NIR-triggered thermosensitive polymer brush coating modified intraocular lens for smart prevention of posterior capsular opacification.

Posterior capsule opacification (PCO) is the most common complication after cataract surgery. Drug-eluting intraocular lens (IOLs) is a promising concept of PCO treatment in modern cataract surgery. However, the large dose of drugs in IOL leads to uncontrollable and unpredictable drug release, which inevitably brings risks of overtreatment and ocular toxicity. Herein, a low-power NIR-triggered thermosensitive IOL named IDG@P(NIPAM-co-AA)-IOL is proposed to improve security and prevent PCO by synergetic controlled drug therapy and simultaneous photo-therapy. Thermosensitive polymer brushes Poly(N-isopropylacrylamide-co-Acrylic acid) (P(NIPAM-co-AA)) is prepared on IOL via surface-initiated reversible addition-fragmentation chain transfer (SI-RAFT) polymerization. Then, Doxorubicin (DOX) and Indocyanine green (ICG) co-loaded Gelatin NPs (IDG NPs) are loaded in P(NIPAM-co-AA) by temperature control. The IDG NPs perform in suit photodynamic & photothermal therapy (PTT&PDT), and the produced heat also provides a trigger for controllable drug therapy with a cascade effect. Such functional IOL shows excellent synergistic drug-phototherapy effect and NIR-triggered drug release behavior. And there is no obvious PCO occurrence in IDG@P(NIPAM-co-AA) IOL under NIR irradiation compared with control group. This proposed IDG@P(NIPAM-co-AA)-IOL serves as a promising platform that combines phototherapy and drug-therapy to enhance the therapeutic potential and medication safety for future clinical application of PCO treatment.

Microscopic Characteristics of Late Intraocular Lens Opacifications.

CONTEXT.­: The increases in overall life expectancy and in lens surgeries performed on younger patients have resulted in a significant increase in the anticipated duration of artificial intraocular lenses (IOLs) in the eye. Thus, the physicochemical properties of the IOL become a critical issue, and several types of postoperative IOL opacifications have been reported. OBJECTIVE.­: To describe the microscopic characteristics of opacified IOLs. Glistenings and subsurface nanoglistenings are fluid-related phenomena developing mainly in hydrophobic acrylic IOLs and are associated with aqueous influx into the IOL matrix. Calcification presents in hydrophilic acrylic or silicone IOLs as deposits of hydroxyapatite or other phases of calcium. Snowflake degeneration is less common, and it manifests in older polymethyl methacrylate IOLs. DATA SOURCES.­: PubMed and ScienceDirect databases were searched for the following keywords: intraocular lens, IOL, cataract surgery, phacoemulsification, opacification, glistening, subsurface nanoglistenings, calcification, snowflake degeneration. English-language articles published up to October 15, 2019 were included in the study. The manuscript contains mainly a literature review; however, it was supplemented with original investigations from the David J. Apple International Laboratory for Ocular Pathology. CONCLUSIONS.­: Glistenings and subsurface nanoglistenings should be evaluated in a hydrated state and at room temperature; they manifest as microvacuoles sized from 1.0 to greater than 25.0 µm and less than 200 nm, respectively. Calcification deposits are situated on or underneath the surface of the IOL and can be stained with a 1% alizarin red solution or with the von Kossa method. Snowflake degeneration manifests as "particles" or "crystals," causing whitish IOL discoloration. Scanning electron microscopy or energy dispersive X-ray spectroscopy may improve the diagnostic accuracy.

The Intraocular Lens as a Drug Delivery Device: In Vitro Screening of Pharmacologic Substances for the Prophylaxis of Posterior Capsule Opacification.

Purpose: Numerous pharmacologic substances have been proposed for preventing posterior capsule opacification (PCO). The following trial was to compare those drugs to find more suitable options. IOL should then be modified by the pharmaceuticals as a drug-delivery device. Methods: A systematic literature search was performed to identify published substances. FHL-124 was used to determine cell proliferation and toxicity using a dye reduction test (XTT). Prescreened substances showing a reduction on cell growth without being toxic were soaked into an IOL. Those IOL were tested for their effect on PCO in an anterior-segment model and the human ex vivo capsular bag model. Toxicity on a corneal endothelial cell line (CEC-SV40) was determined. Release kinetics of methotrexate from the IOL was measured. Toxicity testing in both cell lines was done in serum-free conditions. All growth assays were exposed to 10% fetal calf serum (FCS)-supplemented medium. Results: The substances inhibited cell growth at the following EC50: caffeic acid phenethyl ester 1.6 ± 0.9 nM, disulfiram 359 ± 33 nM, methotrexate 98.0 ± 29.7 nM, rapamycin 70.2 ± 14.0 pM, and retinoic acid 1.1 ± 0.12 nM. All but disulfiram showed an effect in the anterior segment model when soaked into an IOL. Long-term inhibitory effects in the human capsular bag model were observed for caffeic acid phenethyl ester and methotrexate IOLs. Only methotrexate and disulfiram did not show any toxicity on endothelial cells. Methotrexate was released constantly from the hydrophilic IOL for 2 weeks. Conclusions: We could identify caffeic acid phenethyl ester and methotrexate in vitro as potential candidates for IOL modification for PCO prophylaxis.

