screening for vision-threatening proliferative sickle cell retinopathy is limited among patients with sickle cell hemoglobinopathy despite guidelines recommending dilated fundus examinations beginning in childhood. An automated algorithm for detecting sea fan neovascularization from ultra-widefield color fundus photographs could expand access to rapid retinal evaluations to identify patients at risk of vision loss from proliferative sickle cell retinopathy. Objective: To develop a deep learning system for detecting sea fan neovascularization from ultra-widefield color fundus photographs from patients with sickle cell hemoglobinopathy. Design, Setting, and Participants: In a cross-sectional study conducted at a single-institution, tertiary academic referral center, deidentified, retrospectively collected, ultra-widefield color fundus photographs from 190 adults with sickle cell hemoglobinopathy were independently graded by 2 masked retinal specialists for presence or absence of sea fan neovascularization. A third masked retinal specialist regraded images with discordant or indeterminate grades. Consensus retinal specialist reference standard grades were used to train a convolutional neural network to classify images for presence or absence of sea fan neovascularization. Participants included nondiabetic adults with sickle cell hemoglobinopathy receiving care from a Wilmer Eye Institute retinal specialist; the patients had received no previous laser or surgical treatment for sickle cell retinopathy and underwent imaging with ultra-widefield color fundus photographs between January 1, 2012, and January 30, 2019. Interventions: Deidentified ultra-widefield color fundus photographs were retrospectively collected. Main Outcomes and Measures: Sensitivity, specificity, and area under the receiver operating characteristic curve of the convolutional neural network for sea fan detection. Results: A total of 1182 images from 190 patients were included. Of the 190 patients, 101 were women (53.2%), and the mean (SD) age at baseline was 36.2 (12.3) years; 119 patients (62.6%) had hemoglobin SS disease and 46 (24.2%) had hemoglobin SC disease. One hundred seventy-nine patients (94.2%) were of Black or African descent. Images with sea fan neovascularization were obtained in 57 patients (30.0%). The convolutional neural network had an area under the curve of 0.988 (95% CI, 0.969-0.999), with sensitivity of 97.4% (95% CI, 86.5%-99.9%) and specificity of 97.0% (95% CI, 93.5%-98.9%) for detecting sea fan neovascularization from ultra-widefield color fundus photographs. Conclusions and Relevance: This study reports an automated system with high sensitivity and specificity for detecting sea fan neovascularization from ultra-widefield color fundus photographs from patients with sickle cell hemoglobinopathy, with potential applications for improving screening for vision-threatening proliferative sickle cell retinopathy.

A Comparison of Manual and Robot Assisted Retinal Vein Cannulation in Chicken Chorioallantoic Membrane.

Retinal vein occlusion (RVO) is a vision threatening condition occurring in the central or the branch retinal veins. Risk factors include but are not limited to hypercoagulability, thrombus or other cause of low blood flow. Current clinically proven treatment options limit complications of vein occlusion without treating the causative occlusion. In recent years, a more direct approach called Retinal Vein Cannulation (RVC) has been explored both in animal and human eye models. Though RVC has demonstrated potential efficacy, it remains a challenging and risky procedure that demands precise needle manipulation to achieve safely. During RVC, a thin cannula (diameter 70-110 µm) is delicately inserted into a retinal vein. Its intraluminal position is maintained for up to 2 minutes while infusion of a therapeutic drug occurs. Because the tool-tissue interaction forces at the needle tip are well below human tactile perception, a robotic assistant combined with a force sensing microneedle could alleviate the challenges of RVC. In this paper we present a comparative study of manual and robot assisted retinal vein cannulation in chicken chorioallantoic membrane (CAM) using a force sensing microneedle tool. The results indicate that the average puncture force and average force during the infusion period are larger in manual mode than in robot assisted mode. Moreover, retinal vein cannulation was more stable during infusion, in robot assisted mode.

Scleral Force Evaluation During Vitreoretinal Surgery: in an In Vivo Rabbit Eye Model.

