Biocompatibility and Pharmacokinetic Analysis of an Intracameral Polycaprolactone Drug Delivery Implant for Glaucoma.
Kim Jean,Kudisch Max,Mudumba Sri,Asada Hiroyuki,Aya-Shibuya Eri,Bhisitkul Robert B,Desai Tejal A
Investigative ophthalmology & visual science
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.
10.1167/iovs.16-19585
Application of 5-Fluorouracil-Polycaprolactone Sustained-Release Film in Ahmed Glaucoma Valve Implantation Inhibits Postoperative Bleb Scarring in Rabbit Eyes.
Bi Xiu-Zeng,Pan Wei-Hua,Yu Xin-Ping,Song Zong-Ming,Ren Zeng-Jin,Sun Min,Li Cong-Hui,Nan Kai-Hui
PloS one
This study was designed to investigate whether 5-fluorouracil (5-Fu)-polycaprolactone sustained-release film in Ahmed glaucoma valve implantation inhibits postoperative bleb scarring in rabbit eyes. Eighteen New Zealand white rabbits were randomly divided into three groups (A, B and C; n = 6 per group). Group A received combined 5-Fu-polycaprolactone sustained-release film application and Ahmed glaucoma valve implantation, group B received local infiltration of 5-Fu and Ahmed glaucoma valve implantation, and group C received Ahmed glaucoma valve implantation. Postoperative observations were made of the anterior segment, intraocular pressure, central anterior chamber depth, blebs, drainage tube, and accompanying ciliary body detachment. The pathology of the blebs and surrounding tissues were observed at month 3 postoperatively. We revealed that the 5-Fu-polycaprolactone sustained-release film maintained a release concentration range of 13.7 ± 0.12 to 37.41 ± 0.47 μg/ml over three months in vitro. Postoperatively, diffuse blebs with ridges were found in all eyes in group A, two blebs were observed in group B, and no bleb formation was present in group C. The postoperative central anterior chamber depth in group A was significantly less than that of the other two groups. The postoperative intraocular pressure of group A stabilized at 6.33-8.67 mmHg, whereas that of group C gradually remained at 7.55-10.02 mmHg. The histopathology showed that the fibrous tissue thickness of the blebs in group A was significantly thinner than that of the other groups. We conclude that the 5-Fu-polycaprolactone sustained-release film had a sustained drug release effect, which promoted the inhibition of bleb scarring after Ahmed glaucoma valve implantation.
10.1371/journal.pone.0141467
Long-term intraocular pressure reduction with intracameral polycaprolactone glaucoma devices that deliver a novel anti-glaucoma agent.
Journal of controlled release : official journal of the Controlled Release Society
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.
10.1016/j.jconrel.2017.11.008
Complications of tube implants and their management.
Bailey Andrew K,Sarkisian Steven R
Current opinion in ophthalmology
PURPOSE OF REVIEW:The use of glaucoma drainage devices (GDD) in the treatment of glaucoma has become widely accepted for cases of refractory glaucoma. Expansion in the indications for implantation of GDD beyond refractory glaucoma is increasingly common. As such, tube implant complications are reviewed to aid in prevention and improve their management. RECENT FINDINGS:Findings of the Tube Versus Trabeculectomy study resulted in an expanded use of tube implants in cases of refractory glaucoma. As interest in GDD implantation flourished, so too, did investigative comparison between devices; which includes the Ahmed Baerveldt Comparison study and Ahmed Verses Baerveldt study. Comparative analysis of success and complication rates between implantable devices is not only expanding the technology of tube implants, but also building a body of evidence that tube implantation has a strong safety profile and usage among specialists will continue to increase and indications will evolve. Complications resulting from GDD implantation include hypotony, postoperative elevated intraocular pressure, tube erosion, diplopia, motility disturbances, and corneal decompensation. SUMMARY:Tube implant use is increasing and indications are expanding beyond refractory glaucoma. Understanding differences in GDD, their complications and management will result in improved patient care.
10.1097/ICU.0000000000000034
Safety and Effectiveness of CyPass Supraciliary Micro-Stent in Primary Open-Angle Glaucoma: 5-Year Results from the COMPASS XT Study.
Reiss George,Clifford Bill,Vold Steven,He Jonathan,Hamilton Cody,Dickerson Jaime,Lane Stephen
American journal of ophthalmology
PURPOSE:To characterize the long-term (up to 5 years) safety and effectiveness of the supraciliary Micro-Stent (Alcon) implanted at the time of phacoemulsification in eyes with coexisting open-angle glaucoma (OAG) and visually significant cataract. DESIGN:Three-year safety extension of a 2-year randomized clinical trial. METHODS:Patients from the multicenter Study of an Implantable Device for Lowering Intraocular Pressure in Glaucoma Patients Undergoing Cataract Surgery (COMPASS) trial who underwent Micro-Stent implantation plus phacoemulsification (n = 215) or phacoemulsification alone (n = 67) were evaluated 36, 48, and 60 months postoperatively. The primary outcome measurement was the occurrence of sight-threatening ocular adverse events. Evaluations at each time point included best-corrected visual acuity (BCVA), anterior and posterior segment examinations, tonometry, gonioscopy, pachymetry, perimetry, specular microscopy, and assessment of adverse events. RESULTS:Three sight-threatening ocular adverse events occurred, 2 in the Micro-Stent group and 1 in the control group, but none of these events was related to the Micro-Stent device. Ocular adverse events were of similar frequencies in both groups, the most common of which were BCVA loss of ≥2 lines compared with best BCVA in COMPASS and worsening of visual field mean defect (VFMD) ≥2.5 dB compared with month 24. Changes in mean BCVA from baseline, clinical examinations, pachymetry, and VFMD were similar in the 2 groups. At 60 months, a higher proportion of subjects in the Micro-Stent group (46%; 95% confidence interval [CI], 38.9%-53.2%) than in the control group (32.1%; 95% CI 19.9%-46.3%) were able to achieve a reduction of ≥20% in intraocular pressure without using hypotensive medication. CONCLUSIONS:Few sight-threatening serious ocular adverse events occurred following Micro-Stent implantation, and clinical evidence of corneal decompensation was minimal.
10.1016/j.ajo.2019.07.015
Towards smart self-clearing glaucoma drainage device.
Microsystems & nanoengineering
For patients who are unresponsive to pharmacological treatments of glaucoma, an implantable glaucoma drainage devices (GDD) are often used to manage the intraocular pressure. However, the microscale channel that removes excess aqueous humor from the anterior chamber often gets obstructed due to biofouling, which necessitates additional surgical intervention. Here we demonstrate the proof-of-concept for smart self-clearing GDD by integrating magnetic microactuators inside the drainage tube of GDD. The magnetic microactuators can be controlled using externally applied magnetic fields to mechanically clear biofouling-based obstruction, thereby eliminating the need for surgical intervention. In this work, our prototype magnetic microactuators were fabricated using low-cost maskless photolithography to expedite design iteration. The fabricated devices were evaluated for their static and dynamic mechanical responses. Using transient numerical analysis, the fluid-structure interaction of our microactuator inside a microtube was characterized to better understand the amount of shear force generated by the device motion. Finally, the anti-biofouling performance of our device was evaluated using fluorescein isothiocyanate labeled bovine serum albumin. The microactuators were effective in removing proteinaceous film deposited on device surface as well as on the inner surface of the microchannel, which supports our hypothesis that a smart self-clearing GDD may be possible by integrating microfabricated magnetic actuators in chronically implanted microtubes.
10.1038/s41378-018-0032-3