Intravitreal injectable hydrogel rods with long-acting bevacizumab delivery to the retina.

Retinal vascular diseases such as neovascular age-related macular degeneration (nAMD) are the leading cause of blindness worldwide. They can be treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents by inhibiting VEGF which is a major agent of abnormal blood vessel growth. However, because of drug's short half-life, clinical treatment often requires monthly repeated intravitreal injections, causing treatment burden and undertreatment. Among various kinds of drug carriers, in situ forming hydrogels have been studied as potential intravitreal drug carriers for the high drug loading, easy injection, controlled drug release, and protection of encapsulated drugs from the environment. However, gelation time, crosslinking degree, and drug release patterns following injection of a liquid that will be subsequently gelled in situ are susceptible to be hindered by dilution of the hydrogel precursor solution with body fluids (e.g., blood or vitreous). Here, we report an injectable pre-crosslinked hydrogel rod to overcome the limitations of in situ forming hydrogels and to extend intravitreal half-life of anti-VEGF for reducing intraocular injection frequency. Hydrogel rods can be simply prepared using in situ forming hydrogels, and injectable using a designed rod injector. The adjustable crosslinking degree of hydrogel rods easily controlled bevacizumab release profiles in a sustained manner. Compared with in situ forming hydrogels, hydrogel rods effectively reduced initial burst release, and showed sustained release with long-term drug efficacy in vitro. From the 4-month in vivo pharmacokinetic analysis, following the intravitreal injection of hydrogel rods, the half-life of bevacizumab in the vitreous and retina was significantly extended, and drug elimination to aqueous humor was effectively reduced. Finally, intraocular stability, degradation, and inflammatory response of hydrogel rods were evaluated. We expect that the hydrogel rod can be a potential drug delivery system for the treatment of nAMD and other conditions that need long-term and local sustained drug administration. STATEMENT OF SIGNIFICANCE: Herein, we report an injectable pre-crosslinked hydrogel rod based on an in situ forming hydrogel to achieve intravitreal long-acting anti-VEGF delivery to reduce injection frequency and improve the long-term visual outcomes of patients with retinal vascular diseases. Hydrogel rods were readily prepared using removable molds and injected using customized injectors. Compared to the in situ forming hydrogel, hydrogel rods showed significantly reduced initial burst release, controllable release profiles for several months, physical stability, and a long-acting anti-angiogenic effect. Animal studies demonstrated that the hydrogel rods dramatically prolonged the intraocular drug half-life while significantly reducing drug elimination for up to four months. Moreover, the biodegradability and safety of the hydrogel rods suggest their suitability as an advanced intravitreal DDS for treating retinal vascular diseases.

Primary and additional treatment preference in aggressive retinopathy of prematurity and type 1 retinopathy of prematurity.

OBJECTIVE: This study aimed to evaluate the preference for antivascular endothelial growth factor (anti-VEGF) versus laser ablation therapy as primary and additional treatment in aggressive retinopathy of prematurity (ROP) and type 1 ROP. METHODS: This multicentre retrospective study was conducted at nine medical centres across South Korea. A total of 94 preterm infants with ROP who underwent primary treatment between January 2020 and December 2021 were enrolled. All eyes were classified as having type 1 ROP or aggressive ROP. Data on the zone, primary treatment chosen, injection dose, presence of reactivation and additional treatment were collected and analysed. RESULTS: Seventy infants (131 eyes) with type 1 ROP and 24 infants (45 eyes) with aggressive ROP were included. Anti-VEGF injection was selected as the primary treatment in 74.05% of the infants with type 1 ROP and 88.89% with aggressive ROP. Anti-VEGF injection was selected as the ROP was located in zone I or posterior zone II, and laser ablation was selected when it was located in zone II. The anti-VEGF injection doses varied and tended to be higher in the aggressive ROP group. Infants with aggressive ROP were 2.08 times more likely to require additional treatment than those with type 1 ROP. When ROP reactivation occurred, laser therapy was preferred as an additional treatment. CONCLUSION: In Korea, the preference for anti-VEGF therapy or laser therapy differed according to ROP subtype, zone and primary or secondary treatment. These findings suggest that ROP treatment are considered according to ROP subtype, location and reactivation.

Cord blood transforming growth factor-ß-induced as predictive biomarker of retinopathy of prematurity in preterm infants.

PURPOSE: To determine whether 14 inflammation-, angiogenesis-, and adhesion-related proteins in cord blood (CB), alone or in combination with conventional perinatal factors, could predict retinopathy of prematurity (ROP) in preterm infants. METHODS: Data from 111 preterm infants (born at ≤ 32.0 weeks) were retrospectively reviewed. The levels of endoglin, E-selectin, HSP70, IGFBP-3/4, LBP, lipocaline-2, M-CSFR, MIP-1α, pentraxin 3, P-selectin, TGFBI, TGF-ß1, and TNFR2 were assessed in stored CB samples collected at birth using ELISA kits. The primary endpoints included severe ROP (≥ stage 3) and type 1 ROP requiring treatment. RESULTS: ROP was diagnosed in 29 infants (26.1%), among whom 14 (12.6%) had severe ROP and seven (6.3%) had type 1 ROP. Multivariate logistic regression showed that decreased CB TGFBI levels were significantly associated with severe ROP and type 1 ROP after adjusting for gestational age at birth. Stepwise regression analysis allowed to design prediction models with good accuracy, which comprised low CB TGFBI levels and low birth weight (BW) as predictors for severe ROP (area under the curve [AUC] = 0.888), and low CB endoglin levels and low BW as predictors for type 1 ROP (AUC = 0.950). None of the other CB proteins evaluated were found to be associated with severe ROP or type 1 ROP. CONCLUSIONS: Low CB TGFBI levels are associated with severe ROP and type 1 ROP, independently of gestational age. Moreover, combined predictive models based on CB TGFBI and endoglin levels, along with BW data, may act as good indicators at birth for the neonatal risk of ROP progression.

