Value for money of reusable versus disposable ophthalmic instruments for intravitreal injections.

AIM: The aim of this study was to follow the instruments' pathways and cost each segment to calculate whether reusable or disposable ophthalmic instruments offer better value for money for intravitreal injections. METHODS: The cycles and costs of reusable and single-use disposable instruments used for intravitreal injections were mapped out, including purchase costs, transport to and from the place of use, opening and disposal, sterilisation, replacement, salary costs of staff involved, etc. results: The cost of using reusable instruments for intravitreal injections (NZ$29.00) was lower than the cost of using disposable instruments ($30.51) by $1.51 per patient. CONCLUSIONS: Intravitreal injections performed with reusable instruments offer better value for money than when performed with disposable instruments. This equates to a beneficial financial saving just for this one low-complexity case. Such savings can multiply significantly when considering the instruments used in a wider variety of ophthalmic procedures. There are of course trade-offs between safety, quality, cost and sustainability.

Real-time measurement of intraocular pressure variation during automatic intravitreal injections: An ex-vivo experimental study using porcine eyes.

PURPOSE: To measure needle insertion force and change in intraocular pressure (IOP) in real-time during intravitreal injection (IVI). The effects of needle size, insertion speed, and injection rate to IOP change were investigated. METHODS: Needle insertion and fluid injection were performed on 90 porcine eyeballs using an automatic IVI device. The IVI conditions were divided according to needle sizes of 27-gauge (G), 30G, and 33G; insertion speeds of 1, 2, and 5 mm/s; and injection rates of 0.01, 0.02, and 0.05 mL/s. Insertion force and IOP were measured in real-time using a force sensor and a pressure transducer. RESULTS: The peak IOP was observed when the needle penetrated the sclera; the average IOP elevation was 96.3, 67.1, and 59.4 mmHg for 27G, 30G, and 33G needles, respectively. An increase in insertion speed caused IOP elevation at the moment of penetration, but this effect was reduced as needle size decreased: 109.8-85.9 mmHg in 27G for 5-1 mm/s (p = 0.0149) and 61.8-60.7 mmHg in 33G for 5-1 mm/s (p = 0.8979). Injection speed was also related to IOP elevation during the stage of drug injection: 16.65 and 11.78 mmHg for injection rates of 0.05 and 0.01 mL/s (p < 0.001). CONCLUSION: The presented data offers an understanding of IOP changes during each step of IVI. Slow needle insertion can reduce IOP elevation when using a 27G needle. Further, the injection rate must be kept low to avoid IOP elevations during the injection stage.

Intraocular pressure and injection forces during intravitreal injection into enucleated porcine eyes.

Injection of biological molecules into the intravitreous humor is of increasing interest for the treatment of posterior segment eye diseases such as age-related degenerative macular degeneration. The injection volume is limited by an increase in intraocular pressure (IOP) and 50-100 µL are typically used for most intravitreally (IVT) applied commercial products. Direct measurement of IOP is difficult and has not been studied dependent on solution properties and injection rates. We used an instrumental set-up to study IOP ex vivo using healthy enucleated porcine eyes. IOP was determined as a function of injection volume for viscosities between 1 and 100 mPas, injection rates of 0.1, 1, and 1.5 mL/min, and needle length and diameter (27/30G and 0.5/0.75″) using Dextran solutions. IOP increased exponentially for injection volumes larger than 100 µL. We did not observe differences in IOP dependent on viscosity, injection rate, and needle diameter. However, variability increased significantly for injection volumes larger than 100 µL and, unexpectedly, declined with higher viscosities. We demonstrate that the exponential increase in IOP is not reflected by injection force measurements for typical configurations that are used for IVT application. The present findings may guide injection volumes for intravitreal injection and inform injection force considerations during technical drug product development.

Silicone oil-free syringes, siliconized syringes and needles: quantitative assessment of silicone oil release with drugs used for intravitreal injection.

