In Vivo Intraocular Pressure Measurements Using A Miniaturized Nano-Photonic Sensor Implant

Purpose : We have been developing a nanophotonic pressure sensor whose optical resonance is directly related to intraocular pressure (IOP). Bench testing has demonstrated sensor near-infrared (NIR) reflectance to accurately track pressures from 0-50 mmHg. The current study examined sensor performance following implantation into rabbit eyes for up to one month

Towards elucidating photochemical reaction pathways in nickel catalyzed cross coupling and organocatalyzed Birch reduction

2021 Fall.Includes bibliographical references.Carbon-nitrogen (C─N) bond forming reactions to couple aryl halides with amines are essential for the discovery and production of medicinal compounds. The state-of-the-art method uses a precious metal palladium catalyst at high temperatures which poses sustainability concerns. Recently, a method was reported in which an iridium photocatalyst (PC) works in tandem with a nickel catalyst under blue light irradiation to achieve C─N bond formation at room temperature. Herein, it was discovered that the iridium PC could be omitted if 365 nm light is used, constituting a precious metal-free approach. This discovery suggests that a nickel-centered excited state can mediate C─N bond formation, raising the possibility of an energy transfer type pathway in dual catalytic systems. The nickel complexes formed were identified for the first time and mechanistic evidence was found that is consistent with energy transfer with both [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine) and a phenoxazine PC. A series of [NiBr2(amine)n] complexes were isolated, characterized, and detected in C─N coupling reaction mixtures. A theoretical framework for predicting energy transfer rate constant ratios based on Förster theory and UV-visible spectroscopy was developed. The phenoxazine PC was both predicted and found to exhibit faster energy transfer and enhanced reaction performance when compared with [Ru(bpy)3]2+. In addition, a light-driven, organocatalyzed system for Birch reduction was developed. Historically, Birch reduction to reduce an arene to a 1,4-cyclohexadiene has been limited by the required use of alkali metals which are pyrophoric and can be explosive. Under violet light, a benzo[ghi]perylene imide PC was found to reduce challenging arenes such as benzene, constituting the first visible light driven approach capable of this reactivity. Mechanistic studies were performed that are consistent with a catalytic cycle involving addition of OH─ to the PC to form an adduct, [PC─OH]─. Photolysis of the adduct forms OH• and the PC radical anion which subsequently undergoes photoionization, ejecting a solvated electron that reduces the substrate

Tuning the Properties of Multi-Stable Structures Post-Fabrication Via the Two-Way Shape Memory Polymer Effect

Multi-stable elements are commonly employed to design reconfigurable and adaptive structures, because they enable large and reversible shape changes in response to changing loads, while simultaneously allowing self-locking capabilities. However, existing multi-stable structures have properties that depend on their initial design and cannot be tailored post-fabrication. Here, a novel design approach is presented that combines multi-stable structures with two-way shape memory polymers. By leveraging both the one-way and two-way shape memory effect under bi-axial strain conditions, the structures can re-program their 3D shape, bear loads, and self-actuate. Results demonstrate that the structures' shape and stiffness can be tuned post-fabrication at the user's need and the multi-stability can be suppressed or activated on command. The control of multi-stability prevents undesired snapping of the structures and enables higher load-bearing capability, compared to conventional multi-stable systems. The proposed approach offers the possibility to augment the functionality of existing multi-stable concepts, showing potential for the realization of highly adaptable mechanical structures that can reversibly switch between being mono and multi-stable and that can undergo shape changes in response to a change in temperature.ISSN:2198-384