During vitreoretinal surgery, the surgeon is required to precisely manipulate multiple tools in a confined intraocular environment, while the tool tip to retina contact forces are at the limit of human sensation limits. During typical vitrectomy procedures, the surgeon inserts various tools through small incisions performed on the sclera of the eye (sclerotomies), and manipulates them to perform surgical tasks. During intraocular procedures, tool-tissue interactions occur at the sclerotomy ports and at the tool-tip when it contacts retina. Measuring such interactions may be valuable for providing force feedback necessary for robotic guidance. In this paper, we measure and analyze force measurements at the sclerotomy ports. To the best of our knowledge, this is the first time that the scleral forces are measured in an in vivo eye model. A force sensing instrument utilizing Fiber Bragg Grating (FBG) strain sensors was used to measure the scleral forces while two retinal surgeons performed intraocular tool manipulation (ITM) task in rabbit eyes as well as a dry phantom. The mean of the measured sclera forces were 129.11 mN and 80.45 mN in in vivo and dry phantom experiments, respectively.

Robotic Retinal Surgery Impacts on Scleral Forces: In Vivo Study.

Purpose: This study aims to map force interaction between instrument and sclera of in vivo rabbits during retinal procedures, and verify if a robotic active force control could prevent unwanted increase of forces on the sclera. Methods: Experiments consisted in the performance of intraocular movements of a force sensing instrument, adjacent to the retinal surface, in radial directions, from the center to the periphery and back, and compared manual manipulations with robotic assistance and also robotic assistance with an active force control. This protocol was approved by the Animal Use and Ethical Committee and experiments were according to ARVO Statement of Animal Use. Results: Mean forces using manual manipulations were 115 ± 51 mN. Using robotic assistance, mean forces were 118 ± 49 mN. Using an active force control method, overall mean forces reduced to 69 ± 15, with a statistical difference compared with other methods (P < 0.001). Comparing intraocular directions, superior sector required higher forces and the force control method reduced differences in forces between users and retained the same force pattern between them. Conclusions: Results validate that the introduction of robotic assistance might increase the dynamic interactions between instrument and sclera, and the addition of an active force control method reduces the forces at levels lower than manual manipulations. Translational Relevance: All marketing benefits from extreme accuracy and stability from robots, however, redundancy of safety mechanisms during intraocular manipulations, especially on force control and surgical awareness, would allow all utility of robotic assistance in ophthalmology.

An Optimized Tilt Mechanism for a New Steady-Hand Eye Robot.

Robot-assisted vitreoretinal surgery can filter surgeons' hand tremors and provide safe, accurate tool manipulation. In this paper, we report the design, optimization, and evaluation of a novel tilt mechanism for a new Steady-Hand Eye Robot (SHER). The new tilt mechanism features a four-bar linkage design and has a compact structure. Its kinematic configuration is optimized to minimize the required linear range of motion (LRM) for implementing a virtual remote center-of-motion (V-RCM) while tilting a surgical tool. Due to the different optimization constraints for the robots at the left and right sides of the human head, two configurations of this tilt mechanism are proposed. Experimental results show that the optimized tilt mechanism requires a significantly smaller LRM (e.g. 5.08 mm along Z direction and 8.77 mm along Y direction for left side robot) as compared to the slider-crank tilt mechanism used in the previous SHER (32.39 mm along Z direction and 21.10 mm along Y direction). The feasibility of the proposed tilt mechanism is verified in a mock bilateral robot-assisted vitreoretinal surgery. The ergonomically acceptable robot postures needed to access the surgical field is also determined.

FBG-based Kalman Filtering and Control of Tool Insertion Depth For Safe Robot-assisted Vitrectomy.

Vitrectomy is that portion of retinal surgery in which the vitreous gel is removed either as a definitive treatment or to provide direct tool access to the retina. This procedure should be conducted prior to several eye surgeries in order to provide better access to the eyeball posterior. It is a relatively repeatable and straight forward procedure that lends itself to robotic assistance or potentially autonomous performance if tool contact with critical structures can be avoided. One of the detrimental incidences that can occur during the robot-assisted vitrectomy is when the robot penetrates the tool more than allowed boundaries into the eyeball toward retina. In this paper, we provide filtering and control to guide instrument insertion depth in order to avoid tool-to-retina contact. For this purpose, first the tool insertion depth measurement is improved using a Kalman filtering (KF) algorithm. This improved measurement is then used in an adaptive control strategy by which the robot reduces the tool insertion depth based on a predefined and safe trajectory for it, when safe boundaries are overstepped. The performance of the insertion depth safety control system is then compared to one in which the insertion depth is not passed through a Kalman filter prior to being fed to the control system. Our results indicate that applying KF in the adaptive control of the robot enhances procedure safety and enables the robot to always keep the tool insertion depth under the safe levels.