PURPOSE: This study aimed to quantify the amount of silicone oil (SO) released across a variety of syringe and needle models routinely used for intravitreal injection. METHODS: The release of SO was assessed in eight models of syringes, two of which were reported to be 'SO-free', and eleven models of needles with unknown SO content. To evaluate SO release within the context of anti-VEGF therapeutics, syringes were evaluated using aflibercept, bevacizumab, buffer, ziv-aflibercept and formulation buffer. All syringe tests were performed with or without agitation by flicking for syringes. Needles were evaluated without agitation only. Samples were fluorescently labelled to identify SO, and triplicate measurements were collected using imaging flow cytometry. RESULTS: Seven out of 8 syringe models showed a statistically significant increase in the SO particle count after agitation. The two SO-free syringe models (HSW Norm-Ject, Daikyo Crystal Zenith) released the least SO particles, with or without agitation, whereas the BD Ultra-Fine and Saldanha-Rodrigues syringes released the most. More SO was released when the syringes were prefilled with formulation buffer than with ziv-aflibercept. Syringes filled with aflibercept and bevacizumab had intermediate levels. Agitation increased the release of SO into each of the drug solutions. Silicone oil (SO) was detected in all needles. CONCLUSIONS: Agitation of the syringe by flicking leads to a substantial increase in the number of SO particles. Silicone oil (SO)-free syringes had the best performance, but physicians must also be aware that needles are siliconized and also contribute to the injection of SO into the vitreous.

Prospective Study of Silicone Oil Microdroplets in Eyes Receiving Intravitreal Anti-Vascular Endothelial Growth Factor Therapy in 3 Different Syringes.

PURPOSE: To compare the prevalence of intravitreal silicone oil microdroplets detected by slit-lamp biomicroscopy in eyes with 6 or more injections of the same anti-vascular endothelial growth factor (VEGF) drug. DESIGN: Prospective, cross-sectional case series. PARTICIPANTS: A total of 260 consecutive eyes receiving 1 of 3 intravitreal anti-VEGF drugs for choroidal neovascularization, diabetic macular edema, or venous occlusive disease. The control group included 147 fellow eyes with no prior intravitreal injections. METHODS: The anterior and mid-vitreous were carefully examined using 12× to 16× magnification through dilated pupils with ocular saccades before an injection. Silicone oil microdroplets were graded on a scale from 0 to 4+ based on the number and size of droplets. MAIN OUTCOME MEASURES: Presence and severity of silicone oil microdroplets in the vitreous. RESULTS: Silicone oil microdroplets were observed in 78.3% of eyes receiving bevacizumab in Becton Dickinson (BD, Franklin Lakes, NJ) 0.3-mL polypropylene syringes, 14.4% of eyes receiving ranibizumab in 1.0-mL BD polypropylene syringes or more recently glass prefilled syringes, 48.5% of eyes receiving aflibercept in 1.0-mL BD polycarbonate syringes, and 0% of eyes in controls. The differences among the 4 groups were statistically significant at P < 0.001. The severity of silicone oil microdroplets was significantly greater in eyes using BD 0.3-mL polypropylene syringes than BD 1.0-mL polypropylene syringes, BD 1.0-mL polycarbonate syringes, or controls (P < 0.001). The severity of silicone oil microdroplets in eyes using BD 1.0-mL polycarbonate syringes was significantly greater than BD 1.0-mL polypropylene syringes (P = 0.012) and controls (P < 0.001). There was no significant difference between silicone oil microdroplet severity between BD 1.0-mL polypropylene syringes and controls (P = 1.0). CONCLUSIONS: The BD 0.3-mL polypropylene syringes with repackaged bevacizumab and the BD 1.0-mL polycarbonate syringes with aflibercept cause a higher likelihood of silicone oil microdroplets. Intravitreal injections in eyes receiving multiple regular anti-VEGF injections should be supplied in silicone-free syringes.

Critical analysis of techniques and materials used in devices, syringes, and needles used for intravitreal injections.

