Episcleral Implants Research Articles

Novel episcleral implants of sunitinib can depress ocular neovascularization under ex‐vivo conditions

AbstractBackground: Current management of posterior segment disease such as Age‐related Macular degeneration (AMD) and Diabetic Macular Edema (DME) is by monthly Intravitreal injections of Anti‐VEGF agents (IVT). IVT therapy suffers from various serious drawbacks such as highly invasive procedure and risk of ocular tissue damage. Moreover, Lower response rate of Anti‐VEGF agents in patients also demands development of novel alternative therapies. One of the major challenge of posterior segment drug delivery is selection of suitable in‐vivo models for pharmacokinetic and therapeutic screening due to highly localized nature of eye leading limited choices animals that resemble human ocular anatomy. Hence we aim to novel episcleral implant platform for posterior segment drug delivery along with using suitable ex‐vivo assays for therapeutic estimation of developed drug delivery systems.Methods: The Implants loaded with sunitinib malate were fabricated using a polymeric blend of gelatin and polyglycerol sebacate (PGS) by electrospinning technique. The effect of polymer blending and drug loading on morphology and in‐vitro drug release profile by scanning electron microscopy and shaking incubator drug release method. Further, the effect of electrospinning and polymer blending on mucoadhesion was studied by mucin agar plate method. Transscleral drug permeation and the secondary depot formation of sunitinib following episcleral application were studies Franz diffusion cell experiment. The biocompatibility of implant was tested on ARPE‐19 cells and the effect of treatment on cell morphology was studied by crystal violet staining. The therapeutic efficacy of episcleral implants was tested by ex‐vivo choroidal angiogenesis assay.Results: The electrospinning process lead to development of highly porous and flexible implants. It was found that polymer blending has profound effect on the morphology as well as in vitro drug release of implants. The addition of PGS lead to thinner fibres within implant and it also lead to sustained release of sunitinib over the period of one week. The drug loading did not has proficient effect on the morphology of implants; however, higher loading lead to sustained release of sunitinib over the release period. The electrospinning process lead to enhanced mucoadhesion that could possibly due to increased surface area and improved contact angle. The implants were found to be biocompatible and did not alter the morphology of ARPE‐19 cells upon treatment as observed by crystal violet staining. The drug release samples of implants in cell culture media were tested upon ex‐vivo rat choroidal angiogenesis assay where it was observed that the release samples were able to suppress the ocular neovascularization significantly when compared with untreated samples.Conclusions: We can conclude that sunitinib loaded episcleral implants could be a promising alternative for management of disease with posterior segment neovascularization such as AMD and DME. The polymer blending of different polymers along with electrospinning technique could aid in development of novel episcleral implants with sustained release of medicinal agents. The electrospun implant platform could also be used for anterior segment drug delivery as well. Finally ex‐vivo rat choroidal angiogenesis assay could be a great tool for therapeutic screening of ocular drug delivery systems.

Novel electrospun implants of Sunitinib can depress ex-vivo ocular neovascularization

Choroidal neovascularization (CNV) is one of the hallmark symptoms of Wet Age-related Macular Degeneration (wAMD) and DiabeticRetinopathy(DR) which involves formation of neoangiogenic i.e. formation of new abnormal blood vessels emerging from the choroidal blood vessels and protruding through the retinal layer. The current management of wAMD involves intravitreal injections of anti-VEGF such as ranibizumab and aflibercept. We hypothesized the delivery of small molecule anti-angiogenesis agents such as the Sunitinib by episcleral route could be an effective and less challenging solution for the management of choroidal neovascularization. In this research, we have fabricated the sunitinib-loaded implants that are able of sustained the release of drug and possess improved ocular pharmacokinetics with a non-invasive administration. The novel episcleral implants were fabricated by electrospinning and were tested for different physiochemical and well as in-vitro pharmacokinetic properties. Further, these implants were tested for in-vitro biocompatibility and ex-vivo efficacy for the estimation of pharmacodynamic properties.

Commentary: Periocular topotecan for retinoblastoma.

