Rhegmatogenous retinal detachment masquerading as exudative panuveitis with intense anterior chamber inflammatory reaction.

Purpose:This is a retrospective case report illustrating the diagnostic and therapeutic challenges associated with a chronic rhegmatogenous retinal detachment masquerading as a severe panuveitis with intense anterior chamber inflammation. We have included clinical features, anterior segment and fundus photography, B-scan ultrasonography, fluorescein angiography, and intraoperative findings. Observations:A 26-year-old male presented with features of unilateral panuveitis: hypotony, anterior segment inflammation (posterior synechiae and anterior chamber cell with fibrin clumping), diffuse choroidal thickening, and retinal detachment. Laboratory investigations for infectious or rheumatologic processes were negative, and empiric systemic corticosteroid therapy was unsuccessful. This prompted suspicion for an alternate primary etiology, and pars plana vitrectomy revealed small retinal breaks as the underlying cause of the retinal detachment and inflammation. Conclusions:Rhegmatogenous retinal detachments are a known cause of intraocular inflammation. Nevertheless, it remains a challenge to recognize retinal breaks in this setting, particularly with robust anterior segment inflammation and posterior findings resembling severe exudative uveitis. Being aware of this unique presentation may prevent delays in diagnosis and have important prognostic implications

Biocompatibility and Pharmacokinetic Analysis of an Intracameral Polycaprolactone Drug Delivery Implant for Glaucoma

PURPOSE: We developed polycaprolactone (PCL) implants that achieve zero-order release of a proprietary ocular hypotensive agent (DE-117) over 6 months. METHODS: The release rates of DE-117–loaded PCL devices were tuned based on an established predictive model and confirmed by in vitro release studies. Devices containing DE-117 and empty devices were implanted intracamerally in normotensive rabbits for up to 8 weeks' duration. Devices were retrieved after rabbits were euthanized and evaluated for tissue adherence. The drug remaining in each device was analyzed by high performance liquid chromatography. Drug distribution in ocular tissues was measured by liquid chromatography coupled with a tandem mass spectrometry (LC/MS/MS). RESULTS: In vitro release of DE-117 showed zero-order release with a release rate of 0.5 μg/day over 6 months. Implantation in rabbit eyes demonstrated that the devices were well tolerated in the intracameral space. Quantification of DE-117 and hDE-117 (the hydrolyzed active form of DE-117) in ocular tissues (cornea, iris-ciliary body, aqueous humor, and vitreous humor) indicated sustained release of DE-117 and its conversion to hDE-117 when released from the device. Analysis of drug remaining in the device found that concentration of hDE-117 was below the limit of detection, indicating the encapsulated drug was protected from hydrolysis in the device. CONCLUSIONS: Proof-of-concept PCL drug delivery devices containing DE-117 show promise as a long-term glaucoma treatment based on their zero-order drug release profile in vitro, biocompatibility in vivo, and effective distribution of released drug in relevant ocular tissues

Biocompatibility and Pharmacokinetic Analysis of an Intracameral Polycaprolactone Drug Delivery Implant for Glaucoma

PURPOSE: We developed polycaprolactone (PCL) implants that achieve zero-order release of a proprietary ocular hypotensive agent (DE-117) over 6 months. METHODS: The release rates of DE-117–loaded PCL devices were tuned based on an established predictive model and confirmed by in vitro release studies. Devices containing DE-117 and empty devices were implanted intracamerally in normotensive rabbits for up to 8 weeks' duration. Devices were retrieved after rabbits were euthanized and evaluated for tissue adherence. The drug remaining in each device was analyzed by high performance liquid chromatography. Drug distribution in ocular tissues was measured by liquid chromatography coupled with a tandem mass spectrometry (LC/MS/MS). RESULTS: In vitro release of DE-117 showed zero-order release with a release rate of 0.5 μg/day over 6 months. Implantation in rabbit eyes demonstrated that the devices were well tolerated in the intracameral space. Quantification of DE-117 and hDE-117 (the hydrolyzed active form of DE-117) in ocular tissues (cornea, iris-ciliary body, aqueous humor, and vitreous humor) indicated sustained release of DE-117 and its conversion to hDE-117 when released from the device. Analysis of drug remaining in the device found that concentration of hDE-117 was below the limit of detection, indicating the encapsulated drug was protected from hydrolysis in the device. CONCLUSIONS: Proof-of-concept PCL drug delivery devices containing DE-117 show promise as a long-term glaucoma treatment based on their zero-order drug release profile in vitro, biocompatibility in vivo, and effective distribution of released drug in relevant ocular tissues

Rhegmatogenous retinal detachment masquerading as exudative panuveitis with intense anterior chamber inflammatory reaction.

PurposeThis is a retrospective case report illustrating the diagnostic and therapeutic challenges associated with a chronic rhegmatogenous retinal detachment masquerading as a severe panuveitis with intense anterior chamber inflammation. We have included clinical features, anterior segment and fundus photography, B-scan ultrasonography, fluorescein angiography, and intraoperative findings.ObservationsA 26-year-old male presented with features of unilateral panuveitis: hypotony, anterior segment inflammation (posterior synechiae and anterior chamber cell with fibrin clumping), diffuse choroidal thickening, and retinal detachment. Laboratory investigations for infectious or rheumatologic processes were negative, and empiric systemic corticosteroid therapy was unsuccessful. This prompted suspicion for an alternate primary etiology, and pars plana vitrectomy revealed small retinal breaks as the underlying cause of the retinal detachment and inflammation.ConclusionsRhegmatogenous retinal detachments are a known cause of intraocular inflammation. Nevertheless, it remains a challenge to recognize retinal breaks in this setting, particularly with robust anterior segment inflammation and posterior findings resembling severe exudative uveitis. Being aware of this unique presentation may prevent delays in diagnosis and have important prognostic implications

Ocular biocompatibility and structural integrity of micro- and nanostructured poly(caprolactone) films.