Advanced Glycation End-Product Accumulation Reduces Vitreous Permeability

PurposeTo evaluate the effect of nonenzymatic cross-linking (glycation) upon the permeability of the vitreous to small- and large-solute diffusion.MethodsVitreous from freshly excised porcine eyes was treated for 30 minutes with control or 0.01%, 0.1%, or 1% methylglyoxal (MG) solution. The efficacy of the glycation regimen was verified by measuring nonenzymatic cross-link density by fluorescence in the vitreous samples. Resistance to collagenase digestion as well as N(ε)-(carboxyethyl) lysine (CEL) content were also measured. The permeability coefficient for fluorescein and fluorescein isothiocyanate (FITC)-IgG diffusion through 3 mL of the vitreous samples was determined by using a custom permeability tester.ResultsVitreous cross-linking with MG treatment was confirmed by increased fluorescence, increased CEL concentration, and increased resistance to collagenase digestion. Vitreous glycation resulted in a statistically significant decrease in the permeability coefficient for fluorescein diffusion when either 0.1% or 1% MG solution was used (5.36 ± 5.24 × 10(-5) cm s(-1), P = 0.04; and 4.03 ± 2.1 × 10(-5) cm s(-1), P = 0.001; respectively, compared with control, 9.77 ± 5.45 × 10(-5) cm s(-1)). The permeability coefficient for diffusion of FITC-IgG between control (9.9 ± 6.37 × 10(-5) cm s(-1)) and treatment groups was statistically significant at all MG concentrations (0.01% MG: 3.95 ± 3.44 × 10(-5) cm s(-1), P = 0.003; 0.1% MG: 4.27 ± 1.32 × 10(-5) cm s(-1), P = 0.004; and 0.1% MG: 3.72 ± 2.49 × 10(-5) cm s(-1), P = 0.001).ConclusionsAdvanced glycation end-product (AGE) accumulation reduces vitreous permeability when glycation is performed in ex vivo porcine vitreous. The permeability change was more pronounced for the larger solute, suggesting a lower threshold for AGE-induced permeability changes to impact the movement of proteins through the vitreous when compared with smaller molecules

C–N Cross-Coupling via Photoexcitation of Nickel–Amine Complexes

C–N cross-coupling is an important class of reactions with far-reaching impacts across chemistry, materials science, biology, and medicine. Transition metal complexes can elegantly orchestrate diverse aminations but typically require demanding reaction conditions, precious metal catalysts, or oxygen-sensitive procedures. Here, we introduce a mild nickel-catalyzed C–N cross-coupling methodology that operates at room temperature using an inexpensive nickel source (NiBr₂·3H₂O), is oxygen tolerant, and proceeds through direct irradiation of the nickel–amine complex. This operationally robust process was employed for the synthesis of diverse C–N-coupled products (40 examples) by irradiating a solution containing an amine, an aryl halide, and a catalytic amount of NiBr₂·3H₂O with a commercially available 365 nm LED at room temperature without added photoredox catalyst and the amine substrate serving additional roles as the ligands and base. Density functional theory calculations and kinetic isotope effect experiments were performed to elucidate the observed C–N cross-coupling reactivity

Organocatalyzed Birch Reduction Driven by Visible Light

The Birch reduction is a powerful synthetic methodology that uses solvated electrons to convert inert arenes to 1,4-cyclohexadienes—valuable intermediates for building molecular complexity. This reaction historically requires dangerous alkali metals and cryogenic liquid ammonia as the solvent, severely limiting application potential and scalability. Here, we introduce benzo[ghi]perylene imides as new organic photoredox catalysts for Birch reductions performed at ambient temperature and driven by visible light. Using low catalyst loadings (<1 mole percent), benzene and other functionalized arenes can be selectively transformed to 1,4-cyclohexadienes in good yields. Mechanistic studies support that this unprecedented visible light induced reactivity is enabled by the ability of the organic photoredox catalyst to harness the energy from two visible light photons to affect a single, high energy chemical transformation, likely proceeding through a solvated electron.</p

Tetrahedral to Octahedral Nickel(II) as an Initiation Step in Metallaphotoredox Catalysis