We have long surpassed the era when enucleation or external beam radiotherapy (EBRT) was the only option for managing eyes with advanced retinoblastoma. Despite the groundbreaking advancements over the past few decades in the field of retinoblastoma management, persistant/recurrent vitreous seeds continue to remain the nemesis of ocular oncologists all over the world. Shield et al. reported that intravenous chemotherapy could salvage only 30% of eyes with diffuse vitreous seeds.[1] The relative resistance of vitreous seeds to systemic chemotherapy can be attributed to the avascularity of vitreous humor and has always been an impetus for exploring additional and alternate methods of more effective drug delivery into the vitreous. Wilson et al. found that cryotherapy increases the access of systemic chemotherapy into the vitreous.[2] Pascual Pasto et al. studied rabbit eyes and found that inhibition of blood–retinal barrier by systemic pantoprazole can lead to increased delivery of chemotherapy into vitreous.[3] The acceptance of intravitreal chemotherapy as a safe method of drug delivery was a quantam leap in the attempts to control the vitreous seeds.[4] Shields et al. achieved 100% vitreous seed control and 88% globe salvage over 3-year follow-up using intravitreal melphalan and/or topotecan. Employing enhanced safety techniques including choosing the correct site for injection in a region of least or no seeding, triple freeze–thaw cryotherapy at the needle site on withdrawal, and 1 min of constant ocular irrigation, they did not note any case of extraocular extension during 192 injections.[4] Combining intra-arterial chemotherapy with intravitreal chemotherapy has further improved globe salvage in eyes with advanced retinoblastoma.[5] Despite all the precautions, there is always a risk of extraocular tumor spread from intravitreal while injecting an eye with active tumor due to spillover, reflux, or tumor growth along the needle track.[6] Development of endophthalmitis after intravitreal injection in an eye with retinoblastoma, especially in developing countries, is, needless to say, a dreaded complication. Periocular chemotherapy is a relatively safer technique in this regard, as the chemotherapeutic drug is injected into the subtenon's space, thus avoiding any breach in the ocular integrity. Periocular carboplatin has been used in conjunction with systemic chemotherapy for retinoblastoma over two decades. Carcaboso et al. found considerable vitreous levels of topotecan in rabbit eyes after periocular delivery, as a consequence of a favored passage across the blood–retinal barrier.[7] Up to 2 mg periocular topotecan (POT) is considered safe and can be an effective alternative to intravitreal chemotherapy for controlling vitreous seeds.[8] Various modalities of periocular drug delivery have been explored by various authors including episcleral implants, fibrin sealants, and nanomolecular composition. Though periocular chemotherapy entails a risk of optic atrophy and muscle fibrosis, which can lead to strabismus and render enucleation rather difficult, these complications are seen mostly with periocular carboplatin. Periorbital topotecan is associated with mild and transient side effects such as eyelid edema and chemosis. The efficacy of POT in tumor regression has been reported previously. In an article in the current issue of IJO, Sthapit et al. have studied the efficacy of POT along with systemic chemotherapy in managing focal and diffuse vitreous seeds. The author could achieve remission of vitreous seeds (VS) in 63% of eyes and eye salvage in 95% of eyes with focal vitreous seeds and 68% of eyes with diffuse seeds.[9] The complications associated with POT were mild and transient and no metastasis was noted. In our opinion, POT is a safer alternative to intravitreal chemotherapy, especially in eyes with diffuse VS where finding a safe sight for injection is challenging. POT achieves good VS control with minimal complications. The results so far have been promising and there is a need for larger studies with longer follow-up to corroborate the results.

Computer modeling of drug delivery in the anterior human eye after subconjunctival and episcleral implantation

Recently, subconjunctival and episcleral implants have been proposed in the treatment of anterior eye diseases. In order to improve the delivery efficacy, it is important to understand the transport process of the implanted drugs. A 3D computational model, which includes heat transfer, aqueous humor (AH) flow, as well as diffusive and convective transport of the drug concentration, is developed to study the temporal and spatial evolution of the drug in the anterior segment of a human eye after subconjunctival and episcleral implantation, with a focus on drug delivery to three targets: iris, lens, and trabecular meshwork (TM). The release rate of the implanted drug is based on experimental data and effects of implantation location, eye orientation, and AH flow are investigated. Our numerical results indicate that subconjunctival implantation is more effective than episcleral implantation for drug delivery to all the three targets, and the accumulative amount of drug delivered to the three targets is larger in the horizontally-facing eye than in the up-facing eye. Implantation at the 12 o'clock circumferential position is the most effective for drug delivery to iris and lens, and the 3 o'clock position is the most effective for drug delivery to TM. This study may help to better understand the delivery process of implanted drugs in the anterior human eye, and improve delivery efficacy for clinical treatment of anterior eye diseases.