The identification of biomaterials that are well tolerated in the eye is important for the development of new ocular drug delivery devices and implants, and the application of micro- and nanoengineered devices to biomedical treatments is predicated on the long-term preservation within the target organ or tissue of the very small functional design elements. This study assesses the ocular tolerance and durability of micro- and nanostructured biopolymer thin films injected or implanted into the rabbit eye. Structured poly(caprolactone) (PCL) thin films were placed in adult rabbit eyes for survival studies, with serial ophthalmic examinations over 6 months. Morphologic abnormalities and device/tissue reactions were evaluated by histologic studies, and scanning electron microscopy (SEM) of films was used to determine the structural integrity. Structured PCL thin films (20- to 40-μm thick) were constructed to design specifications with 50-μm linear microgrooves or arrays of nanopores with ~30-nm diameters. After up to 9 months of ocular residency, SEM on devices retrieved from the eye showed preservation of micro- and nanostructural features. In ocular safety evaluations carried out over 6 months, serial examinations in 18 implanted eyes showed no evidence of chronic inflammation, cataractogenesis, or retinal toxicity. Postoperative ocular inflammation was seen in 67% of eyes for 1 week, and persistent corneal edema occurred in 1 eye. Histology revealed no ocular inflammation or morphologic abnormalities of ocular tissues. Thin-film/tissue responses such as cellular reaction, fibrosis, or surface biodeposits were not seen. Micro- and nanostructured PCL thin films exhibited acceptable ocular tolerance and maintained the structural integrity of design features while residing in the eye. Thin-film micro- and nanostructured PCL appears to be a feasible biomaterial for intraocular therapeutic applications

Injectable Devices for Delivery of Liquid or Solid Protein Formulations

Sustained delivery of protein therapeutics remains a largely unsolved problem across anatomic locations. Miniaturized devices that can provide sustained delivery of protein formulations have the potential to address this challenge via minimally invasive administration. In particular, methodologies that can optimize protein formulation independent of device manufacture have the greatest potential to provide a platform suitable for wide applications. The techniques developed here demonstrate the fabrication of tubular devices for sustained release of protein therapeutics. Utilizing a dip-casting process, fine-scale tubes can be reliably produced with wall thickness down to 30 μm. Techniques were developed that enabled effective loading of either solid or liquid formulations, while maintaining a cylindrical form-factor compatible with placement in a 22-gauge needle. Further, highly compacted protein pellets that approach the expected density of the raw materials were produced with a diameter (∼300 μm) suitable for miniaturized devices. Release from a solid-loaded device was capable of sustaining release of a model protein in excess of 400 days. Given significant interest in ocular applications, intravitreal injection was demonstrated in a rabbit model with these devices. In addition, to simulate repeated injections in ocular applications, serial intravitreal injection of two devices in a rabbit model demonstrated acceptable ocular safety without significant intraocular inflammation from clinical exam and histology

Device design methodology and formulation of a protein therapeutic for sustained release intraocular delivery.

Despite years of effort, sustained delivery of protein therapeutics remains an unmet need due to three primary challenges - dose, duration, and stability. The work presented here provides a design methodology for polycaprolactone reservoir-based thin film devices suitable for long-acting protein delivery to the back of the eye. First, the challenge of formulating highly concentrated protein in a device reservoir was addressed by improving stability with solubility-reducing excipients. Next, predictive correlations between design parameters and device performance were developed to provide a methodology to achieve a target product profile. Prototype devices were designed using this methodology to achieve desired device size, release rate, therapeutic payload, and protein stability, assessed by in vitro studies. Finally, prototype tolerability was established in a non-human primate model. The design methodology presented here is widely applicable to reservoir-based sustained delivery devices for proteins and provides a general device design framework

In Vitro and In Vivo Sustained Zero-Order Delivery of Rapamycin (Sirolimus) From a Biodegradable Intraocular Device

PURPOSE: We created implantable intraocular devices capable of constant and continuous rapamycin release on the scale of months to years. METHODS: Polycaprolactone (PCL) thin films were used to encapsulate rapamycin to create implantable and biodegradable intraocular devices. Different film devices were studied by modifying the size, thickness, and porosity of the PCL films. RESULTS: In vitro release of rapamycin was observed to be constant (zero-order) through 14 weeks of study. Release rates were tunable by altering PCL film porosity and thickness. In vivo release of rapamycin was observed out through 16 weeks with concentrations in the retina–choroid in the therapeutic range. Rapamycin concentration in the blood was below the lower limit of quantification. The drug remaining in the device was chemically stable in vitro and in vivo, and was sufficient to last for upwards of 2 years of total release. The mechanism of release is related to the dissolution kinetics of crystalline rapamycin. CONCLUSIONS: Microporous PCL thin film devices demonstrate good ocular compatibility and the ability to release rapamycin locally to the eye over the course of many weeks