Lingyun Cheng

Porous silicon in drug delivery devices and materials

Porous Si exhibits a number of properties that make it an attractive material for controlled drug delivery applications: The electrochemical synthesis allows construction of tailored pore sizes and volumes that are controllable from the scale of microns to nanometers; a number of convenient chemistries exist for the modification of porous Si surfaces that can be used to control the amount, identity, and in vivo release rate of drug payloads and the resorption rate of the porous host matrix; the material can be used as a template for organic and biopolymers, to prepare composites with a designed nanostructure; and finally, the optical properties of photonic structures prepared from this material provide a self-reporting feature that can be monitored in vivo. This paper reviews the preparation, chemistry, and properties of electrochemically prepared porous Si or SiO2 hosts relevant to drug delivery applications.

The association between percent disruption of the photoreceptor inner segment-outer segment junction and visual acuity in diabetic macular edema.

PURPOSE To evaluate the integrity of the photoreceptor inner segment/outer segment (IS/OS) junction using spectral-domain optical coherence tomography (SD OCT) in patients with diabetic macular edema and to correlate the relationship between the integrity of the IS/OS junction and visual acuity. DESIGN Retrospective, comparative, consecutive case series. METHODS Sixty-two eyes from 38 patients with diabetic macular edema underwent SD OCT imaging. For each patient, 2 experienced observers masked to visual acuity measured several SD OCT variables, including central macular thickness, retinal volume, global disruption scale of outer retina, percentage disruption of the outer retina, and history of previous treatments. Visual acuity recorded as number of Early Treatment Diabetic Retinopathy Study letters was used as the outcome variable in univariate and multivariate analysis testing the measured SD OCT variables as predictors. RESULTS A statistically significant correlation between percentage disruption of the IS/OS junction and visual acuity was found (P = .0312). Additionally, there was a strong trend suggesting a relationship between macular volume and visual acuity, although borderline significance was found (P = .07). CONCLUSIONS Disruption of the photoreceptor IS/OS junction is an important predictor of visual acuity among diabetic macular edema patients.

The Role of Abnormal Vitreomacular Adhesion in Age-related Macular Degeneration: Spectral Optical Coherence Tomography and Surgical Results

PURPOSE To assess the incidence of vitreomacular adhesion and traction in age-related macular degeneration (AMD), and to evaluate surgical treatment in a subset of patients with choroidal neovascularization (CNV) nonresponsive to anti-neovascular growth factor (anti-VEGF) treatment. DESIGN Retrospective observational case-control and interventional case series. METHODS Spectral optical coherence tomography, combined with simultaneous scanning laser ophthalmoscope (Spectral OCT/SLO), was performed in 170 eyes of 94 elderly patients, 61 with exudative AMD, 59 with nonexudative AMD, and 50 control eyes. The presence of hyaloid adhesion to the posterior pole, and vitreomacular traction (VMT) were determined. Five patients with VMT underwent surgical hyaloid removal. Best-corrected visual acuity (BCVA) and retinal thickness were evaluated as outcomes. RESULTS Hyaloid adhesion was present in 17 eyes with exudative AMD (27.8%), 15 eyes with nonexudative AMD (25.4%), and eight control eyes (16%). Significant difference was found among the groups (P = .002). Among the eyes with hyaloid adhesion, VMT was shown in 10 eyes (59%) with exudative AMD, two eyes (13%) with nonexudative AMD, and one control eye (12%). VMT was associated with the severity of AMD (P = .0082). The area of hyaloid adhesion was significantly smaller than and concentric to the area of CNV complex in eyes with exudative AMD. Eyes with VMT that underwent surgery experienced a modest improvement of BCVA and decrease of retinal thickness. CONCLUSIONS Hyaloid adhesion to the macula is associated with AMD, and frequently causes VMT in eyes with CNV. Tractional forces may antagonize the effect of anti-VEGF treatment, and cause pharmacological resistance in a subpopulation of patients. Future studies are needed to define the role of vitreoretinal surgery in such cases. Spectral OCT/SLO allows careful diagnosis and follow-up.

Intravitreal toxicity of the kenalog vehicle (benzyl alcohol) in rabbits.

Purpose: To test the toxicity of intravitreal injections of benzyl alcohol. Methods: Nine New Zealand rabbits were injected with either a control or a test article at elevating concentrations. The test article was benzyl alcohol calculated to give final injected concentrations of 0.0073%, 0.022%, 0.073%, 0.222%, and 0.733% benzyl alcohol. The 0.022% concentration corresponds to the concentration of benzyl alcohol in human eyes when 0.1 mL of commercial Kenalog (Bristol–Myers Squibb, Princeton, NJ) is used. Baseline examination of the rabbits was performed along with postinjection examinations on days 1, 3, 7, and 14. The eyes were enucleated and examined by light and electron microscopic examinations. Results: Eyes injected with benzyl alcohol concentrations of 0.073%, 0.222%, and 0.733% displayed changes in the outer retina including loss of, and shortening of, outer segments and photoreceptors. Conclusions: Benzyl alcohol at concentrations modestly higher than what is present in commercial Kenalog is toxic to the rabbit eye. This has been shown in other organ systems. If commercial preserved Kenalog is to be used clinically, decanting the supernatant or using other means to remove the benzyl alcohol may be considered, especially if a volume of >0.1 mL of solution is used. We hypothesize that the noninfectious inflammation seen clinically after Kenalog injection is due to the presence of a toxic preservative at unsafe concentrations.