Force-based Safe Vein Cannulation in Robot-assisted Retinal Surgery: A Preliminary Study.

Retinal vein cannulation (RVC) is a potential treatment for retinal vein occlusion (RVO). Manual surgery has limitations in RVC due to extremely small vessels and instruments involved, as well as the presence of physiological hand tremor. Robot-assisted retinal surgery may be a better approach to smooth and accurate instrument manipulation during this procedure. Motion of the retina and cornea related to heartbeat may be associated with unexpected forces between the tool and eyeball. In this paper, we propose a force-based control strategy to automatically compensate for the movement of the retina maintaining the tip force and sclera force in a predetermined small range. A dual force-sensing tool is used to monitor the tip force, sclera force and tool insertion depth, which will be used to derive a desired joint velocity for the robot via a modified admittance controller. Then the tool is manipulated to compensate for the movement of the retina as well as reduce the tip force and sclera force. Quantitative experiments are conducted to verify the efficacy of the control strategy and a user study is also conducted by a retinal surgeon to demonstrate the advantages of our automatic compensation approach.

Autonomously Navigating a Surgical Tool Inside the Eye by Learning from Demonstration.

A fundamental challenge in retinal surgery is safely navigating a surgical tool to a desired goal position on the retinal surface while avoiding damage to surrounding tissues, a procedure that typically requires tens-of-microns accuracy. In practice, the surgeon relies on depth-estimation skills to localize the tool-tip with respect to the retina in order to perform the tool-navigation task, which can be prone to human error. To alleviate such uncertainty, prior work has introduced ways to assist the surgeon by estimating the tool-tip distance to the retina and providing haptic or auditory feedback. However, automating the tool-navigation task itself remains unsolved and largely unexplored. Such a capability, if reliably automated, could serve as a building block to streamline complex procedures and reduce the chance for tissue damage. Towards this end, we propose to automate the tool-navigation task by learning to mimic expert demonstrations of the task. Specifically, a deep network is trained to imitate expert trajectories toward various locations on the retina based on recorded visual servoing to a given goal specified by the user. The proposed autonomous navigation system is evaluated in simulation and in physical experiments using a silicone eye phantom. We show that the network can reliably navigate a needle surgical tool to various desired locations within 137 µm accuracy in physical experiments and 94 µm in simulation on average, and generalizes well to unseen situations such as in the presence of auxiliary surgical tools, variable eye backgrounds, and brightness conditions.

Towards Bimanual Vein Cannulation: Preliminary Study of a Bimanual Robotic System With a Dual Force Constraint Controller.

Retinal vein cannulation is a promising approach for treating retinal vein occlusion that involves injecting medicine into the occluded vessel to dissolve the clot. The approach remains largely unexploited clinically due to surgeon limitations in detecting interaction forces between surgical tools and retinal tissue. In this paper, a dual force constraint controller for robot-assisted retinal surgery was presented to keep the tool-to-vessel forces and tool-to-sclera forces below prescribed thresholds. A cannulation tool and forceps with dual force-sensing capability were developed and used to measure force information fed into the robot controller, which was implemented on existing Steady Hand Eye Robot platforms. The robotic system facilitates retinal vein cannulation by allowing a user to grasp the target vessel with the forceps and then enter the vessel with the cannula. The system was evaluated on an eye phantom. The results showed that, while the eyeball was subjected to rotational disturbances, the proposed controller actuates the robotic manipulators to maintain the average tool-to-vessel force at 10.9 mN and 13.1 mN and the average tool-to-sclera force at 38.1 mN and 41.2 mN for the cannula and the forcpes, respectively. Such small tool-to-tissue forces are acceptable to avoid retinal tissue injury. Additionally, two clinicians participated in a preliminary user study of the bimanual cannulation demonstrating that the operation time and tool-to-tissue forces are significantly decreased when using the bimanual robotic system as compared to freehand performance.

Sclera Force Evaluation During Vitreoretinal Surgeries in Ex Vivo Porcine Eye Model.