Intravitreal injections have become the most commonly performed intraocular treatments worldwide. Because intravitreal injections may induce severe adverse events, such as infectious and noninfectious endophthalmitis, cataract, ocular hypertension, vitreous hemorrhage, or retinal detachment, appropriate awareness of the materials and techniques used are essential to reduce these sight-threatening complications. This review provides insights into the needles, syringes, silicone oil coating, sterilization methods, devices to assist intravitreal injections, scleral piercing techniques using needles, syringe handling, anesthesia, and safety issues related to materials and techniques. It is paramount that physicians be aware of every step involved in intravitreal injections and consider the roles and implications of all materials and techniques used. The ability to understand the theoretical and practical circumstances may definitely lead to state-of-the-art treatments delivered to patients. The most important practical recommendations are: choosing syringes with as little silicone oil as possible, or, preferably, none; avoiding agitation of syringes; awareness that most biologics (e.g., antiangiogenic proteins) are susceptible to changes in molecular properties under some conditions, such as agitation and temperature variation; understanding that improper materials and techniques may lead to complications after intravitreal injections, e.g., inflammation; and recognizing that some devices may contribute to an enhanced, safer, and faster intravitreal injection technique.

The influence of dead spaces and the designs of injectors on the amount of drug dose in intra-vitreal injection.

AIM: To evaluate the dead spaces resulting from different designs of the insulin injectors used for intravitreal injections and the amounts of drug doses. METHODS: In the study, five different brands of sterile insulin injectors of 1 mL were used for the test. The weight of the injectors was determined before and after filling the injectors with 0.05 and 0.1 mL distilled water. The weight of the injectors was measured with and without the needle after the water within the injectors had been taken out and weight differences were measured. The difference between the intended amount of fluid to be thrown out and the weight of the fluid remaining in the injector was calculated as percent error. RESULTS: After throwing out 0.05 mL distilled water from the injector, weights of the Beybi®, Traf®, Becton Dickinson®, Ayset®, and Setojet® brands of injectors with 30 G needle were detected to increase the mean 0.0220 ± 0.006 g, 0.0208 ± 0.008 g, 0.0355 ± 0.016 g, 0.0219 ± 0.017 g, and 0.0150 ± 0.007 g, respectively compared to the weights of the dry injectors. The 0.1 mL injector group was found to be mean 0.0350 ± 0.014 g, 0.0264 ± 0.008 g, 0.0405 ± 0.015 g, 0.0272 ± 0.013 g, and 0.0245 ± 0.014 g, respectively. The maximum increase due to the dead spaces in the injectors was found in the Becton Dickinson® injector, both in the 0.05 mL and the 0.1 mL groups (p < 0.000). CONCLUSION: The injector designs may affect the dose of IVI required to be given. More correct amounts of drugs may be administered via the intra-vitreal route through designs that reduce the dead spaces at the end part of the injector and between the inner wall and the plunger.

End-of-Study Results for the Ladder Phase 2 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To report the end-of-study results from the Ladder clinical trial of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Multicenter, randomized, active treatment-controlled phase 2 clinical trial. PARTICIPANTS: Patients diagnosed with nAMD with a documented response to anti-vascular endothelial growth factor treatment who received study treatment (N = 220). METHODS: Patients were randomized 3:3:3:2 to treatment with the PDS filled with ranibizumab 10-mg/ml, 40-mg/ml, and 100-mg/ml formulations or monthly intravitreal ranibizumab 0.5-mg injections. MAIN OUTCOME MEASURES: End-of-study results for the time to first meeting refill criteria (first refill), mean change from baseline for best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. RESULTS: At study end, the mean time on study was 22.1 months (range, 10.8-37.6 months) for all PDS patients. Median time to first refill was 8.7 months, 13.0 months, and 15.8 months, and 28.9%, 56.0%, and 59.4% of patients went 12 months or longer without meeting refill criteria in the PDS 10-mg/ml, 40-mg/ml, and 100-mg/ml treatment arms, respectively. At month 22, the observed mean BCVA change from baseline was ‒4.6 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒2.3 ETDRS letters, +2.9 ETDRS letters, and +2.7 ETDRS letters in the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg treatment arms, respectively. At month 22, the observed mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg treatment arms. No new safety signals were detected during the additional follow-up. CONCLUSIONS: Over a mean of 22 months on study, vision and anatomic outcomes were comparable between the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms, with a lower total number of ranibizumab treatments with the PDS. The Ladder end-of-study findings were consistent with the primary analysis, and the PDS generally was well tolerated throughout the entire study period. The PDS has the potential to reduce treatment burden in patients with nAMD while maintaining vision.