Characterization of silicone pressure-sensitive adhesive episcleral implant for drug delivery

The development of an effective sustained ocular drug delivery system remains a challenging task. The objective of the present study was to characterize a silicone pressure sensitive adhesive (PSA) episcleral implant system for transscleral drug delivery. Silicone PSA implants for dexamethasone, atenolol, and bovine serum albumin (BSA) were prepared at different polymer-to-drug mass ratios. Implant adhesion to human cadaver sclera was measured. Drug release experiments were conducted in well-stirred containers in vitro. The results were then analyzed using a pharmacokinetic model and in vitro–in vivo data comparison from previous studies. The silicone PSA episcleral implants in the present study had an average diameter of 3.5 mm and a thickness of 0.8 mm. Drug release from the silicone PSA implants was influenced by drug solubility, implant polymer content, and implant coating. Drug release from the implants was observed to follow the receding boundary release mechanism and was solubility dependent with the higher water solubility drug showing higher release rate than the low-solubility drug. Increasing polymer content in the implants led to a significant decrease in the drug release rate. Coated implants reduced the initial burst effect and provided lower release rates than the uncoated implants. These implants provided sustained drug release that could last up to several months in vitro and demonstrated the potential to offer drug delivery for chronic ocular diseases via the transscleral route.

Minimal-invasive Kammerwinkelchirurgie

The classical filtration surgery with trabeculectomy or drainage of chamber fluid with episcleral implants is the most effective method for permanent reduction of intraocular pressure to lower and normal levels. Even though both operative procedures are well-established the high efficiency of the method causes potentially dangerous intraoperative as well as interoperative complications with a frequency which cannot be ignored. In the past this led to a search for low complication alternatives with non-penetrating glaucoma surgery (NPGS) and the search is still continuing. Trabecular meshwork surgery in particular with continuous development of new operation techniques steered the focus to a complication-poor and minimally invasive, gonioscopic glaucoma surgery.

Histopathologic Findings in Early Encapsulated Blebs of Young Patients Treated With the Ahmed Glaucoma Valve

Uncontrolled glaucoma presents a challenge for the ophthalmic surgeon especially in children and juvenile patients. For many patients who have undergone failed surgical procedures before, episcleral implants remain the last choice. Encapsulated blebs forming over antiglaucoma devices present a complication leading to malfunctioning or even failure with reincrease in intraocular pressure. We report our histopathologic findings of such blebs developing around the Ahmed glaucoma valve (AGV) after a short time period in young patients. Nine young patients (2 to 17 y of age) with otherwise uncontrollable glaucoma were treated with AGV (models FP-7 and FP-8, silicone base plate) by 1 surgeon (H.T.). Four eyes needed surgical revision 2 to 6 months after initial implantation owing to encapsulated bleb development over the valve with total loss of function. The dense capsule around the device was surgically removed and investigated macroscopically, microscopically, and ultrastructurally. The cystic wall of these encapsulated blebs had an overall thickness of 1.5 to 2 mm. Macroscopically, the tissue was split into 2 layers. Histopathologically, the smooth inner surface (facing the base plate of the AGV) consisted of compressed collagen fibers with signs of elastoid degeneration and with formation of a pseudoendothelium toward the base plate. There was a pronounced transformation of fibroblasts into myofibroblasts in this inner layer. The outer area was highly vascularized. In these vessels electron microscopy revealed thrombosis. Inflammatory responses were nearly absent in all areas of the excised material. Intraocular pressure could be controlled by removal of the encapsulated blebs in all 4 cases. Encapsulation of the AGV is an early complication in young patients, leading to inhibition of fluid exchange and failure of the procedure. The valve mechanism is blocked by contracted scar tissue, but the device itself is not affected by the encapsulation. Surgical excision of the capsule immediately leads to an aqueous flow and drop of intraocular pressure.

Episcleral Implants for Topotecan Delivery to the Posterior Segment of the Eye

Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.

Immunosuppressive therapy for ocular diseases

To identify advances in immunosuppressive therapy of ocular diseases since 2007. The biologics in current use include antitumour necrosis factor-alpha agents (infliximab, etanercept and adalimumab), cytokine receptor antibodies (daclizumab) and interferon-alpha2a. They are effective and comparatively well tolerated options in the treatment of refractory uveitis in both adults and children in the short term, except for etanercept. Daclizumab had a favourable outcome in treating birdshot chorioretinopathy but not in Behcet's disease. The uncertainty of their long-term results, their high costs as well as the necessity for repeated intravenous infusions in the case of infliximab limit their widespread use. Mycophenolate mofetil is another efficacious, fairly well tolerated and less costly immunosuppressant. It has the additional advantage of an oral formulation. T cell inhibitors, cyclosporine and tacrolimus, were found to be useful steroid-sparing drugs in allergic eye disease and dry eyes. A number of studies on less invasive sustained ocular drug delivery systems, including episcleral implants, nanospheres, and cyclodextrin particles, were conducted on animals with encouraging results. The armamentarium of immunosuppressive agents is constantly expanding and augurs well for the safe and effective treatment of ocular inflammation.

