Loss of barrier integrity precedes the development of pathologies such as metastasis, inflammatory disorders, and blood-retinal barrier breakdown present in neovascular age-related macular degeneration. Rap1 GTPase is involved in regulating both endothelial and epithelial cell junctions; the specific role of Rap1A vs. Rap1B isoforms is less clear. Compromise of retinal pigment epithelium barrier function is a contributing factor to the development of AMD. We utilized shRNA of Rap1 isoforms in cultured human retinal pigment epithelial cells, along with knockout mouse models to test the role of Rap1 on promoting RPE barrier properties, with emphasis on the dynamic junctional regulation that is triggered when the adhesion between cells is challenged. In vitro, Rap1A shRNA reduced steady-state barrier integrity, whereas Rap1B shRNA affected dynamic junctional responses. In a laser-induced choroidal neovascularization (CNV) model of macular degeneration, Rap1b−/− mice exhibited larger CNV volumes compared to wild-type or Rap1a−/−. In vivo, intravitreal injection of a cAMP analog (8CPT-2′-O-Me-cAMP) that is a known Rap1 activator significantly reduced laser-induced CNV volume, which correlated with the inhibition of CEC transmigration across 8CPT-2′O-Me-cAMP-treated RPE monolayers in vitro. Rap1 activation by 8CPT-2′-O-Me-cAMP treatment increased recruitment of junctional proteins and F-actin to cell-cell contacts, increasing both the linearity of junctions in vitro and in cells surrounding laser-induced lesions in vivo. We conclude that in vitro, Rap1A may be important for steady state barrier integrity, while Rap1B is involved more in dynamic junctional responses such as resistance to junctional disassembly induced by EGTA and reassembly of cell junctions following disruption. Furthermore, activation of Rap1 in vivo inhibited development of choroidal neovascular lesions in a laser-injury model. Our data suggest that targeting Rap1 isoforms in vivo with 8CPT-2′-O-Me-cAMP may be a viable pharmacological means to strengthen the RPE barrier against the pathological choroidal endothelial cell invasion that occurs in macular degeneration.

We describe a new capsular stabilization device for suspending a lens with weak zonular support. It is flexible, 10.0 mm in length, and fashioned from 5-0 nylon. The contact portion is bent at 1.25 mm with an end bifurcating to form a T-shape to minimize stress on the capsular equator. After a continuous curvilinear capsulorhexis is created, the capsular stabilization devices to hook the capsulotomy margin are inserted. The T-shaped end is passed around the anterior capsular flap to fit the curvature of the equator. Phacoemulsification and aspiration using this device was performed in 12 eyes of 9 patients, and the usefulness and complications were analyzed. The capsular stabilization devices suspended the capsule and facilitated safe phacoemulsification in all eyes. Posterior capsule rupture occurred in 2 eyes. None of the cases had notable postoperative complications. This device ensures a stable capsule-iris complex and reduces surgical risks.

Directed self-assembly (DSA) has the potential to extend scaling for both line/space and hole patterns. DSA has shown the capability for pitch reduction (multiplication), hole shrinks, CD self-healing as well as a pathway towards line edge roughness (LER) and pattern collapse improvement [1][2][3][4]. The current challenges for industry adoption are materials maturity, practical process integration, hardware capability, defect reduction and design integration. Tokyo Electron (TEL) has created close collaborations with customers, consortia and material suppliers to address these challenges with the long term goal of robust manufacturability.This paper provides a wide range of DSA demonstrations to accommodate different device applications. In collaboration with IMEC, directed line/space patterns at 12.5 and 14 nm HP are demonstrated with PS-b-PMMA (poly(styrene-b-methylmethacrylate)) using both chemo and grapho-epitaxy process flows. Pre-pattern exposure latitudes of >25% (max) have been demonstrated with 4X directed self-assembly on 300 mm wafers for both the lift off and etch guide chemo-epitaxy process flows. Within TEL's Technology Development Center (TDC), directed selfassembly processes have been applied to holes for both CD shrink and variation reduction. Using a PS-b-PMMA hole shrink process, negative tone developed pre-pattern holes are reduced to below 30 nm with critical dimension uniformity (CDU) of 0.9 nm (3σ) and contact edge roughness (CER) of 0.8 nm (3σ). To generate higher resolution beyond a PS-b-PMMA system, a high chi (χ) material is used to demonstrate 9 nm HP line/ space post-etch patterns. In this paper, TEL presents process solutions for both line/space and hole DSA process integrations.