Customized disposable kit versus a conventional stainless steel instrument for an intravitreal injection: A comparison.

Comparison of a customized disposable kit with a conventional stainless steel instrument was performed for an intravitreal injection. A total of 2700 eyes of 2250 patients were enrolled in two groups. Comfort level of the patients was assessed using a 'Pain Scale' and any post intravitreal injection complications were examined clinically by a slit lamp biomicroscopy. Surgeon's ease was assessed by a questionnaire. In group A, no pain was recorded in 1231(82.06%) eyes, mild pain was d escribed in 184(12.27%), moderate pain was documented in 78 (5.2%) while, severe pain was noticed in 7(0.47%). In group B, no pain was seen in 1014(84.5%), mild pain was present in 123(10.25%), moderate pain was perceived in 58 (4.83%) while, severe pain was recorded in 5 (0.42%). With respect to surgeon's ease, 6 out of the 7 surgeons found the kit to be more convenient and cost effective as compared to the conventional instruments. Disposable intravitreal kit is beneficial for both the patients as well as the surgeons.

Degeneração macular relacionada à idade: o potencial terapêutico das células-tronco / Age-related macular degeneration: the therapeutic potential of stem cells

Introdução: A degeneração macular relacionada à idade (DMRI) é uma patologia ocular crônico-degenerativa com perda progressiva e irreversível da visão central. Os avanços no campo da pesquisa das células-tronco têm voltado suas atenções para a aplicação da terapia celular com o intuito de regenerar tecidos oculares que são danificados por essa doença. A DMRI exsudativa possui terapia com anti-fator de crescimento endotelial vascular, e a DMRI seca ou atrófica, não possui terapia aprovada disponível. Objetivo: Avaliar o potencial terapêutico do uso de células-tronco no tratamento de DMRI seca por meio de estudos que demonstraram a segurança e eficácia de experimentos com injeções intravítreas de fração mononuclear da medula óssea contendo células CD34+. Métodos: Revisão da literatura em artigos entre 2009 e 2017, usando como base os bancos de dados Scielo, PubMed e Lilacs. Resultado: Estudos evidenciaram que o uso de injeções intravítreas de fração mononuclear da medula óssea contendo células-tronco CD34+ está associado com melhora significativa da acuidade visual e do limiar de sensibilidade macular. Ademais, a ausência de crescimento tumoral, desenvolvimento de neovascularização coroidal, a não associação com inflamação significativa e o não comprometimento da função visual demonstrou a segurança da utilização da terapia. Conclusão: Os avanços nos estudos demonstraram que o uso da terapia celular na DMRI atrófica acarreta melhora da visão, proporcionando melhor qualidade de vida. Por isso, verifica-se a necessidade do investimento em novas pesquisas para ampliar os testes e confirmar se esta abordagem de tratamento será realmente eficaz e bem tolerada. (AU)