An in vitro evaluation of the Anew Zephyr open-bag IOL in the prevention of posterior capsule opacification using a human capsular bag model.

PURPOSE: During cataract surgery an IOL is placed within the capsular bag. Clinical studies show that IOLs with a square edge profile and complete contact between the IOL and the anterior capsule (AC) are currently the best way to prevent posterior capsule opacification (PCO). This has been challenged by recent clinical and experimental observations, which suggest that if the capsular bag is kept open with separation of contact between the AC and posterior capsule (PC) by an "open-bag device" PCO is dramatically reduced. Therefore, the current study set out to evaluate the putative merits of an open-bag IOL (Anew Zephyr) in a human capsular bag model. METHODS: An in vitro organ culture model using the bag-zonular-ciliary body complex isolated from fellow human donor eyes was prepared. A capsulorhexis and lens extraction were performed, and an Alcon Acrysof IOL or Anew Zephyr IOL implanted. Preparations were secured by pinning the ciliary body to a silicone ring and maintained in 6 mL Eagle's minimum essential medium (EMEM) or EMEM supplemented with 2% vol/vol human serum (HS) and 10 ng/mL TGF-ß2 for 28 days. Cell growth and capsular modifications were monitored with phase-contrast and modified dark-field microscopy. RESULTS: In serum-free EMEM culture conditions, cells were observed growing onto the PC of preparations implanted with an Anew Zephyr IOL, but this was retarded relative to observations in match-paired capsular bags implanted with an Alcon Acrysof IOL. In the case of cultures maintained in 2% HS-EMEM plus TGF-ß2, the movement on to the PC was again delayed with the presence of an Anew Zephyr IOL. Differences in the degree of growth on the PC and matrix modifications were apparent with the different donors, but in each case the match-paired Alcon Acrysof implanted bag exhibited significantly greater coverage and modification of the capsule. CONCLUSIONS: The Anew Zephyr open-bag IOL performs consistently better than the Alcon Acrysof IOL in the human capsular bag model. We propose that the benefits observed with the Anew Zephyr result from a reduction in growth factor levels available within the capsular bag and a barrier function imposed by the ring haptic.

Prevention of capsule opacification after accommodating lens refilling: pilot study of strategies evaluated in a monkey model.

PURPOSE: To test 2 strategies to prevent capsule opacification after accommodating lens refilling in a rhesus monkey model. SETTING: Animal laboratory and laboratory of European university medical centers. DESIGN: Experimental study. METHODS: Six rhesus monkeys had refilling of the lens capsular bag. In the first strategy, before it was filled with a silicone polymer, the capsular bag was treated with noncommercial sodium hyaluronate 1.0% containing cytotoxic substances. In the second strategy, the capsular bag was filled with clinically used sodium hyaluronate 1.0% (Healon) after treatment with actinomycin-D. Slitlamp inspection was performed during a follow-up of 40 to 50 weeks. After enucleation, magnetic resonance images were obtained and confocal fluorescence imaging was performed. RESULTS: Using the first strategy, capsule opacification developed in all eyes. Using the second strategy, 1 monkey did not develop capsule opacification after a 9-month follow-up. In a second monkey, the lens capsule remained clear for 3 months, after which the hyaluronate refill material was exchanged with a silicone polymer and capsule opacification developed. Combining these results with those in a previous study, the difference in opacification between silicone and sodium hyaluronate as refilling materials was statistically significant (P<.01). CONCLUSIONS: That no capsular bag fibrosis occurred in the presence of hyaluronate suggests that the properties of hyaluronate are the reason that remaining lens epithelial cells do not develop into fibrotic cells. The choice of a suitable lens-refilling material prevents the development of capsule opacification. FINANCIAL DISCLOSURE: Mr. Terwee was an employee of Abbott Medical Optics B.V. during the study period. No other author has a financial or proprietary interest in any material or method mentioned.