Real-time monitoring of sustained drug release using the optical properties of porous silicon photonic crystal particles

A controlled and observable drug delivery system that enables long-term local drug administration is reported. Biodegradable and biocompatible drug-loaded porous Si microparticles were prepared from silicon wafers, resulting in a porous 1-dimensional photonic crystal (rugate filter) approx. 12 μm thick and 35 μm across. An organic linker, 1-undecylenic acid, was attached to the Si-H terminated inner surface of the particles by hydrosilylation and the anthracycline drug daunorubicin was bound to the carboxy terminus of the linker. Degradation of the porous Si matrix in vitro was found to release the drug in a linear and sustained fashion for 30 d. The bioactivity of the released daunorubicin was verified on retinal pigment epithelial (RPE) cells. The degradation/drug delivery process was monitored in situ by digital imaging or spectroscopic measurement of the photonic resonance reflected from the nanostructured particles, and a simple linear correlation between observed wavelength and drug release was observed. Changes in the optical reflectance spectrum were sufficiently large to be visible as a distinctive red to green color change.

Changes of intraocular pressure after intravitreal injection of bevacizumab (avastin).

Purpose: To determine changes and need to monitor intraocular pressure (IOP) following intravitreal injection of bevacizumab (Avastin). Methods: Seventy patients (122 injections) underwent an intravitreal injection of Avastin for exudative age-related macular degeneration treatment. Forty-one eyes (59%) had single injection, 29 eyes (41%) had repeated injections. IOP was measured before and after Avastin injection at 3, 10, and 15 minutes. Twenty-nine eyes were evaluated for baseline IOP changes after multiple injections. Statistical analysis was performed. Results: Baseline mean IOP was 15.17 ± 3.42 mm Hg, with range from 08 mm Hg to 23 mm Hg. Postinjection 3 minutes the IOP had risen to a mean of 36.27 ± 5.1 mm Hg and fell spontaneously to a mean of 24.56 ± 5.9 mm Hg at 10 minutes. Ten eyes (14%) needed 15 minutes to drop below 30 mm Hg. All eyes were below 30 mm Hg at 15 minutes. No significant change between multiple baseline IOP measurements was detected. Conclusion: Avastin injections caused a predictable probably volume-related rise in IOP which never occluded the central retinal artery and which spontaneously fell to below 30 mm Hg in all eyes within 15 minutes. This strong safety profile provides guidelines on monitoring IOP after Avastin injections. There was no IOP change after multiple injections.

Disruption of the photoreceptor inner segment/outer segment layer on spectral domain-optical coherence tomography is a predictor of poor visual acuity in patients with epiretinal membranes.

Purpose: The purpose of this study was to evaluate the predictive value of spectral domain-optical coherence tomography-determined integrity of the photoreceptor inner segment/outer segment (IS/OS) junction on visual acuity in patients with epiretinal membranes (ERMs). Methods: This is a retrospective consecutive case series of 54 eyes from 48 patients with primary ERMs who underwent spectral domain-optical coherence tomography scans. Regression analysis was used to calculate the relative contribution of several variables, including photoreceptor IS/OS disruption, grade of IS/OS disruption, macular thickness, and ERM grade on fundus imaging to visual acuity. Results: The strongest individual predictor of visual acuity among patients with ERM was central retinal thickness on spectral domain-optical coherence tomography (r2 = 0.16, P = 0.0024), but the most efficient model was the combination of macular thickness and presence or absence of photoreceptor IS/OS disruption (r2 = 0.24, P = 0.0008). Additional measured variables did not significantly contribute to visual acuity prediction. Inner segment/outer segment layer integrity was also an independent predictor of visual acuity, and patients with IS/OS disruption were 6.88 times as likely to have 20/50 or worse vision than patients with intact photoreceptor layers (odds ratio: 6.88, confidence interval: 1.56–30.43, P = 0.01). Conclusion: Disruption of the photoreceptor IS/OS junction is a statistically significant predictor of poor visual acuity among patients with ERM and is most useful when combined with central retinal thickness measurement.

Intravitreal properties of porous silicon photonic crystals: a potential self-reporting intraocular drug-delivery vehicle.