Introduction: Age-related macular degeneration (AMD) is a chronic degenerative eye condition with progressive and irreversible loss of central vision. Advances in the field of stem cell research have focused on the application of cell therapy in order to regenerate eye tissues that are damaged by this disease. Exudative AMD has anti-vascular endothelial growth factor therapy, and dry or atrophic AMD has no approved therapy available. Objective: To evaluate the therapeutic potential of stem cell use in the treatment of dry AMD through studies demonstrating the safety and efficacy of experiments with intravitreal injections of mononuclear bone marrow fraction containing CD34 + cells. Methods: Literature review in articles between 2009 and 2017, using as basis the databases Scielo, PubMed and Lilacs. Results: Studies have shown that the use of intravitreal injections of mononuclear bone marrow fraction containing CD34 + stem cells is associated with significant improvement in visual acuity and macular sensitivity threshold. In addition, the absence of tumor growth, development of choroidal neovascularization, non-association with significant inflammation and non-impairment of visual function demonstrated the safety of therapy use. Conclusion: Advances in studies have shown that the use of cell therapy in atrophic AMD causes improved vision, providing better quality of life. Therefore, it is necessary to invest in new research to expand the tests and confirm if this treatment approach will be really effective and well tolerated. (AU)

Dispersion characterization of magnetic actuated needleless injections with particle image velocimetry.

Conventional needle-based approaches in intravitreal drug delivery carry needle-stick-injury risk and could scare patients (belonephobia). Alternatively, our group has explored the application of an electromagnetic needleless injector in this paper. This work aims to improve intravitreal drug delivery, which in the future could assist physicians with automation and benefit patients by providing a needleless approach. Electromagnetic needleless intravitreal injections lack quantification studies. We investigate the delivery properties of the needleless injector where the characterization can be used to refine the design parameters of the prototype in subsequent iterations. Experiments were performed to characterize the injectant delivered from the electromagnetic needleless injector. Penetration tests were conducted to observe the influences of various injection barriers and tissues. Ultrasonic imaging modality was explored for future applications of the prototype. The dispersion of the injectant was controllable where injection depth and distribution is dependent on the input voltage. The synthetic barriers highlighted significant energy losses for penetration (maximum velocity falls from 4.46 to 1.57 mm/s with a 0.1-mm barrier). The biological barriers were difficult to penetrate with the current prototype. Our results indicate that the current electromagnetic injector offers controllable dispersion (depth and distribution) correlated with input voltages, which should have increased injection power for use with biological tissue. Ultrasonic imaging modality produced velocity profiles comparable to the optical approach which is promising for future in vivo studies. The influences of injection barriers should be further investigated in in vivo experiments with ultrasonic imaging modalities. Graphical abstract .

Efficacy and safety of intravitreal drug injections using a short 34-gauge needle.

PURPOSE: To evaluate the efficacy and safety of intravitreal drug injections using a short 34-gauge needle. STUDY DESIGN: Retrospective study. METHODS: This study included patients with age-related macular degeneration, diabetic macular edema, or macular edema associated with retinal vein occlusion. We reviewed the medical records of consecutive patients with one of those three diseases treated with antivascular endothelial growth factor (VEGF) agents using an 8-mm-long 34-gauge needle. Sustained intraocular pressure (IOP) elevations were defined as IOP exceeding 21 mmHg or 6-mmHg or higher increases from baseline on 2 consecutive visits at least 1 month apart. The main outcome measures were improved best-corrected visual acuity (BCVA), central retinal thickness (CRT), IOP changes, and incidence of complications related to the 34-gauge needle. RESULTS: Six hundred ninety-eight injections were administered to 243 consecutive patients (mean age, 74.0 years) and reviewed. The mean follow-up time was 30.2 ± 15.9 weeks. The mean number of intravitreal injections/eye was 2.7 ± 1.8 (range, 1-9). The mean BCVA improved significantly (P < .0001), from 0.43 ± 0.4 logarithm of the minimum angle of resolution (logMAR) units at baseline to 0.36 ± 0.41 logMAR units at the last visit. The mean CRT decreased significantly (P < .0001), from 426.9 ± 168.5 microns at baseline to 297.6 ± 121.1 microns at the last visit. The mean IOP decreased significantly (P < .0001), from 13.6 ± 3.0 mmHg at baseline to 12.9 ± 3.1 mmHg at the visit after the first injection. A retinal tear occurred in 0.14%/injection (1/698). A sustained IOP elevation occurred in 1.29%/injection (9/698). CONCLUSION: Despite a few complications, the short 34-gauge needle was efficacious and safe for anti-VEGF intravitreal injections.