In this work we seek to understand the pre-catalytic initiation steps in a classic metallaphotoredox catalysis paring Ir(III) ((Ir[dF(CF$_{3}$)ppy]$_{2}$(dtbbpy))PF$_{6}$) and Ni(II) ((4,4\u27-dtbbpy)NiCl$_{2}$) in dimethoxyethane. We use a combination of transient X-ray and optical absorption spectroscopies to track both nuclear and electronic excited-state dynamics, revealing two steps. First, photoexcitation produces the expected intramolecular oxidation of the iridium center, Ir(III), to Ir(IV)(dtbbpy)$^{\bullet -}$ correlated to the Ir metal-to-ligand charge transfer state. Second, interaction with Ir(IV)(dtbbpy)$^{\bullet -}$ drives the tetrahedral Ni(II) starting material to an unexpected octahedral Ni(II) species. We conclude by proposing the identity of the octahedral Ni(II) and suggest both an electron and an energy transfer mechanism for producing it that are equally consistent with our observations

Halide Non-Innocence and Direct Photo-Reduction of Ni(II) Enables Coupling of Aryl Chlorides in Dual Catalytic, Carbon-Heteroatom Bond Forming Reactions

Recent mechanistic studies of dual photoredox/Ni-catalyzed, light-driven cross-coupling reactions have found that the photocatalyst (PC) operates through either reductive quenching or energy transfer cycles. To date, reports invoking oxidative quenching cycles are comparatively rare and direct observation of such a quenching event has not been reported. However, when PCs with highly reducing excited states are used (e.g. Ir(ppy)3), photo-reduction of Ni(II) to Ni(I) is thermodynamically feasible. Recently, a unified reaction system using Ir(ppy)3 was developed for forming C–O, C–N, and C–S bonds under the same conditions, a prospect that is challenging with PCs that can photo-oxidize these nucleophiles. Herein, in a detailed mechanistic study of this system, we observe oxidative quenching of the PC (Ir(ppy)3 or a phenoxazine) via nanosecond transient absorption spectroscopy. Speciation studies support that a mixture of Ni-bipyridine complexes form under the reaction conditions, and the rate constant for photoreduction increases when more than one ligand is bound. Oxidative addition of an aryl iodide was observed indirectly via oxidation of the resulting iodide by Ir(IV)(ppy)3. Intriguingly, persistence of the Ir(IV)/Ni(I) ion pair formed in the oxidative quenching step was found to be necessary to simulate the observed kinetics. Both bromide and iodide anions were found to reduce the oxidized form of the PC back to its neutral state. These mechanistic insights inspired the addition of a chloride salt additive, which was found to alter Ni speciation, leading to a 36-fold increase in the initial turnover frequency, enabling the coupling of aryl chlorides

Long-term intraocular pressure reduction with intracameral polycaprolactone glaucoma devices that deliver a novel anti-glaucoma agent

Long-term treatment of glaucoma, a major leading cause of blindness, is challenging due to poor patient compliance. Therefore, a drug delivery device that can achieve drug release over several months can be highly beneficial for glaucoma management. Here, we evaluate the long-term pharmacokinetics and therapeutic efficacy of polycaprolactone intracameral drug delivery devices in rabbit eyes. Our study showed that a single drug delivery device loaded with a proprietary hypotensive agent, DE-117, reduced intraocular pressure in normotensive rabbits significantly for 23weeks. In addition, we demonstrated that concentration of DE-117 and its hydrolyzed active form (hDE-117) was maintained in the aqueous humor and the target tissue (iris-ciliary body) up to 24weeks. Our proof-of-concept glaucoma implant shows potential as a long-term treatment that circumvents patient compliance barriers compared to current treatment via eye drops

In vivo and in vitro sustained release of ranibizumab from a nanoporous thin-film device.

Current administration of ranibizumab and other therapeutic macromolecules to the vitreous and retina carries ocular risks, a high patient treatment burden, and compliance barriers that can lead to suboptimal treatment. Here we introduce a device that produces sustained release of ranibizumab in the vitreous cavity over the course of several months. Composed of twin nanoporous polymer thin films surrounding a ranibizumab reservoir, these devices provide release of ranibizumab over 16&nbsp;weeks in vitro and 12&nbsp;weeks in vivo, without exhausting the initial drug payload. Following implantation in vivo, devices were well-tolerated and showed no sign of immune response. This platform presents a potential solution to the challenge of delivering protein therapeutics to the vitreous and retina for sustained periods of time