A Pharmacokinetic and Safety Evaluation of an Episcleral Cyclosporine Implant for Potential Use in High-Risk Keratoplasty Rejection

To determine the short and long-term pharmacokinetics and assess the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection. CsA episcleral implants were made with a high (implant A) or low (implant B) release rate, and in vitro release rates were performed. Short-term pharmacokinetics were performed in rabbits using implant B, and the spatial and temporal spread of drug was observed by sampling from multiple corneal and conjunctival sites at 3 and 72 hours. Implant A was used in long-term pharmacokinetic studies in dogs aged more than 1 year. An ocular toxicity study was performed in dogs older than 1 year. A high release rate was observed with both implants over the initial 5 months followed by a steady state release. The cumulative release over the 400-day assay period from implants A and B was 3.8 +/- 0.3 and 2.3 +/- 0.3 mg, respectively. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 +/- 0.06, 0.07 +/- 0.02, and 0.05 +/- 0.02 microg/mg at sites centered 8, 13, and 18 mm away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 +/- 0.06 to 0.009 +/- 0.004 microg/mg during the 1-year study. There were no signs of ocular toxicity at 1 year. Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, since the implant achieves therapeutic levels as early as 3 hours.

Controlled drug release from an ocular implant: an evaluation using dynamic three-dimensional magnetic resonance imaging.

The ability of an episcleral implant at the equator of the eye to deliver drugs to the posterior segment was evaluated, using a sustained-release implant containing gadolinium-DTPA (Gd-DTPA). The movement of this drug surrogate was assessed with magnetic resonance imaging (MRI) in the rabbit eye. The results were compared with a similar implant placed in the vitreous cavity through a scleral incision at the equator. Polymer-based implants releasing Gd-DTPA were manufactured and placed in the subconjunctival space on the episclera or in the vitreous cavity in live rabbit eyes (in vivo) and in freshly enucleated eyes (ex vivo). Release rates of implants in vitro were also determined. Dynamic three-dimensional MRI was performed using a 4.7-Tesla MRI system for 8 hours. MR images were developed and analyzed on computer. Episcleral implants in vivo delivered a mean total of 2.7 microg Gd-DTPA into the vitreous, representing only 0.12% of the total amount of compound released from the implant in vitro. No Gd-DTPA was detected in the posterior segment of the eye. Ex vivo, the Gd-DTPA concentration in the vitreous was 30 times higher. In vivo eyes with intravitreal implants placed at the equator delivered Gd-DTPA throughout the vitreous cavity and posterior segment. Compartmental analysis of the ocular drug distribution from an episcleral implant showed that the elimination rate constant of Gd-DTPA from the subconjunctival space into the episcleral veins and conjunctival lymphatics was 3-log units higher than the transport rate constant for Gd-DTPA movement into the vitreous. In vivo, episcleral implants at the equator of the eye did not deliver a significant amount of Gd-DTPA into the vitreous, and no compound was identified in the posterior segment. A 30-fold increase in vitreous Gd-DTPA concentration occurred in the enucleated eyes, suggesting that there are significant barriers to the movement of drugs from the episcleral space into the vitreous in vivo. Dynamic three-dimensional MRI using Gd-DTPA, and possibly other contrast agents, may be useful in understanding the spatial relationships of ocular drug distribution and clearance mechanisms in the eye.

Expanded Polytetrafluoroethylene Episcleral Implants Used as Encircling Scleral Buckling

To investigate tissue changes induced by the implantation of expanded polytetrafluoroethylene (e-PTFE) used as encircling scleral buckling, an experimental and histopathological study was performed in rabbits. The eyes of 12 rabbits were implanted during 20–128 days with e-PTFE episcleral implants. Of these, 8 eyes were uncomplicated and enabled us to perform the histopathological study, 2 others were discarded for too short a time of implantation and, in 2 additional eyes, the episcleral implant was exposed with a wide conjunctival erosion. Surrounding the implant, a constant encapsulation was combined with numerous giant cells, forming a granuloma caused by irregularities of the implant outline. Its porous structure allowed a peripheral colonization by fibrovascular tissue. Scleral thinning and scleral invagination were the main scleral changes. No change of the conjunctiva made us suspect that a granuloma occurred before it was found histologically. The granulomatous changes did not seem to modify the apparently good experimental tolerance of the material after its implantation.