Aim: To determine the suitability of porous silicon photonic crystals for intraocular drug-delivery. Methods: A rugate structure was electrochemically etched into a highly doped p-type silicon substrate to create a porous silicon film that was subsequently removed and ultrasonically fractured into particles. To stabilise the particles in aqueous media, the silicon particles were modified by surface alkylation (using thermal hydrosilylation) or by thermal oxidation. Unmodified particles, hydrosilylated particles and oxidised particles were injected into rabbit vitreous. The stability and toxicity of each type of particle were studied by indirect ophthalmoscopy, biomicroscopy, tonometry, electroretinography (ERG) and histology. Results: No toxicity was observed with any type of the particles during a period of >4 months. Surface alkylation led to dramatically increased intravitreal stability and slow degradation. The estimated vitreous half-life increased from 1 week (fresh particles) to 5 weeks (oxidised particles) and to 16 weeks (hydrosilylated particles). Conclusion: The porous silicon photonic crystals showed good biocompatibility and may be used as an intraocular drug-delivery system. The intravitreal injectable porous silicon photonic crystals may be engineered to host a variety of therapeutics and achieve controlled drug release over long periods of time to treat chronic vitreoretinal diseases.

Choroidal Volume Variations with Age, Axial Length, and Sex in Healthy Subjects: A Three-Dimensional Analysis

PURPOSE To demonstrate the 3-dimensional choroidal volume distribution in healthy subjects using enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT) and to evaluate its association with age, sex, and axial length. DESIGN Retrospective case series. PARTICIPANTS A total of 176 eyes from 114 subjects with no retinal or choroidal disease. METHODS The EDI SD-OCT imaging studies of healthy patients who had undergone a 31-raster scanning protocol on a commercial SD-OCT device were reviewed. Manual segmentation of the choroid was performed by 2 retinal specialists. A macular choroidal volume map and 3-dimensional topography were automatically created by the built-in software of the device. Mean choroidal volume was calculated for each Early Treatment Diabetic Retinopathy Study (ETDRS) subfield. Regression analyses were used to evaluate the correlation between macular choroidal volume and age, sex, and axial length. MAIN OUTCOME MEASURES Three-dimensional topography and ETDRS-style volume map of the choroid. RESULTS Three-dimensional topography of the choroid and volume map was obtained in all cases. The mean choroidal volume was 0.228 ± 0.077 mm(3) for the center ring and 7.374 ± 2.181 mm(3) for the total ETDRS grid. The nasal quadrant showed the lowest choroidal volume, and the superior quadrant showed the highest choroidal volume. The temporal and inferior quadrants did not show different choroidal volume values. Choroidal volume in all the EDTRS rings was significantly correlated with axial length after adjustment for age (P < 0.0001), age after adjustment for axial length (P < 0.0001), and sex after adjustment for axial length (P < 0.05). Choroidal volume decreases by 0.54 mm(3) (7.32%) for every decade and by 0.56 mm(3) (7.59%) for every millimeter of axial length. Male subjects have a 7.37% greater choroidal volume compared with that of female subjects. CONCLUSIONS Enhanced depth imaging SD-OCT is a noninvasive and well-tolerated procedure with an excellent ability to visualize 3-dimensional topography of the choroid and to measure choroidal volume at the posterior pole using manual segmentation. Age and axial length are inversely correlated with choroidal volume, most likely leading to changes in retinal metabolic support in elderly, highly myopic patients. Sexual differences should be considered when interpreting an EDI SD-OCT scan of the choroid. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Duration of vitrectomy and postoperative cataract in the vitrectomy for macular hole study.

PURPOSE To report the association between duration of vitrectomy, as well as other risk factors, and the progression of nuclear sclerosis and posterior subcapsular cataract in the Vitrectomy for Macular Hole Study. DESIGN A cohort study nested within a randomized controlled clinical trial. METHODS Using a system similar to the Lens Opacities Classification System II, nuclear sclerosis (NS) and posterior subcapsular cataract (PSC) were scored in the vitrectomy and fellow eye of 74 patients at baseline and at 6, 12, and 24 months postoperatively. Age, baseline blood pressure and refractive power, and duration of surgery were evaluated as risk factors for NS or PSC progression and cataract extraction. RESULTS The incidence of NS progression in the surgical group of vitrectomy eyes was 81% at 6 months, 98% at 1 year, and 100% at 2 years of follow-up. In contrast, NS progression in the control group of fellow eyes was only 18% at 6 months, 20% at 1 year, and 8% at 2 years. The incidence of PSC progression in the surgical group remained at approximately 11% throughout follow-up, which was not significantly higher than the 3% to 5% incidence in the control group. Vitrectomy was significantly related to progression of NS cataract (P <.001) and cataract extraction (P <.01). No statistically significant differences were found for NS scores, PSC scores, or progression rates between eyes that had less than median surgical duration (60 min.) or more than the median surgical duration. Additionally, no significant differences were found when eyes that experienced 45 minutes or less surgical duration were compared with eyes that endured more than 75 minutes surgical duration. Age, blood pressure, and refractive power were not found to be predictors for NS and PSC progression. CONCLUSIONS Although vitrectomy is a risk factor for NS progression, the duration of vitrectomy does not increase the risk.