Vitreoretinal surgery is among the most challenging microsurgical procedures as it requires precise tool manipulation in a constrained environment, while the tool-tissue interaction forces are at the human perception limits. While tool tip forces are certainly important, the scleral forces at the tool insertion ports are also important. Clinicians often rely on these forces to manipulate the eyeball position during surgery. Measuring sclera forces could enable valuable sensory input to avoid tissue damage, especially for a cooperatively controlled robotic assistant that otherwise removes the sensation of these familiar intraoperative forces. Previously, our group has measured sclera forces in phantom experiments. However, to the best of our knowledge, there are no published data measuring scleral forces in biological (ex-vivo/in-vivo) eye models. In this paper, we measured sclera forces in ex-vivo porcine eye model. A Fiber Bragg Grating (FBG) based force sensing instrument with a diameter of ~900 µm and a resolution of ~1 mN was used to measure the forces while the clinician-subject followed retinal vessels in manual and robot-assisted modes. Analysis of measured forces show that the average sclera force in manual mode was 133.74 mN while in robot-assisted mode was 146.03 mN.

Towards securing the sclera against patient involuntary head movement in robotic retinal surgery.

Retinal surgery involves manipulating very delicate tissues within the confined area of eyeball. In such demanding practices, patient involuntary head movement might abruptly raise tool-to-eyeball interaction forces which would be detrimental to eye. This study is aimed at implementing different force control strategies and evaluating how they contribute to attaining sclera force safety while patient head drift is present. To simulate patient head movement, a piezoelectric-actuated linear stage is used to produce random motions in a single direction in random time intervals. Having an eye phantom attached to the linear stage then an experienced eye surgeon is asked to manipulate the eye and repeat a mock surgical task both with and without the assist of the Steady-Hand Eye Robot. For the freehand case, warning sounds were provided to the surgeon as auditory feedback to alert him about excessive slclra forces. For the robot-assisted experiments two variants of an adaptive sclera force control and a virtual fixture method were deployed to see how they can maintain eye safety under head drift circumstances. The results indicate that the developed robot control strategies are able to compensate for head drift and keep the sclera forces under safe levels as well as the free hand operation.

Artificial intelligence, robotics and eye surgery: are we overfitted?

Eye surgery, specifically retinal micro-surgery involves sensory and motor skill that approaches human boundaries and physiological limits for steadiness, accuracy, and the ability to detect the small forces involved. Despite assumptions as to the benefit of robots in surgery and also despite great development effort, numerous challenges to the full development and adoption of robotic assistance in surgical ophthalmology, remain. Historically, the first in-human-robot-assisted retinal surgery occurred nearly 30 years after the first experimental papers on the subject. Similarly, artificial intelligence emerged decades ago and it is only now being more fully realized in ophthalmology. The delay between conception and application has in part been due to the necessary technological advances required to implement new processing strategies. Chief among these has been the better matched processing power of specialty graphics processing units for machine learning. Transcending the classic concept of robots performing repetitive tasks, artificial intelligence and machine learning are related concepts that has proven their abilities to design concepts and solve problems. The implication of such abilities being that future machines may further intrude on the domain of heretofore "human-reserved" tasks. Although the potential of artificial intelligence/machine learning is profound, present marketing promises and hype exceeds its stage of development, analogous to the seventieth century mathematical "boom" with algebra. Nevertheless robotic systems augmented by machine learning may eventually improve robot-assisted retinal surgery and could potentially transform the discipline. This commentary analyzes advances in retinal robotic surgery, its current drawbacks and limitations, and the potential role of artificial intelligence in robotic retinal surgery.

Pilot Study Comparing Topical Anesthetic Agents in Pterygium Surgery: Subconjunctival Injection Versus 2% Lidocaine Gel Versus 5% Lidocaine Gel.

PURPOSE: To compare the efficacy of different concentrations of topical lidocaine gel with standard subconjunctival anesthesia. METHODS: This was a prospective randomized controlled pilot study with 3 different groups. Group SC received subconjunctival lidocaine and proparacaine drops as needed during surgery. Group L2 received 2% lidocaine gel and group L5 received 5% lidocaine gel. Both lidocaine gel groups could receive another gel dose as needed during the procedure. The primary outcome was pain, which was experienced during and after surgery. The assessment was done using a 10-point linear analog scale at predetermined stages of surgery (1-first incision, 2-pterygium body excision, 3-conjunctival suturing, 4-immediate postoperative period after patching, and 5-assessment by a trained nurse in the absence of a surgeon after operation). RESULTS: We enrolled 45 consecutive patients who underwent primary pterygium surgery. Statistical significance between groups was found in mean pain at administration (2.2 vs. 0.4 vs. 0.0 in SC, L2, and L5 groups, respectively, with P < 0.05). The number of reapplications of anesthetic drops did not differ between the groups. We found a correlation between reapplication of the anesthetic and pain at administration and duration of the procedure. CONCLUSIONS: We demonstrated that the use of lidocaine gel at concentrations of 2% and 5% in pterygium surgery was as effective as subconjunctival injection of lidocaine in reducing intraoperative and postoperative pain, producing significantly less pain during initial administration of the anesthetic.