Effect of total lens epithelial cell destruction on intraocular lens fixation in the human capsular bag.

PURPOSE: To evaluate the effect of complete destruction of lens epithelial cells (LECs) in the capsular bag on intraocular lens (IOL) stability. SETTING: School of Biological Sciences, University of East Anglia, Norwich, United Kingdom. DESIGN: Comparative evaluation. METHODS: An in vitro organ culture model using the bag-zonule-ciliary body complex isolated from fellow human donor eyes was prepared. A capsulorhexis and fiber extraction were performed, and an Acrysof IOL was implanted. Preparations were secured by pinning the ciliary body to a silicone ring and maintaining it in 6 mL Eagle minimum essential medium supplemented with 5% v/v fetal calf serum and 10 ng/mL transforming growth factor-ß2 for 3 weeks or more. One bag of each pair was treated with 1 µM thapsigargin to destroy all LECs. Observations of LEC growth were captured by phase-contrast microscopy, IOL stability by video microscopy, and endpoint analysis through scanning electron microscopy and immunocytochemistry. RESULTS: The LECs in control capsular bags migrated centrally, closing the bag and fixating the IOL between the anterior and posterior capsules, as seen clinically. These events were not observed in the thapsigargin-treated group. After a period of controlled orbital movement, the IOL in the control group stabilized quicker than in the treated bags. There was no IOL rotation in the bag; however, the IOLs in the treated group rocked with axial movement. CONCLUSIONS: The LECs appeared to aid stabilization of current IOL designs in the capsular bag. The results have clinical implications for IOL design and for strategies to prevent posterior capsule opacification. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Sulfadiazine modified PDMS as a model material with the potential for the mitigation of posterior capsule opacification (PCO).

Cataract surgery, while the most common surgical procedure performed, leads to posterior capsule opacification in approximately 30% of cases. Transforming growth factor beta 2 (TGF-ß2) and matrix metalloproteinases (MMPs) have been shown to play important roles in the cellular processes leading to posterior capsule opacification. Delivery of inhibitors to MMPs may have the potential to inhibit the initial cascade of events that lead to PCO. However, delivery of these molecules via tethering has proven difficult. In this work, sulfadiazine was tethered to polydimethylsiloxane (PDMS) via a polyethylene glycol (PEG) spacer as a potential MMPI mimic. Surface characterization using a variety of methods demonstrated successful modification with the antibiotic. The surfaces were examined with lens epithelial cells to determine their effect on these cellular processes, including cell transdifferentiation and production of extracellular matrix components. The presence of TGF-ß2 in the cell culture media was found to stimulate the production of ECM components such as collagen, fibronectin, and laminin, as well as alpha smooth muscle actin (α-SMA), and the migration marker Rho by HLE-B3 and FHL124 cells. In all cases, these effects were decreased but not completely eradicated by the presence of sulfadiazine on the PDMS surfaces. While the level of inhibition necessary for inhibition of PCO in vivo is unknown, these results suggest that IOL surface modification with sulfadiazine has the potential to reduce cellular changes associated with PCO. Furthermore, the results demonstrate for the first time that changes consistent with inhibition of fibrosis may be elicited by surfaces modified with sulfadiazine.

A randomized, single-center study of equivalence of 2 intraocular lenses used in cataract surgery.

PURPOSE: To compare the outcomes of 2 intraocular lenses (IOLs) for the treatment of age-related cataracts. DESIGN: Prospective, randomized trial. PARTICIPANTS: Patients with age-related cataracts were recruited and randomized to receive phacoemulsification and implantation of either the AcrySof SA60AT lens (Alcon, Inc, Fort Worth, TX) or the low-cost Tecsoft Flex lens (Fred Hollows Foundation, Tilganga, Nepal). A total of 300 patients were available for description and analysis (148 in the AcrySof group and 152 in the Tecsoft group). METHODS: Patients underwent phacoemulsification and implantation of the AcrySof SA60AT lens or the Tecsoft Flex lens. They were followed up and examined at baseline, 1 week, 1 month, 6 months, and 12 months after cataract surgery. MAIN OUTCOME MEASURES: Uncorrected distance visual acuity (UDVA), best-corrected distance visual acuity (BDVA), incidence of posterior capsule opacification (PCO), Visual Function Index questionnaire results, and safety of the implanted IOLs. RESULTS: No significant difference (P>0.05) was found in UDVA and BDVA after surgery between the 2 groups. The equivalence test of the 95% confidence intervals showed that both lenses had an equal improvement of UDVA and BDVA as well as similar rates of PCO after cataract surgery. There was no significant difference between the 2 groups with regard to visual functioning or the incidence of adverse surgical events during (P>0.05) or after (P>0.05) the surgery. CONCLUSIONS: The Tecsoft Flex IOL is a low-cost suitable alternative that is similar to the AcrySof IOL in terms of safety and visual outcomes.