A New Suggested Strategy for Safe Injection of Ozurdex.

BACKGROUND AND OBJECTIVES: Ozurdex intravitreal injection is performed via a patented injection device. However, there is a common misconception among ophthalmologists regarding the relation between the speed of applicator button depression and the speed of pellet injection. PATIENTS AND METHODS: Six dexamethasone intravitreal implants were injected into a calibrated ex vivo water bath. Three of the pellets were injected via rapid compression, whereas the other three implants were injected using a 3-second compression technique. The procedures were recorded using high-speed photography followed by calculation of pellet velocity and impact force. RESULTS: The mean impact velocity and force of the pellet insertion is significantly higher in the fast injection group compared to the slow injection group. CONCLUSIONS: By depressing the Ozurdex implant injector during a 3-second time interval, the impact force of the implant pellet is reduced by about 95%. This new technique will theoretically reduce the risk of retinal injury and vitreous hemorrhage from Ozurdex injections. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e23-e25.].

ACCURACY AND PRECISION OF INTRAVITREAL INJECTIONS OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS IN REAL LIFE: What Is Actually in the Syringe?

PURPOSE: To evaluate the accuracy and precision of anti-vascular endothelial growth factor volume delivery by intravitreal injections in the clinical setup. METHODS: Volume output was measured in 669 intravitreal injections administered to patients, calculated from the difference in syringe weight before and after expelling the drug. Three groups were included: prefilled bevacizumab 1.0 mL syringe (Group 1, n = 432), pre-filled ranibizumab in a small-volume syringe with low dead-space plunger design (Group 2, n = 125), and aflibercept drawn and injected using a 1.0-mL syringe (Group 3, n = 112). Accuracy was analyzed by mean absolute percentage error, and precision by coefficient of variation. RESULTS: Volume outputs in all 3 groups were significantly different from the target of 50 µL (P < 0.0001 for all), and mean absolute percentage error values were 12.25% ± 5.92% in Group 1, 13.60% ± 8.75% in Group 2, and 24.69% ± 14.84% in Group 3. No difference was found between groups 1 and 2, but both were significantly more accurate than Group 3 (P < 0.0001 for both). CONCLUSION: The current practices used for intravitreal injections are highly variable, with overdelivery of the anti-vascular endothelial growth factor drugs measured in most cases, but underdelivery in 16.3% of injections. Use of a prefilled syringe was associated with improved accuracy, and low dead-space plunger design may improve precision.

A swarm of slippery micropropellers penetrates the vitreous body of the eye.

The intravitreal delivery of therapeutic agents promises major benefits in the field of ocular medicine. Traditional delivery methods rely on the random, passive diffusion of molecules, which do not allow for the rapid delivery of a concentrated cargo to a defined region at the posterior pole of the eye. The use of particles promises targeted delivery but faces the challenge that most tissues including the vitreous have a tight macromolecular matrix that acts as a barrier and prevents its penetration. Here, we demonstrate novel intravitreal delivery microvehicles-slippery micropropellers-that can be actively propelled through the vitreous humor to reach the retina. The propulsion is achieved by helical magnetic micropropellers that have a liquid layer coating to minimize adhesion to the surrounding biopolymeric network. The submicrometer diameter of the propellers enables the penetration of the biopolymeric network and the propulsion through the porcine vitreous body of the eye over centimeter distances. Clinical optical coherence tomography is used to monitor the movement of the propellers and confirm their arrival on the retina near the optic disc. Overcoming the adhesion forces and actively navigating a swarm of micropropellers in the dense vitreous humor promise practical applications in ophthalmology.