Diabetes induces changes in neuroretina before retinal vessels: a spectral-domain optical coherence tomography study.

PURPOSE: To investigate retinal changes prior to vascular signs in patients with type 2 diabetes without diabetic retinopathy or with mild non proliferative diabetic retinopathy. METHODS: A cross-sectional study was performed in three groups: patients without diabetes, patients with type 2 diabetes without diabetic retinopathy, and patients with diabetes with mild diabetic retinopathy. Analysis of retinal layers was performed objectively with the Cirrus Review Software 6.0 (Carl Zeiss Meditec, Dublin, CA, USA). Macular cube scans were analyzed with regard to: the ganglion cell layer + inner plexiform layer analysis, retinal nerve fiber layer thickness, central subfoveal retinal thickness and average macular thickness. RESULTS: In total, 102 patients were included in this study, of which 28 (27.4%) were classified into control group, 46 (45.0%) classified as diabetic patients with no diabetic retinopathy and 28 (27.4%) classified as mild diabetic retinopathy. Quantitative analysis with the Cirrus software showed that the mean ganglion cell layer and mean retinal nerve fiber layer were thinner in diabetes without diabetic retinopathy group when compared to controls. ANOVA with Bonferroni post test indicated a statistically significant reduction in average retinal thickness in mild diabetic retinopathy group (P = 0.032) compared to control and reduction in ganglion cell layer in diabetes with no diabetic retinopathy (P = 0.039) and mild diabetic retinopathy (P = 0.003). Also indicated reduction in retinal nerve fiber layer in diabetic without diabetic retinopathy and eyes with mild diabetic retinopathy (P < 0.001), compared to controls. CONCLUSIONS: Our study found reduction in thickness of ganglion cell layer and retinal nerve fiber layer in patients with diabetes without diabetic retinopathy, which suggests neuroretinal changes before vascular signs of diabetic retinopathy.

Development of an experimental model of proliferative retinopathy by intravitreal injection of VEGF165.

PURPOSE: To develop an experimental model of proliferative retinopathy by intravitreal injection of vascular endothelial growth factor 165 (VEGF165) in pigmented rabbits. METHODS: A prospective, controlled, comparative intervention study. Six pigmented rabbits (Chinchilla breed) were subjected to intravitreal injection of VEGF165 in their right eye. The left eye was used as control and received an injection of balanced salt solution. In group 1, 3 rabbits received a 10-µg injection, and in group 2, 3 rabbits received a 20-µg injection. At baseline, all subjects were analyzed by anterior biomicroscopy, retinography, fluorescein angiography, and optical coherence tomography (OCT) fundus images. Biomicroscopy and all ancillary examinations were repeated at weeks 1, 2, and 5. In the fifth week after the injection, the rabbits were euthanized and the eyes were enucleated and subjected to histological evaluation. RESULTS: Seven days after the intravitreal VEGF165 injection, all rabbits developed intense neovascularization of the retina and anterior segment. Neovascularization of the posterior pole was similar in both groups, and the anterior segment was more florid in group 2. At weeks 1 and 2, neovascularization persisted with a minor decrease in conjunctival hyperemia in both groups. At week 5, there was a partial regression of neovascularization of the posterior pole, which was more prominent in group 1 than group 2, with persistent anterior neovascularization in both groups. OCT showed a statistically significant increase in retinal thickness, hyaloid detachment, and tractional retinal detachment. After the 5-week period, ocular histopathological evaluation showed an increase in retinal thickness, hyaloid detachment, and intense neovascularization in both groups, especially group 2. CONCLUSION: This pilot study of a neovascularization model using intravitreal injection of VEGF165 in pigmented rabbits showed that both doses of 10 and 20 µg were successful and effective in inducing vascular growth in the retina and anterior segment and can therefore be used for evaluating drug efficacy in future studies.