Association of inflammatory and angiogenic biomarkers in maternal plasma with retinopathy of prematurity in preterm infants.

OBJECTIVE: To investigate whether various novel inflammatory and angiogenic biomarkers in maternal plasma, alone or in combination with baseline antenatal factors, could predict retinopathy of prematurity (ROP) in preterm infants. METHODS: A retrospective cohort study was conducted on 140 premature singleton neonates born to women with preterm birth (≤32 weeks) and screened for ROP. Maternal blood obtained at the time of admission was assayed for CRP, endoglin, endostatin, IGFBP-2, IGFBP-3, IL-6, LBP, MMP-8, PlGF, S100A8/A9, TGFBI, and VEGFR-1. The primary outcome measures included severe ROP (stage 3 or higher) and type 1 ROP requiring treatment. RESULTS: ROP was present in 25.7% (36/140) of the study population, including 20 (14.3%) cases of severe ROP and 14 (10%) with type 1 ROP. Multiple logistic regression analyses revealed significant associations between high concentrations of maternal plasma LBP and severe ROP, and between elevated plasma IL-6 and LBP levels and type 1 ROP (all P < 0.05), while adjusting for confounders (i.e., gestational age [GA] at sampling). Prenatal prediction models for severe ROP and type 1 ROP were developed by combining plasma IL-6 or LBP levels with GA at sampling, which showed good discriminatory power (area under the curve = 0.747 and 0.854, respectively). CONCLUSIONS: IL-6 and LBP in maternal plasma were found to be independently associated with severe ROP and type 1 ROP. Prediction models based on these biomarkers along with GA at sampling may serve as good prenatal indicators for the neonatal risk of ROP progression in women at risk of preterm birth.

Association between corneal refractive surgery and the prevalence of glaucoma: Korea National Health and Nutrition Examination Survey 2010-2012.

AIM: To determine the relationship between corneal refractive surgery and the prevalence of glaucoma in the Korean population. METHODS: Data were obtained from the Korea National Health and Nutrition Examination Survey (KNHANES), a population-based cross-sectional study using a complex, stratified, multistage, probability-cluster survey. This study included 604 eyes that had undergone myopic corneal refractive surgery, and 3389 control eyes without a history of any ocular surgery and having a spherical equivalent (SE) <-3.00 D, obtained from the KNHANES database for the years 2010-2012. Glaucoma diagnosis was based on the International Society of Geographical and Epidemiological Ophthalmology criteria. The association between a history of corneal refractive surgery and the prevalence of glaucoma was analysed using logistic regression analysis, after adjusting for potential confounding factors. RESULTS: Glaucoma prevalence did not differ between eyes that had and had not undergone corneal refractive surgery (p=0.675). After adjusting for age, sex, SE, and intraocular pressure, multivariate logistic regression analysis found that corneal refractive surgery was significantly associated with an increased risk of glaucoma (OR 9.14, p=0.002; 95% CI 2.22 to 37.69). Subgroup analysis that only included control eyes with a refraction cut-off <-3.70 D found that corneal refractive surgery was not significantly associated with glaucoma. CONCLUSIONS: History of corneal refractive surgery was associated with a higher prevalence of glaucoma in the Korean population. However, this association was not observed in eyes with a higher degree of myopia.

Comparison of Ocular Biometry and Refractive Outcomes Using IOL Master 500, IOL Master 700, and Lenstar LS900.

PURPOSE: To evaluate the agreement in ocular biometry outcomes measured by three different devices, the IOL Master 500, IOL Master 700, and Lenstar LS900, and compare the refractive outcomes after cataract surgery obtained using those three devices. METHODS: Medical records of 178 eyes of 89 patients who underwent ocular biometry with the three devices were retrospectively reviewed, and 124 eyes met the inclusion criteria. Paired comparisons were performed for axial length (AL), mean keratometry (Km), and anterior chamber depth and quantified their agreement using Bland-Altman plots. Subgroup analyses were done according to the AL and the Km. Refractive outcomes were compared with respect to absolute prediction errors after cataract surgery in 54 eyes. RESULTS: Among 124 eyes, 12, 3, and 5 eyes failed to be measured of AL by IOL Master 500, IOL Master 700 and Lenstar LS900, respectively. The AL measured by Lenstar LS900 was longer than that measured by IOL Master 500 and IOL Master 700 (p < 0.001, p = 0.002, respectively). Subgroup analysis revealed that these results were statistically significant only in long eyes (AL >25.5 mm). Km measured using the IOL Master 500 was steeper than that measured with the IOL Master 700 or Lenstar LS900 (p = 0.001, p < 0.001, respectively). anterior chamber depth measured by IOL Master 500 was shallower than that measured by IOL Master 700 or Lenstar LS900 (p < 0.001, p < 0.001, respectively). Ocular biometry measurements by the three devices showed high agreement with narrow 95% limits of agreement. Absolute prediction errors from the 3 devices showed no statistically significant differences after cataract surgery. CONCLUSIONS: The IOL Master 700 and Lenstar LS900 demonstrated superior acquisition rates of biometric measurements compared with the IOL Master 500. Ocular biometry using the 3 different devices showed high agreement, although statistically significant differences were observed; however, since there was no difference in predicting the refractive outcomes, those differences are clinically negligible.