Modulation of matrix metalloproteinase activity by EDTA prevents posterior capsular opacification.

PURPOSE: To evaluate the effect of ethylenediaminetetraacetic acid (EDTA) on posterior capsular opacification (PCO) of rabbits and to assess its effect on intraocular tissues. METHODS: Modulation of matrix metalloproteinase (MMP) activity in the aqueous following cataract surgery in rabbits and its prevention by different doses of EDTA was determined by zymography. For evaluation of PCO, lensectomized rabbits were intracamerally injected with single dose of either 5 mg EDTA or normal saline. After one month, the degree of PCO was determined by slitlamp biomicroscopy, Miyake-Apple view, and histology of the lens capsule. The effect of EDTA on intra ocular pressure (IOP), corneal endothelial cells, and the retina was evaluated by tonometry, specular microscopy and scanning electron microscopy, and electroretinography. The concentration of EDTA in the aqueous was determined by high performance liquid chromatography (HPLC) at different time points. RESULTS: The MMP activity was significantly increased in the aqueous of the operated eyes, and EDTA reduced the degree of increase in a dose-dependent manner. EDTA treatment significantly reduced the degree of PCO (p<0.05). Histopathology of the lens capsule showed a reduction in the number of proliferating and migrating cells as well as MMP2 expression in the EDTA-treated eyes. EDTA treatment did not change the IOP; density, morphology and ultrastructure of the corneal endothelial cells; and electroretinography (ERG). EDTA was detectable in the aqueous humor up to 72 h following a single intracameral injection. CONCLUSIONS: EDTA reduces the degree of PCO by suppressing the MMP activity and it is not toxic to intra ocular structures at the concentration used.

An experimental study on the effects of curcumin on posterior capsule opacification in young rabbit eyes.

BACKGROUND: Posterior capsule opacification (PCO) compromises vision development in infants after cataract surgery and lead to amblyopia. To observe the effects of curcumin on PCO in infant rabbits, curcumin was injected under the capaule and into the anterior chamber during phacoemulsification. METHODS: Seventy-five 1-month-old healthy New Zealand white rabbits were randomized into 3 groups, one eye of each rabbit was randomly selected to be operated. The operation involved continuous circular capsulorhexis, followed by hydrodissection with 0.6 ml each of balanced salt solution (BSS, group A), hydroxypropyl-ß-dodextrin (HP-ß-CD, 90 µg/ml, group B) or CUR-HP-ß-CD (123 µg/ml, group C), respectively. After phacoemulsification, 0.4 ml of each drug solution was injected into the anterior chamber via an incision. The extent of corneal edema and the inflammatory response within the anterior chamber were considered as measures PCO and observed postoperatively. All eyes were examined 1 and 2 months postoperative by slit lamp microscopy and photography after pupil dilation. On the third day postoperative, 6 rabbits from each group were executed. Paraffin-embedded sections were stained with hematoxylin-eosin (HE) or terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL, indicative of apoptosis). Stained sections were observed under light microscopy. Proliferation of lens epithelial cells (LECs) was observed microscopically on day 3, day 7, month 1 and month 2 after the operation with HE staining. RESULTS: The remission of cornea edema occurred earlier in group C than in groups A and B (P < 0.05); there were no significant differences between groups A and B. The remission of anterior chamber exudation in group C was earlier than those in groups A and B (P < 0.05). No significant difference in the times when PCO occurred, was observed among groups. Compared to groups A and B, the extent of PCO was less severe (P < 0.05). Three days after the operation, LECs aggregated at the orbit. Meanwhile, minor apoptosis was observed in all groups. One month after the operation transparent, cortex and proliferating LECs were observed near the orbit in groups A and B. Two months postoperative, heavy cortex proliferation was observed in all groups: epithelial cells migrated and aggregated at the posterior capsule and rearranged under the anterior capsule in the control group. Proliferation was also observed in group C, but to a less severe extent than in the other two groups. CONCLUSION: CUR-HP-ß-CD exerts an inhibitory effect on PCO.