E-PTFE as scleral buckling episcleral implants: an experimental and histopathologic study.

To investigate the effects of focal implantation of expanded polytetrafluoroethylene (e-PTFE) episcleral implants (i.e., explants or exoplants) on surrounding ocular tissues, an experimental and histopathological study was performed. Twenty-seven Fauve de Bourgogne rabbits eyes were implanted for a period of 3-11 months with oval-shaped e-PTFE episcleral implants. A newly formed capsule constantly encased the implants. Affected by the only two severe complications observed, 2 eyes had an endocapsular acute inflammation and could not be included in the study. Finally, 25 eyes were studied histopathologically. Neither intrusion nor extrusion of episcleral implants was observed. Other changes were related to implant characteristics. The inner surface of the capsule was often covered with numerous giant cells attesting to a foreign-body granuloma developed against the irregular outline of the episcleral implants. The porosity of the material was closely related to its surface irregularity, and also allowed its colonization by a fibrovascular and inflammatory tissue mainly in its peripheral layers. Under episcleral implants, sclera was both thinned and invaginated. Expanded PTFE hydrophobia was the other factor that might have suscitated granuloma. These microscopic changes are in contrast with an overall good apparent experimental tolerance to the material. However, additional studies on the long term behavior of this material would be helpful.

E‐PTFE as scleral buckling episcleral implants: An experimental and histopathologic study

e‐PTFE as scleral buckling episcleral implants: An experimental and histopathologic study

Scleral patch graft for exposed episcleral implants.

A method of covering exposed noninfected episcleral implants after retinal detachment surgery using a graft of preserved sclera is described. Four of seven eyes have had the dehiscence covered for six months or more. In three eyes the dehiscence recurred. The procedure is simple and effective in eyes in which removal of the implant might cause redetachment of the retina.

Development of prophylactic treatment in retinal surgery.

As the years pass, medical science is moving gradually away from the principle of curing disease towards the greater achievement of its prevention. To further this end, community health services are being developed, and pilot studies have already been undertaken in the screening of the population to assist in the early diagnosis of a number of conditions, among them glaucoma. The increased specialization of post-graduate training is providing greater expertise in retinal diagnosis and treatment, and there have been, particularly during the last two decades, substantial advances in the recognition of vitreous and retinal changes which predispose to the development of retinal detachments. More than a century ago, Coccius (I853) described retinal breaks, but it was not until 67 years later that Gonin (1920) correctly interpreted their significance. The observation that retinal breaks were the pathological lesions that led to retinal detachments inspired many workers to investigate the methods by which the breaks could be sealed and choroidoretinal apposition restored. Weve (I930) introduced diathermy as an alternative to electrocautery or chemical cauterization. At the Fourteenth International Ophthalmological Congress in Madrid, Lindner (I933a) discussed the possibility of preventing retinal detachment. He prophesied that one day an operative method would be developed to achieve this. In the same year Bietti (I933) described the use of cryotherapy in the treatment of retinal detachment, a discovery that was to be overlooked until Cooper (i 962) described the principles and rationale of cryogenic surgery, and outlined the use of a cryotherapy instrument using liquid nitrogen as a coolant. Lincoff and McLean (I965) saw a future for this method of producing choroido-retinal reaction in retinal surgery, and published their observations after animal experiments and clinical trials. Major advances have since been made in instrumentation, and both simple and sophisticated instruments are now available. Examples of these are the Amoils cryosurgical unit (Amoils, I966) and the Amoilette which uses either nitrous oxide or carbon dioxide (Fison and Wright, 1968). Between the original description of cryotherapy and its widespread application there were numerous developments in surgical technique, beginning with scleral surgery. Fullthickness scleral resection (Miiller, I903; Lindner, I933b) was succeeded by the lamellar procedure (Shapland, 1951, 1952), and the latter has remained in use until recently. Indeed, there are still indications for this method. Episcleral implants or implants introduced into scleral pockets began with the use of polyviol materials by Custodis (I95I) and of preserved sclera by Paufique (I963). A number of natural and synthetic materials have subsequently been described, those most commonly used at the present time being silicone rubber and silicone rubber sponge. Encircling techniques began with the Arruga